Compounds and methods useful for stabilizing phenylalanine hydroxylase mutations

Abstract

Providing compounds and methods useful for stabilizing phenylalanine hydroxylase mutations. [Solution] This disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein m, R 1 ~R 5 , R 5A , and L are defined herein. These compounds are useful for stabilizing mutant PAH proteins or for 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. TIFF2026090533000718.tif3453

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 314,580, filed on 28 February 2022, the entirety of which is incorporated herein by reference.

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

[0003] Phenylenketonuria (PKU) is an autosomal recessive disorder affecting approximately 1 in 10,000 people worldwide (approximately 1 in 15,000 to 1 in 20,000 in the United States). The number of patients varies by region. PKU occurs in patients with mutations in the gene encoding the phenylalanine hydroxylase (PAH) enzyme, which is involved in the conversion of phenylalanine to tyrosine. PAH is a tetrameric enzyme expressed in the liver that requires the 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 left untreated, high levels of Phe can result in intellectual disability and low IQ in children, and neurocognitive and psychiatric problems in adults, including 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 disturbances, and seizures).

[0004] PKU phenotypes can range from mild hyperphenylalaninemia (HPA) to more severe phenotypes 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 12 years of age and older.

[0005] The standard treatment for PKU is a phenylalanine ammonia lyase diet, which severely restricts the intake of natural proteins. Such a diet is very strict and difficult to follow. Currently, two drugs are approved for the treatment of PKU, each with its own challenges. Kuvan (sapropterin dihydrochloride) is a synthetic BH4 cofactor approved in 2007 for use in infants and adults. Kuvan is not effective for all PKU patients, and current guidelines suggest response testing in patients unless the patient is known to have two null mutations. Pegvaliase is an enzyme replacement therapy approved in 2018 for adults with blood phenylalanine ammonia lyase concentrations 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 phenylalanine by converting phenylalanine to ammonia and trans cinnamic acid instead of tyrosine. One of the main challenges of enzyme substitution therapy is achieving and maintaining therapeutically effective levels of protein in vivo, due to the rapid degradation or inactivation of the injected protein. The current approach to overcome this problem is to administer numerous expensive high-dose injections.

[0006] There is a need for medicines that allow patients to increase their intake of natural proteins. [Overview of the project] [Means for solving the problem]

[0007] In one aspect, the present disclosure provides a compound of formula I:

Chemical formula

Chemical formula

[0008] In other embodiments, the Disclosure provides compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, II, IJ, IK, IL, or IM, or pharmaceutically acceptable salts thereof. [ka]

[0009] Compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, IH, II, IJ, IK, IL, and IM, as well as stereoisomers and mixtures of their pharmaceutically acceptable salts, are also described.

[0010] In a further embodiment, the Disclosure provides a pharmaceutical composition comprising one or more compounds described herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0011] In further embodiments, the Disclosure provides a method 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 a further embodiment, the 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. [Modes for carrying out the invention]

[0013] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to the extent of this disclosure. The terms used herein are for illustrative purposes only to describe specific embodiments and are not intended to limit this disclosure.

[0014] When used in the structure specified herein, [ka] " This indicates the bonding site of a specific illustrated structure or substituent to the appropriate atom in the rest of the molecule.

[0015] As used herein and in the appended claims, the articles “a” and “an” are used herein to refer to one or more of the grammatical objects of the articles (e.g., at least one), unless the context otherwise clearly indicates. For example, “an element” means one or more elements.

[0016] "Pharmacologically acceptable" means that it is approved or eligible for approval by a federal government or a state government regulatory authority or corresponding agency outside the United States, or is listed in the United States Pharmacopeia or other generally accepted pharmacopoeias for use in animals, such as humans.

[0017] "Pharmacologically acceptable salt" means a salt of the compound of this disclosure that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts may be nontoxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts may be (1) formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or (2) 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 (2) Acid addition salts formed with organic acids such as -methylbicyclo[2.2.2]-octa-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthic acid, salicylic acid, stearic acid, and muconic acid, or (2) salts formed when an acidic proton present in the parent compound is substituted with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. The salts further include, for illustrative purposes only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloric acid, hydrobromide, fumarate, tartrate, mesylate, acetate, maleate, and oxalate.

[0018] "Pharmacologically acceptable excipients" refer to substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to targets such as inert substances, and are added to pharmacological compositions or otherwise used as compatible vehicles, carriers, or diluents to facilitate the administration of drugs.

[0019] The term "alkyl" is used, either alone or as part of a substituent, to refer to a group of 1 to 12 carbon atoms ("C"). 1-12 For example, 1 to 6 carbon atoms ("C 1-6 This refers to a linear or branched hydrocarbon group having ''. 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, the alkyl group is C 1-6 It is alkyl, and in other embodiments, C 1-4 It is alkyl, and in other embodiments, C 1-3 It is alkyl.

[0020] The term "alkylene," when used alone or as part of a substituent, refers to an alkyl diradical, i.e., a linear or branched hydrocarbon group bonded to two other groups. For example, one embodiment of C2 alkylene is the diradical -CH2CH2-. In some embodiments, the alkylene group is C 1-6 It is an alkylene, and in other embodiments, C 1-4 It is alkylene.

[0021] When a range of carbon atoms is used herein, for example, C 1-6 This includes all ranges and individual numbers of carbon atoms. For example, "C 1-3 " is C 1-3 , C 1-2 , C 2-3 , including C1, C2, and C3.

[0022] The term "cycloalkyl" refers to a group of 3 to 10 carbon atoms ("C") when used alone or as part of a substituent. 3-10For example, 3 to 7 carbon atoms ("C 3-7 This refers to a non-aromatic hydrocarbon group containing a ring having a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), and cycloheptyl (C7). In some embodiments, the cycloalkyl group is C 3-4 It is a cycloalkyl, and in other embodiments, C 3-6 It is a cycloalkyl, and in other embodiments, C 3-8 It is a cycloalkyl group. The cycloalkyl group is either unsubstituted or substituted. In some embodiments, the cycloalkyl group is substituted with two substituents. In further embodiments, the cycloalkyl group is substituted with one substituent. In yet another embodiment, the cycloalkyl group is substituted with three substituents. In yet another embodiment, the cycloalkyl group is unsubstituted.

[0023] The term "aryl" also refers, when used alone or as part of a substituent, to a monocyclic or bicyclic aromatic hydrocarbon ring structure having six or ten carbon atoms in the ring, where 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 six or ten carbon atoms in the ring, where two adjacent carbon atoms in the ring are optionally substituted 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, and 1,2,3,4-tetrahydronaphthyl. Aryls are unsubstituted or can be substituted. In other embodiments, optionally substituted phenyl has four substituents. In further embodiments, optionally substituted phenyl has three substituents. In yet another embodiment, optionally substituted phenyl has two substituents. In yet another embodiment, optionally substituted phenyl has one substituent. In other embodiments, optionally substituted phenyl is unsubstituted.

[0024] As used herein, the term "alkenyl" refers to a group containing 2 to 12 carbon atoms ("C"). 2-12 This refers to a linear or branched group having a carbon-carbon double bond, and 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, the alkenyl group is C 2-6 It is an alkenyl group, and in other embodiments, C 2-4 It is Alkenil.

[0025] As used herein, the term "alkynyl" refers to a group containing 2 to 12 carbon atoms ("C"). 2-12 This refers to a linear or branched group having a carbon-carbon triple bond, and 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, the alkynyl group is C 2-6 It is an alkynyl group, and in other embodiments, C 2-4 It is alkinyl.

[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, in which at least one carbon is bonded to an oxo group. For example, one embodiment of a C3 alkylcarbonyl is -CH2C(O)CH3. In some embodiments, the alkylcarbonyl group is C 1-6 It is an alkylcarbonyl group.

[0028] The term "alkenylene carbonyl," when used alone or as part of another group, refers to the -C(O)-(alkenylene) group, where alkenylene refers to an alkylenedi radical, i.e., a straight-chain or branched-chain hydrocarbon group containing at least one carbon-carbon double bond 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 alkenylene carbonyl is C 2-6 The alkenylene group is C 2-4 It is alkenylene.

[0029] The term "halo" or "halogen" refers, when used alone or as part of another group, 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 hydrogen atoms are substituted with one or more halogen atoms, which may be identical 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 atoms. Examples of haloalkyl groups include fluoromethyl (CH2F), 1-fluoroethyl (CH(CH3)F), 2-fluoroethyl, difluoromethyl (CHF2), trifluoromethyl (CF3), pentafluoroethyl, 1,1-difluoroethyl (C(CH3)F2), 2,2-difluoroethyl (CH2CHF2), 2,2,2-trifluoroethyl (CH2CF3), 2-fluoropropan-2-yl (C(CH3)2F), 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, trichloromethyl, and the like. In some embodiments, the haloalkyl group is C 1-6 It is a haloalkyl, and in other embodiments, C 1-4 It is a haloalkyl, and in other embodiments, C 1-3 It is a haloalkyl group.

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

[0032] The term "cyanoalkyl" refers to an alkyl group as defined herein, which, when used alone or as part of another group, is substituted with one or more CNs. In some embodiments, the alkyl group is substituted with at least one CN. In other embodiments, the alkyl group is substituted with one, two, or three CNs. In further embodiments, the cyanoalkyl group is C 1-6 It is a cyanoalkyl. In yet another embodiment, the cyanoalkyl is C 1-4 These are cyanoalkyl groups. Examples of cyanoalkyl groups include CH2CN, CH2CH2CN, CH(CN)CH3, CH2CH2CH2CN, C(CH3)2CN, CH2CH(CN)CH3, and CH(CN)CH2CH3.

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

[0034] The term "cycloalkylsulfonyl," when used alone or as part of another group, refers to a cycloalkyl group as defined herein that is bonded to sulfonyl, i.e., -SO2-, where the sulfonyl group forms a bonding site to the rest of the molecule. In some embodiments, the cycloalkylsulfonyl is C 3-8 It is a cycloalkylsulfonyl, and in other embodiments, C 3-6 These are cycloalkylsulfonyl groups. Examples of cycloalkylsulfonyl groups include -SO2-cyclopropyl, -SO2-cyclobutyl, and -SO2-cyclopentyl.

[0035] The term "alkylsulfonyl," when used alone or as part of another group, refers to an alkyl group as defined herein that is bonded to sulfonyl, i.e., -SO2-, where the sulfonyl group forms a bonding site to the rest of the molecule. In some embodiments, alkylsulfonyl is C 1-6 It is an alkylsulfonyl, and in other embodiments, C 1-4 These are alkylsulfonyl groups. Examples of alkylsulfonyl groups include -SO2CH3 and -SO2CH2CH3.

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

[0037] The term "alkoxy," when used alone or as part of another group, refers to an oxygen radical bonded to an alkyl group by a single bond. Examples of alkoxy groups include methoxy (OCH3), ethoxy (OCH2CH3), and propoxy (e.g., -O). n Pr, -O i Pr), or butoxy (e.g., -O n Bu, -O i Bu, -Os Bu, -O t Examples include Bu). In other embodiments, the alkoxy group is C 1-6 It is an alkoxy. In further embodiments, the alkoxy group is C 1-4 It is an alkoxy.

[0038] The term "alkoxy (alkylene)" refers to an alkylene group as defined herein that, when used alone or as part of another group, is bonded to an alkyl group as defined herein. Examples of alkoxy (alkylene) groups include -CH2OCH3 and -CH2CH2OCH3.

[0039] The term "haloalkoxy," when used alone or as part of another group, refers to an oxygen radical bonded to a haloalkyl group by a single bond, where the haloalkyl group is defined above. Examples of haloalkoxy groups include fluoromethoxy (OCH2F), 2-fluoroethoxy, difluoromethoxy (OCHF2), trifluoromethoxy (OCF3), pentafluoroethoxy, 1,1-difluoroethoxy (OC(CH3)F2), 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy (OCH2CF3), 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, and trichloromethoxy. In some embodiments, the haloalkoxy group is C 1-6 It is a haloalkoxy, and in other embodiments, C 1-4 It is a haloalkoxy, and in other embodiments, C 1-3 It is a haloalkoxy.

[0040] The term "haloalkoxy(alkylene)" refers to an alkylene group, as defined herein, that is bonded to a haloalkoxy group, as defined herein, either alone or as part of another group. Examples of haloalkoxy(alkylene) groups include -CH2OCF3.

[0041] The term "heteroaryl," when used alone or as part of a substituent, refers to a monocyclic or bicyclic aromatic ring structure containing a carbon atom and up to four heteroatoms, each independently being nitrogen, oxygen, or sulfur. A heteroaryl ring may contain a total of five, six, nine, or ten ring atoms. In some embodiments, a heteroaryl ring is characterized by the number of ring atoms in the heteroaryl group. For example, a six-membered heteroaryl group refers to a heteroaryl group having six ring atoms in the group. Similarly, a five-membered heteroaryl group refers to a heteroaryl group having five ring atoms in the group. The heteroaryl portion may be unsubstituted, or one or more of the carbon or nitrogen atoms in the ring may be substituted. Examples of heteroaryl groups include thienyl, benzo[b]thienyl, furanyl, benzofuryl, pyranyl, thiophenyl, isobenzofuranyl, benzoxazinyl, clomenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, quinoxalyl, phthalazinyl, naphthilidinyl, sinnolinyl, and tri Azolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, quinazolinil, pteridinil, pyrimidinil, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, flazanil, pyrazolo[1,5-a]pyridinil, benzoisothiazolyl, imidazole[1,5-a]pyridinil, pyrrolo[1,2]pyridadinil, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzoisoxazolyl, isothiazolyl, tetrahydropyrazolo[1,5-a] Pyridinyl is one example. In some embodiments, the heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furanyl, 3-furanyl, 4-furanyl), pyrrolyl (e.g., pyrrole-2-yl, pyrrole-3-yl), imidazolyl (e.g., imidazole-2-yl, imidazole-4-yl), pyrazolyl (e.g., pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl), pyridyl (e.g., pyridine-1-yl, pyridine-2-yl, Pyridine-3-yl and pyridine-4-yl), pyrimidinyl (e.g., pyrimidine-2-yl, pyrimidine-4-yl, and pyrimidine-5-yl), thiazolyl (e.g., thiazole-2-yl, thiazole-4-yl, and thiazole-5-yl), isothiazolyl (e.g., isothiazole-3-yl, isothiazole-4-yl, and isothiazole-5-yl), oxazolyl (e.g., oxazole-2-yl, oxazole-4-yl, and oxazole-5-yl), isoxazolyl (e.g., (Isoxazole-3-yl, isoxazole-4-yl, and isoxazole-5-yl), pyrazinyl (e.g., pyrazine-2-yl, pyrazine-3-yl, pyrazine-5-yl, pyrazine-6-yl), triazolyl (e.g., 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), o Xadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), indazol (e.g., indazole-3-yl), pyrazolo[1,5-a]pyridinyl (e.g., pyrazolo[1,5-a]pyridinyl-3-yl), imidazole[1,5-a]pyridinyl (e.g., imidazole[1,5-a]pyridinyl-1-yl), pyrrolo[1,2]pyridazinyl (e.g., pyrrolo[1,2]pyridazinyl-5-yl, pyrrolo[1,2) Pyridazine-6-yl), benzo[d]thiazolyl (e.g., benzo[d]thiazole-3-yl, benzo[d]thiazole-2-yl), benzo[d]imidazolyl (e.g., benzo[d]imidazole-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]isothiazole-3-yl), benzo[c]isoxazolyl (e.g., benzo[c]isoxazol-3-yl), quinolinyl (e.g., quinoline-3-yl), and pyridazinyl (e.g., pyridazine-3-yl, pyridazine-4-yl). The term "heteroaryl" also includes N-oxides. Heteroaryls are unsubstituted or may be substituted. In some embodiments, the heteroaryl is substituted with two substituents. In further embodiments, the heteroaryl is substituted with one substituent. In yet another embodiment, the heteroaryl is substituted with three substituents. In yet another embodiment, the heteroaryl is unsubstituted. Substitution can occur with any available carbon or heteroatom (e.g., nitrogen), or both, where permitted by the substituent valence.

[0042] In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl. In some embodiments, the heteroaryl is a five-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having five ring atoms, where at least one carbon atom of the ring is substituted with a heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of five-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl. In other embodiments, the heteroaryl is a six-membered heteroaryl, for example, the heteroaryl is a monocyclic aromatic ring system having six ring atoms, where at least one carbon atom of the ring is substituted with a nitrogen atom. Examples of six-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, and pyridadinyl.

[0043] The term "heterocyclyl," when used alone or as part of another group, refers to a cyclic group comprising 1, 2, or 3 rings having 3 to 14 ring members, i.e., a 3 to 14-membered heterocycle, which is non-aromatic, saturated, or partially saturated, and contains one or two double bonds, i.e., a heterocycle in which at least one carbon atom of one of the rings is substituted with a heteroatom. Each heteroatom can be independently selected from oxygen, sulfur, sulfoxides and sulfones and / or nitrogen atoms and can be oxidized or quaternized. The term "heterocyclyl" also includes groups in which the ring -CH2- is substituted with -C(O)-. The term "heterocyclyl" also includes groups fused with an optionally substituted aryl group, such as indolinyl or chroman-4-yl, and groups fused with an optionally substituted cycloalkyl group, such as 6-azaspiro[2.5]octanyl. In some embodiments, the heterocyclyl group is C 4-6 A heterocyclyl is a four-membered, five-membered, or six-membered cyclic group containing one ring and one or two oxygen and / or nitrogen atoms. In other embodiments, the heterocyclyl is a C group containing one ring and one nitrogen atom. 4-6It is heterocyclic. The heterocycle can be optionally bonded to the remainder of the molecule by any available carbon or nitrogen atom that provides a stable structure. Examples of heterocyclic 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, the heterocyclic group includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 6-azaspiro[2.5]octanyl. The heterocycle can be unsubstituted or substituted. In some embodiments, the heterocycle is substituted with two substituents. In further embodiments, the heterocycle is substituted with one substituent. In still other embodiments, the heterocycle is substituted with three substituents. In yet further embodiments, the heterocycle is unsubstituted.

[0044] The term “(heterocyclyl)alkylene,” when used alone or as part of another group, refers to an alkylene group as defined herein that is attached to an alkyl group as defined herein.

[0045] The term “optionally substituted,” when used herein to describe a chemical moiety, means that the moiety may be substituted with one or more suitable functional groups or other substituents provided herein, but need not be so substituted. For example, substituents include halo, cyano, -NO2, -N3, -OH, -SH, C 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 Alkylcarbonyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene thio, (CR v R x ) p NR y R z (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 3-6 cycloalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 (alkylene), or C(O)OC1-6 alkyl, 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 cycloalkyl COOH, -C 1-6 alkylene CONH 2、 C 3-6 cycloalkyl CONH2, -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 It may be optionally substituted with one or more alkylsulfonyl (alkylene), oxo (=O), 3- to 7-membered heterocyclyl, heterocyclyl (alkylene), aryl, aryl (alkylene), or heteroaryl groups. In some embodiments, C in any of the substituents in this paragraph 1-6 Alkyl groups are C 1-4 It is alkyl, and in other embodiments, C 1-3 It is alkyl. In some embodiments, C in any of the substituents in this paragraph 1-6 The alkylene group is C 1-4 It is an alkylene. 1-6 Haloalkyl substituents are C 1-4 It is a haloalkyl, and in other embodiments, C 1-3 It is a haloalkyl. In some embodiments, C 3-6 Cycloalkyl substituents are C 3-4 It is a cycloalkyl substituent. In some embodiments, C 1-6 Alkoxy substituents are C 1-3 It is an alkoxy, and in other embodiments, C 1-4 It is an alkoxy. In some embodiments, C 1-6 Haloalkoxy substituents are C 1-3 It is a haloalkoxy, and in other embodiments, C 1-4 It is a haloalkoxy.

[0046] In some embodiments, the substituent is C 1-6 Alkyl, optionally substituted C 2-6 Alkenil, 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 Alkylcarbonyl, C 3-8 Cycloalkylsulfonyl, C 1-6 Alkyl sulfonyl (alkylene), (CR v R x ) p NR y R z (R v and R x H or C 1-6 It is alkyl, R y and R z H and C are independent of each other. 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 H and C are independent of each other. 1-6 Alkyl, or C 3-6 It can be optionally substituted with one or more of the following (which are cycloalkyl groups).

[0047] The term "nitrogen protecting group" refers to a part that bonds to a nitrogen atom and prevents reactions at that nitrogen atom. Nitrogen protecting groups are known to those skilled in the art and include those described in Wuts, PG, Greene's *Protective Groups in Organic Synthesis*. Wiley; 5th edition (October 27, 2014), which is incorporated herein by reference.

[0048] The enumeration of value ranges in this specification is intended to serve as a convenient way of referring to each individual value within its range, unless otherwise indicated, and each distinct value is incorporated herein as if it were individually enumerated herein. The use of any and all examples and illustrative language provided herein (e.g., “e.g.”) is intended to better describe this disclosure and is not limited to the scope of this disclosure unless otherwise requested. The language herein should not be construed as indicating any non-claimed element essential to the implementation of this disclosure.

[0049] When used in conjunction with a number or range of values, the term “about” means that the value or range of values ​​may deviate to an extent that is considered reasonable to a person skilled in the art.

[0050] The compounds described herein may contain one or more chiral centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture concentrated in one or more stereoisomers. The isomers may be isolated from the mixture 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 may be prepared by asymmetric synthesis. For example, see 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 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0051] Exemplary compounds of the present disclosure containing a chiral center may be shown herein as having a specific stereochemistry, but for which absolute stereochemistry has not been obtained. Absolute stereochemistry can be obtained using methods known in the art.

[0052] As used herein, the term “stereoisomer” refers to compounds that have the same chemical structure and bonding properties but differ with respect to the arrangement of atoms or groups in space, for example, enantiomers or diastereomers.

[0053] When the stereochemical configurations at chiral centers in a compound having one or more chiral centers are illustrated by their chemical name (e.g., the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., the configuration is indicated by a dashed line or wedge bond), the concentration of the indicated configuration relative to the opposing configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. The "concentration of the indicated configuration relative to the opposing configuration" is expressed in mole percent and is determined by dividing the number of compounds having the stereochemical configuration indicated at the chiral center by the total number of compounds in the mixture having the same or opposing stereochemical configuration.

[0054] When a disclosed compound is named or illustrated by its structure without showing its stereochemistry, it is understood that the name or structure may include one of the stereoisomers or geometric isomers, or a mixture of stereoisomers or geometric isomers, that may not include the others.

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

[0056] If the compounds described herein contain an olefinic double bond or other geometrically asymmetric centers, 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., isotopologs. The term “isotopically enriched” refers to an atom having an isotope composition other than that which is abundant in nature. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotope composition other than that which is found in nature. In isotopologs, “isotopically enriched” refers to the proportion of a given atom in a molecule to which a particular isotope of that atom is incorporated instead of its naturally occurring isotope composition. For example, a 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that particular position. Since the spontaneous distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using unenriched starting materials is approximately 0.0156%. In one embodiment, one or more hydrogen atoms on the compound described may be replaced by deuterium.

[0058] Therefore, as used herein, unless otherwise indicated, the term “isotope enrichment factor” refers to the ratio between the isotopic composition of a particular isotope and its natural isotopic composition.

[0059] With respect to the compounds provided herein, the position of a particular atom is deuterium or "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, in certain embodiments, have minimum isotope enrichment factors for each designated deuterium atom of at least 1000 (15% deuterium incorporated), at least 2000 (30% deuterium incorporated), at least 3000 (45% deuterium incorporated), at least 3500 (52.5% deuterium incorporated), at least 4000 (60% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated). The isotopic enrichment and isotopic enrichment factors 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 terms “patient” or “subject” are used throughout this specification to describe an animal, preferably human or livestock, to which a treatment, including prophylactic treatment, using the compounds or compositions of this disclosure is provided. For the 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 livestock such as dogs or cats, or livestock such as horses, cattle, or sheep. In general, throughout this disclosure, the term patient refers to a human patient unless otherwise stated or implied by the context of use of the term.

[0061] The terms “therapeutic effective dose” or “effective dose” mean, generally, an amount or dose of the compound(s)(or pharmaceutically acceptable salts thereof) sufficient to produce the desired therapeutic benefit in a subject requiring such treatment for a specified disease or disorder. Furthermore, with respect to the compounds(s)(s)(s)(s), therapeutic effective dose means an amount of the therapeutic agent, either alone or in combination with other therapies that provide a therapeutic benefit in the treatment or prevention of a disease.

[0062] In one embodiment, “treating” any disease or disorder means improving the disease or disorder (e.g., stopping or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, “treating” means improving at least one physical parameter, which may not be identifiable by the subject. In yet another embodiment, “treating” means modulating the disease or disorder physically (e.g., stabilizing identifiable symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, “treating” means delaying the onset of the disease or disorder.

[0063] The terms “prevent,” “prevention,” and “prevention” refer to the prevention of the onset, recurrence, or spread of a disease in a subject resulting from the administration of a preventive or therapeutic drug.

[0064] compound This disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof. [ka]

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

[0066] In equation I, R 1 teeth, [ka] That is the case.

[0067] R 1In this structure, x is between 0 and 5. In some embodiments, x is 0. In other embodiments, x is 1. In yet another embodiment, x is 2. In yet another embodiment, x is 3. In yet another embodiment, x is 4. In yet another embodiment, x is 5.

[0068] In further embodiments, R 1 teeth, [ka] And x is either 0 or 1, for example, [ka] In other embodiments, R 1 teeth, [ka] In another embodiment, R 1 teeth, [ka] In another embodiment, R 1 teeth, [ka] In another embodiment, R 1 teeth, [ka] In further embodiments, R 1 teeth, [ka] In other embodiments, R 1 teeth, [ka] That is the case.

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

[0070] R 1 In the structure, each R a It is independently, Halo, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 1-6 It is a haloalkoxy. In some embodiments, R a is a halo such as F, Cl, Br, or I. In other embodiments, R a is F, Br, or Cl. In yet another embodiment, R a In a further embodiment, R a In another embodiment, R a In further embodiments, R a In other embodiments, R a C is a compound such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. 1-6 It is alkyl. In further embodiments, R a is methyl, ethyl, or isopropyl. In yet another embodiment, R a is methyl. In further embodiments, R a C is a compound such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-6 It is a cycloalkyl. In further embodiments, R a In further embodiments, R a This includes C3, CHF2, CH2F, CH2CF3, C(CH3)2F, or C(CH3)F2. 1-6 In yet another embodiment, R a is CF3 or CHF2. In further embodiments, R aC is a compound such as methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. 1-6 It is an alkoxy. In yet another embodiment, R a is methoxy or ethoxy. In other embodiments, R a This is C such as OCF3 or OCH2CF3. 1-6 It is a haloalkoxy. In yet another embodiment, one R a This is a halo, and the second R a C 1-6 Alkoxy or C 1-6 It is alkyl.

[0071] In equation I, R 2 C 1-4 Alkyl, optionally substituted C 3-8 The cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R 2 is an arbitrarily substituted C 3-8 The cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In further embodiments, R 2 is unsubstituted C 3-8 It is a cycloalkyl, an unsubstituted heterocyclyl, an unsubstituted aryl, or an unsubstituted heteroaryl. In other embodiments, R 2 is substitution C 3-8 It is a cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl. In some embodiments, R 2 C is a compound such as methyl, ethyl, propyl, butyl, or tert-butyl. 1-4 It is alkyl. In other embodiments, R 2 This is a C compound that is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. 3-8 It is cycloalkyl. In further embodiments, R 2 is an optionally substituted heterocycline such as azetidinil. In yet another embodiment, R 2R is an optionally substituted aryl such as phenyl. In further embodiments, R 2 These are heteroaryl compounds that are optionally substituted with pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, furanil, 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 equation I, R 3 H or C 1-6 It is alkyl. In some embodiments, R 3 In other embodiments, R 3 C is a compound such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. 1-6 It is alkyl. In further embodiments, R 3 is methyl. In yet another embodiment, R 3 In further embodiments, R 3 In other embodiments, R 3 is butyl. In further embodiments, R 3 In another embodiment, R 3 It is hexyl.

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

[0074] Alternatively, R 3 and R 4 However, along with the atoms to which they are bonded, C 3-6 Forms a cycloalkyl group. In some embodiments, R 3 and R 4 They form cyclopropyl together. In other embodiments, R 3 and R 4 These together form cyclobutyl. In a further embodiment, R 3 and R 4 These together form cyclopentyl. In yet another embodiment, R 3 and R 4 They form a cyclohexyl compound together.

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

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

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

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

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

[0080] In some embodiments, L is a bond, -C(O)-, -C(O)CH2-, -C(O)CH2CH2-, -C(O)CH2CH2CH2-, -C(O)CF2-, -C(O)CHF-, -C(O)C(CH3)2-, -C(O)CH=CH-, [ka] -C(O)NHCH2-, -CH2-, or -CH2CH2-. In yet another embodiment, L is a bond, -C(O)-, It is either -C(O)CH2- or -C(O)CF2.

[0081] In some embodiments, R 2 These are 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 may be optionally substituted.

[0082] In further embodiments, R 2The compounds are 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]pyridadinyl, 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 may be optionally substituted.

[0083] In other embodiments, R 2 These are 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 another embodiment, R 2 These are 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]pyridadinyl, 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 further embodiments, R 2 is optionally substituted cyclopentyl. In further embodiments, R 2 is optionally substituted cyclobutyl. In yet another embodiment, R 2 is an optionally substituted cyclopropyl. In yet another embodiment, R 2 is an optionally substituted cyclohexyl. In further embodiments, R 2 is an optionally substituted azetidinyl. In other embodiments, R 2 R is an optionally substituted phenyl. In further embodiments, R 2 is optionally substituted pyrazolyl. In yet another embodiment, R 2 is an optionally substituted oxazolyl. In further embodiments, R 2 is optionally substituted thiazolyl. In other embodiments, R 2 is an optionally substituted triazolyl. In further embodiments, R 2 is an optionally substituted oxadiazolyl. In yet another embodiment, R 2 is an optionally substituted pyridinyl. In further embodiments, R 2 is an optionally substituted pyrimidinyl. In other embodiments, R 2 R is optionally substituted pyrazolo[1,5-a]pyridinyl. In further embodiments, R 2 is an optionally substituted indazolyl. In yet another embodiment, R 2 is optionally substituted thiadiazolyl. In other embodiments, R 2 R is an optionally substituted imidazole[1,5-a]pyridinyl. In further embodiments, R 2 is optionally substituted pyrrolo[1,2]pyridazinyl. In yet another embodiment, R 2 R is an optionally substituted thiophenyl. In further embodiments, R 2 is optionally substituted isoxazolyl. In further embodiments, R 2is optionally substituted isothiazolyl. In other embodiments, R 2 is optionally substituted benzo[d]thiazolyl. In further embodiments, R 2 is optionally substituted benzo[d]imidazolyl. In yet another embodiment, R 2 is optionally substituted benzo[d]oxazolyl. In further embodiments, R 2 In further embodiments, R 2 is optionally substituted benzo[c]isoxazolyl. In further embodiments, R 2 is optionally substituted benzo[d]isothiazolyl. In other embodiments, R 2 is an optionally substituted furanil. In yet another embodiment, R 2 is an optionally substituted pyrazinyl. In further embodiments, R 2 This is a quinolinyl that has been arbitrarily substituted.

[0086] In other embodiments, R 2However, azetidine-1-yl, azetidine-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, 1,2,3-triazole-5-yl, 1,3,4-oxadiazole-2-yl, 1,2,4-oxadiazole-3-yl, 1,2,4-oxadiazole-5-yl, pyrazolo[1,5-a]pyridine-3-yl, indazole-3-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, 1,3,4-thiadiazole-2-yl, pyridine-1-yl, pyridine These are -2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, imidazole[1,5-a]pyrididine-1-yl, pyrrolo[1,2]pyridazine-5-yl, pyrrolo[1,2]pyridazine-6-yl, thiophen-2-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, benzo[d]thiazole-2-yl, benzo[d]thiazole-3-yl, benzo[d]imidazole-2-yl, benzo[d]oxazole-2-yl, benzo[d]isothiazole-3-yl, benzo[d]isothiazole-3-yl, furan-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, or pyrazine-2-yl, each of which may be optionally substituted.

[0087] In yet another embodiment, R 2However, azetidine-1-yl, azetidine-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, 1,2,3-triazole-5-yl, 1,3,4-oxadiazole-2-yl, 1,2,4-oxadiazole-3-yl, 1,2,4-oxadiazole-5-yl, pyrazolo[1,5-a]pyridine-3-yl, indazole-3-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, 1,3,4-thiadiazole-2-yl, pyridine-1-yl, pyridine-2-yl, pyridine-3-yl These are pyridine-4-yl, pyrimidine-2-yl, imidazole[1,5-a]pyrididine-1-yl, pyrrolo[1,2]pyridazine-5-yl, pyrrolo[1,2]pyridazine-6-yl, thiophen-2-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, benzo[d]thiazole-2-yl, benzo[d]thiazole-3-yl, benzo[d]imidazole-2-yl, benzo[d]oxazole-2-yl, benzo[d]isoxazole-3-yl, benzo[d]isothiazole-3-yl, furan-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, pyrazine-2-yl, benzo[c]isoxazole-3-yl, or quinoline-3-yl, each of which may be optionally substituted.

[0088] In further embodiments, R 2 However, C 3-8 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is C 1-6 Alkyl, optionally substituted C 2-6 Alkenil, 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 Alkylcarbonyl, C 3-8 Cycloalkylsulfonyl, C 1-6 Alkyl sulfonyl, C 1-6 Alkyl sulfonyl (alkylene), (CR v R x ) p NR y R z (R v and R x H or C 1-6 It is alkyl, R y and R z H and C are independent of each other. 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 H and C are independent of each other. 1-6 Alkyl, or C 3-6 It is optionally substituted with one or more of the following (which are cycloalkyl). In other embodiments, R 2 C is a compound such as methyl, ethyl, propyl, isopropyl, or tert-butyl. 1-6 It can be optionally substituted with alkyl. In further embodiments, R 2 This includes C such as CH=CH2, CH=CHC(CH3)2OH, or CH=CH-cyclopropyl. 2-6It is optionally substituted with an alkenyl. In further embodiments, R 2 This is optionally replaced with a halo such as Br, Cl, or F. In yet another embodiment, R 2 This is optionally replaced with CN. In further embodiments, R 2 C(CH3)2CN and other C 1-6 It is optionally substituted with a cyanoalkyl group. In other embodiments, R 2 C is a compound such as CF3, CHF2, CH2F, CH(CH3)F, CH2CF3, C(CH3)2F, C(CH3)F2, or CH2CHF2. 1-6 It is optionally substituted with a haloalkyl group. In further embodiments, R 2 is optionally substituted with OH. In yet another embodiment, R 2 This includes optionally substituted C such as optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 3-8 It is optionally substituted with a cycloalkyl group. In further embodiments, R 2 This includes optionally substituted C such as optionally substituted cyclopropyl(alkylene) or optionally substituted cyclobutyl(alkylene). 3-8 It is optionally substituted with a cycloalkyl (alkylene). In other embodiments, R 2 This is an arbitrarily substituted C such as an arbitrarily substituted cyclohexenyl. 3-8 It is optionally substituted with a cycloalkenyl. In further embodiments, R 2 R is optionally substituted with an optionally substituted aryl such as an optionally substituted phenyl. In further embodiments, R 2 R is optionally substituted with an optionally substituted aryl (alkylene), such as optionally substituted benzyl. In other embodiments, R 2 R is optionally substituted with an optionally substituted heteroaryl, such optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl. In further embodiments, R 2R is optionally substituted with an optionally substituted heteroaryl, such optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted pyridazinyl. In further embodiments, R 2 R is optionally substituted with an optionally substituted heterocyclyl such as optionally substituted azetidinil, optionally substituted piperidinil, optionally substituted piperazinil, optionally substituted pyrrolidinil, optionally substituted morpholinil, or optionally substituted 6-azaspiro[2.5]octan-6-yl. In further embodiments, R 2 R is optionally substituted with optionally substituted morpholinyl (alkylene), optionally substituted piperidinyl (alkylene), optionally substituted piperazinyl (alkylene), or optionally substituted azetidinyl (alkylene). In further embodiments, R 2 C(CH3)2OH, CH(CH3)OH, C(CH3)2CH2OH, CH2C(CH3)2OH, or CH(CH2CH3)OH, etc. 1-6 It is optionally substituted with a hydroxyalkyl group. In further embodiments, R 2 This includes C such as OCF3, OCH2CF3, or OCH2CH2CF3. 1-6 It is optionally substituted with a haloalkoxy. In further embodiments, R 2 C such as CH2OCF3 1-6 It is optionally substituted with a haloalkoxy (alkylene). In other embodiments, R 2 C is such as methoxy or ethoxy. 1-6 It is optionally substituted with an alkoxy. In yet another embodiment, R 2 C(CH3)2OCH3, CH2OCH3, or (CH2)2OCH3 are examples of C 1-6 It is optionally substituted with an alkoxy (alkylene). In further embodiments, R 2 C such as CH2OCD3 1-6 It is optionally substituted with a deuterated alkoxy (alkylene). In further embodiments, R 2 C is C(=O)CH3 or CH2C(=O)CH3, etc. 1-6It is optionally substituted with an alkylcarbonyl. In yet another embodiment, R 2 C is a compound such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl. 3-8 It is optionally substituted with a cycloalkylsulfonyl. In other embodiments, R 2 C is a compound such as methylsulfonyl, ethylsulfonyl, or propylsulfonyl. 1-6 It is optionally substituted with an alkylsulfonyl. In yet another embodiment, R 2 C(CH3)2SO2CH3 and other C 1-6 It is optionally substituted with alkylsulfonyl (alkylene). In further embodiments, R 2 (CR v R x ) p NR y R z It is arbitrarily replaced with R v , R x , R y , R z , and p are those defined above, such as NH2, NH-cyclopropyl, 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, or CH2N(CH3)(C(O)Otert-butyl). In some embodiments, p is 0. In other embodiments, p is 1. In further embodiments, p is 2. In yet another embodiment, p is 3. In some embodiments, R v and R x R is independently hydrogen or methyl. In other embodiments, R y and R z R is independently hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, C(O)Omethyl, C(O)Oethyl, C(O)Opropyl, or C(O)Otert-butyl. In other embodiments, R 2 C(O)NR y2 R z2 And R y2 and R z2This is defined above, such as C(O)N(CH3)2 or C(O)NH cyclopropyl. In further embodiments, R y2 and R z2 R is independently hydrogen, methyl, or cyclopropyl. In further embodiments, R 2 However, 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, CH2OCH3, (CH2 Substituted with one or more of the following: 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 further embodiments, R 2 teeth [ka] In other embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0090] In some embodiments, R 2 Hello, C 1-6 A heterocycline optionally substituted with one or more haloalkyls or optionally substituted heteroaryls. In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 Hello, C 1-6 A heterocycline substituted with one or more haloalkyls or optionally substituted heteroaryls. In further embodiments, R 2 teeth, [ka] In further embodiments, R 2 but, [ka] That is the case.

[0091] In some embodiments, R 2 Hello, C 1-6 Alkyl, C 1-6 C is optionally substituted with one or more haloalkyl or OH groups. 3-8 It is cycloalkyl. In other embodiments, R 2 C is optionally substituted with one or more of the halo or OH groups. 3-8 It is cycloalkyl. In yet another embodiment, R 2 These include unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, and unsubstituted cyclohexyl. [ka] In further embodiments, R 2 Hello, C 1-6 Alkyl, C 1-6 C substituted with one or more haloalkyl groups or OH groups 3-8 It is a cycloalkyl. In further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] That is the case.

[0092] In some embodiments, R 2 is a halo or C 1-6 It is an aryl molecule optionally substituted with one or more alkoxys. In other embodiments, R 2 is unsubstituted phenyl, [ka] In another embodiment, R 2 is a halo or C 1-6 It is an aryl substituted with one or more alkoxys. In further embodiments, R 2 teeth, [ka] That is the case.

[0093] In some embodiments, R 2 is optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl. In other embodiments, the pyridinyl, pyrimidinyl, or pyrazinyl group is halo, C 1-6 Haloalkyl, cyano, or NR y R z Replaced with one or more of the following, R y and R z H or C 1-6 It is alkyl.

[0094] In further embodiments, R 2 C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, or C 1-6 It is a heteroaryl substituted with one or more hydroxyalkyl groups. In other embodiments, R 2 C 1-6 It is a heteroaryl substituted with one or more alkyl groups. In yet another embodiment, R 2 C 1-6 It is a heteroaryl substituted with one or more cyanoalkyl groups. In further embodiments, R 2 C 1-6 It is a heteroaryl substituted with one or more haloalkyl groups. In further embodiments, R 2 C 1-6 It is a heteroaryl substituted with one or more fluoroalkyl groups. In yet another embodiment, R 2 C 1-6It is a heteroaryl substituted with one or more hydroxyalkyl groups. In other embodiments, R 2 is a 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 further embodiments, R 2 is a 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 R is a methyl-substituted heteroaryl. In yet another embodiment, R 2 is an isopropyl-substituted heteroaryl. In other embodiments, R 2 is a heteroaryl substituted with tert-butyl. In yet another embodiment, R 2 This is a heteroaryl substituted with C(CH3)2CN. In further embodiments, R 2 is a heteroaryl substituted with CH(CH3)OH. In other embodiments, R 2 is a heteroaryl substituted with C(CH3)2OH. In further embodiments, R 2 is a heteroaryl substituted with CHF2. In yet another embodiment, R 2 is a heteroaryl substituted with CF3. In further embodiments, R 2 is a heteroaryl substituted with CH2CF3. In yet another embodiment, R 2 This is a heteroaryl substituted with CH(CH3)F. In other embodiments, R 2 This is a heteroaryl compound substituted with C(CH3)2F.

[0095] In other embodiments, R 2 C 3-8It is a heteroaryl substituted with a cycloalkyl group, C 3-8 Cycloalkyl itself is a halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 1-6 It is optionally substituted with one or more alkoxys. In further embodiments, R 2 This includes unsubstituted C such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-8 It is a heteroaryl substituted with a cycloalkyl group. In further embodiments, R 2 R is a heteroaryl substituted with cyclopropyl or cyclobutyl. In further embodiments, R 2 C is a compound such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-8 A heteroaryl compound substituted with a cycloalkyl group, C 3-8 Cycloalkyl itself is a halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 1-6 Substituted with one or more alkoxys. In some embodiments, substitution C 3-8 The cycloalkyl group is substituted with an OH group. In further embodiments, substituted C 3-8 The cycloalkyl group is substituted with one or more halos such as F, Cl, or Br. In other embodiments, substituted C 3-8 Cycloalkyls are C such as methyl, ethyl, or propyl. 1-6 Substituted with alkyl. In further embodiments, substituted C 3-8 Cycloalkyls include C3, CH2CF3, or CHF2. 1-6 It is substituted with a haloalkyl group. In yet another embodiment, substituted C 3-8 Cycloalkyls include C such as methoxy, ethoxy, or propoxy. 1-6 Substituted with an alkoxy. In further embodiments, substitution C 3-8 The cycloalkyl group 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] It is a heteroaryl substituted with R. In yet another embodiment, R 2 teeth, [ka] It is a heteroaryl substituted with [the specified compound].

[0096] In other embodiments, R 2 This is a heteroaryl substituted with an aryl, and the aryl itself is a halo, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 3-8 It is optionally substituted with one or more cycloalkyl groups. In further embodiments, R 2 is a heteroaryl substituted with an unsubstituted phenyl. In further embodiments, R 2 These are heteroaryls substituted with aryls such as phenyl, and the aryl itself is a halo, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 3-8 It is substituted with one or more cycloalkyl groups. In some embodiments, the substituted aryl is substituted with one or more halos such as F, Cl, or Br. In yet other embodiments, the substituted aryl is C such as CF3, CH2CF3, or CHF2. 1-6 It is substituted with a haloalkyl group. In further embodiments, the substituted aryl group may be C such as methyl, ethyl, or propyl. 1-6 It is substituted with an alkyl group. In other embodiments, the substituted aryl is C such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-8 It is substituted with a cycloalkyl group. In yet another embodiment, the substituted aryl is a phenyl group substituted with one or more of F, methyl, or CF3. In yet another embodiment, R 2 teeth, [ka] It is a heteroaryl substituted with R. In further embodiments, 2 teeth, [ka] It is a heteroaryl substituted with [the specified compound].

[0097] In further embodiments, R 2 is a heteroaryl substituted with an optionally substituted heteroaryl. In some embodiments, the optionally substituted heteroaryl is an optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, or optionally substituted pyrimidinyl. In yet other embodiments, the optional substitution for the heteroaryl is a 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 It is one or more cycloalkylsulfonyl compounds. In other embodiments, the optionally substituted heteroaryl is substituted with one or more halos such as F, Cl, or Br. In yet another embodiment, the optionally substituted heteroaryl is C such as CF3, CH2CF3, CH2CHF2, or CHF2. 1-6 It is substituted with one or more haloalkyl groups. In other embodiments, the optionally substituted heteroaryl group may be C1, such as methyl, ethyl, propyl, or isopropyl. 1-6 It is substituted with one or more alkyl groups. In further embodiments, the optionally substituted heteroaryl is C such as methoxy, ethoxy, or propoxy. 1-6 It is substituted with one or more alkoxys. In other embodiments, the optionally substituted heteroaryl is C such as OCF3. 1-6 It is substituted with one or more haloalkoxys. In further embodiments, the optionally substituted heteroaryl is C such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-8 It is substituted with one or more cycloalkyl groups. In other embodiments, the optionally substituted heteroaryl group may be C such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl.3-8 It is substituted with one or more cycloalkylsulfonyl compounds. In further embodiments, the optionally substituted heteroaryl is substituted with one or more of F, CF3, CH2CHF2, CHF2, methyl, methoxy, cyclobutyl, or cyclopropylsulfonyl compounds.

[0098] In yet another embodiment, R 2 is a heteroaryl substituted with pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrazine-2-yl, pyrazine-3-yl, pyrazine-4-yl, pyrazine-5-yl, imidazole-4-yl, or imidazole-5-yl, each of which can be optionally substituted. In further embodiments, R 2 is substituted with pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrazine-2-yl, pyrazine-3-yl, pyrazine-4-yl, pyrazine-5-yl, imidazole-4-yl, imidazole-5-yl, pyridazine-3-yl, pyridazine-4-yl, and each of these can be optionally substituted. In further embodiments, R 2 is substituted with optionally substituted pyrazole-1-yl. In other embodiments, R 2 is substituted with optionally substituted pyrazole-3-yl. In further embodiments, R 2 is substituted with optionally substituted pyrazole-4-yl. In further embodiments, R 2 is substituted with optionally substituted pyridine-2-yl. In other embodiments, R 2 is substituted with optionally substituted pyridine-3-yl. In further embodiments, R 2 is substituted with optionally substituted pyridine-4-yl. In further embodiments, R 2is substituted with an optionally substituted imidazole-4-yl. In yet another embodiment, R 2 R is substituted with an optionally substituted imidazole-5-yl. In further embodiments, R 2 is substituted with optionally substituted pyrimidine-2-yl. In other embodiments, R 2 is substituted with optionally substituted pyrimidine-4-yl. In further embodiments, R 2 is substituted with optionally substituted pyrimidine-5-yl. In yet another embodiment, R 2 is substituted with an optionally substituted pyrazine-2-yl. In other embodiments, R 2 is substituted with optionally substituted pyridazine-3-yl. In further embodiments, R 2 It is replaced with an optionally substituted pyridazine-4-yl.

[0099] In some embodiments, R 2 teeth, [ka] It is a heteroaryl substituted with R. In further embodiments, 2 teeth, [ka] It is a heteroaryl substituted with R. In further embodiments, 2 teeth, [ka] It is a heteroaryl substituted with [the specified compound].

[0100] In some embodiments, R 2 teeth, [ka] It is a heteroaryl substituted with R. In other embodiments, R 2 teeth, [ka] It is a heteroaryl substituted with R. In yet another embodiment, R 2 teeth, [ka] It is a heteroaryl substituted with [the specified compound].

[0101] In other embodiments, R 2 This is a heteroaryl substituted with a heterocyclyl or heterocyclyl(alkylene), where the heterocyclyl and heterocyclyl(alkylene) groups themselves are 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 It is optionally substituted with one or more cycloalkyl groups. In further embodiments, R 2 R is a heteroaryl substituted with an unsubstituted heterocyclyl group such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 6-azaspiro[2.5]octan-6-yl, or an unsubstituted heterocyclyl (alkylene) group such as azetidinyl (alkylene), pyrrolidinyl (alkylene), piperidinyl (alkylene), piperazinyl (alkylene), or morpholinyl (alkylene). In further embodiments, R 2 However, these are heterocyclines such as azetidinil, pyrrolidinil, piperidinil, piperazinil, or morpholinil, or heteroaryls substituted with heterocyclines (alkylenes) such as azetidinil (alkylene), pyrrolidinil (alkylene), piperidinil (alkylene), piperazinil (alkylene), or morpholinil (alkylene), where the heterocycline and heterocycline (alkylene) groups themselves are, respectively, halo, OH, and 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 3-8It is substituted with one or more cycloalkyl groups. In further embodiments, the substituted heterocycline or substituted heterocycline (alkylene) is substituted with one or more halos such as F, Cl, or Br. In yet another embodiment, the substituted heterocycline or substituted heterocycline (alkylene) is substituted with one or more OH groups. In yet another embodiment, the substituted heterocycline or substituted heterocycline (alkylene) is C such as CF3, CH2CF3, or CHF2. 1-6 It is substituted with one or more haloalkyl groups. In further embodiments, the substituted heterocycline or substituted heterocycline (alkylene) is C such as methyl, ethyl, or propyl. 1-6 It is substituted with one or more alkyl groups. In further embodiments, the substituted heterocyclyl or substituted heterocyclyl (alkylene) is C(CH3)2OH, or C such as CH(CH3)OH. 1-6 It is substituted with one or more hydroxyalkyl groups. In other embodiments, the substituted heterocyclyl or substituted heterocyclyl (alkylene) is C such as methoxy, ethoxy, or propoxy. 1-6 It is substituted with one or more alkoxys. In further embodiments, the substituted heterocyclyl or substituted heterocyclyl (alkylene) is C(O)O(C 1-6 It is substituted with one or more of the alkyl groups. In further embodiments, the substituted heterocycline or substituted heterocycline (alkylene) is C such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-8 It is substituted with one or more cycloalkyl groups. In further embodiments, the substituted heterocyclyl or substituted heterocyclyl (alkylene) is substituted with one or more F, OH, or methyl groups. 2 In yet another embodiment where is a heteroaryl, R 2 teeth, [ka] It is replaced by R. 2 In a further embodiment where is a heteroaryl, R 2teeth, [ka] It will be replaced with.

[0102] In further embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0103] R 2 In these structures relating to R, 6 and R 7 These are H, CN, and C, each independently. 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 It is an alkylsulfonyl, R 8 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy (alkylene), C 1-6 Alkylcarbonyl, C 1-6 Hydroxyalkyl, (CR v R x ) p NR y R z 、 Arbitrarily substituted C 3-8 Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted (C 3-8 It is a cycloalkyl alkylene, and R v and R x However, independently, H or C 1-6 Alkyl, R y and R z H and C are independent of each other. 1-6 Alkyl, C 1-6 Alkoxy (alkylene), or C 3-6 It is cycloalkyl, R y2 and R z2 H and C are independent of each other. 1-6 Alkyl, or C 3-6 It is a cycloalkyl group, and p is 0, 1, 2, or 3. In some embodiments, R 6 , R 7 , and R 8 H is H.

[0104] In other embodiments, R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Cyanoalkyl, or C 1-6 It is a hydroxyalkyl compound. In further embodiments, R 6 C is a compound such as methyl, ethyl, isopropyl, or tert-butyl. 1-6 It is alkyl. In further embodiments, R 6 This includes C3, CHF2, CH2F, CH2CF3, CH(CH3)F, C(CH3)F2, or C(CH3)2F. 1-6 It is a haloalkyl. In further embodiments, R 6 C(CH3)2CN and other C 1-6 It is a cyanoalkyl. In other embodiments, R 6 This includes C(CH3)2OH, CH(CH3)OH, CH(CH2CH3)OH, CH2C(CH3)2OH, or C(CH3)2CH2OH. 1-6 It is a hydroxyalkyl compound. In further embodiments, R 6 This is methyl, isopropyl, tert-butyl, CF3, CHF2, C(CH3)F 2、 It is either 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 is optionally substituted with one or more alkoxy groups. 3-6 It is cycloalkyl. In further embodiments, R 6 Halo, OH, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 1-6 The cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more alkoxys. In further embodiments, R 6 R is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other embodiments, R 6 C is substituted with one or more halos such as F, Cl, or Br. 3-6 It is cycloalkyl. In yet another embodiment, R 6C is a carbon atom substituted with one or more OH groups. 3-6 It is a cycloalkyl. In further embodiments, R 6 , CF 3、 One or more C such as CH2CF3 or CHF2 1-6 C substituted with haloalkyl 3-6 It is cycloalkyl. In further embodiments, R 6 This is one or more C such as methyl, ethyl, or propyl. 1-6 C substituted with alkyl 3-6 It is a cycloalkyl. In further embodiments, R 6 It is one or more C such as methoxy, ethoxy, or propoxy. 1-6 alkoxy-substituted C 3-6 It is cycloalkyl. In other embodiments, 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] That is the case.

[0106] In further embodiments, R 6 Hello, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 3-6 It is an aryl molecule optionally substituted with one or more cycloalkyl groups. In other embodiments, R 6 Hello, C 1-6 Haloalkyl, C 1-6 Alkyl, or C 3-6 A phenyl molecule optionally substituted with one or more cycloalkyl groups. In further embodiments, R 6 is an aryl atom optionally substituted with one or more halos such as F, Cl, or Br. In yet another embodiment, R 6This includes C such as CF3, CH2CF3, or CHF2. 1-6 It is an aryl that is optionally substituted with one or more haloalkyl groups. In other embodiments, R 6 C is a compound such as methyl, ethyl, or propyl. 1-6 It is an aryl molecule optionally substituted with one or more alkyl groups. In yet another embodiment, R 6 C is a compound such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-6 It is an aryl molecule optionally substituted with one or more cycloalkyl groups. In other embodiments, R 6 is an aryl (e.g., phenyl) optionally substituted with F, methyl, or CF3. In other embodiments, R 6 teeth, [ka] In another embodiment, R 6 teeth, [ka] That is the case.

[0107] In yet another embodiment, R 6 Hello, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, or C 3-6 It is a heteroaryl compound optionally substituted with one or more cycloalkylsulfonyl compounds. In further embodiments, R 6 is pyridinyl, pyrazolyl, pyrazinyl, imidazolyl, or pyrimidinyl, each of which is optionally substituted. In further embodiments, R 6 is pyridinyl, pyrazolyl, pyrazinyl, pyridadinyl, imidazolyl, or pyrimidinyl, each of which is optionally substituted. In further embodiments, R 6is an optionally substituted pyrazinyl such as pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, or pyrazin-5-yl. In other embodiments, R 6 This is a pyrazolyl that is optionally substituted, such as pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl. In further embodiments, R 6 R is an optionally substituted pyridinyl such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In other embodiments, R 6 R is an optionally substituted pyridazinyl such as pyridazin-3-yl or pyridazin-4-yl. In yet another embodiment, R 6 R is an optionally substituted imidazolyl such as imidazole-4-yl or imidazole-5-yl. In further embodiments, R 6 R is an optionally substituted pyrimidinyl such as pyridimidine-2-yl, pyrimidine-4-yl, or pyrimidine-5-yl. In other embodiments, R 6 is pyrazine-2-yl, pyrazine-3-yl, pyrazine-4-yl, pyrazine-5-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, imidazole-4-yl, imidazole-5-yl, pyrimidine-2-yl, pyrimidine-4-yl, or pyrimidine-5-yl, each of which is optionally substituted. In further embodiments, R 6 is pyrazine-2-yl, pyrazine-3-yl, pyrazine-4-yl, pyrazine-5-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, imidazole-4-yl, imidazole-5-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyridazine-3-yl, or pyridazine-4-yl, each of which is optionally substituted. In further embodiments, R 6R is unsubstituted pyridine-2-yl, unsubstituted pyridine-3-yl, unsubstituted pyridine-4-yl, unsubstituted pyrimidine-2-yl, unsubstituted pyrimidine-4-yl, unsubstituted pyrimidine-5-yl, or unsubstituted pyrazine-2-yl. In further embodiments, R 6 R is unsubstituted pyridine-2-yl, unsubstituted pyridine-3-yl, unsubstituted pyridine-4-yl, unsubstituted pyrimidine-2-yl, unsubstituted pyrimidine-4-yl, unsubstituted pyrimidine-5-yl, unsubstituted pyrazine-2-yl, or pyridazine-3-yl. In other embodiments, R 6 This is optionally replaced with one or more halos such as F, Cl, or Br. In yet another embodiment, R 6 This is one or more C such as CF3, CH2CF3, or CHF2. 1-6 It is optionally substituted with a haloalkyl group. In other embodiments, R 6 This is one or more C such as methyl, ethyl, propyl, or isopropyl. 1-6 It is optionally substituted with alkyl. In yet another embodiment, R 6 This is one or more C molecules such as methoxy, ethoxy, or propoxy. 1-6 It is optionally substituted with an alkoxy. In further embodiments, R 6 This is one or more C such as OCF3. 1-6 It is optionally substituted with a haloalkoxy. In further embodiments, R 6 This includes one or more C such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-6 It is optionally substituted with a cycloalkyl group. In further embodiments, R 6 This includes one or more C such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl. 3-6 It is optionally substituted with a cycloalkylsulfonyl. In yet another embodiment, R 6 This is a heteroaryl compound optionally substituted with one or more of the following: F, CF3, CH2CF3, CHF2, methyl, methoxy, OCF3, cyclobutyl, or cyclopropylsulfonyl.

[0108] In other embodiments, R 6R is a five-membered heteroaryl optionally substituted with one or more of CF3, CH2CF3, CHF2, methyl, cyclobutyl, or cyclopropylsulfonyl. In further embodiments, R 6 teeth, [ka] In further embodiments, R 6 teeth, [ka] In other embodiments, R 6 teeth, [ka] In further embodiments, R 6 teeth, [ka] In further embodiments, R 6 teeth, [ka] In further embodiments, R 6 teeth, [ka] In further embodiments, R 6 teeth, [ka] That is the case.

[0109] In other embodiments, R 6 is a six-membered heteroaryl optionally substituted with one or more of F, CF3, methoxy, OCF3, or methyl. In further embodiments, R 6 teeth, [ka] In further embodiments, R6 teeth, [ka] In another embodiment, R 6 teeth, [ka] That is the case.

[0110] In yet another embodiment, R 6 These are heterocyclyl or heterocyclyl (alkylene), each consisting of a halo, OH, and 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 It is optionally substituted with one or more cycloalkyl groups. In further embodiments, R 6 R is optionally substituted azetidinil, optionally substituted pyrrolidinil, optionally substituted piperidinil, optionally substituted piperazinil, or optionally substituted morpholinil. In other embodiments, R 6 is an optionally substituted azetidinyl. In yet another embodiment, R 6 is an optionally substituted pyrrolidinyl. In further embodiments, R 6 is optionally substituted piperidinyl. In yet another embodiment, R 6 is optionally substituted piperazinyl. In further embodiments, R 6 is optionally substituted morpholinyl. In other embodiments, R 6 R is optionally substituted morpholinyl (alkylene), optionally substituted piperidinyl (alkylene), optionally substituted piperazinyl (alkylene), or optionally substituted azetidinyl (alkylene). In further embodiments, R 6 is unsubstituted azetidinil, pyrrolidinil, piperidinil, piperazinil, or morpholinil. In other embodiments, R 6R is an unsubstituted morpholinyl (alkylene), piperidinyl (alkylene), piperazinyl (alkylene), or azetidinyl (alkylene). In further embodiments, R 6 In other embodiments, the heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more halos such as F, Cl, or Br. In yet another embodiment, the heterocyclyl and heterocyclyl(alkylene) groups are optionally substituted with one or more OH groups. In yet another embodiment, the heterocyclyl and heterocyclyl(alkylene) groups are one or more C such as CF3, CH2CF3, or CHF2. 1-6 They are optionally substituted with haloalkyl groups. In further embodiments, the heterocyclyl and heterocyclyl (alkylene) groups are one or more C such as methyl, ethyl, or propyl. 1-6 They are optionally substituted with alkyl groups. In further embodiments, the heterocyclyl and heterocyclyl (alkylene) groups are one or more C such as C(CH3)2OH. 1-6 They are optionally substituted with hydroxyalkyl groups. In further embodiments, the heterocyclyl group and the heterocyclyl (alkylene) group are one or more C such as methoxy, ethoxy, or propoxy. 1-6 They are optionally substituted with alkoxy groups. In other embodiments, the heterocyclyl and heterocyclyl (alkylene) groups are one or more C(O)O(C)methyl, C(O)ethyl, C(O)propyl, or C(O)Otert-butyl groups. 1-6 They are optionally substituted with alkyl groups. In further embodiments, the heterocyclyl and heterocyclyl (alkylene) groups are one or more C such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-6 It is optionally substituted with a cycloalkyl group. In yet another embodiment, R 6 These are heterocyclyl and heterocyclyl(alkylene), each optionally substituted with one or more of the following: F, OH, C(CH3)2(OH), methyl, C(O)O(tert-butyl), or cyclopropyl.

[0111] In further embodiments, R6 teeth, [ka] In another embodiment, R 6 teeth, [ka] In further embodiments, R 6 teeth, [ka] In further embodiments, R 6 teeth, [ka] In another embodiment, R 6 teeth, [ka] In other embodiments, R 6 teeth, [ka] In further embodiments, R 6 teeth, [ka] That is the case.

[0112] In further embodiments, R 6 H, CN, 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 It is an alkylsulfonyl. In other embodiments, R 6 In a further embodiment, R 6 In another embodiment, R 6 C, such as methoxy. 1-6 It is an alkoxy. In yet another embodiment, R 6 C is a C such as CH2OCH3, C(CH3)2OCH3, or (CH2)2OCH3. 1-6 It is an alkoxy (alkylene). In yet another embodiment, R 6 This includes C such as OCF3, OCHF2, OCH2F, or O(CH2)2CF3. 1-6 In other embodiments, R 6 C such as CH2OCF3 1-6 It is a haloalkoxy(alkylene). In yet another embodiment, R 6 C such as CH2OCD3 1-6 It is a deuterated alkoxy (alkylene). In further embodiments, R 6 is a halo such as F, Br, or Cl. In further embodiments, R 6 This includes 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), etc. (CR v R x ) p NR y R z In other embodiments, R 6 This includes C(O)NR such as C(O)N(CH3)2 or C(O)NH(cyclopropyl). y2 R z2 In another embodiment, R 6is C such as C(O)CH3 1-6 alkylcarbonyl. In a further embodiment, R 6 is optionally substituted C such as CH=CH2, CH=CH-cyclopropyl, or CH=CHC(CH3)2OH 2-6 alkenyl. In still other embodiments, R 6 is [Chemical formula] etc., optionally substituted C 3-6 cycloalkenyl. In still other embodiments, R 6 is optionally substituted (C 3-6 cycloalkyl)alkylene such as CH2-cyclopropyl, CH2CH2-cyclopropyl, or C(CH3)OH-cyclopropyl. In a further embodiment, R 6 is optionally substituted (aryl)alkylene such as benzyl. In other embodiments, C alkylsulfonyl(alkylene) such as C(CH3)2SO2CH3. In still other embodiments, R 1-6 is H, CH2OCH3, Cl, NH(cyclopropyl), or C(O)N(CH3)2. 6 is H, CN, C

[0113] In some embodiments, R 7 is H, CN, C 1-6 alkyl, C 1-6 haloalkyl, halo, C 3-8 cycloalkyl, aryl, or heteroaryl. In still other embodiments, R 7 is H. In still further embodiments, R 7 is CN. In other embodiments, R 7 is C alkyl such as methyl, ethyl, or propyl. In a further embodiment, R 1-6 is methyl. In still other embodiments, R 7 is C haloalkyl such as CHF2, CH2F, C(CH3)F2, CH2CHF2, or CF3. In still further embodiments, R 7 is 1-6 is H. In still further embodiments, R 7is CHF2 or CF3. In a further embodiment, R 7 is a halo such as F, Br, or Cl. In yet another embodiment, R 7 is Br or Cl. In still further embodiments, R 7 is a C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, or cyclopentyl. In other embodiments, R 7 is cyclopropyl. In a further embodiment, R 7 is aryl. In yet another embodiment, 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, CF3, CH2F, CHF2, CF2(CH3), CH2CHF2, Br, Cl, cyclopropyl, phenyl, or pyridinyl. In yet another embodiment, R 7 is H, CN, methyl, CHF2, CF3, Br, Cl, cyclopropyl, phenyl, or pyridinyl.

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

[0115] In some embodiments, R v and R x One or both of them are H. In other embodiments, R v and R x One or both of these are C13, such as methyl, ethyl, propyl, or butyl. 1-6 It is alkyl. In yet another embodiment, R v and R x One or both of them are methyl. In some embodiments, R y and Rz One or both of them are H. In other embodiments, R y and R z One or both of them are C 1-6 alkyl such as methyl, ethyl, propyl, or butyl. In still other embodiments, R y and R z One or both of them are C 1-6 alkoxy(alkylene) such as CH2OCH3. In further embodiments, R y and R z One or both of them are C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R y2 and R z2 One or both of them are H. In other embodiments, R y2 and R z2 One or both of them are C 1-6 alkyl such as methyl, ethyl, propyl, or butyl. In further embodiments, R y2 and R z2 One or both of them are C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In further embodiments, p is 0. In other embodiments, p is 1. In further embodiments, p is 2. In still other embodiments, p is 3.

[0116] In some embodiments, R 2 is

Chemical formula

[0117] In other embodiments, R 2 teeth, [ka] And R6 H, CN, 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, R 7 H, C 1-6 Alkyl, C 1-6 Haloalkyl, halo, or C 3-6 It is cycloalkyl. In yet another embodiment, R 6 H, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 It is a hydroxyalkyl, R 7 In a further embodiment, R 6 In other embodiments, R 6 In a further embodiment, R 6 C 1-6 It is alkyl. In further embodiments, R 6 is methyl, isopropyl, or tert-butyl. In yet another embodiment, R 6 C 1-6 In further embodiments, R 6 is CHF2, C(CH3)2F, C(CH3)F2, or CF3. In yet another embodiment, R 6 C 1-6 It is a hydroxyalkyl group. In further embodiments, R 6 In other embodiments, R 6 C 1-6 It is an alkoxy. In further embodiments, R 6 is methoxy or ethoxy. In yet another embodiment, R 6 C 1-6 It is an alkoxy (alkylene). In further embodiments, R 6 In other embodiments, R 6 is an arbitrarily substituted C 3-6It is a cycloalkyl. In further embodiments, R 6 teeth, [ka] In other embodiments, R 6 is an arbitrarily substituted heteroaryl. In yet another embodiment, R 6 is optionally substituted pyridinyl or optionally substituted pyrazolyl. In further embodiments, R 6 teeth, [ka] In other embodiments, R 6 H, tert-butyl, C(CH3)2F, C(CH3)F2, C(CH3)2OH, CH2OCH3, [ka] In further embodiments, R 6 is H or C(CH3)2F. In yet another embodiment, R 7 In other embodiments, R 7 C 1-6 It is alkyl. In further embodiments, R 7 is methyl. In yet another embodiment, R 7 C 1-6 In further embodiments, R 7 is CF2H or CF3. In further embodiments, R 7 In another embodiment, R 7 In further embodiments, R 7 C 3-6 It is cycloalkyl. In other embodiments, R 7 In further embodiments, R 7 The compound is H, methyl, CF2H, CF3, Br, Cl, or cyclopropyl.

[0118] In further embodiments, R 2 teeth [ka] And R 6 and R 7 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, halo, optionally substituted C 3-6 It is a cycloalkyl or optionally substituted aryl. In other embodiments, R 6 and R 7 These are H, respectively. In a further embodiment, R 6 or R 7 One of them is C such as methyl 1-6 It is alkyl. 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 One of these is a halo such as Br or Cl. In further embodiments, R 6 or R 7 One of them is an optionally substituted C such as unsubstituted cyclopropyl. 3-6 It is cycloalkyl. In other embodiments, R 6 or R 7 One of these is an optionally substituted aryl such as an unsubstituted phenyl. In yet another embodiment, R 6 is methyl, CF3, Cl, cyclopropyl, or phenyl, and R 7 In another embodiment, R 7 is methyl, CF3, Cl, cyclopropyl, or phenyl, and R 6 H is H.

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

[0120] In yet another embodiment, R 2 teeth, [ka] And R 6 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 , arbitrarily substituted C 3-6 A cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl, R v and R x H or C 1-6 It is alkyl, R y and R z H and C are independent of each other. 1-6 Alkyl, C 1-6 Alkoxy (alkylene), or C 3-6 It is cycloalkyl, R y2 and R z2 H and C are independent of each other. 1-6Alkyl, or C 3-6 It is a cycloalkyl group, where p is 0, 1, 2, or 3. In further embodiments, R 6 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, optionally substituted C 3-6 The cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R 6 In a further embodiment, R 6 C 1-6 It is alkyl. In other embodiments, R 6 is methyl, ethyl, isopropyl, or tert-butyl. In further embodiments, R 6 is methyl, isopropyl, or tert-butyl. In other embodiments, R 6 C 1-6 It is a haloalkyl. In further embodiments, R 6 This is CHF2, CF3, or C(CH3)2F. In further embodiments, R 6 is CF3, CHF2, C(CH3)F2, or C(CH3)2F. In yet another embodiment, R 6 C 1-6 It is a hydroxyalkyl group. In further embodiments, R 6 is C(CH3)2OH or CH(CH3)OH. In yet another embodiment, R 6 C(O)NR y2 R z2 In further embodiments, R 6 is C(O)N(CH3)2 or C(O)NH(cyclopropyl). In other embodiments, R 6 (CR v R x ) p NR y R z In further embodiments, R 6 is NH2, N(CH3)2, NHCH2CF3, NHCH2CH2OCH 3、These are NH (cyclopropyl), CH2N(CH3)2, CH2NH (cyclopropyl), or CH2CH2NH (cyclopropyl). In further embodiments, R 6 is an arbitrarily substituted C 3-6 It is a cycloalkyl group. In yet another embodiment, it is optionally substituted C 3-6 Cycloalkyls include halogens such as F, or C such as methyl. 1-6 It is substituted with one or more alkyl groups. In further embodiments, R 6 teeth, [ka] In other embodiments, R 6 is an optionally substituted aryl. In yet another embodiment, the optionally substituted aryl is a halo such as F, a methyl such as C 1-6 C such as alkyl or CF3 1-6 Substituted with one or more haloalkyl groups. In further embodiments, R 6 teeth, [ka] In another embodiment, R 6 is an optionally substituted heterocyclyl. In further embodiments, the optionally substituted heterocyclyl is a halo such as F, or a C such as methyl. 1-6 It is substituted with one or more alkyl groups. In further embodiments, R 6 teeth, [ka] In another embodiment, R 6 teeth, [ka] In other embodiments, R 6This is an optionally substituted heteroaryl such as optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridinyl, or optionally substituted pyrazinyl. In further embodiments, the optionally substituted heteroaryl is C such as methyl, ethyl, or isopropyl. 1-6 C such as alkyl, CF3, CH2CF3, or CHF2 1-6 Haloalkyl, such as F, methoxy, ethoxy, or propoxy, such as C 1-6 C such as alkoxy, cyclopropyl, or cyclobutyl 3-6 Cycloalkyl, or C such as cyclopropylsulfonyl, cyclobutylsulfonyl, or cyclopentylsulfonyl 3-6 It is substituted with one or more cycloalkylsulfonyl compounds. In yet another embodiment, R 6 teeth, [ka] In another embodiment, R 6 teeth, [ka] In further embodiments, R 6 This includes 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 further embodiments, R 6 Methyl, isopropyl, tert-butyl, CF3, CHF2, C(CH3)F2, C(CH3)2F, C(CH3)2OH, [ka] That is the case.

[0121] In further embodiments, R 2 teeth, [ka] And R 6 and R 7 These are H, Halo, and C, independently. 1-6 Alkyl, or C 1-6 It is a haloalkyl, R 8 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 It is a cycloalkyl, optionally substituted aryl, or heteroaryl. In yet another embodiment, R 6 and R 7 These are H, Halo, and C, independently. 1-6 Alkyl, C 1-6 Haloalkyl, or NR y R z And R y and R z H or C 1-6 It is alkyl, R 8 H, C 1-6 Alkyl, C 1-6 Alkyl, C 3-6 It is a cycloalkyl or heteroaryl compound. In other embodiments, R 6 and R 7 One or both of these are H. In yet another embodiment, R 6 or R 7 One of them is a halo. In a further embodiment, R 6 or R 7 One of them is Cl or Br. In further embodiments, R 6 or R 7 One of them is Cl. In yet another embodiment, R 6 or R 7 One of them is C 1-6 It is alkyl. In further embodiments, R 6 or R 7 One of them is methyl. In other embodiments, R 6 or R 7 One of them is C 1-6It is a haloalkyl. In further embodiments, R 6 or R 7 One of these is CHF2, CH2CF3, CF2H, or CF3. In other embodiments, R 6 or R 7 One of them is CHF2. In a further embodiment, R 6 or R 7 One of them is NR y R z And R y and R z Independently, C such as H or NH2 1-6 It is alkyl. In yet another embodiment, R 6 or R 7 One of these is Cl, Br, methyl, CHF2, or CF3. In further embodiments, R 6 or R 7 One of these is Cl, methyl, CHF2, or NH2. In other embodiments, R 6 or R 7 One of these is methyl, Cl, CHF2, or CF3. In some embodiments, R 8 In other embodiments, R 8 C 1-6 It is alkyl. In further embodiments, R 8 is methyl, ethyl, isopropyl, or tert-butyl. In further embodiments, R 8 is methyl or isopropyl. In yet another embodiment, R 8 C 1-6 In further embodiments, R 8 This is CHF2, CH2CF3, CF2H, CH2CHF2, or CF3. In further embodiments, R 8 is CHF2, CH2CF3, or CF3. In other embodiments, R 8 C 3-6 It is a cyanoalkyl compound. In further embodiments, R 8 In further embodiments, R 8 is an arbitrarily substituted aryl. In further embodiments, R 8R is phenyl or fluorophenyl. In other embodiments, R 8 is a heteroaryl compound. In further embodiments, R 8 In another embodiment, R 8 is H, methyl, isopropyl, tert-butyl, CHF2, CH2CF3, CH2CHF2, CH2C(=O)CH3, CH2C(CH3)2OH, (CH2)2N(CH3)2, cyclopropyl, fluorophenyl, pyridinyl, CH2-cyclopropyl, or CH2-cyclobutyl. In further embodiments, R 8 These are methyl, isopropyl, CHF2, CH2CF3, CF3, cyclopropyl, and pyridinyl.

[0122] In further embodiments, R 2 teeth, [ka] And R 6 H, C 1-6 alkyl, halo, C 1-6 Haloalkyl, or C 3-6 It is cycloalkyl, R 8 H, C 1-6 Alkyl, or C 1-6 In further embodiments, R 6 H, C 1-6 alkyl, halo, C 1-6 Haloalkyl, or C 3-6 It is cycloalkyl, R 8 H or C 1-6 It is alkyl. In other embodiments, R 6 In another embodiment, R 6 C, such as methyl 1-6 It is alkyl. In yet another embodiment, R 6 is a halo such as Cl or Br. In further embodiments, R 6 In other embodiments, R 6 This is C such as CHF2 or CF3. 1-6 In yet another embodiment, R 6C is a compound such as cyclopropyl. 3-6 It is a cycloalkyl. In further embodiments, R 6 is H, methyl, Cl, CHF2, CF3, or cyclopropyl. In some embodiments, R 8 In other embodiments, R 8 C is a compound such as methyl, ethyl, or isopropyl. 1-6 It is alkyl. In yet another embodiment, R 8 C is a C such as CF3 or CHF2. 1-6 In other embodiments, R 8 It is methyl.

[0123] In yet another embodiment, 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 These are H and C, which are independent of each other. 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 Alkenil, CN, Halo, (CR v R x ) p NR y R z , C(O)NR y2 R z2 , arbitrarily substituted C 3-8 Cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl (alkylene), optionally substituted aryl, or optionally substituted heteroaryl, R vand R x H or C 1-6 It is alkyl, R y and R z H and C are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 It is an alkoxy (alkylene) or C(O)OC1-6 alkyl, and R y2 and R z2 H and C are independent of each other. 1-6 Alkyl, or C 3-6 It is a cycloalkyl group, where p is 0, 1, 2, or 3, and R 15 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 In other embodiments, W 1 In a further embodiment, W 1 , NR 15 In some embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 In a further embodiment, R 10 , R 11 , R 12 , and R 13 In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C 1-6 It is alkyl. In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C 1-6 In yet another embodiment, R 10, R 11 , R 12 , R 13 , and R 14 At least one of them is C 1-6 It is an alkoxy. In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C 1-6 It is an alkoxy (alkylene). In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C 1-6 It is a hydroxyalkyl group. In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C 1-6 In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C 1-6 It is a haloalkoxy(alkylene). In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C 2-6 It is an alkenyl. In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is CN. In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is a halo. In further embodiments, R 10 , R 11 , R 12 , R13 , and R 14 At least one of them is (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 them is C(O)NR y2 R z2 In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is an arbitrarily substituted C 3-8 It is cycloalkyl. In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is an optionally substituted heterocyclyl. In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of these is an optionally substituted heterocyclyl (alkylene). In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is an optionally substituted aryl. In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is an optionally substituted heteroaryl. In some embodiments, R v and R x One or both of them are H. In other embodiments, R v and R x One or both of are C 1-6It is alkyl. In some embodiments, R y and R z One or both of them are H. In other embodiments, R y and R z One or both of are C 1-6 It is alkyl. In further embodiments, R y and R z One or both of are C 3-6 It is cycloalkyl. In yet another embodiment, R y and R z One or both of are C 1-6 It is a hydroxyalkyl group. In further embodiments, R y and R z One or both of are C 1-6 It is a haloalkyl. In further embodiments, R y and R z One or both of them are C(O)OC1-6 alkyl. In some embodiments, R y2 and R z2 One or both of them are H. In other embodiments, R y2 and R z2 One or both of are C 1-6 It is alkyl. In further embodiments, R y2 and R z2 One or both of are C 3-6 It is a cycloalkyl compound. In some embodiments, p is 0. In other embodiments, p is 1. In yet another embodiment, p is 2. In yet another embodiment, p is 3. In some embodiments, R 15 In other embodiments, R 15 C 1-6 It is alkyl.

[0125] In further embodiments, R 2 teeth, [ka] And R 10 , R 11 , R 12 , R 13 , and R 14These are H and C, which are independent of each other. 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 These are H and C, which are independent of each other. 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 In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C such as methyl or ethyl. 1-6 It is alkyl. In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C such as methyl 1-6 It is alkyl. In further embodiments, R 10 , R 11 , R 12 , R13 , and R 14 At least one of them is C such as CF3. 1-6 In further embodiments, R 10 , R 11 , R 12 , R 13 , and / or R 14 At least one of them is C such as cyclopropyl. 3-6 It is cycloalkyl. In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C such as methoxy. 1-6 It is an alkoxy. In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is C such as CH2OCH3 or (CH2)2OCH3. 1-6 It is an alkoxy (alkylene). In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of these is a halo such as F, Br, or Cl. In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is an optionally substituted aryl such as an unsubstituted phenyl. In yet another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is [ka] These are heterocyclines that are arbitrarily substituted, such as R. 10 , R 11 , R 12 , R13 , and R 14 At least one of them is [ka] These are arbitrarily substituted heterocyclines such as the following. In other embodiments, the arbitrarily substituted heteroaryls are [ka] In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of these is an optionally substituted heterocyclyl (alkylene). In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is [ka] In another embodiment, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is [ka] In other embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of these is an optionally substituted heteroaryl such as an optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazolyl. In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is [ka] In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of these is NH2, NH(CH3), N(CH3)2, CH2N(CH3)2, or CH2CH2N(CH3)2, etc. (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 them is N(CH3)2, CH2N(CH3)2, or CH2CH2N(CH3)2, etc. (CR v R x ) p NR y R z In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 These are, independently, H, methyl, C(CH3)2F, cyclopropyl, methoxy, CH2OCH3, (CH2)2OCH3, Br, F, Cl, phenyl, [ka] In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 These are, independently, H, methyl, cyclopropyl, methoxy, CH2OCH3, (CH2)2OCH3, [ka] In other embodiments, R10 , R 13 , and R 14 Each of these is hydrogen. In a further embodiment, R 10 , R 13 , and R 14 Each of them is hydrogen, and R 11 It is a halo.

[0126] In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is a 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(CH3)2OH etc. 1-6 Hydroxyalkyl; such as methoxy, ethoxy, or propoxy C 1-6 Alkoxy; or C such as cyclopropyl, cyclobutyl, or cyclopentyl 3-6 A substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more cycloalkyl groups. In other embodiments, the substituted heterocyclyl or substituted heterocyclyl(alkylene) is substituted with one or more methyl, OH, or F groups.

[0127] In further embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 At least one of them is a 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; such as methoxy, ethoxy, or propoxy C 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 It is a substituted heteroaryl molecule substituted with one or more cycloalkylsulfonyl molecules. In further embodiments, the substituted heteroaryl molecule is substituted with one or more of F, CF3, CHF2, or methyl molecules. In even further embodiments, the optionally substituted heteroaryl molecule is a pyrazolyl molecule substituted with one methyl molecule.

[0128] In other embodiments, R 2 teeth, [ka] And R 10 , R 11 , R 12 , and R 13 These are H and C, which are independent of each other. 1-6 Alkyl or halo, R 15 H or C 1-6 It is alkyl. In further embodiments, R 10 , R 11 , R 12 , and R 13 In other embodiments, R 10 , R 11 , R 12 , and R 13 At least one of them is C 1-6 It is alkyl. In further embodiments, R 10 , R 11 , R 12 , and R 13 At least one of them is a halo. In yet another embodiment, R 10 , R 11 , R 12 , and R 13 At least one of them is Br. In some embodiments, R 15 In other embodiments, R 15 C 1-6 It is alkyl. In further embodiments, R 15 is methyl. In yet another embodiment, R 15 is either H or methyl.

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

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

[0131] In further embodiments, R 2 teeth, [ka] And R 10 , R 11 , R 12 , and R 13 These are H and C, which are independent of each other. 1-6 It is alkyl or halo. In some embodiments, R 2 teeth, [ka] In other embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] In some embodiments, R10 , R 11 , R 12 , and R 13 In other embodiments, R 10 , R 11 , R 12 , and R 13 At least one of them is a halo. In a further embodiment, R 10 , R 11 , R 12 , and R 13 At least one of them is F. In yet another embodiment, R 10 , R 11 , R 12 , and R 13 At least one of them is C 1-6 It is alkyl. In further embodiments, R 10 , R 11 , R 12 , and R 13 At least one of them is methyl. In yet another embodiment, R 10 , R 11 , R 12 , and R 13 Each of these is independently H, methyl, or F.

[0132] In other embodiments, R 2 teeth, [ka] And R 6 R is defined herein as R 7 In another embodiment, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0133] In further embodiments, R 2 teeth [ka] And R 6 R is defined herein as R 7 In other embodiments, R 2 teeth [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0134] In yet another embodiment, R 2 teeth, [ka] And R 6 R is defined herein as R 7 is cyclopropyl. In further embodiments, R 2 teeth, [ka] In further embodiments, R 2 teeth, [ka] That is the case.

[0135] In further embodiments, R 2 teeth, [ka] And R 6 R is defined herein as R 7 In other embodiments, R 2 teeth, [ka] In another embodiment, R 2teeth, [ka] That is the case.

[0136] In other embodiments, R 2 teeth, [ka] And R 6 R is defined herein as R 7 In another embodiment, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0137] In further embodiments, R 2 teeth, [ka] And R 6 R is defined herein as R 7 In further embodiments, R 2 teeth, [ka] That is the case.

[0138] In yet another embodiment, R 2 teeth, [ka] And R 6 R is defined herein as R 7 is Br or Cl. In further embodiments, R 2 teeth, [ka] That is the case.

[0139] In further embodiments, R 2 teeth, [ka] And R 6 R is defined herein as R 7 is phenyl or pyridinyl. In other embodiments, R 2 teeth, [ka] That is the case.

[0140] In further embodiments, R 2 teeth, [ka] And R 6 R is defined herein as R 7 In another embodiment, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0141] In other embodiments, R 2 teeth, [ka] And R 6 ~R 8 R is defined herein. In further embodiments, R 2 teeth [ka] In another embodiment, R2 teeth, [ka] That is the case.

[0142] In further embodiments, R 2 teeth, [ka] And R 6 ~R 8 R is defined herein. In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0143] In other embodiments, R 2 teeth, [ka] And R 6 is an arbitrarily substituted heterocycline. In yet another embodiment, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0144] In further embodiments, R 2 teeth, [ka] And R 6is an optionally substituted heteroaryl. In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] [ka] That is the case.

[0145] In other embodiments, R 2 teeth, [ka] And R 6 is an arbitrarily substituted aryl. In yet another embodiment, R 2 teeth, [ka] That is the case.

[0146] In further embodiments, R 2 teeth, [ka] And R 6 C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 It is a hydroxyalkyl group. In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0147] In other embodiments, R 2 teeth, [ka] And R 6 is an arbitrarily substituted C 3-8 It is cycloalkyl. In yet another embodiment, R 2 teeth, [ka] That is the case.

[0148] In yet another embodiment, R 2 teeth, [ka] And R 6 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 R is defined herein. In other embodiments, R 2 teeth, [ka] That is the case.

[0149] In other embodiments, R 2 teeth, [ka] And R 6 H, C 1-6 It is an alkyl or optionally substituted aryl. In yet another embodiment, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0150] In further embodiments, R 2 teeth, [ka] And R 6 C 1-6 It is a hydroxyalkyl group. In further embodiments, R 2 teeth, [ka] That is the case.

[0151] In other embodiments, R 2 teeth, [ka] And R 8 C 1-6 It is alkyl, R 6 R is defined herein. In further embodiments, R 2 teeth [ka] That is the case.

[0152] In further embodiments, R 2 teeth, [ka] And R 10 ~R 14 R is defined herein. In further embodiments, R 2 teeth, [ka] In another embodiment, R 2 teeth, [ka] That is the case.

[0153] In other embodiments, R 2 teeth, [ka] And R 13 H is R 10 , R 11 , R 12 , R 14 , and R 15 R is defined herein. In further embodiments, R 2 teeth, [ka] That is the case.

[0154] In some embodiments, the compound of formula I is the 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 other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0155] In other embodiments, the compound of formula I is the 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 further embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0156] In further embodiments, the compound of formula I is the 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 other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0157] In yet another embodiment, the compound of formula I is the 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 other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0158] In further embodiments, the compound of formula I is the 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 other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0159] In other embodiments, the compound of formula I is the 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 another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0160] In further embodiments, the compound of formula I is the 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 further embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0161] In yet another embodiment, the compound of formula I is the 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 other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0162] In further embodiments, the compound of formula I is the 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 other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0163] In other embodiments, the compound of formula I is the 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 another embodiment, the compound is [ka] or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0164] In further embodiments, the compound of formula I is the 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 other embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0165] In yet another embodiment, the compound of formula I is the 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 further embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0166] In further embodiments, the compound of formula I is the 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, as well as their pharmaceutically acceptable salts and / or isotopologs. Compounds having formula I are further disclosed in the examples and are included in the present disclosure. These include their pharmaceutically acceptable salts and neutral forms.

[0168] This disclosure further provides R-enantiomers, S-enantiomers, or racemic mixtures 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 a racemic mixture.

[0169] In other embodiments, the compounds of the Disclosure are enantiomerically concentrated, and the enantiomer excess or "ee" of the compound is about 5% or more, as measured, for example, by chiral HPLC. In some embodiments, the ee is about 10% or more. In other embodiments, the ee is about 20% or more. In yet another embodiment, the ee is about 30% or more. In yet another embodiment, the ee is about 40% or more. In yet another embodiment, the ee is about 50% or more. In other embodiments, the ee is about 60% or more. In yet another embodiment, the ee is about 70% or more. In yet another embodiment, the ee is about 80% or more. In yet another embodiment, the ee is about 85% or more. In other embodiments, the ee is about 90% or more. In yet another embodiment, the ee is about 91% or more. In yet another embodiment, the ee is about 92% or more. In yet another embodiment, the ee is about 93% or more. In yet another embodiment, the ee is about 94% or more. In further embodiments, ee is greater than approximately 95%. In yet another embodiment, ee is greater than approximately 96%. In yet another embodiment, ee is greater than approximately 97%. In yet another embodiment, ee is greater than approximately 98%. In yet another embodiment, ee is greater than approximately 99%.

[0170] This disclosure includes the preparation and use of salts of the compounds of this disclosure. Salts of the compounds of this disclosure may be prepared separately during the final isolation and purification of the compounds, or by reacting the compounds with a suitable acid or base.

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

[0172] As used herein, the term “variant PAH gene” refers to a complete DNA sequence of a PAH that differs in one or more ways from a standard, accepted sequence (“basic gene”) published in any of the various curated databases. For example, the sequence described by GenBank accession number 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 the one encoded by 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 yet another embodiment, the mutant PAH protein contains at least one R408W, R243Q, R408Q, V388M, or L348V mutation. In yet another embodiment, the mutant PAH protein contains at least one R408W mutation. In yet another embodiment, the mutant PAH protein contains at least two R408W mutations. In yet another embodiment, the mutant PAH protein contains at least one R261Q mutation. In yet another embodiment, the mutant PAH protein contains at least one R243Q mutation. In yet another embodiment, the mutant PAH protein contains at least one Y414C mutation. In yet another embodiment, the mutant PAH protein contains at least one L48S mutation. In yet another embodiment, the mutant PAH protein contains at least one A403V mutation. In yet another embodiment, the mutant PAH protein contains at least one I65T mutation. In yet another embodiment, the mutant PAH protein contains at least one R241C mutation. In further embodiments, the mutant PAH protein contains at least one L348V mutation. In even further embodiments, the mutant PAH protein contains at least one R408Q mutation. In other embodiments, the mutant PAH protein contains at least one V388M mutation. In other embodiments, the mutant PAH protein contains at least one F39L mutation.In further embodiments, the mutant PAH protein contains at least one A300S mutation. In further embodiments, the mutant PAH protein contains at least one L48S mutation.

[0174] In other embodiments, the disclosure provides methods for stabilizing the activity of a mutant phenylalanine hydroxylase (PAH) protein compared to wild-type PAH. Such methods include contacting phenylalanine hydroxylase with one or more compounds described herein or pharmaceutically acceptable salts thereof. As used herein, the term “stabilizing” refers to adjusting the activity or amount of the PAH enzyme to catalyze the hydroxylation of the aromatic side chain of phenylalanine at a rate more similar to the PAH catalytic flux of a control population having wild-type PAH, i.e., without the mutant PAH gene mutation, compared to the baseline PAH catalytic flux. In some embodiments, the term “stabilizing” refers to adjusting the activity of a PAH in question to catalyze the hydroxylation of the aromatic side chain of phenylalanine at a flux more similar to the PAH catalytic flux of a control population without the mutant PAH gene mutation. In some embodiments, “stabilizing” the activity of the PAH includes increasing the level of the enzyme PAH compared to baseline. By increasing the accumulation of stabilized active PAH proteins, the toxic Phe level of a subject may be reduced compared to the baseline level of dietary Phe in the subject prior to administration of the compound of the disclosed herein or a pharmaceutical composition containing the compound of the disclosed herein.

[0175] In some embodiments, the Disclosure provides a method for reducing the blood phenylalanine concentration in a subject with phenylketonuria to a concentration of about 600 μM or less. In other embodiments, the blood Phe concentration is reduced to a concentration of about 360 μM or less. In other embodiments, the Disclosure provides a method for reducing the blood Phe concentration compared to an untreated baseline. In some embodiments, the blood Phe concentration of a subject 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 blood Phe concentration of a subject compared to an untreated baseline is reduced by at least about 10%. In further embodiments, the blood Phe concentration of a subject compared to an untreated baseline is reduced by at least about 20%. In yet another embodiment, the blood Phe concentration of a subject compared to an untreated baseline is reduced by at least about 30%. In further embodiments, the subject's blood Phe concentration is reduced by at least about 40% compared to an untreated baseline. In other embodiments, the subject's blood Phe concentration is reduced by at least about 50% compared to an untreated baseline. In further embodiments, the subject's blood Phe concentration is reduced by at least about 60% compared to an untreated baseline. In yet another embodiment, the subject's blood Phe concentration is reduced by at least about 70% compared to an untreated baseline. In further embodiments, the subject's blood Phe concentration is reduced by at least about 80% compared to an untreated baseline. In another embodiment, the subject's blood Phe concentration is reduced by at least about 90% compared to an untreated baseline. The subject's Phe concentration may be determined by a blood test, and methods for measuring such levels are known in the art. In some embodiments, the reduction in Phe concentration achieved using the compounds of this disclosure is obtained in conjunction with the subject actively managing their dietary Phe intake. In other embodiments, the reduction in Phe concentration is obtained in conjunction with the subject maintaining a Phe-restricted diet.

[0176] In some embodiments, subjects are treated with the compounds of the Disclosure, or pharmaceutical compositions comprising the compounds of the Disclosure. The compounds are administered in amounts sufficient to stabilize PAH proteins, reduce blood phenylalanine concentrations in the subjects, or a combination thereof in the subjects.

[0177] In further embodiments, the subjects are human patients, such as human adults over 18 years of age requiring treatment. In even further embodiments, the human patients are human children under 18 years of age. In even further embodiments, the human patients are human children aged 12 to 18 years. In yet another embodiment, the human patients are human children under 12 years of age. In any of the embodiments, the subjects have phenylketonuria (PKU), optionally classical PKU, or severe PKU. In some embodiments, the subjects have a blood Phe concentration greater than about 600 μM prior to administration of the compound of the Disclosure or a pharmaceutical composition containing the compound of the 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 even further embodiments, the subject's blood Phe concentration prior to administration is greater than about 900 μM. In yet another embodiment, the subject's blood Phe concentration prior to administration is greater than about 1000 μM. In further embodiments, the subject's blood Phe concentration before administration is greater than approximately 1100 μM. In other embodiments, the subject's blood Phe concentration before administration is greater than approximately 1200 μM.

[0178] The methods of the present invention also involve administering an additional therapeutic agent to the subject in addition to the compounds 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 concentrations. The additional therapeutic agent is different from the compounds 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. Possible nutritional supplements include those containing amino acids and other nutrients. In further embodiments, the nutritional supplement contains large neutral amino acids such as leucine, tyrosine, tryptophan, methionine, histidine, isoleucine, valine, and threonine. In other embodiments, the nutritional supplement contains tyrosine. In further embodiments, the nutritional supplement contains casein glycomacropeptides, i.e., milk peptides that do not naturally contain Phe in their pure form. In other embodiments, 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 biological agent, a synthetic biological agent, a microbiome, or a probiotic. In yet another embodiment, the biological agent, synthetic biological agent, microbiome, or probiotic includes, for example, a genetically modified phenylalanine ammonia lyase (PAL) gene such as E. coli Nissle PAL. Examples of genetically modified E. coli Nissle PAL biological agents include SYNB1934 and SYNB1618. In yet another embodiment, the additional therapeutic agent is an amino acid transporter inhibitor. In some embodiments, the amino acid transporter is B 0 The drug in question is AT1 (also known as SLC6A19), and additional treatment options include SLC6A19 inhibitors. Examples of SLC6A19 inhibitors include nimedzulid, benztropine, NSC63912, NSC22789, simlomid, CB3, E62, and JNT-517.

[0179] The compounds and additional therapeutic agents of this disclosure may be administered simultaneously or sequentially to achieve the desired effect. Furthermore, the compounds and additional therapeutic agents of this disclosure may be administered as a single composition or as two separate compositions.

[0180] Additional therapeutic agents are administered in amounts that provide the desired therapeutic effect. Effective dosage ranges for each additional therapeutic agent are known in the art, and these agents are administered to individuals requiring them within such established ranges.

[0181] The compounds and additional therapeutic agents of this disclosure may be administered as single unit doses or separately as multi-unit doses, with the compounds of this disclosure being administered before or after the additional therapeutic agents. One or more doses of the compounds of this disclosure and / or one or more doses of the additional therapeutic agents may be administered.

[0182] The compounds of this disclosure may also be administered sequentially or concurrently 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. Those skilled in the art will be able to determine the type of diet to maintain an appropriate level of Phe. In some embodiments, this involves phenylamine intake containing 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 involve restricting 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, legumes, and low-fat cottage cheese.

[0183] An example of dosage is in the range of approximately 0.001 to 100 mg of the compound per kg of body weight per day, either as a single or divided dose unit (e.g., BID, TID, QID). For a person weighing 70 kg, a suitable dose is approximately 0.05 to 7 g / day.

[0184] In some embodiments, the therapeutically effective dose of one or more compounds described herein is the amount effective in stabilizing the mutant PAH protein described herein. In other embodiments, the therapeutically effective dose of one or more compounds described herein is the amount effective in reducing the blood phenylalanine concentration.

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

[0186] Pharmaceutical composition This disclosure also provides pharmaceutical compositions comprising the compounds of this disclosure and pharmaceutically acceptable carriers and / or excipients.

[0187] The methods of the disclosed herein can be achieved by administering the compounds of the disclosed herein either as compounds or as pharmaceutical compositions. Administration of the pharmaceutical compositions or compounds of the disclosed herein may be carried out at any time determined by the attending physician. Typically, the pharmaceutical compositions do not contain toxic, carcinogenic, or mutagenic compounds that are likely to cause adverse reactions when administered.

[0188] Pharmaceutical compositions include those in which the compounds of this disclosure are administered in an effective amount to achieve their intended purpose. The exact formulation, route of administration, and dosage will be determined by the individual physician.

[0189] The compounds of this disclosure can be administered by any suitable route, for example, orally, buccally, by inhalation, sublingually, rectally, vaginally, intracisional or subarachnoid by lumbar puncture, transurethrally, transnasally, percutaneously, i.e., percutaneously or parenterally (including intravenous, intramuscular, subcutaneous, intracoronal, intradermal, intramammary, intraperitoneal, intra-articular, subarachnoid, retrobulbar, intrapulmonary injection and / or surgical implantation at specific sites). Parenteral administration can be achieved using needles and syringes or by using high-pressure techniques.

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

[0191] The compounds of this disclosure may be administered in combination with a pharmaceutical carrier selected with respect to the intended route of administration and standard drug implementation. Pharmaceutical compositions for use in accordance with this disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients and / or adjuvants that facilitate the processing of the compounds of this disclosure.

[0192] The administration of the compounds or pharmaceutical compositions of this disclosure may be achieved by any method that enables delivery of the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, intra-arterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical (e.g., perdermal), rectal administration, topical delivery by catheter or stent, or delivery by inhalation. The compounds may also be administered intrafatally or subarachnoidally.

[0193] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the administration rate, the pharmacokinetics of the compound, and the discretion of the prescribing physician. Desired doses may be administered as a single dose or as repeated doses at appropriate intervals, for example, once, twice, three times, four times, or more times daily in partial doses. In some embodiments, the compounds disclosed herein are effective over a wide dose range. For example, in the treatment of adult humans, dosage forms containing approximately 0.01 to 2000 mg of the compounds disclosed herein per day are examples of dosage forms that may be used. The exact dose will depend on the route of administration, the form in which the compound is administered, the subject being treated, the subject's weight, and the preference and experience of the attending physician. In some cases, dose levels below the lower limit of the above 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 higher doses 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 in the form of solid oral dosage forms such as tablets or capsules. However, other routes may be used if necessary. Single doses of the compound may also be used to treat acute conditions.

[0196] In some embodiments, the compounds of this 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 per day. In other embodiments, the compounds and other therapeutic agents described herein are administered approximately once to approximately six times per day. Administration of the compounds disclosed herein may be continued as needed. In some embodiments, the compounds are administered continuously and chronically, for example, to treat chronic effects.

[0197] An effective amount of the compound of this disclosure may be administered in single or multiple doses by any acceptable mode of administration of similar therapeutic agents, including rectal, oral, nasal, and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation.

[0198] The pharmaceutical composition may be in a form suitable for oral administration as, for example, tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions; 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-dose administration of a precise dose. The pharmaceutical composition will contain one or more conventional pharmaceutical carriers or excipients, and compounds disclosed herein as active ingredients. In addition, it may contain other pharmaceuticals or medicinal products, carriers, adjuvants, etc.

[0199] Exemplary parenteral administration forms include solutions or suspensions of the compounds of this disclosure in sterile aqueous solutions, such as aqueous propylene glycol or dextrose solutions. Such dosage forms may be preferably buffered if desired.

[0200] Oral pharmaceutical composition In some embodiments, the Disclosure provides pharmaceutical compositions for oral administration, comprising the compounds of the Disclosure and pharmaceutically acceptable excipients suitable for oral administration.

[0201] In some embodiments, the Disclosure provides an orally administered solid pharmaceutical composition comprising (i) an effective amount of the compound of the Disclosure, optionally (ii) an effective amount of a second therapeutic agent, and (iii) a pharmaceutically acceptable excipient 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 a pharmaceutical composition suitable for oral administration. Pharmaceutical compositions comprising compounds of the 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, aqueous or non-aqueous liquids, oil-in-water emulsions, or water-in-oil liquid emulsions, solutions, or suspensions. Such dosage forms may be prepared by any pharmacopoeial method, all of which include a step of associating the compounds of the Disclosure with a carrier, which constitutes one or more required components. Generally, compositions are prepared by homogeneously and closely mixing the compounds of the Disclosure with a liquid carrier or a micronized solid carrier or both, and then, if necessary, shaping the product into a desired presentation. For example, tablets may be prepared by compression or shaping with optionally one or more minor components. Compressed tablets are prepared by compressing the active ingredient in a free-flowing form such as powder or granules using a suitable machine, and may optionally, but not limited to, be mixed with excipients such as binders, lubricants, inert diluents, and / or surfactants or dispersants. Molded tablets may be produced by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine.

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

[0204] The compounds of this disclosure can be combined by close mixing with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In the preparation of compositions for oral dosage forms, for example, in the case of oral liquid preparations (suspensions, solutions, and elixirs) or aerosols, any of the usual pharmaceutical media such as water, glycol, oil, alcohol, flavoring agents, preservatives, and coloring agents may be used as carriers, or carriers such as starch, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants may be used in the case of oral solid preparations in some embodiments that do not employ the use of lactose. For example, suitable carriers include powders, capsules, and tablets having solid oral preparations. If necessary, tablets may be coated by standard aqueous or non-aqueous techniques.

[0205] Suitable binders 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., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, colloidal silicon dioxide, microcrystalline cellulose, and mixtures thereof.

[0206] 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, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0207] Disintegrants may be used in the compositions of this disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may produce tablets that disintegrate in the bottle. Too little may be insufficient for disintegration to occur, and thus may alter the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant, neither too little nor too much, which would adversely alter the release of the active ingredient, may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary depending on the type of formulation and mode of administration and will be readily apparent to 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, may be used in the pharmaceutical composition. Disintegrants that may be used to form the 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, polaritrin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins, other celluloses, gums, or mixtures thereof.

[0208] Lubricants that may be used to form the pharmaceutical compositions and dosage forms of this 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, siloid silica gel, synthetic silica solidification aerosols, or mixtures thereof. Lubricants may optionally be added in amounts less than about 2 weight percent of the pharmaceutical composition.

[0209] If an aqueous suspension and / or elixir is preferred for oral administration, the active ingredient therein may be combined with various sweeteners or flavorings, colorants or dyes, and preferably emulsifiers and / or suspending agents, along with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0210] The tablets may be uncoated or coated using known coating techniques to delay their breakdown and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. The formulation for oral use may also be a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or it may be a soft gelatin capsule 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 the pharmaceutical compositions and dosage forms of this disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0212] Suitable hydrophilic surfactants generally have an HLB value of at least 10, while suitable lipophilic surfactants 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 have higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions.

[0213] Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than approximately 10, and anionic, cationic, or amphoteric compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value of approximately 10 or less. However, the HLB value of surfactants is merely a rough guideline commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0214] Hydrophilic surfactants may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidates, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysolecitin and hydrogenated lysolecitin, phospholipids and their derivatives, lysophospholipids and their derivatives, carnitine fatty acid ester salts, alkyl sulfates, fatty acid salts, sodium doxate, acyl lactate, mono and diacetylated tartaric acid esters of mono and diglycerides, succinyl mono and diglycerides, citrate esters of mono and diglycerides, and mixtures thereof.

[0215] Within the group described above, examples of ionic surfactants include lecithin, lysolecitin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, sodium doxate, acylcylates, 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, lysol cithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactic acid esters, stearoyl-2-lactic acid, stearoyl lactate, and s These may be ionized forms of xinyl monoglycerides, mono / diacetylated tartrates of mono / diglycerides, citrates of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristic acid, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, doxate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and their salts and mixtures.

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

[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 / caprylate glyceride, PEG-8 caprate / caprylate glyceride, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 plant sterols, PEG-30 soybean sterols, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, PO Examples 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, but are not limited to, 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, lactic acid derivatives of mono and diglycerides, glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and hydrophobic transesterification products of polyols having at least one member from the group consisting of sterols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols having at least one member from the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0220] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compounds of the Disclosure and to minimize precipitation of the compounds of the Disclosure. This may be important for compositions for parenteral use, such as compositions for injection. Solubilizers 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 solubilizers 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, transcatol, dimethyl isosorbide, polyethylene glycol (PEG), polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives, polyethylene glycol ethers having an average molecular weight of about 200 to about 6000 such as tetrahydrofuryl alcohol PEG ether (glycofuryl) or methoxyPEG, and polyethylene glycol 660. Examples of other solubilizers known in the art include 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, acetyltriethyl citrate, acetyltributyl 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 dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0222] Mixtures of solubilizers may also be used. Examples, but not limited to, include triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, glycoflor, transcatol, 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, glycoflor, and propylene glycol.

[0223] The amount of solubilizer that may be included is not particularly limited. A given amount of solubilizer may be limited to a biotolerable amount, which can be readily determined by those skilled in the art. In some situations, for example, to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer much greater than the biotolerable amount, and the excess solubilizer may be removed before the composition is provided to the target using conventional techniques such as distillation or evaporation. Therefore, if present, the solubilizer may be 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 at most less than about 200% by weight, based on the combined weight of the drug and other excipients. If necessary, very small amounts of solubilizer may also be used, such as less than about 5%, less than about 2%, less than about 1%, or even less. Typically, the solubilizer may be present in an amount of about 1% to less than 100% by weight, and more typically, about 5% to less than 25% by weight.

[0224] The composition may further contain one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackeners, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, isotonic agents, flavoring agents, colorants, odorants, emulsifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0225] Pharmaceutical composition for injection In some embodiments, this disclosure provides pharmaceutical compositions for injection comprising the compounds described herein and pharmaceutically acceptable excipients. The components and amounts of the drugs in the composition are as described herein.

[0226] Forms into which the compositions of this 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 may also be used. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin to maintain the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0228] Sterile injectable solutions are prepared by incorporating the compounds of this disclosure, along with various other components listed above, in the required amounts in a suitable solvent, and subsequently by sterilization by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desired preparation methods are vacuum drying and freeze-drying techniques to obtain a powder of the active ingredient from a previously sterile filtered solution, in addition to any additional desired components.

[0229] Other pharmaceutical compositions Pharmaceutical compositions may 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 intrathecal 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 See Press, London, 1999), all of which are incorporated herein by reference in their entirety.

[0230] Synthesis of the Compounds Disclosed The compounds of this disclosure may be prepared by the methods described in the general schemes, procedures, and examples set forth herein, and by related methods known in the art. For example, the compound of formula I may be prepared by the general methods shown in general schemes 1 to 11.

[0231] General Scheme 1: Preparation of the compound of formula I [ka]

[0232] The compound of formula I was obtained through the reaction illustrated in general scheme 1. The amine of formula 1.1 or 1.2 and the aldehyde of formula 1.3 were first reacted under Pictet-Spengler reaction conditions to obtain the coreamine of formula 1.4. The imine byproduct can be converted to the coreamine of formula 1.4 by reaction with sodium borohydride in an alcohol solvent (e.g., methanol or ethanol) to the extent that an imine byproduct is formed during the Pictet-Spengler reaction. Then, various L and R 2 The group was introduced by using one of the following methods: nucleophilic substitution (Method A1), Buchwald or other similar cross-coupling reaction (Method A2), reduction animation reaction (Method B), or amide coupling reaction (Methods C, D, E, and F). In Method A1, R of Equation 1.5 2 An aryl or heteroaryl halide (wherein X is Br, Cl, or F) is bonded to the coreamine of formula 1.4 using a nucleophilic substitution reaction under basic conditions such as DIPEA to obtain the compound of formula 1.6. In method A2, R of formula 1.5 2 An aryl or heteroaryl halide (wherein X is Br, Cl, or I) is coupled with the core amine of formula 1.4 using Buchwald coupling or cross-coupling conditions known in the art, such as using a palladium catalyst (e.g., CPhos-Pd-G3, Pd(OAc)2, Pd(dppf)Cl2) and a base such as Cs2CO3, to obtain the compound of formula 1.6. In method B, R of formula 1.7 2 An aryl or heteroaryl aldehyde is bonded to the core amine of formula 1.4 under reduction animation reaction conditions using a hydride such as sodium triacetoxyborohydride to obtain the compound of formula 1.8. In method C, the R of formula 1.9 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- together with a base such as DIPEA (Hünig base), pyridine, or TEA, to obtain the compound of formula 1.11, where L 2 is a combination of C, which is optionally substituted. 1-6 Alkylene, optionally substituted C 2-6 Alkenylene, or optionally substituted C 1-6 It is a haloalkylene. Alternatively, using method D, R in equation 1.10 2 The acid chloride is bonded to the coreamine of formula 1.4 under basic conditions to obtain the compound of formula 1.11, where L 2 is a combination, optionally C 1-6 Alkylene, optionally substituted C 2-6 Alkenylene, or optionally substituted C 1-6 It is a haloalkylene. In method E, R in equation 1.12 2 The acid chloride is bonded to the coreamine of formula 1.4 under basic conditions to obtain the compound of formula 1.14, where L 3 C is a combination or optionally substituted C 1-6 It is an alkylene. In method F, R in equation 1.13 2 The amine is bonded to the coreamine of formula 1.4 and carbonyl diimidazole under basic conditions to obtain the compound of formula 1.14, where L 3 C is a combination or optionally substituted C 1-6 It is alkylene.

[0233] General Scheme 2: Preparation of the deuterated coreamine intermediate of Equation 2.2 [ka]

[0234] R 5Compounds of formula I where is D are prepared according to General Scheme 2. The amine of formula 1.1 or 1.2 and the aldehyde of formula 1.3 are reacted under Pictet-Spengler reaction conditions to obtain the compound of formula 2.1 or a mixture of the compound of formula 2.1 and the imine byproduct of formula 2.1a. Then, the compound of formula 2.1, or a mixture of the compounds of formulas 2.1 and 2.1a, is reacted with sodium borohydride in deuterated methanol to obtain the deuterated coreamine of formula 2.2. Then, the deuterated coreamine intermediate of formula 2.2 is subjected to various L and R via methods A, B, C, D, E, and F described in General Scheme 1. 2 By further bonding with the group, the compound of formula I can be obtained, where R 5 It is D.

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

[0236] R 6 and / or R 7 Oxazolyl R containing substitution at the position 2The carboxylic acid intermediate was prepared according to general scheme 3. The carboxylic acid of formula 3.1 was reacted with oxalyl chloride and the catalyst N,N-dimethylformamide to obtain the acid chloride of formula 3.2. Next, the chloric acid of formula 3.2 was reacted with the enamine of formula 3.3 to obtain the enamide of formula 3.4. Then, the enamide of formula 3.4 underwent divalent iodine-mediated cyclization after reaction with [bis(trifluoroacetoxy)iodo]benzene and boron trifluoride diethyl ether acid to obtain the oxazole of formula 3.5. The compound of formula 3.6 was obtained by hydrolysis of the ester of the oxazole of formula 3.5 using a base such as LiOH, KOH, or NaOH in THF / water. Alternatively, the basic salt of the carboxylic acid of formula 3.6 (i.e., Li, K, or Na) can be obtained after the hydrolysis reaction by isolating the product at a basic pH. Subsequently, the carboxylic acid or its basic salt can be used without further purification in the coupling reaction described in General Scheme 1, Method C.

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

[0238] R 6 and / or R 7 Oxazolyl R containing substitution at the position 2 The carboxylic acid intermediate was prepared according to General Scheme 4. The β-ketoester of Formula 4.1 was halogenated with a chlorinating agent such as SOCl2 or a bromidating agent such as NBS to obtain the compound of Formula 4.2 (wherein X 1(wherein X is Br or Cl). The compound of formula 4.2 was reacted with urea to obtain the amine oxazole compound of formula 4.3. In addition, the compound of formula 4.2 was reacted with the amide of formula 4.5 to obtain the oxazole compound of formula 4.6. The amine in the compound of formula 4.3 was subjected to Sandmeyer reaction conditions to obtain the compound of formula 4.4 (wherein X is Cl, Br, or F) and the compound of formula 4.10. Alternatively, the compound of formula 4.10 can be obtained by deprotonating the compound of formula 4.8 with a base such as LiHMDS, and then reacting it with the reagent of formula 4.9 (wherein Y is a suitable leaving group such as Br, Cl, mesylate, or tosylate) in a nucleophilic substitution reaction to obtain the compound of formula 4.10. The compounds of formula 4.7 and 4.11 are obtained by hydrolysis of the esters of the compounds of formula 4.6 and 4.10 using a base such as LiOH, KOH, or NaOH in THF / water. Alternatively, the basic salts of the carboxylic acids of formulas 4.7 and 4.11 (i.e., Li, K, or Na) can be obtained after the hydrolysis reaction by isolating the product at a 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.

[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 substitutions at the position 2Carboxylic acid intermediates were prepared according to General Scheme 5. In Method A, the halide of Formula 5.1 was reacted with the heteroaryl or aryl of Formula 5.2 by either Suzuki coupling (where Y is a boronic acid or ester) or Still coupling (where Y is SnR3) to obtain the compound of Formula 5.3. In Method B, the compound of Formula 5.3 was obtained by reacting the compound of Formula 5.4 with the heteroaryl or aryl halide compound of Formula 5.5 in a cross-coupling reaction using a metal catalyst such as a Buchwald catalyst or an Ullmann catalyst. In Method C, the halide of Formula 5.1 can also be reacted in a substitution reaction with the amine of Formula 5.7, or with heterocyclic amines such as piperidine, morpholine, piperazine, azetidine, and pyrrolidine, and a base such as TEA to obtain the compound of Formula 5.8. Compounds of formulas 5.6 and 5.9 are obtained by hydrolysis of the esters of the compounds of formulas 5.3 and 5.8 using a base such as LiOH, KOH, or NaOH in THF / water. Alternatively, basic salts (i.e., Li, K, or Na) of the carboxylic acids of formulas 5.6 and 5.9 can be obtained after the hydrolysis reaction by isolating the product at a 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.

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

[0242] Oxazolyl and thiazolyl R containing hydroxyalkyl and haloalkyl substitutions 2Carboxylic acid intermediates were prepared according to General Scheme 6. In Method A, the halide of Formula 6.1 was reacted with tributyl(1-ethoxyvinyl) stannane by Still coupling, followed by hydrolysis with an acid / water such as TFA to obtain the compound of Formula 6.3. Then, an alkyl group ("R") was added to the ketone in the compound of Formula 6.3 using RMgBr or RLi, or by ketone reduction using NaBR to obtain the compound of Formula 6.4. In Method B, the compound of Formula 6.4 can also be obtained by starting from the compound of Formula 6.1 and undergoing a Grignard addition reaction with the ketone of Formula 6.2 (wherein R is alkyl) or cyclobutanone and RMgCl such as iPrMgCl. The hydroxyl substituent in the compound of Formula 6.4 was converted to a fluorine substituent using a fluorinating agent such as BAST to obtain the compound of Formula 6.6. Compounds of formulas 6.5 and 6.7 are obtained by hydrolysis of the esters of the compounds of formulas 6.4 and 6.6 using a base such as LiOH, KOH, or NaOH in THF / water. Alternatively, basic salts (i.e., Li, K, or Na) of the carboxylic acids of formulas 6.5 and 6.7 can be obtained after the hydrolysis reaction by isolating the product at a 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.

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

[0244] Substituting pyrazolo[1,5-a]pyridinyl R 2 Carboxylic acid intermediates were prepared according to General Scheme 7. In Method A, the halide of Formula 7.1 (wherein X) was prepared. 1A compound of formula 7.3 was obtained by reacting a carbamide of formula 7.2, or a heterocyclic amine such as piperidine, morpholine, piperazine, azetidine, and pyrrolidine, with a metal catalyst such as a Buchwald catalyst or an Ullmann catalyst in a CN cross-coupling reaction. In method B, a halide of formula 7.1 (wherein X is used in the formula) was used. 1 (wherein X is Br or Cl) can also be reacted with a heteroaryl or aryl of formula 7.5 in either a Suzuki coupling (where Y is a boronic acid or ester) or a Still coupling (where Y is SnR3) to obtain the compound of formula 7.6. In method C, the halide of formula 7.1 (wherein X is Br or Cl) can be reacted with a heteroaryl or aryl of formula 7.5. 1 A compound (where X is Br or Cl) was reacted with 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane by Suzuki coupling to obtain the compound of formula 7.8. The olefin in the compound of formula 7.8 was then oxidatively cleaved to an aldehyde to obtain the compound of formula 7.9. In method D, the aldehyde in the compound of formula 7.9 was reduced to an alcohol having a hydride such as NaBH4 in an alcohol solvent such as methanol or ethanol to obtain the compound of formula 7.13. The alcohol in the compound 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 obtain the compound of formula 7.15. In method E, the compound of formula 7.9 was reacted with the amine of formula 7.10 under reduction animation conditions to obtain the compound of formula 7.11. Compounds of formulas 7.4, 7.7, 7.12, and 7.16 are obtained by hydrolysis of the esters of the compounds of formulas 7.3, 7.6, 7.11, and 7.15 using a base such as LiOH, KOH, or NaOH in THF / water. Alternatively, basic 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 a 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.

[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)acetimide to obtain N-aminopyridinium salt 8.1. N-aminopyridinium salt 8.1 was subjected to a cycloaddition reaction with ethyl propiorate and a base such as K2CO3 to obtain ethyl 6-bromo-5-chloropyrazolo[1,5-a]pyridine-3-carboxylate 8.2. Compound 8.2 was reacted with the amine of formula 8.4, or with heterocyclic amines such as piperidine, morpholine, piperazine, azetidine, and pyrrolidine, using a metal catalyst such as a Buchwald catalyst or an Ullmann catalyst in a CN cross-coupling reaction to obtain the compound of formula 8.5. Compounds of formula 8.3 and 8.6 were obtained by 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. Alternatively, the basic salts of the carboxylic acids of formulas 8.3 and 8.6 (i.e., Li, K, or Na) can be obtained after the hydrolysis reaction by isolating the product at a 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® 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 obtain hydrazine of formula 9.2. Then, the compound of formula 9.2 was reacted with ethyl-2-chloro-2-oxoacetate to obtain the compound of formula 9.3, and subsequently, intramolecular cyclization with a base such as p-toluenesulfonyl chloride and TEA was performed to obtain 1,3,4-oxadiazole of formula 9.4. Alternatively, the compound of formula 9.4 can be prepared using method B. In method B, 2-hydrazinyl-2-oxoethyl acetate was reacted with 1,1'-thiocarbonyldiimidazole to form 1,3,4-oxadiazole, which was then alkylated with a base such as methyl iodide and TEA to obtain ethyl 5-(methylthio)-1,3,4-oxadiazole-2-carboxylate. Ethyl 5-(methylthio)-1,3,4-oxadiazole-2-carboxylate was reacted with a heteroaryl or arylboronic acid or ester of formula 9.5 in a desulfurization CC cross-coupling reaction (also known as Liebeskind-Srogl cross-coupling) to obtain the compound of formula 9.4. The compound of formula 9.6 was obtained by hydrolysis of the ester of the compound of formula 9.4 using a base such as LiOH, KOH, or NaOH in THF / water. Alternatively, a basic salt of the carboxylic acid of formula 9.6 (i.e., Li, K, or Na) can be obtained after the hydrolysis reaction by isolating the product at a 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.

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

[0250] Substitution 1,3,4-oxadiazolyl R 2The carboxylic acid intermediate was 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 obtain ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (compound 10.1). The bromo in compound 10.1 was reacted with the amine of formula 10.2, or with heterocyclic amines such as piperidine, morpholine, piperazine, azetidine, and pyrrolidine, and a base such as TEA, to obtain the compound of formula 10.3. The compound of formula 10.4 was obtained by hydrolysis of the ester of the compound of formula 10.3 using a base such as LiOH, KOH, or NaOH in THF / water. Alternatively, the basic salt of the carboxylic acid of formula 10.4 (i.e., Li, K, or Na) can be obtained after the hydrolysis reaction by isolating the product at a basic pH. Subsequently, the carboxylic acid or its basic salt can be used without further purification in the coupling reaction described in General Scheme 1, Method C.

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

[0252] R 5A Compound I of formula I, where is D, is prepared according to General Scheme 11. The amine of formula 2.1, prepared according to General Scheme 2, is protected with a BOC protecting group or other suitable nitrogen protecting group to obtain the compound of formula 11.1. The amine of formula 11.1 is then protected with a dimethylsulfamoyl protecting group to obtain a mixture of compounds of formulas 11.2 and 11.3, which is separated during purification. The compound of formula 11.2 is then deprotonated with butyllithium, and then D2O is added to obtain compounds of formulas 11.4 and 11.5, thereby removing deuterium R 5A Incorporate into position. Deprotection of the nitrogen protecting group with acid yielded the deuterated coreamine intermediate of formula 11.6. The deuterated coreamine intermediate of formula 11.6 was converted to various L and R via methods A, B, C, D, E, and F described in General Scheme 1.2 By further bonding with the group, the compound of formula I can be obtained, where R 5A It is D.

[0253] This disclosure will be better understood by reference to the following examples. The examples provided herein are illustrative but should not be construed as limiting the scope of this disclosure. [Examples]

[0254] In some embodiments, the disclosure provides specific examples of compounds of formula I, as well as pharmaceutically acceptable salts and / or isotopologs thereof, as shown 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 1-78 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 1-100

Table 1-110

Table 1-120

Table 1-150

Table 1-195

Table 1-202

Table 1-204

Table 1-206

Table 1-210

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

[0256] In further embodiments, the compound of formula I is used in 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, One or more of 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 further embodiments, the compound of formula I is used in 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, 9 One or more of 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 yet another embodiment, 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 commercially available sources (such as Alfa, Acros, AstaTech, CombiBlocks, Enamine, Sigma Aldrich, TCI, PharmaBock, Bide Pharmatech Ltd., Accela ChemBio, Aladdin, Shanghai Haohong Pharmaceutical Co.,Ltd, Amkchem, Beijing Ouhe Technology Co.,Ltd, Haoyuan Chemexpress Co.,Ltd, Hualun, Coolpharm, Scochem, Titan, and WuXi LabNetwork) and used without further purification unless otherwise specified. Flash chromatography was performed on a CombiFlash® Rf 150 (ISCO) via a column with 200-300 mesh silica gel particles. HPLC was performed on an Agilent 1100 Liquid Chromatography (Agilent, USA) and a Shimadzu LC20 / 20A (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 (TLC) plates were HSGF 254 (thickness 0.15–0.2 mm, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were obtained using a Brucker AV-400 NMR or Bruker AVIII 500 MHz NMR (Bruker, Switzerland). Chemical shifts were reported as parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were obtained by electrospray ionization (ESI) from a Waters LCT TOF mass spectrometer (Waters, USA). LC-MS was performed on Agilent Prime-6125B / Agilent LC1260-MS6150 / Agilent LC1260-MS6125B / Agilent LC1200-MS6110 (Agilent, USA) and Shimadzu LC20-MS2020.The microwave reaction was performed on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden).

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

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

[0263] B2 was prepared according to the literature procedure, starting with 2-(1H-imidazole-5-yl)acetonitrile (B1). See, for example, WO2008 / 003766 (page 19).

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

[0265] To a solution of 2-(3-tritilimidazole-4-yl)acetonitrile (B2) (10 g, 28.6 mmol) in THF (200 mL), LDA (2 M, 42.9 mL, 3 equivalents) was added dropwise at -78°C. After the addition was complete, the reaction mixture was stirred at -20°C to -10°C for 1 hour. Next, the reaction mixture was cooled to -78°C, and 1,2-dibromoethane (10.75 g, 57.2 mmol, 4.32 mL, 2 equivalents) was added dropwise at -78°C. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for a further 2 hours. The reaction progress was monitored using TLC (PE: Depositphotos = 1:1). The reaction mixture was quenched with saturated NH4Cl solution (200 mL) and stirred at room temperature for 0.5 hours. The aqueous portion was extracted with Depositphotos (100 mL x 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, 0-40% siRNA / PE eluent, gradient @ 40 mL / min) to obtain B3 (23.4 g, yield 72%). 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-trithyrimidazole-4-yl)cyclopropyl]methanamine (B4)

[0267] A mixture of 1-(3-tritilimidazole-4-yl)cyclopropanecarbonitride (B3) (19 g, 50.6 mmol), Raney-Ni (4.60 g, 53.7 mmol, 1.06 equivalents), and NH3.H2O (591 mg, 5.06 mmol, 650 μL, 30% purity, 0.1 equivalents) in MeOH (200 mL) was degassed, purged three times with H2, and then the reaction mixture was stirred at 45°C for 16 hours under an H2 (45 psi) atmosphere. The progress of the reaction was tracked using TLC (DCM:MeOH = 10:1). The reaction mixture was filtered and additional Raney-Ni (4.60 g, 53.7 mmol, 1.06 equivalents) was added. The reaction mixture was stirred for a further 24 hours at 45°C under an H2 (45 psi) atmosphere. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness to obtain B4 (18g), 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-imidazole-5-yl)cyclopropyl]methanamine hydrochloride (B5)

[0269] To a solution of [1-(3-trithyrimidazole-4-yl)cyclopropyl]methaneamine (B4) (18 g, 47.4 mmol) in MeOH (100 mL), HCl / MeOH (4 M, 100 mL, 8.4 equivalents) was added. The reaction mixture was stirred at 60°C for 16 hours. The progress of the reaction was monitored using LC-MS. The reaction mixture was concentrated to dryness, and the residue was polished with HCl (40 mL) and stirred for 15 minutes. The precipitate was collected by filtration and then dried under vacuum to obtain B5 (8.5 g, 2HCl 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-imidazole-5-yl)-2-methylpropane-1-amine hydrochloride [ka]

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

[0272] To a solution of 2-(3-trithyrimidazole-4-yl)acetonitrile (B2) (12 g, 34.3 mmol) in THF (400 mL), LiHMDS (1 M, 96.2 mL, 2.8 equivalents) was added 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 equivalents) was added. The reaction mixture was stirred at -78°C for 1 hour, and then heated to room temperature for 18 hours. The reaction progress was monitored using TLC (PE:HCl = 1:1). The reaction mixture was cooled to 0°C and quenched by adding saturated NH4Cl solution (15 mL), and then H2O (60 mL) was added. The aqueous portion was extracted with HCl (60 mL x 3). The combined organic layers were washed with saline solution (60 mL), dried on anhydrous Na2SO4, and concentrated to dryness. The residue (combined with 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, 0-80% siRNA / PE eluent, gradient @ 60 mL / min) to obtain 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-trithyrimidazole-4-yl)propan-1-amine (B7)

[0274] To a solution of 2-methyl-2-(3-trithyrimidazole-4-yl)propanenitrile (B6) (14 g, 37.1 mmol) in MeOH (350 mL), Raney-Ni (2 g, 23.3 mmol, 0.63 equivalents) was added under N2 conditions. The reaction mixture was degassed under vacuum and purged several times with H2. The reaction mixture was stirred under H2 (50 psi) at 40°C for 36 hours. The reaction progress was monitored using TLC (PE:siRNA = 1:1). The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness to obtain B7 (12 g, 85% yield). 1 LCMS:m / z 382.2[M+H] + .

[0275] Step 3: Preparation of (2-(1H-imidazole-5-yl)-2-methylpropan-1-amine (B8)

[0276] To a solution of 2-methyl-2-(3-trithyrimidazole-4-yl)propan-1-amine (B7) (14 g, 36.7 mmol) in MeOH (150 mL), HCl / MeOH (4 M, 150 mL, 16.4 equivalents) was added, and the reaction mixture was stirred at 50°C for 18 hours. The reaction progress was monitored using TLC(RINKAN). The reaction mixture was concentrated to dryness, and 200 mL of RINKAN was added. The mixture was stirred at 60°C for 1 hour. The precipitate was collected by filtration, rinsed with RINKAN, and then dried under vacuum to obtain B8 (7.0 g, 90% yield, 2HCl 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-imidazole-5-yl)propan-1-amine hydrochloride [ka]

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

[0279] To a solution of 2-(3-tritilimidazole-4-yl)acetonitrile (B2) (15 g, 42.9 mmol) in THF (120 mL), LiHMDS (1 M, 51.5 mL, 1.2 equivalents) was added dropwise at -78°C. After addition, the reaction mixture was stirred for 0.5 hours, and then MeI (10.97 g, 77.3 mmol, 4.81 mL, 1.8 equivalents) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 2 hours. The reaction progress was monitored using TLC (PE:HCl = 2:1). The reaction mixture was quenched by adding saturated NH4Cl solution (120 mL) and stirred for 15 minutes. The aqueous portion was extracted with HCl (400 mL), the organic layer was washed with water (100 mL) and saline solution (60 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue (combined with residue from another reaction carried out using 15 g of B2) was purified by column chromatography on silica gel (PE:siRNA = 20:1 to 2:1) to obtain 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-trithyrimidazole-4-yl)propan-1-amine (B10)

[0281] A mixture of 2-(3-tritilimidazole-4-yl)propanenitrile (B9) (16.5 g, 45.4 mmol), Raney-Ni (4.08 g, 47.7 mmol, 1.05 equivalents), and NH3.H2O (910 mg, 7.79 mmol, 1 mL, 30% purity) in MeOH (300 mL) was degassed under vacuum and purged three times with H2. The reaction mixture was stirred at 45°C for 16 hours under an H2 (45 psi) atmosphere. The reaction progress was monitored using TLC (PE:HCl = 2:1). The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness to obtain 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-imidazole-5-yl)propan-1-amine (B11)

[0283] To a solution of 2-(3-trithyrimidazole-4-yl)propan-1-amine (B10) (23 g, 62.6 mmol) in MeOH (100 mL), HCl / MeOH (4 M, 100 mL) was added. The mixture was stirred at room temperature for 12 hours. The reaction progress was tracked using TLC (HCl). The reaction mixture (combined with a reaction mixture from another reaction carried out using 23 g of B10) was concentrated to dryness. H2O (40 mL) was added to the residue, and the aqueous layer was washed with HCl (50 mL). The aqueous layer was freeze-dried to obtain 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-imidazole-5-yl)propyl]isoindoline-1,3-dione and 2-[(2S)-2-(1H-imidazole-5-yl)propyl]isoindoline-1,3-dione [ka]

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

[0286] To a solution of 2-(1H-imidazole-5-yl)propan-1-amine (B11) (10 g, 50.5 mmol, 2HCl) and phthalic anhydride (7.85 g, 53.0 mmol, 1.05 equivalents) in i-PrOH (400 mL), Et3N (15.32 g, 151 mmol, 21.1 mL, 3 equivalents) was added. The reaction mixture was stirred at 100 °C for 18 hours under an N2 atmosphere. After cooling, the reaction mixture was concentrated to dryness. Then, water (200 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration, rinsed with water (100 mL), and dried under vacuum to obtain 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] Compound 2-[2-(1H-imidazole-5-yl)propyl]isoindoline-1,3-dione (13 g) was separated by SFC separation (column: DAIEL CHIRALPAK AD (250 mm * 50 mm, 10 μm), mobile phase: [0.1% NH3H2O ​​ETOH], B%: 40%~40%, min) to obtain enantiomer 1 (4.8 g, yield 37%, Rt = 3.953 min) and enantiomer 2 (5.2 g, yield 40%, Rt = 4.652 min).

[0289] Enantiomer 1: 2-[(2R)-2-(1H-imidazole-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-imidazole-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 equivalents, HCl) in DMF (200 mL), EDCI (22.17 g, 116 mmol, 1.5 equivalents), DIPEA (29.89 g, 231 mmol, 40.3 mL, 3 equivalents), and HOBt (15.63 g, 116 mmol, 1.5 equivalents) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was checked using TLC (PE:SiO = 1:1). The reaction mixture was combined with a reaction mixture from another reaction carried out using 12.5 g of C1 and concentrated to dryness. The residue was dissolved in DCM (200 mL), the organic layer was washed with saturated Na2CO3 solution (100 mL) and saline solution (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:siRNA = 20:1 to 1:1) to obtain the given C2 (30.5 g, yield 96%). 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), DIBAL-H (1 M, 146.2 mL, 2 equivalents) was added dropwise under N2 at -78°C, and the reaction mixture was stirred under N2 at -78°C for 2 hours. The reaction progress was monitored using TLC (PE:HCl = 1:1). The reaction mixture was combined with a reaction mixture from another reaction carried out using 15 g of C2, quenched by slowly adding saturated NH4Cl solution (200 mL), and stirred for 15 minutes. 1 M HCl solution was added until a clear solution was observed. The aqueous portion was extracted with HCl (250 mL × 3), the combined organic layers were washed with water (100 mL) and saline (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:SiO=20:1~1:1) to obtain the given C3 (14.2g). 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 starting from 3-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid, following the general procedure described above for C3.

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

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

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

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

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

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

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

[0304] A mixture of 2-bromo-3-fluoropyridine (C4) (30 g, 170 mmol), propane-2-in-1 yl acetate (23.41 g, 239 mmol, 1.4 equivalents), Pd(PPh3)2Cl2 (5.98 g, 8.52 mmol, 0.05 equivalents), CuI (1.62 g, 8.52 mmol, 0.05 equivalents), and TEA (51.75 g, 511 mmol, 71.2 mL, 3 equivalents) in dioxane (300 mL) was degassed, purged three times with N2, and then the reaction mixture was stirred at 50°C for 6 hours under an N2 atmosphere. The reaction progress was checked using TLC (PE:HCl = 5:1). The reaction mixture was concentrated to dryness. siRNA (600 mL) was added to the residue, the organic portion was washed with water (300 mL) and saline solution (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, 0-20% siRNA / PE eluent, gradient @ 120 mL / min) to obtain C5 (23.4 g, yield 71%). 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)propa-2-in-1-ol (C6)

[0306] LiOH was added to a solution of 3-(3-fluoro-2-pyridyl)prop-2-inylacetate (C5) (23.4 g, 121 mmol) in THF (300 mL) and H2O (150 mL). H2O (5.34 g, 127 mmol, 1.05 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was checked using TLC (PE:HCl = 1:1). HCl (600 mL) was added to the reaction mixture, the organic layer was washed with H2O (400 mL) and saline solution (400 mL), dried over Na2SO4, filtered, and concentrated to dryness to obtain 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-hydroxypropane-1-in-1-yl)pyridine-1-ium 2,4,6-trimethylbenzenesulfonate (C7)

[0308] To a mixture of H2O (35 mL, 1.94 mol, 17.3 equivalents) and TFA (308.0 g, 2.70 mol, 200 mL, 24.0 equivalents), (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethaneimidate (33.70 g, 118 mmol, 1.05 equivalents) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with ice water (40 mL). The precipitate was filtered and washed with water (20 mL x 2). The precipitate was then dissolved in DCM (200 mL), dried over Na2SO4, and filtered. 3-(3-fluoro-2-pyridyl)propa-2-in-1-ol (C6) (17 g, 112 mmol, 1 equivalent) was added to the filtrate at 0°C. The reaction mixture was heated to room temperature for 16 hours. The reaction progress was checked using TLC (PE:HCl = 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 x 2) to obtain 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]pyridine-2-yl)methanol (C8)

[0310] To a solution of 1-amino-3-fluoro-2-(3-hydroxypropane-1-in-1-yl)pyridine-1-ium-2,4,6-trimethylbenzenesulfonate (C7) (26 g, 71.0 mmol) in MeOH (250 mL), NaOMe (5.4 M, 26.3 mL, 2 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was tracked by TLC (PE:siRNA = 1:1). The reaction mixture was quenched by adding ice-cold H2O (200 mL), concentrated to remove most of the MeOH, and extracted with siRNA (200 mL x 3). The combined organic layers were washed with saline (400 mL), dried over Na2SO4, filtered, and concentrated to dryness to obtain 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]pyridine-2-yl)methanol (C8) (7.5 g, 45.1 mmol) in MeCN (150 mL), IBX (15.17 g, 54.2 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at 80°C for 3 hours. The reaction progress was checked using TLC (PE:HCl = 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, 0-4% HCl / PE eluent, gradient @ 40 mL / min) to obtain C9 (4 g, yield 54%). 1 1H 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 starting from 2-bromo-3-methylpyridine according to the general procedure described above for C9.

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

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

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

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

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

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

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

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

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

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

[0324] To a mixture of TFA (215.60 g, 1.89 mol, 140 mL, 27.8 equivalents) and H2O (20.00 g, 1.11 mol, 20.0 mL, 16.3 equivalents), ethyl (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethaneimide (21.34 g, 74.8 mmol, 1.1 equivalents) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. The reaction was quenched by adding ice water (100 mL), the precipitate was filtered, and rinsed with water (50 mL x 2). The precipitate was then dissolved in DCM (140 mL), dried over Na2SO4, and filtered. 2-(trifluoromethyl)pyridine (C10) (10 g, 68.0 mmol, 7.87 mL) was added to the filtrate at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. TBME (100 mL) was slowly added to the reaction mixture, the precipitate was collected, rinsed with TBME (40 mL x 3), and then dried in vacuum to obtain C11 (8.5 g, yield 35%), 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 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylate dimethyl(C12)

[0326] To a mixture of 1-amino-2-(trifluoromethyl)pyridine-1-ium 2,4,6-trimethylbenzenesulfonate (C11) (8.5 g, 23.5 mmol) and K2CO3 (6.49 g, 46.9 mmol, 2 equivalents) in DMF (100 mL), dimethyl buto-2-indioate (6.66 g, 46.9 mmol, 2 equivalents) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction progress was monitored by TLC (PE:siRNA = 1:1). Water (200 mL) was added, and the solution was stirred for 30 minutes. 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, 0-40% siRNA:PE eluent @ 60 mL / min) to obtain 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 7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2,3-dicarboxylate dimethyl (C12) (2.85 g, 9.43 mmol) in THF (20 mL), LiOH.H2O (1.58 g, 37.7 mmol, 4 equivalents) in H2O (20 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored using TLC (PE:SiO = 1:1). The reaction mixture was concentrated under vacuum to remove most of the THF, and the aqueous phase was adjusted to pH approximately 2 with 4 M HCl. The precipitate was collected by filtration and then dried under vacuum to obtain 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 equivalents) and H2O (11.25 g, 624 mmol, 11.3 mL, 76.1 equivalents) was stirred at 90°C for 16 hours. The reaction progress was monitored using LC-MS. The reaction mixture was cooled to room temperature and water (60 mL) was added. The precipitate was collected by filtration and then dried under vacuum to obtain 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 equivalents, HCl) in DMF (80 mL), HOBt (7.05 g, 52.1 mmol, 1.5 equivalents), EDCI (10.00 g, 52.1 mmol, 1.5 equivalents), and DIPEA (13.48 g, 104 mmol, 18.2 mL, 3 equivalents) were added. The mixture was stirred at room temperature for 16 hours. The reaction progress was monitored using TLC (DCM:MeOH = 10:1). DCM (150 mL) was added, the organic portion was washed with saturated Na2CO3 solution (100 mL x 2) and saline solution (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 80g SepaFlash® Silica Flash Column, 0-10% MeOH:DCM eluent @ 60mL / min) to obtain C15 (6g, 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) (6g, 22.0 mmol) in THF (60 mL), DIBAL-H (1 M, 65.9 mL, 3 equivalents) was added dropwise under N2 at -78°C, and the reaction mixture was stirred under N2 at -78°C for 2 hours. The reaction progress was monitored using TLC (PE:HCl = 5:1). The reaction mixture was quenched by adding saturated NH4Cl solution (150 mL), and then 4 M HCl solution (80 mL) was added. The aqueous portion was extracted with HCl (100 mL x 2), and the combined organic layers were washed with water (80 mL) and saline solution (80 mL). The organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® Silica Flash Column, 0-30% siRNA:PE eluent @ 40 mL / min) to obtain C16 (3.95 g, yield 68%). 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 according to 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), CsF (1.69 g, 11.2 mmol, 411 μL, 3 equivalents) was added, and the reaction mixture was stirred under microwave at 150 °C for 1 hour. The reaction progress was monitored using LC-MS. DCM (60 mL) was added to the reaction mixture, the organic portion was washed with water (30 mL) and saline solution (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / Â=1 / 0~4 / 1) to obtain C18 (450 mg, yield 29%). 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]pyridine-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), LiBH4 (260 mg, 11.9 mmol, 5.5 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored using LC-MS. The reaction mixture was quenched by adding saturated NH4Cl solution (10 mL), and the aqueous portion was extracted with RINKAN (30 mL). The organic layer was washed with water (20 mL) and saline (20 mL), dried over Na2SO4, filtered, and concentrated to dryness to obtain C19 (360 mg), which was used without further purification. LC-MS: 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]pyridine-2-yl)methanol (C19) (360 mg, 2.17 mmol) in MeCN (5 mL), IBX (971 mg, 3.47 mmol, 1.6 equivalents) was added, and the reaction mixture was stirred at 80°C for 1 hour. The reaction progress was monitored using LC-MS. The reaction mixture was filtered and concentrated to dryness to obtain 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 overall scheme 4 [ka]

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

[0346] To a solution of ethyl 4,4-difluoro-3-oxobutanoate (20 g, 120 mmol) in DCM (240 mL), TsOH (4.15 g, 24.1 mmol, 0.2 equivalents) and NBS (22.50 g, 126 mmol, 1.05 equivalents) were added in several portions at 0°C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction progress was checked using TLC (PE:SiO=5:1). DCM (100 mL) was added, the organic portion was washed with saturated Na2CO3 solution (100 mL) and saline solution (150 mL), dried over Na2SO4, filtered, and concentrated to dryness to obtain 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 equivalents) in DMF (30 mL) was stirred at 120 °C for 12 hours. The reaction progress was checked using LC-MS. 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 minutes, the precipitate was collected by filtration, rinsed with water (50 mL), and dried under vacuum to obtain E2 (15.5 g for steps 1 and 2, 63% yield). LC-MS: 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), t-BuONO (30.01 g, 291 mmol, 34.6 mL, 3 equivalents) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. DCM (300 mL) was added, the organic portion was washed with water (200 mL) and saline solution (200 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / siRNA = 1 / 0~10 / 1) to obtain E3 (12.7 g, yield 69%). 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 H2O (20 mL), LiOH.H2O (3.07 g, 73.1 mmol, 1.1 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under vacuum to remove THF. Water (80 mL) was added, and the aqueous portion was extracted with TBME (50 mL). The aqueous layer was then adjusted to approximately pH 6 by adding 0.5 M HCl. The aqueous layer was concentrated to dryness to obtain 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 overall 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), CuBr2 (40.63 g, 182 mmol, 8.5 mL, 1.5 equivalents) was added at 0°C. The mixture turned dark green and was stirred further at room temperature for 15 minutes. t-BuONO (18.76 g, 182 mmol, 21.6 mL, 1.5 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, then heated to 50°C and stirred for 12 hours. The reaction progress was monitored using TLC (siRNA:PE = 5:1). The reaction mixture was filtered. DCM (200 mL) was added to the filtrate, the organic layer was washed with water (100 mL) and saline solution (100 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 at 100 mL / min with a 0-20% siRNA / PE gradient) to obtain E5 (19 g, 58% yield). 1 H NMR (400MHz, CDCl3) δ 7.02(t,1H),4.39(q,2H),1.35(t,3H).

[0356] Intermediate 4-(difluoromethyl)-2-(1-hydroxy-1-methyl-ethyl)oxazole-5-carboxylic acid by overall scheme 6, method A [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), Pd(PPh3)2Cl2 (2.60 g, 3.70 mmol, 0.1 equivalent) and tributyl(1-ethoxyvinyl) stannane (17.39 g, 48.1 mmol, 16.3 mL, 1.3 equivalent) were added. The mixture was stirred at 85°C for 12 hours under an N2 atmosphere. The reaction progress was checked using TLC (PE: siRNA). siRNA (100 mL) was added to the reaction mixture, the organic portion was washed with saturated KF solution (150 mL) and saline solution (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was dissolved in THF (60 mL), treated with HCl (4 M, 60 mL), and then stirred at 40°C for 12 hours. The reaction progress was checked by TLC (petroleum ether: siRNA = 10:1). siRNA (100 mL) was added to the reaction mixture, the organic portion was washed with water (50 mL) and saline solution (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, eluent @ 40 mL / min with a 0-20% siRNA / PE gradient) to obtain E6 (7.1 g, yield 82%). 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), MeMgBr (3 M, 7.15 mL, 2 equivalents) was added at -78°C. The mixture was stirred at -78°C for 1 hour. The reaction progress was checked by TLC (PE:HCl = 2:1). The reaction mixture was quenched by adding saturated NH4Cl solution (50 mL), and then water (100 mL) was added. The aqueous portion was extracted with HCl (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 @ 40 mL / min with a 0-12% HCl / PE gradient) to obtain E7 (3.2 g, 60% yield). 1 ¹H NMR (400MHz, CDCl3) 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 (300mg) 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 H2O (40 mL), LiOH.H2O (690 mg, 16.4 mmol, 1.05 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The reaction progress was checked using TLC (PE:HCl = 5:1). The reaction mixture was concentrated to remove THF. The aqueous mixture was then adjusted to approximately 3 pH by adding 1 M HCl, and then lyophilized under vacuum to obtain 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), t-BuONO (1.84 g, 17.9 mmol, 2.12 mL, 2 equivalents) was added. The reaction mixture was stirred at 55°C for 24 hours. Depositphotos (120 mL) was added to the reaction mixture, the organic portion was washed with water (100 mL) and saline solution (100 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO₂, PE / Depositphotos = 1 / 0 to 8 / 1) to obtain E10 (1.2 g, yield 64%). 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), LiHMDS (1 M, 8.61 mL, 1.5 equivalents) was added at -78°C, and the reaction mixture was stirred at -78°C for 0.5 hours. Cyclobutanone (1.21 g, 17.2 mmol, 1.29 mL, 3 equivalents) in THF (5 mL) was added to the reaction mixture, and the mixture was stirred at -78°C for 2 hours under an N2 atmosphere. The reaction mixture was quenched by adding saturated NH4Cl solution (30 mL), and the aqueous portion was extracted with HCl (100 mL). The organic layer was washed with water (70 mL) and saline solution (70 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / HCl = 1 / 0 to 10 / 1) to obtain E11 (600 mg, yield 37%). 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 H2O (2 mL) and THF (10 mL), LiOH.H2O (99.2 mg, 2.36 mmol, 1.1 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum to remove THF. Water (10 mL) was added, and the aqueous portion was extracted with TBME (30 mL). The aqueous layer was then adjusted to approximately pH 6 by adding 0.5 M HCl, concentrated to dryness, and E12 (540 mg) was obtained, 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 overall 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 approximately 10°C. The reaction mixture was cooled to -80°C, and LiHMDS (1 M, 4.61 mL, 1.30 equivalents) was added dropwise at approximately -80°C. The reaction mixture was stirred at approximately -80°C for 0.5 hours. Then, Br2 (736 mg, 4.61 mmol, 1.3 equivalents) was added dropwise at approximately -80°C. The reaction mixture was stirred at approximately -80°C for 0.5 hours. The reaction progress was checked using LC-MS. The reaction mixture was combined with 19 other reaction products that had been tested using 500 mg of E13. The combined reaction mixture was poured into saturated citric acid at approximately -10°C. The aqueous portion was extracted with Depositphotos (50 mL x 3). The combined organic layers were washed with saline solution (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / ÃO = 1 / 0 to 0 / 1) to obtain E14 (3.00 g, yield 19%). 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 equivalent) was added in THF (15.0 mL) at room temperature. LiHMDS (1 M, 17.2 mL, 1.20 equivalent) was added dropwise at approximately -80°C. Then, I2 (5.45 g, 21.5 mmol, 1.50 equivalent) in THF (15.0 mL) was added dropwise at approximately -80°C. The reaction mixture was stirred at approximately -80°C for 1 hour. The reaction progress was checked using TLC (PE / Â). The reaction mixture was poured into saturated citric acid (30 mL) at approximately -10°C. The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saline solution (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / Â1 / 0~0 / 1) to obtain 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-iodoxazole-5-carboxylate (E15) (1.10 g, 3.18 mmol) was added in THF (10 mL) under N2 at approximately 10°C. The mixture was degassed under high vacuum and purged three times with N2. The mixture was cooled to -80°C, and iPr-MgCl.LiCl (1.3 M, 2.45 mL, 1 equivalent) was added dropwise at approximately -80°C. The reaction mixture was stirred at approximately -80°C for 0.5 hours, and then acetone (222 mg, 3.82 mmol, 1.20 equivalents) was added dropwise at approximately -80°C. The mixture was stirred at approximately -80°C for 0.5 hours. The reaction progress was checked using TLC (PE / Â=5 / 1). The reaction mixture was poured into saturated citric acid solution (5 mL) at approximately -10°C. The aqueous portion was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saline solution (5 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / Â=1 / 0~0 / 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%~45%, 7 min) to obtain E16 (140 mg, yield 16%). 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 overall 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 approximately 10°C. The reaction mixture was cooled to -80°C, and LiHMDS (1 M, 92.1 mL, 1.3 equivalents) was added dropwise at approximately -80°C. The reaction mixture was stirred at approximately -80°C for 0.5 hours, and then NCS (12.3 g, 92.1 mmol, 1.3 equivalents) in THF (50 mL) was added dropwise at approximately -80°C. The mixture was stirred at approximately -80°C for 0.5 hours. The reaction progress was checked using TLC (PE / Â=5 / 1). The reaction mixtures were combined for workup with seven other reactions carried out using 10 g of E13 each. The combined reaction mixtures were poured into saturated citric acid solution (100 mL) at approximately -10°C. The aqueous portion was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saline solution (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / ÃO = 1 / 0 to 0 / 1) to obtain E17 (18.0 g, yield 18%). 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-iodoxazole-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 equivalents) was added dropwise at approximately -80°C, followed by the dropwise addition of I2 (13.0 g, 51.3 mmol, 1.5 equivalents) in THF (30 mL) at approximately -80°C. The reaction mixture was stirred at approximately -80°C for 1 hour. The reaction progress was checked using TLC (PE / Ã=5 / 1). The three parallel reactions were combined for workup. The combined reaction mixture was poured into saturated citric acid solution (100 mL) at approximately -5°C. The aqueous portion was extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saline solution (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / Â1 / 0~0 / 1) to obtain 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 reactions were carried out in parallel. Compound E18 (5.00 g, 16.6 mmol) was added to THF (50 mL) at approximately 10°C under N2. The suspension was degassed under high vacuum and purged three times with N2. The mixture was cooled to -80°C, and iPr-MgCl.LiCl (1.3 M, 12.8 mL, 1 equivalent) was added dropwise at approximately -80°C. The mixture was stirred at approximately -80°C for 0.5 hours, and then acetone (1.16 g, 19.9 mmol, 1.2 equivalents) was added dropwise at approximately -80°C. The mixture was stirred at approximately -80°C for 0.5 hours. The reaction progress was checked using TLC (PE / Ã=5 / 1). The two parallel reactions were combined for workup. The combined reaction mixture was poured into saturated citric acid solution (50 mL) at approximately -10°C. The aqueous portion was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saline solution (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / Â=1 / 0~0 / 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%~50%, 23 min) to obtain E19 (1.80 g, yield 23%). 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-methylpropanoic acid (2 g, 17.7 mmol) and DMF (129 mg, 1.77 mmol, 136 μL, 0.1 equivalent) in DCM (20 mL), oxalyl chloride (2.69 g, 21.2 mmol, 1.86 mL, 1.2 equivalents) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to obtain 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-difluorobuta-2-enoate (E21)

[0388] A solution of ethyl(Z)-3-amino-4,4-difluorobuta-2-enoate (2 g, 12.1 mmol) in dioxane (20 mL) was mixed with a solution of 2-cyano-2-methyl-propanoyl chloride (E20) (2.39 g, 18.2 mmol, 1.5 equivalents) in dioxane (20 mL) at room temperature. The reaction mixture was stirred at 110 °C for 12 hours. The reaction progress was checked 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, eluent @ 40 mL / min with a 0-7% siRNA / PE gradient) to obtain E21 (2.4 g, yield 76%). 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 2-(1-cyano-1-methyl-ethyl)-4-(difluoromethyl)oxazole-5-carboxylate ethyl (E22)

[0390] To a solution of ethyl(Z)-3-[(2-cyano-2-methyl-propanoyl)amino]-4,4-difluorobuta-2-enoate (E21) (2.4 g, 9.22 mmol) in DCE (20 mL), BF3.Et2O (2.62 g, 18.4 mmol, 2.28 mL, 2 equivalents) and PIDA (4.16 g, 12.9 mmol, 1.4 equivalents) were added at room temperature. The mixture was stirred at 90°C for 18 hours. The reaction progress was checked by TLC (PE / siRNA). The reaction mixture was concentrated to dryness. DCM (100 mL) was added to the residue, the organic layer was washed with saturated Na2CO3 solution (10 mL) and saline solution (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 with a 0-7% siRNA / PE gradient @ 30 mL / min) to obtain E22 (0.25 g, yield 11%). 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 H2O (1 mL), LiOH.H2O (48.8 mg, 1.16 mmol, 1.2 equivalents) was added. The mixture was stirred at room temperature for 18 hours. The completeness of the reaction was checked using TLC (PE:HCl = 5:1). The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous portion was adjusted to pH approximately 7 with 2 M HCl, and then lyophilized under vacuum to obtain 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-(pyrimidine-2-yl)oxazole-5-carboxylic acid by overall scheme 5, method B [ka]

[0394] Step 1: Preparation of ethyl 4-(difluoromethyl)-2-pyrimidine-2-yloxazole-5-carboxylate (E24)

[0395] To a solution of ethyl 4-(difluoromethyl)oxazole-5-carboxylate (E4) (1 g, 5.23 mmol), Pd2(dba)3 (240 mg, 262 μmol, 0.05 equivalents), (5-diphenylphosphanyl-9,9-dimethyl-xanthene-4-yl)-diphenylphosphane (151 mg, 262 μmol, 0.05 equivalents), and Cs2CO3 (3.41 g, 10.5 mmol, 2 equivalents) in 1,2-dimethoxyethane (3 mL), 2-chloropyrimidine (599 mg, 5.23 mmol) was added under an N2 atmosphere. The reaction mixture was stirred at 90°C for 12 hours. DCM (50 mL) was added to the reaction mixture, the organic portion was washed with water (40 mL) and saline solution (40 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / Ã=1 / 0~1 / 1) to obtain 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-pyrimidine-2-yl-oxazole-5-carboxylic acid (E25)

[0397] To a solution of ethyl 4-(difluoromethyl)-2-pyrimidine-2-yl-oxazole-5-carboxylate (E24) (450 mg, 1.67 mmol) in THF (2 mL) and H2O (2 mL), LiOH.H2O (77.2 mg, 1.84 mmol, 1.1 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove THF, and H2O (10 mL) was added. The aqueous layer was extracted with TBME (30 mL). The aqueous layer was then adjusted to approximately pH 6 with 0.5 M HCl and extracted three times with DCM / MeOH (30 / 3 mL). The combined DCM / MeOH organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain 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 by 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 equivalents) in DMF (100 mL) was stirred at 120 °C for 12 hours. The reaction progress was checked using TLC (PE:HCl = 5:1). The reaction mixture was cooled to room temperature, poured into H₂O (400 mL), and stirred at 0 °C for 30 minutes. The solid was collected by filtration, rinsed with water (30 mL), and then dried under vacuum to obtain E26 (22.2 g, yield 39%). 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), CuBr2 (21.85 g, 97.9 mmol, 4.58 mL, 1.5 equivalents) was added at 0°C. The mixture turned dark green and was stirred further at room temperature for 15 minutes. t-BuONO (10.09 g, 97.9 mmol, 11.6 mL, 1.5 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours, then heated at 50°C for 4 hours. The reaction progress was checked using TLC (petroleum ether: siRNA = 3:1). The reaction mixture was concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® Silica Flash Column, eluent @ 100 mL / min with a 0-5% siRNA / PE gradient) to obtain 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) stannan (17.59 g, 48.7 mmol, 16.4 mL, 1.2 equivalents), and Pd(PPh3)2Cl2 (2.85 g, 4.06 mmol, 0.1 equivalents) in toluene (200 mL) was stirred at 90 °C for 12 hours under an N2 atmosphere. The reaction progress was checked using TLC (petroleum ether: HCl = 5:1). HCl (300 mL) was added, followed by saturated KF solution (500 mL). The resulting mixture was stirred at room temperature for 40 minutes, filtered, and the filtrate was 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 4N HCl (300 mL) was added. The mixture was stirred at room temperature for 12 hours. LC-MS indicated that the desired mass was detected. The reaction mixture was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (ISCO®, 24 g SepaFlash® Silica Flash Column, eluent @ 35 mL / min with a 0-10% siRNA / PE gradient) to obtain 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), MeMgBr (3 M, 12.7 mL, 3 equivalents) was added dropwise under N2 at -78°C. The reaction mixture was stirred at -78°C for 1.5 hours. The reaction progress was checked using TLC (petroleum ether:HCl = 5:1, by UV). The reaction mixture was quenched by slowly adding saturated NH4Cl solution (30 mL), and the organic portion was extracted with HCl (30 mL x 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, petroleum ether / HCl = 1 / 0 to 1 / 1) to obtain E29 (1.7 g, yield 63%). 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 pure reaction at 150°C for 6 hours.

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

[0409] To a solution of E29 (3.4 g, 16.0 mmol) in THF (30 mL) and H2O (15 mL), LiOH.H2O (803 mg, 19.1 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction progress was monitored using LC-MS. The reaction mixture was adjusted to pH 7 with HCl (1 M), concentrated to dryness, and E30 (4 g) was obtained, 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 overall scheme 4 [ka]

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

[0412] To a solution of ethyl 3-cyclopropyl-3-oxopropanoate (8 g, 51.2 mmol) in DCM (100 mL), NBS (9.12 g, 51.2 mmol) and TsOH.H2O (1.95 g, 10.2 mmol, 0.2 equivalents) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored using TLC (PE:HCl = 10:1). The reaction mixture was concentrated to dryness. HCl (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 / HCl = 1:0~10:1) to obtain E31 (12 g, 100% yield). 1 1H 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), 2-hydroxy-2-methylpropanamide (2.19 g, 21.3 mmol, 5 equivalents) was added. The mixture was stirred at 110 °C for 40 hours. The reaction progress was monitored using LC-MS. The reaction mixture was adjusted to approximately pH 8 by adding saturated water-soluble NaHCO3 at 0 °C. H2O (50 mL) was added, and the aqueous portion was extracted with HCl (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / HCl = 1:0~2:1) to obtain E32 (0.15 g, yield 14%). 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 H2O (4 mL), LiOH.H2O (114 mg, 2.71 mmol, 1.1 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored using LC-MS. The reaction mixture was concentrated and the THF was removed. The aqueous portion was adjusted to approximately pH 7 by adding HCl (1 M), and then lyophilized to obtain 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-cyanoxazole-5-carboxylic acid [ka]

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

[0419] To a solution of ethyl 4-bromooxazole-5-carboxylate (E14) (10 g, 45.5 mmol) in THF (30 mL) and H2O (150 mL), Zn(CN)2 (3.74 g, 31.8 mmol, 2.02 mL, 0.7 equivalents) and t-BuXPhos-Pd-G3 (1.81 g, 2.27 mmol, 0.05 equivalents) were added. The reaction mixture was degassed under vacuum, purged three times with N2, and then stirred under N2 at 40°C for 16 hours. The reaction progress was monitored using TLC (PE:HCl = 5:1). HCl (300 mL) was added to the reaction mixture, the organic layer was washed with H2O (50 mL) and saline solution (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / .''=100 / 1~10 / 1) to obtain E34 (7.5g, 99% yield). 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-cyanoxazole-5-carbonyl)oxylithium (E35)

[0421] To a solution of E34 (5 g, 30.1 mmol) in THF (40 mL) and H2O (80 mL), LiOH.H2O (1.33 g, 31.6 mmol, 1.05 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The reaction progress was monitored using TLC (PE:HCl = 5:1). The reaction mixture was concentrated under vacuum to remove most of the THF, and then lyophilized under vacuum to obtain 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)pyrazole-4-yl]-1,3,4-oxadiazole-2-carbonyl]oxylithium according to overall 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-imidazole-1-yl)methanethion (25.90 g, 145 mmol, 1.2 equivalents) in THF (300 mL) was stirred at room temperature for 12 hours, then heated to 75 °C for 4 hours. After cooling to room temperature, K₂CO₃ (50.21 g, 363 mmol, 3 equivalents) and CH₃I (85.95 g, 606 mmol, 37.7 mL, 5 equivalents) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction progress was monitored using TLC (PE:SiO = 1:1). The reaction mixture was combined with another reaction product carried out with 8.5 g of ethyl 2-hydrazino-2-oxoacetate and quenched by the addition of H₂O (100 mL). DCM (500 mL) was added, the organic layer was separated, washed with saline solution (2 × 100 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by flash silica gel chromatography (0-25% PE: Â eluent @ 40 mL / min) to obtain 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)pyrazole-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 equivalents), Na2CO3 (394 mg, 3.71 mmol, 3 equivalents), thiophene-2-carbonyloxy copper (472 mg, 2.48 mmol, 2 equivalents), and Pd(dppf)Cl2 (181 mg, 248 μmol, 0.2 equivalents) in dioxane (9 mL) was degassed, purged three times with N2, and the reaction mixture was stirred under N2 at 75°C for 16 hours. The reaction progress was monitored using TLC (PE:SiO=2:1). ÃO (100 mL) was added to the reaction mixture, the organic layer was washed with water (30 mL) and saline solution (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / ÃO = 1 / 0 to 2 / 1) to obtain E37 (140 mg, yield 39%). 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)pyrazole-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), LiOH.H2O (22.3 mg, 531 μmol, 1.1 equivalents) in H2O (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored using TLC (DCM:MeOH). The reaction mixture was concentrated under vacuum to remove most of the THF, and then lyophilized under vacuum to obtain 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)pyrazole-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 equivalents) in DMF (45 mL), 2,2,2-trifluoroethyltrifluoromethanesulfonate (21.53 g, 92.8 mmol, 1.3 equivalents) was added dropwise, and the resulting mixture was stirred at 50°C for 6 hours. The reaction progress was monitored using TLC (PE:siRNA = 1:1). siRNA (300 mL) was added to the reaction mixture, the organic layer was washed with H2O (100 mL) and saline solution (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, 0-12% PE / siRNA eluent @ 60 mL / min) to obtain E39 (16 g).1 H 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), NH2NH2.H2O (7.73 g, 151 mmol, 7.5 mL, 98% purity, 2.1 equivalents) was added, and the reaction mixture was stirred at 80°C for 15 hours. The reaction progress was monitored using TLC (PE:HCl = 1:1). The reaction mixture was concentrated to dryness. The residue was polished with TBME (50 mL) and stirred for 15 minutes. The precipitate was collected by filtration and then dried under vacuum to obtain 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), 2-chloro-2-oxoacetate (2.36 g, 17.3 mmol, 1.9 mL, 1.2 equivalents) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration, rinsed with TBME (30 mL), and then dried under vacuum to obtain 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)pyrazole-4-yl]-1,3,4-oxadiazole-2-carboxylate (E37)

[0437] To a solution of E41 (1.5 g, 5.35 mmol) and Et3N (271 mg, 2.68 mmol, 373 μL, 0.5 equivalents) in DCM (30 mL), TsCl (491 mg, 6.96 mmol, 1.3 equivalents) was gradually added at 0°C, and the resulting mixture was stirred at room temperature for 18 hours. The reaction progress was monitored using TLC (PE:HCl = 1:1). DCM (100 mL) was added to the reaction mixture, the organic layer was washed with saturated Na2CO3 solution (60 mL) and saline solution (60 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, 0-16% PE / HCl eluent @ 40 mL / min) to obtain E37 (0.65 g, yield 42%). 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 overall 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), CuBr2 (10.66 g, 47.7 mmol, 2.2 mL, 1.5 equivalents) was added at 0°C. The reaction mixture turned dark green and was stirred at room temperature for 15 minutes. t-BuONO (4.92 g, 47.7 mmol, 5.7 mL, 1.5 equivalents) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours, then heated at 50°C for a further 12 hours. The reaction progress was checked using TLC (PE / siRNA = 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 at 40 mL / min with a 0-50% siRNA / PE gradient) to obtain E42 (4.5 g, yield 64%). 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 equivalents) in THF (40 mL), DIPEA (1.17 g, 9.05 mmol, 1.6 mL, 2 equivalents) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction progress was checked using TLC (PE / HCl = 1 / 1). HCl (100 mL) was added to the reaction mixture, the organic portion was washed with water (30 mL) and saline solution (30 mL x 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 at 35 mL / min with a 0-30% Â1 / PE gradient) to obtain E43 (800 mg, yield 78%). 1 H 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 H2O (12 mL), LiOH.H2O (162 mg, 3.87 mmol, 1.1 equivalents) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was checked using TLC (PE / Â=1 / 1). The reaction mixture was concentrated to dryness to obtain 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] Intermediate [5-(5-fluoro-2-pyridyl)-1,3,4-oxadiazole-2-carbonyl]oxylithium by overall scheme 9, method A [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 equivalents) was stirred at 60°C for 12 hours. The reaction mixture was concentrated under vacuum, the residue was dissolved in HCl (150 mL), and washed with saturated NaHCO3 solution (50 mL) and saline solution (20 mL). The organic layer was 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 with a 0-25% HCl / PE gradient @ 60 mL / min) to obtain E45 (15.24 g, yield 80%). 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) and NH2NH2.H2O (11.06 g, 217 mmol, 10.7 mL, 98% purity, 2.1 equivalents) in EtOH (70 mL) was degassed, purged three times with N2, and then the reaction mixture was stirred at room temperature under an N2 atmosphere for 3 hours. The reaction mixture was concentrated to dryness to obtain 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-oxoacetate (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 equivalents) in DCM (500 mL), ethyl 2-chloro-2-oxoacetate (15.45 g, 113 mmol, 12.7 mL, 1.3 equivalents) was added at 0°C for 10 minutes. The reaction mixture was stirred at room temperature for 2 hours. H2O (100 mL) was added to the reaction mixture, and the aqueous portion was extracted with DCM (300 mL x 3). The combined organic layers were washed with saline solution (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 with a 0-2.5% siRNA / PE gradient at 60 mL / min) to obtain E47 (16 g, yield 53%). 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-oxoacetate (E47) (16 g, 62.7 mmol) in DCM (350 mL), TEA (8.25 g, 81.5 mmol, 11.3 mL, 1.3 equivalents) and TosCl (5.98 g, 31.4 mmol, 0.5 equivalents) were added in three separate additions at 0°C. The mixture was stirred at room temperature for 3 hours. Saturated NaHCO3 solution (200 mL) was added, and the aqueous portion was extracted with DCM (400 mL x 3). The combined organic layers were washed with saline solution (200 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, 0-2.5% MeOH:DCM eluent @ 85 mL / min) to obtain E48 (8.2 g, yield 49%). 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 H2O (180 mL), LiOH.H2O (2.23 g, 53.1 mmol, 1.05 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to remove most of the THF, and the aqueous portion was freeze-dried under vacuum to obtain 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), 2,2,2-trifluoroethylhydrazine (670 mg, 5.88 mmol, 1.3 equivalents) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then stirred at room temperature for 16 hours. The reaction progress was checked using LC-MS. The reaction mixture was concentrated to dryness, and the residue was purified by flash silica gel chromatography (eluent: 0-5% ethyl / PE gradient) to obtain E50 (850 mg, yield 69%). 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 H2O (5 mL), LiOH.H2O (224 mg, 5.35 mmol, 1.6 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The reaction progress was checked using TLC (PE:HCl = 2:1). The reaction mixture was concentrated to remove THF. The aqueous portion was adjusted to approximately 6 pH by adding HCl (1 M). The resulting precipitate was collected by filtration and then dried under vacuum to obtain 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-oxobuta-3-enoate (E52)

[0463] Ethyl 2-oxopropanoate (2 g, 17.2 mmol, 1.9 mL) and 1,1-dimethoxy-N,N-dimethylmethaneamine (2.09 g, 17.6 mmol, 2.3 mL, 1.02 equivalents) were stirred at room temperature for 12 hours. The reaction progress was checked using TLC (PE:SiO = 10:1). The reaction mixture was concentrated to dryness to obtain 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-oxobuta-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 hours. The reaction progress was checked using TLC (PE:HCl = 10:1). The reaction mixture was adjusted to approximately pH 9 by adding saturated Na2CO3 solution. The aqueous portion was extracted with HCl (300 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / HCl = 100 / 1 to 50 / 1) to obtain E53 (1.03 g, yield 34%). 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, yield 6%). 1 ¹H NMR (400 MHz, DMSO-d6) 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 H2O (10 mL), LiOH.H2O (386 mg, 9.21 mmol, 2 equivalents) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction progress was checked using TLC (PE / SiO=1 / 1). The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous portion was adjusted to approximately pH 7 by adding 2 M HCl, and lyophilized under vacuum to obtain (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-carbone xylate was prepared from ethyl 2-amino-2-thioxoacetate according to the procedure in Bioorg. Med. Chem., 26(2016) 3223-3225. The reaction mixture was heated under reflux.

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

[0473] Reagent 2,2-difluoroacetyl chloride was prepared by adding oxalyl dichloride (18.90 g, 149 mmol, 13.0 mL, 1.1 equivalent) dropwise at 0°C 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 equivalent) in DCM (80 mL). The reaction mixture was stirred at room temperature for 1 hour, 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), 2,2-difluoroacetyl chloride (15.47 g, 135 mmol, 2.4 equivalents) was added. The reaction mixture was heated to 120 °C and stirred for 12 hours. The reaction progress was checked using LC-MS. The reaction mixture was concentrated to dryness. DCM (200 mL) was added to the residue, the organic portion was washed with 1 M HCl (30 mL) and saline solution (60 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: Depositphotos = 20:1 to 2:1) to obtain E56 (8.87 g, yield 83%). 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), MeI (22.28 g, 157 mmol, 9.8 mL, 3 equivalents) and K2CO3 (21.69 g, 157 mmol, 3 equivalents) were added. The mixture was stirred at room temperature for 12 hours. The reaction progress was checked using TLC (PE:Â=1:1). The reaction mixture was filtered, and the precipitate was rinsed with Â(150 mL). The filtrate was washed with water (30 mL) and saline (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:Â=20:1~1:1) to obtain E57 (4.46 g, yield 42%). 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 H2O (10 mL), LiOH.H2O (505 mg, 12.0 mmol, 1.05 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was checked using TLC (PE:HCl = 2:1). The reaction mixture was concentrated under vacuum to remove THF. H2O (20 mL) was added, the aqueous portion was extracted with TBME (20 mL), and then lyophilized under vacuum to obtain 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-methylpropanmidine (E59)

[0481] To a solution of 2-hydroxy-2-methyl-propanenitrile (2.14 g, 25.2 mmol, 2.3 mL) in EtOH (20 mL), hydroxylamino hydrochloride (3.49 g, 50.3 mmol, 2 equivalents) and Na2CO3 (5.33 g, 50.3 mmol, 2 equivalents) were added, and the reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was concentrated to dryness. Depositphotos (200 mL) was added to the residue, and the organic portion was washed twice with water (50 mL) and saline solution (50 mL). The mixture was dried over Na2SO4, filtered, and concentrated to dryness to obtain 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-propanmidine (E59) (520 mg, 4.40 mmol) and pyridine (696 mg, 8.80 mmol, 711 μL, 2 equivalents) in toluene (15 mL), ethyl 2-chloro-2-oxoacetate (601 mg, 4.40 mmol, 493 μL) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour, and then stirred at 100°C for 15 hours. The reaction progress was checked using LC-MS. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / siRNA = 1 / 0~2 / 1) and preparative HPLC (column: Boston). Further purification was performed using Uni C18 40*150*5um, mobile phase: [water (0.225% FA)-ACN], B%: 16%~46%, 7.7 mins) to obtain 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 H2O (5 mL), LiOH.H2O (41.9 mg, 999 μmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the aqueous portion was freeze-dried under vacuum to obtain 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), i-PrMgCl-LiCl (1.3 M, 6.03 mL, 2 equivalents) was added 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 equivalents) was added dropwise to the reaction mixture. The reaction mixture was stirred at -78°C for 1 hour. The reaction progress was checked using LC-MS. 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 RINKAN (25 mL x 2). The combined organic layers were washed with saline solution (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / Â=1 / 0~20:1) to obtain 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 H2O (1 mL), LiOH.H2O (116 mg, 2.77 mmol, 1.3 equivalents) was added. The reaction mixture was stirred at 40°C for 12 hours. The reaction progress was checked using LC-MS. The reaction mixture was concentrated under vacuum to remove the MeOH, and water (50 mL) was added. The aqueous portion was extracted with TBME (30 mL), and the aqueous layer was then adjusted to approximately pH 6 by adding 0.5 M HCl. The resulting suspension was extracted three times with DCM / MeOH (100 / 10 mL). The combined DCM / MeOH organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain E64 (420 mg, yield 89%). 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 H2O (1 mL), LiOH.H2O (17.69 mg, 422 μmol, 1.1 equivalents) was added, and the mixture was stirred at 40°C for 12 hours. The reaction progress was checked using LC-MS. The reaction mixture was concentrated under vacuum to remove the MeOH, and water (10 mL) was added. The aqueous portion was extracted with TBME (30 mL), and then the pH was adjusted to approximately 6 by adding 0.5 M HCl. The resulting suspension was extracted three times with DCM / MeOH (30 / 3 mL). The combined DCM / MeOH organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain E65 (100 mg, yield 87%). 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), Pd / C (100 mg, 10% purity) was added under N2. The resulting mixture was degassed under vacuum, purged three times with H2, and then stirred under H2 (15 psi) at room temperature for 1 hour. The reaction was checked using LC-MS. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness under vacuum to obtain E66 (350 mg), which was used without further purification. LC-MS: 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 H2O (1 mL), NaOH (89.64 mg, 2.24 mmol, 1.5 equivalents) was added, and the mixture was stirred at 40°C for 12 hours. The reaction progress was checked using LC-MS. The reaction mixture was concentrated under vacuum to remove the MeOH, and water (10 mL) was added. The aqueous portion was extracted with TBME (30 mL), and then the pH was adjusted to approximately 6 by adding 0.5 M HCl. The resulting suspension was extracted three times with DCM / MeOH (30 / 3 mL). The combined DCM / MeOH organic layer was dried over Na2SO4, filtered, and concentrated to dryness to obtain E67 (320 mg), which was used without further purification. LC-MS: m / z 220.9 [M+H] + .

[0499] Intermediate E72 by 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), K3PO4 (22.47 g, 106 mmol), and Pd(dppf)Cl2 (1.29 g, 1.76 mmol) in dioxane (80 mL) and H2O (40 mL) was stirred at 80°C for 12 hours under N2. The reaction progress was checked using LC-MS. The reaction mixture was combined with another 1 g batch reaction and DCM (200 mL) was added. The organic layer was washed with saline (2 × 80 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / ÃO = 1 / 0 to 4 / 1) to obtain E68 (6.4 g, yield 80.2%). 1 1H NMR (400MHz, CDCl3)δ 8.37(s,1H),8.30(s,1H),8.03(d,1H),7.52(dd,1H),6.61(dd,1H),5.76(d,1H),5.34(d,1H),3.84(s,3H);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 H2O (80 mL), K2OsO4.2H2O (583 mg, 1.58 mmol) and NaIO4 (16.92 g, 79.1 mmol, 4.38 mL) were added at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. The reaction progress was checked using LC-MS. DCM (200 mL) was added to the reaction mixture, the organic layer was washed with brine (2 × 80 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, DCM / siRNA = 1 / 0 to 6 / 1) to obtain E69 (5.9 g, yield 91.3%).1 H 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), NaBH4 (1.78 g, 47.0 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction progress was checked using LC-MS. The reaction mixture was quenched by adding saturated water-soluble NH4Cl (50 mL), and the aqueous portion was extracted with HCl (100 mL). The organic layer was washed with water (50 mL) and saline (40 mL), dried over Na2SO4, filtered, and concentrated to dryness to obtain E70 (2.3 g, yield 94.9%). 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), NaH (512 mg, 12.8 mmol, 60% purity) was added at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, 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 hour, and the reaction progress was checked using LC-MS. The reaction mixture was quenched by adding saturated water-soluble 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 saline (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (SiO2, PE / Â1 / 0~5 / 1) to obtain E71 (1.8g, 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 H2O (40 mL), NaOH (719 mg, 18.0 mmol) was added, and the reaction mixture was stirred at 40°C for 12 hours. The reaction progress was checked using LC-MS. The reaction mixture was concentrated to remove the MeOH, and then H2O (10 mL) was added. The pH of the aqueous mixture was adjusted to approximately 6 by adding 0.5 M HCl, and the aqueous mixture was filtered. The precipitate was dried under vacuum to obtain E72 (1.6 g, yield 94.9%). 1H NMR(400MHz,CDCl3)δ 8.57(s,1H),8.45-8.51(m,1H),8.21(d,1H),7.48(dd,1H...

Claims

[Claim 1] The invention described in the present specification.

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