Compound acting as androgen receptor antagonist

Abstract

Provided are a compound represented by formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising same, and the use thereof acting as an androgen receptor (AR) antagonist. The compound is preferably used for the treatment of androgen receptor-mediated alopecia.

Description

Compounds that act as androgen receptor antagonists

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to and the benefit of the following Chinese patent applications filed with the State Intellectual Property Office of China: Chinese Patent Application No. 202311091809.5 filed on August 28, 2023, and Chinese Patent Application No. 202410802546.2 filed on June 20, 2024. The entire text of the above patent applications is incorporated herein by reference in its entirety. Technical Field

[0003] The present application relates to the field of medicinal chemistry, and in particular to a class of amide compounds or stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use as androgen receptor (AR) antagonists. Background Art

[0004] The androgen receptor (AR) is a member of the nuclear receptor family. It consists of four major regions: the N-terminal active transcriptional control domain (NTD), the DNA binding domain (DBD), the hinge region, and the C-terminal ligand binding domain (LBD). Its activation is implicated in benign prostatic hyperplasia, prostate cancer, seborrheic dermatitis, acne, premenstrual syndrome, lung cancer, polycyclic ovarian syndrome, hirsutism, and alopecia. Therefore, the AR is an important target in multiple areas of drug discovery.

[0005] Androgenic alopecia (AGA) is currently the most common type of hair loss clinically diagnosed, but its specific pathogenesis remains incompletely understood. Most researchers believe it is related to androgen metabolism. Studies have shown that elevated expression of the androgen receptor gene and / or type II 5α-reductase gene in hair follicles in the alopecia area enhances the effects of androgens on susceptible follicles. In AGA, cells in the dermis of susceptible follicles contain a specific type II 5α-reductase enzyme that converts testosterone circulating in the area into dihydrotestosterone. This enzyme binds to androgen receptors within the cells, triggering a series of reactions that lead to progressive miniaturization of the hair follicles and hair loss, ultimately leading to baldness. Currently, only minoxidil and finasteride are approved by the FDA for the treatment of AGA. Minoxidil is a potassium channel opener, and its precise mechanism of efficacy in AGA is not fully understood. It is applied topically to the affected area. However, it has a long onset of action and is associated with adverse reactions such as itching, contact dermatitis, and worsening hair loss after discontinuation of treatment. Finasteride, a type II 5-α-reductase inhibitor, reduces serum and scalp dihydrotestosterone (DHT) levels and is used to treat male AGA. However, long-term use of finasteride can lead to erectile and ejaculatory dysfunction and decreased libido, making it a prohibitive treatment option for men with hair loss. Therefore, investigating novel molecules with AR degradation and / or AR antagonism is crucial for further research related to androgenic alopecia.

[0006] Summary of the Invention

[0007] The present invention provides a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] X is selected from CH or N;

[0010] Y is selected from S, O or NR 7 ;

[0011] R 1 Selected from OH or -O-C1-C6 alkyl;

[0012] R 2 Selected from C1-C6 alkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl;

[0013] R 3 is selected from C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3a replace;

[0014] R 3a Selected from halogen, OH, CN, NH2, -COR 3b 、-COOR 3b 、-NHCOR 3b 、-CONHR 3b , -O-C1-C6 alkyl, phenyl, C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl, wherein the phenyl, C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3c replace;

[0015] R 3b is selected from H, C1-C6 alkyl, phenyl or 5-6 membered heteroaryl;

[0016] R 3c Selected from -COOC1-C6 alkyl, C1-C6 alkyl, -O-C1-C6 alkyl, phenyl or 5-6 membered heteroaryl;

[0017] R 4 Selected from NO2, halogen or CN;

[0018] R 5 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -COOC1-C6 alkyl, -S-C1-C6 alkyl, -O-C1-C6 alkyl, -Se-C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -S(O)-C1-C6 alkyl;

[0019] R 6 is selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -O-C1-C6 alkyl;

[0020] R 7 Selected from H or C1-C6 alkyl.

[0021] In some embodiments, X is N.

[0022] In some embodiments, Y is selected from O or NR 7 .

[0023] In some embodiments, Y is selected from S, O, or NH.

[0024] In some embodiments, Y is selected from S or O.

[0025] In some embodiments, R 1 Selected from OH or -O-CH3.

[0026] In some embodiments, R 1 For OH.

[0027] In some embodiments, R 2 Selected from CH3 or CF3.

[0028] In some embodiments, R 1 OH,R 2 For CH3.

[0029] In some embodiments, R 3 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3a replace.

[0030] In some embodiments, R 3 is selected from C1-C6 alkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3a replace.

[0031] In some embodiments, R 3 is selected from C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3a replace.

[0032] In some embodiments, R 3 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally replaced by R 3a replace.

[0033] In some embodiments, R 3 is selected from C1-C6 alkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C1-C6 alkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally replaced by R 3a replace.

[0034] In some embodiments, R 3 is selected from C1-C6 alkyl or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl or 4-6 membered heterocyclic group is optionally replaced by R 3a replace.

[0035] In some embodiments, R 3 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R 3a replace.

[0036] In some embodiments, R 3is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrazolyl or pyridinyl, wherein the methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrazolyl or pyridinyl is optionally replaced by R 3a replace.

[0037] In some embodiments, R 3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrazolyl or pyridinyl, wherein the methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrazolyl or pyridinyl is optionally replaced by R 3a replace.

[0038] In some embodiments, R 3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, wherein the methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl is optionally replaced by R 3a replace.

[0039] In some embodiments, R 3a Selected from halogen, OH, -COR 3b 、-COOR 3b 、-NHCOR 3b , -O-C1-C6 alkyl, phenyl, C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl, wherein the phenyl, C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3c replace.

[0040] In some embodiments, R 3a is selected from F, OH, -O-CH3, -COCH3, -COOCH2CH3, -CO-phenyl, -NHCO-pyridyl, oxetanyl, pyrrolyl, 1,3-dioxolanyl, phenyl or pyridyl, wherein the oxetanyl, pyrrolyl, 1,3-dioxolanyl, phenyl or pyridyl is optionally replaced by R 3c replace.

[0041] In some embodiments, R 3a Selected from F, OH, -O-CH3, -COCH3, -COOCH2CH3, -CO-phenyl, -NHCO-pyridyl, oxetanyl, pyrrolyl, pyridyl,

[0042] In some embodiments, R 3b Selected from C1-C6 alkyl, phenyl or 5-6 membered heteroaryl.

[0043] In some embodiments, R 3c Selected from C1-C6 alkyl, -O-C1-C6 alkyl, phenyl or 5-6 membered heteroaryl.

[0044] In some embodiments, R 3c Selected from C1-C6 alkyl or -O-C1-C6 alkyl.

[0045] In some embodiments, R 3 Selected from methyl, ethyl, propyl, isopropyl, n-butyl, CH2CH2F, tert-butyl, CH2CF3, Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, CH2CH2OH, (CH2)3OH, (CH2)4OH, (CH2)3OCH3, (CH2)3COCH3, (CH2)3COOCH2CH3, Cyclobutyl or isobutyl.

[0046] In some embodiments, R 4 is selected from halogen or CN.

[0047] In some embodiments, R 4 is selected from F, Cl or CN.

[0048] In some embodiments, R 4 For CN.

[0049] In some embodiments, R 5 Selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -COOC1-C6 alkyl, -S-C1-C6 alkyl or -O-C1-C6 alkyl.

[0050] In some embodiments, R 5 Selected from C1-C6 haloalkyl, -S-C1-C6 alkyl, -O-C1-C6 alkyl, -Se-C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -S(O)-C1-C6 alkyl.

[0051] In some embodiments, R 5 Selected from C1-C6 haloalkyl or -S-C1-C6 alkyl.

[0052] In some embodiments, R 5 Selected from CF3, -S-CH3, -O-CH3, -Se-CH3, -S(O)2-CH3 or -S(O)-CH3.

[0053] In some embodiments, R 5 Selected from CF3 or -S-CH3.

[0054] In some embodiments, R 6 is selected from H or halogen.

[0055] In some embodiments, R 6 Selected from H or F.

[0056] In some embodiments, R 7 For H.

[0057] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (I-1) or its stereoisomer or its pharmaceutically acceptable salt:

[0058] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , X is as defined in the above formula (I).

[0059] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:

[0060] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0061] In another aspect, the present disclosure provides a method for treating a disease mediated by androgen receptor in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0062] In another aspect, the present disclosure provides use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating androgen receptor-mediated diseases.

[0063] In another aspect, the present disclosure provides use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating androgen receptor-mediated diseases.

[0064] In another aspect, the present disclosure provides a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating androgen receptor-mediated diseases.

[0065] In some embodiments, the androgen receptor-mediated disease is selected from androgenic alopecia.

[0066] Any embodiment of any aspect of the present invention can be combined with other embodiments without contradiction. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments without contradiction.

[0067] Definitions and Explanations of Terms

[0068] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0069] In this article Indicates the attachment site.

[0070] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge and dotted wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0071] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0072] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0073] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0074] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0075] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0076] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each Rb There are independent options.

[0077] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0078] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl , 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" may be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" may be understood to mean a straight-chain or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0079] The term "deuterated alkyl" refers to a group in which hydrogen on an alkyl group is replaced by deuterium, including monodeuterated alkyl and polydeuterated alkyl. For example, the term "C1-C6 deuterated alkyl" refers to a C1-C6 alkyl group as defined above that is substituted by one or more deuterium groups, including but not limited to CD3, CH2CD3, and the like.

[0080] The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-C6 haloalkyl" means a C1-C6 alkyl as defined above substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc. The term "cycloalkyl" refers to a fully saturated carbocyclic ring that exists in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10-membered ring. The term "C3-C6 haloalkyl" means a C1-C6 alkyl group as defined above that is substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc. 10 "Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0081] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spirocyclic or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "3-10 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in its ring atoms. “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic group include but are not limited to diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include but are not limited to dihydroisoquinolinyl and the like. "4-10 membered heterocyclyl" may include "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc., and "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0082] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be an aromatic radical having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 The term "C6-C 20 Aryl" may contain "C6-C 10 Aryl".

[0083] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromatic character, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1, 2 or 3, preferably 1-2, heteroatoms independently selected from N, O and S.

[0084] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0085] The term "hydroxy" refers to an -OH group.

[0086] The term "cyano" refers to a -CN group.

[0087] The term "amino" refers to a -NH2 group.

[0088] The term "therapeutically effective amount" means

[0089] An amount of a compound of the present disclosure that (i) treats a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a specific disease, condition, or disorder as described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0090] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0091] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0092] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0093] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0094] As used herein, examples of the term "mammal" include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc.

[0095] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0096] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid addition salts or base addition salts, including salts formed between a compound and an inorganic acid or organic acid, and salts formed between a compound and an inorganic base or an organic base.

[0097] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0098] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0099] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0100] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0101] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0102] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0103] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0104] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0105] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0106] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0107] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0108] In all methods of administration of the compounds of formula (I) described herein, the daily dosage is 0.01 mg / kg to 500 mg / kg body weight, in single or divided doses. DETAILED DESCRIPTION

[0109] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification.

[0110] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0111] Unless otherwise stated, % refers to wt%.

[0112] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0113] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10-6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0114] The eluent described below can be a mixed eluent composed of two or more solvents, with the ratio being the volume ratio of each solvent. For example, "0-10% methanol / dichloromethane" indicates that during gradient elution, the volume ratio of methanol to dichloromethane in the mixed eluent is 0:100 to 10:90. Alternatively, "ethyl acetate / petroleum ether = 5 / 1" indicates that during gradient elution, the volume ratio of ethyl acetate to petroleum ether in the mixed eluent is 5:1.

[0115] Abbreviations:

[0116] TEA: triethylamine; THF: tetrahydrofuran; n-propanol: n-propanol; n-Butanol or n-BuOH: n-butanol; t-BuOH: tert-butanol; ACN: acetonitrile; TMAF: tetramethylammonium fluoride; TMSCF3: (trifluoromethyl)trimethylsilane; AcOH: acetic acid; MeOH: methanol; i-PrOH: isopropanol; EA: ethyl acetate; Cyclohexane: cyclohexane; DMF: N,N-dimethylformamide; NaSMe: sodium methylthiolate; NBS: N-bromosuccinimide; SOCl2: thionyl chloride; PPh3: triphenylphosphine; DIAD: diisopropyl azodicarboxylate; DEAD: diethyl azodicarboxylate; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DCM: dichloromethane; m-CPBA: m-chloroperbenzoic acid; DIEA: N,N-diisopropylethylamine; LiOH·H2O: lithium hydroxide monohydrate; EtOH: ethanol; DCC: dicyclohexylcarbodiimide; DMAP: 4-dimethylaminopyridine; TBAF: tetrabutylammonium fluoride.

[0117] Example 1: 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropionic acid ethyl ester (Compound 001)

[0118] Step 1: Synthesis of 3-ethoxy-2-hydroxy-2-methyl-3-oxopropionic acid

[0119] Intermediate 1-1 (1 g, 5.74 mmol) and cesium carbonate (3.73 g, 11.48 mmol) were added to N,N-dimethylformamide (20 mL), and the reaction mixture was stirred at room temperature in air for 18 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with 150 mL of water and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with water (40 mL*2), saturated brine (40 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate / petroleum ether = 5 / 1) to afford intermediate compound 1-2 (0.6 g).

[0120] MS (ESI): m / z = 161.10 [MH] - .

[0121] Step 2: Synthesis of ethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate

[0122] Intermediate 1-2 (1.56 g, 9.62 mmol) was added to tetrahydrofuran (10 mL), and SOCl2 (953.68 mg, 8.02 mmol, 582.22 μL) was added under ice-water bath and stirred for 2 h. Triethylamine (973.39 mg, 9.62 mmol, 1.34 mL) was added and stirred for 20 min. Intermediate 1-3 (1 g, 5.34 mmol) was added and stirred at room temperature for 18 h. LCMS showed that the reaction was complete. The reaction solution was concentrated and the residue was purified by RP-FLASH [chromatographic column: C18 column, 120 g, 20-35 μm silica, The mixture was purified using decreasingly polar mixtures of water (containing 0.1% formic acid) and acetonitrile as eluent; acetonitrile gradient ratio 45%-55%, flow rate: 65 mL / min; elution time 15 minutes] to give compound 001 (1 g).

[0123] MS (ESI): m / z = 332.10 [M+H] + .

[0124] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.40–9.34(m,1H),8.89–8.83(m,1H),7.08(s,1H),4.26–4.09(m,2H),1.58(s,3H),1.26–1.15(m,3H).

[0125] Example 2-3: (2S) ethyl 3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate and (2R) ethyl 3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compounds 002 & 003)

[0126] Compound 001 (1 g) was separated and purified by SFC [equipment: WATERS150preparative SFC (SFC-26); chromatographic column: Chiral Pak AD, 250×30 mm ID, 10 μm; mobile phase: phase A is carbon dioxide, phase B is methanol; gradient (B%) is 20%; flow rate: 150 mL / min; back pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle time: 8 minutes] to obtain compound 002 (484 mg) and compound 003 (444 mg).

[0127] Compound 002:

[0128] SFC retention time: 2.081 min.

[0129] MS (ESI): m / z = 332.1 [M+H] + .

[0130] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),9.40–9.34(m,1H),8.89–8.83(m,1H),7.08(s,1H),4.26–4.09(m,2H),1.58(s,3H),1.26–1.15(m,3H).

[0131] Compound 003:

[0132] SFC retention time: 2.484 min.

[0133] MS (ESI): m / z = 332.1 [M+H] + .

[0134] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),9.37(d,J=2.2Hz,1H),8.85(d,J=2.3Hz,1H),7.09(s,1H),4.26–4.09(m,2H),1.59(s,3H),1.26–1.15(m,3H).

[0135] Example 4-5: (2S)-3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid propyl ester and (2R)-3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid propyl ester (Compounds 004 & 005)

[0136] Step 1: Synthesis of (2S)-3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid and (2R)-3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid

[0137] Compound 002 (or 003) (100 mg, 301.89 μmol) and lithium hydroxide (36.15 mg, 1.51 mmol) were added to tetrahydrofuran (2 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The reaction mixture was poured into a 0.1 M aqueous HCl solution (30 mL) and extracted with dichloromethane (10 mL*3). The organic phases were combined and washed with saturated brine (50 mL). The organic phases were dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated to obtain intermediate compound 4-1 (or 5-1) (80 mg). MS (ESI): m / z = 304.00 [M+H] + .

[0138] 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.86(s,1H),1.42(s,3H).

[0139] Step 2: Synthesis of (2S)-3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid propyl ester and (2R)-3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid propyl ester (Compounds 004 & 005)

[0140] Intermediate 4-1 (or 5-1) (50 mg, 164.91 μmol) was dissolved in n-propanol (1 mL). Concentrated sulfuric acid (258.79 mg, 2.64 mmol, 140.65 μL) was added under ice-cooling and stirred at room temperature for 15 h. LCMS indicated completion of the reaction. The reaction solution was concentrated, and the residue was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; acetonitrile gradient: 40% to 70% over 12 minutes) to afford target compound 004 (or 005) (20 mg).

[0141] Among them, compound 004 was prepared from compound 002, and compound 005 was prepared from compound 003 using the above preparation method.

[0142] Compound 004:

[0143] MS (ESI): m / z = 346.10 [M+H] + .

[0144] 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),9.36(d,J=2.3Hz,1H),8.84(d,J=2.2H z,1H),7.08(s,1H),4.12–4.02(m,2H),1.64–1.51(m,5H),0.89–0.80(m,3H).

[0145] Compound 005:

[0146] MS (ESI): m / z = 346.10 [M+H] + .

[0147] 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),9.36(d,J=2.2Hz,1H),8.84(d,J=2.3H z,1H),7.08(s,1H),4.12–4.02(m,2H),1.66–1.50(m,5H),0.89–0.80(m,3H).

[0148] Example 6-7: Synthesis of (2S)-3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid butyl ester and (2R)-3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid butyl ester (Compounds 006 & 007)

[0149] Step 1: Synthesis of butyl 3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate

[0150] Compound 9-1 (40 mg, 131.9 μmol) was added to n-butanol (1 mL). Concentrated sulfuric acid (25.88 mg, 263.86 μmol, 14.06 μL) was added at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: mixtures of purified water and acetonitrile of decreasing polarity; acetonitrile gradient: 50%-69% over 9.2 minutes) to yield the target compound 6-1 (11.2 mg).

[0151] MS (ESI): m / z = 360.10 [M+H] + .

[0152] 1H NMR (400MHz, DMSO-d6) δ9.33(d,J=2.2Hz,1H),8.83(d,J=2.3Hz,1H),4.16–4.05(m,2H),1.60–1.48(m,5H),1.36–1.21(m,2H),0.87–0.78(m,3H).

[0153] Step 2: Synthesis of (2S)-butyl 3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate and (2R)-butyl 3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (006 & 007)

[0154] The method described in step 1 was scaled up to obtain intermediate 6-1, and 1 g of intermediate 6-1 was separated and purified by SFC [equipment: WATERS150preparative SFC (SFC-26); chromatographic column: Chiral Pak AD, 250×30 mm ID, 10 μm; mobile phase: phase A is carbon dioxide, phase B is ethanol (containing 0.1% NH3H2O); gradient (B%) is 15%; flow rate: 150 mL / min; back pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle time: 5 minutes] to obtain compound 006 (464 mg) and compound 007 (468 mg).

[0155] Compound 006:

[0156] SFC retention time: 1.552 min.

[0157] MS (ESI): m / z = 360.10 [M+H] + .

[0158] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),9.37(d,J=2.2Hz,1H),8.84(d,J=2.2Hz,1H),7. 07(s,1H),4.16–4.05(m,2H),1.61–1.48(m,5H),1.36–1.21(m,2H),0.87–0.78(m,3H).

[0159] Compound 007:

[0160] SFC retention time: 1.903 min.

[0161] MS (ESI): m / z = 360.10 [M+H] + .

[0162] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),9.36(d,J=2.3Hz,1H),8.84(d,J=2.3Hz,1H),7. 07(s,1H),4.16–4.05(m,2H),1.61–1.48(m,5H),1.36–1.22(m,2H),0.87–0.78(m,3H).

[0163] Example 8: 2-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]carbamoyl]-3,3,3-trifluoro-2-hydroxypropionic acid ethyl ester (Compound 008)

[0164] Step 1: Synthesis of ethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-3-oxopropanoate

[0165] Starting material 1-3 (10 g, 53.44 mmol) and potassium phosphate (16.91 g, 80.16 mmol) were added to tetrahydrofuran (15 mL). Ethyl 3-chloro-3-oxopropanoate (12.07 g, 80.16 mmol) was added to the reaction mixture under an ice-water bath. The reaction mixture was stirred at room temperature for 18 h. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was purified by RP-flash chromatography (column: Welch XB-C18 column, 5 μm silica, 21.2 mm diameter, 250 mm length; eluent: a decreasingly polar mixture of water (containing 0.1% formic acid) and acetonitrile; acetonitrile gradient ratio 40%-63% over 9 minutes) to afford intermediate compound 8-1 (12 g).

[0166] MS (ESI): m / z = 302.1 [M+H] + .

[0167] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),9.01(d,J=2.3Hz,1H),8.66(d,J=2.3Hz,1H),4.20–4.09(m,2H),3.61(s,2H),1.27–1.17(m,3H).

[0168] Step 2: Synthesis of ethyl 3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2,2-dihydroxy-3-oxopropanoate

[0169] Intermediate 8-1 (3 g, 9.96 mmol) was added to acetic acid (8 mL), acetonitrile (10 mL), and water (2 mL). NaClO2 (2.96 g, 26.18 mmol, 80% content) was added under ice-water bath conditions. The reaction mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The reaction mixture was poured into ethyl acetate (50 mL) and water (20 mL). The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield intermediate compound 8-2 (3 g).

[0170] MS (ESI): m / z = 334.1 [M+H] + .

[0171] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.39(d,J=2.2Hz,1H),8.85(d,J=2.3Hz,1H),7.81(s,2H),4.22–4.10(m,2H),1.30–1.06(m,3H).

[0172] Step 3: Synthesis of ethyl 2-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]carbamoyl]-3,3,3-trifluoro-2-hydroxypropionate

[0173] Intermediate 8-2 (100 mg, 317.25 μmol), tetramethylammonium fluoride (59.10 mg, 634.51 μmol), and (trifluoromethyl)trimethylsilane (90.10 mg, 634.51 μmol) were added to tetrahydrofuran (1 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC (Phenomenex C18, 5 μm silica, 30 mm diameter, 80 mm length; using a mixture of pure water and acetonitrile (acetonitrile content: 60%-70%) as the eluent) to obtain the target compound 008 (25 mg).

[0174] MS (ESI): m / z = 386.00 [M+H] + .

[0175] 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),9.38(d,J=2.3Hz,1H),9.17(s,1H),8.82(d,J=2.3Hz,1H),4.33–4.21(m,2H),1.26–1.18(m,3H).

[0176] Example 9: 3-[[6-Cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propionic acid 2-fluoroethyl ester (Compound 009)

[0177] Step 1: 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoic acid (Compound 9-1)

[0178] Compound 001 (200 mg, 603.78 μmol) and lithium hydroxide (72.30 mg, 3.02 mmol) were added to tetrahydrofuran (2 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC [YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a decreasingly polar mixture of water (containing 7 mmol / L NH4HCO3) and acetonitrile; acetonitrile gradient ratio 20%-50%, elution time 7.5 minutes] to afford the title compound 9-1 (50 mg).

[0179] MS (ESI): m / z = 304.00 [M+H] + .

[0180] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.38–9.33(m,1H),8.89–8.84(m,1H),1.51(s,3H).

[0181] Step 2: 3-[[6-Cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propionic acid 2-fluoroethyl ester

[0182] Compound 9-1 (30 mg, 98.95 μmol) was added to 2-fluoroethanol (1 mL). Concentrated sulfuric acid (19.41 mg, 197.89 μmol, 10.55 μL) was added under ice-water bath. The reaction mixture was stirred at room temperature for 18 h. LC-MS indicated the reaction was complete. The reaction mixture was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; acetonitrile gradient: 40%-63% over 8.6 minutes) to afford the target compound 009 (13.5 mg).

[0183] MS m / z(ESI):=350.0[M+H] + .

[0184] 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.83(s,1H),4.70–4.63(m,1H),4.58–4.51(m,1H),4.46–4.26(m,2H),1.60(s,3H).

[0185] Example 10: 2-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]carbamoyl]-3,3,3-trifluoro-2-hydroxypropionic acid propyl ester (Compound 010)

[0186] Step 1: Synthesis of 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-3-oxopropanoic acid

[0187] Intermediate 8-1 (100 mg, 331.98 μmol) and lithium hydroxide monohydrate (23.90 mg, 597.57 μmol) were added to tetrahydrofuran (20 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 18 h. LCMS indicated the reaction was complete. The pH of the reaction mixture was adjusted to 3 with 1M aqueous HCl and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL). The organic phases were dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated to obtain intermediate compound 10-1 (80 mg).

[0188] MS (ESI): m / z = 274.1 [M+H] + .

[0189] Step 2: Synthesis of 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-3-oxopropionic acid propyl ester

[0190] Intermediate 10-1 (100 mg, 366.08 μmol) was added to n-propanol (2 mL). Concentrated sulfuric acid (35.90 mg, 366.08 μmol, 19.51 μL) was added under an ice-water bath. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ethyl acetate (10 mL) and water (10 mL). The layers were separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL). The organic phases were combined and washed once with saturated brine (50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate compound 10-2 (90 mg).

[0191] MS (ESI): m / z = 316.1 [M+H] + .

[0192] Step 3: Synthesis of 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2,2-dihydroxy-3-oxopropionic acid propyl ester

[0193] Intermediate 10-2 (14 g, 44.41 mmol) was added to a mixture of acetonitrile (10 mL), acetic acid (10 mL), and water (2 mL). Sodium chlorite (15.06 g, 133.23 mmol, 80% content) was added under ice-water bath. The reaction mixture was stirred at room temperature for 18 h. LCMS showed the reaction mixture was concentrated, and the resulting residue was purified by RP-flash chromatography [column: Welch XB-C18 column, 5 μm silica, 21.2 mm diameter, 250 mm length; eluent: decreasingly polar mixtures of water (containing 0.1% formic acid) and acetonitrile; acetonitrile gradient ratio 40%-63% over 9 minutes] to afford intermediate compound 10-3 (8 g).

[0194] MS (ESI): m / z = 348.1 [M+H] + .

[0195] Step 4: Synthesis of 2-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]carbamoyl]-3,3,3-trifluoro-2-hydroxypropionic acid propyl ester

[0196] Intermediate 10-3 (100 mg, 287.98 μmol), TMSCF3 (408.93 mg, 2.88 mmol) and tetrabutylammonium fluoride (67.77 mg, 259.18 μmol) were added to tetrahydrofuran (2 mL). The reaction solution was stirred at room temperature for 18 h. LCMS showed that the reaction was complete. 20 mL of water was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic layers were combined and washed with water (30 mL*2), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica, ethyl acetate / petroleum ether = 9 / 1) to obtain the target compound 010 (10 mg).

[0197] MS (ESI): m / z = 400.00 [M+H] + .

[0198] 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),9.41–9.36(m,1H),9.19(s,1H),8.84–8.79(m,1H),4.28–4.12(m,2H),1.68–1.54(m,2H),0.90–0.82(m,3H).

[0199] Example 11: 2-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]carbamoyl]-3,3,3-trifluoro-2-hydroxypropionic acid butyl ester (Compound 011)

[0200] Step 1: Synthesis of butyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-3-oxopropanoate

[0201] Intermediate 10-1 (100 mg, 366.08 μmol) was added to n-butanol (2 mL), and concentrated sulfuric acid (35.90 mg, 366.08 μmol, 19.51 μL) was added under an ice-water bath. The reaction solution was stirred at room temperature for 18 h. The reaction solution was poured into ethyl acetate (10 mL) and water (10 mL), and the layers were separated. The organic phases were extracted twice with ethyl acetate (10 mL). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate compound 11-1 (120 mg).

[0202] MS (ESI): m / z = 330.1 [M+H] + .

[0203] Step 2: Synthesis of 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2,2-dihydroxy-propionic acid butyl ester

[0204] Intermediate 11-1 (600 mg, 1.82 mmol) was added to a mixture of acetonitrile (4 mL), acetic acid (3 mL), and water (2 mL). Sodium chlorite (411.5 mg, 3.64 mmol, 80% content) was added under an ice-water bath. The reaction was stirred at room temperature for 18 h. LCMS indicated the reaction was complete. The reaction solution was concentrated, and the resulting residue was purified by RP-flash chromatography (Welch XB-C18 column, 5 μm silica, 21.2 mm diameter, 250 mm length; eluent: a decreasingly polar mixture of water (containing 0.1% formic acid) and acetonitrile; acetonitrile gradient: 40% to 63% over 9 minutes) to afford compound 11-2 (400 mg).

[0205] MS (ESI): m / z = 362.1 [M+H] + .

[0206] Step 3: Synthesis of butyl 2-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]carbamoyl]-3,3,3-trifluoro-2-hydroxypropionate

[0207] Intermediate 11-2 (115 mg, 317.25 μmol), tetrabutylammonium fluoride (58 mg, 222.08 μmol), and TMSCF3 (450.50 mg, 3.17 mmol) were added to tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with water (30 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The target compound 011 (10 mg) was obtained by column chromatography (silica, ethyl acetate / petroleum ether = 9 / 1).

[0208] MS (ESI): m / z = 414.00 [M+H] + .

[0209] 1 H NMR (400MHz, DMSO-d6) δ9.07–9.02(m,1H),8.66–8.60(m,1H),4.25–4.12(m,2H),1.57–1.45(m,2H),1.32–1.07(m,2H),0.82–0.71(m,3H).

[0210] Example 12: 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropionic acid methyl ester (Compound 012)

[0211] Compound 9-1 (40 mg, 131.9 μmol) was added to methanol (1 mL). Concentrated sulfuric acid (25.88 mg, 263.86 μmol, 14.06 μL) was added at room temperature. The reaction mixture was stirred at room temperature for 18 h. LC-MS indicated the reaction was complete. The reaction mixture was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of purified water and acetonitrile of decreasing polarity; acetonitrile gradient: 37%-67%; elution time: 9.5 minutes) to afford the target compound 012 (12 mg).

[0212] MS (ESI): m / z = 318.10 [M+H] + .

[0213] 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=2.1Hz,1H),8.79(d,J=2.3Hz,1H),6.07(s,1H),3.63(s,3H),1.51(s,3H).

[0214] Example 13: 3-[[6-Cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropionic acid isopropyl ester (Compound 013)

[0215] Compound 9-1 (40 mg, 131.9 μmol) was added to isopropanol (1 mL), followed by concentrated sulfuric acid (25.88 mg, 263.86 μmol, 14.06 μL). The reaction was stirred at room temperature for 18 h. LC-MS indicated the reaction was complete. The reaction was purified by Prep-HPLC using a YMC-TA column (5 μm silica, 30 mm diameter, 150 mm length); eluents were a decreasingly polar mixture of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; the acetonitrile gradient was 50%-69% over a 9.2-minute elution period) to afford the target compound 013 (13.5 mg).

[0216] MS (ESI): m / z = 346.10 [M+H] + .

[0217] 1 H NMR (400MHz, DMSO-d6) δ9.33(d,J=2.1Hz,1H),8.83(d,J=2.1Hz,1H),4.99–4.88(m,1H),1.56(s,3H),1.22–1.14(m,6H).

[0218] Example 14: tert-Butyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compound 014)

[0219] Compound 9-1 (50 mg, 164.91 μmol) was added to ethyl acetate (1 mL) and cyclohexane (1 mL). Tert-butyl 2,2,2-trichloroacetimidate (54.05 mg, 247.37 μmol) was added to the reaction mixture at room temperature, and the reaction was stirred for 18 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by Prep-HPLC using a YMC-TA column (5 μm silica, 30 mm diameter, 150 mm length; eluents were a decreasingly polar mixture of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; the acetonitrile gradient was 50% to 69% over a 9.2 minute elution time) to afford the target compound 014 (15 mg).

[0220] MS (ESI): m / z = 360.10 [M+H] + .

[0221] 1H NMR (400MHz, DMSO-d6) δ9.31(d,J=2.2Hz,1H),8.83(d,J=2.2Hz,1H),1.52(s,3H),1.39(s,9H).

[0222] Example 15: 2-[(4-cyano-2-fluoro-3-methylsulfanyl-phenyl)carbamoyl]-3,3,3-trifluoro-2-hydroxy-propionic acid ethyl ester (Compound 015)

[0223] Step 1: Synthesis of ethyl 2-[(4-cyano-2,3-difluorophenyl)carbamoyl]-3-oxopropanoate

[0224] Starting material 15-1 (100 mg, 648.86 μmol) and potassium phosphate (205.36 mg, 973.29 μmol) were added to tetrahydrofuran (20 mL). Ethyl 3-chloro-3-oxopropanoate (127.00 mg, 843.52 μmol) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. Water (10 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined and rinsed with saturated brine (50 mL*2). The organic phases were dried, filtered, and concentrated to obtain intermediate compound 15-2 (150 mg).

[0225] MS (ESI): m / z = 269.1 [M+H] + .

[0226] Step 2: Synthesis of ethyl 2-[(4-cyano-2,3-difluorophenyl)carbamoyl]-2,2-dihydroxy-3-oxopropanoate

[0227] Intermediate 15-2 (1.5 g, 5.59 mmol) was added to a mixed solvent of acetonitrile (10 mL), acetic acid (10 mL), and water (2 mL). Sodium chlorite (1.9 g, 16.78 mmol, 80% content) was added under an ice-water bath. The reaction mixture was stirred at room temperature for 18 h. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous sodium sulfite (10 mL) and extracted twice with ethyl acetate (10 mL). The organic phases were combined and washed with saturated brine (50 mL x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude intermediate compound 15-3 (2 g).

[0228] MS (ESI): m / z = 301.1 [M+H] + .

[0229] Step 3: Synthesis of ethyl 2-[(4-cyano-2,3-difluorophenyl)carbamoyl]-3,3,3-trifluoro-2-hydroxy-propionate

[0230] The crude intermediate 15-3 (300 mg), TMSCF3 (1.36 g, 9.55 mmol), and TBAF (224.65 mg, 859.21 μmol) were added to tetrahydrofuran (1 mL). The reaction mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with water (30 mL*2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The title compound 15-4 (100 mg) was obtained by column chromatography (silica, ethyl acetate / petroleum ether = 5 / 1).

[0231] MS (ESI): m / z = 353.1 [M+H] + .

[0232] Step 4: Synthesis of ethyl 2-[(4-cyano-2-fluoro-3-methylsulfanyl-phenyl)carbamoyl]-3,3,3-trifluoro-2-hydroxy-propionate

[0233] Intermediate 15-4 (50 mg, 141.96 μmol) was added to N,N-dimethylformamide (1 mL). Sodium thiomethoxide (11.92 mg, 170.35 μmol) was added to the reaction mixture under an ice-water bath. The reaction mixture was stirred at 100°C for 18 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (50 mL). The organic phase was concentrated, and the residue was purified by Prep-HPLC [YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a mixture of purified water and acetonitrile of decreasing polarity; acetonitrile gradient ratio 50%-90% over 10 minutes] to obtain the target compound 015 (2 mg).

[0234] MS (ESI): m / z = 381.1 [M+H] + .

[0235] 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.10(s,1H),7.80–7.70(m,2H),4.34–4.19(m,2H),2.56(s,3H),1.25–1.20(m,3H).

[0236] Example 16: Ethyl 3-[(6-cyano-5-methylthio-pyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compound 016) and Ethyl (2S)-3-[(6-cyano-5-methylthio-pyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxopropanoate / Ethyl (2R)-3-(6-cyano-5-methylthio-pyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxopropanoate (016A & 016B)

[0237] Step 1: Synthesis of 6-bromo-5-fluoropyridin-3-amine

[0238] 5-Fluoropyridin-3-amine (13.0 g, 116 mmol) was dissolved in DMF (60 mL) and cooled in an ice bath. A solution of N-bromosuccinimide (20.64 g, 116 mmol) in DMF (50 mL) was slowly added dropwise while the mixture was still ice-bathed. The reaction was continued for 30 minutes. LC-MS monitoring was performed until the reaction was complete. The reaction solution was poured into 500 mL of water and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed sequentially with water (300 mL x 2) and saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brownish-yellow crude product, which was purified by column chromatography (silica, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to afford Intermediate 16-2 (8.4 g).

[0239] MS(ESI):m / z=190.90,192.90[M+H] + .

[0240] Step 2: Synthesis of 5-amino-3-fluoro-2-pyridinecarbonitrile

[0241] 6-Bromo-5-fluoropyridin-3-amine (3 g, 15.71 mmol) and cuprous cyanide (5.63 g, 62.83 mmol) were dispersed in DMF (50 mL). The mixture was then placed under a nitrogen balloon and the atmosphere was replaced three times. The mixture was then placed in a 130°C oil bath under a protective atmosphere and allowed to react for 6 hours. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 2) to afford the title compound 16-3 (1.3 g).

[0242] MS (ESI): m / z = 138.0 [M+H] +.

[0243] Step 3: Synthesis of 5-amino-3-(methylthio)pyridinecarbonitrile

[0244] 5-Amino-3-fluoro-2-pyridinecarbonitrile (1 g, 7.29 mmol) was added to a reaction flask and dissolved in DMF (15 mL). Sodium thiomethoxide (1.02 g, 14.56 mmol) was added with stirring at room temperature. The resulting reaction solution was stirred at room temperature for 12 hours. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (80 mL x 5). The combined organic phases were washed sequentially with water (200 mL x 2) and saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 16-4 (0.85 g).

[0245] MS (ESI): m / z = 166.0 [M+H] +.

[0246] 1H NMR (400MHz, DMSO-d6) δ7.75 (d, J = 2.3Hz, 1H), 6.84 (d, J = 2.3Hz, 1H), 6.47 (s, 2H), 2.50 (s, 3H).

[0247] Step 4: Synthesis of ethyl 3-[(6-cyano-5-methylthio-pyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxopropanoate

[0248] Intermediate 1-2 (237 mg, 1.47 mmol) was added to tetrahydrofuran (20 mL). Thionyl chloride (348.62 mg, 2.93 mmol) was added under ice-cooling, and the mixture was stirred for 2 h. Triethylamine (395.35 mg, 3.91 mmol) was added under ice-cooling, and the mixture was stirred for 10 min. Intermediate 16-4 (161.4 mg, 0.977 mmol) was added, and the reaction mixture was stirred at room temperature for 6 h. LC-MS indicated the reaction was complete. The mixture was quenched with water (30 mL) and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was purified by Prep-HPLC [column: YMC TA column; mobile phase: A: water; B: acetonitrile; gradient (B%): 35%-65%; retention time: 8.5 min] to obtain the target compound 016 (54 mg).

[0249] MS (ESI): m / z = 310.10 [M+H] + .

[0250] 1 H NMR (400MHz, DMSO-d6) δ8.91(d,J=2.0Hz,1H),8.36(d,J=2.1Hz,1H),4.18–4.13(m,2H),2.58(s,3H),1.57(s,3H),1.21–1.15(m,3H).

[0251] The above method was used to scale up the preparation to obtain compound 016. Compound 016 (100 mg) was separated and purified by SFC [equipment: Waters 200preparative SFC (QC-R-LC-07); chromatographic column: ChiralPak AS, 250×50 mm ID, 10 μm; mobile phase: phase A is carbon dioxide, phase B is methanol (0.05% NH3·H2O); the proportion of mobile phase B is 25%; flow rate: 150 mL / min; back pressure: 100 bar; column temperature: 40°C; detection wavelength: 210 nm] to obtain compound 016A (44.8 mg) and compound 016B (36.5 mg).

[0252] Compound 016A:

[0253] SFC retention time: 2.175 min.

[0254] MS (ESI): m / z = 310.10 [M+H] + .

[0255] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.92(d,J=2.1Hz,1H),8.37(d,J=2.1Hz,1H) ,7.01(s,1H),4.18–4.13(m,2H),2.58(s,3H),1.57(s,3H),1.19(t,J=7.1Hz,3H).

[0256] Compound 016B:

[0257] SFC retention time: 2.359 min.

[0258] MS (ESI): m / z = 310.10 [M+H] + .

[0259] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.93(d,J=2.1Hz,1H),8.37(d,J=2.1Hz,1H) ,7.00(s,1H),4.19–4.11(m,2H),2.59(s,3H),1.58(s,3H),1.19(t,J=7.1Hz,3H).

[0260] Example 17: 2,2,2-Trifluoroethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compound 017)

[0261] Compound 9-1 (50 mg, 164.91 μmol) was added to 2,2,2-trifluoroethanol (1 mL). Concentrated sulfuric acid (32 mg, 329.82 μmol, 18 μL) was added at room temperature, and the mixture was stirred at room temperature for 18 h. LC-MS indicated the reaction was complete. The reaction solution was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 7 mmol / L NH4HCO3) and acetonitrile; acetonitrile gradient: 36% to 66% over 8.0 minutes) to afford Compound 017 (15 mg).

[0262] MS (ESI): m / z = 386.00 [M+H] + .

[0263] 1 H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.82(s,1H),4.92–4.80(m,2H),1.63(s,3H).

[0264] Example 18: Oxetane-3-ylmethyl-3[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 018)

[0265] Compound 9-1 (51 mg, 168.21 μmol), oxetan-3-ylmethanol (18 mg, 201.85 μmol), and triphenylphosphine (53 mg, 201.85 μmol) were added to tetrahydrofuran (2 mL). The atmosphere was replaced with argon three times. Diisopropyl azodicarboxylate (41 mg, 201.85 μmol) was added dropwise under an ice bath. After complete addition, the mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was monitored for completion by LC-MS. The reaction solution was concentrated, and the residue was purified by Prep-HPLC [column: YMC TAR-C18, 30 × 150 mm, 5 μm; mobile phase A: water (7 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; mobile phase B gradient: 55%-75% over 9 min; elution at 254 / 220 nm; RT: 8 min] to afford compound 018 (17 mg).

[0266] MS (ESI): m / z = 374.1 [M+H] + .

[0267] 1H NMR(400MHz,Chloroform-d)δ9.26(s,1H),8.91–8.83(m,1H),8.76–8.70(m,1H),4 .89–4.82(m,2H),4.60–4.45(m,4H),4.42(s,1H),3.46–3.28(m,1H),1.79(s,3H).

[0268] Example 19: Oxetane-3-yl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 019)

[0269] Compound 9-1 (55 mg, 181.40 μmol), oxetane-3-ol (16 mg, 217.68 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (75 mg, 199.54 μmol) and triethylamine (36 mg, 362.80 μmol) were added to N,N-dimethylformamide (1 mL) and stirred at room temperature for 12 h. The reaction was completed after monitoring by LC-MS. The reaction solution was purified by Prep-HPLC [chromatographic column: YMC TAR-C18, 30×150 mm, 5 μm; mobile phase A: water (7 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; mobile phase B gradient: 45%-70%, gradient elution over 8 minutes; 254 / 220 nm; RT: 9 minutes] to obtain compound 019 (3 ​​mg).

[0270] MS (ESI): m / z = 360.00 [M+H] + .

[0271] 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.42–9.31(m,1H),8.90–8.80(m,1H),7.2 4(s,1H),5.54–5.39(m,1H),4.90–4.74(m,2H),4.53–4.40(m,2H),1.62(s,3H).

[0272] Example 20: Tetrahydrofuran-3-yl 3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compound 020)

[0273] Compound 9-1 (40 mg, 131.93 μmol) was dissolved in tetrahydrofuran-3-ol (232 mg, 2.64 mmol), and concentrated sulfuric acid (39 mg, 395.79 μmol, 21 μL) was added. The mixture was stirred at room temperature for 18 h. LC-MS indicated the reaction was complete. The reaction solution was purified by Prep-HPLC using a YMC-TA column (5 μm silica, 30 mm diameter, 150 mm length); eluents were a decreasingly polar mixture of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; the acetonitrile gradient was 36% to 66% over 8.0 minutes) to afford the target compound 020 (7.47 mg).

[0274] MS (ESI): m / z = 374.10 [M+H] + .

[0275] 1 H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.86–8.81(m,1H),5.33–5.26(m,1H),3.84–3.61(m,4H),2.21–2.09(m,1H),1.92–1.80(m,1H),1.58(s,3H).

[0276] Example 21: Tetrahydropyran-4-yl 3-[[6-cyano-5-(trifluoromethyl)pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 021)

[0277] Compound 9-1 (40 mg, 131.93 μmol) was added to tetrahydropyran-4-ol (14 mg, 131.93 μmol), and concentrated sulfuric acid (26 mg, 263.86 μmol, 14 μL) was added at room temperature. The reaction was stirred at room temperature for 18 h. LC-MS indicated the reaction was complete. The reaction was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; acetonitrile gradient: 40% to 63% over 8.6 minutes) to afford Compound 021 (11.6 mg).

[0278] MS (ESI): m / z = 388.00 [M+H] + .

[0279] 1H NMR(400MHz, DMSO-d6)δ9.25(d,J=2.2Hz,1H),8.81(d,J=2.3Hz,1H),4.98–4.87(m ,1H),3.77–3.63(m,2H),3.52–3.40(m,2H),1.89–1.73(m,2H),1.59–1.34(m,5H).

[0280] Example 22: 3-[4-cyano-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxo-butyl propionate (Compound 022)

[0281] Step 1: Synthesis of ethyl 3-[4-cyano-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxo-propionate

[0282] Starting material 1-2 (65 mg, 400.89 μmol) was dissolved in tetrahydrofuran (1 mL), and thionyl chloride (95 mg, 801.73 μmol) was added dropwise. The mixture was stirred at room temperature overnight. Triethylamine (162 mg, 1.60 mmol) was added dropwise under ice-cooling, and the mixture was stirred for 20 min. Subsequently, a solution of 4-cyano-3-(trifluoromethyl)aniline (89 mg, 481.07 μmol) in tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. Stirring was continued at room temperature for 2 h. The reaction was monitored for completion by LC-MS. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (silica, ethyl acetate / petroleum ether = 5 / 1) to afford the title compound 22-2 (70 mg).

[0283] MS (ESI): m / z = 331.1 [M+H] + .

[0284] Step 2: Synthesis of 3-[4-cyano-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxopropionic acid

[0285] Intermediate 22-2 (70 mg, 212.12 μmol) and lithium hydroxide (7.2 mg, 300.65 μmol) were added to tetrahydrofuran (1 mL) and water (0.5 mL) and stirred at room temperature for 4 h. The reaction was complete after LC-MS monitoring. 20 mL of water was added to the reaction system, and the pH was adjusted to weak acidity with dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound 22-3 (50 mg).

[0286] MS (ESI): m / z = 303.0 [M+H] + .

[0287] Step 3: Synthesis of butyl 3-[4-cyano-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxo-propionate

[0288] Intermediate 22-3 (50 mg, 165.55 μmol) was added to 1-butanol (1 mL). Concentrated sulfuric acid (87 mg) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature overnight and monitored for completion by LC-MS. 40 mL of ethyl acetate was added to the reaction system, which was washed once with water and once with saturated brine. The product was concentrated, and the residue was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 7 mmol / L NH4HCO3) and acetonitrile; acetonitrile gradient: 50% to 90% over 10 minutes) to afford the title compound 022 (18 mg).

[0289] MS (ESI): m / z = 359.0 [M+H] + .

[0290] 1 H NMR(400MHz,DMSO-d6)δ8.51–8.45(m,1H),8.29–8.21(m,1H),8.14–8.07(m,1H ),4.15–4.05(m,2H),1.59–1.47(m,5H),1.35–1.21(m,2H),0.92–0.78(m,3H).

[0291] Example 23: 3-[4-chloro-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxo-butyl propionate (Compound 023)

[0292] Step 1: Synthesis of ethyl 3-[4-chloro-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxo-propionate

[0293] Intermediate 1-2 (65 mg, 400.89 μmol) was dissolved in tetrahydrofuran (1 mL), and thionyl chloride (95 mg, 801.73 μmol) was added dropwise. The mixture was stirred overnight. Triethylamine (162 mg, 1.60 mmol) was added dropwise under ice-cooling and stirred for 20 min. Subsequently, a solution of 4-chloro-3-(trifluoromethyl)aniline (94 mg, 481.07 μmol) in tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 2 h. The reaction was monitored for completion by LC-MS. The reaction mixture was purified by column chromatography (silica, ethyl acetate / petroleum ether = 5 / 1) to afford the title compound 23-2 (72 mg).

[0294] MS (ESI): m / z = 340.1 [M+H] + .

[0295] Step 2: Synthesis of 3-[4-chloro-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxo-propionic acid

[0296] Intermediate 23-2 (72 mg, 211.96 μmol) and lithium hydroxide (7.2 mg, 300.65 μmol) were added to tetrahydrofuran (1 mL) and water (0.5 mL) and stirred at room temperature for 4 h. The reaction was complete after LC-MS monitoring. 15 mL of water was added to the reaction system, and the pH was adjusted to weak acidity with dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 23-3 (56 mg).

[0297] MS (ESI): m / z = 310.0 [MH] - .

[0298] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),8.39(d,J=2.6Hz,1H),8.14–8.03(m,1H),7.67(d,J=8.8Hz,1H),1.52(s,3H).

[0299] Step 3: Synthesis of butyl 3-[4-chloro-3-(trifluoromethyl)anilino]-2-hydroxy-2-methyl-3-oxopropionate

[0300] Intermediate 23-3 (46 mg, 147.61 μmol) was added to 1-butanol (1 mL). Concentrated sulfuric acid (87 mg, 47.21 μL) was added dropwise under ice-cooling. The reaction was stirred at room temperature overnight and monitored for completion by LC-MS. 50 mL of ethyl acetate was added to the reaction system, which was washed once with water and once with saturated brine. The product was concentrated and purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 7 mmol / L NH4HCO3) and acetonitrile; elution gradient: 50% to 90% acetonitrile, 10 min). The title compound 023 (28 mg) was obtained.

[0301] MS (ESI): m / z = 368.00 [M+H] + .

[0302] 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.36(d,J=2.6Hz,1H),8.12–8.01(m,1H),7.67(d,J=8.8Hz, 1H), 6.86 (s, 1H), 4.17–4.01 (m, 2H), 1.57–1.49 (m, 5H), 1.35–1.21 (m, 2H), 0.83 (t, J = 7.4Hz, 3H).

[0303] Example 24: 2-Hydroxyethyl 3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-hydroxy-2-methyl-3-oxopropanoate (Compound 024)

[0304] Compound 9-1 (50 mg, 164.91 μmol) was added to ethylene glycol (2 mL), followed by concentrated sulfuric acid (32 mg, 329.82 μmol), and stirred at room temperature overnight. LCMS indicated the reaction was complete. The reaction solution was poured into dichloromethane (20 mL) and water (10 mL), and the layers were separated. The organic phase was washed sequentially with water (10 mL) and saturated brine (10 mL), dried, and concentrated. The residue was purified by Prep-HPLC [YMC TAC18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: a decreasingly polar mixture of water (containing 7 mmol / L NH4HCO3) and acetonitrile; acetonitrile gradient from 33% to 73% over 7.5 minutes] to yield the target compound 024 (20 mg).

[0305] MS (ESI): m / z = 348.00 [M+H] + .

[0306] 1 H NMR (400MHz, DMSO-d6) δ9.10 (d, J = 2.3Hz, 1H), 8.78 (d, J = 2.3Hz, 1H), 4.15-4.01 (m, 2H), 3.55 (t, J = 5.2Hz, 2H), 1.53 (s, 3H).

[0307] Example 25: 3-Hydroxypropyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propionate (Compound 025)

[0308] Compound 9-1 (20 mg, 65.96 μmol) was dissolved in 1,3-propylene glycol (1 mL). Concentrated sulfuric acid (13 mg, 131.93 μmol, 7 μL) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 15 h. LCMS indicated the reaction was complete. The reaction solution was purified by Prep-HPLC using a YMC TA-C18 column (5 μm silica, 30 mm diameter, 150 mm length); eluents were a decreasingly polar mixture of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; the acetonitrile gradient was 50% to 80% over 7.2 minutes to afford the title compound 025 (10 mg).

[0309] MS (ESI): m / z = 362.0 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d6) δ9.23–9.17(m,1H),8.83–8.77(m,1H),4.20–4.08(m,2H),3.45–3.37(m,2H),1.75–1.64(m,2H),1.54(s,3H).

[0311] Example 26: 4-Hydroxybutyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compound 026)

[0312] 1,4-Butanediol (26.75 mg, 296.84 μmol) and compound 9-1 (30 mg, 98.95 μmol) were added to DCM (1 mL). Concentrated sulfuric acid (2 mg, 19.79 μmol, 1 μL) was added under an ice-water bath. The reaction mixture was stirred at room temperature for 18 h. LC-MS indicated the reaction was complete. The reaction mixture was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 7 mmol / L NH4HCO3) and acetonitrile; acetonitrile gradient: 40%-63% over 8.6 minutes) to afford the target compound 026 (13 mg).

[0313] MS (ESI): m / z = 376.0 [M+H] + .

[0314] 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),9.36(s,1H),8.81(s,1H),7.07(s,1H),4.43–4. 35(m,1H),4.15–4.07(m,2H),3.40–3.32(m,2H),1.65–1.53(m,5H),1.47–1.35(m,2H).

[0315] Example 27: 3-Methoxypropyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compound 027)

[0316] Compound 9-1 (30 mg, 98.95 μmol) and 1,3-propylene glycol monomethyl ether (26.75 mg, 296.84 μmol) were added to dichloromethane (3 mL). Concentrated sulfuric acid (19 mg, 197.89 μmol, 11 μL) was added under an ice-water bath. The reaction mixture was stirred at room temperature for 18 h. LC-MS showed that the product was primarily present. The reaction mixture was purified by Prep-HPLC (YMC-TA column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; acetonitrile gradient: 40%-63% over 8.6 minutes) to afford the target compound 027 (10 mg).

[0317] MS (ESI): m / z = 376.00 [M+H] + .

[0318] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),9.37(s,1H),8.85(s,1H),7.10(s,1H),4. 20–4.09(m,2H),3.36–3.27(m,2H),3.16(s,3H),1.85–1.73(m,2H),1.58(s,3H).

[0319] Example 28: 5-(3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-hydroxy-2-methyl-3-oxopropionamido)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (Compound 028)

[0320] Compound 9-1 (40 mg, 131.93 μmol) was added to tetrahydrofuran (3 mL). Thionyl chloride (25 mg, 211.09 μmol) was added under ice-cooling conditions and the mixture was stirred at 0°C for 6 h. Triethylamine (40 mg, 395.79 μmol) was added and the mixture was stirred at 0°C for 20 min. Intermediate 28-1 (22 mg, 131.93 μmol) was added and the mixture was warmed to room temperature and stirred for 20 min. LCMS indicated the reaction was complete. The reaction mixture was poured into dichloromethane (20 mL) and washed twice with water (10 mL x 2). The organic phase was dried, filtered, and concentrated to obtain the crude product. The crude product was purified by HPLC [YMC-TAC column 5 μm silica, 30 mm diameter, 150 mm length; using decreasingly polar mixtures of water (containing 7 mmol / L NH4HCO3) and acetonitrile as eluent; acetonitrile gradient ratio 50%-80%, elution time 9.5 minutes] to obtain the target compound 028 (12 mg).

[0321] MS (ESI): m / z = 455.10 [M+H] + .

[0322] 1 H NMR(400MHz, DMSO-d6)δ9.28(d,J=2.3Hz,1H),8.83(d,J=2.3Hz,1H),6.61(s,1H), 4.28-4.18(m,2H),3.70(s,3H),1.62(s,3H),1.26(t,J=7.1Hz,3H).

[0323] Example 29: 4-Oxopentyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compound 029)

[0324] Compound 9-1 (100 mg, 329.82 μmol) was added to 5-hydroxy-2-pentanone (2 mL), and thionyl chloride (79 mg, 659.64 μmol, 48 μL) was added under ice-cooling. The reaction solution was stirred at 25°C for 15 h. LCMS showed that the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was purified by Prep-HPLC [Phenomenex C 18 , 5 μm silica, 30 mm diameter, 80 mm length; using a mixture of water and acetonitrile (acetonitrile content: 40%-70%) as eluent] purification gave the target compound 029 (9.6 mg).

[0325] MS (ESI): m / z = 388.0 [M+H] + .

[0326] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),9.41–9.30(m,1H),8.96–8.80(m,1H),7.11(s,1 H),4.10–4.04(m,2H),2.48–2.43(m,2H),2.02(s,3H),1.78–1.68(m,2H),1.58(s,3H).

[0327] Example 30: 4-[[3-[[6-Cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoyl]amino]butyric acid ethyl ester (Compound 030)

[0328] Ethyl aminobutyrate (22 mg, 164.91 μmol), compound 9-1 (50 mg, 164.91 μmol), triethylamine (33.37 mg, 329.82 μmol, 46.00 μL), and HATU (68.44 mg, 181.40 μmol) were added to DMF (2 mL). The reaction was stirred at room temperature for 18 h. LC-MS indicated the reaction was complete. The reaction was purified by Prep-HPLC using a YMC-TA column (5 μm silica, 30 mm diameter, 150 mm length; eluents were a decreasingly polar mixture of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; the acetonitrile gradient was 40% to 63% over 8.6 minutes) to afford the target compound 030 (13 mg).

[0329] MS (ESI): m / z = 417.10 [M+H] + .

[0330] 1 H NMR(400MHz,DMSO-d6)δ9.20–9.14(m,1H),8.81–8.76(m,1H),7.97–7.89(m,1H),6.02(s,1H),4.06–3 .95(m,2H),3.16–3.06(m,2H),2.29–2.20(m,2H),1.73–1.61(m,2H),1.52(s,3H),1.18–1.10(m,3H).

[0331] Example 31: 2-(Oxetane-3-yl)ethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 031)

[0332] Compound 9-1 (40 mg, 131.93 μmol) and 2-(oxetan-3-yl)ethanol (16 mg, 158.31 μmol) were dissolved in tetrahydrofuran (1 mL). Triphenylphosphine (42 mg, 158.31 μmol) was added dropwise under nitrogen and in an ice bath. After addition, diethyl azodicarboxylate (32 mg, 158.31 μmol) was added dropwise. The mixture was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The product was filtered, the filtrate concentrated, and the residue was purified by Prep-HPLC (YMC TA-C column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water and acetonitrile; acetonitrile gradient from 37% to 66% over 7.8 min) to afford the title compound 031 (15 mg).

[0333] MS (ESI): m / z = 388.10 [M+H] + .

[0334] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.44–9.32(m,1H),8.91–8.81(m,1H),7.11(s,1H),4.63–4.5 1(m,2H),4.32–4.21(m,2H),4.14–4.04(m,2H),3.05–2.93(m,1H),2.00–1.89(m,2H),1.57(s,3H).

[0335] Example 32: Ethyl 6-(3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-hydroxy-2-methyl-3-oxopropionamido)picolinate (Compound 032)

[0336] Compound 9-1 (40 mg, 131.93 μmol) was added to tetrahydrofuran (3 mL). Thionyl chloride (25 mg, 211.09 μmol) was added under ice-cooling conditions and the mixture was stirred at 0°C for 6 h. Triethylamine (40.05 mg, 395.79 μmol) was added and the mixture was stirred at 0°C for 20 min. Intermediate 32-1 (22 mg, 131.93 μmol) was added and the mixture was heated to 50°C and stirred for 12 h. LCMS indicated the reaction was complete. The reaction mixture was poured into dichloromethane (20 mL) and washed twice with water (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by Prep-HPLC [YMC-TAC column 5 μm silica, 30 mm diameter, 150 mm length; using a decreasingly polar mixture of water (containing 7 mmol / L NH4HCO3) and acetonitrile as the eluent; acetonitrile gradient ratio 42%-72%, elution time 11 minutes] to give compound 032 (20 mg).

[0337] MS (ESI): m / z = 452.00 [M+H] + .

[0338] 1 H NMR(400MHz, DMSO-d6)δ9.30(d,J=2.3Hz,1H),8.79(d,J=2.3Hz,1H),8.31–8.23(m,1H),8. 08–8.00(m,1H),7.88–7.80(m,1H),4.40–4.31(m,2H),1.68(s,3H),1.33(t,J=7.1Hz,3H).

[0339] Example 33: 3-Oxo-3-phenylpropyl 3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-hydroxy-2-methyl-3-oxopropanoate (Compound 033)

[0340] Step 1: Synthesis of 3-hydroxy-1-phenylpropan-1-one

[0341] The starting material 33-1 (5 g, 30.45 mmol) was dissolved in dichloromethane (24 mL), and water (10 mL), hydrogen peroxide (10 mL, 37% H2O2) and aqueous hydrogen bromide (2.1 g, 12.20 mmol, 47% HBr) were added. The reaction solution was stirred at room temperature for 5 h. LC-MS showed that the reaction was complete. The solution was quenched with saturated aqueous sulfurous acid (40 mL), extracted three times with dichloromethane (20 mL*3), and the organic phases were combined, dried, and concentrated. The residue was separated and purified by column chromatography (silica, ethyl acetate / petroleum ether = 1 / 1) to give compound 33-2 (1 g).

[0342] MS (ESI): m / z = 151.10 [M+H] + .

[0343] Step 2: Synthesis of 3-oxo-3-phenylpropyl 3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-hydroxy-2-methyl-3-oxopropanoate

[0344] Compound 9-1 (40 mg, 131.93 μmol) and intermediate 33-2 (20 mg, 131.93 μmol) were dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (45 mg, 171.51 μmol) and diisopropyl azodicarboxylate (35 mg, 171.51 μmol) were added. The mixture was stirred at room temperature overnight. LC-MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by Prep-HPLC [YMC-TAR column 5 μm silica, 30 mm diameter, 150 mm length; a mixture of water (containing 7 mmol / L NH4HCO3) and acetonitrile of decreasing polarity was used as the eluent; the acetonitrile gradient ratio was 60%-90%, and the elution time was 9.7 minutes] to obtain the target compound 033 (15 mg).

[0345] MS (ESI): m / z = 436.00 [M+H] + .

[0346] 1 H NMR(400MHz, DMSO-d6)δ9.23(d,J=2.2Hz,1H),8.73(d,J=2.2Hz,1H),7.88–7.81(m,2H), 7.65–7.55(m,1H),7.50–7.39(m,2H),4.51–4.43(m,2H),3.40–3.34(m,2H),1.53(s,3H).

[0347] Example 34: 2-Pyrrol-1-ylethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 034)

[0348] Compound 9-1 (50 mg, 164.91 μmol), 2-pyrrol-1-ylethanol (37 mg, 329.82 μmol) and triphenylphosphine (56 mg, 214.38 μmol) were added to tetrahydrofuran (1 mL). Under nitrogen protection, a tetrahydrofuran solution of diisopropyl azodicarboxylate (37 mg, 214.38 μmol) (1 mL) was added under ice-bath conditions. The reaction solution was stirred at 25°C for 2 h. LCMS showed that the reaction was complete. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by Prep-HPLC [Phenomenex C 18 , 5 μm silica, 30 mm diameter, 80 mm length; using a mixture of water and acetonitrile (acetonitrile content: 45%-75%) as eluent] to obtain the target compound 034 (2 mg).

[0349] MS (ESI): m / z = 397.1 [M+H] + .

[0350] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.43–9.28(m,1H),8.98–8.71(m,1H),7.15 (s,1H),6.70–6.57(m,2H),5.90–5.74(m,2H),4.38–4.24(m,2H),4.14–4.07(m,2H),1.57(s,3H).

[0351] Example 35: (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 035)

[0352] Compound 35-1 (65.38 mg, 494.73 μmol) and triethylamine (50.06 mg, 494.73 μmol) were added to N,N-dimethylformamide (3 mL) and stirred for 10 min. HATU (80.88 mg, 214.38 μmol) and intermediate 9-1 (50 mg, 164.91 μmol) were then added. SOCl2 (91.13 mg, 766.01 μmol) was added under ice-water bath. The mixture was heated to 80°C and stirred for 6 h. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC [column: YMC TA column; mobile phase: A: water; B: acetonitrile; gradient (B%): 55%-85%; retention time: 9.5 min] to obtain the target compound 035 (4 mg).

[0353] MS (ESI): m / z = 418.1 [M+H]+ .

[0354] 1 H NMR(400MHz, DMSO-d6)δ9.33(d,J=2.2Hz,1H),8.84(d,J=2.2Hz,1H),4.29–4.21(m,1H), 4.20–4.02(m,2H),3.98–3.93(m,1H),3.70–3.62(m,1H),1.59(s,3H),1.27–1.19(m,6H).

[0355] Example 36: 2-(4-methoxyphenyl)ethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 036)

[0356] Compound 9-1 (30 mg, 98.95 μmol) and intermediate 36-1 (45 mg, 296.84 μmol) were added to dichloromethane (2 mL). Concentrated sulfuric acid (20 mg, 197.89 μmol, 11 μL) was added under an ice-water bath. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC [column: YMC TA column; mobile phase: A: water; B: acetonitrile; gradient (B%): 65%-85%; retention time: 9.5 min] to obtain the target compound 036 (5 mg).

[0357] MS (ESI): m / z = 438.10 [M+H] + .

[0358] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.36–9.31(m,1H),8.84–8.79(m,1H),7.12–7.03(m ,2H),6.69–6.60(m,2H),4.34–4.20(m,2H),3.64(s,3H),2.84–2.74(m,2H),1.55(s,3H).

[0359] Example 37: 2-(Pyridin-3-yl)ethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxopropanoate (Compound 037)

[0360] Intermediate 9-1 (30 mg, 98.95 μmol), Intermediate 37-1 (12.19 mg, 98.95 μmol), diisopropyl azodicarboxylate (26.01 mg, 128.63 μmol), and triphenylphosphine (33.74 mg, 128.63 μmol) were added to tetrahydrofuran (3 mL) and stirred at room temperature for 6 h. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC [column: YMC TA column; mobile phase: A: water; B: acetonitrile; gradient (B%): 45%-75%; retention time: 9.8 min] to obtain the target compound 037 (7.92 mg).

[0361] MS (ESI): m / z = 409.00 [M+H] + .

[0362] 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),9.31(s,1H),8.79(s,1H),8.38(s,1H),8.29(s,1H),7 .61(d,J=7.8Hz,1H),7.18–7.14(m,1H),4.37–4.33(m,2H),2.92–2.88(m,2H),1.54(s,3H).

[0363] Example 38: 2-(4-pyridyl)ethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 038)

[0364] Compound 9-1 (40 mg, 131.93 μmol), intermediate 38-1 (16 mg, 131.93 μmol), diisopropyl azodicarboxylate (35 mg, 171.51 μmol), and triphenylphosphine (45 mg, 171.51 μmol) were added to tetrahydrofuran (3 mL) and stirred at room temperature for 6 h. LC-MS indicated the reaction was complete. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC [column: YMC TA column; mobile phase: A: water; B: acetonitrile; gradient (B%): 45%-75%; retention time: 9.8 min] to obtain the target compound 038 (8.17 mg).

[0365] MS (ESI): m / z = 409.10 [M+H] + .

[0366] 1H NMR (400MHz, DMSO-d6) δ10.87(s,1H),9.31(d,J=2.3Hz,1H),8.77(d,J=2.3Hz,1H),8.32–8.25(m,2H),7.2 0(d,J=1.5Hz,1H),7.19(d,J=1.6Hz,1H),7.08(s,1H),4.39–4.35(m,2H),2.94–2.90(m,2H),1.53(s,3H).

[0367] Example 39: 2-(Pyridine-3-carbonylamino)ethyl 3-[[6-cyano-5-(trifluoromethyl)-pyridin-3-yl]amino]-2-hydroxy-2-methyl-3-oxo-propanoate (Compound 039)

[0368] Compound 9-1 (100 mg, 329.82 μmol), N-(2-hydroxyethyl)isonicotinamide (110 mg, 659.64 μmol), and triethylamine (50 mg, 494.73 μmol, 69 μL) were added to N,N-dimethylformamide (3 mL). HATU (186.65 mg, 494.73 μmol) was added under ice-cooling, and the reaction mixture was stirred at 25°C for 15 h. LCMS indicated the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by Prep-HPLC (Phenomenex C18, 5 μm silica, 30 mm diameter, 80 mm length; using a mixture of water and acetonitrile (acetonitrile content: 30%-60%) as eluent) to afford the target compound 039 (10 mg).

[0369] MS (ESI): m / z = 452.0 [M+H] + .

[0370] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),9.31–9.22(m,1H),8.85–8.81(m,1H),8.79–8.75(m,1H),8.69–8.62(m ,2H),8.06–7.99(m,1H),7.46–7.38(m,1H),7.05(s,1H),4.33–4.21(m,2H),3.62–3.46(m,2H),1.58(s,3H).

[0371] Example 40: 3-[(6-cyano-5-methylsulfonylpyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionic acid ethyl ester (Compound 040)

[0372] Compound 016 (50 mg, 161.63 μmol) was added to dichloromethane (3 mL), followed by m-chloroperbenzoic acid (83.68 mg, 484.90 μmol). The mixture was stirred at room temperature for 6 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated, and the residue was purified by Prep-HPLC (Phenomenex C18, 5 μm silica, 30 mm diameter, 80 mm length; using a mixture of pure water and acetonitrile (acetonitrile content: 30%-60%) as the eluent) to obtain the title compound 040 (11 mg).

[0373] MS (ESI): m / z = 342.1 [M+H] + .

[0374] 1 H NMR (400MHz, DMSO-d6) δ9.30(d,J=2.3Hz,1H),9.01(d,J=2.3Hz,1H),4.21–4.08(m,2H),3.45(s,3H),1.58(s,3H),1.23–1.11(m,3H).

[0375] Example 41: 3-[(6-cyano-5-(methylsulfinyl)pyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionic acid ethyl ester (Compound 041)

[0376] Compound 016 (30 mg, 96.98 μmol) was added to dichloromethane (3 mL), followed by m-chloroperbenzoic acid (25.10 mg, 145.47 μmol), and stirred at room temperature for 3 hours. LCMS indicated the reaction was complete. The reaction solution was purified by prep-HPLC using a YMC TAR column, using a mixture of water (containing 0.5% formic acid) and acetonitrile (30%-60% acetonitrile) as the eluent, to afford the target compound 041 (11.2 mg).

[0377] MS (ESI): m / z = 324.1 [MH] - .

[0378] 1 H NMR (400MHz, DMSO-d6) δ9.13–9.07(m,1H),8.93–8.86(m,1H),4.20–4.10(m,2H),2.94–2.87(m,3H),1.59–1.55(m,3H),1.23–1.14(m,3H).

[0379] Example 42: Ethyl 3-((6-cyano-5-(methylselenyl)pyridin-3-yl)amino)-2-hydroxy-2-methyl-3-oxopropanoate (Compound 042)

[0380] Step 1: Synthesis of 5-amino-3-(methylseleno)picolinonitrile

[0381] Dimethyl diselenide (2.74 g, 14.59 mmol), 5-amino-3-fluoropyridine-2-carbonitrile (1 g, 7.29 mmol), N,N-diisopropylethylamine (1.89 g, 14.59 mmol, 2.54 mL), and potassium carbonate (2.01 g, 14.59 mmol) were added to N,N-dimethylformamide (10 mL). The reaction was stirred at 100°C for 18 hours. LCMS indicated the reaction was complete. The reaction was cooled to room temperature and filtered. The filtrate was purified by RP-flash chromatography (Welch XB-C18 column, 21.2 x 250 mm, 5 μm, using a mixture of water (containing 0.1% formic acid) and acetonitrile (acetonitrile content: 40%-63%) as the eluent) to afford the title compound 42-2 (600 mg).

[0382] MS (ESI): m / z = 213.6 [M+H] + .

[0383] Step 2: Synthesis of ethyl 3-((6-cyano-5-(methylseleno)pyridin-3-yl)amino)-2-hydroxy-2-methyl-3-oxopropanoate

[0384] Intermediate 42-2 (100 mg, 471.45 μmol) was dissolved in tetrahydrofuran (2 mL) and stirred in an ice-water bath for 2 hours. Thionyl chloride (112.18 mg, 942.91 μmol) was added and stirred for 20 minutes. Intermediate 1-2 (122.31 mg, 754.32 μmol) was added to the reaction mixture and stirred in an ice-water bath for 2 hours. LCMS indicated the reaction was complete. Water (20 mL) was added to the reaction mixture in an ice-water bath to quench the mixture. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed sequentially with water (40 mL x 2) and saturated brine (40 mL), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate / petroleum ether = 1 / 1) to obtain the title compound 042 (130 mg).

[0385] MS (ESI): m / z = 357.4 [M+H] + .

[0386] 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.97(d,J=2.1Hz,1H),8.45(d,J=2.2Hz,1H), 6.98(s,1H),4.15(q,J=7.1Hz,2H),2.48(s,3H),1.57(s,3H),1.18(t,J=7.1Hz,3H).

[0387] Example 44: Ethyl 3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-methoxy-2-methyl-3-oxopropanoate (Compound 044)

[0388] Step 1: Synthesis of diethyl 2-methoxy-2-methylmalonate

[0389] Diethyl 2-bromo-2-methylmalonate (10 g, 39.51 mmol) and sodium methoxide (3.20 g, 59.27 mmol) were added to tetrahydrofuran (100 mL). The reaction mixture was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL x 4). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 44-2 (6.5 g).

[0390] MS (ESI): m / z = 205.20 [M+H] + .

[0391] 1 H NMR (400MHz, Chloroform-d) δ4.30–4.23(m,4H),3.82–3.78(m,3H),1.65–1.63(m,3H),1.31–1.26(m,6H).

[0392] Step 2: Synthesis of 3-ethoxy-2-methoxy-2-methyl-3-oxopropanoic acid

[0393] Intermediate 44-2 (1 g, 4.90 mmol) was added to a mixture of ethanol (4 mL) and water (8 mL). Potassium hydroxide (274.75 mg, 4.90 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. LCMS indicated the reaction was complete. The pH of the reaction mixture was adjusted to 7-8 with saturated sodium bicarbonate solution. After washing with ethyl acetate (20 mL), the aqueous phase was collected. The aqueous phase was acidified (pH = 2-3) with dilute hydrochloric acid (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound 44-3 (600 mg).

[0394] MS (ESI): m / z = 177.10 [M+H] + .

[0395] 1 H NMR (400MHz, DMSO-d6) δ13.02(s,1H),4.20–4.12(m,2H),3.53–3.22(m,3H),1.50–1.47(m,3H),1.22–1.17(m,3H).

[0396] Step 3: Synthesis of ethyl ((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-methoxy-2-methyl-3-oxopropanoate

[0397] Under a nitrogen atmosphere, Intermediate 1-3 (297.41 mg, 1.59 mmol) and Intermediate 44-3 (420 mg, 2.38 mmol) were dissolved in pyridine (4 mL). Phosphorus oxychloride (487.41 mg, 3.18 mmol) was added under ice-cooling conditions and stirred at room temperature for 15 hours. LCMS indicated the reaction was complete. Pyridine was evaporated under reduced pressure, and the mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated sodium chloride (20 mL*2), filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC (Phenomenex C18, 5 μm silica, 30 mm diameter, 80 mm length; using a mixture of water (containing 0.05% ammonium bicarbonate) and acetonitrile (acetonitrile content: 50-80%) as eluent) to afford the title compound 044 (60 mg).

[0398] MS (ESI): m / z = 346.00 [M+H] + .

[0399] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),9.34(d,J=2.2Hz,1H),8.81(d,J=2.3 Hz,1H),4.25–4.14(m,2H),3.35(s,3H),1.62(s,3H),1.20(t,J=7.1Hz,3H).

[0400] Example 45: Thio-3-[(6-cyano-5-trifluoromethylpyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionic acid-S-ethyl ester (Compound 045)

[0401] Compound 9-1 (50 mg, 164.91 μmol) was dissolved in dichloromethane (5 mL) and cooled to 0°C. 4-Dimethylaminopyridine (2.03 mg, 16.49 μmol), ethanethiol (12.67 mg, 197.89 μmol), and dicyclohexylcarbodiimide (40.83 mg, 197.89 μmol) were added sequentially. The temperature was slowly raised to room temperature and stirring was continued overnight. LCMS indicated the reaction was complete. The reaction solution was diluted with ethyl acetate (20 mL), washed twice with water (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was isolated and purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) to obtain the target compound 045 (20 mg).

[0402] MS (ESI): m / z = 347.90 [M+H] + .

[0403] 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),9.39(d,J=2.3Hz,1H),8.85(d,J=2.3 Hz,1H),7.58(s,1H),2.88–2.70(m,2H),1.58(s,3H),1.16(t,J=7.4Hz,3H).

[0404] Example 46: 3-(4-cyano-2-fluoro-3-methylthioanilino)-2-hydroxy-2-methyl-3-oxopropanoic acid ethyl ester (Compound 046)

[0405] Step 1: Synthesis of 4-cyano-2-fluoro-3-methylthioaniline

[0406] 4-Amino-2,3-difluorobenzonitrile (10 g, 64.89 mmol) was added to N,N-dimethylformamide (100 mL). Sodium thiomethoxide (5.46 g, 77.86 mmol) was added under ice bath condition. The reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reaction was complete. Water (20 mL) was added to dilute the system, filtered, and the filtrate was purified by prep-HPLC [Phenomenex C 18 , 5 μm silica, 30 mm diameter, 80 mm length; using a mixture of water (containing 0.05% ammonium bicarbonate) and acetonitrile (acetonitrile content: 60%-70%) as eluent] purification gave the title compound 46-1 (10.3 g).

[0407] MS (ESI): m / z = 183.0 [M+H] + .

[0408] Step 2: Synthesis of ethyl 3-(4-cyano-2-fluoro-3-methylthioanilino)-2-hydroxy-2-methyl-3-oxopropanoate

[0409] Intermediate 1-2 (66.74 mg, 411.60 μmol) was dissolved in tetrahydrofuran (3 mL). Thionyl chloride (65.29 mg, 548.79 μmol) was added under ice-cooling and stirred for 1 hour. Triethylamine (83.30 mg, 823.19 μmol) was added under ice-cooling and stirred for 1 hour. Intermediate 46-1 (50 mg, 274.40 μmol) was added and stirred at room temperature for 2 hours. LC-MS indicated the reaction was complete. The reaction solution was purified by prep-HPLC (column: YMC TA column; eluent: a mixture of water (containing 0.05% ammonium bicarbonate) and acetonitrile (acetonitrile content: 55%-85%)) to afford the title compound 046 (19 mg).

[0410] MS (ESI): m / z = 327.1 [M+H] + .

[0411] 1 H NMR (400MHz, DMSO-d6) δ8.10–8.02(m,1H),7.73(d,J=8.6Hz,1H),4.19–4.10(m,2H),2.57(s,3H),1.56(s,3H),1.18(t,J=7.1Hz,3H).

[0412] Example 47: 3-(4-cyano-2-fluoro-3-methylthioanilino)-2-hydroxy-2-methyl-3-oxopropionic acid propyl ester (Compound 047)

[0413] Step 1: Synthesis of 3-(4-cyano-2-fluoro-3-methylthioanilino)-2-hydroxy-2-methyl-3-oxopropionic acid

[0414] Compound 046 (300 mg, 919.28 μmol) was added to a mixture of tetrahydrofuran (5 mL) and water (5 mL), followed by the addition of lithium hydroxide monohydrate (53.62 mg, 1.28 mmol). The mixture was stirred at room temperature for 4 hours. LCMS indicated the reaction was complete. The reaction mixture was adjusted to a weakly acidic pH of 2-3 with 1N aqueous HCl and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, ethyl acetate / petroleum ether = 1 / 1) to afford the title compound 47-1 (120 mg).

[0415] MS (ESI): m / z = 299.0 [M+H] +.

[0416] Step 2: Synthesis of 3-(4-cyano-2-fluoro-3-methylthioanilino)-2-hydroxy-2-methyl-3-oxopropionic acid propyl ester

[0417] Intermediate 47-1 (50 mg, 167.62 μmol) was added to dichloromethane (5 mL). n-Propanol (50.37 mg, 838.11 μmol) was added at 0°C, followed by concentrated sulfuric acid (16.44 mg, 167.62 μmol). The mixture was slowly warmed to room temperature and stirred for 12 hours. LCMS indicated the reaction was complete. The reaction solution was purified by Prep-HPLC using a YMC TA column (eluent: a mixture of water (containing 0.05% ammonium bicarbonate) and acetonitrile (55%-85% acetonitrile)) to obtain the target compound 047 (12 mg).

[0418] MS (ESI): m / z = 341.1 [M+H] + .

[0419] 1 H NMR(400MHz,DMSO-d6)δ8.07–8.03(m,1H),7.75–7.70(m,1H),4.19–4.00(m ,2H),2.60–2.50(m,3H),1.62–1.57(m,2H),1.56(s,3H),0.88–0.82(m,3H).

[0420] Example 48: 3-[(6-cyano-5-methoxypyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionic acid tert-butyl ester (Compound 048)

[0421] Step 1: Synthesis of 3-[(6-cyano-5-methoxypyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionic acid

[0422] Compound 056 (100.00 mg, 340.98 μmol) was added to a mixture of tetrahydrofuran (2 mL) and water (2 mL), followed by lithium hydroxide monohydrate (21.78 mg, 519.02 μmol). The mixture was stirred at room temperature for 4 hours. LCMS indicated the reaction was complete. The reaction mixture was adjusted to a weakly acidic pH of 2-3 using 1N aqueous HCl and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound 48-1 (80 mg).

[0423] MS (ESI): m / z = 266.0 [M+H] + .

[0424] Step 2: Synthesis of tert-butyl 3-[(6-cyano-5-methoxypyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionate

[0425] Compound 48-1 (50 mg, 164.91 μmol) was added to ethyl acetate (3 mL) and cyclohexane (3 mL). Tert-butyl 2,2,2-trichloroacetimidate (111.22 mg, 509.01 μmol) was added to the reaction mixture at room temperature, and the reaction was stirred for 18 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by Prep-HPLC using a YMC-TA column (5 μm silica, 30 mm diameter, 150 mm length; eluents were a decreasingly polar mixture of water (containing 7 mmol / L NH₄HCO₃) and acetonitrile; acetonitrile gradient ratio 40%-70%) to afford the target compound 048 (5 mg).

[0426] MS (ESI): m / z = 322.20 [M+H] + .

[0427] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.72(d,J=2.0Hz,1H),8.22(d,J=1.9Hz,1H),6.84(s,1H),3.93(s,3H),1.52(s,3H),1.40(s,9H).

[0428] Example 49: 3-[(6-cyano-5-methylthiopyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionic acid tert-butyl ester (Compound 049)

[0429] Step 1: Synthesis of 3-[(6-cyano-5-methylthiopyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionic acid

[0430] Compound 016 (500 mg, 1.62 mmol) was added to a mixture of tetrahydrofuran (6 mL) and water (6 mL). Lithium hydroxide monohydrate (81.39 mg, 1.94 mmol) was added and stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction solution was diluted with water (20 mL) and washed with ethyl acetate (30 mL x 2). The aqueous phase was then adjusted to a slightly acidic pH of 2-3 with 1N HCl aqueous solution. The mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound 49-1 (320 mg).

[0431] MS (ESI): m / z = 282.0 [M+H]+ .

[0432] Step 2: Synthesis of tert-butyl 3-[(6-cyano-5-methylthiopyridin-3-yl)amino]-2-hydroxy-2-methyl-3-oxo-propionate

[0433] Intermediate 49-1 (180 mg, 639.92 μmol) was added to dichloromethane (3 mL), followed by tert-butyl alcohol (0.3 mL) and tert-butyl 2,2,2-trichloroacetimidate (1.4 g, 6.40 mmol). The mixture was stirred at room temperature for 12 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated, and the residue was purified by Prep-HPLC (Phenomenex C18, 5 μm silica, 30 mm diameter, 80 mm length; using a mixture of pure water and acetonitrile (acetonitrile content: 35%-60%) as the eluent) to obtain the target compound 049 (9 mg).

[0434] MS (ESI): m / z = 336.1 [MH] - .

[0435] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.93(d,J=2.1Hz,1H),8.34(d,J=2.1Hz,1H),2.58(s,3H),1.53(s,3H),1.40(s,9H).

[0436] Example 50 Referring to the synthesis method of the corresponding embodiment in the table, and replacing the corresponding starting materials, the following compounds were synthesized:

[0437] Experimental Example 1: Effects of the Disclosed Compounds on AR Antagonistic Activity

[0438] (1) Materials and reagents:

[0439] (2) Instruments:

[0440] (3) Experimental methods:

[0441] Day 1: Cell plating

[0442] 8x10 5 LNCaP cells.

[0443] Day 2: Transfection

[0444] AR and PSA ARE1 reporter gene plasmids (Anhui Biotechnology Co., Ltd.) were transfected with Lipo3000 and P3000 (Lipofectamine TM 3000) (wherein, a total of 2.5 μg of plasmids were added to each well, with 1.25 μg of each plasmid) and incubated for 10 minutes. Then, 250 μL of the above transfection reagent was added dropwise to each well containing cells and incubated with the cells for 24 hours.

[0445] Day 3: Cell treatment, plating and drug addition

[0446] Wash the cells with PBS and replace the medium with RPMI-1640 without phenol red and 5% charcoal-stripped serum (or 10% fetal bovine serum and 1% penicillin and streptomycin). 4 cells / well), and the cells were re-plated into a 96-well plate (Corning, 3603).

[0447] After cell plating, first add the test compound (or DMSO or positive control drug), incubate for at least 30 minutes, then add DHT (dihydrotestosterone) with a final concentration of 1nM into the culture system, and continue to culture in a carbon dioxide incubator.

[0448] The test compound was prepared as a 10 mM stock solution with a final concentration of 3.3 μM or 6.7 μM. The negative control was 0.1% DMSO. The positive control was 30 μM Enzalutamide.

[0449] Day 4: Luciferase signal detection and data processing

[0450] After incubating the test compound (or DMSO or positive control) with DHT for 24 hours, the luciferase signal was detected using Vazyme Bright-Lite substrate. 70 μL of culture medium was added to each well and the cells were shaken for 2 minutes before reading the luciferase signal.

[0451] (4) Data processing:

[0452] Check assay robustness using DMSO and low concentration control data:

[0453] Ave_H=Ave(DMSO)

[0454] Ave_L = Ave (30 μM enzalutamide)

[0455] Inhibition rate (%) = (Ave_H-Sample) / (Ave_H-Ave_L) x 100%

[0456] Ave_H: measured value of negative control (0.1% DMSO);

[0457] Ave_L: measured value of the positive control (30 μM enzalutamide);

[0458] Sample: the measured value of the compound to be tested;

[0459] The activity test results of the test compounds are shown in Table 1.

[0460] Table 1 Activity test results of the compounds disclosed herein

[0461] a: Dosage concentration: 3.3 μM; b: Dosage concentration: 6.7 μM

[0462] Experimental Example 2: Metabolic Stability Determination of the Compounds of the Present Disclosure in Liver Microsomes

[0463] The metabolic stability of the disclosed compounds in liver microsomes was determined using the following test method.

[0464] 1. Test materials and instruments

[0465] 1. Source of liver microsomes: human liver microsomes (Corning 452117)

[0466] 2.Na2HPO4 (Tianjin Guangfu Fine Chemical Research Institute 20180130)

[0467] 3. KH2PO4 (Tianjin Guangfu Fine Chemical Research Institute 20180920)

[0468] 4.MgCl2 (Tianjin Guangfu Fine Chemical Research Institute 20191216)

[0469] 5. NADPH (Solarbio 1216C022)

[0470] 6. Positive control compound verapamil (Sigma MKBV4993V)

[0471] 7. AB Sciex Triple Quad 4000 LC / MS

[0472] 2. Test steps

[0473] Preparation of 100 mM phosphate buffer (PBS): Weigh 7.098 g of Na₂HPO₄ and dissolve it in 500 mL of pure water by sonication to prepare Solution A. Weigh 3.400 g of KH₂PO₄ and dissolve it in 250 mL of pure water by sonication to prepare Solution B. Place Solution A on a stirrer and slowly add Solution B until the pH reaches 7.4, to prepare 100 mM PBS buffer.

[0474] 2. Preparation of reaction system

[0475] Prepare the reaction system according to the table below

[0476] 3. Preincubate the reaction system in a 37°C water bath for 10 minutes. Add 40 μL of 10 mM NADPH solution (dissolved in 100 mM phosphate buffer) to the reaction system for a final NADPH concentration of 1 mM. Replace the NADPH solution with 40 μL of phosphate buffer as a negative control. This negative control is used to eliminate the effects of the chemical stability of the compound itself.

[0477] 4. 4 μL of 100 μM compounds of the present disclosure and the positive control compound verapamil were added to the reaction system to initiate the reaction. The final concentration of the compounds was 1 μM.

[0478] 5. After thorough mixing on a vortex shaker at 0.5, 15, 30, 45, and 60 minutes, remove 50 μL of the incubation sample and terminate the reaction with 4x volume of glacial acetonitrile containing the internal standard. Centrifuge the sample at 3,220 g for 45 minutes. After centrifugation, transfer 90 μL of the supernatant to the injection plate, add 90 μL of ultrapure water, and mix thoroughly before LC-MS / MS analysis.

[0479] All data were calculated using Microsoft Excel software. Peak areas were detected by extracting ion spectra. The in vitro half-life (T) of the test compound was determined by linear fitting the natural logarithm of the elimination percentage of the test compound with time. 1 / 2 ).

[0480] In vitro half-life 1 / 2 ) is calculated by the slope k:

[0481] in vitro T 1 / 2 =0.693 / k

[0482] In vitro intrinsic clearance (CL int , unit: μL / min / mg protein) was calculated using the following formula:

[0483] in vitro CL int =k×incubation volume / enzyme protein content;

[0484] T calculated by the above formula 1 / 2 and CL int See Table 2 for values.

[0485] Table 2 Half-life and intrinsic clearance values ​​of the disclosed compounds in liver microsomes

[0486] From the above results, it can be seen that the disclosed compounds have the characteristics of high clearance rate and rapid metabolism, which avoids the accumulation of drugs in the body due to long-term administration, thereby affecting the systemic androgen receptor signaling pathway, thereby improving the safety of the drug.

[0487] Experimental Example 3 In vivo efficacy study 1

[0488] 3.1 Experimental Reagents

[0489] Solvent: Propylene glycol / ethanol (30:70, v / v)

[0490] 3.2 Experimental methods

[0491] Animal information: C57BL / 6 male mice, 4-6 weeks old, weighing approximately 18-20 g, were purchased from Shanghai Lingchang Biotechnology Co., Ltd. The mice were housed in an SPF-grade environment with separate ventilation in each cage. All animals had free access to standard certified commercial laboratory diet and free drinking water.

[0492] Skin preparation: After the mice have been adapted for 1-2 weeks, use a shaver to remove the hair in a 2 cm*3 cm area on the back of the mice. Confirm that the hair of the mice is in the resting phase (the skin is pink) and the skin is not damaged.

[0493] Dosing: On the third day after shaving, mice were divided and dosed. Compound 001 was applied to the shaved area at a concentration of 2 wt% twice daily, morning and evening. Compound 008 was applied to the shaved area at a concentration of 0.5 wt% twice daily, morning and evening, for 30 days. The control group was treated with the control solvent. Each group consisted of 12 mice.

[0494] 3.3 Observation of mouse status and hair growth scoring

[0495] During the experiment, the condition of mice in each group was observed to see if there were any rashes, cracks, or dandruff on the skin.

[0496] On days 10, 13, 18, 21, 25, and 30, the mice were weighed, their hair growth was scored, and photographs were taken;

[0497] The scoring criteria are as follows:

[0498] 0 points: no growth, the skin of the shaved area is pink;

[0499] 1 point: the skin in the shaved area is gray (less than 20% growth);

[0500] 2 points: The skin of the shaved area is black (greater than 20% and less than 40%);

[0501] 3 points: The skin of the shaved area is black with a little hair growth (more than 40% but less than 60%);

[0502] 4 points: The skin in the shaved area is black with some hair growth (more than 60% but less than 80%);

[0503] 5 points: The hair in the shaved area has basically grown back (80% to 100% growth).

[0504] 3.4 Experimental Results

[0505] The results of the effects of the disclosed compounds on hair growth in mice are shown in Table 3.

[0506] Table 3 Effect of the disclosed compounds on hair growth in mice

[0507] *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs. vehicle control group

[0508] 3.5 Experimental Conclusion

[0509] In mice whose hair growth is in the telogen phase, the disclosed compound 001 at a concentration of 2% and the compound 008 at a concentration of 0.5%, 20uL / cm 2 BID administration via skin application significantly promoted hair growth in mice. Compound 001 significantly promoted hair growth starting from day 10 (P < 0.01), and Compound 008 significantly promoted hair growth starting from day 13 (P < 0.05). Compounds 001 and 008 did not significantly affect mouse body weight at the doses tested, nor did they cause any skin rashes, cracking, or scaling.

[0510] Experimental Example 4 In vivo efficacy study 2

[0511] 4.1 Experimental Reagents

[0512] Solvent: Propylene glycol / ethanol (30:70, v / v)

[0513] 4.2 Experimental methods

[0514] Animal information: C57BL / 6 male mice, 6 weeks old, weighing approximately 18-20 g, were purchased from Shanghai Lingchang Biotechnology Co., Ltd. The mice were housed in an SPF-grade environment with separate ventilation in each cage. All animals had free access to standard certified commercial laboratory diet and free drinking water.

[0515] Skin preparation: After the mice have been adapted for 1-2 weeks, use a shaver to remove the hair in a 2cm*2cm area on the back of the mouse. Confirm that the mouse hair is in the resting phase (the skin is pink) and the skin is not damaged. Select a 1cm*1cm area in the center of the back skin as the dosing area.

[0516] Dosing: The mice were divided and dosed on the third day after shaving. The disclosed compound 016A was applied to the shaved area twice a day, morning and evening, at a concentration of 0.5 wt% for 22 days. The control group was treated with the control solvent. Each group consisted of 12 mice.

[0517] 4.3 Observation of mouse status and hair growth scoring

[0518] During the experiment, the condition of mice in each group was observed to see if there were any rashes, cracks, or dandruff on the skin.

[0519] On days 9, 12, 15, 19, and 22, mice were weighed, hair growth was scored, and photographs were taken;

[0520] The scoring criteria are as follows:

[0521] 0 points: no growth, the skin of the shaved area is pink;

[0522] 1 point: the skin in the shaved area is gray (less than 20% growth);

[0523] 2 points: The skin of the shaved area is black (greater than 20% and less than 40%);

[0524] 3 points: The skin of the shaved area is black with a little hair growth (more than 40% but less than 60%);

[0525] 4 points: The skin in the shaved area is black with some hair growth (more than 60% but less than 80%);

[0526] 5 points: The hair in the shaved area has basically grown back (80% to 100% growth).

[0527] 4.4 Experimental Results

[0528] The results of the effects of the disclosed compounds on hair growth in mice are shown in Table 4.

[0529] Table 4 Effect of the disclosed compounds on hair growth in mice

[0530] ****P<0.0001 vs. vehicle control group

[0531] 4.5 Experimental Conclusion

[0532] In mice whose hair growth is in the telogen phase, the compound 016A of the present disclosure at a concentration of 0.5 wt %, 20 uL / cm 2BID administration significantly promoted hair growth via skin application. Compound 016A significantly promoted hair growth starting 19 days after administration (P < 0.0001). Compound 016A did not significantly affect mouse body weight at the doses tested, nor did it cause any skin rash, cracking, or scaling.

[0533] Experimental Example 5 Whole Blood Stability

[0534] Test steps:

[0535] 1. Preparation of Stock Solutions

[0536] 1 mM stock solutions of test compounds were prepared in DMSO, and 1 mM stock solutions of the control compound propantheline were prepared in acetonitrile.

[0537] 2. Stability determination method

[0538] 4 μL of the test compound stock solution (or control compound) was added to 796 μL of pre-incubated human blood (whole blood) to achieve a final concentration of 5 μM. The final concentration of the solvent was 0.5%. At different time points (including 5, 15, 30, 60, and 120 min), 50 μL aliquots of the sampled whole blood were added to new test tubes and incubated in a 37°C water bath with shaking at 60 rpm. The experiment was repeated twice. At the specified time point, 300 μL of room temperature quenching solution (acetonitrile solution containing internal standards (100 nM alprazolam, 500 nM labetalol, and 2 μM ketoprofen)) was added to the sampled whole blood sample to terminate the reaction. 50 μL of the sampled whole blood was added to a new test tube containing 300 μL of room temperature quenching solution, and the sample was prepared at 0 minute. All samples were vortexed for 5 minutes. The samples in the plate were centrifuged at 3220 g for 30 minutes at 4°C to precipitate the protein. 100 μL of supernatant was transferred to a new 96-well plate containing 100 μL of water for LC-MS / MS analysis.

[0539] 3. Data Analysis

[0540] All calculations were performed using Microsoft Excel. Peak area ratios were determined from extracted ion chromatograms. The percentage of compound remaining at each time point was calculated using the following formula:

[0541] Remaining percentage tmin (%) = peak area ratio tmin / peak area ratio 0min×100%

[0542] Wherein, peak area ratio t min: the peak area ratio of the reference compound and the test compound at t minutes;

[0543] Peak area ratio 0min: the peak area ratio of the control compound and the test compound at zero time point.

[0544] The slope value was determined by linear regression of the natural logarithm of the remaining percentage of the test compound versus the incubation time curve.

[0545] The in vitro half-life (t 1 / 2 ):

[0546] in vitro t1 / 2 =0.693 / k

[0547] Where: k is the rate constant (k = -slope value)

[0548] The half-lives of the compounds disclosed herein in human blood are shown in Table 5.

[0549] Table 5 Stability of the compounds disclosed herein in human blood

[0550] From the above results, it can be seen that the compounds of the present disclosure have a short half-life in human blood and have the characteristics of high clearance rate and rapid metabolism in the blood, which avoids the accumulation of drugs in the body due to long-term administration, thereby affecting the systemic androgen receptor signaling pathway and thus improving the safety of the drugs.

[0551] Although specific embodiments of the present disclosure have been illustrated and described, those skilled in the art will appreciate that, where feasible, the technical features described in one embodiment may be applied to another embodiment, or combined with the technical features described in another embodiment. Therefore, those skilled in the art will be able to make various changes and modifications to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

Claims

1. A compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, X is selected from CH or N; Y is selected from S, O or NR 7 ; R 1 Selected from OH or -O-C1-C6 alkyl; R 2 Selected from C1-C6 alkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl; R 3 is selected from C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by R 3a replace; R 3a Selected from halogen, OH, CN, NH2, -COR 3b 、-COOR 3b 、-NHCOR 3b ,-CONHR 3b , -O-C1-C6 alkyl, phenyl, C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl, wherein the phenyl, C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3c replace; R 3b is selected from H, C1-C6 alkyl, phenyl or 5-6 membered heteroaryl; R 3c Selected from -COOC1-C6 alkyl, C1-C6 alkyl, -O-C1-C6 alkyl, phenyl or 5-6 membered heteroaryl; R 4 Selected from NO2, halogen or CN; R 5 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -COOC1-C6 alkyl, -S-C1-C6 alkyl, -O-C1-C6 alkyl, -Se-C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -S(O)-C1-C6 alkyl; R 6 is selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or -O-C1-C6 alkyl; R 7 Selected from H or C1-C6 alkyl.

2. The compound of formula (I) according to claim 1, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from OH.

3. The compound of formula (I) according to claim 1 or 2, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from CH3 or CF3.

4. The compound of formula (I) according to any one of claims 1 to 3, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 3 is selected from C1-C6 alkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by R 3a replace; or R 3 is selected from C1-C6 alkyl or 4-6 membered heterocyclic group, wherein the C1-C6 alkyl or 4-6 membered heterocyclic group is optionally replaced by R 3a replace; or R 3 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R 3a replace.

5. The compound of formula (I) according to any one of claims 1 to 4, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 3a Selected from halogen, OH, -COR 3b 、-COOR 3b 、-NHCOR 3b , -O-C1-C6 alkyl, phenyl, C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl, wherein the phenyl, C1-C6 alkyl, 4-6 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3c replace; Or, R 3b is selected from C1-C6 alkyl, phenyl or 5-6 membered heteroaryl; Or, R 3c is selected from C1-C6 alkyl, -O-C1-C6 alkyl, phenyl or 5-6 membered heteroaryl; Or, R 3c Selected from C1-C6 alkyl or -O-C1-C6 alkyl.

6. The compound of formula (I) according to any one of claims 1 to 5, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: X is N.

7. The compound of formula (I) according to any one of claims 1 to 6, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Y is selected from O or NR 7 ; or Y is selected from S, O or NH; Alternatively, Y is selected from S or O.

8. The compound of formula (I) according to any one of claims 1 to 7, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from halogen or CN; Or, R 4 is selected from F, Cl or CN; Or, R 4 For CN.

9. The compound of formula (I) according to any one of claims 1 to 8, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 5 Selected from C1-C6 haloalkyl, -S-C1-C6 alkyl, -O-C1-C6 alkyl, -Se-C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -S(O)-C1-C6 alkyl; or R 5 Selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -COOC1-C6 alkyl, -S-C1-C6 alkyl or -O-C1-C6 alkyl; Or, R 5 Selected from C1-C6 haloalkyl or -S-C1-C6 alkyl.

10. The compound of formula (I) according to any one of claims 1 to 9, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 6 Selected from H or halogen.

11. The compound of formula (I) according to any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (I-1) or its stereoisomer or its pharmaceutically acceptable salt: Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X as defined in any one of claims 1-10.

12. The compound of formula (I) according to claim 1, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:

13. A pharmaceutical composition comprising the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 and a pharmaceutically acceptable excipient.

14. Use of the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for preventing or treating androgen receptor-mediated diseases.

15. A method for preventing or treating a disease mediated by androgen receptor in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 12, or a pharmaceutical composition as described in claim 13 to a mammal, preferably a human, in need of such treatment.

16. The use according to claim 14 or the method according to claim 15, wherein: The androgen receptor-mediated disease is selected from androgenic alopecia.

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