OGA inhibitor and use thereof

Abstract

The present invention belongs to the technical field of medicine. Provided are an OGA inhibitor and the use thereof. The OGA inhibitor has a structure of formula (I). The OGA inhibitor is capable of modulating O-GlcNAcase activity or treating OGA-related neurodegenerative diseases and disorders.

Description

OGA inhibitors and uses thereof TECHNICAL FIELD

[0001] The present invention relates to the field of medicine, in particular to novel compounds useful as OGA inhibitors. BACKGROUND

[0002] O-GlcNacylation is a ubiquitous post-translational monosaccharide modification of proteins in which an N-acetyl-D-glucosamine residue is transferred to the hydroxyl terminus of serine and threonine residues, resulting in O-GlcNacylated proteins. Such target proteins have been shown to be widely present in the cytosol and nucleus of eukaryotes. This acylation modification is regulated by a pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which are believed to be involved in regulating many important cellular functions, including transcription, cytoskeletal processes, cell cycle, proteasomal degradation and cell signaling, among others.

[0003] O-GlcNacylated proteins, as well as OGT and OGA itself, are particularly abundant in the brain and neurons, suggesting that this modification plays an important role in the central nervous system. Indeed, studies have demonstrated that O-GlcNacylation represents a key regulatory mechanism in promoting neuronal communication, memory formation and neurodegenerative diseases. Furthermore, OGA has been shown to be essential for mammalian development. Two independent studies have shown that homozygous null mice for OGA survive for no more than 24-48 hours after birth. Deletion of the Oga gene (MGEA5) leads to defects in glycogen mobilization in pups and it causes cell cycle arrest associated with genomic instability in MEFs derived from homozygous knockout embryos. Heterozygous animals survive to adulthood but they show alterations in both transcription and metabolism.

[0004] Microtubule-associated protein tau oligomerizes into filamentous structures such as paired helical filaments (PHF) and straight or twisted filaments that give rise to neurofibrillary tangles (NFT) and neuropil threads (NT) are one of the defining pathological hallmarks of Alzheimer's disease and other tauopathies. O-GlcNAc modification has been identified on several proteins involved in the development and progression of neurodegenerative diseases, and the correlation of O-GlcNAc levels with tau forming neurofibrillary tangle (NFT) proteins in Alzheimer's disease has been shown. Studies have confirmed that the number of NFTs in the brains of individuals with Alzheimer's disease correlates closely with the severity of the disease, indicating a key role for tau in neuronal dysfunction and neurodegeneration. Tau pathology has been shown to correlate with disease progression in PSP; cases with more aggressive disease courses have higher tau burden than cases with slower progression. In addition, O-GlcNacylation of alpha-synuclein in Parkinson's disease has been described.

[0005] Recent studies support the therapeutic potential of attenuating or preventing Alzheimer's disease and related tau-mediated neurodegenerative disorders by inhibiting OGA activity to limit tau hyperphosphorylation and aggregation into pathological tau. In particular, the OGA inhibitor Thiamet-G was associated with slowed motor neuron loss in the JNPL3 tau mouse model and with reduction of tau pathology and dystrophic neurites in the Tg4510 tau mouse model. Accordingly, OGA inhibitors are recognized as effective therapeutic means to reduce the accumulation of pathological forms of tau hyperphosphorylation such as NFTs and NTs.

[0006] It is desirable that OGA inhibitors as brain penetrant agents provide treatment for tau-mediated neurodegenerative diseases, such as Alzheimer's disease and PSP. There is still a need to develop OGA inhibitor compounds with a favorable balance of properties, for example with improved potency, good bioavailability, pharmacokinetics, brain penetration and / or better toxicity profile. SUMMARY

[0007] One or more embodiments of the present application provide a compound of Formula I or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof,

[0008] wherein

[0009] L is optionally substituted with one or more groups selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6C substituents of alkylamino, -NH2-, and -O- groups 5-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 Aryl, or 5-10 heteroaryl;

[0010] Ring A is

[0011] R1 can be H, halogen, or C independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy groups, 4- to 6-membered heterocyclic groups;

[0012] R2 is H, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy groups, 4- to 6-membered heterocyclic groups;

[0013] Ring B is

[0014] X1 is N or CR4, and R4 is H, halogen, cyano, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy groups, 4- to 6-membered heterocyclic groups;

[0015] X2 is N or CR5, and R5 is H, halogen, cyano, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy groups, 4- to 6-membered heterocyclic groups;

[0016] R3 can be H, halogen, cyano, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl, or C 3-6 cycloalkyl;

[0017] m is 0, 1, or 2;

[0018] n is 0, 1, or 2;

[0019] The heterocyclic group and heteroaryl group each independently contain 1, 2, or 3 heteroatoms selected from N, O, S, S(O) or S(O)2.

[0020] In one or more embodiments, the C 1-6The alkyl group is methyl, ethyl, propyl, isopropyl, or butyl.

[0021] In one or more embodiments, the C 1-6 The alkyl halide is CF3.

[0022] In one or more embodiments, L is C 5-10 Cycloalkyl.

[0023] In one or more embodiments, L is C 5-10 Bridged cycloalkyl, C 6-10 Spirocycloalkyl, C 6- 10-cycloalkyl groups.

[0024] In one or more embodiments, L is a 4-10 member heterocyclic group.

[0025] In one or more embodiments, L is a 4-7 member heterocyclic group.

[0026] In one or more embodiments, L is a 5-9 member heterobridged cycloalkyl, a 6-10 member heterospirocycloalkyl, or a 6-10 member heterocycloalkyl.

[0027] In one or more embodiments, L is a 5-10 member heteroaryl group.

[0028] In one or more embodiments, L is a 5-6 member heteroaryl group.

[0029] In one or more embodiments, L is selected from the following groups that are optionally substituted:

[0030] In one or more embodiments, for the groups with N and O at both ends, the O end is connected to the A ring and the N end is connected to the B ring.

[0031] In one or more embodiments, L is selected from:

[0032] In one or more embodiments, L is selected from:

[0033] In one or more embodiments, L is selected from:

[0034] In one or more embodiments, L is selected from:

[0035] In one or more embodiments, L is selected from:

[0036] In one or more embodiments, formula I is selected from the structure of the following formula:

[0037] in

[0038] R1, R2, X1, X2, R3, m, n, L are as described above.

[0039] In one or more embodiments, the compounds of this application are selected from:

[0040] One or more embodiments of this application provide pharmaceutical compositions comprising preventive and / or therapeutically effective amounts of the compound of this application or its pharmaceutically acceptable salts, crystals, cocrystals, stereoisomers, enantiomers, diastereomers, prodrugs, deuterated derivatives, metabolites, hydrates, or solvates, and pharmaceutically acceptable carriers.

[0041] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the pharmaceutical composition of this application in the preparation of a drug for the treatment and / or prevention of diseases associated with OGA.

[0042] In one or more embodiments, the OGA-related disease is a neurodegenerative disease or disorder, cancer, or a chronic metabolic disease.

[0043] In one or more embodiments, the neurodegenerative disease or disorder is Alzheimer's disease, progressive supranuclear palsy (PSP), or a neurodegenerative disease or disorder mediated by tau protein.

[0044] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the pharmaceutical composition of this application, in the preparation of a medicament used as an OGA inhibitor.

[0045] One or more embodiments of this application provide the use of the compound of this application or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the pharmaceutical composition of this application, in the preparation of a medicament for modulating OGA activity.

[0046] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the pharmaceutical composition of this application, which are used as pharmaceuticals.

[0047] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, crystal, eutectic, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the pharmaceutical composition of this application, for the treatment and / or prevention of diseases associated with OGA.

[0048] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the pharmaceutical composition of this application, which are used as OGA inhibitors.

[0049] One or more embodiments of this application provide the compound of this application or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or the pharmaceutical composition of this application, for modulating OGA activity.

[0050] One or more embodiments of this application provide methods for treating and / or preventing diseases associated with OGA, comprising administering to a subject in need a therapeutically effective amount of a compound of this application or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or a pharmaceutical composition of this application.

[0051] One or more embodiments of this application provide a method for inhibiting OGA, comprising administering to a subject in need a therapeutically effective amount of a compound of this application or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or a pharmaceutical composition of this application.

[0052] One or more embodiments of this application provide a method for modulating OGA activity, comprising administering to a subject in need a therapeutically effective amount of a compound of this application or its pharmaceutically acceptable salt, crystal, cocrystal, stereoisomer, enantiomer, diastereomer, prodrug, deuterated product, metabolite, hydrate, or solvate, or a pharmaceutical composition of this application.

[0053] One or more embodiments of this application provide novel compounds with OGA inhibitory activity and improved pharmacodynamics, pharmacokinetics, and brain penetration properties.

[0054] In one or more embodiments of this application, the compounds of this application as OGA inhibitors can be used to overcome the technical problems in the prior art, have better safety and efficacy, and have broader clinical application prospects.

[0055] In one or more embodiments of this application, the compounds of this application as OGA inhibitors can regulate O-GlcNAc hydrolase activity or treat OGA-related neurodegenerative diseases and disorders, especially Alzheimer's disease, progressive supranuclear palsy (PSP), etc.

[0056] In one or more embodiments of this application, the pharmaceutically acceptable salt may be an inorganic acid salt or an organic acid salt. Inorganic acid salts may be selected from: hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; organic acid salts may be selected from: formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, and camphorsulfonate.

[0057] One or more embodiments of this application relate to compounds used as inhibitors of O-GlcNAc hydrolase (O-GlcNAcase, OGA) and their applications.

[0058] In one or more embodiments of this application, the compounds of this application can be used as inhibitors of OGA for the prevention or treatment of neurodegenerative diseases and disorders, particularly Alzheimer's disease, progressive supranuclear palsy (PSP), and tau protein-mediated neurodegenerative diseases and disorders (tauopathy).

[0059] In one or more embodiments of this application, L is selected from the following group of substituted or unsubstituted groups: 4-7 membered heterocyclic groups containing 1-3 members selected from N, O, S, S(O) or S(O)2; 5-9 membered heterobridged cycloalkyl groups containing 1-3 members selected from N, O, S, S(O) or S(O)2; 5-9 membered bridged cycloalkyl groups; 6-10 membered heterospirocycloalkyl groups containing 1-3 members selected from N, O, S, S(O) or S(O)2; C 6-10 Spirocycloalkyl, containing 1-3 6-10 member heterocycloalkyl groups selected from N, O, S, S(O) or S(O)2, C 6-10 cycloalkyl, containing 1-3 5-6 heteroaryl groups selected from N, O, S, S(O) or S(O)2, C 6-10 Aryl.

[0060] One or more embodiments of this application provide methods for preventing or treating OGA-related diseases, including administering to a subject in need a compound of this application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof, or a pharmaceutical composition containing said compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof.

[0061] One or more embodiments of this application provide a method for inhibiting OGA activity, comprising: contacting OGA with the compound of the application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound or prodrug thereof, thereby inhibiting OGA activity.

[0062] In one or more embodiments of this application, the method is non-therapeutic in vitro.

[0063] One or more embodiments of this application provide a method for modulating OGA activity, including contacting OGA with a compound such as that of this application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotopic compound, or prodrug thereof, thereby modulating OGA activity.

[0064] In one or more embodiments of this application, the method is non-therapeutic in vitro.

[0065] One or more embodiments of this application provide a method for inhibiting cell proliferation, including contacting cells with the compound described in this application to inhibit cell proliferation.

[0066] In one or more embodiments, the cell is a neuron.

[0067] In one or more embodiments, the cells are selected from neural cell lines such as PC12, SH-SY5Y, or combinations thereof.

[0068] In one or more embodiments, the method is non-therapeutic in vitro.

[0069] In one or more embodiments, the compounds of this application have good OGA inhibitory activity and better pharmacodynamic / pharmacokinetic properties.

[0070] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0071] the term

[0072] Unless otherwise specified, the following terms used in this application (including the specification and claims) have the definitions given below.

[0073] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0074] As used in this article, the group is... The indicated bond represents the position where the group is attached to other parts of the compound or molecule.

[0075] "alkyl", alone or as part of other groups, refers to a monovalent straight-chain or branched saturated hydrocarbon group (i.e., C12, C23, C34, C5, C6, C7, C8, C9, C10, C11, or C12) consisting only of carbon and hydrogen atoms. 1-12 Alkyl group). For example, an alkyl group is C10. 1-6 Alkyl (i.e., alkyl containing 1, 2, 3, 4, 5 or 6 carbon atoms), more preferably C4. 1-4 Alkyl (i.e., an alkyl group containing 1, 2, 3, or 4 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc. Unless otherwise stated, in this application, alkyl is also intended to include substituted alkyl, i.e., one or more positions of an alkyl group are substituted, particularly 1-4 substituents, which may be substituted at any position. Unless otherwise stated, in this application, "substituted alkyl" includes, for example, haloalkyl, hydroxyalkyl, etc. As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted by the same or different halogens as defined herein. Haloalkyl is preferably C10. 1-6 Halogenated alkyl, more preferably C10, 1-4Haloalkyl groups. Examples of haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), etc. As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups. Hydroxyalkyl groups are preferably C10-30 ... 1-6 Hydroxyalkyl, more preferably C 1-4 Hydroxyalkyl groups. Examples of hydroxyalkyl groups include -CH2OH, -C(CH3)2OH, etc.

[0076] "alkylene" refers to a divalent alkyl group as defined herein, preferably having 1-4 carbon atoms, i.e., C64. 1-4 Alkylenes. Examples of alkylenes include, for example, -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0077] "Alkoxy group," alone or as part of other groups, refers to an alkyl group having an oxygen-containing group attached thereto, possessing an alkyl O- structure, wherein the alkyl group has the definition described above. Preferably, the alkoxy group is C10. 1-6 Alkoxy (i.e. -OC) 1- 6-alkyl), more preferably, C6-alkyl 1-4 Alkoxy (i.e. -OC) 1-4 Alkyl groups. Alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, etc. "Haloalkoxy" refers to a group of formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0078] "Thioalkyl" refers to an alkyl group in which the carbon atom is replaced by S, S(O) or S(O)2, for example -SC. 1-6 Alkyl, -S(O)C 1-6 Alkyl or -S(O)2C 1-6 alkyl.

[0079] A "carbocyclic system" or "carbocyclic ring" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system, wherein each ring is fully saturated or contains one or more unsaturated units, but none of the rings are aromatic. Preferably, the "carbocyclic system" or "carbocyclic ring" has 6-12 ring atoms, i.e., carbon atoms. 6-12 Carbocyclic group. "Carbocyclic group" refers to a carbocyclic system or a monovalent group of a carbocyclic ring as defined above. Preferably, the carbocyclic group has 6-12 ring atoms, i.e., C atoms. 6-12 Carbocyclic groups. Examples of carbocyclic groups include cycloalkyl groups (such as cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl groups (such as cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).

[0080] "Cycloalkyl" refers to a monovalent saturated carbocyclic group composed of a single or bicyclic ring, having 3-12 carbon atoms (i.e., C12, C23, C32, C42, C53, C62, C7 ... 3-12 Cycloalkyl groups, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, preferably 3-10 (i.e., C12-12 carbon atoms). 3-10 cycloalkyl), more preferably 3-8 cyclic atoms (i.e., C 3-8 Cycloalkyl groups, most preferably 3, 4, 5 or 6 ring atoms (i.e., C14, C24, C34, C44, C54, C64, C74, C84, C9 ... 3-6 (Cycloalkyl). Unless otherwise defined, cycloalkyl groups may optionally be substituted with one or more substituents. Preferably, the substituents of the cycloalkyl group may be independently hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0081] “Cycloalkoxy” refers to a group of the formula -OR, where R is a cycloalkyl group as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. “Cycloalkylalkyl” or “cycloalkylalkylene” refers to an alkylene (cycloalkyl) group, where cycloalkyl and alkylene are as previously defined. “Cycloalkylalkyl” or “cycloalkylalkylene” is bonded to the parent molecule structure via an alkyl group (alkylene).

[0082] A "heterocyclic system" or "heterocycle" refers to a monocyclic, bicyclic, or polycyclic system in which at least one ring is saturated or partially unsaturated (but non-aromatic) and that the ring contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, S, S(O), or S(O)₂ as ring atoms. Heterocyclic systems or heterocycles can be attached to side groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can optionally be substituted.

[0083] "Heterocyclic group" refers to a heterocyclic system or a monovalent group of a heterocycle as defined above, typically referring to a stable monocyclic (e.g., 3-8 quinary, 4-5-6-7-8 quinary, 3-4-5-6-7-8-5-6-7-8-5-6-7-8-5-6-7-6-7-8-5-6-7-6-7-6-7-6-7-6-7-6-7-8-9-10-10-11-12-13-14-7-7-8 ... Representative heterocyclic groups include the following ring systems, wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolylalkyl, pyrrolidoneyl, piperidinyl, pyrrololinyl, decahydroquinolinyl, oxazolylalkyl, piperazineyl, dioxalyl, dioxopentyl, diachexenyl, oxachexenyl, thiaachexenyl, morpholinyl, and quininecycloyl; and (2) at least one ring is non-aromatic. The ring comprises a heteroatom as a ring atom and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and comprises a heteroatom and at least one other ring is aromatic and comprises a heteroatom, for example, 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-diazanaphthalene. A heterocyclic group refers to a heterocyclic group as defined above having two linking sites. In this invention, the heterocyclic group is preferably a bicyclic ring, one ring being a heteroaryl group and linked to the other parts of the general formula via the heteroaryl group. In this invention, the heterocyclic group is preferably a 5-6 member monocyclic heterocyclic group or an 8-10 member bicyclic heterocyclic group. Unless otherwise defined, "heterocyclic group" and "heterocyclic group" include substituted or unsubstituted forms. When the heterocyclic group is saturated, the heterocyclic group can also be called a heterocyclic alkyl group.

[0084] "Heterocyclic alkyl" refers to an alkyl group that has been replaced by a heterocyclic group, where the heterocyclic group and alkyl group are defined as above.

[0085] "Aromatic ring system" or "aromatic ring" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which at least one ring is aromatic. Preferably, the "aromatic ring system" or "aromatic ring" has 6-12 (e.g., 6, 7, 8, 9, 10, 11, or 12) ring atoms, i.e., carbon atoms. 6-12 Aromatic rings, examples of which include benzene rings, naphthalene rings, anthracene rings, etc.

[0086] "Aryl," alone or as part of other groups, refers to a monovalent group in an aromatic ring system (aromatic ring) having, for example, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Representative aryl groups include phalloaromatic ring systems such as phenyl, naphthyl, and anthracene; and ring systems in which an aromatic carbon ring is fused with one or more non-aromatic carbon rings, such as indanyl, phthalimide, naphthylimide, or tetrahydronaphthyl, etc. In this application, the aryl group is preferably C 6-12 Aryl. In this invention, unless otherwise defined, aryl also includes substituted aryl.

[0087] "Arylalkyl" or "arylalkyl group" refers to an alkyl moiety in which one or more hydrogen atoms of the alkyl group are replaced by aryl groups. Arylalkyl groups include groups in which one or more hydrogen atoms of the alkyl group are replaced by aryl groups, as defined above. Examples of "arylalkyl" or "arylalkyl group" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl.

[0088] "Aryloxy group" refers to -O-(aryl), where the aryl part is defined as above.

[0089] A "heteroaromatic ring system" or "heteroaromatic ring" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6-, 7-, 8-, 9-, 10-, 11-, or 12-membered), or polycyclic system in which at least one ring is an aromatic ring containing at least one heteroatom (e.g., N, O, S, S(O) or S(O)₂) as a ring atom and the remaining ring atoms are all carbon. In some cases, the aromatic ring containing at least one heteroatom may contain 1, 2, 3, or 4 heterocyclic atoms. Apart from aromatic rings containing at least one heteroatom as a ring atom, the remaining rings in a "heteroaromatic ring system" or "heteroaromatic ring" may be saturated, partially unsaturated, or fully unsaturated rings.

[0090] "Heteroaryl," alone or as part of other groups, refers to a monovalent group of a "heteroary ring system" or "heteroary ring" as defined above. The linker of a heteroaryl group may be located on an aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzopyranyl, indole, isoindole, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazole, and azazolyl. basalt, diazoxide Acridine, acridine, etc. A heteroaryl group is a heteroaryl group as defined above that has two linking sites. Unless otherwise defined, heteroaryl groups include substituted or unsubstituted forms.

[0091] "Alkylamino" refers to a group having an alkyl-NR- or -NR-alkyl structure, wherein R is H, or an alkyl, cycloalkyl, aryl, heteroaryl, etc. as described above.

[0092] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0093] In this invention, each of the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups mentioned above may be substituted or unsubstituted.

[0094] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R cNR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where R a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic, or aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic ring, can be optionally substituted. Such substituents include (but are not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C... 10 Acyl group, C2-C 10 Ester group, amino group, C1-C6 alkoxy group, C1-C 10 Sulfonyl groups and C1-C6 urea groups, etc.

[0095] "Cyano" refers to the -CN group.

[0096] "Nitro" refers to -NO2.

[0097] "Hydroxy group" refers to -OH.

[0098] "Amino" refers to -NH2 or RNH-, where R is a ketone carbonyl group, sulfonyl group, sulfonamide group, or R a -C(=O)-、R a R b NC(=O)- etc., where R a and R b It can be alkyl, cycloalkyl, aryl, or heteroaryl, etc.

[0099] "Halogen (halogenated)" refers to any halogen group, such as -F, -Cl, -Br or -I.

[0100] "Deuterated compounds" refer to compounds in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0101] In this invention, the term "multiple" can mean 2, 3, 4, 5, etc.

[0102] Active ingredients

[0103] As used herein, the terms “compound of the invention” or “active ingredient of the invention” are used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (such as a deuterated compound), or prodrug thereof. The term also includes racemic mixtures and optical isomers.

[0104] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. Compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0105] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, etc.

[0106] Some compounds of this invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0107] The prodrugs and solvates (or solvents) of the compounds in this invention are also within the scope of this invention.

[0108] The term "prodrug" here refers to a compound that, in the course of treating a related disease, undergoes a metabolic or chemical transformation to produce the compounds, salts, or solvates of this invention. The compounds of this invention include solvates, such as hydrates.

[0109] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0110] All stereoisomers of the compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The compounds of this invention may independently exist in stereoisomers that do not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0111] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0112] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of compounds in this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0113] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0114] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0115] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0116] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0117] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0118] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0119] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0120] The compounds involved in this application and their pharmaceutically acceptable salt metabolites, as well as prodrugs that can be converted in vivo into structures of the compounds involved in this application and their pharmaceutically acceptable salts, are also included in the claims of this application.

[0121] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0122] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0123] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0124] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0125] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0126] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, and transdermal penetration enhancers.

[0127] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond Crowe, 2009 Sixth Edition).

[0128] "Pharmaceutically acceptable excipients" refers to inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0129] Example

[0130] General preparation method

[0131] The following schemes and examples describe methods for preparing compounds of formula I. Starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of steps in performing the reaction scheme may be altered to promote the reaction or avoid unwanted byproducts.

[0132] The preparation method of the compound of Formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations can be easily performed by those skilled in the art.

[0133] Typically, in the preparation process, each reaction is carried out under inert gas protection, in a suitable solvent, at 0 to 150°C, and the reaction time is usually 1 to 24 hours.

[0134] The preparation method is as follows:

[0135] Method 1:

[0136] Step 1: In an inert solvent (such as tetrahydrofuran, N,N-dimethylformamide, dioxane, etc.) under alkaline conditions (such as potassium carbonate, triethylamine, sodium hydride, etc.), react SM1 with SM2 (a reagent containing L) to obtain M1.

[0137] Step 2: In an inert solvent (such as tetrahydrofuran, dichloromethane, methanol, etc.) and under the conditions of a reducing agent (such as sodium borohydride, sodium triacetoxyborohydride, etc.), M1 and SM3 are reacted to generate T (i.e., compound I).

[0138] Method 2:

[0139] Step 1: In an inert solvent (such as tetrahydrofuran, N,N-dimethylformamide, dioxane, etc.) and under alkaline conditions (such as potassium carbonate, triethylamine, sodium hydride, etc.), react SM1 with SM2 (a reagent containing L) to obtain M1.

[0140] Step 2: In an inert solvent (such as N,N-dimethylformamide, dichloromethane, acetonitrile, etc.) under alkaline conditions (such as triethylamine, N,N-diisopropylethylamine, etc.), M1 is reacted with SM3' to generate T (i.e., compound I).

[0141] In the above formulas, ring A, ring B, and L are as described above.

[0142] Unless otherwise specified, all of the above starting materials can be purchased commercially or synthesized according to the reported literature.

[0143] Example 1: Synthesis of Compound T-108

[0144] The synthesis route is as follows:

[0145] Synthesis steps:

[0146] 1. Synthesis of Compound 1

[0147] At room temperature, compound SM2 (500 mg, 1.0 eq) was added to a 100 mL round-bottom flask and dissolved in acetonitrile (5 mL) under nitrogen protection. Cesium carbonate (2.1 g, 3.0 eq) and SM1 (438 mg, 1.5 eq) were added sequentially, and the reaction was carried out at 50 °C for 5 h. The reaction was monitored by TLC until complete. The mixture was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, dried over a rotary evaporator, and purified by column chromatography to give 158 mg of compound 1, yield 22.1%, LC-MS [M+1]: 323.2.

[0148] 2. Synthesis of Compound 2

[0149] Compound 1 (158 mg, 1.0 eq) was dissolved in ethyl acetate (2 mL), and a 4 M HCl solution of dioxane (2 mL) was added dropwise under an ice-water bath. After the addition was complete, the reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until complete, and the product was dried directly by rotary evaporation to give 110 mg of compound 2, with a yield of 86.8%. LC-MS [M+1]: 223.1.

[0150] 3. Synthesis of compound T-108

[0151] Compound 2 (110 mg, 1.0 eq) was added to a 100 mL round-bottom flask, dissolved in methanol (2 mL), followed by sodium acetate (111 mg, 3.0 eq). The mixture was reacted at 50 °C for 2 h, then SM3 (92 mg, 1.0 eq) was added and the reaction continued for another 2 h. Finally, sodium cyanoborohydride (84 mg, 3.0 eq) was added, and the mixture was reacted overnight at 50 °C. The reaction was monitored by TLC until complete. The mixture was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, dried using a rotary evaporator, and purified using a preparative chromatographic plate to give 31 mg of compound T-108, yield 16.7%, LC-MS [M+1]: 411.2, 413.2.

[0152] Following the preparation method of compound T-108, the following compounds were synthesized:

[0153] Example 1 Enzyme Activity Test

[0154] The bioactivity test procedure is as follows:

[0155] Test compound OGA kinase IC 50 Value detection

[0156] 1. Compound preparation:

[0157] The compound powder was dissolved in 100% DMSO to prepare a 10 mM stock solution. The stock solution was further diluted to 1 μM as the starting concentration, and then continuously diluted 4 times to obtain 11 compound solutions of different concentrations.

[0158] 2. Kinase reaction process:

[0159] 1) Add the compounds of each gradient concentration and the positive control to a 384-well plate. Add 5 μl of 4× compound dilution, 5 μl of 4× OGA enzyme and 10 μl of 2× substrate to each well. Each concentration is set up in 3 replicates, with a total volume of 20 μl per well.

[0160] 2) Blank control group: Only 20 μl of 1× reaction buffer (RB) was added, without OGA enzyme and substrate, to detect the background noise of the system.

[0161] 3) Negative control group (Total, i.e. 0nM group): Add 5 μl of 1× reaction buffer (RB), 5 μl of 4× OGA enzyme solution and 10 μl of 2× substrate solution to detect the maximum fluorescence signal of the reaction.

[0162] 4) Substrate only: Add 10 μl of 1× reaction buffer (RB) and 10 μl of 2× substrate solution, without OGA enzyme, to detect the background fluorescence signal of the substrate.

[0163] 5) After all additions are complete, centrifuge (Eppendorf #5810R, RT, Short ~ 4000 rpm), then incubate at 37°C in a microplate shaker for 60 min. Read the values ​​(Ex / Em: 485 / 520 nm). Calculation formula: Activity (%) = ((RFU) Sample -RFU Substrate ) / (RFU Total -RFU Substrate ))×100

[0164] in:

[0165] RFU: Relative Fluorescence Units, used to measure the intensity of a fluorescence signal.

[0166] RFU Sample This is the fluorescence intensity of the experimental group, representing the fluorescence signal after adding a specific concentration of inhibitor, reflecting the enzyme activity under specific experimental conditions.

[0167] RFU Substrate : Contains only the fluorescence intensity of the substrate group, used to measure the fluorescence signal of the substrate itself, that is, the background fluorescence signal without enzyme activity.

[0168] RFU Total The fluorescence intensity of the negative control group typically contains all reaction components (including enzymes and substrates) but no inhibitors, reflecting the maximum enzyme activity in the absence of inhibitors.

[0169] 6) IC is obtained by curve fitting using GraphPad Prism 8 software. 50 Numerical value.

[0170] The above tests were used to determine the IC50 inhibitory activity of the test sample against OGA kinase. 50 The nM values ​​are shown in Table 1.

[0171] Table 1

[0172] As shown in the table above, the compounds in this application exhibit excellent inhibitory activity against OGA kinase through in vitro bioactivity screening, and can be used as drugs to regulate OGA kinase activity or treat OGA-related neurodegenerative diseases and disorders.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, wherein L is optionally substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 alkylamino, -NH2-, -O- substituted by C 5-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; A ring is R1are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 4- to 6-membered heterocyclyl; R2is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 4- to 6-membered heterocyclyl; B ring is X1is N or CR4, R4is H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 4- to 6-membered heterocyclyl; X2is N or CR5, R5is H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 4- to 6-membered heterocyclyl; R3is H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl; m is 0, 1, or 2; n is 0, 1, or 2; each of the heterocyclyl, heteroaryl independently contains 1, 2, or 3 heteroatoms selected from N, O, S, S(O), or S(O)2.

2. The compound of claim 1, or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, wherein the halo is F, CI, Br, or I; preferably, the C 1-6 alkyl is methyl, ethyl, propyl, isopropyl, or butyl; preferably, the C 1-6 haloalkyl is CF3.

3. The compound of claim 1, or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, wherein L is C 5-10 cycloalkyl, more preferably C 5-10 bridged cycloalkyl, C 6-10 spirocycloalkyl, C 6-10 fused cycloalkyl; Preferably, L is a 4-10 membered heterocyclyl, more preferably a 4-7 membered heterocyclyl, more preferably a 5-9 membered heterospirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered heteroannulocycloalkyl. Preferably, L is a 5-10 membered heteroaryl, more preferably a 5-6 membered heteroaryl.

4. The compound of claim 1 or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, L is selected from the following groups optionally substituted: Preferably, for a group where the two ends are N and O, the O end is connected to the A ring and the N end is connected to the B ring.

5. The compound of claim 1 or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, wherein L is selected from: More preferably, L is selected from: More preferably, L is selected from:

6. The compound of claim 1 or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, wherein L is selected from:

7. The compound of claim 1 or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, wherein L is selected from:

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, wherein the Formula I is selected from: wherein R1, R2, X1, X2, R3, m, n, L are as described in any one of claims 1-7.

9. A compound selected from: or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof.

10. A pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier.

11. Use of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, or a pharmaceutical composition of claim 10, in the manufacture of a medicament for treating and / or preventing a disease associated with OGA.

12. The use of claim 11, wherein the disease associated with OGA is a neurodegenerative disease or disorder, cancer, or a chronic metabolic disease; preferably, the neurodegenerative disease or disorder is Alzheimer’s disease, progressive supranuclear palsy (PSP), or a tau protein-mediated neurodegenerative disease and disorder.

13. Use of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, or a pharmaceutical composition of claim 10, in the manufacture of a medicament for use as an OGA inhibitor.

14. Use of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, crystal, co-crystal, stereoisomer, enantiomer, diastereomer, prodrug, deuteride, metabolite, hydrate, or solvate thereof, or a pharmaceutical composition of claim 10, in the manufacture of a medicament for modulating OGA activity.

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