Cyclic lactam derivative and application thereof

Abstract

Compounds of Formula (I) or stereoisomers or pharmaceutically acceptable salts thereof as glutamine cyclase inhibitors, processes for their preparation, pharmaceutical compositions containing the compounds of Formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, and the Formula (I) The invention relates to a use of a compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the prevention or treatment of QPCT and / or QPCTL mediated diseases or conditions including neurodegenerative diseases. # imgabs0 #

Description

[0001] This invention claims the priority of a prior application titled "Cyclic Lactam Derivatives and Their Applications" with patent application number CN202311865979.4, which was filed with the China National Intellectual Property Administration on December 29, 2023. The full text of the above prior application is incorporated into this invention by reference. Technical Field

[0002] This disclosure belongs to the field of pharmaceutical technology. Specifically, this disclosure relates to cyclic lactam derivatives as glutaminyl cyclase inhibitors, their preparation methods, pharmaceutical compositions containing such compounds, and their uses in preventing or treating Alzheimer's disease. Background Art

[0003] Alzheimer's disease (AD) is a neurodegenerative disease characterized by irreversible brain function impairment throughout the brain, leading to a gradual decline in cognitive function, comprehension, and / or consciousness.

[0004] The main histopathological markers of AD are Aβ plaques and neurofibrillary tangles caused by abnormal depositions such as β-amyloid (Aβ) and Tau protein. The currently popular theory holds that the early pathological changes leading to Alzheimer's disease are not plaques, but soluble Aβ aggregates, called Aβ oligomers. Most Aβ peptides in the brains of AD patients exist in the form of N-terminal cleavage and post-translational modifications. Glutaminyl cyclase (QC, also known as glutaminyl-peptide cyclotransferase, QPCT) can catalyze post-translational chemical reactions of proteins or peptides, converting N-terminal glutamine or glutamate residues into N-terminal pyroglutamic acid (pE) by releasing ammonia or water molecules, respectively. In neurodegenerative diseases, QPCT and its isoenzyme QPCTL (glutaminyl-peptide cyclotransferase-like) mediate the formation of pE-Aβ modification in the brain. After forming pE at the N-terminus, Aβ has enhanced hydrophobicity. This form of Aβ has higher neurotoxicity due to its stronger stability and hydrophobicity. In addition, the upregulation of pro-inflammatory factors (cytokines, chemokines) is also a characteristic of the AD pathological process. Among them, chemokine CCL2 [also known as monocyte chemoattractant protein-1 (MCP-1)] plays an important role in the stimulation and overactivation of glial cells. Glutaminyl cyclase can also modify the N-terminal glutamine residue to form pE-CCL2, and this modification can endow CCL2 with anti-degradation ability and mediate receptor activation. CCL2 and other chemokines can induce the expression of QC, thus triggering a vicious cycle between pE-Aβ deposition and neuroinflammation. Therefore, inhibiting QC activity is a potential therapeutic strategy for pE-related diseases, including but not limited to Alzheimer's disease, cancer, etc. In view of this, the present disclosure discloses a class of QPCT and / or QPCTL inhibitors with novel structures, excellent pharmacodynamic properties, high bioavailability, and high drug-likeness. Summary of the Invention

[0005] The present disclosure relates to a compound of formula (I) or its stereoisomers or its pharmaceutically acceptable salts,

[0006]

[0007] wherein,

[0008] R 1 is selected from C1-C6 alkyl, C6-C 10 aryl, C3-C 18 cycloalkyl, 3-18 membered heterocyclic group or 5-10 membered heteroaryl, and the C1-C6 alkyl, C6-C 10 aryl, C3-C 18 cycloalkyl, 3-18 membered heterocyclic group or 5-10 membered heteroaryl are optionally substituted by R1a Substituted;

[0009] R 1a selected from D, OH, NH2, CN, NO2, oxo, halogen, C(O)R 1b , SR 1b , S(O)2R 1b , C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 12-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 12-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by R 1c ;

[0010] R 1b selected from H, OH, NH2, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 12-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the OH, NH2, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 12-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by R 1c ;

[0011] R 1c selected from D, OH, NH2, CN, NO2, halogen, C(O)R 1d , SR 1d , S(O)2R 1d , C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 12-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C8 cycloalkyl, 4- to 12-membered heterocyclic group, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by R 1e ;

[0012] R 1d selected from H, OH, NH2, halogen or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally substituted by R 1e ;

[0013] R 1e is independently selected from D, OH, NH2, CN, NO2, halogen or C1-C6 alkyl;

[0014] Z1 is selected from C(R 2 ); or N;

[0015] Z2 is selected from [C(R 3 )2]m , [C(R 3 )2] n N(R 4 ), [C(R 3 )2] n O or [C(R 3 )2] p C(R 5 )=C(R 6 );

[0016] m is selected from 1, 2 or 3;

[0017] n is selected from 0, 1 or 2;

[0018] p is selected from 0 or 1;

[0019] R 2 is selected from H, D, OH, NH2, halogen or C1-C6 alkyl, and the OH, NH2 or C1-C6 alkyl is optionally substituted by R 2a ;

[0020] R 2a is selected from D, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0021] Each R 3 , R 5 , R 6 is independently selected from H, D, halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, and the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group is optionally substituted by R 3a ;

[0022] R 3a is selected from D, halogen, CN, OH, NH2 or C1-C6 alkyl, and the OH, NH2 or C1-C6 alkyl is optionally substituted by R 3b ;

[0023] R 3b is selected from D, halogen, CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0024] R 4 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, and the C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 4a ;

[0025] R 4aSelected from D, halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally substituted by R 4b substituted;

[0026] R 4b Selected from D, halogen, CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0027] Or two Rs 3 together with the atoms to which they are attached form a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 3a substituted; or R 3 , R 4 together with the atoms to which they are attached form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by R 3a substituted; or R 5 , R 6 together with the atoms to which they are attached form a C4-C8 cycloalkenyl or a 4-7 membered heterocyclic group, wherein the C4-C8 cycloalkenyl or 4-7 membered heterocyclic group is optionally substituted by R 3a substituted;

[0028] Ring A is selected from

[0029] Each X1 is independently selected from C(R 7 )2, NR 8 , S or O;

[0030] Each X2 is independently selected from N or CR 7 ;

[0031] Each R 7 is independently selected from H, D, halogen, CN, NH2, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the NH2, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 7a substituted;

[0032] R 7a is selected from D, halogen, CN, NH2, OH or C1-C6 alkyl, wherein the NH2, OH or C1-C6 alkyl is optionally substituted by R 7b substituted;

[0033] R 7b is selected from D, halogen, CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0034] Each R 8Independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, the C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 8a substituted;

[0035] R 8a is selected from D, halogen, CN, OH, NH2 or C1-C6 alkyl, the OH, NH2 or C1-C6 alkyl is optionally substituted by R 8b substituted;

[0036] R 8b is selected from D, halogen, CN, C1-C6 alkyl or C1-C6 haloalkyl.

[0037] In some embodiments, R 1 is selected from C1-C6 alkyl, phenyl, C3-C 10 cycloalkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl, the C1-C6 alkyl, phenyl, C3-C 10 cycloalkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl is optionally substituted by R 1a substituted.

[0038] In some embodiments, R 1 is selected from C1-C6 alkyl, C3-C 10 cycloalkyl or 4-12 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 cycloalkyl or 4-12 membered heterocyclic group is optionally substituted by R 1a substituted.

[0039] In some embodiments, R 1 is selected from C1-C6 alkyl, C3-C 10 cycloalkyl or 4-10 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R 1a substituted.

[0040] In some embodiments, R 1 is selected from C1-C6 alkyl, C3-C 10 cycloalkyl or 4-7 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 1a substituted.

[0041] In some embodiments, R 1 is selected from C1-C6 alkyl or C3-C 10 cycloalkyl, the C1-C6 alkyl or C3-C 10 cycloalkyl is optionally substituted by R 1a substituted.

[0042] In some embodiments, R 1 is selected from C1-C6 alkyl or C3-C8 cycloalkyl, and the C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted by R 1a .

[0043] In some embodiments, R 1 is selected from C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted by R 1a .

[0044] In some embodiments, R 1 is selected from C3-C 10 cycloalkyl, and the C3-C 10 cycloalkyl is optionally substituted by R 1a .

[0045] In some embodiments, R 1 is selected from 4- to 10-membered heterocyclic groups, and the 4- to 10-membered heterocyclic group is optionally substituted by R 1a . In some embodiments, R 1 is selected from 4- to 7-membered heterocyclic groups, and the 4- to 7-membered heterocyclic group is optionally substituted by R 1a .

[0046] In some embodiments, R 1 is selected from 4-, 5-, 6-, 7-, 8-, 9-, 10-membered heterocyclic groups, and the 4-, 5-, 6-, 7-, 8-, 9-, 10-membered heterocyclic group is optionally substituted by R 1a .

[0047] In some embodiments, the 4- to 10-membered heterocyclic group or 4- to 7-membered heterocyclic group contains 1, 2 or 3 heteroatoms independently selected from N, O or S.

[0048] In some embodiments, the 4- to 10-membered heterocyclic group or 4- to 7-membered heterocyclic group contains 1 or 2 heteroatoms independently selected from O or N.

[0049] In some embodiments, the 4- to 10-membered heterocyclic group or 4- to 7-membered heterocyclic group contains 1 or 2 N atoms.

[0050] In some embodiments, R 1 is selected from

[0051] the

[0052] which is optionally substituted by R 1a .

[0053] In some embodiments, R 1 is selected from

[0054] the

[0055] optionally substituted by R 1a .

[0056] In some embodiments, R 1 is selected from the optionally substituted by R 1a .

[0057] In some embodiments, R 1 is selected from the optionally substituted by R 1a .

[0058] In some embodiments, R 1 is selected from the optionally substituted by R 1a .

[0059] In some embodiments, R 1 is selected from

[0060] In some embodiments, R 1a is selected from D, OH, NH2, CN, NO2, oxo, halogen, C(O)R 1b , SR 1b , S(O)2R 1b , C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl is optionally substituted by R 1c .

[0061] In some embodiments, R 1a is selected from OH, oxo, halogen or C1-C6 alkyl, wherein the OH and C1-C6 alkyl are optionally substituted by R 1c .

[0062] In some embodiments, R 1a is selected from halogen or C1-C6 alkyl.

[0063] In some embodiments, R 1a is selected from F, CH3, oxo, OCH3 or

[0064] In some embodiments, R 1a is selected from F or CH3.

[0065] In some embodiments, R 1a is selected from F.

[0066] In some embodiments, R 1c is independently selected from D, OH, CN, halogen or C1-C6 alkyl, wherein the OH or C1-C6 alkyl is optionally substituted by R 1e .

[0067] In some embodiments, R 1c is independently selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by R 1e .

[0068] In some embodiments, R 1c is selected from CH3.

[0069] In some embodiments, R 1e is selected from F.

[0070] In some embodiments, R 1 is selected from

[0071]

[0072] In some embodiments, R 1 is selected from

[0073] In some embodiments, R 1 is selected from

[0074] In some embodiments, Z2 is selected from [C(R 3 )2] m or [C(R 3 )2] p C(R 5 )=C(R 6 ).

[0075] In some embodiments, Z2 is selected from C(R 3 )2 or C(R 5 )=C(R 6 ).

[0076] In some embodiments, m is selected from 1 or 2.

[0077] In some embodiments, m is selected from 1.

[0078] In some embodiments, p is selected from 0.

[0079] In some embodiments, R 2 is selected from H or C1-C6 alkyl.

[0080] In some embodiments, R 2 is selected from H or CH3.

[0081] In some embodiments, R 2 is selected from H.

[0082] In some embodiments, R 3 is selected from H or C1-C6 alkyl.

[0083] In some embodiments, R 3 is selected from H or CH3.

[0084] In some embodiments, R 3 is selected from H.

[0085] In some embodiments, R 4 、R 5 、R 6 are independently selected from H or CH3.

[0086] In some embodiments, ring A is selected from

[0087] In some embodiments, R 7 is selected from H or NH2.

[0088] In some embodiments, R 8 is selected from H or C1-C6 alkyl.

[0089] In some embodiments, R 8 is selected from H or CH3.

[0090] In some embodiments, R 7 、R 8 are independently selected from H.

[0091] In some embodiments, ring A is selected from

[0092] In some embodiments, ring A is selected from

[0093] In some embodiments, ring A is selected from

[0094] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt,

[0095]

[0096] wherein,

[0097] R 1 is selected from C1-C6 alkyl, C3-C 18 cycloalkyl or 3-18 membered heterocyclic group, and the C1-C6 alkyl, C3-C 18 cycloalkyl or 3-18 membered heterocyclic group is optionally substituted by R 1a with the proviso that: R 1 is not R is selected from H, F, Cl, CH3, CH2F, OCH3, R 2 、R 3 、and ring A is as defined in formula (I).

[0098] In some embodiments, R 1 is selected from C1-C6 alkyl, C3-C 10 cycloalkyl or 4-12 membered heterocyclic group, and the C1-C6 alkyl, C3-C 10 cycloalkyl or 4-12 membered heterocyclic group is optionally substituted by R 1a with the proviso that: R 1 is not In some embodiments, R 1 is selected from C1-C6 alkyl, C3-C 10 cycloalkyl or 4-10 membered heterocyclic group, and the C1-C6 alkyl, C3-C 10 cycloalkyl or 4-10 membered heterocyclic group is optionally substituted by R 1a with the proviso that: R 1 is not In some embodiments, R 1 is selected from C1-C6 alkyl, C3-C 10 cycloalkyl or 4-7 membered heterocyclic group, and the C1-C6 alkyl, C3-C 10 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R 1a with the proviso that: R 1 is not In some embodiments, R 1 is selected from C1-C6 alkyl or C3-C 10cycloalkyl, the C1-C6 alkyl or C3-C 10 cycloalkyl is optionally substituted by R 1a , provided that: R 1 is not In some embodiments, R 1 is selected from C1-C6 alkyl or C3-C8 cycloalkyl, the C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted by R 1a , provided that: R 1 is not In some embodiments, R 1 is selected from C3-C 10 cycloalkyl, the C3-C 10 cycloalkyl is optionally substituted by R 1a , provided that: R 1 is not

[0099] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II-1) or its stereoisomer or its pharmaceutically acceptable salt,

[0100]

[0101] wherein, R 1 , R 2 , R 3 are as defined in formula (II).

[0102] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II-1A) or its stereoisomer or its pharmaceutically acceptable salt,

[0103]

[0104] wherein, R 1 , R 2 , R 3 are as defined in formula (II).

[0105] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (III) or its stereoisomer or its pharmaceutically acceptable salt,

[0106]

[0107] wherein, R 1 , R 5 , R 6 , ring A is as defined in formula (I).

[0108] In some embodiments, the compound of formula (I) or its stereoisomers or its pharmaceutically acceptable salts are selected from the compound of formula (III-1) or its stereoisomers or its pharmaceutically acceptable salts,

[0109]

[0110] wherein R 1 、R 5 、R 6 are as defined in formula (I).

[0111] In some embodiments, the compound of formula (I) or its stereoisomers or its pharmaceutically acceptable salts are selected from the compound of formula (III-1A) or its stereoisomers or its pharmaceutically acceptable salts,

[0112]

[0113]

[0114] wherein R 1 、R 5 、R 6 are as defined in formula (I).

[0115] In some embodiments, the compound of formula (I) or its stereoisomers or its pharmaceutically acceptable salts are selected from the compound of formula (IV) or its stereoisomers or its pharmaceutically acceptable salts,

[0116]

[0117] wherein,

[0118] ring A is selected from

[0119] R 2 is selected from H, D, OH, NH2, halogen or C1-C6 alkyl, and the OH, NH2 or C1-C6 alkyl is optionally substituted by R 2a ;

[0120] R 2a is selected from D, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0121] q is selected from 0, 1, 2, 3, 4 or 5;

[0122] X1, X2, R 3 、R 8 、R 1a are as defined in formula (I);

[0123] provided that: when ring A is selected from , R 2Not H.

[0124] The compound of formula (I) of the present disclosure, or its stereoisomer, or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts,

[0125]

[0126]

[0127]

[0128] On the other hand, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I) of the present disclosure, or its stereoisomer, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

[0129] On the other hand, the present disclosure provides a method for treating a disease mediated by QPCT and / or QPCTL in a mammal, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of the compound of formula (I), or its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0130] On the other hand, the present disclosure provides the use of the compound of formula (I), or its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a disease mediated by QPCT and / or QPCTL.

[0131] On the other hand, the present disclosure provides the use of the compound of formula (I), or its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof in preventing or treating a disease mediated by QPCT and / or QPCTL.

[0132] On the other hand, the present disclosure provides a compound of formula (I), or its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof for preventing or treating a disease mediated by QPCT and / or QPCTL.

[0133] In some embodiments, the disease mediated by QPCT and / or QPCTL is selected from neurodegenerative diseases.

[0134] In some embodiments, the neurodegenerative disease is Alzheimer's disease.

[0135] Term Definitions and Explanations

[0136] Unless otherwise specified, the terms used in this disclosure have the following meanings. The definitions of the groups and terms described in this disclosure, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., may be combined and combined with each other arbitrarily. A particular term should not be considered indeterminate or unclear without a special definition, but should be understood according to its ordinary meaning in the art. When a trade name appears in this text, it is intended to refer to the corresponding commodity or its active ingredient.

[0137] In this text represents a connection site.

[0138] The representations of racemates or enantiomerically pure compounds in this text are from Maehr, J. Chem. Ed. 1985, 62: 114 - 120. Unless otherwise specified, wedge bonds and dashed wedge bonds ( ) are used to represent the absolute configuration of a stereocenter, and solid black bonds and dashed bonds ( ) are used to represent the relative configuration of a stereocenter (such as the cis - trans configuration of alicyclic compounds).

[0139] The term "stereoisomer" refers to isomers produced by different arrangements of atoms in space in a molecule, including cis - trans isomers, enantiomers, and diastereomers.

[0140] The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds. Therefore, the compounds of the present disclosure 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 their racemic mixtures or other mixtures, such as enantiomer - or diastereomer - enriched mixtures. All of the above - mentioned isomers and their mixtures are within the definition scope of the compounds of the present disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may exist in substituents such as alkyl groups. These isomers and their mixtures involved in all substituents are also included within the definition scope of the compounds of the present disclosure. The compounds of the present disclosure containing asymmetric atoms may be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0141] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0142] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and this description includes both the occurrence and non-occurrence of the described event or circumstance. For example, "optionally" substituted by a halogen for an ethyl group means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.) or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0143] When any variable (e.g., R a , R b ) appears more than once in the composition or structure of a compound, its definition in each case is independent. For example, if a group is substituted by two R b , then each R b has an independent option.

[0144] In an embodiment of the present disclosure, the substituent "X" is optionally substituted by the substituent "Y", which means that the substituent "X" is optionally substituted by one or more (e.g., 1, 2, 3, or 4) substituents "Y", and the options of each substituent "Y" are independent of each other. For example, "the C1-C6 alkyl, C2-C6 alkynyl, or C3-C6 cycloalkyl is optionally substituted by R 1a " means that the C1-C6 alkyl, C2-C6 alkynyl, or C3-C6 cycloalkyl is each optionally substituted by one or more R 1a , and the options of each R 1a are independent. When the connecting group involved in this article does not specify its connecting direction, its connecting direction is arbitrary. For example, when Z2 in the structural unit is selected from "CH2NH", at this time Z2 can be connected to Z1 and R in the left-to-right direction to form "Z1-CH2NH-R", or can be connected to Z1 and R in the right-to-left direction to form "Z1-NHCH2-R".

[0145] C m -C nrefers to an integer number of carbon atoms in the range of m - n. For example, "C1 - C 10 " means that the group may 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.

[0146] The term "alkyl" refers to a hydrocarbon group of the general formula C n H 2n+1 and the alkyl group can be straight-chain or branched-chain. The term "C1 - C6 alkyl" should be understood to represent a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Specific examples of the alkyl group 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" can be understood to represent a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 3 carbon atoms. The "C1 - C 10 alkyl" can include ranges such as "C1 - C6 alkyl" or "C1 - C3 alkyl", and the "C1 - C6 alkyl" can further include "C1 - C3 alkyl".

[0147] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The term "C2 - C6 alkenyl" should be understood to represent a straight-chain or branched-chain unsaturated monovalent hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms. "C2 - C6 alkenyl" is preferably "C2 - C4 alkenyl", and more preferably C2 or C3 alkenyl. It should be understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0148] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The term "C2 - C6 alkynyl" can be understood to represent a straight-chain or branched-chain unsaturated monovalent hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5 or 6 carbon atoms. Examples of "C2 - C6 alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、-CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C6 alkynyl" may include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (propargyl).

[0149] The term "cycloalkyl" refers to a fully saturated carbocyclic ring existing in the form of a monocyclic, fused-ring, bridged-ring or spiro-ring, etc. The term "C3-C6 cycloalkyl" can be understood to represent a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.

[0150] The term "cycloalkenyl" refers to an unsaturated non-aromatic carbocyclic ring existing in the form of a monocyclic, fused-ring, bridged-ring or spiro-ring, etc. Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, etc.

[0151] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. The term "C6-C 10 aryl" should be understood as a monovalent aromatic or partially aromatic all-carbon monocyclic or bicyclic group 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 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0152] The term "heteroaryl" refers to a monocyclic or fused polycyclic system with aromaticity, where the aromatic ring group contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" should be understood to include such monovalent monocyclic or bicyclic aromatic ring systems: having 5, 6, 7, 8, 9, or 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and containing 1, 2, 3, 4, 5, preferably 1, 2, 3 heteroatoms independently selected from N, O, and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc. and their benzo derivatives, such as quinolinyl, quinazolinyl, or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, etc. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O, and S.

[0153] The term "heterocyclic group" refers to a monocyclic, fused-ring, spiro or bridged-ring monovalent group that is fully saturated or partially saturated (not aromatic heterocyclic as a whole), and contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms) among its ring atoms. The "heteroatom or heteroatomic group" includes, but is not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH- or -NHC(=O)NH-, etc. The term "4- to 10-membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups. The "4- to 10-membered heterocyclic group" includes the "4- to 7-membered heterocyclic group". Specific examples of the 4-membered heterocyclic group include, but are not limited to, azetidinyl or oxetanyl; specific examples of the 5-membered heterocyclic group include, but are not limited to, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of the 6-membered heterocyclic group include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of the 7-membered heterocyclic group include, but are not limited to, diazepanyl. The heterocyclic group can also be a bicyclic group. Specific examples of the 5,5-bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl or Specific examples of the 5,6-bicyclic group 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, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl, Specific examples of the 6,6-bicyclic group include, but are not limited to Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4- to 7-membered heterocyclic group, and specific examples include, but are not limited to, dihydroisoquinolinyl and the like. The "4- to 10-membered heterocyclic group" may include ranges such as "5- to 10-membered heterocyclic group", "4- to 7-membered heterocyclic group", "5- to 6-membered heterocyclic group", "6- to 8-membered heterocyclic group", "4- to 10-membered heterocycloalkyl", "5- to 10-membered heterocycloalkyl", "4- to 7-membered heterocycloalkyl", "5- to 6-membered heterocycloalkyl", "6- to 8-membered heterocycloalkyl", etc. The "4- to 7-membered heterocyclic group" may further include ranges such as "4- to 6-membered heterocyclic group", "5- to 6-membered heterocyclic group", "4- to 7-membered heterocycloalkyl", "4- to 6-membered heterocycloalkyl", "5- to 6-membered heterocycloalkyl", etc. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0154] The term "halo" or "halogen" means fluorine, chlorine, bromine or iodine.

[0155] The term "haloalkyl" means that one or more hydrogen atoms on the alkyl are replaced by the same or different halogen atoms. The term "C1-C6 haloalkyl" may further include "C1-C3 haloalkyl".

[0156] The term "deuterated alkyl" means that one or more hydrogen atoms on the alkyl are replaced by deuterium atoms. The term "C1-C6 deuterated alkyl" may further include "C1-C3 deuterated alkyl".

[0157] The term "treat" means administering the compounds or formulations described in the present application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0158] (i) inhibiting the disease or disease state, i.e., curbing its development;

[0159] (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to subside.

[0160] The term "prevent" means administering the compounds or formulations described in the present application to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of the disease or disease state in a mammal, particularly when such a mammal is susceptible to the disease state but has not been diagnosed as having the disease state.

[0161] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present disclosure that constitutes a "therapeutically effective amount" will vary 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 of ordinary skill in the art based on their own knowledge and the present disclosure.

[0162] 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 humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0163] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts formed by the compound with inorganic acids or organic acids, and salts formed by the compound with inorganic bases or organic bases.

[0164] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present disclosure to an organism.

[0165] The term "pharmaceutically acceptable excipient" refers to those excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those of ordinary skill in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0166] The word "comprise" or "comprising" and its English variants such as "comprises" or "comprising" should be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0167] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally 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, etc.

[0168] Certain isotopically labeled compounds of the present disclosure (e.g., labeled with 3 H and 14 C) can be used in the analysis of the tissue distribution of compounds and / or substrates. Tritiation (i.e., 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 as 15 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 present disclosure can generally be prepared by substituting non-isotopically labeled reagents with isotopically labeled reagents through procedures similar to those described in the protocols and / or examples disclosed below.

[0169] 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.

[0170] Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, include but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0171] The pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, freeze-drying methods, etc.

[0172] 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, syrups, suspensions, etc. for oral administration to patients.

[0173] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be obtained by the following method: mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or coated tablet. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents, etc.

[0174] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in suitable unit dosage forms.

[0175] In all methods of administration of the compounds of general formula I described herein, the daily dosage is from 0.01 mg / kg to 1000 mg / kg body weight, in single or divided doses.

[0176] The compounds of the present disclosure can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0177] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, sometimes those skilled in the art need to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0178] The following abbreviations are used in the present disclosure:

[0179] Ti(OiPr)4: titanium tetraisopropoxide; THF: tetrahydrofuran; MeOH: methanol; LDA: lithium diisopropylamide; CuI: copper iodide; dioxane: 1,4 - dioxane; TFA: trifluoroacetic acid; DCM: dichloromethane; EBA: ethyl bromoacetate; TMSCl:

[0180] trimethylchlorosilane; SEM: (trimethylsilyl)ethoxymethyl. Specific embodiments

[0181] The invention will be described in detail below by way of examples, which does not mean any adverse limitation to the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0182] Unless otherwise specified, the ratios indicated for mixed solvents are volume mixing ratios. Unless otherwise specified, % refers to wt%.

[0183] Compounds are named manually or by software. For commercially available compounds, the supplier's catalog name is used.

[0184] 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 solvents used for NMR measurements are 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.

[0185] The eluents below can be formed into a mixed eluent by two or more solvents, and their ratio is the volume ratio of each solvent. For example, "0-10% ethyl acetate / petroleum ether" means that during the gradient elution process, the volume ratio of ethyl acetate to petroleum ether in the mixed eluent is 0:100-10:90. Or "dichloromethane / methanol = 20:1" means that during the gradient elution process, the volume ratio of dichloromethane to methanol in the mixed eluent is 20:1.

[0186] Example 1: Preparation of (R)-1-(1H-benzo[d]imidazol-5-yl)-4-cyclobutylazetidin-2-one (Compound 1)

[0187] Step 1: Synthesis of 1-002

[0188] Under nitrogen protection, 1-001 (5.00 g), (S)-tert-butanesulfinamide (8.65 g), and titanium tetraisopropoxide (33.9 g) were dissolved in 50 mL of tetrahydrofuran solution, and the reaction was stirred at 25 °C for 16 hours until completion. The reaction solution was added to 200 mL of saturated sodium bicarbonate aqueous solution and stirred, then filtered. The filtrate was extracted with ethyl acetate (50 mL * 3), and the organic phases were combined and washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient: 0-5% ethyl acetate / petroleum ether) to obtain the title compound 1-002 (10.8 g).

[0189] 1 1H-NMR (400 MHz, CDCl3) δ 8.04 (d, J = 4.9 Hz, 1H), 3.44 - 3.15 (m, 1H), 2.25 - 2.06 (m, 4H), 1.97 (s, 1H), 1.93 - 1.80 (m, 1H), 1.13 (s, 9H).

[0190] MS m / z (ESI): = 188.1 [M+H] + .

[0191] Step 2: Synthesis of 1-003

[0192] Under nitrogen protection, zinc powder (6.00 g) was added to 8 mL of tetrahydrofuran, trimethylchlorosilane (450 mg) was added, and the mixture was stirred at 25 °C for 30 minutes. Subsequently, the temperature was raised to 40 °C, and ethyl bromoacetate (6.20 g) was slowly added dropwise thereto. After stirring and reacting at 40 °C for 1 hour, zinc bromoacetate in ethyl acetate was prepared. Intermediate 1-002 (3.00 g) was dissolved in 10 mL of tetrahydrofuran, and zinc bromoacetate in ethyl acetate was slowly added dropwise at 25 °C. After the addition was complete, the mixture was stirred and reacted at 25 °C for 1 hour. Subsequently, the reaction solution was quenched with a saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL * 3), the organic phases were combined, washed three times with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (gradient: 0 - 15% tetrahydrofuran / petroleum ether) to obtain the title compound 1-003 (4.40 g).

[0193] 1 H NMR (400 MHz, CDCl3) δ 4.19 - 4.07 (m, 2H), 3.43 - 3.29 (m, 1H), 2.60 (dd, J = 4.6, 15.9 Hz, 1H), 2.41 (dd, J = 5.9, 15.9 Hz, 2H), 1.98 (s, 2H), 1.81 - 1.62 (m, 4H), 1.22 - 1.11 (m, 12H).

[0194] MS m / z (ESI): = 276.1 [M+H] + 。

[0195] Step 3: Synthesis of 1-004

[0196] 1-003 (4.30 g) was dissolved in 2 M hydrogen chloride - methanol solution (50 mL), and the reaction solution was stirred at 25 °C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated, the residue was dissolved in water (50 mL), and washed twice with ethyl acetate (20 mL * 2). The aqueous phase was adjusted to pH 7 - 8 with a saturated aqueous sodium bicarbonate solution, extracted three times with dichloromethane (50 mL * 3), the organic phase was dried, and concentrated to obtain the title compound 1-004 (1.40 g).

[0197] 11H NMR (400 MHz, CDCl3) δ 3.71 (s, 3H), 3.16 - 3.02 (m, 1H), 2.50 - 2.36 (m, 1H), 2.25 (s, 1H), 2.15 - 2.05 (m, 2H), 1.96 - 1.87 (m, 2H), 1.80 - 1.66 (m, 3H)

[0198] MS m / z (ESI): =158.2 [M + H] + 。

[0199] Step 4: Synthesis of 1 - 005

[0200] Under nitrogen protection, dissolve 1 - 004 (1.30 g) in 400 mL of tetrahydrofuran. Slowly add a solution of lithium diisopropylamide (2 M, 12.4 mL) dropwise to the reaction solution at -78 °C, and finish dropping in 5 minutes. Stir at -78 °C for 2 hours. LCMS shows that the reaction is complete. Quench the reaction with saturated ammonium chloride aqueous solution (50 mL), extract the reaction solution twice with ethyl acetate (100 mL * 2), combine the organic phases, wash with saturated brine, and wash once with saturated citric acid aqueous solution (50 mL). Dry the organic phase, concentrate to obtain a crude product. The crude product is purified by silica gel column chromatography (gradient: 0 - 30% tetrahydrofuran / petroleum ether) to obtain the title compound 1 - 005 (270 mg).

[0201] 1 1H NMR (400 MHz, CDCl3) δ 6.25 (s, 1H), 3.73 - 3.61 (m, 1H), 3.02 - 2.88 (m, 1H), 2.60 - 2.44 (m, 2H), 2.05 - 1.97 (m, 2H), 1.97 - 1.88 (m, 1H), 1.87 - 1.77 (m, 2H), 1.76 - 1.63 (m, 1H)

[0202] Step 5: Synthesis of 1 - 006

[0203] Under nitrogen protection, dissolve 1 - 005 (100 mg) in 5 mL of dioxane, add 2 - [(5 - iodobenzimidazol - 1 - yl)methoxy]ethyltrimethylsilane (328 mg), copper(I) iodide (60.6 mg), trans - (1R,2R) - N,N - dimethyl - 1,2 - cyclohexanediamine (45.6 mg) and potassium phosphate (508 mg). After heating to 80 °C and stirring for 2 hours, the reaction is complete. Add 50 mL of ethyl acetate for extraction, wash the organic phase with saturated brine, dry the organic phase and concentrate to obtain a crude product. Purify by silica gel column chromatography (gradient elution with petroleum ether / tetrahydrofuran) to obtain the title compound 1 - 006 (295 mg).

[0204] 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.84 - 7.64 (m, 1H), 7.58 - 7.41 (m, 1H), 7.26 - 7.10 (m, 1H), 5.69 - 5.44 (m, 2H), 4.22 - 4.16 (m, 1H), 3.62 - 3.43 (m, 2H), 3.12 (s, 1H), 2.86 (s, 2H), 2.23 - 2.09 (m, 1H), 1.98 - 1.83 (m, 5H), 0.98 - 0.86 (m, 2H), 0.08--0.08 (m, 9H).

[0205] MS m / z (ESI): = 372.1 [M+H] + 。

[0206] Step 6: Synthesis of Compound 1

[0207] Under nitrogen protection, dissolve 1-006 (200 mg) in 2 mL of dichloromethane, add boron trifluoride diethyl etherate (1.11 g), and stir at 25 °C for 3 hours until the reaction is complete. Concentrate the reaction solution under reduced pressure, and purify the crude product by preparative high performance liquid chromatography (C18, 150×40 mm; mobile phase: Phase A: water (5‰ ammonia water), Phase B: acetonitrile; gradient: mobile phase B from 15% to 55%) to obtain the title compound 1 (36.2 mg).

[0208] 1 H-NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.20 (s, 1H), 7.57 - 7.55 (m, 2H), 7.27 - 7.24 (m, 1H), 4.28 - 4.25 (m, 1H), 3.15 - 3.09 (m, 1H), 2.87 - 2.60 (m, 2H), 2.08 - 1.69 (m, 6H).

[0209] MS m / z (ESI): = 242.2 [M+H] + 。

[0210] Referring to the synthesis method of Compound 1, replace 1-001 with the starting materials in the following table to synthesize the following compounds:

[0211]

[0212]

[0213] Biological Activity and Related Property Tests

[0214] Unless otherwise specified, the test methods used in the following experimental examples are all conventional methods; the materials, reagents, etc. used are, unless otherwise specified, reagents and materials that can be obtained commercially.

[0215] Experimental Example 1: Inhibition Experiment of QPCT / QPCTL Enzyme Activity of the Embodiment of the Present Disclosure

[0216] Using Green Glutaminyl Cyclase Activity Assay Kit to detect the inhibition of the activity of human QPCT / QPCTL enzyme by the compound.

[0217] 1. Experimental Reagents, Consumables and Instruments

[0218]

[0219] 2. Experimental Method:

[0220] The 0.5 mM QPCT enzyme substrate was diluted to 5 μM with buffer at a ratio of 1:100; the 50 μg / mL QPCT enzyme was diluted to 125 ng / mL with buffer and placed on ice for use; the QPCT developer was diluted with buffer at a ratio of 1:250 and placed on ice for use (the QPCT enzyme substrate, QPCT enzyme, buffer and QPCT developer are all from the kit); the initial concentration of the test compound working solution was 200 μM, and it was diluted in 6-fold gradient, with a total of 7 concentration points. In a 75 μL reaction system, the initial working concentration of the test compound was 13.3 μM, and the final concentration of DMSO was 0.3%.

[0221] In a 384-well plate, 20 μL of the prepared QPCT enzyme solution, 5 μL of the test compound and 25 μL of the QPCT enzyme substrate were added to each well in sequence. The microplate shaker was used to mix for 1 minute, centrifuged at 400 g for 1 minute, and incubated at 37 °C for 30 minutes. Subsequently, 25 μL of the QPCT developer was added to each well, mixed with the shaker for 1 minute, centrifuged at 400 g for 1 minute; and incubated at 37 °C for another 60 minutes. After the incubation was completed, the fluorescence value was read with an enzyme-labeled instrument, and the parameter settings were: Ex / Em = 490 nm / 520 nm. The calculation formula for the inhibition rate of the compound on the QPCT enzyme activity is: Inhibition rate (inhibition%) = (RFU no treatment -RFU treated ) ÷ (RFU no treatment -RFU background) × 100%. Using GraphPad Prism 9 software, with the compound concentration (nM) as the abscissa and the enzyme activity inhibition rate (%) as the ordinate, draw a curve and perform four-parameter fitting to calculate the IC of the compound's inhibition of QPCT enzyme activity 50 . The specific results are shown in Table 1.

[0222] For the Green Glutaminyl Cyclase Activity Assay Kit, make appropriate adjustments. Replace the QPCT enzyme in it with human QPCTL enzyme (Sino Biological, catalog number NXS6-1) (the working solution concentration remains unchanged) to detect the IC of the compound's inhibition of human QPCTL enzyme activity 50 . The remaining experimental reagents, instruments, preparation of working solutions, operation steps, and data processing methods are the same as those for the detection method of human QPCT enzyme activity. The specific results are shown in Table 1.

[0223] Table 1 Test results of the inhibition activity of the compounds of the present disclosure against human QPCT / QPCTL enzymes

[0224]

[0225] "-" indicates not detected.

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, R 1 Selected from C1-C6 alkyl, C6-C 10 Aryl, C3-C 18 Cycloalkyl, 3-18 membered heterocyclic group or 5-10 membered heteroaryl, the C1-C6 alkyl, C6-C 10 Aryl, C3-C 18 Cycloalkyl, 3-18 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by R 1a replace; R 1a Selected from D, OH, NH2, CN, NO2, oxo, halogen, C(O)R 1b , SR 1b 、S(O)2R 1b , C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclic, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by R 1c replace; R 1b is selected from H, OH, NH2, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the OH, NH2, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by R 1c replace; R 1c Selected from D, OH, NH2, CN, NO2, halogen, C(O)R 1d , SR 1d 、S(O)2R 1d , C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the OH, NH2, C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocyclic, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally substituted by R 1e replace; R 1d is selected from H, OH, NH2, halogen or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 1e replace; R 1e Independently selected from D, OH, NH2, CN, NO2, halogen or C1-C6 alkyl; Z1 is selected from C(R 2 ) or N; Z2 is selected from [C(R 3 )2] m , [C(R 3 )2] n N(R 4 ),[C(R 3 )2] n O or [C(R 3 )2] p C(R 5 )=C(R 6 ); m is selected from 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0 or 1; R 2 is selected from H, D, OH, NH2, halogen or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 2a replace; R 2a is selected from D, halogen, C1-C6 alkyl or C1-C6 haloalkyl; Each R 3 , R 5 , R 6 independently selected from H, D, halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, wherein the OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally replaced by R 3a replace; R 3a is selected from D, halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 3b replace; R 3b is selected from D, halogen, CN, C1-C6 alkyl or C1-C6 haloalkyl; R 4 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R 4a replace; R 4a is selected from D, halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 4b replace; R 4b is selected from D, halogen, CN, C1-C6 alkyl or C1-C6 haloalkyl; Or two R 3 The atoms connected thereto together form a C3-C6 cycloalkyl or a 4-7 membered heterocyclic group, wherein the C3-C6 cycloalkyl or the 4-7 membered heterocyclic group is optionally substituted by R 3a Replace; or R 3 , R 4 The atoms to which it is attached together form a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by R 3a Replace; or R 5 , R 6 The atoms to which it is connected together form a C4-C8 cycloalkenyl or a 4-7 membered heterocyclic group, wherein the C4-C8 cycloalkenyl or the 4-7 membered heterocyclic group is optionally replaced by R 3a replace; Ring A is selected from Each X1 is independently selected from C(R 7 )2. NR 8 , S or O; Each X2 is independently selected from N or CR 7 ; Each R 7 independently selected from H, D, halogen, CN, NH2, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein the NH2, OH, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl is optionally replaced by R 7a replace; R 7a is selected from D, halogen, CN, NH2, OH or C1-C6 alkyl, wherein the NH2, OH or C1-C6 alkyl is optionally replaced by R 7b replace; R 7b is selected from D, halogen, CN, C1-C6 alkyl or C1-C6 haloalkyl; Each R 8 independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R 8a replace; R 8a is selected from D, halogen, CN, OH, NH2 or C1-C6 alkyl, wherein the OH, NH2 or C1-C6 alkyl is optionally replaced by R 8b replace; R 8b Selected from D, halogen, CN, C1-C6 alkyl or C1-C6 haloalkyl.

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C1-C6 alkyl, phenyl, C3-C 10 Cycloalkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl, the C1-C6 alkyl, phenyl, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted by R 1a Replace; or, R 1 Selected from C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group, the C1-C6 alkyl, C3-C 10 Cycloalkyl or 4-7 membered heterocyclic group is optionally replaced by R 1a Replace; or, R 1 Selected from Said Optionally R 1a replace.

3. The compound according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from H or C1-C6 alkyl.

4. The compound according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 Selected from H or C1-C6 alkyl.

5. The compound according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Z2 is selected from [C(R 3 )2] m or [C(R 3 )2] p C(R 5 )=C(R 6 ).

6. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from Alternatively, ring A is selected from 7. A compound of formula (I) according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound of formula (I) is selected from the compound of formula (II) or its stereoisomer or a pharmaceutically acceptable salt thereof: Among them, R 1 Selected from C1-C6 alkyl, C3-C 18 Cycloalkyl or 3-18 membered heterocyclic group, the C1-C6 alkyl, C3-C 18 Cycloalkyl or 3-18 membered heterocyclic group is optionally substituted by R 1a Replace, provided that: R 1 no R is selected from H, F, Cl, CH3, CH2F, OCH3, R 2 , R 3 , Ring A is as defined in any one of claims 1-6.

8. The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof according to claim 7, wherein: The compound of formula (I) is selected from the compound of formula (II-1) or its stereoisomer or a pharmaceutically acceptable salt thereof: Among them, R 1 , R 2 , R 3 As defined in any one of claims 1 to 6.

9. The compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein the compound of formula (I) is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:

10. A pharmaceutical composition, wherein The pharmaceutical composition comprises the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 9, and pharmaceutically acceptable excipients.

11. Use of the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating or preventing a disease or condition mediated by QPCT and / or QPCTL in a mammal, preferably a human.

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