DEUTERATED TETRACYCLIC DERIVATIVE AND ITS APPLICATIONS

Abstract

Disclosed are a deuterated tetracyclic derivative and a use thereof in prevention or treatment of diseases caused by bacterial infections, particularly in pulmonary diseases caused by mycobacterium tuberculosis or drug-resistant mycobacterium tuberculosis.

Description

Deuterated tetracyclic derivatives and their applications Technical Field

[0001] The present disclosure relates to deuterated compounds, pharmaceutical compositions comprising the deuterated compounds and applications thereof, and particularly to deuterated tetracyclic derivatives and medical uses thereof. Background Art

[0002] Deuterated drugs refer to drugs in which some of the hydrogen atoms in the drug molecule are replaced with deuterium. Deuterium (D), as a non-radioactive, stable isotope of hydrogen, has a form and volume similar to hydrogen in drugs, which can keep the biological activity and selectivity of the drug molecule basically unchanged. In addition, the CD bond is more stable than the CH bond, which can delay the decomposition process of the drug, prolong the drug's effect time in the body, affect metabolism, and thus improve pharmacokinetics, reduce drug metabolic toxicity, and increase bioavailability, ultimately achieving the goal of reducing dosing frequency, improving patient medication compliance, achieving the same therapeutic effect with a smaller dose, and reducing adverse drug reactions to achieve clinical benefits. The first deuterated drug, Deutetrabenazine (trade name: Austedo), was approved for marketing by the U.S. Food and Drug Administration (FDA) in 2017.

[0003] Mycobacterium tuberculosis can cause multi-site infections and develop drug resistance, including in the lungs, intestines, peritoneum, kidneys, parasites, ureters, pleura, bones, joints, brain, and reproductive system. Pulmonary tuberculosis is the most common form of infection. Currently, first-line treatments for pulmonary tuberculosis include isoniazid, rifampicin, streptomycin, and ethambutol. However, resistance to these drugs is now widespread, and they also present serious side effects. New anti-tuberculosis drugs and diversified treatment strategies are urgently needed.

[0004] Summary of the Invention

[0005] One aspect of the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or prodrug thereof:

[0006] Where n is 0 or 1;

[0007] R4 is selected from H, halogen, aldehyde, hydroxy, thiol, -NR'R", cyano, nitro, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 14 Aryl, optionally substituted C5-C 10 Heteroaryl, optionally substituted C4-C 10Heterocyclyl and their respective deuterated variants; preferably, R4 is selected from optionally substituted C6-C 14 Aryl C1-C 10 Alkyl, optionally substituted C5-C 10 Heteroaryl C1-C 10 Alkyl, optionally substituted C4-C 10 Heterocyclic C1-C 10 alkyl groups and their respective deuterated variants;

[0008] R7 is selected from H, hydroxy, thiol, cyano, carboxyl, nitro, -NR'R", optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, C1-C 10 Ester group, acylamino group, halogen, optionally substituted C3-C8 carbocyclic group, optionally substituted C1-C 10 Alkoxy, optionally substituted C6-C 14 Aryl, optionally substituted C5-C 10 Heteroaryl, optionally substituted C4-C 10 Heterocyclyl and their respective deuterated variants; wherein R' and R" are each independently selected from: H, optionally substituted C1-C 10 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C1-C 10 alkoxy;

[0009] R1, R2, R3, R6, R9 and R 10 are independently selected from: hydrogen and deuterium; and

[0010] The structure of Formula I contains at least one deuterium atom, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms.

[0011] In a preferred embodiment, R4 is -(CR 11 R 12 ) m -NR a R b ,

[0012] Where m is 1, 2 or 3;

[0013] R 11 and R 12 are independently selected from hydrogen and deuterium; and

[0014] R a and R bEach is independently selected from the following substituents and their respective deuterated variants: H; C1-C1 optionally substituted with 1-5 substituents selected from halogen and hydroxy 10 C2-C8 alkenyl optionally substituted by 1-5 substituents selected from halogen and hydroxy; 3-14 membered carbocyclyl optionally substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 3-14 membered carbocyclyl substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 4-10 membered heterocyclyl substituted by 1-5 substituents selected from halogen, hydroxy and C1-C4 alkyl; C6-C 14 Aryl; and C6-C optionally substituted by 1-5 groups selected from halogen, hydroxy and C1-C4 alkyl 14 Aryl-C1-C6 alkyl; or R a and R b Together with the nitrogen atom to which they are attached, they form an optionally substituted 4- to 7-membered heterocyclyl or benzo 4- to 7-membered heterocyclyl, or a deuterated variant thereof, wherein the 4- to 7-membered heterocyclyl or benzo 4- to 7-membered heterocyclyl is optionally substituted by 1-5 substituents selected from the group consisting of: C1-C6 alkyl optionally substituted by 1-5 substituents selected from the group consisting of halogen and hydroxy; C1-C6 alkoxy optionally substituted by 1-5 substituents selected from the group consisting of halogen and hydroxy; cyano; carboxyl; halogen; -NR c R d ; Hydroxyl; optionally 1-5 selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 C6-C4 substituted aryl and halogenated C1-C4 alkyl 14 Aryl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; NR c R d Substituted C1-C6 acyl; C6-C optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl and hydroxy 14 C1-C4 acyl substituted with aryl; C6-C4 acyl substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; 14C1-C6 alkyl optionally substituted by aryl; C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl C3-C8 cycloalkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl C3-C8 cycloalkyl; 4-7 membered heterocyclyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; C1-C6 alkyl optionally substituted with 4-7 membered heterocyclyl which is substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl which is optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and C1-C6 alkyl which is substituted with 5-10 membered heteroaryl which is optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy.

[0015] In a more preferred embodiment, in R4, -NR a R b Selected from: wherein p is independently 0, 1, 2 or 3, X is halogen, R 20 to R 32 、R 35 to R 41 、R 44 independently selected from: hydrogen and deuterium;

[0016] Preferably, -NR a R b Selected from: where R 20 to R 41 、R 44 Independently selected from: hydrogen and deuterium.

[0017] In a more preferred embodiment, -NR a R b Selected from:

[0018] In a preferred embodiment, R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 halogen and hydroxyl groups, C2-C6 alkenyl optionally substituted by 1-5 halogen and hydroxyl groups, C3-C8 saturated or partially saturated carbocyclyl, halogen, hydroxyl, C6-C 14Aryl-substituted C1-C4 alkoxy, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halo-substituted C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14 Aryl and their respective deuterated variants; preferably, R7 is selected from hydrogen, deuterium and where R 13 to R 19 、R 42 、R 43 Independently selected from hydrogen and deuterium; More preferably, R7 is selected from hydrogen, deuterium and

[0019] In some embodiments, the present invention provides a compound of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof,

[0020] Wherein, R7 is selected from hydrogen, deuterium and where R 13 to R 19 、R 42 、R 43 Independently selected from hydrogen and deuterium; preferably, R7 is

[0021] R1, R2, R3, R6, R 11 、R 12 and R 20 to R 29 are independently selected from hydrogen and deuterium; and

[0022] The structure of Formula II contains at least one deuterium atom; preferably contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms.

[0023] In a preferred embodiment, the structural formula of the compound is shown as follows: IIa, IIb, IIc or IId:

[0024] In some embodiments, the present invention provides a compound of formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof,

[0025] wherein Re is selected from: C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen and hydroxy; C1-C6 alkoxy optionally substituted by 1-5 substituents selected from halogen and hydroxy; cyano; carboxyl; halogen; -NR c Rd ; Hydroxyl; optionally 1-5 selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 C6-C4 substituted aryl and halogenated C1-C4 alkyl 14 Aryl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; NR c R d Substituted C1-C6 acyl; C6-C optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl and hydroxy 14 C1-C4 acyl substituted with aryl; C6-C4 acyl substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; 14 C1-C6 alkyl substituted with aryl; C1-C6 alkyl substituted with C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 4-7 membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 4-7 membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and C1-C6 alkyl substituted with 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and deuterated variants thereof; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy;

[0026] R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 halogen and hydroxyl groups, C2-C6 alkenyl optionally substituted by 1-5 halogen and hydroxyl groups, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxyl, C6-C 14 Aryl-substituted C1-C4 alkoxy, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halo-substituted C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14Aryl and their respective deuterated variants; preferably, R7 is selected from hydrogen, deuterium and where R 13 to R 19 、R 42 、R 43 Each independently selected from: hydrogen and deuterium; More preferably, R7 is hydrogen and deuterium;

[0027] R1, R2, R3, R6, R9 to R 12 、R 20 to R 23 and R 26 to R 30 are each independently selected from hydrogen and deuterium; and

[0028] The structure of Formula III contains at least one deuterium atom; preferably contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms.

[0029] In a preferred embodiment, the structural formula of the compound is as shown below: IIIa, IIIb or IIIc:

[0030] wherein p is independently 0, 1, 2 or 3, X is halogen, R 31 、R 32 、R 35 to R 41 、R 44 independently selected from hydrogen and deuterium;

[0031] In a more preferred embodiment, R1, R2, and R3 are all hydrogen.

[0032] In a preferred embodiment, the structural formula of the compound is shown as follows: IIId, IIIe or IIIf:

[0033] In a preferred embodiment, in the structure of formula III, Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

[0034] In some embodiments, the present invention provides a compound of formula IV, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof,

[0035] Where n is 0 or 1;

[0036] Re is selected from the group consisting of: hydrogen, deuterium, C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen and hydroxy; C1-C6 alkoxy optionally substituted by 1-5 substituents selected from halogen and hydroxy; cyano; carboxyl; halogen; -NR c R d ; Hydroxyl; optionally 1-5 selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 C6-C4 substituted aryl and halogenated C1-C4 alkyl 14 Aryl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; NR c R d Substituted C1-C6 acyl; C6-C optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl and hydroxy 14 C1-C4 acyl substituted with aryl; C6-C4 acyl substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; 14 C1-C6 alkyl optionally substituted by aryl; C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C3-C8 cycloalkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 4-7 membered heterocyclyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 4-7 membered heterocyclyl substituted with 5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and deuterated variants thereof; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy;

[0037] R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 halogen and hydroxyl groups, C2-C6 alkenyl optionally substituted by 1-5 halogen and hydroxyl groups, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxyl, C6-C 14Aryl-substituted C1-C4 alkoxy, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halo-substituted C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14 Aryl and their respective deuterated variants; preferably, R7 is selected from hydrogen, deuterium and where R 13 to R 19 、R 42 、R 43 Each independently selected from: hydrogen and deuterium; More preferably, R7 is selected from hydrogen, deuterium and

[0038] R1, R2, R3, R6, R9, R 10 、R 22 、R 23 、R 26 、R 27 and R 30 Each is independently selected from hydrogen and deuterium; preferably, R1, R2, R3 are all hydrogen, R6, R9, R 10 、R 22 、R 23 、R 26 、R 27 and R 30 are each independently selected from hydrogen and deuterium.

[0039] In a preferred embodiment, in formula IV, Re together with the piperidinyl group to which it is attached constitutes a group selected from the group consisting of:

[0040] In a specific embodiment, the present invention provides a compound selected from the group consisting of the following structural formulas, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof:

[0041] In a specific embodiment, the present invention provides the hydrochloride salt of the above compound:

[0042] Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of any compound provided by the present invention as an active ingredient, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0043] In one aspect, the present invention provides the use of any compound provided by the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing or treating diseases caused by bacterial infection.

[0044] In a preferred embodiment, the bacterium is selected from the group consisting of Mycobacterium tuberculosis, drug-resistant Mycobacterium tuberculosis, Mycobacterium smegmatis, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Mycobacterium leprae, Mycobacterium bovis, Mycobacterium marinum, Corynebacterium diphtheriae, Bordetella pertussis, Haemophilus influenzae, and Streptococcus pneumoniae. More preferably, the bacterium is Mycobacterium tuberculosis or drug-resistant Mycobacterium tuberculosis. Preferably, the disease is a pulmonary infectious disease, more preferably an infectious disease caused by Mycobacterium tuberculosis, and more preferably pulmonary tuberculosis.

[0045] Other aspects and advantages of the present invention will become apparent from the following description of specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] FIG1 is a schematic flow diagram of steps a to g for synthesizing the compounds of the present invention or intermediates thereof according to some embodiments of the present invention.

[0047] FIG2 . Changes in lung bacterial load in mice acutely infected with Mycobacterium tuberculosis 4 weeks after treatment with compounds according to some embodiments of the present invention. DETAILED DESCRIPTION

[0048] definition

[0049] In the present invention, "hydrogen" or "H" are used interchangeably to refer to an atom with one proton in its nucleus, which has three isotopes, namely protium (P), deuterium (D) and tritium (T). "Protium" is one of the isotopes of hydrogen, with the symbol P or 1 H, whose atom consists of one proton and one electron, is the main form of hydrogen, accounting for about 99.98% of ordinary hydrogen. "Deuterium", also known as heavy hydrogen, is another stable isotope of hydrogen, with the element symbol D or 2 H, has 1 proton and 1 neutron in its nucleus, and its abundance is 0.016%. 3 Hydrogen, also known as tritium, has a nucleus containing one proton and two neutrons. Its presence in nature is extremely low, at only 0.004%. In this disclosure, unless a specific isotopic form (e.g., deuterium) is specifically indicated for a "hydrogen" atom, the term "hydrogen" includes all isotopic forms in its natural state.

[0050] As used herein, "deuterated" or "deuterated variant" refers to a compound or group thereof in which one or more hydrogen atoms are 2H (deuterium, D). "Deuterated" can be monosubstituted, disubstituted, polysubstituted or fully substituted.

[0051] The "heteroatom" described herein includes oxygen (O), sulfur (S) and nitrogen (N).

[0052] As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. In certain embodiments, the alkyl group is a C1-C4 alkyl group. In some embodiments, the alkyl group is a C1-C3 alkyl group. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, and octyl.

[0053] As used herein, "alkenyl" refers to a straight or branched unsaturated hydrocarbon group containing 2 to 10 carbon atoms, containing at least one carbon-carbon double bond. In some embodiments, the alkenyl group is a C2-C8 alkenyl group. Exemplary alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0054] As used herein, "alkynyl" refers to a straight or branched unsaturated hydrocarbon group containing 2 to 10 carbon atoms, which contains at least one carbon-carbon triple bond. In some embodiments, the alkynyl group is a C2-C6 alkynyl group. Exemplary alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.

[0055] The "alkoxy" used herein refers to a C1-C 10 Alkyl, preferably C1-C6 alkyl or C1-C4 alkyl or oxy substituted by C1-C3 alkyl, such as methoxy, ethoxy, etc.

[0056] As used herein, "aryl" is a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms. In some embodiments, aryl is C6-C 10 Aryl. Exemplary aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl.

[0057] As used herein, "carbocyclyl" includes saturated and partially saturated carbocyclyl groups. The number of ring carbon atoms in a carbocyclyl group is 3-15. Saturated carbocyclyl groups include cycloalkyl groups, which are typically C3-C8 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Partially saturated carbocyclyl groups include cycloalkenyl groups, such as C3-C8 cycloalkenyl groups, for example cyclopentenyl, cycloheptenyl and cyclooctenyl. Herein, carbocyclyl groups also include bridged ring groups and spirocyclyl groups. Preferably, herein, the number of ring carbon atoms in a bridged ring group and spirocyclyl groups can be 4-12.

[0058] Herein, halogen includes fluorine, chlorine, bromine and iodine.

[0059] As used herein, an acylamino group is any C1-C 10 Acyl, which can be represented by R-NH-, where R is C1-C 10 Acyl. Exemplary acylamino groups include acetylamino, propionylamino, butyrylamino, valerylamino, and hexanoylamino.

[0060] Herein, acyl groups may be represented by RC(O)-, wherein R is H or an alkyl group as described herein. Exemplary acyl groups are C1-C 10 Acyl groups, such as acetyl.

[0061] Herein, an ester group can be represented as RC(O)-O- or ROC(O)-, wherein R is an alkyl group as described herein, or R is a portion of an amino acid molecule other than a carboxyl group (i.e., an ester group is a monovalent group obtained by removing the hydrogen from the carboxyl group of an amino acid molecule).

[0062] As used herein, "heterocyclyl" refers to a saturated or partially saturated 3-7 membered monocyclic group, a 7-10 membered bicyclic group, a spirocyclic group or a bridged cyclic group, which is composed of carbon atoms and 1-4 heteroatoms selected from O, N, and S. The number of ring atoms of the spirocyclic group (also referred to herein as "spiroheterocyclyl") or the bridged cyclic group (also referred to herein as "bridged heterocyclyl") may generally be 4-12. Exemplary heterocyclyl groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, dihydroindolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl and tetramoyl.

[0063] As used herein, "heteroaryl" refers to a group containing 5-14, preferably 5-10, ring atoms, with 6, 10, or 14 π electrons shared in the ring system. The ring atoms contained in the heteroaryl group are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur. Exemplary heteroaryl groups include thienyl, benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthrenyl, thienoxanyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perylene, pyrimidinyl, pyridaz ... Phenyl, phenanthroline, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, tetrahydropyridopyrimidinyl, tetrahydropenta[c]pyrazol-3-yl, benzisoxazolyl such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-hydroxyindolyl, thiadiazide, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridinyl, triazolopyridazinyl, tetrahydropyridopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, triazolopyrazinyl, thienoquinolyl, furanoquinolyl, thiazoquinolyl, pyrazoloquinolyl, pyrroloquinolyl, imidazoquinolyl, oxazoloquinolyl, etc.

[0064] As used herein, unless otherwise indicated, when substituted, the alkyl, carbocyclyl, alkoxy, alkenyl, alkynyl, heterocyclyl, aryl, or heteroaryl groups described in any embodiment herein may be substituted with one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of halogen, hydroxy, thiol, carboxyl, amino, nitro, cyano, C1-C6 acylamino, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl ... 10 Acyl, C6-C 14 Aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkenyl, C2-C6 alkynyl, heterocyclic or heteroaryl, etc. Among these substituents, amino, C1-C6 acylamino, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C 10 Acyl, C6-C 14Aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkenyl, C2-C6 alkynyl, heterocyclyl or heteroaryl itself may also be optionally substituted, for example each may be optionally substituted with 1, 2, 3 or 4 groups selected from halogen, hydroxy, mercapto, carboxyl, amino, nitro, cyano, C1-C6 acylamino, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C6 alkyl, 14 The alkyl group may be substituted with a substituent of an aryl group, a C3-C8 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a heterocyclyl group or a heteroaryl group.

[0065] It should be understood that in each embodiment herein, when the substituent is a carbocyclyl, heterocyclyl, aryl or heteroaryl group, the number of the carbocyclyl, heterocyclyl, aryl or heteroaryl substituents is generally one or two.

[0066] The term "arylalkyl", "heteroarylalkyl" or "heterocyclylalkyl" refers to an alkyl group substituted by an aryl group, a heteroaryl group or a heterocyclyl group, respectively, wherein aryl, heteroaryl, heterocyclyl and alkyl have the same definitions as above. In the present invention, aryl, heteroaryl, heterocyclyl and / or alkyl may have a specific number of carbon atoms, for example, an example of "arylalkyl" is "C6-C 14 Aryl C1-C 10 "Alkyl" refers to a C6-C 14 Aryl-substituted C1-C 10 In the present invention, the term "comprising" means that the pharmaceutical composition may also contain any other components, and these components may be present in any amount, as long as the components present in this amount are acceptable to the human body and have no unacceptable effect on the activity of the active ingredient in the pharmaceutical composition of the present invention.

[0067] "Pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, and the like. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic or organic base that retains the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. In some embodiments, the pharmaceutically acceptable salt of the compound of formula I of the present invention is its hydrochloride or deuterated hydrochloride.

[0068] The term "stereoisomers" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like. The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other. The term "diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0069] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0070] The term "nitrogen oxide" or "N-oxide" refers to the oxidation of one or more nitrogen atoms to form N-oxides when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid). In particular, N-oxides can be formed, for example, by reacting the amine compound with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0071] The term "hydrate" refers to an association in which the solvent molecule is water.

[0072] In the present invention, "solvate" refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include but are not limited to isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate and acetic acid.

[0073] In the present invention, the term "prodrug" includes a compound which may be biologically active or inactive, and which undergoes metabolism or chemical reactions in the human body to be converted into a compound of Formula I to Formula IV and any sub-formula thereof, or a salt thereof, when taken by an appropriate method.

[0074] As used herein, "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not significantly affect the biological activity or properties of the compounds of the invention and is relatively non-toxic. In this application, "pharmaceutically acceptable carriers or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant government regulatory authorities as acceptable for use by humans or livestock.

[0075] As used herein, "preventing" includes reducing the likelihood of a disease or condition occurring or becoming worse in a patient.

[0076] As used herein, "treating" includes the following meanings: inhibiting a disease or condition, that is, curbing its development; alleviating a disease or condition, that is, causing the condition of the disease or condition to subside; and alleviating the symptoms caused by the disease or condition.

[0077] As used herein, an "effective amount" refers to an amount of at least one agent or compound sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for therapeutic purposes is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0078] Deuterated tetracyclic derivatives

[0079] A first aspect of the present invention provides a deuterated tetracyclic derivative, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof.

[0080] In some embodiments, the present invention provides a compound represented by Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof:

[0081] Where n is 0 or 1;

[0082] R4 is selected from H, halogen, aldehyde, hydroxy, thiol, -NR'R", cyano, nitro, optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 14 Aryl, optionally substituted C5-C 10 Heteroaryl, optionally substituted C4-C 10Heterocyclyl and their respective deuterated variants; preferably, R4 is selected from optionally substituted C6-C 14 Aryl C1-C 10 Alkyl, optionally substituted C5-C 10 Heteroaryl C1-C 10 Alkyl, optionally substituted C4-C 10 Heterocyclic C1-C 10 Alkyl groups and their respective deuterated variants;

[0083] R7 is selected from H, hydroxy, thiol, cyano, carboxyl, nitro, -NR'R", optionally substituted C1-C 10 Alkyl, optionally substituted C2-C 10 Alkenyl, optionally substituted C2-C 10 Alkynyl, C1-C 10 Ester group, acylamino group, halogen, optionally substituted C3-C8 carbocyclic group, optionally substituted C1-C 10 Alkoxy, optionally substituted C6-C 14 Aryl, optionally substituted C5-C 10 Heteroaryl, optionally substituted C4-C 10 heterocyclyl and their respective deuterated variants;

[0084] wherein R' and R" are each independently selected from: H, optionally substituted C1-C 10 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C1-C 10 alkoxy;

[0085] R1, R2, R3, R6, R9 and R 10 are independently selected from: hydrogen and deuterium; and

[0086] The structure shown in Formula I contains at least one deuterium atom.

[0087] In some embodiments, R4 is preferably an optionally substituted C6-C 14 Aryl C1-C 10 Alkyl, optionally substituted C5-C 10 Heteroaryl C1-C 10 Alkyl, optionally substituted C4-C 10 Heterocyclic C1-C 10 More preferably, R4 is an optionally substituted C4-C8 heterocyclyl C1-C3 alkyl or a deuterated variant thereof. More preferably, R4 is an optionally substituted C6 heterocyclyl C1-C3 alkyl or a deuterated variant thereof.

[0088] In some embodiments, R4 is -(CR 11 R 12 ) m-NR a R b ,in:

[0089] m is 1, 2, or 3;

[0090] R 11 and R 12 are independently selected from hydrogen and deuterium; and

[0091] R a and R b Each is independently selected from the following substituents and their respective deuterated variants: H; C1-C1 optionally substituted with 1-5 substituents selected from halogen and hydroxy 10 C2-C8 alkenyl optionally substituted by 1-5 substituents selected from halogen and hydroxy; 3-14 membered carbocyclyl optionally substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 3-14 membered carbocyclyl substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 4-10 membered heterocyclyl substituted by 1-5 substituents selected from halogen, hydroxy and C1-C4 alkyl; C6-C 14 Aryl; and C6-C optionally substituted by 1-5 groups selected from halogen, hydroxy and C1-C4 alkyl 14 Aryl-C1-C6 alkyl; or R a and R b Together with the nitrogen atom to which they are attached, they form an optionally substituted 4- to 7-membered heterocyclyl or benzo 4- to 7-membered heterocyclyl, or a deuterated variant thereof, wherein the 4- to 7-membered heterocyclyl or benzo 4- to 7-membered heterocyclyl is optionally substituted by 1-5 substituents selected from the group consisting of: C1-C6 alkyl optionally substituted by 1-5 substituents selected from the group consisting of halogen and hydroxy; C1-C6 alkoxy optionally substituted by 1-5 substituents selected from the group consisting of halogen and hydroxy; cyano; carboxyl; halogen; -NR c R d ; Hydroxyl; optionally 1-5 selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 C6-C4 substituted aryl and halogenated C1-C4 alkyl 14 Aryl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; NR c R d Substituted C1-C6 acyl; C6-C optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl and hydroxy 14C1-C4 acyl substituted with aryl; C6-C4 acyl substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; 14 C1-C6 alkyl optionally substituted by aryl; C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl C3-C8 cycloalkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl C3-C8 cycloalkyl; 4-7 membered heterocyclyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; C1-C6 alkyl optionally substituted with 4-7 membered heterocyclyl which is substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl which is optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and C1-C6 alkyl which is substituted with 5-10 membered heteroaryl which is optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy.

[0092] In a preferred embodiment, R4 is -(CR 11 R 12 ) m -NR a R b ,in:

[0093] m is 1, 2, or 3;

[0094] R 11 and R 12 are independently selected from hydrogen and deuterium; and

[0095] R a and R b Together with the nitrogen atom to which they are attached, they form an optionally substituted 4- to 7-membered heterocyclyl, a benzo 4- to 7-membered heterocyclyl, or a deuterated variant thereof, wherein the 4- to 7-membered heterocyclyl or the benzo 4- to 7-membered heterocyclyl is optionally substituted with 1-5 substituents selected from the group consisting of: C1-C6 alkyl optionally substituted with 1-5 substituents selected from the group consisting of halogen and hydroxy; C1-C6 alkoxy optionally substituted with 1-5 substituents selected from the group consisting of halogen and hydroxy; cyano; carboxyl; halogen; -NR c R d ; Hydroxyl; optionally 1-5 selected from C1-C4 acyl, halogen, NR c R d, C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 C6-C4 substituted aryl and halogenated C1-C4 alkyl 14 Aryl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; NR c R d Substituted C1-C6 acyl; C6-C optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl and hydroxy 14 C1-C4 acyl substituted with aryl; C6-C4 acyl substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; 14 C1-C6 alkyl optionally substituted by aryl; C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl C3-C8 cycloalkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl C3-C8 cycloalkyl; 4-7 membered heterocyclyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; C1-C6 alkyl optionally substituted with 4-7 membered heterocyclyl which is substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl which is optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and C1-C6 alkyl which is substituted with 5-10 membered heteroaryl which is optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy.

[0096] In a preferred embodiment, R4 is -(CR 11 R 12 ) m -NR a R b ,in:

[0097] m is 1, 2, or 3;

[0098] R 11 and R 12 are independently selected from hydrogen and deuterium; and -NR a R b Selected from:

[0099] wherein p is independently 0, 1, 2 or 3, X is halogen, R 20 to R 32 、R 35 to R 41 、R 44 independently selected from: hydrogen and deuterium;

[0100] Preferably, -NR a R b Selected from:

[0101] where R 20 to R 41 、R 44 Independently selected from: hydrogen and deuterium.

[0102] In a preferred embodiment, R4 is -(CR 11 R 12 ) m -NR a R b ,in:

[0103] m is 1, 2, or 3;

[0104] R 11 and R 12 are independently selected from hydrogen and deuterium; and -NR a R b Selected from:

[0105] In any of the above embodiments, R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 halogen and hydroxyl groups, C2-C6 alkenyl optionally substituted by 1-5 halogen and hydroxyl groups, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxyl, C6-C 14 Aryl-substituted C1-C4 alkoxy, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halo-substituted C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14 aryl and their respective deuterated variants.

[0106] R7 is preferably selected from hydrogen, deuterium and where R 13 to R 19 、R 42 、R 43 are independently selected from hydrogen and deuterium.

[0107] In a preferred embodiment, R7 is selected from hydrogen, deuterium and

[0108] In a preferred embodiment, the compound of Formula I comprises 2 to 20 deuterium atoms, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms. In some embodiments, the compound of Formula I comprises 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 12 to 20, 14 to 20, 16 to 20, 18 to 20, 4 to 18, 6 to 16, 8 to 14 or 10 to 12 deuterium atoms.

[0109] In some embodiments, the present invention provides a compound of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof,

[0110] in,

[0111] R7 is selected from hydrogen, deuterium and where R 13 to R 19 、R 42 、R 43 are independently selected from hydrogen and deuterium.

[0112] R1, R2, R3, R6, R 11 、R 12 and R 20 to R 29 are independently selected from hydrogen and deuterium; and

[0113] The structure shown in Formula II contains at least one deuterium atom.

[0114] In a preferred embodiment, R7 is

[0115] In a preferred embodiment, the compound shown in Formula II comprises 2 to 20 deuterium atoms, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms. In some embodiments, the compound shown in Formula II comprises 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 12 to 20, 14 to 20, 16 to 20, 18 to 20, 4 to 18, 6 to 16, 8 to 14 or 10 to 12 deuterium atoms.

[0116] In some embodiments, the present invention provides a compound of formula IIa, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R 11 and R 12 are independently selected from hydrogen and deuterium, R7 has any of the definitions given above, and the structure represented by Formula IIa contains at least one deuterium atom:

[0117] In some embodiments, the present invention provides a compound of formula IIb below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R 11 and R 12 are independently selected from hydrogen and deuterium, R7 has any of the definitions given above, and the structure shown in Formula IIb contains at least one deuterium atom:

[0118] In some embodiments, the present invention provides a compound of formula IIc, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R 11 and R 12 are independently selected from hydrogen and deuterium, R7 has any of the definitions given above, and the structure represented by Formula IIc contains at least one deuterium atom:

[0119] In some embodiments, the present invention provides a compound of the formula shown below IId, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6 and R 22 to R 27 are independently selected from hydrogen and deuterium, R7 has any of the definitions given above, and the structure shown in Formula IId contains at least one deuterium atom:

[0120] In some embodiments, the present invention provides a compound of formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof,

[0121] wherein Re is selected from: C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen and hydroxy; C1-C6 alkoxy optionally substituted by 1-5 substituents selected from halogen and hydroxy; cyano; carboxyl; halogen; -NR c Rd ; Hydroxyl; optionally 1-5 selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 C6-C4 substituted aryl and halogenated C1-C4 alkyl 14 Aryl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; NR c R d Substituted C1-C6 acyl; C6-C optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl and hydroxy 14 C1-C4 acyl substituted with aryl; C6-C4 acyl substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; 14 C1-C6 alkyl substituted with aryl; C1-C6 alkyl substituted with C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 4-7 membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 4-7 membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and C1-C6 alkyl substituted with 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and deuterated variants thereof; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy;

[0122] R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 halogen and hydroxyl groups, C2-C6 alkenyl optionally substituted by 1-5 halogen and hydroxyl groups, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxyl, C6-C 14 Aryl-substituted C1-C4 alkoxy, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halo-substituted C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14 aryl groups and their respective deuterated variants;

[0123] R1, R2, R3, R6, R9 to R 12 、R 20 to R 23 and R 26 to R 30 are each independently selected from hydrogen and deuterium; and

[0124] The structure represented by Formula III contains at least one deuterium atom.

[0125] In a preferred embodiment, wherein Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

[0126] In a preferred embodiment, R7 is selected from hydrogen, deuterium and where R 13 to R 19 、R 42 、R 43 Each is independently selected from the group consisting of hydrogen and deuterium. In a more preferred embodiment, R7 is hydrogen and deuterium.

[0127] In a preferred embodiment, the compound of Formula III comprises 2 to 20 deuterium atoms, For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms. In some embodiments, the compound of Formula III comprises 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 20, 6 to 20, 8 to 20, 10 to 20, 12 to 20, 14 to 20, 16 to 20, 18 to 20, 4 to 18, 6 to 16, 8 to 14 or 10 to 12 deuterium atoms.

[0128] In a preferred embodiment, the present invention provides a compound of formula IIIa, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R9 to R 12 、R 20 to R 23 、R 26 to R 30 、R 38 to R 41 are independently selected from hydrogen and deuterium, X is halogen, R7 has any of the definitions given above, and the structure represented by Formula IIIa contains at least one deuterium atom:

[0129] In a more preferred embodiment, R1, R2, and R3 are all hydrogen.

[0130] In a preferred embodiment, the present invention provides a compound of formula IIIb below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R9 to R 12 、R 20 to R 23 、R 26 to R 32 、R 35 to R 37 are independently selected from hydrogen and deuterium, p is 0, 1, 2 or 3, R7 has any of the definitions given above, and the structure shown in Formula IIIb contains at least one deuterium atom:

[0131] In a more preferred embodiment, R1, R2, and R3 are all hydrogen.

[0132] In a preferred embodiment, the present invention provides a compound as shown in the following structural formula IIIc, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R9 to R 12 、R 20 to R 23 、R 26 to R 32 、R 35 to R 37 、R 44 are independently selected from hydrogen and deuterium, p is 0, 1, 2 or 3, R7 has any of the definitions described above, and the structure shown in Formula IIIc contains at least one deuterium atom:

[0133] In a more preferred embodiment, R1, R2, and R3 are all hydrogen.

[0134] In a further preferred embodiment, the present invention provides a compound of formula IIId below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R9, R 10 、R 22 、R 23 、R 26 、R 27 、R 30 、R 38 to R 41 are independently selected from hydrogen and deuterium, X is halogen, R7 has any of the definitions given above, and the structure represented by Formula IIId contains at least one deuterium atom:

[0135] In a further preferred embodiment, the present invention provides a compound of formula IIIe, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R9, R 10 、R 22 、R 23 、R 26 、R 27 、R 30 to R 32 、R 35 to R 37 are independently selected from hydrogen and deuterium, p is 0, 1, 2 or 3, R7 has any of the definitions described above, and the structure shown in Formula IIIe contains at least one deuterium atom:

[0136] In a further preferred embodiment, the present invention provides a compound of formula IIIf below, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R9, R 10 、R 22 、R 23 、R 26 、R 27 、R 30 to R 32 、R 35 to R 37 、R 44 are independently selected from hydrogen and deuterium, p is 0, 1, 2 or 3, R7 has any of the definitions described above, and the structure shown in Formula IIIf contains at least one deuterium atom:

[0137] In some embodiments, the present invention provides a compound of formula IV, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof,

[0138] Where n is 0 or 1;

[0139] Re is selected from the group consisting of: hydrogen, deuterium, C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen and hydroxy; C1-C6 alkoxy optionally substituted by 1-5 substituents selected from halogen and hydroxy; cyano; carboxyl; halogen; -NR c R d ; Hydroxyl; optionally 1-5 selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C14 C6-C4 substituted aryl and halogenated C1-C4 alkyl 14 Aryl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; NR c R d Substituted C1-C6 acyl; C6-C optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl and hydroxy 14 C1-C4 acyl substituted with aryl; C6-C4 acyl substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxyl; 14 C1-C6 alkyl optionally substituted by aryl; C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C3-C8 cycloalkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 4-7 membered heterocyclyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 4-7 membered heterocyclyl substituted with 5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-C1-C4 alkyl and hydroxy; and deuterated variants thereof; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy;

[0140] R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 halogen and hydroxyl groups, C2-C6 alkenyl optionally substituted by 1-5 halogen and hydroxyl groups, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxyl, C6-C 14 Aryl-substituted C1-C4 alkoxy, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halo-substituted C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14 aryl groups and their respective deuterated variants;

[0141] R1, R2, R3, R6, R9, R 10 、R 22 、R 23 、R 26 、R 27and R 30 Each is independently selected from hydrogen and deuterium; preferably, R1, R2, R3 are all hydrogen, R6, R9, R 10 、R 22 、R 23 、R 26 、R 27 and R 30 are each independently selected from hydrogen and deuterium.

[0142] In a preferred embodiment, preferably, R7 is selected from hydrogen, deuterium and where R 13 to R 19 、R 42 、R 43 Each independently selected from: hydrogen and deuterium. In a more preferred embodiment, R7 is selected from hydrogen, deuterium and

[0143] In a preferred embodiment, Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

[0144] In a more preferred embodiment, Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

[0145] In a preferred embodiment, the compounds provided by the present invention have a maximum blood concentration C of 1.5 mmol / l relative to the corresponding undeuterated compounds. max , in vivo exposure AUC 0-t The highest concentration of C in lung tissue max In some embodiments, the compounds provided by the present invention have a maximum blood concentration C of 100mg / L / min in vivo relative to the corresponding compounds without deuteration. max In some embodiments, the compounds provided herein have an in vivo exposure of AUC relative to their undeuterated counterparts. 0-t In some embodiments, the compounds provided by the present invention have a maximum concentration C in lung tissue relative to their undeuterated counterparts. max In some embodiments, the compounds provided by the present invention have a maximum blood concentration C of 100mg / L / min in vivo relative to the corresponding compounds without deuteration. max The highest concentration of C in lung tissue max In some embodiments, the compounds provided by the present invention have a maximum blood concentration C of 100mg / L compared to the corresponding compounds without deuteration. max and in vivo exposure AUC 0-tIn some embodiments, the compounds provided by the present invention have an in vivo exposure of AUC relative to their undeuterated counterparts. 0-t The highest concentration of C in lung tissue max In some embodiments, the compounds provided by the present invention have a maximum blood concentration C of 100mg / L compared to the corresponding compounds without deuteration. max , in vivo exposure AUC 0-t The highest concentration of C in lung tissue max All significantly improved.

[0146] In preferred embodiments, the significantly increased aspect of the deuterated compound is greater than 1-fold, for example, 1.1 to about 100-fold, 1.1 to about 50-fold, 1.1 to about 30-fold, 1.1 to about 10-fold, 1.1 to about 8-fold, 1.1 to about 5-fold, 1.1 to about 4.5-fold, 1.1 to about 4-fold, 1.1 to about 3.5-fold, 1.1 to about 3-fold, 1.1 to about 2.5-fold, 1.1 to about 2-fold, 1.1 to about 1. 9 times, 1.1 to about 1.8 times, 1.1 to about 1.7 times, 1.1 to about 1.6 times, 1.1 to about 1.5 times, 1.1 to about 1.4 times, 1.1 to about 1.3 times, 1.1 to about 1.2 times, about 2 to about 100 times, about 2 to about 50 times, about 2 to about 10 times, about 2 to about 5 times, about 2 to about 3 times, about 3 to about 10 times, about 3 to about 5 times, about 4 to about 10 times, about 5 to about 10 times, about 6 to about 10 times, about 7 to about 10 times, or about 8 to about 10 times. In preferred embodiments, the significantly increased aspect of the deuterated compound is 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, or 100-fold greater than the corresponding aspect of the non-deuterated counterpart compound.

[0147] In other embodiments, the significantly increased refers to an increase of about 10% to about 500% in the compared aspect of the deuterated compound provided herein, for example, about 10% to about 400%, about 10% to about 300%, about 10% to about 200%, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, or about 10% to about 15% in the compared aspect compared to the corresponding aspect of the non-deuterated counterpart compound. In preferred embodiments, the significantly increased activity of the deuterated compounds provided herein is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, or about 500% higher than the corresponding activity of the deuterated counterparts.

[0148] In the present invention, when the highest blood concentration C max , in vivo exposure AUC 0-t The highest concentration of C in lung tissue max When two or all of them are significantly increased, the magnitude of their increase is independent of each other. For example, for a deuterated compound, the highest blood concentration C max The in vivo exposure AUC is about 3 times that of the non-deuterated counterpart. 0-t It is about 1.5 times that of the non-deuterated counterpart. For example, for a deuterated compound, its in vivo exposure AUC 0-t The highest concentration of C in lung tissue was increased by about 100%. max It is about 1.2 times that of the non-deuterated counterpart.

[0149] In a preferred embodiment, the present invention provides a compound selected from any one of the following structural formulas, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof:

[0150] In a preferred embodiment, the present invention provides the hydrochloride salt YF025 to YF048 of any one of the above compounds YF001 to YF024:

[0151] Pharmaceutical composition

[0152] Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of any one of the compounds provided by the present invention as an active ingredient, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof; and a pharmaceutically acceptable carrier or excipient.

[0153] In some embodiments, the active ingredient may account for 0.01-99 wt%, 0.05-80 wt%, 0.10-70 wt% or 0.10-50 wt% of the total weight of the composition.

[0154] In some embodiments, the pharmaceutical composition of the present invention may further comprise a second active ingredient, which may be an antibacterial agent, for example, another anti-Mycobacterium tuberculosis agent.

[0155] In some embodiments, when administered in combination, the weight ratio of the compound of the present invention to the other antibacterial agent can be determined by those skilled in the art. The ratio and the precise dosage and frequency of administration depend on the specific compound of the present invention and the other antibacterial agent used, the specific symptoms to be treated, the severity of the symptoms to be treated, the age, weight, sex, diet, time of administration and general physical condition of the particular patient, the mode of administration, and other medications taken by the individual, which are well known to those skilled in the art. In addition, it is clear that the effective daily dose can be reduced or increased depending on the response of the subject to be treated and / or the assessment of the compound of the present invention by the physician prescribing the compound of the present invention.

[0156] The compound of the present invention and one or more other antibacterial drugs can be combined into a single preparation, or they can be formulated into separate preparations so that they can be administered simultaneously, separately or sequentially. Therefore, the present invention also relates to a product as a combined preparation for simultaneous, separate or sequential use in the treatment of bacterial infections, which contains a compound of the present invention and one or more other antibacterial drugs.

[0157] Other antibacterial drugs may include β-lactam antibiotics, such as natural penicillins, semi-synthetic penicillins, natural cephalosporins, semi-synthetic cephalosporins, cephamycins, 1-oxocephems, clavulanic acid, penicillins, carbapenems, nocardiacins, monobactams; tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides, such as N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S; macrolides, such as 12-membered ring macrolides, 14-membered ring macrolides, 16-membered ring macrolides; ansamycins; Peptides, for example, bleomycins, gramicidins, polymyxins, bacitracin, macrocyclic peptide antibiotics containing lactone bonds, antinomycins, amphomycins, capreomycins, streptomycins, enramycins, micamycins, neocarzinostatin, streptomycins, viomycins, virginiamycins; cycloheximide; cycloserine; sarcomycin; sarcomycin A; novobiocin; griseofulvin; chloramphenicol; mitomycins; fumagillin; monensin; pyrrolnitrin; fosfomycin; fusidic acid; D-(p-hydroxyphenyl)glycine; D-phenylglycine; enediynes.

[0158] Specific antibiotics that can be combined with the compounds of the present invention are, for example, penicillins (penicillin potassium, procaine penicillin, benzathine penicillin), phenoxymethyl penicillin (potassium), phenoxyethyl penicillin (potassium), propicillin, carbenicillin (disodium, phenyl sodium, indanyl sodium), sulbenicillin, ticarcillin disodium, methicillin sodium, oxacillin sodium, o-cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, mezlocillin, piperacillin sodium, amoxicillin, cyclohexyl, hectacillin, sulbactam sodium, talampicillin hydrochloride, bacampicillin hydrochloride, pivmecillin, cephalexin, cefaclor, cefuroxime, cefadroxil, cephradine, cephalosporin, Cefazolin sodium, Ceftriaxone sodium, Cefacetrile sodium, Cefsulodin sodium, Ceftriaxone, Ceftriaxone, Cefoperazone sodium, Cefmandole, Ceftiam hydrochloride), Cefazolin sodium, Cefazolin sodium, Ceftriaxone sodium, Cefmenoxime hydrochloride, Cefuroxime, Ceftriaxone sodium, Ceftazidime, Cefoxitin, Cefmetazole, Cefotetan, Latamoxef, Clavulanic acid, Imipenem, Aztreonam, Tetracycline, Chlortetracycline hydrochloride, Demeclocycline, Oxytetracycline, Metacycline, Doxycycline, Rolicycline, Minocycline, Daunorubicin hydrochloride, Doxorubicin, Aclarubicin, Kanamycin sulfate, Kanamycin B, Tobramycin cin, gentamicin sulfate, dibekacin, amikacin, ninomicotin, ribosomycin, neomycin sulfate, paromomycin sulfate, streptomycin sulfate, dihydrostrepomycin, hygromycin A, hygromycin B, apramycin, sisomicin, netilmicin sulfate, spectinomycin hydrochloride, astamicin sulfate, validamycin, kasugamycin, polyoxin, baumycin S, erythromycin, erythromycin estolate, oleandomycin phosphate, troleandomycin, kitasamycin, josamycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycin sulfate, peplomycin sulfate, gramicidin S, polymyxin B, cum Strains, polymyxin sulfate, colistin sodium methanesulfonate, enratoxin, mikamycin, virginiamycin, capreomycin sulfate, viomycin, enviromycin, vancomycin, actinomycin D, neocarzinostatin, belastatin, pepstatin, monensin, lasalocid, salinomycin, amphotericin B, nystatin, natamycin, trichostatin, plicamycin, lincomycin, clindamycin, clindamycin palmitate hydrochloride, flavophospholipol, cycloserine, pecillocin, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, nitropyrrolidone, fosfomycin, fusidic acid, dicyclam, tiamulin, sikanidazole.

[0159] Other mycobacterial drugs that can be combined with the compounds of the present invention are, for example, rifampicin, ethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin, amikacin, capreomycin, streptomycin, ethionamide, prothionamide, cycloserine, terizidone, para-aminosalicylic acid, clofazimine, clarithromycin, amoxicillin-clavulanate, delamanid, premanid, bedaquiline, sudapyridine, TB47, GSK 3036656, gepedacin, thiosemicarbazide, meropenem-clavulanate, TBA-7371, OPC-167832, Telecebec (Q203), BTZ-043, Contezolid (MRX-4 / MRX-1), Delpazolid (LCB01–0371), Macozinone, Pretomanid, SPR720, SQ109, TBI-166, TBI-223, and thioridazine.

[0160] The pharmaceutical compositions of the present invention can be administered topically (e.g., through the skin) in the form of creams, solutions, suspensions, aerosols, and dry powder formulations; or systemically, for example, orally in the form of tablets, capsules, syrups, powders, or granules; or gastrointestinal administration in the form of solutions or suspensions; or subcutaneously (injection); or intravenously (injection); or rectal administration in the form of suppositories; or transdermally. The compositions of the present invention can be prepared by conventional methods using conventional pharmaceutical excipients well known in the art. These pharmaceutical compositions are preferably in a single dose form, particularly suitable for oral administration or parenteral injection. For example, when preparing a composition in an oral dosage form, any common pharmaceutical medium, such as water, glycol, oil, alcohol, etc., can be used in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starch, sugar, kaolin, diluents, lubricants, binders, disintegrants, etc., can be used in the case of powders, pills, capsules, and tablets. Because administration is convenient, tablet and capsule represent the most advantageous oral dosage unit form, and obviously adopt solid pharmaceutical carrier in this case.For parenteral composition, carrier usually comprises sterile water that accounts for at least most part, although can comprise other ingredients, for example, to help dissolve.For example can prepare injectable solution, wherein carrier comprises saline solution, glucose solution or the mixed solution of saline solution and glucose.Also can prepare injectable suspension, can adopt suitable liquid carrier, suspending agent etc. in this case.Also comprise the solid form preparation that is designed to be converted into liquid form preparation shortly before use.

[0161] The pharmaceutical composition may further contain various other ingredients well known in the art, such as lubricants, stabilizers, buffers, emulsifiers, viscosity regulators, surfactants, preservatives, flavoring agents, or coloring agents.

[0162] For ease of administration and uniformity of dosage, it is particularly preferred that the pharmaceutical compositions described above be formulated in unit dosage form. As used herein, unit dosage form refers to physically discrete units suitable as single doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in combination with a desired pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions, and the like, and segregated multiples thereof. The daily dosage of the compounds of the present invention will, of course, vary with the compound employed, the route of administration, the desired treatment, and the mycobacterial disease identified.

[0163] Uses and methods

[0164] Another aspect of the present invention provides the use of any of the provided compounds, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or prodrug thereof, in medicine.

[0165] In some embodiments, the present invention provides a compound of any one of Formulas I, II, IIa, IIb, IIc, IId, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, or IV, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or prodrug thereof, for use in the preparation of a medicament for preventing or treating a disease caused by a bacterial infection.

[0166] In some embodiments, the present invention provides a compound of any one of Formula I, II, IIa, IIb, IIc, IId, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IV, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or prodrug thereof for use in preventing or treating diseases caused by bacterial infection.

[0167] In some embodiments, the present invention provides a method for preventing or treating a disease caused by a bacterial infection, comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of any one of the compounds of Formula I, II, IIa, IIb, IIc, IId, III, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IV, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or prodrug thereof.

[0168] In any of the above embodiments, the bacteria is selected from the group consisting of Mycobacterium tuberculosis, drug-resistant Mycobacterium tuberculosis, Mycobacterium smegmatis, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Mycobacterium leprae, Mycobacterium bovis, Mycobacterium marinum, Corynebacterium diphtheriae, Bordetella pertussis, Haemophilus influenzae, and Streptococcus pneumoniae. In some embodiments, the bacteria is Mycobacterium tuberculosis or drug-resistant Mycobacterium tuberculosis. In some embodiments, the drug-resistant Mycobacterium tuberculosis is rifampicin-resistant, isoniazid-resistant, or both rifampicin and isoniazid-resistant.

[0169] In some embodiments, the disease is a pulmonary infectious disease. In a preferred embodiment, the disease is an infectious disease caused by Mycobacterium tuberculosis. In a preferred embodiment, the disease is pulmonary tuberculosis.

[0170] Example

[0171] The present invention deuterates tetracyclic derivatives with Mycobacterium tuberculosis inhibitory activity to obtain a class of deuterated derivatives with good pharmacokinetic properties and significant anti-tuberculosis efficacy in vivo and in vitro.

[0172] Figure 1 and the following synthetic route diagram show the preparation route of the compound of the present invention or its intermediate. The detailed steps of step a to step g shown in Figure 1 are as follows.

[0173] Step a: Under an anhydrous and oxygen-free ice bath, add ultra-dry tetrahydrofuran (THF) to a reaction flask containing lithium aluminum hydride (LiAlD4, 2.0 eq), followed by the dropwise addition of an ultra-dry THF solution containing glutarimide (1.0 eq). The reaction temperature was maintained below 5°C for 30 min. The cooling bath was removed, the mixture was allowed to warm to room temperature, and then heated to reflux for 3 h. The reaction was then cooled to room temperature and, under an ice bath, purified water (10.0 eq) and a 15% aqueous NaOH solution (10.0 eq) were slowly added dropwise to quench the reaction. The THF-water solution containing 2,2,6,6-piperidine-d4 was filtered to obtain a pH of approximately 12-14, which was used directly in the next reaction.

[0174] Step b: Add di-tert-butyl dicarbonate ((Boc)2O, 0.7 eq) to a THF-water solution containing 2,2,6,6-piperidine-d4, stir at room temperature for 3 h, extract with ethyl acetate, wash three times with pure water, dry the organic phase with anhydrous Na2SO4, and concentrate to obtain crude tert-butyl 2,2,6,6-piperidine-d4-1-carboxylate;

[0175] Step c: Dissolve the crude product of tert-butyl 2,2,6,6-piperidine-d4-1-carboxylate in ethyl acetate, add HCl in ethyl acetate solution (3.5 M, 5.0 eq), react at room temperature for 3 h, and concentrate to obtain 2,2,6,6-piperidine-d4 hydrochloride;

[0176] Step d: 3-(2,4-dimethoxyphenyl)-3-oxopropionic acid ethyl ester (1.05eq), copper trifluoromethanesulfonate (0.1eq), and tert-butyl-p-benzoquinone (1.0eq) were added to a reaction flask, toluene (2mL / mmol) was added, and the reaction was carried out at 110°C. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain a crude product, which was then slurried with methanol and filtered to obtain 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl ester;

[0177] Step e: 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl ester (1.0 eq), 2,2,6,6-piperidine-d4 hydrochloride (2.0 eq), triethylamine (2.0 eq), and paraformaldehyde-d2 were added to a reaction flask, and ethanol was added. The reaction was carried out at 80° C. After the reaction was completed as monitored by TLC, the ethanol was removed by concentration, and the product was purified by column chromatography to obtain 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)benzofuran-3-carboxylic acid ethyl ester;

[0178] 2,2,6,6-piperidine-d4 hydrochloride (2.0 eq) was replaced with piperidine hydrochloride to obtain ethyl 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-ylmethyl-d2)benzofuran-3-carboxylate;

[0179] By replacing paraformaldehyde-d2 with 37% formaldehyde aqueous solution, ethyl 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-yl-2,2,6,6-d4)methyl)benzofuran-3-carboxylate can be obtained;

[0180] Step f: 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)benzofuran-3-carboxylic acid ethyl ester (2.0 eq) was dissolved in ultra-dry dichloromethane. Under nitrogen protection, a dichloromethane (DCM) solution of boron tribromide (2 M in DCM, 4.0 eq) was added dropwise at -20 ° C. and then reacted at room temperature overnight. The reaction was monitored by TLC. After the reaction was complete, ethanol was added to the reaction solution to quench the reaction, and the mixture was refluxed for 1 h. A solid precipitated and concentrated to obtain a crude product. Dichloromethane was used to slurry the mixture, and the solid was filtered to obtain a solid. The solid was treated with a saturated sodium bicarbonate solution, filtered, and washed with pure water to obtain 10-(tert-butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)-6H-benzofuran[3,2-c]chromen-6-one (compound YF003).

[0181] Replacing 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-ylmethyl-d2)benzofuran-3-carboxylic acid ethyl ester with 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-ylmethyl-d2)benzofuran-3-carboxylic acid ethyl ester yields 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofuran[3,2-c]chromen-6-one (Compound YF001);

[0182] Replacing 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)benzofuran-3-carboxylic acid ethyl ester with 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-yl-2,2,6,6-d4)methyl)benzofuran-3-carboxylic acid ethyl ester yields 10-(tert-butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl)-6H-benzofuran[3,2-c]chromen-6-one (Compound YF002);

[0183] Step g: 10-(tert-butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)-6H-benzofurano[3,2-c]chromen-6-one (compound YF003) was dissolved in a mixed solvent of dichloromethane and methanol at room temperature, and an excess amount of hydrogen chloride in ethyl acetate (3.5 M in ethyl acetate (EA)) was added. The mixture was reacted at room temperature for 1 h, concentrated, and then slurried with dichloromethane and filtered to obtain a white solid, which was 10-(tert-butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)-6H-benzofurano[3,2-c]chromen-6-one hydrochloride (compound YF027);

[0184] Compound YF026 can be obtained by replacing compound YF003 with compound YF002;

[0185] Compound YF025 can be obtained by replacing compound YF003 with compound YT001;

[0186] Step h: Under nitrogen protection, tert-butyl 4-butyrylpiperidine-1-carboxylate (1.0 eq) and potassium tert-butoxide (t-BuOK, 3.6 eq) were dissolved in dimethyl sulfoxide-d6 (d6-DMSO), reacted at room temperature for 0.5 h, heavy water (D2O, 10.0 eq) was added, and the reaction was carried out at 80°C overnight. The reaction endpoint was detected by LC-MS, extracted with ethyl acetate, and concentrated to obtain a crude product of tert-butyl 4-(butyryl-2,2-d2)piperidine-1-carboxylate-4-d, which was directly used in the next step without purification;

[0187] Step c: Under nitrogen protection, 20% deuterated hydrochloric acid (DCl, 3.0 eq) was added to the crude product containing tert-butyl 4-(butyryl-2,2-d2)piperidine-1-carboxylate-4-d (1.0 eq). The reaction was allowed to proceed overnight at room temperature. The product was concentrated to obtain the crude deuterated hydrochloride of 4-(butyryl-2,2-d2)piperidine-1,4-d2, which was directly used in the next step without purification.

[0188] Step e: 4-(Butyryl-2,2-d2)piperidin-1,4-d2 deuterated hydrochloride (1.5 eq), 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (1.0 eq) (see Example 10 for the preparation method), 37% formaldehyde aqueous solution (3.0 eq), and triethylamine (TEA, 3.0 eq) were dissolved in anhydrous ethanol (EtOH), and the mixture was reacted at 80° C. overnight. After the reaction was completed as monitored by TLC, the mixture was concentrated and purified by column chromatography to obtain 8-((4-(butyryl-2,2-d2)piperidin-1-yl-4-d)methyl-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (Compound YF011);

[0189] Step i: 3-chlorobenzaldehyde (1.0 eq), ethyl acetoacetate (2.0 eq), and 4-methylpiperidine (0.3 eq) were mixed and placed in a reaction flask. The mixture was reacted at room temperature overnight. Solids precipitated, and the solids were slurried with petroleum ether and filtered to obtain white 2-(3-chlorophenyl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylic acid diethyl ester.

[0190] Step j: Add 30% to 50% sodium hydroxide aqueous solution (1 to 2 mL / mmol) to 2-(3-chlorophenyl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylic acid diethyl ester (1.0 eq), react at 100° C., monitor the reaction completion by TLC, cool the reaction solution to room temperature, add pure water (1 to 5 times the amount of sodium hydroxide aqueous solution), adjust the pH to 5 to 6 with concentrated hydrochloric acid, filter and remove impurities, collect the filtrate, continue to add hydrochloric acid to the filtrate, a white solid precipitates, filter, and dry to obtain white 3-(3-chlorophenyl) glutaric acid;

[0191] Step k: 3-(3-chlorophenyl) glutaric acid (1.0 eq) and urea (4.0 eq) were mixed and reacted at 150° C. The reaction was monitored by TLC to be complete. The mixture was slurried with pure water and filtered to obtain 4-(3-chlorophenyl) piperidine-2,6-dione;

[0192] Step a: In an anhydrous and nitrogen atmosphere, lithium aluminum hydride deuteride (2.0 eq) was dissolved in ultra-dry THF (10 mL / g), and ultra-dry THF (1 mL / mmol) containing 4-(3-chlorophenyl)piperidine-2,6-dione (1.0 eq) was added dropwise under ice bath. The reaction temperature was controlled below 5° C. and the reaction was carried out for 30 min, followed by reflux reaction. The reaction was monitored by TLC to be complete. Pure water was added under ice bath to quench the reaction, EA was added, the filtrate was collected by filtration, concentrated, and purified by column chromatography to obtain 4-(3-chlorophenyl)piperidine-2,2,6,6-d4;

[0193] Step 1: Place 2,6-dioxopiperidine-4-carboxylic acid (1.0 eq), 1-hydroxybenzotriazole (HOBT) (1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.3 eq), and methoxymethylamine hydrochloride (2.0 eq) in a reaction flask, add dichloromethane as the solvent, add triethylamine, and react at room temperature overnight. TLC monitors the reaction completion, quench the reaction with pure water, extract with dichloromethane, concentrate the organic phase, and purify by column chromatography to obtain N-methoxy-N-methyl-2,6-dioxopiperidine-4-carboxylic acid amine;

[0194] Step m: To a super-dry THF solution containing N-methoxy-N-methyl-2,6-dioxopiperidine-4-carboxylic acid amide (1.0 eq) was added dropwise a tetrahydrofuran solution of propylmagnesium bromide (4.0 eq, 1 M in THF) in an anhydrous and oxygen-free environment under an ice bath, followed by reaction at room temperature. The reaction was monitored for completion by TLC. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to obtain 4-butyrylpiperidine-2,6-dione.

[0195] Step a: In an ice bath, slowly add ultra-dry tetrahydrofuran to a reaction flask containing LiAlD4 (3.5 eq), followed by the dropwise addition of a THF solution of 4-butyrylpiperidine-2,6-dione (1.0 eq). Reflux overnight. Monitor the reaction for completion by TLC. Quench the reaction with purified water and 15% aqueous NaOH. Filter the resulting THF-water solution of 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-d-1-ol and control the pH to approximately 12-14.

[0196] Step n: To the above THF-water solution containing 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-d-1-ol was added (Boc)2O (1.1 eq), the reaction was carried out at room temperature overnight, extracted with EA, and concentrated to obtain a crude product of tert-butyl 4-(1-hydroxybutyl-1-d)piperidine-1-carboxylate-2,2,6,6-d4;

[0197] Step o: Dissolve the crude product of tert-butyl 4-(1-hydroxybutyl-1-d)piperidine-1-carboxylate-2,2,6,6-d4 in EA, add 2-iodoacylbenzoic acid (IBX, 4.0 eq), and heat to 77°C for reaction. Monitor the reaction completion by TLC. Cool, filter, and concentrate to obtain the crude product of tert-butyl 4-butyrylpiperidine-1-carboxylate-2,2,6,6-d4;

[0198] Step c: Dissolve the crude product of tert-butyl 4-butyrylpiperidine-1-carboxylate-2,2,6,6-d4 in EA, add 4-5.0 eq of hydrogen chloride in ethyl acetate, react at room temperature for 2-3 h, and concentrate to obtain 1-(piperidin-4-yl-2,2,6,6-d4)butan-1-one hydrochloride;

[0199] Step a: To an ultra-dry THF solution containing 2-bromo-5-methoxybenzoyl chloride (1.0 eq) was added a solution of lithium aluminum hydride in tetrahydrofuran (3-4.0 eq) dropwise in an anhydrous and oxygen-free environment under an ice bath. The mixture was reacted at room temperature. After completion of the reaction as monitored by TLC, pure water was added to quench the reaction. The mixture was filtered, and the filtrate was extracted with EA and purified by column chromatography to obtain (2-bromo-5-methoxyphenyl)methanol-d2.

[0200] Step p: (2-bromo-5-methoxyphenyl)methanol-d2 (1.0 eq) and sodium hydride (1.5 eq, 60% dissolved in oil) were dissolved in ultra-dry THF, iodomethane (1.5 eq) was added, and the mixture was reacted at room temperature. After completion of the reaction as monitored by TLC, ice water was added to quench the reaction, and the mixture was extracted with EA and purified by column chromatography to obtain 1-bromo-4-methoxy-2-(methoxymethyl-d2)benzene;

[0201] Step q: 1-bromo-4-methoxy-2-(methoxymethyl-d2)benzene (1.0 eq), 2-vinylethanol (2.0 eq), and potassium carbonate (2.0 eq) were dispersed in water under nitrogen protection, followed by the addition of bis(diphenylphosphino)propane (dppp, 0.05 eq) and palladium acetate (0.025 eq), and the reaction was carried out at 80-90°C overnight. TLC monitoring indicated that the reaction of the raw materials was essentially complete, generating an intermediate transition product. The reaction solution was cooled to room temperature, extracted with EA, and separated. Concentrated hydrochloric acid was added dropwise to the organic phase, and the reaction was carried out at room temperature for approximately 0.5 h. TLC monitoring indicated that the intermediate transition product was completely converted into the product. Water was added to separate the phases, the organic phase was concentrated, and purification by column chromatography afforded 1-(4-methoxy-2-(methoxymethyl-d2)phenyl)ethanone.

[0202] Step r: Diethyl carbonate (2.5 eq) was dissolved in THF, potassium tert-butoxide (3.2 eq) was added, and the mixture was stirred at room temperature for 0.5 h. Then, a THF solution of 1-(4-methoxy-2-(methoxymethyl-d2)phenyl)ethanone (1.0 eq) was added dropwise, and the mixture was reacted at 60-70° C. for about 2 h. After TLC monitoring, the reaction was complete. The reaction solution was poured into ice water to quench, concentrated hydrochloric acid was added to adjust the pH to about 6, and EA was added for extraction. The mixture was purified by column chromatography to obtain ethyl 3-(4-methoxy-2-(methoxymethyl-d2)phenyl)-3-oxopropanoate;

[0203] Step s: ethyl 3-(4-methoxy-2-(methoxymethyl-d2)phenyl)-3-oxopropanoate (1.0 eq), 1,4-benzoquinone-d4 (1.2 eq), and copper trifluoromethanesulfonate (0.1 eq) were dissolved in xylene, and the mixture was reacted at 80-90° C. for about 2-4 h. The completion of the reaction was monitored by TLC, and the reaction solution was directly purified by column chromatography to obtain ethyl 5-hydroxy-2-(4-methoxy-2-(methoxymethyl-d2)phenyl)benzofuran-3-carboxylate-4,6,7-d3;

[0204] Step t: Under anhydrous and oxygen-free conditions, 5-hydroxy-2-(4-methoxy-2-(methoxymethyl-d2)phenyl)benzofuran-3-carboxylic acid ethyl ester-4,6,7-d3 was dissolved in ultra-dry DCM, and a DCM solution of boron tribromide (4.0-6.0eq, 1.0-4.0M) was added dropwise under ice bath, and the reaction was allowed to proceed overnight at room temperature. Ice methanol was added to quench the reaction, and the reaction solution was directly concentrated, 1,4-dioxane and pure water were added, and 10 The reaction was carried out at 0°C for about 3 h. The reaction was completed as monitored by TLC. The reaction solution was concentrated and water was added to precipitate the solid, which was filtered to obtain the crude product of 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,8,10,11-d5. The crude product was purified by beating and obtained as 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,8,10,11-d5.

[0205] Example 1

[0206] 10-(tert-Butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofurano[3,2-c]chromen-6-one (Compound YF001)

[0207] 3-(2,4-dimethoxyphenyl)-3-oxopropionic acid ethyl ester (1.05 eq), copper trifluoromethanesulfonate (0.1 eq), and tert-butyl-p-benzoquinone (1.0 eq) were added to a reaction flask, and toluene (2 mL / mmol) was added. The reaction was carried out at 110° C. After the reaction was completed by TLC monitoring, the reaction solution was concentrated to obtain crude 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl ester, which was then slurried with methanol and filtered to obtain 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl ester;

[0208] 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl ester (1.0 eq), piperidine hydrochloride (2.0 eq), triethylamine (2.0 eq), and paraformaldehyde-d2 were added to a reaction flask, and ethanol was added. The reaction was carried out at 80° C. After the reaction was completed as monitored by TLC, the ethanol was removed by concentration, and the product was purified by column chromatography to obtain 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-(piperidin-1-ylmethyl-d2)benzofuran-3-carboxylic acid ethyl ester;

[0209] 7-(tert-Butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-(piperidin-1-ylmethyl-d2)benzofuran-3-carboxylic acid ethyl ester (2.0 eq) was dissolved in ultra-dry dichloromethane (DCM). Under nitrogen protection, a dichloromethane solution of boron tribromide (2 M in DCM, 4.0 eq) was added dropwise at -20°C, and then reacted at room temperature overnight. After the reaction was completed, the reaction solution was monitored by TLC, and ethanol was added to quench the reaction solution. The reaction solution was refluxed for 1 h, a solid precipitated, and the solution was concentrated to obtain 10 The crude product of -(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofuran[3,2-c]chromen-6-one was slurried with DCM and filtered to obtain a solid. The solid was treated with saturated sodium bicarbonate solution, filtered, and washed with pure water to obtain 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofuran[3,2-c]chromen-6-one (compound YF001) as an off-white solid. 1H NMR (600MHz, DMSO-d6) δ10.89(s,1H),10.33(s,1H),7.99(d,J=8.6Hz,1H),7.07(s,1H),7.01(dd,J=8.6,2.2Hz,1H),6.95(d,J=2.2 Hz,1H),3.27(m,2H),3.14-3.08(m,2H),1.84-1.82(m,2H),1.67-1.61(m,3H),1.51(s,9H),1.50-1.40(m,1H).HRMS(ESI)m / z:Calcd forC 25 H 25 D2NO5(M+H) + 424.21239; Found 424.20770.

[0210] Example 2

[0211] 10-(tert-Butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl)-6H-benzofurano[3,2-c]chromen-6-one (Compound YF002)

[0212] Under anhydrous and oxygen-free conditions and on an ice bath, add ultra-dry tetrahydrofuran (THF) to a reaction flask containing lithium aluminum hydride deuteride (LiAlD4, 2.0 eq). Then, dropwise add a solution of glutarimide (1.0 eq) in ultra-dry THF. The reaction is allowed to proceed at a low temperature (<5°C) for 30 minutes and then heated to reflux for 3 hours. Under an ice bath, the reaction is quenched by the slow addition of pure water (10.0 eq) and then 15% aqueous NaOH (10.0 eq). The THF-water solution containing 2,2,6,6-piperidine-d4 is filtered and used directly in the next reaction at a pH of approximately 12-14.

[0213] To a THF-water solution containing 2,2,6,6-piperidine-d4 was added (Boc)2O (0.7 eq), reacted at room temperature for 3 h, extracted with ethyl acetate, washed three times with pure water, and the organic phase was concentrated to obtain crude tert-butyl 2,2,6,6-piperidine-d4-1-carboxylate;

[0214] The crude product of tert-butyl 2,2,6,6-piperidine-d4-1-carboxylate was dissolved in ethyl acetate (EA), and a 3.5 M HCl solution in EA (5.0 eq) was added. The mixture was reacted at room temperature for 3 h and concentrated to obtain 2,2,6,6-piperidine-d4 hydrochloride.

[0215] The subsequent preparation method is the same as that of Example 1, except that paraformaldehyde-d2 is replaced by 37% formaldehyde aqueous solution, and piperidine hydrochloride is replaced by 2,2,6,6-piperidine-d4 hydrochloride to obtain an off-white solid final product. 1HNMR(600MHz,DMSO-d6)δ10.92(s,1H),10.36(s,1H),7.99(d,J=8.6Hz,1H),7.06(s,1H),7.01(dd,J=8.6,2.2Hz,1H),6.95 (d,J=2.2Hz,1H),4.32(s,2H),1.85-1.78(m,2H),1.67-1.60(m,3H),1.52(s,9H),1.49-1.38(m,1H).HRMS(ESI)m / z:Calcd for C 25 H 23 D4NO5(M+H) + 426.22804; Found 426.22012.

[0216] Example 3

[0217] 10-(tert-Butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)-6H-benzofurano[3,2-c]chromen-6-one (Compound YF003)

[0218] The preparation method is the same as that of Example 2, except that the 37% formaldehyde aqueous solution is replaced by paraformaldehyde-d2 to obtain an off-white solid final product. 1 H NMR (600MHz, DMSO-d6) δ10.90(s,1H),10.33(s,1H),8.00(d,J=8.6Hz,1H),7.07(s,1H),7.02(dd,J=8.6,2.2Hz,1H) ,6.96(d,J=2.2Hz,1H),1.88-1.77(m,2H),1.68-1.60(m,3H),1.52(s,9H),1.49-1.37(m,1H).HRMS(ESI)m / z:Calcd for C 25 H 21 D6NO5(M+H) + 428.24369; Found 428.23270.

[0219] Example 4

[0220] 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-yl)-d 10 )methyl)-6H-benzofuran[3,2-c]chromen-6-one (Compound YF004)

[0221] The preparation method is the same as that of Example 1, except that paraformaldehyde-d2 is replaced by 37% formaldehyde aqueous solution, and piperidine hydrochloride is replaced by piperidine-d 11Deuterated hydrochloride gave an off-white solid final product. 1 H NMR(600MHz,DMSO-d6)δ10.95(s,1H),10.33(s,1H),7.96(d,J=8.7Hz,1H),7.04(s,1H),7.00 (dd,J=8.7,2.3Hz,1H),6.93(d,J=2.3Hz,1H),4.27(s,2H),1.55(s,9H).HRMS(ESI)m / z:Calcd for C 25 H 17 D 10 NO5(M+H) + 432.25201; Found 432.25012.

[0222] Example 5

[0223] 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-yl)-d 10 )methyl-d2)-6H-benzofuran[3,2-c]chromen-6-one (Compound YF005)

[0224] The preparation method is the same as in Example 1, except that piperidine hydrochloride is replaced by piperidine-d 11 Deuterated hydrochloride gave an off-white solid final product. 1 H NMR (600MHz, DMSO-d6) δ10.90(s,1H),10.25(s,1H),7.91(d,J=8.7Hz,1H),7.10(s,1H),7.07(dd,J=8.7,2.4Hz,1H),6.98(d, J=2.4Hz,1H),1.58(s,9H).HRMS(ESI)m / z:Calcd for C 25 H 15 D 12 NO5(M+H) + 434.26400; Found 434.25962.

[0225] Example 6

[0226] 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one (Compound YF006)

[0227] 2-Bromo-5-hydroxybenzaldehyde (1.0 eq) was dissolved in methanol, and sodium borohydride (0.5 eq) was added under ice bath. The mixture was reacted at room temperature for 0.5 h. After completion of the reaction as monitored by TLC, the mixture was directly concentrated under reduced pressure to remove methanol. The mixture was diluted with water and the pH was adjusted to about 6 with 1 M hydrochloric acid. A solid precipitated, which was filtered off, washed with water, and dried to obtain 2-bromo-5-hydroxybenzyl alcohol.

[0228] Under an ice bath, 2-bromo-5-hydroxybenzyl alcohol (1.0 eq) and sodium hydride (2.5 eq) were added to a reaction flask, followed by ultra-dry tetrahydrofuran and dropwise addition of iodomethane (2.5 eq). The reaction was allowed to react overnight at room temperature. After TLC monitoring, the reaction was quenched with ice water, the pH was adjusted to approximately 6 with 1M hydrochloric acid, and the product was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1-bromo-4-methoxy-2-(methoxymethyl)benzene.

[0229] 1-Bromo-4-methoxy-2-(methoxymethyl)benzene (1.0 eq), palladium acetate (0.025 eq), 1,3-bis(diphenylphosphino)propane (0.05 eq), and potassium carbonate (2.0 eq) were added to a reaction flask under nitrogen protection. Water and 2-vinylethanol (2.5 eq) were added and the reaction was carried out at 80°C overnight. The reaction was completed as monitored by TLC to generate an intermediate transition product. The product was extracted with ethyl acetate. Concentrated hydrochloric acid was added to the ethyl acetate phase and the reaction was continued at room temperature for about 1 h. After the reaction of the intermediate transition product was completed as monitored by TLC, a saturated aqueous sodium bicarbonate solution was added to quench the reaction and adjust the pH to about 7. The product was extracted with ethyl acetate and purified by silica gel column chromatography to obtain 2-(methoxymethyl)-4-methoxyacetophenone.

[0230] At room temperature and under nitrogen, sodium hydride (3.2 eq) and diethyl carbonate (2.5 eq) were dissolved in xylene and stirred at room temperature for 30 minutes. 2-(Methoxymethyl)-4-methoxyacetophenone (1.0 eq) was dissolved in xylene and added dropwise to the reaction system. The reaction was continued at 110°C for 30 minutes. After TLC detection of the reaction completion, the reaction solution was poured into ice water, and the pH was adjusted to neutral to slightly acidic with hydrochloric acid. The product was extracted with ethyl acetate and purified by silica gel column chromatography to obtain ethyl 3-[4-methoxy-2-(methoxymethyl)phenyl]-3-oxopropanoate.

[0231] Ethyl 3-[4-methoxy-2-(methoxymethyl)phenyl]-3-oxopropanoate (1.05 eq), copper trifluoromethanesulfonate (0.1 eq), and benzoquinone (1.0 eq) were dissolved in xylene and reacted at 110°C overnight. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 9-hydroxy-3-methoxybenzo[5,6]oxazepam[4,3-b]benzofuran-7(5H)-one.

[0232] 4-(3-chlorophenyl)piperidine hydrochloride (2.0 eq), triethylamine (2.2 eq), paraformaldehyde-d2 (3.3 eq), and 95% ethanol (3-5 mL / mmol) were mixed and stirred at 80°C until the reaction solution was completely clear and transparent. 3-methoxy-9-hydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (1.0 eq) was added and reacted at 80°C overnight. After the reaction was complete after TLC monitoring, the mixture was concentrated and purified by column chromatography to obtain 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3-methoxy-9-hydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one;

[0233] Under anhydrous and oxygen-free conditions, 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3-methoxy-9-hydroxybenzo[5,6]oxazepine[4,3-b]benzofuran-7(5H)-one (1.0 eq) was dissolved in ultra-dry dichloromethane (3-5 mL / mmol). A dichloromethane solution of boron tribromide (1 M in DCM 3.0 eq) was added dropwise at -20°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction monitored by TLC, ethanol (equal volume to DCM) was added to quench the reaction. The mixture was refluxed at 80°C for 1 h, concentrated, and purified by column chromatography to collect the target molecule. The mixture was then added with saturated aqueous sodium bicarbonate solution and stirred at room temperature for 1 h. The mixture was filtered, washed with pure water, and dried to obtain the final product as a gray solid. 1 H NMR (600MHz, DMSO-d6) δ10.65(s,1H),10.46(s,1H),7.89(d,J=8.4Hz,1H),7.75(d, J=8.9Hz,1H),7.36(t,J=7.8Hz,1H),7.31-7.25(m,2H),7.19(d,J=7.8Hz,1H),7.16 -7.11(m,2H),7.08(dd,J=8.5,2.4Hz,1H),5.27(s,2H),3.49-3.39(m,2H),3 .20-3.15(m,2H),2.93-2.90(m,1H),2.07-1.86(m,4H).HRMS(ESI)m / z:Calcd forC 28 H 22 D2ClNO5(M+H) + 492.14995; Found(M+H) + 492.15339.

[0234] Example 7

[0235] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one (Compound YF007)

[0236] 3-Chlorobenzaldehyde (1.0 eq), ethyl acetoacetate (2.0 eq), and 4-methylpiperidine (0.3 eq) were mixed and placed in a reaction flask. The mixture was reacted at room temperature overnight. Solids precipitated, and the solids were slurried with petroleum ether and filtered to obtain white 2-(3-chlorophenyl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylic acid diethyl ester.

[0237] 30% to 50% aqueous sodium hydroxide solution (1 mL / mmol) was added to diethyl 2-(3-chlorophenyl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate (1.0 eq), and the mixture was reacted at 100°C. The reaction was monitored by TLC to be complete. Pure water (4 times the amount of aqueous sodium hydroxide solution) was added, and the pH was adjusted to 5-6 with concentrated hydrochloric acid. The mixture was filtered and the filtrate was collected. Hydrochloric acid was added to the filtrate to precipitate a white solid, which was filtered and dried to obtain white 3-(3-chlorophenyl)glutaric acid.

[0238] 3-(3-chlorophenyl) glutaric acid (1.0 eq) and urea (4.0 eq) were mixed and reacted at 150°C. The reaction was completed after monitoring by TLC. The mixture was slurried with pure water and filtered to obtain 4-(3-chlorophenyl) piperidine-2,6-dione.

[0239] Under anhydrous nitrogen atmosphere, lithium aluminum hydride deuteride (2.0 eq) was dissolved in ultra-dry THF (10 mL / g). Ultra-dry THF (1 mL / mmol) containing 4-(3-chlorophenyl)piperidine-2,6-dione (1.0 eq) was added dropwise under ice-cooling. The reaction temperature was controlled below 5°C for 30 min, and then refluxed. The reaction was complete after monitoring by TLC. Pure water was added under ice-cooling to quench the reaction. EA was added, and the filtrate was collected by filtration, concentrated, and purified by column chromatography to obtain 4-(3-chlorophenyl)piperidine-2,2,6,6-d4.

[0240] 3-[4-methoxy-2-(methoxymethyl)phenyl]-3-oxopropionic acid ethyl ester (1.0 eq) (preparation method refers to Example 6) and benzoquinone (1.2 eq) were dissolved in xylene under nitrogen protection, copper trifluoromethanesulfonate (0.1 eq) was added, and the mixture was reacted at 80-90° C. for 1-2 h. The reaction was stopped when TLC monitoring showed that the reaction of the raw materials was complete and only a small amount of 9-hydroxy-3-methoxybenzo[5,6]oxazepine[4,3-b]benzofuran-7(5H)-one was produced. The mixture was directly purified by column chromatography to obtain 5-hydroxy-2-(4-methoxy-2-(methoxymethyl)phenyl)benzofuran-3-carboxylic acid ethyl ester;

[0241] 5-Hydroxy-2-(4-methoxy-2-(methoxymethyl)phenyl)benzofuran-3-carboxylic acid ethyl ester (1.0 eq), 4-(3-chlorophenyl)piperidine-2,2,6,6-d4 (1.2 eq) and 37% formaldehyde aqueous solution (3.0 eq) were added to ethanol (4 mL / mmol), dissolved at 80°C, and triethylamine was added to adjust the pH to weak alkalinity. The reaction was allowed to proceed overnight at 80°C. The reaction was monitored to be complete by TLC, and the product was purified by column chromatography to obtain 4-(4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl)-5-hydroxy-2-(4-methoxy-2-(methoxymethyl)phenyl)benzofuran-3-carboxylic acid ethyl ester;

[0242] Under anhydrous and oxygen-free conditions, ethyl 4-(4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl)-5-hydroxy-2-(4-methoxy-2-(methoxymethyl)phenyl)benzofuran-3-carboxylate (1.0 eq) was dissolved in ultra-dry DCM (4 mL / mmol). A dichloromethane solution of boron tribromide (2.0 M in DCM, 4.0 eq) was added dropwise at low temperature (0°C). The reaction was allowed to react at room temperature. The reaction was completed as monitored by TLC to generate an intermediate transition state product. Methanol was added at low temperature (0°C) to quench the reaction. The reaction was concentrated, and then 1,4-dioxane and purified water were added. The reaction was allowed to react at 100°C. The intermediate transition state product was completely converted to the target molecule as monitored by TLC. The reaction was stopped, and a saturated sodium bicarbonate solution was added to adjust the pH to a weak base. The mixture was extracted with DCM, and the organic phase was concentrated. The final product was purified by column chromatography to obtain a yellow solid. 1 H NMR(600MHz,DMSO-d6)δ10.60(s,1H),10.53(s,1H),7.85(d,J=8.5Hz,1H) ,7.46(d,J=8.8Hz,1H),7.38-7.29(m,2H),7.28-7.20(m,2H),7.12(d,J=2 .4Hz,1H),7.06(dd,J=8.5,2.4Hz,1H),6.89(d,J=8.8Hz,1H),5.21(s,2H),4.32(s,2H),2.62-2.57(m,1H),2.02-1.92(m,4H).HRMS(ESI)m / z:Calcd forC 28 H 20 D4ClNO5(M+H) + 494.17342; Found(M+H) + 494.26536.

[0243] Example 8

[0244] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one (Compound YF008)

[0245] The preparation method is the same as that of Example 7, except that the 37% formaldehyde aqueous solution is replaced by paraformaldehyde-d2 to obtain a yellow solid final product. 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),10.45(s,1H),7.87(dd,J=8.5,1.8Hz, 1H),7.72(dd,J=8.9,1.9Hz,1H),7.35(td,J=8.0,7.4,1.8Hz,1H),7.31-7.2 4(m,2H),7.23-7.14(m,2H),7.12(d,J=2.1Hz,1H),7.08(dt,J=8.6,2.1Hz,1 H),5.36(s,2H),2.84-2.86(m,1H),2.23-1.74(m,4H).HRMS(ESI)m / z:Calcd for C 28 H 18 D6ClNO5(M+H) + 496.18907; Found(M+H) + 496.18000.

[0246] Example 9

[0247] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4 (Compound YF009)

[0248] To an ultra-dry THF solution containing 2-bromo-5-methoxybenzoyl chloride (1.0 eq) was added a solution of lithium aluminum hydride in tetrahydrofuran (3-4.0 eq) dropwise in an anhydrous and oxygen-free environment under an ice bath. The mixture was allowed to react at room temperature. After completion of the reaction as monitored by TLC, pure water was added to quench the reaction. The mixture was filtered, and the filtrate was extracted with EA. The product was purified by column chromatography to obtain (2-bromo-5-methoxyphenyl)methanol-d2.

[0249] (2-Bromo-5-methoxyphenyl)methanol-d2 (1.0 eq) and sodium hydride (1.5 eq, 60% dissolved in oil) were dissolved in ultra-dry THF, and iodomethane (1.5 eq) was added. The reaction was allowed to react at room temperature. After TLC monitoring, ice water was added to quench the reaction. The reaction was extracted with EA and purified by column chromatography to obtain 1-bromo-4-methoxy-2-(methoxymethyl-d2)benzene.

[0250] 1-Bromo-4-methoxy-2-(methoxymethyl-d2)benzene (1.0 eq), 2-vinylethanol (2.0 eq), and potassium carbonate (2.0 eq) were dispersed in water under nitrogen protection. 1,3-Bis(diphenylphosphino)propane (dppp) (0.05 eq) and palladium acetate (0.025 eq) were then added in sequence and allowed to react overnight at 80-90°C. TLC monitoring indicated that the reaction of the raw materials was essentially complete, producing an intermediate transition product. The reaction solution was cooled to room temperature, extracted with EA, and separated. Concentrated hydrochloric acid was added dropwise to the organic phase, and the reaction was continued at room temperature for approximately 0.5-1 h. TLC monitoring indicated that the intermediate transition product was completely converted to the product. Water was added to separate the phases, the organic phase was concentrated, and purification by column chromatography yielded 1-(4-methoxy-2-(methoxymethyl-d2)phenyl)ethanone.

[0251] Diethyl carbonate (2.5 eq) was dissolved in THF, potassium tert-butoxide (3.2 eq) was added, and the mixture was stirred at room temperature for 0.5 h. Then, a THF solution of 1-(4-methoxy-2-(methoxymethyl-d2)phenyl)ethanone (1.0 eq) was added dropwise, and the mixture was reacted at 60-70° C. for about 2 h. The reaction was monitored to be complete by TLC. The reaction solution was poured into ice water to quench, and concentrated hydrochloric acid was added to adjust the pH to about 6. The mixture was extracted with EA and purified by column chromatography to obtain ethyl 3-(4-methoxy-2-(methoxymethyl-d2)phenyl)-3-oxopropanoate.

[0252] 3-(4-methoxy-2-(methoxymethyl-d2)phenyl)-3-oxopropionic acid ethyl ester (1.0eq), 1,4-benzoquinone-d4 (1.2eq), and copper trifluoromethanesulfonate (0.1eq) were dissolved in xylene and reacted at 80-90°C for about 2 to 4 hours. The completion of the reaction was monitored by TLC. The reaction solution was directly purified by column chromatography to obtain 5-hydroxy-2-(4-methoxy-2(methoxymethyl-d2)phenyl)benzofuran-3-carboxylic acid ethyl ester-4,6,7-d3.

[0253] The subsequent preparation method is the same as that in Example 7, except that 5-hydroxy-2-(4-methoxy-2-(methoxymethyl)phenyl)benzofuran-3-carboxylic acid ethyl ester is replaced by 5-hydroxy-2-(4-methoxy-2-(methoxymethyl-d2)phenyl)benzofuran-3-carboxylic acid ethyl ester-4,6,7-d3 to obtain a yellow solid final product. 1H NMR(600MHz,Chloroform-d)δ10.30(s,1H),10.01(s,1H),7.44(d,J=8.8Hz,1H),7.36-7.27(m,2H),7.21-7.19(m, 2H),6.81(dd,J=8.7,1.9Hz,1H),6.78(d,J=1.9Hz,1H),2.76-2.74(m,1H),2.13-1.91(m,4H).HRMS(ESI)m / z:Calcd for C 28 H 14 D 10 ClNO5(M+H) + 500.20701;Found(M+H) + 500.19705.

[0254] Example 10

[0255] 8-((4-Butyryl)piperidin-1-ylmethyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one (Compound YF010)

[0256] The preparation method is as described in Example 6, except that the steps after 9-hydroxy-3-methoxybenzo[5,6]oxazolidinone[4,3-b]benzofuran-7(5H)-one are as follows:

[0257] 9-Hydroxy-3-methoxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (1.0 eq) was dissolved in ultra-dry dichloromethane, and 1M BBr3 (4.0 eq, 1M in DCM) was added dropwise at -20°C. The mixture was reacted overnight at room temperature. After the reaction was completed as monitored by TLC, the reaction was quenched with methanol and concentrated under reduced pressure to obtain a crude product, which was washed with methanol to obtain 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one.

[0258] 4-Butyrylpiperidine hydrochloride (1.5 eq), 3,9-dihydroxybenzo[5,6]oxazepine[4,3-b]benzofuran-7(5H)-one (1.0 eq), paraformaldehyde-d2 (3.0 eq), and triethylamine (3.0 eq) were dissolved in anhydrous ethanol and reacted at 80°C overnight. After the reaction was completed as monitored by TLC, the mixture was concentrated and purified by column chromatography to obtain a yellow solid final product. 1H NMR(400MHz,DMSO-d6)δ10.50(s,2H),7.84(d,J=8.5Hz,1H),7.45(d,J=8.8Hz,1H), 7.12(d,J=2.5Hz,1H),7.05(dd,J=8.5,2.4Hz,1H),6.87(d,J=8.8Hz,1H),5.15(s,2H ),2.77(s,2H),2.45(t,J=7.1Hz,2H),2.42-2.30(m,1H),2.07(t,J=11.6Hz,2H),1. 76(d,J=12.8Hz,2H),1.50-1.36(m,4H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 25 D2NO6(M+H) + 452.20731; Found (M+H-HCl) + 452.20303.

[0259] Example 11

[0260] 8-((4-(Butyryl-2,2-d2)piperidin-1-yl-4-d)methyl)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one (YF011)

[0261] Under nitrogen protection, tert-butyl 4-butyrylpiperidine-1-carboxylate (1.0 eq) and potassium tert-butoxide (3.6 eq) were dissolved in dimethyl sulfoxide-d6 (d6-DMSO) and reacted at room temperature for 0.5 h. Deuterium hydroxide (10.0 eq) was added and the reaction was continued at 80°C overnight. The reaction endpoint was detected by LC-MS. The mixture was extracted with EA and concentrated to obtain the crude product of tert-butyl 4-(butyryl-2,2-d2)piperidine-1-carboxylate-4-d, which was directly used in the next step without purification.

[0262] Under nitrogen protection, 20% deuterated hydrochloric acid (DCl) aqueous solution (3.0 eq) was added to the crude product of tert-butyl 4-(butyryl-2,2-d2)piperidine-1-carboxylate-4-d (1.0 eq), and the reaction was carried out at room temperature overnight. The solution was concentrated to obtain the crude product of 4-(butyryl-2,2-d2)piperidine-1,4-d2 hydrochloride, which was directly used in the next step without purification;

[0263] 4-(Butyryl-2,2-d2)piperidine-1,4-d2 hydrochloride (1.5 eq), 3,9-dihydroxybenzo[5,6]oxazepine[4,3-b]benzofuran-7(5H)-one (preparation method, see Example 10) (1.0 eq), 37% formaldehyde aqueous solution (3.0 eq), and triethylamine (3.0 eq) were dissolved in anhydrous ethanol and reacted at 80° C. overnight. After the reaction was completed as monitored by TLC, the mixture was concentrated and purified by column chromatography to obtain a light brown solid final product. 1 H NMR (600MHz, DMSO-d6) δ10.48(s,2H),7.84(d,J=8.5Hz,1H),7.47(s,1H),7.12(d,J=2.5Hz,1H),7.05(dd,J=8.5,2.4Hz,1H),6.89(s,1H ),5.16(s,2H),3.95(s,2H),2.99-2.62(m,2H),2.08(s,2H),1.77(s,2H),1.47-1.40(m,4H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 24 D3NO6(M+H) + 453.21513; Found(M+H) + 453.20804.

[0264] Example 12

[0265] 8-((4-Butyrylpiperidin-1-yl-2,2,6,6-d4)-methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one (YF012)

[0266] 2,6-Dioxopiperidine-4-carboxylic acid (1.0 eq), 1-hydroxybenzotriazole (HOBT) (1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.3 eq), and methoxymethylamine hydrochloride (2.0 eq) were placed in a reaction flask, DCM was added as the solvent, triethylamine was added, and the reaction was allowed to proceed overnight at room temperature. TLC monitored the reaction to be complete, the reaction was quenched with pure water, extracted with DCM, and the organic phase was concentrated and purified by column chromatography to obtain N-methoxy-N-methyl-2,6-dioxopiperidine-4-carboxylic acid amine;

[0267] To a super-dry THF solution containing N-methoxy-N-methyl-2,6-dioxopiperidine-4-carboxylic acid amine (1.0 eq) was added dropwise a THF solution of propylmagnesium bromide (4.0 eq, 1 M in THF) in an anhydrous and oxygen-free environment under an ice bath. The mixture was allowed to react at room temperature. The reaction was monitored for completion by TLC. The reaction was quenched with saturated ammonium chloride solution, extracted with EA, and the organic phase was concentrated and purified by column chromatography to obtain 4-butyrylpiperidine-2,6-dione.

[0268] Under an ice bath, slowly add ultra-dry THF to a reaction flask containing LiAlD4 (3.5 eq), followed by a THF solution (1.0 eq) of 4-butyrylpiperidine-2,6-dione. Reflux overnight. Monitor the reaction for completion by TLC. Quench the reaction with purified water and a 15% aqueous NaOH solution. Filter the resulting THF-water solution of 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-d-1-ol and control the pH to approximately 12-14.

[0269] To the above THF-water solution containing 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-d-1-ol was added (Boc)2O (1.1 eq), and the mixture was reacted at room temperature overnight. The mixture was extracted with EA and concentrated to obtain a crude product of tert-butyl 4-(1-hydroxybutyl-1-d)piperidine-1-carboxylate-2,2,6,6-d4.

[0270] The crude product of tert-butyl 4-(1-hydroxybutyl-1-d)piperidine-1-carboxylate-2,2,6,6-d4 was dissolved in EA, 2-iodobenzoic acid (4.0 eq) was added, and the reaction was heated at 77°C. The reaction was monitored to be complete by TLC. The product was cooled, filtered, and concentrated to obtain the crude product of tert-butyl 4-butyrylpiperidine-1-carboxylate-2,2,6,6-d4. The crude product of tert-butyl 4-butyrylpiperidine-1-carboxylate-2,2,6,6-d4 was dissolved in EA, a solution of hydrogen chloride in ethyl acetate (4-5.0 eq) was added, the reaction was carried out at room temperature for 2-3 h, and the product was concentrated to obtain 1-(piperidin-4-yl-2,2,6,6-d4)butan-1-one hydrochloride.

[0271] 1-(Piperidin-4-yl-2,2,6,6-d4)butan-1-one hydrochloride (1.5 eq), 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (preparation method reference Example 10) (1.0 eq), paraformaldehyde-d2 (3.0 eq), and triethylamine (3.0 eq) were dissolved in anhydrous ethanol and reacted at 80° C. overnight. After the reaction was completed as monitored by TLC, the mixture was concentrated and purified by column chromatography to obtain a yellow solid final product. 1H NMR (400MHz, DMSO-d6) δ10.65(s,1H),10.42(s,1H),7.49(d,J=8.6Hz,1H),7.30(d,J=8.9Hz,1H),7.10(d,J=8.9Hz,1H),6.85-6.80(m,2H), 5.22(s,2H),2.65-2.61(m,1H),2.48(t,J=7.4Hz,2H),1.86-1.72(m,4H),1.50(q,J=7.6Hz,2H),0.93(t,J=7.6Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 21 D6NO6(M+H) + 456.53960; Found(M+H) + 456.05103.

[0272] Example 13

[0273] 8-((4-Butyrylpiperidin-1-yl-2,2,6,6-d4)-methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4(YF013)

[0274] The preparation method is the same as that of Example 9, except that the steps after ethyl 5-hydroxy-2-(4-methoxy-2-(methoxymethyl-d2)phenyl)benzofuran-3-carboxylate-4,6,7-d3 are as follows:

[0275] Under anhydrous and oxygen-free conditions, 5-hydroxy-2-(4-methoxy-2-(methoxymethyl-d2)phenyl)benzofuran-3-carboxylic acid ethyl ester-4,6,7-d3 was dissolved in ultra-dry DCM, and a DCM solution of boron tribromide (4.0-6.0eq, 1.0-4.0M) was added dropwise under ice bath. The reaction was allowed to proceed overnight at room temperature, and ice methanol was added to quench the reaction. The reaction solution was directly concentrated, 1,4-dioxane and pure water were added, and the reaction was continued at 100°C. The reaction was complete after 3 to 12 hours of TLC monitoring. The reaction solution was concentrated and water was added to precipitate the solid, which was filtered to obtain the crude product of 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,8,10,11-d5. The crude product was purified by beating and obtained as 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,8,10,11-d5.

[0276] 1-(Piperidin-4-yl-2,2,6,6-d4)butan-1-one hydrochloride (1.5 eq), 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,8,10,11-d5 (1.0 eq), paraformaldehyde-d2 (3.0 eq), and triethylamine (3.0 eq) were dissolved in anhydrous ethanol and reacted at 80°C overnight. After the reaction was completed as monitored by TLC, the mixture was concentrated and purified by column chromatography to obtain a light yellow solid final product. 1 H NMR (400MHz, DMSO-d6) δ10.70(s,1H),10.35(s,1H),7.80(d,J=8.6Hz,1H),7.13(d,J=2.4Hz,1H),7.09(dd,J=8.6,2.4Hz,1H), 2.60-2.54(m,1H),2.48(t,J=7.1Hz,2H),1.99-1.74(m,4H),1.47(q,J=7.3Hz,2H),0.89(t,J=7.3Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 17 D 10 NO6(M+H) + 460.24700;

[0277] Example 14

[0278] 8-((4-(Butyryl-2,2-d2)piperidin-1-yl-4-d)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4(YF014)

[0279] The preparation method is the same as that of Example 13, except that 1-(piperidin-4-yl-2,2,6,6-d4)butan-1-one hydrochloride is replaced by 4-(butyryl-2,2-d2)piperidine-1,4-d2 hydrochloride to obtain a light yellow solid final product. 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),10.46(s,1H),7.74(d,J=8.6Hz,1H),7.14(d,J=2.4Hz,1H),7.03(dd,J=8.6,2.4Hz,1H),3.01 -2.82(m,2H),2.07(s,2H),1.78-1.74(m,2H),1.49-1.47(m,4H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcdfor C 26 H 18 D6NO6(M+H)+ 459.24000; Found(M+H) + 459.25780.

[0280] Example 15

[0281] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl)piperidin-1-yl)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one (Compound YF015)

[0282] Compound YF010 (1.0 eq) was dissolved in methanol, and sodium borohydride (1.0 eq) was added under ice bath. The mixture was reacted at room temperature for 0.5-1 h. After completion of the reaction monitored by TLC, the reaction solution was concentrated and purified by column chromatography to obtain a light yellow solid final product. 1 H NMR (600MHz, DMSO-d6) δ7.98(d,J=8.6Hz,1H),7.51(d,J=2.6Hz,1H),7.48(d,J=8.8Hz,1H),7.36(dd,J=8.6,2.6Hz,1H),6.91(d,J=8.8Hz, 1H),5.22(s,2H),3.41(t,J=11.9Hz,2H),3.22-3.12(m,1H),3.09(t,J=11.3Hz,2H),1 .85(d,J=13.2Hz,1H),1.68-1.23(m,8H),0.85(t,J=6.9Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 27 D2NO6(M+H) + 454.21012;Found(M+H) + 454.22296.

[0283] Example 16

[0284] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1-d)piperidin-1-yl)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one (Compound YF016)

[0285] Compound YF010 (1.0 eq) was dissolved in methanol, and sodium borodeuteride (1.0 eq) was added under ice bath. The mixture was reacted at room temperature for 0.5-1 h. After completion of the reaction monitored by TLC, the reaction solution was concentrated and purified by column chromatography to obtain a light yellow solid final product. 1H NMR (600MHz, DMSO-d6) δ8.01(d,J=8.5Hz,1H),7.59(d,J=2.4Hz,1H),7.50(d,J=8.9Hz,1H),7.45(dd,J=8.5,2.4Hz,1H),6.94(d, J=8.8Hz,1H),5.24(s,2H),3.34-3.10(m,4H),1.80-1.78(m,1H),1.68-1.10(m,8H),0.80(t,J=6.8Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 26 D3NO6(M+H) + 455.22540; Found(M+H) + 455.23078.

[0286] Embodiment 17

[0287] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-2,2-d2)piperidin-1-yl-4-d)methyl)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one (Compound YF017)

[0288] The preparation method is the same as that of Example 15, except that YF010 is replaced by YF011, and a milky yellow solid final product is obtained. 1 H NMR (600MHz, DMSO-d6) δ7.84(d,J=8.5Hz,1H),7.47(d,J=8.8Hz,1H),7.12(d,J=2.5Hz,1H),7.05(dd,J=8.5,2.4Hz,1H),6.89(d,J=8.8Hz,1H) ,5.16(s,2H),3.95(s,2H),3.41(s,1H),2.81(s,2H),2.08(s,2H),1.77(s,2H),1.46-1.41(m,4H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd forC 26 H 26 D3NO6(M+H) + 455.24220;Found(M+H) + 455.23078.

[0289] Embodiment 18

[0290] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1,2,2-d3)piperidin-1-yl-4-d)methyl)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one (Compound YF018)

[0291] The preparation method is the same as that of Example 16, except that YF010 is replaced by YF011, to obtain a yellow-white solid final product. 1 H NMR (600MHz, DMSO-d6) δ7.86(d,J=8.6Hz,1H),7.46(d,J=8.9Hz,1H),7.12(d,J=2.5Hz,1H),7.05(dd,J=8.6,2.5Hz,1H),6.86(d,J=8.8Hz,1H),5 .14(s,2H),4.00(s,2H),2.82-2.79(m,2H),2.10-2.08(m,2H),1.80-1.7 7(m,2H),1.40-1.35(m,4H),0.86(t,J=7.3Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 26 D3NO6(M+H) + 455.24220;Found(M+H) + 455.23078.HRMS(ESI)m / z:Calcd for C 26 H 25 D4NO6(M+H) + 456.32400; Found(M+H) + 456.23861.

[0292] Example 19

[0293] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl)piperidin-2,2,6,6-d4-1-yl)methyl)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one (Compound YF019)

[0294] The preparation method is the same as that of Example 15, except that YF010 is replaced by YF012, to obtain a yellow solid final product. 1H NMR (400MHz, DMSO-d6) δ10.62(s,1H),10.37(s,1H),7.80(d,J=8.5Hz,1H),7.64(d,J=8.9Hz,1H),7.10(d,J=8.9Hz,1H),7.06(d,J=2.4Hz,1H),7. 02(dd,J=8.5,2.4Hz,1H),5.25(s,2H),3.12-3.10(m,1H),1.79(d,J=12.7Hz,1H),1.61-1.15(m,8H),0.79(t,J=6.7Hz,3H).HRMS(ESI)m / z:Calcd forC 26 H 23 D6NO6(M+H) + 458.23700; Found(M+H) + 458.53400.

[0295] Example 20

[0296] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1-d)piperidin-2,2,6,6-d4-1-yl)methyl)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one (Compound YF020)

[0297] The preparation method is the same as that of Example 16, except that YF010 is replaced by YF012, to obtain a yellow solid final product. 1 H NMR (600MHz, Methanol-d4) δ8.05(d,J=8.6Hz,1H),7.59(d,J=2.4Hz,1H),7.56-7.43(m,2H),6. 92(d,J=8.8Hz,1H),5.25(s,2H),1.86-1.20(m,9H),0.79(t,J=7.0Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 22 D7NO6(M+H) + 459.24300; Found(M+H) + 459.25610.

[0298] Example 21

[0299] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl)piperidin-2,2,6,6-d4-1-yl)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one-5,5,10,11-d4 (Compound YF021)

[0300] The preparation method is the same as that of Example 15, except that YF010 is replaced by YF013, to obtain a yellow solid final product. 1 H NMR (600MHz, DMSO-d6) δ7.87(d,J=8.5Hz,1H),7.11(d,J=2.4Hz,1H),7.08(dd,J=8.5,2.4Hz,1H),3 .22-3.19(m,1H),2.10-1.87(m,4H),1.40-1.25(m,5H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 19 D 10 NO6(M+H) + 462.16600; Found(M+H) + 462.28556.

[0301] Example 22

[0302] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1-d)piperidin-2,2,6,6-d4-1-yl)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one-5,5,10,11-d4 (Compound YF022)

[0303] The preparation method is the same as that of Example 16, except that YF010 is replaced by YF013, to obtain a yellow solid final product. 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=8.5Hz,1H),7.12(d,J=2.4Hz,1H),7.08(dd,J=8.5,2.4 Hz,1H),2.05-1.74(m,4H),1.37-1.19(m,5H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 18 D 11 NO6(M+H) + 463.27590;Found(M+H) + 463.29338.

[0304] Example 23

[0305] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-2,2-d2)piperidin-1-yl-1-d)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one-5,5,10,11-d4 (Compound YF023)

[0306] The preparation method is the same as that of Example 15, except that YF010 is replaced by YF014, to obtain a light yellow solid final product. 1 H NMR (400MHz, DMSO-d6) δ7.85(d,J=8.5Hz,1H),7.12(d,J=2.5Hz,1H),7.05(dd,J=8.5,2.5Hz,1H),3.41(s,1H),2.94 -2.89(m,2H),2.11-2.10(m,1H),1.85-1.80(m,2H),1.40-1.37(m,4H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 20 D9NO6(M+H) + 461.26600; Found(M+H) + 461.27773.

[0307] Example 24

[0308] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1,2,2-d3)piperidin-1-yl-1-d)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one-5,5,10,11-d4 (Compound YF024)

[0309] The preparation method is the same as that of Example 16, except that YF010 is replaced by YF014, to obtain a yellow solid final product. 1 H NMR (600MHz, DMSO-d6) δ10.75(s,1H),10.58(s,1H),7.86(d,J=8.5Hz,1H),7.12(d,J=2.5Hz,1H),7.05(dd,J=8.5,2.5Hz,1 H),2.82-2.78(m,2H),2.00-1.97(m,2H),1.78-1.75(m,2H),1.32-1.24(m,4H),0.84(t,J=7.3Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 19 D 10NO6(M+H) + 462.58260;Found(M+H) + 462.29338.

[0310] Example 25

[0311] 10-(tert-Butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofurano[3,2-c]chromen-6-one hydrochloride (Compound YF025)

[0312] At room temperature, 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofuran[3,2-c]chromen-6-one (compound YF001) was dissolved in a mixed solvent of DCM and methanol, and an excess amount of hydrogen chloride in ethyl acetate (3.5 M) was added. The mixture was reacted at room temperature for 1 h, concentrated, and then slurried with DCM and filtered to obtain 10-(tert-butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)-6H-benzofuran[3,2-c]chromen-6-one hydrochloride as a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.99(s,1H),10.43(s,1H),8.64(s,1H),7.98(d,J=8.6Hz,1H),7.13(s,1H),7.02(dd,J=8.6,2.2Hz,1H),6.98(d,J=2. 2Hz,1H),3.44(d,J=11.9Hz,2H),3.15-3.09(m,2H),1.86-1.83(m,2H),1.74-1.62(m,3H),1.52(s,9H),1.51-1.42(s,1H).HRMS(ESI)m / z:Calcd for C 25 H 26 D2ClNO5(M+H) + 460.18907; Found (M+H-HCl) + 424.20770.

[0313] Example 26

[0314] 10-(tert-Butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl)-6H-benzofurano[3,2-c]chromen-6-one hydrochloride (Compound YF026)

[0315] The preparation method is the same as that of Example 25, except that YF001 is replaced by YF002 to obtain a white solid final product. 1H NMR (600MHz, DMSO-d6) δ11.03(s,1H),10.47(s,1H),8.64(s,1H),7.97(d,J=8.6Hz,1H),7.13(s,1H),7.02(dd,J=8.6,2.1Hz,1H),6.9 8(d,J=2.1Hz,1H),4.81(d,J=5.3Hz,2H),1.87-1.77(m,2H),1.67-1.62(m,3H),1.51(s,9H),1.49-1.40(m,1H).HRMS(ESI)m / z:Calcd for C 25 H 24 D4ClNO5(M+H) + 462.20472; Found (M+H-HCl) + 426.22074.

[0316] Example 27

[0317] 10-(tert-Butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl-d2)-6H-benzofurano[3,2-c]chromen-6-one hydrochloride (Compound YF027)

[0318] The preparation method is the same as that of Example 25, except that YF001 is replaced by YF003 to obtain a white solid final product. 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),10.44(s,1H),8.64(s,1H),7.97(d,J=8.6Hz,1H),7.13(s,1H),7.02(dd,J=8.6,2.2 Hz,1H),6.97(d,J=2.2Hz,1H),1.82-1.79(m,2H),1.67-1.63(m,3H),1.51(s,9H),1.48-1.40(m,1H).HRMS(ESI)m / z:Calcd for C 25 H 22 D6ClNO5(M+H) + 464.22037; Found (M+H-HCl) + 428.23172.

[0319] Example 28

[0320] 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-yl)-d 10 )methyl)-6H-benzofuran[3,2-c]chromen-6-one hydrochloride (Compound YF028)

[0321] The preparation method is the same as that of Example 25, except that YF001 is replaced by YF004, to obtain a white solid final product. 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.30(s,1H),8.74(s,1H),7.89(d,J=8.7Hz,1H),7.00(s,1H),7.05(dd,J=8.7,2.1Hz,1H),6.96 (d,J=2.1Hz,1H),4.86(d,J=5.5Hz,2H),1.51(s,9H).HRMS(ESI)m / z:Calcd forC 25 H 18 D 10 ClNO5(M+H) + 467.22801; Found (M+H-HCl) + 432.55100.

[0322] Example 29

[0323] 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-yl)-d 10 )methyl-d2)-6H-benzofuran[3,2-c]chromen-6-one hydrochloride (Compound YF029)

[0324] The preparation method is the same as that of Example 25, except that YF001 is replaced by YF005 to obtain a white solid final product. 1 H NMR (600MHz, DMSO-d6) δ10.89(s,1H),10.14(s,1H),8.77(s,1H),7.92(d,J=8.7Hz,1H),7.14 (s,1H),7.00(dd,J=8.7,2.3Hz,1H),6.87(d,J=2.3Hz,1H),1.60(s,9H).HRMS(ESI)m / z:Calcd for C 25 H 16 D 12 ClNO5(M+H) + 470.24096; Found (M+H-HCl) + 434.56620.

[0325] Example 30

[0326] 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one hydrochloride (Compound YF030)

[0327] At room temperature, 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (YF006) was dissolved in ethyl acetate or dichloromethane, and an excess amount of hydrogen chloride in ethyl acetate was added. The mixture was reacted at room temperature for 1 h or overnight, and the mixture was directly concentrated to dryness or filtered and dried to obtain 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one hydrochloride as a white solid. 1 H NMR (600MHz, DMSO-d6) δ10.64(s,1H),10.43(s,1H),9.57(s,1H),7.88(d,J=8.5Hz,1H),7.73(d ,J=8.9Hz,1H),7.35(d,J=7.7Hz,1H),7.31-7.26(m,2H),7.20(d,J=7.9Hz,1H),7.17(d,J=8.8Hz ,1H),7.13(d,J=2.4Hz,1H),7.08(dd,J=8.5,2.4Hz,1H),5.33(s,2H),3.61(d,J=12.0Hz,2H),3 .34-3.28(m,2H),2.96-2.86(m,1H),2.12-2.08(m,2H),2.01-1.91(m,2H).HRMS(ESI)m / z:Calcd for C 28 H 23 D2Cl2NO5(M+H) + 528.13445; Found (M+H-HCl) + 492.15334.

[0328] Example 31

[0329] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one hydrochloride (Compound YF031)

[0330] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF007, and a white solid final product is obtained. 1H NMR (600MHz, DMSO-d6) δ10.66(s,1H),10.46(s,1H),9.78(s,1H),7.87(d,J=8.5Hz,1H),7.72(d,J=8.8Hz,1H),7.35(t,J=7.6Hz,1H),7.28 (d,J=8.1Hz,2H),7.19(dd,J=10.5,8.1Hz,2H),7.12(d,J=2.5Hz,1H),7.08(dd,J=8.5,2.3Hz,1H),5. 34(s,2H),4.79(s,2H),2.92-2.88(m,1H),2.23-2.05(m,2H),1.98-1.93(m,2H).HRMS(ESI)m / z:Calcd for C 28 H 21 D4Cl2NO5(M+H) + 530.15010;Found(M+H-HCl) + 494.26536.

[0331] Example 32

[0332] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one hydrochloride (Compound YF032)

[0333] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF008, and a white solid final product is obtained. 1 H NMR (600MHz, DMSO-d6) δ10.65(s,1H),10.45(s,1H),9.76(s,1H),7.87(d,J=8.5Hz, 1H),7.72(d,J=8.9Hz,1H),7.35(t,J=7.6Hz,1H),7.28(dd,J=8.4,1.8Hz,2H),7.19 (dd,J=10.0,8.0Hz,2H),7.12(d,J=2.4Hz,1H),7.09(dd,J=8.5,2.5Hz,1H),5.38(s ,2H),2.93-2.90(m,1H),2.13-2.10(m,2H),1.95-1.92(m,2H).HRMS(ESI)m / z:Calcd for C 28 H 19 D6Cl2NO5(M+H) + 532.16575; Found (M+H-HCl) +496.17764.

[0334] Example 33

[0335] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (Compound YF033)

[0336] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF009, and a white solid final product is obtained. 1 H NMR(600MHz,Chloroform-d)δ10.30(s,1H),10.01(s,1H),8.38(s,1H),7.44(d,J=8.8Hz,1H),7.35-7.27(m,2H),7.24(dd,J=2.1,1.5Hz ,1H),7.23-7.19(m,1H),6.81(dd,J=8.7,1.9Hz,1H),6.78(d,J=2.0Hz,1H),2.97-2.86(m,1H),2.24-2.21(m,4H).HRMS(ESI)m / z:Calcd for C 28 H 15 D 10 Cl2NO5(M+H) + 536.17404; Found (M+H-HCl) + 500.18920.

[0337] Example 34

[0338] 8-((4-Butyryl)piperidin-1-ylmethyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one hydrochloride (Compound YF034)

[0339] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF010, and a light brown solid final product is obtained. 1H NMR (600MHz, DMSO-d6) δ10.66(s,1H),10.45(s,1H),9.60(s,1H),7.86(d,J=8.5Hz,1H),7.71(d,J=8.9Hz,1H ),7.17(d,J=8.9Hz,1H),7.12(d,J=2.5Hz,1H),7.08(dd,J=8.5,2.3Hz,1H),5.34(s,2H),3.42(d,J=12.2Hz, 2H),3.21-3.10(m,2H),2.70-2.66(m,1H),2.47(t,J=7.1Hz,2H),2.02-1.94(m,2H), 1.84-1.79(m,2H),1.46(q,J=7.3Hz,2H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 26 D2ClNO6(M+H) + 488.18399; Found (M+H-HCl) + 452.20287.

[0340] Example 35

[0341] 8-((4-(Butyryl-2,2-d2)piperidin-1-yl-4-d)methyl)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one hydrochloride (YF035)

[0342] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF011, and a yellow-white solid final product is obtained. 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),10.46(s,1H),9.51(s,1H),7.86(d,J=8.5Hz,1H) ,7.71(d,J=8.9Hz,1H),7.17(d,J=8.9Hz,1H),7.11(s,1H),7.08(dd,J=8.5,2.4Hz,1H) ,5.33(s,2H),4.72(s,2H),3.42(d,J=11.7Hz,2H),3.20-3.11(m,2H),2.00-1.95(m,2H ),1.82-1.76(m,2H),1.44(q,J=7.2Hz,2H),0.82(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 25 D3ClNO6(M+H) +489.19181; Found (M+H-HCl) + 453.56020.

[0343] Example 36

[0344] 8-((4-Butyrylpiperidin-1-yl-2,2,6,6-d4)-methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one hydrochloride (YF036)

[0345] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF012, and a white solid final product is obtained. 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),10.42(s,1H),9.32(s,1H),7.87(d,J=8. 5Hz,1H),7.72(d,J=8.9Hz,1H),7.20-7.11(m,2H),7.08(dd,J=8.5,2.4Hz,1H), 5.33(s,2H),2.72-2.70(m,1H),2.47(t,J=7.2Hz,2H),2.03-1.96(m,2H),1.79- 1.74(m,2H),1.47(q,J=7.3Hz,2H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 22 D6ClNO6(M+H) + 492.99760; Found (M+H-HCl) + 456.05245.

[0346] Example 37

[0347] 8-((4-Butyrylpiperidin-1-yl-2,2,6,6-d4)-methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (YF037)

[0348] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF013, and a white solid final product is obtained. 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.64(s,1H),9.03(s,1H),7.80(d,J=8.5Hz,1H),7.25(d,J=2.4Hz,1H) ,7.10(dd,J=8.5,2.4Hz,1H),2.83-2.79(m,1H),2.48(t,J=7.1Hz,2H),2.10-2.00(m,2H),1.87-1.78(m,2H), 1.47(q,J=7.3Hz,2H),0.89(t,J=7.3Hz,3H).HRMS(ESI)m / z:Calcd forC 26 H 18 D 10 ClNO6(M+H) + 496.22300; Found (M+H-HCl) + 460.56400.

[0349] Example 38

[0350] 8-((4-(Butyryl-2,2-d2)piperidin-1-yl-4-d)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (YF038)

[0351] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF014, and a white solid final product is obtained. 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),10.32(s,1H),9.25(s,1H),7.78(d,J=8.6Hz,1H),7.13(d,J=2.4Hz,1H),7.10(dd,J=8.6,2.4Hz,1H),3.4 3-3.42(m,2H),3.19-3.11(m,2H),1.99-1.96(m,2H),1.81(d,J=13.1Hz,2H),1.48(q,J=7.2Hz,2H),0.89(t,J=7.3Hz,3H).HRMS(ESI)m / z:Calcd forC 26 H 19 D6ClNO6(M+H) + 495.21700; Found (M+H-HCl) + 459.24700.

[0352] Example 39

[0353] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl)piperidin-1-yl)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one hydrochloride (Compound YF039)

[0354] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF015 to obtain a white solid final product. 1 H NMR(600MHz,DMSO-d6)δ10.66(s,1H),10.41(s,1H),9.14(s,1H),7.86(d,J=8.5Hz, 1H),7.70(d,J=8.9Hz,1H),7.16(d,J=8.9Hz,1H),7.12(d,J=2.5Hz,1H),7.08(dd,J= 8.5,2.4Hz,1H),5.31(s,2H),3.43-3.39(m,2H),3.20–3.07(m,3H),1.88-1.83(m,1H) ),1.74-1.37(m,5H),1.36-1.19(m,3H),0.87(t,J=6.9Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 28 D2ClNO6(M+H) + 490.19120; Found (M+H-HCl) + 454.22300.

[0355] Example 40

[0356] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1-d)piperidin-1-yl)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one hydrochloride (Compound YF040)

[0357] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF016 to obtain a white solid final product. 1H NMR (400MHz, DMSO-d6) δ10.62(s,1H),10.37(s,1H),9.10(s,1H),7.80(d,J= 8.5Hz,1H),7.64(d,J=8.9Hz,1H),7.10(d,J=8.9Hz,1H),7.06(d,J=2.4Hz,1 H),7.02(dd,J=8.5,2.4Hz,1H),5.25(s,2H),3.34(s,2H),3.02(s,2H),1.79 -1.76(m,1H),1.69-1.04(m,8H),0.79(t,J=6.8Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 27 D6ClNO6(M+H-HCl) + 491.19000; Found(M+H) + 455.23081.

[0358] Example 41

[0359] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-2,2-d2)piperidin-1-yl-4-d)methyl)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one hydrochloride (Compound YF041)

[0360] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF017 to obtain a white solid final product. 1 H NMR(600MHz,DMSO-d6)δ10.66(s,1H),10.50(s,1H),9.51(s,1H),7.86(d,J=8.5Hz,1H ),7.70(d,J=8.9Hz,1H),7.16(d,J=8.9Hz,1H),7.11(d,J=2.4Hz,1H),7.07(dd,J=8.5 ,2.4Hz,1H),5.32(s,2H),4.71(s,2H),3.43-3.40(m,3H),3.17-3.12(m,2H),1.98(s, 2H),1.81-1.78(m,2H),1.38(q,J=7.2Hz,2H),0.81(t,J=7.4Hz,3H).(ESI)m / z:Calcd for C 26 H 27 D3ClNO6(M+H) + 494.20746; Found (M+H-HCl) + 455.23100.

[0361] Example 42

[0362] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1,2,2-d3)piperidin-1-yl-4-d)methyl)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one hydrochloride (Compound YF042)

[0363] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF018 to obtain a white solid final product. 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),10.60(s,1H),9.85(s,1H),7.91(d,J=8.5Hz, 1H),7.71(d,J=8.8Hz,1H),7.15(d,J=8.8Hz,1H),7.11(d,J=2.4Hz,1H),7.06(dd,J =8.5,2.4Hz,1H),5.33(s,2H),4.68(s,2H),3.50-3.45(m,2H),3.17-3.12(m,2H),1 .90-1.80(m,4H),1.35(q,J=7.3Hz,2H),0.85(t,J=7.3Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 26 D4ClNO6(M+H) + 492.21529; Found (M+H-HCl) + 456.23541.

[0364] Example 43

[0365] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl)piperidin-2,2,6,6-d4-1-yl)methyl)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one hydrochloride (Compound YF043)

[0366] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF019 to obtain a white solid final product. 1H NMR(600MHz,DMSO-d6)δ10.66(s,1H),10.42(s,1H),9.15(s,1H),7.87(d,J =8.5Hz,1H),7.70(d,J=8.9Hz,1H),7.17(d,J=8.9Hz,1H),7.13(d,J=2.5Hz, 1H),7.09(dd,J=8.5,2.4Hz,1H),5.37(s,2H),3.23-3.17(m,1H),1.88-1.8 6(m,1H),1.73-1.19(m,8H),0.86(t,J=6.9Hz,3H).HRMS(ESI)m / z:Calcdfor C 26 H 24 D6ClNO6(M+H) + 493.21400; Found (M+H-HCl) + 458.55560.

[0367] Example 44

[0368] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1-d)piperidin-2,2,6,6-d4-1-yl)methyl)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one hydrochloride (Compound YF044)

[0369] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF020 to obtain a white solid final product. 1 H NMR (600MHz, DMSO-d6) δ10.64(s,1H),10.41(s,1H),9.35(s,1H),7.87(d,J=8.5Hz,1H),7.71(d,J=8.9Hz,1H),7.16(d,J=8.9Hz, 1H),7.12(d,J=2.4Hz,1H),7.08(dd,J=8.5,2.4Hz,1H),5.33(s,2H),1.95-1.37(m,9H),0.85(t,J=7.1,3H).HRMS(ESI)m / z:Calcd for C 26 H 23 D7ClNO6(M+H) + 494.22000; Found (M+H-HCl) + 459.26617.

[0370] Example 45

[0371] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl)piperidin-2,2,6,6-d4-1-yl)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (Compound YF045)

[0372] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF021 to obtain a white solid final product. 1 H NMR (600MHz, DMSO-d6) δ10.70(s,1H),10.52(s,1H),9.00(s,1H),7.89(d,J=8.6Hz,1H),7.12(d,J=2.4Hz,1H),7.09(dd,J=8.6,2. 4Hz,1H),3.20-3.17(m,1H),2.00-1.97(m,2H),1.79-1.74(m,2H),1.30-1.10(m,5H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 20 D 10 ClNO6(M+H) + 498.26224; Found (M+H-HCl) + 462.28600.

[0373] Example 46

[0374] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1-d)piperidin-2,2,6,6-d4-1-yl)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (Compound YF046)

[0375] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF022 to obtain a white solid final product. 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.62(s,1H),8.87(s,1H),7.88(d,J=8.5Hz,1H),7.12(d,J=2.4Hz,1H), 7.08(dd,J=8.5,2.4Hz,1H),2.06-1.77(m,4H),1.38-1.16(m,5H),0.83(t,J=7.4Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H19 D 11 ClNO6(M+H) + 499.27006; Found (M+H-HCl) + 463.30027.

[0376] Example 47

[0377] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-2,2-d2)piperidin-1-yl-1-d)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (Compound YF047)

[0378] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF023 to obtain a milky white solid final product. 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),10.60(s,1H),8.97(s,1H),7.86(d,J=8.5Hz,1H),7.11(d,J=2.4Hz,1H),7.07(dd,J=8.5,2.4 Hz,1H),3.45-3.17(m,5H),2.00-1.95(m,2H),1.79-1.76(m,2H),1.18(q,J=7.2Hz,2H),0.83(t,J=7.3Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 21 D9ClNO6(M+H) + 497.25441; Found (M+H-HCl) + 461.27560.

[0379] Example 48

[0380] 3,9-Dihydroxy-8-((4-(1-hydroxybutyl-1,2,2-d3)piperidin-1-yl-1-d)methyl-d2)benzo[5,6]oxepin [4,3-b]Benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (Compound YF048)

[0381] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF024 to obtain a white solid final product. 1H NMR (600MHz, DMSO-d6) δ10.82(s,1H),10.71(s,1H),9.12(s,1H),7.90(d,J=8.5Hz,1H),7.11(d,J=2.4Hz,1H),7.06(dd,J=8.5,2.4Hz,1H),3 .43-3.34(m,2H),3.10-3.06(m,2H),1.81-1.77(m,2H),1.66-1.61(m,2H),1.19(q,J=7.3Hz,2H),0.84(t,J=7.3Hz,3H).HRMS(ESI)m / z:Calcd forC 26 H 20 D 10 ClNO6(M+H) + 498.26224; Found (M+H-HCl) + 462.28556.

[0382] Example 49: In vitro pharmacodynamic evaluation of the compounds of the present invention against Mycobacterium tuberculosis

[0383] This example detects the minimum inhibitory concentration (MIC) of the compound of the present invention against the standard strain of Mycobacterium tuberculosis H37Rv.

[0384] 1.1 Experimental Materials

[0385] The compounds of the present invention, non-deuterated control compounds A, B, C, and D (structures shown in the figure below), and Mycobacterium tuberculosis H37Rv (cultured in Middlebrook 7H9 culture medium) were provided by Shanghai Pulmonary Hospital.

[0386] 1.2 Preparation of test compounds

[0387] The test compound was completely dissolved in dimethyl sulfoxide (DMSO) to prepare a 1 mg / mL stock solution, which was then sterilized by filtration. As needed, the stock solution was serially diluted with Middlebrook 7H9 medium to obtain solutions of the test compound at varying concentrations. 100 μL was added to each well of a 96-well culture plate.

[0388] 1.3 Experimental methods

[0389] Mycobacterium tuberculosis H37Rv (standard strain) in the logarithmic growth phase was diluted with Middlebrook 7H9 culture medium to a turbidity OD600 of 1.0 (approximately 5×10 6CFU / mL), 200 μL of the culture medium was diluted to 10 mL with Middlebrook 7H9 culture medium to obtain a bacterial solution containing H37Rv. 100 μL of the H37Rv-containing bacterial solution was then added to the culture plate containing the test compound to create the experimental group. The final concentrations of the test compound were 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125, 0.0156, 0.0078, and 0.0039 μg / mL, respectively.

[0390] The drug-free control groups were set up with 100% inoculation (100 μL diluted H37Rv bacterial solution + 100 μL Middlebrook 7H9 culture medium), 10% inoculation (10 μL diluted H37Rv bacterial solution + 190 μL Middlebrook 7H9 culture medium) or no inoculation group (200 μL Middlebrook 7H9 culture medium).

[0391] After 15 days of culture, the size of the bacterial plaque observed with the naked eye was no larger than 10% of the inoculum size of the drug-free control group, which was taken as the minimum inhibitory concentration (MIC) of the compound to inhibit 90% of the growth of Mycobacterium tuberculosis H37Rv. 90 The activity results are shown in Table 1.

[0392] Table 1. MIC of the compounds of the present invention against Mycobacterium tuberculosis H37Rv 90 Value data

[0393] As shown in Table 1, the compounds of the present invention exhibited good resistance to Mycobacterium tuberculosis.

[0394] Example 50: Pharmacokinetic Evaluation of Deuterated Compounds in Mice

[0395] This example tests the pharmacokinetic parameters and lung tissue distribution of representative deuterated compounds YF027, YF032, YF036, and YF044 and their non-deuterated control compounds (A, B, C, and D).

[0396] 1.1 Experimental Animals

[0397] Balb / C mice, male (each time point is counted as one group, 5 mice per group, a total of 55 mice per compound), 7-8 weeks old, weighing approximately 20 g, animal source: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0398] 1.2 Preparation of test samples

[0399] The test compound was fully dissolved in 8% Tween-80 aqueous solution to prepare a drug solution with a concentration of 10 mg / mL for intraperitoneal injection and oral administration.

[0400] 1.3 Experimental methods

[0401] The pharmacokinetic differences of deuterated compounds YF027, YF032, YF036 and YF044 were compared with their respective non-deuterated reference substances A, B, C and D after a single oral administration at a dose of 100 mg / kg.

[0402] The mice were fasted overnight before administration. The orbital venous blood and lung tissues of the mice were collected from the non-administered group (0 min) and 10 min, 20 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h after oral administration. About 300 μL of blood was collected each time by removing the eyeballs.

[0403] Place the collected blood sample in an anticoagulant tube, quickly invert to mix thoroughly, label the tube, and temporarily store it on ice. Within 1 hour of storing the sample on ice, perform a low-temperature centrifugation at 4°C, 3000 rpm, and centrifuge for 10 minutes. The supernatant is plasma, which is transferred to a new centrifuge tube and stored at -80°C until testing.

[0404] The lung tissue of the mouse was collected and placed in pre-cooled physiological saline to wash away the residual blood and tissue fluid. After drying on absorbent paper, it was weighed using a balance and placed in a centrifuge tube. The tube was marked and stored in a -80°C refrigerator.

[0405] The concentrations of the compounds of the present invention and the control compounds in plasma and lung tissue were determined using LC-MS / MS. The test results are shown in Tables 2 to 5.

[0406] Table 2. Pharmacokinetic parameters of the present compound YF027 and the control compound A

[0407] The results showed that the highest blood concentration of compound YF027 in the present invention was C max (100.26 ng / mL) and the C of the non-deuterated control compound A max (120.1 ng / mL) is close, but the in vivo exposure of YF027 AUC 0-t (367.05 ng·h / mL) was significantly higher than the AUC of the control compound A 0-t (117.00 ng·h / mL); In addition, the highest concentration of YF027 in lung tissue was C max (1406.73 ng / g) was also significantly higher than the control compound A in lung tissue C max (947.88ng / g).

[0408] Table 3. Pharmacokinetic parameters of the present compound YF032 and the control compound B

[0409] The results showed that the highest blood concentration of compound YF032 in the present invention was C max (4332.29 ng / mL) was significantly higher than the C of the non-deuterated control compound B. max (3572.6ng / mL); in vivo exposure AUC of YF032 0-t (14030.17 ng·h / mL) was significantly higher than the AUC of the control compound B 0-t (10327.84 ng·h / mL); In addition, the highest concentration of YF032 in lung tissue was C max (26338.0ng / g) was also significantly higher than the control compound B in lung tissue C max (23434.77ng / g).

[0410] Table 4. Pharmacokinetic parameters of the present compound YF036 and the control compound C

[0411] The results showed that the highest blood concentration of compound YF036 in vivo was C max (2084.39 ng / mL) was significantly higher than the C of the non-deuterated control compound C. max (943.7 ng / mL); in vivo exposure AUC of YF036 0-t (5655.66 ng·h / mL) was significantly higher than the AUC of the control compound C 0-t (4960.45 ng·h / mL); In addition, the highest concentration of YF036 in lung tissue was C max (13097.46 ng / g) was also significantly higher than the control compound C in lung tissue. max (5418.41ng / g).

[0412] Table 5. Pharmacokinetic parameters of the present compound YF044 and the control compound D

[0413] The results showed that the highest blood concentration of compound YF044 in the present invention was C max (4041.90 ng / mL) was significantly higher than the C of the non-deuterated control compound D. max (2109.55 ng / mL); in vivo exposure AUC of YF044 0-t (11104.68 ng·h / mL) was significantly higher than the AUC of the control compound D 0-t (4474.91 ng·h / mL); In addition, the highest concentration of YF044 in lung tissue was C max(43437.42 ng / g) was also significantly higher than the control compound D in lung tissue C max (13533.72ng / g).

[0414] From the results, it can be seen that compared with the control compounds, the deuterated compounds YF027, YF032, YF036 and YF044 of the present invention have better pharmacokinetic and lung tissue distribution characteristics in animals and lung tissue (see Tables 2 to 5), and thus have better pharmacodynamics and therapeutic effects.

[0415] Example 51: Enzyme Metabolism Phenotype Study of Compounds

[0416] This example is to detect the CYP450 metabolic enzyme phenotype of the deuterated compound YF027 and its non-deuterated control compound A (using the CYP450 enzyme metabolic phenotype research kit (recombinant enzyme method / 7 enzymes)-mouse liver microsome test).

[0417] 1.1 Sample solution preparation:

[0418] a. Prepare the test compound into a stock solution at a concentration of 40 mM. Take 2.5 μL of the stock solution and dilute it to a concentration of 200 μM of the test compound using DMSO. This concentration of compound is used in subsequent experiments.

[0419] b. The working concentration of the positive substrate drug phenacetin and testosterone mixture is 200 μM.

[0420] 1.2 Prepare the incubation system and start the reaction:

[0421] 1) Thaw all components of the kit in an ice bath, vortex to mix, and place on ice until ready to use;

[0422] 2) Except for the microparticles, the other components of each incubation system were mixed according to the ratio and pipetted to mix thoroughly. The incubation system ratios are shown below;

[0423] Table 6. Positive control group incubation system

[0424] Table 7. Incubation system of experimental control group

[0425] Table 8. Incubation system of experimental groups

[0426] Among them, the inhibitors are: quinidine, naphthoflavone, pilocarpine, sodium diethyldithiocarbamate, ticlopidine, ketoconazole, and sulfaphenazole, and the corresponding inhibited CYP450 enzymes are CYP2D6, CYP1A2, CYP2A6, CYP2E1, CYP2C19, CYP3A4, and CYP2C9.

[0427] Table 9. Incubation system of negative control group

[0428] 3) In the above incubation systems, except for the negative control group (Table 9), 3.125 μL of liver microsomes were added to prepare 125 μL of reaction solution. After vortex mixing, the reaction was started in a 37°C water bath and the timer was started.

[0429] 4) At time points 0 and 90 min, 50 μL of the reaction solution was taken, pre-cooled acetonitrile solution was added to the reaction solution, and the mixture was quickly vortexed to terminate the reaction.

[0430] 5) Pre-treatment of the reaction solution for mass spectrometry detection

[0431] The reaction solution was frozen at -80°C overnight, centrifuged, and subjected to mass spectrometry detection.

[0432] 1.3 Experimental Results

[0433] The experimental results showed that the incubation system and the enzymes in the liver microsomes functioned properly and exhibited good activity. After 90 minutes of incubation, the positive substrates phenacetin and testosterone were nearly completely metabolized, falling below the mass spectrometry detection limit. The metabolic rates of the compounds in the different experimental groups after 90 minutes of incubation were calculated by comparing the values ​​detected after 90 minutes to the values ​​detected at 0 minutes. The metabolic inhibition rate was calculated using the formula: % inhibition = (1 - metabolic rate of the sample with inhibitor added / metabolic rate of the sample without inhibitor), as shown in Table 10 below. According to the "Technical Guidelines for Drug Interaction Studies (Trial)" issued by the Center for Drug Evaluation of the National Medical Products Administration, if a specific metabolic enzyme contributes ≥25% to the total elimination of a drug, it is considered to have a significant contribution to drug clearance and is therefore the primary metabolizer of the drug. The metabolic inhibition rate reflects the effect of selective inhibitors on drug elimination. Therefore, when the metabolic inhibition rate of a specific enzyme is ≥25%, it can be inferred from the in vitro metabolism study results that its contribution to the clearance of the investigational drug is ≥25%.

[0434] Experimental results showed that CYP3A4 is the primary metabolizer of Compound A, but none of the seven CYP metabolizers mentioned above is the primary metabolizer of YF027. Therefore, deuterated YF027 alters its primary metabolic pathway in the body, no longer being metabolized by CYP3A4, the primary CYP450 enzyme, opening the possibility of combining YF027 with other drugs in clinical practice. For example, isoniazid strongly inhibits the enzymatic activity of CYP3A4, and the combined use of Compound A with isoniazid may cause drug interactions.

[0435] Table 10. CYP450 enzyme metabolic phenotyping study results

[0436] Example 52: Anti-tuberculosis activity of the compound in mice

[0437] Experimental materials and reagents:

[0438] Deuterated compounds YF027, YF032, and YF036 and their non-deuterated control compounds (A, B, and C); 5-6 week-old BALB / c mice, sourced from Zhejiang Weitong Lihua Experimental Animal Co., Ltd.; Mycobacterium tuberculosis H37Rv; vehicle 10% Tween 80-water.

[0439] Experimental methods:

[0440] An acute infection model was established by aerosol-infecting mice with Mycobacterium tuberculosis H37Rv (approximately 100-1000 CFU / lung) for 2 days. Six mice were administered the compound orally for 4 weeks (5 days per week, once daily). A 10% Tween 80 vehicle control group was also established. Three days after the end of the treatment, the mice were killed, and the lung bacterial load was measured (plate count method) to evaluate the in vivo antibacterial activity of the compound. The specific dosage is shown in Table 11.

[0441] The experimental results were analyzed using the Student's two-sided t-test (unpaired, equal variance). Differences were considered statistically significant when p ≤ 0.05. ns represents p > 0.05, * represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, and **** represents p < 0.0001.

[0442] Table 11. Specific dosage

[0443] Experimental results:

[0444] As shown in Figure 2, after 4 weeks of treatment with Compound A, the bacterial load in the lungs of mice decreased by 0.91 log (Figure 2A), while after 4 weeks of treatment with deuterated YF027, the bacterial load in the lungs of mice decreased by 1.98 log (Figure 2B). This indicates that the clearance rate of Mycobacterium tuberculosis in the lungs of mice increased from 87.7% to 99.0% after deuteration. Deuterated Compound B also had a similar effect, showing no antibacterial activity in mice (Figure 2C). Deuterated YF032, treated with half the original dose for 4 weeks, showed a 0.81 log decrease in bacterial load (Figure 2D), significantly increasing its in vivo antibacterial activity. Meanwhile, YF036 (50 mg / kg, 1.87 log decrease, Figure 2F) achieved a similar therapeutic effect with only half the dose of Compound C (100 mg / kg, 1.99 log decrease, Figure 2E). This indicates that deuteration significantly enhances its antibacterial activity against Mycobacterium tuberculosis in vivo.

[0445] Example 53: Repeated-dose toxicity of the compound in animals

[0446] Experimental methods:

[0447] Compound YF027 of the present invention and its non-deuterated control compound A were administered to mice for 28 days of repeated dosing toxicity testing. Each compound was administered to 10 Balb / c mice (5 female and 5 male, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) by gavage, once a day for 6 consecutive days a week for 4 weeks. An 8% Tween 80 vehicle control group (10 Balb / c mice, 5 female and 5 male) was administered with an equal volume in the same manner. The specific daily dosage and dosing schedule are shown in Table 12.

[0448] Table 12. Dosing information for repeated dose toxicity studies

[0449] During the administration period, the mice were observed daily, and their body weight, physical appearance, behavioral activity, fecal characteristics, and local reactions to administration were recorded. After the administration, the mice in the treatment group and the control group were subjected to gross autopsy, and mouse serum was collected. The heart, liver, spleen, kidney, lung, and brain tissues were weighed and the organ coefficients were calculated. Tissue samples from all groups were subjected to pathological examination, and serum samples were tested for liver and kidney function biochemical indicators. Blood biochemical indicators included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea (UREA), creatinine (CREA), total protein (TP), and albumin (ALB). Statistical analysis was used to evaluate the possible toxic effects of the compounds.

[0450] Experimental results:

[0451] During the drug administration period, no mice died in the two compound administration groups, YF027 and Compound A. Compared with the solvent control group, the weight gain of mice in the drug administration groups was normal. Male mice in the YF027 and Compound A groups showed piloerection during the drug administration period, and no obvious abnormalities were found in other physical signs. After the completion of the drug administration, gross dissection was performed to calculate the body ratios of major tissues and organs. No significant statistical differences were found between the mice in the YF027 and Compound A groups and the solvent control group. Although the creatinine ratio of the YF027 group was slightly lower than that of the solvent control group, it had no pathological significance. No significant statistical differences were found between the mice in the Compound A group and the solvent control group. Pathological examinations of major tissues and organs also showed no obvious drug-related lesions.

[0452] The results showed that the compound YF027 provided by the present invention was repeatedly administered at a dose of 100 mg / kg for 28 days without obvious toxic reactions in mice; under the same dose administration conditions, no obvious toxicity enhancement was observed in mice compared with its non-deuterated compound Compound A.

Claims

1. A compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor drug thereof: where n is 0 or 1; R4 is selected from H, halogen, aldehyde group, hydroxy, sulfhydryl, -NR'R'', cyano, nitro, optionally substituted C1-C 10 alkyl optionally substituted with C2-C 10 alkenyl optionally substituted with C2-C 10 alkynyl optionally substituted with C3-C8 carbocyclyl optionally substituted with C6-C 14 aryl optionally substituted with C5-C 10 heteroaryl optionally substituted with C4-C 10 heterocyclyl and the corresponding deuterated variants; preferably R4 is selected from optionally substituted C6-C 14 aryl C1-C 10 alkyl optionally substituted with C5-C 10 heteroaryl C1-C 10 alkyl optionally substituted with C4-C 10heterocyclyl C1-C 10 alkyl and the corresponding deuterated variants; R7 is selected from H, hydroxy, sulfhydryl, cyano, carboxyl, nitro, -NR'R'', optionally substituted with C1-C 10 alkyl optionally substituted with C2-C 10 alkenyl optionally substituted with C2-C 10 alkynyl, C1-C 10 ester group, amido, halogen, optionally substituted C3-C8 carbocyclyl, optionally substituted C1-C 10 alkoxy optionally substituted with C6-C 14 aryl optionally substituted with C5-C 10 heteroaryl optionally substituted with C4-C 10 heterocyclyl and their corresponding deuterated variants, wherein R' and R'' are each independently selected from: H, optionally substituted with C1-C 10 alkyl, optionally substituted C2-C8 alkenyl and optionally substituted C1-C 10 alkoxy; R1, R2, R3, R6, R9 and R 10 independently selected from hydrogen and deuterium; and the structure represented by formula I contains at least one deuterium atom.

2. The compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to claim 1, wherein R4 is -(CR 11 R 12 ) m -NR a R b , where m is 1, 2 or 3; R 11 and R 12 independently selected from hydrogen and deuterium; and R a and R b each independently selected from the following substituents and their corresponding deuterated variants: H; C1-C 10alkyl optionally substituted with 1-5 substituents selected from halogen and hydroxy; C2-C8 alkenyl optionally substituted with 1-5 substituents selected from halogen and hydroxy; 3- to 14-membered carbocyclyl optionally substituted with 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl substituted with 3- to 14-membered carbocyclyl optionally substituted with 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl substituted with 4- to 10-membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, hydroxy and C1-C4 alkyl; C6-C 14 aryl optionally substituted with 1-5 substituents selected from halogen, hydroxy and C1-C4 alkyl; and C6-C 14 aryl-C1-C6alkyl optionally substituted with 1-5 substituents selected from halogen, hydroxy and C1-C4alkyl; or R a and R b, together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 7-membered heterocyclyl or benzo 4- to 7-membered heterocyclyl or a deuterated variant thereof, wherein the 4- to 7-membered heterocyclyl or benzo 4- to 7-membered heterocyclyl is optionally substituted with 1-5 substituents selected from: C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen and hydroxy; C1-C6 alkoxy optionally substituted with 1-5 substituents selected from halogen and hydroxy; cyano; carboxyl; halogen; -NR c R d ; hydroxy; C6-C 14 aryl optionally substituted with 1-5 substituents selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 aryl and halogenated C1-C4 alkyl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; C1-C6 acyl substituted with NR c R d ; C1-C4 acyl substituted with C6-C14 aryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with C6-C 14aryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; 4- to 7-membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 4- to 7-membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; 5- to 10-membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy;and C1-C6 alkyl substituted with 5- to 10-membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy, where R; c and R d each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy.

3. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to claim 2, wherein -NR a R b selected from: where p is independently 0, 1, 2, or 3, X is halogen, and R 20 to R 32 , from R 35 to R 41 and R 44 each independently selected from hydrogen and deuterium; preferably -NR a R b selected from: where from R 20 to R 41 and R 44each independently selected from hydrogen and deuterium; more preferable -NR a R b selected from: , , , , , , , , , , , And .

4. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to any one of claims 1 to 3, wherein R7 is selected from H, C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted with 1-5 substituents selected from halogen and hydroxy, saturated or partially saturated C3-C8 carbocyclyl, halogen, hydroxy, C1-C4 alkoxy substituted with C6-C 14 aryl, 5- to 10-membered heteroaryl, and C6-C 14aryl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxy, as well as the corresponding deuterated versions thereof; preferably R7 is selected from hydrogen, deuterium and where from R 13 to R 19 , R 42 and R 43 independently selected from hydrogen and deuterium; preferably R7 is selected from hydrogen, deuterium and .

5. A compound or pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to any one of claims 1 to 4, wherein the structure represented by formula I contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 deuterium atoms.

6. A compound represented by formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor drug thereof, Where R7 is selected from hydrogen, deuterium and where from R 13 to R 19 , R 42 and R 43 independently selected from hydrogen and deuterium; preferably R7 is ; R1, R2, R3, R6, R 11 , R 12 and from R 20 to R 29 independently selected from hydrogen and deuterium; and the structure represented by formula II contains at least one deuterium atom, preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms.

7. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to claim 6, wherein the structural formula of the compound is shown below as IIa, IIb, IIc, or IId: .

8. A compound represented by formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor drug thereof, where Re is selected from: C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen and hydroxy; C1-C6 alkoxy optionally substituted with 1-5 substituents selected from halogen and hydroxy; cyano; carboxyl; halogen; -NR c R d ; hydroxy; C6-C 14 aryl optionally substituted with 1-5 substituents selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 aryl and halogenated C1-C4 alkyl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; C1-C6 acyl substituted with NR c R d ; C1-C4 acyl substituted with C6-C 14aryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with C6-C 14aryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; 4- to 7-membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 4- to 7-membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; 5- to 10-membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy;and C1-C6 alkyl substituted with 5- to 10-membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; and the corresponding deuterated variants thereof, where R; c and R d each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy; R7 is selected from H, C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted with 1-5 substituents selected from halogen and hydroxy, saturated or partially saturated C3-C8 carbocyclyl, halogen, hydroxy, C1-C4 alkoxy substituted with C6-C 14 aryl, 5-10-membered heteroaryl and C6-C 14 aryl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxy, as well as the corresponding deuterated variants; preferably R7 is selected from hydrogen, deuterium and where from R13 to R 19 , R 42 and R 43 each is independently selected from hydrogen and deuterium; more preferably R7 is hydrogen or deuterium; R1, R2, R3, R6, R9 to R 12 , from R 20 to R 23 and from R 26 to R 30 each independently selected from hydrogen and deuterium; and the structure represented by formula III contains at least one deuterium atom, preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms.

9. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to claim 8, wherein the compound has a structural formula shown as IIIa, IIIb, or IIIc below: where p is independently 0, 1, 2, or 3, X is halogen, and R 31 , R 32 , from R 35 to R 41 and R 44 independently selected from hydrogen and deuterium; preferably R1, R2, and R3 all represent hydrogen.

10. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to claim 9, wherein the compound has a structural formula represented as IIId, IIIe, or IIIf below: .

11. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to claim 8, wherein Re, together with the piperidinyl attached thereto, forms a group selected from: , , , , ; , , , And .

12. A compound of formula IV or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor drug thereof, where n is 0 or 1; Re is selected from: hydrogen, deuterium, C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen and hydroxy; C1-C6 alkoxy optionally substituted with 1-5 substituents selected from halogen and hydroxy; cyano; carboxyl; halogen; -NR c R d ; hydroxy; C6-C 14 aryl optionally substituted with 1-5 substituents selected from C1-C4 acyl, halogen, NR c R d , C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxy, C1-C4 alkoxycarbonyl, C6-C 14 aryl and halogenated C1-C4 alkyl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; C1-C6 acyl substituted with NR c R d; C1-C4 acyl substituted with C6-C 14 aryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with C6-C 14aryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C3-C8 cycloalkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; 4- to 7-membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; C1-C6 alkyl substituted with 4- to 7-membered heterocyclyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; 5- to 10-membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy;C1-C6 alkyl substituted with 5- to 10-membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxy; and the corresponding deuterated variants thereof, where R; c and R d each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy; R7 is selected from H, C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted with 1-5 substituents selected from halogen and hydroxy, saturated or partially saturated C3-C8 carbocyclyl, halogen, hydroxy, C1-C4 alkoxy substituted with C6-C 14 aryl, 5- to 10-membered heteroaryl, and C6-C 14 aryl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxy, as well as the corresponding deuterated variants; preferably R7 is selected from hydrogen, deuterium and where from R 13 to R 19 , R 42 and R 43 each independently selected from hydrogen and deuterium; more preferably R7 is selected from hydrogen, deuterium and ; R1, R2, R3, R6, R9, R 10 , R 22 , R 23 , R 26 , R 27 and R 30 each independently selected from hydrogen and deuterium; preferably R1, R2, and R3 are all hydrogen, and R6, R9, R 10 , R 22 , R 23 , R 26 , R 27 and R 30 each independently selected from hydrogen and deuterium.

13. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to claim 12, wherein Re, together with the piperidinyl attached thereto, forms a group selected from: , , , , And .

14. A compound having a structural formula selected from the following structural formulas, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor drug thereof: .

15. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate, or precursor thereof according to any one of claims 1 to 14, wherein the pharmaceutically acceptable salt is a hydrochloride.

16. A pharmaceutical composition containing: (i) a prophylactically or therapeutically effective amount of a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or precursor thereof according to any one of claims 1 to 15 as an active ingredient; and (ii) a pharmaceutically acceptable carrier or excipient, wherein the pharmaceutical composition optionally comprises: (iii) a second active ingredient, wherein preferably the second active ingredient is an antibacterial agent, preferably selected from: rifampicin, ethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin, amikacin, capreomycin, streptomycin, ethionamide, prothionamide, cycloserine, terizidone, para-aminosalicylic acid, clofazimine, clarithromycin, amoxicillin-clavulanate, delamanid, pretomanid, bedaquiline, sutezolid, TB47, GSK 3036656, gepotidacin, thioacetazone, meropenem-clavulanate, TBA-7371, OPC-167832, Telacebeca (Q203), BTZ-043, Contesolid (MRX-4 / MRX-1), Delpazolide (LCB01-0371), Macosinone, Pretomanid, SPR720, SQ109, TBI-166, TBI-223 and thioridazine.

17. The use of a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or precursor thereof according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16 for the preparation of a medicament for the prevention or treatment of a disease caused by a bacterial infection, wherein preferably the bacterium is selected from: Mycobacterium tuberculosis, drug-resistant Mycobacterium tuberculosis, Mycobacterium smegmatis, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Mycobacterium leprae, Mycobacterium bovis, Mycobacterium marinum, Corynebacterium diphtheriae, Bordetella pertussis, Haemophilus influenzae and Streptococcus pneumoniae; particularly preferably, the bacterium is Mycobacterium tuberculosis or drug-resistant Mycobacterium tuberculosis.

18. The use according to claim 17, wherein the disease is a pulmonary infectious disease, preferably an infectious disease caused by pulmonary tuberculosis bacillus, and more preferably tuberculosis.

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