Deuterated tetracyclic derivative and application thereof

Abstract

The invention discloses a deuterated tetracyclic derivative and application of the deuterated tetracyclic derivative in prevention or treatment of diseases caused by bacterial infection, and particularly application of the deuterated tetracyclic derivative in prevention or treatment of lung diseases caused by mycobacterium tuberculosis or drug-resistant mycobacterium tuberculosis.

Description

Technical Field

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

[0002] Deuterated drugs refer to drugs in which some 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 drug molecules basically unchanged. In addition, CD bonds are more stable than CH bonds, which can slow down the decomposition process of drugs, prolong the drug's action 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 infection in multiple parts of the body and is drug-resistant, such as the lungs, intestines, peritoneum, kidneys, parasites, ureters, pleura, bones, joints, brain, reproductive system, etc. The most common infection is lung infection - pulmonary tuberculosis. Currently, the first-line treatment drugs for pulmonary tuberculosis include isoniazid, rifampicin, streptomycin and ethambutol. However, these drugs now generally have drug resistance and more serious side effects, and new anti-tuberculosis drugs and diversified treatment strategies are urgently needed. Summary of the invention

[0004] 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:

[0005]

[0006] Where n is 0 or 1;

[0007] R4 is selected from H, halogen, aldehyde, hydroxyl, 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 10 Heterocyclyl and their respective deuterated variants; preferably, R4 is selected from optionally substituted C6-C 14Aryl 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 group, 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 comprises 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 b Each is independently selected from the following substituents and their respective deuterated variants: H; C1-C2 optionally substituted with 1-5 substituents selected from halogen and hydroxyl; 10C2-C8 alkenyl optionally substituted by 1-5 substituents selected from halogen and hydroxyl; 3-14 membered carbocyclic group optionally substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 3-14 membered carbocyclic group substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen, hydroxyl and C1-C4 alkyl 4-10 membered heterocyclic group substituted; C6-C8 alkyl optionally substituted by 1-5 substituents selected from halogen, hydroxyl and C1-C4 alkyl 14 Aryl; and C6-C4 substituted with 1-5 groups selected from halogen, hydroxyl 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 following: 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 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; 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 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl 4-7 membered heterocyclyl substituted; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl; and C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl 5-10 membered heteroaryl substituted; 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:

[0016] 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;

[0017] Preferably, -NR a R b Selected from: Where R 20 To R 41 , R 44 Independently selected from: hydrogen and deuterium.

[0018] In a more preferred embodiment, -NR a R b Selected from:

[0019]

[0020] In a preferred embodiment, R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted by 1-5 selected from halogen and hydroxy, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxy, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated 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 More preferably, R7 is selected from hydrogen, deuterium and

[0021] 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,

[0022]

[0023] in,

[0024] 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

[0025] R1, R2, R3, R6, R 11 , R 12 and R 20 To R 29 are independently selected from hydrogen and deuterium; and

[0026] The structure of Formula II comprises at least one deuterium atom; preferably comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms.

[0027] In a preferred embodiment, the structural formula of the compound is as shown below IIa, IIb, IIc or IId:

[0028]

[0029]

[0030] 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,

[0031]

[0032] 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 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted 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-substituted C1-C4 alkyl and hydroxy; and deuterated variants thereof; wherein R c and R dEach is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy;

[0033] R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted by 1-5 selected from halogen and hydroxy, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxy, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated 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 is independently selected from: hydrogen and deuterium; More preferably, R7 is hydrogen and deuterium;

[0034] 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

[0035] 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.

[0036] In a preferred embodiment, the structural formula of the compound is as shown below IIIa, IIIb or IIIc:

[0037]

[0038] 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;

[0039] In a more preferred embodiment, R1, R2, and R3 are all hydrogen.

[0040] In a preferred embodiment, the structural formula of the compound is as shown in the following IIId, IIIe or IIIf:

[0041]

[0042] 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:

[0043]

[0044]

[0045] 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,

[0046]

[0047] Where n is 0 or 1;

[0048] Re is selected from: 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 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; 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 substituted with 4-7 membered heterocyclyl substituted with 5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted 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-substituted C1-C4 alkyl and hydroxy; and their respective deuterated variants; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy;

[0049] R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted by 1-5 selected from halogen and hydroxy, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxy, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated 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

[0050]

[0051] 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 , R26 , R 27 and R 30 are each independently selected from hydrogen and deuterium.

[0052] In a preferred embodiment, in formula IV, Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

[0053]

[0054] 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:

[0055]

[0056]

[0057] In a specific embodiment, the present invention provides the hydrochloride salt of the above compound:

[0058]

[0059]

[0060] Another aspect of the present invention provides a pharmaceutical composition comprising a preventively 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.

[0061] 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 a disease caused by a bacterial infection.

[0062] In a preferred embodiment, 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. 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, more preferably pulmonary tuberculosis.

[0063] Other aspects and advantages of the present invention will become apparent from the following description of specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 . Schematic diagram of steps a to g for synthesizing the compounds of the present invention or their intermediates according to some embodiments of the present invention. DETAILED DESCRIPTION

[0065] definition

[0066] In the present invention, "hydrogen" or "H" is used interchangeably in the present invention and refers to an atom with one proton in the 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 atoms consist 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, there is 1 proton and 1 neutron in the nucleus, with an abundance of 0.016%.

[0067] "Tritium", the element symbol is T or 3 H, also known as tritium, has one proton and two neutrons in its nucleus. Its content in nature is extremely small, only 0.004%. In the present invention, if it is not specifically pointed out that a certain "hydrogen" atom is its specific isotopic form (such as "deuterium"), the "hydrogen" atom in its natural state includes all its isotopic forms.

[0068] As used herein, "deuterated" or "deuterated variant" refers to a compound or a group thereof in which one or more hydrogen atoms are 2 H (deuterium, D). "Deuterated" may be monosubstituted, disubstituted, polysubstituted or fully substituted.

[0069] The "heteroatom" described herein includes oxygen (O), sulfur (S) and nitrogen (N).

[0070] As used herein, "alkyl" refers to a straight or branched 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.

[0071] As used herein, "alkenyl" refers to a straight or branched unsaturated hydrocarbon group containing 2 to 10 carbon atoms, which contains at least one carbon-carbon double bond in the chain. In some embodiments, the alkenyl is a C2-C8 alkenyl. Exemplary alkenyls include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0072] 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 the chain. 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.

[0073] As used herein, "alkoxy" 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 and the like.

[0074] 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.

[0075] As used herein, "carbocyclic group" includes saturated and partially saturated carbocyclic groups. The number of ring carbon atoms of the carbocyclic group is 3-15. Saturated carbocyclic groups include cycloalkyl, which is typically C3-C8 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Partially saturated carbocyclic groups include cycloalkenyl, such as C3-C8 cycloalkenyl, for example cyclopentenyl, cycloheptenyl and cyclooctenyl. Herein, carbocyclic groups also include bridged ring groups and spirocyclic groups. Preferably, herein, the number of ring carbon atoms of bridged ring groups and spirocyclic groups can be 4-12.

[0076] Herein, halogen includes fluorine, chlorine, bromine and iodine.

[0077] As used herein, acylamino 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.

[0078] 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 An acyl group, such as acetyl.

[0079] Herein, the 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 other than the carboxyl group in the amino acid molecule (i.e., the ester group is a monovalent group obtained by removing H from the carboxyl group of the amino acid molecule).

[0080] 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 "spiro heterocyclic group") or the bridged cyclic group (also referred to herein as "bridged heterocyclic group") can generally be 4-12. Exemplary heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, dihydroindole, isoindole, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl and tetramoyl.

[0081] As used herein, "heteroaryl" refers to a group containing 5-14, preferably 5-10 ring atoms, and having 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, thienyl, 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, pyrimidine, pyridazinyl ... 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, thiadiazo, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridinyl, triazolopyridazinyl, tetrahydropyridopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, triazolopyrazinyl, thienoquinolyl, furanoquinolyl, thiazoquinolyl, pyrazoloquinolyl, pyrroloquinolyl, imidazoquinolyl, oxazoloquinolyl, etc.

[0082] 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 following groups: 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 14 The aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkenyl, C2-C6 alkynyl, heterocyclyl or heteroaryl radicals themselves may also be optionally substituted, for example each may be optionally substituted with 1, 2, 3 or 4 radicals 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-C 14 The substituents are aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl or heteroaryl.

[0083] 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 substituent is usually 1 or 2.

[0084] 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 above-mentioned definitions. 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 content, as long as the components present in this content 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.

[0085] "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 free bases without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include, but are not limited to, format, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, 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, etc. "Pharmaceutically acceptable base addition salt" refers to salts formed with inorganic or organic bases that can maintain 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, etc. 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, the following salts: primary amines, secondary amines 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, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. 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.

[0086] The term "stereoisomer" refers to compounds with the same chemical constitution, but with different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like. The term "enantiomer" refers to two isomers of a compound that are not superimposable but are mirror images of each other. The term "diastereomer" 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.

[0087] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by 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-ene-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 stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0088] The term "nitrogen oxide" or "N-oxide" means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid) to form an N-oxide. In particular, the N-oxide can be reacted, for example, by reacting the amine compound with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0089] The term "hydrate" refers to an association in which the solvent molecule is water.

[0090] In the present invention, "solvate" refers to an association formed by 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.

[0091] In the present invention, the term "prodrug" includes a compound which itself may be biologically active or inactive, and which, when taken by an appropriate method, undergoes metabolism or chemical reaction in the human body and is converted into a compound or salt of Formula I to Formula IV and any sub-formula thereof.

[0092] 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 present invention and is relatively non-toxic. In this application, "pharmaceutically acceptable carriers or excipients" include but are not limited to any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, etc., which are permitted by relevant government regulatory authorities to be acceptable for use by humans or livestock.

[0093] As used herein, "prevention" includes reducing the likelihood of a disease or condition occurring or becoming worse in a patient.

[0094] As used herein, "treatment" includes the following meanings: inhibiting a disease or condition, that is, curbing its development; alleviating a disease or condition, that is, causing the state of the disease or condition to subside; and alleviating the symptoms caused by the disease or condition.

[0095] Herein, "effective amount" refers to the amount of at least one agent or compound that is sufficient to relieve one or more symptoms of the disease or condition being treated to some extent after administration. The result can be the reduction and / or alleviation of symptoms or causes, or any other desired changes in biological systems. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a significant symptom alleviation effect clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.

[0096] Deuterated tetracyclic derivatives

[0097] 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.

[0098] In some embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof:

[0099]

[0100] Where n is 0 or 1;

[0101] R4 is selected from H, halogen, aldehyde, hydroxyl, 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 10Heteroaryl, optionally substituted C4-C 10 Heterocyclyl 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;

[0102] 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 group, 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;

[0103] 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;

[0104] R1, R2, R3, R6, R9 and R 10 are independently selected from: hydrogen and deuterium; and

[0105] The structure shown in Formula I contains at least one deuterium atom.

[0106] 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.

[0107] In some embodiments, R4 is -(CR 11R 12 ) m -NR a R b ,in:

[0108] m is 1, 2 or 3;

[0109] R 11 and R 12 are independently selected from hydrogen and deuterium; and

[0110] R a and R b Each is independently selected from the following substituents and their respective deuterated variants: H; C1-C2 optionally substituted with 1-5 substituents selected from halogen and hydroxyl; 10 C2-C8 alkenyl optionally substituted by 1-5 substituents selected from halogen and hydroxyl; 3-14 membered carbocyclic group optionally substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 3-14 membered carbocyclic group substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen, hydroxyl and C1-C4 alkyl 4-10 membered heterocyclic group substituted; C6-C8 alkyl optionally substituted by 1-5 substituents selected from halogen, hydroxyl and C1-C4 alkyl 14 Aryl; and C6-C4 substituted with 1-5 groups selected from halogen, hydroxyl 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 following: 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 with aryl and halogenated C1-C4 alkyl 14 Aryl; C1-C6 acyl; C1-C6 alkoxycarbonyl; C2-C8 alkenyloxycarbonyl; NR c R dSubstituted C1-C6 acyl; C6-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 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; 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 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl 4-7 membered heterocyclyl substituted; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl; and C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl 5-10 membered heteroaryl substituted; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy.

[0111] In a preferred embodiment, R4 is -(CR 11 R 12 ) m -NR a R b ,in:

[0112] m is 1, 2 or 3;

[0113] R 11 and R 12 are independently selected from hydrogen and deuterium; and

[0114] 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 by 1-5 substituents selected from the following: 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 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; 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 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl 4-7 membered heterocyclyl substituted; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl; and C1-C6 alkyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxyl 5-10 membered heteroaryl substituted; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy.

[0115] In a preferred embodiment, R4 is -(CR 11 R 12 ) m -NR a R b ,in:

[0116] m is 1, 2 or 3;

[0117] R 11 and R 12 is independently selected from hydrogen and deuterium; and -NR a R b Selected from:

[0118] 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;

[0119] Preferably, -NR a R b Selected from: Where R 20 To R 41 , R 44 Independently selected from: hydrogen and deuterium.

[0120] In a preferred embodiment, R4 is -(CR 11 R 12 ) m -NR a R b ,in:

[0121] m is 1, 2 or 3;

[0122] R 11 and R 12 is independently selected from hydrogen and deuterium; and -NR a R b Selected from:

[0123]

[0124] In any of the above embodiments, R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 halogens and hydroxyls, C2-C6 alkenyl optionally substituted by 1-5 halogens and hydroxyls, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxyl, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14 Aryl and their respective deuterated variants.

[0125] 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.

[0126] In a preferred embodiment, R7 is selected from hydrogen, deuterium and

[0127] 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.

[0128] 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,

[0129]

[0130] in,

[0131] R7 is selected from hydrogen, deuterium and Where R 13 To R 19 , R 42 , R 43 are independently selected from hydrogen and deuterium.

[0132] R1, R2, R3, R6, R 11 , R 12 and R 20 To R 29 are independently selected from hydrogen and deuterium; and

[0133] The structure shown in Formula II contains at least one deuterium atom.

[0134] In a preferred embodiment, R7 is

[0135] 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 certain 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.

[0136] In some embodiments, the present invention provides a compound with the structural formula shown in the following 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 R7 is independently selected from hydrogen and deuterium, and R7 has any of the definitions given above, and the structure shown in Formula IIa contains at least one deuterium atom:

[0137]

[0138] In some embodiments, the present invention provides a compound of formula IIb, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R6, R 11 and R 12 R7 is independently selected from hydrogen and deuterium, and R7 has any of the definitions given above, and the structure shown in Formula IIb contains at least one deuterium atom:

[0139]

[0140] In some embodiments, the present invention provides a compound with the structural formula shown in the following 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 shown in Formula IIc contains at least one deuterium atom:

[0141]

[0142] In some embodiments, the present invention provides a compound with the structural formula shown in the following 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 R7 is independently selected from hydrogen and deuterium, and R7 has any of the definitions given above, and the structure shown in Formula IId contains at least one deuterium atom:

[0143]

[0144] 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,

[0145]

[0146] 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 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted 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-substituted 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;

[0147] R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted by 1-5 selected from halogen and hydroxy, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxy, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14 Aryl and their respective deuterated variants;

[0148] 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

[0149] The structure shown in Formula III contains at least one deuterium atom.

[0150] In a preferred embodiment, wherein Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

[0151]

[0152]

[0153] 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: hydrogen and deuterium. In a more preferred embodiment, R7 is hydrogen and deuterium.

[0154] In a preferred embodiment, the compound shown in 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 shown in 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.

[0155] 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 as described above, and the structure represented by Formula IIIa contains at least one deuterium atom:

[0156]

[0157] In a more preferred embodiment, R1, R2, and R3 are all hydrogen.

[0158] In a preferred embodiment, the present invention provides a compound of formula IIIb, 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 is 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 IIIb contains at least one deuterium atom:

[0159]

[0160] In a more preferred embodiment, R1, R2, and R3 are all hydrogen.

[0161] In a preferred embodiment, the present invention provides a compound of 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 is 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:

[0162]

[0163] In a more preferred embodiment, R1, R2, and R3 are all hydrogen.

[0164] In a further preferred embodiment, the present invention provides a compound of the structural formula shown in the following IIId, 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 as described above, and the structure shown in Formula IIId contains at least one deuterium atom:

[0165]

[0166] 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 is 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:

[0167]

[0168] 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 35To R 37 , R 44 is 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:

[0169]

[0170] 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,

[0171]

[0172] Where n is 0 or 1;

[0173] Re is selected from: 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 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; 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 substituted with 4-7 membered heterocyclyl substituted with 5 substituents selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl and hydroxy; 5-10 membered heteroaryl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halo-substituted 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-substituted C1-C4 alkyl and hydroxy; and their respective deuterated variants; wherein R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy;

[0174] R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted by 1-5 selected from halogen and hydroxy, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxy, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated C1-C4 alkyl, halogen, C2-C4 alkenyl and hydroxyl. 14 Aryl and their respective deuterated variants;

[0175] 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.

[0176] In a preferred embodiment, preferably, R7 is selected from hydrogen, deuterium and Where R 13 To R 19 , R42 , R 43 Each is independently selected from: hydrogen and deuterium. In a more preferred embodiment, R7 is selected from hydrogen, deuterium and

[0177] In a preferred embodiment, Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

[0178]

[0179] In a more preferred embodiment, Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

[0180]

[0181] In a preferred embodiment, the compounds provided by the present invention have a maximum blood concentration C of 1.50 mmol / l in vivo relative to the corresponding undeuterated compounds. max , in vivo exposure AUC 0-t The highest concentration in lung tissue is C max In some embodiments, the compounds provided by the present invention have a maximum blood concentration C in vivo relative to the corresponding compounds without deuteration. max In some embodiments, the compounds provided by the present invention have an in vivo exposure amount AUC of 1.1% relative to the corresponding undeuterated compounds. 0-t In some embodiments, the compounds provided by the present invention have a maximum concentration C in lung tissue relative to the corresponding compounds without deuteration. max In some embodiments, the compounds provided by the present invention have a maximum blood concentration C of 1.5 wt % in vivo relative to the corresponding undeuterated compounds. max The highest concentration in lung tissue is C max In some embodiments, the compounds provided by the present invention have a maximum blood concentration C in vivo relative to the corresponding compounds without deuteration. max and in vivo exposure AUC 0-t In some embodiments, the compounds provided by the present invention have an in vivo exposure amount AUC of 1.1% relative to the corresponding undeuterated compounds. 0-t The highest concentration in lung tissue is C max In some embodiments, the compounds provided by the present invention have a maximum blood concentration C in vivo relative to the corresponding compounds without deuteration. max , in vivo exposure AUC 0-t The highest concentration in lung tissue is C max All significantly improved.

[0182] In a preferred embodiment, the significantly increased means that the deuterated compound is more than 1 times, such as 1.1 to about 100 times, 1.1 to about 50 times, 1.1 to about 30 times, 1.1 to about 10 times, 1.1 to about 8 times, 1.1 to about 5 times, 1.1 to about 4.5 times, 1.1 to about 4 times, 1.1 to about 3.5 times, 1.1 to about 3 times, 1.1 to about 2.5 times, 1.1 to about 2 times, 1.1 to about 1. From about 1.9 times, from 1.1 to about 1.8 times, from 1.1 to about 1.7 times, from 1.1 to about 1.6 times, from 1.1 to about 1.5 times, from 1.1 to about 1.4 times, from 1.1 to about 1.3 times, from 1.1 to about 1.2 times, from about 2 to about 100 times, from about 2 to about 50 times, from about 2 to about 10 times, from about 2 to about 5 times, from about 2 to about 3 times, from about 3 to about 10 times, from about 3 to about 5 times, from about 4 to about 10 times, from about 5 to about 10 times, from about 6 to about 10 times, from about 7 to about 10 times, or from about 8 to about 10 times. In preferred embodiments, the significantly increased aspect of the deuterated compound is 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, 10 times, 15 times, 20 times, 50 times, or 100 times greater than the corresponding aspect of the non-deuterated counterpart compound.

[0183] In other embodiments, the significantly increased refers to that the deuterated compounds provided herein are increased by about 10% to about 500% in the compared aspects compared to the corresponding aspects of the undeuterated counterpart compounds, 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 preferred embodiments, the significantly increased refers to that the deuterated compounds provided herein are increased by 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% in the compared aspects compared to the corresponding aspects of the undeuterated counterpart compounds.

[0184] In the present invention, when the highest blood concentration C max , in vivo exposure AUC0-t The highest concentration in lung tissue is C max When two or all of the above are significantly increased, the magnitude of their increase is independent of each other. For example, for a deuterated compound, the highest blood concentration in vivo is C max The in vivo exposure AUC is about 3 times that of the non-deuterated counterpart. 0-t 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.

[0185] 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:

[0186]

[0187]

[0188] In a preferred embodiment, the present invention provides the hydrochloride YF025 to YF048 of any of the above compounds YF001 to YF024:

[0189]

[0190]

[0191]

[0192] Pharmaceutical composition

[0193] Another aspect of the present invention provides a pharmaceutical composition comprising a preventively 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.

[0194] 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.

[0195] In some embodiments, the pharmaceutical composition of the present invention may further comprise a second active ingredient, which may be an antibacterial agent, such as another anti-Mycobacterium tuberculosis agent.

[0196] In some embodiments, when administered in combination, the weight ratio of the compound of the present invention and other antibacterial drugs can be determined by those skilled in the art. The ratio and the exact dosage and frequency of administration depend on the specific compound of the present invention and other antibacterial drugs used, the specific symptoms to be treated, the severity of the symptoms to be treated, the age, weight, sex, diet, administration time and general physical condition of the specific patient, the mode of administration and other drugs taken by each person, 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 evaluation of the compound of the present invention by the physician who prescribes the compound of the present invention.

[0197] 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 for simultaneous, separate or sequential use in the treatment of bacterial infections as a combined preparation, which contains a compound of the present invention and one or more other antibacterial drugs.

[0198] Other antibacterial drugs may include β-lactam antibiotics, such as natural penicillins, semi-synthetic penicillins, natural cephalosporins, semi-synthetic cephalosporins, cephamycins, 1-oxocephem, 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, bacitracins, macrocyclic peptide antibiotics containing lactone bonds, antinomycins, amphomycins, capreomycins, staminomycins, enramycins, micamycins, neocarzinostatin, streptomycin, puromycin, virginiamycin; cycloheximide; cycloserine; sarcomycin; sarcomycin A; neomycin; griseofulvin; chloramphenicol; mitomycins; fumagillin; monensin; pyrrolnitrin; fosfomycin; fusidic acid; D-(p-hydroxyphenyl)glycine; D-phenylglycine; enediynes.

[0199] 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, cyclohexylcillin, hectacillin, sulbactam sodium, talampicillin hydrochloride, bacampicillin hydrochloride, pivmecillin, cephalexin, cefaclor, cefuroxime, cefadroxil, cephradine, cephalosporin, cefoperazone sodium, cephalothin sodium, cephacetrile sodium, cefsulodin sodium, cephalothin, ceftriaxone, cefoperazone sodium, cefamandole, cefotiam hydrochloride), cefazolin sodium, ceftizoxime sodium, cefotaxime 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 , gentamicin sulfate, dibekacin, amikacin, nicotinamide, 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, pelocycin sulfate, gramicidin S, polymyxin B, cytomemycin Strains, polymyxin sulfate, colistin sodium mesylate, enratoxin, mikamycin, virginiamycin, capreomycin sulfate, puromycin, enviromycin, vancomycin, actinomycin D, neocarcinostatis, belastatin, pepstatin, monensin, lasalocid, salinomycin, amphotericin B, nystatin, natamycin, trichostatin, plicamycin, lincomycin, clindamycin, clindamycin palmitate hydrochloride, flavophospholipol, cycloserine, pesirocin, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, nitropyrrolidine, fosfomycin, fusidic acid, dicyclan, tiamulin, sikanin.

[0200] 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, Telacebec (Q203), BTZ-043, Contezolid (MRX-4 / MRX-1), Delpazolid (LCB01–0371), Macozinone, Pretomanid, SPR720, SQ109, TBI-166, TBI-223, and thioridazine.

[0201] The pharmaceutical composition of the present invention can be administered topically (e.g., through the skin) in the form of creams, solutions, suspensions, aerosols, and dry powder preparations; or systemically, for example, in the form of tablets, capsules, syrups, powders, or granules for oral administration; or in the form of solutions or suspensions for gastrointestinal administration; or subcutaneous (injection) administration; or intravenous (injection) administration; or rectal administration in the form of suppositories; or transdermal administration. The composition of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. These pharmaceutical compositions are preferably in a single dose form suitable for oral administration or parenteral injection. For example, when preparing a composition in an oral dosage form, in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions, any common pharmaceutical medium, such as water, ethylene glycol, oil, alcohol, etc., can be used; or in the case of powders, pills, capsules, and tablets, solid carriers such as starch, sugar, kaolin, diluents, lubricants, binders, disintegrants, etc. are used. Tablets and capsules represent the most advantageous oral dosage unit forms due to ease of administration, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier typically comprises at least a majority of sterile water, although other ingredients may be included, for example, to aid dissolution. For example, injectable solutions may be prepared in which the carrier comprises a saline solution, a glucose solution, or a mixed solution of saline and glucose. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents, etc. may be used. Solid form preparations designed to be converted into liquid form preparations shortly before use are also included.

[0202] 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.

[0203] For ease of administration and uniformity of dosage, it is particularly preferred that the above-mentioned pharmaceutical composition is formulated into a unit dosage form. The unit dosage form used herein refers to a physically discrete unit suitable for a single dose, 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, injection solutions or suspensions, and the like, and their separated multiple dose forms (segregated multilples). The daily dose of the compound of the present invention will of course vary with the compound used, the mode of administration, the desired treatment, and the confirmed mycobacterial disease.

[0204] Uses and methods

[0205] Another aspect of the present invention provides a medical use of any of the provided compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof.

[0206] In some embodiments, the present invention provides any compound 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 the preparation of a medicament for preventing or treating a disease caused by a bacterial infection.

[0207] In some embodiments, the present invention provides any compound 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.

[0208] In some embodiments, the present invention provides a method for preventing or treating a disease caused by a bacterial infection, the method comprising administering to a subject in need thereof a preventive or therapeutically effective amount of any compound 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.

[0209] In any of the above embodiments, 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. In some embodiments, the bacterium is Mycobacterium tuberculosis or drug-resistant Mycobacterium tuberculosis. In some embodiments, the drug-resistant Mycobacterium tuberculosis is rifampicin-resistant bacteria, isoniazid-resistant bacteria or rifampicin and isoniazid double-resistant bacteria.

[0210] 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.

[0211] Example

[0212] The 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.

[0213] Figure 1 The following synthetic schemes show the preparation routes of the compounds of the present invention or their intermediates. Figure 1 The detailed steps of step a to step g are as follows.

[0214] Step a: Under anhydrous and oxygen-free ice bath conditions, add ultra-dry tetrahydrofuran (THF) to a reaction bottle containing lithium aluminum hydride deuteride (LiAlD4, 2.0 eq), and then drop an ultra-dry THF solution containing glutarimide (1.0 eq), control the reaction temperature below 5°C, react for 30 minutes, remove the cold bath, naturally warm to room temperature, and heat to reflux for 3 hours. Naturally cool to room temperature, under an ice bath, slowly drop pure water (10.0 eq) and 15% NaOH aqueous solution (10.0 eq) in sequence to quench the reaction, filter to obtain a THF-water solution containing 2,2,6,6-piperidine-d4, pH about 12 to 14, and directly use it in the next step reaction;

[0215] 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 with pure water three times, dry the organic phase with anhydrous Na2SO4, and concentrate to obtain a crude product of tert-butyl 2,2,6,6-piperidine-d4-1-carboxylate;

[0216] 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;

[0217] Step d: Add 3-(2,4-dimethoxyphenyl)-3-oxopropionic acid ethyl ester (1.05eq), copper trifluoromethanesulfonate (0.1eq), and tert-butyl-p-benzoquinone (1.0eq) into a reaction bottle, add toluene (2mL / mmol), react at 110°C, monitor the reaction by TLC, and concentrate the reaction solution to obtain a crude product, which is then slurried with methanol and filtered to obtain 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl ester;

[0218] Step e: Add 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 into a reaction bottle, add ethanol, react at 80° C., monitor the reaction completion by TLC, concentrate to remove ethanol, and purify 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;

[0219] 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;

[0220] Replace paraformaldehyde-d2 with 37% formaldehyde aqueous solution to obtain ethyl 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxy-4-((piperidin-1-yl-2,2,6,6-d4)methyl)benzofuran-3-carboxylate;

[0221] 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, and a dichloromethane (DCM) solution of boron tribromide (2 M in DCM, 4.0 eq) was added dropwise at -20°C under nitrogen protection, and then reacted at room temperature overnight. The reaction was monitored by TLC. After the reaction was completed, ethanol was added to the reaction solution to quench, and the mixture was refluxed for 1 hour. Solids precipitated and concentrated to obtain a crude product. Dichloromethane was used for slurrying, and solids were filtered out. The solids were treated with saturated sodium bicarbonate solution, filtered out, 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);

[0222] 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-ylmethyl-d2)benzofuran-3-carboxylic acid ethyl ester can give 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofuran[3,2-c]chromen-6-one (Compound YF001);

[0223] 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 can give 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);

[0224] Step g: 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) was dissolved in a mixed solvent of dichloromethane and methanol at room temperature, and an excess amount of hydrogen chloride in ethyl acetate solution (3.5 M in ethyl acetate (EA)) was added, and the mixture was reacted at room temperature for 1 h, concentrated, and then slurried with dichloromethane and filtered to obtain a white solid, which is 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 (compound YF027);

[0225] Compound YF026 can be obtained by replacing compound YF003 with compound YF002;

[0226] Compound YF025 can be obtained by replacing compound YF003 with compound YT001;

[0227]

[0228] 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 end point was detected by LC-MS, and the mixture was 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 for the next step without purification;

[0229] Step c: Under nitrogen protection, add 20% deuterated hydrochloric acid (DCl, 3.0 eq) to the crude product containing tert-butyl 4-(butyryl-2,2-d2)piperidine-1-carboxylate-4-d (1.0 eq), react overnight at room temperature, and concentrate to obtain the crude product of deuterated hydrochloride of 4-(butyryl-2,2-d2)piperidine-1,4-d2, which is directly used for the next step without purification;

[0230] 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);

[0231]

[0232] 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 bottle, and reacted at room temperature overnight. Solids were precipitated, and petroleum ether was used for slurrying. The solids were filtered to obtain white 2-(3-chlorophenyl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylic acid diethyl ester;

[0233] 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 of the sodium hydroxide aqueous solution), adjust the pH to 5 to 6 with concentrated hydrochloric acid, filter to 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;

[0234] Step k: 3-(3-chlorophenyl)pentanedioic 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;

[0235] Step a: In anhydrous and nitrogen protection, 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, and the reaction temperature was controlled below 5° C. The reaction was carried out for 30 min, and then refluxed to complete the reaction. 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;

[0236]

[0237] Step 1: 2,6-dioxopiperidin-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 bottle, dichloromethane was added as a solvent, triethylamine was added, and the reaction was allowed to proceed overnight at room temperature. TLC monitored the reaction to be complete, pure water was used to quench the reaction, dichloromethane was used to extract, the organic phase was concentrated, and column chromatography was used to purify the N-methoxy-N-methyl-2,6-dioxopiperidin-4-carboxylic acid amine;

[0238] Step m: under anhydrous and oxygen-free environment and in an ice bath, a tetrahydrofuran solution of propylmagnesium bromide (4.0 eq, 1 M in THF) was added dropwise to a super dry THF solution containing N-methoxy-N-methyl-2,6-dioxopiperidine-4-carboxylic acid amide (1.0 eq), and then reacted at room temperature. The reaction was completed after monitoring by TLC. The reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated. The mixture was purified by column chromatography to obtain 4-butyrylpiperidine-2,6-dione;

[0239] Step a: In an ice bath, slowly add ultra-dry tetrahydrofuran to a reaction bottle containing LiAlD4 (3.5 eq), and then dropwise add a THF solution of 4-butyrylpiperidine-2,6-dione (1.0 eq), and reflux overnight. TLC monitors the reaction to be complete, add pure water and 15% NaOH aqueous solution to quench the reaction, filter to obtain a THF-water solution of 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-d-1-ol, and control the pH to about 12 to 14;

[0240] Step n: Add (Boc)2O (1.1 eq) to the above THF-water solution containing 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-d-1-ol, react overnight at room temperature, extract with EA, and concentrate to obtain a crude product of tert-butyl 4-(1-hydroxybutyl-1-d)piperidine-1-carboxylate-2,2,6,6-d4;

[0241] 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), heat to 77°C for reaction, monitor the reaction completion by TLC, cool and filter, and concentrate to obtain the crude product of tert-butyl 4-butyrylpiperidine-1-carboxylate-2,2,6,6-d4;

[0242] Step c: Dissolve the crude product of tert-butyl 4-butyrylpiperidine-1-carboxylate-2,2,6,6-d4 in EA, add ethyl acetate solution of hydrogen chloride (4-5.0 eq), react at room temperature for 2-3 h, and concentrate to obtain 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-one hydrochloride;

[0243]

[0244] Step a: In anhydrous and oxygen-free environment and under an ice bath, a solution of lithium aluminum hydride in tetrahydrofuran (3-4.0 eq) was added dropwise to a super-dry THF solution containing 2-bromo-5-methoxybenzoyl chloride (1.0 eq), and the reaction was carried out at room temperature. After the reaction was completed as monitored by TLC, pure water was added to quench the reaction, and the reaction was filtered. The filtrate was extracted with EA and purified by column chromatography to obtain (2-bromo-5-methoxyphenyl)methanol-d2;

[0245] 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 the reaction was completed 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;

[0246] 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 mixed and dispersed in water, and nitrogen was protected. Then, diphenylphosphine propane (dppp, 0.05 eq) and palladium acetate (0.025 eq) were added in sequence, and the reaction was carried out at 80-90°C overnight. TLC monitored that the reaction of the raw materials was basically complete, and an intermediate transition product was generated. The reaction solution was cooled to room temperature, extracted with EA, separated, and concentrated hydrochloric acid was added dropwise to the organic phase. The reaction was carried out at room temperature for about 0.5 h. TLC monitored that the intermediate transition product was completely converted into the product. Water was added to separate the organic phase, and the organic phase was concentrated and purified by column chromatography to obtain 1-(4-methoxy-2-(methoxymethyl-d2)phenyl)ethanone;

[0247] Step r: Dissolve diethyl carbonate (2.5 eq) in THF, add potassium tert-butoxide (3.2 eq), stir at room temperature for 0.5 h, then add dropwise a THF solution of 1-(4-methoxy-2-(methoxymethyl-d2)phenyl)ethanone (1.0 eq), react at 60-70° C. for about 2 h, monitor the reaction completion by TLC, pour the reaction solution into ice water to quench, add concentrated hydrochloric acid to adjust the pH to about 6, extract with EA, and purify by column chromatography to obtain ethyl 3-(4-methoxy-2-(methoxymethyl-d2)phenyl)-3-oxopropanoate;

[0248] Step s: dissolving 3-(4-methoxy-2-(methoxymethyl-d2)phenyl)-3-oxopropionic acid ethyl ester (1.0 eq), 1,4-benzoquinone-d4 (1.2 eq), and copper trifluoromethanesulfonate (0.1 eq) in xylene, reacting at 80-90° C. for about 2-4 h, monitoring the completion of the reaction by TLC, and directly purifying the reaction solution by column chromatography to obtain 5-hydroxy-2-(4-methoxy-2-(methoxymethyl-d2)phenyl)benzofuran-3-carboxylic acid ethyl ester-4,6,7-d3;

[0249] 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 (4.0-6.0 eq, 1.0-4.0 M) was added dropwise under an ice bath, and the reaction was allowed to react 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 hours. 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 pulping to obtain 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,8,10,11-d5.

[0250] Embodiment 1:

[0251] 10-(tert-Butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofuran[3,2-c]chromen-6-one (Compound YF001)

[0252] 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 bottle, and toluene (2mL / 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 a crude product of 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl ester, and then slurried with methanol and filtered to obtain 7-(tert-butyl)-2-(2,4-dimethoxyphenyl)-5-hydroxybenzofuran-3-carboxylic acid ethyl ester;

[0253] 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 bottle, 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 reaction 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;

[0254] 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, ethanol was added to the reaction solution for quenching, and the reaction solution was refluxed for 1 h. Solid precipitated and 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 a 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 for C 25 H 25 D2NO5(M+H) + 424.21239; Found 424.20770.

[0255] Embodiment 2:

[0256] 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)

[0257] Under anhydrous and oxygen-free conditions and in an ice bath, add ultra-dry tetrahydrofuran (THF) to a reaction bottle containing lithium aluminum hydride deuteride (LiAlD4, 2.0eq), and then drop an ultra-dry THF solution containing glutarimide (1.0eq), react at low temperature (<5°C) for 30min, and heat to reflux for 3h. In an ice bath, slowly drop pure water (10.0eq) and 15% NaOH aqueous solution (10.0eq) in sequence to quench the reaction, filter to obtain a THF-water solution containing 2,2,6,6-piperidine-d4, pH about 12-14, which is directly used in the next step reaction;

[0258] Add (Boc)2O (0.7 eq) to a THF-water solution containing 2,2,6,6-piperidine-d4, react at room temperature for 3 h, extract with ethyl acetate, wash with pure water three times, and concentrate the organic phase to obtain a crude product of tert-butyl 2,2,6,6-piperidine-d4-1-carboxylate;

[0259] The crude product of tert-butyl 2,2,6,6-piperidine-d4-1-carboxylate was dissolved in ethyl acetate (EA), and a solution of HCl in EA (3.5 M, 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;

[0260] The subsequent preparation method is the same as that in 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. 1H NMR (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.

[0261] Embodiment three:

[0262] 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)

[0263] 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.

[0264] Embodiment 4:

[0265] 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-yl)-d 10 )methyl)-6H-benzofuran[3,2-c]chromen-6-one (Compound YF004)

[0266] 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 to obtain 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.

[0267] Embodiment five:

[0268] 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-yl)-d 10 )methyl-d2)-6H-benzofuran[3,2-c]chromen-6-one (Compound YF005)

[0269] The preparation method is the same as in Example 1, except that piperidine hydrochloride is replaced by piperidine-d 11 Deuterated hydrochloride to obtain 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.

[0270] Embodiment six:

[0271] 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazolidin-4,3-b]benzofuran-7(5H)-one (Compound YF006)

[0272] 2-Bromo-5-hydroxybenzaldehyde (1.0 eq) was dissolved in methanol, sodium borohydride (0.5 eq) was added under ice bath, and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed as monitored by TLC, the mixture was directly concentrated under reduced pressure to remove methanol, and the mixture was diluted with water. 1 M hydrochloric acid was used to adjust the pH to about 6, and a solid precipitated. The solid was filtered off, washed with water, and dried to obtain 2-bromo-5-hydroxybenzyl alcohol.

[0273] Under ice bath, 2-bromo-5-hydroxybenzyl alcohol (1.0 eq) and sodium hydride (2.5 eq) were added to the reaction bottle, ultra-dry tetrahydrofuran was added, iodomethane (2.5 eq) was added dropwise, and the reaction was allowed to proceed overnight at room temperature. After TLC monitoring of the reaction was complete, the reaction was quenched with ice water, the pH was adjusted to about 6 with 1M hydrochloric acid, the reaction was extracted with ethyl acetate, 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;

[0274] 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, and nitrogen was protected. 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 hour. After the reaction of the intermediate transition product was completed as monitored by TLC, a saturated sodium bicarbonate aqueous solution was added to quench the reaction and the pH was adjusted to about 7. The product was extracted with ethyl acetate and purified by silica gel column chromatography to obtain 2-(methoxymethyl)-4-methoxyacetophenone.

[0275] At room temperature and under nitrogen protection, sodium hydride (3.2 eq) and diethyl carbonate (2.5 eq) were dissolved in xylene, 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, and the reaction was continued at 110°C for 30 minutes. After TLC detection of the reaction was complete, the reaction solution was poured into ice water, hydrochloric acid was added to adjust the pH value to neutral to slightly acidic, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain 3-[4-methoxy-2-(methoxymethyl)phenyl]-3-oxopropionic acid ethyl ester;

[0276] 3-[4-methoxy-2-(methoxymethyl)phenyl]-3-oxopropionic acid ethyl ester (1.05eq), copper trifluoromethanesulfonate (0.1eq), and benzoquinone (1.0eq) were dissolved in xylene and reacted overnight at 110°C. After the reaction was completed 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]oxazo[4,3-b]benzofuran-7(5H)-one;

[0277] 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, 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 the reaction was carried out 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-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3-methoxy-9-hydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one;

[0278] In the absence of water and oxygen, 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3-methoxy-9-hydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (1.0 eq) was dissolved in ultra-dry dichloromethane (3-5 mL / mmol), and a dichloromethane solution of boron tribromide (1M in DCM 3.0 eq) was added dropwise at -20°C. The mixture was reacted 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, purified by column chromatography, the target molecule was collected, concentrated, and then added with saturated sodium bicarbonate aqueous solution and stirred at room temperature for 1 h. The mixture was filtered, washed with pure water, and dried to obtain a gray solid final product. 1 HNMR(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 for C 28 H 22 D2ClNO5(M+H) + 492.14995; Found(M+H) + 492.15339.

[0279] Embodiment seven:

[0280] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl)-3,9-dihydroxybenzo[5,6]oxazolidin-4,3-b]benzofuran-7(5H)-one (Compound YF007)

[0281] 3-Chlorobenzaldehyde (1.0 eq), ethyl acetoacetate (2.0 eq) and 4-methylpiperidine (0.3 eq) were mixed and placed in a reaction bottle, and reacted overnight at room temperature. Solids precipitated, and petroleum ether was used for slurrying. The solids were filtered to obtain white 2-(3-chlorophenyl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylic acid diethyl ester;

[0282] Add 30% to 50% sodium hydroxide aqueous solution (1 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, add pure water (4 times of sodium hydroxide aqueous solution), adjust the pH to 5 to 6 with concentrated hydrochloric acid, filter, collect the filtrate, add hydrochloric acid to the filtrate, a white solid precipitates, filter, and dry to obtain white 3-(3-chlorophenyl) glutaric acid;

[0283] 3-(3-chlorophenyl)pentanedioic 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.

[0284] In anhydrous and nitrogen protection, 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, and the reaction temperature was controlled below 5°C, and the reaction was carried out for 30 min, and then refluxed to react. The reaction was complete after TLC monitoring, and pure water was added under ice bath 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;

[0285] 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, and 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]oxazo[4,3-b]benzofuran-7(5H)-one was generated, and the mixture was directly purified by column chromatography to obtain 5-hydroxy-2-(4-methoxy-2-(methoxymethyl)phenyl)benzofuran-3-carboxylic acid ethyl ester;

[0286] 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, triethylamine was added to adjust the pH to weak alkalinity, reacted at 80°C overnight, the reaction was completed after TLC monitoring, and 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;

[0287] 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), and 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, and the reaction was concentrated. Then 1,4-dioxane and pure water were added, and the reaction was allowed to react at 100°C. The intermediate transition state product was completely converted into the target molecule as monitored by TLC. The reaction was stopped, and a saturated sodium bicarbonate solution was added to adjust the pH to be weakly alkaline. The mixture was extracted with DCM, and the organic phase was concentrated. The final yellow solid product was purified by column chromatography. 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 for C 28 H 20 D4ClNO5(M+H) + 494.17342; Found(M+H) + 494.26536.

[0288] Embodiment eight:

[0289] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (Compound YF008)

[0290] 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.

[0291] Embodiment nine:

[0292] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4 (Compound YF009)

[0293] In anhydrous and oxygen-free environment and under ice bath, a solution of lithium aluminum hydride in tetrahydrofuran (3-4.0 eq) was added dropwise to a super-dry THF solution containing 2-bromo-5-methoxybenzoyl chloride (1.0 eq), and the mixture was reacted at room temperature. After the reaction was completed as monitored by TLC, pure water was added to quench the reaction, and the mixture was filtered. The filtrate was extracted with EA and purified by column chromatography to obtain (2-bromo-5-methoxyphenyl)methanol-d2.

[0294] Dissolve (2-bromo-5-methoxyphenyl)methanol-d2 (1.0 eq) and sodium hydride (1.5 eq, 60% dissolved in oil) in ultra-dry THF, add iodomethane (1.5 eq), react at room temperature, monitor the reaction completion by TLC, add ice water to quench the reaction, extract with EA, and purify by column chromatography to obtain 1-bromo-4-methoxy-2-(methoxymethyl-d2)benzene;

[0295] 1-Bromo-4-methoxy-2-(methoxymethyl-d2)benzene (1.0 eq), 2-vinylethanol (2.0 eq), potassium carbonate (2.0 eq) were dispersed in water, nitrogen was protected, and then 1,3-bis(diphenylphosphino)propane (dppp) (0.05 eq) and palladium acetate (0.025 eq) were added in sequence, and the reaction was carried out at 80-90°C overnight. TLC monitored that the reaction of the raw materials was basically complete, and an intermediate transition product was produced. The reaction solution was cooled to room temperature, extracted with EA, separated, and concentrated hydrochloric acid was added dropwise to the organic phase. The reaction was carried out at room temperature for about 0.5 to 1 h. TLC monitored that the intermediate transition product was completely converted into the product, water was added to separate, the organic phase was concentrated, and 1-(4-methoxy-2-(methoxymethyl-d2)phenyl)ethanone was purified by column chromatography;

[0296] Dissolve diethyl carbonate (2.5 eq) in THF, add potassium tert-butoxide (3.2 eq), stir at room temperature for 0.5 h, then add dropwise a THF solution of 1-(4-methoxy-2-(methoxymethyl-d2)phenyl)ethanone (1.0 eq), react at 60-70° C. for about 2 h, monitor the reaction completion by TLC, pour the reaction solution into ice water to quench, add concentrated hydrochloric acid to adjust the pH to about 6, extract with EA, and purify by column chromatography to obtain ethyl 3-(4-methoxy-2-(methoxymethyl-d2)phenyl)-3-oxopropanoate;

[0297] 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 2-4h. The reaction was completed after monitoring 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.

[0298] 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.

[0299] Embodiment ten:

[0300] 8-((4-Butyryl)piperidin-1-ylmethyl-d2)-3,9-dihydroxybenzo[5,6]oxazolidin-4,3-b]benzofuran-7(5H)-one (Compound YF010)

[0301] The preparation method is as in Example 6, except that the steps after 9-hydroxy-3-methoxybenzo[5,6]oxazolidinone[4,3-b]benzofuran-7(5H)-one are:

[0302] 9-Hydroxy-3-methoxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (1.0 eq) was dissolved in ultra-dry dichloromethane, 1M BBr3 (4.0 eq, 1M in DCM) was added dropwise at -20°C, and the mixture was reacted overnight at room temperature. After the reaction was completed as monitored by TLC, the reaction was quenched with methanol, and the crude product was concentrated under reduced pressure to obtain the crude product, which was washed with methanol to obtain 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one;

[0303] 4-Butyrylpiperidine hydrochloride (1.5 eq), 3,9-dihydroxybenzo[5,6]oxazo[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.

[0304] Embodiment eleven:

[0305] 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 (YF011)

[0306] 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), reacted at room temperature for 0.5 h, heavy water (10.0 eq) was added, and the reaction was carried out at 80°C overnight. The reaction end point was detected by LC-MS, extracted with EA, and concentrated to obtain a crude product of tert-butyl 4-(butyryl-2,2-d2)piperidine-1-carboxylate-4-d, which was directly used for the next step without purification;

[0307] Under nitrogen protection, add 20% deuterated hydrochloric acid (DCl) aqueous solution (3.0 eq) to the crude product of tert-butyl 4-(butyryl-2,2-d2)piperidine-1-carboxylate-4-d (1.0 eq), react overnight at room temperature, and concentrate to obtain the crude product of 4-(butyryl-2,2-d2)piperidine-1,4-d2 hydrochloride, which is directly used for the next step without purification;

[0308] 4-(Butyryl-2,2-d2)piperidine-1,4-d2 hydrochloride (1.5 eq), 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (preparation method refers to 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.

[0309] Embodiment 12:

[0310] 8-((4-Butyrylpiperidin-1-yl-2,2,6,6-d4)-methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (YF012)

[0311] 2,6-dioxopiperidin-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 bottle, and DCM was added as a solvent, and triethylamine was added, and the reaction was allowed to proceed overnight at room temperature. TLC monitored the reaction to be complete, and 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-dioxopiperidin-4-carboxylic acid amine;

[0312] To a super dry THF solution containing N-methoxy-N-methyl-2,6-dioxopiperidine-4-carboxylic acid amide (1.0 eq) was added a THF solution of propylmagnesium bromide (4.0 eq, 1 M in THF) dropwise in an anhydrous and oxygen-free environment and under an ice bath, and then reacted at room temperature. The reaction was complete when monitored by TLC. The reaction was quenched with a saturated ammonium chloride solution, extracted with EA, and the organic phase was concentrated. 4-butyrylpiperidine-2,6-dione was purified by column chromatography.

[0313] Under ice bath, slowly add ultra-dry THF to the reaction bottle containing LiAlD4 (3.5eq), and then dropwise add THF solution of 4-butyrylpiperidine-2,6-dione (1.0eq), and reflux overnight. TLC monitors the reaction to be complete, add pure water and 15% NaOH aqueous solution to quench the reaction, filter to obtain THF-water solution of 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-d-1-ol, and control the pH to about 12-14;

[0314] (Boc)2O (1.1 eq) was added to the THF-water solution containing 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-d-1-ol, 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.

[0315] 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 completed after monitoring by TLC, and the reaction was cooled and filtered. The crude product of tert-butyl 4-butyrylpiperidine-1-carboxylate-2,2,6,6-d4 was obtained. 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 reaction was concentrated to obtain 1-(piperidin-4-yl-2,2,6,6-d4)butane-1-one hydrochloride.

[0316] 1-(Piperidin-4-yl-2,2,6,6-d4)butane-1-one hydrochloride (1.5 eq), 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one (preparation method refers to 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.

[0317] Embodiment 13:

[0318] 8-((4-Butyrylpiperidin-1-yl-2,2,6,6-d4)-methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4(YF013)

[0319] The preparation method is the same as that of Example 9, except that the steps after 5-hydroxy-2-(4-methoxy-2-(methoxymethyl-d2)phenyl)benzofuran-3-carboxylic acid ethyl ester-4,6,7-d3 are:

[0320] In the absence of water and oxygen, 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 an ice bath. The reaction was allowed to react 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. After 3 to 12 hours, the reaction is complete as monitored by TLC. The reaction solution is concentrated, and water is added to precipitate the solid, which is 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 is purified by pulping to obtain 3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,8,10,11-d5.

[0321] 1-(Piperidin-4-yl-2,2,6,6-d4)butane-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;

[0322] Embodiment 14:

[0323] 8-((4-(Butyryl-2,2-d2)piperidin-1-yl-4-d)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4(YF014)

[0324] 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:Calcd for C 26 H 18 D6NO6(M+H)+ 459.24000; Found(M+H) + 459.25780.

[0325] Embodiment 15:

[0326] 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)

[0327] Compound YF010 (1.0 eq) was dissolved in methanol, sodium borohydride (1.0 eq) was added under ice bath, and the mixture was reacted at room temperature for 0.5-1 h. After the reaction was completed as 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.

[0328] Embodiment 16:

[0329] 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)

[0330] Compound YF010 (1.0 eq) was dissolved in methanol, sodium borodeuteride (1.0 eq) was added under ice bath, and the mixture was reacted at room temperature for 0.5-1 h. After the reaction was completed as monitored by TLC, the reaction solution was concentrated and purified by column chromatography to obtain a light yellow solid final product.

[0331] 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.

[0332] Embodiment 17:

[0333] 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)

[0334] The preparation method is the same as that of Example 15, except that YF010 is replaced by YF011 to obtain a creamy yellow solid final product. 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 for C 26 H 26 D3NO6(M+H) + 455.24220; Found(M+H) + 455.23078.

[0335] Embodiment 18:

[0336] 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)

[0337] 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.

[0338] Embodiment 19:

[0339] 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)

[0340] 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. 1HNMR (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 for C 26 H 23 D6NO6(M+H) + 458.23700; Found(M+H) + 458.53400.

[0341] Embodiment 20:

[0342] 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)

[0343] 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 HNMR(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.

[0344] Embodiment 21:

[0345] 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)

[0346] 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 HNMR(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.

[0347] Embodiment 22:

[0348] 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)

[0349] 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 HNMR(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.

[0350] Embodiment 23:

[0351] 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)

[0352] 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.

[0353] Embodiment 24:

[0354] 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)

[0355] 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 HNMR (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 10 NO6(M+H)+ 462.58260; Found (M+H) + 462.29338.

[0356] Embodiment 25:

[0357] 10-(tert-Butyl)-3,8-dihydroxy-7-(piperidin-1-ylmethyl-d2)-6H-benzofuran[3,2-c]chromen-6-one hydrochloride (Compound YF025)

[0358] 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 solution (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.

[0359] Embodiment 26:

[0360] 10-(tert-Butyl)-3,8-dihydroxy-7-((piperidin-1-yl-2,2,6,6-d4)methyl)-6H-benzofuran[3,2-c]chromen-6-one hydrochloride (Compound YF026)

[0361] 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.

[0362] Embodiment 27:

[0363] 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 (Compound YF027)

[0364] 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.

[0365] Embodiment 28:

[0366] 10-(tert-butyl)-3,8-dihydroxy-7-(piperidin-1-yl)-d 10 )methyl)-6H-benzofuran[3,2-c]chromen-6-one hydrochloride (Compound YF028)

[0367] 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),7.0 5(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 for C 25 H 18 D 10 ClNO5(M+H) + 467.22801; Found (M+H-HCl) + 432.55100.

[0368] Embodiment 29:

[0369] 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)

[0370] 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.

[0371] Embodiment 30:

[0372] 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)

[0373] At room temperature, 8-((4-(3-chlorophenyl)piperidin-1-yl)methyl-d2)-3,9-dihydroxybenzo[5,6]oxa[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]oxa[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.

[0374] Embodiment 31:

[0375] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one hydrochloride (Compound YF031)

[0376] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF007 to obtain a white solid final product. 1HNMR(600MHz,DMSO-d6)δ10.66(s,1H),10.46(s,1H),9.78(s,1H),7.87(d,J=8.5Hz,1 H),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 forC 28 H 21 D4Cl2NO5(M+H) + 530.15010; Found (M+H-HCl) + 494.26536.

[0377] Embodiment 32:

[0378] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one hydrochloride (Compound YF032)

[0379] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF008 to obtain a white solid final product. 1 HNMR(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 forC 28 H 19 D6Cl2NO5(M+H) + 532.16575; Found (M+H-HCl) +496.17764.

[0380] Embodiment 33:

[0381] 8-((4-(3-chlorophenyl)piperidin-1-yl-2,2,6,6-d4)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (Compound YF033)

[0382] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF009 to obtain a white solid final product. 1 HNMR(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=2.1,1.5H z,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.

[0383] Embodiment 34:

[0384] 8-((4-Butyryl)piperidin-1-ylmethyl-d2)-3,9-dihydroxybenzo[5,6]oxazepin[4,3-b]benzofuran-7(5H)-one hydrochloride (Compound YF034)

[0385] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF010 to obtain a light brown solid final product. 1HNMR(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.

[0386] Embodiment 35:

[0387] 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 hydrochloride (YF035)

[0388] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF011 to obtain a yellow-white solid final product. 1 HNMR(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:Calcdfor C 26 H 25 D3ClNO6(M+H) +489.19181; Found (M+H-HCl) + 453.56020.

[0389] Embodiment 36:

[0390] 8-((4-Butyrylpiperidin-1-yl-2,2,6,6-d4)-methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one hydrochloride (YF036)

[0391] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF012 to obtain a white solid final product. 1 HNMR (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.

[0392] Embodiment 37:

[0393] 8-((4-Butyrylpiperidin-1-yl-2,2,6,6-d4)-methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (YF037)

[0394] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF013 to obtain a white solid final product. 1HNMR (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 for C 26 H 18 D 10 ClNO6(M+H) + 496.22300; Found (M+H-HCl) + 460.56400.

[0395] Embodiment 38:

[0396] 8-((4-(Butyryl-2,2-d2)piperidin-1-yl-4-d)methyl-d2)-3,9-dihydroxybenzo[5,6]oxazo[4,3-b]benzofuran-7(5H)-one-5,5,10,11-d4 hydrochloride (YF038)

[0397] The preparation method is the same as that of Example 30, except that YF006 is replaced by YF014 to obtain a white solid final product. 1 HNMR (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 for C 26 H 19 D6ClNO6(M+H) + 495.21700; Found (M+H-HCl) + 459.24700.

[0398] Embodiment 39:

[0399] 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)

[0400] 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 HNMR(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 forC 26 H 28 D2ClNO6(M+H) + 490.19120; Found (M+H-HCl) + 454.22300.

[0401] Embodiment 40:

[0402] 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)

[0403] 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. 1HNMR(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.

[0404] Embodiment 41:

[0405] 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)

[0406] 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 HNMR(600MHz,DMSO-d6)δ10.66(s,1H),10.50(s,1H),9.51(s,1H),7.86(d,J=8.5Hz,1 H),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 forC 26 H 27 D3ClNO6(M+H) + 494.20746; Found (M+H-HCl) + 455.23100.

[0407] Embodiment 42:

[0408] 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)

[0409] 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 HNMR(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 forC 26 H 26 D4ClNO6(M+H) + 492.21529; Found (M+H-HCl) + 456.23541.

[0410] Embodiment 43:

[0411] 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)

[0412] 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. 1HNMR(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=2.5H z,1H),7.09(dd,J=8.5,2.4Hz,1H),5.37(s,2H),3.23-3.17(m,1H),1.88-1 .86(m,1H),1.73-1.19(m,8H),0.86(t,J=6.9Hz,3H).HRMS(ESI)m / z:Calcd for C 26 H 24 D6ClNO6(M+H) + 493.21400; Found (M+H-HCl) + 458.55560.

[0413] Embodiment 44:

[0414] 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)

[0415] 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 HNMR (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 forC 26 H 23 D7ClNO6(M+H) + 494.22000; Found (M+H-HCl) + 459.26617.

[0416] Embodiment 45:

[0417] 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)

[0418] 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 HNMR(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 forC 26 H 20 D 10 ClNO6(M+H) + 498.26224; Found (M+H-HCl) + 462.28600.

[0419] Embodiment 46:

[0420] 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)

[0421] 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 HNMR (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.

[0422] Embodiment 47:

[0423] 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)

[0424] 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.

[0425] Embodiment 48:

[0426] 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)

[0427] 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. 1HNMR(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 for C 26 H 20 D 10 ClNO6(M+H) + 498.26224; Found (M+H-HCl) + 462.28556.

[0428] Example 49: In vitro pharmacodynamic evaluation of the compounds of the present invention against Mycobacterium tuberculosis

[0429] This example detects the minimum inhibitory concentration (MIC) of the compound of the present invention against the standard strain of Mycobacterium tuberculosis (Mycobacterium tuberculosis H37Rv).

[0430] 1.1 Experimental Materials

[0431] The compounds of the present invention, non-deuterated control compounds A, B, C, D (structures shown in the figure below); Mycobacterium tuberculosis H37Rv (cultured in Middlebrook 7H9 culture medium), provided by Shanghai Pulmonary Hospital.

[0432]

[0433] 1.2 Preparation of test compounds

[0434] The test compound was completely dissolved in dimethyl sulfoxide (DMSO) to prepare a mother solution with a concentration of 1 mg / mL, and then sterilized by filtration. The mother solution was gradiently diluted with Middlebrook 7H9 culture medium as needed to obtain solutions of the test compound with different concentrations, and 100 μL was added to each well of a 96-well culture plate.

[0435] 1.3 Experimental methods

[0436] Mycobacterium tuberculosis H37Rv (standard strain) in the logarithmic growth phase was diluted with Middlebrook 7H9 culture medium to a turbidity OD600 of 1.0 (about 5×10 6CFU / mL), 200 μL of which was diluted to 10 mL with Middlebrook 7H9 culture medium to obtain a bacterial solution containing H37Rv, and 100 μL of the bacterial solution containing H37Rv was added to the above-mentioned culture plate containing the test compound to obtain an experimental group. Among them, 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.

[0437] The drug-free control groups were set up with 100% inoculum (100 μL diluted H37Rv bacterial solution + 100 μL Middlebrook 7H9 culture medium), 10% inoculum (10 μL diluted H37Rv bacterial solution + 190 μL Middlebrook 7H9 culture medium) or no inoculum group (200 μL Middlebrook 7H9 culture medium).

[0438] After 15 days of culture, the size of the bacterial plaque observed by naked eyes was no larger than 10% of the inoculum amount in the drug-free control group, which was taken as the minimum inhibitory concentration (MIC) of the compound to inhibit 90% growth of Mycobacterium tuberculosis H37Rv 90 The activity results are shown in Table 1.

[0439] Table 1: MIC of the compounds of the present invention against Mycobacterium tuberculosis H37Rv 90 Value Data

[0440]

[0441]

[0442] As can be seen from Table 1, the compounds of the present invention exhibit good resistance to Mycobacterium tuberculosis.

[0443] Example 50: Pharmacokinetic evaluation of deuterated compounds in mice

[0444] This example detects 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).

[0445] 1.1 Experimental animals

[0446] Balb / C mice, male (one group at each time point, 5 mice in each group, 55 mice in total for each compound), 7-8 weeks old, weighing about 20 g, animal source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0447] 1.2 Preparation of samples to be tested

[0448] 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.

[0449] 1.3 Experimental methods

[0450] The pharmacokinetic differences of deuterated compounds YF027, YF032, YF036 and YF044 and their respective non-deuterated reference substances A, B, C and D were compared by single oral administration at a dose of 100 mg / kg.

[0451] The mice were fasted overnight before administration. The orbital venous blood and lung tissues of the mice were collected from the unadministered 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.

[0452] The collected blood sample was placed in an anticoagulant tube, quickly inverted to mix, and then the tube was placed on ice for temporary storage after labeling. The blood sample temporarily stored on ice was subjected to low-temperature centrifugation within 1 hour, with the centrifugation conditions being 4°C, 3000rpm, and centrifugation for 10 minutes. The supernatant obtained after centrifugation was plasma, which was taken into another new centrifuge tube and stored in a -80°C refrigerator for testing.

[0453] The lung tissues of mice were collected and placed in pre-cooled saline to wash away residual blood and tissue fluid. After being dried on absorbent paper, they were weighed using a balance and placed in a centrifuge tube. The tubes were marked and stored in a -80°C refrigerator.

[0454] The concentrations of the compounds of the present invention and the control compounds in plasma and lung tissue were tested using LC-MS / MS. The test results are shown in Tables 2 to 5.

[0455] Table 2 Pharmacokinetic parameters of the compound YF027 of the present invention and the control compound A

[0456]

[0457] The results showed that the highest blood concentration of the compound YF027 in vivo was C max (100.26 ng / mL) and the C of the non-deuterated control compound A max (120.1ng / mL) is close, but the in vivo exposure AUC of YF027 is 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 Cmax (947.88ng / g).

[0458] Table 3 Pharmacokinetic parameters of compound YF032 of the present invention and control compound B

[0459]

[0460] The results showed that the highest blood concentration of compound YF032 in vivo 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 (10327.84ng·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).

[0461] Table 4 Pharmacokinetic parameters of the compound YF036 of the present invention and the control compound C

[0462]

[0463]

[0464] The results showed that the highest blood concentration of the 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 (943.7ng / 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 (4960.45ng·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).

[0465] Table 5 Pharmacokinetic parameters of the compound YF044 of the present invention and the control compound D

[0466]

[0467] The results showed that the highest blood concentration of compound YF044 in vivo was Cmax (4041.90 ng / mL) was significantly higher than the C of the non-deuterated control compound D. max (2109.55ng / 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 (4474.91ng·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).

[0468] From the results, it can be seen that compared with the control compound, 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.

[0469] Example 51: Enzyme Metabolism Phenotype Study of Compounds

[0470] 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) test). 1.1 Sample solution preparation:

[0471] a. Prepare the test compound into a 40mM concentration stock solution for standby use, take 2.5μL of the above stock solution, use DMSO to dilute it to a 200μM concentration of the test compound, and the compound used in subsequent experiments is this concentration;

[0472] b. The working concentration of the positive substrate drug phenacetin and testosterone mixture is 200 μM.

[0473] 1.2 Prepare the incubation system and start the reaction:

[0474] 1) Thaw the components of the kit in an ice bath, vortex to mix, and place on ice for later use;

[0475] 2) Except for the microparticles, the other components of each incubation system are mixed according to the ratio and mixed by pipetting. The ratio of the incubation system is as follows;

[0476] Table 6. Positive control group incubation system

[0477] name Addition volume (μL) Kit B Solution 1.25 Positive substrate drug 0.625 0.1M phosphate buffer solution 120

[0478] Table 7. Incubation system of experimental control group

[0479] name Addition volume (μL) Kit B Solution 1.25 Compound YF027 0.625 0.1M phosphate buffer solution 120

[0480] Table 8. Incubation system of experimental groups

[0481] name Addition volume (μL) Kit B Solution 1.25 Compound YF027 0.625 Selective inhibitor (200×) 0.625 0.1M phosphate buffer solution 119.375

[0482] 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.

[0483] Table 9. Negative control group incubation system

[0484] name Addition volume (μL) Kit B Solution 1.25 Compound A 0.625 0.1M phosphate buffer solution 123.125

[0485] 3) In the above incubation systems except the negative control group (Table 9), 3.125 μL of liver microsomes were added to prepare 125 μL of reaction solution, vortexed and placed in a 37°C water bath to start the reaction and start timing.

[0486] 4) Take 50 μL of the reaction solution at 0 min and 90 min, add pre-cooled acetonitrile solution to the reaction solution and quickly vortex to mix to terminate the reaction.

[0487] 5) Pre-treatment of reaction solution for mass spectrometry detection

[0488] The reaction solution was frozen at -80°C overnight, centrifuged and subjected to mass spectrometry detection.

[0489] 1.3 Experimental Results

[0490] The experimental results showed that the incubation system set in the experiment and the enzymes in the liver microsomes worked normally and had good activity. After 90 minutes of incubation, the positive substrates phenacetin and testosterone were almost completely metabolized, which was below the lower limit of mass spectrometry detection. The detection value after 90 minutes of incubation was used to perform ratio processing on the detection value at 0 minutes to obtain the metabolic rate of the compound after 90 minutes of incubation in different experimental groups, which was calculated by the calculation formula of metabolic inhibition rate, that is, inhibition rate % = (1-metabolic rate of sample with inhibitor added / metabolic rate of sample in the group without inhibitor) as shown in Table 10 below. According to the "Technical Guidelines for Drug Interaction Studies (Trial)" issued by the Drug Review Center of the State Food and Drug Administration, if a specific metabolic enzyme contributes ≥25% to the total elimination of a drug, it can be considered that the enzyme has a significant contribution to the clearance of the drug, that is, it is the main metabolic enzyme of the drug. The metabolic inhibition rate reflects the effect of adding different selective inhibitors on the metabolic elimination of the drug. Therefore, when the metabolic inhibition rate of a specific enzyme is ≥25%, it can be inferred from the results of in vitro metabolism studies that its contribution rate to the clearance of the drug under study is ≥25%.

[0491] The experimental results show that CYP3A4 is the main metabolizing enzyme of compound A, but none of the above 7 CYP metabolizing enzymes are the main metabolizing enzymes of YF027. Therefore, after deuteration, the main metabolic mode of YF027 in the body changes, and it is no longer metabolized by CYP3A4, the main metabolizing enzyme subtype of CYP450 enzyme, which provides the possibility for the clinical combination of YF027 with other drugs. For example: isoniazid has a strong inhibitory effect on the enzyme activity of CYP3A4, and compound A may cause drug interactions if used in combination with isoniazid.

[0492] Table 10 CYP450 enzyme metabolic phenotype study experimental results

[0493]

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof: in, n is 0 or 1; R4 is selected from H, halogen, aldehyde, hydroxyl, 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 10 Heterocyclyl 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; 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 group, 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; R1, R2, R3, R6, R9 and R 10 are independently selected from: hydrogen and deuterium; and The structure shown in Formula I contains at least one deuterium atom.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R4 is -(CR 11 R 12 ) m -NR a R b , Where m is 1, 2 or 3; R 11 and R 12 are independently selected from hydrogen and deuterium; and R a and R b Each is independently selected from the following substituents and their respective deuterated variants: H; C1-C2 optionally substituted with 1-5 substituents selected from halogen and hydroxyl; 10 C2-C8 alkenyl optionally substituted by 1-5 substituents selected from halogen and hydroxyl; 3-14 membered carbocyclic group optionally substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 3-14 membered carbocyclic group substituted by 1-5 substituents selected from halogen and C1-C4 alkyl; C1-C6 alkyl optionally substituted by 1-5 substituents selected from halogen, hydroxyl and C1-C4 alkyl 4-10 membered heterocyclic group substituted; C6-C8 alkyl optionally substituted by 1-5 substituents selected from halogen, hydroxyl and C1-C4 alkyl 14 Aryl; and C6-C4 substituted with 1-5 groups selected from halogen, hydroxyl 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 following: 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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; wherein, R c and R d Each is independently selected from H, C1-C6 alkyl, C2-C8 alkenyl and C1-C6 alkoxy.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein -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; Preferably, -NR a R b Selected from: Where R 20 To R 41 , R 44 independently selected from: hydrogen and deuterium; More preferably, -NR a R b Selected from:

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted by 1-5 selected from halogen and hydroxy, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxy, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated 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; preferably, R7 is selected from hydrogen, deuterium and 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein the structure shown in 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 of formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, in, 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 R1, R2, R3, R6, R 11 , R 12 and R 20 To R 29 are independently selected from hydrogen and deuterium; and The structure of Formula II comprises at least one deuterium atom; preferably comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 deuterium atoms.

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

8. A compound of formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, 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 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 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; 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 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; 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; R7 is selected from H, C1-C6 alkyl optionally substituted by 1-5 selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted by 1-5 selected from halogen and hydroxy, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxy, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated 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 is independently selected from: hydrogen and deuterium; More preferably, R7 is hydrogen and deuterium; 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 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.

9. The compound according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein the structural formula of the compound is as shown in the following IIIa, IIIb or IIIc: 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; preferably, R1, R2, and R3 are all hydrogen.

10. The compound according to claim 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein the structural formula of the compound is as shown in the following IIId, IIIe or IIIf:

11. The compound according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

12. A compound of formula IV, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, Where n is 0 or 1; Re is selected from: 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 with 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-C4 alkyl optionally substituted by 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl and hydroxyl 14 C1-C4 acyl substituted with aryl; C6-C4 acyl optionally substituted with 1-5 substituents selected from halogen, C1-C4 alkyl, halogenated 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 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; 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 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 their respective deuterated variants; wherein, 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 by 1-5 selected from halogen and hydroxy, C2-C6 alkenyl optionally substituted by 1-5 selected from halogen and hydroxy, C3-C8 saturated or partially saturated carbocyclic group, halogen, hydroxy, C6-C 14 C1-C4 alkoxy substituted with aryl, 5-10 membered heteroaryl, and C6-C4 alkyl optionally substituted with 1-3 substituents selected from C1-C4 alkyl, halogenated 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 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.

13. The compound according to claim 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, wherein Re together with the piperidinyl group to which it is attached constitutes a group selected from the following:

14. 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:

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

16. A pharmaceutical composition comprising (i) a preventively or therapeutically effective amount of a compound according to any one of claims 1 to 15 as an active ingredient, or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof; and (ii) a pharmaceutically acceptable carrier or excipient; The pharmaceutical composition optionally contains: (iii) a second active ingredient; 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, premanid, bedaquiline, sudapyridine, TB47, GSK 3036656, gepedacin, thiosemicarbazide, meropenem-clavulanate, TBA-7371, OPC-167832, Telacebec (Q203), BTZ-043, Contezolid (MRX-4 / MRX-1), Delpazolid (LCB01–0371), Macozinone, Pretomanid, SPR720, SQ109, TBI-166, TBI-223, and thioridazine.

17. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide, hydrate, solvate or prodrug thereof, or a pharmaceutical composition according to claim 16, for use in the preparation of a medicament for preventing or treating a disease caused by a bacterial infection; preferably, 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, and 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, more preferably pulmonary tuberculosis.

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