Amide derivative and composition and application thereof

Abstract

The invention relates to an amide derivative as well as a composition and application thereof. The amide derivative is a compound shown in a formula (I), or a tautomer, a stereoisomer, a prodrug, a crystal form, pharmaceutically acceptable salt, hydrate or solvate of the amide derivative, a pharmaceutical composition of the amide derivative and application of the amide derivative and the pharmaceutical composition in treatment and / or prevention of virus infection. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to amide derivatives for treating and / or preventing viral infections, pharmaceutical compositions containing the same, and preparation methods and uses thereof. Background Art

[0002] Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of December 2, 2022, over 643 million confirmed cases have been reported worldwide. Antiviral drugs for COVID-19 are being developed, and several vaccines have been approved and are being used in various countries.

[0003] SARS-CoV-2 is a member of the Coronaviridae family, which includes the largest positive-sense, single-stranded RNA viruses. These viruses are divided into four genera: alpha, beta, gamma, and delta. SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 are betacoronaviruses. Genomic sequence analysis of these three viruses showed that SARS-CoV-2 is more identical to SARS-CoV than to MERS-CoV. The major structural proteins encoded by SARS-CoV-2 include spike protein (S), membrane protein (M), envelope protein (E), and nucleocapsid protein (N). The binding of the S protein to the host cell receptor angiotensin-converting enzyme 2 (ACE2) is a key event for SARS-CoV-2 to enter the host cell. The non-structural proteins (nsps) encoded by SARS-CoV-2, such as 3C-like protease (3CL pro ), papain-like protease (PL pro ), etc., also play a key role in viral replication and are also important targets for drug development.

[0004] 3C-like protease (3CL pro , 3C-like protease) or main protease (M pro ), is the main protease found in coronaviruses. It cleaves coronavirus polyproteins at 11 conserved sites. It is a cysteine ​​protease and a member of the protease PA family. It hydrolyzes viral polyproteins pp1a and pp1ab to produce functional proteins during coronavirus replication. It has a cysteine-histidine catalytic dimer in its active site and cleaves the Gln-(Ser / Ala / Gly) peptide bond. Due to its highly conserved sequence and basic functional properties, 3CL proIt is considered one of the most attractive targets for the treatment of COVID-19 and has been verified as a potential target for the development of drugs for the treatment of SARS, MERS and COVID-19. Currently, a variety of drugs targeting 3CL have been developed. pro Natural and synthetic inhibitors at different sites and regions, which can be divided into peptidomimetic and non-peptide inhibitors according to their structural types, provide more potential active compounds or drug candidates for the development of new drugs against COVID-19.

[0005] Pfizer PF-07321332 is an amide-based oral antiviral drug that targets 3C-like proteases and inhibits viral 3CL pro , inhibiting RNA replication and the production of related non-structural proteins, thereby inhibiting viral replication. PF-07321332 has been approved by the FDA for emergency drug use for the treatment of COVID-19. Because PF-07321332 is easily broken down by the liver, it needs to be used in combination with ritonavir, which slows the metabolism or breakdown of PF-07321332 by cytochrome enzymes to maintain the circulating concentration of PF-07321332, allowing it to maintain an effective concentration in the body for a longer period of time, thereby enhancing its antiviral activity. However, when PF-07321332 is used to treat COVID-19, if it is combined with other prescription drugs, such as antilipidemia drugs statins, anticoagulants, and antidepressants, it will increase the toxic side effects of these drugs and may even lead to serious adverse reactions such as death.

[0006] Therefore, developing a safer, more effective and more convenient drug for treating COVID-19 has become an urgent need in this field. SUMMARY OF THE INVENTION

[0008] The present invention provides a novel amide derivative, a composition comprising the compound, and uses thereof. The novel amide derivative has high inhibitory activity against viral 3C-like proteases, can be used to treat infections in the Coronaviridae, Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, and Orthomyxoviridae families, and has excellent pharmacokinetic properties and can be used for oral administration.

[0009] To this end, the present invention adopts the following technical solutions:

[0010] In one aspect, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0011]

[0012] in,

[0013] Z is NH, O or a chemical bond;

[0014] R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5 to 10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R;

[0015] p is 0, 1, or 2;

[0016] Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0017] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0018] R a1 and R a2 is H;

[0019] R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0020] Or, R a1and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace;

[0021] Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0022] R4 is CN, CHO or -C(O)-5- to 10-membered heteroaryl;

[0023] m is 1 or 2;

[0024] n is 0, 1, 2, 3, 4, 5 or 6;

[0025] Each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0026] Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen;

[0027] The condition is that the compound of formula (I) satisfies at least one of the following conditions:

[0028] 1) R1 is -CF2Cl, -CF2Br or C 2-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R;

[0029] 2) When R2 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 When it is an alkylene-3 to 7-membered heterocyclic group, R2 is substituted by at least one or more R;

[0030] 3) Two R on the same atom b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0031] 4) Two R on adjacent atoms b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0032] 5) When R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-

[0033] C 6-10 Aryl or -C 1-6 When it is alkylene-5 to 10 membered heteroaryl, R1 is substituted by at least one or more R, and p is 1 or 2;

[0034] 6) When two R c Together with the atoms to which they are attached, they form C 3-6 When cycloalkyl, wherein the C 3-6 The cycloalkyl group is substituted with at least one or more halogens;

[0035] 7) Two Rs c Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group.

[0036] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable excipient, and optionally, other therapeutic agents.

[0037] In another aspect, the present invention relates to the use of a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing viral infections and viral infection-related symptoms and / or diseases.

[0038] In another aspect, the present invention relates to a method for treating and / or preventing viral infection and viral infection-related symptoms and / or diseases in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition of the present invention.

[0039] In another aspect, the present invention relates to a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the present invention, for use in treating and / or preventing viral infections and viral infection-related symptoms and / or diseases.

[0040] In more specific aspects, the viral infection of the present invention is a Coronaviridae infection, a Paramyxoviridae infection, a Pneumoviridae infection, a Picornaviridae infection, a Flaviviridae infection, a Filoviridae infection, an Arenaviridae infection, an Orthomyxoviridae infection, or a Monkeypox infection.

[0041] In more specific aspects, the coronavirus described in the present invention is HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV or SARS-CoV-2 and variants thereof.

[0042] In a more specific aspect, the coronavirus infection described herein is a viral infection caused by SARS-CoV-2 and its variants. SARS-CoV-2 and its variants should be understood to encompass the originally discovered virus strains, as well as mutant strains that have emerged, including but not limited to strains such as B.1.427, B.1.429, P.2, B.1.351, B.1.1.207, C.37, B.1.1.7, B.1.1.298, B.1.617.2, B.1.617.1, P.1, B.1.525, P.3, B.1.621, B.1.1.529, XBB.1.5, BQ.1, BA.2.75, CH.1.1, XBB.1.16, and XBF.

[0043] In a more specific aspect, the viral infection-related symptoms and / or diseases described in the present invention are cold-like symptoms accompanied by fever, chills, headache, muscle pain, loss of taste or loss, general fatigue, etc., or respiratory inflammation such as sore throat, runny nose, nasal congestion, cough, sputum, abdominal pain, vomiting, and diarrhea; gastrointestinal symptoms; pneumonia, especially pneumonia caused by novel coronavirus (SARS-CoV-2) infection, symptoms include inflammatory reactions characterized by deep airway and alveolar damage, pulmonary fibrosis, pulmonary exudative reactions, etc., and further accompanied by complications such as acute encephalopathy, kidney damage, liver damage, heart failure, myocarditis, etc.

[0044] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.

[0045] definition

[0046] Chemical definition

[0047] Definitions of specific functional groups and chemical terms are described in more detail below.

[0048] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0049] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-4 Alkyl is particularly preferred. Examples of the alkyl include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Regardless of whether the alkyl group is modified with "substituted", each of the alkyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined as follows.

[0050] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, C 2-4 Alkenyl is particularly preferred. Examples of the alkenyl include, but are not limited to, vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Regardless of whether the alkenyl is modified with "substituted", each of the alkenyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, and suitable substituents are defined below.

[0051] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-4 Alkynyl is particularly preferred. In some embodiments, alkynyl does not contain any double bond. One or more carbon triple bonds can be internal (e.g., in 2-butynyl) or end (e.g., in 1-butynyl). Examples of the alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. Regardless of whether "substituted" is modified before the alkynyl, each of the alkynyl groups is optionally substituted independently, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, and suitable substituents are defined as follows.

[0052] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene is particularly preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0053] “C 0-6 "Alkylene" includes chemical bonds and C 1-6 Alkylene.

[0054] “C 1-6 "Alkoxy" refers to a group -OR, where R is a substituted or unsubstituted C1-6 In some embodiments, C 1-4 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0055] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halo group is F, Cl, or Br. In some embodiments, the halo group is F or Cl. In some embodiments, the halo group is F.

[0056] Therefore, “C 1-6 Haloalkyl" and "C 1-6 "Haloalkoxy" refers to the above-mentioned "C 1-6 Alkyl" and "C 1-6 Alkoxy", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2 In some embodiments, C 1-4 Halogenated alkoxy is particularly preferred, more preferably C 1-2 Halogenated alkoxy. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Exemplary haloalkoxy groups include, but are not limited to, -OCH2F, -OCHF2, -OCF3, and the like.

[0057] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 Cycloalkyl is preferred, C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-6Cycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodec ... 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ), etc. Regardless of whether the cycloalkyl group is preceded by "substituted", each of the cycloalkyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent, and suitable substituents are defined below.

[0058] "3- to 10-membered heterocyclyl" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, a 3- to 7-membered heterocyclyl is preferred, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, a 3- to 6-membered heterocyclyl is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, a 5- to 6-membered heterocyclyl is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Regardless of whether the heterocyclyl group is preceded by "substituted", each of the heterocyclyl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitable substituents being defined below.

[0059] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyls containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyls containing one heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiocanyl. Exemplary 5-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0060] “C 6-14 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 In some embodiments, C 6-10Aryl is particularly preferred, with C6 aryl being more preferred. Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclic groups, with the point of attachment being on the aryl ring. In this case, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is preceded by "substituted," each aryl group is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined below.

[0061] "5- to 10-membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Regardless of whether the heteroaryl group is preceded by "substituted", each of the heteroaryl groups is independently optionally substituted, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are defined below.

[0062] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepine, oxepinyl, and thiepine. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0063] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb)2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NRbb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0064] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0065] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0066] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(Rcc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0067] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0068] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0069] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0070] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 Rgg group substitution;

[0071] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclic group, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0072] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2Rcc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0073] "Deuterated" or "D" refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium; deuteration can be mono-, di-, poly-, or per-substituted. The term "deuterated" and "deuterated one or more times" are used interchangeably.

[0074] A "non-deuterated compound" refers to a compound that contains deuterium atoms in a proportion not greater than the natural deuterium isotope content (0.015%).

[0075] The deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0076] The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Salts formed using conventional methods in the art, such as ion exchange methods, are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, if appropriate.

[0077] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0078] "Disease," "disorder," and "condition" are used interchangeably herein.

[0079] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduce the severity of, or delay or slow the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject becomes ill with a particular disease, disorder, or condition ("prophylactic treatment").

[0080] "Combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents of the invention. For example, a compound of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously with another therapeutic agent in a single unit dosage form. DETAILED DESCRIPTION

[0081] Compound

[0082] Herein, "compounds of the present invention" refers to the following compounds of formula (I) to formula (IV) (including subsets of each formula, such as formula (II-1)), or their tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

[0083] In one embodiment, the present invention relates to compounds of formula (I):

[0084]

[0085] in,

[0086] Z is NH, O or a chemical bond;

[0087] R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C1-6 Alkylene-5 to 10 membered heteroaryl, wherein the above groups are optionally substituted with one or more R;

[0088] p is 0, 1, or 2;

[0089] Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0090] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0091] R a1 and R a2 is H;

[0092] R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0093] Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace;

[0094] Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0095] R4 is CN, CHO or -C(O)-5- to 10-membered heteroaryl;

[0096] m is 1 or 2;

[0097] n is 0, 1, 2, 3, 4, 5 or 6;

[0098] Each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0099] Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen;

[0100] The condition is that the compound of formula (I) satisfies at least one of the following conditions:

[0101] 1) R1 is -CF2Cl, -CF2Br or C 2-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R;

[0102] 2) When R2 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 When it is an alkylene-3 to 7-membered heterocyclic group, R2 is substituted by at least one or more R;

[0103] 3) Two R on the same atom b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0104] 4) Two R on adjacent atoms b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0105] 5) When R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 When it is alkylene-5 to 10 membered heteroaryl, R1 is substituted by at least one or more R, and p is 1 or 2;

[0106] 6) When two R c Together with the atoms to which they are attached, they form C 3-6 When cycloalkyl, wherein the C 3-6 The cycloalkyl group is substituted with at least one or more halogens;

[0107] 7) Two Rs c Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group.

[0108] Z

[0109] In some embodiments, Z is NH, O, or a chemical bond; in some embodiments, Z is O or a chemical bond; in some embodiments, Z is NH; in some embodiments, Z is O; in some embodiments, Z is a chemical bond.

[0110] R1

[0111] In some embodiments, R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5 to 10 membered heteroaryl, wherein the above groups are optionally substituted by one or more R; in some embodiments, R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0112] In some embodiments, R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted by one or more R; in some embodiments, R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; in some embodiments, R1 is C 1-6Haloalkyl, optionally substituted with one or more D, up to full deuteration; in some embodiments, R1 is -CF2Cl, -CF2Br or C 2-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R; in some embodiments, R1 is -CF2Cl, -CF2Br, -CF2CH3, or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; in some embodiments, R1 is -CF2Br, -CF2CH3, or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0113] In other embodiments, R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5 to 10 membered heteroaryl, wherein the above groups are substituted by one or more R; in other embodiments, R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 1-6 Alkylene-phenyl, wherein the above groups are substituted by one or more R; in other embodiments, R1 is C 3-6 Cycloalkyl or -C 1-6 In some embodiments, R1 is cyclopropane or benzyl, wherein the above groups are substituted by one or more R; In some embodiments, R1 is cyclopropane, wherein the above groups are substituted by one or more R; In some embodiments, R1 is cyclopropane, wherein the above groups are substituted by one or more R; In some embodiments, R1 is cyclopropane, wherein the above groups are substituted by one or more groups selected from D or F; In some embodiments, R1 is -C 1-6 Alkylene-phenyl, wherein the above groups are substituted with one or more groups selected from D or F; in other embodiments, R1 is benzyl, wherein the above groups are substituted with one or more R; in other embodiments, R1 is benzyl, wherein the above groups are substituted with one or more groups selected from D or F;

[0114] In some embodiments, R1 is -CF3, -CF2Cl, -CF2Br, -CF2CH3, or -CF2CF3; in some embodiments, R1 is -CF3, -CF2Cl, -CF2CH3, or -CF2CF3; in some embodiments, R1 is -CF2Cl or -CF2Br; in some embodiments, R1 is -CF3 or -CF2Cl; in some embodiments, R1 is or -CF2Br; in some embodiments, R1 is -CF2Cl;

[0115] In other specific embodiments, R1 is 1-fluorocyclopropane-1-yl, 1-chlorocyclopropane-1-yl, 1-bromocyclopropane-1-yl, 1-methylcyclopropane-1-yl, 2,2-difluoro-1-methylcyclopropane-1-yl, 1-trifluoromethylcyclopropane-1-yl, benzyl, 4-fluorobenzyl or 4-methylbenzyl; in other specific embodiments, R1 is 1-fluorocyclopropanealkyl, 2,2-difluoro-1-methylcyclopropanealkyl or 1-trifluoromethylcyclopropanealkyl; in other specific embodiments, R1 is 1-fluorocyclopropanealkyl or 2,2-difluoro-1-methylcyclopropanealkyl; in other specific embodiments, R1 is 1-fluorocyclopropanealkyl; in other specific embodiments, R1 is benzyl, 4-fluorobenzyl or 4-methylbenzyl; in other specific embodiments, R1 is 4-fluorobenzyl or 4-methylbenzyl; in other specific embodiments, R1 is 4-fluorobenzyl.

[0116] p

[0117] In some embodiments, p is 0, 1, or 2; in some embodiments, p is 0 or 1; in some embodiments, p is 1 or 2; in some specific embodiments, p is 0; in some specific embodiments, p is 1.

[0118] R2

[0119] In some embodiments, each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; in some embodiments, each R2 is independently C 1-6 Alkyl, C 3-6 Cycloalkyl or 3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; in some embodiments, each R2 is independently C 3-6 Cycloalkyl or 3 to 7 membered heterocyclyl, wherein the above groups are substituted by one or more R; in some embodiments, each R2 is independently C1-6 alkyl, which is optionally substituted with one or more D, up to fully deuterated; in some embodiments, each R2 is independently tert-butyl, isopropyl, isobutyl, 1-tert-butoxyethyl, (1-methylcyclobutyloxy)ethyl, 1-methylcyclopentyl, 1-methylcyclohexyl, tetrahydropyran-4-yl or 4-methyltetrahydropyran-4-yl, wherein the above groups are optionally substituted with one or more D, up to fully deuterated; in some embodiments, each R2 is independently ... In some embodiments, each R is independently tert-butyl, 1-tert-butoxyethyl, (1-methylcyclobutoxy)ethyl, 1-methylcyclopentyl, 1-methylcyclohexyl, tetrahydropyran-4-yl, or 4-methyltetrahydropyran-4-yl, wherein the above groups are optionally substituted with one or more D, up to fully deuterated; in some embodiments, each R is independently tert-butyl, 1-tert-butoxyethyl, (1-methylcyclobutoxy)ethyl, or 1-methylcyclopentyl, wherein the above groups are optionally substituted with one or more D, up to fully deuterated; in some embodiments, wherein each R2 is independently tert-butyl, 1-tert-butoxyethyl, or (1-methylcyclobutoxy)ethyl, wherein the foregoing groups are optionally substituted with one or more Ds, up to the point of complete deuteration; in some embodiments, each R2 is independently 1-tert-butoxyethyl or (1-methylcyclobutoxy)ethyl, wherein the foregoing groups are optionally substituted with one or more Ds, up to the point of complete deuteration; in some embodiments, each R2 is independently tert-butyl or 1-tert-butoxyethyl, wherein the foregoing groups are optionally substituted with one or more Ds, up to the point of complete deuteration; in some embodiments, each R2 is independently tert-butyl, which is optionally substituted with one or more Ds, up to the point of complete deuteration; in some embodiments, each R2 is independently 1-methylcyclopentyl, 1-methylcyclohexyl, or 4-methyltetrahydropyran-4-yl, wherein the foregoing groups are optionally substituted with one or more Ds; in some embodiments, each R2 is independently 1-methylcyclopentyl, wherein the foregoing groups are optionally substituted with one or more Ds;

[0120] In some embodiments, each R2 is independently tert-butyl, isopropyl, isobutyl, 1-tert-butoxyethyl, (1-methylcyclobutyloxy)ethyl, 1-methylcyclopentyl, 1-methylcyclohexyl, tetrahydropyran-4-yl, or 4-methyltetrahydropyran-4-yl;

[0121] In some embodiments, each R2 is independently tert-butyl, isopropyl, isobutyl, 1-tert-butoxyethyl, (1-methylcyclobutoxy)ethyl; in some embodiments, each R2 is independently tert-butyl, 1-tert-butoxyethyl or (1-methylcyclobutoxy)ethyl; in some embodiments, each R2 is independently tert-butyl or 1-tert-butoxyethyl; in some embodiments, each R2 is independently tert-butyl; in some embodiments, each R2 is independently 1-tert-butoxyethyl; in some embodiments, each R2 is independently (1-methylcyclobutoxy)ethyl;

[0122] In other specific embodiments, each R2 is independently 1-methylcyclopentyl, 1-methylcyclohexyl, tetrahydropyran-4-yl or 4-methyltetrahydropyran-4-yl; in other specific embodiments, each R2 is independently 1-methylcyclopentyl, 1-methylcyclohexyl or 4-methyltetrahydropyran-4-yl; in other specific embodiments, each R2 is independently 1-methylcyclopentyl; in other specific embodiments, each R2 is independently 1-methylcyclohexyl; in other specific embodiments, each R2 is independently 4-methyltetrahydropyran-4-yl.

[0123] R

[0124] In some embodiments, each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 In some embodiments, each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen; in some embodiments, each R is independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally replaced by one or more D or C 1-6 In some embodiments, each R is independently D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen; in some embodiments, each R is independently D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0125] In some embodiments, each R is independently D, F, Cl, Br, -CH3, -CD3, -CF3, tert-butoxy, or 1-methylcyclobutoxy; in some embodiments, each R is independently D, F, Cl, Br, -CH3, -CD3, or -CF3; in some embodiments, each R is independently D, Cl, Br, -CH3, or -CD3; in some embodiments, each R is independently D, F, -CH3, -CD3, or -CF3; in some embodiments, each R is independently D, -CH3, -CD3, or -CF3; in some embodiments, each R is independently D, -CH3, -CD3, or -CF3; in some embodiments, each R is independently tert-butoxy or 1-methylcyclobutoxy; in some embodiments, each R is independently tert-butoxy; in some embodiments, each R is independently 1-methylcyclobutoxy.

[0126] R3

[0127] In some embodiments, R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; in some embodiments, R3 is C 1-6Alkyl or -C 0-6 Alkylene-C 3-6 Cycloalkyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; in some embodiments, R3 is C 1-6 Alkyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; in some embodiments, R3 is -C 0-6 Alkylene-C 3-6 Cycloalkyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0128] In other embodiments, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c In other embodiments, R a1 and R3 together with the atoms to which they are attached form a 4- to 6-membered heterocyclic group, which is c In other embodiments, R a1 and R3 together with the atoms to which they are attached form a 5-membered heterocyclic group, which is c replace;

[0129] In some embodiments, R3 is isobutyl or cyclohexylmethyl; in other embodiments, R a1 and R3 together with the atoms to which they are attached form

[0130] R c

[0131] In some embodiments, both R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 In some embodiments, two R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, wherein the C 3-6 Cycloalkyl is substituted with one or more halogens; in some embodiments, two R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is optionally substituted with one or more C 1-6 Alkyl substituted; in some embodiments, two R c together with the atoms to which they are attached, form a 3- to 7-membered heterocyclyl, wherein said 3- to 7-membered heterocyclyl is optionally substituted with one or more halogens;

[0132] In some embodiments, two R c Together with the atoms they are connected to form In some embodiments, two R c Together with the atoms they are connected to form In some embodiments, two R c Together with the atoms they are connected to form In some embodiments, two R c Together with the atoms they are connected to form In some embodiments, two R c Together with the atoms they are connected to form

[0133] R4

[0134] In some embodiments, R4 is CN, CHO, or -C(O)-5- to 10-membered heteroaryl; in some embodiments, R4 is CN or CHO; in some embodiments, R4 is CN; in some embodiments, R4 is CHO.

[0135] m

[0136] In some embodiments, it is 1 or 2; in some embodiments, it is 1; in some embodiments, it is 2.

[0137] n

[0138] In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6; in some embodiments, n is 0, 1, or 2; in some embodiments, n is 0; in some embodiments, n is 1; in some embodiments, n is 2.

[0139] R b

[0140] In some embodiments, each R b H, D, C independently 1-6 Alkyl or C 1-6 haloalkyl; in some embodiments, each R b are independently H, D or C 1-6 Alkyl; in some embodiments, each R b is independently H, D or -CH3; in some embodiments, each R b independently H or D;

[0141] In other embodiments, two R b Together with the atoms to which they are attached, they form C3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 In other embodiments, two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen;

[0142] In other embodiments, two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted with one or more D, up to full deuteration; in other embodiments, two R b Together with the atoms to which they are attached, they form a cyclopropane, which is optionally substituted with one or more Ds up to full deuteration;

[0143] In other embodiments, two R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D or -C(O)C 1-6 In other embodiments, two R b Together with the atoms to which they are attached, they form a 6-membered heterocyclic group, which is optionally substituted by one or more selected from D or -C(O)C 1-6 Alkyl groups are substituted until fully deuterated; in other embodiments, two R b Together with the atoms to which they are attached, they form piperidinyl or tetrahydropyranyl, wherein the above groups are optionally substituted by one or more radicals selected from D or -C(O)C 1-6 In other embodiments, two R b Together with the atoms to which they are attached, they form tetrahydropyranyl, optionally substituted with one or more D, up to full deuteration;

[0144] In some embodiments, two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 In some embodiments, two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted with one or more D, up to full deuteration; in some embodiments, two R on adjacent atoms bTogether with the atoms to which they are attached, they form a cyclopropane group, which is optionally substituted with one or more Ds, up to full deuteration; in some embodiments, two Rs on adjacent atoms b Together with the atoms to which they are attached, they form a cyclopropane group;

[0145] In other embodiments, two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 In other embodiments, two R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 In other embodiments, two R b Together with the atoms to which they are attached, they form a 6-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 In other embodiments, two R b Together with the atoms to which they are attached, they form piperidinyl or tetrahydropyranyl, wherein the above groups are optionally substituted by one or more radicals selected from D or -C(O)C 1-6 In other embodiments, two R b Together with the atoms to which they are attached, they form a tetrahydropyranyl group, which is optionally substituted with one or more D, up to full deuteration; in other embodiments, two R on the same atom b Together with the atoms to which they are attached, they form a tetrahydropyranyl group; in other embodiments, two R b Together with the atoms to which they are attached, they form a piperidinyl group, which is optionally substituted by one or more radicals selected from D or -C(O)C 1-6 In other embodiments, two R b Together with the atoms to which they are attached, they form 1-acetylpiperidinyl, which is optionally substituted with one or more D, up to full deuteration; in other embodiments, two R on the same atom b Together with the atoms to which they are attached, they form 1-acetylpiperidinyl.

[0146] In some other embodiments, R a2 and an R bTogether with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted with one or more groups selected from D or halogen; in some other embodiments, R a2 and an R b Together with the atoms to which they are attached, they form a 4- to 6-membered heterocyclic group, wherein the above groups are optionally substituted with one or more groups selected from D or halogen; in some other embodiments, R a2 and an R b Together with the atoms to which they are attached, they form a 5-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

[0147] In another embodiment, the present invention relates to compounds of formula (I):

[0148]

[0149] in,

[0150] Z is O or a chemical bond;

[0151] R1 is -CF2Cl, -CF2Br or C 2-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R;

[0152] p is 0, 1, or 2;

[0153] Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0154] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0155] R a1 and Ra2 is H;

[0156] R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0157] Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace;

[0158] Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0159] R4 is CN or CHO;

[0160] m is 1 or 2;

[0161] n is 0, 1, 2, 3, 4, 5 or 6;

[0162] Each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0163] Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

[0164] In another embodiment, the present invention is directed to compounds of formula (I):

[0165]

[0166] in,

[0167] Z is O or a chemical bond;

[0168] R1 is C1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0169] p is 0, 1, or 2;

[0170] Each R2 is independently C 3-6 Cycloalkyl or 3- to 7-membered heterocyclyl, wherein the above groups are substituted by one or more R;

[0171] Wherein each R is independently D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen;

[0172] R a1 and R a2 is H;

[0173] R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0174] Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace;

[0175] Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0176] R4 is CN or CHO;

[0177] m is 1 or 2;

[0178] n is 0, 1, 2, 3, 4, 5 or 6;

[0179] Each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R bTogether with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0180] Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

[0181] In another embodiment, the present invention is directed to compounds of formula (I):

[0182]

[0183] in,

[0184] Z is O or a chemical bond;

[0185] R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R;

[0186] p is 0, 1, or 2;

[0187] Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0188] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0189] R a1 and R a2 is H;

[0190] R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0191] Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace;

[0192] Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0193] R4 is CN or CHO;

[0194] m is 1 or 2;

[0195] n is 2;

[0196] Two R on the same atom b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl groups are substituted.

[0197] In another embodiment, the present invention is directed to compounds of formula (I):

[0198]

[0199] in,

[0200] Z is O or a chemical bond;

[0201] R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R;

[0202] p is 0, 1, or 2;

[0203] Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0204] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0205] R a1 and R a2 is H;

[0206] R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0207] Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace;

[0208] Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0209] R4 is CN or CHO;

[0210] m is 1 or 2;

[0211] n is 2;

[0212] Two R on adjacent atoms b Together with the atoms to which they are attached, they form C 3-6Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl groups are substituted.

[0213] In another embodiment, the present invention is directed to compounds of formula (I):

[0214]

[0215] in,

[0216] Z is O or a chemical bond;

[0217] R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5 to 10 membered heteroaryl, wherein the above groups are substituted by one or more R;

[0218] p is 1 or 2;

[0219] Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0220] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0221] R a1 and R a2 is H;

[0222] R3 is H, D, C 1-6 Alkyl, C 1-6Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0223] Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace;

[0224] Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0225] R4 is CN or CHO;

[0226] m is 1 or 2;

[0227] n is 0, 1, 2, 3, 4, 5 or 6;

[0228] Each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0229] Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

[0230] In another embodiment, the present invention is directed to compounds of formula (I):

[0231]

[0232] in,

[0233] Z is O or a chemical bond;

[0234] R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0235] p is 0, 1, or 2;

[0236] Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0237] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen;

[0238] R a2 is H;

[0239] R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace;

[0240] Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is substituted with one or more halogens;

[0241] R4 is CN or CHO;

[0242] m is 1 or 2;

[0243] n is 0, 1, 2, 3, 4, 5 or 6;

[0244] Each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution;

[0245] Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

[0246] In one embodiment, the present invention relates to compounds of formula (II):

[0247]

[0248] in,

[0249] R1 is -CF2Cl, -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted by one or more D until fully deuterated;

[0250] p is 0 or 1;

[0251] R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0252] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0253] m is 1 or 2;

[0254] n is 0, 1, 2, 3, 4, 5 or 6;

[0255] Each R b H, D, C independently 1-6Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl groups are substituted.

[0256] In another more specific embodiment, R1 is -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; p is 0 or 1; R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more R; wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 substituted with a haloalkyl group; m is 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl groups are substituted.

[0257] In another more specific embodiment, R1 is -CF2Cl, -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; p is 0 or 1; R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more R; wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 substituted with a haloalkyl group; m is 1; n is 0, 1 or 2; each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl groups are substituted.

[0258] In another more specific embodiment, R1 is -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; p is 0 or 1; R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more R; wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6substituted with a haloalkyl group; m is 1; n is 0, 1 or 2; each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl groups are substituted.

[0259] In another more specific embodiment, R1 is -CF2Cl, -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; p is 0 or 1; R2 is C 1-6 Alkyl, C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more R; wherein each R is independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally replaced by one or more D or C 1-6 Alkyl substituted, up to full deuteration; m is 1; n is 0, 1 or 2; each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 wherein the above groups are optionally substituted by one or more selected from D, up to full deuteration.

[0260] In another more specific embodiment, R1 is -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; p is 0 or 1; R2 is C 1-6 Alkyl, C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more R; wherein each R is independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally replaced by one or more D or C 1-6 Alkyl substituted, up to full deuteration; m is 1; n is 0, 1 or 2; each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 wherein the above groups are optionally substituted by one or more selected from D, up to full deuteration.

[0261] In another more specific embodiment, R1 is -CF2Cl, -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; p is 0 or 1; R2 is tert-butyl, isopropyl, isobutyl, 1-tert-butoxyethyl, (1-methylcyclobutyloxy)ethyl, 1-methylcyclopentyl, 1-methylcyclohexyl, tetrahydropyran-4-yl or 4-methyltetrahydropyran-4-yl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; m is 1; n is 0, 1 or 2; each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 wherein the above groups are optionally substituted by one or more selected from D, up to full deuteration.

[0262] In another more specific embodiment, R1 is -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; p is 0 or 1; R2 is tert-butyl, isopropyl, isobutyl, 1-tert-butoxyethyl, (1-methylcyclobutyloxy)ethyl, 1-methylcyclopentyl, 1-methylcyclohexyl, tetrahydropyran-4-yl or 4-methyltetrahydropyran-4-yl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; m is 1; n is 0, 1 or 2; each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6wherein the above groups are optionally substituted by one or more selected from D, up to full deuteration.

[0263] In another specific embodiment, the present invention relates to compounds of formula (II-1):

[0264]

[0265] in,

[0266] R1 is -CF2Cl, -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted by one or more D until fully deuterated;

[0267] R2 is tert-butyl, 1-tert-butoxyethyl, (1-methylcyclobutyloxy)ethyl or 1-methylcyclopentyl, wherein the above groups are optionally substituted by one or more Ds up to full deuteration;

[0268] Each R b are independently H or D.

[0269] In another more specific embodiment, R1 is -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted with one or more D, up to full deuteration; R2 is tert-butyl, 1-tert-butoxyethyl, (1-methylcyclobutyloxy)ethyl or 1-methylcyclopentyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0270] Each R b are independently H or D.

[0271] In another more specific embodiment, R1 is -CF2Cl or -CF2Br; R2 is tert-butyl or 1-tert-butoxyethyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; each R b are independently H or D.

[0272] In another more specific embodiment, R1 is -CF2Br; R2 is tert-butyl or 1-tert-butoxyethyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; each R b are independently H or D.

[0273] In another embodiment, the present invention relates to compounds (II-1):

[0274]

[0275] in,

[0276] R1 is C 1-6 Alkyl or C 1-6Haloalkyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0277] R2 is C 3-6 Cycloalkyl or 3- to 7-membered heterocyclyl, wherein the above groups are substituted by one or more R;

[0278] Wherein each R is independently D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen;

[0279] Each R b are independently H or D.

[0280] In another more specific embodiment, R1 is CF3 or CF2Cl; R2 is 1-methylcyclopentyl, 1-methylcyclohexyl or 4-methyltetrahydropyran-4-yl, wherein the above groups are optionally substituted with one or more D; each R b are independently H or D.

[0281] In another more specific embodiment, R1 is CF3 or CF2Cl; R2 is 1-methylcyclopentyl, wherein the above groups are optionally substituted with one or more D; each R b are independently H or D.

[0282] In another embodiment, the present invention relates to compounds (II-1):

[0283]

[0284] in,

[0285] R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R;

[0286] R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0287] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0288] Two R's b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D or -C(O)C 1-6 Alkyl groups are substituted.

[0289] In another more specific embodiment, R1 is C 1-6 Haloalkyl, which is optionally substituted with one or more D, up to full deuteration; R2 is C 1-6 Alkyl, which is optionally substituted by one or more D, up to full deuteration; two R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D or -C(O)C 1-6 Alkyl groups are substituted.

[0290] In another more specific embodiment, R1 is C 1-6 Haloalkyl, which is optionally substituted with one or more D, up to full deuteration; R2 is C 1-6 Alkyl, which is optionally substituted by one or more D, up to full deuteration; two R b Together with the atoms to which they are attached, they form a 6-membered heterocyclic group, which is optionally substituted by one or more selected from D or -C(O)C 1-6 The alkyl group is substituted until it is fully deuterated.

[0291] In another more specific embodiment, R1 is -CF3 or -CF2Cl; R2 is tert-butyl, which is optionally substituted with one or more D, up to full deuteration; both R b Together with the atoms to which they are attached, they form piperidinyl or tetrahydropyranyl, wherein the above groups are optionally substituted by one or more radicals selected from D or -C(O)C 1-6 Alkyl groups are substituted.

[0292] In another more specific embodiment, R1 is -CF3 or -CF2Cl; R2 is tert-butyl, which is optionally substituted with one or more D, up to full deuteration; both R b Together with the atoms to which they are attached they form a tetrahydropyranyl group, which is optionally substituted with one or more Ds, up to full deuteration.

[0293] In another more specific embodiment, the present invention relates to compound (II-2):

[0294]

[0295] in,

[0296] R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R;

[0297] R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0298] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0299] Two R's b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

[0300] In another more specific embodiment, R1 is C 1-6 Haloalkyl, which is optionally substituted with one or more D, up to full deuteration; R2 is C 1-6 Alkyl, which is optionally substituted by one or more D, up to full deuteration; two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted with one or more D, up to full deuteration.

[0301] In another more specific embodiment, R1 is -CF3 or -CF2Cl; R2 is tert-butyl, which is optionally substituted with one or more D, up to full deuteration; both R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted with one or more D, up to full deuteration.

[0302] In another more specific embodiment, R1 is -CF2Cl; R2 is tert-butyl, which is optionally substituted with one or more D, up to full deuteration; both R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, which is optionally substituted with one or more D, up to full deuteration.

[0303] In another more specific embodiment, R1 is -CF3 or -CF2Cl; R2 is tert-butyl, which is optionally substituted with one or more D, up to full deuteration; both R b Together with the atoms to which they are attached they form a cyclopropane, which is optionally substituted with one or more Ds up to full deuteration.

[0304] In another more specific embodiment, R1 is -CF2Cl; R2 is tert-butyl, which is optionally substituted with one or more D, up to full deuteration; both R b Together with the atoms to which they are attached they form a cyclopropane, which is optionally substituted with one or more Ds up to full deuteration.

[0305] In another embodiment, the present invention relates to compounds of formula (III):

[0306]

[0307] in,

[0308] Z is O or a chemical bond;

[0309] R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 1-6 Alkylene-phenyl, wherein the above groups are substituted with one or more R;

[0310] R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0311] Wherein each R is independently D, halogen, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0312] Each R b are independently H or D.

[0313] In another embodiment, the present invention relates to a compound of formula (III-1)

[0314]

[0315] in,

[0316] Z is O or a chemical bond;

[0317] R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 1-6 Alkylene-phenyl, wherein the above groups are substituted with one or more R;

[0318] Wherein each R is independently D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more D, up to full deuteration;

[0319] Each R b are independently H or D.

[0320] In another more specific embodiment, Z is a chemical bond; R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 1-6 Alkylene-phenyl, wherein the above groups are substituted by one or more R; wherein each R is independently D, F, Cl, Br, -CH3, -CD3 or -CF3; each R b are independently H or D.

[0321] In another more specific embodiment, Z is a chemical bond; R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 1-6Alkylene-phenyl, wherein the above groups are substituted by one or more R; wherein each R is independently D, Cl, Br, -CH3 or -CD3; each R b are independently H or D.

[0322] In another more specific embodiment, Z is a chemical bond; R1 is C 3-6 Cycloalkyl or -C 1-6 Alkylene-phenyl, wherein the above groups are substituted by one or more R; wherein each R is independently D, F, -CH3 or -CD3; each R b are independently H or D.

[0323] In another more specific embodiment, Z is a chemical bond; R1 is C 3-6 Cycloalkyl or -C 1-6 Alkylene-phenyl, wherein the above groups are substituted by one or more R; wherein each R is independently D, -CH3 or -CD3; each R b are independently H or D.

[0324] In another more specific embodiment, Z is a chemical bond; R1 is cyclopropane or benzyl, wherein the above groups are substituted by one or more R; wherein each R is independently D, F, -CH3 or -CD3; each R b are independently H or D.

[0325] In another more specific embodiment, Z is a chemical bond; R1 is cyclopropane or benzyl, wherein the above groups are substituted by one or more R; wherein each R is independently D, -CH3 or -CD3; each R b are independently H or D.

[0326] In another more specific embodiment, Z is a chemical bond; R1 is benzyl, wherein the above groups are substituted by one or more R; wherein each R is independently D, F, -CH3 or -CD3; each R b are independently H or D.

[0327] In another more specific embodiment, Z is O; R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 1-6 Alkylene-phenyl, wherein the above groups are substituted by one or more R; wherein each R is independently D, F, -CH3 or -CD3; each R b are independently H or D.

[0328] In another more specific embodiment, Z is O; R1 is -C 1-6 Alkylene-phenyl, wherein the above groups are substituted by one or more groups selected from D or F; each R b are independently H or D.

[0329] In another more specific embodiment, Z is O; R1 is benzyl, wherein the above groups are substituted with one or more groups selected from D or F; each R b are independently H or D.

[0330] In another embodiment, the present invention relates to compounds of formula (IV):

[0331]

[0332] in,

[0333] Z is O or a chemical bond;

[0334] R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0335] R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0336] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0337] m is 1 or 2;

[0338] n is 0, 1, 2, 3, 4, 5 or 6;

[0339] Each R b H, D, C independently 1-6 Alkyl or C1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl groups are substituted.

[0340] In another specific embodiment, the present invention relates to compounds of formula (IV-1):

[0341]

[0342] in,

[0343] R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R;

[0344] R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R;

[0345] Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution;

[0346] Each R b H, D, C independently 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl groups are substituted.

[0347] In another more specific embodiment, R1 is C 1-6 haloalkyl, which is optionally substituted with one or more D, up to fully deuterated; R2 is tert-butyl, isopropyl, isobutyl, 1-tert-butoxyethyl, (1-methylcyclobutyloxy)ethyl, 1-methylcyclopentyl, 1-methylcyclohexyl, tetrahydropyran-4-yl or 4-methyltetrahydropyran-4-yl, wherein the above groups are optionally substituted with one or more D, up to fully deuterated; each R b are independently H or D.

[0348] In another more specific embodiment, R1 is C 1-6 haloalkyl, which is optionally substituted with one or more D, up to full deuteration; R2 is isopropyl, isobutyl, 1-tert-butoxyethyl, (1-methylcyclobutyloxy)ethyl, 1-methylcyclopentyl, 1-methylcyclohexyl, tetrahydropyran-4-yl or 4-methyltetrahydropyran-4-yl, wherein the above groups are optionally substituted with one or more D, up to full deuteration; each R b are independently H or D.

[0349] In another more specific embodiment, R1 is -CF3, -CF2Cl, -CF2CH3 or -CF2CF3; R2 is tert-butyl, 1-tert-butoxyethyl or (1-methylcyclobutyloxy)ethyl, which is optionally substituted with one or more D until fully deuterated; each R b are independently H or D.

[0350] In another more specific embodiment, R1 is -CF3, -CF2Cl, -CF2CH3 or -CF2CF3; R2 is 1-tert-butoxyethyl or (1-methylcyclobutyloxy)ethyl, which is optionally substituted with one or more D until fully deuterated; each R b are independently H or D.

[0351] In a more specific embodiment, the present invention relates to the following compounds:

[0352]

[0353]

[0354]

[0355]

[0356]

[0357] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0358] "Tautomer" refers to a functional group in certain compounds that changes its structure to become another functional group isomer, and can rapidly convert into each other, forming two isomers in dynamic equilibrium, and these two isomers are called tautomers.

[0359] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0360] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0361] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·xH2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0362] The compounds of the present invention can be in amorphous or crystalline form (crystal form or polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0363] The present invention also includes isotopically labeled compounds which are identical to those described in formula (I) but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0364] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

[0365] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or its salt.

[0366] Pharmaceutical compositions, preparations and kits

[0367] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0368] The pharmaceutically acceptable excipient for the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound prepared together. The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the present composition include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salt or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0369] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0370] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0371] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0372] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0373] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0374] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by push injection, for example, in order to rapidly increase the concentration of the compound in the blood to an effective level. The push dose depends on the target systemic level of the active ingredient, for example, an intramuscular or subcutaneous push dose slowly releases the active ingredient, and a push (for example, by IV intravenous drip) delivered directly to the vein can be delivered more rapidly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the push dose can be first given, and then continuous infusion.

[0375] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0376] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0377] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0378] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0379] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0380] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0381] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0382] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0383] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0384] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0385] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0386] Indications

[0387] In another aspect, the present invention relates to a method for treating and / or preventing a viral infection in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition of the present invention.

[0388] In one embodiment, the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, polymorphs, prodrugs or isotopic variants, or the pharmaceutical compositions of the present invention can be used to treat and / or prevent coronavirus infection. In a more specific embodiment, the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, polymorphs, prodrugs or isotopic variants, or the pharmaceutical compositions of the present invention can inhibit the replication of coronaviruses. In a more specific embodiment, the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, polymorphs, prodrugs or isotopic variants, or the pharmaceutical compositions of the present invention can be used to inhibit the 3C-like protease of coronaviruses.

[0389] In one embodiment, the compounds of the present invention or its pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, polymorphs, prodrugs or isotopic variants, or pharmaceutical compositions of the present invention can be used to treat and / or prevent diseases associated with coronavirus infection. In a more specific embodiment, the compounds of the present invention or its pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, polymorphs, prodrugs or isotopic variants, or pharmaceutical compositions of the present invention can prevent, treat and / or alleviate symptoms and / or diseases caused by coronavirus. The symptoms and / or diseases include, but are not limited to, for example, cold-like symptoms with fever, chills, headache, muscle pain, loss of taste or loss of taste, general fatigue, or gastrointestinal symptoms such as respiratory inflammation, abdominal pain, vomiting, and diarrhea, etc., or sore throat, runny nose, nasal congestion, cough, sputum, etc. In particular, it can prevent, treat and / or alleviate pneumonia caused by coronavirus, especially pneumonia caused by novel coronavirus (SARS-CoV-2) infection, whose symptoms include inflammatory response characterized by deep airway and alveolar damage, pulmonary fibrosis, pulmonary exudative response, etc., and further accompanied by complications such as acute encephalopathy, kidney damage, liver damage, heart failure, myocarditis, etc.

[0390] Dosage

[0391] The compounds of the present invention (herein referred to as active ingredients) or pharmaceutically acceptable salts, stereoisomers, solvates, hydrates, polymorphs, prodrugs or isotopic variants thereof, or pharmaceutical compositions of the present invention are administered by any route suitable for the condition to be treated. The preferred route may vary depending on, for example, the condition of the subject. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

[0392] In one embodiment, the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug or isotopic variant, or the pharmaceutical composition of the present invention can be administered according to any acceptable mode of administration available to those skilled in the art. In a more specific embodiment, suitable modes of administration include, but are not limited to, oral administration, nasal administration, pulmonary administration, parenteral administration, topical administration, intravenous injection, subcutaneous injection, transdermal administration and rectal administration. In a more specific embodiment, the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug or isotopic variant, or the pharmaceutical composition of the present invention are preferably administered orally, intravenously, subcutaneously and nasally.

[0393] Combination therapy

[0394] In another aspect, a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, or a pharmaceutical composition of the present invention can be used in combination with one or more additional agents for treating and / or preventing Coronaviridae, Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, and Orthomyxoviridae infections.

[0395] In one embodiment, the additional reagent can be one or more of small molecule drugs, protein drugs, nucleic acid drugs, traditional Chinese medicines or traditional Chinese medicines.

[0396] In a specific embodiment, the small molecule drug can be one or more of an antiviral agent, a papain-like protease inhibitor, a 3C-like protease inhibitor, an RNA polymerase inhibitor, a fusion protease inhibitor, an M2 proton channel inhibitor, a neuraminidase inhibitor, a reverse transcriptase inhibitor, a viral entry inhibitor, and a pharmacokinetic enhancer.

[0397] In a more specific embodiment, the antiviral agent can be selected from, but is not limited to, for example, remdesivir, galisvir, favipiravir, afaviravir, monolavir, AT-527, AT-301, BLD-2660, favipiravir, camostat, SLV213, emtricitabine, tenofovir, clevudine, dalcetrapib, boceprevir, ABX464, efavirenz, elbavir, nevirapine, rilpivirine, pariprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, alavirox, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, or Bisacavir, lamivudine, ribavirin, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, nitazoxanide, novir, plerixafor, PRO140, raltegravir, pyrimidine, saquinavir, telbivudine, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, stavudine, caltegravir, cytarabine, etravirine, fostamxavir, gemcitabine, imunovir, indinavir, maraviroc, methylthiothionine, MK-2048, nefimavir, nevirapine, TNX-355, valacyclovir, VIR-576 and zalcitabine, etc.

[0398] In a more specific embodiment, the papain-like protease inhibitor can be selected from the group including, but not limited to, apimod, EIDD-2801, ribavirin, valacyclovir, β-thymidine, aspartame, oxprenolol, doxycycline, acephenazine, iopromide, riboflavin, reproterol, 2,2'-cyclocytidine, chloramphenicol, chlorphenesin carbamate, levodropropizine, cefmandole, floxuridine, tigecycline, pemetrexed, L(+)-ascorbic acid, glutathione, hesperetin, adenosylmethionine, masoprofol, isotretinoin, dantrolene, sulfasalazine, silybin, nicardipine, sildenafil, platycodin, chrysin, neohesperidin, baicalin, sucralose-3,9-diacetate, (-)-epigallocatechin gallate, Phaitanthrin D, proanthocyanidins, 2,2-di(3-indolyl)-3-indolone, piceatannol, rosmarinic acid and magnolol, etc.

[0399] In more specific embodiments, 3C-like protease inhibitors can be selected from the group including, but not limited to, lymecycline, chlorhexidine, alfuzosin, cilastatin, famotidine, almitrine, progamide, nepafenac, carvedilol, amprenavir, tigecycline, montelukast, carminic acid, mimosine, xanthophyllin, lutein, cefpiramide, pheneticillin, canxadroxanthin, nicardipine, estradiol valerate, pioglitazone, conivaptan, telmisartan, doxycycline, oxytetracycline, Betulonal, chrysin-7-O-β-glucuronide, andrographolide, isodecortinol, cerosterol, hesperidin, neohesperidin, neoandrographolide aglycone, cosmosides, cleistocaltone A, 2,2-di(3-indolyl)-3-indolone, kaempferol 3-O-acaciaside, ganidilin, phyllaemblinol, 3,3'-digallate theaflavins, rosmarinic acid, kouitchenside I, oleanolic acid, β-sitosterol, deacetylcentapicrin and berchemol, etc.

[0400] In a more specific embodiment, the RNA polymerase inhibitor can be selected from the group including but not limited to: valacyclovir, chlorhexidine, ceftibuten, fenoterol, fludarabine, itraconazole, cefuroxime, atovaquone, chenodeoxycholic acid, cromoglycic acid, pancuronium bromide, cortisone, tibolone, novobiocin, silybin, idarubicin bromocriptine, diphenoxylate, benzylpenicillin G, dabigatran etexilate, Betulonal, geniditrin, 2β,30β-dihydroxy-3,4-dihydro-3,4-dihydro-andrographolide-27-olide, 14-deoxy-11,12-didehydroandrographolide, giniditrin, 3,3'-digallate theaflavin, 2β-hydroxy-3,4-dihydro-3,4-dihydro-andrographolide-27-olide, proanthocyanidin, phyllaemblicin B, 14-hydroxycyperone, andrographolide glycosides, andrographolide, sugetriol-3,9-diacetate, baicalin and gentianin, etc.

[0401] In more specific embodiments, the fusion protease inhibitor can be selected from the group including but not limited to BMY-27709, CL61917, and CL62554.

[0402] In more specific embodiments, the M2 proton channel inhibitor can be selected from the group including but not limited to amantadine and rimantadine.

[0403] In more specific embodiments, the neuraminidase inhibitor can be selected from the group including but not limited to zanamivir, oseltamivir, peramivir, and ABT-675.

[0404] In more specific embodiments, the reverse transcriptase inhibitor can be selected from the group including but not limited to abacavir, adefovir, delavirdine, didanosine, efavirenz, emtricitabine, lamivudine, nevirapine, stavudine, tenofovir and zalcitabine.

[0405] In more specific embodiments, the viral entry inhibitor may be selected from the group including but not limited to, for example, enfuvirtide, maraviroc, and the like.

[0406] In more specific embodiments, the pharmacokinetic enhancer can be selected from the group including, but not limited to, ritonavir, nelfinavir, darunavir, and cobicistat.

[0407] In a specific embodiment, the protein drug can be remdesivir, reslizumab, sotovir, VIR-7832, BRII-196, BRII-198, COVI-AMG, COVI-DROPS, barnivir, mavrilimab, lelizumab, AZD7442, lanzelimumab, infliximab, adalimumab, JS 016, STI-1499, lanarizumab, canakinumab, netilumab, otelimumab, casprevir, imipenem, MK-7110, tocilizumab, talizumab, interferon, nivolumab, atezolizumab, pembrolizumab, durvalumab, BMS-936559, avelumab, cobrelizumab, SGN-40, CP-870893, RO7009789, sabatolimab, elalimumab, TSR-033 and mololimab, etc. One or more.

[0408] In a specific embodiment, the nucleic acid drug can be one or more of afovirsen, fomivirsen, tracovirsen, miravisen, radavisen, temavisen, amulavisen, beprovirsen, and the like.

[0409] In a specific embodiment, the Chinese medicine or Chinese patent medicine can be Shufeng Jiedu Capsules (granules), Qingfei Paidu Granules (decoction), Sanhan Huashi Granules, Ganmao Qingre Capsules (soft capsules, granules, oral liquid, chewable tablets), Jingfang Granules (compound), Zhengchaihuyin Granules (compound, capsules), Jiuwei Qianghuo Pills (granules, tablets, oral liquid), Four Seasons Cold Tablets (capsules), Ganmao Shufeng Capsules (tablets, granules), Lianhua Qingwen Capsules (granules, tablets), Jinhua Qinggan Granules, Huashi Baidu Granules, Xuanfei Baidu Granules, Reyanning Mixture (granules), Yinhuang Qingfei Capsules, Lianhua Qingke Tablets, Liushen Pills (capsules), Yinqiao Jiedu Granules (soft capsules, mixtures, tablets, capsules), Jinye Baidu Granules, Lanqin Oral Liquid (Granules), Compound Qinlan Oral Liquid, Qingyan Drops, Houyanqing Granules (Oral Liquid), Sangju Cold Tablets (Pills, Granules, Mixture), Xiasangju Granules, Tanreqing Capsules, Shuanghuanglian Oral Liquid (Tablets, Granules, Capsules), Chaiqin Qingning Capsules, Antiviral Oral Liquid (Granules, Syrup, Pills, Tablets, Capsules), Cold and Fever Relief Granules, Xiaoyan and Fever Relief Granules (Capsules), Qingkailing Tablets (Capsules, Granules, Soft Capsules), Xiaochaihu Granules (Tablets, Capsules, Pills), Jizhi Syrup (Granules), Kexuting Syrup (Capsules), Xuanfei Zhisou Mixture, Tongxuan Lifei Pills (Granules, Oral Liquid, Tablets, Capsules), Xingsu Zhike Granules (Syrup, Oral Liquid), Xingbei Cough granules, Tangerine peel cough solution (granules, decoction), cold cough granules (mixture, syrup), Fangfeng Tongsheng pills (granules), sinusitis oral solution, Sanfeng Tongqiao drops, children's Chaigui antipyretic granules (oral liquid), children's Fengreqing oral solution (granules), Jinzhen oral solution, children's lung-clearing oral solution, children's Xiaoji cough oral solution (granules), reduced-flavor children's phlegm powder, Jianer Qingjie solution, children's Chiqiao Qingre granules, children's Qingyan granules, Kaihoujian spray (including children's version), Qingxuan cough granules, children's cough syrup, children's Qingfei cough tablets, Yupingfeng granules (soft capsules, capsules, pills, oral liquid), Chuanshegan flavonoids capsules, Sangjiang cold tablets (capsules), Lianhua cough tablets, One or more of Compound Yinchai Granules, Huoxiang Zhengqi Capsules (soft capsules, pills, granules, water, oral liquid, tablets), Shenling Baizhu Capsules (oral liquid, powder, pills, granules, tablets), Qixiang Yiqi Jiedu Granules, Shenhe Yifei Capsules, Shengmai Drink (capsules, granules, tablets), Gejie Dingchuan Capsules (pills), Buzhong Yiqi Pills (granules, tablets, oral liquid), Shenqi Oral Liquid, Ludangshen Oral Liquid, Xiangsha Liujun Pills (tablets), Jiawei Xiaoyao Pills (tablets, capsules, granules), Bailemian Capsules, Shugan Jieyu Capsules, Yinqiao Powder Modified, Shanggan Granules (tablets), Qingqiao Kangdu Granules, Adenophora and Ophiopogon Decoction Combined with Sijunzi Decoction Modified, Bufei Decoction Combined with Sanzi Yangqin Decoction Modified, Jinshuibao Tablets (capsules), etc.

[0410] Example

[0411] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, parts and percentages are by weight.

[0412] Typically, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 100°C, preferably 0°C to 80°C). The reaction time is typically 0.1-60 hours, preferably 0.5-24 hours.

[0413] The abbreviations used herein have the following meanings:

[0414]

[0415]

[0416] Synthesis of related intermediate compounds

[0417] Intermediate A-1 compound (1R,2S,5S)-3-(N-((benzyloxy)carbonyl)-O-tert-butyl-L-threonyl)-6- Preparation of 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0418]

[0419] The following synthetic route is used

[0420]

[0421] Step 1: Synthesis of (1R,2S,5S)-3-(N-((benzyloxy)carbonyl)-O-tert-butyl-L-threonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester

[0422] To a three-necked flask equipped with a magnetic stirrer, acetonitrile (100 mL) and N-((benzyloxy)carbonyl)-O-tert-butyl-L-threonine (10 g, 32.3 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The temperature was then lowered to 0°C. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17.2 g, 45.2 mmol), (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride (6.64 g, 32.3 mmol), and N,N-diisopropylethylamine (16.7 g, 129 mmol) were added and reacted at 0°C for 30 minutes. The ice bath was removed and the reaction was allowed to proceed overnight at room temperature. Water (80 mL) and ethyl acetate (150 mL x 3) were added, the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 14.7 g of a yellow oil, with a yield of 98.8%. LC-MS (APCI): m / z = 461 (M+1) + .

[0423] Step 2 Synthesis of Intermediate A-1

[0424] To a 100 mL single-necked flask equipped with a magnetic stirrer were added tetrahydrofuran (50 mL), water (30 mL), (1R,2S,5S)-3-(N-((benzyloxy)carbonyl)-O-tert-butyl-L-threonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester (14.7 g, 31.9 mmol) and lithium hydroxide monohydrate (2.7 g, 63.9 mmol, 2 M) in sequence. The reaction was allowed to proceed at room temperature overnight. Citric acid (4 g, 21 mmol) was added and the pH was adjusted to 7. 10.7 g of a white solid was precipitated with a yield of 75.3%. LC-MS (APCI): m / z=447 (M+1) + .

[0425] Intermediate A-2 compound (1R, 2S, 5S)-3-(O-tert-butyl-L-threonyl)-6,6-dimethyl-3-azabis Preparation of cyclo[3.1.0]hexane-2-carboxylic acid

[0426]

[0427] The following synthetic route is used

[0428]

[0429] To a 250 mL single-necked flask equipped with a magnetic stirrer, methanol (100 mL), intermediate A-1 (10.7 g, 31.9 mmol), and palladium on carbon (2 g, w / w 10%) were added sequentially. The mixture was evacuated and replaced with hydrogen three times. The reaction was allowed to proceed overnight at room temperature under a hydrogen atmosphere. The palladium on carbon was filtered off, and the filtrate was concentrated and passed through a silica gel column to obtain 6.88 g of a white solid, with a yield of 92%. LC-MS (APCI): m / z = 313 (M+1) + .

[0430] Intermediate A-3 compound (3S)-2-(tert-butyloxycarbonyl)-6-oxa-2-azaspiro[4.5]decane-3-carboxylic acid preparation

[0431]

[0432] The following synthetic route is used

[0433]

[0434] Step 1: Synthesis of compound 1-benzyl 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate

[0435] To a 250 mL single-necked flask equipped with a magnetic stirrer, dichloromethane (200 mL) and 1-benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (14.29 g, 51.1 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times, then cooled to 0°C. Dess-Martin reagent (23.8 g, 56.2 mmol) was added portionwise. After addition, the mixture was warmed to room temperature and allowed to react for 1 hour. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8. Water (100 mL) and dichloromethane (150 mL x 3) were added, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 14 g of a yellow oil in a 98.7% yield. LC-MS (APCI): m / z = 278 (M+1). + .

[0436] Step 2: Synthesis of compound 1-benzyl 2-methyl (2S)-4-allyl-4-hydroxypyrrolidine-1,2-dicarboxylate

[0437] To a 100 mL two-necked flask equipped with a magnetic stirrer, add anhydrous N,N-dimethylformamide (30 mL) and zinc (4.9 g, 75.8 mmol) sequentially. Vacuum and replace the atmosphere with nitrogen three times. Trimethylsilyl chloride (1.31 g, 12.1 mmol) was added dropwise at room temperature. After addition, the mixture was allowed to react at room temperature for 20 minutes. The mixture was filtered, and the filter cake was washed with a small amount of anhydrous N,N-dimethylformamide. The solid was collected and added to a 150 mL two-necked flask equipped with a magnetic stirrer. Anhydrous N,N-dimethylformamide (50 mL) was added, and the atmosphere was vacuumed and replaced with nitrogen three times. The mixture was cooled to 0°C, and 3-bromopropylene (9.17 g, 75.8 mmol) was added dropwise. The reaction was continued at 0°C for 30 minutes. 1-Benzyl 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (14 g, 50.5 mmol) was added at 0°C. The mixture was warmed to room temperature and allowed to react overnight. Water (100 mL) and ethyl acetate (150 mL x 3) were added, the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 12 g of a yellow oil, with a yield of 74.5%. LC-MS (APCI): m / z = 320 (M+1) + .

[0438] Step 3: Synthesis of compound 1-benzyl 2-methyl (2S)-4-allyl-4-(allyloxy)pyrrolidine-1,2-dicarboxylate

[0439] To a 100 mL two-necked flask equipped with a magnetic stirrer were added tetrahydrofuran (30 mL), 1-benzyl 2-methyl (2S)-4-allyl-4-hydroxypyrrolidine-1,2-dicarboxylate (3.5 g, 1.57 mmol), allyl tert-butyl carbonate (3.5 g, 10.9 mmol), tris(dibenzylideneacetone)dipalladium (0.253 g, 0.27 mmol), and 1,4-bis(diphenylphosphino)butane (0.233 mg, 0.55 mmol). The flask was evacuated and replaced with nitrogen three times. The temperature was raised to 75°C and the reaction was allowed to proceed for 1.5 hours. Water (70 mL) and ethyl acetate (100 mL x 3) were added. The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 3.34 g of a yellow solid (85% yield). LC-MS (APCI): m / z = 360 (M+1) + .

[0440] Step 4: Synthesis of Compound 2-Benzyl 3-methyl (3S)-6-oxa-2-azaspiro[4.5]dec-8-ene-2,3-dicarboxylate

[0441] To a 50 mL single-necked flask equipped with a magnetic stirrer, dichloromethane (15 mL) and 1-benzyl 2-methyl (2S)-4-allyl-4-(allyloxy)pyrrolidine-1,2-dicarboxylate (1 g, 2.8 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. A second-generation Grubbs catalyst (1.18 g, 1.4 mmol) was added and the reaction was allowed to proceed overnight at room temperature. Water (30 mL) and ethyl acetate (50 mL x 3) were added. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 0.7 g of a yellow solid in a 76.1% yield. LC-MS (APCI): m / z = 332 (M+1). + .

[0442] 1 H NMR(400MHz,DMSO-d6)δ(ppm):7.38-7.29(m,5H),5.78-5.68(m,2H),5.13-5.00(m,2H),4.5 2-4.44(m,1H),3.97-3.92(m,1H),3.65-3.55(m,3H),3.49-3.44(m,1H),2.31-2.06(m,4H).

[0443] Step 5: Synthesis of Compound (3S)-6-oxa-2-azaspiro[4.5]decane-3-carboxylic acid methyl ester

[0444] To a 50 mL single-necked flask equipped with a magnetic stirrer, methanol (10 mL), 2-benzyl 3-methyl (3S)-6-oxa-2-azaspiro[4.5]dec-8-ene-2,3-dicarboxylate (0.7 g, 2.1 mmol), and palladium on carbon (70 mg, w / w 10%) were added sequentially. The mixture was evacuated and replaced with hydrogen three times. The reaction was allowed to proceed at room temperature under a hydrogen atmosphere for 2.5 hours. The palladium on carbon was filtered off, the filtrate was concentrated, and passed through a silica gel column to afford 0.4 g of a yellow solid in a 95% yield. LC-MS (APCI): m / z = 200 (M+1) + .

[0445] Step 6: Synthesis of Compound 2-tert-butyl 3-methyl (3S)-6-oxa-2-azaspiro[4.5]decane-2,3-dicarboxylate

[0446] To a 50 mL single-necked flask equipped with a magnetic stirrer, dichloromethane (15 mL), methyl (3S)-6-oxa-2-azaspiro[4.5]decane-3-carboxylate (0.4 g, 2.0 mmol), and triethylamine (0.40 g, 4.0 mmol) were added sequentially. The temperature was lowered to 0°C, and di-tert-butyl dicarbonate (0.657 g, 3.0 mmol) was added. The mixture was reacted at room temperature for 30 minutes. Water (30 mL) and dichloromethane (30 mL x 3) were added, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 0.58 g of a yellow solid (97% yield). LC-MS (APCI): m / z = 300 (M+1). + .

[0447] Step 7 Synthesis of Intermediate A-3

[0448] To a 250 mL single-necked flask equipped with a magnetic stirrer, tetrahydrofuran (50 mL), water (30 mL), 2-tert-butyl 3-methyl (3S)-6-oxa-2-azaspiro[4.5]decane-2,3-dicarboxylate (10 g, 33.4 mmol), and lithium hydroxide monohydrate (2.8 g, 66.8 mmol, 2 M) were added sequentially and allowed to react at room temperature overnight. Citric acid (4.28 g, 22.3 mmol) was added and the pH was adjusted to 7. A white solid precipitated, and the filter cake was filtered and dried to obtain 7.5 g of the white solid, with a yield of 78.5%. LC-MS (APCI): m / z = 286 (M+1). + .

[0449] 1 H NMR(400MHz,DMSO-d6)δ(ppm):12.43(br s,1H),4.21-4.02(m,3H),3.63-3.50(m,2H),3.38-3.21(m,3H),2.26- 2.04(m,2H),1.63-1.47(m,3H),1.42-1.39(m,5H),1.35-1.32(m,6H).

[0450] Intermediate A-4 compound (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutyryl Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0451]

[0452] The following synthetic route is used

[0453]

[0454] Step 1: Synthesis of (1R,2S,5S)-3-((S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester

[0455] To a 1000 mL two-necked flask equipped with a magnetic stirrer were added N,N-dimethylformamide (300 mL), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (46.2 g, 200 mmol), (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride (41 g, 200 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (50.9 g, 291 mmol), 1-hydroxybenzotriazole (36 g, 291 mmol) and N,N-diisopropylethylamine (68.6 g, 388 mmol) in sequence, and the reaction was carried out at room temperature for 4 hours. Water (500 mL) and ethyl acetate (200 mL x 3) were added for extraction. The organic phases were combined, washed with saturated brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 55 g of a yellow oil, with a yield of 71.9%. LC-MS (APCI): m / z = 383.2 (M+1) + .

[0456] Step 2 Synthesis of Intermediate A-4

[0457] To a 1000 mL single-necked flask equipped with a magnetic stirrer, (1R,2S,5S)-methyl 3-((S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (50 g, 130 mmol) and tetrahydrofuran (250 mL) were added sequentially. The solution was stirred until clear. Water (250 mL) and lithium hydroxide monohydrate (10.9 g, 260 mmol) were added and the mixture was allowed to react at room temperature overnight. The organic solvent was evaporated under reduced pressure, and the residual aqueous solution was cooled in an ice-water bath. Solid citric acid (16.6 g, 86.7 mmol) was slowly added with stirring, resulting in the precipitation of a large amount of white solid. The solid was filtered, washed with water (20 mL), and dried to yield 42 g of dry matter, with a yield of 87.7%. LC-MS (APCI): m / z = 369.2 (M+1) + .

[0458] Preparation of intermediate A-5 compound (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propionamide hydrochloride

[0459]

[0460] The following synthetic route is used

[0461]

[0462] Step 1: Synthesis of dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(2-cyanoethyl)glutarate

[0463] To a 250 mL three-necked flask equipped with a magnetic stirrer, tetrahydrofuran (100 mL) and dimethyl N-tert-butyloxycarbonyl-L-glutamate (10 g, 36.3 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The temperature was then lowered to -80°C, and lithium bis(trimethylsilyl)amide (43.6 mL, 43.6 mmol, 1 M) was added dropwise. The mixture was allowed to react at -80°C for 1 hour. A solution of 3-bromopropionitrile in tetrahydrofuran (4.87 g, 36.3 mmol, 20 mL) was then added dropwise. The reaction was continued at -80°C for 1 hour. Water (70 mL) and ethyl acetate (100 mL x 3) were added. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 1 g of a yellow oil in an 8.4% yield. LC-MS (APCI): m / z = 329 (M+1). + .

[0464] Step 2: Synthesis of Compound (S)-2-((tert-butyloxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoic acid methyl ester

[0465] To a 50 mL three-necked flask equipped with a magnetic stirrer, methanol (15 mL) and dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(2-cyanoethyl)pentanedioate (1 g, 3.05 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The temperature was lowered to 0°C, and sodium borohydride (0.69 g, 18.3 mmol) and cobalt chloride (0.197 g, 1.53 mmol) were added. The mixture was reacted at 0°C for 3 hours. Water (30 mL) and dichloromethane (50 mL x 3) were added. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 0.6 g of a yellow oil (65% yield). LC-MS (APCI): m / z = 301 (M+1). + .

[0466] Step 3: Synthesis of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamate

[0467] To a 50 mL sealed tube equipped with a magnetic stirrer, methanolic ammonia solution (10 mL) and methyl (S)-2-((tert-butyloxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoate (0.6 g, 2.0 mmol) were added sequentially. The temperature was raised to 65°C and the reaction was allowed to proceed overnight. The product was directly concentrated and passed through a silica gel column to afford 0.5 g of a yellow oil, with a yield of 88%. LC-MS (APCI): m / z = 286 (M+1). + .

[0468] Step 4 Synthesis of Intermediate A-5

[0469] To a 25 mL single-necked flask equipped with a magnetic stirrer, tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamate (500 mg, 1.75 mmol) and a solution of hydrogen chloride in ethyl acetate (5 mL, 2 M) were added sequentially. The mixture was reacted at room temperature for 30 minutes. The mixture was concentrated to obtain an oil, which was used directly in the subsequent synthetic steps.

[0470] Preparation of intermediate A-6 compound (S)-3-((S)-2-amino-3-hydroxypropyl)pyrrolidin-2-one hydrochloride

[0471]

[0472] The following synthetic route is used

[0473]

[0474] Step 1: Synthesis of tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate

[0475] To a 500 mL three-necked flask equipped with a magnetic stirrer, tetrahydrofuran (100 mL) and methyl (S)-2-((tert-butyloxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (8 g, 28.0 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times, then cooled to 0°C. A solution of lithium borohydride in tetrahydrofuran (70 mL, 140 mmol, 2 M) was added dropwise. The mixture was warmed to room temperature and allowed to react for 2 hours. Water (100 mL) and ethyl acetate (150 mL x 3) were added, and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 3.8 g of a yellow oil (53% yield). LC-MS (APCI): m / z = 259 (M+1). + .

[0476] Step 2 Synthesis of Intermediate A-6

[0477] To a 25 mL single-necked flask equipped with a magnetic stirrer, add tert-butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (350 mg, 1.36 mmol) and a solution of hydrogen chloride in ethyl acetate (5 mL, 2 M). React at room temperature for 30 minutes. Concentrate to obtain an oil, which is used directly in the subsequent synthetic steps.

[0478] Intermediate A-7 compound (1R,2S,5S)-3-(L-isoleucyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Preparation of hexane-2-carboxylic acid hydrochloride

[0479]

[0480] The following synthetic route is used

[0481]

[0482] Step 1: Synthesis of (1R,2S,5S)-3-((tert-butyloxycarbonyl)-L-isoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester

[0483] To a 100 mL three-necked flask equipped with a magnetic stirrer were added (tert-butyloxycarbonyl)-L-isoleucine (3 g, 12.971 mmol), (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride (2.801 g, 13.619 mmol), acetonitrile (45 mL), N,N-diisopropylethylamine (5.020 g, 38.913 mmol) and N,N-dimethylformamide (45 mL). L), evacuated and replaced with nitrogen three times, cooled in an ice-water bath, added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.408 g, 16.862 mmol), reacted at room temperature for 4 hours, quenched with water (100 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 4.5 g of a white solid, in a yield of 90.8%. LC-MS (APCI): m / z = 383.0 (M+1). + .

[0484] Step 2: Synthesis of compound (1R,2S,5S)-3-((tert-butyloxycarbonyl)-L-isoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0485] To a 100 mL single-necked flask equipped with a magnetic stirrer were added (1R,2S,5S)-methyl 3-((tert-butyloxycarbonyl)-L-isoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.5 g, 11.780 mmol), lithium hydroxide monohydrate (2.474 g, 58.900 mmol), tetrahydrofuran (50 mL), and water (10 mL). The mixture was evacuated and replaced with nitrogen three times. The reaction was allowed to react at room temperature for 12 hours. Water (100 mL) was added to quench the reaction. The pH was adjusted to approximately 2 with hydrochloric acid solution (1N). The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 4.33 g of a white solid (99.0% yield). LC-MS (APCI): m / z = 369.0 (M+1). + .

[0486] Step 3 Synthesis of Intermediate A-7

[0487] To a 100 mL single-necked flask equipped with a magnetic stirrer, (1R,2S,5S)-3-((tert-butyloxycarbonyl)-L-isoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4.33 g, 11.766 mmol) and dichloromethane (5 mL) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The mixture was cooled in an ice-water bath, and 1,4-dioxane hydrochloric acid solution (15 mL, 4 M) was added. The reaction was allowed to proceed at room temperature for 1 hour. The crude product was concentrated to give 3.582 g of a white solid, with a yield of 99.0%. LC-MS (APCI): m / z = 269.0 (M+1). + .

[0488] Preparation of Intermediate A-8 Compound 1-(4-nitropiperidin-1-yl)ethan-1-one

[0489]

[0490] The following synthetic route is used

[0491]

[0492] Step 1 Synthesis of compound 4-nitropiperidine hydrochloride

[0493] To a 100 mL single-necked flask equipped with a magnetic stirrer, tert-butyl 4-nitropiperidine-1-carboxylate (10.0 g, 43.4 mmol) and ethyl acetate (20 mL) were added sequentially. Stirring until dissolved, hydrogen chloride in ethyl acetate (25 mL, 5 M) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to dryness to obtain 10.0 g of a white solid, with a yield of 100%. LC-MS (APCI): m / z = 131.08 (M+1). + .

[0494] Step 2 Synthesis of Intermediate A-8

[0495] To a 500 mL single-necked flask equipped with a magnetic stirrer, 4-nitropiperidine hydrochloride (10.0 g, 77.1 mmol) and dichloromethane (100 mL) were added sequentially. Triethylamine (11.6 g, 115.5 mmol) was added with stirring. The mixture was stirred until clear, cooled in an ice-water bath, and acetic anhydride (7.85 g, 78.5 mmol) was slowly added dropwise. After completion of the dropwise addition, the ice bath was removed and the mixture was allowed to react at room temperature under a nitrogen atmosphere for 2 hours. Water (50 mL) was added to quench the reaction. The organic phase was separated and extracted with dichloromethane (50 mL). The combined organic phases were washed sequentially with hydrochloric acid solution (1 M), aqueous sodium bicarbonate solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column to afford 10.1 g of a white solid (73.2% yield). LC-MS (APCI): m / z = 173.09 (M+1). + .

[0496] Preparation of intermediate A-9 compound (S)-2-((tert-butoxycarbonyl)amino)-4-methyleneglutaric acid dimethyl ester

[0497]

[0498] The following synthetic route is used

[0499]

[0500] Step 1: Synthesis of 1-tert-butyl 2-methyl (S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate

[0501] To a 100 mL single-necked flask equipped with a magnetic stirrer and a condenser, ethylene glycol dimethyl ether (300 mL) and 1-tert-butyl 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (30.0 g, 123 mmol) were added sequentially. Stirring allowed to dissolve until clear. Tert-butoxybis(dimethylamino)methane (32.2 g, 185.1 mmol) was added and the mixture was heated to 80°C under a nitrogen atmosphere. The mixture was stirred and allowed to react overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure. Saturated brine (100 mL) and ethyl acetate (300 mL) were added and stirred for 10 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 27.5 g of a white solid (65.3% yield). LC-MS (APCI): m / z = 299.16 (M+1). + .

[0502] 1H NMR(500MHz,DMSO-d6)δ(ppm):4.86-4.80(m,1H),4.44-4.16(m,1H),3.82-2.77(m,1H),3.2 1-3.16(m,1H),2.85-2.79(m,1H),2.23-2.15(m,2H),1.94-1.87(m,1H),1.77-1.69(m,1H).

[0503] Step 2: Synthesis of compound 1-tert-butyl 2-methyl (S)-4-methylene-5-oxopyrrolidine-1,2-dicarboxylate

[0504] To a 1000 mL three-necked flask equipped with a magnetic stirrer, 1-tert-butyl 2-methyl (S,E)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (27.5 g, 92.3 mmol) and anhydrous tetrahydrofuran (300 mL) were added sequentially. Stirring until dissolved, the mixture was evacuated and replaced with nitrogen three times. The temperature was lowered to -75°C, and then a solution of diisobutylaluminum hydride in tetrahydrofuran (80 mL, 120 mmol, 1.5 M) was slowly added dropwise. The mixture was stirred and allowed to react overnight. The temperature was slowly raised to room temperature, and the reaction was quenched by the addition of saturated brine (200 mL). Ethyl acetate (200 mL) was added and stirred for 10 minutes. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 16.8 g of a white solid (70.3% yield). LC-MS (APCI): m / z = 256.1 (M+1) + .

[0505] Step 3 Synthesis of Intermediate A-9

[0506] To a 100 mL three-necked flask equipped with a magnetic stirrer, 1-tert-butyl 2-methyl (S)-4-methylene-5-oxopyrrolidine-1,2-dicarboxylate (16.8 g, 65.8 mmol) and tetrahydrofuran (200 mL) were added sequentially. Stirring until the solution was clear, the mixture was evacuated and replaced with nitrogen three times. The temperature was lowered to -40°C, and a 10% methanol solution of lithium methoxide (84 mL, 79 mmol) was slowly added dropwise. The mixture was stirred and allowed to react overnight. The temperature was raised to room temperature, and the reaction was quenched by the addition of saturated brine (100 mL). Ethyl acetate (150 mL) was added and stirred for 10 minutes. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was passed through a silica gel column to obtain 9.3 g of a white solid (55.6% yield). LC-MS (APCI): m / z = 288.1 (M+1) + .

[0507] Intermediate A-10 compound (2S)-3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]dec-3-yl)-2- Preparation of methyl ((tert-butoxycarbonyl)amino)propionate

[0508]

[0509] The following synthetic route is used

[0510]

[0511] Step 1: Synthesis of dimethyl (4S)-2-((1-acetyl-4-nitropiperidin-4-yl)methyl)-4-((tert-butoxycarbonyl)amino)glutarate

[0512] To a 100 mL single-necked flask equipped with a magnetic stirrer, intermediate A-9 (9.3 g, 32.4 mmol) and acetonitrile (100 mL) were added sequentially. Stirring allowed the mixture to dissolve. Intermediate A-8 (6.5 g, 38.9 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (12.1 g, 64.6 mmol) were then added. The mixture reacted at room temperature under a nitrogen atmosphere for 12 hours. The solvent was evaporated under reduced pressure, and ethyl acetate (100 mL) and hydrochloric acid (80 mL, 1 M) were added. The mixture was stirred and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were washed sequentially with water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 5.6 g of a white solid (45.8% yield). LC-MS (APCI): m / z = 460.2 (M+1). + .

[0513] Step 2 Synthesis of Intermediate A-10

[0514] To a 100 mL single-necked flask equipped with a magnetic stirrer, dimethyl (4S)-2-((1-acetyl-4-nitropiperidin-4-yl)methyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (5.6 g, 12.2 mmol) and methanol (60 mL) were added sequentially. The mixture was stirred until clear and cooled to 0°C. Nickel chloride (1.8 g, 13.4 mmol) and sodium borohydride (3.2 g, 63.1 mmol) were added under a nitrogen atmosphere. The mixture was stirred and allowed to react overnight. Saturated brine (50 mL) was added to quench the reaction. Ethyl acetate (100 mL) was added and stirred. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column to afford 3.8 g of a white solid (67.3% yield). LC-MS (APCI): m / z = 398.2 (M+1). + .

[0515] 1H NMR (400MHz, DMSO-d6) δ (ppm): 7.23 (d, J = 8.4Hz, 1H), 6.15 (s, 1H), 5.74 (s, 1H), 1.19-4. 16(m,1H),3.70(s,3H),3.61(s,3H),2.75-2.70(m,1H),2.53-2.47(m,1H),1.36(s,9H).

[0516] Preparation of Intermediate A-11 Compound 4-Nitrotetrahydro-2H-pyran

[0517]

[0518] The following synthetic route is used

[0519]

[0520] To a 100 mL flask equipped with a magnetic stirrer and a condenser, 4-iodotetrahydro-2H-pyran (10.0 g, 47.3 mmol) and dimethyl sulfoxide (50 mL) were added sequentially. Stirring allowed to dissolve, pyrogallol (9.5 g, 75.6 mmol) and sodium nitrite (6.5 g, 94.6 mmol) were added. The temperature was raised to 50°C under a nitrogen atmosphere and the reaction was stirred overnight. After cooling to room temperature, saturated brine (50 mL) and ethyl acetate (50 mL) were added and stirred. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column to obtain 5.3 g of a white solid, with a yield of 56.2%. LC-MS (APCI): m / z = 132.06 (M+1). + .

[0521] 1 H NMR (400MHz, CDCl3) δ (ppm): 4.59-4.51 (m, 1H), 4.05-3.95 (m, 2H), 3.51-3.44 (m, 2H), 2.24-2.20 (m, 4H).

[0522] Intermediate A-12 compound (2S)-2-((tert-butyloxycarbonyl)amino)-3-(2-oxo-8-oxa-1-azaspiro Preparation of methyl [4.5]dec-3-yl)propionate

[0523]

[0524] Intermediate A-12 was prepared according to the preparation method of intermediate A-10, using intermediate A-11 instead of intermediate A-8 as the starting material. 3.8 g of white solid was obtained with a yield of 87.3%. LC-MS (APCI): m / z = 357.2 (M+1) + .

[0525] Intermediate A-13 compound (2S)-2-((tert-butyloxycarbonyl)amino)-3-(5-methyl-2-oxopyrrolidine-3- Preparation of methyl propionate

[0526]

[0527] Intermediate A-13 was prepared according to the preparation method of intermediate A-10, using nitroethane instead of intermediate A-8 as the starting material. 3.8 g of white solid was obtained, with a yield of 67.3%. LC-MS (APCI): m / z = 301.17 (M+1) + .

[0528] Intermediate A-14 compound (2S)-2-amino-3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propionamide salt Preparation of acid salt

[0529]

[0530] The following synthetic route is used

[0531]

[0532] Step 1: Synthesis of dimethyl (2S)-2-((tert-butyloxycarbonyl)amino)-4-(2-methyl-2-nitropropyl)glutarate

[0533] To a 100 mL flask equipped with a magnetic stirrer, intermediate A-9 (5.0 g, 17.4 mmol) and acetonitrile (50 mL) were added sequentially. Stirring dissolved the mixture, followed by 2-nitropropane (2.1 g, 24.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 g, 34.8 mmol). The mixture was stirred at room temperature overnight under a nitrogen atmosphere. Ethyl acetate (200 mL) was added for dilution, and the mixture was washed sequentially with hydrochloric acid solution (50 mL × 2, 1 M) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column to afford 4.0 g of a white solid (61.1% yield). LC-MS (APCI): m / z = 377.2 (M+1). + .

[0534] Step 2: Synthesis of methyl (2S)-2-((tert-butyloxycarbonyl)amino)-3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propionate

[0535] To a 100 mL single-necked flask equipped with a magnetic stirrer, dimethyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-methyl-2-nitropropyl)pentanedioate (3.5 g, 9.3 mmol) and methanol (60 mL) were added sequentially. Stirring allowed to dissolve, the mixture was cooled in an ice-water bath, and nickel chloride (1.8 g, 15.84 mmol) and sodium borohydride (2.3 g, 26.4 mmol) were added under a nitrogen atmosphere. After addition, the ice bath was removed and the reaction was stirred at room temperature overnight. Saturated brine (50 mL) and ethyl acetate (50 mL) were added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column to afford 2.0 g of a white solid (68.4% yield). LC-MS (APCI): m / z = 315.2 (M+1). + .

[0536] Step 3: Synthesis of tert-butyl ((2S)-1-amino-3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)-1-oxopropyl-2-yl)carbamate

[0537] To a 350 mL sealed tube equipped with a magnetic stirrer, methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (2.0 g, 6.40 mmol) and methanolic ammonia (70 mL, 5 M) were added sequentially. The tube was sealed and stirred at 70°C overnight. The reaction was allowed to cool to room temperature and the screw cap was carefully opened in an ice-water bath. The reaction solution was concentrated and passed through a silica gel column to afford 1.8 g of a white solid, a 94.0% yield. LC-MS (APCI): m / z = 300.2 (M+1). + .

[0538] Step 4 Synthesis of Intermediate A-14

[0539] To a 100 mL single-necked flask equipped with a magnetic stirrer, tert-butyl ((2S)-1-amino-3-(5,5-dimethyl-2-oxopyrrolidin-3-yl)-1-oxopropan-2-yl)carbamate (1.5 g, 5.01 mmol) and ethyl acetate (10 mL) were added sequentially. Stirring allowed the mixture to dissolve. Hydrogen chloride in ethyl acetate (20 mL, 5 M) was added and the mixture reacted at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated under reduced pressure to dryness to obtain 1.8 g of a white solid, with a yield of 100%. LC-MS (APCI): m / z = 200.2 (M+1). + .

[0540] Preparation of intermediate A-15 compound nitrocyclobutane

[0541]

[0542] The following synthetic route is used

[0543]

[0544] To a 100 mL flask equipped with a magnetic stirrer and a condenser, add bromocyclobutane (10.0 g, 75.0 mmol) and dimethyl sulfoxide (50 mL). Stir to dissolve. Then add pyrogallol (9.5 g, 75 mmol), sodium nitrite (25.3 g, 375 mmol), and urea (8.6 g, 150 mmol). Vacuum and replace with nitrogen three times. Stir and react at 50°C overnight. Cool to room temperature, add saturated brine (50 mL) and ethyl acetate (50 mL). Separate the organic phase, extract the aqueous phase with ethyl acetate (30 mL x 2). Combine the organic phases, wash with saturated brine (50 mL x 3), dry over anhydrous sodium sulfate, concentrate, and pass through a silica gel column to obtain 5.3 g of a white solid, in a 69.9% yield. LC-MS (APCI): m / z = 102.1 (M+1). + .

[0545] Intermediate A-16 compound (2S)-2-amino-3-(6-oxo-5-azaspiro[3.4]octan-7-yl)propionamide hydrochloride Salt preparation

[0546]

[0547] Intermediate A-16 was prepared according to the preparation method of Intermediate A-14, using Intermediate A-15 instead of 2-nitropropane as the starting material. 1.1 g of a white solid was obtained with a yield of 100%. LC-MS (APCI): m / z = 212.2 (M+1) + .

[0548] Intermediate A-17 compound (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl-5,5-D2)propionamide hydrochloride Salt preparation

[0549]

[0550] The following synthetic route is used

[0551]

[0552] Step 1: Synthesis of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)glutarate

[0553] To a 500 mL three-necked flask equipped with a magnetic stirrer, dimethyl N-tert-butyloxycarbonyl-L-glutamic acid ester (10.0 g, 36.3 mmol) was added sequentially. The mixture was evacuated and replaced with nitrogen three times. Anhydrous tetrahydrofuran (100 mL) was added dropwise via a syringe under a nitrogen atmosphere. The mixture was stirred until clear. The mixture was cooled to -78°C and lithium bis(trimethylsilyl)amide (54.4 mL, 54.4 mmol, 1 M) was slowly added dropwise. The mixture was stirred for 30 minutes. Bromoacetonitrile (7.0 g, 58.5 mmol) was added and the mixture was stirred at -78°C for 8 hours. The mixture was warmed to room temperature, saturated brine (100 mL) and ethyl acetate (100 mL) were added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column to obtain 6.4 g of a white solid with a yield of 56.1%. LC-MS (APCI): m / z = 315.2 (M+1) + .

[0554] Step 2: Synthesis of Compound (S)-2-((tert-Butyloxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl-5,5-d2)methyl propionate

[0555] To a 100 mL single-necked flask equipped with a magnetic stirrer, dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate (5.1 g, 16.1 mmol) was added sequentially. The mixture was evacuated and replaced with nitrogen three times. Deuterated methanol (50 mL) was added via syringe and stirred until dissolved. The mixture was cooled in an ice-water bath. Sodium borodeuteride (4.1 g, 96.6 mmol) and anhydrous cobalt chloride (1.05 g, 8.1 mmol) were added. The ice bath was removed and the reaction was stirred at room temperature overnight. Saturated brine (50 mL) and ethyl acetate (50 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and passed through a silica gel column to afford 3.5 g of a white solid (75.4% yield). LC-MS (APCI): m / z = 289.2 (M+1). + .

[0556] Step 3: Synthesis of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl-5,5-d2)propyl)carbamate

[0557] To a 350 mL sealed tube equipped with a magnetic stirrer, (S)-methyl 2-((tert-butyloxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl-5,5-d2)propanoate (3.5 g, 12.1 mmol) and methanolic ammonia (80 mL, 7 M) were added sequentially. The tube was sealed and stirred at 70°C overnight. The tube was cooled to room temperature and the screw cap was carefully opened under ice-water cooling. The reaction solution was concentrated and passed through a silica gel column to obtain 2.8 g of a white solid, with a yield of 84.7%. LC-MS (APCI): m / z = 274.2 (M+1). + .

[0558] Step 4 Synthesis of Intermediate A-17

[0559] To a 100 mL single-necked flask equipped with a magnetic stirrer, tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl-5,5-d2)propyl)carbamate (2.8 g, 10.2 mmol) and ethyl acetate (10 mL) were added sequentially. Hydrogen chloride in ethyl acetate (30 mL, 5 M) was also added, and the mixture was reacted at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated to dryness under reduced pressure to obtain 2.1 g of a white solid in a 100% yield. LC-MS (APCI): m / z = 174.2 (M+1). + .

[0560] Intermediate A-18 compound (1R,2S,5S)-3-((S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetyl Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride

[0561]

[0562] The following synthetic route is used

[0563]

[0564] Step 1: Synthesis of (1R,2S,5S)-3-((S)-2-((tert-butyloxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester

[0565] To a 250 mL three-necked flask equipped with a magnetic stirrer, (S)-2-((tert-butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (2 g, 7.71 mmol) and anhydrous acetonitrile (18 mL) were added in sequence, stirred to dissolve, cooled to 0°C, and (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride (1.58 g, 7.71 mol), N,N-diisopropylethylamine (2.98 g, 23.2 mol) and N,N-dimethylformamide (2 The mixture was stirred for 3 hours at room temperature. After nitrogen replacement, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.22 g, 8.48 mol) was added. The reaction was allowed to react at room temperature for 3 hours. Thin-layer chromatography showed that the reaction was complete. Water was added to quench the reaction. Ethyl acetate (50 mL) and water (50 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 mL), washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and purified by column chromatography with petroleum ether / ethyl acetate to obtain 2.42 g of the product in a yield of 76.68%. LC-MS (APCI): m / z = 411.1 (M+1) + .

[0566] Step 2: Synthesis of compound (1R,2S,5S)-3-((S)-2-((tert-butyloxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0567] To a 100 mL single-necked flask equipped with a magnetic stirrer, (1R,2S,5S)-methyl 3-((S)-2-((tert-butyloxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.4 g, 5.84 mol) and tetrahydrofuran (14 mL) were added sequentially. The mixture was stirred until dissolved. Water (3 mL) and lithium hydroxide (736 mg, 17.5 mol) were added, and the mixture was stirred at room temperature overnight. Water (10 mL) was added, and the pH was adjusted to 3-4. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.1 g, a yield of 90.72%. LC-MS (APCI): m / z = 397.1 (M+1). + .

[0568] Step 3 Synthesis of Intermediate A-18

[0569] To a 50 mL single-necked flask equipped with a magnetic stirrer, (1R,2S,5S)-3-((S)-2-((tert-Butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1 g, 2.53 mmol) and dichloromethane (10 mL) were added sequentially. A 1,4-dioxane hydrochloric acid solution (10 mL, 4 M) was added at room temperature. The reaction was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the residue was used directly in the other synthetic steps. LC-MS (APCI): m / z = 333.1 (M+1) + .

[0570] Preparation of intermediate A-19 compound (3R,5'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide

[0571]

[0572] The following synthetic route is used

[0573]

[0574] Step 1: Synthesis of Compound (S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride

[0575] To a 250 mL single-necked flask equipped with a magnetic stirrer, L-tryptophan methyl ester (5.1 g, 20 mmol) and methanol (50 mL) were added sequentially. Stirring allowed the solution to dissolve. Aqueous formaldehyde (1.83 g, 22 mmol, 36% w / w) was then added. The temperature was raised to 65°C and refluxed under a nitrogen atmosphere for 3 hours. The solvent was evaporated under reduced pressure and the product was purified by silica gel column to obtain 3.1 g of a white solid (yield 67.4%). LC-MS (APCI): m / z = 231.0 (M+1). + .

[0576] Step 2: Synthesis of 2-tert-butyl 3-methyl (S)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2,3-dicarboxylate

[0577] To a 250 mL single-necked flask equipped with a magnetic stirrer, (S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride (3.1 g, 13.5 mmol) and 2-methyltetrahydrofuran (50 mL) were added sequentially. Stirring until dissolved, triethylamine (2.7 g, 27 mmol) was added, and di-tert-butyl dicarbonate (3.27 g, 15 mmol) was slowly added dropwise over approximately 10 minutes. After completion of the addition, the ice-water bath was removed, the temperature was naturally raised to room temperature, and the reaction was continued for 2 hours. The solvent was evaporated under reduced pressure, and water (50 mL) and ethyl acetate (50 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was filtered through a column to obtain 4 g of a white solid (90% yield). LC-MS (APCI): m / z = 331.0 (M+1) + .

[0578] Step 3: Synthesis of Compound 2-tert-butyl 3-methyl (3S)-4a-bromo-9a-hydroxy-1,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indole-2,3-dicarboxylate

[0579] Under an ice-salt bath, to a 250 mL three-necked flask equipped with a magnetic stirrer, 2-tert-butyl 3-methyl (S)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2,3-dicarboxylate (3.3 g, 10 mmol), tetrahydrofuran (50 mL), and water (20 mL) were added sequentially. The mixture was cooled to 0°C with stirring, and glacial acetic acid (9 g, 150 mmol) was added. The temperature was further cooled to -1°C, and N-bromosuccinimide (1.78 g, 10 mmol) was added. The reaction was maintained at a temperature between -7°C and -2°C for 1 hour. The mixture was slowly added to a saturated sodium bicarbonate solution (200 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a reddish-brown oil. The mixture was then passed through a silica gel column to afford 1.85 g of a yellow oil (53.5% yield). LC-MS (APCI): m / z = 347.0 (M+1) + .

[0580] Step 4: Synthesis of tert-butyl (3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate

[0581] To a 120 mL pressure-resistant reaction flask equipped with a magnetic stirrer, 2-tert-butyl 3-methyl (3S)-4a-bromo-9a-hydroxy-1,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indole-2,3-dicarboxylate (1.85 g, 5.35 mmol) and methanolic ammonia (50 mL, 7 M) were added and reacted at 55°C overnight. The solvent was evaporated under reduced pressure, and the product was purified by silica gel column to obtain 1.47 g of a yellow oil (83% yield). LC-MS (APCI): m / z = 332.2 (M+1). + .

[0582] Step 5 Synthesis of Intermediate A-19

[0583] To a 100 mL single-necked flask equipped with a magnetic stirrer, tert-butyl (3R,5'S)-5'-carbamoyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (1.47 g, 4.44 mmol) and a solution of hydrogen chloride in ethyl acetate (50 mL, 200 mmol, 4 M) were added sequentially. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The solvent was evaporated under reduced pressure to obtain 1.19 g of a white solid, which was used directly in the subsequent synthesis. LC-MS (APCI): m / z = 232.0 (M+1) + .

[0584] Intermediate A-20 compound (1R, 2S, 5S)-3-(L-valyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Preparation of hexane-2-carboxylic acid hydrochloride

[0585]

[0586] Intermediate A-20 was prepared according to the preparation method of Intermediate A-7, using (tert-butyloxycarbonyl)-L-valine instead of (tert-butyloxycarbonyl)-L-isoleucine as the starting material. 3.41 g of a white solid was obtained, with a yield of 99.0%. LC-MS (APCI): m / z = 255.1 (M+1) + .

[0587] Intermediate A-21 compound (1R, 2S, 5S)-3-(L-leucyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Preparation of hexane-2-carboxylic acid hydrochloride

[0588]

[0589] Intermediate A-21 was prepared according to the preparation method of Intermediate A-7, using (tert-butyloxycarbonyl)-L-leucine instead of (tert-butyloxycarbonyl)-L-isoleucine as the starting material. 2.0 g of a white solid was obtained, with a yield of 96.6%. LC-MS (APCI): m / z = 269.0 (M+1) + .

[0590] Intermediate A-22 compound (2S,4R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- Preparation of 4-(trifluoromethyl)pyrrolidine-2-carboxamide hydrochloride

[0591]

[0592] The following synthetic route is used

[0593]

[0594] Step 1: Synthesis of tert-butyl (2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate

[0595] To a three-necked flask equipped with a magnetic stirrer, acetonitrile (5 mL), N,N-dimethylformamide (5 mL), and (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (0.5 g, 1.7 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The temperature was then lowered to 0°C. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.06 g, 2.6 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (0.453 g, 2.6 mmol), and N,N-diisopropylethylamine (0.683 g, 5.2 mmol) were added and reacted at 0°C for 30 minutes. The ice bath was removed and the reaction was allowed to proceed overnight at room temperature. The mixture was concentrated and passed through a silica gel column to obtain 0.623 g of a yellow oil with a yield of 81.0%. LC-MS (APCI): m / z=437 (M+1) + .

[0596] Step 2 Synthesis of Intermediate A-22

[0597] To a 50 mL single-necked flask equipped with a magnetic stirrer, add tert-butyl (2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate and a 5 mL, 2 M solution of hydrogen chloride in ethyl acetate. The mixture was reacted at room temperature for 30 minutes. The mixture was concentrated to yield an oily intermediate, A-22, which was used directly in subsequent synthetic steps.

[0598] Preparation of intermediate A-23 compound 2-(2,4-dichlorophenoxy)acetic acid

[0599]

[0600] The following synthetic route is used

[0601]

[0602] Step 1 Synthesis of compound 2-(2,4-dichlorophenoxy)acetic acid methyl ester

[0603] To a 100 mL single-necked flask equipped with a magnetic stirrer, 2,4-dichlorophenol (2 g, 12.27 mmol) and acetonitrile (20 mL) were added sequentially. Stirring was continued until the mixture dissolved. Potassium carbonate (5 g, 36.81 mmol) and methyl 2-bromoacetate (2.25 g, 14.72 mmol) were added and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. The organic solvent was evaporated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 1.8 g of a light yellow oil (yield 62.72%). LC-MS (APCI): m / z = 235.0 (M+1) + .

[0604] Step 2 Synthesis of Intermediate A-23

[0605] To a 100 mL single-necked flask equipped with a magnetic stirrer, methyl 2-(2,4-dichlorophenoxy)acetate (1.8 g, 7.69 mmol), tetrahydrofuran (10 mL), and water (10 mL) were added sequentially. Stirring was continued until dissolved, and lithium hydroxide monohydrate (1.6 g, 38.46 mmol) was added. The reaction was stirred at room temperature for 2 hours. Dilute hydrochloric acid (1 M) was added to adjust the pH to approximately 4. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 1.6 g of a white solid with a yield of 94.7%. LC-MS (APCI): m / z = 220.0 (M+1) + .

[0606] Intermediate A-24 compound ((S)-4-chloro-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino Preparation of tert-butyl formate

[0607]

[0608] The following synthetic route is used

[0609]

[0610] To a 250 mL two-necked flask equipped with a magnetic stirrer, tetrahydrofuran (100 mL), methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5 g, 17.4 mmol), and chloroiodomethane (12.3 g, 69.8 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times, and the temperature was lowered to -70°C. Lithium diisopropylamide (52.3 mL, 104.7 mmol, 2 M) was added dropwise. The reaction was maintained at -70°C and allowed to react for 1 hour. The reaction was then quenched with a solution of acetic acid (18.7 mL) in tetrahydrofuran (90 mL) while maintaining the temperature at -70°C. Water (80 mL) and ethyl acetate (100 mL x 3) were added, and the mixture was extracted with saturated sodium bicarbonate solution (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 3.0 g of a yellow oil, with a yield of 56.7%. LC-MS (APCI): m / z = 305 (M+1) + .

[0611] Preparation of Intermediate A-25 Compound N-((Benzyloxy)carbonyl)-O-(1-methylcyclobutyl)-L-threonine

[0612]

[0613] The following synthetic route is used

[0614]

[0615] Step 1 Synthesis of trityl-L-threonine methyl ester

[0616] To a 1000 mL three-necked flask equipped with a magnetic stirrer, L-threonine methyl ester (16.0 g, 94.3 mmol) and dichloromethane (300 mL) were added sequentially. Stirring until dissolved, triethylamine (19.0 g, 190 mmol) was added. Under a nitrogen atmosphere, the temperature was lowered to 0°C, and a dichloromethane solution (200 mL) of triphenylmethane (26.3 g, 94.3 mmol) was slowly added dropwise. The addition was complete over approximately 10 minutes. After the temperature was naturally raised to room temperature, the reaction was continued for 16 hours. Completion of the reaction was monitored by thin-layer chromatography and HPLC-MS. The temperature was lowered to 0°C, and water (30 mL) was added with stirring. The layers were separated, and the organic phase was washed sequentially with 10% citric acid solution (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through a silica gel column to obtain 31 g of a colorless oil in an 87.7% yield. LC-MS: m / z = 376.2 (M+1). + .

[0617] Step 2 Synthesis of methyl (2S, 3S)-3-methyl-1-tritylaziridine-2-carboxylate

[0618] To a 1000 mL three-necked flask equipped with a magnetic stirrer, trityl-L-threonine methyl ester (30 g, 80.1 mmol) and tetrahydrofuran (300 mL) were added sequentially. Stirring until dissolved, triethylamine (16.2 g, 16.2 mmol) was added, and the mixture was cooled in an ice-water bath. Methanesulfonyl chloride (9.0 g, 80.1 mmol) was slowly added dropwise under a nitrogen atmosphere. After approximately 10 minutes, the temperature was slowly raised to room temperature and then continued to rise to 65°C for 48 hours. Completion of the reaction was confirmed by thin-layer chromatography and HPLC-MS. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was washed sequentially with 10% citric acid solution (200 mL x 2) and saturated sodium bicarbonate solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure through a silica gel column to afford 14.1 g of a white solid in a 49.3% yield. LC-MS: m / z = 378.2 (M+1). + .

[0619] Step 3 Synthesis of methyl (2S, 3S)-3-methylaziridine-2-carboxylate

[0620] To a 250 mL two-necked flask equipped with a magnetic stirrer, methyl (2S,3S)-3-methyl-1-tritylaziridine-2-carboxylate (10 g, 27.98 mmol), dichloromethane (50 mL), and methanol (50 mL) were added sequentially. The mixture was cooled to 0°C under a nitrogen atmosphere. Trifluoroacetic acid (77 g, 675 mmol) was slowly added dropwise over approximately 10 minutes. The reaction was then continued at 0°C for 1 hour. The reaction was monitored for completion by thin-layer chromatography and HPLC-MS. The mixture was concentrated to dryness under reduced pressure to yield a yellow oil, which was used directly in subsequent synthetic steps.

[0621] Step 4 Synthesis of 1-benzyl 2-methyl (2S, 3S)-3-methylaziridine-1,2-dicarboxylate

[0622] To a container, methyl (2S,3S)-3-methylaziridine-2-carboxylate (the compound obtained in Step 3), isopropanol (50 mL), and water (50 mL) were added sequentially. Stirring was continued until the solution became clear. The mixture was cooled in an ice-water bath and solid sodium bicarbonate was slowly added to adjust the pH to 8. The temperature was then lowered to 0°C and benzoyloxycarbonyl succinimide (7.67 g, 30.8 mmol) was slowly added. After addition, the mixture was allowed to warm to room temperature and the reaction was continued for 16 hours. Completion of the reaction was confirmed by thin-layer chromatography and HPLC-MS. The organic solvent was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through a silica gel column to afford 4.4 g of a colorless oil (63.3% yield). LC-MS: m / z = 250.1 (M+1). + .

[0623] Step 5 Synthesis of N-((Benzyloxy)carbonyl)-O-(1-methylcyclobutyl)-L-threonine methyl ester

[0624] To a 100 mL three-necked flask equipped with a magnetic stirrer, 1-benzyl 2-methyl (2S,3S)-3-methylaziridine-1,2-dicarboxylate (4.4 g, 17.7 mmol) and 1-methylcyclobutanol (1.8 g, 21.2 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. Anhydrous dichloromethane (60 mL) was added under a nitrogen atmosphere and stirred to dissolve. Boron trifluoride etherate (1.8 mL, 1.8 mmol, 1 M) was slowly added dropwise under an ice-water bath. After completion of the addition, the reaction was continued at room temperature for 16 hours. Completion of the reaction was confirmed by thin-layer chromatography and HPLC-MS. The mixture was cooled to 0°C, and water (30 mL) was added and stirred. The layers were separated, and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through a silica gel column to obtain 2.47 g of a yellow oil in a 41.5% yield. LC-MS: m / z = 336.1 (M+1). + .

[0625] 1 H NMR(400MHz, DMSO-d6):7.40-7.27(m,6H),7.21(d,J=9.2Hz,1H),5.06(s,2H),4.18-4.15(m,1H),4.06-4.03(m ,1H),3.64(s,3H),2.06-1.95(m,2H),1.75-1.69(m,2H),1.61-1.44(m,2H),1.24(s,3H),1.09(d,J=6.0Hz,3H).

[0626] Step 6 Synthesis of Intermediate A-25

[0627] To a 100 mL single-necked flask equipped with a magnetic stirrer, N-((benzyloxy)carbonyl)-O-(1-methylcyclobutyl)-L-threonine methyl ester (1.9 g, 5.67 mmol), tetrahydrofuran (20 mL), and water (20 mL) were added sequentially. Stirring allowed to dissolve, lithium hydroxide monohydrate (1.47 g, 35 mmol) was added, and the mixture was allowed to react overnight at room temperature. The reaction was complete as monitored by thin-layer chromatography and HPLC-MS. The tetrahydrofuran was evaporated under reduced pressure, the pH was adjusted to approximately 4 with dilute hydrochloric acid (1 M), and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 1.62 g of a white solid (88.7% yield). LC-MS: m / z = 322.1 (M+1). + .

[0628] Intermediate A-26 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- Preparation of 3-amino-1,3-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride

[0629]

[0630] According to the preparation method of intermediate A-22, (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was used instead of (2S,4R)-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid as the raw material to prepare intermediate A-26, which was directly used in the subsequent synthesis steps.

[0631] Intermediate B-1 compound (1R,2S,5S)-3-(O-tert-butyl-N-(2-chloro-2,2-difluoroacetyl)-L-threonine Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0632]

[0633] The following synthetic route is used

[0634]

[0635] To a 25 mL two-necked flask equipped with a magnetic stirrer, methanol (10 mL), intermediate A-2 (1 g, 3.2 mmol), N,N-diisopropylethylamine (0.83 g, 6.4 mmol), and ethyl 2-chloro-2,2-difluoroacetate (0.82 g, 5.1 mmol) were added sequentially. The reaction was allowed to proceed overnight at room temperature. The sample was directly spin-dried and passed through a silica gel column to obtain 0.756 g of a yellow oil, with a yield of 55.6%. LC-MS (APCI): m / z = 425 (M+1). + .

[0636] Intermediate B-2 compound (1R,2S,5S)-3-(O-tert-butyl-N-(2,2,2-trifluoroacetyl)-L-threonyl Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0637]

[0638] Intermediate B-2 was prepared according to the preparation method of Intermediate B-1, using ethyl 2,2,2-trifluoroacetate instead of ethyl 2-chloro-2,2-difluoroacetate as the starting material. 0.804 g of a yellow oil was obtained, with a yield of 61.5%. LC-MS (APCI): m / z = 409 (M+1) + .

[0639] Intermediate B-3 compound (1R,2S,5S)-3-((2-chloro-2,2-difluoroacetyl)-L-valyl)-6,6-difluoroacetyl Preparation of methyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0640]

[0641] The following synthetic route is used

[0642]

[0643] To a 100 ml three-necked flask equipped with a magnetic stirrer and a condenser, intermediate A-20 (1.0 g, 3.45 mmol) and methanol (20 mL) were added. Stirring dissolved the mixture, followed by the addition of N,N-diisopropylethylamine (1.925 g, 14.924 mmol) and ethyl 2-chloro-2,2-difluoroacetate (946.4 mg, 5.970 mmol). The mixture was reacted at 50°C under a nitrogen atmosphere for 12 hours. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 700.0 mg of a white solid (50.8% yield). LC-MS (APCI): m / z = 367.0 (M+1). + .

[0644] Intermediate B-4 compound (1R,2S,5S)-3-((2-chloro-2,2-difluoroacetyl)-L-leucyl)-6,6-difluoroacetyl Preparation of methyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0645]

[0646] Intermediate B-4 was prepared according to the preparation method of intermediate B-3, using intermediate A-21 instead of A-20 as the starting material. 950 mg of colorless oil was obtained, with a yield of 76.2%. LC-MS (APCI): m / z = 381.0 (M+1) + .

[0647] Intermediate C-1 compound (1S,3aR,6aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- Preparation of 3-(3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide hydrochloride

[0648]

[0649] The following synthetic route is used

[0650]

[0651] Step 1: Synthesis of methyl (1S,3aR,6aS)-2-((S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylate

[0652] To a 100 mL two-necked flask equipped with a magnetic stirrer were added N,N-dimethylformamide (30 mL), (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid methyl ester hydrochloride (4.5 g, 19.4 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (3 g, 19.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.09 g, 29.1 mmol), 1-hydroxybenzotriazole (3.6 g, 29.1 mmol), and N,N-diisopropylethylamine (6.86 g, 38.8 mmol) in sequence. The reaction was allowed to proceed at room temperature for 4 hours. Water (80 mL) and ethyl acetate (100 mL x 3) were added, the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 5.21 g of a yellow oil, with a yield of 70.1%. LC-MS (APCI): m / z = 383 (M+1) + .

[0653] Step 2: Synthesis of (1S,3aR,6aS)-2-((S)-2-((tert-butyloxycarbonyl)amino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid

[0654] To a 50 mL single-necked flask equipped with a magnetic stirrer were added tetrahydrofuran (40 mL), methyl (1S,3aR,6aS)-2-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylate (2 g, 5.23 mmol), water (30 mL), and lithium hydroxide monohydrate (0.659 g, 15.7 mmol, 2 M). The reaction was allowed to proceed overnight at room temperature. Citric acid (1.01 g, 5.3 mmol) was added and the pH was adjusted to 7. 1.2 g of a white solid was precipitated, with a yield of 62.5%. LC-MS (APCI): m / z = 369 (M+1) + .

[0655] Step 3: Synthesis of tert-butyl ((S)-1-((1S,3aR,6aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0656] To a three-necked flask equipped with a magnetic stirrer was added dichloromethane (35 mL), N,N-dimethylformamide (35 mL) and (1S,3aR,6aS)-2-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (1.2 g, 3.2 mmol) in sequence. The mixture was evacuated and replaced with nitrogen three times. The temperature was lowered to 0°C, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.73 g, 4.5 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)malonamide (0.677 g, 3.52 mmol) and N-methylmorpholine (1.319 g, 12.8 mmol) were added, and the mixture was reacted at 0°C for 30 min. Remove the ice bath and allow the reaction to proceed overnight at room temperature. Add water (60 mL) and ethyl acetate (100 mL x 3). Combine the organic phases, wash with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter, concentrate, and pass through a silica gel column to obtain 0.52 g of a yellow oil, with a yield of 31.7%. LC-MS (APCI): m / z = 504 (M+1). + .

[0657] Step 4 Synthesis of Intermediate C-1

[0658] To a 100 mL single-necked flask equipped with a magnetic stirrer was added tert-butyl ((S)-1-((1S,3aR,6aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (0.52 g, 1 mmol) and a solution of hydrogen chloride in ethyl acetate (10 mL, 2 M). The mixture was reacted at room temperature for 30 minutes. The mixture was concentrated to obtain an oil, which was used directly in the subsequent synthetic steps.

[0659] Intermediate C-2 compound (3S)-3-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) Preparation of tert-butyl (2-propan-2-yl)carbamoyl)-6-oxa-2-azaspiro[4.5]decane-2-carboxylate

[0660]

[0661] The following synthetic route is used

[0662]

[0663] To a three-necked flask equipped with a magnetic stirrer, N,N-dimethylformamide (30 mL), acetonitrile (5 mL), and intermediate A-3 (2.6 g, 9.1 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The temperature was then lowered to 0°C. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.2 g, 13.7 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (3.1 g, 1.8 mmol), and N,N-diisopropylethylamine (3.5 g, 27.4 mmol) were added and reacted at 0°C for 30 minutes. The ice bath was removed and the reaction was allowed to proceed overnight at room temperature. Water (60 mL) and ethyl acetate (100 mL × 3) were added, the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 2 g of a yellow oil with a yield of 50.1%. LC-MS (APCI): m / z = 439 (M+1) + .

[0664] Intermediate C-3 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- 1-(2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- Preparation of 2-formamide

[0665]

[0666] The following synthetic route is used

[0667]

[0668] Step 1: Synthesis of tert-butyl ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl))propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0669] Under ice-water bath, to a 1000 mL three-necked flask equipped with a magnetic stirrer were added intermediate A-4 (36.85 g, 100 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (22.84 g, 110 mmol), acetonitrile (400 mL), N,N-dimethylformamide (40 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (57 g, 150 mmol) and N,N-diisopropylethylamine (38.7 g, 300 mmol) in sequence. The mixture was reacted under nitrogen protection in an ice-water bath for 30 minutes. After removing the ice-water bath, the reaction was continued for 4 hours. Water (300 mL) was added, and most of the acetonitrile was removed by rotary evaporation. The mixture was stirred until uniform, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a reddish-brown oil. The product was purified by silica gel column chromatography to obtain 36 g of a light yellow oil, with a yield of 69.2%. LC-MS (APCI): m / z = 522.2 (M+1). + .

[0670] Step 2 Synthesis of Intermediate C-3

[0671] To a 500 mL single-necked flask equipped with a magnetic stirrer was added tert-butyl ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl))propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (36 g, 690 mmol) and a solution of hydrogen chloride in ethyl acetate (250 mL, 4 M). The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The solvent was evaporated under reduced pressure to obtain 31.6 g of a white solid. LC-MS (APCI): m / z = 422.2 (M+1) + .

[0672] Intermediate C-4 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidine-3- 1-(2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- Preparation of 2-formamide hydrochloride

[0673]

[0674] The following synthetic route is used

[0675]

[0676] Step 1: Synthesis of tert-butyl ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl))propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0677] To a 100 mL single-necked flask equipped with a magnetic stirrer, intermediate A-5 (1.6 g, 7.24 mmol), intermediate A-4 (3.2 g, 8.68 mmol), and anhydrous acetonitrile (30 mL) were added sequentially. The mixture was stirred and dispersed. N,N-dimethylformamide (5 mL), N-methylmorpholine (2.72 g, 27.1 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.16 g, 13.56 mmol) were then added. The mixture was evacuated and replaced with nitrogen three times. The reaction was stirred at room temperature for 2 hours. Saturated brine (30 mL) and ethyl acetate (40 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 1.2 g of a white solid (31.0% yield). LC-MS (APCI): m / z = 536.3 (M+1) + .

[0678] Step 2 Synthesis of intermediate C-4

[0679] To a 100 mL single-necked flask equipped with a magnetic stirrer was added tert-butyl ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl))propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (1.0 g, 1.87 mmol) and a solution of hydrogen chloride in ethyl acetate (20 mL, 4 M). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was evaporated under reduced pressure to obtain 880 mg of a discolored solid in a 100% yield. LC-MS (APCI): m / z = 436.2 (M+1). + .

[0680] Intermediate C-5 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidine-3- 1-(2-(4-(2-(4-(2-(dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)-3-(O-tert-butyl-L-threonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide) Preparation

[0681]

[0682] The following synthetic route is used

[0683]

[0684] Step 1: Synthesis of benzyl ((2S,3R)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-(tert-butoxy)-1-oxobutan-2-yl)carbamate

[0685] To a 100 mL single-necked flask equipped with a magnetic stirrer, intermediate A-5 (1.6 g, 7.24 mmol), intermediate A-1 (3.2 g, 8.68 mmol), and anhydrous acetonitrile (30 mL) were added sequentially. The mixture was stirred and dispersed. N,N-dimethylformamide (5 mL), N-methylmorpholine (2.72 g, 27.1 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.16 g, 13.56 mmol) were then added. The mixture was evacuated and replaced with nitrogen three times. The reaction was stirred at room temperature for 2 hours. Saturated brine (30 mL) and ethyl acetate (40 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 1.9 g of a white solid (42.8% yield). LC-MS (APCI): m / z = 614.1 (M+1) + .

[0686] Step 2 Synthesis of intermediate C-5

[0687] To a 100 mL single-necked flask equipped with a magnetic stirrer was added benzyl ((2S,3R)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-(tert-butoxy)-1-oxobutan-2-yl)carbamate (1.9 g, 3.10 mmol) and methanol (30 mL). The mixture was stirred to dissolve clearly, and palladium on carbon (200 mg, w / w 10%) was added. The mixture was evacuated and replaced with hydrogen three times. The reaction was stirred at room temperature under a hydrogen atmosphere overnight. Methanol (40 mL) was added to dilute the reaction solution, palladium carbon was filtered off, and washed with methanol (10 mL). The filtrate was concentrated to dryness to obtain 1.4 g of colorless oil, with a yield of 94.2%. LC-MS (APCI): m / z = 480.1 (M+1) + .

[0688] Intermediate C-6 compound (1R, 2S, 5S)-N-((2S)-1-amino-1-oxo-3-(2-oxopyrrolidin-3-yl- 5,5-d2)propan-2-yl)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] Preparation of hexane-2-carboxamide hydrochloride

[0689]

[0690] The following synthetic route is used

[0691]

[0692] Step 1: Synthesis of tert-butyl ((2S)-1-((1R,2S,5S)-2-(((2S)-1-amino-1-oxo-3-(2-oxopyrrolidin-3-yl-5,5-d2)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0693] To a 50 mL single-necked flask equipped with a magnetic stirrer, intermediate A-4 (0.37 g, 1.0 mmol), intermediate A-17 (0.21 g, 1.0 mmol), and anhydrous N,N-dimethylformamide (5 mL) were added sequentially. Stirring dissolved the mixture, followed by N,N-diisopropylethylamine (0.38 g, 3.0 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.57 g, 1.5 mmol). After addition, the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Saturated brine (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 0.30 g of a white solid (yield 57.3%). LC-MS (APCI): m / z = 524.2 (M+1) + .

[0694] Step 2 Synthesis of Intermediate C-6

[0695] To a 50 mL single-necked flask equipped with a magnetic stirrer, tert-butyl ((2S)-1-((1R,2S,5S)-2-(((2S)-1-amino-1-oxo-3-(2-oxopyrrolidin-3-yl-5,5-d2)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (0.3 g, 0.57 mmol) and ethyl acetate (2 mL) were added sequentially. The mixture was stirred until dissolved. A solution of hydrogen chloride in ethyl acetate (6 mL, 4 M) was added, and the reaction was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated under reduced pressure to dryness to obtain 0.26 g of a yellow solid with a yield of 100%. LC-MS (APCI): m / z = 424.2 (M+1) + .

[0696] Intermediate C-7 compound (S)-2-((S)-2-amino-3-cyclohexylpropionylamino)-3-((S)-2-oxopyrrole Preparation of methyl 2-(2-alkyl-3-yl)propionate

[0697]

[0698] The following synthetic route is used

[0699]

[0700] Step 1: Synthesis of methyl (S)-2-((S)-2-((tert-butyloxycarbonyl)amino)-3-cyclohexylpropionylamino)-3-((S)-2-oxopyrrolidin-3-yl)propionate

[0701] To a 50 mL three-necked flask equipped with a magnetic stirrer were added (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropionic acid (2.0 g, 7.37 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionic acid methyl ester hydrochloride (1.64 g, 7.37 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.08 g, 8.11 mmol) and N,N-dimethylformamide (20 mL) in sequence. The mixture was evacuated and replaced with nitrogen three times. The reaction was stirred at 0°C for uniform reaction. N-methylmorpholine (2.5 mL, 22.11 mmol) was slowly added dropwise and stirred at room temperature for 4 hours. The reaction was quenched by adding saturated brine (20 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.52 g of a colorless oily liquid, with a yield of 77.8%. LC-MS (APCI): m / z = 440.0 (M+1). + .

[0702] Step 2 Synthesis of Intermediate C-7

[0703] To a 50 mL single-necked flask equipped with a magnetic stirrer, (S)-methyl 2-((S)-2-((tert-Butoxycarbonyl)amino)-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (2.52 g, 5.74 mmol) and a 4 M solution of hydrogen chloride in ethyl acetate (20 mL) were added sequentially, stirred, and allowed to react at room temperature for 1 hour. The mixture was concentrated to give 2.15 g of a white solid, with a yield of 99.9%. LC-MS (APCI): m / z = 340.0 (M+1). + .

[0704] Intermediate C-8 compound ((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyridine) (3-(trifluoromethyl)pyrrolidin-1-yl)-3-cyclobutyl-1-oxopropan-2-yl)-4-(trifluoromethyl)pyrrolidin-1-yl)-3-cyclobutyl-1-oxopropan-2-yl) Preparation of tert-butyl carbamate

[0705]

[0706] The following synthetic route is used

[0707]

[0708] To a 25 mL two-necked flask equipped with a magnetic stirrer was added acetonitrile (5 mL), N,N-dimethylformamide (5 mL), intermediate A-22 (327 mg, 0.88 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3-cyclobutylpropionic acid (278 mg, 1.144 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (219 mg, 1.144 mmol), 1-hydroxybenzotriazole (154 mg, 1.144 mmol), and triethylamine (133 mg, 1.32 mmol). The reaction was allowed to proceed at room temperature for 4 hours. Water (20 mL) and ethyl acetate (40 mL x 3) were added, and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 400 mg of a yellow oil (81.0% yield). LC-MS (APCI): m / z = 562 (M+1) + .

[0709] Intermediate C-9 compound (1S,3aR,6aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- Preparation of 3-(3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide hydrochloride

[0710]

[0711] The following synthetic route is used

[0712]

[0713] Step 1: Synthesis of 2-tert-butyl 1-ethyl (1S, 3aR, 6aS)-hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate

[0714] To a container, add (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester hydrochloride (3.0 g, 13.67 mmol), 1,4-dioxane (75 mL), and water (25 mL) in sequence. Stir to dissolve. Add sodium hydroxide solution (1.64 g, 41.01 mmol) and di-tert-butyl dicarbonate (5.97 g, 27.34 mmol). After addition, stir at room temperature for 3 hours. Add saturated brine (30 mL) and ethyl acetate (50 mL), stir for 5 minutes, separate the organic phase, extract the aqueous phase with ethyl acetate (30 mL x 2), combine the organic phases, wash with saturated brine (80 mL), dry over anhydrous sodium sulfate, filter, concentrate, and pass through a silica gel column to obtain 3.1 g of a light yellow oil (yield 80.1%). LC-MS (APCI): m / z = 284.2 (M+1) + .

[0715] Step 2: Synthesis of (1S,3aR,6aS)-2-(tert-butyloxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid

[0716] 2-tert-Butyl 1-ethyl (1S,3aR,6aS)-hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate (3 g, 10.6 mmol), tetrahydrofuran (20 mL), water (20 mL), and lithium hydroxide monohydrate (2.23 g, 53.0 mmol) were added to a container in sequence. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Dilute hydrochloric acid solution (1 M) was added to adjust the pH to approximately 4. Ethyl acetate (30 mL) was added and stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.5 g of a white solid (yield 89.6%). LC-MS (APCI): m / z = 256.2 (M+1) + .

[0717] Step 3: Synthesis of tert-butyl (1S,3aR,6aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0718] To the container, (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (642 mg, 2.52 mmol), N,N-dimethylformamide (10 mL) and dichloromethane solution (10 mL) were added in sequence and stirring was started. At 0°C, (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (548 mg, 2.65 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.92 g, 5.04 mmol) and N-methylmorpholine (764 mg, 7.56 mmol) were added in sequence. After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Water (30 mL) was added, and dichloromethane was evaporated under reduced pressure. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 500 mg of the desired product in a yield of 48.6%. LC-MS (APCI): m / z = 409.2 (M+1) + .

[0719] Step 4 Synthesis of Intermediate C-9

[0720] To the container were added tert-butyl (1S,3aR,6aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (500 mg, 1.22 mmol) and ethyl acetate (5 mL) in sequence. Hydrogen chloride ethyl acetate solution (10 mL, 4 M) was added dropwise under an ice bath. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was concentrated under reduced pressure to dryness to obtain 420 mg of a white solid, with a yield of 100%. LC-MS (APCI): m / z = 309.2 (M+1). + .

[0721] Intermediate C-10 compound (S)-3-amino-2-oxo-4-((S)-2-oxopyrrolidin-3-yl)2,6-dichlorobenzene Preparation of Butyl Formate Hydrochloride

[0722]

[0723] The following synthetic route is used

[0724]

[0725] Step 1: Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-2-oxo-4-((S)-2-oxopyrrolidin-3-yl)butyl 2,6-dichlorobenzoate

[0726] To a three-necked flask equipped with a magnetic stirrer, N,N-dimethylformamide (10 mL), intermediate A-24 (1.7 g, 5.9 mmol), 2,6-dichlorobenzoic acid (1.47 g, 7.7 mmol), and cesium fluoride (2.62 g, 13.6 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times, and the temperature was raised to 65°C for 4 hours. Water (50 mL) and ethyl acetate (100 mL x 3) were added. The organic phases were combined, washed with saturated brine (75 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 1.44 g of a yellow oil (53.1% yield). LC-MS (APCI): m / z = 459 (M+1). + .

[0727] Step 2 Synthesis of intermediate C-10

[0728] To a 50 mL single-necked flask equipped with a magnetic stirrer, add (S)-butyl 3-((tert-butoxycarbonyl)amino)-2-oxo-4-((S)-2-oxopyrrolidin-3-yl) 2,6-dichlorobenzoate (1.44 g, 3.1 mmol) and a solution of hydrogen chloride in ethyl acetate (15 mL, 2 M). The mixture was allowed to react at room temperature for 30 minutes. The mixture was concentrated to afford the intermediate C-10 as an oil, which was used directly in subsequent synthetic steps.

[0729] Intermediate C-11 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-(2-methyl-3-yl)propan-2-yl)-6,6-dimethyl-3-(O-(1-methylcyclobutyl)-N-(2,2,2-trifluoroacetyl)-L-threonyl) Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide

[0730]

[0731] The following synthetic route is used

[0732]

[0733] Step 1: Synthesis of benzyl ((2S,3R)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-(1-methylcyclobutyloxy)-1-oxobutan-2-yl)carbamate

[0734] To a 100 mL three-necked flask equipped with a magnetic stirrer, intermediate A-25 (1.4 g, 4.35 mmol), intermediate A-26 (1.47 g, 4.79 mmol), and N,N-dimethylformamide (60 mL) were added sequentially. Stirring dissolved the mixture, followed by the addition of N,N-diisopropylethylamine (1.68 g, 13 mmol). The mixture was then cooled to -30°C under a nitrogen atmosphere. 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.15 g, 5.655 mmol) was added in three batches, with 5-minute intervals between each batch. After addition, the reaction was continued at -30°C for 30 minutes. The temperature was then raised to 0°C and the reaction continued for 30 minutes. The reaction was complete as monitored by thin-layer chromatography and HPLC-MS. Water (50 mL) was added with stirring, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (150 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through a silica gel column to obtain 2.02 g of a white solid, with a yield of 76%. LC-MS: m / z = 612.1 (M+1). + .

[0735] Step 2 Synthesis of intermediate C-11

[0736] To a 250 mL single-necked flask equipped with a magnetic stirrer, benzyl ((2S,3R)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-(1-methylcyclobutyloxy)-1-oxobutan-2-yl)carbamate (2 g, 3.3 mmol) and isopropyl alcohol (80 mL) were added sequentially. The mixture was stirred to dissolve, and palladium hydroxide on carbon (500 mg, w / w 10%) was added. The mixture was evacuated and replaced with hydrogen three times. The reaction was stirred at room temperature under a hydrogen atmosphere overnight. The reaction was diluted with dichloromethane (100 mL), the catalyst was filtered off, and the mixture was washed with dichloromethane (50 mL). The mixture was concentrated under reduced pressure to obtain 1.5 g of a light yellow oil with a yield of 95.3%. LC-MS: m / z = 478.2 (M+1) + .

[0737] Intermediate P-1 compound (1R,2S,5S)-3-(O-tert-butyl-N-(2,2,2-trifluoroacetyl)-L-threonyl 1-Hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo [3.1.0] Preparation of hexane-2-carboxamide

[0738]

[0739] The following synthetic route is used

[0740]

[0741] To a three-necked flask equipped with a magnetic stirrer, acetonitrile (5 mL), N,N-dimethylformamide (5 mL) and intermediate B-2 (330 mg, 0.81 mmol) were added in sequence. The mixture was evacuated and replaced with nitrogen three times. The temperature was lowered to 0°C, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (461 mg, 1.21 mmol), intermediate A-6 (98 mg, 1.36 mmol) and N,N-diisopropylethylamine (156 mg, 2.42 mmol) were added. The mixture was reacted at 0°C for 30 minutes. The ice bath was removed and the reaction was allowed to proceed at room temperature overnight. The residue was concentrated and passed through a silica gel column to obtain 306 mg of a yellow oil with a yield of 69%. LC-MS (APCI): m / z = 549 (M+1) + .

[0742] Intermediate P-2 compound (3aR, 6aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- (S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutane Preparation of octahydrocyclopenta[c]pyrrole-1-carboxamide

[0743]

[0744] The following synthetic route is used

[0745]

[0746] To a three-necked flask equipped with a magnetic stirrer, acetonitrile (10 mL), N,N-dimethylformamide (10 mL), and (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid (158 mg, 0.56 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The temperature was then lowered to 0°C. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (275 mg, 1.7 mmol), Intermediate C-1 (208 mg, 0.5 mmol), and N-methylmorpholine (209 mg, 2.0 mmol) were added and reacted at 0°C for 30 minutes. The ice bath was removed and the reaction was allowed to proceed overnight at room temperature. Water (30 mL) and ethyl acetate (60 mL x 3) were added. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 195 mg of a yellow oil (73.2% yield). LC-MS (APCI): m / z = 518 (M+1) + .

[0747] Intermediate P-3 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- 2-(2-chloro-2,2-difluoroacetyl)-L-threonyl)-6,6-dimethyl-3-aza Preparation of bicyclo[3.1.0]hexane-2-carboxamide

[0748]

[0749] The following synthetic route is used

[0750]

[0751] To a three-necked flask equipped with a magnetic stirrer, N,N-dimethylformamide (5 mL), acetonitrile (5 mL), and intermediate B-1 (0.5 g, 1.2 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The temperature was then lowered to 0°C. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.672 g, 1.7 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (0.366 g, 1.7 mmol), and N,N-diisopropylethylamine (0.456 g, 3.5 mmol) were added and reacted at 0°C for 30 minutes. The ice bath was removed and the reaction was allowed to proceed at room temperature overnight. The residue was concentrated and passed through a silica gel column to obtain 0.557 g of a yellow oil (82.0% yield). LC-MS (APCI): m / z = 578 (M+1). + .

[0752] Intermediate P-4 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- 2-(2-(2-(2,2,2-trifluoroacetyl)-L-threonyl)-6,6-dimethyl-3-azabis(2-(2,2,2-trifluoroacetyl)-L-threonyl)-3-(O-tert-butyl-N ...3-azabis(2-(2,2,2- Preparation of cyclo[3.1.0]hexane-2-carboxamide

[0753]

[0754] Intermediate P-4 was prepared according to the preparation method of intermediate P-3, using intermediate B-2 instead of intermediate B-1 as the starting material. 0.51 g of yellow oil was obtained, with a yield of 74.3%. LC-MS (APCI): m / z = 562 (M+1) + .

[0755] Intermediate P-5 compound (3S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane- 2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)-6-oxa-2-azaspiro[4.5]decyl Preparation of alkane-3-carboxamide

[0756]

[0757] The following synthetic route is used

[0758]

[0759] Step 1: Synthesis of compound (3S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-oxa-2-azaspiro[4.5]decane-3-carboxamide

[0760] To a 50 mL single-necked flask equipped with a magnetic stirrer, intermediate C-2 (1.44 g, 4.57 mmol) and a 2 M solution of hydrogen chloride in ethyl acetate (20 mL) were added sequentially. The mixture was reacted at room temperature for 30 minutes. The oily compound was concentrated and used directly in the subsequent synthesis steps.

[0761] Step 2: Synthesis of tert-butyl ((2S)-1-((3S)-3-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6-oxa-2-azaspiro[4.5]decane-2-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0762] To a 50 mL three-necked flask equipped with a magnetic stirrer was added acetonitrile (10 mL), N,N-dimethylformamide (10 mL), and N-tert-butyloxycarbonyl-L-tert-leucine (1.62 g, 7.0 mmol) in sequence. The mixture was evacuated and replaced with nitrogen three times, then cooled to 0°C. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.98 g, 10.5 mmol), (3S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-oxa-2-azaspiro[4.5]decane-3-carboxamide (the compound obtained in Step 2), and N,N-diisopropylethylamine (2.7 g, 21 mmol) were added and reacted at 0°C for 30 minutes. The ice bath was removed and the reaction was allowed to proceed overnight at room temperature. Water (50 mL) and ethyl acetate (100 mL x 3) were added, the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 3.05 g of a yellow oil, with a yield of 79%. LC-MS (APCI): m / z = 553 (M+1) + .

[0763] Step 3: Synthesis of compound (3S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-amino-3,3-dimethylbutyryl)-6-oxa-2-azaspiro[4.5]decane-3-carboxamide hydrochloride

[0764] To a 50 mL single-necked flask equipped with a magnetic stirrer was added tert-butyl ((2S)-1-((3S)-3-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6-oxa-2-azaspiro[4.5]decan-2-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (1 g, 1.8 mmol) and a solution of hydrogen chloride in ethyl acetate (10 mL, 2 M). The mixture was reacted at room temperature for 30 minutes. The mixture was concentrated to obtain an oily compound, which was used directly in the subsequent synthetic steps.

[0765] Step 4 Synthesis of intermediate P-5

[0766] To a 25 mL two-necked flask equipped with a magnetic stirrer was added methanol (10 mL), (3S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-amino-3,3-dimethylbutanoyl)-6-oxa-2-azaspiro[4.5]decane-3-carboxamide hydrochloride (0.82 g, 1.8 mmol), N,N-diisopropylethylamine (0.701 g, 5.4 mmol), and ethyl 2,2,2-trifluoroacetate (0.77 g, 5.4 mmol). The mixture was heated to 80°C and allowed to react overnight. The sample was directly spin-dried and passed through a silica gel column to obtain 0.659 g of a yellow oil (yield 67.0%). LC-MS (APCI): m / z = 548 (M+1). + .

[0767] Intermediate P-6 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- (S)-2-(2-bromo-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- Preparation of Azabicyclo[3.1.0]hexane-2-carboxamide

[0768]

[0769] The following synthetic route is used

[0770]

[0771] To a 50 mL three-necked flask equipped with a magnetic stirrer, acetonitrile (5 mL), N,N-dimethylformamide (5 mL), and 2-bromo-2,2-difluoroacetic acid (125 mg, 0.71 mmol) were added sequentially. The mixture was evacuated and replaced with nitrogen three times. The temperature was then lowered to 0°C. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (270 mg, 0.71 mmol), intermediate C-3 (200 mg, 0.47 mmol), and N,N-diisopropylethylamine (184 mg, 1.42 mmol) were added and reacted at 0°C for 30 minutes. The ice bath was removed and the reaction was allowed to proceed overnight at room temperature. Water (30 mL) and ethyl acetate (50 mL x 3) were added. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 227 mg of a yellow oil (83% yield). LC-MS (APCI): m / z = 578 (M+1) + .

[0772] Intermediate P-7 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- (S)-2-(2,2-difluoropropionylamino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabis( ... Preparation of cyclo[3.1.0]hexane-2-carboxamide

[0773]

[0774] Intermediate P-7 was prepared according to the preparation method of intermediate P-6, using 2,2-difluoropropionic acid instead of 2-bromo-2,2-difluoroacetic acid as the starting material. 185 mg of yellow oil was obtained, with a yield of 76%. LC-MS (APCI): m / z = 514 (M+1) + .

[0775] Intermediate P-8 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- 2-(2-chloro-2,2-difluoroacetylamino)-2-cyclopentylacetyl)-6,6-dimethyl-3-nitropropane Preparation of heterobicyclo[3.1.0]hexane-2-carboxamide

[0776]

[0777] The following synthetic route is used

[0778]

[0779] Step 1: Synthesis of (1R,2S,5S)-3-((S)-2-((tert-butyloxycarbonyl)amino)-2-cyclopentylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester

[0780] To a 100 mL three-necked flask equipped with a magnetic stirrer was added (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid (6.52 g, 26.82 mmol), (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride (5.0 g, 24.38 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.2 g, 16.82 mmol), acetonitrile (45 mL) and N,N-dimethylformamide (5 mL) in sequence, and the mixture was stirred at 0°C. N,N-diisopropylethylamine (13 mL, 73.14 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated brine (50 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 9.5 g of a colorless oily liquid (yield 98.8%). LC-MS (APCI): m / z = 395.0 (M+1) + .

[0781] Step 2: Synthesis of compound (1R,2S,5S)-3-((S)-2-((tert-butyloxycarbonyl)amino)-2-cyclopentylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0782] To a 250 mL single-necked flask equipped with a magnetic stirrer and a condenser was added (1R,2S,5S)-methyl 3-((S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (9.5 g, 24.10 mmol), lithium hydroxide monohydrate (6.07 g, 144.6 mmol), tetrahydrofuran (50 mL), and water (50 mL) in sequence, and stirred at 50°C for 4 hours. After cooling to room temperature, the reaction was quenched by the addition of hydrochloric acid solution (30 mL, 1 N). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 9.0 g of a white solid (95.7% yield). LC-MS (APCI): m / z = 381.0 (M+1) + .

[0783] Step 3: Synthesis of compound (1R,2S,5S)-3-((S)-2-amino-2-cyclopentylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride

[0784] To a 50 mL single-necked flask equipped with a magnetic stirrer, (1R,2S,5S)-3-((S)-2-((tert-Butoxycarbonyl)amino)-2-cyclopentylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (9.0 g, 23.06 mmol) and a solution of hydrogen chloride in ethyl acetate (50 mL, 4 M) were added sequentially. The mixture was stirred and dispersed. The reaction was stirred at room temperature for 1 hour. Concentration afforded 7.26 g of a white solid, with a yield of 99.6%. LC-MS (APCI): m / z = 340.0 (M+1). + .

[0785] Step 4: Synthesis of compound (1R,2S,5S)-3-((S)-2-(2-chloro-2,2-difluoroacetylamino)-2-cyclopentylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0786] To a 50 mL three-necked flask equipped with a magnetic stirrer were added (1R,2S,5S)-3-((S)-2-amino-2-cyclopentylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride (2.0 g, 6.3 mmol), ethyl 2-chloro-2,2-difluoroacetate (1.6 mL, 12.2 mmol), N,N-diisopropylethylamine (4.5 mL, 25.2 mmol), and methanol (20 mL) in sequence. The mixture was stirred at 50°C overnight. After cooling to room temperature, the reaction was quenched by the addition of saturated brine (20 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 2.0 g of a colorless oily liquid (80.9% yield). LC-MS (APCI): m / z = 393.0 (M+1) + .

[0787] Step 5 Synthesis of intermediate P-8

[0788] Into a 100 mL three-necked flask equipped with a magnetic stirrer were added (1R,2S,5S)-3-((S)-2-(2-chloro-2,2-difluoroacetylamino)-2-cyclopentylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.0 g, 5.1 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (959.4 mg, 5.61 mmol) and the like. mol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.13 g, 5.61 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.17 g, 6.12 mmol), and N,N-dimethylformamide (20 mL) were stirred at 0°C. N,N-diisopropylethylamine (2.73 mL, 15.3 mmol) was slowly added dropwise and stirred at room temperature for 4 hours. The reaction was quenched by the addition of saturated brine (20 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 1.5 g of a colorless oily liquid in a yield of 53.9%. LC-MS (APCI): m / z = 546.0 (M+1). + .

[0789] Intermediate P-9 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3- 2-(2-chloro-2,2-difluoroacetylamino)-2-cyclohexylacetyl)-6,6-dimethyl-3-nitropropane Preparation of heterobicyclo[3.1.0]hexane-2-carboxamide

[0790]

[0791] Intermediate P-9 was prepared according to the preparation method of intermediate P-8, using (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid instead of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid as the starting material. 830 mg of a colorless oily liquid was obtained, with a yield of 46.3%. LC-MS (APCI): m / z = 560.0 (M+1). + .

[0792] Intermediate P-10 compound (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propane- 2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)-2-azaspiro[4.4]nonane-3-carboxylic Preparation of amides

[0793]

[0794] The following synthetic route is used

[0795]

[0796] Step 1: Synthesis of compound (R)-1-(3-(benzyloxy)-2-hydroxypropyl)cyclopentane-1-carbonitrile

[0797] To a 100 mL three-necked flask equipped with a magnetic stirrer, (R)-2-((benzyloxy)methyl)oxirane (5.5 g, 33.5 mmol) and tetrahydrofuran (50 mL) were added sequentially. The mixture was cooled to -78°C and slowly added dropwise with lithium diisopropylamide (26.2 mL, 52.5 mmol). The reaction was stirred at -78°C for one hour. Cyclopentanecarbonitrile (5.0 g, 52.5 mmol) was then added dropwise and stirred at -78°C for one hour. The mixture was then allowed to warm to room temperature and allowed to react overnight. The reaction was quenched by the addition of saturated brine (50 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 7.9 g of a colorless oily liquid (91.1% yield). LC-MS (APCI): m / z = 260.0 (M+1). + .

[0798] Step 2: Synthesis of Compound (R)-tert-Butyl ((1-(3-(benzyloxy)-2-hydroxypropyl)cyclopentyl)methyl)carbamate

[0799] To a 250 mL three-necked flask equipped with a magnetic stirrer were added (R)-1-(3-(benzyloxy)-2-hydroxypropyl)cyclopentane-1-carbonitrile (7.9 g, 30.5 mmol), cobalt chloride hexahydrate (14.7 g, 60.7 mmol), and methanol (80 mL). The mixture was cooled to 0°C, and sodium borohydride (1.75 g, 45.75 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours. Di-tert-butyl dicarbonate (20.7 g, 91.5 mmol) was added, and the reaction was stirred at room temperature overnight. The solvent was removed by rotary evaporation under reduced pressure, and saturated brine (80 mL) was added. The aqueous phase was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 9.4 g of a colorless oily liquid (84.9% yield). LC-MS (APCI): m / z = 364.0 (M+1). + .

[0800] Step 3: Synthesis of Compound (S)-3-((Benzyloxy)methyl)-2-azaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

[0801] To a 250 mL three-necked flask equipped with a magnetic stirrer were added tert-butyl (R)-((1-(3-(benzyloxy)-2-hydroxypropyl)cyclopentyl)methyl)carbamate (9.4 g, 25.88 mmol), trimethyl orthoacetate (4.66 g, 38.82 mmol), and dichloromethane (80 mL) in sequence. The mixture was cooled to 0°C, and boron trifluoride etherate (1.64 mL, 12.94 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 3 hours. The three-necked flask was placed in an ice bath and stirred. Saturated brine (80 mL) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (80 mL x 2). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 3.5 g of a colorless oily liquid in a yield of 39.2%. LC-MS (APCI): m / z = 346.0 (M+1). + .

[0802] Step 4: Synthesis of Compound (S)-3-(Hydroxymethyl)-2-azaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

[0803] To a 100 mL single-necked flask equipped with a magnetic stirrer, tert-butyl (S)-3-((benzyloxy)methyl)-2-azaspiro[4.4]nonane-2-carboxylate (1.5 g, 4.3 mmol), palladium on carbon (150 mg, w / w 10%), and methanol (30 mL) were added sequentially. The mixture was evacuated and replaced with hydrogen three times. The reaction was stirred at room temperature overnight. The filtrate was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain 1.0 g of a colorless oily liquid in a 90.7% yield. LC-MS (APCI): m / z = 256.0 (M+1). +.

[0804] Step 5 Synthesis of Compound (S)-2-(tert-Butyloxycarbonyl)-2-azaspiro[4.4]nonane-3-carboxylic acid

[0805] To a 50 mL three-necked flask equipped with a magnetic stirrer was added (S)-3-(hydroxymethyl)-2-azaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (1.0 g, 3.9 mmol), 2,2,6,6-tetramethylpiperidinium oxide (609 mg, 1.17 mmol), a saturated aqueous solution of sodium dihydrogen phosphate (5 mL) and acetonitrile (5 mL) in sequence, stirred for 5 minutes, sodium chlorite (2.1 g, 23.4 mmol) and sodium hypochlorite (0.17 mL) were added, and the reaction was stirred at room temperature overnight. The solvent was removed by rotary evaporation under reduced pressure, hydrochloric acid solution (10 mL, 1 N) was added, and the mixture was extracted with ethyl acetate (10 ml × 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 460 mg of a white solid with a yield of 43.8%. LC-MS (APCI): m / z=270 (M+1) + .

[0806] Step 6: Synthesis of Compound (S)-3-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-2-azaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester

[0807] To a 25 mL three-necked flask equipped with a magnetic stirrer were added (S)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]nonane-3-carboxylic acid (460 mg, 1.71 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (350.9 mg, 2.05 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (715.2 mg, 1.88 mmol) and N,N-dimethylformamide (5 mL) in sequence. The mixture was stirred at 0°C and N-methylmorpholine (0.77 mL, 6.84 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated brine (10 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 540 mg of a colorless oily liquid, with a yield of 60.5%. LC-MS (APCI): m / z = 423.0 (M+1) + .

[0808] Step 7: Synthesis of compound (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-azaspiro[4.4]nonane-3-carboxamide hydrochloride

[0809] To a 50 mL single-necked flask equipped with a magnetic stirrer, (S)-tert-butyl 3-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-2-azaspiro[4.4]nonane-2-carboxylate (540 mg, 1.28 mmol) and a solution of hydrogen chloride in ethyl acetate (5 mL, 4 M) were added sequentially. The mixture was stirred and dispersed, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain 430.2 mg of a white solid, with a yield of 93.8%. LC-MS (APCI): m / z = 359.0 (M+1). + .

[0810] Step 8 Synthesis of intermediate P-10

[0811] To a 25 mL three-necked flask equipped with a magnetic stirrer was added formamide hydrochloride (430.2 mg, 1.20 mmol), (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butyric acid (435.8 mg, 1.92 mmol), 1-hydroxybenzotriazole (210.8 mg, 1.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (276.05 mg, 1.44 mmol) and dichloromethane (6 mL) in sequence, stirred evenly at 0°C, and triethylamine (0.33 mL, 2.40 mmol) was slowly added dropwise, and stirred at room temperature for 4 hours. The reaction was quenched by adding saturated brine (10 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 360 mg of a colorless oily liquid, with a yield of 56.5%. LC-MS (APCI): m / z = 532.0 (M+1) + .

[0812] Intermediate P-11 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidine-3- 2-(2,2,3,3,3-pentafluoropropionylamino)butanoyl)-6,6-dimethyl-3- Preparation of Azabicyclo[3.1.0]hexane-2-carboxamide

[0813]

[0814] The following synthetic route is used

[0815]

[0816] To a 25 mL three-necked flask equipped with a magnetic stirrer were added intermediate C-4 (500.0 mg, 1.06 mmol), 2,2,3,3,3-pentafluoropropionic acid (260.7 mg, 1.59 mmol), 1-hydroxybenzotriazole (186.0 mg, 1.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (244.2 mg, 1.38 mmol), and N,N-dimethylformamide (5 mL). The mixture was stirred at 0°C until homogeneity was achieved. Triethylamine (0.44 mL, 3.18 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of saturated brine (10 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 250 mg of a colorless oily liquid (40.6% yield). LC-MS (APCI): m / z = 582.0 (M+1) + .

[0817] Intermediate P-12 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((2-chloro-2,2-difluoroacetyl)-L-isoleucyl)-6,6-dimethyl-3-azabicyclo [3.1.0] Preparation of hexane-2-carboxamide

[0818]

[0819] The following synthetic route is used

[0820]

[0821] Step 1 Synthesis of compound (1R,2S,5S)-3-((2-chloro-2,2-difluoroacetyl)-L-isoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0822] To a 100 mL three-necked flask equipped with a magnetic stirrer were added intermediate A-7 (1.0 g, 3.731 mmol), N,N-diisopropylethylamine (1.925 g, 14.924 mmol), ethyl 2-chloro-2,2-difluoroacetate (946.4 mg, 5.970 mmol), and methanol (20 mL). The mixture was evacuated and replaced with nitrogen three times. The reaction was allowed to proceed at 50°C under a nitrogen atmosphere for 12 hours. The reaction was quenched by the addition of water (30 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 720.0 mg of a white solid in a 50.8% yield. LC-MS (APCI): m / z = 381.0 (M+1). + .

[0823] Step 2 Synthesis of intermediate P-12

[0824] To a 50 mL three-necked flask equipped with a magnetic stirrer were added (1R, 2S, 5S)-3-((2-chloro-2,2-difluoroacetyl)-L-isoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (720 mg, 1.894 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propionamide hydrochloride (421.2 mg, 2.463 mmol), N,N-diisopropylethylamine (733.0 mg, 5.682 mmol) and N,N-dimethyl Formamide (10 mL) was evacuated and replaced with nitrogen three times, cooled in an ice-water bath, and 2-hydroxypyridine-N-oxide (63.1 mg, 0.568 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (544.6 mg, 2.841 mmol) were added. The mixture was allowed to react at room temperature for 12 hours. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 750 mg of a white solid, in a yield of 74.2%. LC-MS (APCI): m / z = 534.0 (M+1). + .

[0825] Intermediate P-13 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-yl)propan-2-yl)-6,6-dimethyl-3-((2,2,2-trifluoroacetyl)-L-isoleucyl)-3-azabicyclo [3.1.0] Preparation of hexane-2-carboxamide

[0826]

[0827] Intermediate P-13 was prepared according to the preparation method of intermediate P-12, using ethyl 2,2,2-trifluoroacetate instead of ethyl 2-chloro-2,2-difluoroacetate as the starting material. 800 mg of white solid was obtained with a yield of 84.7%. LC-MS (APCI): m / z = 518.0 (M+1) + .

[0828] Intermediate P-14 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-(2-oxoimidazolin-1-yl) (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)-6,6-dimethyl-3-azabis(propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)- Preparation of cyclo[3.1.0]hexane-2-carboxamide

[0829]

[0830] The following synthetic route is used

[0831]

[0832] Step 1: Synthesis of Compound (S)-2-(((benzyloxy)carbonyl)amino)-3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)propanoic acid methyl ester

[0833] To a 100 mL three-necked flask equipped with a magnetic stirrer were added methyl (S)-3-amino-2-(((benzyloxy)carbonyl)amino)propanoate hydrochloride (3 g, 10.390 mmol), tert-butyl (2-oxoethyl)carbamate (1.819 g, 11.429 mmol), acetic acid (29.7 mL), and methanol (0.3 mL) in sequence. The mixture was evacuated and replaced with nitrogen three times, cooled in an ice-water bath, and sodium cyanoborohydride (816.1 mg, 12.988 mmol) was added. The reaction was allowed to react at room temperature for 2 hours. Water (30 mL) was added to quench the reaction, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 1.65 g of a white solid in a 40.2% yield. LC-MS (APCI): m / z = 396.0 (M+1). + .

[0834] Step 2: Synthesis of Compound (S)-3-((2-aminoethyl)amino)-2-(((benzyloxy)carbonyl)amino)propionic acid methyl ester hydrochloride

[0835] To a 100 mL single-necked flask equipped with a magnetic stirrer, methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)propanoate (1.65 g, 4.177 mmol) and ethyl acetate (2 mL) were added sequentially. The mixture was evacuated and replaced with nitrogen three times, cooled in an ice-water bath, and a solution of hydrogen chloride in ethyl acetate (20 mL, 4 M) was added. The mixture was reacted at room temperature for 30 minutes. The crude product was concentrated to give 1.23 g of a white solid, in a 99.0% yield. LC-MS (APCI): m / z = 296.0 (M+1). + .

[0836] Step 3: Synthesis of Compound (S)-2-(((Benzyloxy)carbonyl)amino)-3-(2-oxoimidazolin-1-yl)propanoic acid methyl ester

[0837] To a 100 mL three-necked flask equipped with a magnetic stirrer were added (S)-methyl 3-((2-aminoethyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate hydrochloride (1.23 g, 4.170 mmol), triethylamine (1.701 g, 16.68 mmol), N,N'-carbonyldiimidazole (675.54 mg, 4.170 mmol), and tetrahydrofuran (15 mL). The mixture was evacuated and replaced with nitrogen three times. The reaction was allowed to react at room temperature for 12 hours. The reaction was quenched by the addition of water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 600 mg of a white solid in a 45.0% yield. LC-MS (APCI): m / z = 322.0 (M+1). + .

[0838] Step 4: Synthesis of compound (S)-(1-amino-1-oxo-3-(2-oxoimidazolin-1-yl)propan-2-yl)carbamic acid benzyl ester

[0839] To a 45 mL sealed tube equipped with a magnetic stirrer, (S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-(2-oxoimidazolin-1-yl)propanoate (600 mg, 1.869 mmol) and methanolic ammonia solution (10 mL, 7 M) were added sequentially. The mixture was reacted at 70°C under a nitrogen atmosphere for 12 hours. The mixture was concentrated and passed through a silica gel column to afford 300.0 mg of a white solid in a 52.4% yield. LC-MS (APCI): m / z = 307.0 (M+1). + .

[0840] Step 5: Synthesis of compound (S)-2-amino-3-(2-oxoimidazolin-1-yl)propionamide hydrochloride

[0841] To a 50 mL single-necked flask equipped with a magnetic stirrer was added benzyl (S)-(1-amino-1-oxo-3-(2-oxoimidazolin-1-yl)propan-2-yl)carbamate (300 mg, 0.980 mmol), palladium on carbon (30 mg, w / w 10%), and methanol (10 mL). The mixture was evacuated and replaced with hydrogen three times. The reaction was allowed to proceed at room temperature under a hydrogen atmosphere for 12 hours. The mixture was filtered, concentrated, and passed through a silica gel column to afford 151.7 mg of a white solid (90.0% yield). LC-MS (APCI): m / z = 173.0 (M+1). + .

[0842] Step 6: Synthesis of tert-butyl ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-(2-oxoimidazolin-1-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0843] To a 50 mL three-necked flask equipped with a magnetic stirrer, (S)-2-amino-3-(2-oxoimidazolin-1-yl)propionamide hydrochloride (151.7 mg, 0.882 mmol), intermediate A-4 (422.5 mg, 1.147 mmol), N,N-diisopropylethylamine (341.3 mg, 2.646 mmol), acetonitrile (5 mL) and N,N-dimethylformamide (5 ml) were added in sequence, and the mixture was evacuated and replaced with nitrogen. The reaction mixture was stirred 3 times, cooled in an ice-water bath, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (502.7 mg, 1.323 mmol) was added. The reaction was allowed to react at room temperature for 4 hours. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 368.3 mg of a white solid, with a yield of 80.0%. LC-MS (APCI): m / z = 523.0 (M+1) + .

[0844] Step 7: Synthesis of compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-(2-oxoimidazolin-1-yl)propan-2-yl)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0845] To a 50 mL single-necked flask equipped with a magnetic stirrer, tert-butyl ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-(2-oxoimidazolin-1-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (368.3 mg, 0.705 mmol) and ethyl acetate (2 mL) were added sequentially. The mixture was evacuated and replaced with nitrogen three times, cooled in an ice-water bath, and a solution of hydrogen chloride in ethyl acetate (8 mL, 4 M) was added. The reaction was allowed to proceed at room temperature for 1 hour. The crude product was concentrated to give 297 mg of a white solid, in a 99.0% yield. LC-MS (APCI): m / z = 423.0 (M+1). + .

[0846] Step 8 Synthesis of intermediate P-14

[0847] To a 50 mL three-necked flask equipped with a magnetic stirrer were added (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-(2-oxoimidazolin-1-yl)propan-2-yl)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (297 mg, 0.704 mmol), N,N-diisopropylethylamine (363 .3 mg, 2.816 mmol), ethyl 2,2,2-trifluoroacetate (200.0 mg, 1.408 mmol) and methanol (10 mL) were added to the reaction mixture, evacuated and replaced with nitrogen three times, and reacted at 65°C under a nitrogen atmosphere for 12 hours. The reaction was quenched by adding water (10 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 182.3 mg of a white solid, with a yield of 50.0%. LC-MS (APCI): m / z = 519.0 (M+1). + .

[0848] Intermediate P-15 compound (1R,2S,5S)-N-((S)-3-((R)-8-acetyl-2-oxo-1,8-diazaspiro [4.5]dec-3-yl)-1-amino-1-oxopropan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino) Preparation of (butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0849]

[0850] The following synthetic route is used

[0851]

[0852] Step 1: Synthesis of tert-butyl ((2S)-3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]dec-3-yl)-1-amino-1-oxopropan-2-yl)carbamate

[0853] To a 110 mL sealed tube equipped with a magnetic stirrer, add intermediate A-10 (1.2 g, 3 mmol) and methanolic ammonia (20 mL, 7 M) in sequence. The tube was sealed and stirred at 80°C overnight. The mixture was cooled to room temperature, then cooled in an ice-water bath. The tube was carefully opened, concentrated under reduced pressure, and passed through a silica gel column to afford 0.91 g of a white solid, yield 79.1%. LC-MS (APCI): m / z = 383.2 (M+1). + .

[0854] Step 2: Synthesis of compound (2S)-3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]dec-3-yl)-2-aminopropionamide hydrochloride

[0855] To a 50 mL single-necked flask equipped with a magnetic stirrer, tert-butyl ((2S)-3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]dec-3-yl)-1-amino-1-oxopropan-2-yl)carbamate (0.90 g, 2.35 mmol) and ethyl acetate (5 mL) were added sequentially. Stirring allowed the mixture to dissolve. Hydrogen chloride in ethyl acetate (10 mL, 40 mmol, 4 M) was added, and the mixture was allowed to react at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated under reduced pressure to dryness to obtain 0.75 g of a white solid, with a yield of 100%. LC-MS (APCI): m / z = 283.2 (M+1). + .

[0856] Step 3 Synthesis of intermediate P-15

[0857] To a 50 mL single-necked flask equipped with a magnetic stirrer were added (2S)-3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]dec-3-yl)-2-aminopropionamide hydrochloride (0.5 g, 1.57 mmol), (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)-6,6-dimethyl-3-nitropropionamide, and the like. Heterobicyclo[3.1.0]hexane-2-carboxylic acid (0.78 g, 2.16 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.0 g, 2.7 mmol), N-methylmorpholine (0.375 g, 3.6 mmol), and N,N-dimethylformamide (10 mL) were evacuated and replaced with nitrogen three times. The mixture was stirred at 25°C for 2 hours. Saturated brine (10 mL) was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 0.36 g of a white solid in a 36.4% yield. LC-MS (APCI): m / z = 629.3 (M+1). + .

[0858] Intermediate P-16 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((R)-2-oxo-8-oxa- 1-azaspiro[4.5]dec-3-yl)propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butyryl Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0859]

[0860] Intermediate P-16 was prepared according to the preparation method of intermediate P-15, using intermediate A-12 instead of intermediate A-10 as the starting material. 0.31 g of white solid was obtained, with a yield of 29.3%. LC-MS (APCI): m / z = 588.3 (M+1) + .

[0861] Intermediate P-17 compound (1R,2S,5S)-N-((2S)-1-amino-3-((3S)-5-methyl-2-oxopyrrole alkyl-3-yl)-1-oxopropan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetylamino)butanoyl)-6,6- Preparation of dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0862]

[0863] Intermediate P-17 was prepared according to the preparation method of intermediate P-15, using intermediate A-13 instead of intermediate A-10 as the starting material. 0.33 g of white solid was obtained, with a yield of 65.4%. LC-MS (APCI): m / z = 532.27 (M+1) + .

[0864] Intermediate P-18 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide

[0865]

[0866] Intermediate P-18 was prepared according to the preparation method of intermediate P-6, using 1-fluorocyclopropanecarboxylic acid instead of 2-bromo-2,2-difluoroacetic acid as the starting material. 190 mg of a yellow oil was obtained, with a yield of 52.7%. LC-MS (APCI): m / z = 508.1 (M+1) + .

[0867] Intermediate P-19 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-3,3-dimethyl-2-(1-methylcyclopropane-1-carboxamido)butanoyl)-6,6-dimethyl Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide

[0868]

[0869] Intermediate P-19 was prepared according to the preparation method of intermediate P-6, using 1-methylcyclopropane-1-carboxylic acid instead of 2-bromo-2,2-difluoroacetic acid as the starting material. 195 mg of a yellow oil was obtained, with a yield of 54.6%. LC-MS (APCI): m / z = 503.1 (M+1) + .

[0870] Intermediate P-20 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-3,3-dimethyl-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)butanoyl)-6,6- Preparation of dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0871]

[0872] Intermediate P-20 was prepared according to the preparation method of intermediate P-6, using 1-trifluoromethyl-1-cyclopropanecarboxylic acid instead of 2-bromo-2,2-difluoroacetic acid as the starting material. 200 mg of yellow oil was obtained, with a yield of 50.5%. LC-MS (APCI): m / z = 558.1 (M+1) + .

[0873] Intermediate P-21 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((2S)-2-(2,2-difluoro-1-methylcyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)- Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0874]

[0875] Intermediate P-21 was prepared according to the preparation method of intermediate P-6, using 2,2-difluoro-1-methylcyclopropanecarboxylic acid instead of 2-bromo-2,2-difluoroacetic acid as the starting material. 180 mg of a yellow oil was obtained, with a yield of 47.0%. LC-MS (APCI): m / z = 540.1 (M+1) + .

[0876] Intermediate P-22 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-3,3-dimethyl-2-(2-(p-tolyl)acetylamino)butanoyl)-6,6-dimethyl-3- Preparation of Azabicyclo[3.1.0]hexane-2-carboxamide

[0877]

[0878] Intermediate P-22 was prepared according to the preparation method of intermediate P-6, using 4-methylphenylacetic acid instead of 2-bromo-2,2-difluoroacetic acid as the starting material. 190 mg of a yellow oil was obtained, with a yield of 48.4%. LC-MS (APCI): m / z = 554.1 (M+1) + .

[0879] Intermediate P-23 compound ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxo (substituted pyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl -1-oxobutan-2-yl)

[0880] Preparation of (2,2-difluoro-1-methylcyclopropyl)methyl carbamate

[0881]

[0882] The following synthetic route is used

[0883]

[0884] Under an ice-water bath, 2,2-difluoro-1-methyl-cyclopropylmethanol (77 mg, 0.635 mmol), triethylamine (76 mg, 0.76 mmol), acetonitrile (5 mL), and dichloromethane (5 mL) were added sequentially to a 100 mL three-necked flask equipped with a magnetic stirrer. p-Nitrophenyl chloroformate (183 mg, 0.71 mmol) was added under a nitrogen atmosphere, and the reaction was continued in the ice-water bath for 1 hour. The ice-water bath was removed and the reaction was continued for 2 hours. Intermediate C-3 (218 mg, 0.475 mmol) and a dichloromethane solution of triethylamine (50 mg, 0.5 mmol, 5 mL) were added dropwise to the above reaction system. After addition, the reaction was allowed to react at room temperature for 3 hours. The product was concentrated under reduced pressure and passed through a silica gel column to obtain 120 mg of a light yellow oil with a yield of 44.3%. LC-MS (APCI): m / z = 570.2 (M+1) + .

[0885] Intermediate P-24 compound ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxo (substituted pyrrolidin-3-yl) (propyl-2-yl) (carbamoyl) (6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl) (3,3-dimethyl- Preparation of 4-fluorobenzyl (methyl-1-oxobutan-2-yl)carbamate

[0886]

[0887] Intermediate P-24 was prepared according to the preparation method of intermediate P-23, using (4-fluorophenyl)methanol instead of 2,2-difluoro-1-methyl-cyclopropylmethanol as the starting material. 110 mg of a yellow oil was obtained, with a yield of 40.4%. LC-MS (APCI): m / z = 574.2 (M+1) + .

[0888] Intermediate P-25 compound ((S)-1-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxo (substituted pyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl Preparation of 3,3-difluorocyclobutyl-1-oxobutan-2-yl)carbamate

[0889]

[0890] Intermediate P-25 was prepared according to the preparation method of intermediate P-23, using 3,3-difluorocyclobutan-1-ol instead of 2,2-difluoro-1-methyl-cyclopropylmethanol as the starting material. 100 mg of a yellow oil was obtained, with a yield of 28.3%. LC-MS (APCI): m / z = 556.2 (M+1) + .

[0891] Intermediate P-26 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethyl Preparation of (butyryl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0892]

[0893] The following synthetic route is used

[0894]

[0895] To a 100 mL three-necked flask equipped with a magnetic stirrer was added intermediate C-3 (173 mg, 0.38 mmol), (S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetic acid (130 mg, 0.50 mmol), acetonitrile (8 mL) and N,N-dimethylformamide (2 mL) in sequence, stirred until dissolved, cooled in an ice-water bath, and N-methylmorpholine (153 mg, 1.52 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (220 mg, 0.57 mmol) were added under a nitrogen atmosphere. After the addition was complete, the ice bath was removed and the reaction was allowed to react at room temperature under a nitrogen atmosphere overnight. Ethyl acetate (30 mL) and saturated brine (20 mL) were added, the organic phase was separated, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was filtered to obtain 180 mg of the product with a yield of 71.1%. LC-MS (APCI): m / z = 667.2 (M+1) + .

[0896] Intermediate P-27 compound (1R,2S,5S)-N-((2S)-1-amino-3-(5,5-dimethyl-2-oxopyrrolidine- 3-yl)-1-oxopropan-2-yl)-3-((S)-2-(2-chloro-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-6,6- Preparation of dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0897]

[0898] The following synthetic route is used

[0899]

[0900] To a 50 mL single-necked flask equipped with a magnetic stirrer were added intermediate A-14 (0.53 g, 2.26 mmol), (1R,2S,5S)-3-((S)-2-(2-chloro-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.03 g, 2.71 mmol) and anhydrous N,N-dimethylformamide (10 mL) in sequence. The mixture was stirred to dissolve, and N-methylmorpholine (0.68 g, 6.78 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.29 g, 3.39 mmol) were added. After the addition was complete, the mixture was evacuated and replaced with nitrogen three times, and the reaction was stirred at room temperature for 2 hours. Saturated brine (30 mL) and ethyl acetate (40 mL) were added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 0.25 g of a white solid, with a yield of 19.7%. LC-MS (APCI): m / z = 562.2 (M+1) + .

[0901] Intermediate P-28 compound (1R, 2S, 5S)-N-((2S)-1-amino-1-oxo-3-(6-oxo-5-azaspiro) [3.4]octan-7-yl)propan-2-yl)-3-((S)-2-(2-chloro-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-6,6- Preparation of dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0902]

[0903] Intermediate P-28 was prepared according to the preparation method of intermediate P-27, using intermediate A-16 instead of intermediate A-14 as the starting material. 0.31 g of white solid was obtained, with a yield of 23.9%. LC-MS (APCI): m / z = 574.2 (M+1) + .

[0904] Intermediate P-29 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidine-3- (S)-2-(2-chloro-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- Preparation of Azabicyclo[3.1.0]hexane-2-carboxamide

[0905]

[0906] Intermediate P-29 was prepared according to the preparation method of intermediate P-27, using intermediate A-5 instead of intermediate A-14 as the starting material. 0.16 g of white solid was obtained, with a yield of 16.1%. LC-MS (APCI): m / z = 548.2 (M+1) + .

[0907] Intermediate P-30 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidine-3- (S)-2-(2-bromo-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3- Preparation of Azabicyclo[3.1.0]hexane-2-carboxamide

[0908]

[0909] The following synthetic route is used

[0910]

[0911] To a 50 mL single-necked flask equipped with a magnetic stirrer, intermediate C-4 (0.47 g, 1.0 mmol) and anhydrous N,N-dimethylformamide (5 mL) were added sequentially. Stirring dissolved the mixture, followed by the addition of 2-bromo-2,2-difluoroacetic acid (0.34 g, 2.0 mmol), N,N-diisopropylethylamine (0.26 g, 2.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.31 g, 2.0 mmol), and 1-hydroxybenzotriazole (0.27 g, 2.0 mmol). The mixture was stirred at room temperature overnight under a nitrogen atmosphere. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 0.28 g of a white solid (yield 47.3%). LC-MS (APCI): m / z = 592.1 (M+1). + .

[0912] Intermediate P-31 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidine-3- 2-(2-bromo-2,2-difluoroacetyl)-O-tert-butyl-L-threonyl)-6,6-dimethyl-3-aza Preparation of bicyclo[3.1.0]hexane-2-carboxamide

[0913]

[0914] Intermediate P-31 was prepared according to the preparation method of intermediate P-30, using intermediate C-5 instead of intermediate C-4 as the starting material. 0.30 g of white solid was obtained, with a yield of 47.2%. LC-MS (APCI): m / z = 636.1 (M+1) + .

[0915] Intermediate P-32 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-(5,5-dimethylamino)-6,6-difluoro-3-(2-chloro-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-2-(2-chloro-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-6,6-difluoro- Preparation of dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0916]

[0917] Intermediate P-32 was prepared according to the preparation method of intermediate P-27, using intermediate A-17 instead of intermediate A-14 as the starting material. 0.20 g of white solid was obtained, with a yield of 19.5%. LC-MS (APCI): m / z = 536.2 (M+1) + .

[0918] Intermediate P-33 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-(2-oxopyrrolidin-3-yl- 5,5-d2)propan-2-yl)-3-((S)-2-(2-bromo-2,2-difluoroacetylamino)-3,3-dimethylbutanoyl)-6,6-dimethyl Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide

[0919]

[0920] The following synthetic route is used

[0921]

[0922] To a 50 mL single-necked flask equipped with a magnetic stirrer, intermediate C-6 (0.42 g, 1.0 mmol) and anhydrous N,N-dimethylformamide (5 mL) were added sequentially. Stirring dissolved the mixture, 2-bromo-2,2-difluoroacetic acid (0.34 g, 2.0 mmol), N,N-diisopropylethylamine (0.26 g, 2.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.31 g, 2.0 mmol), and 1-hydroxybenzotriazole (0.27 g, 2.0 mmol) were added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 0.25 g of a white solid, with a yield of 43.2%. LC-MS (APCI): m / z = 580.2 (M+1). +.

[0923] Intermediate P-34 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-(2-oxopyrrolidin-3-yl- 5,5-d2)propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,3,3,3-pentafluoropropionylamino)butanoyl)-6,6-dimethyl Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide

[0924]

[0925] The following synthetic route is used

[0926]

[0927] To a 50 mL two-necked flask equipped with a magnetic stirrer, intermediate C-6 (0.26 g, 0.57 mmol) and anhydrous dichloromethane (3 mL) were added sequentially. Stirring was followed by the addition of triethylamine (0.17 g, 1.71 mmol), which was dissolved. The mixture was cooled to -40°C, and pentafluoropropionic anhydride (0.26 g, 0.85 mmol) in dichloromethane (2 mL) was slowly added dropwise. The mixture was stirred and allowed to react for 2 hours. The temperature was slowly raised to room temperature, and water (10 mL) and dichloromethane (10 mL) were added. The organic phase was separated and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 0.18 g of a light yellow solid (55.5% yield). LC-MS (APCI): m / z = 570.2 (M+1). + .

[0928] Intermediate P-35 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-yl-5,5-d2)propan-2-yl)-3-(O-tert-butyl-N-(2,2,2-trifluoroacetyl)-L-threonyl)-6,6-dimethyl- Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide

[0929]

[0930] The following synthetic route is used

[0931]

[0932] To a 50 mL single-necked flask equipped with a magnetic stirrer, intermediate B-2 (0.41 g, 1.0 mmol) and anhydrous N,N-dimethylformamide (5 mL) were added sequentially. Stirring dissolved the mixture, intermediate A-17 (0.21 g, 1.0 mmol), N,N-diisopropylethylamine (0.39 g, 3.0 mmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.57 g, 1.5 mmol) were added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 0.25 g of a white solid, with a yield of 42.1%. LC-MS (APCI): m / z = 564.3 (M+1) + .

[0933] Intermediate P-36 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-2-(1-methylcyclohexyl)-2-(2,2,2-trifluoroacetylamino)acetyl)-6,6-dimethyl Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide

[0934]

[0935] The following synthetic route is used

[0936]

[0937] Step 1 Synthesis of compound (1-methylcyclohexyl)methanol

[0938] Lithium aluminum hydride (2.14 g, 56.34 mmol) was added to a 100 mL dry three-necked flask equipped with a magnetic stirrer. Dry tetrahydrofuran (30 mL) was slowly added under an ice bath. After addition, the mixture was heated to room temperature and stirred for 1 hour. The mixture was then cooled to 0°C and 1-methylcyclohexane-1-carboxylic acid (4.0 g, 28.17 mmol) was added portionwise. After addition, the ice bath was removed and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Thin-layer chromatography indicated that the reaction was complete. The mixture was cooled in an ice-water bath and solid sodium sulfate decahydrate (20 g) was slowly added until no bubbles appeared. Ethyl acetate (100 mL) was added to dilute the mixture and filter. The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.73 g of a colorless oily liquid. Yield: 75.6%. LC-MS (APCI): m / z = 129.0 (M+1) + .

[0939] Step 2: Synthesis of compound 1-methylcyclohexane-1-carboxaldehyde

[0940] To the container, (1-methylcyclohexyl)methanol (2.7 g, 20.77 mmol) and dichloromethane (20 mL) were added sequentially. Dess-Martin reagent (17.6 g, 41.54 mmol) was added in portions under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature under a nitrogen atmosphere for 1 hour. Aqueous sodium sulfite solution (15 mL) and aqueous sodium bicarbonate solution (15 mL) were added and stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.2 g of a colorless oily liquid with a yield of 81.5%. LC-MS (APCI): m / z = 129.0 (M+1) + .

[0941] Step 3: Synthesis of Compound (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclohexyl)acetonitrile

[0942] 1-Methylcyclohexane-1-carbaldehyde (2 g, 17.54 mmol) and dichloromethane (20 mL) were added sequentially to the container, the temperature was lowered to 0°C, and (R)-2-amino-2-phenylethane-1-ol (2.64 g, 19.30 mmol) was added at 0°C. After the addition, the reaction was stirred at room temperature under a nitrogen atmosphere for 1 hour. Trimethylsilyl cyanide (2.6 g, 26.32 mmol) was then added dropwise, and the reaction was stirred at room temperature overnight. Water (30 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.2 g of a colorless oily liquid, with a yield of 51.4%. LC-MS (APCI): m / z = 275.1 (M+1) + .

[0943] Step 4: Synthesis of Compound (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclohexyl)acetic acid

[0944] To the container, (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclohexyl)acetonitrile (2.2 g, 8.46 mmol) and glacial acetic acid (14 mL) were added sequentially. Concentrated hydrochloric acid (32 mL) was added with stirring. After addition, the temperature was raised to 85°C and the mixture was stirred under a nitrogen atmosphere for 3 hours. After the reaction was complete, the mixture was directly dried and used in the next step. LC-MS (APCI): m / z = 294.1 (M+1) + .

[0945] Step 5: Synthesis of Compound (S)-2-amino-2-(1-methylcyclohexyl)acetic acid

[0946] To the container, (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclohexyl)acetic acid (the compound obtained in Step 4), methanol (20 mL), and palladium on carbon (300 mg, w / w 10%) were added sequentially. The atmosphere was replaced with hydrogen three times and stirred at room temperature overnight. The palladium on carbon was filtered off, the solvent was concentrated to dryness, and used directly in the next step. LC-MS (APCI): m / z = 174.1 (M+1) + .

[0947] Step 6: Synthesis of Compound (S)-2-((tert-Butyloxycarbonyl)amino)-2-(1-methylcyclohexyl)acetic acid

[0948] To the container, (S)-2-amino-2-(1-methylcyclohexyl)acetic acid (the compound obtained in step 5), dichloromethane (20 mL), N,N-diisopropylethylamine (3.25 g, 25.18 mmol), and di-tert-butyl dicarbonate (3.66 g, 16.78 mmol) were added in sequence. After the addition, the reaction was stirred at room temperature for 4 hours. Water (20 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 860 mg of the product. The yield of steps 4 to 6 was 37.4%. LC-MS (APCI): m / z = 274.1 (M+1) + .

[0949] Step 7: Synthesis of tert-butyl ((S)-2-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-(1-methylcyclohexyl)-2-oxoethyl)carbamate

[0950] To a 50 mL single-necked flask equipped with a magnetic stirrer, (S)-2-((tert-butyloxycarbonyl)amino)-2-(1-methylcyclohexyl)acetic acid (450 mg, 1.66 mmol), acetonitrile (10 mL) and N,N-dimethylformamide (20 mL) were added in sequence, stirred to dissolve, and (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)-1-nitropropane was added. 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (946 mg, 2.49 mmol), and N,N-diisopropylethylamine (857 mg, 6.64 mmol) were stirred at room temperature under a nitrogen atmosphere for 1 hour. Water (20 mL) and ethyl acetate (30 mL) were added and stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 800 mg of a colorless oily liquid in a yield of 85.6%. LC-MS (APCI): m / z = 562.0 (M+1). + .

[0951] Step 8: Synthesis of compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-2-(1-methylcyclohexyl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride

[0952] To the container, tert-butyl ((S)-2-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-(1-methylcyclohexyl)-2-oxoethyl)carbamate (800 mg, 1.42 mmol) and dichloromethane (10 mL) were added sequentially, and a 1,4-dioxane hydrochloric acid solution (10 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. After the reaction, the mixture was directly spin-dried and used in the next step.

[0953] Step 9 Synthesis of intermediate P-36

[0954] To a container were added (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-2-(1-methylcyclohexyl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (the compound obtained in step 8), methanol (10 mL), N,N-diisopropylethylamine (733 mg, 5.68 mmol) and ethyl 2,2,2-trifluoroacetate (303 mg, 2.13 mmol) in sequence. After the addition was complete, the temperature was raised to 50°C and the reaction was stirred overnight. After cooling to room temperature, saturated brine (20 mL) and ethyl acetate (20 mL) were added and stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 450 mg of a colorless oily liquid. The yield for steps 8 and 9 was 56.7%. LC-MS (APCI): m / z = 558.0 (M+1). + .

[0955] Intermediate P-37 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-2-(4-methyltetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroacetamido)acetyl)propan-2-yl Preparation of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0956]

[0957] The following synthetic route is used

[0958]

[0959] Step 1 Synthesis of compound (4-methyltetrahydro-2H-pyran-4-yl)methanol

[0960] Lithium aluminum hydride (2.14 g, 56.34 mmol) was added to a 100 mL dry three-necked flask equipped with a magnetic stirrer. Dry tetrahydrofuran (30 mL) was slowly added under an ice bath. After addition, the mixture was warmed to room temperature and stirred for 1 hour. The mixture was then cooled to 0°C and 4-methyltetrahydro-2H-pyran-4-carboxylic acid (4.1 g, 28.17 mmol) was added portionwise. After addition, the ice bath was removed and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Thin-layer chromatography indicated that the reaction was complete. Cooled in an ice-water bath, solid sodium sulfate decahydrate (20 g) was slowly added until no bubbles appeared. Ethyl acetate (100 mL) was added to dilute the mixture and filter. The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.5 g of a colorless oily liquid. Yield: 68.3%. LC-MS (APCI): m / z = 131.0 (M+1) + .

[0961] Step 2: Synthesis of compound 4-methyltetrahydro-2H-pyran-4-carbaldehyde

[0962] To the container, (4-methyltetrahydro-2H-pyran-4-yl)methanol (2.5 g, 19.2 mmol) and dichloromethane (20 mL) were added sequentially. Dess-Martin reagent (17.6 g, 41.54 mmol) was added portionwise under an ice bath. After the addition, the ice bath was removed and the reaction was stirred at room temperature under a nitrogen atmosphere for 1 hour. Aqueous sodium sulfite solution (15 mL) and aqueous sodium bicarbonate solution (15 mL) were added and stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.0 g of a colorless oily liquid with a yield of 81.5%. LC-MS (APCI): m / z = 129.0 (M+1) + .

[0963] Step 3: Synthesis of compound (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(4-methyltetrahydro-2H-pyran-4-yl)acetonitrile

[0964] 4-Methyltetrahydro-2H-pyran-4-carbaldehyde (2 g, 17.54 mmol) and dichloromethane (20 mL) were added sequentially to the container, the temperature was lowered to 0°C, and (R)-2-amino-2-phenylethane-1-ol (2.64 g, 19.30 mmol) was added at 0°C. After the addition, the reaction was stirred at room temperature under a nitrogen atmosphere for 1 hour. Trimethylsilyl cyanide (2.6 g, 26.32 mmol) was then added dropwise, and the reaction was stirred at room temperature overnight. Water (30 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 2.0 g of a colorless oily liquid, with a yield of 41.6%. LC-MS (APCI): m / z = 275.1 (M+1) + .

[0965] Step 4: Synthesis of Compound (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(4-methyltetrahydro-2H-pyran-4-yl)acetic acid

[0966] To the container, (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(4-methyltetrahydro-2H-pyran-4-yl)acetonitrile (2.0 g, 7.30 mmol) and glacial acetic acid (14 mL) were added sequentially. Concentrated hydrochloric acid (32 mL) was added with stirring. After addition, the temperature was raised to 85°C and the mixture was stirred under a nitrogen atmosphere for 3 hours. After the reaction was complete, the product was directly dried and used in the next step. LC-MS (APCI): m / z = 294.1 (M+1) + .

[0967] Step 5: Synthesis of compound (S)-2-amino-2-(4-methyltetrahydro-2H-pyran-4-yl)acetic acid

[0968] To the vessel, (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(4-methyltetrahydro-2H-pyran-4-yl)acetic acid (the compound obtained in Step 4), methanol (20 mL), and palladium on carbon (300 mg, w / w 10%) were added sequentially. The atmosphere was replaced with hydrogen three times and stirred at room temperature overnight. The palladium on carbon was filtered off, the solvent was concentrated to dryness, and used directly in the next step. LC-MS (APCI): m / z = 174.1 (M+1) + .

[0969] Step 6: Synthesis of Compound (S)-2-((tert-Butyloxycarbonyl)amino)-2-(4-methyltetrahydro-2H-pyran-4-yl)acetic acid

[0970] To the container, (S)-2-amino-2-(4-methyltetrahydro-2H-pyran-4-yl)acetic acid (the compound obtained in Step 5), dichloromethane (20 mL), N,N-diisopropylethylamine (3.25 g, 25.18 mmol), and di-tert-butyl dicarbonate (3.66 g, 16.78 mmol) were added in sequence. After the addition, the reaction was stirred at room temperature for 4 hours. Water (20 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 800 mg of the product. The yield of Steps 4 to 6 was 40.1%. LC-MS (APCI): m / z = 274.1 (M+1) + .

[0971] Step 7: Synthesis of tert-butyl ((S)-2-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-(4-methyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate

[0972] To a 50 mL single-necked flask equipped with a magnetic stirrer, (S)-2-((tert-butoxycarbonyl)amino)-2-(4-methyltetrahydro-2H-pyran-4-yl)acetic acid (450 mg, 1.66 mmol), acetonitrile (10 mL) and N,N-dimethylformamide (20 mL) were added in sequence, stirred until dissolved, and (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (700 mg, 1.72 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (946 mg, 2.49 mmol), and N,N-diisopropylethylamine (857 mg, 6.64 mmol) were stirred at room temperature under a nitrogen atmosphere for 1 hour. Water (20 mL) and ethyl acetate (30 mL) were added and stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 650 mg of a colorless oily liquid in a yield of 69.5%. LC-MS (APCI): m / z = 564.0 (M+1) + .

[0973] Step 8: Synthesis of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-2-(4-methyltetrahydro-2H-pyran-4-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride

[0974] To the container, tert-butyl ((S)-2-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-(4-methyltetrahydro-2H-pyran-4-yl)-2-oxoethyl)carbamate (600 mg, 1.42 mmol) and dichloromethane (10 mL) were added sequentially, and a 1,4-dioxane hydrochloric acid solution (10 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour, and the reaction was directly spin-dried for the next step.

[0975] Step 9 Synthesis of intermediate P-37

[0976] To the container was added (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-2-(4-methyltetrahydro-2H-pyran-4-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (the compound obtained in step 8), methanol (10 mL), N,N-diisopropylethylamine (733 mg, 5.68 mmol) and ethyl 2,2,2-trifluoroacetate (303 mg, 2.13 mmol) in sequence. After the addition was complete, the temperature was raised to 50°C and the reaction was stirred overnight. The mixture was cooled to room temperature, and saturated brine (20 mL) and ethyl acetate (20 mL) were added. The mixture was stirred for 5 minutes, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 350 mg of a colorless oily liquid. The yield for steps 8 and 9 was 44.0%. LC-MS (APCI): m / z = 560.0 (M+1). + .

[0977] Intermediate P-38 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-2-(1-methylcyclopentyl)-2-(2,2,2-trifluoroacetylamino)acetyl)-6,6-dimethyl Preparation of 3-azabicyclo[3.1.0]hexane-2-carboxamide

[0978]

[0979] The following synthetic route is used

[0980]

[0981] Step 1 Synthesis of Compound 1-Methylcyclopentane-1-carbonitrile

[0982] To a 100 mL three-necked flask equipped with a magnetic stirrer, cyclopentanecarbonitrile (3.81 g, 40 mmol) and dry tetrahydrofuran (30 mL) were added sequentially. Under a nitrogen atmosphere, the temperature was lowered to -78°C, and lithium bis(trimethylsilyl)amide (48 mL, 48 mmol, 1 M) was added dropwise. After the addition was complete, the mixture was stirred and insulated for 30 minutes. Methyl iodide (3.74 mL, 60 mmol) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. Saturated aqueous ammonium chloride (20 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and used directly in the next step.

[0983] Step 2: Synthesis of compound 1-methylcyclopentane-1-carbaldehyde

[0984] 1-Methylcyclopentane-1-carbonitrile (the compound obtained in Step 1) and dichloromethane (20 mL) were added sequentially to a container. The mixture was cooled to -20°C under a nitrogen atmosphere, and diisobutylaluminum hydride (48 mL, 72 mmol, 1.5 M) was slowly added dropwise. After addition, the mixture was stirred and maintained for 3 hours. The mixture was warmed to room temperature, saturated brine (40 mL) was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (40 mL x 2). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to afford 1.8 g of a colorless oily liquid. The yield for Steps 1 and 2 was 40.1%. LC-MS (APCI): m / z = 113.0 (M+1). + .

[0985] Step 3: Synthesis of Compound (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclopentyl)acetonitrile

[0986] 1-Methylcyclopentane-1-carbaldehyde (1.8 g, 16.1 mmol) and dichloromethane (20 mL) were added to the container in sequence, and (R)-2-amino-2-phenylethane-1-ol was added at 0°C. After the addition, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Trimethylsilyl cyanide (2.6 g, 26.32 mmol) was then added dropwise, and the reaction was stirred at room temperature overnight. Water (30 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 1.6 g of a colorless oily liquid, with a yield of 38.5%. LC-MS (APCI): m / z = 259.1 (M+1) + .

[0987] Step 4: Synthesis of Compound (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclopentyl)acetic acid

[0988] To the container, (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclopentyl)acetonitrile (1.6 g, 6.2 mmol) and glacial acetic acid (14 mL) were added in sequence. Concentrated hydrochloric acid (32 mL) was added with stirring. After the addition, the temperature was raised to 85° C. and the mixture was stirred under a nitrogen atmosphere for 3 hours. After the reaction was complete, the mixture was directly spin-dried and used in the next step. LC-MS (APCI): m / z=278.1 (M+1) + .

[0989] Step 5: Synthesis of compound (S)-2-amino-2-(1-methylcyclopentyl)acetic acid

[0990] To the container, (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclopentyl)acetic acid (the compound obtained in Step 4), methanol (20 mL), and palladium on carbon (300 mg, w / w 10%) were added sequentially. The atmosphere was replaced with hydrogen three times and stirred at room temperature overnight. The palladium on carbon was filtered off, the solvent was concentrated to dryness, and used directly in the next step. LC-MS (APCI): m / z = 158.1 (M+1) + .

[0991] Step 6: Synthesis of Compound (S)-2-((tert-butyloxycarbonyl)amino)-2-(1-methylcyclopentyl)acetic acid

[0992] To the container, (S)-2-amino-2-(1-methylcyclopentyl)acetic acid (the compound obtained in step 5), dichloromethane (20 mL), N,N-diisopropylethylamine (3.25 g, 25.18 mmol), and di-tert-butyl dicarbonate (3.66 g, 16.78 mmol) were added in sequence. After the addition, the reaction was stirred at room temperature for 4 hours. Water (20 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 510 mg of the product. The yield of steps 4 to 6 was 32.0%. LC-MS (APCI): m / z = 258.1 (M+1) + .

[0993] Step 7: Synthesis of tert-butyl ((S)-2-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-(1-methylcyclopentyl)-2-oxoethyl)carbamate

[0994] To a 50 mL single-necked flask equipped with a magnetic stirrer, (S)-2-((tert-butoxycarbonyl)amino)-2-(1-methylcyclopentyl)acetic acid (427 mg, 1.66 mmol), acetonitrile (10 mL) and N,N-dimethylformamide (20 mL) were added. After stirring until dissolved, (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)-1-nitropropane-2 ... (2-Propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (700 mg, 1.72 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (946 mg, 2.49 mmol), and N,N-diisopropylethylamine (857 mg, 6.64 mmol) were stirred at room temperature under a nitrogen atmosphere for 1 hour. Water (20 mL) and ethyl acetate (30 mL) were added and stirred for 5 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 610 mg of a colorless oily liquid in a yield of 67.0%. LC-MS (APCI): m / z = 548.2 (M+1) + .

[0995] Step 8: Synthesis of compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-2-(1-methylcyclopentyl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride

[0996] To the container, tert-butyl ((S)-2-((1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-(1-methylcyclopentyl)-2-oxoethyl)carbamate (500 mg, 0.91 mmol) and dichloromethane (10 mL) were added sequentially, and a 1,4-dioxane hydrochloric acid solution (10 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. After the reaction, the mixture was directly spin-dried and used in the next step.

[0997] Step 9 Synthesis of intermediate P-38

[0998] To the container was added (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-((S)-2-amino-2-(1-methylcyclopentyl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (the compound obtained in step 8), methanol (10 mL), N,N-diisopropylethylamine (733 mg, 5.68 mmol) and ethyl 2,2,2-trifluoroacetate (303 mg, 2.13 mmol) in sequence. After the addition was complete, the temperature was raised to 50°C and the reaction was stirred overnight. The mixture was cooled to room temperature, and saturated brine (20 mL) and ethyl acetate (20 mL) were added. The mixture was stirred for 5 minutes, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to obtain 300 mg of a colorless oily liquid. The yield for Steps 8 and 9 was 56.7%. LC-MS (APCI): m / z = 544.2 (M+1). + .

[0999] Intermediate P-39 compound (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine- 3-((S)-2-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroacetamido)acetyl)-6,6- Preparation of dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[1000]

[1001] The following synthetic route is used

[1002]

[1003] Step 1: Synthesis of compound (1R,2S,5S)-6,6-dimethyl-3-((S)-2-(tetrahydro-2H-pyran-4-yl)-2-(2,2,2-trifluoroacetyla...

Claims

1. A compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof: in, Z is NH, O or a chemical bond; R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5 to 10 membered heteroaryl, wherein the above groups are optionally substituted by one or more R; p is 0, 1, or 2; Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R a1 and R a2 is H; R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more D until fully deuterated; Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace; Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R4 is CN, CHO or -C(O)-5- to 10-membered heteroaryl; m is 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen; The condition is that the compound of formula (I) satisfies at least one of the following conditions: 1) R1 is -CF2Cl, -CF2Br or C 2-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R; 2) When R2 is -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 When it is alkylene-3 to 7-membered heterocyclic group, R2 is substituted by at least one or more R; 3) Two R on the same atom b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; 4) Two R on adjacent atoms b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; 5) When R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 When it is alkylene-5 to 10 membered heteroaryl, R1 is substituted by at least one or more R, and p is 1 or 2; 6) When two R c Together with the atoms to which they are attached, they form C 3-6 When the cycloalkyl group is 3-6 The cycloalkyl group is substituted with at least one or more halogens; 7) Two Rs c Together with the atoms to which they are attached they form a 3- to 7-membered heterocyclic group.

2. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: Z is O or a chemical bond; R1 is -CF2Cl, -CF2Br or C 2-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R; p is 0, 1, or 2; Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R a1 and R a2 is H; R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more D until fully deuterated; Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace; Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R4 is CN or CHO; m is 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

3. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: Z is O or a chemical bond; R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; p is 0, 1, or 2; Each R2 is independently C 3-6 Cycloalkyl or 3 to 7 membered heterocyclyl, wherein the above groups are substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen; R a1 and R a2 is H; R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more D until fully deuterated; Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace; Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R4 is CN or CHO; m is 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

4. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: Z is O or a chemical bond; R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R; p is 0, 1, or 2; Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R a1 and R a2 is H; R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more D until fully deuterated; Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace; Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R4 is CN or CHO; m is 1 or 2; n is 2; Two R on the same atom b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radicals are substituted.

5. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: Z is O or a chemical bond; R1 is C 1-6 Alkyl or C 1-6 Haloalkyl, wherein the above groups are optionally substituted with one or more R; p is 0, 1, or 2; Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R a1 and R a2 is H; R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more D until fully deuterated; Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace; Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R4 is CN or CHO; m is 1 or 2; n is 2; Two R on adjacent atoms b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radicals are substituted.

6. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: Z is O or a chemical bond; R1 is -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl or -C 1-6 Alkylene-5 to 10 membered heteroaryl, wherein the above groups are substituted by one or more R; p is 1 or 2; Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R a1 and R a2 is H; R3 is H, D, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more D until fully deuterated; Or, R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace; Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; R4 is CN or CHO; m is 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

7. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: Z is O or a chemical bond; R1 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; p is 0, 1, or 2; Each R2 is independently C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more groups selected from D or halogen; R a2 is H; R a1 and R3 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic group, which is c replace; Two of the R c Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl, wherein the C 3-6 The cycloalkyl group is substituted with one or more halogens; R4 is CN or CHO; m is 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; Or, R a2 and an R b Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the above groups are optionally substituted by one or more groups selected from D or halogen.

8. The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of formula (II): in, R1 is -CF2Cl, -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted by one or more D until fully deuterated; p is 0 or 1; R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; m is 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; Preferably, R1 is -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted by one or more D until fully deuterated; p is 0 or 1; R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; m is 1 or 2; n is 0, 1, 2, 3, 4, 5 or 6; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radicals are substituted.

9. The compound of claim 8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: R1 is -CF2Cl, -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted by one or more D until fully deuterated; p is 0 or 1; R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; m is 1; n is 0, 1 or 2; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radical substitution; Preferably, R1 is -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted by one or more D until fully deuterated; p is 0 or 1; R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkylene-C 3-6 Cycloalkyl or -C 0-6 Alkylene-3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Wherein each R is independently D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally substituted by one or more selected from D, halogen, C 1-6 Alkyl or C 1-6 haloalkyl radical substitution; m is 1; n is 0, 1 or 2; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or 3 to 7 membered heterocyclic group; wherein the above groups are optionally substituted by one or more selected from D, halogen or -C(O)C 1-6 Alkyl radicals are substituted.

10. The compound of claim 8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: R1 is -CF2Cl, -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted by one or more D until fully deuterated; p is 0 or 1; R2 is C 1-6 Alkyl, C 3-6 Cycloalkyl or 3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Where each R is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally replaced by one or more D or C 1-6 Alkyl substitution until complete deuteration; m is 1; n is 0, 1 or 2; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl; wherein the above groups are optionally substituted by one or more selected from D, until fully deuterated; Preferably, R1 is -CF2Br, -CF2CH3 or -CF2CF3, wherein the above groups are optionally substituted by one or more D until fully deuterated; p is 0 or 1; R2 is C 1-6 Alkyl, C 3-6 Cycloalkyl or 3 to 7 membered heterocyclyl, wherein the above groups are optionally substituted by one or more R; Where each R is independently C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 0-6 Alkylene-C 3-6 Cycloalkyl, -C 0-6 Alkylene-3 to 7 membered heterocyclic group, -OC 0-6 Alkylene-C 3-6 Cycloalkyl or -OC 0-6 Alkylene-3 to 7 membered heterocyclic group, wherein the above groups are optionally replaced by one or more D or C 1-6 Alkyl substitution until complete deuteration; m is 1; n is 0, 1 or 2; Each R b Independently H, D, C 1-6 Alkyl or C 1-6 Haloalkyl, or two R b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl; wherein the above groups are optionally substituted by one or more selected from D, until fully deuterated.

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