Spirocyclic gsdme inhibitors

Abstract

The present disclosure relates to ephrin inhibitors, in particular ephrin E inhibitors. In particular, the present disclosure relates to a compound of Formula (A), or a stereoisomer, a tautomer, a stable isotopic variant, a prodrug, or a salt thereof, or a crystalline form thereof, and uses thereof in the treatment and / or prevention of diseases associated with proinflammatory cell death. (A)

Description

Technical Field

[0001] This disclosure relates to gasdermin inhibitors, particularly gasdermin E inhibitors. Specifically, this disclosure relates to a compound having formula (A) or (I), or a stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof, or a pharmaceutically acceptable salt thereof, and its use in the treatment and / or prevention of pro-inflammatory cell death-related diseases. Background Technology

[0002] Pejvakin proteins are a newly discovered family of porogens that, upon the release of intramolecular autoinhibition, disrupt the plasma membrane and induce pyroptosis, a lytic pro-inflammatory cell death process. The human pejvakin family consists of pejvakin A (GSDMA), GSDMB, GSDMC, GSDMD, GSDME, and Pejvakin (PJVK). All GSDMAs are characterized by an effector N-terminal domain and an inhibitory C-terminal domain linked by a flexible linker. Proteolytic cleavage of the GSDMA domain linker releases the autoinhibition of the N-terminal domain, allowing it to insert into the cell membrane and oligomerize to form large transmembrane pores, serving as channels for releasing cellular contents and triggering pyroptosis.

[0003] GSDME (also known as ICERE-1 or DFNA5) was initially identified as being encoded by a candidate gene whose mutations lead to autosomal dominant nonsyndromic hearing loss. Van Laer, L., et al. (1998). Nonsyndromic Hearing impairment is associated with a mutation in DFNA5. [Non-syndromic hearing impairment] [Associated with DFNA5 mutation] Nature Genetics 20, 194-197 Later, it was discovered that GSDME has significant sequence and structural similarity to the GSDM protein. Op de Beeck, K., et al. , (2011). The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein. [The DFNA5 gene is associated with hearing loss and is involved in cancer; it encodes a...] [Novel Apoptosis-Inducing Protein] European Journal of Human Genetics: EJHG 19, 965-973）。 GSDME expression is variable in different human cells and tissues, including the brain, endometrium, placenta, and intestines. Wang, J., et al. , (2022). Molecular mechanisms and therapeutic The relevance of gasdermin E in human diseases. [Therapeutic significance] Cellular signaling 90, 110189 The molecular mechanism of GSDME activation has been revealed to depend on cleavage by caspase 3. Wang, Y., et al. , (2017). Chemotherapy drugs induce pyroptosis occurs through caspase-3 cleavage of a gasdermin. [Chemotherapy drugs cleave through caspase-3 cleavage of a gasdermin.] [3. Cleavage of dermal cytokines induces pyroptosis] Nature [Nature] 547, 99 -103). After being cleaved by caspase-3, GSDME releases its N-terminal pore-forming domain and ultimately triggers pyroptosis.

[0004] To date, there are no approved GSDME inhibitors globally. Developing a highly effective and selective GSDME inhibitor would provide a new solution to all of the aforementioned unmet medical needs. Summary of the Invention

[0005] The inventors completed this invention based on the discovery that GSDME exhibits a conserved self-inhibiting structure common to the entire GSDM family. The release of the GSDME-N pore-forming domain after cleavage by caspase-3 is a prerequisite for its membrane targeting and pyroptosis induction. A chemical compound capable of simultaneously binding both the GSDME-N and GSDME-C domains with high affinity will act as an intramolecular glue, locking GSDME in a self-inhibiting state, thereby effectively inhibiting its pyroptosis activity.

[0006] Based on this strategy, GSDME-specific inhibitors were developed. To this end, a GSDME binding assay was designed to screen for one or more such compounds. Furthermore, a domain dissociation assay was developed to monitor the release of the GSDME-N pore-forming domain from the GSDME-C inhibitory domain in vitro.

[0007] In one respect, this disclosure is characterized by compounds having formula (A), or stereoisomers, tautomers, stable isotopic variants, prodrugs or crystalline forms thereof, or pharmaceutically acceptable salts thereof:

[0008] (A)

[0009] The variables can be defined as they are anywhere in this document.

[0010] On the other hand, this disclosure is characterized by compounds having formula (I), or stereoisomers, tautomers, stable isotopic variants, prodrugs or crystalline forms thereof, or pharmaceutically acceptable salts thereof:

[0011] (I)

[0012] The variables can be defined as they are anywhere in this document.

[0013] On the other hand, the pharmaceutical composition is characterized by comprising the chemical entity described herein and one or more pharmaceutically acceptable excipients.

[0014] On the other hand, the kit is characterized by comprising a first container containing the chemical entity described herein; and optionally, a second container containing one or more other therapeutic agents; and optionally, a third container containing one or more pharmaceutically acceptable excipients for diluting or suspending the compound and / or one or more other therapeutic agents.

[0015] On the other hand, it is characterized by the use of the chemical entities described herein in the preparation of medicaments for the treatment and / or prevention of pro-inflammatory cell death-related diseases.

[0016] On the other hand, it is characterized by the chemical entities described herein, which are used in the treatment and / or prevention of pro-inflammatory cell death-related diseases.

[0017] In another aspect, a method for treating and / or preventing pro-inflammatory cell death-related diseases is characterized by administering an effective amount of the chemical entity described herein to a subject in need.

[0018] On the other hand, a method for preventing pro-inflammatory cell death in a subject in need includes administering a chemical compound to the subject to maintain intramolecular self-inhibition of the effector N-terminal domain and the inhibitory C-terminal domain of GSDME, optionally after the flexible linker connecting the two domains has been cleaved by proteolytic hydrolysis.

[0019] Other embodiments include those described in the detailed description and / or the claims.

[0020] Chemical definition

[0021] The definitions of specific functional groups and chemical terms are described in more detail below.

[0022] When listing a range of values, each value within that range and its subranges is intended to be included. For example, "C 1-6 "Alkyl" is intended to include 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.

[0023] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. C 1-6Examples of alkyl groups include 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). The term "C" is used in conjunction with alkyl groups. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may optionally be substituted with one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (CH2CH(CH3)2).

[0024] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C 2-6 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may optionally be substituted by one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0025] “C 2-6 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 The alkynyl group is preferred. C 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), and hexynyl (C6). The term "C" is used in conjunction with other alkynyl groups. 2-6"Alkyne" also includes heteroyne, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be substituted by one or more substituents, such as 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0026] “C 1-6 "alkylene" refers to "C" as defined above. 1-6 Alkyl groups are divalent groups. Specifically, "C" is a divalent group. 1-6 "Alkylene" refers to the process of removing C 1-6 The alkyl group is a divalent group formed by the other hydrogen atom of the alkyl group, and can be a substituted or unsubstituted alkylene group. In some embodiments, C 2-6 Alkylene, C 1-4 Alkylene and C 2-3 Alkylenes are particularly preferred. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Examples of substituted alkylene groups, such as those 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-), etc.

[0027] “C 0-6 "alkylene" includes chemical bonds and "C" 1-6 Alkylene. Similarly, "C 0-4 "alkylene" includes chemical bonds and "C" 1-4 Alkylene".

[0028] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0029] “C 1-6 "Halogenated alkyl" indicates that the above "C" is replaced by one or more halogen groups. 1-6Alkyl group. Examples include monohalogenated, dihalogenated, and polyhalogenated alkyl groups, including perhalogenated alkyl groups. The monohalogen substituent in this group can be an iodine, bromine, chlorine, or fluorine atom; dihalogenated and polyhalogenated substituents can be two or more identical halogen atoms or combinations of different halogens. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred. Examples of preferred halogenated alkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. The halogenated alkyl group may be substituted at any available attachment site, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] Similarly, "C 2-6 "Haloalkenyl" and "C" 2-4 "Haloalkenyl" indicates the above "C" group substituted with one or more halogen groups. 2-6 "Alkenyl" and "C" 2-4 "Alkenyl". "C" 2-6 "Halogenated alkynyl" and "C" 2-4 "Haloacetylenic" indicates that the above "C" is replaced by one or more halogen groups. 2-6 "Alkyne" and "C" 2-4 "Alkyne group".

[0031] “C 1-6 "Alkoxy" refers to -OC 1-6 Alkyl groups, while "C 1-4 "Alkoxy" refers to -OC 1-4 Alkyl groups (e.g., -OCH3). "C 1-6 "Haloalkoxy" refers to -OC 1-6 Haloalkyl groups, while "C 1-4 "Haloalkoxy" refers to -OC 1-4 Halogenated alkyl groups (e.g., -OCF3).

[0032] “C 3-20 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 20 cyclic carbon atoms and zero heteroatoms, which may be multiple fused rings and / or bridging rings. The term cycloalkyl may include one or more double or triple bonds, as long as it is non-aromatic. In some embodiments, C 3-10 Cycloalkyl groups are particularly preferred. In some embodiments, C 3-6 Cycloalkyl groups are particularly preferred. In some embodiments, C 3-8 Cycloalkyl groups are particularly preferred. In some embodiments, C 3-6 Cycloalkyl groups are particularly preferred. In some embodiments, C 5-6Cycloalkyl groups are particularly preferred. In some embodiments, C 4-6 Cycloalkyl groups are particularly preferred. In some embodiments, C 3-5 Cycloalkyl groups are particularly preferred. In some embodiments, C 3-4 Cycloalkyl groups are particularly preferred. Cycloalkyl groups also include ring systems fused with one or more aryl or heteroaryl groups as described herein, wherein the attachment point is on the cycloalkyl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the cycloalkyl system. Cycloalkyl groups may be substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0033] Exemplary cycloalkyl groups 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), cycloheptanetrienyl (C7), etc. Examples of cycloalkyl groups further include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl group may comprise multiple fused rings and / or bridging rings. Non-limiting examples of fused / bridging cycloalkyl groups include C... 4-8 Bridging bicycloalkyl groups include, for example, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, etc. Cycloalkyl groups also include spirocyclic (e.g., spirobicyclo, where the two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, spiro[5.7]tridecyl, etc.

[0034] "4- to 20-membered heterocyclic group" refers to a group having a cyclic carbon atom and 1 to 8 cyclic heteroatoms in a non-aromatic ring system of 4 to 20 members, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, or in oxidized forms such as S(O) and S(O)₂. The ring system can be multiple fused rings and / or bridging rings. In heterocyclic groups containing one or more nitrogen atoms, the attachment point can be a carbon atom or a nitrogen atom, provided the valence allows. The term heterocyclic group can include one or more double or triple bonds, provided they are non-aromatic. In some embodiments, 4- to 10-membered heterocyclic groups are preferred, which are groups having a cyclic carbon atom and 1 to 5 cyclic heteroatoms in a non-aromatic ring system of 4 to 10 members. In some embodiments, 5- to 10-membered heterocyclic groups are preferred, which are groups having a cyclic carbon atom and 1 to 5 cyclic heteroatoms in a non-aromatic ring system of 5 to 10 members. In some embodiments, 5- to 7-membered heterocyclic groups are preferred, which are groups having a cyclic carbon atom and 1 to 5 cyclic heteroatoms in a 5- to 7-membered non-aromatic ring system. In some embodiments, 5- to 6-membered heterocyclic groups are more preferred, which are groups having a cyclic carbon atom and 1 to 3 cyclic heteroatoms in a 5- to 6-membered non-aromatic ring system. In some embodiments, 4- to 6-membered heterocyclic groups are preferred, which are groups having a cyclic carbon atom and 1 to 3 cyclic heteroatoms in a 4- to 6-membered non-aromatic ring system. Heterocyclic groups also include ring systems in which the heterocyclic group is fused with one or more cycloalkyl groups, wherein the attachment point is on the cycloalkyl ring; or in which case the heterocyclic group is fused with one or more aryl or heteroaryl groups, wherein the attachment point is on the heterocyclic ring; and in this case, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, ethylene oxide, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azahexacyclic butyl, oxacyclic butyl, and thiocyclic butyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolane-2-one, oxathiofuranyl, dithiofuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptyl, and thioheptyl.Exemplary 5-membered heterocyclic groups fused to a C6 aryl group (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to a C6 aryl group (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclic group may be substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] Specific examples of preferred heterocyclic groups include: pyrrolinyl, imidazoalkyl, pyrazolyl, tetrahydropyranyl, dihydropyranyl, dihydrofuranyl, thiazoalkyl, dihydrothiazoyl, 2,3-dihydrobenzo[1,4]dioxacyclopentene, indolinyl, isoindolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, isodihydrobenzopyranyl, dihydrobenzopyranyl, 1,2-dihydroisoquinoline, 1, 2,3,4-Tetrahydroisoquinoline, 1,2,3,4-Tetrahydroquinoline, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorene, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinoline, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzo[l,4]dioxacyclopentenyl, 2,3-dihydro-lH-lk'-benzo[ d] Isothiazol-6-yl, 2,3-dibenzo[l,4]dioxacyclohexenyl, dihydrobenzofuran, 2-oxoaziridin-1-yl, 2-oxoaziridane-1-yl, 2-oxopyrrolidone-1-yl, 2-oxopiperidin-1-yl, 2-oxoaziridane-1-yl, 2-oxoaziridane-1-yl, 2-oxoaziridane-1-yl, 2-oxoaziridane-1-yl, 2-oxoaziridane-1-yl, 2-oxoaziridane-1-yl Cyclodecane-1-yl, aziridinium, aziridine, pyrrolidinyl, piperidine, aziridine-heptane, aziridine-octane, aziridine-nonane, aziridine-decane, piperidinyl, piperazinyl, morpholinyl, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.4]nonane, diazaspiro[4.5]decane and diazaspiro[5.5]undecane.

[0036] Other examples of heterocyclic groups include piperazine, pyrrolyl, dioxane, morpholinyl, tetrahydrofuranyl, etc. Heterocyclic groups can include multiple fused rings and bridging rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopentadien[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3 -Azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2-oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, etc. Heterocyclic groups also include spirocyclic rings (e.g., spirobicyclo, where the two rings are connected by only one atom). Non-limiting examples of spirocyclic heterocyclic groups include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 2,5-diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxaspiro[3.5]decyl, and others. Spiro[2.2]pentyl, 4-oxaspiro[2.5]octyl, 1-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl, etc. As used herein, the term "saturated" means that only single bonds exist between the constituent ring atoms, and other available valence states are occupied by hydrogen and / or other substituents as defined herein.

[0037] “C 6-10"Aryl" refers to a group in a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having 6 or 10 π electrons shared in a ring array). In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C... 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl groups also include ring systems in which the aforementioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the attachment point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group can be substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] "5- to 10-membered heteroaryl" refers to a group having a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) with a ring carbon atom 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 attachment point can be a carbon atom or a nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may contain one or more heteroatoms in one or two rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the attachment point is on the heteroaryl ring. In this case, the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 9-membered heteroaryl groups are particularly preferred, which are groups having a 5- to 9-membered monocyclic or bicyclic 4n+2 aromatic ring system with a ring carbon atom and 1-4 ring heteroatoms. In some embodiments, 5- to 6-membered heteroaryl groups are particularly preferred, which are groups having a 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms. In some embodiments, 5-membered heteroaryl groups are particularly preferred, which are groups having a 5-membered monocyclic or bicyclic 4n+2 aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiopheneyl. 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 (e.g., 1,2,4-oxadiazolyl), and thiazolyl. 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, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indoleyl, isoindoleyl, indazoleyl, benzotriazolyl, benzothiopheneyl, isobenzothiopheneyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzooxazolyl, benzoisooxazolyl, benzooxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indoleazinyl, and purineyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cyclophosphinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0039] Specific examples of preferred heteroaryl groups include: pyrrole, imidazolyl, pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), pyranyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl), thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl).

[0040] Further examples of heteroaryl groups include thiophene, pyridinyl, furanyl, oxazolyl, oxadiazolyl, pyrroleyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothiophene, benzooxadiazolyl, benzofuranyl, benzoimidazolyl, benzotriazolyl, cenylyl, indazole, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, purinyl, thiophene-pyridinyl, pyrido[2,3-] d ]pyrimidinyl, pyrrolo[2,3- b ]pyridyl, quinazolinyl, quinolinyl, thiophene[2,3- c ]pyridyl, pyrazolo[3,4- b ]pyridyl, pyrazolo[3,4- c ]pyridyl, pyrazolo[4,3- c ]pyridyl, pyrazolo[4,3- b ]pyridyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[ b [1,4] Dioxinyl, Benzo[ d [1,3]dioxacyclopentenyl, benzo[d]thiazolyl, 2,3-dihydrobenzofuran, tetrahydroquinolinyl, 2,3-dihydrobenzo[ b [1,4]oxathiinyl, indololinyl, isoindololinyl, and others. In some embodiments, the heteroaryl group is selected from thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, isoindololinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0041] As used herein, when a ring is described as “aromatic,” it means that the ring has a continuous, delocalized π-electron system. Typically, the number of out-of-plane π electrons follows Hückel’s rule (4n+2).

[0042] "Oxyto" means =O.

[0043] For the avoidance of doubt, and unless otherwise stated, for ring and cyclic groups (e.g., aryl, heteroaryl, heterocyclic, heterocyclic alkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) containing ring atoms sufficient to form bicyclic or higher-order ring systems (e.g., tricyclic, polycyclic systems), it should be understood that such ring and cyclic groups include those having fused rings, including those where the fusion point is located on (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero-atom bridge (e.g., ...). (ii) On a single ring atom (spirofused ring system) (e.g., , or ), or (iii) on a continuous array of ring atoms (with all bridge lengths > 0 in a bridging ring system) (e.g., , or ) rings and cyclic groups.

[0044] Furthermore, the atoms constituting the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include… 13 C and 14 C.

[0045] Furthermore, the compounds generally or specifically disclosed herein are intended to include all tautomer forms. Therefore, by way of example, compounds containing the following moiety are considered: It covers tautomer forms containing the following parts: Similarly, the pyridyl or pyrimidinyl moiety described as optionally hydroxylated covers the pyridinone or pyrimidinone tautomer forms.

[0046] An "amino protecting group" is used to prevent the amino group from undergoing undesirable reactions. The selection of appropriate protecting groups and suitable protecting and deprotecting conditions for specific functional groups is well known in the art. For example, many protecting groups and their introduction and removal are described in TW Greene and PGM Wuts, *Protective Groups in Organic Synthesis*, 2nd ed., Wiley, New York, 1991, and the references cited therein. Exemplary amino protecting agents are selected from Cbz, Boc, Fmoc, Alloc, and Teoc.

[0047] The alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0048] Exemplary substituents on carbon atoms include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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 aa3. -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)(NR bb )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, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0049] Or two hydrogen atom on a carbon atom are surrounded by =O, =S, =NN(R) groups. 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 Substitute;

[0050] Each R aa Independently selected from alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. aa The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0051] Each R bb 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(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, ynyl, 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, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0052] Each R cc Independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0053] Each R ddare 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, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently marked by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal R groups dd Substituents can combine to form =O or =S;

[0054] Each R ee Independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocyclic, and heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently separated by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0055] Each R ff Independently selected from hydrogen, alkyl, haloalkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R groups. ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution;

[0056] Each R gg Independently selected from halogens, -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 groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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 groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl group), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -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 groups, -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 group, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2、-OP(=O)(C 1-6 Alkyl)2、-OP(=O)(OC1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2- C6 alkenyl, C 2- C6 ynyl group, C 3- C7 carbon cyclogroup, C 6- C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two ethryl groups gg Substituents can combine to form =O or =S; where X - It is an anti-charge ion.

[0057] Exemplary substituents on the nitrogen atom include, but are not limited to, hydrogen, -OH, and -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、-SO2R cc -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, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R atoms attached to a nitrogen atom. cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently surrounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc and R dd As described in this article.

[0058] Other definitions

[0059] To facilitate understanding of the disclosures set forth herein, many other terms are defined below. Generally, the nomenclature used herein, and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein, are well-known and commonly used in the art; for example, nomenclature can be generated using software such as ChemDraw. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Every patent, application, published application, and other publication mentioned throughout this specification and its appendices is incorporated herein by reference in its entirety.

[0060] The terms “comprising,” “including,” “having,” or “containing” mean “including, but not limited to,” and “consisting of,” for example, a composition “comprising” X may consist entirely of X, or may include other items, such as X+Y. Furthermore, whenever “comprising” or other open-ended terms are used in the embodiments, it should be understood that the same embodiments may be claimed more narrowly using the intermediate term “substantially constitutes” or the closed term “consisting of.” As used herein, the articles “a” and “an” refer to one or more (e.g., at least one) grammatical objects defined by that article. Unless the context clearly indicates otherwise, the term “or” as used herein means the term “and / or” and may be used interchangeably with the term “and / or.”

[0061] As used herein, the term "GSDME inhibitor" refers to any compound that can inhibit the dissociation of the effector N-terminal domain from the inhibitory C-terminal domain of GSDME, thereby causing intramolecular self-inhibition of the effector N-terminal domain, which is capable of inserting into the cell membrane and oligomerizing to form large transmembrane pores, serving as channels for releasing cellular contents and triggering pyroptosis.

[0062] In the context of treating a disease, disorder, or condition, the term "treatment" means including relieving or eliminating a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or slowing the progression, spread, or worsening of a disease, disorder, or condition or one or more symptoms thereof. Typically, the beneficial effects obtained by a subject from a treatment do not completely cure the disease, disorder, or condition. In some embodiments, the term "treatment" includes curing a viral disorder, disease, or condition using virological methods; reducing viral shedding; reducing viral RNA load (e.g., by PCR measurement); shortening hospital stay; shortening the time spent in infectious disease wards and / or intensive care units; or slowing the progression / development of respiratory (or other severe) symptoms, including cessation of breathing.

[0063] “Cancer treatment” means one or more of the following effects: (1) inhibiting tumor growth to some extent, including (i) slowing and (ii) completely stopping growth; (2) reducing the number of tumor cells; (3) maintaining tumor size; (4) reducing tumor size; (5) inhibiting tumor cell infiltration into peripheral organs, including (i) reducing, (ii) slowing or (iii) completely stopping; (6) inhibiting metastasis, including (i) reducing, (ii) slowing or (iii) completely stopping; (7) enhancing the antitumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing tumor growth, (iv) reducing, slowing or stopping invasion, and / or (8) alleviating to some extent the severity or number of one or more symptoms associated with the disorder.

[0064] The term "therapeuticly effective amount" refers to the amount of a drug or other agent (e.g., the compounds disclosed herein) that will elicit (e.g., a biological and / or medical response in a tissue, system, animal, or human (e.g., a subject or patient) as desired by the investigator or clinician. Furthermore, the term "therapeuticly effective amount" means any amount that, compared to a corresponding subject (e.g., a patient) who did not receive that amount, is sufficient to reduce the rate of progression of the treated condition or disorder, halt its development, or alleviate one or more of its symptoms to a certain extent. Therapeuticly effective amounts will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated. Additionally, therapeutically effective amounts may be administered in one or more applications, doses, or administrations, and are not intended to be limited to a particular formulation or route of administration.

[0065] As used herein, the interchangeable term "subject or patient" refers to an animal, including but not limited to primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. In some embodiments, a subject is a person to be treated by the methods and compositions disclosed herein. In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) who requires such treatment (e.g., by means of biopsy, endoscopy, or other conventional methods known in the art).

[0066] As used herein, the term "cancer" refers to a physiological condition in a subject characterized by unregulated or disordered cell growth or death. The term "cancer" includes solid tumors and hematogenous tumors, whether malignant or benign.

[0067] As used herein, the term “acceptable” in relation to a formulation, composition, or ingredient means that it does not have a lasting adverse effect on the overall health of the subject being treated.

[0068] "API" refers to active pharmaceutical ingredient.

[0069] The term "excipient" or "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is "pharmaceuticalally acceptable" in the sense that it is compatible with other components of a pharmaceutical formulation and is suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy [Remington: Pharmaceutical Science and Practice], 21st edition; Lippincott Williams and Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; Edited by Rowe et al.; The Pharmaceutical Press and American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; Edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation [Pre- and Pre-Formulation Drugs], 2nd Edition; edited by Gibson; CRC Press LLC: Boca Raton, FL, 2009.

[0070] The term "pharmaceutically acceptable salt" refers to a compound formulation that does not cause significant irritation to the body upon administration and does not eliminate the biological activity and properties of the compound. In some cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In other cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acidic groups with a base to form a salt, such as ammonium salts, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and organic bases (e.g., dicyclohexylamine, etc.). NSalts of methyl-D-glucosamine, tris(hydroxymethyl)methylamine, and salts of amino acids such as arginine and lysine; or obtained by other methods previously determined. There are no particular limitations on pharmacologically acceptable salts, provided they can be used in medicine. Examples of salts formed by the compounds described herein with bases include: salts of these compounds with inorganic bases (such as sodium, potassium, magnesium, calcium, and aluminum); salts of these compounds with organic bases (such as methylamine, ethylamine, and ethanolamine); salts of these compounds with basic amino acids (such as lysine and ornithine); and ammonium salts. These salts can be acid addition salts, particularly exemplified by acid addition salts with the following acids: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0071] The compounds described herein may contain one or more asymmetric centers, thereby existing in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.

[0072] In addition, prodrugs are also included within the scope of this disclosure. As used herein, the term "prodrug" refers to a compound that is converted in vivo into its active form, which has medical effects, through hydrolysis, for example, in the blood. T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; 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) describe pharmaceutically acceptable prodrugs.

[0073] A prodrug is any covalently bonded carrier that, upon administration to a patient, releases a compound having formula (A) or (I) in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that these modifications can be performed by conventional methods or cleaved in vivo to produce the parent compound. Prodrugs include, for example, compounds disclosed herein, in which a hydroxyl, amino, or thiol group is bonded to any group that can be cleaved in vivo to form a hydroxyl, amino, or thiol group. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of compounds having alcohol, thiol, and amine functional groups of formula (A) or (I). Furthermore, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, etc., can be used. The ester itself may be active and / or hydrolyzable under in vivo conditions. Suitable pharmaceutically acceptable hydrolyzable in vivo ester groups include those groups that readily decompose in vivo to release the parent acid or its salts.

[0074] This document also discloses all suitable isotopic derivatives of the compounds disclosed herein. An isotopic derivative of the compounds disclosed herein is defined as one in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that found in nature. Examples of isotopes that can be listed as compounds disclosed herein include hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine isotopes, as follows: 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S and 36 Cl. Certain isotopic derivatives of the compounds disclosed in this article (such as 3 H and 14 Radioactive isotopes of C are also included, and can be used in tissue distribution experiments of drugs and substrates. Tritium (i.e., radioactive isotopes of C) 3 H) and carbon-14 (i.e., ... 14 C) is easier to prepare and detect, and is the first choice for isotopes. Additionally, isotopes such as deuterium (i.e., 2 H) Substitution is advantageous in some therapies due to its good metabolic stability (e.g., prolonged in vivo half-life or reduced dose), and therefore may be preferred in some cases. Isotopic derivatives of the compounds disclosed herein can be prepared by conventional procedures, such as by descriptive methods or by preparations described in the examples below, using appropriate isotopic derivatives with suitable reagents. The term "stable isotope" refers to an isotope that is stable in nature.

[0075] The term "pharmaceutical composition" refers to a mixture of the compound described herein with other chemical components (collectively referred to herein as "excipients," such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners). Pharmaceutical compositions facilitate the administration of the compound to a living organism. Various techniques for administering compounds exist in the art, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0076] Detailed descriptions of one or more embodiments disclosed herein are set forth below. Other features and advantages of the invention will be apparent from the specification and claims. Detailed Implementation

[0077] This disclosure relates to inhibitors of dermaclopramide (particularly dermaclopramide E). Specifically, this disclosure relates to compounds having formula (A) or (I), or stereoisomers, tautomers, stable isotope variants, prodrugs or crystalline forms thereof, or pharmaceutically acceptable salts thereof, and their use in the treatment and / or prevention of pro-inflammatory cell death-related diseases.

[0078] Detailed description of the embodiments

[0079] In one respect, this disclosure provides compounds having formula (A):

[0080] (A)

[0081] in

[0082] Indicates a single bond or a double bond;

[0083] Ring A is selected from C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups;

[0084] T is selected from bond, O, S, S(O), S(O)2, NR T2 CHR T2 Or CH2CH2;

[0085] R T1 Selected from H, D, CN, -C 1-4 Alkylene-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic groups;

[0086] R T2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0087] When T is NR T2 At that time, R T1 R T2 Together with N, it forms 4- to 10-membered heterocyclic groups; when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-8 Cycloalkyl, or 4- to 10-membered heterocyclic groups; and when T is CHR T2 At that time, R T2 and R N Connection forms C 1-4 Alkylene;

[0088] EF is selected from NR E C(O), NR E -C(S), O-CH2, NR E -CH2 or CH=CH;

[0089] R E Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)R a ;

[0090] G is selected from O, NH, NC 1-6 Alkyl, CH2, CHD, CD2, CHC 1-6 Alkyl, or C(C) 1-6 Alkyl)2;

[0091] X is selected from N or CR x ;

[0092] R x Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0093] Q is selected from O, S, CH2, CHD, CD2, C(O) or CH2CH2;

[0094] W1 and W2 are independently selected from the bond, CH2, CHD, or CD2;

[0095] W3 is selected from CH2, CHD, CD2, and CHC. 1-6 Alkyl or C(O);

[0096] X1 is selected from N or CR 2a ;

[0097] X2 is selected from N or CR 4a ;

[0098] R1 is selected from H, D, CN, and C(O)R. a C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 3-20 Cycloalkyl, 4- to 20-membered heterocyclic groups, C 6-10Aryl or 5- to 10-membered heteroaryl groups, each optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace;

[0099] R 1s Selected from H, D, CN, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a 、S(NH)(O)R a OP(O)(OH)2, NHS(O)R a NHS(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0100] Or R1, R E Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted;

[0101] Or R1, R 2a Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted;

[0102] R 1a Selected from H, D, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, NHC(O)R a ;

[0103] R2 and R 2a Independently selected from H, D, or halogenated;

[0104] R3 is selected from H, D, halogen, OR a NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or C(O)NH2;

[0105] R4 is selected from H, D, halogen, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0106] R 4a Selected from H, D, halogenated, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0107] Or R4, R 4a Together with the atoms they are attached to, they form phenyl or 5- to 6-membered heteroaryl groups;

[0108] R5 is selected from H, D, halogenated, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 5- to 6-membered heterocyclic groups;

[0109] p = 0, 1, 2, 3 or 4;

[0110] R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0111] q = 1, 2, or 3;

[0112] or R T1 R6, together with the atoms they are attached to, form C. 5-8 Cycloalkyl, 5- to 8-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl;

[0113] L is selected from either a key or C. 1-6 Alkylene;

[0114] R N Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0115] Y is selected from C(O), S(O) or S(O)2;

[0116] R m Selected from H, D, halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -C 1-4 Alkylene-NR b R c ;

[0117] Rn Selected from H, D, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or halogenated;

[0118] or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups;

[0119] R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 aryl, or -C 0-4 Alkylene-5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic groups; each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0120] Optional, R T1 and R N Together they form C(R)(R) S3 )-CH(R S4 ), phenylene or 5- to 6-membered heteroaryl;

[0121] R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, -C 1-6 Alkylene-halogenated, -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c-C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl;

[0122] R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0123] R s4 Selected from H, D, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl;

[0124] Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace;

[0125] R ss Selected from H, D, or halogenated;

[0126] or R s3 R s4 Together with the atoms they are attached to, they form C 5-8 Cycloalkyl or 5- to 8-membered heterocyclic groups;

[0127] Further, optionally, when T is NR T2 At that time, R T2 Together with R, it forms CH2C(R) S1 (R) S2 Z3;

[0128] Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2;

[0129] R S1 and R S2 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0130] RS4 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0131] And choose any place, It can be replaced by H, and R6 is CR. p =CR q YR Y ;

[0132] R p and R q Independently selected from H, D, CN, or halogenated;

[0133] or R p and R q They connect together to form additional bonds;

[0134] R Y Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0135] The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration;

[0136] Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

[0137] In another aspect, this disclosure provides compounds having formula (I):

[0138] (I)

[0139] in

[0140] Indicates a single bond or a double bond;

[0141] T is selected from bond, O, S, S(O), S(O)2, NR T2 CHR T2 Or CH2CH2;

[0142] R T1 Selected from H, D, CN, -C 1-4 Alkylene-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic groups;

[0143] R T2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0144] When T is NR T2 At that time, R T1 R T2 Together with N, it forms 4- to 10-membered heterocyclic groups; and when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-8 Cycloalkyl groups, or 4- to 10-membered heterocyclic groups;

[0145] EF is selected from NR E C(O), NR E -C(S), O-CH2, NR E -CH2 or CH=CH;

[0146] R E Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)R a ;

[0147] G is selected from O, NH, NC 1-6 Alkyl, CH2, CHD, CD2, CHC 1-6 Alkyl, or C(C) 1-6 Alkyl)2;

[0148] X is selected from N or CR x ;

[0149] R x Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0150] Q is selected from O, S, CH2, CHD, CD2, C(O) or CH2CH2;

[0151] W1 and W2 are independently selected from the bond, CH2, CHD, or CD2;

[0152] W3 is selected from CH2, CHD, CD2, and CHC. 1-6 Alkyl or C(O);

[0153] Z1 is selected from N or CR7;

[0154] Z2 is selected from N or CR8;

[0155] R1 is selected from H, D, CN, and C(O)R. a C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6Haloalkyl, -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace;

[0156] R 1s Selected from H, D, CN, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a 、S(NH)(O)R a OP(O)(OH)2, NHS(O)R a NHS(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0157] Or R1, R E Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted;

[0158] Or R1, R 2a Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted;

[0159] R 1a Selected from H, D, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, NHC(O)R a ;

[0160] R2, R 2a R7 is independently selected from H, D, or halogenated;

[0161] R3 is selected from H, D, halogen, OR a NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or C(O)NH2;

[0162] R4 is selected from H, D, halogenated, or CN;

[0163] R 4a Selected from H, D, halogenated, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0164] Or R4, R 4a Together with the atoms they are attached to, they form phenyl or 5- to 6-membered heteroaryl groups;

[0165] R5 is selected from H, D, halogenated, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 5- to 6-membered heterocyclic groups;

[0166] p = 0, 1, 2, 3 or 4;

[0167] R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0168] R8 is selected from H or D;

[0169] or R T1 R8 and the atoms they are attached to form C. 5-8 Cycloalkyl, 5- to 8-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl;

[0170] R N Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0171] Y is selected from C(O), S(O) or S(O)2;

[0172] R m Selected from H, D, halogenated, C 1-6 Alkyl, C1-6 Halogenated alkyl or -C 1-4 Alkylene-NR b R c ;

[0173] R n Selected from H, D, CN, or halogenated;

[0174] or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups;

[0175] R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 aryl, or -C 0-4 Alkylene-5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic groups; each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0176] Optional, R T1 and R N Together they form C(R)(R) S3 )-CH(R S4 ), phenylene or 5- to 6-membered heteroaryl;

[0177] R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, -C 1-6 Alkylene-halogenated, -C 1-6 Alkylene-ORa -C 1-6 Alkylene-NR b R c -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl;

[0178] R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0179] R s4 Selected from H, D, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl;

[0180] Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace;

[0181] R ss Selected from H, D, or halogenated;

[0182] or R s3 R s4 Together with the atoms they are attached to, they form C 5-8 Cycloalkyl or 5- to 8-membered heterocyclic groups;

[0183] Further, optionally, when T is NR T2 At that time, R T2 Together with R, it forms CH2C(R) S1 (R) S2 Z3;

[0184] Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2;

[0185] R S1 and R S2 Independently selected from H, D, halogenated, C 1-6Alkyl or C 1-6 Halogenated alkyl groups;

[0186] R S4 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0187] And choose any place, It can be replaced by H, and R6 is CR. p =CR q YR Y ;

[0188] R p and R q Independently selected from H, D, CN, or halogenated;

[0189] or R p and R q They connect together to form additional bonds;

[0190] R Y Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0191] The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration;

[0192] Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

[0193]

[0194] In some embodiments, Indicates a single bond; in some embodiments, It represents a double bond.

[0195] Ring A

[0196] In some embodiments, ring A is C 3-8 Cycloalkyl; in some embodiments, ring A is a 4- to 10-membered heterocyclic group; in some embodiments, ring A is a C 6-10 Aryl; in some embodiments, ring A is a 5- to 10-membered heteroaryl group.

[0197] T, R T1 R T2

[0198] In some embodiments, T is a key; in some embodiments, T is O; in some embodiments, T is S; in some embodiments, T is S(O); in some embodiments, T is S(O)2; in some embodiments, T is NR. T2In some embodiments, T is CHR T2 In some embodiments, T is CH2CH2.

[0199] In some embodiments, R T1 It is H; in some embodiments, R T1 It is D; in some embodiments, R T1 It is CN; in some embodiments, R T1 It is -C 1-4 Alkylene-NR b R c In some embodiments, R T1 It is C 1-6 Alkyl; in some embodiments, R T1 It is C 1-6 Halogenated alkyl; in some embodiments, R T1 It is C 3-8 cycloalkyl; in some embodiments, R T1 It is a heterocyclic group ranging from 4 to 10 members.

[0200] In some embodiments, R T2 It is H; in some embodiments, R T2 It is D; in some embodiments, R T2 It is C 1-6 Alkyl; in some embodiments, R T2 It is C 1-6 Halogenated alkyl groups.

[0201] In some embodiments, when T is NR T2 At that time, R T1 R T2 Together with N, it forms a 4- to 10-membered heterocyclic group; in some embodiments, when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-8 Cycloalkyl; in some embodiments, when T is CHR T2 At that time, R T1 R T2 Together with CH, it forms a 4- to 10-membered heterocyclic group; in some embodiments, when T is CHR T2 At that time, R T2 and R N Connection forms C 1-4 Alkylene.

[0202] E, F, G, X, Q, W1, W2, W3

[0203] In some embodiments, EF is NR E C(O); in some embodiments, EF is NR E-C(S); In some embodiments, EF is O-CH2; In some embodiments, EF is NR E -CH2; in some embodiments, EF is CH=CH.

[0204] In some embodiments, R E It is H; in some embodiments, R E It is C 1-6 Alkyl; in some embodiments, R E It is C 1-6 Halogenated alkyl; in some embodiments, R E It is C(O)R a .

[0205] In some embodiments, G is O; in some embodiments, G is NH; in some embodiments, G is NC. 1-6 Alkyl group; in some embodiments, G is CH2; in some embodiments, G is CHD; in some embodiments, G is CD2; in some embodiments, G is CHC 1-6 Alkyl; in some embodiments, G is C(C) 1-6 Alkyl)2.

[0206] In some embodiments, X is N; in some embodiments, X is CR. x .

[0207] In some embodiments, R x It is H; in some embodiments, R x It is D; in some embodiments, R x It is C 1-6 Alkyl; in some embodiments, R x It is C 1-6 Halogenated alkyl groups.

[0208] In some embodiments, Q is O; in some embodiments, Q is S; in some embodiments, Q is CH2; in some embodiments, Q is CHD; in some embodiments, Q is CD2; in some embodiments, Q is C(O); in some embodiments, Q is CH2CH2.

[0209] In some embodiments, W1 is a key; in some embodiments, W1 is CH2; in some embodiments, W1 is CHD; in some embodiments, W1 is CD2.

[0210] In some embodiments, W2 is a key; in some embodiments, W2 is CH2; in some embodiments, W2 is CHD; in some embodiments, W2 is CD2.

[0211] In some embodiments, W3 is CH2; in some embodiments, W3 is CHD; in some embodiments, W3 is CD2; in some embodiments, W3 is CHC. 1-6 Alkyl group; in some embodiments, W3 is C(O).

[0212] X1, X2

[0213] In some embodiments, X1 is N; in other embodiments, X1 is CR. 2a .

[0214] In some embodiments, X2 is N; in some embodiments, X2 is CR. 4a .

[0215] Z1, Z2

[0216] In some embodiments, Z1 is N; in some embodiments, Z1 is CR7.

[0217] In some embodiments, Z2 is N; in some embodiments, Z2 is CR8.

[0218] R1, R 1s R 1a R2, R 2a R3, R4, R 4a R5, R6, R7, R8

[0219] In some embodiments, R1 is H; in some embodiments, R1 is D; in some embodiments, R1 is CN; in some embodiments, R1 is C(O)R a In some embodiments, R1 is C(O)OR a In some embodiments, R1 is C(O)NR b R c In some embodiments, R1 is C 1-6 Alkyl; in some embodiments, R1 is C 1-6 Halogenated alkyl; in some embodiments, R1 is -C 1-6 Alkylene-S(O)2R a In some embodiments, R1 is -C 1-6 Alkylene-OR a In some embodiments, R1 is -C 1-6 Alkylene-NR b R c In some embodiments, R1 is C 3-20 cycloalkyl groups, such as C 3-8 Cycloalkyl; in some embodiments, R1 is a 4- to 20-membered heterocyclic group, such as a 4- to 10-membered heterocyclic group; in some embodiments, R1 is C 6-10Aryl; in some embodiments, R1 is a 5- to 10-membered heteroaryl group; in some embodiments, each of the above groups is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace.

[0220] In some embodiments, R 1s It is H; in some embodiments, R 1s It is D; in some embodiments, R 1s It is CN; in some embodiments, R 1s It is halogenated; in some embodiments, R 1s It is OH; in some embodiments, R 1s It is C 1-6 Alkoxy; in some embodiments, R 1s It is C 1-6 Halogenated alkoxy groups; in some embodiments, R 1s It is NH2; in some embodiments, R 1s It is NHC 1-6 Alkyl; in some embodiments, R 1s It is N(C) 1-6 Alkyl)2; in some embodiments, R 1s It is C(O)R a In some embodiments, R 1s It is S(O)R a In some embodiments, R 1s is S(O)2R a In some embodiments, R 1s It is NHS(O)R a In some embodiments, R 1s It is S(NH)(O)R a In some embodiments, R 1s It is OP(O)(OH)2; in some embodiments, R 1s It is NHS(O)2R a In some embodiments, R 1s It is C 1-6 Alkyl; in some embodiments, R 1s It is C 1-6 Halogenated alkyl; in some embodiments, R 1s It is C 3-8 cycloalkyl; in some embodiments, R 1s It is a 4- to 10-membered heterocyclic group; in some embodiments, R 1s It is C 6-10 Aryl; in some embodiments, R 1s It is a 5- to 10-membered heteroaryl group; in some embodiments, each group is optionally halogenated or C-substituted. 1-6 Alkyl or C 1-6Halogenated alkyl substitution.

[0221] In some embodiments, R1, R E Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted.

[0222] In some embodiments, R1, R 2a Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted.

[0223] In some embodiments, R 1a It is H; in some embodiments, R 1a It is D; in some embodiments, R 1a It is OH; in some embodiments, R 1a It is C 1-6 Alkyl; in some embodiments, R 1a It is C 1-6 Halogenated alkyl; in some embodiments, R 1a It is NHC(O)R a .

[0224] In some embodiments, R2 is H; in some embodiments, R2 is D; in some embodiments, R2 is halogenated.

[0225] In some embodiments, R 2a It is H; in some embodiments, R 2a It is D; in some embodiments, R 2a It is halogenated.

[0226] In some embodiments, R3 is H; in some embodiments, R3 is D; in some embodiments, R3 is halogenated; in some embodiments, R3 is OR. a In some embodiments, R3 is NR b R c In some embodiments, R3 is C 1-6 Alkyl; in some embodiments, R3 is C 1-6 Halogenated alkyl; in some embodiments, R3 is C(O)NH2.

[0227] In some embodiments, R4 is H; in some embodiments, R4 is D; in some embodiments, R4 is halogenated; in some embodiments, R4 is CN; in some embodiments, R4 is C. 1-6 Alkyl; in some embodiments, R4 is C 1-6Halogenated alkyl groups.

[0228] In some embodiments, R 4a It is H; in some embodiments, R 4a It is D; in some embodiments, R 4a It is halogenated; in some embodiments, R 4a It is CN; in some embodiments, R 4a It is C 1-6 Alkyl; in some embodiments, R 4a It is C 1-6 Halogenated alkyl groups.

[0229] In some embodiments, R4, R 4a Together with the atoms they are attached to, they form a phenyl group; in some embodiments, R4, R 4a Together with the atoms they are attached to, they form 5- to 6-membered heteroaryl groups.

[0230] In some embodiments, R5 is H; in some embodiments, R5 is D; in some embodiments, R5 is halogenated; in some embodiments, R5 is CN; in some embodiments, R5 is OR. a In some embodiments, R5 is NR b R c In some embodiments, R5 is C 1-6 Alkyl; in some embodiments, R5 is C 1-6 Halogenated alkyl; in some embodiments, R5 is C 3-6 Cycloalkyl; in some embodiments, R5 is a 5- to 6-membered heterocyclic group.

[0231] In some embodiments, p = 0; in some embodiments, p = 1; in some embodiments, p = 2; in some embodiments, p = 3; in some embodiments, p = 4.

[0232] In some embodiments, R6 is H; in some embodiments, R6 is D; in some embodiments, R6 is halogenated; in some embodiments, R6 is OH; in some embodiments, R6 is C. 1-6 alkoxy group; in some embodiments, R6 is C 1-6 Haloalkoxy group; in some embodiments, R6 is C 1-6 Alkyl; in some embodiments, R6 is C 1-6 Halogenated alkyl groups.

[0233] In some embodiments, q = 1; in some embodiments, q = 2; in some embodiments, q = 3.

[0234] In some embodiments, R T1R6, together with the atoms they are attached to, form C. 5-8 cycloalkyl; in some embodiments, R T1 R6, together with the atoms they are attached to, form 5- to 8-membered heterocyclic groups; in some embodiments, R T1 R6, together with the atoms they are attached to, form a phenyl group; in some embodiments, R T1 R6, together with the atoms they are attached to, form 5- to 6-membered heteroaryl groups.

[0235] In some embodiments, R7 is H; in some embodiments, R7 is D; in some embodiments, R7 is halogenated.

[0236] In some embodiments, R8 is H; in other embodiments, R8 is D.

[0237] In some embodiments, R T1 R8 and the atoms they are attached to form C. 5-8 cycloalkyl; in some embodiments, R T1 R8, together with the atoms they are attached to, forms 5- to 8-membered heterocyclic groups; in some embodiments, R T1 R8, together with the atoms they are attached to, forms a phenyl group; in some embodiments, R T1 R8, together with the atoms they are attached to, form 5- to 6-membered heteroaryl groups.

[0238] L, R N Y, R m R n

[0239] In some embodiments, L is a key; in other embodiments, L is a C. 1-6 Alkylene.

[0240] In some embodiments, R N It is H; in some embodiments, R N It is C 1-6 Alkyl; in some embodiments, R N It is C 1-6 Halogenated alkyl groups.

[0241] In some embodiments, Y is C(O); in some embodiments, Y is S(O); in some embodiments, Y is S(O)2.

[0242] In some embodiments, R m It is H; in some embodiments, R m It is D; in some embodiments, R m It is halogenated; in some embodiments, R m It is C 1-6 Alkyl; in some embodiments, Rm It is C 1-6 Halogenated alkyl; in some embodiments, R m It is -C 1-4 Alkylene-NR b R c .

[0243] In some embodiments, R n It is H; in some embodiments, R n It is D; in some embodiments, R n It is CN; in some embodiments, R n It is C 1-6 Alkyl; in some embodiments, R n It is C 1-6 Halogenated alkyl; in some embodiments, R n It is halogenated.

[0244] In some embodiments, R m and R n They connect together to form additional bonds.

[0245] In some embodiments, R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl.

[0246] In some embodiments, R m R n Together with the atoms they are attached to, they form 5- to 10-membered heterocyclic groups.

[0247] In some embodiments, R T1 and R N Together they form C(R)(R) S3 )-CH(R S4 In some embodiments, R T1 and R N Together they form phenylene; in some embodiments, R T1 and R N Together they form 5- to 6-membered heteroaryl groups.

[0248] In some embodiments, R is H; in some embodiments, R is D; in some embodiments, R is halogenated; in some embodiments, R is C. 1-6 Alkyl; in some embodiments, R is C 1-6 Halogenated alkyl; in some embodiments, R is C 2-6 Alkenyl; in some embodiments, R is C 2-6 Haloalkenyl; in some embodiments, R is C 2-6 Alkyne group; in some embodiments, R is C 2-6Halogenated alkynyl group; in some embodiments, R is -C 1-6 Alkylene-halogenated; in some embodiments, R is -C 1-6 Alkylene-OR a In some embodiments, R is -C 1-6 Alkylene-NR b R c In some embodiments, R is -C 0-4 Alkylene-C 3-8 cycloalkyl; in some embodiments, R is -C 0-4 Alkylene-4- to 10-membered heterocyclic group; in some embodiments, R is -C 0-4 Alkylene-C 6-10 Aryl; in some embodiments, R is -C 0-4 Alkylene-5- to 10-membered heteroaryl groups.

[0249] In some embodiments, R s3 It is H; in some embodiments, R s3 It is D; in some embodiments, R s3 It is halogenated; in some embodiments, R s3 It is C 1-6 Alkyl; in some embodiments, R s3 It is C 1-6 Halogenated alkyl groups.

[0250] In some embodiments, R s4 It is H; in some embodiments, R s4 It is D; in some embodiments, R s4 It is -C 0-4 Alkylene-C 3-8 cycloalkyl; in some embodiments, R s4 It is -C 0-4 alkylene-4- to 10-membered heterocyclic groups; in some embodiments, R s4 It is -C 0-4 Alkylene-C 6-10 Aryl; in some embodiments, R s4 It is -C 0-4 Alkylene-5- to 10-membered heteroaryl groups.

[0251] In some embodiments, R, R s3 Together with the atoms they are attached to, they form C 4-6 cycloalkyl; in some embodiments, R, R s3 Together with the atoms to which they are attached, they form 4- to 6-membered heterocyclic groups; in some embodiments, each of the above groups is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace.

[0252] In some embodiments, R ss It is H; in some embodiments, R ss It is D; in some embodiments, R ss It is halogenated.

[0253] In some embodiments, R s3 R s4 Together with the atoms they are attached to, they form C 5-8 cycloalkyl; in some embodiments, R s3 R s4 Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups.

[0254] In some further embodiments, when T is NR T2 At that time, R T2 Together with R, it forms CH2C(R) S1 (R) S2 )Z3.

[0255] In some embodiments, Z3 is C(R) S4 )2; In some embodiments, Z3 is C(R) S4 )2C(R S4 )2.

[0256] In some embodiments, R S1 It is H; in some embodiments, R S1 It is D; in some embodiments, R S1 It is halogenated; in some embodiments, R S1 It is C 1-6 Alkyl; in some embodiments, R S1 It is C 1-6 Halogenated alkyl groups.

[0257] In some embodiments, R S2 It is H; in some embodiments, R S2 It is D; in some embodiments, R S2 It is halogenated; in some embodiments, R S2 It is C 1-6 Alkyl; in some embodiments, R S2 It is C 1-6 Halogenated alkyl groups.

[0258] In some embodiments, R S4 It is H; in some embodiments, R S4 It is D; in some embodiments, R S4 It is C 1-6 Alkyl; in some embodiments, R S4 It is C 1-6 Halogenated alkyl groups.

[0259] In some other embodiments, Replaced by H, and R6 is CR p =CR q YR Y .

[0260] In some embodiments, R p It is H; in some embodiments, R p It is D; in some embodiments, R p It is CN; in some embodiments, R p It is halogenated.

[0261] In some embodiments, R q It is H; in some embodiments, R q It is D; in some embodiments, R q It is CN; in some embodiments, R q It is halogenated.

[0262] In some embodiments, R p and R q They connect together to form additional bonds.

[0263] In some embodiments, R Y It is H; in some embodiments, R Y It is D; in some embodiments, R Y It is C 1-6 Alkyl; in some embodiments, R Y It is C 1-6 Halogenated alkyl groups.

[0264] R a R b R c

[0265] In some embodiments, R a It is H; in some embodiments, R a It is C 1-6 Alkyl; in some embodiments, R a It is C 1-6 Halogenated alkyl; in some embodiments, R a It is -C 0-4 Alkylene-C 3-8 cycloalkyl; in some embodiments, R a It is -C 0-4 alkylene-4- to 10-membered heterocyclic groups; in some embodiments, R a It is -C 0-4 Alkylene-C 6-10 Aryl; in some embodiments, R a It is -C 0-4 Alkylene-5- to 10-membered heteroaryl groups.

[0266] In some embodiments, R b It is H; in some embodiments, R b It is C 1-6 Alkyl; in some embodiments, R b It is C 1-6 Halogenated alkyl; in some embodiments, R b It is -C 0-4 Alkylene-C 3-8 cycloalkyl; in some embodiments, R b It is -C 0-4 alkylene-4- to 10-membered heterocyclic groups; in some embodiments, R b It is -C 0-4 Alkylene-C 6-10 Aryl; in some embodiments, R b It is -C 0-4 Alkylene-5- to 10-membered heteroaryl groups.

[0267] In some embodiments, R c It is H; in some embodiments, R c It is C 1-6 Alkyl; in some embodiments, R c It is C 1-6 Halogenated alkyl; in some embodiments, R c It is -C 0-4 Alkylene-C 3-8 cycloalkyl; in some embodiments, R c It is -C 0-4 alkylene-4- to 10-membered heterocyclic groups; in some embodiments, R c It is -C 0-4 Alkylene-C 6-10 Aryl; in some embodiments, R c It is -C 0-4 Alkylene-5- to 10-membered heteroaryl groups.

[0268] In some embodiments, R b and R c Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic groups.

[0269] In some embodiments, each of the above groups is optionally substituted with one or two halogenated, OH, or C groups. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0270] Detailed description of the embodiments

[0271] This invention discloses novel heterocyclic compounds as GSDME inhibitors.

[0272] General methods for series A compounds (intermediates):

[0273] Synthesis of intermediates

[0274]

[0275] Step 1: Synthesis of tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate

[0276]

[0277] A mixture of tert-butyl 4-oxopiperidinium-1-carboxylate (50 g, 250.95 mmol), ethyl 2-cyanoacetate (28.39 g, 250.95 mmol, 26.71 mL), NH4OAc (1.93 g, 25.09 mmol), and AcOH (1.51 g, 25.09 mmol) was co-evaporated with toluene (500 mL) at 110°C for 16 h to remove water via a Dean-Stark water separator. The resulting mixture was extracted with ethyl acetate (3 × 300 mL). The organic layers were combined, washed with a saturated sodium bicarbonate solution (3 × 300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to provide the title compound as a white solid (62.5 g, 212.34 mmol, 84.6% yield). MS (ESI) m / z [M-Boc+H] + 295.1.

[0278] Step 2: Synthesis of tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-(3-fluorophenyl)piperidine-1-carboxylate

[0279]

[0280] To a solution of CuCN (12.59 g, 134.54 mmol) in THF (300 mL), magnesium bromo-(3-fluorophenyl) (55.86 g, 280.28 mmol, 280.6 mL) was added dropwise at -50°C under a nitrogen atmosphere. The mixture was heated to room temperature and stirred for 1 h. Then, the mixture was cooled to -50°C. Tert-butyl 4-(1-cyano-2-ethoxy-2-oxo-ethylene)piperidine-1-carboxylate (33 g, 112.11 mmol) was added dropwise to the above mixture. The resulting mixture was stirred at -50°C for another 3 h and quenched at 0°C with a saturated solution of ammonium chloride (100 mL). After filtration, the filtrate was diluted with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The organic layers were combined, washed with water (3 × 300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 1 / 5) to provide the title compound as a yellow oil (37.2 g, 95.28 mmol, 85% yield). MS (ESI) m / z [M-Boc+H] + 291.2.

[0281] Step 3: Synthesis of tert-butyl 4-(cyanomethyl)-4-(3-fluorophenyl)piperidine-1-carboxylate

[0282]

[0283] A solution of tert-butyl 4-(1-cyano-2-ethoxy-2-oxo-ethyl)-4-(3-fluorophenyl)piperidine-1-carboxylate (37.2 g, 95.28 mmol) and lithium chloride (5.65 g, 133.39 mmol) in water (10 mL) and DMSO (400 mL) was stirred at 160°C for 3 h. The reaction was quenched with ice water at 0°C. The resulting mixture was extracted with ethyl acetate (3 × 300 mL). The organic layers were combined, washed with water (3 × 300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 7) to give the title compound as a white solid (27.34 g, 85.87 mmol, 90.1% yield). MS (ESI) m / z [M-Boc+H] + 219.1.

[0284] Step 4: Synthesis of 2-(1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)piperidin-4-yl)acetic acid

[0285]

[0286] A solution of tert-butyl 4-(cyanomethyl)-4-(3-fluorophenyl)piperidin-1-carboxylate (27.34 g, 85.87 mmol) and NaOH (44.65 g, 1.12 mol) in water (60 mL) and EtOH (300 mL) was stirred at 90°C for 72 h. The resulting mixture was concentrated under vacuum. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The organic layers were combined, washed with water (3 × 300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (28.0 g, 82.99 mmol, 96.6% yield) as a yellow oil. The byproduct in water (de-Boc, about 10%) could be converted to the product by adding di-tert-butyl dicarbonate (5.0 eq). MS (ESI) m / z [M- t -Bu+H] + 282.1.

[0287] Step 5: Synthesis of tert-butyl 6-fluoro-3-oxo-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate

[0288]

[0289] A solution of 2-[1-tert-butoxycarbonyl-4-(3-fluorophenyl)-4-piperidinyl]acetic acid (22.37 g, 66.30 mmol) in trifluoromethanesulfonic acid (150 mL) was stirred at 50°C for 16 h. The pH of the solution was adjusted to 10 with NaOH (1.0 M). Di-tert-butyl dicarbonate (21.68 g, 99.46 mmol) was added dropwise to the mixture at room temperature over 2 min. The resulting mixture was stirred at room temperature for another 16 h and extracted with DCM (3 × 200 mL). The organic layers were combined, washed with water (3 × 300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 5) to give the title compound as a white solid (16.5 g, 51.66 mmol, 77.9% yield). 1 H NMR (400 MHz, DMSO-) d 6) δ 7.78-7.55 (m, 2H), 7.37-7.16 (m, 1H), 4.00 (dd, J=18.1, 11.1 Hz, 2H), 2.62-2.03 (m, 4H), 2.05-1.76 (m, 2H), 1.57-1.30 (m, 11H). MS(ESI) m / z [M+H] + 320.1.

[0290] Step 6: Synthesis of the mixture of tert-butyl 3-(2-ethoxy-2-oxoethylene)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate and tert-butyl 3-(2-ethoxy-2-oxoethyl)-6-fluorospiro[indene-1,4'-piperidine]-1'-carboxylate.

[0291]

[0292] A solution of tert-butyl 6-fluoro-3-oxo-spiro[indan-1,4'-piperidine]-1'-carboxylate (13.2 g, 41.33 mmol), ethyl 2-diethoxyphosphoryl acetate (16.68 g, 74.40 mmol, 14.83 mL), and potassium tert-butoxide (6.94 g, 62.00 mmol) in THF (150 mL) was stirred at 70°C for 16 h under a nitrogen atmosphere. The reaction was quenched at 0°C with a saturated solution of ammonium chloride (50 mL). The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 5) to give the title compound as a colorless oil (13.58 g, 34.87 mmol, 84.4% yield). MS (ESI) m / z [M- t -Bu+H] + 334.2, [M+Na] + 412.2.

[0293] Step 7: Synthesis of tert-butyl 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate

[0294]

[0295] Pd / C (617.47 mg, 10%) was added to a solution of the above product (13.58 g, 34.89 mmol) in THF (200 mL). The mixture was stirred at 25°C for 16 h under a hydrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with DCM. The filtrate was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 5) to give the title compound (9.94 g, 25.42 mmol, 72.9% yield) as a colorless oil. MS (ESI) m / z [M+Na] + 414.2.

[0296] Step 8: ( R )-3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester and ( S Synthesis of tert-butyl 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate

[0297]

[0298] 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylic acid tert-butyl ester (9.94 g, 25.42 mmol) was separated by chiral separation under the following conditions:

[0299] Instrument: SFC Thar prep 80

[0300] Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm

[0301] Modifier: 25% MeOH (0.2% NH4OH)

[0302] Total flow rate: 40 g / min

[0303] Peak 1: tR = 2.73 min, R Isomer (3.85 g, 9.82 mmol, 40.2% yield). MS (ESI) m / z [M+Na] + 414.2.

[0304] Peak 2: tR = 3.16 min, configuration determined by single-crystal X-ray diffraction. S Configuration (4.14 g, 10.56 mmol, 41.56% yield). MS (ESI) m / z[M+Na] + 414.2.

[0305] Step 9: Synthesis of ethyl acetate 2-(6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidine]-3-yl)

[0306]

[0307] Hydrogen chloride (15 mL, 4.0 M in 1,4-dioxane) was added to a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (8.2 g, 20.96 mmol) in 1,4-dioxane (150 mL). The mixture was stirred at room temperature for 3 h and concentrated under vacuum to provide the title compound as a white solid (6.85 g, 20.96 mmol, 100% yield). MS (ESI) m / z [M+H] + 292.2.

[0308] General methods for series B compounds:

[0309]

[0310] R1 = H or C(O)NR b R c 1. Cycloalkyl, substituted alkyl or heterocyclic groups; R2, R3, R4 = H or F; R5 = F, Cl or CN; Z1, Z2 = N or CF; R6 = alkyl, alkoxy or amine; R N = H or CH3.

[0311] Intermediate II is coupled via Buchwald coupling or S-coupling between I and various aromatic halides. N The reaction is performed with Ar. After hydrolysis, the resulting acid intermediate III reacts with different amines to obtain IV. The amine intermediate V, obtained by removal of Boc or reduction of nitro, reacts with acryloyl chloride to give the target compound VI.

[0312] Example 1:

[0313] N -(4-(6-Fluoro-3-(2-((( R )-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)propyl-2-yl) Preparation of (amino)-2-oxoethyl)-2,3-dihydrospiro[inden-1,4'-piperidine]-1'-yl)phenyl)acrylamide (compound B1)

[0314]

[0315] Step 1: Synthesis of ethyl 2-(1'-(4-((tert-butoxycarbonyl)amino)phenyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)

[0316]

[0317] A sealed tube was loaded with ethyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate (200 mg, 686.44 μmol), tert-butyl (4-bromophenyl)carbamate (224 mg, 823.11 μmol), Pd2(dba)3 (63 mg, 68.85 μmol), Sphos (56 mg, 136.59 μmol), cesium carbonate (671 mg, 2.06 mmol), and 1,4-dioxane (10 mL). The mixture was stirred at 100°C for 16 h under a nitrogen atmosphere. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 5) to give the title compound as a yellow solid (190 mg, 393.71 μmol, 57.7% yield). MS (ESI) m / z [M+H] + 483.2, [M+Na] + 505.2.

[0318] Step 2: Synthesis of 2-(1'-(4-((tert-butoxycarbonyl)amino)phenyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid

[0319]

[0320] Sodium hydroxide (79 mg, 1.98 mmol) was added to a solution of ethyl 2-(1'-(4-((tert-butoxycarbonyl)amino)phenyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetate (190 mg, 393.71 μmol) in water (3 mL), MeOH (3 mL), and THF (3 mL). The mixture was stirred at room temperature for 30 min and then concentrated under vacuum. The mixture was diluted with water (30 mL). The pH of the mixture was adjusted to 6 with citric acid. The resulting mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under vacuum to give the title compound (170 mg, 374.01 μmol, 95% yield) as a yellow oil. MS (ESI) m / z [M+H] + 455.2.

[0321] Step 3: (4-(6-fluoro-3-(2-((( RSynthesis of tert-butyl carbamate (1-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)phenyl)carbamate

[0322]

[0323] Add ( ) to a solution of 2-(1'-(4-((tert-butoxycarbonyl)amino)phenyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (100 mg, 220.01 μmol) dissolved in DMF (3 mL) R )-2-amino- N 3-Methyl-3-(3,4,5-trifluorophenyl)acrylamide hydrochloride (58.89 mg, 220.01 μmol), DIEA (85.30 mg, 660.02 μmol, 114.96 μL), and HATU (125.48 mg, 330.01 μmol). The mixture was stirred at room temperature for 1 h and quenched with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL), washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (eluting with DCM / MeOH = 20 / 1) to give the title compound (130 mg, 194.40 μmol, 88.4% yield) as a yellow oil. MS (ESI) m / z [M+H] + 669.1, [M+Na] + 691.1.

[0324] Step 4: (2) R )-2-(2-(1'-(4-aminophenyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamido)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)acrylamide hydrochloride

[0325]

[0326] towards (4-(6-fluoro-3-(2-((( R1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)propyl-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)phenyl)carbamate tert-butyl ester (180 mg, 269.17 μmol) was dissolved in DCM (5 mL) with hydrogen chloride (2 mL, 4 M in 1,4-dioxane). The mixture was stirred at room temperature for 3 h. The solvent was evaporated under vacuum to give the title compound (140 mg, 246.22 μmol, 91.5% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 569.1.

[0327] Step 5: N -(4-(6-Fluoro-3-(2-((( R Synthesis of 1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)phenyl)acrylamide (compound B1)

[0328]

[0329] (2) R )-2-(2-(1'-(4-aminophenyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamido)- N A solution of methyl-3-(3,4,5-trifluorophenyl)acrylamide hydrochloride (50 mg, 82.64 μmol) and sodium bicarbonate (34 mg, 414.6 μmol) in water (5 mL) and THF (5 mL) was stirred at 0°C for 10 min. At 0°C, acrylonitrile chloride (7.5 mg, 82.64 μmol, in 0.3 mL THF) was added dropwise to the above mixture over 5 min. The resulting mixture was stirred for another 30 min. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by rapid chromatography of octadecylsilane under the following conditions: column, C18 silica gel; mobile phase, CH3CN in water, in a 5% to 35% gradient over 15 min; detector, UV 254 nm, to give the title compound as a white solid (20.4 mg, 32.76 μmol, 39.6% yield). 1 H NMR (400 MHz, DMSO- d 6) δ9.91 (s, 1H), 8.23 ​​(d, J = 8.7 Hz,1H), 8.01-7.87 (m, 1H), 7.59-7.47 (m, 2H), 7.25-7.01 (m, 4H), 6.99-6.88 (m,3H), 6.46-6.35 (m, 1H), 6.21 (dd, J = 17.0, 2.2 Hz, 1H), 5.69 (dd, J = 10.1,2.1 Hz, 1H), 4.61-4.51 (m, 1H), 3.64-3.51 (m, 2H), 3.45-3.32 (m, 1H), 3.07-2.97 (m, 1H), 2.79-2.57 (m, 7H), 2.27-2.11 (m, 3H), 1.78-1.64 (m, 1H), 1.58-1.43 (m, 3H). MS(ESI) m / z [M+H] + 623.1, [M+Na] + 645.1.

[0330] Example 2:

[0331] N -(4-(( S )-6-Fluoro-3-(2-((( R )-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2- (indole)amino)-2-oxoethyl)-2,3-dihydrospiro[indole-1,4'-piperidine]-1'-yl)phenyl)acrylamide (compound B2) preparation

[0332]

[0333] Step 1: N -(4-(( S )-6-Fluoro-3-(2-((( R Synthesis of 1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)phenyl)acrylamide (compound B2)

[0334]

[0335] Compound B2 was obtained by SFC separation under the following separation conditions:

[0336] Instrument: SFC Thar prep 80

[0337] Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm

[0338] Modifier: 28% MeOH (0.2% NH4OH)

[0339] Total flow rate: 35 mL / min

[0340] Compound B2: 4.36 mg, 1 H NMR (400 MHz, DMSO- d 6) δ 9.94 (s, 1H), 8.28 (d, J = 8.7 Hz, 1H), 8.01-7.91 (m, 1H), 7.57-7.49 (m, 2H), 7.21 (dd, J = 9.1, 6.7Hz, 2H), 7.07 (dd, J = 9.5, 2.5 Hz, 1H), 6.99-6.89 (m, 3H), 6.83 (td, J =8.8, 2.5 Hz, 1H), 6.41 (dd, J = 17.0, 10.1 Hz, 1H), 6.21 (dd, J = 17.0, 2.2Hz, 1H), 5.70 (dd, J = 10.1, 2.2 Hz, 1H), 4.55 (ddd, J = 10.5, 8.6, 4.5 Hz,1H), 3.58 (t, J = 13.3 Hz, 2H), 3.41-3.34 (m, 1H), 3.02 (dd, J = 13.8, 4.5Hz, 1H), 2.81-2.56 (m, 7H), 2.29-2.13 (m, 3H), 1.71 (dt, J = 12.7, 6.6 Hz, 1H), 1.57-1.44 (m, 3H). MS(ESI) m / z [M+H] + 623.1, [M+Na] + 645.1.

[0341] Example 3:

[0342] N -(5-(6-Fluoro-3-(2-((( R )-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)propyl-2-yl) (Amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)pyridin-2-yl)acrylamide (compound B7) Preparation

[0343]

[0344] Step 1: Synthesis of ethyl 2-(6-fluoro-1'-(6-nitropyridin-3-yl)-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)

[0345]

[0346] A sealed tube was filled with ethyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate (100.0 mg, 343.22 μmol), 5-bromo-2-nitropyridine (104.51 mg, 514.83 μmol), Pd2(dba)3 (31.43 mg, 34.32 μmol), Sphos (28.18 mg, 68.64 μmol), cesium carbonate (335.67 mg, 1.03 mmol), and 1,4-dioxane (10 mL). The mixture was stirred overnight at 100°C under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by silica gel rapid chromatography (DCM / MeOH = 15 / 1) to give the title compound (80 mg, 56.4% yield) as a brown oil. MS (ESI) m / z [M+H] + 414.2.

[0347] Step 2: Synthesis of 2-(6-fluoro-1'-(6-nitropyridin-3-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid

[0348]

[0349] Sodium hydroxide (23.22 mg, 580.49 μmol) was added to a solution of ethyl 2-(6-fluoro-1'-(6-nitropyridin-3-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetate (80 mg, 193.50 μmol) in MeOH (2 mL), THF (2 mL), and H₂O (2 mL). The mixture was stirred at room temperature for 3 h. The pH of the mixture was adjusted to 7 with hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under vacuum to give the title compound (75 mg, crude product) as a yellow solid. The crude product was used for the next step. MS (ESI) m / z [M+H] + 386.1.

[0350] Step 3: (2) R )-2-(2-(6-fluoro-1'-(6-nitropyridin-3-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamido)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)propionamide

[0351]

[0352] Add DIEA (75.31 mg, 583.83 μmol) to a solution of 2-(6-fluoro-1'-(6-nitropyridin-3-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (75 mg, 194.61 μmol) in MeCN (5 mL). R )-2-amino- N 3-Methyl-3-(3,4,5-trifluorophenyl)propionamide (67.78 mg, 291.92 μmol) and T3P (111.22 mg, 291.92 μmol, 50% in ethyl acetate). The mixture was stirred at room temperature for 3 h and then quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (60 mg, 51.4% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 600.2.

[0353] Step 4: (2) R )-2-(2-(1'-(6-aminopyridin-3-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamido)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)propionamide

[0354]

[0355] To (2) R )-2-(2-(6-fluoro-1'-(6-nitropyridin-3-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamido)- N3-Methyl-3-(3,4,5-trifluorophenyl)propionamide (60 mg, 100.07 μmol) was prepared in a solution of ethanol (3 mL) and water (3 mL) with added iron powder (55.88 mg, 1.00 mmol) and ammonium chloride (53.53 mg, 1.00 mmol). The mixture was stirred at 70°C for 3 h and then diluted with water (10 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a brown solid (55 mg, 96.5% yield). MS (ESI) m / z [M+H] + 570.3.

[0356] Step 5: N -(5-(6-Fluoro-3-(2-((( R Synthesis of 1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)pyridin-2-yl)acrylamide (compound B7)

[0357]

[0358] At 0°C, towards (2 R )-2-(2-(1'-(6-aminopyridin-3-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamido)- N 1-Methyl-3-(3,4,5-trifluorophenyl)propionamide (55 mg, 96.56 μmol) was prepared in a solution of THF (8 mL) and water (2 mL) with sodium bicarbonate (81.21 mg, 965.60 μmol) and acrylonitrile chloride (8.74 mg, 96.56 μmol). The mixture was stirred at 0°C for 30 min and then diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by preparative TLC to give the title compound as a white solid (2.45 mg, 4.1% yield). 1 H NMR (400 MHz, DMSO- d 6) δ10.48 (s, 1H), 8.26-8.23 (m, 1H), 8.08-8.06(m, 2H), 7.98-7.93 (m, 1H), 7.47-7.44 (m, 1H), 7.22-7.06 (m, 4H), 6.95-6.81(m, 1H), 6.57 (dd, J = 20.0, 12.0 Hz, 1H), 6.26 (d, J = 17.2 Hz, 1H), 5.72(d, J = 10.3 Hz, 1H), 4.61-4.53 (m, 1H), 3.64 (t, J = 11.8 Hz, 2H), 3.02 (dd, J = 13.7, 2.6 Hz, 1H), 2.80-2.65 (m, 4H), 2.62-2.59 (m, 3H), 2.29-2.14 (m,3H), 2.03-1.93 (m, 1H), 1.76-1.66 (m, 1H), 1.56-1.43 (m, 3H). MS(ESI) m / z [M+H] + 624.2.

[0359] Example 4:

[0360] N -(4-(6-Fluoro-3-(2-((( R )-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)propyl-2-yl) (amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2-isopropoxyphenyl)acrylamide (chemical) Preparation of compound B12

[0361]

[0362] Step 1: Synthesis of 4-bromo-2-isopropoxy-1-nitrobenzene

[0363]

[0364] Propane-2-ol (273.16 mg, 4.55 mmol, 347.98 μL) and cesium carbonate (2.22 g, 6.82 mmol) were added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol) in acetonitrile (50 mL). The mixture was stirred at 100°C for 2 h and quenched with water (100 mL). The aqueous phase was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound as a pale yellow solid (320 mg, 1.23 mmol, 54.1% yield). MS (ESI) m / z [M+H] + 260.2, 262.2 (Br).

[0365] Step 2: Synthesis of ethyl 2-(6-fluoro-1'-(3-isopropoxy-4-nitrophenyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)

[0366]

[0367] A sealed tube was filled with 4-bromo-2-isopropoxy-1-nitrobenzene (141.93 mg, 545.72 μmol), ethyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetate (106 mg, 363.81 μmol), Pd2(dba)3 (33.29 mg, 36.38 μmol), Sphos (29.83 mg, 72.76 μmol), cesium carbonate (355.81 mg, 1.09 mmol), and 1,4-dioxane (10 mL). The mixture was stirred overnight at 110°C under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 15 / 1) to give the title compound as a yellow oil (140 mg, 291.58 μmol, 80.2% yield). MS (ESI) m / z [M+H] + 471.2.

[0368] Step 3: Synthesis of 2-(6-fluoro-1'-(3-isopropoxy-4-nitrophenyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid

[0369]

[0370] Sodium hydroxide (35.70 mg, 892.62 μmol) was added to a solution of ethyl 2-(6-fluoro-1'-(3-isopropoxy-4-nitrophenyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate (140 mg, 297.54 μmol) in THF (3 mL), methanol (3 mL), and water (3 mL). The mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The mixture was diluted with water (30 mL). The pH of the solution was adjusted to pH 6 with hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under vacuum to give the title compound as a yellow solid (105 mg, 237.30 μmol, 79.8% yield). MS (ESI) m / z [M+H] + 443.2.

[0371] Step 4: (2) R )-2-(2-(6-fluoro-1'-(3-isopropoxy-4-nitrophenyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamido)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)propionamide

[0372]

[0373] Towards( R )-2-amino- N A solution of methyl-3-(3,4,5-trifluorophenyl)propionamide (66.12 mg, 284.76 μmol) in acetonitrile (5 mL) was supplemented with 2-(6-fluoro-1'-(3-isopropoxy-4-nitrophenyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (105 mg, 237.30 μmol), DIEA (91.83 mg, 711.90 μmol), and HATU (108.27 mg, 284.76 μmol). The mixture was stirred at room temperature for 3 h and quenched with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 15 / 1) to give the title compound as a pale yellow solid (75 mg, 114.21 μmol, 48.1% yield). MS (ESI) m / z [M+H] + 657.3.

[0374] Step 5: (2) R )-2-(2-(1'-(4-amino-3-isopropoxyphenyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamido)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)propionamide

[0375]

[0376] To (2) R )-2-(2-(6-fluoro-1'-(3-isopropoxy-4-nitrophenyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamido)- N 3-Methyl-3-(3,4,5-trifluorophenyl)propionamide (75 mg, 114.21 μmol) was dissolved in a solution of EtOH (10 mL) and water (5 mL) with iron powder (63.79 mg, 1.14 mmol) and hydrochloric acid (0.1 mL). The mixture was stirred at 80°C for 3 h. After filtration, the filtrate was concentrated to dryness under vacuum to give the title compound as a yellow solid (35 mg, 55.85 μmol, 48.9% yield). MS (ESI) m / z [M+H] + 627.2.

[0377] Step 6: N -(4-(6-Fluoro-3-(2-((( R Synthesis of 1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-2-isopropoxyphenyl)acrylamide (compound B12)

[0378]

[0379] At 0°C, towards (2 R )-2-(2-(1'-(4-amino-3-isopropoxyphenyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamido)- N3-Methyl-3-(3,4,5-trifluorophenyl)propionamide (35 mg, 55.85 μmol) and sodium bicarbonate (14.24 mg, 167.55 μmol) in THF (5 mL) and water (4 mL) were mixed dropwise with acrylonitrile chloride (4.55 mg, 50.26 μmol, in 5 mL THF). The mixture was stirred at 0°C for 0.5 h and then diluted with water (30 mL). The mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (H2O / CH3CN + 1% FA, 45% to 85%) to give the title compound as a white solid (12.03 mg, 17.32 μmol, 31% yield). 1 H NMR (400 MHz, DMSO-) d 6) δ 8.91 (s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.96 (dd, J =16.6, 4.6 Hz, 1H), 7.78 (dd, J = 8.8, 2.9 Hz, 1H), 7.25-7.05 (m, 4H), 6.99-6.85 (m, 1H), 6.68-6.54 (m, 2H), 6.53 (dd, J = 8.9, 2.2 Hz, 1H), 6.18 (d, J =18.6 Hz, 1H), 5.67 (dd, J =10.2,1.8 Hz, 1H), 4.65-4.50 (m, 2H), 3.60 (t, J =11.3 Hz, 2H), 3.02 (dt, J = 14.0, 3.9 Hz, 1H), 2.75-2.58 (m, 7H), 2.30-2.06(m, 4H), 1.78-1.68 (m, 1H), 1.56-1.42 (m, 3H), 1.29 (d, J = 6.0 Hz, 6H). MS (ESI) m / z [M+H] + 681.2.

[0380] Example 5:

[0381] N -(4-(6-Fluoro-3-(2-((( R )-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)propyl-2-yl) (amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-1-methyl-1 H -Indol-7-yl)Acryloyl Preparation of amine (compound B18)

[0382]

[0383] Step 1: 4-Fluoro-1-methyl-7-nitro-1 H - Synthesis of indole

[0384]

[0385] At 0°C, to 4-fluoro-7-nitro-1 H -Indole (223 mg, 1.24 mmol) was added to a solution of sodium hydride (35.84 mg, 1.49 mmol) and methyl iodide (211.99 mg, 1.49 mmol) in THF (10 mL). The mixture was stirred overnight at 60°C and quenched with water (10 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound as a yellow solid (197 mg, 81.9% yield). MS (ESI) m / z [M+H] + 195.0.

[0386] Step 2: 2-(6-fluoro-1'-(1-methyl-7-nitro-1) H Synthesis of ethyl indole-4-yl)-2,3-dihydrospiro[indole-1,4'-piperidine]-3-yl)

[0387]

[0388] Add 4-fluoro-1-methyl-7-nitro-1-ethyl acetate (120 mg, 411.86 μmol) to a solution of 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) in acetonitrile (15 mL) H-Indole (95.96 mg, 494.23 μmol) and cesium carbonate (268.53 mg, 823.72 μmol). The mixture was stirred at 100°C for 3 days. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (80 mg, 41.7% yield) as a yellow solid. MS (ESI) m / z [M+H] + 466.1.

[0389] Steps 3-6: N -(4-(6-Fluoro-3-(2-((( R Synthesis of 1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-1-methyl-1H-indole-7-yl)acrylamide (compound B18)

[0390]

[0391] Following the method of steps 3-6 in Example 4 (B12), 2-(6-fluoro-1'-(1-methyl-7-nitro-1) H Ethyl indole-4-yl)-2,3-dihydrospiro[indole-1,4'-piperidine]-3-yl) was used to give the title compound as a white solid (27 mg, 39.96 μmol, 16.9% overall yield over 4 steps). 1 H NMR (400 MHz, DMSO- d 6) δ 9.79 (s, 1H), 8.26 (dd, J = 8.9, 2.7 Hz, 1H), 7.98-7.92 (m, 1H), 7.25-7.11 (m, 5H), 6.97-6.92 (m,1H), 6.78 (dd, J = 7.9, 2.2 Hz, 1H), 6.54-6.43 (m, 2H), 6.40-6.39 (m, 1H), 6.24 (d, J = 17.3 Hz, 1H), 5.76 (dd, J= 10.2, 1.7 Hz, 1H), 4.62-4.52 (m,1H), 3.80 (s, 3H), 3.50 (d, J = 8.1 Hz, 2H), 3.03-3.01 (m, 1H), 2.82-2.66 (m,4H), 2.61 (t, J = 4.8 Hz, 3H), 2.36-2.15 (m, 3H), 1.92-1.78 (m, 1H), 1.58-1.48 (m, 3H), 1.29 (dd, J = 12.9, 8.8 Hz, 1H). MS(ESI) m / z [M+H] + 675.8.

[0392] Example 6:

[0393] N -(4-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H -pyran-4-yl)ethyl)amino (indene-1,4'-piperidine)-1'-yl)-5-fluoro-2-(piperidine-1-yl)phenyl) Preparation of Acrylamide (Compound B19)

[0394]

[0395] Step 1: 2-(3,4-difluorophenyl)-1-(tetrahydro-2-difluorophenyl) H Synthesis of pyran-4-yl)ethyl-1-one

[0396]

[0397] To 4-bromo-1,2-difluorobenzene (3.4 g, 17.62 mmol, 1.99 mL) and 1-(tetrahydro-2-difluorobenzene) H 4-pyran-4-yl)ethyl-1-one (4.52 g, 35.24 mmol, 4.41 mL) was added to a solution of Pd2(dba)3 (2.42 g, 2.64 mmol), Xantphos (3.06 g, 5.29 mmol), and sodium tert-butoxide (5.08 g, 52.85 mmol) in THF (50 mL). The resulting mixture was stirred at 60°C for 16 h and diluted with ethyl acetate (200 mL). The organic phase was washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 9 / 1) to give the title compound (3.6 g, 14.98 mmol, 85.1% yield) as a yellow oil. MS (ESI) m / z [M+H] + 241.1.

[0398] Step 2: 2-(3,4-difluorophenyl)-1-(tetrahydro-2-difluorophenyl) H Synthesis of pyran-4-yl)ethyl-1-amine

[0399]

[0400] 2-(3,4-difluorophenyl)-1-(tetrahydro-2- H 3-pyran-4-yl)ethyl-1-one (3.6 g, 14.98 mmol) and ammonium acetate (11.55 g, 149.85 mmol) were added to a solution of MeOH (50 mL) with sodium cyanoborohydride (1.88 g, 29.97 mmol). The resulting mixture was stirred at room temperature for 16 h and diluted with ethyl acetate (100 mL). The organic phase was washed with water (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 7 / 3) to give the title compound (3.5 g, 14.51 mmol, 96.8% yield) as a white solid. MS (ESI) m / z [M+H] + 242.1.

[0401] Step 3: ( R )-(2-(3,4-difluorophenyl)-1-(tetrahydro-2 H Synthesis of 4-pyran-ethyl(tert-butyl)carbamate

[0402]

[0403] 2-(3,4-difluorophenyl)-1-(tetrahydro-2- H 1-pyran-4-yl)ethyl-1-amine (2.2 g, 9.12 mmol), DMAP (111.39 mg, 911.82 μmol), and triethylamine (2.77 g, 27.35 mmol, 3.81 mL) in THF (14.50 mL) was supplemented with di-tert-butyl dicarbonate (5.97 g, 27.35 mmol, 6.28 mL). The resulting mixture was stirred at room temperature for 16 h and diluted with ethyl acetate (50 mL). The organic phase was washed with water (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1). The product was then purified by SFC under the following separation conditions:

[0404] Instrument: SFC Thar prep 80

[0405] Column: CHIRALPAK IC, 250 mm × 20 mm, 5 μm

[0406] Modifier: 40% IPA: 60% CO2

[0407] Total flow rate: 40 g / min

[0408] Peak 1: tR = 2.35 min, configuration determined by biological data. R Configuration (1.18 g, 3.45 mmol, 75.9% yield). MS (ESI) m / z [M+H] + 342.2.

[0409] Peak 2: tR = 3.49 min, configuration determined by biological data. S Configuration (1.07 g, 3.13 mmol, 68.8% yield). MS (ESI) m / z [M+H] + 342.2.

[0410] Step 4: ( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H Synthesis of pyran-4-yl)ethyl-1-amine hydrochloride

[0411]

[0412] Towards( R )-(2-(3,4-difluorophenyl)-1-(tetrahydro-2 H 1.18 g (3.46 mmol) of tert-butyl pyran-4-yl)ethyl)carbamate was dissolved in DCM (20 mL) with hydrogen chloride (10 mL, 4.0 M in dioxane). The resulting mixture was stirred at room temperature for 1 h. The solvent was evaporated under vacuum to give the title compound as a white solid (800 mg, 3.32 mmol, 95.9% yield). MS (ESI) m / z [M+H] + 242.1.

[0413] Step 5: Synthesis of 1-(5-bromo-4-fluoro-2-nitrophenyl)piperidine

[0414]

[0415] DIEA (543.06 mg, 4.20 mmol, 731.88 μL) and piperidine (196.78 mg, 2.31 mmol, 228.28 μL) were added to a solution of 1-bromo-2,5-difluoro-4-nitrobenzene (500 mg, 2.10 mmol) in THF (10 mL). The mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 15) to give the title compound as a yellow oil (560 mg, 1.85 mmol, 87.9% yield). MS (ESI) m / z [M+H] + 303.0, 305.0 (Br).

[0416] Step 6: Synthesis of ethyl (S)-2-(6-fluoro-1'-[2-fluoro-4-nitro-5-(1-piperidinyl)phenyl]-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)

[0417]

[0418] 1-(5-bromo-4-fluoro-2-nitrophenyl)piperidine (200 mg, 659.79 μmol) was added to a sealed tube. S Ethyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate hydrochloride (216.30 mg, 659.79 μmol), Pd2(dba)3 (60.42 mg, 65.98 μmol), Brettphos (70.83 mg, 131.96 μmol), cesium carbonate (430.18 mg, 1.32 mmol), and 1,4-dioxane (5 mL). The mixture was stirred overnight at 100°C under nitrogen atmosphere. After concentration under vacuum, the residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (300 mg, 584.14 μmol, 88.5% yield) as a yellow oil. MS (ESI) m / z [M+H] + 514.2, [M+Na] + 536.1.

[0419] Step 7: Synthesis of (S)-2-(6-fluoro-1'-[2-fluoro-4-nitro-5-(1-piperidinyl)phenyl]-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)acetic acid

[0420]

[0421] Towards( S Ethyl ethyl acetate (300 mg, 584.14 μmol) of 2-(6-fluoro-1'-[2-fluoro-4-nitro-5-(1-piperidinyl)phenyl]-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) was prepared in MeOH (5 mL) and water (5 mL) with sodium hydroxide (116 mg, 2.9 mmol). The mixture was stirred at room temperature for 3 h. The pH of the solution was adjusted to 6 with citric acid. The mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under vacuum to give the title compound (280 mg, 576.70 μmol, 98.7% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 486.2.

[0422] Step 8: N -(( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H -pyran-4-yl)ethyl)-2-(( S Synthesis of 6-fluoro-1'-[2-fluoro-4-nitro-5-(1-piperidinyl)phenyl]-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamide

[0423]

[0424] Towards( S )-2-(6-fluoro-1'-[2-fluoro-4-nitro-5-(1-piperidinyl)phenyl]-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (100 mg, 205.96 μmol) was added to a solution of DMF (8 mL). R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H1,4-pyran-4-yl)ethyl-1-amine (49.69 mg, 205.96 μmol), DIEA (53.24 mg, 411.93 μmol, 71.75 μL), and HATU (117.47 mg, 308.95 μmol). The mixture was stirred at room temperature for 1 h and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound as a white solid (130 mg, 183.41 μmol, 89.1% yield). MS (ESI) m / z [M+H] + 709.3.

[0425] Step 9: 2-(( S )-1'-[4-amino-2-fluoro-5-(1-piperidinyl)phenyl]-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H Synthesis of pyran-4-yl)ethyl)acetamide

[0426]

[0427] Towards N -(( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H -pyran-4-yl)ethyl)-2-(( S Iron powder (102.44 mg, 1.83 mmol) and ammonium chloride (99.04 mg, 1.83 mmol) were added to a solution of 6-fluoro-1'-[2-fluoro-4-nitro-5-(1-piperidinyl)phenyl]-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamide (130 mg, 183.41 μmol) in EtOH (10 mL) and water (1 mL). The mixture was stirred overnight at 80°C. After filtration, the filtrate was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound as a yellow oil (100 mg, 147.32 μmol, 80.3% yield). MS (ESI) m / z [M+H]+ 679.3.

[0428] Step 10: N -(4-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H Synthesis of pyran-4-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-5-fluoro-2-(1-piperidinyl)phenyl)acrylamide (compound B19)

[0429]

[0430] At 0°C, towards 2-(( S )-1'-[4-amino-2-fluoro-5-(1-piperidinyl)phenyl]-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H 1,4-pyran-4-yl)ethyl)acetamide (100 mg, 147.32 μmol) was prepared in a solution of THF (5 mL) and water (5 mL) with sodium bicarbonate (24.16 mg, 294.64 μmol) and propylene-2-enoyl chloride (13.33 mg, 147.32 μmol, in 5 mL THF). The mixture was stirred at 0°C for 30 min and diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by rapid chromatography with octadecylsilane under the following conditions: column, C18 silica gel; mobile phase, CH3CN in water, in a 5% to 40% gradient over 15 min; detector, UV 254 nm, to give the title compound as a white solid (75.60 mg, 103.16 μmol, 70% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 8.99 (s, 1H), 7.83 (d, J = 14.4 Hz, 1H), 7.73(d, J = 9.3 Hz, 1H), 7.34-7.25 (m, 2H), 7.13 (dd, J= 9.5, 2.5 Hz, 1H), 7.10-7.04 (m, 1H), 6.96 (dd, J = 8.3, 5.3 Hz, 1H), 6.91-6.83 (m, 2H), 6.64 (dd, J = 16.9, 10.2 Hz, 1H), 6.23 (dd, J = 16.9, 1.9 Hz, 1H), 5.75 (dd, J = 10.2,1.9 Hz, 1H), 3.98-3.83 (m, 3H), 3.30-3.20 (m, 4H), 2.86 (dd, J = 13.9, 3.7Hz, 1H), 2.81-2.66 (m, 6H), 2.61-2.52 (m, 2H), 2.31-2.18 (m, 2H), 2.08 (dd, J = 13.6, 9.2 Hz, 1H), 1.81-1.45 (m, 13H), 1.41-1.27 (m, 2H). MS(ESI) m / z [M+H] + 733.4.

[0431] Example 7:

[0432] N -(6-(( S )-6-Fluoro-3-(2-((( R )-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2- (indole)amino)-2-oxoethyl)-2,3-dihydrospiro[indole-1,4'-piperidine]-1'-yl)-4-methoxypyridine-3-yl)acryloyl Preparation of amine (compound B20)

[0433]

[0434] Step 1: Synthesis of 2-chloro-4-methoxy-5-nitropyridine

[0435]

[0436] A mixture of 4-methoxy-5-nitropyridine-2-ol (100 mg, 587.81 μmol) and POCl3 (2 mL) was stirred overnight at 100°C. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (72 mg, 381.82 μmol, 65% yield) as a yellow oil. MS (ESI) m / z [M+H] + 189.0.

[0437] Step 2: Synthesis of ethyl 2-(6-fluoro-1'-(4-methoxy-5-nitropyridin-2-yl)-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)

[0438]

[0439] DIEA (246.74 mg, 1.91 mmol, 332.53 μL) was added to a solution of 2-chloro-4-methoxy-5-nitropyridine (72 mg, 381.82 μmol) and 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate hydrochloride (124.79 mg, 381.82 μmol) in dioxane (3 mL). The mixture was stirred overnight at 120°C and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 15 / 1) to give the title compound (86 mg, 193.93 μmol, 50.8% yield) as a yellow oil. MS (ESI) m / z [M+H] + 444.1, [M+H] + 466.1.

[0440] Step 3: Synthesis of ethyl 2-(1'-(5-amino-4-methoxypyridin-2-yl)-6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)

[0441]

[0442] Iron powder (44.08 mg, 789.24 μmol) and ammonium chloride (42.22 mg, 789.24 μmol) were added to a solution of ethyl 2-(6-fluoro-1'-(4-methoxy-5-nitropyridin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) (70 mg, 157.85 μmol) in EtOH (2 mL) and water (0.2 mL). The mixture was stirred at 90°C for 2 h. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 16 / 1) to give the title compound as a yellow oil (60 mg, 145.11 μmol, 91.9% yield). MS (ESI) m / z [M+H] + 414.2.

[0443] Step 4: Synthesis of 2-(1'-(5-amino-4-methoxypyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid

[0444]

[0445] Sodium hydroxide (11.61 mg, 290.22 μmol) was added to a solution of ethyl 2-(1'-(5-amino-4-methoxypyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) in MeOH (3 mL) and water (3 mL). The mixture was stirred at room temperature for 3 h. The pH of the solution was adjusted to 6 with citric acid. The mixture was then extracted with DCM (3 × 40 mL), washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (50 mg, 129.72 μmol, 89.4% yield) as a yellow oil. MS (ESI) m / z [M+H] + 386.2.

[0446] Step 5: Synthesis of 2-(1'-(5-acrylamido-4-methoxypyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid

[0447]

[0448] Sodium bicarbonate (54.48 mg, 648.62 μmol) and acrylonitrile chloride (11.74 mg, 129.72 μmol, in 3 mL THF) were added to a solution of 2-(1'-(5-amino-4-methoxypyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (50 mg, 129.72 μmol, in 3 mL THF) in THF (3 mL) and water (5 mL) at 0°C. The mixture was stirred at 0°C for 30 min and diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound as a white solid (50 mg, 113.77 μmol, 87.7% yield). MS (ESI) m / z [M+H] + 440.1.

[0449] Step 6: N -(6-(( S )-6-Fluoro-3-(2-((( R Synthesis of 1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-4-methoxypyridin-3-yl)acrylamide (compound B20)

[0450]

[0451] Add ( ) to a solution of 2-(1'-(5-acrylamido-4-methoxypyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (50 mg, 113.77 μmol) in acetonitrile (6 mL) R )-2-amino- N 1,3-methyl-3-(3,4,5-trifluorophenyl)acrylamide hydrochloride (26.42 mg, 98.70 μmol), DIEA (73.52 mg, 568.86 μmol, 99.08 μL), and T3P (108.60 mg, 170.66 μmol, 50% in ethyl acetate). The mixture was stirred at room temperature for 3 h and quenched with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by rapid chromatography with octadecylsilane under the following conditions: column, C18 silica gel; mobile phase, CH3CN in water, in a 5% to 35% gradient over 15 min; detector, UV 254 nm, to give the title compound as a white solid (15.04 mg, 23.01 μmol, 20.2% yield). 1 H NMR (400 MHz, DMSO-) d 6) δ 9.25 (s, 1H), 8.31 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H),7.98-7.90 (m, 1H), 7.28-7.15 (m, 2H), 7.03 (dd, J = 9.5, 2.5 Hz, 1H), 6.91(dd, J = 8.4, 5.3 Hz, 1H), 6.82 (td, J = 8.8, 2.5 Hz, 1H), 6.56 (dd,J =17.0, 10.2 Hz, 1H), 6.45 (s, 1H), 6.18 (dd, J = 17.0, 2.1 Hz, 1H), 5.68 (dd, J = 10.2, 2.1 Hz, 1H), 4.63-4.51 (m, 1H), 4.29 (t, J = 16.4 Hz, 2H), 3.86 (s,3H), 3.39 (t, J = 7.7 Hz, 1H), 3.02 (dd, J = 13.8, 4.5 Hz, 1H), 2.90-2.73 (m,3H), 2.65-2.57 (m, 4H), 2.39-2.31 (m, 1H), 2.22 (dd, J = 14.3, 8.2 Hz, 1H), 2.10-1.98 (m, 1H), 1.63-1.45 (m, 4H). MS(ESI) m / z [M+H] + 654.3.

[0452] Example 8:

[0453] N -(6-(( S )-6-Fluoro-3-(2-((( R )-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2- (indole)amino)-2-oxoethyl)-2,3-dihydrospiro[indole-1,4'-piperidine]-1'-yl)-4-morpholinopyridin-3-yl)acryloyl Preparation of amine (compound B23)

[0454]

[0455] Step 1: Synthesis of 4-(2-bromo-5-nitropyridin-4-yl)morpholine

[0456]

[0457] 2-Bromo-4-chloro-5-nitropyridine (1.5 g, 6.32 mmol) was subjected to... N Morpholine (578.13 mg, 6.64 mmol) was added to a solution of methyl-2-pyrrolidone (10 mL). The mixture was stirred overnight at room temperature. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the title compound as a yellow solid (1.15 g, 63.2% yield). MS (ESI) m / z [M+H]+ 287.9, 289.9 (Br).

[0458] Step 2: Synthesis of ethyl 2-(6-fluoro-1'-(4-morpholino-5-nitropyridin-2-yl)-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)

[0459]

[0460] A sealed tube was filled with ethyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetate (500.0 mg, 1.72 mmol), 4-(2-bromo-5-nitropyridin-4-yl)morpholine (494.40 mg, 1.72 mmol), Pd2(dba)3 (157.50 mg, 172.00 μmol), Sphos (141.22 mg, 344.00 μmol), cesium carbonate (1.68 g, 5.16 mmol), and 1,4-dioxane (15 mL). The mixture was stirred overnight at 100°C under a nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound as a yellow solid (660 mg, 77.1% yield). MS (ESI) m / z [M+H] + 499.3.

[0461] Step 3: Synthesis of 2-(6-fluoro-1'-(4-morpholino-5-nitropyridin-2-yl)-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)acetic acid

[0462]

[0463] Sodium hydroxide (158.86 mg, 3.97 mmol) was added to a solution of ethyl 2-(6-fluoro-1'-(4-morpholino-5-nitropyridin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) in MeOH / THF / H2O (5 mL / 5 mL / 5 mL). The mixture was stirred at room temperature for 3 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a yellow solid (590 mg, 95% yield). MS (ESI) m / z [M+H] + 471.1.

[0464] Step 4: (2) R )-2-(2-(6-fluoro-1'-(4-morpholino-5-nitropyridin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamido)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)propionamide

[0465]

[0466] Add DIEA (485.30 mg, 3.76 mmol) to a solution of 2-(6-fluoro-1'-(4-morpholino-5-nitropyridin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (590 mg, 1.25 mmol) in acetonitrile (20 mL). R )-2-amino- N 3-Methyl-3-(3,4,5-trifluorophenyl)propionamide (436.77 mg, 1.88 mmol) and T3P (598.50 mg, 1.88 mmol, 50% in ethyl acetate). The mixture was stirred at room temperature for 3 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (550 mg, 64.1% yield) as a yellow solid. MS (ESI) m / z [M+H] + 685.3.

[0467] Step 5: (2) R )-2-(2-(1'-(5-amino-4-morpholinopyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamido)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)propionamide

[0468]

[0469] To (2) R )-2-(2-(6-fluoro-1'-(4-morpholino-5-nitropyridin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamido)- N3-Methyl-3-(3,4,5-trifluorophenyl)propionamide (550 mg, 803.30 μmol) was prepared in a solution of EtOH (20 mL) and H₂O (5 mL) with iron powder (448.64 mg, 8.03 mmol) and ammonium chloride (425.75 mg, 8.03 mmol). The mixture was stirred at 70°C for 3 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a brown solid (480 mg, 91.3% yield). MS (ESI) m / z [M+H] + 655.3.

[0470] Step 6: N -(6-(( S )-6-Fluoro-3-(2-((( R Synthesis of 1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-4-morpholinopyridin-3-yl)acrylamide (compound B23)

[0471]

[0472] At 0°C, towards (2 R )-2-(2-(1'-(5-amino-4-morpholinopyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamido)- N2-Methyl-3-(3,4,5-trifluorophenyl)propionamide (250 mg, 381.86 μmol) was prepared in a solution of THF (10 mL) and water (10 mL) with sodium bicarbonate (321.14 mg, 3.82 mmol) and acrylonitrile chloride (34.56 mg, 381.86 μmol). The mixture was stirred at 0°C for 30 min. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was then purified by preparative HPLC (column: Welch XB-C18 21.2 × 100 mm × 5 μm; mobile phase: [water(FA)-CH3CN]; B: 20%–50%, 8 min) to give the compound as a white solid (165 mg, yield: 61%). The racemic product was separated by a chiral SFC (instrument: SFC Thar prep 80; column: CHIRALPAK IC250 mm × 20 mm, 5 μm; modifier: 40% EtOH: 60% CO2; total flow rate: 40 g / min) to obtain the title compound (40.5 mg, 0.057 mmol, 24.5% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 9.19 (s, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H), 7.97-7.94 (m, 1H), 7.21 (dd, J = 9.1, 6.7 Hz, 2H), 7.03 (dd, J = 9.5, 2.5 Hz, 1H), 6.91 (dd, J = 8.4, 5.3 Hz, 1H), 6.82 (td, J = 8.7, 2.5 Hz, 1H), 6.53 (dd, J = 17.0, 10.2 Hz, 1H), 6.30 (s,1H), 6.20 (dd, J = 17.1, 2.1 Hz, 1H), 5.71 (dd, J = 10.1, 2.1 Hz, 1H), 4.59-4.53 (m, 1H), 4.25 (t, J= 16 Hz, 2H), 3.71 (t, J = 4.4 Hz, 4H), 3.44-3.35(m, 1H), 3.01-2.96 (m, 4H), 2.91-2.70 (m, 4H), 2.63-2.58 (m, 3H), 2.33 (dd, J = 12.8, 7.9 Hz, 1H), 2.21 (dd, J = 14.3, 8.2 Hz, 1H), 2.07-2.01 (m, 1H), 1.67-1.42 (m, 5H). MS(ESI) m / z [M+H] + 709.3.

[0473] Example 9:

[0474] N -(4-(2-(dimethylamino)ethoxy)-6-(( S )-6-Fluoro-3-(2-((( R )-1-(5-methyl-1,3,4-oxa (diazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]- Preparation of 1'-yl)pyridin-3-yl)acrylamide (compound B28)

[0475]

[0476] Step 1: Synthesis of tert-butyl (2-((2-bromo-5-nitropyridin-4-yl)oxy)ethyl)(methyl)carbamate

[0477]

[0478] Sodium hydride (29.90 mg, 1.30 mmol) was added to a solution of (2-hydroxyethyl)(methyl)carbamate tert-butyl ester (192.82 mg, 1.10 mmol) in THF (10 mL) at 0°C. The mixture was stirred at 0°C for 15 min under a nitrogen atmosphere. Then, 2,4-dibromo-5-nitropyridine (282 mg, 1.00 mmol) was added to the above mixture. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h and quenched with a saturated solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 7) to provide the title compound as a yellow oil (258 mg, 685.80 μmol, 68.5% yield). MS (ESI) m / z [M+H] + 376.0.

[0479] Step 2: ( S)-2-(1'-(4-(2-(( Uncle Synthesis of ethyl butoxycarbonyl(methyl)amino)ethoxy)-5-nitropyridin-2-yl)-6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)

[0480]

[0481] Fill the sealed tube with ( S Ethyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate (135 mg, 463.34 μmol), tert-butyl (2-((2-bromo-5-nitropyridin-4-yl)oxy)ethyl)(methyl)carbamate (191.74 mg, 509.68 μmol), Pd2(dba)3 (63.59 mg, 69.50 μmol), Sphos (56.99 mg, 139.00 μmol), cesium carbonate (453.15 mg, 1.39 mmol), and 1,4-dioxane (5 mL) were added. The mixture was stirred at 100°C for 16 h under a nitrogen atmosphere and quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 5) to provide the title compound as a yellow oil (201 mg, 342.62 μmol, 73.9% yield). MS (ESI) m / z [M+H] + 587.3.

[0482] Step 3: ( S Synthesis of ethyl acetate 2-(6-fluoro-1'-(4-(2-(methylamino)ethoxy)-5-nitropyridin-2-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)

[0483]

[0484] Towards( S )-2-(1'-(4-(2-(( UncleEthyl butoxycarbonyl(methyl)amino)ethoxy)-5-nitropyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate (201 mg, 343.0 μmol) was added to a solution of dioxane (5 mL) with hydrogen chloride (1 mL, 4 M in 1,4-dioxane). The mixture was stirred at room temperature for 3 h. The solvent was evaporated under vacuum to give the title compound (166 mg, 343.0 μmol, 100% yield) as a yellow oil. MS (ESI) m / z [M+H] + 487.2.

[0485] Step 4: ( S Synthesis of ethyl acetate 2-(1'-(4-(2-(dimethylamino)ethoxy)-5-nitropyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)

[0486]

[0487] Towards( S A solution of ethyl acetate (166 mg, 343.0 μmol) and formaldehyde (206 mg, 686.0 mmol) in MeOH (5 mL) was prepared with NaBH3CN (109.2 mg, 686.0 μmol). The mixture was stirred at room temperature for 6 h and quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 1) to provide the title compound as a yellow oil (147 mg, 294.4 μmol, 86.6% yield). MS (ESI) m / z [M+H] + 501.2.

[0488] Steps 5-8: N -(4-(2-(dimethylamino)ethoxy)-6-(( S )-6-Fluoro-3-(2-((( RSynthesis of 1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)amino)-2-oxoethyl)-2,3-dihydrospiro[inden-1,4'-piperidin]-1'-yl)pyridin-3-yl)acrylamide (compound B28)

[0489]

[0490] Following the method of steps 3-6 in Example 11 (B12), use ( S Ethyl ethyl acetate of 2-(1'-(4-(2-(dimethylamino)ethoxy)-5-nitropyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) was used to give the title compound as a grayish-white solid (4.24 mg, 5.77 μmol, 14% overall yield in 4 steps). 1 H NMR (400 MHz, CD3OD) δ 8.57(s, 1H), 7.18-7.09 (m, 2H), 7.05-7.00 (m, 1H), 6.90-6.80 (m, 2H), 6.57-6.46(m, 2H), 6.39-6.31 (m, 1H), 5.77 (dd, J = 10.2, 1.7 Hz, 1H), 5.54 (dd, J =10.2, 5.4 Hz, 1H), 4.36-4.15 (m, 4H), 3.57-3.46 (m, 1H), 3.41 (dd, J = 14.1,5.4 Hz, 1H), 3.26-3.11 (m, 1H), 3.08-2.93 (m, 4H), 2.72 (dd, J = 14.2, 5.9Hz, 1H), 2.58-2.42 (m, 10H), 2.29 (dd, J = 14.3, 9.0 Hz, 1H), 2.11 (td, J =13.2, 4.5 Hz, 1H), 1.76-1.55 (m, 5H). MS(ESI) m / z [M+H] + 736.3.

[0491] Example 10:

[0492] N -(4-Cyclohexyl-6-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl) Ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)pyridin-3-yl)acrylamide Preparation of (compound B31)

[0493]

[0494] Step 1: Synthesis of tert-butyl (6-chloro-4-(cyclohex-1-en-1-yl)pyridin-3-yl)carbamate

[0495]

[0496] A solution of tert-butyl (6-chloro-4-iodopyridin-3-yl)carbamate (1.06 g, 3.00 mmol) and cyclohexyl-1-en-1-ylboronic acid (415.00 mg, 3.29 mmol) in water (3 mL) and 1,4-dioxane (12 mL) was added to Pd(dppf)Cl2 (367.51 mg, 449.28 μmol) and sodium carbonate (952.46 mg, 8.99 mmol). The mixture was stirred at 100°C for 6 h. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 5) to give the title compound (600 mg, 1.94 mmol, 64.9% yield) as a yellow oil. MS (ESI) m / z [M+H] + 309.1.

[0497] Step 2: ( S )-2-(1'-(5-(( Uncle Synthesis of ethyl butoxycarbonyl)amino)-4-(cyclohex-1-en-1-yl)pyridin-2-yl)-6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)

[0498]

[0499] Add tert-butyl 6-chloro-4-(cyclohexyl-1-en-1-yl)pyridin-3-yl)carbamate (330 mg, 1.07 mmol) to a sealed tube. SEthyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate (311.36 mg, 1.07 mmol), Sphos (131.44 mg, 320.59 μmol), Pd2(dba)3 (146.83 mg, 160.30 μmol), cesium carbonate (1.05 g, 3.21 mmol), and 1,4-dioxane (10 mL) were added. The mixture was stirred at 100°C for 16 h under a nitrogen atmosphere and quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 5) to provide the title compound as a yellow oil (400 mg, 709.60 μmol, 66.4% yield). MS (ESI) m / z [M+H] + 564.3.

[0500] Step 3: ( S )-2-(1'-(5-(( Uncle Synthesis of ethyl butoxycarbonyl)amino)-4-cyclohexylpyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)

[0501]

[0502] Towards( S )-2-(1'-(5-(( Uncle (Butoxycarbonyl)amino)-4-(cyclohex-1-en-1-yl)pyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate (120 mg, 212.88 μmol) was added to a solution of ethyl acetate (3 mL) and EtOH (3 mL) with Pd / C (103.42 mg, 10%). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the title compound as a pale yellow solid (118 mg, 208.58 μmol, 98% yield). MS (ESI) m / z [M+H] + 566.3.

[0503] Steps 4-7: N -(4-Cyclohexyl-6-(( S )-3-(2-((( RSynthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)pyridin-3-yl)acrylamide (compound B31)

[0504]

[0505] Following the method in steps 2-5 of Example 1 (B1), use ( S Ethyl acetate of 2-(1'-(5-((tert-butoxycarbonyl)amino)-4-cyclohexylpyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) was used to give the title compound as a grayish-white solid (26 mg, 37.21 μmol, 21.2% overall yield over 4 steps). 1 H NMR (400 MHz, DMSO- d 6) δ 8.94(s, 1H), 7.92 (s, 1H), 7.34-7.14 (m, 2H), 7.14-7.07 (m, 1H), 6.99 (dd, J =8.2, 5.2 Hz, 1H), 6.92-6.78 (m, 2H), 6.76 (s, 1H), 6.49 (dd, J = 17.0, 10.1Hz, 1H), 6.35 (dd, J = 17.1, 1.8 Hz, 1H), 5.81 (dd, J = 10.1, 1.8 Hz, 1H), 5.61 (dd, J = 10.0, 5.6 Hz, 1H), 4.33-4.07 (m, 2H), 3.66-3.38 (m, 2H), 3.21(dd, J = 14.1, 10.1 Hz, 1H), 3.11-2.92 (m, 2H), 2.72 (dd, J = 14.2, 5.9 Hz,1H), 2.68-2.60 (m, 1H), 2.45 (dd, J = 13.0, 7.8 Hz, 1H), 2.33-2.25 (m, 1H), 1.91-1.56 (m, 10H), 1.51-1.27 (m, 6H). MS(ESI) m / z [M+H] + 699.3.

[0506] Example 11:

[0507] N -(4-Cyclohexyl-6-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl) Ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)pyridin-3-yl)- N -methyl Preparation of Acrylamide (Compound B32)

[0508]

[0509] Step 1: ( S )-2-(1'-(5-(( Uncle Synthesis of ethyl butoxycarbonyl(methyl)amino)-4-cyclohexylpyridin-2-yl)-6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)

[0510]

[0511] Towards( S )-2-(1'-(5-(( Uncle A solution of ethyl butoxycarbonyl(amino)-4-cyclohexylpyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetate (107 mg, 189.14 μmol) in acetonitrile (5 mL) was mixed with cesium carbonate (184.98 mg, 567.42 μmol) and methyl iodoform (80.54 mg, 567.42 μmol, 35.32 μL). The mixture was stirred at 50°C for 6 h under a nitrogen atmosphere and quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the title compound as a pale yellow solid (100 mg, 172.49 μmol, 91.2% yield). MS (ESI) m / z [M+H] + 580.3.

[0512] Steps 2-5: N -(4-Cyclohexyl-6-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)pyridin-3-yl)- N Synthesis of -methacrylamide (compound B32)

[0513]

[0514] Following the method in steps 2-5 of Example 1 (B1), use ( S )-2-(1'-(5-(( Uncle Ethyl butoxycarbonyl(methyl)amino)-4-cyclohexylpyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) was used to give the title compound as a white solid (40.9 mg, 57.38 μmol, 41% overall yield in 4 steps). 1 H NMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 8.86 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.30-7.16 (m, 2H), 7.12(s, 1H), 7.01 (dd, J = 8.3, 5.1 Hz, 1H), 6.93-6.80 (m, 3H), 6.30 (dd, J =16.9, 2.0 Hz, 1H), 6.09 (dd, J = 16.8, 10.3 Hz, 1H), 5.68-5.55 (m, 2H), 4.41-4.20 (m, 2H), 3.54-3.41 (m, 2H), 3.24 (s, 3H), 3.23-3.18 (m, 1H), 3.15-2.96(m, 2H), 2.74(dd, J = 14.2, 5.9 Hz, 1H), 2.53-2.37 (m, 2H), 2.29 (dd, J =14.3, 9.0 Hz, 1H), 2.21-2.03 (m, 1H), 1.93-1.73 (m, 4H), 1.72-1.59 (m, 5H), 1.56-1.50 (m, 2H), 1.44-1.25 (m, 3H). MS(ESI) m / z [M+H] + 713.2.

[0515] Example 12:

[0516] N -(6-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino (indole)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indole-1,4'-piperidine]-1'-yl)-4-(2-methoxyphenyl)pyridine-3- Preparation of (B33) acrylamide (compound B33)

[0517]

[0518] Step 1: Synthesis of tert-butyl (6-chloro-4-(2-methoxyphenyl)pyridin-3-yl)carbamate

[0519]

[0520] To a solution of (6-chloro-4-iodopyridin-3-yl)carbamate tert-butyl ester (200 mg, 564.06 μmol) in water (1 mL) and 1,4-dioxane (10 mL), (2-methoxyphenyl)boronic acid (102.85 mg, 676.87 μmol), Pd(dppf)Cl2 (51.61 mg, 56.41 μmol), and cesium carbonate (551.65 mg, 1.69 mmol) were added. The resulting solution was stirred at 80°C for 15 h under a nitrogen atmosphere. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The organic layers were combined, washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 3 / 1) to give the title compound as a yellow solid (190 mg, 539.13 μmol, 95.6% yield). MS (ESI) m / z [M+H] + 335.0.

[0521] Step 2: ( S )-2-(1'-(5-(( Uncle Synthesis of ethyl butyryl(butoxycarbonyl)amino)-4-(2-methoxyphenyl)pyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)

[0522]

[0523] Fill the sealed tube with ( SEthyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)carbamate (170 mg, 583.47 μmol), tert-butyl (6-chloro-4-(2-methoxyphenyl)pyridin-3-yl)carbamate (234.41 mg, 700.17 μmol), Pd2(dba)3 (53.39 mg, 58.35 μmol), Sphos (47.84 mg, 116.69 μmol), cesium carbonate (570.64 mg, 1.75 mmol), and 1,4-dioxane (10 mL) were added. The mixture was stirred at 100°C for 15 h under a nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The organic layers were combined, washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 3 / 1) to give the title compound as a yellow solid (180 mg, 305.24 μmol, 52.3% yield). MS (ESI) m / z [M-Boc+H] + 490.2.

[0524] Steps 3-6: N -(6-(( S )-3-(2-((( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-4-(2-methoxyphenyl)pyridin-3-yl)acrylamide (compound B33)

[0525]

[0526] Following the method in steps 2-5 of Example 1 (B1), use ( S )-2-(1'-(5-(( Uncle Acetic acid ethyl butoxycarbonyl)amino)-4-(2-methoxyphenyl)pyridin-2-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) was used to give the title compound as a white solid (53.36 mg, 73.83 μmol, 24.2% overall yield over 4 steps). 1 H NMR (400 MHz, DMSO- d 6) δ 9.38 (s, 1H), 9.25 (s, 1H), 8.73 (d, J= 8.5 Hz, 1H), 7.72 (s, 1H), 7.55-7.29 (m, 2H), 7.21-7.12 (m, 1H), 7.05 (dd, J = 9.5, 2.5 Hz, 1H), 6.94(dd, J = 8.4, 5.4 Hz, 1H), 6.85 (td, J = 8.7, 2.4 Hz, 1H), 6.40 (dd, J =17.1, 10.2 Hz, 1H), 6.19 (dd, J = 17.1, 1.9 Hz, 1H), 5.71 (dd, J = 10.2, 2.0Hz, 1H), 5.54-5.42 (m, 1H), 4.62 (t, J = 13.0 Hz, 2H), 3.46 (t, J = 5.3 Hz, 4H), 3.15 (dd, J = 13.9, 10.5 Hz, 1H), 2.89-2.85 (m, 2H), 2.68-2.60 (m, 2H), 2.37-2.29 (m, 1H), 2.18 (dd, J = 14.0, 8.3 Hz, 1H), 2.01-1.91 (m, 1H), 1.58-1.44 (m, 9H). MS(ESI) m / z [M+H] + 723.2.

[0527] Example 13:

[0528] N -(4-(6-cyano-3-(2-((( R )-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2- (B47) Acrylamide (compound B47)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)phenyl) Preparation

[0529]

[0530] Step 1: Synthesis of tert-butyl 4-(3-bromophenyl)-4-cyanopiperidine-1-carboxylate

[0531]

[0532] Sodium hydride (1.02 g, 25.50 mmol, 60% purity) was added to a solution of 2-(3-bromophenyl)acetonitrile (5.0 g, 25.50 mmol) and tert-butyl bis(2-chloroethyl)carbamate (6.18 g, 25.50 mmol) in THF (80 mL) at 0°C. The mixture was stirred at 80°C for 3 h. After cooling to room temperature, the reaction was quenched with water (100 mL). The mixture was extracted with ethyl acetate (3 × 80 mL), washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 6) to give the title compound (8.1 g, 22.18 mmol, 86.9% yield) as a yellow oil. MS (ESI) m / z [M+Na] + 387.1, 389.1 (Br).

[0533] Step 2: Synthesis of 4-(3-bromophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

[0534]

[0535] Sodium hydride (17.74 g, 443.51 mmol) was added fractionally to a solution of tert-butyl 4-(3-bromophenyl)-4-cyanopiperidin-1-carboxylate (8.1 g, 22.18 mmol) in EtOH (100 mL) and water (100 mL) at 0°C. The mixture was stirred at 90°C for 24 h. The pH of the solution was adjusted to 6 with hydrochloric acid. The mixture was extracted with ethyl acetate (4 × 150 mL), washed with brine (2 × 200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a white solid (6.0 g, 15.61 mmol, 70.4% yield). MS (ESI) m / z [M+Na] + 406.0, 408.0 (Br).

[0536] Step 3: Synthesis of tert-butyl 4-(3-bromophenyl)-4-(chlorocarbonyl)piperidine-1-carboxylate

[0537]

[0538] At 0°C, oxaloyl chloride (2.97 g, 23.42 mmol, 2.04 mL) was added dropwise to a solution of 4-(3-bromophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (6.0 g, 15.61 mmol) in DCM (100 mL). Then, DMF (0.1 mL) was slowly added to the above solution. The mixture was stirred at room temperature for 3 h. The solvent was evaporated under vacuum to give the title compound (5.4 g, 13.41 mmol, 85.9% yield) as a yellow oil, which was used directly in the next step.

[0539] Step 4: Synthesis of tert-butyl 4-(3-bromophenyl)-4-(2-diazaacetyl)piperidine-1-carboxylate

[0540]

[0541] At 0°C, TMSCHN2 (13.41 mL, 16.82 mmol in THF, 2 M) was added dropwise to a solution of tert-butyl piperidine-1-carboxylate (5.4 g, 13.41 mmol) in acetonitrile (60 mL). The mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum to give the title compound (5.0 g, 12.25 mmol, 91.3% yield) as a yellow oil, which was used directly in the next step. MS (ESI) m / z [M+Na] + 430.1, 432.1 (Br).

[0542] Step 5: Synthesis of tert-butyl 4-(3-bromophenyl)-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate

[0543]

[0544] A solution of tert-butyl 4-(3-bromophenyl)-4-(2-diazaacetyl)piperidine-1-carboxylate (3.6 g, 8.82 mmol) in MeOH (40 mL) was stirred at room temperature under irradiation (365 nm) for 4 h. The mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to give the title compound (2.3 g, 5.58 mmol, 63.3% yield) as a yellow oil. MS (ESI) m / z [M+Na] + 434.0, 436.1 (Br).

[0545] Step 6: Synthesis of tert-butyl 6-bromo-3-oxo-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate

[0546]

[0547] A solution of tert-butyl 4-(3-bromophenyl)-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (2.3 g, 5.58 mmol) in trifluoromethanesulfonic acid (10 mL) was stirred at 50°C for 2 h. The pH of the solution was adjusted to 10 with sodium hydroxide (2 N). THF (10 mL) and di-tert-butyl dicarbonate (1.83 g, 8.37 mmol) were added to the mixture. The resulting mixture was stirred overnight at room temperature. The mixture was extracted with DCM (3 × 80 mL). The combined organic layers were washed with brine (2 × 80 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 8) to give the title compound (1.7 g, 4.47 mmol, 80.2% yield) as a yellow oil. MS (ESI) m / z [M+Na] + 402.0, 404.0 (Br).

[0548] Step 7: Synthesis of a mixture of tert-butyl 6-bromo-3-(2-ethoxy-2-oxoethylene)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate and tert-butyl 6-bromo-3-(2-ethoxy-2-oxoethyl)spiro[indene-1,4'-piperidine]-1'-carboxylate.

[0549]

[0550] To a solution of tert-butyl 6-bromo-3-oxo-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (1.5 g, 3.94 mmol) in THF (30 mL), ethyl 2-(diethoxyphosphoryl)acetate (1.59 g, 7.10 mmol, 1.41 mL) and potassium tert-butoxide (663.92 mg, 5.92 mmol) were added. The mixture was stirred overnight at 70°C. After cooling to room temperature, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to give the title compound (1.3 g, 2.89 mmol, 73.2% yield) as a yellow oil. MS (ESI) m / z [M+Na] +471.8, 473.8 (Br).

[0551] Step 8: Synthesis of the mixture of tert-butyl 6-cyano-3-(2-ethoxy-2-oxoethylene)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate and tert-butyl 6-cyano-3-(2-ethoxy-2-oxoethyl)spiro[indene-1,4'-piperidine]-1'-carboxylate

[0552]

[0553] The mixture of products obtained in the above steps (100 mg, 222.04 μmol), Zn(CN)₂ (39.11 mg, 333.06 μmol), and Pd(PPh₃)₄ (25.66 mg, 22.20 μmol) in DMF (2 mL) was stirred overnight at 110°C. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by TLC (ethyl acetate / petroleum ether = 1 / 4) to give the title compound (52 mg, 131.15 μmol, 59.1% yield) as a pale yellow oil. MS (ESI) m / z [M+Na] + 418.9.

[0554] Step 9: Synthesis of tert-butyl 6-cyano-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate

[0555]

[0556] Pd / C (30 mg, 10%) was added to a solution of the above mixture (130 mg, 327.89 μmol) in MeOH (3 mL). The mixture was stirred at room temperature for 3 h under a hydrogen atmosphere. After filtration, the filtrate was concentrated under vacuum to give the title compound (120 mg, 301.13 μmol, 91.8% yield) as a yellow oil. MS (ESI) m / z [M+Na] + 420.9.

[0557] Step 10: Synthesis of 2-(6-cyano-2,3-dihydrospiro[inden-1,4'-piperidine]-3-yl)ethyl acetate hydrochloride

[0558]

[0559] Hydrogen chloride (1 mL, 4 M in 1,4-dioxane) was added to a solution of tert-butyl 6-cyano-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (120 mg, 301.13 μmol) in DCM (6 mL). The mixture was stirred at room temperature for 3 h. The solvent was evaporated under vacuum to give the title compound as a white solid (86 mg, 257.61 μmol, 85.6% yield). MS (ESI) m / z [M+H] + 299.2.

[0560] Steps 11-15: N -(4-(6-cyano-3-(2-((( R Synthesis of 1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)phenyl)acrylamide (compound B47)

[0561]

[0562] Following the method of steps 1-5 in Example 1 (B1), using ethyl acetate 2-(6-cyano-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl) hydrochloride, the title compound was obtained as a white solid (31.32 mg, 49.74 μmol, 28.3% overall yield from 5 steps). 1 H NMR (400 MHz, DMSO- d 6) δ 9.93 (s, 1H), 8.28 (dd, J = 8.7, 2.6 Hz,1H), 8.04-7.90 (m, 1H), 7.74 (dd, J = 4.3, 1.5 Hz, 1H), 7.63-7.49 (m, 3H),7.33 (d, J = 7.9 Hz, 1H), 7.25-7.12 (m, 2H), 6.95 (dd, J = 9.1, 2.4 Hz, 2H), 6.41 (ddd, J = 17.1, 10.2, 1.3 Hz, 1H), 6.21 (dd, J = 17.0, 2.1 Hz, 1H), 5.70(dd, J= 10.1, 2.2 Hz, 1H), 4.61-4.49 (m, 1H), 3.66-3.43 (m, 3H), 3.01 (dd, J = 13.8, 4.5 Hz, 1H), 2.82-2.55 (m, 7H), 2.33-2.18 (m, 3H), 1.81-1.66 (m, 1H), 1.59-1.45 (m, 3H). MS(ESI) m / z [M+H] + 630.2.

[0563] The following compounds (Series B) in Table 1 were synthesized using appropriate starting materials and corresponding intermediates, following a similar procedure to that described for Examples 1-13.

[0564] Table 1:

[0565]

[0566] Table 1a:

[0567]

[0568] General methods for series C compounds:

[0569] Synthesis of intermediates

[0570]

[0571] Intermediate VIII was synthesized via two different routes using 1-fluoro-2-nitrobenzene I or 2-aminophenol as starting materials. I reacted with ethyl glycolate or methyl glycolate to yield II. After reduction of the nitro group using iron powder, the resulting III could be converted to VI via intramolecular ammonolysis. VI could also be obtained from intermediate V, which was obtained through a condensation reaction between IV and bromoacetic acid, followed by intramolecular S... N2. Reaction Synthesis. The amide in VI was reduced using borane. The resulting amine intermediate VII was reacted with Boc₂O to give the target intermediate VIII.

[0572]

[0573] X = N or CH; Q = O or CH2; R5 = F or small alkyl group; Z1 = N, CH or CF; R6 = halo, small alkyl or alkoxy group; T = CH2, O, S, SO or SO2; R, R s3 = H, halogenated, alkyl, or R and R s3 Form a ring; R1 = H or C(O)NR b R c 1. Cycloalkyl, substituted alkyl or heterocyclic groups; R2, R3, R4 = H or F; R m = H, halogenated or alkylene-amine; R n = H or halogenated;

[0574] Intermediate II is obtained via a Buchwald coupling reaction between I and various aromatic bromides. Following hydrolysis, the resulting acidic intermediate III reacts with different amines to obtain IV. Amine intermediate V, obtained through the removal of the Boc group or the reduction of the nitro group, reacts with acryloyl chloride to give the target compound VI.

[0575] Example 14:

[0576] ( R )-2-(2-(( S )-1'-(4-Acryloyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro- 2,3-Dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamyl)- N 3-Methyl-3-(3,4,5-trifluorophenyl)propionamide (compound) Preparation of substance C2)

[0577]

[0578] Step 1: Synthesis of tert-butyl 2-(5-bromo-2-nitrophenoxy)acetate

[0579]

[0580] Cesium carbonate (48.8 g, 149.7 mmol) was added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (10.94 g, 49.9 mmol) and tert-butyl 2-hydroxyacetate (9.88 g, 74.85 mmol) in acetonitrile (50 mL). The mixture was stirred at 80°C for 16 h under a nitrogen atmosphere and quenched with water (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 7) to provide the title compound as a yellow oil (13.58 g, 40.91 mmol, 82.1% yield). MS (ESI) m / z [M+H] + 332.2.

[0581] Step 2: Synthesis of tert-butyl 2-(2-amino-5-bromophenoxy)acetate

[0582]

[0583] Iron powder (13.74 g, 245.4 mmol) was added to a solution of tert-butyl 2-(5-bromo-2-nitrophenoxy)acetate (13.58 g, 40.91 mmol) and hydrochloric acid (one drop) in water (15 mL) and EtOH (15 mL). The mixture was stirred at 70°C for 3 h and filtered. The filtrate was concentrated under vacuum. The mixture was diluted with ethyl acetate (100 mL) and water (80 mL). The organic layer was separated. The aqueous phase was extracted with ethyl acetate (3 × 80 mL). The organic layers were combined, washed with brine (3 × 80 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (11.0 g, 36.41 mmol, 89.1% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 302.2.

[0584] Step 3: 7-Bromo-2 H -benzo[ b [1,4]Oxazine-3(4 H Synthesis of )-ketones

[0585]

[0586] Trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 2-(2-amino-5-bromophenoxy)acetate (11.0 g, 36.41 mmol) in DCM (150 mL). The mixture was stirred at 45°C for 4 h. The mixture was concentrated under vacuum to give the title compound (8.11 g, 35.57 mmol, 97.7% yield) as a yellow oil. MS (ESI) m / z [M+H] + 228.0.

[0587] Step 4: 7-Bromo-3,4-Dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine

[0588]

[0589] 7-bromo-2 H -benzo[ b [1,4]Oxazine-3(4 H A solution of the β-keto compound (8.11 g, 35.57 mmol) in THF (150 mL) was added to a borane-tetrahydrofuran complex (70 mL, 1.0 M in THF). The mixture was heated at 70°C for 2 h under a nitrogen atmosphere and quenched with EtOH (20 mL). The mixture was then heated at 80°C for 2 h and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to provide the title compound (6.7 g, 31.30 mmol, 88% yield) as a yellow oil. MS (ESI) m / z [M+H] + 214.1.

[0590] Step 5: 7-Bromo-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0591]

[0592] At 0°C, to 7-bromo-3,4-dihydro-2 H -benzo[ b[1,4]Oxazine (6.7 g, 31.30 mmol) was added to a solution of LiHMDS (37.56 mL, 1.0 M in THF) in 30 mL of THF. The mixture was stirred at 0°C for 15 min. Di-tert-butyl dicarbonate (8.19 g, 37.56 mmol) was added to the above mixture. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and quenched with a saturated solution of ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to provide the title compound (7.98 g, 25.41 mmol, 81.2% yield) as a yellow oil. MS (ESI) m / z [M+H] + 314.2.

[0593] Step 6: Synthesis of ethyl acetate 2-(6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidine]-3-yl)

[0594]

[0595] Hydrogen chloride (15 mL, 4.0 M in 1,4-dioxane) was added to a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-carboxylate (8.2 g, 20.96 mmol) in 1,4-dioxane (150 mL). The mixture was stirred at room temperature for 3 h and concentrated under vacuum to provide the title compound as a white solid (6.85 g, 20.96 mmol, 100% yield). MS (ESI) m / z [M+H] + 292.2.

[0596] Step 7: 7-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0597]

[0598] Acetyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) hydrochloride (2.91 g, 8.92 mmol), 7-bromo-2,3-dihydro-4 H -benzo[ bA mixture of tert-butyl 1,4-oxazine-4-carboxylate (3.35 g, 10.7 mmol), Pd2(dba)3 (1.22 g, 1.34 mmol), Sphos (1.10 g, 2.68 mmol), and cesium carbonate (8.73 g, 26.77 mmol) in 1,4-dioxane (30 mL) was heated at 100°C for 16 h under a nitrogen atmosphere. The reaction was quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 6) to provide the title compound (3.46 g, 6.61 mmol, 74.1% yield) as a yellow oil. MS (ESI) m / z [M+H] + 525.3.

[0599] Step 8: 2-(1'-(4-(tert-butoxycarbonyl)-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid

[0600]

[0601] 7-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2,3-dihydro-4 H -benzo[ b [1,4]Oxazine-4-carboxylic acid tert-butyl ester (1.6 g, 3.05 mmol) was dissolved in THF (5 mL), water (5 mL), and MeOH (5 mL) with sodium hydroxide (608.82 mg, 15.22 mmol). The mixture was stirred at room temperature for 6 h and concentrated under vacuum. The residue was diluted with ethyl acetate (20 mL) and water (20 mL). The pH of the solution was adjusted to 6 with hydrochloric acid (1 N). The organic layer was separated. The organic phase was extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (1.48 g, 2.99 mmol, 98% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 497.2.

[0602] Step 9: 7-(6-Fluoro-3-(2-((( R)-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0603]

[0604] To 2-(1'-(4-( Uncle (butoxycarbonyl)-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid (70.95 mg, 0.143 mmol), ( R )-2-amino- N 3-Methyl-3-(3,4,5-trifluorophenyl)propionamide hydrochloride (38.28 mg, 142.85 μmol), HATU (70.56 mg, 185.70 μmol), and DIEA (55.34 mg, 0.429 mmol) were added to a solution of THF (5 mL). The mixture was stirred at room temperature for 4 h and quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 1) to provide the title compound as a colorless oil (86.75 mg, 122.19 μmol, 85.4% yield). MS (ESI) m / z [M+H] + 711.3.

[0605] Step 10: (2) R )-2-(2-(1'-(3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamyl)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)acrylamide trifluoroacetate

[0606]

[0607] To 7-(6-fluoro-3-(2-((( R)-1-(methylamino)-1-oxo-3-(3,4,5-trifluorophenyl)prop-2-yl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2,3-dihydro-4 H -benzo[ b A solution of [1,4]oxazine-4-carboxylate tert-butyl ester (86.75 mg, 122.19 μmol) in DCM (5 mL) was supplemented with trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 4 h and concentrated under vacuum to provide the title compound as a yellow oil (86.4 mg, 122.19 μmol, 100% yield). MS (ESI) m / z [M+H] + 611.3.

[0608] Step 11: (2) R )-2-(2-(1'-(4-Acryloyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamyl)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)propionamide

[0609]

[0610] To (2) R )-2-(2-(1'-(3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamyl)- N 3-Methyl-3-(3,4,5-trifluorophenyl)propionamide trifluoroacetate (86.4 mg, 122.19 μmol) was dissolved in water (5 mL) and THF (5 mL) with sodium bicarbonate (42.18 mg, 502.2 μmol). Acrylonitrile chloride (21.99 mg, 244.38 μmol, in 1 mL THF) was added dropwise to the mixture. The mixture was stirred for 10 min and diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC to provide the title compound as a grayish-white solid (57.63 mg, 86.75 μmol, 71% yield). MS (ESI) m / z [M+H] +665.3.

[0611] Step 12: ( R )-2-(2-(( S )-1'-(4-Acryloyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamyl)- N Synthesis of methyl-3-(3,4,5-trifluorophenyl)acrylamide (compound C2)

[0612]

[0613] Compound C2 was obtained by SFC separation under the following separation conditions:

[0614] Instrument: SFC Thar prep 80

[0615] Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm

[0616] Modifier: 39% MeOH (0.2% NH4OH)

[0617] Total flow rate: 40 g / min

[0618] Compound C2: 18.21 mg 1 H NMR (400 MHz, DMSO- d 6) δ 8.24 (d, J = 8.7 Hz, 1H), 7.93 (q, J = 4.4 Hz, 1H), 7.28-7.15 (m, 2H), 7.06 (dd, J = 9.5, 2.4 Hz, 1H), 6.92 (dd, J = 8.1, 5.4 Hz, 1H), 6.87-6.69 (m, 2H), 6.57 (dd, J = 9.0, 2.7 Hz, 1H), 6.47 (d, J = 2.2 Hz, 1H), 6.24 (d, J = 16.8 Hz, 1H), 5.79 (dd, J = 10.4, 2.1 Hz, 1H), 4.55 (td, J= 10.3, 4.5 Hz, 1H), 4.29-4.20 (m, 2H), 3.95-3.84 (m, 2H), 3.62 (dd, J = 27.2, 13.9 Hz, 2H), 3.37 (dd, J = 15.4, 8.0Hz, 1H), 3.02 (dd, J = 13.7, 4.4 Hz, 1H), 2.82-2.56 (m, 7H), 2.30-2.08 (m,3H), 1.71 (dt, J = 12.5, 9.9 Hz, 1H), 1.56-1.43 (m, 3H). MS(ESI) m / z [M+H] + 665.3.

[0619] Example 15:

[0620] 2-(( S )-1'-(4-Acryloyl-6-fluoro-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2, 3-Dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl Preparation of acetamide (compound C5)

[0621]

[0622] Step 1: ( R Synthesis of tert-butyl carbamate (3-(3,4-difluorophenyl)-1-(2-formylhydrazido)-1-oxopropyl-2-yl)carbamate

[0623]

[0624] Towards( R 2-((tert-butoxycarbonyl)amino)-3-(3,4-difluorophenyl)propionic acid (5.00 g, 16.60 mmol) was reacted with formylhydrazine (1.20 g, 19.91 mmol), DIEA (6.42 g, 49.79 mmol), and HATU (7.57 g, 19.91 mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (300 mL). The aqueous phase was extracted with ethyl acetate (2 × 200 mL). The organic layers were combined, washed with brine (2 × 80 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to provide the title compound as a grayish-white solid (4.70 g, 12.32 mmol, 74.2% yield). MS (ESI) m / z [M+Na] + 366.1.

[0625] Step 2: (R Synthesis of tert-butyl carbamate (2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)carbamate

[0626]

[0627] Towards( R )-(3-(3,4-difluorophenyl)-1-(2-formylhydrazine)-1-oxopropyl-2-yl)carbamic acid Uncle Butyl ester (4.70 g, 13.69 mmol) was added to a solution of acetonitrile (50 mL) along with DIEA (5.30 g, 41.07 mmol), triphenylphosphine (5.38 g, 20.53 mmol), and carbon tetrachloride (6.32 g, 41.07 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL). The aqueous phase was extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 2 / 1) to provide the title compound as a white solid (3.50 g, 10.76 mmol, 78.6% yield). MS (ESI) m / z [M+H] + 326.3.

[0628] Step 3: ( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl-1-amine

[0629]

[0630] Towards( R 3.50 g (10.76 mmol) of tert-butyl carbamate (2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)carbamate was added to a solution in DCM (50 mL) with 3 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 3 h. The mixture was concentrated under vacuum. The residue was dissolved in a saturated solution of sodium bicarbonate (50 mL). The aqueous phase was extracted with ethyl acetate (2 × 100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 50 / 1) to provide the title compound (2.1 g, 8.95 mmol, 83.2% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 226.1.

[0631] Step 4: 7-Bromo-6-Fluoro-2 H -benzo[ b [1,4]Oxazine-3(4 H Synthesis of )-ketones

[0632]

[0633] Sodium bicarbonate (420 mg, 5.0 mmol) was added to a solution of 2-amino-5-bromo-4-fluorophenol (205 mg, 1.0 mmol) in THF (10 mL) and water (10 mL). The mixture was cooled to 0°C. A solution of 2-bromoacetyl bromide (240 mg, 1.2 mmol) in THF (3 mL) was added at 0°C. The mixture was stirred at 0°C for 10 min and then at 80°C for 16 h. The mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 8) to provide the title compound as a yellow oil (201.3 mg, 0.822 mmol, 82.2% yield). MS (ESI) m / z [M+H] + 245.9.

[0634] Step 5: 7-Bromo-6-fluoro-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine

[0635]

[0636] To 7-bromo-6-fluoro-2 H -benzo[ b [1,4]Oxazine-3(4 H The 201.3 mg (0.822 mmol) ketone was added to a solution of borane-tetrahydrofuran complex (1.6 mL, 1.0 M in THF) in 10 mL of THF. The mixture was stirred at 70°C for 2 h under a nitrogen atmosphere and quenched with MeOH (20 mL). The mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to provide the title compound as a yellow oil (173.5 mg, 0.748 mmol, 91.0% yield). MS (ESI) m / z [M+H] + 232.0.

[0637] Step 6: 7-Bromo-6-fluoro-2,3-dihydro-4H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0638]

[0639] To 7-bromo-6-fluoro-3,4-dihydro-2 H -benzo[ b [1,4]Oxazine (173.5 mg, 0.748 mmol), DMAP (9.2 mg, 0.075 mmol), and triethylamine (227 mg, 2.24 mmol) were added to a solution of di-tert-butyl dicarbonate (326.1 mg, 1.496 mmol) in THF (20 mL). The mixture was stirred at 50°C for 16 h. The reaction was quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to provide the title compound as a yellow oil (209.8 mg, 0.632 mmol, 84.5% yield). MS (ESI) m / z [M+H] + 332.0.

[0640] Step 7: Synthesis of (S)-2-(6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidine]-3-yl)ethyl acetate hydrochloride

[0641]

[0642] To (3) S tert-butyl 3-(2-ethoxy-2-oxo-ethyl)-6-fluoro-spiro[indan-1,4'-piperidine]-1'-carboxylate (4.14 g, 10.56 mmol) was dissolved in 1,4-dioxane (100 mL) with hydrogen chloride (20 mL, 4.0 M in 1,4-dioxane). The mixture was stirred at room temperature for 4 h and concentrated under vacuum to provide the title compound (3.45 g, 10.56 mmol, 100% yield) as a yellow oil. MS (ESI) m / z [M+H] + 292.1.

[0643] Step 8: ( S )-7-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,3-dihydro-4 H -benzo[b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0644]

[0645] Fill the sealed tube with ( S 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)ethyl acetate hydrochloride (164 mg, 0.502 mmol), 7-bromo-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b [1,4]oxazine-4-carboxylic acid tert-butyl ester (200 mg, 0.602 mmol), Pd2(dba)3 (82.7 mg, 0.09 mmol), Sphos (73.8 mg, 0.18 mmol), cesium carbonate (490.9 mg, 1.50 mmol), and 1,4-dioxane (30 mL). The mixture was stirred at 100°C for 16 h under nitrogen atmosphere. The reaction was quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 6) to provide the title compound as a yellow oil (237.1 mg, 0.437 mmol, 87.1% yield). MS (ESI) m / z [M+H] + 543.3.

[0646] Step 9: ( S )-2-(1'-(4-( Uncle (butoxycarbonyl)-6-fluoro-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid

[0647]

[0648] Towards( S )-7-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,3-dihydro-4 H -benzo[ b[1,4]Oxazine-4-carboxylate tert-butyl ester (237.1 mg, 0.437 mmol) was dissolved in THF (5 mL), water (5 mL), and MeOH (5 mL) with sodium hydroxide (87.4 mg, 2.185 mmol). The mixture was stirred at room temperature for 6 h and concentrated under vacuum. The mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The pH of the solution was adjusted to 6 with hydrochloric acid (1 N). The mixture was extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a pale yellow solid (220.2 mg, 0.428 mmol, 98% yield). MS (ESI) m / z [M+H] + 515.2.

[0649] Step 10: 7-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0650]

[0651] Towards( S )-2-(1'-(4-tert-butoxycarbonyl)-6-fluoro-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid (220.2 mg, 0.428 mmol), ( RA solution of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl-1-amine (115.6 mg, 0.513 mmol) and HATU (194.9 mg, 0.513 mmol) in THF (5 mL) was supplemented with DIEA (165.6 mg, 1.284 mmol). The mixture was stirred at room temperature for 4 h and quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 1) to provide the title compound as a colorless oil (250.6 mg, 0.347 mmol, 81.2% yield). MS (ESI) m / z [M+H] + 722.3.

[0652] Step 11: N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-6-fluoro-1'-(6-fluoro-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide trifluoroacetate

[0653]

[0654] To 7-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,3-dihydro-4 H -benzo[ b [1,4]Oxazine-4-carboxylate tert-butyl ester (250.6 mg, 0.347 mmol) was dissolved in DCM (5 mL) with 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 4 h and concentrated under vacuum to provide the title compound as a yellow oil (249.2 mg, 0.347 mmol, 100% yield). MS (ESI) m / z [M+H] + 622.2.

[0655] Step 12: 2-(( S)-1'-(4-Acryloyl-6-fluoro-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N Synthesis of -(®-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C5)

[0656]

[0657] At 0°C, towards N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-6-fluoro-1'-(6-fluoro-3,4-dihydro-2 H -benzo[ b [1,4]oxazin-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide trifluoroacetate (249.2 mg, 0.347 mmol) was dissolved in water (5 mL) and THF (5 mL) with sodium bicarbonate (145.7 mg, 1.73 mmol). A solution of acrylonitrile-2-enoyl chloride (47.3 mg, 0.520 mmol) in dry THF (1 mL) was added dropwise to the above mixture. The mixture was stirred for 10 min and diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to provide the title compound as an off-white solid (121.3 mg, 0.180 mmol, 52% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 9.24 (s, 1H), 8.73 (d, J =8.5 Hz, 1H), 7.48-7.32 (m, 2H), 7.21-7.05 (m, 2H), 6.99-6.77 (m, 3H), 6.58(d, J = 8.5 Hz, 1H), 6.25 (dd, J = 16.7, 2.0 Hz, 1H), 5.83 (dd, J= 10.4, 2.0Hz, 1H), 5.56-5.44 (m, 1H), 4.31-4.22 (m, 2H), 3.98-3.88 (m, 2H), 3.30-3.22(m, 5H), 3.19-3.08 (m, 1H), 2.78-2.53 (m, 3H), 2.33-2.12 (m, 3H), 1.80-1.68 (m, 1H), 1.55-1.38 (m, 3H). MS(ESI) m / z [M+H] + 676.2.

[0658] Example 16:

[0659] 2-(( S )-1'-(4-Acryloyl-2,2-difluoro-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6- Fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazole-2- Preparation of ethyl acetamide (compound C7)

[0660]

[0661] Step 1: 2-Bromo- N Synthesis of -(4-bromo-2-hydroxyphenyl)-2,2-difluoroacetamide

[0662]

[0663] Methyl 2-bromo-2,2-difluoroacetate (844.17 mg, 4.47 mmol) and triethylamine (376.73 mg, 3.72 mmol, 518.91 μL) were added to a solution of 2-amino-5-bromophenol (700 mg, 3.72 mmol) in ethyl acetate. The mixture was refluxed for 1 h and quenched with water (10 mL). The mixture was extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a pale yellow solid (820 mg, 2.38 mmol, 63.8% yield). MS (ESI) m / z [M+H] + 343.8, 345.8, 347.8 (2 Br).

[0664] Step 2: 7-Bromo-2,2-Difluoro-2 H -benzo[ b [1,4]Oxazine-3(4 H Synthesis of )-ketones

[0665]

[0666] To 2-bromo- N4-Bromo-2-hydroxyphenyl)-2,2-difluoroacetamide (820 mg, 2.38 mmol) was dissolved in DMF (10 mL) with potassium carbonate (984.18 mg, 7.13 mmol). The mixture was stirred at 60°C for 3 h. The reaction was quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (2 × 150 mL), washed with brine (2 × 150 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give the title compound (500 mg, 1.89 mmol, 79.7% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 264.1, 266.2 (Br).

[0667] Step 3: 7-Bromo-2,2-difluoro-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine

[0668]

[0669] To 7-bromo-2,2-difluoro-2 H -benzo[ b [1,4]Oxazine-3(4 H )-ketone (500 mg, 1.89 mmol) was added to a solution of borane-tetrahydrofuran complex (5 mL, 1.0 M in THF) in 5 mL of THF. The mixture was stirred at 80°C for 3 h. The reaction was quenched with MeOH (20 mL) and water (50 mL). The mixture was extracted with ethyl acetate (2 × 150 mL). The organic layer was washed with brine (2 × 150 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give the title compound (400 mg, 1.60 mmol, 84.5% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 249.9, 251.9 (Br).

[0670] Step 4: 7-Bromo-2,2-difluoro-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0671]

[0672] Add 7-bromo-2,2-difluoro-3,4-dihydro-2-dicarbonate to a solution of di-tert-butyl dicarbonate (400 mg, 1.83 mmol, 420.61 μL) in THF (11.41 mL). H -benzo[ b [1,4]Oxazine (500 mg, 2.00 mmol), triethylamine (607.04 mg, 6.00 mmol, 836.15 μL), and DMAP (244.30 mg, 2.00 mmol). The mixture was stirred at room temperature for 12 h. The reaction was quenched with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (420 mg, 1.20 mmol, 60% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 350.1, 352.2 (Br).

[0673] Steps 5-9: 2-(( S )-1'-(4-Acryloyl-2,2-difluoro-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C7)

[0674]

[0675] Following the method of steps 9-13 in Example 15 (C5), 7-bromo-2,2-difluoro-2,3-dihydro-4 H -benzo[ b [1,4]oxazine-4-carboxylic acid tert-butyl ester was used to give the title compound as a white solid (9.11 mg, 13.13 μmol, 2.7% overall yield over 5 steps). 1 H NMR (400 MHz, DMSO- d 6) δ 9.23 (s, 1H), 8.72 (d, J= 8.4 Hz, 1H),7.46-7.35 (m, 2H), 7.19-7.09 (m, 1H), 7.08-7.03 (m, 1H), 6.96-6.91 (m, 1H),6.89-6.82 (m, 2H), 6.77 (s, 1H), 6.35 (dd, J = 16.6, 1.9 Hz, 1H), 5.90 (dd, J = 10.4, 1.8 Hz, 1H), 5.54-5.44 (m, 1H), 4.41 (t, J = 7.2 Hz, 2H), 3.40-3.30(m, 2H), 3.15 (dd, J = 13.8, 10.5 Hz, 1H), 2.86-2.70 (m, 2H), 2.62-2.56 (m,1H), 2.34-2.25 (m, 2H), 2.22-2.13 (m, 2H), 2.00-1.90 (m, 2H), 1.69-1.58 (m,1H), 1.53-1.43 (m, 4H). MS(ESI) m / z [M+H] + 694.2.

[0676] Example 17:

[0677] 2-(( S )-1'-(4-Acryloyl-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]Oxazine-7- (indene-1,4'-piperidine)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-1-(3,4-difluorophenyl)-3-methoxypropyl-2- Preparation of acetamide (compound C17)

[0678]

[0679] Step 1: ( R Synthesis of tert-butyl 1-(1-(3,4-difluorophenyl)-3-hydroxypropyl-2-yl)carbamate

[0680]

[0681] Will( R )-2-(( UncleA solution of butoxycarbonyl)amino)-3-(3,4-difluorophenyl)propionic acid (1.0 g, 3.32 mmol) in THF (20 mL) was added to lithium aluminum hydride (378.38 mg, 9.96 mmol). The mixture was stirred at 0°C for 15 h. The reaction was quenched with sodium sulfate decahydrate (10 g). After filtration, the filtrate was concentrated under vacuum to give the title compound as a white solid (720 mg, 2.51 mmol, 75.5% yield). MS (ESI) m / z [M- t -Bu+H] + 232.0.

[0682] Step 2: ( R Synthesis of tert-butyl 1-(1-(3,4-difluorophenyl)-3-methoxypropyl-2-yl)carbamate

[0683]

[0684] At 0°C, towards ( R 1-(1-(3,4-difluorophenyl)-3-hydroxypropyl-2-yl)carbamic acid Uncle Butyl ester (250 mg, 870.17 μmol) was added to a stirred solution of iodomethane (185.26 mg, 1.31 mmol, 81.26 μL) and sodium hydride (104.41 mg, 2.61 mmol, 60% oil) in THF (1.92 mL). The resulting solution was stirred at room temperature for 15 h. The reaction was quenched with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (180 mg, 597.36 μmol, 68.6% yield) as a pale yellow solid. MS (ESI) m / z [M- t -Bu+H] + 246.1.

[0685] Step 3: ( R Synthesis of 1-(3,4-difluorophenyl)-3-methoxypropyl-2-amine

[0686]

[0687] Towards( R1-(3,4-difluorophenyl)-3-methoxypropyl-2-yl)carbamate tert-butyl ester (180 mg, 597.36 μmol) was dissolved in DCM (5 mL) with hydrogen chloride (5 mL, 4.0 M in 1,4-dioxane). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was dissolved in a saturated solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (120 mg, 596.38 μmol, 99.8% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 201.2.

[0688] Step 4: Synthesis of tert-butyl 2-(5-bromo-4-fluoro-2-nitrophenoxy)-2-methylpropionate

[0689]

[0690] To a solution of 1-bromo-2,5-difluoro-4-nitrobenzene (5.0 g, 21.01 mmol) in acetonitrile (100 mL), tert-butyl 2-hydroxy-2-methylpropionate (3.70 g, 23.11 mmol) and cesium carbonate (20.55 g, 63.03 mmol) were added. The mixture was stirred at 60°C for 2 h. The reaction was quenched with water (30 mL). The mixture was extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (4.0 g, 10.58 mmol, 50.3% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 378.1.

[0691] Step 5: Synthesis of tert-butyl 2-(2-amino-5-bromo-4-fluorophenoxy)-2-methylpropionate

[0692]

[0693] Iron powder (5.91 g, 105.77 mmol) and hydrochloric acid (40 μL) were added to a solution of tert-butyl 2-(5-bromo-4-fluoro-2-nitrophenoxy)-2-methylpropionate (4.0 g, 10.58 mmol) in ethanol (10 mL) and water (2 mL). The mixture was stirred at 80°C for 15 h. After filtration, the filtrate was concentrated under vacuum to give the title compound as a yellow solid (3.5 g, 10.05 mmol, 95% yield). MS (ESI) m / z [M- t -Bu+H] + 291.9, 293.9 (Br).

[0694] Step 6: 7-Bromo-6-fluoro-2,2-dimethyl-2 H -benzo[ b [1,4]Oxazine-3(4 H Synthesis of )-ketones

[0695]

[0696] TFA (7.40 g, 64.90 mmol, 5 mL) was added to a solution of tert-butyl 2-(2-amino-5-bromo-4-fluorophenoxy)-2-methylpropionate (3.5 g, 10.05 mmol) in DCM (5 mL). The mixture was stirred at 45°C for 15 h. The solvent was evaporated under vacuum. The residue was dissolved in a saturated solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (2.8 g, 8.17 mmol, 81.3% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 274.1, 276.1 (Br).

[0697] Step 7: 7-Bromo-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine

[0698]

[0699] To 7-bromo-6-fluoro-2,2-dimethyl-4 H1,4-Benzoxazin-3-one (2.8 g, 10.22 mmol) was added to a solution of borane-tetrahydrofuran complex (5 mL, 1.0 M in THF) in 5 mL of THF. The mixture was stirred at 80°C for 15 h. After cooling to room temperature, the reaction was quenched with MeOH (20 mL). The mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give the title compound (2.4 g, 9.23 mmol, 90.3% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 260.0, 262.0 (Br).

[0700] Step 8: 7-Bromo-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0701]

[0702] Add DIEA (3.57 g, 27.68 mmol) and 7-bromo-6-fluoro-2,2-dimethyl-3,4-dihydro-2-dimethyl esters (4.03 g, 18.45 mmol, 4.24 mL) to a solution of di-tert-butyl dicarbonate in THF (5.76 mL). H -benzo[ b [1,4]Oxazine (2.4 g, 9.23 mmol) and DMAP (112.73 mg, 922.71 μmol). The mixture was stirred at room temperature for 15 h. The reaction was quenched with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 50 mL), washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give the title compound (1.0 g, 2.78 mmol, 30.1% yield) as a pale yellow solid. MS (ESI) m / z [M-Boc+H] + 260.0, 262.0 (Br).

[0703] Step 9: ( S )-7-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0704]

[0705] 7-bromo-6-fluoro-2,2-dimethyl-2,3-dihydro-4 ... H -benzo[ b [1,4]Oxazine-4-carboxylic acid tert-butyl ester (815.98 mg, 2.27 mmol), ( S Ethyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) hydrochloride (600 mg, 2.06 mmol), Pd2(dba)3 (188.43 mg, 205.93 μmol), Ruphos (191.93 mg, 411.86 μmol), cesium carbonate (2.01 g, 6.18 mmol), and 1,4-dioxane (10 mL) were added. The resulting solution was stirred at 100°C for 5 h under a nitrogen atmosphere. The resulting solution was diluted with water (50 mL) and then extracted with ethyl acetate (3 × 40 mL). The organic layers were combined, washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 3 / 1) to give the title compound as a yellow solid (1.05 g, 1.75 mmol, 84.9% yield). MS (ESI) m / z [M+H] + 571.3.

[0706] Step 10: ( S )-2-(1'-(4-( Uncle (butoxycarbonyl)-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid

[0707]

[0708] Will( S )-7-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b [1,4]Oxazine-4-carboxylic acid Uncle DingA solution of the ester (1.05 g, 1.84 mmol) in THF (10 mL), methanol (5 mL), and water (2 mL) was added to sodium hydroxide (368 mg, 9.2 mmol). The mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum and diluted with water (30 mL). The pH of the solution was adjusted to 6 with hydrochloric acid (1 N). The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give the title compound as a yellow solid (980 mg, 1.81 mmol, 98.2% yield). MS (ESI) m / z [M+H] + 543.2.

[0709] Step 11: 7-(( S )-3-(2-((( R )-1-(3,4-difluorophenyl)-3-methoxypropyl-2-yl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0710]

[0711] Will( S )-2-(1'-(4-( Uncle (butoxycarbonyl)-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b A solution of [1,4]oxazin-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid (300 mg, 552.88 μmol) in acetonitrile (5 mL) was added to ( R1-(3,4-difluorophenyl)-3-methoxypropyl-2-amine (122.37 mg, 608.17 μmol), DIEA (213.96 mg, 1.66 mmol), and T3P (263.72 mg, 829.32 μmol, 50% in ethyl acetate) were reacted. The mixture was stirred at room temperature for 3 h. The reaction was quenched with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give the title compound (270 mg, 372.00 μmol, 67.3% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 726.3.

[0712] Step 12: N -(( R )-1-(3,4-difluorophenyl)-3-methoxypropyl-2-yl)-2-(( S )-6-fluoro-1'-(6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide

[0713]

[0714] To 7-(( S )-3-(2-((( R )-1-(3,4-difluorophenyl)-3-methoxypropyl-2-yl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b [1,4]oxazine-4-carboxylate tert-butyl ester (270 mg, 372.00 μmol) was dissolved in DCM (10 mL) with 5 mL of trifluoroacetic acid added. The mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum. The residue was dissolved in sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (220 mg, 351.61 μmol, 94.5% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 626.3.

[0715] Step 13: 2-(( S )-1'-(4-Acryloyl-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(3,4-difluorophenyl)-3-methoxypropyl-2-yl)acetamide (compound C17)

[0716]

[0717] At room temperature, to N -(( R )-1-(3,4-difluorophenyl)-3-methoxypropyl-2-yl)-2-(( S )-6-fluoro-1'-(6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazin-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide (220 mg, 351.61 μmol) was added to a solution of THF and water (10 mL) with sodium bicarbonate (88.61 mg, 1.05 mmol). The mixture was stirred at 0°C for 30 min. The mixture was concentrated under vacuum to obtain a residue, which was dissolved in an aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water / CH3CN + 1% FA, 28% to 80%) to give the title compound as a white solid (52.45 mg, 77.16 μmol, 22% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 7.90 (d, J =8.6 Hz, 1H), 7.38-7.25 (m, 2H), 7.16-7.07 (m, 2H), 7.06-6.90 (m, 1H), 6.86(td, J = 8.8, 2.4 Hz, 2H), 6.52 (d, J = 8.3 Hz, 1H), 6.29 (dd, J = 16.7, 1.9Hz, 1H), 5.86 (dd, J= 10.5, 1.9 Hz, 1H), 4.25-4.10 (m, 1H), 3.72 (s, 2H), 3.40-3.33 (m, 2H), 3.28 (s, 6H), 2.90-2.70 (m, 6H), 2.39-2.24 (m, 1H), 2.20-2.00 (m, 2H), 1.73 (t, J = 10.9 Hz, 1H), 1.55-1.43 (m, 3H), 1.24 (s, 6H). MS(ESI) m / z [M+H] + 680.3.

[0718] Example 18:

[0719] 2-(( S )-1'-(4-Acryloyl-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]Oxazine-7- (indene-1,4'-piperidine)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl) Preparation of (propyl-2-yl)acetamide (compound C18)

[0720]

[0721] Step 1: 4-Methylbenzenesulfonic acid ( R Synthesis of 2-((tert-butoxycarbonyl)amino)-3-(3,4-difluorophenyl)propyl ester

[0722]

[0723] Towards( R 1-(1-(3,4-difluorophenyl)-3-hydroxypropyl-2-yl)carbamic acid Uncle Butyl ester (25 g, 87.0 mmol), DMAP (106.31 mg, 870.17 μmol), and triethylamine (26.4 g, 261.0 mmol) were added to a solution of 4-methylbenzenesulfonyl chloride (19.9 g, 104.4 mmol) in DCM (200 mL). The mixture was stirred at room temperature for 16 h and quenched with water (200 mL). The organic phase was separated. The aqueous phase was extracted with DCM (3 × 200 mL). The organic layers were combined, washed with brine (3 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (with ethyl acetate / petroleum ether = 1 / 5) to provide the title compound as a white solid (25.9 g, 58.7 mmol, 67.4% yield). MS (ESI) m / z [M+H] + 442.1.

[0724] Step 2: ( RSynthesis of tert-butyl carbamate (1-(3,4-difluorophenyl)-3-(methylthio)propyl-2-yl)carbamate

[0725]

[0726] 4-Methylbenzenesulfonic acid ( R 2-((tert-butoxycarbonyl)amino)-3-(3,4-difluorophenyl)propyl ester (22 g, 49.83 mmol) was dissolved in DMF (100 mL) with sodium thiomethoxy (6.99 g, 99.66 mmol). The mixture was stirred at 50°C for 3 h. The mixture was then poured into ice water (400 mL). The mixture was filtered, and the filter cake was collected to provide the title compound as a white solid (15 g, 47.26 mmol, 94.8% yield). MS (ESI) m / z [M+H] + 318.1.

[0727] Step 3: ( R Synthesis of tert-butyl carbamate (1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)carbamate

[0728]

[0729] Towards( R 1-(3,4-difluorophenyl)-3-(methylthio)propyl-2-yl)carbamate tert-butyl ester (15 g, 47.26 mmol) was dissolved in DCM (400 mL) with 3-chlorophenylperoxyformic acid (20.39 g, 118.15 mmol). The mixture was stirred at room temperature for 6 h. The solvent was evaporated under vacuum. A solution of sodium hydroxide (300 mL, 2 N) was added to the residue. The mixture was stirred at room temperature for 1 h and filtered. A white filter cake was collected and then resuspended in 300 mL of water. The mixture was stirred for 0.5 h and filtered. The filter cake was washed with water (2 × 100 mL) and dried under vacuum to provide the title compound as a white solid (14.9 g, 42.65 mmol, 90.2% yield). MS (ESI) m / z [M+H] + 350.1.

[0730] Step 4: ( R Synthesis of 1-(3,4-difluorophenyl)-3-(methylsulfonyl)prop-2-amine hydrochloride

[0731]

[0732] Towards( R)-(1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)carbamic acid Uncle Butyl ester (14.9 g, 42.65 mmol) was added to a solution of dioxane (100 mL) with hydrogen chloride (21 mL, 4.0 M in 1,4-dioxane). The mixture was stirred at room temperature for 3 h. The solvent was evaporated under vacuum to provide the title compound as a white solid (10 g, 40.12 mmol, 94.1% yield). MS (ESI) m / z [M+H] + 250.1.

[0733] Step 5: 7-(( S )-3-(2-((( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0734]

[0735] Towards( S )-2-(1'-(4-( tert-butoxy (carbonyl)-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid (400 mg, 737.17 μmol), ( R 1-(3,4-difluorophenyl)-3-(methanesulfonyl)prop-2-amine hydrochloride (220.51 mg, 884.61 μmol) was added to a solution of HATU (420.44 mg, 1.11 mmol) and DIEA (285.29 mg, 2.21 mmol) in THF (10 mL). The mixture was stirred at room temperature for 4 h. The reaction was quenched with water (30 mL). The mixture was extracted with ethyl acetate (2 × 50 mL), washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give the title compound (360 mg, 465.19 μmol, 63.1% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 774.3.

[0736] Step 6: N -(( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)-2-(( S )-6-fluoro-1'-(6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide

[0737]

[0738] To 7-(( S )-3-(2-((( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b [1,4]oxazine-4-carboxylate tert-butyl ester (270 mg, 372.00 μmol) was dissolved in DCM (10 mL) with 5 mL of trifluoroacetic acid added. The mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum. The resulting residue was dissolved in a saturated solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (220 mg, 351.61 μmol, 94.52% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 673.1.

[0739] Step 7: 2-(( S )-1'-(4-Acryloyl-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(3,4-difluorophenyl)-3-(methylsulfonyl)prop-2-yl)acetamide (compound C18)

[0740]

[0741] At 0°C, towards N -(( R)-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)-2-(( S )-6-fluoro-1'-(6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b Sodium bicarbonate (74.80 mg, 890.53 μmol) was added to a solution of 200 mg (296.84 μmol) in THF (5 mL) and water (1 mL). The mixture was stirred at 0°C for 5 min. Acryloyl chloride (32.24 mg, 356.21 μmol) in THF (5 mL) was added to the above mixture. The resulting mixture was stirred at 0°C for 1 h. The mixture was diluted with ethyl acetate, washed with water and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (water / CH3CN + 1% FA, 28% to 80%) to give the title compound as a white solid (94 mg, 129.16 μmol, 43.5% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 8.10 (d, J = 8.7 Hz, 1H), 7.40-7.26 (m, 2H), 7.10-7.05 (m, 2.8 Hz, 2H), 6.97-6.82 (m,3H), 6.52 (d, J = 8.3 Hz, 1H), 6.29 (dd, J = 16.7, 1.7 Hz, 1H), 5.85 (dd, J =10.6, 1.7 Hz, 1H), 4.52-4.47 (m, 1H), 3.72 (s, 2H), 3.40-3.34 (m, 5H), 3.04-2.96 (m, 4H), 2.81-2.68 (m, 3H), 2.56-2.52 (m, 1H), 2.37-2.31 (m, 1H), 2.26-2.09 (m, 2H), 2.00-1.95 (m, 1H), 1.73 (t, J = 10.7 Hz, 1H), 1.53-1.41 (m, 3H), 1.25 (s, 6H). MS(ESI) m / z [M+H] +728.2.

[0742] Example 19:

[0743] 2-(( S )-1'-(4-Acryloyl-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]Oxazine-7- (indene-1,4'-piperidine)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H -pyr Preparation of (4-yl)ethyl)acetamide (compound C23)

[0744]

[0745] Step 1: 7-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H -pyran-4-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0746]

[0747] Towards( S )-2-(1'-(4-( Uncle (butoxycarbonyl)-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid (300 mg, 552.88 μmol) was added to a solution of THF (50 mL). R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H 1,4-pyran-4-yl)ethyl-1-amine hydrochloride (160.08 mg, 663.46 μmol), DIEA (213.96 mg, 1.66 mmol), and T3P (421.96 mg, 663.46 μmol, 50% in ethyl acetate). The mixture was stirred at room temperature for 3 h and quenched with water (30 mL). The mixture was extracted with ethyl acetate (2 × 50 mL). The organic layer was washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 10 / 1) to give the title compound (270 mg, 352.54 μmol, 63.8% yield) as a pale yellow solid. MS (ESI) m / z [M+H] + 766.3.

[0748] Step 2: N -(( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H -pyran-4-yl)ethyl)-2-(( S )-6-fluoro-1'-(6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide

[0749]

[0750] To 7-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H -pyran-4-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-6-fluoro-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b [1,4]oxazine-4-carboxylate tert-butyl ester (270 mg, 352.54 μmol) was dissolved in DCM (50 mL) with 5 mL of trifluoroacetic acid added. The mixture was stirred at room temperature for 3 h. The mixture was concentrated under vacuum to give a residue. The residue was dissolved in a saturated solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (180 mg, 270.37 μmol, 76.7% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 666.3.

[0751] Step 3: 2-(( S )-1'-(4-Acryloyl-6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H Synthesis of pyran-4-yl)ethyl)acetamide (compound C23)

[0752]

[0753] At 0°C, towards N-(( R )-2-(3,4-difluorophenyl)-1-(tetrahydro-2 H -pyran-4-yl)ethyl)-2-(( S )-6-fluoro-1'-(6-fluoro-2,2-dimethyl-3,4-dihydro-2 H -benzo[ b Sodium bicarbonate (68.13 mg, 811.11 μmol) was added to a solution of [1,4]oxazin-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetamide (180 mg, 270.37 μmol) in THF (10 mL) and water (3 mL). The mixture was stirred at 0°C for 5 min. A solution of acrylonitrile-2-enoyl chloride (29.36 mg, 324.44 μmol) in THF (10 mL) was added to the above mixture. The mixture was stirred at room temperature for 0.5 h. The mixture was diluted with ethyl acetate, washed with water and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (water / CH3CN + 1% FA, 68% to 82%) to give the title compound as a white solid (48.18 mg, 65.60 μmol, 24.3% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 7.95 (d, J =8.6 Hz, 1H), 7.37-7.24 (m, 2H), 7.12-7.00 (m, 2H), 6.99-6.90 (m, 1H), 6.86(td, J = 8.8, 2.4 Hz, 2H), 6.52 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 16.7 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 4.25-4.10 (m, 1H), 3.72 (s, 2H), 3.50-3.33(m, 4H), 3.28 (s, 6H), 2.90-2.70 (m, 6H), 2.39-2.24 (m, 1H), 2.20-2.00 (m,4H), 1.73 (t, J = 10.9 Hz, 1H), 1.55-1.43 (m, 3H), 1.24 (s, 6H). MS(ESI) m / z [M+H]+ 720.8.

[0754] Example 20:

[0755] 2-((3 S )-1'-(4-Acryloyl-2-vinyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6- Fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazole-2- Preparation of ethyl acetamide (compound C24)

[0756]

[0757] Step 1: Synthesis of ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate

[0758]

[0759] Ethyl 1-hydroxycyclopropanecarboxylate (572.63 mg, 4.40 mmol) was added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (880 mg, 4.00 mmol) and cesium carbonate (3.91 g, 12.00 mmol) in acetonitrile (20 mL). The mixture was stirred at 80°C for 16 h under a nitrogen atmosphere. The reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 7) to provide the title compound as a yellow oil (1.1 g, 3.33 mmol, 83.3% yield). MS (ESI) m / z [M+H] + 329.9.

[0760] Step 2: Synthesis of ethyl 1-(2-amino-5-bromophenoxy)cyclopropane-1-carboxylate

[0761]

[0762] Iron powder (1.53 g, 27.3 mmol) and hydrochloric acid (1 drop) were added to a solution of ethyl 1-(5-bromo-2-nitrophenoxy)cyclopropane-1-carboxylate (900 mg, 2.73 mmol) in water (2 mL) and EtOH (10 mL). The mixture was stirred overnight at 60°C. After filtration, the filtrate was concentrated under vacuum. The mixture was diluted with water (80 mL). The aqueous phase was extracted with ethyl acetate (3 × 80 mL). The organic layers were combined, washed with brine (3 × 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (800 mg, 2.67 mmol, 97.8% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 302.0.

[0763] Step 3: 7-Bromospiro[benzo[] b [1,4]oxazine-2,1'-cyclopropane]-3(4 H Synthesis of )-ketones

[0764]

[0765] Sodium hydroxide (425.12 mg, 10.63 mmol) was added to a solution of ethyl 1-(2-amino-5-bromophenoxy)cyclopropane-1-carboxylate (638 mg, 2.13 mmol) in water (5 mL), MeOH (5 mL), and THF (5 mL). The mixture was stirred at room temperature for 4 h and concentrated under vacuum. The mixture was diluted with water (20 mL). The pH of the solution was adjusted to 4 with hydrochloric acid (1 N). The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (518 mg, 2.04 mmol, 95.9% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 253.9.

[0766] Step 4: 7-Bromo-3,4-dihydrospiro[benzo[] b Synthesis of [1,4]oxazine-2,1'-cyclopropane

[0767]

[0768] To 7-bromospiro[benzo[ b [1,4]oxazine-2,1'-cyclopropane]-3(4 H The β-ketone (585 mg, 2.30 mmol) was dissolved in THF (10 mL) and a borane-tetrahydrofuran complex (4.6 mL, 1.0 M in THF) was added. The mixture was stirred overnight at 70°C under a nitrogen atmosphere and quenched with MeOH (20 mL). The solvent was evaporated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to provide the title compound as a yellow oil (384 mg, 1.60 mmol, 69.5% yield). MS (ESI) m / z [M+H] + 240.0.

[0769] Step 5: 7-Bromospiro[benzo[] b[1,4]oxazine-2,1'-cyclopropane]-4(3 H Synthesis of tert-butyl formate

[0770]

[0771] To 7-bromo-3,4-dihydrospiro[benzo[ b [1,4]oxazine-2,1'-cyclopropane] (542 mg, 2.26 mmol) was dissolved in THF (10 mL) with di-tert-butyl dicarbonate (1.97 g, 9.03 mmol, 2.07 mL), DMAP (27.58 mg, 225.74 μmol), and triethylamine (685.29 mg, 6.77 mmol, 944 μL). The mixture was heated overnight at 50°C under nitrogen atmosphere and quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 9) to provide the title compound as a yellow oil (390 mg, 1.15 mmol, 50.8% yield). MS (ESI) m / z [M+H] + 340.0.

[0772] Step 6: 7-(( S )-3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2-vinyl-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0773]

[0774] Fill the sealed tube with ( S 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl) ethyl acetate hydrochloride (130 mg, 446.18 μmol), 7-bromospiro[benzo[ b [1,4]oxazine-2,1'-cyclopropane]-4(3 Htert-butyl formate (182.16 mg, 535.42 μmol), Sphos (54.88 mg, 133.86 μmol), Pd2(dba)3 (61.31 mg, 66.93 μmol), cesium carbonate (436.37 mg, 1.34 mmol), and 1,4-dioxane (10 mL). The mixture was stirred at 100°C for 16 h under nitrogen atmosphere and quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 5) to provide the title compound as a yellow oil (145 mg, 263.32 µmol, 59% yield). MS (ESI) m / z [M+H] + 551.2.

[0775] Step 7: 2-((3) S )-1'-(4-(tert-butoxycarbonyl)-2-vinyl-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid

[0776]

[0777] To 7-(( S )-3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2-vinyl-2,3-dihydro-4 H -benzo[ b [1,4]Oxazine-4-carboxylate tert-butyl ester (180 mg, 326.88 μmol) was dissolved in water (3 mL), THF (3 mL), and MeOH (3 mL) with sodium hydroxide (65.38 mg, 1.63 mmol). The solution was stirred at room temperature for 2 h and concentrated under vacuum. The mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The pH of the solution was adjusted to 6 with hydrochloric acid (1 N). The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (150 mg, 287.02 μmol, 87.8% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 523.3.

[0778] Step 8: ( S )-7-(3-(2-((( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2-vinyl-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl 4-oxazine-4-carboxylate

[0779]

[0780] To 2-((3) S )-1'-(4-(tert-butoxycarbonyl)-2-vinyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid (150 mg, 287.02 μmol), ( R HATU (163.70 mg, 430.53 μmol) was added to a solution of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl-1-amine (77.56 mg, 344.43 μmol) and DIEA (111.08 mg, 861.07 μmol) in THF (10 mL). The mixture was stirred at room temperature for 2 h and quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 1) to provide the title compound as a yellow oil (180 mg, 246.65 µmol, 85.9% yield). MS (ESI) m / z [M+H] + 730.3.

[0781] Step 9: N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-((3 S )-6-fluoro-1'-(2-vinyl-3,4-dihydro-2 H -benzo[ b Synthesis of [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide

[0782]

[0783] To 7-(( S )-3-(2-((( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2-vinyl-2,3-dihydro-4 H -benzo[ b [1,4]oxazine-4-carboxylate tert-butyl ester (120 mg, 164.43 μmol) was dissolved in DCM (5 mL) with 0.5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum to provide the title compound as a yellow oil (100 mg, 158.81 μmol, 96.6% yield). MS (ESI) m / z [M+H] + 630.3.

[0784] Step 10: 2-((3) S )-1'-(4-Acryloyl-2-vinyl-3,4-dihydro-2 H -benzo[ b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C24)

[0785]

[0786] Towards N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-((3 S )-6-fluoro-1'-(2-vinyl-3,4-dihydro-2 H -benzo[ b[1,4]oxazin-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide (98 mg, 155.64 μmol) was added to a solution of sodium bicarbonate (65.37 mg, 778.19 μmol) in water (5 mL) and THF (5 mL). A solution of acryloyl chloride (28.17 mg, 311.27 μmol) in THF (2 mL) was added to the above solution. The mixture was stirred at room temperature for 10 min. The mixture was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to provide the title compound as an off-white solid (42 mg, 61.43 μmol, 39.5% yield). 1 H NMR (400 MHz, DMSO -d 6) δ 9.22 (s, 1H), 8.72 (d, J = 8.4 Hz,1H), 7.48-7.32 (m, 2H), 7.21-7.14 (m, 1H), 7.05 (dd, J = 9.5, 2.3 Hz, 1H), 6.98-6.83 (m, 3H), 6.69 (dd, J = 8.8, 2.7 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H),6.21-6.06 (m, 2H), 5.61 (dd, J = 9.3, 3.2 Hz, 1H), 5.52-5.46 (m, 1H), 5.30-5.00 (m, 3H), 4.79-4.32 (m, 2H), 3.68 (t, J = 12.8 Hz, 3H), 3.45-3.29 (m,2H), 3.21-3.10 (m, 1H), 2.85-2.67 (m, 2H), 2.59 (dd, J = 14.3, 6.3 Hz, 1H),2.32-2.06 (m, 3H), 1.66 (dd, J = 12.7, 9.1 Hz, 1H), 1.56-1.41 (m, 3H). MS(ESI) m / z [M+H] + 684.0.

[0787] Example 21:

[0788] 2-(( S )-1'-(4-Acryloyl-3,4-dihydrospiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-7-yl)- 6-Fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)prop- Preparation of 2-yl)acetamide (compound C25)

[0789]

[0790] Step 1: 1-Bromo- N Synthesis of 1-(4-bromo-2-hydroxyphenyl)cyclobutane-1-carboxamide

[0791]

[0792] To a solution of 2-amino-5-bromophenol (500 mg, 2.66 mmol) in DCM (935.44 mL), 1-bromocyclobutane-1-carboxylic acid (476.04 mg, 2.66 mmol), DIEA (687.37 mg, 5.32 mmol, 926.37 μL), and HATU (1.52 g, 3.99 mmol) were added. The mixture was stirred at room temperature for 1 h and quenched with water (30 mL). The aqueous phase was extracted with DCM (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to give the title compound as a gray solid (420 mg, 1.20 mmol, 45.2% yield). MS (ESI) m / z [M+H] + 347.9, 349.9, 352.0 (2Br).

[0793] Step 2: 7-Bromospiro[benzo[] b [1,4]oxazine-2,1'-cyclobutane]-3(4 H Synthesis of )-ketones

[0794]

[0795] To 1-bromo- N1-(4-bromo-2-hydroxyphenyl)cyclobutane-1-carboxamide (420 mg, 1.20 mmol) was dissolved in DMF (6 mL) with potassium carbonate (830.33 mg, 6.02 mmol). The mixture was stirred overnight at 80°C and then quenched with water (60 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to give the title compound as a gray solid (220 mg, 820.57 μmol, 68.2% yield). MS (ESI) m / z [M+H] + 268.0, 270.0 (Br).

[0796] Step 3: 7-Bromo-3,4-dihydrospiro[benzo[] b Synthesis of [1,4]oxazine-2,1'-cyclobutane

[0797]

[0798] To 7-bromospiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-3(4 H A solution of 220 mg (820.57 μmol) of borane-tetrahydrofuran complex (3 mL, 1.0 M in THF) was added to a solution of 2-ketone (3 mL). The mixture was stirred at 70°C for 2 h. After cooling to 0°C, the reaction was quenched with EtOH (5 mL). The resulting mixture was stirred at 80°C for 2 h and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to give the title compound (200 mg, 787.02 μmol, 95.9% yield) as a yellow oil. MS (ESI) m / z [M+H] + 253.8, 255.8 (Br).

[0799] Step 4: 7-Bromospiro[benzo[] b [1,4]oxazine-2,1'-cyclobutane]-4(3 H Synthesis of tert-butyl formate

[0800]

[0801] At 0°C, 7-bromo-3,4-dihydrospiro[benzo[] bLiHMDS (1 mL, 1.0 M in THF) was added to a solution of [1,4]oxazine-2,1'-cyclobutane (100 mg, 393.51 μmol) in THF (5 mL). The mixture was stirred at 0°C for 40 min. Di-tert-butyl dicarbonate (111.65 mg, 511.56 μmol) was added to the above mixture. The resulting mixture was stirred at room temperature for 2 h and then quenched with a saturated solution of ammonium chloride (10 mL). The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 20) to give the title compound (100 mg, 282.30 μmol, 71.7% yield) as a yellow oil. MS (ESI) m / z [M- t -Bu+H] + 297.8, 299.8 (Br), [M-Boc+H] + 253.8, 255.8 (Br).

[0802] Step 5: ( S )-7-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)spiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-4(3 H Synthesis of tert-butyl formate

[0803]

[0804] Fill the sealed tube with ( S 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)ethyl acetate hydrochloride (100 mg, 305.99 μmol), 7-bromospiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-4(3 Htert-butyl formate (119.23 mg, 336.58 μmol), Pd2(dba)3 (28.02 mg, 30.60 μmol), Sphos (25.12 mg, 61.20 μmol), cesium carbonate (299.25 mg, 917.96 μmol), and 1,4-dioxane (2 mL). The mixture was stirred overnight at 100°C and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 8) to give the title compound (120 mg, 212.51 μmol, 69.4% yield) as a yellow oil. MS (ESI) m / z [M+H] + 564.8, [M+Na] + 586.7.

[0805] Step 6: ( S )-2-(1'-(4-( Uncle (butoxycarbonyl)-3,4-dihydrospiro[benzo[ b Synthesis of [1,4]oxazine-2,1'-cyclobutane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid

[0806]

[0807] Towards( S )-7-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)spiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-4(3 H 120 mg (212.51 μmol) of tert-butyl formate was added to a solution of lithium hydroxide monohydrate (17.85 mg, 425.02 μmol) in MeOH (5 mL), THF (3 mL), and water (3 mL). The mixture was stirred overnight at room temperature. The pH of the solution was adjusted to 6 with citric acid. The mixture was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (100 mg, 186.35 μmol, yield: 87.7%) as a yellow oil. MS (ESI) m / z [M+H] + 536.8.

[0808] Step 7: 7-(( S )-3-(2-((( R)-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)spiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-4(3 H Synthesis of tert-butyl formate

[0809]

[0810] Towards( S )-2-(1'-(4-(tert-butoxycarbonyl)-3,4-dihydrospiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid (100 mg, 186.35 μmol) was added to a solution of DMF (3 mL). R 1-(3,4-difluorophenyl)-3-(methanesulfonyl)prop-2-amine (58.36 mg, 204.98 μmol, CL), DIEA (72.25 mg, 559.04 μmol, 97.37 μL), and HATU (106.28 mg, 279.52 μmol). The mixture was stirred at room temperature for 2 h and quenched with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (120 mg, 156.27 μmol, 83.9% yield) as a yellow oil. MS (ESI) m / z [M+H] + 5767.6, [M+Na] + 789.5.

[0811] Step 8: N -(( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)-2-(( S )-1'-(3,4-dihydrospiro[benzo[ b Synthesis of [1,4]oxazine-2,1'-cyclobutane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide trifluoroacetate

[0812]

[0813] To 7-(( S)-3-(2-((( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)spiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-4(3 H tert-butyl formate (120 mg, 156.27 μmol) was added to a solution of trifluoroacetic acid in DCM (15 mL). The mixture was stirred at room temperature for 4 h and concentrated under vacuum to give the title compound (110 mg, 140.70 μmol, 90% yield) as a yellow oil. MS (ESI) m / z [M+H] + 668.2.

[0814] Step 9: 2-(( S )-1'-(4-Acryloyl-3,4-dihydrospiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(3,4-difluorophenyl)-3-(methylsulfonyl)prop-2-yl)acetamide (compound C25)

[0815]

[0816] Towards N -(( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)-2-(( S )-1'-(3,4-dihydrospiro[benzo[ b[1,4]oxazine-2,1'-cyclobutane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide trifluoroacetate (110 mg, 140.70 μmol, TF) in THF (3 mL) and water (3 mL) was mixed with sodium bicarbonate (59.09 mg, 703.50 μmol). A solution of acrylonitrile-2-enoyl chloride (12.73 mg, 140.70 μmol) in THF (0.3 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C for 20 min and diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to obtain the residue, which was then purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [water(FA)-CH3CN]; CH3CN: 25%-65%, 8 min) to obtain the title compound as a white solid (36.36 mg, 50.37 μmol, 35.8% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 8.10 (d, J = 8.7 Hz, 1H), 7.42-7.23 (m, 2H), 7.13-7.01 (m, 2H), 6.99-6.63 (m, 4H), 6.57 (dd, J = 9.1, 2.7 Hz, 1H), 6.50-6.39 (m, 1H), 6.29 (dd, J = 16.8, 2.1Hz, 1H), 5.82 (dd, J = 10.3, 2.2 Hz, 1H), 4.60-4.44 (m, 1H), 3.88 (s, 2H), 3.69-3.55 (m, 2H), 3.46-3.36 (m, 2H), 3.07-2.93 (m, 4H), 2.84-2.66 (m, 4H),2.56-2.52 (m, 1H), 2.33 (dd, J= 13.0, 7.8 Hz, 1H), 2.23-2.08 (m, 4H), 2.03-1.91 (m, 2H), 1.87-1.75 (m, 1H), 1.73-1.60 (m, 2H), 1.55-1.41 (m, 3H). MS(ESI) m / z [M+H] + 721.6.

[0817] Example 22:

[0818] 2-(( S )-1'-(4-Acryloyl-3',3'-difluoro-3,4-dihydrospiro[benzo[ b [1,4]oxazine-2,1'-cyclo [butane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-1-(3,4-difluorophenyl)-3-(methyl) Preparation of (-(-(-(-(-(-(-(-(-(-(-(-(-(-(----)-)-(---)-)-)-acetamide)-)-(-(-(-(-(-(-(-(-(-(-(-(-(-(-(-(-(-(--) ...(---)-)-)-)-)-)-)-)-)-)-)""" ((-("-""-,,"2—525-—represent2' " """""""")")"))-)-)-)-)-)-")-)-2-" """""" """""""""""""""""""""""""""

[0819]

[0820] Step 1: Synthesis of 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxynitrile

[0821]

[0822] TMSCN (4.22 g, 42.56 mmol) was added to a solution of 3-(benzyloxy)cyclobutane-1-one (5.0 g, 28.38 mmol) in DCM (50 mL). Then, boron trifluoride diethyl ether (4.03 g, 28.38 mmol) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C for 2 h and quenched with a saturated sodium bicarbonate solution (100 mL). The mixture was extracted with DCM (2 × 100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (5.2 g, 25.59 mmol, 90.2% yield) as a yellow oil, which was used directly in the next step. MS (ESI) m / z [M+Na] + 226.1.

[0823] Step 2: Synthesis of 3-(benzyloxy)-1-(5-bromo-2-nitrophenoxy)cyclobutane-1-carboxynitrile

[0824]

[0825] At -10°C, 3-(benzyloxy)-1-hydroxycyclobutane-1-carboxynitrile (5.82 g, 28.64 mmol) and sodium hydride (818.20 mg, 20.45 mmol, 60% oil) were added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (3.0 g, 13.64 mmol) in THF (80 mL). The mixture was stirred at -10°C for 30 min and then heated to room temperature. The mixture was stirred overnight and quenched with a saturated solution of ammonium chloride (100 mL). The aqueous solution was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 12) to give the title compound (1.7 g, 4.22 mmol, 30.9% yield) as a yellow oil. MS (ESI) m / z [M+Na] + 424.9, 426.9 (Br).

[0826] Step 3: 3'-(benzyloxy)-7-bromospiro[benzo[] b [1,4]oxazine-2,1'-cyclobutane]-3(4 H Synthesis of )-ketones

[0827]

[0828] Iron powder (1.18 g, 21.08 mmol) was added to a solution of 3-(benzyloxy)-1-(5-bromo-2-nitrophenoxy)cyclobutane-1-carboxynitrile (1.7 g, 4.22 mmol) in acetic acid (20 mL). The mixture was stirred overnight at 80°C. After cooling to room temperature, the reaction was quenched with a saturated sodium bicarbonate solution (200 mL). The mixture was filtered. The filtrate was extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 5) to give the title compound as a yellow solid (1.1 g, 2.94 mmol, 69.7% yield). MS (ESI) m / z [M+H] + 374.0, 376.0 (Br), [M+Na] + 396.0, 398.0 (Br).

[0829] Step 4: 7-Bromo-3'-hydroxyspiro[benzo[] b [1,4]oxazine-2,1'-cyclobutane]-3(4 HSynthesis of )-ketones

[0830]

[0831] To 3'-(benzyloxy)-7-bromospiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-3(4 H )-keto (200 mg, 534.43 μmol) was added to a solution of boron tribromide (401.66 mg, 1.60 mmol) in DCM (10 mL). The mixture was stirred overnight at room temperature and quenched with a saturated sodium bicarbonate solution (30 mL). The mixture was extracted with DCM (2 × 20 mL). The organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to give the title compound as a white solid (130 mg, 457.58 μmol, 85.6% yield). MS (ESI) m / z [M+H] + 284.0, 286.0 (Br).

[0832] Step 5: 7-Bromospiro[benzo[] b [1,4]oxazine-2,1'-cyclobutane]-3,3'(4 H Synthesis of )-dione

[0833]

[0834] At room temperature, to 7-bromo-3'-hydroxyspiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-3(4 H The ketone (390 mg, 1.37 mmol) was dissolved in DCM (10 mL) with Dysmartin periodane (698.68 mg, 1.65 mmol). The mixture was stirred overnight at room temperature. The reaction was quenched with a saturated solution of sodium sulfite (10 mL) and a saturated solution of sodium bicarbonate (10 mL). The mixture was extracted with DCM (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a white solid (340 mg, 1.21 mmol, 87.8% yield). MS (ESI) m / z [M+H] + 282.0, 284.0 (Br).

[0835] Step 6: 7-Bromo-3',3'-difluorospiro[benzo[] b[1,4]oxazine-2,1'-cyclobutane]-3(4 H Synthesis of )-ketones

[0836]

[0837] At 0°C, 7-bromospiro[benzo[] b [1,4]oxazine-2,1'-cyclobutane]-3,3'(4 H DAST (971.40 mg, 6.03 mmol, 796.23 μL) was added to a solution of 340 mg (1.21 mmol) in DCM (20 mL). The mixture was stirred overnight at room temperature and quenched with a saturated sodium bicarbonate solution (50 mL). The mixture was extracted with DCM (2 × 30 mL). The organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 6) to give the title compound (110 mg, 361.74 μmol, 30% yield) as a yellow oil. MS (ESI) m / z [M+H] + 303.9, 305.9 (Br).

[0838] Steps 7-12: 2-(( S )-1'-(3',3'-difluoro-3,4-dihydrospiro[benzo[ b [1,4]oxazine-2,1'-cyclobutane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(3,4-difluorophenyl)-3-(methylsulfonyl)prop-2-yl)acetamide trifluoroacetate

[0839]

[0840] Following steps 3-8 of Example 21 (C25), the title compound was obtained in six steps with 7-bromo-3',3'-difluorospiro[benzo[b][1,4]oxazine-2,1'-cyclobutane]-3(4H)-one in 34.6% yield. MS (ESI) m / z [M+H] + 704.3.

[0841] Step 13: 2-(( S )-1'-(4-Acryloyl-3',3'-difluoro-3,4-dihydrospiro[benzo[ b[1,4]oxazine-2,1'-cyclobutane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(3,4-difluorophenyl)-3-(methylsulfonyl)prop-2-yl)acetamide (compound C26)

[0842]

[0843] At 0°C, sodium bicarbonate (25.68 mg, 305.70 μmol) and acrylonitrile chloride (5.53 mg, 61.14 μmol, in 0.2 mL THF) were added to a solution of 2-((S)-1'-(3',3'-difluoro-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclobutane]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)-N-((R)-1-(3,4-difluorophenyl)-3-(methanesulfonyl)prop-2-yl)acetamide trifluoroacetate (50 mg, 61.14 μmol, TF) in THF (3 mL) and water (3 mL). The mixture was stirred at 0°C for 20 min and diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give a crude product, which was then purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [water(FA)-CH3CN]; CH3CN: 25%–65%, 8 min) to give the title compound as a pale yellow solid (26.0 mg, 34.31 μmol, 56.1% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 8.11 (d, J = 8.7 Hz, 1H), 7.41-7.24(m, 2H), 7.11-7.00 (m, 2H), 6.97-6.90 (m, 1H), 6.89-6.71 (m, 2H), 6.63 (dd, J = 9.1, 2.3 Hz, 1H), 6.51 (s, 1H), 6.29 (d, J = 16.9 Hz, 1H), 5.85 (dd,J =10.5, 1.5 Hz, 1H), 4.59-4.47 (m, 1H), 3.99 (s, 2H), 3.64 (t, J = 10.4 Hz,2H), 3.44-3.34 (m, 3H), 3.30-3.24 (m, 1H), 3.06-2.94 (m, 4H), 2.89-2.70 (m,7H), 2.54 (d, J = 6.2 Hz, 1H), 2.33 (dd, J = 12.8, 8.0 Hz, 1H), 2.12 (dd, J =14.1, 8.6 Hz, 2H), 1.72-1.60 (m, 1H), 1.55-1.42 (m, 3H). MS(ESI) m / z [M+H] + 758.2.

[0844] Example 23:

[0845] 2-(( S )-1'-(4-Acryloyl-2',3,3',4,5',6'-Hexahydrospiro[benzo[ b [1,4]Oxazine-2,4'-pyridine [indene-1,4'-piperidine]-3-yl)- N -(( R )-1-(3,4-difluorophenyl)-3-(methyl Preparation of sulfonyl)prop-2-yl)acetamide (compound C27)

[0846]

[0847] Step 1: 4-(5-bromo-2-nitrophenoxy)tetrahydro-2 H Synthesis of methyl pyran-4-carboxylate

[0848]

[0849] Add 4-hydroxytetrahydro-2- nitrobenzene (500 mg, 2.27 mmol) to a solution of 4-bromo-2-fluoro-1-nitrobenzene in acetonitrile (10 mL). H Methyl pyran-4-carboxylate (436.83 mg, 2.73 mmol) and cesium carbonate (2.22 g, 6.82 mmol). The mixture was stirred overnight at 80°C. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under vacuum to give the title product (700 mg, crude) as a brown oil. This was used directly in the next step. MS (ESI) m / z [M+Na] + 382.0, 384.0 (Br).

[0850] Step 2: 7-Bromo-2',3',5',6'-Tetrahydrospiro[benzo[] b[1,4]oxazine-2,4'-pyran]-3(4 H Synthesis of )-ketones

[0851]

[0852] To 4-(5-bromo-2-nitrophenoxy)tetrahydro-2 H Methyl pyran-4-carboxylate (728.37 mg, 1.62 mmol) was added to a solution of iron powder (451.80 mg, 8.09 mmol) and ammonium chloride (436.83 mg, 8.09 mmol) in EtOH (10 mL) and water (1 mL). The mixture was stirred overnight at 90°C. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a brown solid (450 mg, 1.21 mmol, 74.6% yield). This was used directly in the next step. MS (ESI) m / z [M+H] + 298.0, 300.0 (Br).

[0853] Step 3: 7-Bromo-2',3,3',4,5',6'-hexahydrospiro[benzo[] b Synthesis of [1,4]oxazine-2,4'-pyran]

[0854]

[0855] At 0°C, 7-bromo-2',3',5',6'-tetrahydrospiro[benzo[] b [1,4]oxazine-2,4'-pyran]-3(4 H )-ketone (450 mg, 1.21 mmol) was added to a solution of borane-tetrahydrofuran complex (5 mL, 1.0 M in THF) in THF (5 mL). The mixture was stirred at 70°C for 2 h. After cooling to 0°C, the reaction was quenched with EtOH (10 mL). The resulting mixture was stirred at 80°C for 2 h and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to give the title compound (320 mg, 1.13 mmol, 93.3% yield) as a yellow oil. MS (ESI) m / z [M+H] + 284.0, 286.0 (Br).

[0856] Step 4: 7-Bromo-2',3',5',6'-Tetrahydrospiro[benzo[] b [1,4]oxazine-2,4'-pyran]-4(3 H Synthesis of tert-butyl formate

[0857]

[0858] To 7-bromo-2',3,3',4,5',6'-hexahydrospiro[benzo[ b [1,4]oxazine-2,4'-pyran] (380 mg, 1.34 mmol) was dissolved in DCM (10 mL) with di-tert-butyl dicarbonate (379.43 mg, 1.74 mmol), triethylamine (405.97 mg, 4.01 mmol), and DMAP (81.69 mg, 668.66 μmol). The mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to give the title compound as a yellow oil (170 mg, 442.40 μmol, 33.1% yield). MS (ESI) m / z [M- t -Bu+H] + 327.9, 329.9, [M+Na] + 406.0, 408.0.

[0859] Steps 5-8: N -(( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)-2-(( S )-6-fluoro-1'-(2',3,3',4,5',6'-hexahydrospiro[benzo[ b Synthesis of [1,4]oxazine-2,4'-pyran]-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide trifluoroacetate

[0860]

[0861] Following the method of steps 5-8 in Example 21 (C25), 7-bromo-2',3',5',6'-tetrahydrospiro[benzo[] b [1,4]oxazine-2,4'-pyran]-4(3 H tert-butyl formate was reacted to yield the title compound. MS (ESI) m / z [M+H] + 698.2.

[0862] Step 9: 2-(( S)-1'-(4-Acryloyl-2',3,3',4,5',6'-Hexahydrospiro[benzo[ b [1,4]oxazine-2,4'-pyran]-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(3,4-difluorophenyl)-3-(methylsulfonyl)prop-2-yl)acetamide (compound C27)

[0863]

[0864] Towards N -(( R )-1-(3,4-difluorophenyl)-3-(methylsulfonyl)propyl-2-yl)-2-(( S )-6-fluoro-1'-(2',3,3',4,5',6'-hexahydrospiro[benzo[ b Sodium bicarbonate (93.13 mg, 1.11 mmol) was added to a solution of [1,4]oxazine-2,4'-pyran]-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide trifluoroacetate (180 mg, 221.72 μmol) in THF (5 mL) and water (5 mL). A solution of acrylonitrile-2-enoyl chloride (20.07 mg, 221.72 μmol) in THF (0.5 mL) was added dropwise to the above solution at 0°C. The mixture was stirred at 0°C for 20 min and diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to obtain the residue, which was then purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 μm; mobile phase: [water(FA)-CH3CN]; CH3CN: 25%-65%, 8 min) to obtain the title compound as a white solid (83.79 mg, 111.44 μmol, 50.3% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 8.10 (d, J = 8.7Hz, 1H), 7.41-7.24 (m, 2H), 7.13-7.01 (m, 2H), 6.99-6.67 (m, 4H), 6.58 (dd, J= 9.1, 2.7 Hz, 1H), 6.49 (d, J = 2.7 Hz, 1H), 6.27 (dd, J = 16.7, 2.2 Hz, 1H), 5.81 (dd, J = 10.3, 2.2 Hz, 1H), 4.61-4.46 (m, 1H), 3.81 (s, 2H), 3.74-3.56 (m, 6H), 3.44-3.35 (m, 2H), 3.29-3.24 (m, 1H), 3.06-2.93 (m, 4H), 2.84-2.66 (m, 3H), 2.56-2.52 (m, 1H), 2.33 (dd, J = 13.0, 7.8 Hz, 1H), 2.19-2.08(m, 2H), 1.71-1.43 (m, 8H). MS(ESI) m / z [M+H] + 752.3.

[0865] Example 24:

[0866] 2-((S)-1'-(4-Acryloyl-2,2-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4]) Thiazidin-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)-N-((R)-2-(3,4-difluorophenyl)-1-(5- Preparation of methyl-1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C29)

[0867]

[0868] Step 1: Synthesis of methyl 2-((5-bromo-2-nitrophenyl)thio)-2-methylpropionate

[0869]

[0870] Methyl 2-mercapto-2-methylpropionate (1.21 g, 9.00 mmol) was added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.8 g, 8.18 mmol) and triethylamine (2.48 g, 24.55 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 1 h and quenched with water (20 mL). The mixture was extracted with DCM (3 × 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to provide the title compound as a yellow oil (2.15 g, 6.43 mmol, 78.6% yield). MS (ESI) m / z [M+H] +334.0, 335.9 (Br).

[0871] Steps 2-5: 7-Bromo-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b Synthesis of tert-butyl thiazide-4-carboxylate [1,4]

[0872]

[0873] Following the method of steps 2-5 in Example 20 (C24), the title compound was obtained using methyl 2-((5-bromo-2-nitrophenyl)thio)-2-methylpropionate. MS (ESI) m / z [M-Boc+H] + 258.0, 260.0 (Br).

[0874] Step 6: 7-Bromo-2,2-dimethyl-2,3-dihydro-4 H -benzo[ b Synthesis of 1,1-dioxide of tert-butyl 4-thiazine carboxylate [1,4]

[0875]

[0876] To 7-bromo-2,2-dimethyl-3 H 1,4-Benzothiazine-4-carboxylic acid tert-butyl ester (30 mg, 83.73 μmol) was added to a solution of DCM (10 mL). m -CPBA (36.00 mg, 209.33 μmol). The mixture was stirred at 45°C for 16 h under a nitrogen atmosphere and quenched with sodium hydroxide (20 mL, 2 N). The mixture was extracted with DCM (3 x 20 mL). The organic layers were combined, washed with brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (in DCM / MeOH = 1 / 15) to provide the title compound as a white solid. MS (ESI) m / z [M-Boc+H] + 290.0, 291.9 (Br).

[0877] Steps 7-10: N-(( R )-2-(3,4-difluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-2- (( S )-1'-(2,2-dimethyl-1,1-dioxide-3,4-dihydro-2 H -benzo[ b [1,4]thiazine-7-yl)-6-fluoro-2,3-di Hydrospiro[indene-1,4'-piperidine]-3-yl)acetamide Synthesis

[0878]

[0879] Following the method of steps 5-8 in Example 21 (C25), 7-bromo-2,2-dimethyl-2,3-dihydro-4- H-benzo[ b [1,4]thiazine-4-carboxylic acid tert-butyl ester 1,1-dioxide yielded the title compound. MS (ESI) m / z [M+H] + 694.3.

[0880] Step 11: 2-(( S )-1'-(4-Acryloyl-2,2-dimethyl-1,1-dioxide-3,4-dihydro-2 H -benzo[ b [1,4]thiazin-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 2-(3,4-difluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C29)

[0881]

[0882] Towards N -[(1 R )-2-(3,4-difluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-2-[(1 S 1'-(2,2-dimethyl-1,1-dioxo-3,4-dihydro-1,4-benzothiazin-7-yl)-5-fluoro-spiro[indan-3,4'-piperidin]-1-yl]acetamide (60 mg, 86.48 μmol), triethylamine (26.20 mg, 259.45 μmol), and acrylonitrile chloride (15.65 mg, 172.97 μmol) were added to a solution in DCM (10 mL). The mixture was stirred for 2 h and quenched with water (10 mL). The mixture was extracted with DCM (3 x 20 mL), and the organic layers were combined, washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography to provide the title compound (20 mg, 26.74 μmol, 30.9% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO -d 6) δ 8.68(d, J = 8.5 Hz, 1H), 7.47-7.22 (m, 5H), 7.18-7.13 (m, 1H), 7.08 (dd, J = 9.5, 2.3 Hz, 1H), 6.95 (dd, J= 8.2, 5.5 Hz, 1H), 6.87 (td, J = 8.8, 2.4 Hz, 1H), 6.63 (dd, J = 16.6, 10.3 Hz, 1H), 6.31 (dd, J = 16.7, 1.9 Hz, 1H), 5.85 (dd, J = 10.3, 1.9 Hz, 1H), 5.49-5.37 (m, 1H), 4.17 (s, 2H), 3.75 (t, J = 14.4 Hz, 2H), 3.30 (dd, J = 14.0, 5.1 Hz, 2H), 3.10 (dd, J = 13.8, 10.5 Hz, 1H), 2.92-2.74 (m, 2H), 2.58 (dd, J = 14.2, 6.2 Hz, 1H), 2.45 (s, 3H), 2.36-2.04 (m,3H), 1.79-1.64 (m, 1H), 1.60-1.43 (m, 3H), 1.32 (s, 6H). MS(ESI) m / z [M+H] + 748.3.

[0883] Example 25:

[0884] 2-(( S )-1'-(4-Acryloyl-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-6-fluoro- 2,3-Dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5- Preparation of trifluorophenyl)ethyl)acetamide (compound C31)

[0885]

[0886] Step 1: Synthesis of tert-butyl 2-((2-bromo-5-nitropyridin-4-yl)oxy)acetate

[0887]

[0888] NaH (6.91 g, 172.72 mmol) was slowly added to a solution of tert-butyl 2-hydroxyacetate (15.20 g, 115.15 mmol) in THF (150 mL) at 0°C. The mixture was stirred at 0°C for 0.5 h under a nitrogen atmosphere. Then, 2,4-dibromo-5-nitropyridine (26.8 g, 95.95 mmol) was added to the above mixture. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h and quenched with a saturated solution of ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 7) to provide the title compound (26.12 g, 78.67 mmol, 82% yield) as a yellow oil. MS (ESI) m / z [M+H] + 333.0.

[0889] Step 2: Synthesis of tert-butyl 2-((5-amino-2-bromopyridin-4-yl)oxy)acetate

[0890]

[0891] Iron powder (33.90 g, 605.4 mmol) was added to a solution of 2-((2-bromo-5-nitropyridin-4-yl)oxy)tert-butyl acetate (20.1 g, 60.54 mmol) and hydrochloric acid (one drop) in water (20 mL) and EtOH (200 mL). The mixture was stirred at 70°C for 3 h and filtered. The filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (100 mL) and water (80 mL). The solution was extracted with ethyl acetate (3 × 80 mL). The organic layers were combined, washed with brine (3 × 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (16.87 g, 55.88 mmol, 92.3% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 303.0.

[0892] Step 3: 7-Bromo-2 H -pyrido[4,3- b [1,4]Oxazine-3(4 H Synthesis of )-ketones

[0893]

[0894] Trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 2-((5-amino-2-bromopyridin-4-yl)oxy)acetate (16.0 g, 48.31 mmol) in DCM (150 mL). The mixture was stirred at 45°C for 4 h. The mixture was concentrated under vacuum to give the title compound (12.0 g, 46.68 mmol, 96.6% yield) as a yellow oil. MS (ESI) m / z [M+H] + 228.9.

[0895] Step 4: 7-Bromo-3,4-Dihydro-2 H -pyrido[4,3- b Synthesis of [1,4]oxazine

[0896]

[0897] To 7-bromo-2 H -pyrido[4,3- b [1,4]Oxazine-3(4 H A solution of 12.0 g (52.63 mmol) of the ketone in THF (150 mL) was added to a borane-tetrahydrofuran complex (105 mL, 1.0 M in THF). The mixture was stirred at 70°C for 2 h under a nitrogen atmosphere and quenched with MeOH (20 mL). The solvent was evaporated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 10) to provide the title compound as a yellow oil (9.78 g, 45.70 mmol, 86.8% yield). MS (ESI) m / z [M+H] + 214.9.

[0898] Step 5: 7-Bromo-3,4-Dihydro-2 H -pyrido[4,3- b Synthesis of [1,4]oxazine

[0899]

[0900] To 7-bromo-3,4-dihydro-2 H -pyrido[4,3- b[1,4]Oxazine (9.78 g, 45.70 mmol), triethylamine (13.84 g, 137.10 mmol), and DMAP (562.11 mg, 4.57 mmol) were added to a solution of di-tert-butyl dicarbonate (43.03 g, 197.17 mmol, 45.25 mL) in THF (200 mL). The mixture was stirred at 50°C for 16 h under a nitrogen atmosphere and quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 × 80 mL). The organic layers were combined, washed with brine (3 × 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 15) to provide the title compound (13.11 g, 41.77 mmol, 91.4% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 315.0.

[0901] Steps 6-9: 2-(( S )-1'-(3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)acetamide

[0902]

[0903] Following the method of steps 9-12 in Example 15 (C5), 7-bromo-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine, yielding the title compound. MS (ESI) m / z [M+H] + 637.2.

[0904] Step 10: 2-(( S )-1'-(4-Acryloyl-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)acetamide (compound C31)

[0905]

[0906] To 2-(( S )-1'-(3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Sodium bicarbonate (32.99 mg, 392.69 μmol) was added to a solution of 1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)acetamide (50 mg, 78.54 μmol) in THF (5 mL) and water (5 mL). A solution of acrylonitrile chloride (7.11 mg, 78.54 μmol) in THF (0.1 mL) was added dropwise to the above mixture at 0°C. The mixture was stirred at 0°C for 30 min and diluted with water (30 mL). The aqueous phase was extracted with DCM (3 × 30 mL). The organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was subjected to reversed-phase rapid chromatography (column: C18 silica gel; mobile phase: CH3CN in water, in a 5% to 35% gradient over 15 min; detector: UV 254 nm) to give the title compound as a white solid (9.1 mg, 13.18 μmol, 16.8% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 8.67 (d, J = 8.5 Hz, 1H), 7.97-7.60 (m, 1H), 7.41-7.25 (m, 2H), 7.07-6.93 (m, 2H), 6.91-6.69 (m, 2H), 6.40-6.20 (m, 2H), 5.82 (dd, J = 10.4, 2.2 Hz, 1H), 5.51-5.39 (m, 1H), 4.32 (t, J = 4.6 Hz, 2H),4.27-4.13 (m, 2H), 4.01-3.88 (m, 2H), 3.45-3.35 (m, 1H), 3.29-3.26 (m, 1H),3.11 (dd, J= 13.9, 10.5 Hz, 1H), 2.90-2.72 (m, 2H), 2.60 (dd, J = 14.2, 6.1Hz, 1H), 2.46 (s, 3H), 2.32 (dd, J = 13.0, 7.5 Hz, 1H), 2.18 (dd, J = 14.2,8.6 Hz, 1H), 2.08-1.94 (m, 1H), 1.64-1.40 (m, 4H). MS(ESI) m / z [M+H] + 691.2.

[0907] Example 26:

[0908] 2-(( S )-6-Fluoro-1'-(4-(( E )-4-morpholinobut-2-enoyl)-3,4-dihydro-2 H -pyrido[4,3- b ] [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-1-(5-methyl-1,3,4-oxadiazole- Preparation of 2-yl)-2-(3,4,5-trifluorophenyl)ethyl)acetamide (compound C39)

[0909]

[0910] Step 1: ( E Synthesis of 4-bromobut-2-enoyl chloride

[0911]

[0912] Under a nitrogen atmosphere, at 0°C, towards ( E 4-Bromobut-2-enoic acid (40 mg, 242.45 μmol) was added dropwise to a stirred solution in DCM (3 mL) with oxalyl chloride (46 mg, 362.42 μmol, 31.62 μL) and DMF (2 mg, 27.36 μmol, 2.12 μL). The mixture was stirred at room temperature for 20 min. The resulting mixture was concentrated under vacuum to give the title compound (40 mg, 218.07 μmol, 89.9% yield) as a colorless oil. This was used directly in the next step.

[0913] Step 2: 2-(( S )-1'-(4-(( E )-4-bromobut-2-enoyl)-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( RSynthesis of 1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)acetamide

[0914]

[0915] Under a nitrogen atmosphere at 0°C, towards 2-(( S )-1'-(3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)acetamide (90 mg, 141.37 μmol) and DIPEA (91 mg, 705.43 μmol) were added dropwise to a stirred solution of THF (3 mL). E 4-Bromobut-2-enoyl chloride (39 mg, 212.61 μmol). The mixture was stirred at room temperature for 30 min. The reaction solution was used directly in the next step without further purification. MS (ESI) m / z [M+H] + 783.1, 785.1 (Br).

[0916] Step 3: 2-(( S )-6-Fluoro-1'-(4-(( E )-4-morpholinobut-2-enoyl)-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)acetamide (compound C39)

[0917]

[0918] 2-(( S )-1'-(4-(( E )-4-bromobut-2-enoyl)-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( RA solution of 1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(3,4,5-trifluorophenyl)ethyl)acetamide (40 mg, 51.05 μmol), morpholine (4.9 mg, 56.16 μmol), and DIPEA (20 mg, 155.04 μmol) in THF (3 mL) was stirred at room temperature for 1 h. The solvent was evaporated under vacuum. The residue was purified by reversed-phase rapid chromatography (column: C18 silica gel; mobile phase: CH3CN in water, 5% to 30% gradient over 15 min; detector: UV 254 nm) to give the title compound as a white solid: (9.49 mg, 16.57 μmol, two-step yield 9.8%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.67 (d, J = 8.5 Hz, 1H), 7.99-7.61(m, 1H), 7.39-7.27 (m, 2H), 7.07-6.94 (m, 2H), 6.86 (td, J = 8.8, 2.5 Hz,1H), 6.80-6.70 (m, 1H), 6.69-6.55 (m, 1H), 6.34 (s, 1H), 5.45 (ddd, J = 10.7,8.5, 5.0 Hz, 1H), 4.31 (t, J = 4.6 Hz, 2H), 4.20 (t, J = 16.6 Hz, 2H), 3.92(s, 2H), 3.57 (t, J = 4.6 Hz, 4H), 3.45-3.35 (m, 2H), 3.31-3.27 (m, 1H), 3.17-3.09 (m, 2H), 2.89-2.72 (m, 2H), 2.60 (dd, J = 14.2, 6.1 Hz, 1H), 2.46(s, 3H), 2.42-2.27 (m, 5H), 2.18 (dd, J = 14.2, 8.6 Hz, 1H), 2.07-1.95 (m,1H), 1.64-1.42 (m, 4H). MS(ESI) m / z [M+H] + 790.3.

[0919] Example 27:

[0920] N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-6-Fluoro-1'-(4- (2-Fluoroacryloyl)-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperazine] Preparation of [-3-yl]acetamide (compound C46)

[0921]

[0922] Step 1: N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-6-fluoro-1'-(4-(2-fluoroacryloyl)-3,4-dihydro-2 H -pyrido[4,3- b Synthesis of [1,4]oxazin-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide (compound C46)

[0923]

[0924] Towards N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-1'-(3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazin-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide (30 mg, 49.62 μmol) was added to a solution of 2-fluoroacrylic acid (4.69 mg, 52.10 μmol), DIPEA (12.83 mg, 99.24 μmol, 17.28 μL), and HATU (28.30 mg, 74.43 μmol) in DMF (3 mL). The mixture was stirred at room temperature for 1 h and then quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The organic layers were combined, washed with brine (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography (column: C18 silica gel; mobile phase: CH3CN in water, in a 5% to 30% gradient over 15 min; detector: UV 254 nm) to give the title compound as a white solid (14.22 mg, 21.02 μmol, 42.4% yield). 1 H NMR (400MHz, DMSO- d 6) δ 9.23 (s, 1H), 8.73 (d, J= 8.4 Hz, 1H), 8.52-8.20 (m, 1H), 7.48-7.32 (m, 2H), 7.22-7.12 (m, 1H), 7.00 (dd, J = 9.6, 2.5 Hz, 1H), 6.94(dd, J = 8.2, 5.4 Hz, 1H), 6.85 (td, J = 8.8, 2.5 Hz, 1H), 6.34 (s, 1H), 5.54-5.44 (m, 2H), 5.44-5.32 (m, 1H), 4.39-4.30 (m, 2H), 4.20 (t, J = 15.6Hz, 2H), 3.93 (d, J = 5.1 Hz, 2H), 3.43-3.36 (m, 1H), 3.15 (dd, J = 13.9,10.4 Hz, 1H), 2.92-2.71 (m, 2H), 2.59 (dd, J = 14.3, 6.2 Hz, 1H), 2.36-2.27(m, 1H), 2.19 (dd, J = 14.3, 8.4 Hz, 1H), 2.07-1.93 (m, 2H), 1.57-1.41 (m, 4H). MS(ESI) m / z [M+H] + 677.3.

[0925] Example 28:

[0926] N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-6-Fluoro-1'-(4- (2-(morpholinomethyl)acryloyl)-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-2,3-dihydrospirocyclohexane Preparation of [indene-1,4'-piperidine]-3-yl)acetamide (compound C47)

[0927]

[0928] Step 1: Synthesis of 2-(morpholinomethyl)acrylic acid

[0929]

[0930] A mixture of 2-(bromomethyl)acrylic acid (330 mg, 2.00 mmol), morpholine (261.38 mg, 3.00 mmol, 262.43 μL), and potassium carbonate (414.65 mg, 3.00 mmol) in acetonitrile (10 mL) was stirred at room temperature for 4 h. The reaction mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under vacuum to give the title compound (345 mg, crude) as a colorless oil, which was used directly in the next step. MS (ESI) m / z [M+H] + 172.1.

[0931] Step 2: N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-6-fluoro-1'-(4-(2-(morpholinomethyl)acryloyl)-3,4-dihydro-2 H -pyrido[4,3- b Synthesis of [1,4]oxazin-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide (compound C47)

[0932]

[0933] Under a nitrogen atmosphere, towards N -[(1 R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl]-2-[(1 S )-1'-(3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazin-7-yl)-5-fluoro-spiro[indan-3,4'-piperidin]-1-yl]acetamide (30 mg, 49.62 μmol) and 2-(morpholinomethyl)acrylic acid (10.19 mg, 59.54 μmol) were added to a solution of DMF (2 mL) with DIEA (19.24 mg, 148.85 μmol, 25.93 μL) and HATU (22.64 mg, 59.54 μmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (5 mg, 6.60 μmol, 13.3% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.22 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.47-7.29 (m, 2H), 7.19-7.12 (m,1H), 6.98 (dd, J = 9.5, 2.4 Hz, 1H), 6.93 (dd, J = 8.2, 5.4 Hz, 1H), 6.85(td, J = 8.9, 2.4 Hz, 1H), 6.26 (s, 1H), 5.56-5.43 (m, 2H), 5.24 (s, 1H), 4.29-4.17 (m, 2H), 4.07-3.92 (m, 4H), 3.60-3.42 (m, 6H), 3.25-3.01 (m, 7H),2.76-2.55 (m, 3H), 2.28 (dd, J = 12.9, 7.8 Hz, 1H), 2.18 (dd, J = 14.3, 8.4Hz, 1H), 2.06-1.95 (m, 1H), 1.61-1.38 (m, 4H). MS(ESI) m / z [M+H] + 758.3.

[0934] Example 29:

[0935] N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-6-Fluoro-1'-(4- (vinylsulfonyl)-3,4-dihydro-2 H -pyrido[4,3- b [1,4]oxazine-7-yl)-2,3-dihydrospiro[indene-1,4'-piperazine] Preparation of [-3-yl]acetamide (compound C53)

[0936]

[0937] Step 1: N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-6-fluoro-1'-(4-(vinylsulfonyl)-3,4-dihydro-2 H -pyrido[4,3- b Synthesis of [1,4]oxazin-7-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide (compound C53)

[0938]

[0939] At 0°C, towardsN -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S )-1'-(3,4-dihydro-2 H -pyrido[4,3- b A solution of 2-chloroethanesulfonyl chloride (27.22 mg, 166.98 μmol) in DCM (5 mL) was added dropwise to a solution of [1,4]oxazine-7-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide trifluoroacetate (120 mg, 166.98 μmol) and triethylamine (50.69 mg, 500.94 μmol) in DCM (5 mL). The mixture was stirred at 0°C for 20 min and quenched with water (20 mL). The mixture was extracted with DCM (2 × 20 mL), washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC (column: WatersXbridge Prep OBD C18 150×40 mm×10 μm; mobile phase: [water(FA)-CH3CN]; CH3CN: 25%-65%, 8 min) to give the title compound as a white solid (25.66 mg, 36.94 μmol, 22.1% yield). 1 H NMR (400 MHz, DMSO-) d 6) δ 9.23 (d, J = 1.1 Hz, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.17(s, 1H), 7.48-7.31 (m, 2H), 7.20-7.11 (m, 1H), 7.05-6.90 (m, 3H), 6.86 (td, J = 8.7, 2.4 Hz, 1H), 6.30 (s, 1H), 6.22-6.09 (m, 2H), 5.55-5.43 (m, 1H), 4.33-4.10 (m, 4H), 3.79 (t, J = 4.6 Hz, 2H), 3.55-3.38 (m, 2H), 3.15 (dd, J =13.9, 10.4 Hz, 1H), 2.90-2.71 (m, 2H), 2.59 (dd, J = 14.2, 6.3 Hz, 1H), 2.31(dd,J = 12.9, 7.6 Hz, 1H), 2.19 (dd, J = 14.2, 8.4 Hz, 1H), 1.99 (td, J =13.0, 4.3 Hz, 1H), 1.61-1.41 (m, 4H). MS(ESI) m / z [M+H] + 695.2.

[0940] Example 30:

[0941] 2-(( S )-1'-(1-Acryloylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3- base)- N -(( R Preparation of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C54)

[0942]

[0943] Step 1: 5-Bromo-1 H Synthesis of tert-butyl indole-1-carboxylate

[0944]

[0945] At 0°C, to 5-bromo-1 H -Indole (500 mg, 2.55 mmol) was added to a solution of NaH (91.82 mg, 3.83 mmol) in THF (10 mL). The mixture was stirred at 0°C for 30 min. Then, di-tert-butyl dicarbonate (1.11 g, 5.10 mmol) was added to the above mixture at 0°C. The mixture was stirred at 0°C for 1 h. The reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 40 / 1) to give the title compound (730 mg, 96.6% yield) as a colorless oil.

[0946] Step 2: ( S )-5-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-1 H Synthesis of tert-butyl indole-1-carboxylate

[0947]

[0948] Fill the sealed tube with ( S)-2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)ethyl acetate (200 mg, 686.44 μmol), 5-bromo-1 H -Indole-1-carboxylic acid tert-butyl ester (297.15 mg, 823.73 μmol), Pd2(dba)3 (62.86 mg, 68.64 μmol), Ruphos (61.85 mg, 137.29 μmol), cesium carbonate (671.34 mg, 2.06 mmol), and 1,4-dioxane (10 mL). The mixture was stirred at 100°C for 60 h. The reaction was quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL). The organic layers were combined, washed with brine (2 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (190 mg, 54.6% yield) as a yellow oil. MS (ESI) m / z [M+H] + 507.2.

[0949] Step 3: ( S Synthesis of tert-butyl indoline-1-carboxylic acid ester (3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)

[0950]

[0951] Towards( S )-5-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-1 H 1,4-Indole-1-carboxylic acid tert-butyl ester (190 mg, 375.04 μmol) was mixed with Pd / C (45.55 mg, 10%) in a methanol (10 mL) solution. The mixture was stirred at 55°C for 6 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound (150 mg, 78.6% yield) as a colorless oil. MS (ESI) m / z [M+H] + 509.3.

[0952] Step 4: ( S )-2-(1'-(1-( Uncle Synthesis of butoxycarbonyl)indoline-5-yl)-6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidin]-3-yl)acetic acid

[0953]

[0954] Towards( S 5-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)indoline-1-carboxylic acid tert-butyl ester (150 mg, 294.91 μmol) was mixed with lithium hydroxide (14.13 mg, 589.83 μmol) in a methanol / THF / water solution (3 mL / 3 mL / 3 mL). The mixture was stirred at room temperature for 3 h. The pH of the solution was adjusted to 7. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound (120 mg, 90% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 481.2.

[0955] Step 5: 5-(( S )-3-(2-((( R Synthesis of tert-butyl indoline-1-carboxylic acid 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)indoline-1-carboxylic acid

[0956]

[0957] Towards( S )-2-(1'-(1-( Uncle Butoxycarbonyl)indoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (120 mg, 249.70 μmol) was added to a solution of acetonitrile (5 mL) with DIEA (96.64 mg, 749.11 μmol). R 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl-1-amine (84.35 mg, 374.56 μmol) and T3P (119.18 mg, 374.56 μmol, 50% in ethyl acetate). The mixture was stirred at room temperature for 3 h and diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (89 mg, 51.8% yield) as a white solid. MS (ESI) m / z [M+H] + 688.3.

[0958] Step 6: N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S Synthesis of 6-fluoro-1'-(indoline-5-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide

[0959]

[0960] Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl indoline-1-carboxylate (89 mg, 129.41 μmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum to give the compound as a brown oil (70 mg, 92.1% yield). The crude product was used for the next step. MS (ESI) m / z [M+H] + 589.2.

[0961] Step 7: 2-(( S )-1'-(1-Acryloylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C54)

[0962]

[0963] At 0°C, towards N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-(( S6-Fluoro-1'-(indoline-5-yl)-2,3-dihydrospiro[indole-1,4'-piperidin]-3-yl)acetamide (70 mg, 118.92 μmol) was prepared in a solution of THF / water (4 mL / 1 mL) with sodium bicarbonate (100.01 mg, 1.19 mmol) and acryl-2-enoyl chloride (10.76 mg, 118.92 μmol). The mixture was stirred at 0°C for 30 min and diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Welch XB-C18 21.2×100 mm×5 μm; mobile phase: [water(FA)-CH3CN]; CH3CN: 30%-55%, 15 min) to give the title compound as a white solid (7.74 mg, 10.1% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 9.22 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.45-7.32 (m, 2H), 7.18-7.14 (m, 1H), 7.06 (dd, J =9.5, 2.3 Hz, 1H), 6.96-6.85 (m, 3H), 6.81-6.69 (m, 2H), 6.26 (dd, J = 16.6, 2.0 Hz, 1H), 5.77 (dd, J = 10.3, 2.1 Hz, 1H), 5.52-5.47 (m, 1H), 4.19 (t, J =8.3 Hz, 2H), 3.56 (t, J = 10.3 Hz, 2H), 3.14 (dd, J = 15.2, 9.2 Hz, 3H),2.74-2.57 (m, 4H), 2.27-2.13 (m, 3H), 1.70 (dd, J = 12.4, 9.1 Hz, 1H), 1.54-1.40 (m, 4H). MS(ESI) m / z [M+H] + 642.2.

[0964] Example 31:

[0965] 2-((3 S )-1'-(1-Acryloyl-3-isopropylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'- [piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound) Preparation of C58

[0966]

[0967] 2-(( S )-1'-(( R )-1-Acryloyl-3-isopropylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1, 4'-piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound) Preparation of substance C59

[0968]

[0969] 2-(( S )-1'-(( S )-1-Acryloyl-3-isopropylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1, 4'-piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound) Preparation of compound C60

[0970]

[0971] Step 1: Synthesis of 5-bromo-3-(propane-2-ylidene)indoline-2-one

[0972]

[0973] Acetone (1.10 g, 18.86 mmol, 1.39 mL) was added to a solution of 5-bromoindoline-2-one (2 g, 9.43 mmol) and pyrrolidine (67.08 mg, 943.20 μmol, 78.37 μL) in methanol (50 mL). The resulting mixture was stirred at 70°C for 3 h. The mixture was concentrated under vacuum to give the title compound as a yellow solid (2.0 g, 7.93 mmol, 84.1% yield). MS (ESI) m / z [M+H] + 252.0, 253.9 (Br).

[0974] Step 2: Synthesis of 5-bromo-3-isopropylindoline-2-one

[0975]

[0976] Sodium cyanoborohydride (3.99 g, 63.47 mmol) was added to a solution of 5-bromo-3-(propane-2-ylidene)indoline-2-one (2 g, 7.93 mmol) in methanol (100 mL) at 0°C. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (5 mL). The mixture was concentrated under vacuum to give the title compound (1.8 g, 7.08 mmol, 89.3% yield) as a yellow oil. MS (ESI) m / z [M+H]+ 254.0, 256.0 (Br).

[0977] Step 3: Synthesis of 5-bromo-3-isopropylindoline

[0978]

[0979] At 0°C, a borane-tetrahydrofuran complex (6.55 mL, 66.90 mmol, 1 M solution in THF) was added to a solution of 5-bromo-3-isopropylindolin-2-one (1.7 g, 6.69 mmol) in THF (20 mL). The resulting mixture was stirred at 60°C for 3 h. The reaction was quenched with MeOH (5 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound as a yellow oil (800 mg, 3.33 mmol, 49.8% yield). MS (ESI) m / z [M+H] + 240.1, 242.1 (Br).

[0980] Step 4: Synthesis of tert-butyl 5-bromo-3-isopropylindoline-1-carboxylate

[0981]

[0982] Di-tert-butyl dicarbonate (908.84 mg, 4.16 mmol) was added to a solution of 5-bromo-3-isopropylindoline (500 mg, 2.08 mmol) and sodium carbonate (662.05 mg, 6.25 mmol, 261.47 μL) in THF (10 mL) and water (10 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound as a colorless oil (640 mg, 1.88 mmol, 90.3% yield). MS (ESI) m / z [M+H] + 340.0, 342.1 (Br).

[0983] Step 5: 5-(( S Synthesis of tert-butyl 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-3-isopropylindoline-1-carboxylic acid

[0984]

[0985] Fill the sealed tube with ( S Ethyl 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)ethyl acetate (200 mg, 686.44 μmol), tert-butyl 5-bromo-3-isopropylindoline-1-carboxylate (256.92 mg, 755.08 μmol), Pd2(dba)3 (62.86 mg, 68.64 μmol), S-Phos (56.36 mg, 137.29 μmol), cesium carbonate (670.96 mg, 2.06 mmol), and 1,4-dioxane (5 mL) were added. The resulting mixture was stirred at 105°C for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound as a yellow oil (260 mg, 472.12 μmol, 68.8% yield). MS (ESI) m / z [M+H] + 551.3.

[0986] Step 6: 2-((3) S )-1'-(1-( Uncle Synthesis of butoxycarbonyl)-3-isopropylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[inden-1,4'-piperidine]-3-yl)acetic acid

[0987]

[0988] To 5-(( S 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-3-isopropylindoline-1-carboxylic acid tert-butyl ester (260 mg, 472.12 μmol) was prepared in a solution of water (3 mL), methanol (3 mL), and THF (3 mL) with lithium hydroxide monohydrate (59.43 mg, 1.42 mmol). The mixture was incubated at room temperature for 16 h. The pH of the solution was adjusted to 5 with hydrochloric acid (2 N). The reaction mixture was diluted with brine (50 mL). The resulting solution was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a white solid (240 mg, 459.20 μmol, 97.3% yield). MS (ESI) m / z [M+H] + 523.3.

[0989] Step 7: 5-(( S )-3-(2-((( R Synthesis of tert-butyl 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-3-isopropylindoline-1-carboxylic acid

[0990]

[0991] At room temperature, to ( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl-1-amine (56.87 mg, 252.56 μmol), 2-((3 S )-1'-(1-( Uncle HATU (130.95 mg, 344.40 μmol) was added to a solution of butoxycarbonyl)-3-isopropylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (120 mg, 229.60 μmol) and DIEA (89.02 mg, 688.80 μmol, 119.97 μL) in acetonitrile (5 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 95 / 5) to give the title compound as a yellow solid (90 mg, 123.32 μmol, 53.7% yield). MS (ESI) m / z [M+H] + 730.3.

[0992] Step 8: N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-((3 S Synthesis of 6-fluoro-1'-(3-isopropylindoline-5-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide

[0993]

[0994] To 5-(( S )-3-(2-((( R2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)amino)-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-3-isopropylindoline-1-carboxylic acid tert-butyl ester (90 mg, 123.32 μmol) was added to a solution of trifluoroacetic acid (1 mL) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was concentrated under vacuum to give the title compound as a yellow solid (65 mg, 103.22 μmol, 83.7% yield). MS (ESI) m / z [M+H] + 630.3.

[0995] Step 9: 2-((3) S )-1'-(1-Acryloyl-3-isopropylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C58)

[0996]

[0997] At 0°C, towards N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)-2-((3 S Acrylonitrile (65 mg, 103.22 μmol) was added to a solution of 6-fluoro-1'-(3-isopropylindoline-5-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetamide (86.72 mg, 1.03 mmol, 40.17 μL) in water (2 mL) and THF (5 mL). The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 90 / 10) to give the title compound as a white solid (22.32 mg, 32.64 μmol, 31.6% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 9.22 (s, 1H), 8.73 (d, J= 8.4 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.48-7.30(m, 2H), 7.20-7.13 (m, 1H), 7.06 (dd, J = 9.5, 2.3 Hz, 1H), 6.98-6.73 (m,5H), 6.26 (dd, J = 16.6, 2.1 Hz, 1H), 5.77 (dd, J = 10.3, 2.1 Hz, 1H), 5.49(ddd, J = 10.4, 8.6, 5.2 Hz, 1H), 4.15 (t, J = 10.4 Hz, 1H), 4.00 (dd, J =11.0, 4.9 Hz, 1H), 3.64-3.50 (m, 2H), 3.41-3.35 (m, 2H), 3.32-3.30 (m, 1H), 3.15 (dd, J = 13.7, 10.6 Hz, 1H), 2.77-2.56 (m, 3H), 2.31-2.02 (m, 4H), 1.78-1.67 (m, 1H), 1.57-1.38 (m, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.73 (dd, J = 6.8,2.2 Hz, 3H). MS(ESI) m / z [M+H] + 684.3.

[0998] Step 10: Synthesis of 2-((S)-1'-((R)-1-acryloyl-3-isopropylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)-N-((R)-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C59) and 2-((S)-1'-((S)-1-acryloyl-3-isopropylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)-N-((R)-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C60)

[0999]

[1000] The configurations of the two isomers are not determined and are arbitrarily assigned.

[1001] Compounds C59 and C60 were obtained by SFC separation of the mixture compound C58 (65 mg) under the following separation conditions:

[1002] Instrument: SFC Thar prep 80

[1003] Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm

[1004] Modifier: 40% EtOH (0.2% NH4OH)

[1005] Total flow rate: 40 g / min

[1006] Compound C59 (14.16 mg, 21.8% yield): a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.21 (s, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.43 (ddd, J = 11.8, 7.9, 1.9 Hz, 1H), 7.39-7.30 (m, 1H), 7.20-7.13 (m, 1H), 7.06 (dd, J = 9.5, 2.3 Hz, 1H), 6.97-6.77 (m, 5H), 6.26 (dd, J = 16.6, 2.1 Hz, 1H), 5.77(dd, J = 10.3, 2.2 Hz, 1H), 5.53-5.43 (m, 1H), 4.15 (t, J = 10.4 Hz, 1H), 3.99 (dd, J = 11.0, 4.9 Hz, 1H), 3.62-3.50 (m, 2H), 3.37-3.34 (m, 2H), 3.14(dd, J = 13.8, 10.6 Hz, 1H), 2.73-2.57 (m, 3H), 2.29-1.95 (m, 5H), 1.76-1.66(m, 1H), 1.51 (d, J= 12.5 Hz, 2H), 1.44 (dd, J = 12.8, 8.7 Hz, 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H). MS (ESI) m / z [M+H] + 684.1.

[1007] Compound C60 (15.54 mg, 23.9% yield): a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.21 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.43 (ddd, J = 11.9, 7.8, 2.1 Hz, 1H), 7.41-7.31 (m, 1H), 7.19-7.12 (m, 1H), 7.06 (dd, J = 9.5, 2.3 Hz, 1H), 6.97-6.76 (m, 5H), 6.26 (dd, J = 16.6, 2.1 Hz, 1H), 5.77(dd, J = 10.3, 2.2 Hz, 1H), 5.49 (ddd, J = 10.5, 8.4, 5.1 Hz, 1H), 4.15 (t, J = 10.4 Hz, 1H), 3.99 (dd, J = 11.0, 5.0 Hz, 1H), 3.62-3.50 (m, 2H), 3.41-3.35(m, 2H), 3.14 (dd, J = 13.9, 10.4 Hz, 1H), 2.77-2.64 (m, 2H), 2.60 (dd, J =14.3, 6.3 Hz, 1H), 2.33-2.04 (m, 5H), 1.77-1.67 (m, 1H), 1.51 (d, J = 12.7Hz, 2H), 1.44 (dd, J= 13.0, 8.6 Hz, 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H). MS (ESI) m / z [M+H] + 684.0.

[1008] Example 32:

[1009] 2-((3 S )-1'-(1-Acryloyl-3-phenylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperazine] [Pyridine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C65) Preparation

[1010]

[1011] Step 1: 5-Bromo-3-phenyl-1 H - Synthesis of indole

[1012]

[1013] 2-Phenylacetaldehyde (720.89 mg, 6.00 mmol, 670.59 μL) was added to a solution of (4-bromophenyl)hydrazine (935.18 mg, 5 mmol) in ethanol (30 mL). The mixture was stirred at 80°C for 4 h. The solvent was evaporated to dryness. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound as a white solid (1.1 g, 4.04 mmol, 80.8% yield). MS (ESI) m / z [M+H] + 272.1, 274.1 (Br).

[1014] Step 2: Synthesis of 5-bromo-3-phenylindoline

[1015]

[1016] To 5-bromo-3-phenyl-1 H -Indole (1.11 g, 4.08 mmol) was added to a solution of triethylsilane (4.37 g, 37.57 mmol, 6 mL) in DCM (15 mL). The mixture was stirred at room temperature for 12 h. The solvent was evaporated to dryness to give a crude product as a colorless oil, which was used directly in the next step. MS (ESI) m / z [M+H] + 274.0, 276.0 (Br).

[1017] Step 3: Synthesis of tert-butyl 5-bromo-3-phenylindoline-1-carboxylate

[1018]

[1019] Di-tert-butyl dicarbonate (1.31 g, 6.00 mmol, 1.38 mL) was added to a solution of 5-bromo-3-phenylindoline (1.10 g, 4 mmol) and sodium carbonate (1.27 g, 12.00 mmol, 502.32 μL) in water (20 mL) and THF (20 mL) at room temperature. The resulting mixture was stirred at 60°C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the title compound as a colorless oil (970 mg, 2.59 mmol, 64.8% yield). MS (ESI) m / z [M- t -Bu+H] + 318.1, 320.0 (Br).

[1020] Steps 4-8: 2-((3) S )-1'-(1-Acryloyl-3-phenylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C65)

[1021]

[1022] Following the method of steps 5-9 in Example 31 (C58), tert-butyl 5-bromo-3-phenylindoline-1-carboxylate was used to give the title compound as a white solid (39 mg, 54.33 μmol, 37.8% overall yield over 5 steps). 1 H NMR (400 MHz, DMSO- d 6) δ 9.20 (d, J = 3.0 Hz, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.11 (d, J =8.8 Hz, 1H), 7.42 (ddd, J= 12.0, 7.9, 2.1 Hz, 1H), 7.38-7.31 (m, 3H), 7.31-7.20 (m, 4H), 7.18-7.11 (m, 1H), 7.02 (dd, J = 9.5, 2.5 Hz, 1H), 6.95-6.89(m, 1H), 6.89-6.81 (m, 2H), 6.75 (dd, J = 16.6, 10.3 Hz, 1H), 6.59 (d, J =2.5 Hz, 1H), 6.29 (dd, J = 16.6, 2.3 Hz, 1H), 5.76 (dd, J = 10.3, 2.3 Hz,1H), 5.48 (ddd, J = 10.4, 8.4, 5.2 Hz, 1H), 4.71-4.59 (m, 2H), 4.15-4.04 (m,1H), 3.54-3.39 (m, 2H), 3.13 (dd, J = 13.9, 10.5 Hz, 1H), 2.71-2.53 (m, 4H), 2.25-2.03 (m, 3H), 1.72-1.57 (m, 1H), 1.51-1.35 (m, 3H). MS(ESI) m / z [M+H] + 718.2.

[1023] Example 33:

[1024] 2-(( S )-1'-(1'-acryloylspiro[cyclopentane-1,3'-indoline]-5'-yl)-6-fluoro-2,3-dihydrospiro [indene-1,4'-piperidine]-3-yl)- N -(( R 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide Preparation of (compound C70)

[1025]

[1026] Step 1: Synthesis of 5'-bromospiro[cyclopentane-1,3'-indoline]-2'-one

[1027]

[1028] At -20°C, add to a solution of 5-bromoindoline-2-one (1.0 g, 4.72 mmol) in THF (40 mL). t-BuOK (1 M, 14 mL in THF). The mixture was stirred for 30 min. Then, a solution of 1,4-diiodobutane (1.75 g, 5.66 mmol) in THF (20 mL) was added dropwise to the above solution at -20°C. The mixture was heated to room temperature and stirred for 3 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 × 60 mL). The organic layers were combined, washed with brine (2 × 60 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (920 mg, 3.46 mmol, 73.3% yield) as a yellow oil. MS (ESI) m / z [M+H] + 266.0, 268.0 (Br), [M+Na] + 288.0, 290.0 (Br).

[1029] Step 2: Synthesis of 5'-bromospiro[cyclopentane-1,3'-indoline]

[1030]

[1031] At 0°C, a borane-tetrahydrofuran complex (10 mL, 0.5 M in THF) was added to a solution of 5'-bromospiro[cyclopentan-1,3'-indoline]-2'-one (920 mg, 3.46 mmol) in 5 mL of THF. The mixture was stirred overnight at 75°C. After cooling to room temperature, the reaction was quenched with EtOH (5 mL). The mixture was stirred at 80°C for 3 h. The solvent was evaporated under vacuum. The residue was purified by silica gel rapid chromatography (DCM / MeOH = 20 / 1) to give the title compound (830 mg, 3.29 mmol, 95.2% yield) as a pale yellow oil. MS (ESI) m / z [M+H] + 252.0, 254.0 (Br).

[1032] Step 3: Synthesis of tert-butyl 5'-bromospiro[cyclopentane-1,3'-indoline]-1'-carboxylate

[1033]

[1034] To a solution of 5'-bromospiro[cyclopentane-1,3'-indoline] (830 mg, 3.29 mmol) in acetonitrile (5 mL), di-tert-butyl dicarbonate (932.87 mg, 4.28 mmol) and DMAP (402.14 mg, 3.29 mmol) were added. The mixture was stirred overnight at 50°C and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 15) to give the title compound as a yellow oil (620 mg, 1.76 mmol, 53.5% yield). MS (ESI) m / z [Mt-Bu+H] + 296.0, 298.0 (Br).

[1035] Steps 4-8: 2-(( S )-1'-(1'-acryloylspiro[cyclopentane-1,3'-indoline]-5'-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C70)

[1036]

[1037] Following the method of steps 5-9 in Example 31 (C58), tert-butyl 5'-bromospiro[cyclopentane-1,3'-indoline]-1'-carboxylate was used to give the title compound as a white solid (98.29 mg, 141.27 μmol, 38.6% overall yield over 5 steps). 1 HNMR (400 MHz, DMSO- d 6) δ 9.22 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.01 (d, J =8.7 Hz, 1H), 7.49-7.31 (m, 2H), 7.20-7.12 (m, 1H), 7.07 (dd, J = 9.5, 2.5 Hz,1H), 6.99-6.84 (m, 3H), 6.81 (dd, J = 8.8, 2.5 Hz, 1H), 6.74 (dd, J = 16.7,10.3 Hz, 1H), 6.26 (dd, J= 16.6, 2.4 Hz, 1H), 5.76 (dd, J = 10.2, 2.4 Hz,1H), 5.49 (ddd, J = 10.5, 8.4, 5.1 Hz, 1H), 3.99 (s, 2H), 3.57 (t, J = 11.6Hz, 2H), 3.43-3.32 (m, 2H), 3.14 (dd, J = 13.9, 10.5 Hz, 1H), 2.76-2.57 (m,3H), 2.30-2.11 (m, 3H), 1.92-1.67 (m, 9H), 1.57-1.40 (m, 3H). MS(ESI) m / z [M+H] + 696.3.

[1038] Example 34:

[1039] 2-((3 S )-1'-(1-Acryloyl-2-phenylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperazine] [Pyridine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C72) Preparation

[1040]

[1041] Step 1: Synthesis of 4-bromo-2-(phenylethynyl)aniline

[1042]

[1043] Et3N (407.59 mg, 4.03 mmol) was added to a solution of 4-bromo-2-iodoaniline (600 mg, 2.01 mmol), phenylacetylene (246.83 mg, 2.42 mmol), Pd(PPh3)2Cl2 (141.36 mg, 201.40 μmol), and cuprous iodide (76.71 mg, 402.79 μmol) in THF (255.37 μL). The mixture was stirred at room temperature for 16 h. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a crude oil, which was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 20) to give the title compound as a yellow solid (450 mg, 1.65 mmol, 82.1% yield). MS (ESI) m / z [M+H] + 272.0, 274.0 (Br).

[1044] Step 2: 5-Bromo-2-phenyl-1 H - Synthesis of indole

[1045]

[1046] PdCl₂ (59.07 mg, 333.14 μmol) was added to a solution of 4-bromo-2-(phenylethynyl)aniline (450 mg, 1.65 mmol) in acetonitrile (10 mL). The reaction was stirred at 80°C for 1 h. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a crude oil, which was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 20) to give the title compound as a yellow solid (400 mg, 1.47 mmol, 89.1% yield). MS (ESI) m / z [M+H] + 272.0, 274.0 (Br).

[1047] Step 3: 5-Bromo-2-phenyl-1 H Synthesis of tert-butyl indole-1-carboxylate

[1048]

[1049] To 5-bromo-2-phenyl-1 H -Indole (400 mg, 1.47 mmol) was added to a solution of di-tert-butyl dicarbonate (481.19 mg, 2.20 mmol) and DMAP (107.74 mg, 881.90 μmol) in acetonitrile (10 mL). The reaction was stirred at room temperature for 2 h. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a crude oil, which was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 100) to give the title compound (460 mg, 1.24 mmol, 84.1% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO- d 6) δ 8.05 (d, J = 8.8 Hz, 1H), 7.82 (d, J= 2.1 Hz, 1H), 7.49-7.41 (m, 6H), 6.69 (s, 1H), 1.25 (s, 9H).

[1050] Step 4: ( S )-5-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2-phenyl-1 H Synthesis of tert-butyl indole-1-carboxylate

[1051]

[1052] Fill the sealed tube with ( S ethyl acetate 2-(6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl) (100 mg, 343.22 μmol), 5-bromo-2-phenyl-1 H 1,4-Indole-1-carboxylic acid tert-butyl ester (127.76 mg, 343.22 μmol), Pd2(dba)3 (31.43 mg, 34.32 μmol), S-phos (32.03 mg, 68.64 μmol), cesium carbonate (223.65 mg, 686.44 μmol), and 1,4-dioxane (10 mL). The reaction was stirred at 100°C for 18 h under a nitrogen atmosphere. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a crude oil, which was purified by silica gel rapid chromatography (ethyl acetate / petroleum ether = 1 / 20) to give the title compound (130 mg, 223.10 μmol, 65% yield) as a yellow oil. MS (ESI) m / z [M+H] + 583.2.

[1053] Step 5: 5-(( S Synthesis of tert-butyl 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2-phenylindoline-1-carboxylic acid

[1054]

[1055] Towards( S )-5-(3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-1'-yl)-2-phenyl-1 H1,4-Indole-1-carboxylic acid tert-butyl ester (100.00 mg, 175.85 μmol) was mixed with Pd(OH)₂ / C (12.35 mg, 10%) in a solution of THF (5 mL) and methanol (5 mL). The reaction mixture was stirred at room temperature for 18 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound as a yellow oil (80 mg, 136.82 μmol, 77.8% yield). MS (ESI) m / z [M+H] + 585.3.

[1056] Step 6: 2-((3) S Synthesis of ethyl acetate 6-fluoro-1'-(2-phenylindoline-5-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)

[1057]

[1058] To 5-(( S 3-(2-ethoxy-2-oxoethyl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-2-phenylindoline-1-carboxylic acid tert-butyl ester (80 mg, 136.82 μmol) was added to a solution of TFA (1 mL) in DCM (5 mL). The solution was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under vacuum to give the title compound (60 mg, 123.81 μmol, 90.5% yield) as a yellow oil. MS (ESI) m / z [M+H] + 485.2.

[1059] Step 7: 2-((3) S Synthesis of 6-fluoro-1'-(2-phenylindoline-5-yl)-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)acetic acid

[1060]

[1061] To 2-((3) SEthyl ethyl acetate (60.00 mg, 123.56 μmol) of 6-fluoro-1'-(2-phenylindoline-5-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl) was reacted with sodium hydroxide (49.42 mg, 1.24 mmol) in a solution of THF (5 mL) and water (5 mL). The reaction was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 7 with hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (3 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound as a yellow oil (45 mg, 123.56 μmol, 86.2% yield). MS (ESI) m / z [M+H] + 457.2.

[1062] Step 8: 2-((3) S Synthesis of 1'-(1-Acryloyl-2-phenylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid

[1063]

[1064] To 2-((3) S 6-fluoro-1'-(2-phenylindoline-5-yl)-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (45 mg, 106.50 μmol), sodium bicarbonate (26.84 mg, 319.50 μmol), and acrylonitrile chloride (9.64 mg, 106.50 μmol) were added to a solution of water (3.00 mL) and THF (3.00 mL). The reaction was stirred at 0°C for 1 h. After the reaction was complete, the pH of the solution was adjusted to 7 with hydrochloric acid (2 N). The mixture was extracted with ethyl acetate (3 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound (30 mg, 62.95 μmol, 59.1% yield) as a yellow oil. MS (ESI) m / z [M+H] + 511.2.

[1065] Step 9: 2-((3) S )-1'-(1-Acryloyl-2-phenylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidine]-3-yl)- N -(( R Synthesis of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetamide (compound C72)

[1066]

[1067] To 2-((3) S )-1'-(1-Acryloyl-2-phenylindoline-5-yl)-6-fluoro-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)acetic acid (10 mg, 19.58 μmol) and ( R T3P (12.46 mg, 39.17 μmol, 50% in ethyl acetate) and DIEA (7.59 mg, 58.75 μmol) were added to a solution of 2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl-1-amine (4.41 mg, 19.58 μmol) in acetonitrile (1 mL). The mixture was stirred at room temperature for 30 min and quenched with water. The mixture was extracted with ethyl acetate (3 × 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC using silica gel rapid chromatography (column: Phenomenex Luna 80 × 30 mm × 3 μm; mobile phase: [water(FA)-CH3CN]; CH3CN: 60%-85%, 8 min) to give the title compound as a white solid (4 mg, 5.57 μmol, 28.4% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 9.21 (s, 1H), 8.72 (d, J = 8.3 Hz, 1H), 8.24-8.08 (m, 1H), 7.47-7.20 (m, 5H), 7.17-7.14 (m, 2H), 7.06 (dd, J = 9.5, 2.1 Hz, 1H), 6.98-6.80 (m, 3H), 6.51-6.35 (m, 1H), 6.20(dd, J = 16.6, 2.0 Hz, 1H), 5.83 (d, J = 9.5 Hz, 1H), 5.60 (d, J = 10.4 Hz,1H), 5.55-5.46 (m, 1H), 3.79 (dd, J = 16.3, 10.3 Hz, 2H), 3.61-3.54 (m, 2H), 3.14 (dd, J= 13.6, 10.6 Hz, 1H), 2.90-2.54 (m, 6H), 2.30-1.96 (m, 4H), 1.75-1.64 (m, 1H), 1.55-1.39 (m, 3H). MS(ESI) m / z [M+H] + 718.3.

[1068] Example 35:

[1069] 2-((3 S )-1'-(9-Acryloyl-2,3,4,4a,9,9a-hexahydro-1 H -carbazole-6-yl)-6-fluoro-2,3-dihydro Spiro[indene-1,4'-piperidine]-3-yl)- N -(( R )-2-(3,4-difluorophenyl)-1-(1,3,4-oxadiazol-2-yl)ethyl)acetyl Preparation of amine (compound C74)

[1070]

[1071] Step 1: 6-Bromo-2,3,4,9-Tetrahydro-1 H - Carbazole Synthesis

[1072]

[1073] Cyclohexanone (588.86 mg, 6.00 mmol, 621.29 μL) was added to a solution of (4-bromophenyl)hydrazine (935.18 mg, 5 mmol) in AcOH...

Claims

1. A compound having formula (A): (A) in Indicates a single bond or a double bond; Ring A is selected from C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups; T is selected from bond, O, S, S(O), S(O)2, NR T2 CHR T2 Or CH2CH2; R T1 Selected from H, D, CN, -C 1-4 Alkylene-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic groups; R T2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; When T is NR T2 At that time, R T1 R T2 Together with N, it forms 4- to 10-membered heterocyclic groups; when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-8 Cycloalkyl, or 4- to 10-membered heterocyclic groups; and when T is CHR T2 At that time, R T2 and R N Connection forms C 1-4 Alkylene; EF is selected from NR E C(O), NR E -C(S), O-CH2, NR E -CH2 or CH=CH; R E Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)R a ; G is selected from O, NH, NC 1-6 Alkyl, CH2, CHD, CD2, CHC 1-6 Alkyl, or C(C) 1-6 Alkyl)2; X is selected from N or CR x ; R x Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Q is selected from O, S, CH2, CHD, CD2, C(O) or CH2CH2; W1 and W2 are independently selected from the bond, CH2, CHD, or CD2; W3 is selected from CH2, CHD, CD2, and CHC. 1-6 Alkyl or C(O); X1 is selected from N or CR 2a ; X2 is selected from N or CR 4a ; R1 is selected from H, D, CN, and C(O)R. a C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 3-20 Cycloalkyl, 4- to 20-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, CN, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a 、S(NH)(O)R a OP(O)(OH)2, NHS(O)R a NHS(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Or R1, R E Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted; Or R1, R 2a Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted; R 1a Selected from H, D, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, NHC(O)R a ; R2 and R 2a Independently selected from H, D, or halogenated; R3 is selected from H, D, halogen, OR a NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or C(O)NH2; R4 is selected from H, D, halogen, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4a Selected from H, D, halogenated, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R4, R 4a Together with the atoms they are attached to, they form phenyl or 5- to 6-membered heteroaryl groups; R5 is selected from H, D, halogenated, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 5- to 6-membered heterocyclic groups; p = 0, 1, 2, 3 or 4; R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; q = 1, 2, or 3; Or R T1 R6, together with the atoms they are attached to, form C. 5-8 Cycloalkyl, 5- to 8-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl; L is selected from either a key or C. 1-6 Alkylene; R N Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Y is selected from C(O), S(O) or S(O)2; R m Selected from H, D, halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -C 1-4 Alkylene-NR b R c ; R n Selected from H, D, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or halogenated; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 aryl, or -C 0-4 Alkylene-5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic groups; each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Optional, R T1 and R N Together they form C(R)(R) S3 )-CH(R S4 ), phenylene or 5- to 6-membered heteroaryl; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, -C 1-6 Alkylene-halogenated, -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R s4 Selected from H, D, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R ss Selected from H, D, or halogenated; Or R s3 R s4 Together with the atoms they are attached to, they form C 5-8 Cycloalkyl or 5- to 8-membered heterocyclic groups; Further, optionally, when T is NR T2 At that time, R T2 Together with R, it forms CH2C(R) S1 (R) S2 Z3; Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2; R S1 and R S2 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S4 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; And choose any place, It can be replaced by H, and R6 is CR. p =CR q YR Y ; R p and R q Independently selected from H, D, CN, or halogenated; Or R p and R q They connect together to form additional bonds; R Y Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

2. A compound having formula (I): (I) in Indicates a single bond or a double bond; T is selected from bond, O, S, S(O), S(O)2, NR T2 CHR T2 Or CH2CH2; R T1 Selected from H, D, CN, -C 1-4 Alkylene-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic groups; R T2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; When T is NR T2 At that time, R T1 R T2 Together with N, it forms 4- to 10-membered heterocyclic groups; and when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-8 Cycloalkyl groups, or 4- to 10-membered heterocyclic groups; EF is selected from NR E C(O), NR E -C(S), O-CH2, NR E -CH2 or CH=CH; R E Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)R a ; G is selected from O, NH, NC 1-6 Alkyl, CH2, CHD, CD2, CHC 1-6 Alkyl, or C(C) 1-6 Alkyl)2; X is selected from N or CR x ; R x Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Q is selected from O, S, CH2, CHD, CD2, C(O) or CH2CH2; W1 and W2 are independently selected from the bond, CH2, CHD, or CD2; W3 is selected from CH2, CHD, CD2, and CHC. 1-6 Alkyl or C(O); Z1 is selected from N or CR7; Z2 is selected from N or CR8; R1 is selected from H, D, CN, and C(O)R. a C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, CN, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a 、S(NH)(O)R a OP(O)(OH)2, NHS(O)R a NHS(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Or R1, R E Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted; Or R1, R 2a Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted; R 1a Selected from H, D, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, NHC(O)R a ; R2, R 2a R7 is independently selected from H, D, or halogenated; R3 is selected from H, D, halogen, OR a NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or C(O)NH2; R4 is selected from H, D, halogenated, or CN; R 4a Selected from H, D, halogenated, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R4, R 4a Together with the atoms they are attached to, they form phenyl or 5- to 6-membered heteroaryl groups; R5 is selected from H, D, halogenated, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 5- to 6-membered heterocyclic groups; p = 0, 1, 2, 3 or 4; R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R8 is selected from H or D; Or R T1 R8 and the atoms they are attached to form C. 5-8 Cycloalkyl, 5- to 8-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl; R N Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Y is selected from C(O), S(O) or S(O)2; R m Selected from H, D, halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -C 1-4 Alkylene-NR b R c ; R n Selected from H, D, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or halogenated; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 aryl, or -C 0-4 Alkylene-5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic groups; each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Optional, R T1 and R N Together they form C(R)(R) S3 )-CH(R S4 ), phenylene or 5- to 6-membered heteroaryl; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, -C 1-6 Alkylene-halogenated, -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R s4 Selected from H, D, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R ss Selected from H, D, or halogenated; Or R s3 R s4 Together with the atoms they are attached to, they form C 5-8 Cycloalkyl or 5- to 8-membered heterocyclic groups; Further, optionally, when T is NR T2 At that time, R T2 Together with R, it forms CH2C(R) S1 (R) S2 Z3; Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2; R S1 and R S2 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S4 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; And choose any place, It can be replaced by H, and R6 is CR. p =CR q YR Y ; R p and R q Independently selected from H, D, CN, or halogenated; Or R p and R q They connect together to form additional bonds; R Y Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

3. The compound of claim 2, wherein it is a compound having formula (II): (II) in Indicates a single bond or a double bond; T is selected from bond, O, S, S(O), S(O)2, NR T2 or CHR T2 ; R T1 Selected from H, D, CN, -C 1-4 Alkylene-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic groups; R T2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; When T is NR T2 At that time, R T1 R T2 Together with N, it forms 4- to 10-membered heterocyclic groups; and when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-8 Cycloalkyl groups, or 4- to 10-membered heterocyclic groups; EF is selected from NR E C(O), NR E -C(S), O-CH2, NR E -CH2 or CH=CH; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; G is selected from O, NH, NC 1-6 Alkyl, CH2, CHD, CD2, CHC 1-6 Alkyl, or C(C) 1-6 Alkyl)2; X is N or CR x ; R x Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Q is selected from O, S, CH2, CHD, CD2, C(O) or CH2CH2; W1 and W2 are independently selected from the bond, CH2, CHD, or CD2; W3 is selected from CH2, CHD, CD2, and CHC. 1-6 Alkyl or C(O); Z1 is selected from N or CR7; Z2 is selected from N or CR8; R1 is selected from -C 1-6 Alkylene-S(O)2R a -C 1-4 Alkylene-OR a -C 1-4 Alkylene-NR b R c C(O)OR a C(O)NR b R c C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2, R 2a R7 is independently selected from H, D, or halogenated; R3 is selected from halogenated compounds; R4 and R 4a Independently selected from H, D, halogenated, or CN; R5 is selected from H, D, halogenated, or CN; p = 0, 1, 2, 3 or 4; R8 is selected from H or D; Or R T1 R8 and the atoms they are attached to form C. 5-8 Cycloalkyl, 5- to 8-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl; R N Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Y is selected from C(O), S(O) or S(O)2; R m Selected from H, D, halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -C 1-4 Alkylene-NR b R c ; R n Selected from H, D, CN, or halogenated; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

4. The compound of claim 3, wherein it is a compound having formula (II-1): (II-1) in T is selected from bond, O, NR T2 or CHR T2 ; R T1 Selected from H, D, CN, -C 1-4 Alkylene-NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic groups; R T2 Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; When T is NR T2 At that time, R T1 R T2 Together with N, it forms 4- to 10-membered heterocyclic groups; and when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-8 Cycloalkyl groups, or 4- to 10-membered heterocyclic groups; Z1 is selected from N or CR7; Z2 is selected from N or CR8; R1 is selected from -C 1-6 Alkylene-S(O)2R a -C 1-4 Alkylene-OR a -C 1-4 Alkylene-NR b R c C(O)OR a C(O)NR b R c C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2 and R7 are independently selected from H, D, or halogenated; R3 is selected from halogenated compounds; R4 is selected from H, D, halogenated, or CN; R5 is selected from H, D, halogenated, or CN; R8 is selected from H or D; Or R T1 R8 and the atoms they are attached to form C. 5-8 Cycloalkyl, 5- to 8-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R N Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups, each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

5. The compound of claim 3, wherein it is a compound having formula (II-2a), formula (II-2b), formula (II-2c), or formula (II-2d): (II-2a), (II-2b), (II-2c) or (II-2d) in T is selected from O and NR. T2 or CHR T2 ; R T1 and R T2 Selected independently from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; When T is NR T2 At that time, R T1 R T2 Together with N, it forms 4- to 8-membered heterocyclic groups; and when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-8 Cycloalkyl groups, or 4- to 8-membered heterocyclic groups; Z1 and Z2 are independently selected from CH, CD, or N; and alternatively, at least one of Z1 and Z2 is N; R1 is selected from -C 1-6 Alkylene-S(O)2R a -C 1-4 Alkylene-OR a -C 1-4 Alkylene-NR b R c C(O)OR a C(O)NR b R c C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2 and R4 are independently selected from H, D, or halogenated; R3 is selected from halogenated compounds; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R N Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5- to 10-membered heteroaryl (alternatively, H, C) 1-6 Alkyl or C 1-6 (halogenated alkyl), or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups, which are optionally surrounded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

6. The compound having formula (II-2a), formula (II-2b), formula (II-2c) or formula (II-2d) as described in claim 5, wherein: T is selected from O and NR. T2 or CHR T2 Alternatively, O or NR T2 ; R T1 and R T2 Selected independently from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; When T is NR T2 At that time, R T1 R T2 Together with N, it forms a 5- to 6-membered heterocyclic group; and when T is CHR T2 At that time, R T1 R T2 Together with CH, they form C 3-6 Cycloalkyl groups, or 5- to 6-membered heterocyclic groups; Z1 and Z2 are independently selected from CH, CD, or N; and alternatively, at least one of Z1 and Z2 is N; R1 is selected from , , , , , , or Alternatively, , , or ; R2 is selected from H, D, or F; R3 and R4 are both F; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; and R N Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

7. The compound of claim 3, wherein it is a compound having formula (II-3a), formula (II-3b), formula (II-3c), or formula (II-3d): (II-3a), (II-3b), (II-3c) or (II-3d) in R T1 and R T2 Together they form C 4-5 Alkylene; R1 is selected from -C 1-4 Alkylene-OR a -C 1-4 Alkylene-NR b R c C 3-6 Cycloalkyl or 5- to 6-membered heterocyclic groups; R2 is selected from H or D; R3 and R4 are both halogenated; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R a R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups, each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

8. The compound having formula (II-3a), formula (II-3b), formula (II-3c) or formula (II-3d) as claimed in claim 7, wherein: R T1 and R T2 Together they form C 4-5 Alkylene; R1 is selected from or ; R2 is selected from H or D; R3 and R4 are both F; and R E Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl; alternatively H; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

9. The compound of claim 2, wherein it is a compound having formula (III) or formula (III'): (III) or (III') in Indicates a single bond or a double bond; T is selected from bond, O, S, S(O), S(O)2, NH, CH2 or CH2CH2; EF is selected from NR E C(O), NR E -C(S), O-CH2, NR E -CH2 or CH=CH; R E Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C(O)R a ; G is selected from O, NH, NC 1-4 Alkyl, CH2, CHD, CD2, CHC 1-4 Alkyl, or C(C) 1-4 Alkyl)2; X is selected from N or CR x ; R x Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Q is selected from O, S, CH2, CHD, CD2, C(O) or CH2CH2; W1 and W2 are independently selected from the bond, CH2, CHD, or CD2; W3 is selected from CH2, CHD, CD2, and CHC. 1-6 Alkyl or C(O); X1 is selected from N or CR 2a ; X2 is selected from N or CR 4a ; Z1 is selected from N or CR7; Z2 is selected from N or CR8; R1 is selected from H, D, CN, and C(O)R. a C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 4-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R 1s replace; R 1s Selected from H, D, CN, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, S(O)R a S(O)2R a NHS(O)R a NHS(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C-terminated groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Or R1, R E Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted; Or R1, R 2a Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted; R 1a Selected from H, D, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, NHC(O)R a ; R2, R 2a R7 is independently selected from H, D, or halogenated; R3 is selected from H, D, halogen, OR a NR b R c C 1-6 Alkyl, C 1-6 Halogenated alkyl groups or C(O)NH2; R4 is selected from H, D, halogen, CN, and C. 1-6 Alkyl or C 1-6 Haloalkyl; alternatively, R4 is selected from H, D, halogenated or CN; R 4a Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R4, R 4a Together with the atoms they are attached to, they form phenyl or 5- to 6-membered heteroaryl groups; R5 is selected from H, D, halogenated, CN, OR a NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 5- to 6-membered heterocyclic groups; p = 0, 1, 2, 3 or 4; R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R8 is selected from H or D; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, -C 1-6 Alkylene-halogenated, -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R s4 Selected from H, D, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 Aryl or -C 0-4 Alkylene-5- to 10-membered heteroaryl; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; or R s3 R s4 Together with the atoms they are attached to, they form C 5-8 Cycloalkyl or 5- to 8-membered heterocyclic groups, Y is selected from C(O), S(O) or S(O)2; R m Selected from H, D, halogenated or -C 1-4 Alkylene-NR b R c ; R n Selected from H, D, CN, or halogenated; or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or halogenated; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 aryl, or -C 0-4 Alkylene-5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic groups; each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

10. The compound of claim 9, wherein it is a compound having formula (III-1) or formula (III'-1): (III-1) or (III'-1) in Indicates a single or double bond; alternatively, a double bond. T is selected from O, S, S(O) or S(O)2; G is selected from O, NH, NC 1-4 Alkyl, CH2, CHD, CD2, CHC 1-4 Alkyl, or C(C) 1-4 Alkyl)2; X1 is selected from N or CH; X2 is selected from N or CR 4a ; Z1 is selected from N or CR7; R1 is selected from CN, C(O)R a C(O)OR a C(O)NR b R c C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 4-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, S(O)R a S(O)2R a NHS(O)R a NHS(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 Aryl or 5- to 6-membered heteroaryl groups, each optionally divided by one or two halogenated or C-terminated groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2 and R7 are independently selected from H, D, or halogenated; R3 is halogenated; R4 is selected from H, D, halogen, CN, and C. 1-6 Alkyl or C 1-6 Haloalkyl; alternatively, R4 is selected from H, D, halogenated or CN; R 4a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R5 is selected from halogenated, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, -C 1-6 Alkylene-halogenated or -C 1-6 Alkylene-OR a ; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R s4 Selected from H or D; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D, halogenated or -C 1-4 Alkylene-NR b R c Alternatively, H, D, or CH2N(Me)2; R n Selected from H, D, CN, or halogenated; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or halogenated; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 0-4 Alkylene-C 3-8 cycloalkyl, -C 0-4 Alkylene-4 to 10-membered heterocyclic groups, -C 0-4 Alkylene-C 6-10 aryl, or -C 0-4 Alkylene-5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

11. The compound having formula (III-1) as claimed in claim 10, wherein: Indicates a single or double bond; alternatively, a double bond. T is selected from O, S, S(O) or S(O)2; G is selected from NH and NC. 1-4 Alkyl, CH2, CHD, CD2, CHC 1-4 Alkyl, or C(C) 1-4 Alkyl)2; Z1 is selected from N or CR7; R1 is selected from CN, Me, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R2 and R7 are independently selected from H, D, or halogenated; R3 is halogenated; R4 is selected from H, D, halogenated, or CN; R 4a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R5 is selected from halogenated, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl group, C 2-6 Halogenated alkynyl group, -C 1-6 Alkylene-halogenated or -C 1-6 Alkylene-OR a ; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R s4 Selected from H or D; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D, halogenated or -C 1-4 Alkylene-NR b R c Alternatively, H, D, or CH2N(Me)2; R n Selected from H, D, CN, or halogenated; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or halogenated; R a R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally converted by 1 or 2 halogenated, C-shaped groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

12. The compound having formula (III-1) as claimed in claim 10, wherein: Indicates a single or double bond; alternatively, a double bond. T is selected from O, S, S(O) or S(O)2; G is selected from NH, CH2, CHD, or CD2; Z1 is selected from N or CR7; R1 is selected from CN, Me, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R2 and R7 are independently selected from H, D, or F; R3 is F; R4 is selected from H, D, F, Cl, or CN; R 4a Selected from H, D, or Me; R5 is selected from F, CN, or Me; R6 is selected from H, D, F, Cl, Me, or OMe; R E Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl; alternatively H; R is selected from H, D, F, C 1-4 Alkyl, -C 1-4 Alkylene-halogenated, -C 1-4 Alkylene-OR a Or -CH=CH2; R s3 Selected from H, D, F, or Me; R s4 Selected from H or D; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D, Cl or -C 1-4 Alkylene-NR b R c Alternatively, H, D, or CH2N(Me)2; R n Selected from H, D, CN, or F; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or F; R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally converted by 1 or 2 halogenated, C-shaped groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

13. The compound of claim 9, wherein it is a compound having formula (III-1a), formula (III-1b), formula (III-1c), or formula (III-1d): (III-1a) (III-1b) (III-1c) or (III-1d) in Indicates a single or double bond; alternatively, a double bond. T is selected from O, S, S(O) or S(O)2; alternatively, O or S; Z1 is selected from N or CR7; R1 is selected from -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 4-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl groups, each optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl groups, each of which is optionally divided by one or two halogenated, C-terminated groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2 and R7 are independently selected from H, D, or halogenated; R3 is halogenated; R4 is selected from H, D, halogenated, or CN; R 4a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R5 is selected from halogenated, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D, halogenated or -C 1-4 Alkylene-NR b R c Alternatively, H, D, or CH2N(Me)2; R n Selected from H, D, CN, or halogenated; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or halogenated; R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally converted by 1 or 2 halogenated, C-shaped groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

14. The compound having formula (III-1a), (III-1b), (III-1c), or (III-1d) as described in claim 13, wherein: Indicates a single or double bond; alternatively, a double bond. T is selected from O, S, S(O) or S(O)2; alternatively, O or S; Z1 is selected from N or CR7; R1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R2 and R7 are independently selected from H, D, or halogenated; R3 is halogenated; R4 is selected from H, D, halogenated, or CN; R 4a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R5 is selected from halogenated, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D, halogenated or -C 1-4 Alkylene-NR b R c Alternatively, H, D, or CH2N(Me)2; R n Selected from H, D, CN, or halogenated; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or halogenated; R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally converted by 1 or 2 halogenated, C-shaped groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

15. The compound having formula (III-1a), (III-1b), (III-1c), or (III-1d) as claimed in claim 13, wherein: Indicates a single or double bond; alternatively, a double bond. T is selected from O, S, S(O) or S(O)2; alternatively, O or S; Z1 is selected from N or CR7; R1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R2 is selected from H, D, or F; R3 is F; R4 is selected from H, D, F, Cl, or CN; R 4a Selected from H, D, or Me; R5 is selected from F, CN, or Me; R6 is selected from H, D, F, Cl, Me, or OMe; R7 is selected from H, D, or F; R E Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl; alternatively H; R is selected from H, D, F, Me, or -CH=CH2; R s3 Selected from H, D, F, or Me; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D, Cl or -C 1-4 Alkylene-NR b R c Alternatively, H, D, or CH2N(Me)2; R n Selected from H, D, CN, or F; Or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or halogenated; R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally converted by 1 or 2 halogenated, C-shaped groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

16. The compound of claim 9, wherein it is a compound having formula (III-2a), formula (III-2b), formula (III-2c), or formula (III-2d): (III-2a) (III-2b) (III-2c) or (III-2d) in T is either O or S; R1 is selected from -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 4-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl groups, each optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl groups, each of which is optionally divided by one or two halogenated, C-terminated groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2 is selected from H, D, or halogenated; R3 and R4 are each halogenated (e.g., F); R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R and R s3 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D or -C 1-6 Alkylene-NR b R c ; R ss Selected from H, D, or halogenated; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups, which are optionally surrounded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

17. The compound having formula (III-2a), (III-2b), (III-2c), or (III-2d) as claimed in claim 16, wherein: T is O; R1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R2 is selected from H, D, or halogenated; R3 and R4 are each halogenated (e.g., F); R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R and R s3 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D, or CH2N(Me)2; R ss Selected from H, D, or halogenated; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

18. The compound having formula (III-2a), (III-2b), (III-2c), or (III-2d) as claimed in claim 16, wherein: T is O; R1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R2 is selected from H, D, or F; R3 and R4 are both F; R E Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl; alternatively H; R and R s3 Independently selected from H, D, F, or Me; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; R m Selected from H, D, or CH2N(Me)2; and R ss Selected from H, D, or F; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

19. The compound of claim 9, wherein it is a compound having formula (III-3a), formula (III-3b), formula (III-3c), or formula (III-3d): (III-3a), (III-3b), (III-3c) or (III-3d) in Indicates a single or double bond; alternatively, a double bond. T is selected from O, S, S(O), S(O)2 or NR T2 ; R T2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Z1 is selected from N or CR7; R1 is selected from C(O)R a C(O)OR a C(O)NR b R c -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 4-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl groups, each of which is optionally divided by one or two halogenated, C-terminated groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2 and R7 are independently selected from H, D, or halogenated; R3 is halogenated; R4 is selected from H, D, halogenated, or CN; R 4a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R5 is selected from halogenated, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is selected from H, D, halogen, OH, C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl group; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; Optionally, when T is NR T2 At that time, R T2 Together with R, it forms CH2C(R) S1 (R) S2 Z3; Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2; R S1 and R S2 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S4 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m Selected from H, D, halogenated or -C 1-4 Alkylene-NR b R c Alternatively, H, D, or CH2N(Me)2; R n Selected from H, D, CN, or halogenated; or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or halogenated; R a R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally converted by 1 or 2 halogenated, C-shaped groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

20. The compound having formula (III-3a), (III-3b), (III-3c), or (III-3d) as claimed in claim 19, wherein: Indicates a double bond; T is selected from O or NR T2 ; R T2 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Z1 is selected from N or CR7; R1 is selected from -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 4-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl groups, each of which is optionally divided by one or two halogenated, C-terminated groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2 and R7 are independently selected from H or D; R3 is halogenated; R4 is selected from H, D, halogenated, or CN; R 4a Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R5 is selected from halogenated, CN, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R6 is selected from H or D; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R is selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkynyl or C 2-6 Halogenated alkynyl groups; R s3 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or R, R s3 Together with the atoms they are attached to, they form C 4-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. ss replace; Optionally, when T is NR T2 At that time, R T2 Together with R, it forms CH2C(R) S1 (R) S2 Z3; Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2; R S1 and R S2 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S4 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m Selected from H, D, or halogenated; R n Selected from H, D, CN, or halogenated; or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R ss Selected from H, D, or halogenated; R a R b and R c Independently selected from H and C 1-6 Alkyl or C 1-6 Halogenated alkyl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally converted by 1 or 2 halogenated, C-shaped groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

21. The compound of claim 1, wherein it is a compound having formula (IV) or formula (IV'): (IV) or (IV') in Indicates a single bond or a double bond; EF is selected from NR E C(O), NR E -C(S) or CH=CH; R E Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; G is selected from O, NH, NC 1-4 Alkyl, CH2, CHD, CD2, CHC 1-4 Alkyl, or C(C) 1-4 Alkyl)2; X is selected from N or CR x Alternatively, X is CR x ; R x Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Q is selected from CH2, CHD, CD2, C(O) or CH2CH2; alternatively, Q is selected from CH2, CHD, CD2 or CH2CH2; W1 and W2 are independently selected from the bond, CH2, CHD, or CD2; W3 is selected from CH2, CHD, CD2, and CHC. 1-6 Alkyl or C(O); X1 is selected from N or CR 2a ; X2 is selected from N or CR 4a ; Z1 is selected from N or CR7; Z2 is selected from N or CR8; Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2; R1 is selected from C(O)NR b R c -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5- to 10-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; Or R1, R E Together with the atoms they are attached to, they form 5- to 8-membered heterocyclic groups, which are optionally halogenated, C-substituted, or C-substituted. 1-6 Alkyl, C 1-6 Halogenated alkyl or oxosubstituted; R2, R 2a R 4a R7 is independently selected from H, D, or halogenated; R4 is selected from H, D, halogen, CN, and C. 1-6 Alkyl or C 1-6 Haloalkyl; alternatively, R4 is selected from H, D or halogen; R3 is halogenated; R5 is selected from halogenated or CN; p = 0, 1, 2, 3 or 4; R6 is selected from H, D, halogen, OH, and C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R8 is selected from H or D; R S1 and R S2 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S3 and R S4 Independently selected from H, D, and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Y is selected from C(O), S(O) or S(O)2; R m Selected from H, D or -C 1-4 Alkylene-NR b R c ; R n Selected from H, D, CN, or halogenated; or R m and R n Connected together to form an additional bond, or R m R n Together with the atoms they are attached to, they form C 5-10 Cycloalkyl or 5- to 10-membered heterocyclic groups; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups; each of which is optionally bonded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

22. The compound of claim 21, wherein it is a compound having formula (IV-1a), formula (IV-1b), formula (IV-1c), or formula (IV-1d): (IV-1a) (IV-1b) (IV-1c) or (IV-1d) in Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2; R1 is selected from C(O)NR b R c -C 1-6 Alkylene-S(O)2R a -C 1-6 Alkylene-OR a -C 1-6 Alkylene-NR b R c C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5- to 10-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally divided by 1 or 2 halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2, R4 and R S2 Independently selected from H, D, or halogenated; R3 is halogenated; R5 is selected from halogenated or CN; R6 is selected from H, D, halogen, OH, and C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R S1 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S3 and R S4 Independently selected from H, D, and C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m Selected from H, D or -C 1-4 Alkylene-NR b R c ; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups, which are optionally surrounded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

23. The compound having formula (IV-1a), (IV-1b), (IV-1c), or (IV-1d) as described in claim 22, wherein: Z3 is selected from CHR S4 Or CH2CH2; R1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R2 is selected from H or D; R3 is halogenated; R4 and R S2 Independently selected from H, D, or halogenated; R5 is selected from halogenated or CN; R6 is selected from H, D, halogen, OH, and C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R S1 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S3 and R S4 Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m Selected from H, D or CH2N(C 1-6 Alkyl)2; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

24. The compound of claim 21, wherein it is a compound having formula (IV-1a): (IV-1a), in Z3 is selected from C(R) S4 )2, or C(R) S4 )2C(R S4 )2; R1 is selected from C(O)NR b R c -C 1-6 Alkylene-NR b R c C 3-8 Cycloalkyl or 4- to 10-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R2, R4 and R S2 Independently selected from H, D, or halogenated; R3 is halogenated; R5 is selected from halogenated or CN; R6 is selected from H, D, halogen, OH, and C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R S1 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S3 and R S4 Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m Selected from H, D or -C 1-4 Alkylene-NR b R c ; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl, or R b and R c Together with the atoms they are attached to, they form 5- to 6-membered heterocyclic groups, which are optionally surrounded by one or two halogenated, OH, or C atoms. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

25. The compound having formula (IV-1a) as described in claim 24, wherein: Z3 is CHR S4 ; R1 is selected from , , , , , , , , , , , , , , or ; R2 is selected from H or D; R3 and R4 are halogenated; R5 is selected from halogenated or CN; R6 is selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R S1 Selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R S2 Selected from H, D, or halogenated; R S3 and R S4 Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m Selected from H, D or CH2N(C 1-6 Alkyl)2; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

26. The compound of claim 21, wherein it is a compound having formula (IV-2a), formula (IV-2b), formula (IV-2c), or formula (IV-2d): (IV-2a) (IV-2b) (IV-2c) or (IV-2d) in R1 is selected from -C 1-4 Alkylene-S(O)2R a -C 1-4 Alkylene-OR a -C 1-4 Alkylene-NR b R c C 5-6 Cycloalkyl or 5- to 6-membered heterocyclic groups, each of which is optionally surrounded by 1, 2, 3, 4, 5 or more R groups. 1s replace; R 1s Selected from H, D, halogenated, OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C(O)R a S(O)R a S(O)2R a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclic groups, C 6-10 aryl or 5- to 6-membered heteroaryl groups, each of which is optionally divided by one or two halogenated, C-terminated groups. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; R2 is selected from H or D; R3 and R4 are both halogenated; R5 is selected from halogenated or CN; R6, R S1 and R S2 Independently selected from H, D, or halogenated; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R S3 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m Selected from H, D or CH2N(C 1-6 Alkyl)2; R a R b and R c Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups, each optionally bonded by one or two halogenated, OH, or C groups. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, C 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

27. The compound having formula (IV-2a), (IV-2b), (IV-2c), or (IV-2d) as claimed in claim 26, wherein: R1 is selected from , , , , , , , , , , , , , , , , , or ; R2 is selected from H or D; R3 and R4 are both F; R5 is selected from F or CN; R6 is selected from H, D, F, or Cl; R E Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl; alternatively H; R S1 and R S2 Each is selected from H, D, or F; R S3 Selected from H, D, or Me; and R m Selected from H, D, or CH2N(Me)2; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

28. The compound of claim 21, wherein it is a compound having formula (IV-2a): (IV-2a) in R1 is a 5- to 6-membered heterocyclic group, optionally surrounded by 1, 2, 3, 4, 5, or more R groups. 1s replace; R 1s Selected from H, D, halogenated, S(O)2R a C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R2 is selected from H or D; R3 and R4 are both halogenated; R5 is selected from halogenated or CN; R6, R S1 and R S2 Independently selected from H, D, halogenated, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R E Selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; alternatively H; R S3 Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R m Selected from H, D or CH2N(C 1-6 Alkyl)2; R a Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic groups, C 6-10 Aryl or 5- to 10-membered heteroaryl groups; and The above-mentioned groups can be replaced by 1, 2, 3, 4, 5 or more deuteriums, up to full deuteration; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

29. The compound having formula (IV-2a) as claimed in claim 28, wherein: R1 is selected from , or ; R2 is selected from H or D; R3 and R4 are both F; R5 is F; R6 is selected from H, D, F, or Cl; R E Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl; alternatively H; R S1 and R S2 Each is selected from H, D, or F; R S3 Selected from H, D, or Me; and R m Selected from H, D, or CH2N(Me)2; Or its stereoisomers, tautomers, stable isotopic variants, prodrugs or crystal forms, or pharmaceutically acceptable salts thereof.

30. A compound selected from the group consisting of the compounds listed in Tables 1 to 3, or a stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising: The compound of any one of claims 1 to 30, or a stereoisomer, tautomer, stable isotope variant, prodrug or crystal form thereof, or a pharmaceutically acceptable salt thereof; One or more pharmaceutically acceptable excipients; and Optionally, one or more other therapeutic agents.

32. A reagent kit comprising: A first container containing a compound as described in any one of claims 1 to 30, or a stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof, or a pharmaceutically acceptable salt thereof. as well as Optionally, a second container contains one or more other therapeutic agents; as well as Optionally, a third container contains one or more pharmaceutically acceptable excipients for diluting or suspending the compound and / or one or more other therapeutic agents.

33. Use of the compound of any one of claims 1 to 30, or a stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment and / or prevention of pro-inflammatory cell death-related diseases.

34. The compound of any one of claims 1 to 30, or a stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pro-inflammatory cell death-related diseases.

35. A method for treating and / or preventing pro-inflammatory cell death-related disease in a subject of need, the method comprising administering to the subject a compound as described in any one of claims 1 to 30, or a stereoisomer, tautomer, stable isotope variant, prodrug, or crystalline form thereof, or a pharmaceutically acceptable salt thereof.

36. The use as described in claim 33, or the compound for use as described in claim 34, or the method as described in claim 35, wherein these pro-inflammatory cell death-related diseases are selected from genetic diseases, viral infections, cancer, adverse effects of cancer therapies, CNS diseases, autoimmune diseases, kidney diseases, and other diseases.

37. The use, or the compound or method of use as described in claim 36, wherein the genetic disease is hearing loss, such as progressive hearing loss, particularly progressive sensorineural hearing loss, alternatively caused by the killing of hair cells.

38. The use, or the compound or method of use as described in claim 36, wherein the viral infections are selected from influenza virus infections (such as H1N1 virus infection or H7N9 virus infection), Zika virus infection, and EV71 virus infection.

39. The use, or the compound or method of use as described in claim 36, wherein the adverse effects of these cancer therapies are caused by treatment with topotecan, etoposide, cisplatin, and CPT-11, or the adverse effects are cytokine release syndrome.

40. The use, or the compound or method of use as described in claim 36, wherein the CNS diseases are selected from frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and neuroinflammation.

41. The use, or the compound or method of use as described in claim 36, wherein the autoimmune diseases are selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and renal tubular epithelial cell pyroptosis.

42. The use, or the compound or method of use as described in claim 36, wherein the kidney diseases are selected from renal dysfunction, acute kidney injury, and diabetic nephropathy.

43. The use, or the compound or method of use as described in claim 36, wherein these other diseases are selected from dry age-related macular degeneration (AMD) and latent STGD1 (dry AMD and STGD1).

44. The use, or the compound or method of use as described in claim 36, wherein the compound of any one of claims 1 to 30, or a stereoisomer, tautomer, stable isotope variant, prodrug or crystalline form thereof, or a pharmaceutically acceptable salt thereof, is used in combination with anti-PD-1, or anti-PD-L1, or other therapeutic modalities.

45. The use, or the compound or method of use as described in claim 44, wherein the efficacy of the cancer immunotherapy is enhanced.

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