Heterocyclic compound and preparation method and medical application thereof

Abstract

The invention relates to a heterocyclic compound as well as a preparation method and medical application thereof. Specifically, the invention discloses a compound shown as a formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, and a preparation method and application thereof, and the definition of each group in the formula is shown in the specification and the claims. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a class of heterocyclic compounds, a preparation method thereof, a pharmaceutical composition containing the heterocyclic compound, and the use thereof as a therapeutic agent. Background Art

[0002] The somatostatin receptor family (SSTRs) is a family of G-protein coupled receptors that mediate somatostatin and its analogs and have various biological effects. Its physiological functions and mechanisms of action have long been of great concern. Research has shown that specific membrane receptors exist on these cell membranes, including SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5. They can play important roles in biological processes such as regulating growth hormone (GH) secretion, inducing apoptosis, inhibiting tumor cell proliferation, inhibiting insulin action, and inhibiting cell growth through cAMP, PTP, and MAPK signaling pathways. At the same time, they also exhibit kinetic characteristics similar to those of other G-protein coupled receptors.

[0003] Among these five receptors, SSTR4 has come to the forefront as a potential mediator of central nervous system pathology, inflammation, and even pain mechanisms. Somatostatin receptor 4 (SSTR4) is a G-protein coupled receptor for the peptide somatostatin. SSTR4 is coupled to the inhibitory G protein Gi, which inhibits the production of cyclic AMP. SSTR4 is highly expressed in the central nervous system (CNS) and is also expressed to a lesser extent in the dorsal root ganglia and the intestine. See M.A. Meyer, "Highly Expressed Genes within Hippocampal Sector CA1: Implications for the Physiology of Memory", Neurology International 6(2):5388 (2014). SSTR4 is highly conserved among different species. For example, the human, mouse, and rat SSTR4 protein sequences share greater than 87% identity at the amino acid level. These factors - major expression in the brain and high sequence homology among different species - indicate that SSTR4 plays an important role in physiology.

[0004] In addition, recent studies have also pointed out that excessive hippocampal activity is the main driving force for the disease progression and impaired cognitive ability in patients with Alzheimer's disease. See M.A. Busche et al., "Decreased Amyloid-β and Increased Neuronal Hyperactivity by Immunotherapy in Alzheimer's Models", Nature Neuroscience 18(12):1725-27(2015); also see K. Yamamoto et al., "Chronic Optogenetic Activation Augments Aβ Pathology in a Mouse Model of Alzheimer Disease", Cell Reports 11(6):859-65(2015). Activation of the SSTR4 receptor has been shown to play a role in controlling neuronal activity. See C. Qiu et al., "Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures", Journal of Neuroscience 28(14):3567-76(2008). Therefore, agonists of said receptor will likely represent good pharmacological tools for inhibiting and controlling neuronal activity in the cortex and hippocampus. The development of novel SSTR4 agonists has broad application prospects and is also urgently needed. SUMMARY OF THE INVENTION

[0005] In a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, said compound having a structure represented by formula (I), formula (II) or formula (III):

[0006]

[0007] In formula (I),

[0008] Ring B is a benzene ring, a 5- or 6-membered heteroaryl ring, a benzo cycloalkyl ring;

[0009] R a 、R b are each independently hydrogen, halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), and R a 、R bNot hydrogen simultaneously; wherein said C 1-10 alkoxy, C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of: halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl;

[0010] (R c ) m is hydrogen on the ring atoms of ring B substituted by m R c substituents, m is 0, 1, 2 or 3, each R c is the same or different and each independently is halogen, halo C 1-10 alkoxy (preferably halo C 1-6 alkoxy, more preferably halo C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl); wherein said C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of: halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl;

[0011] Ring C is a 5 - or 6 - membered heteroaromatic ring;

[0012] (R d ) n is hydrogen on the ring atoms of ring C substituted by n R d substituents, n is 0, 1, 2 or 3, each R d is the same or different and each independently is halogen or C 1-10 alkyl;

[0013] (R e ) p is hydrogen on the saturated nitrogen - containing heterocyclic ring atoms substituted by p R e substituents, p is 0, 1, 2 or 3, each R e is the same or different and each independently is hydrogen, halogen or C 1-10 alkyl; or two R e connected to the same carbon atom are connected to form a C 3-8 cycloalkyl ring; or two R e connected to different carbon atoms are connected to form a 7 - to 10 - membered bridged heterocyclic ring together with the saturated heterocycle;

[0014] r is 1, 2 or 3;

[0015] R f is hydrogen or C 1-10 alkyl; wherein said C 1-10The alkyl group is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of: halogen, -C(O)-5-membered or 6-membered heteroaryl, -C(O)-phenyl; wherein the 5-membered or 6-membered heteroaryl and phenyl are optionally substituted by 1, 2, 3 or 4 halogens;

[0016] In formula (II),

[0017] Ring A is a benzene ring or a 5-membered or 6-membered heteroaromatic ring;

[0018] (R0) t is that the hydrogen on the ring atom of ring A is substituted by t R0s, t is 0, 1, 2 or 3, each R0 being the same or different and each independently being halogen, halo-C 1-10 alkoxy (preferably halo-C 1-6 alkoxy, more preferably halo-C 1-3 alkoxy) or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl); wherein the C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of: halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl;

[0019] R1 and R2 are each independently hydrogen, halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); wherein the C 1-10 alkoxy and C 1-10 alkyl are unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of: halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl;

[0020] R3 and R4 are each independently hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);

[0021] R5 is hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); wherein the C 1-10The alkyl group is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl;

[0022] (R6) s The hydrogen on the ring carbon atom of piperidine is substituted by s R6 groups, where s is 0, 1, 2 or 3, and each R6 is the same or different and is independently halogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), wherein the C 1-10 alkyl group is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl;

[0023] In formula (III),

[0024] Ring D is a 5- or 6-membered heteroaromatic ring;

[0025] R6 and R7 are each independently hydrogen, halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); wherein the C 1-10 alkoxy, C 1-10 alkyl group is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl;

[0026] L is a bond or -(CH2) u -O-;

[0027] u is 1, 2 or 3;

[0028] Ring E is a benzene ring or a 5- to 10-membered heteroaromatic ring;

[0029] (R8) q The hydrogen on the ring atoms of ring E is substituted by q R8 groups, where q is 0, 1, 2 or 3, and each R8 is the same or different and is independently C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or halogen; wherein the C 1-10 alkyl group is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl.

[0030] In some embodiments, in formula (I), the 5- or 6-membered heteroaryl ring in ring B is selected from thiophene, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

[0031] In some embodiments, in formula (I), ring B is a benzene ring, a pyridine ring or a 2,3-dihydro-1H-indenyl ring.

[0032] In some embodiments, in formula (I), the structure is selected from:

[0033] where the wavy line represents the connection point to the O atom.

[0034] In some embodiments, in formula (I), the structure is selected from:

[0035]

[0036] where the wavy line represents the connection point to the O atom.

[0037] In some embodiments, in formula (I), ring C is 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole or 1,3,4-triazole or pyrazole.

[0038] In some embodiments, in formula (I), ring C is the structure where the wavy line represents the connection point to the carbon atom jointly connected to R a , R b ; and the asterisk represents the connection point to the saturated nitrogen-containing monocyclic heteroaromatic ring.

[0039] In some embodiments, in formula (II), the 5- or 6-membered heteroaryl ring in ring A is selected from thiophene, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

[0040] In some embodiments, in formula (II), ring A is a benzene ring or a pyridine ring.

[0041] In some embodiments, in formula (II), ring A is selected from the structures: Wherein the wavy line represents the connection point with the cross double bond.

[0042] In some embodiments, in formula (II), ring A is selected from:

[0043] Wherein the wavy line represents the connection point with the cross double bond.

[0044] In some embodiments, in formula (III), ring D is selected from thiophene, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

[0045] In some embodiments, in formula (III), ring D is 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole or 1,3,4-triazole.

[0046] In some embodiments, in formula (III), ring D has the structure Wherein the wavy line represents the connection point with the (1R,5S)-3-azabicyclo[3.1.0]hexane ring, and the asterisk represents the connection point with the carbon atom jointly connected to R6 and R7.

[0047] In some embodiments, in formula (III), ring E is a benzene ring, a pyridine ring or an indazole ring.

[0048] In some embodiments, in formula (III), the structure is selected from: Wherein the wavy line represents the connection point with L.

[0049] In some embodiments, in formula (III), the structure is selected from: Wherein the wavy line represents the connection point with L.

[0050] In some embodiments, R f is hydrogen, C 1-6 alkyl or -C 1-2 alkylene-C(O)-phenyl; the phenyl is optionally substituted by halogen.

[0051] In some embodiments, R f is hydrogen, methyl or -CH2-C(O)-halophenyl.

[0052] In some embodiments, in formula (I), Re Same or different, each independently is halogen or C 1-6 alkyl; or two Rs attached to the same carbon atom e are attached to form C 3-6 cycloalkyl ring (preferably cyclopropyl ring).

[0053] In some embodiments, in formula (I), when two Rs attached to different carbon atoms e are attached to together form a 7- to 10-membered bridged heterocycle with a saturated heterocycle, it has the following structure:

[0054]

[0055] wherein g is 1, 2, 3 or 4.

[0056] In some embodiments, in formula (I), the structure is the structure wherein each R e Same or different, each independently is hydrogen, halogen (more preferably fluorine or chlorine) or C 1-6 alkyl (more preferably C 1-3 alkyl); or two Rs attached to the same carbon atom e are attached to form C 3-6 cycloalkyl ring (more preferably cyclopropyl ring, cyclobutyl ring).

[0057] In some embodiments, the compound of formula (I) is a specific compound selected from the following group:

[0058]

[0059]

[0060] In some embodiments, the compound of formula (II) is a specific compound selected from the following group:

[0061]

[0062] In some embodiments, the compound of formula (III) is a specific compound selected from the following group:

[0063]

[0064] The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof; and a pharmaceutically acceptable carrier.

[0065] The third aspect of the present invention provides the use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for treating diseases or disorders related to SSTR4; wherein the diseases or disorders are selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and attention deficit hyperactivity disorder.

[0066] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Detailed Description of the Invention

[0067] After extensive and in-depth research, the inventors unexpectedly found that this type of heterocyclic compound with novel structure has excellent human somatostatin type IV receptor SSTR4 agonist activity. Therefore, this series of compounds is expected to be developed into a medicament for treating diseases or disorders related to SSTR4. On this basis, the inventors completed the present invention.

[0068] Term Definition

[0069] As used herein, "alkyl" refers to straight-chain and branched-chain saturated aliphatic hydrocarbon groups, C 1-10 The alkyl is an alkyl containing 1 to 10 carbon atoms, preferably C 1-6 alkyl, more preferably C 1-3Alkyl has a similar definition; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof are more preferred.

[0070] As used herein, "cycloalkyl" and "cycloalkyl ring" are used interchangeably and both refer to a saturated or partially unsaturated monocyclic hydrocarbon group. "C 3-8 cycloalkyl" refers to a cycloalkyl group containing 3 to 8 carbon atoms, preferably C 3-6 cycloalkyl, with a similar definition. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., and cyclopropyl, cyclopentyl, cyclohexenyl are preferred.

[0071] As used herein, "bridged ring" refers to a polycyclic group sharing two or more carbon atoms. The shared carbon atoms are called bridgehead carbons. There can be a carbon chain or a bond between two bridgehead carbons, which is called a bridge. These can contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably a bicyclic or tricyclic bridged ring. For example:

[0072]

[0073] As used herein, "bridged heterocycle" refers to a polycyclic group sharing two or more atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) na heteroatom (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably a bicyclic or tricyclic bridged heterocycle, more preferably a 7- to 10-membered bridged heterocycle. For example:

[0074]

[0075] As used herein, "C 1-10 alkoxy" means -O-(C 1-10 alkyl), where alkyl is defined as above. Preferred is C 1-6 alkoxy, more preferably C 1-3 alkoxy. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy, etc.

[0076] As used herein, "aryl" and "aromatic ring" are used interchangeably and both refer to a monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, an aryl group containing 6 to 10 carbon atoms; preferably phenyl and naphthyl, more preferably phenyl.

[0077] As used herein, "a bond" means that the two groups connected by it are connected by a covalent bond.

[0078] As used herein, "halogen" means fluorine, chlorine, bromine or iodine.

[0079] As used herein, "halo" means that one or more (such as 1, 2, 3, 4 or 5) hydrogens in a group are replaced by a halogen.

[0080] For example, "halo C 1-10 alkyl" means that the alkyl is replaced by one or more (such as 1, 2, 3, 4 or 5) halogens, where alkyl is defined as above. Selected is halo C 1-6 alkyl, more preferably halo C 1-3 alkyl. Examples of haloalkyl include (but are not limited to) chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, 1,2-dichloroethyl, trichloroethyl, bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, etc.

[0081] Again, for example, "halo C 1-10 alkoxy" means that the alkoxy is replaced by one or more (such as 1, 2, 3, 4 or 5) halogens, where alkoxy is defined as above. Preferred is halo C 1-6 alkoxy, more preferably halo C 1-3 alkoxy. Include (but are not limited to) trifluoromethoxy, trifluoroethoxy, fluoromethoxy, fluoroethoxy, difluoromethoxy, difluoroethoxy, etc.

[0082] As used herein, "amino" refers to NH2, "cyano" refers to CN, "nitro" refers to NO2, "benzyl" refers to -CH2-phenyl, "oxo" refers to =O, "carboxyl" refers to -C(O)OH, "acetyl" refers to -C(O)CH3, "hydroxymethyl" refers to -CH2OH, "hydroxyethyl" refers to -CH2CH2OH or -CHOHCH3, "hydroxyl" refers to -OH, "thiol" refers to SH, and the "cyclopropylidene" structure is:

[0083] As used herein, "heteroaryl ring" and "heteroaryl" are used interchangeably and refer to a group having 5 to 10 ring atoms, preferably a 5- or 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl; sharing 6, 10, or 14 π electrons in the ring array; and having 1 to 5 heteroatoms in addition to carbon atoms. "Heteroatom" refers to nitrogen, oxygen, or sulfur.

[0084] As used herein, "5- to 6-membered monocyclic heteroaryl ring" and "5- to 6-membered monocyclic heteroaryl" are used interchangeably and both refer to a monocyclic heteroaryl ring containing 5 to 6 ring atoms, such as including (but not limited to): thiophene ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, etc.

[0085] As used herein, "8- to 10-membered bicyclic heteroaryl ring" and "8- to 10-membered bicyclic heteroaryl" are used interchangeably and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, such as including (but not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine.

[0086] As used herein, "substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5 hydrogen atoms, are independently replaced by the corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) the possible or impossible substitutions without too much effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0087] Unless otherwise defined, the "substituents independently selected from... " described in the present invention means that when more than one hydrogen on a group is replaced by substituents, the types of the substituents can be the same or different, and the selected substituents are independent types.

[0088] Unless otherwise defined, the "same or different and each independently being... " described in the present invention means that when there are more than one identical substituent groups in the general formula, the groups can be the same or different and are independent types. For example, when L is (CR 01 R 02 ) s , when s is 2, that is, L is (CR 01 R 02 )-(CR 01 R 02 ), the two Rs 01 or Rs 02 can be the same or different and are independent types. For example, L can be C(CH3)(CN)-C(CH2CH3)(OH), C(CH3)(CN)-C(CH3)(OH) or C(CN)(CH2CH3)-C(OH)(CH2CH3).

[0089] As used herein, any group herein can be substituted or unsubstituted. When the above groups are substituted, the substituents are preferably 1 to 5 of the following groups, independently selected from CN, halogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halo C 1-8 alkyl (preferably halo C 1-6 alkyl, more preferably halo C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halo C 1-8 alkoxy (preferably halo C 1-6 alkoxy, more preferably halo C 1-3 alkoxy), C 1-8 alkyl-substituted amino, amino, halo C 1-8 alkyl-substituted amino, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, nitro, C 6-10 aryl (preferably phenyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl), -C(O)NR a0 R b0 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -CHO, -OC(O)C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO2C 1-10 alkyl (preferably -SO2C 1-6 alkyl, more preferably -SO2C 1-3 alkyl), -SO2C 6-10 aryl (preferably -SO2C6 aryl, such as -SO2-phenyl), -C(O)C 6-10 aryl (preferably -C(O)C6 aryl, such as -C(O)-phenyl), a 4- to 6-membered saturated or unsaturated monocyclic heterocycle, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring, an 8- to 10-membered bicyclic heteroaryl ring, a spiro ring, a spiro heterocycle, a bridged ring or a bridged heterocycle, wherein R a0 , R b0 are each independently hydrogen or C 1-3 alkyl. Each of the various substituents described above herein may itself be substituted by the groups described herein.

[0090] The "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0091] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids or organic acids that can retain the biological effectiveness of the free base without other side effects.

[0092] "Pharmaceutically acceptable base addition salts" include, but are not limited to, salts of inorganic bases such as sodium salts, potassium salts, calcium salts, and magnesium salts, etc. Include, but are not limited to, salts of organic bases, such as ammonium salts, triethylamine salts, lysine salts, arginine salts, etc.

[0093] The compounds represented by formula (I), formula (II) or formula (III) of the present invention may contain two or more chiral centers and exist in different optically active forms. The stereoisomers of the compounds represented by formula (I), formula (II) or formula (III) of the present invention may be enantiomers or diastereomers. The compounds represented by formula (I), formula (II) or formula (III) may exist in the form of a separated optically pure specific stereoisomer, for example, in the form of an enantiomer or a diastereomer, or may exist in the form of a mixture of two stereoisomers, for example, in the form of a mixture of enantiomers, such as a racemic mixture, or a mixture of diastereomers, or a mixture of enantiomers and diastereomers. Among them, enantiomers can be separated by methods known in the art, such as crystallization and chiral chromatography. Diastereomers can be separated by methods known in the art, such as crystallization and preparative chromatography. The enantiomers or diastereomers of the compounds represented by formula (I), formula (II) or formula (III), as well as the mixtures of these stereoisomers are all within the protection scope of the present invention.

[0094] Generally, the compounds of the present invention or their pharmaceutically acceptable salts, or their solvates, or their stereoisomers, or prodrugs can be administered in a suitable dosage form formed with one or more pharmaceutical carriers. These dosage forms are suitable for oral administration, rectal administration, topical administration, buccal administration and other parenteral administrations (for example, subcutaneous, intramuscular, intravenous, etc.). For example, the dosage forms suitable for oral administration include capsules, tablets, granules and syrups, etc. The compounds of the present invention contained in these preparations can be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water or water-in-oil emulsions, etc. The above dosage forms can be prepared from the active compound and one or more carriers or excipients by general pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid preparations, common non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. The carriers for liquid preparations include water, physiological saline, glucose aqueous solution, ethylene glycol and polyethylene glycol, etc. The active compound can form a solution or a suspension with the above carriers.

[0095] The compositions of the present invention are formulated, quantified and administered in a manner consistent with medical practice norms. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific disease to be treated, the individual being treated, the cause of the disease, the target of the drug, and the mode of administration.

[0096] As used herein, a "therapeutically effective amount" refers to the amount of the compound of the present invention that will cause a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating diseases, slowing down or delaying the disease process or preventing diseases, etc.

[0097] The therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, or its solvate, or its stereoisomer contained in the pharmaceutical composition of the present invention is preferably 0.1 mg - 5 g / kg (body weight).

[0098] As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient, which is compatible with the patient, preferably a mammal, more preferably a human, and is suitable for delivering the active agent to the target site without terminating the activity of the agent.

[0099] As used herein, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.

[0100] As used herein, "treatment" refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or disorder (such as cancer). Treatment also includes curing a disease or disorder, preventing its development, or alleviating one or more symptoms thereof to a certain extent.

[0101] Preparation Method

[0102] For the experimental methods without specific conditions noted in the following examples, they are generally carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer.

[0103] Unless otherwise defined, the terms used herein have the same meanings as those familiar to persons skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the present invention.

[0104] The present invention will be further illustrated below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. For the experimental methods without specific conditions noted in the following examples, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, the terms used herein have the same meanings as those familiar to persons skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the present invention.

[0105] As used herein, room temperature refers to about 20 - 25 °C.

[0106] Example 1: Preparation of Compound Z1

[0107]

[0108] Step 1: At room temperature, disperse compound 1a (4.5 g, 21.30 mmol) and potassium carbonate (5.89 g, 42.60 mmol) in methanol (20 mL). Under stirring in an ice bath, dropwise add dimethyl (1-diazo-2-oxopropyl)phosphonate (4.09 g, 21.30 mmol). After the addition, slowly warm the reaction mixture to room temperature and react for 3 hours. Rotate evaporate the solvent from the reaction mixture. The obtained residue is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain white solid 1b (3.5 g, yield: 79%). 1 H NMR (400 MHz, CDCl3) δ 3.67–3.56 (m, 2H), 3.35–3.33 (m, 2H), 1.88 (d, J = 2.0 Hz, 1H), 1.82 (t, J = 2.8 Hz, 2H), 1.43 (s, 9H), 1.12–1.01 (m, 1H).

[0109] Step 2: At room temperature, add 2-fluoro-3-methylpyridine (1.0 g, 9.00 mmol) to DMF (20 mL). Under stirring in an ice bath, slowly add sodium hydride (378 mg, 60 wt%, 9.45 mmol) portionwise. After the addition, dropwise add 2-amino-2-methyl-1-propanol (1.0 g, 11.25 mmol) slowly. Slowly warm the reaction mixture to room temperature and react for 3 hours. TLC (developing solvent: petroleum ether:ethyl acetate = 10:1) shows the disappearance of the starting material. Dropwise add saturated aqueous ammonium chloride solution (10 mL) to the reaction mixture, and extract with ethyl acetate (50 mL×3). Combine the obtained organic phases, rotate evaporate the solvent. The obtained residue is purified by column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain colorless oil 1c (0.51 g, yield: 31%). 1 H NMR (400 MHz, CDCl3) δ 7.97–7.95 (m, 1H), 7.38 (d, J = 7.2 Hz, 1H), 6.80 - 6.77 (m, 1H), 4.12 (s, 2H), 2.67 (s, 2H), 2.24 (s, 3H), 1.28 (s, 6H).

[0110] Step 3: At room temperature, compound 1c (200 mg, 1.11 mmol), copper(II) sulfate pentahydrate (3 mg, 11.10 μmol), 1H-imidazole-1-sulfonyl azide (230 mg, 1.33 mmol), and potassium carbonate (230 mg, 1.66 mmol) were successively added to methanol (10 mL), and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were evaporated to remove the solvent, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain white solid 1d (100 mg, yield: 43%). LC-MS: 85% purity (Sig = 254 nm); MS m / z (ESI): 207.1 [M+H] + .

[0111] Step 4: At room temperature, compound 1d (80 mg, 0.387 mmol), copper(II) sulfate pentahydrate (2 mg, 7.7 μmol), compound 1b (80 mg, 0.387 mmol), and sodium L-ascorbate (8 mg, 38 μmol) were successively added to tert-butanol / water (1 mL / 1 mL), and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were evaporated to remove the solvent, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain compound 1e (50 mg, yield: 31%). LC-MS: 84% purity (Sig = 254 nm), MS m / z (ESI): 414.3 [M+H] + .

[0112] Step 5: At room temperature, compound 1e (40 mg, 0.12 mmol) was added to methanol / water (0.5 mL / 0.5 mL), and the mixture was subjected to microwave reaction at 130 °C for 2 hours. The solvent was evaporated, and the residue was purified by column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain white solid Z1 (16 mg, yield: 42%). LC-MS: 95.4% purity (Sig = 254 nm); MS m / z (ESI): 314.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.94–7.93 (m, 1H), 7.51–7.49 (m, 1H), 6.90–6.87 (m, 1H), 4.47 (s, 2H), 3.07 (d, J = 11.6 Hz, 2H), 2.89 (d, J = 10.8 Hz, 2H), 2.01 (s, 3H), 1.93 (t, J = 3.6 Hz, 1H), 1.75 (s, 2H), 1.69 (s, 6H).

[0113] Example 2: Preparation of Compound Z2

[0114]

[0115] Step 1: At room temperature, compound 2a (1.0 g, 6.06 mmol) was added to DMF (20 mL). Under stirring in an ice bath, sodium hydride (378 mg, 60 wt%, 9.45 mmol) was slowly added portionwise. After the addition was complete, 2-amino-2-methyl-1-propanol (0.674 g, 7.57 mmol) was slowly added dropwise. The reaction mixture was slowly warmed to room temperature and reacted for 3 hours. A saturated ammonium chloride aqueous solution (10 mL) was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The obtained organic phases were combined, and the solvent was removed by rotary evaporation. The obtained residue was purified by column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain a colorless oil 2b (0.8 g, yield: 56%). MS m / z (ESI): 235.0 [M+H] +

[0116] Step 2: At room temperature, compound 2b (200 mg, 0.853 mmol), copper sulfate pentahydrate (2 mg, 8.54 μmol), 1H-imidazole-1-sulfonyl azide (144 mg, 1.02 mmol), and potassium carbonate (177 mg, 1.28 mmol) were successively added to methanol (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was slowly added to water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The obtained organic phases were combined, and the solvent was removed by rotary evaporation. The obtained residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain a colorless oil 2c (240 mg, crude product). MS m / z (ESI): 261.0 [M+H] + It was used directly in the next step without further treatment.

[0117] Step 3: At room temperature, compound 2c (240 mg, 0.922 mmol), copper sulfate pentahydrate (4 mg, 18 μmol), compound 1b (191 mg, 0.922 mmol) (the synthesis of 1b refers to Step 1 of Example 1), and sodium L-ascorbate (18 mg, 92 μmol) were successively added to tert-butanol / water (2 mL / 2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was slowly added to water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The obtained organic phases were combined, and the solvent was removed by rotary evaporation. The obtained residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain a white solid 2d (45 mg, yield: 10%). MS m / z (ESI): 468.3 [M+H] +

[0118] Step 4: At room temperature, compound 2d (42 mg, 0.089 mmol) was added to methanol / water (0.5 mL / 0.5 mL), and the mixture was subjected to microwave reaction at 130 °C for 2 hours. The solvent was removed by rotary evaporation, and the resulting residue was purified by column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain white solid Z2 (21 mg, yield: 63%). LC-MS: 97.8% purity (Sig = 254 nm); MS m / z (ESI): 368.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.27–8.26 (m, 1H), 7.86–7.84 (m, 1H), 7.56 (s, 1H), 7.00–6.97 (m, 1H), 4.58 (s, 2H), 3.48 (d, J = 11.6 Hz, 2H), 3.35 (d, J = 11.2 Hz, 2H), 2.21 (t, J = 3.6 Hz, 1H), 2.13 (s, 3H), 1.79 (s, 6H).

[0119] Example 3: Preparation of Compound Z3

[0120]

[0121] Step 1: At room temperature, compound 3a (500 mg, 2.87 mmol) was added to a dry tetrahydrofuran solution (10 mL). Under stirring at -78 °C, methylmagnesium bromide (1.9 mL g, 3 M, 5.7 mmol) was slowly added dropwise. The reaction mixture was slowly warmed to room temperature and reacted for 4 hours. Saturated aqueous ammonium chloride solution (10 mL) was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phases were evaporated to remove the solvent, and the resulting residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain white solid 3b (395 mg, yield: 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.4 Hz, 1H), 7.38–7.33 (m, 2H), 7.15–6.11 (m, 1H), 4.01 (s, 3H), 2.93 (s, 1H), 1.75 (s, 6H).

[0122] Step 2: Under an ice-salt bath, compound 3b (100 mg, 0.525 mmol), sodium azide (68 mg, 1.05 mmol), and trifluoroacetic acid (257 mg, 2.63 mmol) were successively added to chloroform (5 mL), and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to saturated aqueous sodium bicarbonate (10 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic phases were evaporated to remove the solvent, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain colorless oil 3c (102 mg, yield: 90%); LC-MS: 98.1% purity (Sig = 254 nm); MS m / z (ESI): 230.1 [M+H] +

[0123] Step 3: At room temperature, compound 3c (102 mg, 0.444 mmol), copper sulfate pentahydrate (5.5 mg, 22 μmol), 1b (184 mg, 0.889 mmol) (synthesis of 1b refers to Step 1 of Example 1), and sodium L-ascorbate (8.8 mg, 44 μmol) were successively added to tert-butanol / water (2 mL / 2 mL), and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to water (10 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic phases were evaporated to remove the solvent, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain colorless oil 3d (140 mg, yield: 74%); 1H NMR (400 MHz, CDCl3) δ 7.37–7.35 (m, 2H), 7.13 (s, 1H), 7.08–7.06 (m, 1H), 7.03–6.99 (m, 1H), 4.06 (s, 3H), 3.70–3.60 (m, 2H), 3.41–3.39 (m, 2H), 2.20 (s, 6H), 2.04–1.97 (m, 2H), 1.68–1.67 (m, 1H), 1.42 (s, 9H).

[0124] Step 4: At room temperature, compound 3d (70 mg, 0.165 mmol) was added to methanol / water (0.5 mL / 0.5 mL), and reacted under microwave at 130 °C for 3 hours. The solvent was evaporated to dryness, and the residue was purified by column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain compound Z3 (22 mg, yield: 41%). After freeze-drying, it was a white solid, which quickly absorbed moisture and became viscous. LC-MS: 97.23% purity (Sig = 254 nm); MS m / z (ESI): 323.2 [M+H] +1H NMR (400 MHz, CDCl3) δ 7.36–7.33 (m, 2H), 7.15 (s, 1H), 7.06–6.97 (m, 2H), 4.06 (s, 3H), 3.35 (d, J = 11.6 Hz, 2H), 3.23 (d, J = 11.6 Hz, 2H), 2.18 (s, 6H), 2.06–2.03 (m, 3H).

[0125] Example 4: Preparation of Compound Z4

[0126]

[0127] Step 1: At room temperature, compound 4a (12 g, 99.2 mmol) was added to a chloroform solution (150 mL). While stirring at room temperature, tert-butyl nitrite (21.4 g, 207.9 mmol) was added dropwise. After stirring at room temperature for 20 minutes, potassium acetate (19.4 g, 198.05 mmol) and 18-crown-6 (2.62 g, 9.9 mmol) were added in batches. After addition, the mixture was heated to reflux and stirred for three hours. LC-MS showed that the raw material had disappeared. The reaction solution was slowly added to water (500 mL), and extracted with ethyl acetate (250 mL × 3). The obtained organic phases were combined, the solvent was removed by rotary evaporation, and the obtained residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 9 / 1) to obtain yellow solid 4b (4 g, yield: 31%); LC-MS: 93.2% purity (Sig = 254 nm); MS m / z (ESI): 133.2 [M + H] +

[0128] Step 2: At room temperature, compound 4b (400 mg, 3.03 mmol) was added to a dichloromethane solution (4 mL). While stirring at room temperature, NIS (749 mg, 3.33 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was slowly added to water (100 mL), and extracted with ethyl acetate (50 mL × 3). The obtained organic phases were combined, the solvent was removed by rotary evaporation, to obtain yellow solid 4c (650 mg, yield: 83%). LC-MS: 85.2% purity (Sig = 254 nm); MS m / z (ESI): 259.0 [M + H] +

[0129] Step 3: Under ice bath conditions, compound 4c (650 mg, 2.52 mmol) was added to a DMF solution (5 mL). Under stirring at room temperature, methyl iodide (715 mg, 5.04 mmol) and potassium carbonate (1.39 g, 10.08 mmol) were added. After addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was slowly added to water (50 mL), and extracted with ethyl acetate (20 mL×3). The obtained organic phases were combined, the solvent was removed by rotary evaporation, and the obtained residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain yellow solid 4d (450 mg, yield: 65%). LC-MS: purity 83.2% (Sig = 254 nm); MS m / z (ESI): 273.0 [M+H] +

[0130] Step 4: At room temperature, compound 4d (300 mg, 1.01 mmol) was added to a methanol solution (4 mL). Under stirring at room temperature, triethylamine (1.45 g, 14.3 mmol) and Pd(dppf)Cl2 (160 mg, 0.22 mmol) were added. The reaction system was evacuated and filled with carbon monoxide three times, and then stirred at 80 °C overnight under a carbon monoxide atmosphere. The reaction solution was slowly added to water (50 mL), and extracted with ethyl acetate (30 mL×3). The obtained organic phases were combined, the solvent was removed by rotary evaporation, and the obtained residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1) to obtain yellow solid 4e (200 mg, yield: 88%). LC-MS: purity 89.2% (Sig = 254 nm); MS m / z (ESI): 205.2 [M+H] +

[0131] Step 5: Under an ice-salt bath, compound 4e (400 mg, 1.96 mmol) and methylmagnesium bromide (1.17 g, 3 M, 9.79 mmol) were added to tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was slowly added to water (10 mL), and extracted with ethyl acetate (10 mL×3). The obtained organic phases were combined, the solvent was removed by rotary evaporation, and the obtained residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 - 10 / 1) to obtain colorless oil 4f (350 mg, yield: 87.5%); 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 1H), 7.16–6.91 (m, 2H), 4.28 (s, 3H), 2.76 (d, J = 5.7 Hz, 3H), 1.74 (s, 6H).

[0132] Step 6: Under an ice-salt bath, compound 4f (100 mg, 0.489 mmol), sodium azide (63 mg, 0.97 mmol), and trifluoroacetic acid (240 mg, 2.45 mmol) were successively added to chloroform (3 mL), and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to saturated aqueous sodium bicarbonate (10 mL), and extracted with dichloromethane (10 mL × 3). The obtained organic phase was evaporated to dryness to give a yellow oil 4g (110 mg, crude product); MS m / z (ESI): 230.1 [M+H] +

[0133] Step 7: At room temperature, compound 4g (110 mg, 0.479 mmol), copper sulfate pentahydrate (5.5 mg, 22 μmol), 1b (198 mg, 0.950 mmol) (the synthesis of 1b refers to Step 1 of Example 1), and sodium L-ascorbate (9.5 mg, 44 μmol) were successively added to tert-butanol / water (2 mL / 2 mL), and the mixture was stirred at room temperature overnight. The reaction solution was slowly added to water (10 mL), and extracted with ethyl acetate (10 mL × 3). The obtained organic phases were combined and the solvent was removed by rotary evaporation. The obtained residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give a colorless oil 4h (80 mg, yield: 39.1%). MS m / z (ESI): 437.3 [M+H] +

[0134] Step 8: At room temperature, compound 4h (80 mg, 0.165 mmol) was added to methanol / water (0.5 mL / 0.5 mL), and reacted under microwave at 130 °C for 3 hours. The solvent was removed by lyophilization. The obtained residue was subjected to column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give compound Z4 (11 mg, yield: 18.1%). After lyophilization, it was a white solid and quickly became viscous after absorbing moisture. LC-MS: 98.7% purity (Sig = 254 nm); MS m / z (ESI): 337.2 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 7.03 (d, J = 4.0 Hz, 1H), 6.84–6.82 (m, 2H), 4.31 (s, 3H), 3.72 (s, 1H), 3.37 (d, J = 11.6 Hz, 2H), 3.27 (s, 2H), 2.75 (s, 3H), 2.16 (s, 6H), 2.07 (s, 3H).

[0135] Example 5: Preparation of Compound Z5

[0136]

[0137] Step 1: At room temperature, compound 5a (1.0 g, 7.57 mmol) was added to dichloromethane (20 mL). Under stirring in an ice bath, DMP (4.81 g, 11.35 mmol) was added to the reaction solution. After the addition, the reaction was stirred at room temperature overnight. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated by rotary evaporation to remove the solvent. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to obtain a colorless oil 5b (0.6 g, crude product). 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 3.76 (s, 3H), 1.36 (s, 6H).

[0138] Step 2: At room temperature, compound 5c (1.0 g, 2.14 mmol) was added to anhydrous tetrahydrofuran (20 mL). At -78 °C, n-BuLi (1.1 mL, 2.5 mol / L, 2.75 mmol) was added dropwise. After the addition, the reaction was carried out at -78 °C for 0.5 h. Then, crude product 5b (278 mg, 2.14 mmol) was added to the reaction system. After the addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction solution was concentrated by rotary evaporation to remove the solvent. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain a colorless oil 5d (60 mg, yield: 11%). MS m / z (ESI): 239.1 [M+H] +

[0139] Step 3: At room temperature, compound 5d (60 mg, 0.251 mmol) was added to tetrahydrofuran / water (1 mL / 1 mL). Lithium hydroxide monohydrate (53 mg, 1.26 mmol) was added. After the addition, the reaction was stirred at room temperature overnight. 3M hydrochloric acid was added dropwise to the reaction system to adjust the pH to 6. The mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was dried by rotary evaporation to obtain a pale yellow oil 5e (41 mg, crude product). Without further treatment, it was directly used in the next reaction.

[0140] Step 4: The crude product of compound 5e (41 mg, 0.182 mmol) was added to DMF (2 mL) at room temperature. (3S,4S)-tert-Butyl 4-amino-3-fluoropiperidine-1-carboxylate (48 mg, 0.219 mmol), HATU (83 mg, 0.218 mmol), and DIEA (70 mg, 0.547 mmol) were successively added. After the addition, the mixture was stirred at room temperature overnight. Ethyl acetate (20 mL) was added to the reaction solution, and it was washed with saturated brine (5 mL × 6). The obtained organic phase was dried by rotation, and yellowish oil 5f (64 mg, yield: 82%) was obtained by Prep-TLC (eluent: petroleum ether:ethyl acetate = 5:1). 1H NMR (400 MHz, CDCl3) δ 7.38–7.19 (m, 4H), 6.58 (d, J = 12.4 Hz, 1H), 5.84–5.81 (m, 2H), 4.28–4.10 (m, 2H), 3.87–3.75 (m, 2H), 2.95–2.85 (m, 2H), 1.79–1.76 (m, 1H), 1.45 (s, 9H), 1.43–1.42 (m, 1H), 1.27–1.25 (m, 6H).

[0141] Step 5: Compound 5f (62 mg, 0.145 mmol) was added to ethyl acetate (2 mL) at room temperature. Hydrochloric acid 1,4-dioxane solution (0.4 mL, 4 M, 1.6 mmol) was added dropwise, and the reaction was carried out for 3 hours. An aqueous sodium bicarbonate solution was added to the reaction system to adjust the pH to 7. It was extracted with ethyl acetate (5 mL × 2), and the organic phase was dried by rotation. The obtained residue was prepared by thick plate preparation (eluent: dichloromethane / methanol = 10 / 1) to obtain compound Z5 (40 mg, yield: 84%), which was freeze-dried to obtain a colorless viscous substance. LC-MS: 98.3% purity (Sig = 254 nm); MS m / z (ESI): 325.2 [M+H] + , 1H NMR (400 MHz, CDCl3) δ 7.52–7.19 (m, 4H), 6.58 (d, J = 12.4 Hz, 1H), 5.86–5.78 (m, 2H), 4.29–4.11 (m, 1H), 4.05–3.82 (m, 1H), 3.37–3.21 (m, 1H), 2.89–2.84 (m, 1H), 2.72–2.58 (m, 2H), 2.13–1.80 (m, 1H), 1.26 (d, J = 8.8 Hz, 6H), 1.19–1.10 (m, 1H).

[0142] Example 6: Preparation of Compound Z6

[0143]

[0144] Step 1: Add SOCl2 (4.8 mL, 66.1 mmol) and ACN (160 mL) into a 500 mL three-necked flask at room temperature, stir at room temperature for 30 minutes, control the temperature to -40 °C, dissolve compound 6a (5.0 g, 26.4 mmol) in ACN (50 mL) and slowly add it. After the addition is complete, stir for 10 minutes and then add pyridine (7.5 mL, 92.5 mmol). React at this temperature for half an hour, and then raise the temperature to 0 °C and react for 1 hour. Add ethyl acetate (250 ml) to the reaction solution to quench the reaction, then wash with HCl (150 ml, 1 M), collect the organic phase, and wash with an aqueous sodium bicarbonate solution. The obtained organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is rotary evaporated to obtain a yellow oil 6b (6.0 g, crude product). 1 H NMR (400 MHz, CDCl3) δ 4.83 (d, J = 8.8 Hz, 1H), 4.34 (d, J = 8.8 Hz, 1H), 1.61 (s, 3H), 1.53 (s, 9H), 1.42 (s, 3H).

[0145] Step 2: Add compound 6b (6.00 g, 25.5 mmol), ACN (80 mL), and H2O (80 mL) into a 500 mL single-necked flask in sequence, control the temperature to 0 °C, add NaIO4 (6.82 g, 31.9 mmol) and RuCl3 (26.5 mg, 0.128 mmol), and slowly raise the temperature to room temperature and stir for 30 minutes. Add ethyl acetate (200 mL) and water (200 mL) to the reaction solution for extraction, and collect the organic phase. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter and rotary evaporate to obtain a solid residue, and the obtained residue is purified by column chromatography (eluent: PE / EA = 100 / 1 - 10 / 1) to obtain a white solid 6c (5.6 g, yield: 87.4%). 1 H NMR (400 MHz, CDCl3) δ 4.23 (s, 2H), 1.59 (s, 6H), 1.56 (s, 9H).

[0146] Step 3: Add 2-chlorophenol (300 mg, 2.33 mmol), compound 6c (645 mg, 2.57 mmol), K2CO3 (968 mg, 7.00 mmol), and DMF (4 mL) into a 100 mL single-necked flask in sequence at room temperature. React in an oil bath at 80 °C for 2 hours. Add water (30 mL) to the reaction solution to quench it, extract with ethyl acetate (40 mL), and collect the organic phase. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. After filtering and rotary evaporating, the obtained residue is purified by column chromatography (eluent: PE / EA = 100 / 1 - 8 / 1) to obtain a light yellow oil 6d (570 mg, yield: 81.5%). MS m / z (ESI): 244.1 [M - 56 + H] +。

[0147] Step 4: Add compound 6d (500 mg, 1.67 mmol), HCl / 1,4-dioxane (2.5 mL, 4 M) to a 50 mL single-necked flask in sequence, and stir at room temperature for 20 minutes. Rotate the reaction solution to dryness, add water (20 mL) and ethyl acetate (20 mL) to the reaction solution, adjust the pH to 7 with an aqueous sodium bicarbonate solution, collect the organic phase, add ethyl acetate (20 mL) to extract the obtained aqueous phase again, and combine the organic phases. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter and rotate to dryness to obtain a yellow oil 6e (300 mg, crude product). MS m / z (ESI): 199.9 [M+H] + 。

[0148] Step 5: Add compound 6e (150 mg, 0.751 mmol), 1H-imidazole-1-sulfonyl azide (189 mg, 0.901 mmol), CuSO4·5H2O (1.88 mg, 7.51 μmol), K2CO3 (156 mg, 1.13 mmol), MeOH (8 mL) to a 100 mL single-necked flask in sequence at room temperature. React at room temperature for 18 hours. Rotate the reaction solution directly to dryness and mix the sample, and subject the obtained residue to column chromatography (eluent: petroleum ether) to obtain a colorless oil 6f (140 mg, yield: 82.6%). MS m / z (ESI): 198.1 [M - 28+H] + 。

[0149] Step 6: Add (methoxymethyl)triphenylphosphonium chloride (12.6 g, 36.9 mmol), dry -THF (80 mL) to a 250 mL three-necked flask in sequence at room temperature, control the temperature to -78 °C, and slowly add n-BuLi (14.8 mL, 36.9 mmol, 2.5 M) dropwise under a nitrogen atmosphere. After the addition is complete, react for 40 minutes, and add compound 6g (5.00 g, 24.6 mmol) dropwise at this temperature, and slowly warm up to room temperature and stir for 2 hours. Quench the reaction with water at low temperature, extract with ethyl acetate (200 mL), and collect the organic phase. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. After filtering and rotating to dryness, subject the obtained residue to column chromatography purification (PE / EA = 100 / 1 - 10 / 1) to obtain a pale yellow oil 6h (2.80 g, yield: 49.2%). MS m / z (ESI): 232.2 [M+H] + 。

[0150] Step 7: To a 100 mL single-necked flask at room temperature, add compound 6h (2.00 g, 8.65 mmol), THF (10 mL), concentrated HCl (10 mL) in sequence, and react at 50 °C for 4 hours. Rotate the reaction solution to dryness, add water (20 mL) and EA (30 mL) for extraction. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and rotation to dryness, the obtained residue is purified by column chromatography (PE / EA = 100 / 1 - 5 / 1) to obtain a pale yellow oil 6i (1.80 g, crude product). MS m / z (ESI): 218.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 9.59 (d, J = 3.2 Hz, 1H), 7.34–7.27 (m, 5H), 3.50 (s, 2H), 2.96–2.82 (m, 2H), 1.99–1.87 (m, 3H), 1.74–1.66 (m, 3H), 0.91 (d, J = 6.4 Hz, 3H).

[0151] Step 8: To a 100 mL single-necked flask at room temperature, add compound 6i (1.00 g, 4.60 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (972 mg, 5.06 mmol), MeOH (30 mL), K2CO3 (954 mg, 6.90 mmol) in sequence, and react at room temperature for 18 hours. Rotate the reaction solution to dryness, and the obtained residue is purified by column chromatography (PE / EA = 100 / 1 - 9 / 1) to obtain a yellow oil 6j (800 mg, yield: 81.5%). MS m / z (ESI): 214.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.34–7.28 (m, 4H), 7.28–7.23 (m, 1H), 3.48 (s, 2H), 2.91–2.80 (m, 2H), 2.07 (d, J = 2.0 Hz, 1H), 1.93–1.58 (m, 6H), 1.00 (d, J = 6.4 Hz, 3H).

[0152] Step 9: To a 100 mL single-necked flask at room temperature, add compound 6j (134 mg, 0.627 mmol), compound 6f (140 mg, 0.620 mmol), sodium L-ascorbate (12.3 mg, 62.0 μmol), CuSO4·5H2O (7.74 mg, 31.0 μmol), t-BuOH (4 mL), and H2O (4 mL) in sequence, and react at room temperature for 18 hours. Heat the reaction to 50 °C and react for 18 hours. Rotate off t-BuOH in the reaction solution, add EA (10 mL) for extraction, collect the organic phase, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtration and rotation to dryness, purify the obtained residue by column chromatography (PE / EA = 2 / 1) to obtain a pale yellow solid 6k (130 mg, yield: 47.7%). MS m / z (ESI): 438.8 [M+H] + 。

[0153] Step 10: To a 100 mL single-necked flask at room temperature, add compound 6k (90 mg, 0.205 mmol), DCE (4 mL), ethyl chloroformate (0.1 mL, 0.820 mmol), and react at 80 °C for 18 hours. LCMS monitoring shows that there is 50% intermediate. Continue the reaction for 18 hours. Rotate the reaction solution to dryness, add DCE (4 mL), and react at 80 °C for 18 hours. Add MeOH (2 mL) and react at 80 °C for 2 hours. LCMS detection shows that the intermediate is completely converted into the target product. Rotate and evaporate the solvent from the reaction solution, add DCM (20 mL) and H2O (20 mL), adjust the pH to 7 with aqueous sodium bicarbonate solution, collect the organic phase, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtration and rotation to dryness, purify the obtained residue by preparative thick plate (DCM / MeOH = 10 / 1) to obtain a pale yellow solid Z6 (24.75 mg, yield: 34.6%). LC-MS: 95.1% purity (Sig = 254 nm); MS m / z (ESI): 349.1 [M+H] + ; 1 HNMR (400 MHz, CDCl3) δ 9.96–9.58 (m, 1H), 7.73 (s, 1H), 7.31 (dd, J = 7.6, 1.6 Hz, 1H), 7.18–7.14 (m, 1H), 6.89–6.86 (m, 1H), 6.81–6.79 (m, 1H), 4.23–4.17 (m, 2H), 3.60–3.49 (m, 2H), 3.01–2.98 (m, 1H), 2.75–2.64 (m, 2H), 2.30–2.08 (m, 3H), 1.86 (s, 6H), 0.86 (d, J = 6.8 Hz, 3H).

[0154] Example 7: Preparation of Compound Z7

[0155]

[0156] Step 1: To a 50 mL single-necked flask at room temperature, add compound 7a (214 mg, 0.823 mmol), intermediate A (172 mg, 0.823 mmol), sodium L-ascorbate (81.5 mg, 0.41 mmol), CuSO4·5H2O (20.5 mg, 0.082 mol), tert-butanol (5 mL), and water (5 mL) in sequence, and react overnight at room temperature. Rotate the reaction solution to remove tert-butanol, add ethyl acetate (10 mL) for extraction, and collect the organic phase. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter, and after the filtrate is evaporated to dryness, the residue obtained is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 - 2 / 1) to obtain compound 7b as a pale yellow solid (221 mg, yield: 57.4%). MS m / z (ESI): 470.3 [M+H] + 。

[0157] Step 2: To a 50 mL single-necked flask, add compound 7b (221 mg, 0.471 mmol) and HCl / 1,4-dioxane (6 mL, 4 M) in sequence, and stir at room temperature for 4 hours. Rotate the reaction solution to dryness to obtain white solid 7c (200 mg, crude product). MS m / z (ESI): 370.2 [M+H] + 。

[0158] Step 3: To a 100 mL single-necked flask at room temperature, add compound 7c (100 mg, 0.25 mmol), sodium triacetoxyborohydride (104.7 mg, 0.494 mmol), paraformaldehyde (37.54 mg, 1.25 mmol), and DCE (8 mL) in sequence. Stir and react overnight at room temperature, then heat to 50 °C and react for 4 hours. Rotate the reaction solution to remove DCE, add ethyl acetate (50 mL) and water (50 mL) for extraction, and collect the organic phase. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and evaporation to dryness, the residue obtained is purified by preparative thick plate (developing agent: dichloromethane / methanol = 10 / 1) to obtain colorless oil Z7 (28.3 mg, yield: 27.3%). LC-MS: 98.4% purity (Sig = 254 nm); MS m / z (ESI): 383.8 [M+H] + , 11H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 4.0 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.98 (s, 1H), 7.19 (dd, J = 7.2, 5.2 Hz, 1H), 4.67 (s, 2H), 3.22–3.15 (m, 2H), 2.79–2.67 (m, 3H), 2.53 (s, 3H), 2.03–2.00 (m, 2H), 1.79–1.70 (m, 8H).

[0159] Example 8: Preparation of Compound Z8

[0160]

[0161] Step 1: To a 50 mL single-necked flask at room temperature were successively added compound 8a (300 mg, 2.68 mmol), 6c (740 mg, 2.94 mmol) (the synthesis of 6c was carried out according to Step 2 of Example 6), K2CO3 (1.11 g, 8.03 mmol), and DMF (6 mL). The reaction was carried out in an oil bath at 80 °C for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The obtained organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate obtained by filtration was concentrated in vacuo to obtain an oily residue, and the obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 10 / 1) to obtain a pale yellow oily substance 8b (750 mg, yield: 98.9%). MS m / z (ESI): 183.9 [M - Boc + H] +

[0162] Step 2: To a 50 mL single-necked flask were successively added compound 8b (75 mg, 2.65 mmol) and HCl / 1,4-dioxane (3 mL, 4 M, 12 mmol), and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated in vacuo. Water (10 mL) and ethyl acetate (30 mL) were added to the reaction solution, and the pH was adjusted to 7 - 8 with an aqueous sodium bicarbonate solution. The organic phase was collected. Ethyl acetate (20 mL) was added to the aqueous phase again for extraction, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a yellow oily substance 8c (320 mg, crude product). MS m / z (ESI): 184.2 [M + H] + ,

[0163] Step 3: To a 100 mL single-necked flask at room temperature, add compound 8c (150 mg, 0.819 mmol), 1H-imidazole-1-sulfonyl azide (206 mg, 0.982 mmol), CuSO4·5H2O (2.04 mg, 8.19 μmol), K2CO3 (170 mg, 1.23 mmol), and MeOH (4 mL) in sequence. React at room temperature for 2 hours. Add silica gel to the reaction solution, rotary evaporate to dryness, and perform column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 - 10 / 1) to obtain a yellow oil 8d (140 mg, yield: 81.7%); MS m / z (ESI): 182.2 [M-N2+H] +

[0164] Step 4: To a 50 mL single-necked flask at room temperature, add compound 8d (140 mg, 0.669 mmol), compound 6j (144 mg, 0.675 mmol) (the synthesis of 6j can be carried out with reference to Step 8 of Example 6), sodium L-ascorbate (13.3 mg, 66.9 μmol), CuSO4·5H2O (8.35 mg, 33.5 μmol), tert-butanol (4 mL), and water (4 mL) in sequence. React at room temperature for 18 hours. Rotary evaporate to remove tert-butanol, add ethyl acetate (10 mL) for extraction, collect the organic phase, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtration and rotary evaporation to dryness, the obtained residue is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 - 1 / 1) to obtain a yellow oil 8e (110 mg, yield: 37.5%); MS m / z (ESI): 423.2 [M+H] +

[0165] Step 5: To a 50 mL single-necked flask at room temperature, add compound 8e (100 mg, 0.237 mmol), ethyl acetate (10 mL), Pd / C (20 mg, 10 wt%), and react under hydrogen for 18 hours. Filter the reaction solution through diatomaceous earth, collect the filtrate and rotary evaporate to dryness. The obtained residue is purified by preparative thick plate (developer: DCM / MeOH = 10 / 1) to obtain a pale yellow solid Z8 (22.72 mg, yield: 28.9%). LC-MS: 97.1% purity (Sig = 254 nm); MS m / z (ESI): 333.1 [M+H] + ; 11H NMR (400 MHz, CDCl3) δ 9.76 (br, 1H), 7.65 (s, 1H), 7.06–6.99 (m, 2H), 6.97–6.80 (m, 2H), 4.22 (d, J = 1.6 Hz, 2H), 3.60–3.50 (m, 2H), 3.01–2.96 (m, 1H), 2.76–2.65 (m, 2H), 2.30–2.00 (m, 3H), 1.83 (s, 6H), 0.86 (d, J = 6.5 Hz, 3H).

[0166] Example 9: Preparation of Compound Z9

[0167]

[0168] To a 50 mL single-necked flask at room temperature were successively added compound 7c (60 mg, 0.148 mmol) (for the synthesis of 7c, refer to Step 2 of Example 7), 2-bromo-1-(4-chlorophenyl)ethan-1-one (37.97 mg, 0.163 mmol), potassium carbonate (40.91 mg, 0.296 mmol), and DMF (6 mL). The reaction was carried out at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (50 mL) and water (50 mL), and the organic phase was collected. The obtained organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and evaporation of the filtrate, the resulting residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow oil Z9 (36.3 mg, yield: 42.8%). LC-MS: 87.6% purity (Sig = 254 nm); MS m / z (ESI): 522.2 [M + H] + ; 1 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 3.6 Hz, 1H), 7.98 (d, J = 6.0 Hz, 2H), 7.84 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 6.98 (dd, J = 7.2, 4.8 Hz, 1H), 4.58 (s, 2H), 3.78 (s, 2H), 3.06–3.02 (m, 2H), 2.83–2.77 (m, 1H), 2.34–2.29 (m, 2H), 2.04–2.01 (m, 2H), 1.82–1.74 (m, 8H).

[0169] Example 10: Preparation of Compound Z10

[0170]

[0171] Step 1: Add compound 10a (5.0 g, 29.31 mmol) to a 100 mL three-necked flask at room temperature, add SOCl2 (20 mL), and stir overnight at room temperature. Rotate the reaction solution to dryness, add dichloromethane (50 mL) to the residue and rotate to dryness to obtain a colorless oil 10b (4.80 g, crude product). MS m / z (ESI): [M-Cl + OMe] + = 185.1.

[0172] Step 2: Add compound 10b (4.80 g, 25.39 mmol), DCM (70 mL), compound 10b1 (13.27 g, 38.09 mmol), and Et3N (7.1 mL, 50.18 mmol) to a 250 mL single-necked flask in sequence at room temperature, and stir overnight at room temperature. Add water (30 mL) to the reaction solution, extract with ethyl acetate (100 mL × 3), and collect the organic phase. Dry the organic phase with anhydrous sodium sulfate, filter and rotate to dryness to obtain a residue, and purify the obtained residue by column chromatography (eluent: PE / EA = 100 / 1 - 20 / 1) to obtain a pale yellow oil 10c (4.48 g, yield: 79.24%). 1 1H NMR (400 MHz, CDCl3) δ 7.40–7.34 (m, 2H), 7.25–7.12 (m, 2H), 6.90 (q, J = 2.8 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.00 (d, J = 2.8 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[0173] Step 3: Add compound 10c (1.00 g, 4.22 mmol), CuCl (42 mg, 0.42 mmol), and toluene (20 mL) to a 100 mL three-necked flask in sequence at room temperature, cool to -78 °C in a dry ice-acetone bath, slowly add methylmagnesium bromide solution (4.2 mL, 3 M, 12.6 mmol), and react for 2 hours. Dropwise add methyl p-toluenesulfonate (2.55 mL, 21.12 mmol) to the reaction solution, continue to react at -78 °C for 1 hour, slowly rise to room temperature, and continue to react for 16 hours. Quench the reaction solution with saturated NH4Cl aqueous solution (20 mL), and extract with ethyl acetate (40 mL * 3). Combine the organic phases, wash with saturated brine (20 mL × 4), and dry with anhydrous sodium sulfate. Filter and rotate the obtained organic phase to dryness, and then purify the obtained residue by column chromatography (eluent: PE / EA = 100 / 1 - 3 / 1) to obtain a pale yellow oil 10d (351 mg, yield: 31.1%). 11H NMR (400 MHz, CDCl3) δ 7.39–7.35 (m, 1H), 7.24–7.20 (m, 2H), 7.20–7.14 (m, 1H), 6.45 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 1.69 (d, J = 1.2 Hz, 3H), 1.44 (s, 6H), 1.26 (t, J = 7.2 Hz, 4H).

[0174] Step 4: Add compound 10d (351 mg, 1.48 mmol), NaOH (297 mg, 7.41 mmol), THF (5 mL), MeOH (5 mL), and H2O (5 mL) to a 50 mL single-necked flask in sequence, and react at 50 °C overnight. Rotavaporize the methanol and tetrahydrofuran in the reaction solution, adjust the pH to 4 - 5 with 4 M aqueous hydrochloric acid, add ethyl acetate (50 mL) to the reaction solution, extract with water (50 mL), and collect the organic phase. Wash the obtained organic phase with saturated brine and dry over anhydrous sodium sulfate. Filter and rotavaporize to obtain yellow solid 10e (254 mg, crude product). MS m / z (ESI): 239.1 [M + H] + 。

[0175] Step 5: Add compound 10e (150 mg, 0.630 mmol), DCM (10 mL), HATU (262.2 mg, 0.69 mmol), (3S,4S)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate (151.1 mg, 0.69 mmol), and DIEA (0.33 mL, 1.89 mmol) to a 100 mL single-necked flask in sequence at room temperature, and react overnight at room temperature. Add dichloromethane (50 mL) and water (50 mL) to the reaction solution for extraction, and collect the organic phase. Wash the obtained organic phase with saturated brine and dry over anhydrous sodium sulfate. Filter and rotavaporize to obtain a residue, and purify the obtained residue by column chromatography (eluent: PE / EA = 100 / 1 - 10 / 1) to obtain yellow oil 10f (210 mg, yield: 76.1%). MS m / z (ESI): 383.1 [M - 56 + H] + 。

[0176] Step 6: To the flask containing compound 10f (210 mg, 0.48 mmol), add HCl / 1,4-dioxane (10 mL, 4 M), and stir at room temperature for 4 hours. Remove the solvent by rotary evaporation, adjust the pH to 7 - 8 with aqueous sodium bicarbonate solution, add ethyl acetate (50 mL) to the reaction solution for extraction, and collect the organic phase. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and rotary evaporation to dryness, the obtained residue is purified by preparative thin-layer chromatography (PE:EA = 1:4) to obtain a pale yellow oil Z10 (88.82 mg, yield: 54.8%). LC-MS: 96.9% purity (Sig = 254 nm); MS m / z (ESI): 339.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.42–7.40 (m, 1H), 7.28–7.18 (m, 3H), 6.58 (s, 1H), 6.05 (d, J = 8.0 Hz, 1H), 4.35–4.17 (m, 1H), 4.08–3.97 (m, 1H), 3.33–3.27 (m, 1H), 2.98–2.94 (m, 1H), 2.79–2.67 (m, 2H), 2.35 (s, 1H), 2.11–2.03 (m, 1H), 1.63 (s, 3H), 1.44 (s, 6H), 1.40–1.28 (m, 1H).

[0177] Example 11: Preparation of Compound Z11

[0178]

[0179] Step 1: At room temperature, add 2-amino-2-methylpropan-1-ol (465 mg, 5.21 mmol) and dry THF (30 mL) to a 100 mL three-necked flask in sequence. Control the temperature to 0 °C, add NaH (227 mg, 5.69 mmol, 60 wt%), and react at room temperature for half an hour. Control the temperature to 0 °C again, and slowly add compound 11a (650 mg, 4.74 mmol). React at room temperature for 18 hours. Add water (30 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (60 mL × 2), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. After filtration, rotary evaporate the obtained filtrate to dryness to obtain an oily residue. The obtained residue is purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 4 / 1) to obtain a yellow oil 11b (450 mg, yield: 52.8%). MS m / z (ESI): 293.1 [M+H] + 。

[0180] Step 2: To a 50 mL single-necked flask, add compound 11b (200 mg, 0.685 mmol), 1H-imidazole-1-sulfonyl azide (172 mg, 0.821 mmol), CuSO4·5H2O (1.71 mg, 6.85 μmol), K2CO3 (142 mg, 1.03 mmol), and MeOH (4 mL) in sequence, and react at room temperature for 2 hours. Rotate the reaction solution to dryness, and perform column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 - 15 / 1) to obtain yellow oil 11c (125 mg, yield: 57.4%); MS m / z (ESI): 318.9 [M+H] + .

[0181] Step 3: To a 50 mL single-necked flask, add compound 11c (125 mg, 0.393 mmol), 6j (84.6 mg, 0.397 mmol) (the synthesis of 6j can be carried out with reference to Step 8 of Example 6), sodium L-ascorbate (7.78 mg, 39.3 μmol), CuSO4·5H2O (4.91 mg, 19.7 μmol), tert-butanol (3 mL), and water (3 mL) in sequence at room temperature, and react at 50 °C for 18 hours. Rotate and evaporate to remove tert-butanol, extract twice with ethyl acetate (10 mL), collect the organic phase, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtration and rotation to dryness, purify the obtained residue by column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 - 1 / 2) to obtain yellow oil 11d (170 mg, 0.320 mmol, yield: 81.4%). MS m / z (ESI): 532.1 [M+H] + ; 1 1H NMR (400 MHz, CDCl3) δ 8.04 - 7.98 (m, 2H), 7.66 (s, 1H), 7.40–7.26 (m, 5H), 6.66–6.63 (m, 1H), 4.53–4.51 (m, 2H), 3.55 (s, 2H), 3.05–2.87 (m, 2H), 2.45–2.38 (m, 1H), 1.89–1.65 (m, 11H), 0.73 (d, J = 6.4 Hz, 3H).

[0182] Step 4: To a 100 mL single-necked flask at room temperature, add compound 11d (140 mg, 0.263 mmol), cyclopropylboronic acid (33.9 mg, 0.395 mmol), Pd(PPh3)4 (30.4 mg, 26.3 μmol), K2CO3 (72.8 mg, 0.527 mmol), 1,4-dioxane (10 mL), and water (1 mL) in sequence, and react at 110 °C for 18 hours. Add water (30 mL) to quench the reaction solution, extract with ethyl acetate (50 mL × 2), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. After filtering and concentrating the obtained filtrate, an oily residue is obtained. The obtained residue is purified by column chromatography (eluent: ethyl acetate = 100%) to obtain a yellow oily substance 11e (120 mg, crude product). MS m / z (ESI): 446.2 [M+H] + 。

[0183] Step 5: To a 50 mL single-necked flask at room temperature, add compound 11e (110 mg, 0.247 mmol), DCE (8 mL), and triethylamine (0.34 mL, 2.47 mmol). Control the temperature to 0 °C and slowly add dropwise (0.27 mL, 2.47 mmol). Raise the temperature to room temperature and react for 2 hours. Add water (10 mL) to quench the reaction solution, extract with ethyl acetate (20 mL × 2), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. After filtering and concentrating the obtained filtrate, an oily residue is obtained. The obtained residue is purified by thick preparative plate (developing agent: DCM / MeOH = 7 / 1) to obtain 50 mg of crude product. The crude product is obtained by Prep-HPLC (FA) to obtain a pale yellow oily substance Z11 (9.12 mg, yield: 28.9%). MS m / z (ESI): 356.2 [M+H] + ; LC-MS: 98.4% purity (Sig = 254 nm); 1 1H NMR (400 MHz, CDCl3) δ 7.91–7.90 (m, 1H), 7.62 (s, 1H), 7.14–7.12 (m, 1H), 6.81–6.78 (m, 1H), 5.88 (br, 1H), 4.59 (s, 2H), 3.48–3.38 (m, 2H), 2.93–2.90 (m, 1H), 2.66–2.62 (m, 2H), 2.15–2.03 (m, 3H), 1.83 (m, 7H), 0.87–0.80 (m, 5H), 0.57–0.56 (m, 2H).

[0184] Example 12: Preparation of Compound Z12

[0185]

[0186] Step 1: Add 2-amino-2-methylpropan-1-ol (149 mg, 1.67 mmol), dry-DMF (10 mL) to a 100 mL three-necked flask in sequence at room temperature. Control the temperature to 0 °C, add NaH (72.9 mg, 1.82 mmol, 60 wt%), and raise the temperature to room temperature for reaction for 1 hour. Control the temperature to 0 °C again, slowly add compound 12a (650 mg, 4.74 mmol), and react at 50 °C for 18 hours. Add water (100 mL) and ethyl acetate (100 mL) to the reaction solution, adjust the pH to 8 with 1 M HCl, collect the organic phase, and extract the aqueous phase with ethyl acetate (100 mL) once again. Combine the organic phases, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering and concentrating the obtained filtrate, an oily residue is obtained. The obtained residue is purified by column chromatography (ethyl acetate = 100%) to obtain a yellow oily substance 12b (140 mg, yield: 36.8%). MS m / z (ESI): 251.1 [M+H] + 。

[0187] Step 2: Add compound 12b (140 mg, 0.559 mmol), 1H-imidazole-1-sulfonyl azide (141 mg, 0.671 mmol), CuSO4·5H2O (1.40 mg, 5.60 μmol), K2CO3 (116 mg, 0.839 mmol), and MeOH (4 mL) to a 50 mL single-necked flask in sequence at room temperature, and react at room temperature for 2 hours. Add silica gel to the reaction solution for sample mixing, concentrate, and perform column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 - 20 / 1) to obtain a colorless oily substance 12c (120 mg, yield: 77.6%). MS m / z (ESI): 277.1 [M+H] + 。

[0188] Step 3: Add compound 12c (120 mg, 0.434 mmol), compound 6j (102 mg, 0.478 mmol) (the synthesis of 6j can be carried out with reference to Step 8 of Example 6), sodium L-ascorbate (8.61 mg, 43.4 μmol), CuSO4·5H2O (5.42 mg, 21.7 μmol), tert-butanol (3 mL), and water (3 mL) to a 50 mL single-necked flask in sequence at room temperature, and react at 50 °C for 18 hours. Rotavapor to remove tert-butanol, extract twice with ethyl acetate (10 mL), collect the organic phase, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtering and concentrating, the obtained residue is purified by column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 - 1 / 1) to obtain a yellow oily substance 12d (80 mg, yield: 37.7%). MS m / z (ESI): 490.4 [M+H] + 。

[0189] Step 4: To a 50 mL single-necked flask at room temperature, add compound 12d (80 mg, 0.163 mmol), ethyl acetate (4 mL), Pd / C (20 mg, 10 wt%), and react under hydrogen for 36 hours. Filter the reaction solution through diatomaceous earth, collect the filtrate and concentrate it by rotary evaporation. The resulting residue is purified by HPLC preparation (TFA) to obtain a pale yellow oil Z12 (8.00 mg, yield: 12.3%). LC-MS: 90.4% purity (Sig = 254 nm); MS m / z (ESI): 400.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 9.77 (br, 1H), 8.03 (dd, J = 5.2 Hz, 1.6 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 6.91 (dd, J = 8.0 Hz, 5.2 Hz 1H), 4.62 (s, 2H), 3.53–3.43 (m, 2H), 3.00–2.71 (m, 3H), 2.16–2.07 (m, 3H), 1.82 (s, 6H), 0.82 (d, J = 6.4 Hz, 3H).

[0190] Example 13: Preparation of Compound Z13

[0191]

[0192] Step 1: Under argon protection at room temperature, add methoxymethyltriphenylphosphonium chloride (2.04 g, 5.95 mmol) and dry-THF (15 mL) to a 100 mL three-necked flask. Control the temperature to -78 °C and slowly add n-BuLi (2.4 mL, 2.5 N, 6.0 mmol) dropwise. React at this temperature for 30 minutes, then slowly add compound 13a (900 mg, 3.97 mmol) and raise the temperature to room temperature and react overnight. Concentrate the solvent by rotary evaporation. Add water (100 mL) to the reaction solution and extract with ethyl acetate (100 mL × 2). Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter the resulting filtrate and concentrate it by rotary evaporation to obtain an oily residue. Purify the resulting residue by column chromatography (eluent: ethyl acetate: petroleum ether = 1:20) to obtain a yellow oil 13b (682 mg, 2.67 mmol, yield: 67.5%). MS m / z (ESI): 200.2 [M-56+H] + 。

[0193] Step 2: Add compound 13b (600 mg, 2.353 mmol) and HCl / 1,4-dioxane (8 mL) to a 100 mL single-necked flask. React at room temperature for 4 hours. Directly concentrate the reaction solution by rotary evaporation to obtain a yellow oil 13c (440 mg, crude product).

[0194] Step 3: Add DMF (8 mL), K₂CO₃ (1.03 g, 7.47 mmol) and BnBr (0.3 mL, 2.49 mmol) to a 100 mL single-necked flask containing compound 13c (440 mg, 2.49 mmol). Then react overnight at room temperature. Add water (20 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter the obtained filtrate, rotary evaporate to dryness to obtain an oily residue. Purify the obtained residue by column chromatography (eluent: ethyl acetate:p petroleum ether = 1:1) to obtain a yellow oil 13d (170 mg, 0.736 mmol, yield: 23.6%). MS m / z (ESI): 232.2 [M+H] +

[0195] Step 4: Add MeOH (10 mL), K₂CO₃ (306.8 mg, 2.22 mmol) and dimethyl (1 - dioxolan - 2 - ylpropyl)phosphonate (0.17 mL, 1.1 mmol) to a 100 mL single-necked flask containing compound 13d (170 mg, 0.74 mmol). Stir and react overnight at room temperature. Rotary evaporate the solvent, add water (20 mL) to the reaction solution, extract with dichloromethane (20 mL × 3), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter the obtained filtrate, rotary evaporate to dryness to obtain an oily residue. Prepare the obtained residue on a thick preparative plate (developing agent: methanol:dichloromethane = 1:10) to obtain a yellow oil 13e (90 mg, yield: 53.9%). MS m / z (ESI): 228.3 [M+H] +

[0196] Step 5: Add compound 13e (90 mg, 0.396 mmol), compound 2c (103.1 mg, 0.396 mmol) (the synthesis of 2c refers to the synthesis in Step 2 of Example 2), sodium L - ascorbate (39.2 mg, 0.198 mmol), CuSO₄·5H₂O (9.9 mg, 0.04 mol), tert - butanol (2 mL), water (2 mL) to a 50 mL single-necked flask in sequence at room temperature, and react at 50 °C for 18 hours. LCMS detection shows that it is mainly the target product. Rotary evaporate to remove tert - butanol, extract twice with ethyl acetate (10 mL × 2), collect the organic phase, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and rotary evaporate the obtained residue, and purify it by column chromatography (eluent: ethyl acetate:p petroleum ether = 1:1) to obtain a pale yellow oil 13f (105 mg, yield: 54.4%). MS m / z (ESI): 488.3 [M+H] + 。

[0197] Step 6: To a 50 mL single-necked flask at room temperature, sequentially add compound 13f (105 mg, 0.22 mmol), ethyl acetate (10 mL), Pd / C (23 mg, 0.22 mmol), and heat to 50 °C under hydrogen for overnight reaction. Filter the reaction mixture through diatomaceous earth, and rotary evaporate the filtrate to obtain a yellow oil 13g (47 mg, crude product). MS m / z (ESI): 398.2 [M+H] +

[0198] Step 7: To a 50 mL single-necked flask at room temperature, sequentially add compound 13g (40 mg, 0.10 mmol), 1,2-dichloroethane (6 mL), paraformaldehyde (15 mg, 0.51 mmol), and sodium borohydride acetate (42.7 mg, 0.20 mmol), and heat to 50 °C for 4 hours. Rotary evaporate the solvent, add water (200 mL) and dichloromethane (200 mL) to the reaction mixture, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter the obtained filtrate and rotary evaporate to obtain an oily residue. Prepare the obtained residue by preparative TLC (eluent: methanol:dichloromethane = 1:10) to obtain a pale yellow oil Z13 (24.43 mg, yield: 50.2%). LC-MS: 93.8% purity (Sig = 254 nm); MS m / z (ESI): 412.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.28–8.27 (m, 1H), 7.84–7.82 (m, 1H), 7.59 (s, 1H), 7.00–6.97 (m, 1H), 4.70–4.63 (m, 2H), 3.44–3.41 (m, 2H), 2.80–2.72 (m, 5H), 2.42–2.00 (m, 4H), 1.81 (s, 6H), 1.49–1.40 (m, 1H), 1.19–1.08 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H).

[0199] Example 14: Preparation of Compound Z14

[0200]

[0201] Step 1: Add compound 14a (5.0 g, 37.0 mmol), acetone (25 mL), and water (25 mL) to a 250 mL three-necked flask at room temperature. Cool the mixture to 0 °C. Dissolve sodium nitrite (13.0 g, 188.7 mmol) in water (25 mL) and slowly add it dropwise. After the addition is complete, add aqueous hydrochloric acid solution (33.5 mL, 3 N, 100.5 mmol) dropwise. Stir the mixture at 0 °C for 20 minutes, then remove the ice-water bath and allow the reaction to proceed overnight at room temperature. Add ethyl acetate (100 mL × 3) and water (100 mL) to the reaction mixture for extraction, and collect the organic phase. Wash the obtained organic phase with saturated brine and dry it over anhydrous sodium sulfate. Filter and concentrate the solution to obtain a residue. Purify the obtained residue by column chromatography (eluent: PE:EA = 8:1) to obtain a rose-red solid 14b (980 mg, yield: 16.1%). MS m / z (ESI): 162.9 [M-H] - 。

[0202] Step 2: Add compound 14b (980 mg, 5.98 mmol), DMF (15 mL), potassium carbonate (1.65 g, 12.0 mmol), and CH3I (0.41 mL, 6.6 mmol) to a 250 mL single-necked flask in sequence at room temperature. React the mixture at room temperature for 4 hours. Add ethyl acetate (100 mL) to the reaction mixture, wash it with water (60 mL × 5), and collect the organic phase. Dry the obtained organic phase over anhydrous sodium sulfate, filter and concentrate the solution to obtain a residue. Purify the obtained residue by column chromatography (eluent: PE:EA = 5:1) to obtain a rose-red solid 14c (456 mg, yield: 43.0%). MS m / z (ESI): 179.1 [M+H] + 。

[0203] Step 3: Add compound 14c (400 mg, 2.25 mmol), DMF (10 mL), K2CO3 (932.9 mg, 6.75 mmol), and MeSNa (236.2 mg, 3.371 mmol) to a 100 mL single-necked flask in sequence at room temperature. Heat the mixture to 70 °C and react it overnight. Add ethyl acetate (100 mL) and water (80 mL × 4) to the reaction mixture for extraction, and collect the organic phase. Filter and concentrate the obtained organic phase, and then purify the obtained residue by column chromatography (eluent: PE:EA = 8:1) to obtain a light brown solid 14d (55 mg, yield: 10.6%). MS m / z (ESI): 207.1 [M+H] + 。

[0204] Step 4: Add compound 14d (55 mg, 0.27 mmol), THF (5 mL) into a 50 mL three-necked flask in sequence, displace the gas (N2), cool down to 0 °C, slowly add vinylmagnesium bromide (2.7 mL, 1 mol / L, 2.7 mmol) dropwise. After the addition, react at this temperature for 20 minutes. Slowly warm up to room temperature and react overnight. Rotate and evaporate the THF in the reaction solution, add ethyl acetate (20 mL) to the reaction solution, extract with water (20 mL), and collect the organic phase. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Then purify the obtained residue by preparative TLC (eluent: PE:EA = 4:1) to obtain yellow oil 14e (69 mg, crude product). MS m / z (ESI): 235.0 [M+H] + .

[0205] Step 5: Add compound 14e (69 mg, 0.295 mmol), ethyl acetate (8 mL), T3P (0.3 mL, 50 wt% ethyl acetate solution, 0.59 mmol) and compound 14e1 (73.3 mg, 0.324 mmol) into a 50 mL single-necked flask at room temperature in sequence, then heat up to 90 °C and react for 2 hours. Add ethyl acetate (20 mL) and water (20 mL) to the reaction solution for extraction, and collect the organic phase. The obtained organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. Filter and rotate to dryness to obtain a residue. Purify the obtained residue by preparative TLC (eluent: PE:EA = 1:1) to obtain yellow oil 14f (42 mg, yield: 32.3%). MS m / z (ESI): 443.2 [M-56+H] +

[0206] Step 6: Add 14f (42 mg, 0.16 mmol), H2O (1 mL), MeOH (1 mL) into a 10 mL microwave tube, then react at 130 °C for 3 hours. Rotate and evaporate the solvent. Purify the obtained residue by preparative TLC (eluent: DCM:MeOH = 8:1) to obtain yellow oil Z14 (11.76 mg, yield: 36.2%). LC-MS: 89.6% purity (Sig = 254 nm); MS m / z (ESI): 343.2 [M+H] + , 1 HNMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.2 Hz 1H), 7.27–7.26 (m, 1H), 7.08–7.04 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.10–5.98 (m, 2H), 5.34–5.23 (m, 2H), 4.42 (s, 3H), 3.56–3.41 (m, 4H), 2.52 (s, 3H), 2.30–2.19 (m, 2H), 2.02–1.93 (m, 2H).

[0207] Example 15: Preparation of Compound Z15

[0208]

[0209] Step 1: Add compound 15a (5.0 g, 50.4 mmol) and DMF (80 mL) to a 500 mL three-necked flask at room temperature. Control the temperature to 0 °C and add NaH (3.03 g, 75.7 mmol, 60%) in three portions. Stir at room temperature for 1 hour. Stir at room temperature for another 1 hour, then slowly add benzyl bromide (7.19 mL, 60.5 mmol). After the addition is complete, react at 60 °C for 5 hours. Add water (400 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (400 mL), and collect the organic phase, which is washed with saturated brine. The obtained organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain an oily residue. The obtained residue is purified by column chromatography (eluent: PE / EA = 100 / 1 - 2 / 1) to obtain a pale yellow oily substance 15b (8.6 g, yield: 90.1%). MS m / z (ESI): 190.2 [M+H] + ; 1 1H NMR (400 MHz, CDCl3) δ 7.37–7.20 (m, 5H), 4.96 (d, J = 15.2 Hz, 1H), 3.99 (d, J = 15.2 Hz, 1H), 3.58–3.46 (m, 1H), 2.56–2.33 (m, 2H), 2.22–2.11 (m, 1H), 1.66–1.54 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H).

[0210] Step 2: Add compound 15b (5 g, 26.4 mmol) and THF (150 mL) to a 500 mL three-necked flask in sequence. Replace the gas in the system with argon. Control the temperature to -78 °C and add LDA (19.8 mL, 39.6 mmol, 2M). After reacting at this temperature for half an hour, add DMC (3.6 mL, 42.3 mmol), and slowly raise the temperature to room temperature and stir for 18 hours. At 0 °C, add an aqueous ammonium chloride solution (300 mL) to the reaction solution to quench the reaction, extract twice with ethyl acetate (300 mL), and collect the organic phase. The obtained organic phase is dried over anhydrous sodium sulfate. Filter and concentrate by rotary evaporation to obtain an oily residue. The obtained residue is purified by column chromatography (eluent: PE / EA = 100 / 1 - 3 / 1) to obtain a yellow oily substance 15c (4.3 g, yield: 65.8%); MS m / z (ESI): 248.2 [M+H] + 。

[0211] Step 3: To a 500 mL three-necked flask at room temperature, add compound 15c (4.30 g, 17.4 mmol) and THF (150 mL) successively, and displace the gas in the system with argon. Control the temperature to 0 °C, and add lithium aluminum hydride (1.65 g, 43.5 mmol) in three portions. Slowly warm to room temperature and stir for 18 hours. Add water (1.7 mL), 15% NaOH (1.7 mL), and water (5.2 mL) to the reaction solution in sequence to quench the reaction. Stir at room temperature for half an hour, and dry with anhydrous sodium sulfate. Filter through diatomaceous earth, collect the filtrate, concentrate it by rotary evaporation, and purify the obtained residue by column chromatography (eluent: DCM / MeOH = 20 / 1) to obtain a pale yellow oil 15d (1.83 g, yield: 51.3%). MS m / z (ESI): 206.2 [M - 56 + H] + 。

[0212] Step 4: To a 100 mL three-necked flask, add oxalyl chloride (0.1 mL, 1.17 mmol) and DCM (15 mL) successively, and displace the gas in the system with argon. Control the temperature to -78 °C, and slowly add DMSO (0.21 mL, 2.92 mmol). React at this temperature for 15 minutes. Then add compound 15d (200 mg, 0.974 mmol) dissolved in DCM (2 mL) to the reaction solution. React at this temperature for 1.5 hours, and then add triethylamine (0.68 mL, 4.87 mmol). Concentrate the reaction solution by rotary evaporation, add water (5 mL) and ethyl acetate (10 mL), and extract twice. Collect the organic phase. Dry the obtained organic phase with anhydrous sodium sulfate. Filter and concentrate by rotary evaporation to obtain a yellow oil 15e (200 mg, crude product).

[0213] Step 5: To a 100 mL single-necked flask at room temperature, add compound 15e (200 mg, 0.984 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.15 mg, 0.984 mmol), MeOH (10 mL), and K2CO3 (204 mg, 1.48 mmol). React at room temperature for 18 hours. Add water (400 mL) to the reaction solution, extract with ethyl acetate (400 mL), collect the organic phase, and wash with saturated brine. Dry the obtained organic phase with anhydrous sodium sulfate. Filter and concentrate by rotary evaporation to obtain a yellow oil 15f (200 mg, crude product). MS m / z (ESI): 200.2 [M + H] + 。

[0214] Step 6: To a 100 mL single-necked flask at room temperature, successively add compound 6f (136 mg, 0.602 mmol) (the synthesis of 6f refers to the synthesis in Step 5 of Example 6), crude product of compound 15f (100 mg, 0.502 mmol), sodium L-ascorbate (9.94 mg, 50.2 μmol), CuSO4·5H2O (6.26 mg, 25.1 μmol), t-BuOH (5 mL), and H2O (5 mL). React at 60 °C for 18 hours. Spin out t-BuOH in the reaction solution, add EA (20 mL) for extraction, collect the organic phase, wash it with saturated brine, and dry it over anhydrous sodium sulfate. Filter, and after spinning dry the filtrate, purify the obtained residue by column chromatography (DCM / MeOH = 20 / 1) to obtain 15g as a pale yellow oil (110 mg, yield: 51.6%). MS m / z (ESI): 425.2 [M+H] +

[0215] Step 7: To a 50 mL three-necked flask at room temperature, successively add compound 15g (100 mg, 0.235 mmol), DCE (6 mL), triethylamine (0.33 mL, 2.35 mmol), and 1-chloroethyl chloroformate (0.25 mL, 2.35 mmol). React at room temperature for 18 hours. Rotavap the reaction solution to remove the solvent, add MeOH (2 mL) to dissolve it, and obtain pale yellow solid Z15 by Prep-HPLC (FA) (7.84 mg, yield: 9.95%). LC-MS: 97.2% purity (Sig = 254 nm); MS m / z (ESI): 335.05 [M+H] + ; 1 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.90–7.87 (m, 1H), 7.33–7.31 (m, 1H), 7.19–7.15 (m, 1H), 6.91–6.87 (m, 1H), 6.81–6.79 (m, 1H), 4.19 (s, 1H), 3.82–3.73 (m, 3H), 3.39 (s, 2H), 2.58–1.80 (m, 2H), 1.86 (s, 6H), 1.48–1.43 (m, 3H).

[0216] Example 16: Preparation of Compound Z16

[0217]

[0218] Step 1: Methoxymethyltriphenylphosphonium chloride (1.14 g, 3.33 mmol) and dry - THF (30 mL) were successively added to a 100 - mL three - necked flask at room temperature. The temperature was controlled to - 78 °C, and n - BuLi (1.59 mL, 3.33 mmol, 2.1 M) was slowly added dropwise under a nitrogen atmosphere. After the addition was completed, the reaction was carried out for 40 minutes. At this temperature, compound 16a (500 mg, 2.22 mmol) was added dropwise, and the temperature was slowly raised to room temperature and stirred for 5 hours. The reaction was quenched by adding water at low temperature, extracted with EA (100 mL), the organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and rotary evaporation, the obtained residue was purified by column chromatography (PE / EA = 100 / 1 - 5 / 1) to obtain a pale yellow oil 16b (250 mg, crude product). MS m / z (ESI): 254.0 [M + H] + ; 1H NMR (400 MHz, CDCl3) δ 5.81–5.67 (m, 1H), 3.55–3.50 (m, 3H), 3.15 (d, J = 6.8 Hz, 2H), 2.37–2.01 (m, 2H), 1.47–1.43 (m, 9H), 0.84 (s, 4H), 0.63–0.48 (m, 2H).

[0219] Step 2: Compound 16b (250 mg, 0.987 mmol), cerium(III) chloride (365 mg, 1.48 mmol), NaI (44.4 mg, 0.296 mmol), and ACN (6 mL) were successively added to a 100 - mL single - necked flask at room temperature, and the reaction was carried out at 80 °C for 18 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was collected and rotary evaporated to obtain a yellow oil 16c (250 mg, crude product). MS m / z (ESI): 238.0 [M - H] - 。

[0220] Step 3: Compound 16c (250 mg, 1.04 mmol), dimethyl (1 - diazo - 2 - oxopropyl)phosphonate (0.17 mL, 1.17 mmol), MeOH (8 mL), and K2CO3 (217 mg, 1.57 mmol) were successively added to a 100 - mL single - necked flask at room temperature, and the reaction was carried out at room temperature for 18 hours. Water (15 mL) and EA (20 mL) were added to the reaction solution for extraction, the organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and rotary evaporation, a yellow oil 16d (150 mg, crude product) was obtained.

[0221] Step 4: To a 100 mL single-necked flask at room temperature, sequentially add compound 16d (140 mg, 0.595 mmol), compound 6f (174 mg, 0.773 mmol) (the synthesis of 6f refers to the synthesis in Step 5 of Example 6), sodium L-ascorbate (23.6 mg, 0.118 μmol), CuSO4·5H2O (14.8 mg, 59.5 μmol), t-BuOH (2 mL), and H2O (4 mL). React at 60 °C for 18 hours. Rotate out t-BuOH in the reaction solution, extract twice with EA (15 mL), collect the organic phase, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtration and concentration, purify the obtained residue by column chromatography (PE / EA = 100 / 1 - 3 / 1) to obtain colorless oil 16e (70 mg, yield: 25.5%). MS m / z (ESI): 461.2 [M+H] + .

[0222] Step 5: To a 50 mL single-necked flask at room temperature, sequentially add compound 16e (60 mg, 0.130 mmol), DCM (1 mL), and TFA (1 mL). React at room temperature for 18 hours. Rotate out the solvent in the reaction solution, add DCM (20 mL) and aqueous sodium bicarbonate solution (10 mL) for extraction twice, collect the organic phase, wash with saturated brine, and dry with anhydrous sodium sulfate. After filtration and concentration, subject the obtained residue to Prep-HPLC (FA) to obtain yellow oil Z16 (5.84 mg, yield: 12.4%). LC-MS: 97.1% purity (Sig = 254 nm); MS m / z (ESI): 361.1 [M+H] + , 1 1H NMR (400 MHz, CDCl3) δ 8.8.59 (s, 1H), 7.77 (s, 1H), 7.34–7.32 (m, 1H), 7.19–7.15 (m, 1H), 6.92–6.88 (m, 1H), 6.81–6.79 (m, 1H), 4.18 (s, 2H), 3.32–3.13 (m, 3H), 2.78–2.75 (m, 2H), 2.36–2.26 (m, 2H), 1.86 (s, 6H), 0.63–0.54 (m, 4H).

[0223] Example 17: Preparation of Compound Z17

[0224]

[0225] Step 1: Add methoxymethyltriphenylphosphonium chloride (14.78 g, 43.10 mmol) and dry THF (40 mL) into a 250 mL three-necked flask in sequence at room temperature. Control the temperature to -78 °C, add n-BuLi (17.24 mL, 43.10 mmol), react for 1 hour at this temperature, then dissolve compound 17a (4 g, 28.74 mmol) with dry THF (20 mL) and add it slowly. Raise the temperature to room temperature and react overnight. Add methanol (2 mL) to quench the reaction mixture, stir for 10 minutes, filter out the solid with diatomaceous earth. After rotary evaporation of the filtrate obtained by filtration, an oily residue is obtained. Purify the obtained residue by column chromatography (dichloromethane:methanol = 10:1) to obtain a yellow oily substance 17b (1.08 g, 6.47 mmol, yield: 22.5%). MS m / z (ESI): 168.2 [M+H] +

[0226] Step 2: Add compound 17b (400 mg, 2.39 mmol), HCl (1 mL, 12 M, 12 mmol), and THF (4 mL) into a 25 mL single-necked flask in sequence and stir at room temperature for 1 hour. Rotary evaporate the reaction mixture, then place it on a freeze dryer to dry. Purify the obtained residue by column chromatography (dichloromethane:methanol = 10:1) to obtain a yellow oily substance 17c (220 mg, crude product). MS m / z (ESI): 154.2 [M+H] + 。

[0227] Step 3: Add compound 17c (200 mg, 1.31 mmol), MeOH (3 mL), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.215 mL, 1.44 mmol), and K2CO3 (270 mg, 1.96 mmol) into a 25 mL single-necked flask in sequence at room temperature and react overnight. Filter out the solid with filter paper. After rotary evaporation of the filtrate obtained by filtration, a yellow oily substance 17d (200 mg, crude product) is obtained. MS m / z (ESI): 150.2 [M-N2+H] + 。

[0228] Step 4: To a 25 mL single-necked flask at room temperature, successively add compound 6f (150 mg, 0.67 mmol) (the synthesis of 6f refers to the synthesis in Step 5 of Example 6), tert-butanol (1 mL), water (1 mL), compound 17d (200 mg, 1.34 mmol), sodium L-ascorbate (13.27 mg, 67.01 μmol), CuSO4·5H2O (8.37 mg, 33.5 μmol), and react overnight under heating at 50 °C. Rotary evaporate to remove tert-butanol, add DCM (10 mL) for extraction, collect the organic phase, and after rotary evaporation to dryness, the resulting residue is purified by scraping a large plate (developing agent: dichloromethane / anhydrous methanol = 10 / 1) to obtain a pale yellow oil Z17 (1.25 mg, yield: 2.49%). LC-MS: 84.1% purity (Sig = 254 nm); MS m / z (ESI): 375.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.33–7.30 (m, 1H), 7.16–7.14 (m, 1H), 6.91–6.88 (m, 1H), 6.82–6.80 (m, 1H), 4.19 (s, 2H), 3.70 (s, 2H), 3.39–3.28 (m, 1H), 2.68 (s, 3H), 2.50–2.45 (m, 2H), 2.30–2.20 (m, 2H), 2.20–1.97 (m, 4H), 1.84 (s, 6H).

[0229] Example 18: Preparation of Compound Z18

[0230]

[0231] Step 1: Dissolve compound 18a (450 mg, 1.79 mmol) in DCM (10 mL), then add Dess-Martin (1.22 g, 2.87 mmol), and react at room temperature for 12 hours. Dilute the reaction solution with dichloromethane, add saturated sodium thiosulfate solution and stir for 5 minutes, then separate the organic phase, wash it with saturated sodium bicarbonate, wash it with brine, dry it, and concentrate to obtain a brown solid. The brown solid is subjected to silica gel column chromatography (PE:EA = 5:1) to obtain a colorless oil 18b (285 mg, yield: 63.8%). MS m / z (ESI): 194.1 [M-56+H] + 。

[0232] Step 2: Dimethyl (diazomethyl)phosphonate (281.78 mg, 1.88 mmol) was dissolved in THF (7.51 mL). At -78 °C, T-BuOK (1 M, 1.88 mL) was slowly added. The mixture was stirred at low temperature (-78 °C) for 0.5 h. Finally, compound 18b (390 mg, 1.56 mmol) dissolved in THF (2.82 mL) was slowly added dropwise. Finally, the temperature was slowly raised to room temperature and stirred for 1 h. The reaction solution was quenched with aqueous ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and directly concentrated by rotary evaporation to obtain a brown oil. The brown oil was purified by silica gel column chromatography (PE:EA = 10:1) to obtain brown oil 18c (210 mg, yield: 54.7%). MS m / z (ESI): 190.0 [M - 56 + H] +

[0233] Step 3: Reactant 6f (150 mg, 664.67 μmol) (the synthesis of 6f refers to the synthesis in Step 5 of Example 6) and compound 18c (163.02 mg, 664.67 μmol) were added to THF (0.8 mL) and H2O (0.8 mL) successively. Then, CuSO4·5H2O (33.19 mg, 132.93 μmol) and sodium L-ascorbate (26.34 mg, 132.93 μmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was concentrated, a brown oil was obtained. After rotary evaporation, a brown oil was obtained. The brown oil was purified by silica gel column chromatography (PE:EA = 3:1) to obtain brown oil 18d (150 mg, yield: 47.9%). MS m / z (ESI): 471.0 [M + H] + 。

[0234] Step 4: Compound 18d (150 mg, 318.51 μmol) was added to THF (3 mL) and methanol (2 mL). Finally, HCl-dioxane (4 M, 2.39 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated to obtain a brown oil. After rotary evaporation of the reaction, a brown oil was obtained. The brown oil was separated by acidic preparation to obtain white solid Z18 (75 mg, 202.25 μmol, yield: 63.5%); LC-MS: 100% purity (Sig = 254 nm); MS m / z (ESI): 371.0 [M + H] +; 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.38 (dd, J = 7.9, 1.6 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.11 (dd, J = 8.3, 1.4 Hz, 1H), 7.00–6.91 (m, 1H), 4.34 (s, 2H), 3.64–3.48 (m, 2H), 3.20–3.05 (m, 3H), 2.90–2.77 (m, 1H), 2.07 - 1.93 (m, 2H), 1.75 (s, 6H).

[0235] Example 19: Preparation of Compound Z19

[0236]

[0237] Step 1: Solid T-BuOK (6 g, 53.57 mmol) was added to THF (50 mL). The reaction system was cooled to 0 °C. At this temperature, compound 19a (10 g, 52.84 mmol) was slowly added dropwise to the above reaction system. After stirring at 0 °C for 30 minutes, 2-iodopropane (9.88 g, 58.12 mmol) was slowly added dropwise. The reaction was gradually warmed to room temperature and stirred for 16 hours. The reaction was diluted with THF, and the solid inside was directly filtered. The filtrate was concentrated in vacuo to obtain a brown liquid. The brown liquid was subjected to silica gel column chromatography (PE:EA = 10:1) to obtain a brown oil 19b (3.5 g, yield: 28.6%); MS m / z (ESI): 232.2 [M + H] +

[0238] Step 2: Methyltriphenylphosphonium iodide (8.39 g, 20.75 mmol) was added to THF (40 mL). The reaction was cooled to 0 °C. Under argon protection, T-BuOK (1 M, 20.75 mL) was slowly added dropwise. After reacting at 0 °C for 40 minutes, compound 19b (3.2 g, 13.83 mmol) dissolved in THF (10 mL) was slowly added dropwise at this temperature. The reaction was stirred at room temperature for 12 hours. The reaction was quenched by adding ammonium chloride for protection, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate, and concentrated to obtain a brown oil. After concentrating the solvent in vacuo, it was separated by silica gel column chromatography (PE:EA = 20:1) to obtain a colorless oil 19c (2.1 g, yield: 66.1%). MS m / z (ESI): 230.1 [M + H] + 。

[0239] Step 3: Compound 19c (2.1 g, 9.16 mmol) was added to THF (40 mL), followed by the addition of solid 9-BBN dimer (3.35 g, 13.73 mmol). The reaction was heated to 60 °C and stirred for 1.5 h. After the raw materials were consumed, the reaction was cooled to 0 °C. NaOH (2 M, 13.73 mL) was added to the reaction solution and stirred for 5 min. Then, H2O2 (4.15 g, 36.62 mmol, 30% purity) was added again, and the temperature was slowly raised to room temperature and stirred for 17 h. The reaction was quenched with saturated aqueous sodium thiosulfate solution, stirred for 10 min, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. After purification by silica gel column chromatography (PE:EA = 5:1), a brown oil 19d (1.3 g, yield: 57.4%) was obtained. MS m / z (ESI): 248.2 [M+H] + .

[0240] Step 4: Compound 19d (1.3 g, 5.26 mmol) was added to ACN (20 mL), followed by the addition of IBX (2.94 g, 10.51 mmol). The reaction was heated to 85 °C and stirred for 1 h. The reaction was filtered through diatomaceous earth, and the filtrate was evaporated to dryness to obtain a brown oil. After evaporation to dryness, 19e (1.3 g, crude) was obtained as a brown oil, and the crude product was directly used in the next step. MS m / z (ESI): 246.2 [M+H] +

[0241] Step 5: 19e (1 g, 4.08 mmol) was dissolved in methanol (10 mL). Potassium carbonate (1.13 g, 8.15 mmol) was added at room temperature, and finally dimethyl (1-diazo-2-oxopropyl)phosphonate (782.97 mg, 4.08 mmol, 611.70 μL) was slowly added dropwise to the above reaction system. The reaction was stirred at room temperature for 12 h. The reaction solution was filtered and directly evaporated to dryness to obtain a brown oil. The brown oil was purified by silica gel column chromatography (PE:EA = 10:1) to obtain a brown oil 19f (430 mg, yield: 43.7%). MS m / z (ESI): 242.1 [M+H] + .

[0242] Step 6: Add compound 6f (200 mg, 886.23 μmol) (the synthesis of 6f refers to the synthesis in Step 5 of Example 6), 19f (213.91 mg, 886.23 μmol) to H2O (1 mL) and THF (1 mL). Then add CuSO4·5H2O (66.38 mg, 265.87 μmol) and sodium L-ascorbate (52.67 mg, 265.87 μmol) in sequence. Stir the reaction at room temperature for 12 hours. After concentration of the reaction, a brown oil is obtained. After rotary evaporation, a brown oil is obtained. Through silica gel column chromatography (PE:EA = 1:1), brown oil 19g (180 mg, yield: 43.5%) is obtained. MS m / z (ESI): 467.1 [M+H] + 。

[0243] Step 7: Dissolve compound 19g (160 mg, 342.58 μmol) in DCE (10 mL) until clear. Add TEA (277.33 mg, 2.74 mmol, 382.25 μL), and slowly add 1-chloroethyl chloroformate (195.91 mg, 1.37 mmol). Stir the reaction at room temperature for 0.5 hour, then heat the reaction to 80 °C and react for 18 hours. Then rotary evaporate the solvent, add Methanol (6 mL), and heat the reaction to 80 °C and reflux and stir for 2 hours. After concentration of the reaction, a crude brown oil is obtained. After acidic preparative separation, compound Z19 (39.5 mg, 19.7%) is obtained. LC-MS: 100% purity (Sig = 254 nm); MS m / z (ESI): 377.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.90 - 8.50 (br, 1H), 8.01 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 4.33 (s, 2H), 3.21 (t, J = 14.0 Hz, 2H), 2.89 (d, J = 11.4 Hz, 1H), 2.67 (s, 1H), 1.84 (dd, J = 26.5, 11.8 Hz, 3H), 1.72 (s, 6H), 1.40 (s, 1H), 0.75 (d, J = 7.0 Hz, 3H), 0.66 (d, J = 6.9 Hz, 3H).

[0244] Example 20: Preparation of Compound Z20

[0245]

[0246] Step 1: Suspend compound 20a (500 mg, 4.20 mmol), ethyl 2-bromo-2-methylpropionate (900 mg, 4.62 mmol), palladium(II) acetate (47 mg, 0.209 mmol), Xantphos (242 mg, 0.420 mmol), and cesium carbonate (2.73 g, 8.39 mmol) in toluene (15 mL). Under nitrogen protection, stir the reaction mixture at room temperature for 10 h. Concentrate the reaction mixture and purify it by column chromatography (PE:EA = 20:1) to obtain compound 20b (400 mg, yellow oil), with a yield of 40%. MS m / z (ESI): 234.1 [M+1].

[0247] Step 2: Dissolve compound 20b (200 mg, 0.857 mmol) and sodium hydroxide (137 mg, 3.43 mmol) in a solution of tetrahydrofuran (3 mL) and water (1.5 mL). Stir the reaction mixture at 90 °C for 12 h. Acidify the reaction mixture with concentrated hydrochloric acid, concentrate it, and purify it by column chromatography (PE:EA = 5:1) to obtain compound 20c (110 mg, yellow oil), with a yield of 62%. MS m / z (ESI): 206.1 [M+1].

[0248] Step 3: Dissolve compound 20c (100 mg, 0.487 mmol), 20d (106 mg, 0.487 mmol), and triethylamine (443 mg, 4.38 mmol) in tetrahydrofuran (2 mL). At room temperature, add T3P (465 mg, 0.730 mmol, 50% in EA) and stir for 5 h. Concentrate the reaction mixture and purify it by column chromatography (PE:EA = 1:1) to obtain compound 20e (150 mg, yellow oil), with a yield of 75%. MS m / z (ESI): 406.1 [M+1].

[0249] Step 4: A solution of compound 20e (150 mg, 0.370 mmol) in TFA (0.5 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by preparative liquid chromatography (preparative column: Waters-SunFire C18, eluent: 0.05% aqueous NH4HCO3 / acetonitrile, elution gradient: starting from 20% acetonitrile - ending with 80% acetonitrile, flow rate: 30 mL / min) to obtain the product Z20 (23.29 mg, white solid) with a yield of 20%. MS m / z (ESI): 306.1 [M+1]. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 4.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 6.97 (d, J = 16.0 Hz, 1H), 6.75 (d, J = 16.0 Hz, 1H), 6.20 (d, J = 12.0 Hz, 1H), 4.65 (d, J = 52.0 Hz, 1H), 4.07 (d, J = 28.0 Hz, 1H), 3.37 (t, J = 12.0 Hz, 1H), 3.17 (t, J = 12.0 Hz, 1H), 2.93 - 2.70 (m, 2H), 2.35 (s, 3H), 1.74 - 1.68 (m, 2H), 1.42 (s, 6H).

[0250] Example 21 Preparation of Compound Z21

[0251]

[0252] Step 1: Compound 21a (500 mg, 4.23 mmol), ethyl 2-bromo-2-methylpropionate (900 mg, 6.35 mmol), palladium acetate (47.5 mg, 0.209 mmol), Xantphos (244.8 mg, 0.423 mmol), and cesium carbonate (2.76 g, 8.46 mmol) were suspended in toluene (15 mL). Under nitrogen protection, the reaction mixture was stirred at room temperature for 10 h. The reaction mixture was concentrated and purified by column chromatography (PE:EA 15:1) to obtain compound 21b (400 mg, yellow oil) with a yield of 40%. MS m / z (ESI): 233.1 [M+1].

[0253] Step 2: Compound 21b (400 mg, 0.857 mmol), sodium hydroxide (137 mg, 3.43 mmol) were dissolved in a solution of tetrahydrofuran (6 mL) and water (3 mL). The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was acidified with concentrated hydrochloric acid, concentrated, and purified by column chromatography (PE: EA 5:1) to obtain compound 21c (280 mg, yellow oil), yield: 62%. MS m / z (ESI): 205.1 [M+1].

[0254] Step 3: Compound 21c (100 mg, 0.489 mmol), 20d (106 mg, 0.489 mmol), and triethylamine (445 mg, 4.41 mmol) were dissolved in tetrahydrofuran (2 mL). At room temperature, T3P (465 mg, 0.730 mmol, 50% in EA) was added and stirred for 5 h. The reaction mixture was concentrated and purified by column chromatography (PE: EA 1:1) to obtain compound 21e (130 mg, yellow oil), yield: 65%. MS m / z (ESI): 394.1 [M+1-56].

[0255] A solution of compound 21e (130 mg, 0.370 mmol) in TFA (0.5 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by preparative liquid chromatography (preparative column: Waters-SunFire C18, eluent: 0.05% aqueous NH4HCO3 / acetonitrile, elution gradient: starting from 20% acetonitrile - ending with 80% acetonitrile, flow rate: 30 mL / min) to obtain the product Z21 (47.83 mg, white solid), yield, 42%. MS m / z (ESI): 305.2 [M+1]. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.0 Hz, 1H), 7.19~7.17 (m, 3H), 6.76 (d, J = 16.0 Hz, 1H), 6.23~6.16 (m, 1H), 6.06 (d, J = 4.0 Hz, 0.8H), 5.94 (d, J = 4.0 Hz, 0.2H), 4.65 (d, J = 48.0 Hz, 1H), 4.42 (d, J = 48.0 Hz, 1H), 3.44~3.20 (m, 2H), 3.02~2.73 (m, 3H), 2.34 (s, 3H), 1.76 - 1.69 (m, 2H), 1.41 (s, 6H).

[0256] Example 22 Preparation of Compound Z22

[0257]

[0258] Step 1: Dissolve methyltriphenylphosphonium bromide (11.27 g, 31.56 mmol) in tetrahydrofuran (50 mL) solution. Dropwise add t-BuOK (18.4 mL, 36.8 mmol, 2 M in THF) at room temperature, stir for 15 min, and then dropwise add the tetrahydrofuran (50 mL) solution of compound 22a (5 g, 26.30 mmol). The reaction mixture is continuously stirred at room temperature for 1 h. The reaction mixture is concentrated and purified by column chromatography (PE:EA 50:1) to obtain compound 22b (2.2 g, colorless oil), with a yield of 44%. It is directly used for the next reaction without further detection.

[0259] Step 2: Suspend compound 22b (500 mg, 2.66 mmol), ethyl 2-bromo-2-methylpropionate (777 mg, 3.99 mmol), palladium acetate (30 mg, 0.132 mmol), Xantphos (154 mg, 0.265 mmol), and cesium carbonate (1.73 g, 5.32 mmol) in toluene (15 mL) solution. Under nitrogen protection, the reaction mixture is stirred at room temperature for 10 h. The reaction mixture is concentrated and purified by column chromatography (PE:EA 20:1) to obtain compound 22c (300 mg, yellow oil), with a yield of 37%. It is directly used for the next reaction without further detection.

[0260] Step 3: Dissolve compound 22c (300 mg, 0.992 mmol) and sodium hydroxide (397 mg, 9.92 mmol) in 1,4-dioxane (5 mL) and water (5 mL) solution. The reaction mixture is stirred at 100 °C for 12 h. The reaction mixture is acidified with concentrated hydrochloric acid, concentrated, and purified by column chromatography (PE:EA 5:1) to obtain compound 22d (150 mg, yellow solid), with a yield of 55%. MS m / z (ESI): 293.1 [M+1+18].

[0261] Step 4: Dissolve compound 22d (100 mg, 0.364 mmol), compound 20d (79 mg, 0.364 mmol), and triethylamine (332 mg, 3.28 mmol) in tetrahydrofuran (2 mL). At room temperature, add T3P (348 mg, 0.547 mmol, 50% in EA) and stir for 1 h. The reaction mixture is concentrated and purified by column chromatography (PE:EA 1:1) to obtain compound 22e (120 mg, yellow oil), with a yield of 69%. MS m / z (ESI): 419.2 [M+1-56].

[0262] Step 5: A solution of compound 22e (120 mg, 0.252 mmol) in TFA (0.5 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by preparative liquid chromatography (preparative column: Waters-SunFire C18, eluent: 0.05% aqueous NH4HCO3 / acetonitrile, elution gradient: starting from 20% acetonitrile - ending at 80% acetonitrile, flow rate: 30 mL / min) to obtain the product Z22 (47.83 mg, colorless oil) with a yield of 16%. MS m / z (ESI): 375.2 [M+1]. 1H NMR (400 MHz, CDCl3) δ 7.56 - 7.53 (m, 1H), 7.32 - 7.23 (m, 3H), 6.80 - 6.76 (m, 1H), 6.38 (dd, J = 16.0, 4.0 Hz, 1H), 5.92 (d, J = 4.0 Hz, 1H), 4.57 (d, J = 48.0 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.31 - 3.28 (m, 1H), 3.11 (d, J = 16.0 Hz, 1H), 2.86 - 2.64 (m, 3H), 1.70 - 1.53 (m, 2H), 1.25 (s, 6H).

[0263] Example 23: Preparation of Compound Z23

[0264]

[0265] Step 1: Compound 6f (87 mg, 215.89 μmol) and compound 1b (44.75 mg, 215.89 μmol) were dissolved in THF (1.5 mL) and H2O (1.5 mL), and then sodium ascorbate (4.28 mg, 21.59 μmol) and CuSO4 (6.89 mg, 43.18 μmol) were added. The reaction was stirred at 20 °C for 14 h. The reaction mixture was poured into a separatory funnel, water (100 mL) was added, and the mixture was extracted with ethyl acetate (2 × 40 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by CombiFlash silica gel column (4 g, 0 - 40% ethyl acetate / petroleum ether) gave a colorless oily liquid 23a (132 mg, 189.03 μmol, 87.56% yield, 62% purity). MS m / z (ESI): 433.3 [M+1] + 。

[0266] Step 2: Compound 23a (192 mg, 274.96 μmol) was dissolved in MeOH (1.0 mL) and THF (1 mL), and then HCl (100.25 mg, 2.75 mmol) was added. The reaction was stirred at 20 °C for 1 hr. DCM (40 mL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. It was purified by preparative liquid chromatography (Waters-SunFire C18, 0.05% FA, water / acetonitrile, 5% acetonitrile - 85% acetonitrile, 30 mL / min) to obtain yellow solid Z23 (74 mg, 213.02 μmol, 77.47% yield, 95.81% purity). MS m / z (ESI): 333.2 [M+1] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 8.25 (s, 1H), 7.97 (s, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 4.29 (s, 2H), 3.16 (d, J = 11.4 Hz, 2H), 3.02 (d, J = 11.3 Hz, 2H), 1.98 (d, J = 3.6 Hz, 1H), 1.84 (t, J = 2.9 Hz, 2H), 1.69 (s, 6H).

[0267] Example 24: Preparation of Compound Z24

[0268]

[0269] Step 1: Compound 24b (480.92 mg, 4.90 mmol) was dissolved in Et2O (30 mL), under N2, placed in an ice - water bath at 0 °C. n - Butyllithium (313.64 mg, 4.90 mmol, 3.1 mL) and trimethylaluminum (323.55 mg, 4.49 mmol, 2.25 mL) were added successively, and the temperature was gradually raised to room temperature. Compound 24a (813 mg, 4.08 mmol) was dissolved in dry ether (4 mL), added to the reaction solution, and placed in a dry ice - ethanol bath at - 78 °C. Then, a mixture of boron trifluoride and ether (1:1) (2.49 g, 8.16 mmol, 1.04 mL, 46.5% purity) was added, and the reaction was continued with stirring for 2 h. Methanol (6 mL) was injected into the reaction solution, and stirring was continued for 15 min. Then, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the temperature was gradually raised to room temperature over a period of 30 min. The reaction solution was poured into a separatory funnel, water (20 mL) was added, and extraction was carried out with ether (2×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation. Purification was carried out on a Combi Flash silica gel column (20 g, 0 - 25% ethyl acetate / petroleum ether) to obtain a colorless oily liquid 24c (761 mg, 2.56 mmol, 62.70% yield). MS m / z (ESI): 242.1 [M + 1 - 56] + 。

[0270] Step 2: Compound 24c (761 mg, 2.56 mmol) was dissolved in THF (1 mL), tetrabutylammonium fluoride (2.01 g, 7.67 mmol) was added, and the reaction was stirred at 20 °C for 30 min. The reaction solution was poured into a separatory funnel, water (150 mL) was added, and extraction was carried out with ethyl acetate (2×30 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation. Purification was carried out on a CombiFlash silica gel column (12 g, 0 - 35% ethyl acetate / petroleum ether) to obtain a colorless oily liquid 24d (533 mg, 2.37 mmol, 92.48% yield). MS m / z (ESI): 170.1 [M + 1 - 56] + 。

[0271] Step 3: Compound 24d (226 mg, 1.00 mmol) was dissolved in DCM (15 mL), under N2, placed in a -78 °C dry ice - ethanol bath, N-ethyl-N-(trifluorothio)ethylamine (339.58 mg, 2.11 mmol) was added, and the mixture was stirred for 3 h. The reaction solution was poured into a separatory funnel, ethyl acetate (20 mL) was added, washed with saturated NaHCO3 solution (50 mL), and then extracted with ethyl acetate (2 × 40 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Combi Flash silica gel column (4 g, 0 - 25% ethyl acetate / petroleum ether) gave yellow oily liquid 24e (200 mg, 352.00 μmol, 35.09% yield, 40% purity) MS m / z (ESI): 172.1 [M+1 - 56] + 。

[0272] Step 4: Compound 2c (78 mg, 263.78 μmol) and compound 24e (59.95 mg, 263.78 μmol) were dissolved in THF (1.0 mL) and H2O (1.0 mL), then sodium ascorbate (5.23 mg, 26.38 μmol) and CuSO4 (8.42 mg, 52.76 μmol) were added, and the mixture was stirred at 25 °C for 2 h. The reaction solution was filtered through a layer of diatomaceous earth, concentrated under reduced pressure and dried with an oil pump. The crude product was redissolved in DCM (30 mL) / MeOH (10 mL), and the reaction solution was filtered through a second layer of diatomaceous earth. Concentrated under reduced pressure and dried with an oil pump to obtain a yellowish-brown oily liquid 24f (164 mg, 114.38 μmol, 43.36% yield, 34% purity) MS m / z (ESI): 432.2 [M+1] + 。

[0273] Step 5: Compound 24f (419 mg, 292.23 μmol) was dissolved in THF (1 mL) and MeOH (1 mL), then HCl / dioxane (106.55 mg, 2.92 mmol) was added, and the mixture was stirred at 25 °C for 2 h. DCM (40 mL) was added to the reaction solution, and it was concentrated under reduced pressure. Purification by preparative liquid chromatography (Waters - SunFire C18, 0.05% FA water / acetonitrile, 5% acetonitrile - 90% acetonitrile, 30 mL / min) gave a brownish-black viscous solid Z24 (104.08 mg, 268.68 μmol, 91.94% yield, 100% purity) MS m / z (ESI): 388.0 [M+1] + ; 11H NMR (DMSO-d6, 400 MHz): δ 8.38 (dd, J = 5.1, 1.8 Hz, 1H), 8.18 (s, 1H), 8.12–8.00 (m, 2H), 7.16 (dd, J = 7.5, 5.1 Hz, 1H), 4.75–4.55 (m, 3H), 3.28 (ddd, J = 12.6, 8.8, 4.4 Hz, 1H), 3.20–2.90 (m, 2H), 2.78–2.57 (m, 2H), 1.99–1.85 (m, 1H), 1.70 (d, J = 1.6 Hz, 6H), 1.68–1.62 (m, 1H).

[0274] Example 25: Preparation of Compound Z25

[0275]

[0276] Step 1: Compound 25a (416 mg, 1.66 mmol) and compound 25b (299 mg, 1.66 mmol) were dissolved in DMF (4.5 mL), K2CO3 (690.61 mg, 5.00 mmol) was added, and the mixture was heated at 80 °C with microwave irradiation and stirred for 3.0 h. The reaction solution was evaporated to dryness under reduced pressure using an oil pump. The obtained crude product was separated and purified by Combi Flash silica gel column (4 g, 0–10% ethyl acetate / petroleum ether) to give a colorless oily liquid 25c (220 mg, 626.18 μmol, 37.83% yield) MS m / z (ESI): 296.0 [M + 1 - 56] + 。

[0277] Step 2: Compound 25c (239 mg, 680.26 μmol) was dissolved in 1,4-dioxane (0.5 mL), stirred at 20 °C, HCl (248.02 mg, 6.80 mmol) (4 M in 1,4-dioxane) was added, and the mixture was stirred for another 2 h. The reaction solution was diluted with DCM (20 mL), evaporated to dryness under reduced pressure, redissolved in DCM (20 mL) and an excess of triethylamine was added to dissolve and alkalize, and then evaporated to dryness under reduced pressure. The obtained crude product was fully dissolved in ethyl acetate (30 mL), filtered, and the filtrate was evaporated to dryness under reduced pressure and then dried with an oil pump to give a colorless oily liquid 25d (170 mg, 676.70 μmol, 99.48% yield) MS m / z (ESI): 252.1 [M + 23] + 。

[0278] Step 3: Compound 25d (170 mg, 676.70 μmol) was dissolved in MeOH (1.5 mL), CuSO4 (10.80 mg, 67.67 μmol) and K2CO3 (141 mg, 1.02 mmol) were added, at 23 °C, then compound 25e (170 mg, 811.01 μmol, HCl) was added, and the reaction was stirred for 2 h. The reaction solution was rotary evaporated under reduced pressure. Ethyl acetate (30 mL) was added to the crude product, and the target product was ultrasonically dissolved into the solution, filtered through a layer of diatomaceous earth and rotary evaporated under reduced pressure. Then DCM (60 mL) was added to the crude product, silica gel powder was added, and it was rotary evaporated under reduced pressure. It was separated and purified by a Combi Flash silica gel column (4 g, 0 - 9% ethyl acetate / petroleum ether) to obtain colorless oily liquid 25f (121 mg, 436.48 μmol, 64.50% yield) MS m / z (ESI): 250.1 [M - 28] + 。

[0279] Step 4: Compound 25f (121 mg, 452.54 μmol) and compound 24e (121 mg, 436.48 μmol) were dissolved in THF (0.6 mL) and H2O (0.6 mL), stirred at 20 °C, then CuSO4 (13.93 mg, 87.30 μmol) and sodium ascorbate (8.65 mg, 43.65 μmol) were added. After the addition was complete, the reaction was stirred for 1.5 h. The reaction solution was rotary evaporated under reduced pressure and dried under an oil pump. The obtained crude product was separated and purified by a Combi Flash silica gel column (4 g, 0 - 26% ethyl acetate / petroleum ether) to obtain colorless oily liquid 25g (205 mg, 406.35 μmol, 93.10% yield) MS m / z (ESI): 449.2 [M - 56 + 1] + 。

[0280] Step 5: Compound 25g (205 mg, 406.35 μmol) was dissolved in 1,4 - dioxane (0.5 mL), stirred at 20 °C, HCl (148.15 mg, 4.06 mmol) (4M in 1,4 - dioxane) was added, and the reaction was stirred for 30 min. The reaction solution was diluted with DCM (20 mL) and rotary evaporated under reduced pressure. It was purified by preparative liquid chromatography (Waters - SunFire C18, 0.5% NH4HCO3 water / acetonitrile, 31% - 88% acetonitrile, 30 mL / min) and lyophilized to obtain white viscous solid Z25 (84.12 mg, 208.02 μmol, 51.19% yield, 100.00% purity) MS m / z (ESI): 405.2 [M + 1] + ; 11H NMR (400 MHz, DMSO-d6): δ 8.10 (d, J = 25.2 Hz, 1H), 7.64–7.55 (m, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.26 (td, J = 8.1, 4.6 Hz, 1H), 6.10 (s, 1H), 4.64–4.44 (m, 1H), 4.42 (d, J = 1.8 Hz, 2H), 3.00–2.73 (m, 3H), 2.54–2.48 (m, 1H), 2.43 (d, J = 13.1 Hz, 1H), 1.90–1.77 (m, 1H), 1.70 (s, 6H), 1.66–1.52 (m, 1H).

[0281] Example 26: Preparation of Compound Z26

[0282]

[0283] Step 1: Compound 25a (502 mg, 2.00 mmol) and Compound 26a (483 mg, 2.00 mmol) were dissolved in DMF (5.0 mL), K2CO3 (832 mg, 6.02 mmol) was added, and the mixture was heated and stirred at 80 °C by microwave for 3.5 h. The reaction solution was dried under reduced pressure with an oil pump. The obtained crude product was separated and purified by a Combi Flash silica gel column (4 g, 0–11% ethyl acetate / petroleum ether) to obtain a colorless oily liquid 26b (310 mg, 563.99 μmol, 28.23% yield, 75% purity) MS m / z (ESI): 312.0 [M+1-100] + .

[0284] Step 2: Compound 26b (310 mg, 751.99 μmol) and 2,4,6-trimethyl-1,3,5,2,4,6-hexamethoxytriborane (188.80 mg, 1.50 mmol) were dissolved in H2O (0.5 mL) and 1,4-dioxane (4.0 mL), stirred at room temperature, K2CO3 (311.79 mg, 2.26 mmol) was added, N2 was introduced, and then Pd(dppf)Cl2 (55.02 mg, 75.20 μmol) was added. The mixture was heated and stirred at 95 °C by microwave for 1 h. The reaction solution was rotary evaporated under reduced pressure. The obtained crude product was separated and purified by a Combi Flash silica gel column (4 g, 0–10% ethyl acetate / petroleum ether) to obtain a colorless oily liquid 26c (229 mg, 369.17 μmol, 49.09% yield, 56% purity) MS m / z (ESI): 248.1 [M+1-100] + .

[0285] Step 3: Compound 26c (283 mg, 456.23 μmol) was dissolved in 1,4-dioxane (0.5 mL), stirred at 20 °C, and HCl (166.34 mg, 4.56 mmol) (4 M in 1,4-dioxane) was added. Stirring was continued for another 2 h. The reaction mixture was diluted with DCM (20 mL), concentrated under reduced pressure, redissolved in DCM (20 mL) and an excess of triethylamine to dissolve and basify, and then concentrated under reduced pressure again. The resulting crude product was fully dissolved in ethyl acetate (30 mL), filtered, and the filtrate was concentrated under reduced pressure and dried with an oil pump to obtain a colorless oily liquid 26d (211 mg, 452.28 μmol, 99.14% yield, 53% purity) MS m / z (ESI): 248.1 [M+1] + .

[0286] Step 4: Compound 26d (211 mg, 452.28 μmol) was dissolved in MeOH (1.5 mL), CuSO4 (7.22 mg, 45.23 μmol) and K2CO3 (94.24 mg, 681.86 μmol) were added, at 23 °C, and then compound 25e (114 mg, 543.86 μmol, HCl) was added. Stirring was continued for 2 h. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the crude product, and the target product was ultrasonically dissolved into the solution, filtered through a diatomaceous earth layer and concentrated under reduced pressure. Then DCM (60 mL) was added to the crude product, silica gel powder was added for sample mixing, and concentrated under reduced pressure. It was separated and purified by a Combi Flash silica gel column (4 g, 0 - 12% ethyl acetate / petroleum ether) to obtain a colorless oily liquid 26e (82 mg, 300.09 μmol, 66.35% yield) MS m / z (ESI): 246.1 [M-28] + .

[0287] Step 5: Compound 24e (84 mg, 314.16 μmol) and 26e (82 mg, 300.09 μmol) were dissolved in THF (0.5 mL) and H2O (0.5 mL), stirred at 20 °C, and then CuSO4 (9.58 mg, 60.02 μmol) and sodium ascorbate (5.94 mg, 30.01 μmol) were added. After the addition was complete, stirring was continued for 1.5 h. The reaction mixture was concentrated under reduced pressure and dried with an oil pump. The resulting crude product was separated and purified by a Combi Flash silica gel column (4 g, 0 - 35% ethyl acetate / petroleum ether) to obtain a colorless oily liquid 26f (141 mg, 281.70 μmol, 93.87% yield) MS m / z (ESI): 445.2 [M+1-56] + .

[0288] Step 6: Compound 26f (141 mg, 281.70 μmol) was dissolved in 1,4-dioxane (0.5 mL), stirred at 20 °C, and HCl (102.71 mg, 2.82 mmol) (4 M in 1,4-dioxane) was added. Stirring was continued for 30 min. The reaction mixture was diluted with DCM (20 mL) and concentrated in vacuo. The crude product was purified by preparative liquid chromatography (Waters-SunFire C18, 0.05% NH4HCO3 in water / acetonitrile, 5% - 85% acetonitrile, 30 mL / min) and lyophilized to give a white viscous solid Z26 (64.37 mg, 160.76 μmol, 57.07% yield, 100.00% purity). MS m / z (ESI): 401.2 [M + 1] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 7.98 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.13 (s, 1H), 4.63–4.38 (m, 1H), 4.33 (s, 2H), 3.22–3.06 (m, 2H), 2.85 (dd, J = 22.0, 11.7 Hz, 2H), 2.43 (d, J = 13.0 Hz, 1H), 2.36 (q, J = 3.8 Hz, 3H), 1.83 (dtd, J = 12.2, 4.9, 2.6 Hz, 1H), 1.69 (s, 6H), 1.65–1.51 (m, 1H).

[0289] Example 27: Preparation of Compound Z27

[0290]

[0291] Step 1: Compound 27a (350 mg, 1.66 mmol) was dissolved in DCM (1.5 mL), stirred under N2 at room temperature, and a solution of N-ethyl-N-(trifluorothio)ethylamine (534.61 mg, 3.32 mmol) in DCM (0.3 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was poured into a separatory funnel, washed with saturated aqueous NaHCO3 (60 mL), extracted with DCM (2 × 30 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by Combi Flash silica gel column (4 g, 0 - 2% ethyl acetate / petroleum ether) gave a colorless oily liquid 27b (167 mg, 716.58 μmol, 43.21% yield).

[0292] Step 2: Compound 27b (179 mg, 768.07 μmol) and bis(pinacolato)diboron (273.06 mg, 1.08 mmol) were dissolved in 1,4-dioxane (3.00 mL). 1,1'-Bis(diphenylphosphino)ferrocene palladium(II) dichloride Pd(dppf)Cl2 (56.20 mg, 76.81 μmol) and KOAc (226.13 mg, 2.30 mmol) were added. Under N2 atmosphere, the mixture was placed in an 85 °C oil bath and heated with stirring for 6 h. The obtained borate intermediate was purified by dissolving it in THF (0.5 mL) and stirring at room temperature. Then N-butylimidazole hydrochloride (13.42 mg, 76.81 μmol) and hydrogen peroxide (60.95 mg, 537.65 μmol, 30% purity) were added, and the reaction was carried out with an open mouth for 10 min. After the reaction stopped, DCM (30 mL) and silica gel powder were added to mix the sample, and the solvent was removed under reduced pressure by rotary evaporation. The product was purified by Combi Flash silica gel column (4 g, 0 - 7% ethyl acetate / Pet. ether) to obtain white solid 27c (74 mg, 434.90 μmol, 56.62% yield). MS m / z (ESI): 171.0 [M+1] + 。

[0293] Step 3: Compound 27c (111.00 mg, 441.70 μmol) and compound 25a (74 mg, 434.90 μmol) were dissolved in DMF (1.4 mL). K2CO3 (180.63 mg, 1.31 mmol) was added. The mixture was heated at 85 °C under microwave irradiation and stirred for 4.0 h. The reaction solution was concentrated under reduced pressure and then dried under high vacuum by an oil pump. The obtained crude product was separated and purified by Combi Flash silica gel column (4 g, 0 - 8% ethyl acetate / petroleum ether) to obtain colorless solid 27d (54 mg, 158.18 μmol, 36.47% yield). MS m / z (ESI): 242.1 [M+1 - 100] + 。

[0294] Step 4: Compound 27d (88 mg, 257.77 μmol) was dissolved in dioxane (1 mL). HCl (93.98 mg, 2.58 mmol) was added, and the mixture was stirred at 20 °C for 2 h. DCM (20 mL) was added to dilute the reaction solution, and the solvent was removed under reduced pressure by rotary evaporation. Then DCM (20 mL) and excessive triethylamine were added to dissolve and alkalize the product, and the solvent was removed under reduced pressure again. The obtained crude product was fully dissolved in ethyl acetate (30 mL), filtered, and the filtrate was concentrated under reduced pressure and dried under high vacuum by an oil pump to obtain colorless oily liquid 27e (61 mg, 252.82 μmol, 98.08% yield). MS m / z (ESI): 242.1 [M+1] + 。

[0295] Step 5: Compound 27e (61 mg, 252.82 μmol) was dissolved in MeOH (1.5 mL), CuSO4 (4.04 mg, 25.28 μmol) and K2CO3 (52.41 mg, 379.23 μmol) were added. At 20 °C, 25e (63.51 mg, 303.00 μmol, HCl) was added, and the mixture was stirred for 2 h. The reaction solution was rotary evaporated under reduced pressure. Ethyl acetate (30 mL) was added to the crude product, and the target product was fully dissolved in the solution by ultrasonic treatment. It was filtered through a layer of diatomaceous earth and rotary evaporated under reduced pressure. Then, DCM (60 mL) was added to the crude product, silica gel powder was added, and it was rotary evaporated under reduced pressure. It was separated and purified by a Combi Flash silica gel column (4 g, 0–6% ethyl acetate / petroleum ether) to obtain colorless oily liquid 27f (48 mg, 179.59 μmol, 71.03% yield) MS m / z (ESI): 240.0 [M - 28] + 。

[0296] Step 6: Compound 24e (52 mg, 183.04 μmol) and compound 27f (48 mg, 179.59 μmol) were dissolved in THF (0.5 mL) and H2O (0.5 mL), stirred at 20 °C, and then CuSO4 (5.73 mg, 35.92 μmol) and sodium ascorbate (3.56 mg, 17.96 μmol) were added. After the addition was complete, the mixture was stirred for 1.5 h. The reaction solution was rotary evaporated under reduced pressure and dried under a vacuum pump. The obtained crude product was separated and purified by a Combi Flash silica gel column (4 g, 0–3% MeOH / DCM) to obtain colorless oily liquid 27g (77 mg, 155.70 μmol, 86.70% yield) MS m / z (ESI): 439.0 [M + 1 - 56] + 。

[0297] Step 7: Compound 27g (77 mg, 155.70 μmol) was dissolved in 1,4 - dioxane (0.5 mL), stirred at 20 °C, and HCl (56.77 mg, 1.56 mmol) (4 M in 1,4 - dioxane) was added. The mixture was stirred for 30 min. The reaction solution was diluted with DCM (20 mL) and rotary evaporated under reduced pressure. The obtained crude product was purified by preparative liquid chromatography (Waters - SunFire C18, 0.5% NH4HCO3 aqueous solution / acetonitrile, 5% acetonitrile - 90% acetonitrile, 30 mL / min) and then freeze - dried to obtain white viscous solid Z27 (42.12 mg, 106.79 μmol, 68.59% yield, 100.00% purity) MS m / z (ESI): 395.2 [M + 1] + ; 11H NMR (DMSO-d6, 400 MHz): δ 8.14 (br, 1H), 7.17 (t, J = 7.9 Hz, 1H), 6.87–6.78 (m, 2H), 6.12 (s, 1H), 4.64–4.43 (m, 1H), 4.21 (d, J = 3.2 Hz, 2H), 4.05–3.89 (m, 2H), 3.38 (t, J = 14.9 Hz, 2H), 3.28 - 3.17 (m, 1H), 3.11 (d, J = 14.7 Hz, 2H), 3.05 - 2.68 (m, 2H), 1.89 - 1.77 (m, 1H), 1.71 (s, 6H), 1.67–1.53 (m, 1H).

[0298] Example 28: Preparation of Compound Z28

[0299]

[0300] Step 1: Compound 28a (2.94 g, 20.00 mmol) and methyl 2-bromo-2-methylpropionate (3.81 g, 21.07 mmol) were dissolved in DMF (28 mL), and then Cs2CO3 (9.78 g, 30.01 mmol) was added. The mixture was placed in an oil bath at 90 °C and stirred under heating for 4 h. The reaction solution was concentrated under reduced pressure and dried with an oil pump. Silica gel powder was added for sample mixing. Purification by Combi Flash silica gel column (40 g, 0 - 25% ethyl acetate / petroleum ether) gave a colorless oily liquid 28b (3.39 g, 13.72 mmol, 68.59% yield). MS m / z (ESI): 249.0 [M+1] + .

[0301] Step 2: Compound 28b (1.68 g, 6.80 mmol) and compound 28c (2.21 g, 7.14 mmol) were dissolved in 1,4-dioxane (22 mL). A solution of Na2CO3 (2.16 g, 20.40 mmol) in H2O (3.0 mL) was added, and N2 was bubbled in. Then Pd(dppf)Cl2 (498 mg, 680.60 μmol) was added. The mixture was placed in an oil bath at 95 °C and stirred under heating for 16 h. The reaction solution was filtered, washed with DCM (80 mL) and MeOH (10 mL), and concentrated under reduced pressure. Purification by Combi Flash silica gel column (40 g, 0 - 35% ethyl acetate / petroleum ether) gave a yellow oily liquid 28d (1.27 g, 3.64 mmol, 53.54% yield). MS m / z (ESI): 350.2 [M+1] + .

[0302] Step 3: Compound 28d (1.54 g, 4.41 mmol) was dissolved in THF (15.0 mL), under N2, placed in an ice - water bath at 0 °C and stirred. BH3 - THF (121.90 mg, 8.81 mmol) was slowly added, and the reaction was stirred at 20 °C for 3 h. The reaction solution was quenched with methanol, rotary evaporated under reduced pressure, and mixed with silica gel powder. It was purified by Combi Flash silica gel column (12 g, 0 - 95% ethyl acetate / petroleum ether) to obtain yellow oily liquid 28e (185 mg, 503.49 μmol, 11.42% yield) MS m / z (ESI): 368.1 [M + 1] + 。

[0303] Step 4: Compound 28e (185 mg, 503.49 μmol) was dissolved in DCM (2.0 mL), DAST (121.74 mg, 755.23 μmol) was added, and the reaction was stirred at room temperature (20 °C) for 1 h. The reaction solution was poured into a separatory funnel, water (60 mL) was added, and it was extracted with ethyl acetate (25 * 2 mL). The organic phases were combined and washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was dried by an oil pump to obtain yellow oily liquid 28f (330 mg, 89.33 μmol, 17.74% yield, 10% purity) MS m / z (ESI): 370.2 [M + 1] + 。

[0304] Step 5: Compound 28f (330 mg, 89.33 μmol) was dissolved in THF (2 mL), under N2, stirred at 20 °C, and LiAlH4 (20.34 mg, 535.96 μmol) (2.5 M) was added dropwise. After the addition was complete, the reaction was continued to stir for 1 h. 0.1 mL of water was added dropwise to the continuously stirred reaction solution to quench the reaction, then 0.1 mL of 15% a.q. NaOH was added dropwise. After 10 min, 0.25 mL of water was added, and sodium sulfate solid was added for drying. The treated reaction solution was filtered, washed with ethyl acetate (30 mL), and the filtrates were combined. The obtained filtrate was rotary evaporated under reduced pressure and separated and purified by prep - TLC (PE / EA = 55 / 45) to obtain colorless oily liquid 28g (19 mg, 55.65 μmol, 62.30% yield) MS m / z (ESI): 342.2 [M + 1] + 。

[0305] Step 6: 28 g (19 mg, 55.65 μmol) of the compound was dissolved in DMF (1.2 mL), stirred under N2 at room temperature, NaH (6.71 mg, 175.02 μmol, 60% purity) was added, and the mixture was stirred for 30 min. Then a solution of 2-chloro-3-(trifluoromethyl)pyridine (13.78 mg, 83.47 μmol) in DMF (0.2 mL) was added dropwise. After the addition was complete, the reaction was stirred for 1.0 h. Methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The crude product was separated and purified by prep-TLC (PE / EA = 82 / 18) to obtain a pale yellow solid 28h (25 mg, 15.93 μmol, 28.63% yield, 31% purity). MS m / z (ESI): 487.1 [M+1] + .

[0306] Step 7: 28h (31 mg, 19.75 μmol) of the compound was dissolved in 1,4-dioxane (0.5 mL), stirred at 20 °C, HCl (7.20 mg, 197.53 μmol) was added, and the mixture was stirred for 30 min. The reaction solution was diluted with DCM (20 mL) and concentrated under reduced pressure. The crude product was purified by preparative liquid chromatography (Waters-SunFire C18, 0.5% NH4HCO3 in water / acetonitrile, 5% - 85% acetonitrile, 30 mL / min), and then lyophilized to obtain a colorless viscous solid Z28 (1.76 mg, 4.26 μmol, 21.54% yield, 93.42% purity). MS m / z (ESI): 387.2 [M+1] + .

[0307] Test Example 1: Test for the agonist activity of human somatostatin type IV receptor SSTR4

[0308] In this study, a HEK293 cell line stably expressing the SSTR4 receptor was used and incubated with test compounds at different concentrations. After induction with Forskolin (Selleck - S2449), the agonist activity of the compounds on the SSTR4 receptor was determined using an HTRF cAMP kit (Perkin Elmer - TRF0263). The HEK293 cell line stably expressing SSTR4 was cultured in DMEM medium (Corning - 10 - 013 - CVR) containing 10% fetal bovine serum (AusGeneX - FBS500 - S) and 0.1 mg / mL Hygromycin B (Solarbio - H8080 - 1g) at a culture temperature of 37 °C and a carbon dioxide concentration of 5%. The specific experimental steps are as follows:

[0309] 1. Prepare 1×Stimulation Buffer according to the kit instructions for later use;

[0310] 2. Gradiently dilute the compound to 10 concentrations, and then dilute it to 10× with 1× Stimulation Buffer.

[0311] 3. Culture SSTR4-HEK293 cells until 80% confluent, collect the cells after trypsin digestion, and inoculate 5 μL / well into a 384-well plate after counting, with 2000 cells per well.

[0312] 4. Take 1 μL of the diluted 10× compound and add it to the corresponding experimental wells. Prepare Forskolin with 1× Stimulation Buffer, and then take 4 μL / well and add it to the corresponding experimental wells for incubation for 30 min to induce cAMP production.

[0313] 5. Dilute Eu-cAMP to the working concentration with Detection buffer, and take 5 μL / well and add it to the corresponding experimental wells.

[0314] 6. Dilute ULight TM -anti-cAMP antibody to the working concentration with Detection buffer, take 5 μL / well and add it to the corresponding experimental wells, and incubate at room temperature for 1 h after centrifugation.

[0315] 7. After incubation, use an enzyme-linked immunosorbent assay (ELISA) reader to detect the readings at 665 nm and 620 nm under excitation at a wavelength of 330 nm. Plot Ratio (665 / 620) against the compound concentration, and use the nonlinear regression method of GraphPad Prism 8 software for curve fitting and EC50 calculation.

[0316] Table 1. Results of the determination of the agonist activity of human somatostatin type IV receptor SSTR4

[0317] Example EC50 (nM) Example EC50 (nM) 2 746 17 84 5 9 18 18 6 31 19 1.7 8 453 21 215 9 615 22 28 10 102 23 761 11 50 24 159 12 88 25 100 13 11 26 95 14 19 27 228 15 233 28 366 16 0.8

[0318] All documents mentioned in the present invention are incorporated herein by reference as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, said compound having the structure represented by formula (I), formula (II) or formula (III): In formula (I), Ring B is a benzene ring, a 5- or 6-membered heteroaryl ring, a benzocycloalkyl ring; R a and R b each independently represents hydrogen, halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), and R a and R b are not simultaneously hydrogen; wherein the C 1-10 alkoxy and C 1-10 alkyl are unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl; (R c ) m is hydrogen on the ring atoms of ring B substituted by m R c groups, where m is 0, 1, 2 or 3, and each R c is the same or different and is independently selected from the group consisting of halogen, halo-C 1-10 alkoxy (preferably halo-C 1-6 alkoxy, more preferably halo-C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl); wherein said C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl; Ring C is a 5- or 6-membered heteroaryl ring; (R d ) n wherein the hydrogen on the ring atom of ring C is substituted by n Rs d , n is 0, 1, 2 or 3, and each R d is the same or different and is independently halogen or C 1-10 alkyl; (R e ) p is hydrogen on the nitrogen-containing saturated heterocyclic ring atom substituted by p R e groups, p is 0, 1, 2 or 3, and each R e is the same or different and is independently hydrogen, halogen or C 1-10 alkyl; or two R e groups attached to the same carbon atom are attached to form a C 3-8 cycloalkyl ring; or two R e groups attached to different carbon atoms are attached to together with the saturated heterocycle to form a 7- to 10-membered bridged heterocycle; r is 1, 2 or 3; R f is hydrogen or C 1-10 alkyl; wherein said C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of: halogen, -C(O)-5-membered or 6-membered heteroaryl, -C(O)-phenyl; wherein said 5-membered or 6-membered heteroaryl, phenyl is optionally substituted by 1, 2, 3 or 4 halogens; In formula (II), Ring A is a benzene ring or a 5- or 6-membered heteroaryl ring; (R0) t Hydrogen on the ring atoms of ring A is replaced by t R0 groups, where t is 0, 1, 2 or 3, each R0 being the same or different and independently being halogen, halo-C 1-10 alkoxy (preferably halo-C 1-6 alkoxy, more preferably halo-C 1-3 alkoxy) or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl); wherein said C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl; R1 and R2 are each independently hydrogen, halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); wherein the C 1-10 alkoxy, C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl; R3 and R4 are each independently hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); R5 is hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); wherein said C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of: halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl; (R6) s The hydrogen on the ring carbon atom of piperidine is substituted by s R6 groups, where s is 0, 1, 2 or 3, and each R6 is the same or different and independently is halogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), where the C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl; In formula (III), Ring D is a 5- or 6-membered heteroaryl ring; R6 and R7 are each independently hydrogen, halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); wherein said C 1-10 alkoxy, C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl; L is a key or -(CH2) u -O-; u is 1, 2 or 3; Ring E is a benzene ring or a 5- to 10-membered heteroaryl ring; (R8) q The hydrogen on the ring atom of ring E is substituted by q R8 groups, where q is 0, 1, 2 or 3, each R8 being the same or different and independently being C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or halogen; wherein the C 1-10 alkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, NH2, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring B is a benzene ring, a pyridine ring or a 2,3-dihydro-1H-indenyl ring.

3. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Structure Selected from: Wherein the wavy line represents the connection point to the O atom.

4. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Structure Selected from: Wherein the wavy line represents the connection point to the O atom.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring C is 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole or 1,3,4-triazole or pyrazole.

6. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring C is a structure where the wavy line represents the connection point of the carbon atom jointly connected to R a , R b ; and the asterisk represents the connection point to the saturated nitrogen-containing monocyclic heterocycle.

7. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring A is a benzene ring or a pyridine ring.

8. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring A is selected from the structures: where the wavy line represents the point of attachment to the cross double bond.

9. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring A is selected from: Wherein the wavy line indicates the connection point with the cross double bond.

10. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring D is selected from thiophene, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.

11. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring D is the structure where the wavy line represents the point of attachment to the (1R,5S)-3-azabicyclo[3.1.0]hexane ring, and the asterisk represents the point of attachment to the carbon atom jointly attached to R6 and R7.

12. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Ring E is a benzene ring, a pyridine ring or an indazole ring.

13. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Structure Selected from: Where the wavy line indicates the connection point to L.

14. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Structure Selected from: Where the wavy line indicates the connection point to L.

15. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, R f is hydrogen, C 1-6 alkyl or -C 1-2 alkylene-C(O)-phenyl; said phenyl is optionally substituted by halogen.

16. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, R e Same or different, each independently is halogen or C 1-6 alkyl; or two Rs attached to the same carbon atom e are attached to form a C 3-6 cycloalkyl ring (preferably a cyclopropyl ring).

17. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, When two Rs attached to different carbon atoms e are connected to form a 7- to 10-membered bridged heterocycle together with a saturated heterocycle, the structure is as follows: Wherein g is 1, 2, 3 or 4.

18. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, Structure is a structure where each R e is the same or different and is independently hydrogen, a halogen (more preferably fluorine or chlorine), or a C 1-6 alkyl group (more preferably a C 1-3 alkyl group); or two Rs attached to the same carbon atom e are attached to form a C 3-6 cycloalkyl ring (more preferably a cyclopropyl ring, a cyclobutyl ring).

19. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, The compound of formula (I) is a specific compound selected from the following group:

20. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, The compound of formula (II) is a specific compound selected from the following group:

21. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that, The compound of formula (III) is a specific compound selected from the following group:

22. A pharmaceutical composition, said pharmaceutical composition comprising the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

23. Use of the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating a disease or disorder associated with SSTR4.

24. The use according to claim 23, characterized in that, The diseases or disorders associated with SSTR4 are selected from Alzheimer's disease, depression, anxiety, schizophrenia, bipolar disorder, autism, epilepsy, pain and attention deficit hyperactivity disorder.

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