Fused ring amine compounds, methods of making and uses thereof

Abstract

The application provides a fused ring amine compound, a preparation method and application thereof. Specifically provided is a compound shown in formula I or a pharmaceutically acceptable salt thereof, which has one or more of the following effects: good dopamine D2 receptor activity and serotonin 5-HT 1A receptor activity, good antipsychotic effect, good absorption and blood-brain barrier passing ability, low side effect, high safety, and good effect of improving cognitive dysfunction.

Description

[0001] This application claims priority to Chinese patent application 2025102340608, filed February 27, 2025; Chinese patent application 2025116127640, filed November 5, 2025; and Chinese patent application 2026102150650, filed February 13, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to fused-ring amine compounds, their preparation methods, and uses. Background Technology

[0003] Schizophrenia affects more than 20 million people worldwide. It is a serious mental illness with a complex pathogenesis, which mainly affects young adults. It impacts patients' thoughts, feelings and behaviors, and brings huge impact and burden to patients, their families and society.

[0004] Schizophrenia is a syndrome comprised of a group of clinical symptoms, the main symptoms of which can be divided into three categories: positive symptoms (mania, hallucinations, delusions, etc.), negative symptoms (emotional blunting, reduced social activity), and cognitive impairment (impaired cognitive and memory functions). In the central nervous system, abnormalities in various monoamine neurotransmitters (such as dopamine, serotonin / 5-hydroxytryptamine) and related signaling pathways are considered to be the cause of the clinical symptoms associated with schizophrenia.

[0005] Since the 1950s, three generations of antipsychotic drugs have been marketed for the treatment of schizophrenia. The first generation of drugs, characterized by dopamine D2 receptor antagonists such as chlorpromazine and haloperidol, are also known as typical antipsychotics. They work by potently blocking dopamine D2 receptors and are effective against the positive symptoms of schizophrenia (such as mania, hallucinations, and delusions), but can cause severe extrapyramidal reactions and other side effects. The second generation uses D2 receptors and serotonin 5-HT... 2A Characterized by dual antagonists of the receptor, such as clozapine, olanzapine, and risperidone. Due to inhibition of 5-HT... 2ADopamine receptors can indirectly promote the release of dopamine from dopamine neurons, thus reducing the extrapyramidal side effects induced by second-generation drugs. However, they can cause serious side effects such as elevated prolactin levels and granulocytopenia. Simultaneously, second-generation drugs can cause metabolic-related side effects such as weight gain and elevated blood sugar. Third-generation drugs mainly include aripiprazole, brexpiprazole, and cariprazine. Third-generation antipsychotic drugs possess the pharmacological characteristics of D2 receptor partial agonists and are also known as dopamine modulators. These drugs have high affinity for dopamine D2 receptors and moderate intrinsic agonistic activity (partial agonism), avoiding excessive D2 receptor blockade. This results in reliable antipsychotic effects while reducing extrapyramidal reactions (EPS) and elevated prolactin levels.

[0006] ; However, current third-generation antipsychotic drugs still have several significant drawbacks in treating schizophrenia: (1) they have a low rate of controlling negative symptoms in schizophrenia patients; (2) they do not significantly improve schizophrenia-related cognitive impairment; and (3) they have many side effects. Therefore, there is an urgent need to develop drugs with novel structures and pharmacological properties.

[0007] Serotonin 5-HT 1A 5-HT receptors are expressed in the cerebral cortex and hippocampus, areas closely related to mood, negative symptoms, and cognitive impairment. 5-HT receptors are effective against negative symptoms and cognitive impairment in patients with mental disorders. 1A Receptor agonists have shown considerable potential. For example, tandospirone is a 5-HT receptor agonist. 1A Tandospirone, a receptor agonist, is commonly used clinically to treat anxiety. Clinical studies have shown that in patients with schizophrenia, the combined use of tandospirone with antipsychotic medication significantly improves executive function and verbal memory, and can also improve executive function in patients with schizophrenia.

[0008] Although third-generation drugs such as aripiprazole and cariprazine are effective against 5-HT 1A These receptors have a certain degree of partial agonist effect, which can be effective for the negative symptoms of schizophrenia and can improve cognitive function to some extent. However, these drugs have some effect on 5-HT. 1A The receptor affinity is weak, and the intrinsic agonistic activity is not high. Therefore, while maintaining the partial agonistic effect of third-generation drugs on dopamine D2 receptors, further increasing 5-HT... 1A The receptor is activated, acquiring D2 receptors and 5-HT. 1AMulti-target compounds targeting receptors can help improve negative symptoms and cognitive impairment while simultaneously improving positive symptoms, leading to more effective antipsychotic drugs. Furthermore, research has shown that activating D3 receptors can effectively improve cognitive function by regulating dopamine levels in key brain regions; and inhibiting serotonin 5-HT... 2A Receptors help reduce side effects such as extrapyramidal symptoms. Summary of the Invention

[0009] This invention provides a compound of formula I or a pharmaceutically acceptable salt thereof;

[0010] in, Ring B is , , or ; X1 is either N or CH; X2 is either N or CH; X3 is CH2, O, NH, S or C=O, X4 is a single bond, CH2, -CH2CH2- or C=O, and X3 and X4 are not both C=O at the same time; X5 is either N or CH; X6 is N, N=CH, NH, CH or CH2; X7 is N, C, or CH; And when X6 is NH, X5 is N; R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or one or more R 1-1 Replacement C 1-6 Alkyl or with one or more R 1-2 Replacement C 1-6 Alkyl groups; R 1-1 and R 1-2 Independently, it can be deuterium, halogen, or hydroxyl; k can be 0, 1, 2, 3, 4, 5, or 6; m can be 0, 1, 2, 3, or 4; L1 is a single bond, O, or S; Ring A is C 3-6 Cycloalkylene, R 3 for ; Alternatively, ring A is R 3 For H; It can be a single bond or a double bond independently; X8 can be CH2, O, NH or S; X9 is CH2 or C=O; R 3-1 R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Independently, it can be deuterium, halogen, or hydroxyl; Or, R 3-2 R 3-3 The N atom bonded to it forms a 3-7 membered monocyclic heterocycle, the 3-7 membered monocyclic heterocycle containing one, two, or three heteroatoms selected from one, two, or three of N, O, and S, and containing at least one N atom; the 3-7 membered monocyclic heterocycle is optionally bounded by one, two, or three R atoms. 3a replace; R 3a Independently, it can be deuterium, halogen, or hydroxyl; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n can be 0, 1, 2, or 3.

[0011] In one embodiment, certain groups in the compound represented by Formula I or its pharmaceutically acceptable salt have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment").

[0012] In one of the schemes, R 1 In, the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0013] In one of the schemes, R 1 In, the C 1-6 Alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, such as methoxy.

[0014] In one of the schemes, R 1 In this context, the halogen is independently fluorine, chlorine, or bromine, for example, fluorine or chlorine.

[0015] In one of the schemes, R 1 In, the one or more R 1-1 Replacement C 1-6 The alkyl group is independently represented by 1, 2, or 3 (preferably 3) R. 1-1 Replacement C 1-6 Alkyl groups, such as trifluoromethyl groups.

[0016] In one of the schemes, R 1 In, the one or more R 1-2 Replacement C 1-6 The alkoxy group is independently formed by 1, 2, or 3 R groups. 1-2 Replacement C 1-6 Alkyl group.

[0017] In one of the schemes, R 1-1 and R 1-2 In this context, the halogen is independently fluorine, chlorine, or bromine, for example, fluorine.

[0018] In one scheme, in ring A, the C 3-6 Cycloalkylene groups are monocyclic or bridged rings, such as C16-C ... 3-6 Monocyclic cycloalkyl or C 4-6 Bridged cyclohexane, the C 3-6 The monocyclic cycloalkyl group is preferably cyclobutylene, cyclopentylene, or cyclohexylene, wherein C 4-6 Bridged cyclohexane is preferred .

[0019] In one of the schemes, R 3-1 R 3-2 and R 3-3 In, the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0020] In one of the schemes, R 3-1 R 3-2 and R 3-3 In, the one or more R 3-1-1 Replacement C 1-6 The alkyl group is independently represented by 1, 2, or 3 (preferably 3) R. 3-1-1 Replacement C 1-6 Alkyl groups, such as trideuterated methyl groups.

[0021] In one of the schemes, R 3-1-1 In this context, the halogen is independently fluorine, chlorine, or bromine.

[0022] In one embodiment, the 3-7 member monocyclic heterocycle is a saturated monocyclic heterocycle, preferably a 4-6 member saturated monocyclic heterocycle, and / or the heteroatom is selected from one or two of N, S, or O, the number of heteroatoms can be one or two, and it must contain at least one N, for example... or .

[0023] In one of the schemes, R 3a In this context, the halogen is independently fluorine, chlorine, or bromine, for example, fluorine.

[0024] In one of the schemes, R2 In this context, the halogen is independently fluorine, chlorine, or bromine.

[0025] In one scheme, ring B is Preferred .

[0026] In one scheme, X1 is CH.

[0027] In one scheme, X2 is CH.

[0028] In one scheme, X3 is CH2, O, or NH.

[0029] In one scheme, X3 is CH2, O, NH or S, and X4 is a single bond, CH2, -CH2CH2- or C=O; or, X3 is C=O and X4 is CH2.

[0030] In one scheme, X3 is CH2, O, or NH, and X4 is a single bond, CH2, -CH2CH2-, or C=O; or, X3 is C=O and X4 is CH.

[0031] In one scheme, X3 is CH2.

[0032] In one scheme, X3 is CH2 and X4 is CH2.

[0033] In one scheme, X6 is N=CH, NH, or CH.

[0034] In one scheme, X7 is either N or C.

[0035] In one of the schemes, R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or by one or more R 1-1 Replacement C 1-6 alkyl.

[0036] In one of the schemes, R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 alkoxy or halogen; for example, R 1 Independent of deuterium and C 1-6 Alkyl, C 1-6 Alkyl or halogen, for example R 1 Independently for C 1-3 Alkyl, C 1-3 Alkyl or halogen (preferably, R) 1 (Independently methyl, methoxy, fluorine, or chlorine); for example, R 1 Halogens (e.g., chlorine) can be used independently.

[0037] In one of the schemes, R1-1 and R 1-2 Independently deuterium or halogen, preferably, R 1-1 and R 1-2 Independently halogenated, more preferably, R 1-1 and R 1-2 It is fluorine on its own.

[0038] In a certain scheme, k can be 0, 1, 2, 3 or 4, for example, k can be 2.

[0039] In a certain scheme, m is 1, 2, or 3; for example, m is 1.

[0040] In one scheme, L1 is a single bond or 0, for example, L1 is a single bond.

[0041] In one scheme, ring A is C. 3-6 Cycloalkylene, R 3 for For example, ring A is C. 3-6 Monocyclic cycloalkylene compounds, preferably cyclobutylene or cyclohexylene.

[0042] In one scheme, ring A is R 3 Let H be the ring A; where, for example, ring A is... or .

[0043] In one scheme, ring A is C. 3-6 Cycloalkylene, R 3 for m is 1 or 2, L1 is a single bond, or, ring A is... R 3 H is 3, m is 3, L1 is O or a single bond, preferably, ring A is C. 3-6 Monocyclic cycloalkylene, R 3 for m is 1, and L1 is a single bond.

[0044] In one scheme, X8 is NH.

[0045] In one particular scheme, X9 is C=O.

[0046] In one of the schemes, R 3-1 For H, R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 Alkyl; for example, R 3-1 For H, R 3-2 and R 3-3 Independently for C 1-6 Alkyl or with one or more R3-1-1 Replacement C 1-6 Alkyl, for example, R 3-1 For H, R 3-2 and R 3-3 Independently for H and C 1-3 Alkyl or with one or more R 3-1-1 Replacement C 1-3 Alkyl (preferably, R) 3-1 For H, R 3-2 and R 3-3 (independently H, methyl, or trideuterated methyl), further for example, R 3-1 For H, R 3-2 and R 3-3 Independently for C 1-3 Alkyl or with one or more R 3-1-1 Replacement C 1-3 Alkyl groups, for example, R 3-1 For H, R 3-2 and R 3-3 It is methyl on its own.

[0047] In one of the schemes, R 3-1-1 It is deuterium.

[0048] In one of the schemes, R 3-2 R 3-3 It forms a 3-7 membered monocyclic heterocycle (e.g., a saturated monocyclic heterocycle) with the N atom attached thereto, the 3-7 membered monocyclic heterocycle (e.g., a saturated monocyclic heterocycle) containing one heteroatom N, the 3-7 membered monocyclic heterocycle optionally being bounded by one or two R atoms. 3a Replacement, for example, the 3-7 member monocyclic heterocycle is a 4-6 member monocyclic heterocycle (e.g., a saturated monocyclic heterocycle), the 4-6 member monocyclic heterocycle (e.g., a saturated monocyclic heterocycle) containing one heteroatom N, the 4-6 member monocyclic heterocycle optionally being replaced by one or two R atoms. 3a replace.

[0049] In one embodiment, the 3-7 nucleotide monocyclic heterocycle (e.g., a 3-7 nucleotide saturated monocyclic heterocycle) is optionally divided by one or two R... 3a replace.

[0050] In one embodiment, the 4-6 nucleotide monocyclic heterocycle (e.g., a 4-6 nucleotide saturated monocyclic heterocycle) is optionally divided by one or two R... 3a replace.

[0051] In one of the schemes, R 3a It can be a halogen on its own; for example, fluorine.

[0052] In one particular scheme, n is 0.

[0053] In one of the schemes, R 1 Located on the aromatic ring.

[0054] In one embodiment, the compound represented by Formula I; Ring B is , , or ; X1 is either N or CH; X2 is either N or CH; X3 is CH2, O, or NH, and X4 is a single bond, CH2, -CH2CH2-, or C=O; or, X3 is C=O and X4 is CH2. X5 is either N or CH; X6 represents N=CH, NH, or CH; X7 is either N or C; And when X6 is NH, X5 is N; R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or by one or more R 1-1 Replacement C 1-6 alkyl; R 1-1 Independently halogen or deuterium; k can be 0, 1, 2, 3 or 4; m is 1, 2, or 3; L1 is a single bond or O; Ring A is C 3-6 Cycloalkylene, R 3 for ; Alternatively, ring A is R 3 For H; It can be a single bond or a double bond independently; X8 is NH; X9 is C=O; R 3-1 R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Deuterium is independent of other substances; Or, R 3-2 R 3-3It forms a 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) with the N atom it is attached to, wherein the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) contains one, two, or three heteroatoms selected from one, two, or three of N, O, and S, and contains at least one N atom; the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) is optionally bounded by one or two R atoms. 3a replace; R 3a Halogens are independent of each other; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0055] In one embodiment, the compound represented by Formula I; Ring B is ; X1 is either N or CH; X2 is either N or CH; X3 is CH2, O or NH, and X4 is a single bond, CH2, -CH2CH2- or C=O; Alternatively, X3 is C=O and X4 is CH2; R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or by one or more R 1-1 Replacement C 1-6 alkyl; R 1-1 It can be either deuterium or a halogen independently; k can be 0, 1, 2, 3 or 4; m is 1 or 2; L1 is a single bond; Ring A is C 3-6 Cycloalkylene, R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Deuterium is independent of other substances; Or, R 3-2 R 3-3It forms a 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) with the N atom it is attached to, the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) containing one heteroatom selected from the N atom; the 3-7 membered monocyclic heterocycle is optionally surrounded by one or two R atoms. 3a replace; R 3a Halogens are independent of each other; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0056] In one embodiment, the compound represented by Formula I; Ring B is ; X1 is CH; X2 is CH; X3 is CH2; X4 is CH2; R 1 Independent of deuterium and C 1-6 Alkyl, C 1-6 Alkyl or halogen; k can be 0, 1, 2, 3 or 4; m is 1 or 2; L1 is a single bond; Ring A is C 3-6 Cycloalkylene, R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Deuterium is independent of other substances; Or, R 3-2 R 3-3 It forms a 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) with the N atom attached thereto, wherein the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) contains one heteroatom N; the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) is optionally surrounded by one or two R atoms. 3a replace; R 3a Halogens are independent of each other; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0057] In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof; Ring B is ; X1 is CH; X2 is CH; X3 is CH2; X4 is CH2; R 1 Independently for C 1-3 Alkyl (e.g., methyl), C 1-3 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine or fluorine); k can be 0, 1, 2, 3 or 4; m is 1; L1 is a single bond; Ring A is C 3-6 Cycloalkylene (preferably C14) 3-6 Monocyclic cycloalkylene (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-3 Alkyl groups (e.g., trideuterated methyl groups); Or, R 3-2 R 3-3 It forms a 4-6 membered monocyclic heterocycle (e.g., a 4-6 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) with the N atom attached thereto, wherein the 4-6 membered monocyclic heterocycle (e.g., a 4-6 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) contains one heteroatom N; the 4-6 membered monocyclic heterocycle (e.g., a 4-6 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) is surrounded by one or two R atoms. 3a replace; R 3a It can be a halogen (e.g., fluorine) on its own. R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0058] In one embodiment, the compound represented by Formula I or a pharmaceutically acceptable salt thereof; Ring B is ; X1 is CH; X2 is CH; X3 is CH2; X4 is CH2; R 1 Independently halogenated (e.g., chlorine); k is 2; m is 1; L1 is a single bond; Ring A is C 3-6 Monocyclic cycloalkylene (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0059] In one embodiment, the compound represented by Formula I is the same as the compound represented by Formula II;

[0060] Among them, X1, X2, X3, X4, R 1 ,k,m,L1,ring A,R 3 R 2 And n as described in any embodiment of the present invention.

[0061] In one embodiment, the compound represented by Formula II is the compound represented by Formula II-1;

[0062] in, X3 is CH2 or C=O; R 1 ,k,m,L1,ring A,R 3 R 2 And n as described in any embodiment of the present invention.

[0063] In one embodiment, the compound represented by formula II-1; X3 is CH2 or C=O; R 1 Independent of deuterium and C 1-6 Alkyl, C 1-6 Alkyl or halogen; k can be 0, 1, 2, 3 or 4; m is 1 or 2; L1 is a single bond; Ring A is C 3-6 Cycloalkylene, R3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Deuterium is independent of other substances; Or, R 3-2 R 3-3 It forms a 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) with the N atom attached thereto, wherein the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) contains one heteroatom N; the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) is optionally surrounded by one or two R atoms. 3a replace; R 3a Halogens are independent of each other; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0064] In one embodiment, the compound represented by formula II-1, X3 is CH2; R 1 Independently for C 1-3 Alkyl (e.g., methyl), C 1-3 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine or fluorine); k can be 0, 1, 2, 3 or 4; m is 1; L1 is a single bond; Ring A is C 3-6 Cycloalkylene (preferably C14) 3-6 Monocyclic cycloalkylene (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-3 Alkyl groups (e.g., trideuterated methyl groups); Or, R 3-2 R 3-3It forms a 4-6 membered monocyclic heterocycle (e.g., a 4-6 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) with the N atom attached thereto, wherein the 4-6 membered monocyclic heterocycle (e.g., a 4-6 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) contains one heteroatom N; the 4-6 membered monocyclic heterocycle (e.g., a 4-6 membered saturated monocyclic heterocycle, preferably azirrobutyl or azirropentyl) is surrounded by one or two R atoms. 3a replace; R 3a It can be a halogen (e.g., fluorine) on its own. R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0065] In one embodiment, the compound represented by formula II-1, X3 is CH2; R 1 Independently halogenated (e.g., chlorine); k is 2; m is 1; L1 is a single bond; Ring A is C 3-6 Monocyclic cycloalkylene (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0066] In one embodiment, the compound represented by formula II-1 is the compound represented by formula II-1-1, the compound represented by formula II-1-2, or the compound represented by formula II-1-3;

[0067] Ring P is a 3-7 membered monocyclic heterocycle, which contains one, two, or three heteroatoms selected from one, two, or three of N, O, and S, and contains at least one N atom; preferably, the 3-7 membered monocyclic heterocycle is a saturated monocyclic heterocycle, and / or, the 3-7 membered monocyclic heterocycle contains one heteroatom N (e.g., azirrobutyl or azirropentyl). i and ii are independently 1 or 2; R 3aIndependently, it can be deuterium, halogen, or hydroxyl; iii can be 0, 1, 2, or 3; R 1 k, X3, m, L1, R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention.

[0068] For example, the compound represented by formula II-1-1 is the compound represented by formula II-1-1A;

[0069] X3, R 1 ,k,m,L1,i,ii,R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention.

[0070] In one embodiment, the compound represented by formula II-1-1 (e.g., the compound represented by formula II-1-1A), X3 can be CH2 or C=O independently; i and ii are independently 1 or 2; R 3-1 R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 Alkyl; for example, R 3-1 For H, R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 1 ,k,m,L1,R 3-1-1 R 2 And n as described in any embodiment of the present invention.

[0071] In one embodiment, the compound represented by formula II-1-1 (e.g., the compound represented by II-1-1A); X3 is CH2 or C=O; R 1 Independent of deuterium and C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine, fluorine); k can be 0, 1, 2, 3 or 4; m is 1 or 2; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-6 Alkyl groups (e.g., trideuterated methyl groups); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0072] In one embodiment, the compound represented by formula II-1-1 (e.g., the compound represented by II-1-1A); X3 is CH2; R 1 Independently for C 1-3 Alkyl (e.g., methyl), C 1-3 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine or fluorine); k can be 0, 1, 2, 3 or 4; m is 1; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-3 Alkyl groups (e.g., trideuterated methyl groups); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0073] In one embodiment, the compound represented by formula II-1-1 (e.g., the compound represented by II-1-1A); X3 is CH2; R 1 Independently halogenated (e.g., chlorine); k is 2; m is 1; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3Alkyl (e.g., methyl); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0074] For example, the compound represented by formula II-1-2 is the compound represented by formula II-1-2A;

[0075] X3, R 1 ,k,m,L1,i,ii,R 3-1 , ring P, R 3a iii, R 2 And n as described in any embodiment of the present invention.

[0076] In one embodiment, the compound shown in formula II-1-2 (e.g., the compound shown in II-1-2A), X3 is CH2 independently; Ring P is a 3-7 membered monocyclic heterocycle, which contains one, two, or three heteroatoms selected from one, two, or three of N, O, and S, and contains at least one N atom; preferably, the 3-7 membered monocyclic heterocycle is a saturated monocyclic heterocycle, and / or, the 3-7 membered monocyclic heterocycle contains one heteroatom N (e.g., azirrobutyl or azirropentyl). R 3a Independently deuterium, halogen, or hydroxyl (preferably halogen, such as F); iii is 0, 1, 2 or 3 (preferably 1 or 2); R 1 ,k,m,L1,i,ii,R 3-1 R 2 And n as described in any embodiment of the present invention.

[0077] For example, the compound represented by formula II-1-3 is the compound represented by formula II-1-3A;

[0078] X3, R 1 ,k,m,L1,i,R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention.

[0079] In one embodiment, the compound shown in formula II-1-3 (e.g., the compound shown in II-1-3A), X3 is CH2 independently; R 3-1 R 3-2 and R3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; Preferably, R 3-1 For H, R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl (e.g., methyl) or by one or more R 3-1-1 Replacement C 1-6 Alkyl groups (e.g., deuterated methyl groups, or even trideuterated methyl groups); R 1 ,k,m,L1,i,R 3-1-1 R 2 And n as described in any embodiment of the present invention.

[0080] In one embodiment, the compound represented by formula II-1-1 is either the compound represented by formula II-1-1-a or the compound represented by formula II-1-1-b.

[0081] Among them, X3 and R 1 , k, R 3-1 R 3-2 and R 3-3 As described in any embodiment of the present invention.

[0082] For example, the compound represented by formula II-1-1a is the compound represented by formula II-1-1-aA;

[0083] Among them, X3 and R 1 ,k,R 3-1 R 3-2 and R 3-3 As described in any embodiment of the present invention.

[0084] For example, the compound represented by formula II-1-1b is the compound represented by formula II-1-1-bB;

[0085] Among them, X3 and R 1 ,k,R 3-1 R 3-2 and R 3-3 As described in any embodiment of the present invention.

[0086] In one embodiment, the compound represented by formula II-1-2 is either the compound represented by formula II-1-2-a or the compound represented by formula II-1-2-b.

[0087] Among them, X3 and R 1 ,k,R 3-1 , ring P, R 3a And iii, as described in any embodiment of the present invention.

[0088] For example, the compound represented by formula II-1-2-a is the compound represented by formula II-1-2-aA;

[0089] Among them, X3 and R 1 ,k,R 3-1 , ring P, R 3a And iii, as described in any embodiment of the present invention.

[0090] For example, the compound represented by formula II-1-2-b is the compound represented by formula II-1-2-bB;

[0091] Among them, R 1 k, X3, R 3-1 , ring P, R 3a And iii, as described in any embodiment of the present invention.

[0092] In one of the schemes, for , , , , , , , , , , , , , , , , , , , , , or For example, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or For example, , , , , , , , , or .

[0093] In one of the schemes, for Preferred , , or .

[0094] In one embodiment, the compound represented by Formula II is the compound represented by Formula II-2;

[0095] in, X4 is CH2 or -CH2CH2-; X1, X2, R 1 ,k,m,L1,ring A,R 3 R 2 And n as described in any embodiment of the present invention.

[0096] In one embodiment, the compound represented by formula II-2 is the compound represented by formula II-2-1;

[0097] in, X4 is CH2 or -CH2CH2-; i and ii are independently 1 or 2; X1, X2, R 1 ,k,m,L1,R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention.

[0098] In one embodiment, the compound represented by formula II-2-1, X1 is CH; X2 is CH; X4 is CH2 or -CH2CH2-; R 1 Independently for C 1-6 Alkoxy, hydroxyl, halogen, or by one or more R 1-1 Replacement C 1-6 alkyl; R 1-1 Halogens are independent of each other; k is 0, 1, or 2; m is 1; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-6 Alkyl (e.g., methyl); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0099] In one embodiment, the compound represented by formula II-2-1 is either the compound represented by formula II-2-1-a or the compound represented by formula II-2-1-b;

[0100] in, X4 is CH2 or -CH2CH2-; X1, X2, R 1 ,k,R 3-1 R 3-2 and R 3-3 As described in any embodiment of the present invention.

[0101] In one embodiment, the compound represented by Formula II is the compound represented by Formula II-3;

[0102] X1 is CH, X2 is N; or, X2 is CH, X1 is N; X4 is CH2 or -CH2CH2-; i and ii are independently 1 or 2; R 1 ,k,m,L1,R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention.

[0103] In one embodiment, the compound represented by formula II-3, X1 is CH, X2 is N; or, X2 is CH, X1 is N; X4 is CH2 or -CH2CH2-; R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or by one or more R 1-1 Replacement C 1-6 alkyl; R 1-1 Independently halogen or deuterium; k is 0; m is 1; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-6 Alkyl groups (e.g., methyl groups); R 2Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0104] In one embodiment, the compound represented by formula II-3 is either the compound represented by formula II-3-1 or the compound represented by formula II-3-2;

[0105] X1 is CH, X2 is N; or, X2 is CH, X1 is N; X4 is CH2 or -CH2CH2-; R 1 ,k,R 3-1 R 3-2 and R 3-3 As described in any embodiment of the present invention.

[0106] In one embodiment, the compound represented by Formula II is the compound represented by Formula II-4;

[0107] in, X4 is CH2, -CH2CH2-, or C=O; X1, X2, R 1 ,k,m,L1,ring A,R 3 R 2 And n as described in any embodiment of the present invention.

[0108] In one embodiment, the compound represented by formula II-4 is the compound represented by formula II-4-1;

[0109] in, X4 is CH2, -CH2CH2-, or C=O; i and ii are independently 1 or 2; R 11 For H, C 1-6 Alkyl or with one or more R 11-1 Replacement C 1-6 Alkyl; R 11-1 Independently halogen, hydroxyl, or deuterium; k1 is 0, 1, 2, 3, 4 or 5; R 1 m, L1, R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention.

[0110] In one embodiment, the compound represented by formula II-4-1, X4 is CH2, -CH2CH2-, or C=O; R 1 Halogens (e.g., chlorine) can be used independently. k1 is either 0 or 1; R 11 C 1-6 Alkyl groups (e.g., methyl groups); m is 1; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-6 Alkyl groups (e.g., methyl groups); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0111] In one embodiment, the compound represented by formula II-4-1 is either the compound represented by formula II-4-1-a or the compound represented by formula II-4-1-b.

[0112] in, X4 is CH2, -CH2CH2-, or C=O; R 11 For H or C 1-6 alkyl; k1 is 0, 1, 2, 3, 4 or 5; R 1 R 3-1 R 3-2 and R 3-3 As described in any embodiment of the present invention.

[0113] In one embodiment, the compounds represented by formulas II-4-1-a and II-4-1-b, X4 is CH2, -CH2CH2-, or C=O; R 1 Halogens (e.g., chlorine) can be used independently. k1 is either 0 or 1; R 11 C 1-6 Alkyl groups (e.g., methyl groups); R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-6 Alkyl (e.g., methyl).

[0114] In one embodiment, the compound represented by Formula II is the compound represented by Formula II-5;

[0115] in, R 12 Independently for H and C 1-6 Alkyl or with one or more R 12-1 Replacement C 1-6 alkyl; R 12-1 Independently halogen, hydroxyl, or deuterium; i and ii are independently 1 or 2; k2 is 0, 1, 2, 3 or 4; R 1 m, L1, R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention.

[0116] In one embodiment, the compound represented by formula II-5, R 1 Halogens (e.g., chlorine) can be used independently. k2 is 0; R 12 H is independent; m is 1; L1 is a single bond; i and ii are 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-6 Alkyl groups (e.g., methyl groups); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0117] In one embodiment, the compound represented by formula II-5 is either the compound represented by formula II-5-1 or the compound represented by formula II-5-2;

[0118] R 12 Independent of H, deuterium or C 1-6 Alkyl (R) 12 H is preferred). R 1 k2, R 3-1 R 3-2 and R3-3 As described in any embodiment of the present invention.

[0119] In one embodiment, the compound represented by Formula II is the compound represented by Formula II-6;

[0120] in, It can be a single bond or a double bond independently; X1, X2, X3, X4, R 1 k, m, L1, X8, X9, R 2 And n as described in any embodiment of the present invention.

[0121] In one embodiment, the compound represented by formula II-6, It can be a single bond or a double bond independently; X1 is either N or CH; X2 is CH; X3 is CH2 or NH, and X4 is CH2, -CH2CH2- or C=O; R 1 Independently halogen or C 1-6 Alkyl groups (e.g., methyl groups); k is 0 or 1; m is 3; L1 is a single bond or O; X8 is NH; X9 is C=O; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0122] In one embodiment, the compound represented by Formula I is the same as the compound represented by Formula III;

[0123] Among them, m, L1, ring A, R 3 R 2 And n as described in any embodiment of the present invention.

[0124] In one embodiment, the compound represented by Formula III; m is 1; L1 is a single bond; Ring A is C 3-6 Monocyclic cycloalkylene groups (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R3-3 Independently for C 1-6 Alkyl groups (e.g., methyl groups); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0125] In one embodiment, the compound represented by Formula I is the same as the compound represented by Formula IV.

[0126] in, It can be a single bond or a double bond independently; X5, X6, X7, m, L1, ring A, R 3 R 2 And n as described in any embodiment of the present invention.

[0127] In one embodiment, the compound represented by formula IV; X5 is either N or CH; X6 represents N=CH, NH, or CH; X7 is either N or C; And when X6 is NH, X5 is N; m is 1; L1 is a single bond; Ring A is C 3-6 Monocyclic cycloalkylene groups (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-6 Alkyl groups (e.g., methyl groups); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0128] In one embodiment, the compound represented by formula I is the same as the compound represented by formula V;

[0129] Among them, m, L1, ring A, R 3 R 2 And n as described in any embodiment of the present invention.

[0130] In one embodiment, the compound represented by formula V is the same as the compound represented by formula V-1;

[0131] Where i and ii are independently 1 or 2; R 3-1 R 3-2 and R 3-3 As described in any embodiment of the present invention.

[0132] In one of the schemes, for asterisk ( The label C is used to indicate an S-configuration C atom, an R-configuration C atom, or a mixture thereof (referring to S-configuration and R-configuration).

[0133] In one of the schemes, for asterisk ( When the asterisk (C) is chiral, the asterisk (C) indicates that the chirality of the symbol C is present. The label C is used to indicate an S-configuration C atom, an R-configuration C atom, or a mixture thereof (referring to S-configuration and R-configuration).

[0134] In one of the schemes, In the middle, ring A is C 3-6 Cycloalkylene (e.g., C16) 3-6 Monocyclic cycloalkyl or C 4-6 When bridged cyclohexane (R), 3 With (The connection key between ring A and L1) is replaced by a reverse alignment method, for example, for i and ii are independently 1 or 2; R 3-1 R 3-2 R 3-3 R 2 and n is as described in any embodiment of the present invention, or, is i is 1 or 2; R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention, Preferred or , where R 3-1 R 3-2 R 3 -3 R 2 And n as described in any embodiment of the present invention.

[0135] In one of the schemes, X1 and X2 are CH; X3 is CH2 or C=O (preferably CH2); X4 is CH2; R 1 Independent of deuterium and C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine, fluorine); k can be 0, 1, 2, 3 or 4.

[0136] For example, X1 and X2 are CH; X3 and X4 are CH2; R 1 Independently halogens (e.g., chlorine, fluorine), C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl groups (e.g., methoxy groups); k can be 0, 1, 2, 3 or 4.

[0137] For example, for R 1 For aryl substituents, R 1 Independently for C 1-6 Alkyl, C 1-6 Alkoxy or halogen (e.g., R) 1 (Independently methyl, methoxy, fluorine or chlorine); k is 0, 1, 2, 3 or 4.

[0138] In one of the schemes, m is 1; L1 is a single bond; In ring A, the C 3-6 The cycloalkylene group is a cyclobutylene group (e.g., cycloalkylene). ) or cyclohexylene (e.g., for ) or bicyclic [1.1.1]pentyl (e.g., ) ); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

[0139] In one of the schemes, In the middle, R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-6 Alkyl groups (e.g., trideuterated methyl groups).

[0140] In one of the schemes, R 1 It can be independently deuterium, hydroxyl, methyl, methoxy, fluorine, chlorine or trifluoromethyl.

[0141] In one of the schemes, for , , , , , (For example or ), , , , , (For example or ), , , or Preferred (For example ).

[0142] In one of the schemes, for , , or .

[0143] In one of the schemes, for , , , , , , , , , , , , , , , , , , , , , , , or Preferred , , , , , , , , or For example, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or For example, it is... , , , , , , , , or .

[0144] In one of the schemes, for (For example ), , or Preferred (For example ).

[0145] In one of the schemes, for , , , , , , , , , , , , , , or Preferred , , , , or .

[0146] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0147]

[0148]

[0149] .

[0150] The present invention provides a method for preparing the compound of formula II or a pharmaceutically acceptable salt thereof, comprising the following steps: in an organic solvent (e.g., an alcohol solvent, such as methanol), the compound of formula IIg or a pharmaceutically acceptable salt thereof undergoes a coupling reaction with the compound of formula IIh to obtain the compound of formula II; ; Y is -CHO or -CH2-halogen (e.g. -CH2Br); X1, X2, X3, X4, R 1 ,k,m,L1,ring A,R 3 R 2 And n as described in any embodiment of the present invention.

[0151] Preferably, the coupling reaction further includes a reducing agent, such as sodium cyanoborohydride.

[0152] In one embodiment, the method for preparing the compound of formula II or its pharmaceutically acceptable salt further comprises the following steps: in an organic solvent (e.g., an ether solvent, or dioxane), the compound of formula IIg-1 or its pharmaceutically acceptable salt is subjected to a deprotection reaction to obtain the compound of formula IIg or its pharmaceutically acceptable salt.

[0153] PR stands for amino protecting group, such as -CO-OC. 1-6 Alkyl groups, such as the BOC group; X1, X2, X3, X4, k, and R 1 As described in any embodiment of the present invention.

[0154] This invention provides a compound of formula IIg, IIg-1 or IIh or a pharmaceutically acceptable salt thereof;

[0155] X1, X2, X3, X4, R 1 ,k,m,L1,ring A,R 3 , n and R 2 As described in any embodiment of the present invention.

[0156] Preferably, the compound represented by formula IIh is or .

[0157] Preferably, the compound represented by formula IIg is .

[0158] Preferably, the compound represented by formula IIg-1 is or .

[0159] The present invention provides a method for preparing the compound of formula II or a pharmaceutically acceptable salt thereof, comprising the following steps: in an organic solvent (e.g., a haloalkane solvent, preferably dichloromethane), in the presence of an organic base (e.g., triethylamine), an amidation reaction is carried out between the compound of formula IIa or a salt thereof and the compound of formula IIb to obtain the compound of formula II; ; R 4 Halogens (e.g., chlorine); Ring A is C 3-6 cycloalkylene; R 3 for ; X1, X2, X3, X4, R 1 ,k,m,L1,R 3-1 R 3-2 R 3-3 R 2 And n as described in any embodiment of the present invention.

[0160] In one embodiment, the salt of the compound represented by formula IIa is a hydrochloride salt or a trifluoroacetate salt of the compound represented by formula IIa, such as a hydrochloride salt of the compound represented by IIa or a trifluoroacetate salt of the compound represented by IIa.

[0161] This invention provides a compound of formula IIa or a salt thereof; ; Where ring A is C 3-6 Cycloalkylene; X1, X2, X3, X4, R 1 ,k,m,L1,R 3-1 R 2 And n as described in any embodiment of the present invention.

[0162] In one embodiment, the compound shown in IIa is: Preferably, the salt is the trifluoroacetate of the above-mentioned compound.

[0163] This invention provides a pharmaceutical composition comprising (i) a compound of Formula I as described in any embodiment of this invention or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical excipient. Preferably, the compound of Formula I is the active ingredient.

[0164] This invention provides a compound of Formula I according to any embodiment of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a partial agonist of dopamine D2 receptor and / or serotonin 5-HT. 1A Receptor agonists and / or serotonin 5-HT 2A Use of receptor inhibitors and / or dopamine D3 receptor partial agonists and / or dopamine D3 receptor agonists.

[0165] This invention provides a compound of Formula I according to any embodiment of the invention, or a pharmaceutically acceptable salt thereof, or the above-described pharmaceutical composition, for the preparation of a treatment and / or prevention of dopamine D2 receptor and / or serotonin 5-HT. 1A receptors and / or 5-HT 2A Application in medications for diseases related to receptors and / or dopamine D3 receptors, preferably, the disease being schizophrenia.

[0166] This invention provides the use of the compound of Formula I according to any embodiment of the invention, or a pharmaceutically acceptable salt thereof, or the above-described pharmaceutical composition, in the preparation of a medicament for treating and / or preventing a disease, wherein the disease is schizophrenia.

[0167] This invention provides a partial agonist of dopamine D2 receptor and / or serotonin 5-HT 1A Receptor agonists and / or serotonin 5-HT 2A The compound of Formula I as described in any embodiment of the present invention, or a pharmaceutically acceptable salt thereof, or the above-described pharmaceutical composition thereof, is a receptor inhibitor and / or a partial agonist of dopamine D3 receptors and / or a dopamine D3 receptor agonist. Preferably, the dopamine D2 receptor partial agonist and / or serotonin 5-HT is... 1A Receptor agonists and / or serotonin 5-HT 2A Receptor inhibitors and / or dopamine D3 receptor partial agonists and / or dopamine D3 receptor agonists are drugs for the treatment and / or prevention of schizophrenia.

[0168] This invention provides a treatment and / or prevention of dopamine D2 receptor and / or serotonin 5-HT 1A receptors and / or 5-HT 2AA method for treating receptor and / or dopamine D3 receptor-related diseases, comprising administering to a subject in need a therapeutically effective amount of a compound of Formula I as described in any embodiment of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The disease is, for example, schizophrenia.

[0169] The present invention provides a method for treating and / or preventing schizophrenia, comprising administering to a subject in need a therapeutically effective amount of a compound of Formula I as described in any embodiment of the present invention, or a pharmaceutically acceptable salt thereof, or the above-described pharmaceutical composition.

[0170] Terminology definition: Unless otherwise stated, the terms used in this application have the following definitions, and the definitions of terms not referred to below are as commonly understood by those skilled in the art to which this invention pertains.

[0171] In this invention, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When a compound of this invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

[0172] In this invention, the term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions; they are substances included in pharmaceutical preparations other than the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0173] In this invention, the term "multiple" refers to a natural number greater than 2, such as 2, 3, 4, 5, 6, 7, 8, or 9.

[0174] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0175] In this invention, the term "hydroxyl group" refers to –OH.

[0176] In this invention, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group having a certain number of carbon atoms. 1–6Alkyl refers to an alkyl group having 1–6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6), including C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, such as 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, etc.

[0177] In this invention, the term "alkoxy" refers to -O-alkyl, wherein alkyl is defined as described above.

[0178] In this invention, the term "cycloalkylene" refers to a saturated cyclic hydrocarbon group, such as monocyclic cycloalkylene or bridged cycloalkylene (preferably monocyclic). The term "C"... 3- "C6 cycloalkylene" refers to a cycloalkylene group having 3 to 6 (e.g., 3, 4, 5, or 6) ring carbon atoms, including C3, C4, C5, or C6 monocyclic cycloalkylene or C4, C5, or C6 bridged cycloalkylene, specific examples including but not limited to cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, or bicyclic [1.1.1]pentylene (e.g. )wait.

[0179] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise explicitly stated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0180] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...each independently is" used in this application should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently is" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0181] The term “optionally replaced by” means either “replaced by” or “not replaced”.

[0182] In this application, the term “treatment” means a therapeutic therapy. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the disease or one or more biological manifestations of the condition. Attached Figure Description

[0183] Figure 1 The figure shows the results of the test on the effect of the compound on MK-801-induced hyperactivity in mice.

[0184] Figure 2 This is a graph showing the changes in body temperature in mice after oral administration of the drug.

[0185] Figure 3 The figure shows the effect of the compound on the motor balance and coordination ability of mice.

[0186] Figure 4 The results of the experiment to identify new objects are shown in the figure.

[0187] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0188] The positive and progressive effects of this invention are that the compounds of this invention have one or more of the following effects: (1) The compounds of the present invention simultaneously possess good dopamine D2 receptor partial agonist activity and serotonin 5-HT activity. 1A Receptor agonist activity. Preferably, it simultaneously possesses good dopamine D2 receptor partial agonist activity and serotonin 5-HT activity. 1A In addition to receptor agonist activity, it may optionally further possess serotonin 5-HT. 2A Receptor inhibitory activity and / or D3 receptor agonist or partial agonist activity.

[0189] (2) The compound of the present invention has good antipsychotic efficacy and can effectively improve positive symptoms.

[0190] (3) The compounds of the present invention have good absorption and blood-brain barrier crossing ability, high plasma and brain tissue exposure, and high brain / blood ratio.

[0191] (4) The compounds of the present invention have low side effects and high safety.

[0192] (5) The compounds of the present invention can effectively improve cognitive impairment. Detailed Implementation

[0193] The present invention is further illustrated below by way of examples, but these examples do not limit the invention to the scope of the embodiments described. Experimental methods not specifically described in the following examples were performed according to conventional methods and conditions, or as selected according to the product instructions. All reagents and raw materials used in this invention are commercially available or can be synthesized by known methods.

[0194] Example 1: Synthesis of Compound I-1

[0195] Step 1: Synthesis of intermediates 1-2

[0196] Compound 1-1 (50 g, 0.23 mol, 1 eq) was placed in a 1 L reaction flask and dissolved in 500 mL of dichloromethane. Pyridine (73.1 g, 0.93 mol, 4 eq) was added to the reaction system. The mixture was cooled to 0°C, and then thionyl chloride (33.0 g, 0.28 mol, 1.2 eq) was added dropwise, with the temperature controlled between 0 and 5°C during the addition. After the addition was complete, the system was brought to room temperature and stirred for 4 hours. After the reaction was completed as monitored by LCMS, 400 mL of water was added, and the system was stirred and separated. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 1-2, a yellow solid (59.62 g, crude product). LCMS (ESI): m / z C 10 H 18 N2O4SNa + [M+Na] + Calculated value = 285.09, Measured value [M+Na] + = 285.1.

[0197] Step 2: Synthesis of intermediates 1-3

[0198] Sodium periodate (63.12 g, 0.295 mol, 1.28 eq) and RuCl3 (94.3 mg, 0.45 mmol, 0.002 eq) were weighed and added to 281 mL of water. The mixture was cooled to 0°C and stirred. Separately, intermediate 1-2 (59.60 g, 0.23 mol, 1 eq.) was dissolved in a mixture of 834 mL of acetonitrile and 167 mL of ethyl acetate. The prepared intermediate 1-2 solution was added dropwise to the reaction system, maintaining the temperature between 0 and 5°C. After the addition was complete, the mixture was brought to room temperature and stirred. The reaction was confirmed by LCMS. 500 mL of water was added, the mixture was stirred, and the layers were separated. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. Intermediates 1-3 were purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 2 / 1) as a yellow solid (60.80 g). LCMS (ESI): m / z C 10 H 19 N2O5S + [M+H-Boc] + Calculated value = 179.09, Measured value [M + H - Boc] + = 179.0.

[0199] Step 3: Synthesis of intermediates 1-4

[0200] Intermediate 1-3a (47.11 g, 0.24 mol, 1.1 eq) was dissolved in 600 mL of tetrahydrofuran, and the system was cooled to -10°C. Sodium hydride (60% purity) (34.95 g, 0.87 mol, 4 eq) was added in portions. After the addition was complete, the reaction was stirred at -5°C for half an hour. Intermediate 1-3 (60.80 g, 0.22 mol, 1 eq) was weighed and dissolved in 400 mL of tetrahydrofuran. The prepared tetrahydrofuran solution of intermediate 1-3 was slowly added dropwise to the reaction system, with the temperature controlled between -5°C and 0°C during the addition. After the addition was complete, the system was brought to room temperature and stirred overnight. After the reaction was completed, 500 mL of water was added to quench the reaction, and the mixture was stirred to separate the organic phase. The aqueous phase was extracted with ethyl acetate (200 mL × 3). After combining the organic phases, the mixture was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 1-4, which was a yellow solid (106.0 g, crude product). 1 HNMR (400 MHz, DMSO- d6) δ ppm 7.55 (d, J=8.0 Hz, 1H), 7.32 (dd, J=7.6, 18 Hz,2H), 6.91 (t, J=7.6 Hz, 1H), 6.51 (d, J=2.8 Hz, 1H), 4.94 (br, s, 1H), 4.70(br, s, 1H), 4.07 (br, s, 1H), 3.62 (br, s, 1H), 3.32-3.25 (m, 2H), 3.12-3.02(m, 3H), 1.40-1.15 (m, 10H).

[0201] Step 4: Synthesis of intermediates 1-5

[0202] Crude intermediates 1-4 (36.00 g, 91 mmol) were dissolved in 36 mL of dichloromethane, and saturated isopropanol hydrochloride solution (108 mL) was added. The mixture was stirred at room temperature for 1 hour. After complete consumption of the starting material by LCMS, the reaction was quenched with 500 mL of saturated sodium bicarbonate aqueous solution, stirred, and separated into liquid and liquid phases. The aqueous phase was extracted with ethyl acetate (200 mL × 3), and the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (eluent ratio n-heptane / ethyl acetate = 2 / 1) to obtain intermediates 1-5 as a yellow solid (13.10 g, yield: 49.0%). LCMS (ESI): m / z C 13 H 17 BrN3 + [M+H] + Calculated value = 294.05, Measured value [M+H] + =294.1.

[0203] Step 5: Synthesis of intermediates 1-6

[0204] Intermediate 1-5 (13.10 g, 44.5 mmol, 1 eq) was dissolved in 131 mL of dioxane, and Pd2(dba)3 (4.08 g, 4.45 mmol, 0.1 eq), Ruphos (4.15 g, 8.89 mmol, 0.2 eq), and cesium carbonate (43.50 g, 133.8 mmol, 3 eq) were added sequentially. The reaction system was purged with nitrogen three times, heated to 100°C under a nitrogen atmosphere, and stirred for 18 hours. LC-MS monitoring showed complete consumption of the starting materials and product formation. The mixture was filtered while hot, and the residue was washed twice with ethyl acetate (20 mL). 200 mL of water was added to the filtrate, and the mixture was stirred vigorously and separated. The aqueous phase was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then purified by silica gel column chromatography (eluent ratios of dichloromethane / methanol = 50 / 1, 30 / 1, 20 / 1) to give intermediates 1-6 as yellow solids (7.91 g, yield: 83.4%). LCMS (ESI): m / z C 13 H 16 N3 + [M+H] + Calculated value = 214.13, Measured value [M+H] + = 214.1.

[0205] Step 6: Synthesis of intermediates 1-7

[0206] Intermediate 1-6 (3.00 g, 14.1 mmol, 1 eq) was dissolved in 60 mL of dichloromethane, and compound 1-6a (3.56 g, 14.8 mmol, 1.05 eq) was added. The reaction mixture was stirred at room temperature, and sodium borohydride acetate (8.96 g, 42.3 mmol, 3 eq) was added in portions to the solution. The reaction mixture was stirred at room temperature for another 18 hours. LC-MS monitoring showed complete consumption of the starting material and formation of product. The reaction solution was quenched with 150 mL of water, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 5 / 1, 3 / 1, 2 / 1) to give intermediates 1-7 as a yellow solid (3.91 g, yield: 63.3%). LCMS (ESI): m / z C 26 H 39 N4O2 + [M+H] +Calculated value = 439.30, Measured value [M+H] + = 439.3.

[0207] Step 7: Synthesis of intermediates 1-8

[0208] Intermediates 1-7 (3.80 g, 8.66 mmol) were dissolved in 20 mL of dichloromethane, and saturated isopropanol hydrochloride solution (38 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. LCMS analysis showed that the reaction was complete and products were formed. The system was directly concentrated to give intermediates 1-8 as a white solid (4.86 g, crude product). LCMS (ESI): m / z C 21 H 31 N4 + [M+H] + Calculated value = 339.25, Measured value [M+H] + = 339.3.

[0209] Step 8: Synthesis of Compound I-1

[0210] Intermediate 1-8 (4.80 g, 12.8 mmol, crude product, 1 eq) was dissolved in 60 mL of DMF, and triethylamine (6.48 g, 64.1 mmol, 5 eq) was added. The reaction system was yellow with suspended matter present. The mixture was cooled to 0°C, and intermediate 1-8a (2.06 g, 19.2 mmol, 1.5 eq.) was added dropwise to the above system. After the addition was complete, the system was brought to room temperature and stirred for 2 hours. The reaction was monitored by LCMS until it ended. The mixture was quenched with 500 mL of water and extracted with dichloromethane (200 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1, 30 / 1, 20 / 1) to give compound I-1 as a gray solid (1.65 g, yield: 31.5%). LCMS (ESI): m / z C 24 H 36 N5O + [M+H] + Calculated value = 410.28, Measured value [M+H] + =410.3. 1H NMR (400MHz, DMSO-d6 ) δ ppm 7.21 (br s, 1H), 6.94 (br d, J=7.9 Hz,1H), 6.85 (br t, J=7.6 Hz, 1H), 6.41 (br d, J=7.6 Hz, 1H), 6.32 (br d, J=2.3Hz, 1H), 5.86 (br d, J=7.9 Hz, 1H), 4.38 (br d, J=9.9 Hz, 1H), 3.88 (br t, J=10.7 Hz, 1H), 3.76 (br d, J=11.0 Hz, 1H), 3.20 - 2.98 (m, 3H), 2.75 (s, 7H), 2.43 - 2.30 (m, 2H), 2.19 (br s, 1H), 2.03 - 1.89 (m, 1H), 1.75 (br d, J=9.5Hz, 4H), 1.41 (br s, 2H), 1.31 - 1.14 (m, 4H), 1.05 - 0.92 (m, 2H)

[0211] Example 2: Synthesis of compounds I-2, I-2A and I-2B

[0212] Step 1: Synthesis of intermediate 2-2

[0213] Intermediate 2-1a (2.84 g, 15.81 mmol, 1.2 eq), intermediate 2-1 (3 g, 13.18 mmol, 1 eq) (synthetic method reference J Am Chem Soc, 2017, 139, 1037-1040), and potassium iodide (3.28 g, 19.76 mmol, 1.5 eq) were dissolved in 30 mL of tetrahydrofuran. The reaction mixture was stirred at 25°C for 0.5 h until the mixture became a clear yellow solution. The solution was then cooled to 0°C, and sodium hydride (790.48 mg, 19.76 mmol, 60% purity, 1.5 eq) was slowly added. The reaction mixture was stirred at 0°C for 2 h until the yellow color disappeared. 100 mL of water was added to the system, and the mixture was extracted with ethyl acetate (50 mL × 3). After combining the organic phases, the mixture was washed with saturated brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then purified by rapid silica gel chromatography (ISCO®; 80 g SepaFlash® silica gel column, 0-10% ethyl acetate / petroleum ether, 60 mL / min) to obtain intermediate 2-2 as a yellow oil (3.2 g, yield: 65.5%). LCMS (ESI): m / z C 21 H 24 ClN2O2 + [M+H] + Calculated value = 371.15, Measured value [M+H] + = 371.1.

[0214] Step 2: Synthesis of intermediates 2-3

[0215] Intermediate 2-2 (3.2 g, 8.63 mmol, 1 eq) was dissolved in 250 mL of toluene, and potassium iodide (3.58 g, 21.57 mmol, 2.5 eq) was added. The reaction mixture was stirred at 115°C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain intermediate 2-3 (2.8 g, crude product). LCMS (ESI): m / z C 21 H 23 N2O2 + [M+H] + Calculated value = 335.18, Measured value [M+H] + = 335.2.

[0216] Step 3: Synthesis of intermediates 2-4

[0217] Intermediate 2-3 (2.5 g, 5.4 mmol, 1 eq) was dissolved in 25 mL of ethanol. Sodium borohydride (990 mg, 26.17 mmol, 4.84 eq) was slowly added to the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. LC-MS monitoring was performed to ensure complete consumption of the starting material and formation of the main product. The reaction mixture was quenched at 20 °C with 2 mL of 0.5 M HCl solution. The reaction mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 0 to 35 / 1) to give intermediate 2-4 as a yellow solid (240 mg, yield: 13.2%). LC-MS (ESI): m / z C 21 H 25 N2O2 + [M+H] + Calculated value = 337.19, measured value = 337.2.

[0218] Step 4: Synthesis of intermediates 2-5

[0219] Intermediate 2-4 (200 mg, 594.48 μmol, 1 eq) was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (3.07 g, 26.93 mmol, 45.29 eq) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 25°C for 1 hour. TLC (petroleum ether:ethyl acetate = 1:1) showed complete disappearance of the starting material and the formation of the main product. The reaction mixture was evaporated to dryness under reduced pressure to give intermediate 2-5 as a yellow oil (176 mg, TFA salt, crude product). LCMS (ESI): m / z C 16 H 17 N2 + [M+H] + Calculated value = 237.14, measured value = 237.1.

[0220] Step 5: Synthesis of intermediates 2-6.

[0221] Intermediate 1-6a (53.04 mg, 219.79 μmol, 1.1 eq) and intermediate 2-5 (70 mg, 199.81 μmol, 1 eq, TFA salt) were dissolved in 5 mL of methanol, and sodium cyanoborohydride (62.78 mg, 999.05 μmol, 5 eq) was slowly added. The reaction mixture was stirred at 25°C for 2 hours. LCMS analysis confirmed complete consumption of the starting materials. The reaction mixture was poured into 30 mL of water, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 35 / 1) to obtain intermediate 2-6 as a yellow oil (98 mg, crude). LCMS (ESI): m / zC 29 H 40 N3O2 + [M+H] + Calculated value = 462.31, measured value = 462.2.

[0222] Step 6: Synthesis of intermediates 2-7

[0223] Intermediate 2-6 (98 mg, 212.29 μmol, 1 eq) was dissolved in 2 mL of dioxane, and dioxane hydrochloride solution (4 M, 2 mL) was added dropwise. The reaction was stirred at 25°C for 1 hour. TLC monitoring (petroleum ether: ethyl acetate = 1:1) showed complete consumption of the starting material. The solvent was evaporated under reduced pressure to obtain intermediate 2-7 as a yellow solid (81 mg, crude product, HCl salt). LCMS (ESI): m / z C 24 H 32 N3 + [M+H] + Calculated value = 362.26, measured value = 362.3.

[0224] Step 7: Synthesis of Compound I-2

[0225] Intermediate 2-7 (70 mg, 175.89 μmol, 1 eq, HCl salt) was dissolved in 2 mL of dichloromethane, followed by the sequential addition of triethylamine (53.39 mg, 527.66 μmol, 3 eq) and compound 1-8a (22.70 mg, 211.06 μmol, 19.37 μL, 1.2 eq). The reaction mixture was stirred at 25°C for 1 hour. LC-MS analysis confirmed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was then subjected to reversed-phase column chromatography (column: Welch xtimg C18 150). 25mm Compound I-2 was prepared and purified as a white solid (3.2 mg, yield: 4.2%) using a mobile phase of [water (0.04% NH3H2O ​​+ 10mM NH4HCO3)-acetonitrile], gradient: 55%-85% B, for 7 minutes. LCMS (ESI): m / z C 27 H 37 N4O + [M+H] + Calculated value = 433.29, measured value = 433.2. 1 H NMR (400 MHz, CD3OD) δ ppm 7.75 (dd, J=7.0, 14.1 Hz, 2H),7.37 - 7.17 (m, 4H), 6.96 - 6.83 (m, 2H), 5.88 (d, J=8.4 Hz,1H), 4.37-4.34(m, 1H), 3.96-3.93 (m, 1H), 3.53 - 3.42 (m, 1H), 3.15-3.09 (m, 2H), 2.99 -2.91 (m, 1H), 2.86 (s, 6H), 2.48-2.44 (m, 2H), 2.37 - 2.27 (m, 2H), 1.90-1.80(m, 4H), 1.51-1.46 (m, 2H), 1.33-1.24 (m, 3H), 1.11-1.06 (m, 2H).

[0226] Step 8: Compound I-2 is chirally resolved into compounds I-2A and I-2B.

[0227] Compound I-2 (250 mg, 0.58 mmol) was further separated by chiral SFC under the following conditions: chiral column CHIRALPAK IC (size: 250 mm). 30 mm, particle size 10 μm), elution phase was CO2 (A): ethanol containing 0.1% ammonia (B), isogradient (A / B = 50 / 50). Compound I-2A was separated, showing the first peak, as a white solid (91 mg, yield: 36.3%, purity: 99%). LCMS (ESI): m / z C 27 H 37 N4O + [M+H] + Calculated value = 433.3, Measured value [M+H] + = 433.3. 1H NMR(400 MHz, CD3OD) δ ppm 7.75 (dd, J=7.1, 13.9 Hz, 2H), 7.38 - 7.17 (m,4H), 6.95 - 6.82 (m, 2H), 5.85 (br d, J=8.0 Hz, 1H), 4.40 - 4.31 (m, 1H), 3.93 (br d, J=13.4 Hz, 1H), 3.49 (br s, 1H), 3.20 - 3.05 (m, 2H), 2.93 (br d,J=12.4 Hz, 1H), 2.86 (s, 6H), 2.44 (q, J=7.5 Hz, 2H), 2.38 - 2.27 (m, 2H), 1.94 - 1.76 (m, 4H), 1.53 - 1.42 (m, 2H), 1.35 - 1.17 (m, 3H), 1.13 - 0.99 (m, 2H). Compound I-2B was isolated, with a later peak, as a white solid (69.5 mg, yield: 27.7%, purity: 99%). LCMS (ESI): m / z C 27 H 37 N4O + [M+H] + Calculated value = 433.3, Measured value [M+H] + = 433.3. 1H NMR (400MHz, CD3OD) δ ppm 7.75 (dd, J=7.0, 13.8 Hz, 2H), 7.38 - 7.16 (m, 4H), 6.95 -6.82 (m, 2H), 5.85 (br d, J=8.1 Hz, 1H), 4.35 (br d, J=8.0 Hz, 1H), 3.93 (brd, J=13.5 Hz, 1H), 3.48 (br s, 1H), 3.21 - 3.05 (m, 2H), 2.94 (br d, J=11.4Hz, 1H), 2.86 (s, 6H), 2.44 (br d, J=7.9 Hz, 2H), 2.33 (br t, J = 11.1 Hz, 2H), 1.94 - 1.76 (m, 4H), 1.54 - 1.43 (m, 2H), 1.26 (br d, J = 12.4 Hz, 3H), 1.07 (br d, J = 12.8 Hz, 2H). Chiral analysis conditions: Instrument: Waters UPCC with PDA detector; ChiralCel OJ-H column (size: 150 mm). 4.6 mm (particle size 5 μm), elution phase was CO2 (A): ethanol containing 0.02% ethylenediamine (B), isogradient (A / B = 50 / 50); flow rate 2.5 mL / min, column temperature 40 °C; retention time of compound I-2A: approximately 3.30 min; retention time of compound I-2B: approximately 3.44 min.

[0228] Example 3: Synthesis of Compound I-3

[0229] Step 1: Synthesis of intermediate 3-2

[0230] Intermediates 3-1 (100 mg, 0.58 mmol, 1 eq) and 3-1a (133 mg, 0.58 mmol, 1 eq) were dissolved in 5 mL of tetrahydrofuran, and DEAD (120 mg, 0.69 mmol, 1.1 eq) and Cy3P (193 mg, 0.69 mmol) were added sequentially. The reaction system was purged with nitrogen three times. The reaction was stirred at 70°C for 18 hours under a nitrogen atmosphere. The reaction system was cooled to room temperature, and the reaction solution was poured into 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane, gradient 0%–10%) to obtain intermediate 3-2 as a pale yellow oil (156 mg, yield 69.8%). LCMS (ESI): m / z C 17 H 26 BrN2O3 + [M+H] + Calculated value = 385.10, measured value = 385.2.

[0231] Step 2: Synthesis of intermediate 3-3

[0232] Intermediate 3-2 (150 mg, 0.39 mmol, 1 eq) was dissolved in 6 mL of DMF, and BINAP (10 mg, 0.015 mmol, 0.04 eq), Pd2(dba)3 (7 mg, 0.0078 mmol, 0.02 eq), and cesium carbonate (197 mg, 0.60 mmol, 1.5 eq) were added sequentially. The reaction system was purged with nitrogen three times and stirred at 100°C for 18 hours. The reaction system was cooled to room temperature and poured into 20 mL of water. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. Intermediate 3-3 was obtained by silica gel column chromatography (mobile phase: methanol / dichloromethane, gradient 0%–10%) as a yellow oil (52 mg, yield: 43.8%). LCMS (ESI): m / z C 17 H 25 N2O3 + [M+H] + Calculated value = 305.18, measured value = 305.2.

[0233] Step 3: Synthesis of intermediates 3-4

[0234] Following the method in step 4 of Example 2, intermediate 3-4 was prepared from intermediate 3-3 as a raw material. The intermediate was a yellow oily substance (40 mg, crude product, TFA salt). LCMS (ESI): m / z C 12 H 17 N2O + [M+H] + Calculated value = 205.13, measured value = 205.2.

[0235] Step 4: Synthesis of intermediates 3-5

[0236] Following the method in step 5 of Example 2, intermediate 3-5 was prepared from intermediates 3-4 and 1-6a as raw materials, and was a pale yellow oily substance (55 mg). LCMS (ESI): m / z C 25 H 40 N3O3 + [M+H] + Calculated value = 430.30, measured value = 430.3.

[0237] Step 5: Synthesis of intermediates 3-6

[0238] Intermediate 3-5 (55 mg, 128 μmol) was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to give intermediate 3-6, a yellow oily substance (45 mg, crude product, TFA salt). LCMS (ESI): m / z C 20 H 32 N3O + [M+H] + Calculated value = 330.25, measured value [M+H] + =330.4.

[0239] Step 6: Synthesis of Compound I-3

[0240] Following the method in step 7 of Example 2, compound I-3 was prepared from intermediates 3-6 and 1-8a as raw materials, as a white solid (11 mg, yield: 27.1%). LCMS (ESI): m / z C 23 H 37 N4O2 + [M+H] + Calculated value = 401.28, measured value = 401.2. 1H NMR (400 MHz, CD3OD) δ ppm 6.98 (d, J=4.0 Hz, 2H), 6.96-6.92 (m, 1H), 6.83 (d, J=7.6 Hz, 1H), 4.49-4.44 (m, 1H), 4.16-4.13 (m, 1H), 3.58-3.54 (m,1H), 3.49-3.35 (m, 4H), 3.25-3.27 (m, 1H), 3.03-3.01 (m, 3H), 2.99-2.87(m,7H), 2.20-2.10 (m, 1H), 1.93-1.83 (m, 5H), 1.65-1.63 (m, 2H), 1.31-1.28(m,3H), 1.22-1.14(m,2H).

[0241] Example 4: Synthesis of compound I-4

[0242] Step 1: Synthesis of intermediate 4-2

[0243] Intermediate 4-1 (1.0 g, 7.1 mmol, 1 eq) was dissolved in 10 mL of DMF, and intermediate 3-1a (1.96 g, 8.5 mmol, 1.2 eq) and triethylamine (2.15 g, 21.3 mmol, 3 eq) were added sequentially. The system was stirred at 120°C for 18 hours under nitrogen protection. After cooling to room temperature, the mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was then subjected to silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0%–50%) to give intermediate 4-2 as a yellow oil (810 mg, yield: 32.5%). LCMS (ESI): m / z C 17 H 26 N3O5 + [M+H] + Calculated value = 352.18, measured value = 352.2.

[0244] Step 2: Synthesis of intermediate 4-3

[0245] Intermediate 4-2 (200 mg, 0.568 mmol, 1 eq) was dissolved in 5 mL of acetonitrile, and IBX (318 mg, 1.136 mmol, 2 eq) was added. The reaction mixture was kept at 65 °C. oThe mixture was stirred at C for 2 hours. The reaction system was then cooled and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain intermediate 4-3, a yellow oily substance (200 mg, crude product). LCMS (ESI): m / z C 17 H 24 N3O5 + [M+H] + Calculated value = 350.16, measured value = 350.2.

[0246] Step 3: Synthesis of intermediate 4-4

[0247] Compound 4-3 (195 mg, 0.56 mmol) was dissolved in 30 mL of an ethanol / water (3:1) mixture, and iron powder (188 mg, 3.36 mmol, 6 eq) and ammonium chloride (100 mg, 1.87 mmol, 3.3 eq) were added sequentially. The system was heated to 80°C and stirred for 2 hours. The iron powder was removed by hot filtration, and the filter cake was washed with 10 mL of ethanol. The combined filtrates were cooled to room temperature and used as the reaction solution for the next step. Sodium borohydride acetate (178 mg, 0.84 mmol) was added to the above reaction solution. The reaction was stirred at room temperature for 1 hour. LCMS monitoring showed complete consumption of the starting material and partial formation of intermediate 4-4. The reaction solution was used directly for the next step without further treatment. LCMS (ESI): m / z C 17 H 26 N3O2 + [M+H] + Calculated value = 304.19, measured value = 304.2.

[0248] Step 4: Synthesis of intermediates 4-5

[0249] To the 30 mL ethanol / water (3:1) solution containing intermediate 4-4 obtained in the previous step, add 0.5 mL of formaldehyde aqueous solution (37% purity). Stir the reaction mixture at room temperature for 10 minutes. Add sodium borohydride acetate (178 mg, 840 μmol) to the above system and stir at room temperature for 18 hours. Keep the reaction mixture below 35°C. o The ethanol solvent was removed by vacuum distillation at C, yielding a residue. 150 mg of potassium carbonate was added. The mixture was stirred and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. This residue was then subjected to silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0%–30%) to give intermediate 4–5, a pale yellow oil (70 mg, overall yield of 39.3%). LCMS (ESI): m / z C 18 H 28 N3O2+ [M+H] + Calculated value = 318.21, measured value = 318.3.

[0250] Step 5: Synthesis of intermediates 4-6

[0251] Intermediate 4-5 (70 mg, 220 μmol, 1 eq) was dissolved in 2 mL of dichloromethane. The reaction mixture was cooled to -5°C, and TMSI (53 mg, 265 μmol, 1.2 eq) was added dropwise. After the addition was complete, the system was stirred at 0°C for 0.5 h. The reaction was quenched with saturated sodium bicarbonate solution (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give intermediate 4-6 as a yellow oil (50 mg, crude). LCMS (ESI): m / z C 13 H 20 N3 + [M+H] + Calculated value = 218.16, measured value = 218.2.

[0252] Step 6: Synthesis of intermediates 4-7

[0253] Following the method in step 5 of Example 2, intermediate 4-7 was prepared from intermediates 4-6 and 1-6a as raw materials. The intermediate was a pale yellow oil (70 mg, yield 68.8%). LCMS (ESI): m / z C 26 H 43 N4O2 + [M+H] + Calculated value = 443.33, Measured value = 443.3.

[0254] Step 7: Synthesis of intermediates 4-8

[0255] Following the method in step 5 of Example 3, intermediate 4-8 was prepared from intermediates 4-7 as raw materials, and was a yellow oily substance (50 mg, crude product). LCMS (ESI): m / z C 21 H 35 N4 + [M+H] + Calculated value = 343.28, measured value = 343.3.

[0256] Step 8: Synthesis of Compound I-4

[0257] Following the method in step 7 of Example 2, compound I-4 was prepared from intermediates 4-8 and 1-8a as raw materials, as a white solid (2 mg, yield 3.3%). LCMS (ESI): m / z C 24 H 40 N5O + [M+H] + Calculated value = 414.32, measured value = 414.3. 1 H NMR (400 MHz, CD3OD) δ ppm 7.03-6.99 (m, 1H), 6.89-6.95 (m, 2H), 6.87-6.84 (m, 1H), 3.57-3.48 (m, 2H), 3.30-3.29 (m, 1H), 3.10-2.96 (m, 2H),2.88 (s, 6H), 2.76 - 2.70 (m, 6H), 2.55 - 2.49 (m, 2H), 2.42- 2.28 (m, 2H),1.95 - 1.81 (m, 5H), 1.58-1.49 (m, 3H), 1.48-1.47 (m, 3H), 1.41 - 1.42 (m,2H).

[0258] Example 5: Synthesis of Compound I-5

[0259] Step 1: Synthesis of intermediate 5-2

[0260] Intermediate 5-1 (1.8 g, 9.6 mmol, 1 eq) was dissolved in 20 mL of DMF, and potassium carbonate (3.97 g, 28.8 mmol, 3 eq) was added. The reaction mixture was stirred at room temperature for 20 minutes, followed by the addition of compound 5-1a (2.05 g, 10.2 mmol, 1.06 eq). The mixture was then stirred at 50°C for 4 hours under nitrogen protection. LC-MS monitoring showed complete consumption of the starting material and product formation. The reaction mixture was cooled to room temperature, poured into 50 mL of water, and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0%–20%) to give intermediate 5-2 as a colorless oil (1.5 g, yield: 68.5%). 1 HNMR (400 MHz, CDCl3) δ ppm 7.13 (dd, J = 8.0, 1.6 Hz, 1H), 6.85 (dd, J= 8.1, 1.6 Hz, 1H), 6.71 (t, J = 8.0 Hz, 1H), 4.27 - 4.21 (m, 2H), 4.20 - 4.14 (m, 2H), 2.19-2.15 (m, 2H).

[0261] Step 2: Synthesis of intermediate 5-3

[0262] Intermediate 5-2 (500 mg, 2.18 mmol, 1 eq) and intermediate 5-2a (500 mg, 2.68 mmol, 1.2 eq) were dissolved in 10 mL of 1,4-dioxane, and BINAP (70 mg, 0.11 mmol, 0.05 eq), Pd2(dba)3 (55 mg, 0.06 mmol, 0.027 eq), and potassium tert-butoxide (400 mg, 3.57 mmol, 1.6 eq) were added sequentially. The system was purged with nitrogen three times. The mixture was stirred at 100 °C for 20 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and evaporated to dryness. Intermediate 5-3 was obtained by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0%–40%) as a yellow oil (150 mg, yield 20.6%). LCMS (ESI): m / z C 18 H 27 N2O4 + [M+H] + Calculated value = 335.19, measured value = 335.2.

[0263] Step 3: Synthesis of intermediate 5-4

[0264] Compound 5-3 (150 mg, 450 μmol) was dissolved in 5 mL of ethyl acetate, and 2 mL of 4 M HCl aqueous solution was added dropwise. The reaction system was stirred at room temperature for 2 hours. After the reaction was complete, 5 mL of water was added for dilution, and the mixture was extracted with ethyl acetate (10 mL × 3). The pH of the aqueous phase was adjusted to approximately 9 with potassium carbonate. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 5-4 as a colorless oil (102 mg, yield 96.5%). LCMS (ESI): m / z C 13 H 19 N2O2 + [M+H] + Calculated value = 235.14, measured value = 235.2.

[0265] Step 4: Synthesis of intermediate 5-5

[0266] Following the method in step 5 of Example 2, intermediate 5-5 was prepared from intermediates 5-4 and 1-6a as raw materials, and was a white solid (52 mg, yield 26%). LCMS (ESI): m / z C 26 H 42 N3O4 + [M+H] + Calculated value = 460.31, measured value = 460.2.

[0267] Step 5: Synthesis of intermediates 5-6

[0268] Following the method in step 5 of Example 3, intermediate 5-6 was prepared from intermediate 5-5 as a raw material. The intermediate was a white solid (36 mg, yield 88.5%). LCMS (ESI): m / z C 21 H 34 N3O2 + [M+H] + Calculated value = 360.26, measured value = 360.3.

[0269] Step 6: Synthesis of Compound I-5

[0270] Following the method described in step 7 of Example 2, intermediates 5-6 and 1-8a were used as starting materials and purified by thin-layer chromatography (developing solvent: methanol / dichloromethane = 10:1) to obtain compound I-5 as a white solid (12 mg, yield: 27.8%). LCMS (ESI): m / z C 24 H 39 N4O3 + [M+H] + Calculated value = 431.30, measured value = 431.3. 1 H NMR (400 MHz, CDCl3)δ ppm 6.78 (t, J = 8.1 Hz, 1H), 6.65 (dd, J = 8.2, 1.5 Hz, 1H), 6.55 (dd, J =8.0, 1.6 Hz, 1H), 4.26-4.21 (m, 4H), 4.07 (d, J = 7.6 Hz, 1H), 3.54 - 3.50 (m1H), 3.35 (s, 3H), 2.96 (m, 4H), 2.81 (s, 6H), 2.14 (p, J= 5.7 Hz, 2H), 1.97(m, 2H), 1.71 (m, 5H), 1.29 – 1.15 (m, 2H), 1.13-1.06 (m, 4H).

[0271] Example 6: Synthesis of compounds I-6 and I-6B

[0272] Step 1: Synthesis of intermediate 6-2

[0273] Compound 1-1 (2 g, 9.25 mmol, 1 eq) was dissolved in 20 mL of DMSO, and compound 6-1 (1.91 g, 12.02 mmol, 1.33 mL, 1.3 eq) and potassium hydroxide (1.56 g, 27.74 mmol, 3 eq) were added sequentially. The reaction mixture was stirred at 25°C for 3 hours, resulting in a brown, transparent solution. The reaction was then heated to 80°C and stirred for another 8 hours. TLC monitoring (petroleum ether: ethyl acetate = 1:1) showed complete consumption of the starting material and formation of the main product. The reaction mixture was poured into 50 mL of water, and the mixture was extracted with ethyl acetate (60 mL × 2). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then separated by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-50% ethyl acetate / petroleum ether, 30 mL / min) to prepare intermediate 6-2 as a yellow solid (1.6 g, yield 51.6%). LCMS (ESI): m / z C 16 H 22 N3O5 + [M+H] + Calculated value = 336.15, Measured value [M - (t - Bu) + H] + = 279.9. 1H NMR (400 MHz, CD3OD) δ ppm 7.80 (dd, J=2.6, 9.1 Hz,1H), 7.66 (d, J=2.6 Hz, 1H), 6.76 (d, J=9.1 Hz, 1H), 4.30 (dd, J=3.0, 11.0Hz, 1H), 4.25 - 4.04 (m, 2H), 3.99 (dd, J=8.0, 11.0 Hz, 1H), 3.84 - 3.76 (m,1H), 3.33 (tdd, J=3.2, 7.9, 11.1 Hz, 1H), 3.12 - 2.90 (m, 2H), 2.67 (br s,1H), 1.49 (s,9H).

[0274] Step 2: Synthesis of Intermediate 6-3

[0275] Intermediate 6-2 (1.60 g, 4.77 mmol, 1 eq) was dissolved in 30 mL of tetrahydrofuran, and 10% palladium on carbon (0.5 g, 4.77 mmol, 1 eq) was added. The reaction system was evacuated under reduced pressure, purged three times with nitrogen, and then purged three times with hydrogen. The reaction system was stirred at 30°C for 5 hours in a hydrogen atmosphere (50 Psi). TLC monitoring (petroleum ether: ethyl acetate = 1:1) showed complete consumption of the starting material. The reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure to give intermediate compound 6-3 as a colorless oil (1.4 g, yield: 96.1%). LCMS (ESI): m / z C 16 H 24 N3O3 + [M+H] + Calculated value = 306.18, measured value = 305.9.

[0276] Step 3: Synthesis of intermediate 6-4

[0277] Intermediate 6-3 (500 mg, 1.64 mmol, 1 eq) was dissolved in 10 mL of 1,4-dioxane, and the reaction mixture was cooled to 0°C. Then, 234.11 μL of 30% HCl aqueous solution was slowly added dropwise. Sodium nitrite (135.56 mg, 1.96 mmol, 1.2 eq) was added to the above system, and the mixture was stirred for 10 minutes. Potassium iodide (543.61 mg, 3.27 mmol, 2 eq) was then added, and the mixture was stirred at 0°C for another 50 minutes. TLC monitoring (petroleum ether:ethyl acetate = 1:1) showed complete consumption of the starting material and formation of the main product. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (50 mL × 2). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then subjected to silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent: 0-20% ethyl acetate / petroleum ether, 20 mL / min) to prepare intermediate 6-4, a colorless oil (311 mg, yield: 45.6%). LCMS (ESI): m / z C 16 H 22 IN2O3 + [M+H] + Calculated value = 417.07, [M-(t-Bu)+H] + Measured value = 360.9.

[0278] Step 4: Synthesis of intermediate 6-5

[0279] Intermediate 6-4 (310 mg, 744.74 μmol, 1 eq) was dissolved in 3 mL of dichloromethane, and zinc bromide (1.68 g, 7.45 mmol, 372.70 μL, 10 eq) was added. The reaction mixture was stirred at 25°C for 5 hours. TLC monitoring (petroleum ether: ethyl acetate = 1:1) showed complete consumption of the starting material. Triethylamine (1.0 g, 9.88 mmol) was added to the reaction mixture, and the mixture was evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent 0-20% dichloromethane / methanol, 20 mL / min) to prepare intermediate 6-5 as a yellow solid (210 mg, yield: 89.2%). LCMS (ESI): m / z C 11 H 14 IN2O + [M+H] + Calculated value = 317.01, measured value = 317.1.

[0280] Step 5: Synthesis of intermediate 6-6

[0281] Intermediate 6-5 (100 mg, 316.32 μmol, 1 eq) was dissolved in 4 mL of DMF, and intermediate 6-5a (122.01 mg, 379.58 μmol, 1.2 eq) (synthetic method according to patent: CN114634479A) and cesium carbonate (309.19 mg, 948.96 μmol, 3 eq) were added. The reaction system was stirred at 80°C for 4 hours. LCMS was used to monitor complete consumption of the starting materials and the formation of products. The reaction solution was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was then subjected to silica gel column chromatography (ISCO®; 4 g SepaFlash® silica gel column, eluent 0-45% ethyl acetate / petroleum ether, 20 mL / min) to give intermediate 6-6 as a colorless oil (126 mg, yield: 73.56%). LCMS (ESI): m / z C 24 H 37 IN3O3 + [M+H] + Calculated value = 542.19, measured value = 542.1.

[0282] Step 6: Synthesis of intermediates 6-7

[0283] Following the method in step 5 of Example 3, intermediate 6-7 was prepared from intermediate 6-6 as a raw material, and was a yellow oily substance (228 mg, crude product). LCMS (ESI): m / z C 19 H 29 IN3O + [M+H] + Calculated value = 442.13, measured value = 442.0.

[0284] Step 7: Synthesis of intermediates 6-8

[0285] Following the method in step 7 of Example 2, intermediate 6-8 was prepared from intermediates 6-7 and 1-8a as raw materials, and was a yellow oily substance (186 mg). LCMS (ESI): m / z C 22 H 34 IN4O2 + [M+H] + Calculated value = 513.17, measured value = 513.2.

[0286] Step 8: Synthesis of Compound I-6

[0287] Intermediate 6-8 (30 mg, 58.55 μmol, 1 eq) was dissolved in 8 mL of methanol, followed by the addition of 10% palladium on carbon (62.30 mg). The reaction system was evacuated, purged three times with nitrogen, and finally purged with hydrogen. The reaction solution was stirred at 25°C for 1 hour under a hydrogen atmosphere (15 Psi). LC-MS analysis confirmed the reaction was complete and product was formed. The reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure to obtain the residue. The residue was then subjected to reversed-phase column chromatography (column type: Welch xtimg C18 150). 30mm Compound I-6 was prepared as a white solid (3.2 mg, yield 14.0%) using a mobile phase of [water (0.25% formic acid)-acetonitrile] and a gradient of 0%-40% B for 9 minutes. LCMS (ESI): m / z C 22 H 35 N4O2 + [M+H] + Calculated value = 387.28, measured value = 387.3. 1 H NMR (400 MHz, CD3OD) δ ppm 6.85-6.79 (m, 2H), 6.69-6.66 (m, 2H), 4.23-4.20 (m, 1H), 3.96-3.91 (m, 1H), 3.76-3.73 (m, 1H), 3.49 - 3.31 (m, 1H), 3.12-3.06 (m, 2H), 2.98-2.95 (m, 1H), 2.87 (s, 6H), 2.76-2.69 (m, 1H), 2.48 -2.44 (m, 2H), 2.27-2.20 (m, 1H), 1.92-1.80 (m, 5H), 1.51-1.46 (m, 2H), 1.32-1.23 (m, 3H), 1.13-1.06 (br s, 2H).

[0288] Synthesis of compound I-6B

[0289] Referring to the synthesis method of I-6, with ( R Compound I-6B was prepared from 1-BOC-3-hydroxymethylpiperazine as a starting material. It was a white solid (138 mg, yield: 43.72%). LCMS (ESI): m / z C 22 H 35 N4O2 + [M+H] +Calculated value = 387.28, Measured value [M+H] + = 387.3. 1 H NMR (400 MHz, CD3OD) δ ppm 6.88 - 6.76 (m,2H), 6.72 - 6.63 (m, 2H), 5.87 (d, J=8.0 Hz, 1H), 4.21 (dd, J=2.7, 10.6 Hz,1H), 3.99 - 3.88 (m, 1H), 3.74 (d, J=11.7 Hz, 1H), 3.57-3.48(m, 1H), 3.18-3.12 (m, 2H), 3.10 - 3.06 (m, 1H), 2.87 (s, 6H), 2.78 - 2.68 (m, 1H), 2.50 -2.41 (m, 2H), 2.29 - 2.19 (m, 1H), 1.96 - 1.77 (m, 5H), 1.53 - 1.43 (m, 2H), 1.28-1.25 (m, 3H), 1.16 - 1.02 (m, 2H).

[0290] Example 7: Synthesis of Compound I-7

[0291] Step 1: Synthesis of intermediate 7-2

[0292] Referring to the method in step 1 of Example 4, intermediate 7-2, a red oily substance, was prepared using o-fluoronitrobenzene (4-1) and 1-1 as raw materials. LCMS (ESI): m / z C 16 H 24 N3O5 + [M+H] + Calculated value = 338.16, measured value = 338.2.

[0293] Step 2: Synthesis of intermediate 7-3

[0294] Intermediate 7-2 (500 mg, 1.48 mmol, 1 eq) was dissolved in 5 mL of dichloromethane, and triethylamine (1.0 g, 9.9 mmol, 6.7 eq) was added. The mixture was stirred at room temperature. Methanesulfonic anhydride (386 mg, 2.22 mmol, 1.5 eq) was dissolved in 2 mL of dichloromethane and slowly added to the above reaction mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was then subjected to silica gel column chromatography (mobile phase: methanol / dichloromethane, gradient 0% - 5%) to give intermediate 7-3 as a yellow oil (510 mg, yield 83.0%). LCMS (ESI): m / z C 17 H 26 N3O7S + [M+H] + Calculated value = 416.14, measured value = 416.2.

[0295] Step 3: Synthesis of intermediate 7-4

[0296] Compound 7-3 (500 mg, 1.2 mmol) was dissolved in 4 mL of dichloromethane, and trifluoroacetic acid (2 mL) was added dropwise. The reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure and dissolved in 10 mL of HCl solution (1 M). The solution was diluted with 10 mL of ethyl acetate, and after separation of the aqueous phase, the pH was adjusted to approximately 9 with potassium carbonate. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give intermediate 7-4 as a yellow oil (280 mg, crude product). LCMS (ESI): m / z C 12 H 18 N3O5S + [M+H] + Calculated value = 316.09, measured value = 316.2.

[0297] Step 4: Synthesis of intermediate 7-5

[0298] Referring to the method in step 4 of Example 5, intermediate 7-5 was prepared from intermediates 7-4 and 1-6a as raw materials, and it was a yellow oily substance. LCMS (ESI): m / z C 25 H 41 N4O7S + [M+H] + Calculated value = 541.26, measured value = 541.3.

[0299] Step 5: Synthesis of intermediates 7-6

[0300] Referring to the method in step 5 of Example 3, intermediate 7-6 was prepared from intermediate 7-5 as a raw material, and it is a yellow oily substance. LCMS (ESI): m / z C 20 H 33 N4O5S + [M+H] + Calculated value = 441.21, measured value = 441.2.

[0301] Step 6: Synthesis of intermediate 7-7

[0302] Following the method in step 7 of Example 2, intermediate 7-7 was prepared from intermediates 7-6 and 1-8a as raw materials, and was a yellow oily substance (220 mg). LCMS (ESI): m / z C 23 H 38 N5O6S + [M+H] + Calculated value = 512.25, measured value = 512.2.

[0303] Step 7: Synthesis of intermediates 7-8

[0304] Intermediate 7-7 (226 mg, 442 μmol) was dissolved in 10 mL of methanol. 10% Pd / C (10 mg) and sodium borohydride (81 mg, 2.13 mmol, 4.8 eq) were added sequentially with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was cooled to below 30 °C. o Crude intermediate 7-8 was obtained by vacuum concentration at C, which was a red oily substance (120 mg, crude product). LCMS (ESI): m / z C 22 H 36 N5O + [M+H] + Calculated value = 386.28, measured value = 386.3.

[0305] Step 8: Synthesis of Compound I-7

[0306] Intermediate 7-8 (120 mg, 312 μmol) was dissolved in 5 mL of methanol, and 0.5 mL of 37% formaldehyde aqueous solution was added. The reaction system was stirred at room temperature for 10 minutes. Sodium borohydride acetate (100 mg, 472 μmol, 1.5 eq) was added to the above reaction system, and stirring was continued for 18 hours. The reaction solution was concentrated under reduced pressure to obtain the residue, which was dissolved in 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The residue of the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase: methanol / dichloromethane = 1:10) to give compound I-7 as a white solid (30 mg, yield: 24.1%, purity 99.3%). LCMS (ESI): m / z C 23 H 38 N5O + [M+H] + Calculated value = 400.30, measured value = 400.2. 1 H NMR (400 MHz, CDCl3) δ ppm 6.78 (m,1H), 6.74 - 6.65 (m, 2H), 6.64 - 6.54 (m, 1H), 4.14 (d, J = 7.7 Hz, 1H), 3.69(d, J = 11.9 Hz, 1H), 3.59 (m, 1H), 3.30 (m, 1H), 3.18 (d, J = 6.0 Hz, 2H),3.12 - 3.01 (m, 1H), 2.95 (m, 1H), 2.90 (s, 6H), 2.87 (s, 3H), 2.45 (m, 2H),2.27 (m, 1H), 2.04 (m, 2H), 1.93 (m, 1H), 1.79 (m, 2H), 1.49 (m, 2H), 1.28(m, 1H), 1.14-1.06 (m, 4H).

[0307] Example 8: Synthesis of Compound I-8

[0308]

[0309]

[0310] Step 1: Synthesis of intermediate 8-2

[0311] Compound 8-1 (3 g, 8.29 mmol, 1 eq) was dissolved in 8 mL of N-methyl-2-pyrrolidone, and triethylamine (4.20 g, 41.47 mmol, 5.77 mL, 5 eq) and compound 8-1a (7.31 g, 33.17 mmol, 6.40 mL, 4 eq) were added. The reaction mixture was microwaved at 140°C for 3 hours. TLC monitoring (petroleum ether: ethyl acetate = 2:1) showed some reactants remaining and the formation of the main product. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was then subjected to silica gel column chromatography (ISCO®; 80 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 45 mL / min) to give intermediate 8-2, a yellow oily substance (1.7 g, crude product, purity: 89.2%). LCMS (ESI): m / z C 25 H 34 BrN4O3Si + [M+H] + Calculated value = 545.15, measured value = 545.2.

[0312] Step 2: Synthesis of intermediate 8-3

[0313] Intermediate 8-2 (2 g, 3.67 mmol, 1 eq) was dissolved in 20 mL of ethanol, and compound 8-2a (2.46 g, 18.33 mmol, 5 eq), tetraphenylphosphine palladium (211.82 mg, 183.30 μmol, 0.05 eq), and potassium carbonate (2.53 g, 18.33 mmol, 5 eq) were added. The reaction system was evacuated and purged three times with nitrogen. The reaction system was stirred at 110°C for 2 hours under a nitrogen atmosphere. TLC monitoring (petroleum ether: ethyl acetate = 1:1) showed that the starting material reacted completely and the main product was formed. The reaction solution was concentrated to remove ethanol, and the residue was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 2). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then subjected to silica gel column chromatography (ISCO®; 24 g SepaFlash® silica gel column, eluent: 0-100% ethyl acetate / petroleum ether 35 mL / min) to obtain intermediate 8-3, a yellow oily substance (2 g, crude product, purity 88.7%). LCMS (ESI): m / z C 27 H 37N4O3Si + [M+H] + Calculated value = 493.26, measured value = 493.2.

[0314] Step 3: Synthesis of step 8-4

[0315] Intermediate 8-3 (1.6 g, 3.25 mmol, 1 eq) was dissolved in 15 mL of 1,4-dioxane and 15 mL of water, followed by the addition of potassium osmium tetroxide dihydrate (119.66 mg, 324.75 μmol, 0.1 eq) and sodium periodate (1.74 g, 8.12 mmol, 449.88 μL, 2.5 eq). The reaction mixture was stirred at 0°C for 0.5 h. TLC monitoring (petroleum ether:ethyl acetate = 1:1) showed complete reaction of the starting material and formation of the main product. The reaction solution was diluted with 10 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was then subjected to silica gel column chromatography (ISCO®; 24 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 30 mL / min) to give intermediate 8-4, a yellow oil (688 mg, yield: 42.4%). LCMS (ESI): m / z C 26 H 35 N4O4Si + [M+H] + Calculated value = 495.24, measured value = 495.2.

[0316] Step 4: Synthesis of intermediate 8-5

[0317] Intermediate 8-4 (853 mg, 1.72 mmol, 1 eq) was dissolved in 15 mL of ethanol, followed by the addition of 8-4a (642.28 mg, 3.45 mmol, 2 eq) and acetic acid (20.71 mg, 344.89 μmol, 19.74 μL, 0.2 eq). The reaction mixture was stirred at 80°C for 4 hours under nitrogen protection. TLC monitoring (petroleum ether: ethyl acetate = 1:1) showed that the reactants reacted completely and the main product was formed. The reaction mixture was concentrated to remove ethanol, and the residue was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was then subjected to silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 30 mL / min) to give intermediate 8-5, a yellow oil (1.07 g, yield: 75.6%, purity 80%). LCMS (ESI): m / z C 33 H 43 O5N6SSi + [M+H] + Calculated value = 663.27, measured value = 663.3.

[0318] Step 5: Synthesis of intermediate 8-6

[0319] Intermediate 8-5 (800 mg, 1.21 mmol, 1 eq) was dissolved in 10 mL of toluene, and sodium hydride (386.16 mg, 9.65 mmol, 60% purity, 8 eq) was added. The mixture was then stirred at 140 °C for 1 hour. TLC monitoring (petroleum ether:ethyl acetate = 1:1) showed that the reaction proceeds were complete and the main product was formed. The reaction mixture was quenched with 10 mL of water and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was then subjected to silica gel column chromatography (ISCO®; 24 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 5 mL / min) to obtain intermediate 8-6 as a yellow oil (328 mg). LCMS (ESI): m / zC 26 H 35 SiO3N4 + [M+H] + Calculated value = 479.24, measured value = 479.2.

[0320] Step 6: Synthesis of intermediates 8-7

[0321] Intermediate 8-6 (320 mg, 668.54 μmol, 1 eq) was dissolved in 5 mL of ethanol, followed by the addition of wet palladium on carbon (213.44 mg, 200.56 μmol, 10% purity, 0.3 eq) and ammonium formate (337.24 mg, 5.35 mmol, 8 eq). The reaction mixture was evacuated and purged three times with nitrogen. The reaction mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. TLC monitoring (dichloromethane / methanol = 10 / 1) showed the presence of the starting material and the formation of the main product. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was then subjected to silica gel column chromatography (ISCO®; 80 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 45 mL / min) to give intermediate 8-7, a yellow oil (60 mg, yield: 26.1%). LCMS (ESI): m / z C 18 H 29 N4OSi + [M+H] + Calculated value = 345.20, measured value = 345.2.

[0322] Step 7: Synthesis of intermediate 8-8

[0323] Following the method in step 5 of Example 2, intermediate 8-8 was prepared from intermediates 8-7 and 1-6a as raw materials. The intermediate was a colorless oil (60 mg, yield: 60.5%). LCMS (ESI): m / z C 31 H 52 N5O3Si + [M+H] + Calculated value = 570.38, measured value = 570.3.

[0324] Step 8: Synthesis of intermediates 8-9

[0325] Following the method in step 5 of Example 3, intermediate 8-9 was prepared from intermediate 8-8 as a raw material, and was a yellow oily substance (25 mg, crude product). LCMS (ESI): m / z C 20 H 30 N5 + [M+H] + Calculated value = 340.25, measured value = 340.2.

[0326] Step 9: Synthesis of Compound I-8

[0327] Referring to step 7 of Example 2, intermediates 8-9 and 1-8a were used as raw materials, and the mixture was subjected to reversed-phase column chromatography (column: Welch Ultimate C18 150). 25mm Compound I-8 was prepared as a white solid (2 mg, yield 8.8%) using a mobile phase of [water (NH4HCO3)-acetonitrile] and a gradient of 30%-60% B for 7 minutes (5 μm). LCMS (ESI): m / z C 23 H 35 N6O + [M+H] + Calculated value = 411.28, measured value = 411.4. 1 H NMR (400 MHz, CD3OD) δ ppm 7.92 (d, J=6.0 Hz, 1H), 6.78 (s, 1H), 6.42 (d, J=6.0 Hz, 1H), 3.93 (br d, J=12.5 Hz,1H), 3.56 - 3.44 (m, 1H), 3.41 - 3.33 (m, 1H), 3.24 - 3.14 (m, 2H), 3.13 -3.00 (m, 2H), 2.87 (s, 6H), 2.89-2.77 (m, 1H), 2.58 - 2.50 (m, 2H), 2.42 -2.31 (m, 1H), 2.19 (t, J=11.3 Hz, 1H), 1.95 - 1.79 (m, 4H), 1.56 - 1.47 (m, 2H), 1.35 - 1.20 (m, 3H), 1.15 - 1.03 (m, 2H).

[0328] Example 9: Synthesis of Compound I-9

[0329]

[0330] Step 1: Synthesis of intermediate 9-2

[0331] Compound 9-1 (synthetic method reference: Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 24, p. 5877 – 5882) (5.0 g, 16.9 mmol, 1 eq) was dissolved in 50 mL of DMF. NaH (1.1 g, 25.4 mmol, 60% purity, 1.5 eq) was carefully added. After 10 minutes, BnBr (5.2 g, 30.5 mmol, 3.6 mL, 1.8 eq) was added. The reaction system was stirred at 25°C for 10 hours. After the reaction was completed, the reaction solution was poured into 100 mL of ethyl acetate and 100 mL of water. The organic phase was then separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-100% petroleum ether / ethyl acetate, 45 mL / min) to obtain intermediate 9-2 as a yellow solid (1.5 g, yield 23.0%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.48 - 7.29 (m, 4H), 7.24 - 7.15 (m, 2H), 6.83 (dd, J=2.1, 7.3 Hz, 1H), 4.81 (d, J=14.7 Hz, 1H), 4.60 (d, J=14.7 Hz, 1H), 4.15 (dd,J=3.8, 14.2 Hz, 1H), 3.87 (td, J=3.4, 12.4 Hz, 1H), 3.61 (dt, J=4.2, 11.7 Hz,1H), 3.46 - 3.31 (m, 2H), 3.21 - 3.06 (m, 1H), 2.87 (dd, J = 14.2, 16.8 Hz, 1H).

[0332] Step 2: Synthesis of Intermediate 9-3

[0333] Intermediate 9-2 (1.5 g, 3.89 mmol, 1...) eq Dissolve in 15 mL of 1,4-dioxane, then add cesium carbonate (3.81 g, 11.68 mmol, 3...) sequentially. eq ), tert-butyl carbamate (1.37 g, 11.68 mmol, 3 eq ), Xantphos (225.29 mg, 389.35 μmol, 0.1 eq) and Pd2(dba)3 (356.54 mg, 389.35 μmol, 0.1 eq The reaction system was purged with nitrogen three times. After 10 minutes, the reaction system was stirred at 110°C for 2 hours. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-70% petroleum ether / ethyl acetate, 45 mL / min) to obtain intermediate 9-3 (1.3 g, yield: 79.2%). LCMS (ESI): m / z C 24 H 28 O4N3 + [M+H] + Calculated value = 422.21, measured value = 422.2.

[0334] Step 3: Synthesis of intermediate 9-4

[0335] Intermediate 9-3 (1.3 g, 3.08 mmol, 1) eq The sample was dissolved in 13 mL of trifluoroacetic acid and stirred at 25°C for 10 minutes. The starting material disappeared under TLC monitoring. Excess trifluoroacetic acid was removed under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate solution. The organic phase was then separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-70% petroleum ether / ethyl acetate, 45 mL / min) to give intermediate 9-4 as a yellow solid (950 mg, yield: 96.1%). LCMS (ESI): m / z C 19 H 20 N3O2 + [M+H] + Calculated value = 322.16, measured value = 322.2.

[0336] Step 4: Synthesis of intermediate 9-5

[0337] Intermediate 9-4 (800 mg, 2.49 mmol, 1) eq Dissolved in 20 mL of toluene under a nitrogen atmosphere, acetylene-based magnesium bromide (0.5 M, 39.83 mL, 8...) eqThe solution was added to the reaction system, and the reaction was carried out at 50 °C for 1 hour. After the reaction was completed as detected by TLC, 50 mL of 1M dilute hydrochloric acid was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried, and concentrated to obtain intermediate 9-5 (800 mg, crude product), which was used directly in the next step. LCMS (ESI): m / z C 21 H 22 N3O2 + [M+H-H2O] + Calculated value = 330.2, Measured value = 330.2

[0338] Step 5: Synthesis of intermediate 9-6

[0339] Intermediate 9-5 (800 mg, crude product) was dissolved in 20 mL of methanol under a nitrogen atmosphere. Copper chloride (30.96 mg, 230.28 μmol, 0.1...) eq The crude product was added to the reaction system and reacted at 50 °C for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was concentrated, the crude product was dissolved in ethyl acetate, filtered, dried, and concentrated to obtain crude product purified by reverse-phase column chromatography (column: C18; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient: 5%-95% B) to obtain intermediate 9-6, a yellow solid (60 mg, two-step yield: 7.3%). 1 H NMR (400 MHz, CD3OD) δ ppm 8.71 (d, J=4.5 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.38 - 7.24 (m,6H), 6.96 (d, J=7.8 Hz, 1H), 4.80 - 4.63 (m, 2H), 4.17 (dd, J=3.3, 13.1 Hz,1H), 4.05 (dd, J=3.5, 11.5 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.70 - 3.64 (m, 1H),3.48 - 3.38 (m, 2H), 3.21 (dt, J=4.0, 12.3 Hz, 1H).

[0340] Step 6: Synthesis of intermediate 9-7

[0341] Intermediate 9-6 (60 mg, 182.15 μmol, 1) eqDissolved in 4 mL of tetrahydrofuran under a nitrogen atmosphere, boranetetrahydrofuran (1 M, 1.82 mL, 10) eq The reagent was added to the reaction system, and the reaction was carried out at 50°C for 1 hour. After the reaction was completed by TLC, the reaction was quenched with 1 mL of methanol. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent: 0-10% methanol / dichloromethane, 25 mL / min) to give intermediate 9-7 (40 mg, yield: 69.62%) as a yellow oil. LCMS (ESI): m / z C 21 H 22 N3 + [M+H] + Calculated value = 316.18, Measured value = 316.1

[0342] Step 7: Synthesis of intermediates 9-8

[0343] Intermediate 9-7 (50 mg, 158.52 μmol, 1) eq Dissolve in 5 mL of ethanol and add ammonium formate (99.96 mg, 1.59 mmol, 10 mg). eq The reactants were reacted with palladium on carbon (20 mg, 10% purity). The reaction system was stirred at 100°C for 2 hours. LCMS was used to monitor the completeness of the reaction. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain intermediate 9-8, a colorless oily substance (48 mg, crude product). LCMS (ESI): m / z C 14 H 16 N3 + [M+H] + Calculated value = 226.14, measured value = 226.1.

[0344] Step 8: Synthesis of intermediate 9-9

[0345] Intermediate 9-8 (48 mg, crude product) was dissolved in 2 mL of methanol, and intermediate 1-6a (47.49 mg, 196.77 μmol) and sodium cyanoborohydride (49.46 mg, 787.08 μmol, 4...) were added. eq The reaction system was stirred at 25°C for 2 hours. TLC monitoring (dichloromethane / methanol = 10 / 1) showed complete consumption of the starting material and the formation of product spots. The reaction solution was concentrated under reduced pressure to obtain the residue, which was then processed into a thin-layer chromatography plate (developing solvent:dichloromethane:methanol = 10:1) to give intermediate 9-9, a colorless oil (30 mg, two-step yield 42.0%). LCMS (ESI): m / z C 27 H39 N4O2 + [M+H] + Calculated value = 451.31, measured value = 451.3.

[0346] Step 9: Synthesis of intermediates 9-10

[0347] Referring to the method in step 5 of Example 3, intermediate 9-10 was prepared from intermediate 9-9 as a raw material. The intermediate was a colorless oil (41 mg, crude product). LCMS (ESI): m / z C 22 H 31 N4 + [M+H] + Calculated value = 351.25, Measured value = 351.3

[0348] Step 10: Synthesis of Compound I-9

[0349] Referring to step 7 of Example 2, intermediates 9-10 and 1-8a were used as raw materials, and the mixture was subjected to reversed-phase column chromatography (column: Phenomenex C18 75). 30mm 3µm mobile phase: [water (0.04% NH3H2O ​​+ 10mM NH4HCO3) - acetonitrile]; gradient: 38%-68% B, 7 min) to obtain compound I-9 as a white solid (13 mg, two-step yield 46.3%, purity 96.8%). LCMS (ESI): m / z C 25 H 36 N5O + [M+H] + Calculated value = 422.29, measured value = 422.4. 1H NMR (400 MHz, CD3OD) δ ppm 8.63 (d, J=4.5 Hz, 1H), 7.62 (t, J=8.2 Hz, 1H), 7.39 (d, J=7.2Hz, 1H), 7.18 (d, J=4.5 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 5.88 (d, J=7.9 Hz,1H), 3.87 (br d, J=11.9 Hz, 1H), 3.57 - 3.43 (m, 1H), 3.27 - 3.12 (m, 4H), 3.10 - 3.00 (m, 1H), 2.95 - 2.81 (m, 7H), 2.53 - 2.46 (m, 2H), 2.40 - 2.30(m, 1H), 2.09 (br t, J=10.8 Hz, 1H), 1.94 - 1.80 (m, 4H), 1.56 - 1.47 (m,2H), 1.31 - 1.24 (m, 3H), 1.15 - 1.04 (m, 2H).

[0350] Example 10: Synthesis of Compound I-10

[0351]

[0352] Step 1: Synthesis of intermediate 10-2

[0353] Compound 3-1a (1.8 g, 7.82 mmol, 1 eq) was dissolved in 15 mL of tetrahydrofuran, and sodium bicarbonate aqueous solution (3 M, 10.42 mL, 4 eq) and benzyl chloroformate (2.67 g, 15.63 mmol, 2.23 mL, 2 eq) were added. The reaction mixture was stirred at 20°C for 1 hour. TLC was used to monitor complete consumption of the starting material and formation of the product. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was then subjected to silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether, gradient 0%–30%) to give intermediate 10⁻² as a colorless oil (2.8 g, yield: 98.30%). LCMS (ESI): m / z C 19 H 29 N2O5 + [M+H] + Calculated value = 365.21, measured value = 365.2.

[0354] Step 2: Synthesis of intermediate 10-3

[0355] DMSO (3.60 g, 46.10 mmol, 3.60 mL, 6 eq) was added to 50 mL of dichloromethane, and oxaloyl chloride (3.90 g, 30.73 mmol, 2.69 mL, 4 eq) was slowly added dropwise to the above solution. The reaction system was stirred at -78°C for 1 hour. Subsequently, at -78°C, a dichloromethane solution (20 mL) of intermediate 10⁻² (2.8 g, 7.68 mmol, 1 eq) was added dropwise to the above reaction system. After the addition was complete, the reaction solution was stirred for another hour. The reaction was then quenched by adding triethylamine (6.22 g, 61.47 mmol, 8.56 mL, 8 eq). TLC monitoring showed complete consumption of the starting material and the formation of a product spot with decreasing polarity. The reaction solution was washed with 50 mL of water to separate the organic phase. The aqueous solution was extracted with ethyl acetate (10 mL × 2). The organic phases were combined and washed with saturated brine (10 mL × 2). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was then subjected to rapid silica gel chromatography (ISCO®; 30 g SepaFlash® silica gel column, eluent 0-60% ethyl acetate / petroleum ether, 30 mL / min) to give intermediate 10⁻³ as a colorless oil (2.3 g, yield: 82.60%). 1 H NMR (400MHz, CDCl3) δ ppm 9.75(br s, 1H), 7.44 - 7.31 (m, 5H), 5.14 (s, 2H), 4.76 (br s, 1H), 4.00 (br d, J=12.0 Hz, 3H), 3.05 (br s, 2H), 2.89 - 2.70 (m, 2H), 2.62 (br s, 1H), 1.45(s, 9H).

[0356] Step 3: Synthesis of intermediate 10-4

[0357] Compound 10⁻³a (984.44 mg, 4.41 mmol, 2 eq) was dissolved in 10 mL of tetrahydrofuran. The reaction system was cooled to 0°C, and a tetrahydrofuran solution of iPrMgCl-LiCl (1.3 M, 3.40 mL, 2 eq) was added dropwise to the above solution. The reaction system was stirred at 0°C for 30 minutes. Then, a tetrahydrofuran solution (2 mL) of intermediate 10⁻³ (800 mg, 2.21 mmol, 1 eq) was added dropwise to the above system. After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour. LCMS monitoring showed that the starting material reacted completely and products were formed. The reaction solution was concentrated under reduced pressure to obtain a residue, which was then subjected to silica gel column chromatography (ISCO®; 20 g SepaFlash® silica gel column, eluent: 0-30% ethyl acetate / petroleum ether, 30 mL / min) to give intermediate 10⁻⁴, a colorless oil (810 mg, yield: 79.86%). LCMS (ESI): m / z C 24 H 30 O5N3FNa + [M+Na] + Calculated value = 482.21, measured value = 482.1.

[0358] Step 4: Synthesis of intermediate 10-5

[0359] Intermediate 10⁻⁴ (600 mg, 1.31 mmol, 1 eq) was dissolved in 10 mL of methanol, and wet palladium on carbon (0.39 g, 10% purity) was added. The reaction mixture was stirred at 50°C for 17 hours under a hydrogen atmosphere (40 psi). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give intermediate 10⁻⁵ as a colorless oil (402 mg, crude product). LCMS (ESI): m / zC 16 H 25 N3O2F + [M+H] + Calculated value = 310.20, measured value = 310.2.

[0360] Step 5: Synthesis of intermediate 10-6

[0361] Intermediate 10-5 (500 mg, 1.62 mmol, 1 eq) was dissolved in 5 mL of DMF, and potassium carbonate (446.72 mg, 3.23 mmol, 2 eq) was added. The reaction mixture was stirred at 130°C for 1 hour. The reaction solution was filtered, the filtrate was diluted with 20 mL of water, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was then prepared by reversed-phase column chromatography (Phenomenex C18 75). 30mm 3µm; Mobile phase: [water (0.04% NH3H2O ​​+ 10mM NH4HCO3) - acetonitrile]; Gradient 50%-80% within 7 minutes. B) Intermediate 10⁻⁶ was obtained as a white solid (30 mg, yield: 6.41%). LCMS (ESI): m / z C 16 H 24 N3O2 + [M+H] + Calculated value = 290.19, measured value = 290.1.

[0362] Step 6: Synthesis of intermediate 10-7

[0363] Referring to step 4 of Example 2, 10⁻⁶ was prepared from intermediate 10⁻⁶ as a raw material, and it was a colorless oily substance. LCMS(ESI): m / z C 11 H 16 N3 + [M+H] + Calculated value = 190.14, measured value = 190.1.

[0364] Step 7: Synthesis of intermediate 10-8

[0365] Referring to step 5 of Example 2, intermediate 10-8 was prepared from intermediates 10-7 and 1-6a as raw materials. It is a colorless oily substance. LCMS (ESI): m / z C 24 H 39 N4O2 + [M+H] + Calculated value = 415.31, measured value = 415.3.

[0366] Step 8: Synthesis of intermediate 10-9

[0367] Following the method in step 5 of Example 3, intermediate 10-9 was prepared from intermediate 10-8 as a raw material, and was a colorless oily substance (22 mg, crude product). LCMS (ESI): m / z C19 H 31 N4 + [M+H] + Calculated value = 315.26, measured value = 315.2.

[0368] Step 9: Synthesis of Compound I-10

[0369] Referring to step 7 of Example 2, intermediates 10-9 and 1-8a were used as raw materials, and the mixture was subjected to reversed-phase column chromatography (column: Welch Ultimate C18 150). 25mm Compound I-10 was prepared as a white solid (14 mg) at 5 μm in a mobile phase of [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) - acetonitrile] and a gradient of 35%-65% B for 7 minutes. LCMS (ESI): m / z C 22 H 36 N5O + [M+H] + Calculated value = 386.29, measured value = 386.3. 1 HNMR (400MHz, CD3OD) δ ppm 7.89(d, J=4.4 Hz, 1H), 7.25 (d, J=7.0 Hz, 1H), 6.59 (dd, J=5.1, 7.0 Hz, 1H), 5.90(br d, J=7.9 Hz, 1H), 4.57 (d, J=2.4 Hz, 1H), 3.50-3.52 (m, 1H), 3.32 - 3.26(m, 1H), 3.05 (br t, J=10.7 Hz, 2H), 2.89 (s, 6H), 2.88 - 2.79 (m, 2H), 2.77- 2.68 (m, 1H), 2.49 - 2.42 (m, 2H), 2.13 (dt, J=3.2, 11.8 Hz, 1H), 2.05 -1.97 (m, 1H), 1.91 (br d, J=11.2 Hz, 3H), 1.87 - 1.80 (m, 2H), 1.78 - 1.64(m, 1H), 1.56 - 1.45 (m, 2H), 1.36 - 1.23 (m, 3H), 1.19 - 1.05 (m, 2H).

[0370] Example 11: Synthesis of Compound I-11

[0371] Step 1: Synthesis of Intermediate 11-2

[0372] Compound 11-1 (618.06 mg, 3.59 mmol, 2 eq) was dissolved in 10 mL of tetrahydrofuran, and a tetrahydrofuran solution of NaHMDS (1 M, 3.59 mL, 2 eq) was added dropwise with stirring at 0°C. After the addition was complete, intermediate 1-3 (500.00 mg, 1.80 mmol, 1 eq) was added to the above reaction system, and the reaction system was stirred at 0°C for 1 hour. The starting material was monitored for complete consumption by LCMS. The reaction solution was diluted with 30 mL of water, 30 mL of petroleum ether, and 50 mL of ethyl acetate. After separation of the organic phase, extraction was performed with 0.1 M HCl aqueous solution (10 mL × 2). The aqueous phases were combined and concentrated under reduced pressure to obtain the residue, which was then subjected to reversed-phase column chromatography (HPLC column: Xtimate C18 150). 40mm Intermediate 11-2 was prepared as a white solid (710 mg, yield 47.33%) using a mobile phase of [water (0.25% formic acid)-acetonitrile] and a gradient of 18%-48% B for 7 minutes. LCMS (ESI): m / z C 16 H 25 BrN3O2 + [M+H] + Calculated value = 370.12, measured value = 370.12, 371.9.

[0373] Step 2: Synthesis of Intermediate 11-3

[0374] A mixture of compounds 11-2 (130 mg, 351.08 μmol, 1 eq), Pd2(dba)3 (32.15 mg, 35.11 μmol, 0.1 eq), Xantphos (30.47 mg, 52.66 μmol, 0.15 eq), and Cs2CO3 (343.17 mg, 1.05 mmol, 3 eq) was dissolved in 3 mL of 1,4-dioxane. The system was evacuated and purged three times with nitrogen. The mixture was then microwave-stirred at 110 °C for 1 hour under a nitrogen atmosphere. LC-MS monitoring showed product formation. The reaction mixture was filtered and concentrated to the residue, and analyzed by high-performance liquid chromatography (column: Boston Green ODS 150). 30mm 5 μm, mobile phase: [water (0.25% formic acid) - acetonitrile], gradient: 15%-45% B, 6 min) to purify intermediate 11-3 as a white solid (100 mg, yield: 98.4%). LCMS (ESI): m / z C 16 H 24 N3O2 + [M+H] + Calculated value = 290.19, measured value = 290.30.

[0375] Step 3: Synthesis of intermediate 11-4

[0376] Referring to the method in step 4 of Example 2, intermediate 11-4 was prepared from intermediate 11-3 as raw material. It was a colorless oily substance (59 mg, TFA salt, crude product).

[0377] Step 4: Synthesis of intermediate 11-5

[0378] Referring to step 5 of Example 2, intermediate 11-5 was prepared from intermediates 11-4 and 1-6a as raw materials. It is a colorless oily substance. LCMS (ESI): m / z C 24 H 39 N4O2 + [M+H] + Calculated value = 415.31, measured value = 415.2.

[0379] Step 5: Synthesis of intermediate 11-6

[0380] Referring to the method in step 5 of Example 3, intermediate 11-6 was prepared from intermediate 11-5 as a raw material. This intermediate was a colorless oil (75 mg, TFA salt, crude product). LCMS (ESI): m / z C 19 H 31 N4 + [M+H] + Calculated value = 315.25, measured value = 315.2.

[0381] Step 6: Synthesis of Compound I-11

[0382] Referring to step 7 of Example 2, intermediates 11-6 and 1-8a were used as raw materials, and the mixture was subjected to reversed-phase column chromatography (column: Phenomenex C18 80). 40mm Compound I-11 was purified at 3 μm, mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) - acetonitrile], gradient: 35%-65% B, 7 min, as a white solid. LCMS (ESI): m / z C22 H 36 N5O + [M+H] + Calculated value = 386.29, Measured value = 386.2. 1 H NMR (400 MHz, CD3OD) δ ppm 7.78 (d, J=4.6 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.10 (dd, J=4.8, 8.3 Hz, 1H), 5.90 (br d, J=7.9Hz, 1H), 3.79 (br d, J=12.2 Hz, 1H), 3.52-3.47 (m, 1H), 3.12 - 2.93 (m, 4H), 2.92 - 2.76 (m, 8H), 2.51 - 2.40 (m, 2H), 2.26 - 2.14 (m, 1H), 2.06-2.03 (m,1H), 1.97 - 1.75 (m, 6H), 1.54 - 1.44 (m, 2H), 1.32-1.26 (m, 3H), 1.16 - 1.02(m, 2H).

[0383] Example 12: Synthesis of Compound I-12

[0384]

[0385] Step 1: Synthesis of Intermediate 12-2

[0386] Compound 10-3a (3.6 g, 16.1 mmol, 1 eq) and compound 12-1 (3.24 g, 32.2 mmol, 2 eq) were dissolved in 24 mL of NMP, and the reaction mixture was stirred at 130°C for 17 hours. LC-MS monitoring showed product formation. The reaction mixture was diluted with 60 mL of ethyl acetate and 60 mL of water. The organic phases were separated, and the aqueous solution was extracted with ethyl acetate (60 mL × 6). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solid residue from the concentrated filtrate under reduced pressure was subjected to rapid silica gel column chromatography (ISCO®; 20 g SepaFlash® silica gel column, eluent 0–30% ethyl acetate / petroleum ether, 30 mL / min) to give intermediate 12-2 as a colorless oil (3.2 g, 10.56 mmol, yield 65.39%). LCMS (ESI): m / z C9H 11 N3IO +[M+H] + Calculated value = 303.99, Measured value = 304.0.

[0387] Step 2: Synthesis of intermediate 12-3

[0388] Intermediate 12-2 (3 g, 9.90 mmol, 1 eq) was dissolved in 60 mL of DMF, and sodium hydride (792 mg, 19.8 mmol, 2 eq, 60%) and benzyl bromide (5.07 g, 29.7 mmol, 3.54 mL, 3 eq) were added. The reaction mixture was stirred at 20°C for 12 hours. The reaction solution was diluted with 60 mL of ethyl acetate and 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (70 mL). The organic layers were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solid residue from the concentrated filtrate under reduced pressure was subjected to silica gel column chromatography (ISCO®; 80 g SepaFlash® silica gel column, eluent 0–60% ethyl acetate / petroleum ether, 60 mL / min) to prepare intermediate 12-3 as a white solid (3.8 g, yield: 97.64%). LCMS (ESI): m / z C 16 H 17 N3IO + [M+H] + Calculated value = 394.04, measured value = 394.0.

[0389] Step 3: Synthesis of intermediate 12-4

[0390] Intermediate 12-3 (3.7 g, 9.41 mmol, 1 eq) was dissolved in 60 mL of tetrahydrofuran, and a tetrahydrofuran solution of LiHMDS (1 M, 11.29 mL, 1.2 eq) was slowly added dropwise. After the addition was complete, compound 12-3a (2.28 g, 18.82 mmol, 2 eq) was added dropwise to the above solution. The reaction system was then stirred at -78 °C for 1 hour. The reaction solution was poured into 60 mL of ethyl acetate and diluted with 100 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (70 mL). The organic layers were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The solid residue of the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (ISCO®; 80 g SepaFlash® silica gel column, eluent 0–60% ethyl acetate / petroleum ether, 60 mL / min). The intermediate 12-4 was obtained as a white solid (3.7 g, yield 90.75%). LCMS (ESI): m / z C 19 H 21N3IO + [M+H] + Calculated value = 434.08, measured value = 434.0. 1 H NMR (400MHz, CDCl3) δ ppm8.33 (dd, J=1.6, 4.6 Hz, 1H), 8.09 (dd, J=1.7, 7.7 Hz, 1H), 7.43 - 7.29 (m,5H), 6.76 (dd, J=4.6, 7.7 Hz, 1H), 5.90-5.84 (m, 1H), 5.10 - 4.96 (m, 2H), 4.77 - 4.60 (m, 3H), 3.67 - 3.51 (m, 1H), 3.43 - 3.28 (m, 2H), 3.22 - 3.11(m, 1H), 2.79-2.75 (m, 1H), 2.66 - 2.53 (m, 1H).

[0391] Step 4: Synthesis of intermediate 12-5: Intermediate 12-4 (2.4 g, 5.54 mmol, 1 eq) was dissolved in 30 mL of tetrahydrofuran, and 9-boronbicyclo[3.3.1]nonane (dimer) (1.47 g, 6.09 mmol, 1.1 eq) was added. The mixture was stirred at 20 °C for 1 hour. The reaction solution was concentrated to obtain a residue, which was then redissolved in 40 mL of 1,4-dioxane. Sodium carbonate (2 M, 5.54 mL, 2 eq) and Pd(PPh3)4 (320.04 mg, 276.95 μmol, 0.05 eq) were then added to the above solution. The system was microwaved at 120 °C for 2 hours. LCMS was used to monitor complete consumption of the starting materials and the formation of products. The reaction solution was diluted with 80 mL of ethyl acetate and 50 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (35 mL × 2). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The solid residue from the filtrate, concentrated under reduced pressure, was purified by silica gel column chromatography (ISCO®; 60 g SepaFlash® silica gel column, eluent 0-60% ethyl acetate / petroleum ether, 60 mL / min) to give intermediate 12-5 as a white solid (1.05 g, yield 61.67%). LCMS (ESI): m / z C 19 H 22 N3O + [M+H] + Calculated value = 308.17, measured value = 308.1. 1H NMR (400 MHz, CDCl3) δppm 8.10 (dd, J=1.8, 4.9 Hz, 1H), 7.40- 7.29 (m, 6H), 6.79 (dd, J=4.9, 7.3 Hz, 1H), 4.81 - 4.58 (m, 2H), 3.92 (dd,J=2.4, 11.3 Hz, 1H), 3.71 - 3.51 (m, 3H), 3.34 - 3.26 (m, 1H), 2.98 - 2.86(m, 1H), 2.70 (ddd, J=2.6, 9.4, 14.8 Hz, 1H), 2.54 - 2.41 (m, 1H), 2.15 -2.07 (m, 1H), 2.00 - 1.86 (m, 1H), 1.82 - 1.73 (m, 1H).

[0392] Step 5: Synthesis of intermediate 12-6

[0393] Following the method in step 6 of Example 9, intermediate 12-6 was prepared from intermediate 12-5 as a raw material. The intermediate was a colorless oil (830 mg, yield 82.81%). LCMS (ESI): m / z C 19 H 24 N3 + [M+H] + Calculated value = 294.20, measured value = 294.1.

[0394] Step 6: Synthesis of intermediate 12-7

[0395] Following the method in step 7 of Example 9, intermediate 12-7 was prepared from intermediate 12-6 as a raw material. The intermediate was a colorless oil (480 mg, crude product). LCMS (ESI): m / zC 12 H 18 N3 + [M+H] + Calculated value = 204.15, measured value = 204.1.

[0396] Step 7: Synthesis of intermediate 12-8

[0397] Following the method in step 5 of Example 2, intermediate 12-8 was prepared from intermediates 12-7 and 1-6a as raw materials. The intermediate was a colorless oil (80 mg, yield 7.9%). LCMS (ESI): m / z C 25 H 41 N4O2 + [M+H] +Calculated value = 429.33, measured value = 429.3.

[0398] Step 8: Synthesis of intermediates 12-9:

[0399] Following the method in step 5 of Example 3, intermediate 12-9 was prepared from intermediate 12-8 as a raw material, and was a colorless oily substance (61 mg, crude product). LCMS (ESI): m / z C 20 H 33 N4 + [M+H] + Calculated value = 329.27, Measured value = 329.4.

[0400] Step 9: Synthesis of Compound I-12

[0401] Referring to step 7 of Example 2, intermediates 12-9 and 1-8a were used as raw materials, and the mixture was subjected to reversed-phase column chromatography (column: Welch Ultimate C18 150). 25mm Compound I-12 was prepared as a white solid (5 μm); mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) - acetonitrile]; gradient: 38%-68% B, 7 min). LCMS (ESI): m / z C 23 H 38 N5O + [M+H] + Calculated value = 400.31, measured value = 400.3. 1H NMR (400MHz, CD3OD) δ ppm 8.05 (dd, J=1.8, 5.1 Hz, 1H), 7.42 (dd, J=1.7, 7.2 Hz, 1H), 6.86 (dd, J=5.1, 7.2 Hz, 1H), 5.89 (d, J=8.0 Hz, 1H), 3.69 (td, J=2.7, 12.8 Hz, 1H), 3.61 - 3.45 (m, 1H), 3.39 - 3.33 (m, 1H), 3.30-3.27 (m, 1H), 2.98 (d, J=11.1 Hz, 1H), 2.93 - 2.72(m, 9H), 2.54 - 2.45(m, 2H), 2.33 (dt, J=3.0, 11.2 Hz, 1H), 2.21 (t, J=10.6Hz, 1H), 1.93-1.90(m, 2H), 1.88 - 1.79 (m, 3H), 1.78 - 1.69 (m, 1H), 1.68 -1.57 (m, 2H), 1.54 - 1.46 (m, 2H), 1.36 - 1.22 (m, 3H), 1.16 - 1.03 (m, 2H).

[0402] Example 13: Synthesis of Compound I-13

[0403] Step 1: Synthesis of Intermediate 13-1

[0404] Compounds 13-1a (6 g, 24.74 mmol, 1 eq) and 13-2a (2.32 g, 32.17 mmol, 2.77 mL, 1.3 eq) were dissolved in 13 mL of DMF, and lithium acetate dihydrate (3.03 g, 29.69 mmol, 1.2 eq), lithium chloride (3.15 g, 74.23 mmol, 1.52 mL, 3 eq), tetrabutylammonium bromide (3.99 g, 12.37 mmol, 0.5 eq), and Pd(OAc)₂ (555.48 mg, 2.47 mmol, 0.1 eq) were added sequentially. The reaction mixture was stirred at 80 °C for 12 hours. LCMS monitoring showed complete consumption of the starting materials and product formation. TLC monitoring (petroleum ether:ethyl acetate = 2:1) showed the disappearance of the starting material spot and the formation of a new product spot. The reaction solution was diluted with 200 mL of water and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was then subjected to silica gel column chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, mobile phase gradient 0–30%, 50 mL / min) to prepare intermediate 13-1, a yellow oily substance (2.35 g). LCMS (ESI): m / z C 13 H 13 ClNO + [M+H] + Calculated value = 234.07, measured value = 234.1. 1 H NMR (400 MHz, CDCl3) δ ppm 9.78 (s, 1 H), 8.08 (d, J=8.56 Hz, 1 H), 7.81 (s, 1 H), 7.76 (d, J=8.31 ​​Hz, 1 H), 7.42 (dd, J=8.31, 1.59 Hz, 1H), 7.33 - 7.38 (m, 1 H), 2.88 (t, J=7.58 Hz, 2 H), 2.52 (td, J=7.27, 1.34Hz, 2 H), 2.02 - 2.12 (m, 2 H).

[0405] Step 2: Synthesis of Intermediate 13-2

[0406] Intermediate 12-7 (100 mg, 491.93 μmol, 1 eq) was dissolved in 2 mL of methanol, and sodium cyanoborohydride (155.03 mg, 2.46 mmol, 5 eq) and intermediate 13-1 (137.95 mg, 590.31 μmol, 1.2 eq) were added. The reaction mixture was stirred at 25°C for 2 hours. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. Intermediate 13-2 was prepared by silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent: 0-100% ethyl acetate / petroleum ether, 30 mL / min), as a pale yellow oil (107 mg, yield: 51.7%). LCMS (ESI): m / z C 25 H 30 ClN4 + [M+H] + Calculated value = 421.22, measured value = 421.2.

[0407] Step 3: Synthesis of Compound I-13

[0408] Intermediate 13-2 (97 mg, 230.42 μmol, 1 eq) was dissolved in 1 mL of acetic acid and 1 mL of water. The reaction mixture was stirred at 100°C for 8 hours. LC-MS monitoring showed complete consumption of the starting material and formation of the main product. The reaction solution was concentrated under reduced pressure to obtain the residue, which was then subjected to reversed-phase column chromatography (HPLC column: Phenomenex C18 80). 40mm Compound I-13 was purified at 3 μm, mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) - acetonitrile], gradient: 45%-75% B, 7 min, as a white solid (43 mg, 46% yield). LCMS (ESI): m / z C 25 H 31 N4O + [M+H] + Calculated value = 403.25, measured value = 403.2. 1 H NMR (400 MHz, CD3OD) δ ppm 8.02(dd, J = 1.8, 5.0 Hz, 1H), 7.93 (d, J = 9.5 Hz 1H), 7.63-7.56 (m, 1H), 7.39 (dd, J= 1.6, 7.2 Hz 1H), 7.24 -7.18(m, 1H), 7.18-7.12 (m, 1H), 6.86-6.79 (m, 1H), 6.58-6.52 (m, 1H), 3.73 - 3.58(m, 1H), 3.26 (br, d, J = 2.3 Hz, 2H), 2.92 (br, d, J = 11.3 Hz, 2H), 2.87-2.66 (m, 5H), 2.55-2.37 (m, 2H), 2.35 – 2.25 (m, 1H), 2.23 (br, d, J = 3.1Hz, 1H), 1.85-1.67 (m, 4H), 1.66-1.52 (m, 4H).

[0409] Example 14: Synthesis of Compound I-14

[0410]

[0411] Step 1: Synthesis of Intermediate 14-2

[0412] Compound 4-1 (3.0 g, 21.27 mmol, 1 eq) was dissolved in 24 mL of DMF, and potassium carbonate (8.82 g, 63.78 mmol, 3 eq) and compound 14-1 (6.24 g, 25.5 mmol, 1.2 eq) were added. The reaction mixture was stirred at 100°C for 16 hours. TLC monitoring (petroleum ether / ethyl acetate = 1 / 1) confirmed complete consumption of the starting material and product formation. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (100 mL × 3). After combining the organic phases, the reaction solution was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to the residue, and purified by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 40 mL / min) to give intermediate 14-2 as a yellow oil (7.29 g, yield 97.59%). LCMS (ESI): m / z C 16 H 22 N3O6 + [M+H] + Calculated value = 352.15, Measured value [M+H-56] + = 296.1.

[0413] Step 2: Synthesis of Intermediate 14-3

[0414] Intermediate 14-2 (8.1 g, 23.01 mmol, 1 eq) was dissolved in 10 mL of DMF, and iodomethane (6.54 g, 46.11 mmol, 2 eq) and potassium carbonate (9.57 g, 69.15 mmol, 3 eq) were added. The reaction mixture was stirred at 25°C for 2 hours. TLC monitoring (petroleum ether / ethyl acetate = 1 / 1) showed the formation of a new product spot. The reaction mixture was diluted with 180 mL of ethyl acetate and 180 mL of water, and the organic phases were separated. The aqueous phase was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to the residue, and then subjected to silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 40 mL / min) to prepare intermediate 14-3, a yellow oil (6.99 g, yield: 83.10%). LCMS (ESI): m / z C 17 H 24 N3O6 + [M+H] + Calculated value = 366.17, Measured value [M+H-56] + = 310.1.

[0415] Step 3: Synthesis of Intermediate 14-4

[0416] Intermediate 14-3 (2 g, 5.47 mmol, 1 eq) was dissolved in 10 mL of ethanol and 2 mL of water, and iron powder (3.06 g, 54.74 mmol, 10 eq) and ammonium chloride (2.93 g, 54.74 mmol, 10 eq) were added. The reaction mixture was stirred at 75°C for 0.5 h. TLC monitoring (petroleum ether / ethyl acetate = 1 / 1) showed complete consumption of the starting material and product formation. The reaction mixture was filtered under reduced pressure, and the filtrate was concentrated to give intermediate 14-4 as a yellow solid (375 mg, crude product). LCMS (ESI): m / zC 16 H 22 N3O3 + [M+H] + Calculated value = 304.17, Measured value [M+H-56] + = 248.1.

[0417] Step 4: Synthesis of Intermediate 14-5

[0418] Intermediate 14-4 (375 mg, 1.24 mmol, 1 eq) was dissolved in 6 mL of DMF, and iodomethane (263.19 mg, 1.85 mmol, 115.43 μL, 1.5 eq) and cesium carbonate (1.21 g, 3.71 mmol, 3 eq) were added. The reaction mixture was stirred at 25°C for 2 hours, and product formation was observed under LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was dissolved in 10 mL of water and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to the residue, and purified by silica gel column chromatography (ISCO®; 4 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 20 mL / min) to give intermediate 14-5 as a yellow oil (324 mg, yield 82.6%). LCMS (ESI): m / z C 17 H 23 N3O3Na + [M+Na] + Calculated value = 340.16, measured value = 340.0.

[0419] Step 5: Synthesis of intermediate 14-6

[0420] Following the method in step 6 of Example 2, intermediate 14-6 was prepared from intermediate 14-5 as a raw material, and was a yellow solid (223 mg, crude product). LCMS (ESI): m / z C 12 H 16 N3O + [M+H] + Calculated value = 218.13, measured value = 217.8.

[0421] Step 6: Synthesis of intermediate 14-7

[0422] Following the method in step 5 of Example 2, intermediate 14-7 was prepared from intermediates 14-6 and 1-6a as raw materials. The intermediate was a yellow oil (176 mg, yield 38.7%). LCMS (ESI): m / zC 25 H 39 N4O3 + [M+H] + Calculated value = 443.30, measured value = 443.2.

[0423] Step 7: Synthesis of intermediate 14-8

[0424] Following the method in step 6 of Example 2, intermediate 14-8 was prepared from intermediate 14-7 as a raw material. The intermediate was a gray solid (132 mg, crude product, HCl salt). LCMS (ESI): m / z C 20 H 31 N4O + [M+H] + Calculated value = 343.25, measured value = 342.9.

[0425] Step 8: Synthesis of compound I-14

[0426] Referring to step 7 of Example 2, intermediates 14-8 and 1-8a were used as raw materials, and the mixture was subjected to reversed-phase column chromatography (column: Phenomenex C18 80). 40mm Compound I-14 was purified at 3 μm, mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) - acetonitrile], gradient: 45%-75% B, 7 min, as a white solid (51 mg, yield 35.4%). LCMS (ESI): m / z C 23 H 36 N5O2 + [M+H] + Calculated value = 414.28, measured value = 414.4. 1 H NMR (400 MHz, CD3OD) δ ppm7.11 - 7.05 (m, 2H), 6.98 - 6.90 (m, 2H), 5.89 (br d, J=7.9 Hz, 1H), 3.61 (brd, J=11.6 Hz, 1H), 3.50 - 3.45 (m, 3H), 3.43 (s, 3H), 3.09 (br d, J=10.6 Hz,1H), 2.88 (s, 6H), 2.82 - 2.79 (m, 1H), 2.54 - 2.50 (m, 2H), 2.24 - 2.13 (m,2H), 1.92 - 1.83 (m, 4H), 1.53 - 1.47 (m, 2H), 1.32-1.26 (m, 3H), 1.14 - 1.07(m, 2H).

[0427] Example 15: Synthesis of Compound I-15

[0428] Following the synthetic method of I-13, intermediate 14-6 was used as the starting material, and the mixture was subjected to reversed-phase column chromatography (HPLC column: Welchxtimg C18 150). 30mm Compound I-15 was purified to a white solid at 5 μm (mobile phase: [water (0.25% formic acid)-acetonitrile], gradient: 5%-45% B, 9 min). LCMS (ESI): m / z C 25 H 29 N4O2 + [M+H] + Calculated value = 417.22, measured value = 417.1. 1 H NMR (400 MHz, CD3OD) δ ppm 7.93 (d, J = 9.4 Hz, 1H), 7.66 - 7.55(m, 1H), 7.26 - 7.14 (m, 2H), 7.12 - 7.03 (m, 2H), 7.01 - 6.86 (m, 2H), 6.61- 6.50 (m, 1H), 3.68 - 3.57 (m, 1H), 3.53 - 3.41 (m, 2H), 3.37 - 3.34 (m,3H), 3.16 - 3.04 (m, 1H), 2.88 - 2.73 (m, 3H), 2.63 - 2.52 (m, 2H), 2.34 -2.15 (m, 2H), 1.84 - 1.71 (m, 2H), 1.71 - 1.57 (m, 2H).

[0429] Example 16: Synthesis of Compound I-16

[0430]

[0431] Step 1: Synthesis of Intermediate 16-2

[0432] Intermediate 14-1 (2 g, 8.19 mmol, 1 eq) and intermediate 16-1 (1.3 g, 8.19 mmol, 1 eq) were dissolved in 8 mL of DMF, and DIEA (5.60 g, 43.4 mmol, 5.3 eq) was added. The reaction mixture was stirred at 100°C for 8 hours. LCMS was used to determine the completeness of the reaction. The reaction mixture was poured into 80 mL of water and extracted with ethyl acetate (2 × 80 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to the residue, and purified by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-20% petroleum ether / ethyl acetate, 25 mL / min) to obtain intermediate 16-2 as a yellow oil (2.3 g). LCMS (ESI): m / z C 16 H 23 N4O6 + [M+H] + Calculated value = 367.16, measured value = 367.1.

[0433] Step 2: Synthesis of Intermediate 16-3

[0434] Following the method in step 3 of Example 14, intermediate 16-3 was prepared from intermediate 16-2 as a raw material, and was a white solid (1.6 g). LCMS (ESI): m / z C 15 H 21 N4O3 + [M+H] + Calculated value = 305.16, measured value = 305.1.

[0435] Step 3: Synthesis of Intermediate 16-4

[0436] Intermediate 16-3 (1.4 g, 4.60 mmol, 1 eq) was dissolved in 10 mL of DMF, and sodium hydride (276.00 mg, 6.90 mmol, 60% purity, 1.5 eq) was added. The reaction mixture was stirred at 25 °C for 30 min, followed by the addition of iodomethane (979.39 mg, 6.90 mmol, 429.56 μL, 1.5 eq). The reaction mixture was stirred at 25 °C for another 30 min. TLC monitoring (petroleum ether: ethyl acetate = 2:1) confirmed complete consumption of the starting material. The reaction mixture was quenched with 30 mL of water and extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to the residue, and purified by silica gel column chromatography (ISCO®; 24 g SepaFlash® silica gel column, eluent 0-40% petroleum ether / ethyl acetate, 25 mL / min) to give intermediate 16-4 as a colorless oil (1.3 g). LCMS (ESI): m / z C 16 H 22 N4O3Na + [M+Na] + Calculated value = 341.16, measured value = 341.0.

[0437] Step 4: Synthesis of Intermediate 16-5

[0438] Following the method in step 6 of Example 2, intermediate 16-5 was prepared from intermediate 16-4 as a raw material. The intermediate was a gray solid (591 mg, crude product, HCl salt). LCMS (ESI): m / z C 11 H 15 N4O + [M+H] + Calculated value = 219.12, measured value = 218.8.

[0439] Step 5: Synthesis of intermediate 16-6

[0440] Intermediate 16-5 (150 mg, 588.89 μmol, 1 eq, HCl salt) was dissolved in 2 mL of DMF, and intermediate 6-5a (227.15 mg, 706.67 μmol, 1.2 eq) and triethylamine (178.77 mg, 1.77 mmol, 245.90 μL, 3 eq) were added sequentially. The reaction mixture was stirred at 85°C for 3 hours. The reaction was confirmed to be complete by LCMS. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to the residue, and purified by silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent 0-10% dichloromethane / methanol, 20 mL / min) to obtain intermediate 16-6 as a red oil (185 mg). LCMS (ESI): m / z C 24 H 38 N5O3 + [M+H] + Calculated value = 444.29, measured value = 444.2.

[0441] Step 6: Synthesis of intermediate 16-7

[0442] Following the method in step 6 of Example 2, intermediate 16-7 was prepared from intermediate 16-6 as a raw material, and was a grayish-brown solid (118 mg, crude product). LCMS (ESI): m / z C 19 H 30 N5O + [M+H] + Calculated value = 344.24, measured value = 343.9.

[0443] Step 7: Synthesis of Compound I-16

[0444] Referring to step 7 of Example 2, intermediates 16-7 and 1-8a were used as raw materials, and the mixture was subjected to reversed-phase column chromatography (column: Phenomenex C18 80). 40mm Compound I-16 was purified at 3 μm, mobile phase: [water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) - acetonitrile], gradient: 38%-68% B, 7 min, as a white solid (11 mg). LCMS (ESI): m / z C 22 H 35 N6O2 + [M+H] + Calculated value = 415.28, measured value = 415.4.1 H NMR (400 MHz, CD3OD) δ ppm 7.86 (d, J=3.7Hz, 1H), 7.32 (d, J=6.6 Hz, 1H), 6.85 (dd, J=5.1, 7.8 Hz, 1H), 5.89 (br d, J=8.1 Hz, 1H), 4.29 (br d, J=13.1 Hz, 1H), 3.89 (br d, J=7.4 Hz, 1H), 3.61-3.45(m, 2H), 3.33 (s, 3H), 3.05 (br d, J=7.3 Hz, 1H), 2.91-2.85 (m, 7H), 2.55 -2.47 (m, 2H), 2.18-2.10 (m, 2H), 1.94 - 1.81 (m, 4H), 1.55 - 1.44 (m, 2H), 1.32-1.23 (m, 3H), 1.13-1.07 (m, 2H).

[0445] Example 17: Synthesis of Compound I-17

[0446] Step 2: Synthesis of Intermediate 17-2

[0447] Referring to step 2 of Example 13, intermediate 17-2 was prepared from intermediates 16-5 and 13-1 as raw materials. It was a yellow oily substance (296 mg, crude product). LCMS (ESI): m / zC 24 H 27 ClN5O + [M+H] + Calculated value = 436.18, measured value = 436.1.

[0448] Step 3: Synthesis of Compound I-17

[0449] Referring to step 3 of Example 13, using intermediate 17-2 as raw material, the mixture was subjected to reversed-phase column chromatography (column: Boston Green ODS150). 30mm Compound I-17 was purified at 5 μm, mobile phase: [water (0.25% formic acid)-acetonitrile], gradient: 15% - 45% B, 6 min, as a white solid (18 mg). LCMS (ESI): m / z C 24 H 28 N5O2 + [M+H] +Calculated value = 418.22, measured value = 418.3. 1 H NMR (400 MHz, CD3OD) δ ppm 7.92 (d, J=9.4 Hz, 1H), 7.87 - 7.81(m, 1H), 7.63 - 7.54 (m, 1H), 7.34 - 7.26 (m, 1H), 7.25 - 7.11 (m, 2H), 6.87- 6.79 (m, 1H), 6.57 - 6.51 (m, 1H), 4.37 - 4.23 (m, 1H), 3.96 - 3.84 (m,1H), 3.55 - 3.40 (m, 1H), 3.31 (s, 3H), 3.12 (br d, J=12.5 Hz, 1H), 2.96 -2.73 (m, 3H), 2.66 - 2.55 (m, 2H), 2.41 - 2.12 (m, 2H), 1.81 - 1.70 (m, 2H), 1.69 - 1.59 (m, 2H).

[0450] Example 18: Synthesis of Compound I-18

[0451] Step 1: Synthesis of intermediate 18-2

[0452] Referring to step 5 of Example 2, intermediate 18-2 was prepared from intermediates 18-1 and 1-6a as raw materials. It was a colorless oily substance. LCMS (ESI): m / z C 25 H 40 N3O2 + [M+H] + Calculated value = 414.30, measured value = 414.4.

[0453] Step 2: Synthesis of intermediate 18-3

[0454] Referring to step 6 of Example 2, intermediate 18-3, a yellow oily substance, was prepared using intermediate 18-2 as a raw material. LCMS(ESI): m / z C 20 H 32 N3 + [M+H] + Calculated value = 314.25, measured value = 314.4.

[0455] Step 3: Synthesis of compound I-18

[0456] Referring to step 7 of Example 2, intermediates 18-3 and 1-8a were used as raw materials, and the mixture was subjected to reversed-phase column chromatography (HPLC column: Welchxtual C18 150). 30mm Compound I-18 was purified to a white solid at 5 μm (mobile phase: [water (formic acid)-acetonitrile]; gradient: 8%-48% B, 9 min). LCMS (ESI): m / z C 23 H 37 N4O + [M+H] + Calculated value = 385.29, measured value = 385.3. 1 H NMR (400 MHz, METHANOL-d4) δ ppm 7.09 - 7.02 (m, 1H), 6.97 (d, J =7.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.70 (t, J = 7.3 Hz, 1H), 3.96 (br d, J = 13.1 Hz, 1H), 3.54 - 3.44 (m, 1H), 3.27 - 3.19 (m, 1H), 3.15 - 3.02 (m,1H), 2.96 - 2.82 (m, 9H), 2.71-2.66 (m, 3H), 2.68 - 2.56 (m, 1H), 2.44 - 2.28(m, 1H), 2.01 - 1.94 (m, 1H), 1.94 - 1.88 (m, 2H), 1.87 - 1.79 (m, 2H), 1.79- 1.68 (m, 1H), 1.63 - 1.53 (m, 2H), 1.34 - 1.23 (m, 3H), 1.17 - 1.05 (m, 2H).

[0457] Example 19: Synthesis of Compound I-19

[0458] Step 1: Synthesis of Intermediate 19-2

[0459] Compound 8-7 (30 mg, 87.08 μmol, 1) eq Dissolve in 2 mL of methanol, and then add intermediate 19-1a (18.57 mg, 87.08 μmol, 1) sequentially. eq(Preparation method refers to patent WO2020 / 106627 A1) and sodium cyanoborohydride (32.83 mg, 522.46 μmol, 6) eq The reaction system was stirred at 25°C for 2 hours. TLC monitoring (dichloromethane / methanol = 10 / 1) showed complete consumption of the starting material and the formation of product spots. The reaction solution was concentrated under reduced pressure to obtain the residue, which was then used to prepare a thin-layer chromatography plate (developing solvent:dichloromethane:methanol = 10:1) to give intermediate 19-2, a colorless oil (47 mg, yield 99%). LCMS (ESI): m / z C 29 H 48 SiO3N5 + [M+H] + Calculated value = 542.35, measured value = 542.4.

[0460] Step 2: Synthesis of Intermediate 19-3

[0461] Intermediate 19-2 (47 mg, 86.75 μmol, 1) eq Dissolve in 2 mL of trifluoroacetic acid, stir at 25°C for 1 hour, then concentrate the reaction solution, add 3 mL of methanol and 1 mL of ammonia, 50 o Stirred again at C for 1 hour. LCMS monitoring showed the starting material disappeared. The reaction solution was concentrated under reduced pressure to give intermediate 19-3, a colorless oil (41 mg, crude product). LCMS (ESI): m / z C 18 H 26 N5 + [M+H] + = 312.22, Measured value = 312.3

[0462] Step 3: Synthesis of intermediate I-19

[0463] Referring to step 7 of Example 2, using intermediates 19-3 and 1-8a as raw materials, the mixture was subjected to reversed-phase column chromatography (column: Welch Ultimate C18 150). 25mm 5µm mobile phase: [water (0.04% NH3H2O ​​+ 10mM NH4HCO3) - acetonitrile]; gradient: 35%-65% B, 7 min) Compound I-19 was purified as a white solid (6.4 mg). LCMS (ESI): m / z C 21 H 31 N6O + [M+H] + Calculated value = 383.26, Measured value = 383.3. 1H NMR (400 MHz, METHANOL-d4) δ= 7.93 (d,J=5.8 Hz, 1H), 6.79 (s, 1H), 6.39 (d, J=5.8 Hz, 1H), 4.31 (br t, J=7.4 Hz,1H), 3.92 (br d, J=12.3 Hz, 1H),3.37 (br s, 1H), 3.18 (br t, J=11.3 Hz, 2H),3.13 - 3.00 (m, 2H), 2.90 (s, 6H), 2.85-2.78 (m, 1H), 2.49 - 2.41 (m, 2H),2.41 - 2.33 (m, 1H), 2.24 -2.12 (m, 4H), 2.12 - 2.05 (m, 2H), 1.85 - 1.77 (m,2H)

[0464] Example 20 Synthesis of compounds I-20, I-20A and I-20B

[0465] Following the synthetic method for I-19, compound I-20 was prepared from compound 10-7 as a starting material; it was a white solid. LCMS (ESI): m / z C 20 H 32 N5O + [M+H] + Calculated value = 358.27, measured value = 358.3. 1 H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J=4.5 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 6.57 (dd, J=5.1,7.2 Hz, 1H), 4.60 - 4.47 (m, 1H), 4.32-4.24 (m, 1H), 3.30 - 3.25 (m, 1H), 3.03 (br t, J=9.7 Hz, 2H), 2.92 - 2.78 (m, 8H), 2.75 - 2.67 (m, 1H), 2.40 -2.31 (m, 2H), 2.20 - 1.97 (m, 7H), 1.89 (t, J=10.9 Hz, 1H), 1.80 - 1.62 (m,3H).

[0466] Compound I-20 (7.21 mg) was further separated by chiral SFC under the following conditions: chiral column CHIRALPAKIC (size: 250 mm). 30 mm, particle size 10 μm), elution phase was CO2 (A): ethanol containing 0.1% ammonia (B), isogradient (A / B = 50 / 50). Compound I-20A was separated, with the first peak, as a white solid (2.25 mg). LCMS (ESI): m / z calculated value C 20 H 32 N5O + [M+H] + = 358.3, Measured value [M+H] + = 358.3. Compound I-20B was isolated, with a later peak, and was a white solid (2.24 mg). LCMS (ESI): m / z Calculated value C 20 H 32 N5O + [M+H] + = 358.3, Measured value [M+H] + =358.3. Chiral analysis conditions: Chiral column Chiralpak IC-3 (size: 100 mm) 4.6 mm (particle size 3 μm), elution phase was CO2 (A): ethanol containing 0.02% ethylenediamine (B), isogradient (B%: 50%%); flow rate 2.8 mL / min, column temperature 35°C; retention time of compound I-20A: 2.67 min; retention time of compound I-20B: 3.65 min.

[0467] Example 21 Synthesis of Compound I-21

[0468] Following the synthetic method for I-19, compound I-21 was prepared from compound 11-4 as a starting material; it was a white solid. LCMS (ESI): m / z C 20 H 32 N5O + [M+H] + Calculated value = 358.27, measured value = 358.3. 1H NMR (400 MHz, CD3OD) δ= 7.77 (d, J=4.3 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.09 (dd, J=4.7,8.4 Hz, 1H), 4.31-4.24 (m, 1H), 3.78 (br d,J=11.9 Hz, 1H), 3.10 - 3.00 (m,3H), 2.96 (dd, J=6.1, 12.0 Hz, 1H), 2.91 - 2.85 (m, 7H), 2.84 - 2.76 (m, 1H),2.40 - 2.33 (m, 2H), 2.25 - 2.09 (m, 4H), 2.09 -2.01 (m, 3H), 1.93 (t, J=10.9Hz, 1H), 1.86 - 1.71 (m, 3H).

[0469] Example 22 Synthesis of compounds I-22, I-22A and I-22B

[0470] Following the synthetic method for I-19, compound I-22 was prepared from compound 18-1 as a starting material; it was a white solid. LCMS (ESI): m / z C 21 H 33 N4O + [M+H] + Calculated value = 357.26, measured value = 357.4. 1 H NMR (400 MHz, METHANOL-d4) δ ppm 7.05 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.85(d, J = 8.3 Hz, 1H), 6.68 (t, J = 7.3 Hz, 1H), 4.34-4.27 (m, 1H), 3.85 (br d, J = 12.2 Hz, 1H), 3.16 - 3.07 (m, 1H), 3.06 - 2.96 (m, 2H), 2.95 - 2.66 (m,9H), 2.45 - 2.35 (m, 2H), 2.28 (dt, J= 3.2, 11.7 Hz, 1H), 2.23 - 1.89 (m, 7H), 1.85 - 1.71 (m, 3H).

[0471] Compound I-22 (168 mg) was further separated by chiral SFC under the following conditions: chiral column DAICELCHIRALCEL OJ (size: 250 mm). 30 mm, particle size 10 μm), elution phase was CO2 (A): ethanol containing 0.1% ammonia (B), isogradient (A / B = 80 / 20). Compound I-22A was separated, showing the first peak, as a white solid (68.3 mg, yield 40.7%). LCMS (ESI): m / z C 21 H 33 ON4 + [M+H] + Calculated value = 357.3, Measured value = 357.3. 1 H NMR (400 MHz, CD3OD) δ ppm 7.07 - 6.99 (m, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 8.2Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 4.35 - 4.21 (m, 1H), 3.87 - 3.77 (m, 1H),3.13 - 3.04 (m, 1H), 3.03 - 2.94 (m, 2H), 2.89 (s, 6H), 2.87 - 2.82 (m, 1H),2.82 - 2.74 (m, 1H), 2.74 - 2.66 (m, 1H), 2.41 - 2.32 (m, 2H), 2.28 - 2.20(m, 1H), 2.19 - 2.09 (m, 3H), 2.09 - 2.02 (m, 2H), 1.99 - 1.90 (m, 2H), 1.82 - 1.70 (m, 3H). Compound I-22B was isolated, with a later peak, as a white solid (69.5 mg, yield 41.3%). LCMS (ESI): m / z C 21 H 33 ON4 + [M+H] + Calculated value = 357.3, Measured value = 357.3. 1H NMR (400 MHz, CD3OD) δ ppm 7.07 - 6.99 (m, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 8.2Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 4.35 - 4.21 (m, 1H), 3.87 - 3.77 (m, 1H),3.13 - 3.04 (m, 1H), 3.03 - 2.94 (m, 2H), 2.89 (s, 6H), 2.87 - 2.82 (m, 1H),2.82 - 2.74 (m, 1H), 2.74 - 2.66 (m, 1H), 2.41 - 2.32 (m, 2H), 2.28 - 2.20 (m, 1H), 2.19 - 2.09 (m, 3H), 2.09 - 2.02 (m, 2H), 1.99 - 1.90 (m, 2H), 1.82 - 1.70 (m, 3H). Chiral analysis conditions: Instrument: Water s UPCC with PDA detector; Chiral column: ChiralCel OJ-H (specification: 150 mm). The column was prepared using a 4.6 mm (particle size 5 μm) elution phase of CO2 (A) followed by ethanol (B) containing 0.02% ethylenediamine, in a gradient (5% B to 40% B for 4.5 min, then 5% B for 1.5 min); the flow rate was 2.5 mL / min, and the column temperature was 40 °C. The retention time for compound I-22A was 3.30 min, and for compound I-22B it was 3.44 min. The retention times of the first peaks were consistent with those of the products prepared using the chiral synthesis method described below, thus determining the configuration.

[0472] Compound I-22A can also be prepared using the following chiral synthetic methods:

[0473]

[0474]

[0475]

[0476] Step 1: Synthesis of intermediate 18-1a-3

[0477] Compound 18-1a-1 (7.85 g, 27.74 mmol, 3.56 mL, 1.2...) eq) and compound 18-1a-2 (5 g, 23.12 mmol, 1 eq Dissolve it in 25 mL of DMSO, and then add cesium carbonate (15.06 g, 46.24 mmol, 2 mg) sequentially. eq ) and cuprous iodide (1.32 g, 6.94 mmol, 0.3 eq The reaction system was purged with nitrogen three times and stirred at 110°C for 16 hours. TLC monitoring (petroleum ether / ethyl acetate = 1 / 1) showed complete consumption of the starting material and product formation. The reaction system was diluted with 100 mL of water and extracted with ethyl acetate (100 mL × 2). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. Intermediate 18-1a-3 was prepared by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-60% ethyl acetate / petroleum ether, flow rate: 40 mL / min), as a yellow oil (3.1 g, yield: 36.0%). LCMS (ESI): m / z C 16 H 24 BrN2O3 + [M+H] + Calculated values ​​= 371.1, 373.1; Measured values ​​= 371.1, 373.1. 1 H NMR (400 MHz, CDCl3) δ ppm 7.63(dd, J = 1.4, 8.0 Hz, 1H), 7.35 - 7.29 (m, 1H), 7.25 - 7.16 (m, 1H), 7.11 -6.95 (m, 1H), 3.88 (dd, J = 2.7, 13.4 Hz, 1H), 3.78 - 3.67 (m, 1H), 3.63 -3.52 (m, 2H), 3.47 - 3.37 (m, 3H), 3.19 (ddd, J = 3.3, 5.4, 11.8 Hz, 1H), 2.76 (ddd, J = 3.2, 8.3, 11.7 Hz, 1H), 1.52 (s, 9H).

[0478] Step 2: Synthesis of intermediate 18-1a-4

[0479] Intermediate 18-1a-3 (1.4 g, 3.77 mmol, 1 eq) was dissolved in 15 mL of dichloromethane, and Dysmartin oxidant (2.40 g, 5.66 mmol, 1.75 mL, 1.5 eq) was added. The reaction mixture was stirred at 25 °C for 10 hours. TLC (petroleum ether:ethyl acetate = 4:1) showed complete consumption of the starting material and formation of the main product. The system was diluted with 30 mL of dichloromethane and 30 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). After combining the organic phases, the mixture was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then subjected to rapid silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent: 0-60% ethyl acetate / petroleum ether, flow rate: 30 mL / min) to prepare intermediate 18-1a-4 as a colorless oil (559.8 mg, yield: 40.22%). LCMS (ESI): m / z C 16 H 22 BrN2O3 + [M+H] + Calculated values ​​= 369.1, 371.1, Measured values ​​= 369.1, 371.1.

[0480] Step 3: Synthesis of intermediate 18-1a-6

[0481] Intermediate 18-1a-5 (4.41 g, 12.35 mmol, 2.4 g) was used. eq Dissolve in 40 mL of tetrahydrofuran and add potassium tert-butoxide (1.27 g, 11.32 mmol, 2.2 mmol). eq The reaction system was stirred at 25°C for 10 minutes. Intermediate 18-1a-4 (1.9 g, 5.15 mmol, 1...) was added dropwise to the above reaction solution. eq 10 mL of tetrahydrofuran was added dropwise. After the addition was complete, the reaction system was stirred at 60°C for 50 minutes. TLC monitoring showed complete consumption of the starting material and the formation of product spots. The reaction solution was concentrated under reduced pressure to obtain the residue, which was then subjected to rapid silica gel chromatography (ISCO®; 30 g SepaFlash® silica gel column, eluent: 0-20% ethyl acetate / petroleum ether, flow rate: 30 mL / min) to prepare intermediate 18-1a-6 as a colorless oil (1.79 g, yield: 95%). LCMS (ESI): m / z C 17 H 24 BrN2O2 + [M+H] +Calculated values ​​= 367.1, 369.1; Measured values ​​= 367.1, 369.1.

[0482] Step 4: Synthesis of intermediate 18-1a-7

[0483] Intermediate 18-1a-6 (800 mg, 2.18 mmol, 1 eq) was dissolved in 15 mL of tetrahydrofuran, and 9-boronbicyclo[3.3.1]nonane (dimer) (685.29 mg, 2.83 mmol, 1.3 eq) was added. eq The reaction system was stirred at 30 °C for 1 hour. The reaction solution was concentrated to obtain a residue, which was then redissolved with 15 mL of dioxane. Sodium carbonate (2 M, 2.18 mL, 2 eq) and Pd(PPh3)4 (125.85 mg, 108.91 μmol, 0.05 eq) were added sequentially to the above solution. The system was then microwaved at 120 °C for 2 hours. LCMS monitoring was used to confirm complete consumption of the starting materials and the formation of products. The reaction solution was diluted with 80 mL of ethyl acetate and 50 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (35 mL × 2). After the organic layers were combined, the mixture was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then subjected to silica gel column chromatography (ISCO®; 20 g SepaFlash® silica gel column, eluent: 0-20% ethyl acetate / petroleum ether, flow rate: 30 mL / min) to prepare intermediate 18-1a-7 as a colorless oil (603 mg, yield: 96%). LCMS (ESI): m / zC 17 H 25 N2O2 + [M+H] + Calculated value = 289.2, Measured value = 289.2.

[0484] Step 5: Synthesis of intermediate 18-1a

[0485] Intermediate 18-1a-7 (210 mg, 728.20 μmol, 1 eq) was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (6.64 g, 58.26 mmol, 4.33 mL, 80 eq) was added dropwise. The reaction mixture was stirred at 25 °C for 20 min. LCMS was used to monitor complete consumption of the starting material. The solvent was evaporated under reduced pressure to obtain intermediate 18-1a, a colorless oil (200 mg, crude trifluoroacetate). LCMS (ESI): m / z C 12 H 17 N2 + [M+H]+ Calculated value = 189.1, Measured value = 189.1.

[0486] Step 6: Synthesis of Compound I-22A

[0487] Following the synthetic method of compound I-19, and replacing the corresponding starting materials, compound I-22A was prepared using intermediate 18-1a as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 33 N4O + [M+H] + Calculated value = 357.2, Measured value = 357.2. Referring to the chiral analysis method of compound I-22 in Example 22, the retention time of the obtained compound in the chiral analysis method was 3.30 minutes, which is consistent with the retention time of product I-22A (precursor peak) obtained by chiral preparation and separation.

[0488] Example 23 Synthesis of Compound I-23

[0489] Following the synthetic method for I-19, compound I-23 was prepared from compound 5-4 as a starting material; it was a white solid. LCMS (ESI): m / z C 22 H 35 N4O3 + [M+H] + Calculated value = 403.27, measured value = 403.3. 1 H NMR (400 MHz, CD3OD) δ ppm 6.91 - 6.80 (m, 1H), 6.72 - 6.61 (m, 2H), 4.35 - 4.24 (m, 1H), 4.16 (td, J=5.4, 14.5 Hz, 4H), 3.07 (br s, 4H), 2.94 -2.80 (m, 6H), 2.74 -2.55 (m, 4H), 2.44 - 2.30 (m, 2H), 2.24 - 2.01 (m, 7H), 1.83 - 1.69 (m, 2H).

[0490] Example 24 Synthesis of compounds I-24A and I-24B

[0491] Compound I-24A:

[0492]

[0493] Step 1: Synthesis of intermediate 24A-2

[0494] Compound 24A-1 (5 g, 30.64 mmol, 1 eq) was dissolved in 30 mL of tetrahydrofuran, and triethylamine (9.30 g, 91.93 mmol, 12.80 mL, 3 eq) and di-tert-butyl dicarbonate (10.03 g, 45.96 mmol, 10.56 mL, 1.5 eq) were added. The mixture was stirred at 25 °C for 1 hour. TLC monitoring showed the formation of a product spot in the starting material. The reaction solution was evaporated to dryness under reduced pressure to obtain a residue, which was dissolved in 90 mL of ethyl acetate and washed with saturated ammonium chloride solution (20 mL × 3), followed by washing with saturated brine (30 mL). The residue was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain a residue. Intermediate 24A-2 was prepared by silica gel column chromatography (ISCO®; 40 g, SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 40 mL / min) as a yellow solid (5.9 g, yield: 73.13%). LCMS (ESI): m / z Calculated value C 14 H 18 NO4 + [M+H] + =264.12, Measured value [M+H-Boc] + = 164.1.

[0495] Step 2: Synthesis of intermediate 24A-3

[0496] Intermediate 24A-2 (5.9 g, 22.41 mmol, 1 eq) was dissolved in 30 mL of DMF, and intermediates glycine methyl ester hydrochloride (3.38 g, 26.89 mmol, 1.2 eq), DIEA (8.69 g, 67.23 mmol, 11.71 mL, 3 eq), and BOP (11.89 g, 26.89 mmol, 1.2 eq) were added sequentially. The reaction mixture was stirred at 25°C for 1 hour. TLC monitoring (petroleum ether / ethyl acetate = 10 / 1) showed complete consumption of the starting material and the formation of product spots. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (20 mL × 3). After combining the organic phases, the mixture was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then subjected to silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel flash column, eluent 0-100% ethyl acetate / petroleum ether, 40 mL / min) to prepare intermediate 24A-3 as a white solid (7.1 g, yield 94.8%). LCMS (ESI): m / z Calculated value C 17 H 23 N2O5 + [M+H] + = 335.16, Measured value [M+H-Boc] + = 235.1.

[0497] Step 3: Synthesis of intermediate 24A-4

[0498] Intermediate 24A-3 (7.1 g, 21.23 mmol, 1 eq) was dissolved in 8 mL of trifluoroacetic acid, and the mixture was stirred at 25°C for 0.5 h. TLC (ethyl acetate) was used to monitor complete consumption of the starting material and the formation of a product spot. The reaction solution was concentrated under reduced pressure to give intermediate 24A-4 as a yellow solid (5 g, crude product). LCMS (ESI): m / z Calculated value C 12 H 15 N2O3 + [M+H] + =235.11, Measured value [M+H] + = 235.0.

[0499] Step 4: Synthesis of intermediate 24A-5

[0500] Intermediate 24A-4 (7.4 g, 21.34 mmol, 1 eq) was dissolved in 50 mL of methanol, and sodium methoxide solution (11.53 g, 64.03 mmol, 30% purity, 3 eq) was added. The reaction mixture was stirred at 70°C for 1 hour. TLC monitoring (dichloromethane / methanol = 10 / 1) showed complete consumption of the starting material and the formation of a product spot. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was diluted with 30 mL of water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was then subjected to silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel flash column, eluent 0-10% dichloromethane / methanol, 40 mL / min) to obtain intermediate 24A-5 as a yellow solid (1.56 g, yield 36.2%). LCMS (ESI): m / z calculated value C 11 H 11 N2O2 + [M+H] + = 203.08, Measured value [M+H] + =203.0.

[0501] Step 5: Synthesis of intermediate 24A-6

[0502] Intermediate 24A-5 (400 mg, 1.98 mmol, 1 eq) was dissolved in 10 mL of tetrahydrofuran, and borane tetrahydrofuran solution (1 M, 5.93 mL, 3 eq) and sodium borohydride (299.35 mg, 7.91 mmol, 4 eq) were added sequentially under a nitrogen atmosphere. The reaction mixture was stirred at 70°C for 1 hour. TLC monitoring (dichloromethane / methanol = 10 / 1) showed complete consumption of the starting material and the formation of product spots. The reaction mixture was quenched by slow dropwise addition of methanol until no obvious bubbles were generated. The residue was then concentrated under reduced pressure and purified by silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel flash column, eluent 0-10% dichloromethane / methanol, 25 mL / min) to prepare intermediate 24A-6 as a yellow solid (220 mg, yield: 63.8%). LCMS (ESI): m / z calculated value C 11 H 15 N2 + [M+H] + = 175.12, Measured value [M+H] + = 175.0.

[0503] Step 6: Synthesis of intermediate 24A-7

[0504] Intermediate 24A-6 (200 mg, 1.15 mmol, 1 eq) was dissolved in 10 mL of methanol, and intermediate 19-1a (269.28 mg, 1.26 mmol, 1.1 eq) and sodium cyanoborohydride (216.39 mg, 3.44 mmol, 3 eq) were added sequentially. The reaction mixture was stirred at 25°C for 1 hour. TLC monitoring (petroleum ether / ethyl acetate = 3 / 1) showed complete consumption of the starting material and the formation of product spots. The reaction mixture was diluted with 15 mL of water and extracted with ethyl acetate (15 mL × 3). After combining the organic phases, the mixture was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. This residue was then subjected to silica gel column chromatography (ISCO®; 4 g SepaFlash® silica gel column, eluent 0-100% ethyl acetate / petroleum ether, 30 mL / min) to give intermediate 24A-7 as a white solid (174 mg, yield 40.72%). LCMS (ESI): m / zC 22 H 34 N3O2 + [M+H] + Calculated value = 372.26, [M+H] + Measured value = 372.2.

[0505] Step 7: Synthesis of intermediate 24A-8

[0506] Intermediate 24A-7 (170 mg, 457.59 μmol, 1 eq) was dissolved in 2 mL of trifluoroacetic acid, and the mixture was stirred at 25°C for 0.5 h. TLC (ethyl acetate) was used to monitor complete consumption of the starting material and the formation of a product spot. The reaction solution was concentrated under reduced pressure to give intermediate 24A-8 as a white solid (120 mg, crude product). LCMS (ESI): m / z C 17 H 26 N3 + [M+H] + Calculated value = 272.21, [M+H] + Measured value = 272.0.

[0507] Step 8: Synthesis of Compound I-24A

[0508] Intermediate 24A-8 (164.6 mg, 442 μmol, 1 eq) was dissolved in 2 mL of dichloromethane, and triethylamine (447.41 mg, 4.42 mmol, 10 eq) and dimethylcarbamoyl chloride (1-8a) (475.48 mg, 4.42 mmol, 10 eq) were added. The reaction mixture was stirred at 25°C for 1 hour. LC-MS monitoring showed product formation, indicating complete reaction of the starting materials. The reaction solution was diluted with 10 mL of water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was then purified by reversed-phase column chromatography (Phenomenonex C18 column; size: 80×30 mm; particle size: 5 mm; mobile phase: [phase A: water (0.05% NH3·H2O + 10mM NH4HCO3) - phase B: acetonitrile]; gradient: 40%-70% B, 7 min) to give compound I-24A as a white solid (60 mg, yield 39.6%). LCMS (ESI): m / z C 20 H 31 N4O + [M+H] + Calculated value = 343.25, [M+H] + Measured value = 343.3. 1 HNMR (400 MHz, CD3OD) δ ppm 7.12 - 6.95 (m, 2H), 6.61 (t, J = 7.4 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 4.27 (br d, J = 7.5 Hz, 1H), 3.62 (br dd, J = 1.3,11.6 Hz, 1H), 3.59 - 3.48 (m, 1H), 3.06 - 2.89 (m, 3H), 2.88 - 2.86 (m, 6H),2.86 - 2.81 (m, 1H), 2.54 (dd, J = 7.3, 15.0 Hz, 1H), 2.37 - 2.28 (m, 2H), 2.23 - 2.16 (m, 1H), 2.16 - 2.11 (m, 2H), 2.09 (br d, J = 6.6 Hz, 1H), 2.08 -1.97 (m, 3H), 1.79 - 1.69 (m, 2H).

[0509] Synthesis of compound I-24B:

[0510] Referring to the synthesis method of I-24A, with ( S Compound I-24B, a white solid, was prepared from α-indoline-2-carboxylic acid. LCMS (ESI): m / z C 20 H 31 N4O + [M+H] + Calculated value = 343.25, [M+H] + Measured value = 343.3. 1 HNMR (400 MHz, CD3OD) δ ppm 7.09 - 6.97 (m, 2H), 6.62 (t, J=7.3 Hz, 1H), 6.49 (d, J=7.7 Hz, 1H), 4.32 - 4.21 (m, 1H), 3.63 (br d, J=12.3 Hz, 1H), 3.54 (brd, J=7.5 Hz, 1H), 3.06 - 2.89 (m, 3H), 2.88 (s, 7H), 2.54 (dd, J=7.4, 15.0Hz, 1H), 2.33 (br dd, J=5.8, 8.4 Hz, 2H), 2.23 - 1.98 (m, 8H), 1.79 - 1.69 (m, 2H).

[0511] Example 25: Synthesis of Compound I-25

[0512]

[0513]

[0514] Following the chiral synthesis of I-22A in Example 22, and replacing the corresponding starting materials, compound I-25 was prepared using compound 25-1 as the starting material. It is a white solid. LCMS (ESI): m / z calculated value C 21 H 32 ClN4O + [M+H] + = 391.2, Measured value [M+H] + = 391.2. 1H NMR (400 MHz, CD3OD) δ ppm 7.11 - 7.03 (m, 1H), 6.92 -6.79 (m, 2H), 4.38 - 4.23 (m, 1H), 4.13 - 3.96 (m, 1H), 3.52 - 3.37 (m, 2H),3.21 - 3.11 (m, 1H), 3.01 - 2.88 (m, 8H), 2.87 - 2.73 (m, 4H), 2.62 - 2.49(m, 1H), 2.26 - 2.15 (m, 3H), 2.14 - 2.03 (m, 3H), 1.97 - 1.86 (m, 2H), 1.85- 1.69 (m, 1H).

[0515] Example 26: Synthesis of Compound I-26

[0516]

[0517]

[0518]

[0519] Following the chiral synthesis of I-22A in Example 22, and replacing the corresponding starting materials, compound I-26 was prepared using compound 26-1 as the starting material. It is a white solid. LCMS (ESI): m / z calculated value C 22 H 35 N4O2 + [M+H] + = 387.28, Measured value [M+H] + = 387.2. 1H NMR (400 MHz, CD3OD) δ ppm 7.14 - 7.00 (m, 1H), 6.64 -6.53 (m, 1H), 6.50 - 6.38 (m, 1H), 4.38 - 4.26 (m, 1H), 4.10 - 3.98 (m, 1H),3.47 (br d, J = 10.7 Hz, 1H), 3.39 (br d, J = 11.4 Hz, 1H), 3.33 (s, 3H), 3.17 - 3.05 (m, 1H), 2.97 - 2.78 (m, 11H), 2.65 - 2.52 (m, 2H), 2.25 - 2.15(m, 3H), 2.14 - 2.06 (m, 2H), 2.05 - 1.98 (m, 1H), 1.96 - 1.86 (m, 2H), 1.78- 1.64 (m, 1H).

[0520] Example 27: Synthesis of I-27

[0521]

[0522]

[0523] Step 1: Synthesis of Intermediate 27-1

[0524] Intermediate 26-2 (200 mg, 498.39 μmol, 1 eq) was dissolved in 10 mL of toluene, and BrettPhos Pd G3 (45.18 mg, 49.84 μmol, 0.1 eq) and cesium carbonate (324.77 mg, 996.77 μmol, 2 eq) were added. The reaction system was maintained at 120 °C under nitrogen protection. o Stirred at C for 12 hours. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was dissolved in 10 mL of ethyl acetate, washed with saturated ammonium chloride solution (5 mL × 2), washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Intermediate 27-1 was prepared by silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent: 0-100% ethyl acetate / petroleum ether, flow rate: 40 mL / min), as a colorless oil (80 mg). LCMS (ESI): m / z C 17 H 25 N2O4+ [M+H] + Calculated value = 321.18, Measured value = 321.1.

[0525] Step 2: Synthesis of Intermediate 27-2

[0526] Following the synthesis method in step 3 of Example 3, and replacing the corresponding starting materials, compound 27-2 was prepared using intermediate 27-1 as the starting material. This compound is a light yellow oily substance. LCMS (ESI): m / z C 12 H 17 N2O2 + [M+H] + Calculated value = 221.13, Measured value = 221.1.

[0527] Step 3: Synthesis of Compound I-27

[0528] Following the synthetic method for compound I-19, and replacing the corresponding starting materials, compound I-27 was prepared using intermediates 27-2 and 1-6a as starting materials. It was a white solid. LCMS (ESI): m / z C 23 H 37 N4O3 + [M+H] + Calculated value = 417.29, Measured value = 417.3. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 6.78 - 6.66 (m, 1H), 6.51 (d, J = 8.2 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 5.85 (d, J = 8.0 Hz, 1H), 4.25 (dd, J = 2.6, 10.6 Hz, 1H), 3.88 - 3.78 (m, 1H), 3.69 (s, 4H), 3.06 -2.85 (m, 3H), 2.75 (s, 6H), 2.70 - 2.54 (m, 2H), 2.39 - 2.28 (m, 2H), 2.16 -1.99 (m, 1H), 1.82 - 1.68 (m, 5H), 1.44 - 1.32 (m, 2H), 1.24 - 1.15 (m, 3H), 1.01 - 0.87 (m, 2H).

[0529] Example 28: Synthesis of I-28

[0530]

[0531]

[0532] Step 1: Synthesis of intermediate 28-7

[0533] Referring to the synthetic methods of compounds I-26 and I-27, and replacing the corresponding starting materials, compound 28-1 was used as the starting material (preparation method reference [J Org Chem, 2019, 84, 2911 - 2921], white solid). 1 ¹H NMR (400 MHz, CD₃Cl) δ ppm 7.57 - 7.46 (m, 3H), 7.45 - 7.39 (m, 2H), 7.39 - 7.33 (m, 1H), 7.03 - 6.96 (m, 1H), 6.95 - 6.87 (m, 1H), 5.17 (s, 2H), yielding intermediate 28-7, a white solid. LCMS (ESI): m / z C 29 H 41 N4O3 + [M+H] + Calculated value = 493.32, Measured value = 493.3.

[0534] Step 2: Synthesis of Compound I-28

[0535] Intermediate 28-7 (150 mg, 304.47 μmol, 1 eq) was dissolved in 20 mL of methanol, and palladium hydroxide (4.28 mg, 30.45 μmol, 0.1 eq) was added. The reaction system was evacuated and purged three times with hydrogen. The system was then incubated for 25 days in a hydrogen (15 psi) atmosphere. o The mixture was stirred at C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) monitored complete consumption of the starting material, and LCMS showed product formation. The reaction mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain the residue. Reverse-phase column chromatography (column specifications: Welch Ultimate C18 150×30mm; particle size: 5μm; mobile phase: [A phase: water (0.225% formic acid)-acetonitrile]; gradient: 65%-95% B, 7 min) yielded compound I-28 as a white solid (45 mg, yield: 36.71%). LCMS (ESI): m / z C 22 H 35 N4O3 + [M+H] + Calculated value = 403.27, measured value = 403.2.1 H NMR (400 MHz, DMSO- d6 )δ ppm 8.80 - 8.55 (m, 1H), 6.63 - 6.48 (m, 1H), 6.38 - 6.26 (m, 1H), 6.26 -6.17 (m, 1H), 5.97 - 5.74 (m, 1H), 4.34 - 4.15 (m, 1H), 3.94 - 3.77 (m, 1H), 3.63 (br d, J = 11.7 Hz, 1H), 3.05 - 2.87 (m, 3H), 2.75 (s, 6H), 2.66 - 2.53(m, 2H), 2.40 - 2.25 (m, 2H), 2.12 - 1.99 (m, 1H), 1.83 - 1.60 (m, 5H), 1.36 (q, J = 7.1 Hz, 2H), 1.28 - 1.09 (m, 3H), 1.06 - 0.84 (m, 2H).

[0536] Example 29: Synthesis of I-29

[0537]

[0538] Following the synthesis method of Example I-27, and replacing the corresponding starting materials, compound I-29 was prepared using intermediate 25-6 as the starting material. It is a white solid. LCMS (ESI): m / z C 23 H 36 ClN4O + [M+H] + Calculated value = 419.26, measured value = 419.3. 1H NMR (400 MHz, CD3OD) δ ppm 7.08 - 6.97 (m, 1H), 6.82 (d, J = 8.3 Hz,1H), 6.78 (d, J = 7.7 Hz, 1H), 5.91 (d, J = 8.0 Hz, 1H), 3.84 (d, J = 12.2Hz, 1H), 3.60 - 3.40 (m, 1H), 3.10 (d, J = 11.1 Hz, 1H), 3.06 - 2.93 (m, 3H), 2.89 (s, 6H), 2.85 - 2.68 (m, 2H), 2.53 - 2.44 (m, 2H), 2.28-2.24 (m, 1H),2.05 - 1.88 (m, 4H), 1.84 (d, J = 11.6 Hz, 2H), 1.72 (J = 3.9, 6.2 Hz, 1H), 1.55 - 1.46 (m, 2H), 1.35 - 1.22 (m, 3H), 1.16 - 1.03 (m, 2H).

[0539] Example 30: Synthesis of I-30

[0540] Intermediate 25-6 (95 mg, 282.12 μmol, 1 eq, TFA) and compound 30-1 (92.53 mg, 310.33 μmol, 1.1 eq) were dissolved in 30 mL of acetonitrile, and potassium carbonate (77.98 mg, 564.24 μmol, 2 eq) was added. The reaction system was heated at 80 °C. o The mixture was stirred at C for 1 hour. The starting material was monitored for complete consumption by LCMS. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue. Intermediate I-30 was prepared by silica gel column chromatography (ISCO®; 20 g SepaFlash® silica gel column, eluent: 0-100% ethyl acetate / petroleum ether, flow rate: 35 mL / min) as a white solid (30 mg, yield: 24.17%). LCMS (ESI): m / z C 25 H 31 ClN3O2 + [M+H] + Calculated value = 440.21, Measured value = 440.2. 1H NMR (400 MHz, CD3OD) δ ppm 7.14 - 6.98 (m, 2H), 6.79 (dd, J = 8.1, 16.1 Hz, 2H), 6.57 (dd,J = 2.5, 8.2 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 4.01(t, J = 5.8 Hz, 2H), 3.86- 3.75 (m, 1H), 3.09 (dd, J = 2.3, 11.2 Hz, 1H), 3.05 - 2.99 (m, 1H), 2.98 -2.92 (m, 1H), 2.88 (t, J = 7.5 Hz, 3H), 2.83 - 2.67 (m, 2H), 2.58 - 2.46 (m,4H), 2.26-2.22 (m, 1H), 2.02 - 1.90 (m, 2H), 1.87 - 1.66 (m, 5H).

[0541] Example 31: Synthesis of I-31

[0542] Intermediate 25-6 (60 mg, 178.18 μmol, 1 eq, TFA) and compound 31-1 (58.05 mg, 196.00 μmol, 1.1 eq) were dissolved in 10 mL of acetonitrile, and triethylamine (49.25 mg, 486.74 μmol, 67.75 μL, 2.73 eq) was added. The reaction system was heated at 50 °C. o The mixture was stirred at C for 1 hour. The starting material was monitored by LCMS to ensure complete consumption. The reaction mixture was hydraulically concentrated to a residue, which was then subjected to reversed-phase column chromatography (column specifications: Xtimate C18 150×40 mm; particle size: 10 μm; mobile phase: [phase A: water (0.225% formic acid)-acetonitrile]; gradient: 23%-53% B, 10 min) to prepare compound I-31 as a white solid (30 mg, yield: 38.44%). LCMS (ESI): m / z C 25 H 29 ClN3O2 + [M+H] + Calculated value = 438.19, measured value = 438.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 11.59 (s, 1H), 7.80 (d, J = 9.4 Hz,1H), 7.56 (d, J = 9.3 Hz, 1H), 7.07 - 6.99 (m, 1H), 6.89 - 6.71 (m, 4H), 6.29(dd, J = 1.5, 9.4 Hz, 1H), 4.05 (t, J = 6.4 Hz, 2H), 3.78 (d, J = 11.9 Hz,1H), 3.01 - 2.84 (m, 3H), 2.82 - 2.71 (m, 1H), 2.69 - 2.57 (m, 2H), 2.41 -2.31 (m, 2H), 2.07-2.03 (m, 1H), 1.94 - 1.85 (m, 1H), 1.83 - 1.69 (m, 3H), 1.68 - 1.51 (m, 3H).

[0543] Example 32: Synthesis of I-32

[0544] Following the synthesis method of Example I-27, and replacing the corresponding starting materials, compound I-32 was prepared using intermediate 26-6 as the starting material. It is a white solid. LCMS (ESI): m / z C 24 H 39 N4O2 + [M+H] + Calculated value = 415.31, measured value = 415.3. 1H NMR (400 MHz, CD3OD) δ ppm 7.03 (t, J = 8.3 Hz, 1H), 6.54 (d, J = 8.5Hz, 1H), 6.40 (d, J = 8.1 Hz, 1H), 5.91 (d, J = 7.9 Hz, 1H), 3.84 - 3.81 (m,1H), 3.79 (s, 3H), 3.55 - 3.45 (m, 1H), 3.09 - 3.06 (m, 1H), 3.00 - 2.98 (m,1H), 2.96 - 2.91 (m, 1H), 2.89 (s, 6H), 2.83 - 2.70 (m, 2H), 2.61 - 2.56 (m,1H), 2.49 - 2.39 (m, 2H), 2.29 - 2.16 (m, 1H), 1.96 - 1.91 (m, 4H), 1.86 -1.82 (m, 2H), 1.68 - 1.64 (m, 1H), 1.54 - 1.44 (m, 2H), 1.36 - 1.20 (m, 3H), 1.17 - 1.01 (m, 2H).

[0545] Example 33: Synthesis of I-33

[0546]

[0547]

[0548] Step 1: Synthesis of Intermediate 33-2

[0549] Compound 33-1 (3.6 g, 14.80 mmol, 1 eq) was dissolved in 4 M dioxane hydrochloride solution (18 mL). The reaction mixture was stirred at 25 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 6:1) was used to monitor complete consumption of the starting material and the formation of product. The reaction mixture was concentrated under reduced pressure to give intermediate 33-2 as a white solid (2.5 g, yield: 94.40%). 1 H NMR (400 MHz, CDCl3) δ ppm 8.30 (s, 3H), 3.95 (d, J = 1.3 Hz, 1H), 3.66 (s, 3H), 2.98-2.94 (m, 1H), 2.64 - 2.50 (m, 4H), 2.30 - 2.10 (m, 2H).

[0550] Step 2: Synthesis of intermediate 33-3

[0551] Intermediate 33-2 (2.5 g, 13.97 mmol, 1 eq) was dissolved in 30 mL of dichloromethane, and triethylamine (11.31 g, 111.75 mmol, 8 eq) was added. Compound 1-8a (7.51 g, 69.84 mmol, 6.41 mL, 5 eq) was added dropwise to the above solution. The reaction system was stirred at 25 °C for 2 hours. TLC (ethyl acetate:methanol = 10:1) showed the formation of a product spot. The reaction solution was concentrated under reduced pressure to the residue, and intermediate 33-3 was prepared by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent: 0-100% ethyl acetate (containing 10% methanol) / petroleum ether, flow rate: 40 mL / min) as a colorless oil (2.5 g, yield: 83.53%). 1 H NMR (400 MHz, CDCl3) δ ppm 4.42-4.34 (m, 1H), 3.68 (s, 3H), 2.91 (s, 6H), 2.69 - 2.58 (m, 1H), 2.58 - 2.51(m, 2H), 2.23 - 2.14 (m, 2H), 2.13 - 2.03 (m, 2H).

[0552] Step 3: Synthesis of intermediate 33-4

[0553] Intermediate 33-3 (2.5 g, 11.67 mmol, 1 eq) was dissolved in 50 mL of tetrahydrofuran, and a DIBAL-H toluene solution (1 M, 35.00 mL, 3 eq) was slowly added dropwise at 0 °C. The reaction system was protected under nitrogen and stirred at 0 °C for 1 hour. TLC (ethyl acetate:methanol = 10:1) was used to monitor complete consumption of the starting material and the formation of a product spot. Sodium sulfate decahydrate (5 g) was added to the system, and stirring was continued for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then subjected to silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent: 0-100% ethyl acetate (containing 10% methanol) / petroleum ether, flow rate: 40 mL / min) to prepare intermediate 33-4 as a colorless oil (1.82 g, yield: 83.53%). 1H NMR(400 MHz, CDCl3) δ ppm 4.41 - 4.27 (m, 1H), 3.59 (t, J = 6.6 Hz, 2H), 2.88(s, 6H), 2.15 - 2.08 (m, 2H), 2.03 - 1.93 (m, 4H), 1.81 - 1.69 (m, 2H).

[0554] Step 4: Synthesis of intermediate 33-5

[0555] Intermediate 33-4 (3.4 g, 18.25 mmol, 1 eq) was dissolved in 50 mL of acetonitrile, and IBX (20.45 g, 73.02 mmol, 4 eq) was added. The reaction mixture was stirred at 80 °C for 1 hour. TLC (ethyl acetate:methanol = 10:1) showed that the starting material reacted completely and a product was formed. The reaction mixture was concentrated under reduced pressure to the residue, and intermediate 33-5 was prepared by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent: 0-100% ethyl acetate (containing 10% methanol) / petroleum ether, flow rate: 50 mL / min), as a light yellow oil (2.79 g, yield: 82.96%).

[0556] 1 H NMR (400 MHz, CDCl3) δ ppm 9.75 (s, 1H), 4.43-4.35 (m, 1H), 2.90 (s, 6H), 2.73 - 2.64 (m, 3H), 2.20 - 2.09 (m, 4H).

[0557] Step 5: Synthesis of intermediate 33-6

[0558] Referring to the synthesis method of intermediate 18-1a in the chiral synthesis method of Example 22, and replacing the corresponding starting materials, intermediate 33-6 was prepared using compound 2-bromo-1-fluoro-3-iodobenzene as the starting material. This intermediate was a colorless oil. LCMS (ESI): m / z calculated value C 12 H 16 FN2 + [M+H] + = 207.27, Measured value [M+H] + = 207.2.

[0559] Step 6: Synthesis of Compound I-33

[0560] Intermediate 33-6 (155.28 mg, 484.83 μmol, 1 eq) (prepared according to the method for intermediate 25-6 in Example 25, using 2-bromo-1-fluoro-3-iodobenzene as the starting material) was dissolved in 10 mL of methanol, and intermediate 33-5 (178.64 mg, 969.66 μmol, 2 eq) and sodium cyanoborohydride (91.40 mg, 1.45 mmol, 3 eq) were added sequentially. The reaction system was stirred at 25 °C for 2 hours. The reaction solution was diluted with 20 mL of water and extracted with ethyl acetate (20 mL × 3). After combining the organic phases, the mixture was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. Compound I-33 was prepared as a white solid (40 mg, yield: 22.03%) by reversed-phase column chromatography (column type: C18 150×30 mm; mobile phase: phase A: water (0.05% NH3H2O ​​+ 10 M NH4HCO3) - phase B: acetonitrile; gradient: 65%-95% B, 7 min). LCMS (ESI): m / z calculated value C 21 H 32 FN4O + [M+H] + = 375.26, Measured value [M+H] + = 375.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.03-7.00 (m, 1H), 6.65 (d, J =8.6 Hz, 1H), 6.45 (t, J = 8.6 Hz, 1H), 6.34 (d, J = 7.4 Hz, 1H), 4.23 - 4.07(m, 1H), 3.76 (d, J = 11.9 Hz, 1H), 2.98 - 2.83 (m, 3H), 2.75 (s, 6H), 2.71 -2.53 (m, 3H), 2.22 (t, J = 7.3 Hz, 2H), 2.09 - 1.98 (m, 4H), 1.93 - 1.83 (m,3H), 1.74 (t, J = 11.3 Hz, 1H), 1.65 - 1.50 (m, 3H).

[0561] Example 34: Synthesis of I-34

[0562] Referring to the synthesis method of Example 33 and the synthesis method of intermediate 18-1a in the chiral synthesis method of Example 22, and replacing the corresponding starting materials, compound I-34 was prepared from compound 2-bromo-4-fluoro-1-iodobenzene as the starting material. It is a white solid. LCMS (ESI): m / z calculated value C 21 H 32 FN4O + [M+H] + = 375.26, Measured value [M+H] + = 375.3. 1 H NMR (400 MHz, DMSO-) d6 ) δ ppm 6.87 - 6.73 (m, 3H), 6.34 (d, J = 7.4 Hz, 1H), 4.22- 4.11 (m, 1H), 3.70 - 3.68 (m, 1H), 2.97 - 2.78 (m, 4H), 2.75 (s, 6H), 2.69- 2.56 (m, 2H), 2.24 (t, J = 7.3 Hz, 2H), 2.12 - 1.99 (m, 4H), 1.92 - 1.74(m, 4H), 1.67 - 1.53 (m, 3H).

[0563] Example 35: Synthesis of I-35

[0564] Referring to the synthesis method of Example 33 and the synthesis method of intermediate 18-1a in the chiral synthesis method of Example 22, and replacing the corresponding starting materials, compound I-35 was prepared from compound 1-bromo-4-fluoro-2-iodobenzene as the starting material. It is a white solid. LCMS (ESI): m / z calculated value C 21 H 32 FN4O + [M+H] + = 375.26, Measured value [M+H] + = 375.2. 1 H NMR (400 MHz, DMSO-) d6) δ ppm 6.95 - 6.86 (m, 1H), 6.69 - 6.43 (m, 1H), 6.44 -6.28 (m, 2H), 4.16 (d, J = 7.4 Hz, 1H), 3.72 (d, J = 12.4 Hz, 1H), 2.98 -2.86 (m, 3H), 2.75 (s, 6H), 2.71 - 2.54 (m, 3H), 2.24 (t, J = 7.0 Hz, 2H), 2.10 - 1.99 (m, 4H), 1.92 - 1.83 (m, 3H), 1.75 (t, J = 10.6 Hz, 1H), 1.66 -1.51 (m, 3H).

[0565] Example 36: Synthesis of I-36

[0566] Referring to the synthesis method in Example 33 and the synthesis method of intermediate 18-1a in the chiral synthesis method of Example 22, and replacing the corresponding starting materials, compound I-36 was prepared from compound 1-bromo-3-fluoro-2-iodobenzene as a starting material. It is a white solid. LCMS (ESI): m / z calculated value C 21 H 32 FN4O + [M+H] + = 375.26, Measured value [M+H] + = 375.2. 1 H NMR (400 MHz, DMSO-) d6 ) δ ppm 7.03-6.97 (m, 1H), 6.65 (d, J = 8.5 Hz, 1H), 6.44(t, J = 8.6 Hz, 1H), 6.34 (d, J = 7.3 Hz, 1H), 4.26 - 4.06 (m, 1H), 3.75 (d,J = 11.8 Hz, 1H), 2.96 - 2.84 (m, 3H), 2.79 - 2.72 (m, 6H), 2.70 - 2.55 (m,3H), 2.22 (t, J = 7.3 Hz, 2H), 2.12 - 1.98 (m, 4H), 1.94 - 1.82 (m, 3H), 1.74(t, J = 11.2 Hz, 1H), 1.66 - 1.50 (m, 3H).

[0567] Example 37: Synthesis of I-37

[0568]

[0569]

[0570]

[0571] Step 1: Synthesis of Intermediate 37-1

[0572] Intermediate 25-4 (3 g, 7.47 mmol, 1 eq) was dissolved in 30 mL of tetrahydrofuran, and 9-BBN dimer (2.35 g, 9.71 mmol, 1.3 eq) was added. The reaction mixture was stirred at 50 °C for 1 hour. Subsequently, hydrogen peroxide (3.27 g, 28.83 mmol, 2.77 mL, 30% purity, 3.86 eq) was added dropwise to the mixture while stirring at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 30 minutes, and then 2 M sodium hydroxide aqueous solution (3.73 mL) was added. The reaction mixture was stirred for another 1.5 hours. LCMS monitoring showed product formation. The reaction solution was quenched with 20 mL of saturated sulfurous acid solution, then extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then separated by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent: 0-50% ethyl acetate / petroleum ether, flow rate: 35 mL / min) to obtain intermediate 37-1 as a colorless oil (3.0 g, yield: 95.71%). LCMS (ESI): m / z Calculated value C 17 H 25 BrClN2O3 + [M+H] + = 419.07, 421.07, Measured value [M+H] + =419.1, 421.2.

[0573] Step 2: Synthesis of Intermediate 37-2

[0574] Intermediate 37-1 (3.0 g, 7.15 mmol, 1 eq) was dissolved in 60 mL of acetonitrile, and 2-iodobenzoic acid (IBX) (8.01 g, 28.59 mmol, 4 eq) was added. The reaction mixture was stirred at 70 °C for 2 hours. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then separated by silica gel column chromatography (ISCO®; 80 g SepaFlash® silica gel column, eluent: 0-30% ethyl acetate / petroleum ether, flow rate: 50 mL / min) to obtain intermediate 37-2 as a colorless oil (2.4 g, yield: 80.39%). LCMS (ESI): m / z Calculated value C 17 H 23 BrClN2O3 + [M+H] + = 417.0, 419.06 Measured values ​​[M+H] + = 417.2, 419.2.

[0575] Step 3: Synthesis of Intermediate 37-3

[0576] Following the synthetic method of step 3 in the chiral synthesis of I-22A in Example 22, and replacing the corresponding starting materials, intermediate 37-2 was used as the starting material. Compound 37-3 was prepared as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.26- 7.17 (m, 2H), 6.97 (s, 1H), 5.72 - 5.56 (m, 1H), 5.05 - 4.90 (m, 2H), 3.83- 3.04 (m, 6H), 2.67 (d, J = 1.5 Hz, 1H), 2.34 - 2.09 (m, 1H), 2.02 (s, 1H), 1.49 (s, 9H).

[0577] Step 4: Synthesis of intermediate 37-4

[0578] Intermediate 37-3 (2.8 g, 6.73 mmol, 1 eq) was dissolved in 10 mL of DMF, and Pd(OAc)₂ (151.20 mg, 673.48 μmol, 0.1 eq), triethylamine (2.04 g, 20.20 mmol, 2.81 mL, 3 eq), lithium chloride (342.62 mg, 8.08 mmol, 165.68 μL, 1.2 eq), and triphenylphosphine (353.29 mg, 1.35 mmol, 0.2 eq) were added sequentially. The reaction system was stirred at 115 °C for 10 hours under nitrogen protection. LCMS monitoring showed complete consumption of the starting materials and product formation. The reaction solution was diluted with 100 mL of ethyl acetate and 100 mL of water, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). After combining the organic phases, the mixture was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then separated by silica gel column chromatography (ISCO®; 60 g SepaFlash® silica gel column, eluent: 0-20% ethyl acetate / petroleum ether, flow rate: 50 mL / min) to obtain intermediate 37-4 as a colorless oil (1.6 g, yield: 70.95%). LCMS (ESI): m / z Calculated value C 18 H 24 ClN2O2 + [M+H] + = 335.85 measured value [M+H] + = 335.8. H NMR (400 MHz, CDCl3) δ ppm 7.03 (t, J = 8.2 Hz, 1H), 6.83 (d,J = 7.3 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 5.72 (s, 1H), 5.35 (s, 1H), 4.18 -3.96 (m, 2H), 3.76 (d, J = 11.8 Hz, 1H), 3.22-3.18 (m, 1H), 3.10 - 2.99 (m,1H), 2.97 - 2.88 (m, 1H), 2.80 - 2.68 (m, 1H), 2.65-2.60 (m, 1H), 2.41 - 2.35(m, 1H), 1.49 (s, 9H).

[0579] Step 5: Synthesis of Intermediate 37-5

[0580] Intermediate 37-4 (450 mg, 1.34 mmol, 1 eq) was dissolved in 20 mL of dioxane and 4 mL of water, and then potassium osmium tetroxide dihydrate (49.52 mg, 134.39 μmol, 0.1 eq) and sodium periodate (2.30 g, 10.75 mmol, 8 eq) were added sequentially. The reaction mixture was stirred at 20 °C for 5 hours. LCMS was used to monitor complete consumption of the starting material and the formation of the product. The reaction solution was diluted with 30 mL of ethyl acetate and 30 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium sulfite solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then separated by silica gel column chromatography (ISCO®; 80 g SepaFlash® silica gel column, eluent: 0-30% ethyl acetate / petroleum ether, flow rate: 50 mL / min) to obtain intermediate 37-5 as a colorless oil (150 mg, yield: 33.14%). LCMS (ESI): m / z Calculated value C 17 H 22 ClN2O3 + [M+H] + = 337.82 measured value [M- t Bu+H] + = 281.2.

[0581] Step 6: Synthesis of Compound I-37

[0582] Following the synthetic method of steps 5 and 6 in the chiral synthesis of I-22A in Example 22, and replacing the corresponding starting materials, compound I-37 was prepared using intermediates 37-5 and 33-5 as starting materials. It is a white solid. LCMS (ESI): m / z calculated value C 21 H 30 ClN4O2 + [M+H] + = 405.21, Measured value [M+H] + = 405.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 7.40 - 7.29 (m, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.82 (d, J = 7.6 Hz,1H), 6.34 (d, J = 7.3 Hz, 1H), 4.26 - 4.09 (m, 1H), 3.89 (d, J = 11.9 Hz,1H), 3.47 - 3.41 (m, 1H), 3.06 - 2.95 (m, 2H), 2.76 (s, 7H), 2.63 - 2.53 (m,2H), 2.32 - 2.20 (m, 2H), 2.14-2.12 (m, 1H), 2.09 - 2.00 (m, 3H), 1.95 - 1.84 (m, 3H), 1.65-1.60 (m, 2H). Compound I-37 (60 mg) was further separated by chiral SFC under the following conditions: chiral column DAICEL CHIRALPAK AD (size: 250 mm × 30 mm, particle size 10 μm), eluent CO2 (A): ethanol containing 0.1% ammonia (B), isogradient (A / B = 50 / 50). Compound I-37a was separated, showing the first peak as a white solid (25 mg, ee value: 99%). Compound I-37b was separated, showing the last peak as a white solid (27 mg, ee value: 100%). Chiral analysis conditions: Instrument: Waters UPCC with PDA detector; Chiralpak AD-3 chiral column (size: 50 mm × 4.6 mm, particle size 3 μm); eluent: CO2 (A): methanol containing 0.05% ethylenediamine (B), isogradient (A / B = 60 / 40); flow rate: 4.0 mL / min; column temperature: 35 °C; retention time of compound I-37a: approximately 0.72 min; retention time of compound I-37b: 1.08 min.

[0583] Example 38: Synthesis of I-38

[0584]

[0585]

[0586]

[0587] Step 1: Synthesis of Intermediate 38-1

[0588] Following the synthetic method of step 1 in Example 37, and replacing the corresponding starting materials, compound 38-1 was prepared using intermediate 18-1a-6 as the starting material. It is a colorless oil. LCMS (ESI): m / z calculated value C 17 H 26 BrN2O3 + [M+H] + =385.11, 387.11. Measured values ​​[M+H] + = 385.1, 387.1. 1 H NMR (400 MHz, CDCl3) δ ppm7.61 (d, J = 8.0 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.10 (d, J = 6.4 Hz, 1H), 6.99(t, J = 7.4 Hz, 1H), 3.88 - 3.44 (m, 8H), 3.27-3.25 (m, 1H), 2.72-2.70 (m,1H), 1.67 - 1.60 (m, 2H), 1.51 (s, 9H).

[0589] Step 2: Synthesis of Intermediate 38-2

[0590] Intermediate 38-1 (3 g, 7.79 mmol, 1 eq) was dissolved in 10 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. The reaction mixture was stirred at 25 °C for 20 min. LCMS monitoring showed complete consumption of the starting material and formation of product. The reaction solution was concentrated under reduced pressure to give intermediate 38-2, a pale yellow oil (2 g, crude product). LCMS (ESI): m / z Calculated value C 12 H 18 BrN2O + [M+H] + = 285.06, 287.06. Measured values ​​[M+H] + = 285.0, 287.1.

[0591] Step 3: Synthesis of intermediate 38-3

[0592] Intermediate 38-2 (2.8 g, 7.01 mmol, 1 eq) was dissolved in 80 mL of dichloromethane solution, and 30 mL of an aqueous solution containing sodium bicarbonate (2.95 g, 35.07 mmol, 5 eq) was added. At 0 °C, benzyloxyformyl chloride (1.79 g, 10.52 mmol, 1.5 eq) was added dropwise to the above system. After the addition was complete, the reaction system was stirred at 20 °C for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1) was used to monitor complete consumption of the starting material and the formation of product. The reaction solution was diluted with 100 mL of water, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then separated by silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent: 0-60% ethyl acetate / petroleum ether, flow rate: 50 mL / min) to obtain intermediate 38-3 as a colorless oil (1.7 g, yield: 57.81%). LCMS (ESI): m / z Calculated value C 20 H 24 BrN2O3 + [M+H] + =419.10, 421.10 Measured values ​​[M+H] + = 419.1, 421.0.

[0593] Step 4: Synthesis of intermediate 38-6

[0594] Following the synthetic method of steps 2-4 in Example 37, and replacing the corresponding starting materials, intermediate 38-3 was used as the starting material. Compound 38-6 was prepared, which is a light green oily substance. LCMS (ESI): m / z calculated value C 21 H 23 N2O2 + [M+H] + =335.18 Measured value [M+H] + = 335.1.

[0595] Step 4: Synthesis of Compound I-38

[0596] Intermediate 38-6 (82.65 mg, 247.16 μmol, 1 eq) and intermediate 33-5 (54.64 mg, 296.60 μmol, 1 eq) were dissolved in ethanol. Under nitrogen protection, palladium hydroxide on carbon (315.08 mg, 10% purity) was added. The reaction system was evacuated and purged with nitrogen three times, followed by purging with hydrogen. The system was stirred at 50°C for 12 hours under a hydrogen atmosphere (15 Psi). LCMS monitoring showed complete consumption of the starting materials and product formation. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to reversed-phase column chromatography (column type: Welch Xtimate C18 150×30mm; mobile phase: A phase: water (0.08% NH4HCO3) - B phase: acetonitrile; gradient: 50%-80% B, 7 min) to prepare compound I-38 as a white solid (35.71 mg, yield: 39.0%). LCMS (ESI): m / z calculated value C 22 H 35 N4O + [M+H] + = 371.28, Measured value [M+H] + = 371.3. Compound I-38 (35.71 mg) was further separated by chiral SFC under the following conditions: chiral column DAICEL CHIRALPAK AD (size: 250 mm × 30 mm, particle size 10 μm), eluent CO2 (A): ethanol containing 0.1% ammonia (B), isogradient (A / B = 30 / 70). Compound I-38a was separated, showing the first peak as a white solid (13 mg, ee value: 99%). Compound I-38b was separated, showing the last peak as a white solid (12 mg, ee value: 100%). Chiral analysis conditions: Instrument: Waters UPCC with PDA detector; Chiralpak IG-3 chiral column (size: 100 mm × 4.6 mm, particle size 3 μm); eluent: CO2 (A): methanol containing 0.05% ethylenediamine (B), isogradient (A / B = 60 / 40); flow rate: 2.8 mL / min; column temperature: 35 °C; retention time for compound I-38a: approximately 2.72 min; retention time for compound I-38b: 6.45 min.

[0597] Example 39: Synthesis of I-39

[0598]

[0599] Step 1: Synthesis of Intermediate 39-1

[0600] Intermediate 39-1a (1.25 g, 3.25 mmol, 4 eq) was dissolved in 30 mL of tetrahydrofuran under nitrogen protection. A solution of n-butyllithium in n-hexane (2.5 M, 2.05 mL, 6.31 eq) was slowly added dropwise to the above solution at 0°C. After the addition was complete, a solution of tetrahydrofuran containing intermediate 38-4 (339 mg, 812.45 μmol, 1 eq) (2 mL) was added dropwise to the system. The reaction was stirred at 0°C for 1 hour. LC-MS monitoring showed product formation. The reaction solution was quenched with saturated ammonium chloride solution, diluted with 30 mL of ethyl acetate and 30 mL of water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2). After combining the organic phases, the mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then separated by silica gel column chromatography (ISCO®; 4 g SepaFlash® silica gel column, eluent: 0-30% ethyl acetate / petroleum ether, flow rate: 60 mL / min) to obtain intermediate 39-1 as a colorless oil (160 mg, yield: 45.86%). LCMS (ESI): m / z Calculated value C 22 H 26 BrN2O2 + [M+H] + = 429.12, 431.12 Measured values ​​[M+H] + =429. 2, 431. 2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.56 (dd, J = 1.4, 7.9 Hz, 1H), 7.38 (d, J = 4.6 Hz, 5H), 7.20 (t, J = 7.6 Hz, 1H), 7.00 - 6.85 (m, 2H), 5.19(s, 2H), 5.01 - 4.87 (m, 1H), 4.03 - 3.77 (m, 3H), 3.60 - 3.43 (m, 1H), 3.35- 2.97 (m, 2H), 2.74 - 2.48 (m, 1H), 1.58 - 1.54 (m, 6H).

[0601] Step 2: Synthesis of Intermediate 39-2

[0602] Intermediate 39-1 (60 mg, 139.75 μmol, 1 eq) was dissolved in 3 mL of dichloromethane, and aluminum trichloride (55.90 mg, 419.24 μmol, 22.91 μL, 3 eq) was added. The reaction mixture was stirred at 30 °C for 1 hour. TLC (petroleum ether:ethyl acetate = 4:1) was used to monitor complete consumption of the starting material and the formation of a new product spot. The reaction mixture was diluted with 10 mL of saturated sodium bicarbonate solution and 30 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). After combining the organic phases, the mixture was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. The residue was then separated by silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent: 0-1% ethyl acetate / petroleum ether, flow rate: 30 mL / min) to obtain intermediate 39-2 as a colorless oil (55 mg, yield: 91.6%). LCMS (ESI): m / z Calculated value C 22 H 26 BrN2O2 + [M+H] + = 429.12, 431.12 Measured values ​​[M+H] + =429.0, 431.0.

[0603] Step 3: Synthesis of Compound I-39

[0604] Intermediate 39-2 (53.27 mg, 124.08 μmol, 1 eq) and intermediate 33-5 (22.86 mg, 124.08 μmol, 1 eq) were dissolved in ethanol. Under nitrogen protection, palladium hydroxide on carbon (132.05 mg, 10% purity) was added. The reaction system was evacuated and purged with nitrogen three times, followed by purging with hydrogen. The system was stirred at 50°C for 17 hours under a hydrogen atmosphere (15 Psi). LCMS monitoring showed complete consumption of the starting materials and product formation. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to the residue. The residue was then subjected to reversed-phase column chromatography (Welch Xtimate C18 150×30mm; mobile phase: A phase: water (0.08% NH4HCO3) - B phase: acetonitrile; gradient: 50%-80% B, 7 min) to prepare compound I-39 as a white solid (17 mg, yield: 35.63%). LCMS (ESI): m / z calculated value C 23 H 37 N4O + [M+H] + = 385.30, Measured value [M+H]+ =385.3. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.18 (d, J = 7.5 Hz, 1H), 6.98 (t, J =7.5 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.65 (t, J = 7.3 Hz, 1H), 6.33 (d, J =7.0 Hz, 1H), 4.25 - 4.10 (m, 1H), 3.74 (d, J = 11.5 Hz, 1H), 2.96 (d, J = 9.5Hz, 2H), 2.85 (d, J = 10.5 Hz, 1H), 2.79 - 2.70 (m, 6H), 2.64 - 2.52 (m, 2H),2.23 (t, J = 7.3 Hz, 2H), 2.06 (d, J = 7.3 Hz, 4H), 1.87 (t, J = 8.0 Hz, 2H), 1.73 (t, J = 10.4 Hz, 1H), 1.67 - 1.59 (m, 2H), 1.56 - 1.48 (m, 1H), 1.25 (s,3H), 1.19 (s,3H).

[0605] Example 40: Synthesis of I-40

[0606]

[0607]

[0608] Step 1: Synthesis of Intermediate 40-2

[0609] Referring to step 1 of the chiral synthesis of compound I-22A in Example 22, and replacing the corresponding starting materials, intermediate 40-2 was prepared using compound 40-1 as the starting material. This intermediate was a light yellow oily substance. LCMS (ESI): m / z C 17 H 26 BrN2O4 + [M+H] + Calculated values ​​= 401.11, 403.11; Measured values ​​= 401.3, 403.3. 1H NMR (400 MHz, CDCl3) δ ppm 7.49(d, J = 8.8 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.61 (dd, J = 2.8, 8.8 Hz,1H), 3.83 (dd, J = 2.7, 13.4 Hz, 1H), 3.78 (s, 3H), 3.74 - 3.65 (m, 1H), 3.64- 3.53 (m, 2H), 3.48 - 3.33 (m, 3H), 3.17 (ddd, J = 3.3, 5.6, 11.7 Hz, 1H), 2.74 (ddd, J = 3.1, 8.3, 11.5 Hz, 1H), 1.50 (s, 9H).

[0610] Step 2: Synthesis of Intermediate 40-3

[0611] Referring to step 2 of the chiral synthesis of compound I-22A in Example 22, and replacing the corresponding starting materials, intermediate 40-3 was prepared using compound 40-2 as the starting material. This intermediate was a light yellow oily substance. LCMS (ESI): m / z C 17 H 24 BrN2O4 + [M+H] + Calculated values ​​= 399.09, 401.09; Measured values ​​= 399.1, 401.1. 1 H NMR (400 MHz, CDCl3) δ ppm 9.55(s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.76 (br d, J = 2.3 Hz, 1H), 6.54 (dd, J =2.8, 8.8 Hz, 1H), 4.23 - 4.01 (m, 3H), 3.80-3.76 (m, 4H), 3.66 - 3.53 (m,2H), 3.42 (ddd, J = 3.0, 8.8, 12.2 Hz, 1H), 1.48 (s, 9H).

[0612] Step 3: Synthesis of intermediate 40-4

[0613] Referring to step 3 of the chiral synthesis of compound I-22A in Example 22, and replacing the corresponding starting materials, intermediate 40-4, a light yellow oily substance, was prepared using compound 40-3 as the starting material. LCMS (ESI): m / z C 18 H 26 BrN2O3+ [M+H] + Calculated values ​​= 397.11, 399.11; Measured values ​​= 397.2, 399.2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.44(d, J = 8.7 Hz, 1H), 6.57 (d, J = 2.7 Hz, 1H), 6.53 (dd, J = 2.9, 8.7 Hz,1H), 5.70 - 5.47 (m, 1H), 5.19 - 5.05 (m, 2H), 3.76 (s, 6H), 3.45 (d, J = 1.9Hz, 1H), 3.22 (d, J = 11.6 Hz, 2H), 2.61 (s, 1H), 1.50 (s, 9H).

[0614] Step 4: Synthesis of intermediate 40-5

[0615] Referring to step 4 of the chiral synthesis of compound I-22A in Example 22, and replacing the corresponding starting materials, intermediate 40-5, a colorless oil, was prepared using compound 40-4 as the starting material. LCMS (ESI): m / z C 18 H 27 N2O3 + [M+H] + Calculated value = 319.20 Measured value = 319.2.

[0616] Step 5: Synthesis of Compound I-40

[0617] Following steps 5 and 6 of the chiral synthesis of I-22A, and substituting the corresponding starting materials, compound I-40 was prepared using intermediates 40-5 and 33-5 as starting materials. It is a white solid. LCMS (ESI): m / z calculated value C 22 H 35 N4O2 + [M+H] + = 387.28, Measured value [M+H] + = 387.3. 1 H NMR (400 MHz, DMSO- d6) δ ppm 6.80 (d, J= 8.1 Hz, 1H), 6.41 - 6.28 (m, 2H), 6.20 (dd, J = 2.2, 8.2 Hz, 1H), 4.24 -4.07 (m, 1H), 3.71 (d, J = 11.8 Hz, 1H), 3.66 (s, 3H), 2.93 - 2.84 (m, 3H), 2.75 (s, 6H), 2.72 - 2.55 (m, 3H), 2.21 (t, J = 7.1 Hz, 2H), 2.10 - 1.97 (m,4H), 1.91 - 1.79 (m, 3H), 1.73 (t, J =11.0 Hz, 1H), 1.66 - 1.48 (m, 3H).

[0618] Example 41: Synthesis of I-41

[0619]

[0620] Step 1: Synthesis of Intermediate 41-2

[0621] Compound 41-1 (15 g, 42.75 mmol, 1 eq) and compound 18-1a-2 (13.87 g, 64.12 mmol, 1.5 eq) were dissolved in 150 mL of DMSO, followed by the sequential addition of cesium carbonate (20.89 g, 64.12 mmol, 1.5 eq) and cuprous iodide (2.44 g, 12.82 mmol, 0.3 eq). The reaction mixture was purged with nitrogen three times and stirred at 100°C for 12 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) confirmed complete consumption of the starting materials and product formation. The reaction mixture was diluted with 200 mL of water and extracted with ethyl acetate (100 mL × 3). After combining the organic phases, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. Intermediate 41-2 was then prepared by silica gel column chromatography (ISCO®; 120 g SepaFlash® silica gel column, eluent: 0-60% ethyl acetate / petroleum ether, flow rate: 100 mL / min), as a yellow oil (700 mg, yield: 4.57%). LCMS (ESI): m / z C 17 H 22 F3N2O3 + [M+H] + Calculated value = 359.16, Measured value = 359.1.1 H NMR (400 MHz, CDCl3) δ ppm 7.11 - 6.95 (m, 2H), 6.86 (d, J = 8.8 Hz, 1H), 4.30 (dd, J = 2.8, 10.8 Hz, 1H), 4.27 - 4.06 (m, 2H), 4.03 (dd, J = 8.6, 10.7 Hz, 1H), 3.70 (d, J = 11.3 Hz, 1H), 3.14 (dd, J =8.5, 11.3 Hz, 1H), 3.10 - 2.97 (m, 1H), 2.81-2.75 (m 1H), 2.65-2.61 (s, 1H),1.51 (s, 9H).

[0622] Step 2: Synthesis of Compound I-41

[0623] Following the synthetic methods in steps 5 and 6 of the chiral synthesis of I-22A, and replacing the corresponding starting materials, compound I-41 was prepared using intermediate 41-2 as the starting material. It is a white solid. LCMS (ESI): m / z calculated value C 21 H 30 F3N4O2 + [M+H] + = 427.23, Measured value [M+H] + = 427.1. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.08 (d, J= 1.4 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.32 (d, J= 7.4 Hz, 1H), 4.32 (dd, J = 2.7, 10.7 Hz, 1H), 4.16 (d, J = 7.5 Hz, 1H), 3.93 (dd, J = 9.1, 10.6 Hz, 1H), 3.78 (d, J = 11.2 Hz, 1H), 3.07 (t, J = 9.7Hz, 1H), 3.00 - 2.88 (m, 2H), 2.75 (s, 6H), 2.71 - 2.60 (m, 1H), 2.36 - 2.16 (m, 2H), 2.11 - 1.97 (m, 4H), 1.92 - 1.81 (m, 2H), 1.72 - 1.55 (m, 3H).

[0624] Example 42: Synthesis of I-42

[0625] Step 1: Synthesis of intermediates 42-1a and 42-1b

[0626] Intermediate 25-5 (200 mg, 619.52 μmol, 1 eq) was dissolved in 5 mL of acetonitrile, and N-chlorosuccinimide (82.73 mg, 619.52 μmol, 1 eq) was added. The reaction mixture was stirred at 25°C for 12 hours. LCMS monitoring showed complete consumption of the starting material and product formation. TLC (petroleum ether:ethyl acetate = 5:1) showed two product spots, with Rf values ​​of approximately 0.4 for 42-1a and approximately 0.6 for 42-1b. The reaction solution was concentrated under reduced pressure to the residue, dissolved in 10 mL of dichloromethane, and washed successively with saturated ammonium chloride solution (5 mL × 2), water (5 mL × 2), and saturated brine (5 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. Intermediate 42-1b was prepared by silica gel column chromatography (ISCO®; 20 g SepaFlash® silica gel column, eluent: 0-20% ethyl acetate / petroleum ether, flow rate: 30 mL / min) as a colorless oil (60 mg, yield: 27.10%). LCMS (ESI): m / zC 17 H 23 Cl2N2O2 + [M+H] + Calculated value = 357.11, Measured value = 357.1. Simultaneously, intermediate 42-1a was prepared as a colorless oil (100 mg, yield: 45.18%). LCMS (ESI): m / z C 17 H 23 Cl2N2O2 + [M+H] + Calculated value = 357.11, Measured value = 357.0. 1H NMR (400 MHz, CDCl3) δ ppm 7.10 (d, J = 9.1 Hz, 1H), 6.59 (d, J = 9.1 Hz, 1H), 4.16 - 3.82 (m, 2H), 3.62 (d, J = 12.5 Hz, 1H), 3.02 - 2.81 (m, 3H), 2.74 - 2.56 (m, 3H), 1.93 - 1.89 (m, 1H), 1.69 - 1.62 (m, 1H), 1.41 (s, 9H).

[0627] Step 2: Synthesis of Compound I-42

[0628] Following steps 5 and 6 of the chiral synthesis of I-22A, and substituting the corresponding starting materials, compound I-42 was prepared using intermediates 42-1a and 33-5 as starting materials. It was a white solid. LCMS (ESI): m / z C 21 H 31 Cl2N4O + [M+H] + Calculated value = 425.19, Measured value = 425.1. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.25 (d, J= 9.2 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 6.34 (d, J = 7.3 Hz, 1H), 4.22 -4.12 (m, 1H), 3.76 (d, J = 12.0 Hz, 1H), 2.92 (d, J = 7.7 Hz, 3H), 2.81 -2.79 (m, 1H), 2.76 (s, 6H), 2.72 - 2.63 (m, 2H), 2.23 (t, J = 6.9 Hz, 2H), 2.09 - 2.01 (m, 4H), 1.95 - 1.83 (m, 3H), 1.75 (t, J = 11.1 Hz, 1H), 1.66 -1.56 (m, 3H).

[0629] Example 43: Synthesis of I-43

[0630] Following the synthetic method of steps 5 and 6 in the chiral synthesis of I-22A in Example 22, and replacing the corresponding starting materials, compound I-43 was prepared using intermediates 42-1b and 33-5 as starting materials. It is a white solid. LCMS (ESI): m / zC 21 H 31 Cl2N4O + [M+H] + Calculated value = 425.19, Measured value = 425.1. 1 H NMR (400 MHz, DMSO- d6 ) δppm 7.25 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.33 (d, J = 7.3 Hz,1H), 4.23 - 4.08 (m, 1H), 3.26 - 3.13 (m, 1H), 2.97 (d, J = 12.0 Hz, 2H),2.88 - 2.79 (m, 1H), 2.75 (s, 6H), 2.72 - 2.63 (m, 3H), 2.43 (dd, J = 3.3,11.0 Hz, 1H), 2.31 - 2.12 (m, 4H), 2.10 - 2.00 (m, 3H), 1.93 - 1.82 (m, 2H),1.71 - 1.51 (m, 3H).

[0631] Example 44: Synthesis of I-44

[0632] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-44 was prepared using 2-bromo-1-chloro-3-iodo-5-methoxybenzene (CAS: 2384789-44-8) as the starting material. It was a white solid. LCMS (ESI): m / z C 22 H 34 ClN4O2 + [M+H] + Calculated value = 421.24, Measured value = 421.2. 1H NMR (400 MHz, CD3OD) δ ppm6.41 (d, J = 2.0 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 4.32 – 4.26 (m, 1H), 3.85 (d, J = 12.6 Hz, 1H), 3.73 (s, 3H), 3.20 (d, J =11.6 Hz, 1H), 3.13 (d, J =11.3 Hz, 1H), 3.07 - 2.98 (m, 1H), 2.88 (s, 8H), 2.69 - 2.59 (m, 1H), 2.56 -2.49 (m, 2H), 2.45 – 2.41 (m, 1H), 2.18 - 2.11 (m, 4H), 2.08 - 2.03 (m, 2H), 2.02 - 1.95 (m, 1H), 1.84 - 1.76 (m, 2H), 1.74 - 1.63 (m, 1H).

[0633] Example 45: Synthesis of I-45

[0634] Following the synthesis method of Example 40, and replacing the corresponding starting materials, compound I-45 was prepared using compound 45-1 (CAS: 2386869-73-2) as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 31 Cl2N4O + [M+H] + Calculated value = 425.19, Measured value = 425.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 6.84(dd, J = 1.8, 15.7 Hz, 2H), 6.35 (d, J = 7.3 Hz, 1H), 4.23 - 4.10 (m, 1H), 3.79 (d, J = 11.7 Hz, 1H), 3.04 - 2.84 (m, 3H), 2.80 - 2.73 (m, 7H), 2.71 -2.55 (m, 2H), 2.22 (d, J = 5.4 Hz, 2H), 2.10 - 1.85 (m, 7H), 1.73 (t, J =10.4 Hz, 1H), 1.66 - 1.51 (m, 3H).

[0635] Example 46: Synthesis of I-46

[0636] Following the synthesis method of Example 40, and replacing the corresponding starting materials, compound I-46 was prepared using 1-bromo-3-chloro-2-iodobenzene (CAS: 450412-28-9) as the starting material. It was a white solid. LCMS (ESI): m / z C 21 H 32 ClN4O + [M+H] + Calculated value = 391.23, Measured value = 391.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.16 (d, J = 8.0Hz, 1H), 7.02 (d, J = 6.9 Hz, 1H), 6.92 - 6.80 (m, 1H), 6.35 (d, J = 7.3 Hz,1H), 4.24 - 4.09 (m, 1H), 3.14 (br s, 2H), 3.04 - 2.97 (m, 1H), 2.85 - 2.78(m, 2H), 2.76 (s, 6H), 2.69 - 2.55 (m, 2H), 2.34 (dt, J = 1.8, 4.4 Hz, 1H),2.26 - 2.17 (m, 2H), 2.10 - 2.01 (m, 4H), 2.00 - 1.82 (m, 3H), 1.65 - 1.54 (m, 3H).

[0637] Example 47: Synthesis of I-47

[0638] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-47 was prepared using 1-bromo-4-chloro-2-iodobenzene (CAS: 148836-41-3) as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 32 ClN4O + [M+H] + Calculated value = 391.23, Measured value = 391.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 6.91 (d, J= 8.0 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 6.61 (dd, J = 1.8, 7.9 Hz, 1H), 6.35(d, J = 7.4 Hz, 1H), 4.21 - 4.13 (m, 1H), 3.74 (d, J = 11.7 Hz, 1H), 2.99 -2.87 (m, 3H), 2.76 (s, 6H), 2.70 - 2.60 (m, 2H), 2.22 (t, J = 6.8 Hz, 2H), 2.08 - 2.00 (m, 5H), 1.91 - 1.83 (m, 4H), 1.65 - 1.57 (m, 3H).

[0639] Example 48: Synthesis of I-48

[0640] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-48 was prepared using 2-bromo-4-chloro-1-iodobenzene (CAS: 31928-44-6) as the starting material. It was a white solid. LCMS (ESI): m / z C 21 H 32 ClN4O + [M+H] + Calculated value = 391.23, Measured value = 391.2. 1 H NMR (400 MHz, CD3OD) δ ppm 6.99 (dd, J =2.5, 8.8 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.28(t, J = 7.3 Hz, 1H), 3.82 - 3.73 (m, 1H), 3.10 - 2.94 (m, 3H), 2.91 - 2.74(m, 8H), 2.73 - 2.64 (m, 1H), 2.40 - 2.32 (m, 2H), 2.26 - 2.09 (m, 4H), 2.08- 2.01 (m, 2H), 1.97 - 1.87 (m, 2H), 1.80 - 1.65 (m, 3H).

[0641] Example 49: Synthesis of I-49

[0642] Compound I-48 (54.83 mg, 140.25 μmol, 1 eq) was dissolved in 5 mL of hexafluoroisopropanol, and N-chlorosuccinimide (56.18 mg, 420.75 μmol, 3 eq) was added. The reaction mixture was stirred at 50°C for 2 hours. LCMS was used to monitor complete consumption of the starting material. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (ISCO®; 20 g SepaFlash® silica gel column, eluent: 0-20% ethyl acetate / petroleum ether, flow rate: 35 mL / min) to prepare compound I-49 as a white solid (28 mg, yield: 46.93%). LCMS (ESI): m / z C 21 H 31 Cl2N4O + [M+H] + Calculated value = 425.19, Measured value = 425.19. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 6.87 (d, J =1.7 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.35 (d, J = 7.4 Hz, 1H), 4.22 - 4.08(m, 1H), 3.79 (br d, J = 11.6 Hz, 1H), 3.02 - 2.88 (m, 3H), 2.80 - 2.72 (m,7H), 2.71 - 2.55 (m, 2H), 2.23 (br s, 2H), 2.10 - 1.99 (m, 4H), 1.97 - 1.84(m, 3H), 1.73 (br t, J = 10.6 Hz, 1H), 1.67 - 1.49 (m, 3H).

[0643] Example 50: Synthesis of I-50

[0644] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-50 was prepared using 1-bromo-3,4-dichloro-2-iodobenzene (CAS: 2383852-97-7) as the starting material. It was a white solid. LCMS (ESI): m / z C 21 H 31 Cl2N4O + [M+H] + Calculated value = 425.19, Measured value = 425.2. 1H NMR (400 MHz, DMSO- d6 ) δ ppm 7.15 -7.09 (m, 1H), 7.07 - 7.00 (m, 1H), 6.33 (d, J = 7.3 Hz, 1H), 4.26 - 4.03 (m,1H), 3.13 (s, 2H), 3.01 (dd, J = 1.8, 11.3 Hz, 1H), 2.83 - 2.71 (m, 9H), 2.67- 2.53 (m, 2H), 2.40 - 2.30 (m, 1H), 2.22 (td, J = 3.7, 7.5 Hz, 2H), 2.10 -1.99 (m, 4H), 1.91 - 1.83 (m, 2H), 1.65 - 1.55 (m, 3H).

[0645] Example 51: Synthesis of I-51

[0646] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-51 was prepared using 1-bromo-4,5-dichloro-2-iodobenzene (CAS: 289038-31-9) as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 31 Cl2N4O + [M+H] + Calculated value = 425.19, Measured value = 425.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.12 (s,1H), 6.97 (s, 1H), 6.34 (d, J = 7.3 Hz, 1H), 4.23 - 4.10 (m, 1H), 3.75 (d, J= 12.2 Hz, 1H), 2.99 - 2.86 (m, 3H), 2.76 - 2.64 (m, 9H), 2.26 - 2.17 (m,2H), 2.08 - 1.98 (m, 4H), 1.86 (t, J = 8.0 Hz, 3H), 1.72 (t, J = 10.8 Hz,1H), 1.65 - 1.50 (m, 3H).

[0647] Example 52: Synthesis of I-52

[0648] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-52 was prepared using 2-bromo-3-chloro-1-iodo-4-toluene (CAS: 2387353-61-7) as the starting material. It is a white solid. LCMS (ESI): m / z C 22 H 34 ClN4O + [M+H] + Calculated value = 405.24, Measured value = 405.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 6.99 (d, J= 8.5 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.34 (d, J = 7.4 Hz, 1H), 4.24 -4.06 (m, 1H), 3.71 (d, J = 11.7 Hz, 1H), 2.93 (s, 2H), 2.85 - 2.76 (m, 2H),2.75 (s, 6H), 2.69 - 2.57 (m, 2H), 2.25 - 2.16 (m, 5H), 2.10 - 1.99 (m, 4H),1.96 - 1.83 (m, 3H), 1.73 (t, J = 10.6 Hz, 1H), 1.65 - 1.53 (m, 3H).

[0649] Example 53: Synthesis of I-53

[0650] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-53 was prepared using 2-bromo-3-chloro-1-iodo-4-methoxybenzene (CAS: 2386882-35-3) as the starting material. It was a white solid. LCMS (ESI): m / z C 22 H 34 ClN4O2 + [M+H] + Calculated value = 421.24, Measured value = 421.3. 1 H NMR (400 MHz, DMSO- d6) δppm 6.88 - 6.83 (m, 1H), 6.82 - 6.75 (m, 1H), 6.34 (d, J = 7.4 Hz, 1H), 4.24- 4.08 (m, 1H), 3.73 (s, 3H), 3.67 (d, J = 11.7 Hz, 1H), 2.96 - 2.84 (m, 2H), 2.81 - 2.76 (m, 1H), 2.75 (s, 7H), 2.70 - 2.53 (m, 2H), 2.22 (t, J = 7.1 Hz,2H), 2.11 - 2.00 (m, 4H), 1.94 - 1.82 (m, 3H), 1.74 (t, J = 10.6 Hz, 1H),1.66 - 1.48 (m, 3H).

[0651] Example 54: Synthesis of I-54

[0652] Referring to the synthesis method in step 1 of Example 42, and replacing the corresponding starting materials, compound I-54 was prepared using compound I-26 as the starting material. It is a white solid. LCMS (ESI): m / z C 22 H 34 ClN4O2 + [M+H] + Calculated value = 421.23, Measured value = 421.2. 1 H NMR (400 MHz, CD3OD) δ ppm 7.13 (d, J = 8.7 Hz, 1H), 6.56 (d,J = 8.7 Hz, 1H), 6.34 (d, J = 6.6 Hz, 1H), 4.60 - 4.56 (m, 1H), 4.35 - 4.20(m, 1H), 3.79 (s, 3H), 3.05 (d, J = 11.2 Hz, 1H), 2.92 - 2.78 (m, 9H), 2.75 -2.66 (m, 1H), 2.63 - 2.49 (m, 2H), 2.46 - 2.35 (m, 2H), 2.19 - 2.04 (m, 6H),1.81 - 1.66 (m, 3H).

[0653] Examples 55 and 56: Synthesis of I-55 and I-56

[0654] Referring to the synthesis method in step 1 of Example 42, and replacing the corresponding starting materials, compound I-55 was prepared using compound I-40 as the starting material. It is a white solid. LCMS (ESI): m / z C 22 H 34 ClN4O2 + [M+H] + Calculated value = 421.24, Measured value = 421.3. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 6.91 (s, 1H), 6.52 (s, 1H), 6.35 (d, J = 7.4 Hz, 1H), 4.25 - 4.10 (m, 1H), 3.84 (d, J = 12.3 Hz, 1H), 3.78 (s,3H), 2.97 - 2.87 (m, 3H), 2.76 (s, 6H), 2.73 - 2.64 (m, 2H), 2.61 - 2.53 (m,1H), 2.24 (d, J = 6.6 Hz, 2H), 2.05 (t, J = 6.9 Hz, 4H), 1.92 - 1.81 (m, 3H),1.79 - 1.70 (m, 1H), 1.67 - 1.52 (m, 3H). Compound I-56 was also prepared as a white solid. LCMS (ESI): m / z C 22 H 34 ClN4O2 + [M+H] + Calculated value = 421.24, Measured value = 421.3. 1 H NMR (400 MHz, CD3OD) δ ppm 6.93 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.28 (t, J =7.4 Hz, 1H), 3.81 (s, 3H), 3.54 - 3.37 (m, 1H), 3.26 - 3.15 (m, 1H), 3.13 -3.03 (m, 1H), 2.88 (s, 6H), 2.84 - 2.67 (m, 4H), 2.64 - 2.52 (m, 2H), 2.42 -2.28 (m, 2H), 2.21 - 2.01 (m, 6H), 1.82 - 1.65 (m, 3H).

[0655] Example 57: Synthesis of I-57

[0656] Referring to the synthesis method of Example 49, and replacing the corresponding starting materials, compound I-57 was prepared from compound I-26 as the starting material. It is a white solid. LCMS (ESI): m / z C 22 H 33 Cl2N4O2 + [M+H] + Calculated value = 455.20, Measured value = 455.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.37 (s, 1H), 6.39 - 6.32 (m, 1H), 4.24 - 4.10 (m, 1H), 3.78 - 3.71 (m, 3H), 3.56 (s, 1H), 3.13 (s, 1H), 3.01 -2.93 (m, 1H), 2.87 (dd, J = 5.2, 17.3 Hz, 1H), 2.78 - 2.74 (m, 6H), 2.72 -2.56 (m, 3H), 2.37 - 2.27 (m, 1H), 2.25 - 2.17 (m, 2H), 2.13 - 1.98 (m, 5H),1.93 - 1.84 (m, 2H), 1.68 - 1.58 (m, 3H).

[0657] Example 58: Synthesis of I-58

[0658] Following the synthesis method of Example 49, and replacing the corresponding starting materials, compound I-58 was prepared by adding 2.5 equivalents of N-chlorosuccinimide to compound I-40 as the starting material. The compound was a white solid. LCMS (ESI): m / z C 22 H 33 Cl2N4O2 + [M+H] + Calculated value = 455.20, Measured value = 455.2. 1H NMR (400 MHz, CD3OD) δ ppm 7.03 (s,1H), 4.28 – 4.24 (m, 1H), 3.80 (s, 3H), 3.52 – 3.39 (m, 1H), 3.20 – 3.16 (m,1H), 3.12 – 3.05 (m, 1H), 2.87 (s, 6H), 2.83 - 2.74 (m, 2H), 2.73 - 2.64 (m,2H), 2.62 - 2.51 (m, 2H), 2.37 - 2.28 (m, 2H), 2.20 - 2.09 (m, 3H), 2.09 -2.01 (m, 3H), 1.78 - 1.65 (m, 3H).

[0659] Example 59: Synthesis of I-59

[0660] Referring to the synthesis method in step 1 of Example 42, and replacing the corresponding starting materials, compound I-59 was prepared from compound I-44 as the starting material. It is a white solid. LCMS (ESI): m / z C 22 H 33 Cl2N4O2 + [M+H] + Calculated value = 455.20, Measured value = 455.2. 1 H NMR (400 MHz, CD3OD) δ ppm 6.79 (s, 1H), 4.31 - 4.24 (m, 1H), 3.86 - 3.84 (m, 1H), 3.82 (s, 3H), 3.08 - 3.02 (m, 1H), 2.91-2.88 (m, 8H),2.77 - 2.72 (m, 1H), 2.71 - 2.61 (m, 3H), 2.59 - 2.48 (m, 1H), 2.39 - 2.30(m, 2H), 2.19 - 2.10 (m, 4H), 2.08 - 2.03 (m, 2H), 1.78 - 1.71 (m, 3H).

[0661] Example 60: Synthesis of I-60

[0662] Following the synthesis method in Example 49, and replacing the corresponding starting materials, compound I-47 was used as the starting material, with the addition of 2.5 equivalents of NCS, to prepare compound I-60, which is a white solid. LCMS (ESI): m / z C 21 H 30 Cl3N4O + [M+H] + Calculated value = 459.15, Measured value = 459.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.34 - 7.33 (m,1H), 7.35 (s, 1H), 6.34 (d, J = 7.4 Hz, 1H), 4.27 - 4.05 (m, 1H), 3.13 (s,2H), 3.06 - 2.98 (m, 1H), 2.79 (dd, J = 4.3, 8.7 Hz, 2H), 2.75 (s, 6H), 2.64- 2.56 (m, 1H), 2.42 - 2.31 (m, 1H), 2.28 - 2.17 (m, 2H), 2.09 - 1.93 (m,5H), 1.90 - 1.82 (m, 2H), 1.67 - 1.55 (m, 3H).

[0663] Example 61: Synthesis of I-61

[0664] Following the synthesis method in Example 49, and replacing the corresponding starting materials, compound I-45 was used as the starting material, with the addition of 2.5 equivalents of NCS, to prepare compound I-61, which is a white solid. LCMS (ESI): m / z C 21 H 29 Cl4N4O + [M+H] + Calculated value = 493.11, Measured value = 493.1. 1 H NMR (400 MHz, DMSO- d6) δ ppm 6.34 (d, J = 7.5Hz, 1H), 4.33 - 4.09 (m, 1H), 3.24 - 3.16 (m, 1H), 3.05 - 2.86 (m, 3H), 2.76(s, 6H), 2.73 - 2.63 (m, 2H), 2.33 - 2.16 (m, 3H), 2.14 - 1.96 (m, 4H), 1.93 - 1.83 (m, 2H), 1.77 - 1.56 (m, 3H), 1.52 - 1.41 (m, 1H), 1.32 - 1.25 (m,1H).

[0665] Example 62: Synthesis of I-62

[0666] Following the synthesis method in Example 49, and replacing the corresponding starting materials, compound I-44 was used as the starting material, with the addition of 2.5 equivalents of NCS, to prepare compound I-62, which is a white solid. LCMS (ESI): m / z C 22 H 32 Cl3N4O2 + [M+H] + Calculated value = 489.16, Measured value = 489.1. 1 H NMR (400 MHz, CD3OD) δ ppm 4.31 – 4.26 (m,1H), 3.84 (s, 3H), 3.26 (s, 2H), 3.07 – 3.00 (m, 1H), 2.96 (dd, J = 4.7, 17.6Hz, 1H), 2.89 (s, 6H), 2.74-2.70 (m, 3H), 2.65 - 2.60 (m, 1H), 2.51 (d, J =6.3 Hz, 1H), 2.39 - 2.28 (m, 2H), 2.24 - 2.11 (m, 4H), 2.10 - 2.03 (m, 2H),1.80 - 1.70 (m, 3H).

[0667] Example 63: Synthesis of I-63

[0668] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-63 was prepared using 2-bromo-1-iodo-4-methoxybenzene (CAS: 466639-53-2) as the starting material. It was a white solid. LCMS (ESI): m / z C 22 H 35 N4O2 + [M+H] + Calculated value = 387.28, Measured value = 387.3. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 6.74 (d, J = 9.1 Hz, 1H), 6.64 - 6.59 (m, 1H), 6.56 (d, J = 2.9 Hz, 1H), 6.34 (d, J =7.4 Hz, 1H), 4.23 - 4.10 (m, 1H), 3.68 – 3.66 (m, 1H), 3.65 (s, 3H), 3.02 -2.86 (m, 2H), 2.83 - 2.71 (m, 8H), 2.65 - 2.54 (m, 2H), 2.36 - 2.18 (m, 2H),2.12 - 1.95 (m, 4H), 1.94 - 1.76 (m, 4H), 1.69 - 1.53 (m, 3H).

[0669] Example 64: Synthesis of I-64

[0670] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-64 was prepared using 1-bromo-4-chloro-2-iodo-5-methoxybenzene (CAS: 1648626-94-1) as the starting material. It was a white solid. LCMS (ESI): m / z C 22 H 34 ClN4O2 + [M+H] + Calculated value = 421.24, Measured value = 421.2. 1 H NMR (400 MHz, DMSO- d6) δppm 6.85 (s, 1H), 6.77 (s, 1H), 6.34 (d, J = 7.3 Hz, 1H), 4.27 - 4.07 (m,1H), 3.73 (s, 3H), 3.65 (d, J = 11.8 Hz, 1H), 2.96 - 2.71 (m, 10H), 2.69 -2.54 (m, 2H), 2.22 (t, J = 7.1 Hz, 2H), 2.10 - 1.99 (m, 4H), 1.92 - 1.81 (m,3H), 1.75 (t, J = 10.4 Hz, 1H), 1.67 - 1.52 (m, 3H).

[0671] Example 65: Synthesis of I-65

[0672] Referring to the synthesis method in step 1 of Example 42, and replacing the corresponding starting materials, compound I-65 was prepared from compound I-53 as the starting material. It is a white solid. LCMS (ESI): m / z C 22 H 33 Cl2N4O2 + [M+H] + Calculated value = 455.20, Measured value = 455.1. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.09 (s, 1H), 6.34 (d, J = 7.4Hz, 1H), 4.22 - 4.11 (m, 1H), 3.81 (s, 3H), 3.14 (br d, J = 11.7 Hz, 1H), 2.93 - 2.88 (m, 1H), 2.85 (d, J = 6.6 Hz, 1H), 2.76 (s, 8H), 2.73 - 2.56 (m,2H), 2.41 - 2.32 (m, 1H), 2.31 - 2.13 (m, 4H), 2.11 - 1.99 (m, 3H), 1.95 -1.83 (m, 2H), 1.68 - 1.54 (m, 3H).

[0673] Example 66: Synthesis of I-66

[0674] Step 1: Synthesis of intermediate 41-2

[0675] Intermediate 25-3 (200 mg, 495.42 μmol, 1 eq) was dissolved in 4 mL of methanol, and methylamine hydrochloride (133.80 mg, 1.98 mmol, 4 eq) and sodium cyanoborohydride (124.53 mg, 1.98 mmol, 4 eq) were added. The reaction mixture was stirred at 40 °C for 2 hours. LCMS monitoring showed complete consumption of the starting material and product formation. The residue after evaporation under reduced pressure was subjected to silica gel column chromatography (ISCO®; 20 g SepaFlash® silica gel column, eluent: 0-100% ethyl acetate / petroleum ether, flow rate: 30 mL / min) to prepare intermediate 66-1 as a colorless oil (120 mg, yield: 57.84%). LCMS (ESI): m / z C 17 H 26 BrClN3O2 + [M+H] + Calculated value = 418.09, Measured value = 418.0.

[0676] Step 2: Synthesis of intermediate 66-2

[0677] Intermediate 66-1 (100 mg, 238.80 μmol, 1 eq) was dissolved in 8 mL of dioxane, and cesium carbonate (155.61 mg, 477.61 μmol, 2 eq), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (14.87 mg, 23.88 μmol, 0.1 eq), and Pd2(dba)3 (21.87 mg, 23.88 μmol, 0.1 eq) were added sequentially. The reaction system was stirred at 100 °C for 12 hours under nitrogen protection. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction system was diluted with 20 mL of water and extracted with ethyl acetate (10 mL × 3). After combining the organic phases, the mixture was washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. This residue was then subjected to silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluent 0-30% ethyl acetate / petroleum ether, flow rate: 35 mL / min) to prepare intermediate 66-2 as a colorless oil (50 mg, yield: 61.97%). LCMS (ESI): m / z C 17 H 25 ClN3O2 + [M+H] + Calculated value = 338.16, measured value = 338.1.

[0678] Step 3: Synthesis of compound I-66

[0679] Following the synthetic methods of steps 5 and 6 in the chiral synthesis of I-22A in Example 22, and replacing the corresponding starting materials, compound I-66 was prepared using intermediate 66-2 as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 33 ClN5O + [M+H] + Calculated value = 406.24, Measured value = 406.2. 1 H NMR (400 MHz, CD3OD) δ ppm 6.94 - 6.83(m, 2H), 6.77 (dd, J = 2.6, 6.5 Hz, 1H), 4.30 (t, J = 7.4 Hz, 1H), 3.88 (d, J= 11.9 Hz, 1H), 3.16 - 3.07 (m, 2H), 3.01 (dd, J = 2.3, 13.5 Hz, 1H), 2.96 (d, J = 11.0 Hz, 1H), 2.90 (s, 6H), 2.87 - 2.79 (m, 2H), 2.79 - 2.74 (m, 3H),2.43 - 2.34 (m, 2H), 2.27 - 2.04 (m, 6H), 1.86 - 1.69 (m, 3H).

[0680] Example 67: Synthesis of I-67

[0681] Referring to the synthesis method of Example 27, and replacing the corresponding starting materials, compound I-67 was prepared using intermediates 25-2 and 19-1a as starting materials. It is a white solid. LCMS (ESI): m / z C 20 H 30 ClN4O2 + [M+H] + Calculated value = 393.21, Measured value = 393.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 6.87 - 6.80 (m, 1H), 6.79 - 6.74 (m, 2H), 6.34 (d, J = 7.2 Hz, 1H), 4.37 (dd, J = 2.7, 10.6 Hz, 1H), 4.24 -4.06 (m, 1H), 3.94 (dd, J = 9.0, 10.5 Hz, 1H), 3.71 (br d, J = 11.4 Hz, 1H), 3.12 - 3.01 (m, 1H), 3.00 - 2.88 (m, 2H), 2.76 (s, 6H), 2.69 - 2.61 (m, 1H),2.32 - 2.20 (m, 2H), 2.13 - 2.02 (m, 4H), 1.94 - 1.82 (m, 2H), 1.73 - 1.55 (m, 3H).

[0682] Example 68: Synthesis of I-68

[0683] Referring to the synthesis method of Example 42, and replacing the corresponding starting materials, compound I-68 was prepared using intermediate 67-1 as the starting material. It is a white solid. LCMS (ESI): m / z C 20 H 29 Cl2N4O2 + [M+H] + Calculated value = 427.17, Measured value = 427.1. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.00 (d, J = 8.9 Hz, 1H), 6.85 (d, J =9.1 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 4.41 (d, J = 10.5 Hz, 1H), 4.22 - 4.11(m, 1H), 3.97 (t, J = 9.7 Hz, 1H), 3.69 (d, J = 11.3 Hz, 1H), 3.06 (t, J =9.5 Hz, 1H), 2.93 (t, J = 8.9 Hz, 2H), 2.75 (s, 6H), 2.69 - 2.61 (m, 1H),2.30 - 2.18 (m, 2H), 2.10 - 2.00 (m, 4H), 1.91 - 1.81 (m, 2H), 1.71 - 1.57 (m, 3H).

[0684] Example 69: Synthesis of I-69

[0685] Following the synthesis methods of Examples 42 and 43, and replacing the corresponding starting materials, compound I-69 was prepared using intermediate 67-1 as the starting material. It is a white solid. LCMS (ESI): m / z C 20 H 29 Cl2N4O2 + [M+H] + Calculated value = 427.17, measured value = 427.1. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.13 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 7.3 Hz, 1H), 4.50 - 4.38 (m, 1H), 4.30 (dd,J = 2.1, 10.5 Hz, 1H), 4.22 - 4.08 (m, 1H), 3.50 - 3.45 (m, 1H), 3.11 (d, J =10.4 Hz, 1H), 3.00 - 2.91 (m, 1H), 2.87 - 2.78 (m, 2H), 2.75 (s, 6H), 2.41(dd, J = 4.1, 12.0 Hz, 1H), 2.27 - 2.12 (m, 3H), 2.04 (s, 3H), 1.93 - 1.81 (m, 2H), 1.58 (d, J = 6.4 Hz, 2H).

[0686] Example 70: Synthesis of I-70

[0687] Step 1: Synthesis of intermediate 70-3

[0688] Referring to steps 3 to 5 of the chiral synthesis of compound I-22A in Example 22, and replacing the corresponding starting materials, intermediate 70-3 was prepared using intermediates 25-3 and 70-1a as starting materials. This intermediate was a colorless oil. LCMS (ESI): m / zC 12 H 14 D2ClN2 + [M+H] + Calculated value = 225.11, Measured value = 225.1.

[0689] Step 2: Synthesis of Compound I-70

[0690] Referring to the synthesis method in step 6 of Example 33, and replacing the corresponding starting materials, intermediate 70-3 was used as the starting material to prepare compound I-70, which is a white solid. LCMS (ESI): m / z C 21 H 30 D2ClN4O + [M+H] + Calculated value = 393.24, measured value = 393.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.09 - 6.96 (m, 1H), 6.82 (d,J = 8.5 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 6.33 (d, J = 7.4 Hz, 1H), 4.26 -4.07 (m, 1H), 3.77 (d, J = 11.9 Hz, 1H), 2.98 - 2.86 (m, 3H), 2.76 (s, 6H), 2.71 - 2.61 (m, 1H), 2.23 (t, J = 7.2 Hz, 2H), 2.10 - 2.00 (m, 4H), 1.95 -1.84 (m, 3H), 1.75 (s, 1H), 1.66 - 1.53 (m, 3H).

[0691] Example 71: Synthesis of I-71

[0692] Referring to the synthesis method of Example 42, and replacing the corresponding starting materials, compound I-71 was prepared using intermediate I-70 as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 29 D2Cl2N4O + [M+H] + Calculated value = 427.20, Measured value = 427.1. 1 H NMR (400 MHz, DMSO- d6) δ ppm 7.25 (br d, J = 9.1 Hz, 1H), 6.86 (d,J = 9.2 Hz, 1H), 6.37 - 6.29 (m, 1H), 4.23 - 4.10 (m, 1H), 3.81 - 3.71 (m,1H), 2.92 (d, J = 6.4 Hz, 3H), 2.76 (s, 6H), 2.71 - 2.62 (m, 2H), 2.25 - 2.21(m, 2H), 2.05 (d, J = 8.8 Hz, 4H), 1.97 - 1.84 (m, 3H), 1.76 - 1.72 (m, 1H),1.63 - 1.60 (m,2H).

[0693] Example 72: Synthesis of I-72

[0694] Following the synthesis methods of Examples 42 and 43, and replacing the corresponding starting materials, compound I-72 was prepared using intermediate I-70 as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 29 D2Cl2N4O + [M+H] + Calculated value = 427.20, measured value = 427.1. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.25 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 6.9 Hz, 1H), 4.26 - 4.07 (m, 1H), 3.19 (d,J = 10.0 Hz, 2H), 3.06 - 2.90 (m, 2H), 2.75 (s, 6H), 2.69 - 2.66 (s, 2H), 2.44 (d, J = 11.2 Hz, 1H), 2.32 - 2.18 (m, 3H), 2.12 - 2.02 (m, 3H), 1.89 (d,J = 7.0 Hz, 2H), 1.73 - 1.54 (m, 3H).

[0695] Example 73: Synthesis of I-73

[0696] Step 1: Synthesis of intermediate 73-2

[0697] Following the synthesis method in steps 1 and 2 of Example 19, and replacing the corresponding starting materials, compound 73-2 was prepared using intermediate 42-2 as the starting material. This compound is a colorless oil. LCMS (ESI): m / z C 18 H 26 Cl2N3 + [M+H] + Calculated value = 354.15, Measured value = 354.1.

[0698] Step 2: Synthesis of intermediate 73-3

[0699] Intermediate 73-2 (150 mg, 423.35 μmol, 1 eq) and compound 73-2a (99.42 mg, 635.03 μmol, 1.5 eq) were dissolved in 30 mL of dichloromethane, and triethylamine (85.68 mg, 846.70 μmol, 2 eq) was added. The reaction mixture was stirred at 20 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1) was used to monitor complete consumption of the starting material and the formation of product spots. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then subjected to silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-10% ethyl acetate / petroleum ether, flow rate: 50 mL / min) to prepare intermediate 73-3 as a pale yellow oil (190 mg, yield: 94.6%). LCMS (ESI): m / z C 25 H 30 Cl2N3O2 + [M+H] + Calculated value = 474.17, Measured value = 474.1.

[0700] Step 3: Synthesis of compound I-73

[0701] Intermediate 73-3 (30 mg, 63.23 μmol, 1 eq) was dissolved in 20 mL of acetonitrile, followed by the sequential addition of triethylamine (12.80 mg, 126.47 μmol, 2 eq) and compound 73-3a (9.18 mg, 98.69 μmol, 1.56 eq). The reaction mixture was stirred at 80 °C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then subjected to reversed-phase column chromatography (column type: Welch Xtimate C18 150×30 mm; mobile phase: phase A: water (0.08% NH4HCO3) - phase B: acetonitrile; gradient: 56%-86% B, 7 min) to prepare compound I-73 as a white solid (15 mg, yield: 50.11%). LCMS (ESI): m / z C 22 H 29 Cl2F2N4O + [M+H] + Calculated value = 473.17, Measured value = 473.1. 1 H NMR (400 MHz, DMSO-) d6 ) δ ppm 7.13 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 7.3 Hz, 1H), 4.50 - 4.38 (m, 1H), 4.30 (dd, J = 2.1, 10.5 Hz,1H), 4.22 - 4.08 (m, 1H), 3.50 - 3.45 (m, 1H), 3.11 (d, J = 10.4 Hz, 1H), 3.00 - 2.91 (m, 1H), 2.87 - 2.78 (m, 2H), 2.75 (s, 6H), 2.41 (dd, J = 4.1,12.0 Hz, 1H), 2.27 - 2.12 (m, 3H), 2.04 (s, 3H), 1.93 - 1.81 (m, 2H), 1.58 (d, J = 6.4 Hz, 2H).

[0702] Example 74: Synthesis of I-74

[0703] Following the synthesis method of Example 73, and replacing the corresponding starting materials, compound I-74 was prepared using compound 3-fluoroazacyclobutane hydrochloride (Cas: 617718-46-4) as the starting material. It is a white solid. LCMS (ESI): m / z C22 H 30 Cl2FN4O + [M+H] + Calculated value = 455.18, Measured value = 455.1. 1 H NMR (400 MHz, DMSO- d6 ) δppm 7.24 (d, J = 8.9 Hz, 1H), 6.85 (d, J = 9.1 Hz, 1H), 6.66 (d, J = 7.5 Hz,1H), 5.43 - 5.17 (m, 1H), 4.20 - 4.02 (m, 3H), 3.82 (d, J = 8.8 Hz, 1H), 3.78- 3.71 (m, 2H), 2.98 - 2.77 (m, 4H), 2.74 - 2.61 (m, 2H), 2.22 (d, J = 6.0Hz, 2H), 2.11 - 1.84 (m, 7H), 1.79 - 1.69 (m, 1H), 1.65 - 1.54 (m, 3H).

[0704] Example 75: Synthesis of I-75

[0705] Following the synthesis method of Example 73, and replacing the corresponding starting materials, compound I-75 was prepared from compound (S)-(+)-3-fluoropyrrolidine hydrochloride (Cas: 136725-53-6) as the starting material. It is a white solid. LCMS (ESI): m / z C 23 H 32 Cl2FN4O + [M+H] + Calculated value = 469.19, Measured value = 469.2. 1 H NMR (400 MHz, DMSO- d6) δppm 7.24 (d, J = 8.9 Hz, 1H), 6.85 (br d, J = 9.2 Hz, 1H), 6.33 (br d, J =7.4 Hz, 1H), 5.38 - 5.18 (m, 1H), 4.25 - 4.13 (m, 1H), 3.75 (br d, J = 11.8Hz, 1H), 3.56 - 3.48 (m, 2H), 3.29 - 3.18 (m, 2H), 2.96 - 2.86 (m, 3H), 2.85- 2.78 (m, 1H), 2.73 - 2.62 (m, 2H), 2.22 (br t, J = 6.9 Hz, 2H), 2.06 (br s,5H), 2.00 - 1.83 (m, 4H), 1.73 (br t, J = 11.2 Hz, 1H), 1.62 (br d, J = 4.9Hz, 3H).

[0706] Example 76: Synthesis of I-76

[0707] Following the synthesis method of Example 73, and replacing the corresponding starting materials, compound I-76 was prepared from compound (R)-(-)-3-fluoropyrrolidine hydrochloride (Cas: 679431-51-7) as the starting material. It is a white solid. LCMS (ESI): m / z C 23 H 32 Cl2FN4O + [M+H] + Calculated value = 469.19, Measured value = 469.2. 1 H NMR (400 MHz, DMSO- d6) δppm 7.25 (d, J = 9.1 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 4.28 - 4.10 (m, 1H), 3.82 - 3.69 (m, 1H), 3.55 - 3.41 (m, 3H), 3.28 -3.20 (m, 2H), 2.97 - 2.87 (m, 3H), 2.81 (dd, J = 2.6, 6.0 Hz, 1H), 2.78 -2.60 (m, 3H), 2.23 (t, J = 6.6 Hz, 2H), 2.10 - 2.05 (m, 4H), 2.00 - 1.84 (m,4H), 1.74 (t, J = 11.3 Hz, 1H), 1.67 - 1.58 (m, 2H).

[0708] Example 77: Synthesis of I-77

[0709] Referring to the synthesis method of Example 73, by replacing the corresponding starting materials, the compound dimethyl- d6 Compound I-77, a white solid, was prepared from amine hydrochloride (Cas:53170-19-7). LCMS (ESI): m / z C 21 H 25 D6Cl2N4O + [M+H] + Calculated value = 431.22, Measured value = 431.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.24 (d, J= 8.9 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 6.33 (br d, J = 7.3 Hz, 1H), 4.25 -4.10 (m, 1H), 3.76 (d, J = 11.9 Hz, 1H), 2.96 - 2.78 (m, 4H), 2.74 - 2.63 (m,2H), 2.23 (t, J = 6.9 Hz, 2H), 2.09 - 1.84 (m, 7H), 1.74 (t, J = 10.8 Hz,1H), 1.68 - 1.52 (m, 3H).

[0710] Example 78: Synthesis of I-78

[0711] Step 1: Synthesis of intermediate 78-2

[0712] Following the synthesis methods of steps 1 and 2 in Example 42, and replacing the corresponding starting materials, compound 78-2 was prepared using intermediate 70-2 as the starting material. It is a colorless oily substance. LCMS (ESI): m / z C 12 H 13 D2Cl2N2 + [M+H] + Calculated value = 259.07, Measured value [M+H] + = 259.1.

[0713] Step 2: Synthesis of compound I-78

[0714] Following the synthesis method of Example 73, and replacing the corresponding starting materials, compound I-78 was prepared using intermediate 78-2 and compound 78-5a as starting materials. It is a white solid. LCMS (ESI): m / z C 21 H 23 D8Cl2N4O + [M+H] + Calculated value = 433.24, Measured value [M+H] + = 433.2. 1 H NMR (400 MHz, CD3OD) δ ppm 7.17 (d, J = 8.9Hz, 1H), 6.80 (d, J = 9.1 Hz, 1H), 4.32 - 4.20 (m, 1H), 3.79 (d, J = 11.4 Hz,1H), 3.10 - 2.92 (m, 3H), 2.83 - 2.75 (m, 1H), 2.42 - 2.31 (m, 2H), 2.26 -1.86 (m, 9H), 1.80 - 1.63 (m, 3H).

[0715] Example 79: Synthesis of I-79

[0716] Referring to step 2 of Example 42 and the synthesis method of Example 73, the corresponding starting materials were replaced, using intermediate 42-1b and compound dimethyl- d6 Compound I-79, a white solid, was prepared from amine hydrochloride (Cas: 53170-19-7). LCMS (ESI): m / z C21 H 25 D6Cl2N4O + [M+H] + Calculated value = 431.22, Measured value = 431.2. 1 H NMR (400 MHz, DMSO-) d6 ) δ ppm 7.25 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.32 (d, J = 7.4 Hz, 1H), 4.23 - 4.10 (m, 1H), 3.20 - 3.17 (m, 1H), 3.02 -2.91 (m, 2H), 2.84 (dd, J = 6.2, 17.9 Hz, 1H), 2.72 - 2.63 (m, 3H), 2.42 (d,J = 2.4 Hz, 1H), 2.33 - 2.16 (m, 4H), 2.10 - 2.02 (m, 3H), 1.91 - 1.82 (m,2H), 1.71 - 1.57 (m, 3H).

[0717] Example 80: Synthesis of I-80

[0718] Intermediate 42-2 (1.2 g, 3.23 mmol, 1 eq) was dissolved in 30 mL of methanol, and compound 80-1 (892.20 mg, 4.20 mmol, 1.3 eq) (prepared according to reference CN104496854 A) and sodium cyanoborohydride (609.49 mg, 9.70 mmol, 3 eq) were added. The reaction mixture was stirred at 25 °C for 2 hours. LCMS monitoring showed complete consumption of the starting material and formation of the main product. The reaction mixture was concentrated under reduced pressure to the residue, and then subjected to silica gel column chromatography (ISCO®; 40 g SepaFlash® silica gel column, eluent 0-10% (ethyl acetate / methanol = 10:1) / petroleum ether, flow rate: 35 mL / min) to prepare compound I-80 as a white solid (950 mg, yield: 64.86%). LCMS (ESI): m / zC 23 H 35 Cl2N4O + [M+H] + Calculated value = 453.22, Measured value = 453.2. 1 H NMR (400 MHz, DMSO- d6) δppm 7.24 (d, J = 8.9 Hz, 1H), 6.85 (d, J = 9.2 Hz, 1H), 5.83 (d, J = 7.7 Hz,1H), 3.75 (d, J = 11.6 Hz, 1H), 3.00 - 2.88 (m, 3H), 2.87 - 2.77 (m, 2H),2.74 (s, 6H), 2.70 - 2.60 (m, 2H), 2.29 (t, J = 7.2 Hz, 2H), 2.05 - 1.90 (m,2H), 1.72 (d, J = 5.4 Hz, 5H), 1.65 - 1.54 (m, 1H), 1.39 - 1.31 (m, 2H), 1.24-1.13 (m, 3H), 0.99-0.88 (m, 2H).

[0719] Example 81: Synthesis of I-81

[0720] Following the synthesis method of Example 80, and replacing the corresponding starting materials, compound I-81 was prepared using intermediate 42-1b as the starting material. It is a white solid. LCMS (ESI): m / z C 23 H 35 Cl2N4O + [M+H] + Calculated value = 453.22, Measured value = 453.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.26 (d, J = 8.6 Hz, 1H), 7.08 (d, J =8.5 Hz, 1H), 5.85 (d, J = 7.9 Hz, 1H), 3.23 - 3.18 (m, 1H), 3.04 - 2.93 (m,2H), 2.89 - 2.80 (m, 1H), 2.75 (s, 6H), 2.72 - 2.62 (m, 3H), 2.44 (d, J = 3.1Hz, 2H), 2.35 - 2.23 (m, 3H), 2.19 - 2.10 (m, 1H), 1.80 - 1.64 (m, 5H), 1.39- 1.30 (m, 2H), 1.28 - 1.13 (m, 3H), 1.04 - 0.86 (m, 2H).

[0721] Example 82: Synthesis of I-82

[0722] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-82 was prepared using 2-bromo-1-chloro-5-fluoro-3-iodobenzene (CAS: 2385641-26-7) as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 31 ClFN4O + [M+H] + Calculated value = 409.22, Measured value = 409.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 6.69(dd, J = 2.1, 12.9 Hz, 1H), 6.64 (dd, J = 2.3, 8.3 Hz, 1H), 6.34 (d, J = 7.4Hz, 1H), 4.20 - 4.11 (m, 1H), 3.75 (d, J = 12.3 Hz, 1H), 2.99 - 2.90 (m, 3H), 2.75 (s, 6H), 2.74 - 2.64 (m, 2H), 2.64 - 2.52 (m, 1H), 2.23 (s, 2H), 2.09 -2.00 (m, 4H), 1.95 - 1.91 (m, 1H), 1.89 - 1.83 (m, 2H), 1.77 - 1.69 (m, 1H), 1.65 - 1.54 (m, 3H).

[0723] Example 83: Synthesis of I-83

[0724] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-83 was prepared using 2-bromo-4-chloro-3-fluoro-1-iodobenzene (CAS: 2385938-72-5) as the starting material. It was a white solid. LCMS (ESI): m / z C 21 H 31 ClFN4O + [M+H] + Calculated value = 409.22, Measured value = 409.2. 1H NMR (400 MHz, CD3OD) δ ppm 7.07 (t, J= 8.5 Hz, 1H), 6.64 (d, J = 9.3 Hz, 1H), 4.28 (d, J = 6.9 Hz, 1H), 3.82 (d, J= 12.3 Hz, 1H), 3.17 - 2.97 (m, 4H), 2.88 (s, 6H), 2.84 - 2.77 (m, 2H), 2.71 (dd, J = 6.7, 12.1 Hz, 1H), 2.46 - 2.36 (m, 2H), 2.27 (d, J = 2.0 Hz, 1H), 2.20 - 2.10 (m, 4H), 2.08 - 2.02 (m, 2H), 1.80 - 1.73 (m, 3H), 1.66 - 1.62 (m, 1H).

[0725] Example 84: Synthesis of I-84

[0726] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-83 was prepared using 2-bromo-4-chloro-1-fluoro-3-iodobenzene (CAS: 2385924-24-1) as the starting material. It was a white solid. LCMS (ESI): m / z C 21 H 31 ClFN4O + [M+H] + Calculated value = 409.22, Measured value = 409.2. 1 H NMR (400 MHz, CD3OD) δ ppm 7.15 (dd,J = 6.1, 8.6 Hz, 1H), 6.65 (t, J = 8.6 Hz, 1H), 6.33 (d, J = 6.3 Hz, 1H), 4.59 (s, 2H), 4.36 - 4.18 (m, 1H), 3.14 - 3.03 (m, 1H), 2.88 (s, 6H), 2.75 -2.64 (m, 3H), 2.56 (t, J = 8.1 Hz, 1H), 2.41 - 2.29 (m, 2H), 2.21 - 2.01 (m,6H), 1.79 - 1.71 (m, 3H), 1.37 - 1.26 (m, 2H).

[0727] Example 85: Synthesis of I-85

[0728] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-85 was prepared using 2-bromo-1-chloro-3-iodo-5-methylbenzene (CAS: 2384411-08-7) as the starting material. It was a white solid. LCMS (ESI): m / z C 22 H 34 ClN4O + [M+H] + Calculated value = 405.24, Measured value = 405.2. 1 H NMR (400 MHz, CD3OD) δ ppm6.63 (s, 1H), 6.60 (s, 1H), 6.33 (d, J = 6.9 Hz, 1H), 4.32 - 4.25 (m, 1H), 3.81 (d, J = 12.2 Hz, 1H), 3.06 (d, J = 9.2 Hz, 1H), 3.02 - 2.93 (m, 2H), 2.90 - 2.86 (m, 8H), 2.83 - 2.74 (m, 1H), 2.73 - 2.62 (m, 1H), 2.39 - 2.32(m, 2H), 2.23 (s, 3H), 2.19 - 2.09 (m, 4H), 2.09 - 2.01, (m, 2H), 1.95 - 1.91(m, 1H), 1.78 - 1.71 (m, 2H), 1.71 - 1.61 (m, 1H).

[0729] Example 86: Synthesis of I-86

[0730] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-86 was prepared using 2-bromo-1,4-difluoro-3-iodobenzene (CAS: 1208074-72-9) as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 31 F2N4O + [M+H] + Calculated value = 393.25, Measured value = 393.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 6.94 (ddd,J = 5.5, 8.8, 13.9 Hz, 1H), 6.56 (dt, J = 3.2, 8.6 Hz, 1H), 6.36 (d, J = 7.4Hz, 1H), 4.22 - 4.13 (m, 1H), 3.89 (d, J = 11.4 Hz, 1H), 3.07 (t, J = 8.9 Hz,1H), 3.00 - 2.87 (m, 3H), 2.77 - 2.73 (m, 7H), 2.69 (s, 1H), 2.64 - 2.57 (m,1H), 2.44 - 2.36 (m, 2H), 2.26 - 2.14 (m, 1H), 2.09 - 2.02 (m, 3H), 1.92 -1.83 (m, 3H), 1.69 - 1.54 (m, 3H).

[0731] Example 87: Synthesis of I-87

[0732] Following the synthesis method in Example 40, and replacing the corresponding starting materials, compound I-87 was prepared using 2-bromo-1-chloro-4-fluoro-3-iodobenzene (CAS: 1935178-59-8) as the starting material. It was a white solid. LCMS (ESI): m / z C 21 H 31 ClFN4O + [M+H] + Calculated value = 409.22, Measured value = 393.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 6.97(dd, J = 8.8, 13.5 Hz, 1H), 6.85 (dd, J = 4.2, 8.7 Hz, 1H), 6.33 (d, J = 7.3Hz, 1H), 4.25 - 4.07 (m, 1H), 3.70 (d, J = 11.0 Hz, 1H), 3.05 - 2.96 (m, 1H),2.90 (t, J = 9.6 Hz, 1H), 2.78 (s, 1H), 2.75 (s, 6H), 2.73 - 2.56 (m, 3H),2.32 - 2.17 (m, 3H), 2.11 - 1.98 (m, 4H), 1.86 (t, J = 8.2 Hz, 3H), 1.72 -1.55 (m, 3H).

[0733] Example 88: Synthesis of I-88

[0734] Referring to the synthesis method in Example 49, and replacing the corresponding starting materials, compound I-88 was prepared from compound I-87 as the starting material. It is a white solid. LCMS (ESI): m / z C 21 H 30 Cl2FN4O + [M+H] + Calculated value = 443.18, Measured value = 443.18. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.38 (d, J = 13.1 Hz, 1H), 6.34 (d, J= 7.0 Hz, 1H), 4.23 - 4.09 (m, 1H), 3.77 - 3.61 (m, 1H), 3.06 - 3.00 (m, 1H), 2.92 (d, J = 9.3 Hz, 1H), 2.87 - 2.79 (m, 2H), 2.75 (s, 6H), 2.72 - 2.67 (m,1H), 2.38 - 2.20 (m, 3H), 2.07 - 2.03 (m, 5H), 1.88 (d, J = 7.0 Hz, 3H), 1.70- 1.57 (m, 3H).

[0735] Example 89: Synthesis of I-89

[0736] Following the synthesis methods of steps 1-4 in Example 40 and steps 4-7 in Example 2, and replacing the corresponding starting materials, compound I-89 was prepared using 2-bromo-1,5-dichloro-3-iodobenzene (CAS: 2386869-73-2) as the starting material. It is a white solid. LCMS (ESI): m / z C 23 H 35 Cl2N4O + [M+H] + Calculated value = 453.22, Measured value = 453.2. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 6.85 (s, 1H), 6.82 (d, J = 1.7 Hz, 1H), 5.84 (d, J = 7.7 Hz,1H), 3.78 (d, J = 12.0 Hz, 1H), 3.42 (s, 1H), 2.98 - 2.87 (m, 3H), 2.76 -2.72 (m, 7H), 2.69 - 2.54 (m, 2H), 2.34 - 2.25 (m, 2H), 2.03 - 1.89 (m, 2H),1.77 - 1.67 (m, 5H), 1.64 - 1.50 (m, 1H), 1.34 (q, J = 7.0 Hz, 2H), 1.23 -1.12 (m, 3H), 0.99 - 0.88 (m, 2H).

[0737] Example 90: Synthesis of I-90

[0738] Referring to step 2 of Example 42 and the synthesis method of Example 73, the corresponding starting materials were replaced, using intermediate 42-1a, compound 1-6a and dimethyl- d6 Compound I-90, a white solid, was prepared from amine hydrochloride (Cas: 53170-19-7). LCMS (ESI): m / z C 23 H 29 D6Cl2N4O + [M+H] + Calculated value = 459.26, Measured value = 459.3. 1 H NMR (400 MHz, CD3OD) δ ppm 7.17 (d, J = 8.8 Hz, 1H), 6.80 (d, J= 9.3 Hz, 1H), 5.85 (d, J = 8.0 Hz, 1H), 3.78 (d, J = 12.0 Hz, 1H), 3.50 - 3.46 (m, 1H), 3.05 (d, J = 11.3 Hz, 1H), 3.01 - 2.88 (m, 3H), 2.83 - 2.68 (m, 2H), 2.48 -2.38 (m, 2H), 2.22 - 2.16 (m, 1H), 2.03 - 1.95 (m, 1H), 1.93 - 1.86 (m, 3H),1.82 (d, J = 12.0 Hz, 2H), 1.76 - 1.63 (m, 1H), 1.51 - 1.42 (m, 2H), 1.31 -1.21 (m, 3H), 1.13 - 1.01 (m, 2H).

[0739] Example 91: Synthesis of I-91

[0740] Following the synthesis method described in steps 6 to 8 of Example 1, and replacing the corresponding starting materials, intermediate 42-2 and compound (3-(2-oxyethyl)bicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (1935050-89-7) were used as starting materials to prepare compound I-91, which is a white solid. LCMS (ESI): m / z C 22 H 31 Cl2N4O + [M+H] + Calculated value = 437.19, Measured value = 437.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 7.24 (d, J = 9.0 Hz, 1H), 6.86 (d,J = 9.3 Hz, 1H), 6.75 (s, 1H), 3.75 (d, J = 12.0 Hz, 1H), 3.41 - 3.37 (m,1H), 2.89 (d, J = 7.8 Hz, 3H), 2.74 - 2.70 (m, 7H), 2.65 - 2.59 (m, 1H), 2.26(t, J = 7.3 Hz, 2H), 2.07 - 1.98 (m, 1H), 1.97 - 1.89 (m, 1H), 1.80 - 1.77(m, 6H), 1.76 - 1.70 (m, 1H), 1.68 - 1.55 (m, 3H).

[0741] Example 92: Synthesis of I-92

[0742] Referring to the synthesis method of Example 42, and replacing the corresponding starting materials, using compound I-81 as the starting material and employing 2 equivalents of N-chlorosuccinimide, compound I-92 was prepared as a white solid. LCMS (ESI): m / z C 23 H 34 Cl3N4O + [M+H] + Calculated value = 487.18, Measured value = 487.2. 1 H NMR (400 MHz, CD3OD) δ ppm 7.60 (s,1H), 5.84 (d, J = 7.9 Hz, 1H), 3.40 - 3.32 (m, 1H), 3.22 - 3.14 (m, 1H), 3.00- 2.90 (m, 2H), 2.87 (d, J = 5.8 Hz, 1H), 2.79-2.69 (m, 7H), 2.71 - 2.64 (m,2H), 2.41 (dd, J = 3.0, 11.0 Hz, 1H), 2.34 - 2.21 (m, 3H), 2.20 - 2.05 (m,1H), 1.79 - 1.64 (m, 5H), 1.36-1.30 (q, J = 7.1 Hz, 2H), 1.25 - 1.12 (m, 3H), 0.99-0.93 (m, 2H).

[0743] Example 93: Synthesis of I-93

[0744] Following the synthesis method described in steps 6 to 8 of Example 1, and replacing the corresponding starting materials, using intermediate 42-2 and N-[(1S,3R)-3-(3-oxopropyl)cyclobutyl]carbamate tert-butyl ester as starting materials, compound I-93 was prepared as a white solid. LCMS (ESI): m / z C 22 H 33 Cl2N4O + [M+H] + Calculated value = 439.20, Measured value = 439.2. 1 H NMR (400 MHz, CD3OD) δ ppm 7.17 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H), 4.25 (t, J = 7.6 Hz, 1H), 3.89 - 3.75 (m, 1H), 3.05 (dd, J = 2.4, 8.8 Hz,1H), 3.01 - 2.85 (m, 9H), 2.82 - 2.71 (m, 2H), 2.40 (t, J = 7.0 Hz, 2H), 2.23- 2.07 (m, 4H), 2.05 - 1.96 (m, 3H), 1.93 - 1.85 (m, 1H), 1.65-1.75 (m, 1H),1.59 - 1.44 (m, 4H).

[0745] Example 94: Synthesis of I-94

[0746] Following the synthesis method described in Example 73, and replacing the corresponding starting materials, intermediate 1-6a was used as the starting material to prepare compound I-94, which is a white solid. LCMS (ESI): m / z C 24 H 33 Cl2F2N4O + [M+H] + Calculated value = 501.20, Measured value = 501.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 7.24 (d, J = 9.1 Hz, 1H), 6.85 (d,J = 9.2 Hz, 1H), 6.51 (d, J = 7.9 Hz, 1H), 4.15 (t, J = 12.8 Hz, 4H), 3.75(d, J = 12.0 Hz, 1H), 2.96 - 2.79 (m, 4H), 2.74 - 2.61 (m, 2H), 2.29 (t, J =7.3 Hz, 2H), 2.07 (s, 1H), 2.04 - 1.91 (m, 2H), 1.80 - 1.68 (m, 5H), 1.66 -1.54 (m, 1H), 1.36-1.32 (m, 2H), 1.23 - 1.08 (m, 3H), 1.02 - 0.87 (m, 2H).

[0747] Example 95: Synthesis of I-95

[0748] Referring to the synthesis method in step 2 of Example 73, and replacing the corresponding raw materials, intermediate 94-3 and ammonia were used as raw materials to prepare compound I-95, which is a white solid. LCMS (ESI): m / z C 21 H 31 Cl2N4O + [M+H] + Calculated value = 425.19, Measured value = 425.3. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.26 (d, J = 9.1 Hz,1H), 6.93 - 6.83 (m, 1H), 5.77 (d, J = 7.9 Hz, 1H), 5.33 - 5.22 (m, 2H), 3.91- 3.69 (m, 1H), 3.50 - 3.38 (m, 1H), 3.24 - 3.16 (m, 1H), 3.05 - 2.78 (m,4H), 2.74 - 2.62 (m, 2H), 2.41 - 2.30 (m, 1H), 2.00 - 1.93 (m, 1H), 1.84 -1.67 (m, 5H), 1.66 - 1.54 (m, 1H), 1.45 - 1.33 (m, 2H), 1.28 - 1.15 (m, 2H), 1.09 - 0.90 (m, 4H).

[0749] Example 96: Synthesis of I-96

[0750] Referring to the synthesis method in step 2 of Example 73, and replacing the corresponding starting materials, compound I-96 was prepared using intermediate 94-3 and methylamine as starting materials. It is a white solid. LCMS (ESI): m / z C 22 H 33 Cl2N4O + [M+H] + Calculated value = 439.20, Measured value = 439.3. 1 H NMR (400 MHz, DMSO- d6 ) δ ppm 7.28 - 7.20 (m, 1H), 6.90 - 6.83 (m, 1H), 5.67 (d, J = 8.1 Hz, 1H), 5.55 (d, J = 4.5 Hz, 1H), 3.76(d, J = 11.7 Hz, 1H), 3.27-3.21 (m, 1H), 2.98 - 2.78 (m, 4H), 2.73 - 2.63 (m,2H), 2.54 - 2.53 (m, 3H), 2.34 - 2.26 (m, 2H), 2.05 - 1.93 (m, 2H), 1.82 -1.69 (m, 4H), 1.65 - 1.52 (m, 1H), 1.35 (d, J = 7.4 Hz, 2H), 1.25 - 1.16 (m, 2H), 1.09 - 0.89 (m, 4H).

[0751] Example 97: Synthesis of I-97

[0752] Following the synthesis method in step 2 of Example 73, and replacing the corresponding starting materials, intermediate I-97 was prepared using intermediate 94-3 and compound azacyclobutane (Cas: 503-29-7) as starting materials. It is a white solid. LCMS (ESI): m / zC 24 H 35 Cl2N4O + [M+H] + Calculated value = 465.22, Measured value = 465.2. 1 H NMR (400 MHz, DMSO- d6) δppm 7.24 (d, J = 9.1 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 5.88 (d, J = 8.2 Hz, 1H), 3.73 (t, J = 7.5 Hz, 4H), 3.29 - 3.22 (m, 1H), 2.94 - 2.80 (m, 3H), 2.74- 2.60 (m, 2H), 2.34 - 2.27 (m, 2H), 2.13 - 1.93 (m, 4H), 1.76 - 1.69 (m,4H), 1.64 - 1.55 (m, 1H), 1.55 - 1.27 (m, 3H), 1.28-1.22 (m, 2H), 1.21-1.07(m, 3H), 1.01-0.85(m, 2H).

[0753] Example 98: Synthesis of I-98

[0754] Following the synthesis method in step 2 of Example 73, and replacing the corresponding starting materials, intermediate I-98 was prepared using intermediate 94-3 and compound 3-fluorozacriane hydrochloride (Cas: 617718-46-4) as starting materials. The compound was a white solid. LCMS (ESI): m / z C 24 H 34 Cl2FN4O + [M+H] + Calculated value = 483.21, Measured value = 483.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 7.24 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 9.2 Hz, 1H), 6.19 (d, J= 8.0 Hz, 1H), 5.51 - 5.10 (m, 1H), 4.15 - 3.95 (m, 2H), 3.84 - 3.72 (m, 3H),2.97 - 2.87 (m, 3H), 2.86 - 2.75 (m, 1H), 2.77 - 2.57 (m, 3H), 2.34 - 2.27(m, 2H), 2.05 - 1.91 (m, 2H), 1.78-1.68 (m, 5H), 1.66 - 1.53 (m, 1H), 1.40 -1.31 (m, 2H), 1.22 - 1.08 (m, 3H), 1.00 - 0.89 (m, 2H).

[0755] Example 99: Synthesis of I-99

[0756] Step 1: Synthesis of intermediate 99-1

[0757] Referring to the synthesis method in steps 1 to 4 of Example 40, and replacing the corresponding starting materials, using 2-bromo-1-chloro-4-fluoro-3-iodobenzene (CAS: 1935178-59-8) as the starting material, intermediate 99-1 was prepared as a colorless oil. LCMS (ESI): m / zC 17 H 23 ClFN2O2 + [M+H] + Calculated value = 341.14, Measured value = 341.1. 1 H NMR (400 MHz, CD3Cl) δppm 6.77 (d, J = 8.8 Hz, 2H), 3.99 - 3.71 (m, 3H), 3.26 (t, J = 10.2 Hz, 1H), 3.12 - 2.81 (m, 4H), 2.69-2.59 (m, 1H), 1.89 (d, J = 12.5 Hz, 1H), 1.69 (s, 1H), 1.45 (s, 9H).

[0758] Step 2: Synthesis of intermediate 99-2

[0759] Referring to the synthesis method in step 1 of Example 42, and replacing the corresponding raw materials, intermediate 99-1 was used as the raw material to prepare intermediate 99-2, which is a colorless oily substance. LCMS (ESI): m / z C 17 H 22 Cl2FN2O2 + [M+H] + Calculated value = 375.10, measured value = 375.1. 1 H NMR (400 MHz, CD3Cl) δ ppm 7.05 (d, J = 12.8 Hz, 1H), 4.03 -3.81 (m, 2H), 3.75 (d, J = 10.5 Hz, 1H), 3.36 - 3.26 (m, 1H), 3.10 - 2.87 (m,4H), 2.77 - 2.64 (m, 1H), 2.01 - 1.89 (m, 1H), 1.80 - 1.69 (m, 1H), 1.50 (s,9H).

[0760] Step 3: Synthesis of Compound I-99

[0761] Referring to the synthesis method in step 2 of Example 42, and replacing the corresponding starting materials, intermediates 99-2 and 80-1 were used as starting materials to prepare compound I-99, which is a white solid. LCMS (ESI): m / z C 23 H 34 Cl2FN4O + [M+H] + Calculated value = 471.21, Measured value = 471.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 7.37 (d, J = 13.4 Hz, 1H), 5.84 (d, J = 7.9 Hz, 1H), 3.66 (d, J = 12.3 Hz, 1H), 3.04-2.94 (m, 1H), 2.91 (t, J = 9.7 Hz, 1H), 2.86 - 2.79 (m, 1H), 2.76 (s, 1H), 2.74 (s, 6H), 2.72 - 2.65 (m, 2H), 2.34 - 2.22 (m, 3H), 2.10 - 1.99 (m, 1H), 1.91 - 1.81(m, 1H), 1.76 - 1.64 (m, 5H), 1.36 - 1.28 (m, 2H), 1.26 - 1.12 (m, 4H), 1.01 - 0.87 (m, 2H).

[0762] Example 100: Synthesis of I-100

[0763] Referring to the synthesis method of Example 94, the corresponding starting materials were replaced, using intermediate 99-3 and compound dimethyl- d6 Compound I-100, a white solid, was prepared from amine hydrochloride (Cas: 53170-19-7). LCMS (ESI): m / z C 23 H 28 D6Cl2FN4O + [M+H] + Calculated value = 477.25, Measured value = 477.3.

[0764] Example 101: Synthesis of I-101

[0765] Referring to steps 1 to 4 of Example 40 and the synthesis method of Example 99, and replacing the corresponding starting materials, 2-bromo-1,4-difluoro-3-iodobenzene (CAS: 1208074-72-9) was used as the starting material to prepare compound I-101, which is a white solid. LCMS (ESI): m / z C 23 H 34 ClF2N4O + [M+H] + Calculated value = 455.24, Measured value = 455.2. 1 H NMR (400 MHz, DMSO- d6) δ ppm 7.26 (dd, J = 7.4, 13.4 Hz, 1H), 5.83 (d, J = 7.9 Hz, 1H), 3.79 (d, J = 12.0 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.06 - 2.97 (m, 1H), 2.95 -2.84 (m, 1H), 2.80 (d, J = 10.3 Hz, 1H), 2.76 - 2.70 (m, 8H), 2.68 - 2.58 (m,1H), 2.35 - 2.25 (m, 2H), 2.23 - 2.13 (m, 1H), 1.97 (t, J = 10.0 Hz, 1H),1.91 - 1.81 (m, 1H), 1.72 (t, J = 11.0 Hz, 4H), 1.65 - 1.51 (m, 1H), 1.37 -1.28 (m, 2H), 1.25 - 1.11 (m, 3H), 0.99 - 0.85 (m, 2H).

[0766] Biological Test Example 1: Activity Test of the Compounds of the Invention for Dopamine D2 Receptors

[0767] 1. Experimental objective: To evaluate the agonistic activity of the compounds of this invention on the D2 receptor.

[0768] 2. Experimental principle: The dopamine D2 receptor is coupled with the inhibitory G protein Gi / o, which inhibits the production of the second messenger cAMP. By using cell lines transfected with the D2 receptor, the intracellular cAMP level can be detected by the cAMP Assay to reflect the agonistic activity of the compound on the D2 receptor.

[0769] 3. Test methods: 3.1 Cell Culture and Reagent Preparation a) Cell line: Flpin-CHO-D stably expressing the human D2 receptor 2L cell.

[0770] b) Complete culture medium: F12K + 10% fetal bovine serum + 1× penicillin-streptomycin + 600μg / ml hygromycin.

[0771] c) Experimental buffer: 1×HBSS + 20mM HEPES + 0.1% BSA + 500μM IBMX.

[0772] 3.2 Determination of the activity of the test compound against the D2 receptor

[0773] a) Digest the cells, resuspend them in experimental buffer, and seed them into 384 cell culture plates at a seeding density of 8000 cells per well and a seeding volume of 15 μL per well.

[0774] b) Dilute the test compound with experimental buffer (final concentration range: 1000 nM to 0.05 nM).

[0775] c) Add 2.5 μL of the test compound solution to each well and incubate at 37 °C for 10 minutes.

[0776] d) Dilute forskolin to 8 μM (8×) with experimental buffer.

[0777] e) Add 2.5 μL of diluted 8×forskolin to each well and incubate at 37°C for 30 minutes.

[0778] f) Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP, then dilute them with lysis buffer.

[0779] g) Add 10 μL of Eu-cAMP tracer to the well, and then add 10 μL of Ulight-anti-cAMP to the well.

[0780] h) The reaction plate was centrifuged at 200g for 30s at room temperature, and then allowed to stand at 25℃ for 1h before data were collected using Envision.

[0781] 4. Data Analysis: Activation activity (% Activity) = (Signal) cmpd -Signal Ave_VC ) / (Signal Ave_PC -Signal Ave_VC )×100. Where Signal Ave_VC The average signal value of the solvent control well is represented by Signal. Ave_PC This represents the average signal value of the 500 nM dopamine positive control well. cmpd This represents the average signal value of the pores of the compound being tested.

[0782] EC values ​​of the agonist activity of the test compound were calculated using a GraphPad nonlinear fitting formula. 50 And the Top value of maximum agonistic activity.

[0783] E max (% of caliprazine maximum agonist activity) is expressed as the percentage of the maximum agonist activity (Top) of the test compound to the maximum agonist activity (Top) of caliprazine.

[0784] 5. Experimental Results: The efficacy of the compound of this invention against the D2 receptor (EC) 50 The maximum agonistic effect relative to cariprazine is shown in Table 1.

[0785] Table 1. D2 receptor EC 50 and the maximum agonistic effect relative to cariprazine

[0786] a E of cariprazine max The value is set at 100%, and other compounds are expressed as a percentage equivalent to cariprazine.

[0787] The compounds of this invention all exhibit strong agonistic activity towards D2, and their agonistic effect on D2 is comparable to that of third-generation D2 partial agonists such as cariprazine, buripiperazole, and / or aripiprazole (E... max (±15% of cariprazine).

[0788] Biological test example 2: The compound of the present invention for 5-HT 1A Receptor agonist activity test

[0789] 1. Experimental Objective: To evaluate the effect of the compounds of this invention on 5-HT 1A Receptor agonistic activity.

[0790] 2. Experimental Principle: 5-HT 1A The receptor is coupled to the inhibitory G protein Gi / o, which inhibits the production of the second messenger cAMP. Therefore, transfection with 5-HT is used. 1A In cell lines containing the receptor, intracellular cAMP levels can be detected using a cAMP assay to reflect the effect of a compound on 5-HT. 1A Receptor agonistic activity.

[0791] 3. Test methods: 3.1 Cell Culture and Reagent Preparation a) Cell line: stably expressing human 5-HT 1A receptor hTR 1A - Gα15-CHO-Clone#6.

[0792] b) Complete culture medium: F12K + 10% fetal bovine serum + 1× penicillin-streptomycin + 600μg / mL hygromycin.

[0793] c) Experimental buffer: 1×HBSS + 20mM HEPES + 0.1% BSA + 500μM IBMX.

[0794] 3.2 The effect of the test compound on 5-HT1A Receptor activity assay

[0795] a) Dilute the test compound with DMSO in a gradient (DMSO stock solution was used to dilute 10 concentrations in a 3-fold gradient, with a final concentration of 1000~0.05 nM).

[0796] b) Use the ECHO nano-level pipetting system to transfer 20 nL of the test compound solution to a cell culture plate.

[0797] c) Digest the cells, resuspend them in experimental buffer, and seed them into 384 cell culture plates at a density of 4000 cells per well and a seeding volume of 15 μL per well.

[0798] d) Incubate at 37°C for 10 minutes.

[0799] e) Dilute forskolin to 4 μM (4×) with experimental buffer.

[0800] f) Add 5 μL of the diluted 4× forskolin from the previous step to each well and incubate at 37°C for 30 minutes.

[0801] g) Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP, then dilute them with lysis buffer.

[0802] h) Add 5 μL of Eu-cAMP tracer to the well, and then add 5 μL of L Light-anti-cAMP to the well.

[0803] i) After centrifuging the reaction plate at 200g for 30s at room temperature and letting it stand at 25℃ for 1h, data were collected using Envision.

[0804] 4. Data Analysis: Activation activity (% Activity) = (Signal) cmpd -Signal Ave_VC ) / (Signal Ave_PC -Signal Ave_VC )×100. Where Signal Ave_VC The average signal value of the solvent control well is represented by Signal. Ave_PC This represents the average signal value of the 500 nM Serotonin (5-hydroxytryptamine) positive control wells. cmpd This represents the average signal value of the pores of the compound being tested.

[0805] EC values ​​of compound activating activity were calculated using a GraphPad nonlinear fitting formula. 50 And the Top value of maximum agonistic activity.

[0806] E max (%) (% of cariprazine maximum agonist activity) is expressed as the percentage of the compound’s maximum activity (Top) to the maximum agonist activity (Top) of cariprazine.

[0807] 5. Experimental Results: The compound of this invention has a positive effect on 5-HT. 1A receptor agonist activity intensity (EC) 50 The maximum agonistic effect relative to cariprazine is shown in Table 2.

[0808] Table 2. 5-HT 1A receptor EC 50 and the maximum agonistic effect relative to cariprazine

[0809] a E of cariprazine max The value is set at 100%, and other compounds are expressed as a percentage equivalent to cariprazine.

[0810] The compound of this invention affects 5-HT 1A It has strong agonistic activity, E max It is significantly superior to the third-generation control compounds aripiprazole, cariprazine, or buripiperazole.

[0811] Biological Test Example 3: Study on the effect of the compound of this invention on MK-801-induced hyperactivity in mice

[0812] 1. Experimental objective: To evaluate the effect of the compound of the present invention on MK-801-induced hyperactivity in mice.

[0813] 2. Experimental Principle: MK-801 (CAS: 77086-22-7) is a non-competitive antagonist of the NMDA receptor, which acutely induces hyperspontaneous movement in animals to mimic positive symptoms of schizophrenia. This study evaluates the potential antipsychotic efficacy of the compound using a MK-801-induced hyperactive mouse model. The potential therapeutic effect of the test substance is typically assessed by changes in the movement distance of the MK-801-induced animals.

[0814] 3. Test methods: 3.1 Experimental Animals Male C57BL / 6 mice (purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.), 7-8 weeks old. Housing conditions: temperature 25℃, daily temperature difference less than 3℃, relative humidity 50%, feed sterilized by high temperature and pressure, and free access to feed and water. Adaptation period: at least 3 days; 3.2 Reagents Modeling agent: MK-801 (dissolved in physiological saline, concentration: 0.03 mg / mL).

[0815] 3.3 Solvent

[0816] 5% DMSO + 30% PEG400 + 65% physiological saline.

[0817] 3.4 Test Equipment

[0818] Precision balance, weighing paper, pipette, centrifuge tubes, electronic scale, 1mL syringe, mouse gavage needle, mouse open field test equipment.

[0819] 3.5 Test Procedure: a) One hour before the experiment, the animals were moved to the open field testing laboratory to acclimatize.

[0820] b) Mice were weighed and randomly divided into three groups according to their weight: normal animal group (no MK-801 modeling), solvent group (MK-801 modeling + solvent), and drug-treated group (MK-801 modeling + test compound), with 6 mice in each group.

[0821] c) After grouping, the test compound (administered group) was administered 0.4 mg / kg by gavage as pretreatment, with an administration volume of 10 mL / kg. The normal animal group and the solvent group were given only the corresponding volume of solvent. Fifteen minutes after administration, the solvent group and the administered group were intraperitoneally injected with 10 mL / kg MK-801 (0.3 mpk) to establish the model (the normal animal group was intraperitoneally injected with the corresponding volume of physiological saline).

[0822] d) Fifteen minutes after MK-801 injection, mice were placed in an open field experimental device for monitoring for 15 minutes.

[0823] e) After the experiment, the total distance traveled by the mice was statistically analyzed. Data were plotted using GraphPad Prism software, and data analysis employed one-way ANOVA with multiple comparisons.

[0824] 4. Test Results: (e.g.) Figure 1 ( Figure 1 middle This indicates that P < 0.05. This means P ≤ 0.002. This means P ≤ 0.0002. As shown in the figure, P < 0.0001.

[0825] The compounds of this invention can significantly reduce MK-801-induced hyperactivity in mice and improve positive symptoms.

[0826] Biological Test Example 4: Study on the absorption and blood-brain barrier crossing ability of the compound of this invention

[0827] 1. Experimental objective: To evaluate the ability of the compounds of the present invention to be absorbed and to cross the blood-brain barrier.

[0828] 2. Laboratory animals: Male C57BL / 6 mice (purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.), 7-8 weeks old. Housing conditions: temperature 25℃, daily temperature difference less than 3℃, relative humidity 50%, feed sterilized by high temperature and pressure, and free access to feed and water. Adaptation period: at least 3 days.

[0829] 3. Test methods:

[0830] Three animals per group were administered the test compound at a dose of 10 mg / kg via gavage, using a solvent of 5% DMSO + 30% PEG400 + 65% physiological saline, at a volume of 10 mL / kg. Four hours after administration, venous blood and brain tissue were collected. Whole blood was placed in EDTA-K2 tubes, centrifuged at 11,000 rpm for 5 minutes, and plasma was separated and stored at -80°C. Brain tissue was washed with ice-cold physiological saline to remove contents and residual blood, blotted dry with filter paper, homogenized at a 1:4 ratio with 50% methanol / water, and stored at -80°C.

[0831] Concentration analysis of plasma and brain tissue homogenate samples was performed using HPLC-MS / MS.

[0832] 4. Experimental Results:

[0833] The concentrations of the test compound in plasma and brain tissue, and the brain-blood ratio, after oral administration to mice are shown in Table 3.

[0834] Table 3. Brain tissue and plasma concentrations in mice 4 hours after a single oral administration

[0835] The compounds of this invention have high plasma and brain tissue exposure levels, significantly higher than those of third-generation antipsychotic drugs, and a high brain-blood ratio, exhibiting good absorption and brain penetration capabilities.

[0836] Biological Test Example 5: Study on the effect of oral administration of the compound of the present invention on body temperature in mice

[0837] 1. Experimental Objective: This experiment aims to evaluate the side effects of the compound by measuring its effect on the body temperature of mice after oral administration via gavage.

[0838] 2. Experimental animals: Male C57BL / 6 mice (purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.).

[0839] 3. Test methods:

[0840] 3.1 The mice were weighed and grouped into groups of 6 mice each.

[0841] 3.2 The blank solvent (5% DMSO + 30% PEG400 + 65% Saline) and the test compounds (10, 20, 40 mpk, dissolved in the blank solvent) were administered by gavage at a volume of 10 mL / kg.

[0842] 3.3 The rectal temperature of mice was tested at 1, 2 and 4 hours after administration, following the steps below.

[0843] a) Prepare tools and materials: thermometer, gloves, sterile lubricant.

[0844] b) Put on gloves and remove the mouse from the cage.

[0845] c) Place the mouse on a flat surface and gently hold its tail with one hand to prevent it from moving.

[0846] d) Pick up the thermometer with your other hand and apply an appropriate amount of sterile lubricant to it.

[0847] e) Insert the thermometer into the mouse's anus to a depth of about 1-2 cm.

[0848] f) Keep the thermometer in the rectum for about 30 seconds, until the thermometer reading stabilizes.

[0849] g) Remove the thermometer and record the displayed number.

[0850] 4. Experimental Results: After oral administration of the test compound to mice, the effect of the compound on the body temperature of the mice was as follows: Figure 2 As shown.

[0851] The compound of this invention has no significant effect on mouse body temperature and has good safety; its effect on mouse body temperature is significantly lower than that of cariprazine, and its safety window is larger.

[0852] Biological Test Example 6: Effects of the Compounds of the Invention on the Motor Balance and Coordination Ability of Mice

[0853] 1. Experimental objective: The effects of the compound of this invention on the neuromotor balance and coordination ability of mice were evaluated using a rotarod test, and the side effects of the compound were assessed.

[0854] 2. Laboratory animals

[0855] Male C57BL / 6J mice, 20-23g, were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.

[0856] 3. Test methods: The day before the experiment, all mice were pre-trained. The rotarod fatigue tester was set to 6 rpm, ensuring that only mice remained on the bar for at least 1 minute in each of three consecutive trials (1 minute per trial). Before the formal experiment, the mice were weighed and randomly divided into groups of 6 mice each. At the start of the experiment, mice were administered the test compound at a dose of 20 mg / kg via gavage (solvent: 5% DMSO + 30% PEG400 + 65% physiological saline); mice were also administered the test compound via gavage at a dose of 10 mL / kg based on their body weight.

[0857] The fatigue meter was set to a rotation speed of 6 rpm and a time of 3 minutes. Two hours after drug administration, mice were placed sequentially on the rotating rods of each channel of the fatigue meter. After observing that the mice could move stably on the rotating rods for at least 2 seconds, the "Run" button was clicked to start timing, and the time it took for the mouse to fall off the rotating rod was recorded. This was repeated 3 times. If the mouse did not fall off after 60 seconds, it was counted as 60 seconds. The time the animal remained on the rotating rod was calculated.

[0858] 4. Experimental Results: The effects of the compound on the motor balance and coordination ability of mice are as follows: Figure 3 As shown ( Figure 3 middle This means P ≤ 0.01. This means P ≤ 0.0001.

[0859] The compound of this invention has no significant effect on the motor balance and coordination ability of mice, and its safety window is superior to that of cariprazine and buriperazole.

[0860] Biological Test Example 7: Novel Object Recognition (NOR) Experiment Using the Compounds of this Invention

[0861] 1. Experimental objective: The effects of the compound of this invention on the cognitive abilities of mice were evaluated using a Novel Object Recognition (NOR) experiment.

[0862] 2. Laboratory animals: Ninety male C57BL / 6J mice, weighing 20-25g, were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.

[0863] 3. Test methods: After the experimental animals arrived and acclimatized for 7 days, the formal experiment began. The experimental animals were randomly divided into 6 groups of 15 mice each. Except for the normal animal group (no modeling), all mice received PCP (7.5 mg / kg, 10 mL / kg) once a day via subcutaneous injection. The normal animal group was injected with an equal volume of physiological saline at the same time. The modeling was completed after 14 days of continuous administration of PCP or physiological saline.

[0864] Five days after the modeling was completed, the experimental animals were transferred to the behavioral testing room for environmental adaptation and weighed 2 hours before the test. The drugs were administered according to the information in Table 4 below.

[0865] Table 4. Grouping and Dosing Information for Laboratory Animals

[0866] Thirty minutes after drug administration, a NOR test was performed to measure the exploration time of new and old objects. The experimental animals were allowed free movement in the experimental chamber for 5 minutes, and the exploration time of the animals for both new and old objects was recorded on video. The Recognition Index (RI) value was then calculated using the following formula: RI% = Exploration time of new objects / Total exploration time of both new and old objects 100% Note: Exclusion criteria: If an experimental animal takes 0 seconds to explore both new and old objects during the experiment, it is excluded as an outlier.

[0867] 4. Experimental Results: The experimental results for identifying new compounds are as follows: Figure 4 As shown (# indicates p < 0.05 compared to the normal animal group), This indicates that p < 0.01 compared to the solvent group.

[0868] The compounds of this invention have a dose-dependent effect in improving cognitive dysfunction in PCP-induced schizophrenia model mice, while cariprazine has no such effect.

[0869] Biological test example 8: The effect of the compounds of the present invention on the expression of D2, D3, 5-HT 1A 5-HT 2A Receptor affinity activity assay

[0870] 1. Experimental objective: Evaluation of the compounds of this invention for D2, D3, 5-HT 1A 5-HT 2A Receptor affinity.

[0871] 2. Test methods: 2.1 Compound Treatment a) The test compound was diluted to 30 μM with DMSO, and then serially diluted 4-fold with DMSO, resulting in 8 concentration gradients. The final concentrations of the test compound were 300 nM, 75 nM, 18.75 nM, 4.688 nM, 1.172 nM, 0.2930 nM, 0.07324 nM, and 0.01831 nM.

[0872] 2.2 Detection of D2 and D3 activities

[0873] 1) Add 5 μL of the test compound (1% DMSO) and 95 μL of experimental buffer to a 96-well deep plate.

[0874] 2) Add 10 μL of D2 or D3 cell membrane and 290 μL of experimental buffer to each well.

[0875] 3) Add [3H]-methylspiperone (0.5 or 1 nM), 100 μL of experimental buffer, and incubate at room temperature for 30 minutes.

[0876] 4) Pre-incubate Unifilter-96 GF / C filter plates with 0.5% PEI for 1 hour.

[0877] 5) Wash the Unifilter-96 GF / C filter plate twice with 1 mL of washing buffer, transfer the cell membrane reaction mixture into the Unifilter-96 GF / C filter plate, and wash 4 times.

[0878] 6) Incubate at 55℃ for 30 minutes to dry the Unifilter-96 GF / C filter plate.

[0879] 7) Add 40 μL of ULTIMA GOLD to each well and read the CPM value using TopCount.

[0880] 2.3 5-HT 1A 5-HT 2A Activity detection

[0881] 1) Add 5 μL of the test compound (1% DMSO) and 95 μL of experimental buffer to a 96-well deep plate.

[0882] 2) Add 1.5 μL of 5-HT to each well. 1A or 5-HT 2A Cell membrane and 298.5 μL of experimental buffer.

[0883] 3) 5-HT 1A The test involved adding [3H]-8-Hydroxy-DPAT (0.5 nM) and 100 μL of experimental buffer, and incubating at room temperature for 60 minutes; 5-HT 2A The test was performed by adding [3H]-Ketanserin Hydrochloride (2 nM) and 100 μL of experimental buffer, and incubating at room temperature for 60 minutes.

[0884] 4) The Unifilter-96 GF / C filter plate was pre-incubated with 0.5% PEI for 1 hour.

[0885] 5) Wash the Unifilter-96 GF / C filter plate twice with 1 mL of washing buffer, transfer the cell membrane reaction mixture into the Unifilter-96 GF / C filter plate, and wash 4 times.

[0886] 6) Incubate at 55℃ for 30 minutes to dry the Unifilter-96 GF / C filter plate.

[0887] 7) Add 40 μL of ULTIMA GOLD to each well and read the CPM value using TopCount.

[0888] 3. Data Analysis: Calculating the IC of compound using GraphPad nonlinear fitting formula 50 : Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X) HillSlope)); Ki = IC 50 / (1+([L] / K D ), where [L] is the concentration of the radioactive ligand, K D is the dissociation constant between the ligand and the receptor.

[0889] 4. Experimental results: The results of receptor affinity activity detection are shown in Table 5.

[0890] Table 5. Effects of compounds on the expression of D2, D3, and 5-HT 1A and 5-HT 2A Receptor affinity activity assay results

[0891] Biological test example 9: The effect of the compound of the present invention on the expression of 5-HT 2A Receptor antagonistic activity assay

[0892] 1. Experimental Objective: To evaluate the effect of the compounds of this invention on 5-HT 2A Receptor antagonistic activity.

[0893] 2. Test methods: 2.1 Cell Culture and Reagent Preparation 1) Cell line: expressing human 5-HT 2A Flp-In-CHO-5HT2A cells of the receptor.

[0894] 2) Complete culture medium: Ham's F-12K + 10% FBS + 1x Penicillin-Streptomycin (PS) + 600 μg / mL Hygromycin B.

[0895] 3) Inoculation medium: Ham's F-12K + 10% Dialyzed FBS.

[0896] 4) Experimental buffer: 1X HBSS + 20mM HEPES.

[0897] 2.25-HT 2A Antagonist activity assay

[0898] 1) Flp-In-CHO-5HT2A stable pool cell lines were cultured in complete medium at 37°C and 5% CO2 until 70%~90% confluence.

[0899] 2) After trypsin digestion, the cells were resuspended in seeding medium and seeded into 384-well cell culture plates (Corning, 3764), with 10,000 cells per well, and cultured overnight at 37°C with 5% CO2.

[0900] 3) Freeze-thaw 20X Component A to room temperature, dilute it with experimental buffer to a working concentration of 2X containing 5 mM borobenecid, and store at room temperature until use.

[0901] 4) Remove the cell culture plate and let it stand at room temperature for 10 min. Dilute the FBS concentration to 0.03% using Apricot and experimental buffer, leaving 20 μL in the 3764 culture plate. Then add 20 μL of 2X Component A containing 5 mM bromobenonecid to each well. Centrifuge at 200g for 3-5 seconds at RT and incubate at 37°C for 2 hours.

[0902] 5) Prepare working solutions (6X) of the positive control compound and the test compound, and set aside for later use.

[0903] 6) Remove the cell culture plate and let it stand at room temperature for 10 minutes. Add 10 μL of the 6X compound working solution from step 5) to the corresponding experimental wells of the 384-well cell culture plate and incubate at room temperature for 30 minutes.

[0904] 7) Dilute 5HT to 6 nM (6X) with experimental buffer, transfer 50 μL to a 384-well plate (Corning, 3657), and let it stand at room temperature.

[0905] 8) Using FLIPR Tetra, add 10 μL of the diluted 5HT working solution from step 7) to the corresponding experimental well and collect data.

[0906] 3. Data Analysis: Calculating the IC of compound using GraphPad nonlinear fitting formula 50 : Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X) HillSlope)); 4. Experimental Results: 5-HT 2A The results of receptor antagonistic activity assays are shown in Table 6.

[0907] Table 6. Effects of compounds on 5-HT expression 2A Receptor antagonistic activity test results .

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof; ； in, Ring B is , , or ; X1 is either N or CH; X2 is either N or CH; X3 is CH2, O, NH, S or C=O, X4 is a single bond, CH2, -CH2CH2- or C=O, and X3 and X4 are not both C=O at the same time; X5 is either N or CH; X6 is N, N=CH, NH, CH or CH2; X7 is N, C, or CH; And when X6 is NH, X5 is N; R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or one or more R 1-1 Replacement C 1-6 Alkyl or with one or more R 1-2 Replacement C 1-6 Alkyl groups; R 1-1 and R 1-2 Independently, it can be deuterium, halogen, or hydroxyl; k can be 0, 1, 2, 3, 4, 5, or 6; m can be 0, 1, 2, 3, or 4; L1 is a single bond, O, or S; Ring A is C 3-6 Cycloalkylene, R 3 for ; Alternatively, ring A is R 3 For H; It can be a single bond or a double bond independently; X8 can be CH2, O, NH or S; X9 is CH2 or C=O; R 3-1 R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Independently, it can be deuterium, halogen, or hydroxyl; Or, R 3-2 R 3-3 The N atom bonded to it forms a 3-7 membered monocyclic heterocycle, the 3-7 membered monocyclic heterocycle containing one, two, or three heteroatoms selected from one, two, or three of N, O, and S, and containing at least one N atom; the 3-7 membered monocyclic heterocycle is optionally bounded by one, two, or three R atoms. 3a replace; R 3a Independently, it can be deuterium, halogen, or hydroxyl; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n can be 0, 1, 2, or 3.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1) R 1 In the middle, the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (2) R 1 In the middle, the C 1-6 The alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, such as methoxy; (3) R 1 In this context, the halogen is independently fluorine, chlorine, or bromine, for example, fluorine or chlorine; (4) R 1 In, the one or more R 1-1 Replacement C 1-6 Alkyl groups are independently formed by 1, 2, or 3 R groups. 1-1 Replacement C 1-6 Alkyl groups, such as trifluoromethyl groups; (5) R 1 In, the one or more R 1-2 Replacement C 1-6 The alkoxy group is independently formed by 1, 2 or 3 R groups. 1-2 Replacement C 1-6 Alkyl groups; (6) R 1-1 and R 1-2 In this context, the halogen is independently fluorine, chlorine, or bromine, for example, fluorine; (7) In ring A, the C 3-6 Cycloalkylene groups are monocyclic or bridged rings, such as C16-C ... 3-6 Monocyclic cyclohexane or C 4-6 Bridged cyclohexane, the C 3-6 The monocyclic cycloalkyl group is preferably cyclobutylene, cyclopentylene, or cyclohexylene, wherein C 4-6 Bridged cyclohexane is preferred ; (8) R 3-1 R 3-2 and R 3-3 In the middle, the C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (9) R 3-1 R 3-2 and R 3-3 In, the one or more R 3-1-1 Replacement C 1-6 Alkyl groups are independently formed by 1, 2, or 3 R groups. 3-1-1 Replacement C 1-6 Alkyl groups, such as trideuterated methyl groups; (10) R 3-1-1 In this context, the halogen is independently fluorine, chlorine, or bromine; (11) R 3-2 R 3-3 It forms a 3-7 member monocyclic heterocycle with the N atom it is attached to, wherein the 3-7 member monocyclic heterocycle is a saturated monocyclic heterocycle, preferably a 4-6 member saturated monocyclic heterocycle, and / or, the heteroatom is selected from one or two of N, S or O, the number of heteroatoms is one or two, and it contains at least one N, for example, or ; (12) R 3a In this context, the halogen is independently fluorine, chlorine, or bromine, for example, fluorine; (13) R 2 In this context, the halogen is independently fluorine, chlorine, or bromine.

3. The compound of Formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1) X1 is CH; (2) X2 is CH; (3) X3 is CH2, O, NH or C=O; (4) X3 is CH2, O, NH or S, and X4 is a single bond, CH2, -CH2CH2- or C=O; or, X3 is C=O and X4 is CH2; preferably, X3 is CH2, O or NH, and X4 is a single bond, CH2, -CH2CH2- or C=O; or, X3 is C=O and X4 is CH2; more preferably, X3 is CH2 and X4 is CH2. (5) X6 is N=CH, NH or CH; (6) X7 is N or C; (7) R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or by one or more R 1-1 Replacement C 1-6 Alkyl; preferably, R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkyl or halogen; more preferably, R 1 Independent of deuterium and C 1-6 Alkyl, C 1-6 alkoxy or halogen; more preferably, R 1 Independently for C 1-3 Alkyl, C 1-3 alkoxy or halogen; more preferably, R 1 Halogens are independent of each other; (8) R 1-1 and R 1-2 Independently deuterium or halogen, preferably, R 1-1 and R 1-2 Independently halogenated, more preferably, R 1-1 and R 1-2 Independent of fluorine; (9) k is 0, 1, 2, 3 or 4, for example, k is 2; (10) m is 1, 2 or 3; for example, m is 1; (11) L1 is a single bond or O, for example, L1 is a single bond; (12) Ring A is C 3-6 Cycloalkylene, R 3 for For example, ring A is C. 3-6 Monocyclic cycloalkylene, preferably cyclobutylene or cyclohexylene; Alternatively, ring A is R 3 Let H be the ring A; for example, ring A is... or ; (13) Ring A is C 3-6 Cycloalkylene, R 3 for m is 1 or 2, L1 is a single bond, or, ring A is... R 3 H is 3, m is 3, L1 is O or a single bond, preferably, ring A is C. 3-6 Monocyclic cycloalkylene, R 3 for m is 1, and L1 is a single bond; (14) X8 is NH; (15) X9 is C=O; (16) R 3-1 For H, R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 Alkyl; for example, R 3-1 For H, R 3-2 and R 3-3 Independently for H and C 1-3 Alkyl or with one or more R 3-1-1 Replacement C 1-3 Alkyl; preferably, R 3-1 For H, R 3-2 and R 3-3 Independently H, methyl, or trideuterated methyl, further for example, R 3-1 For H, R 3-2 and R 3-3 Independently for C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 Alkyl; preferably, R 3-1 For H, R 3-2 and R 3-3 Independently for C 1-3 Alkyl or with one or more R 3-1-1 Replacement C 1-3 Alkyl; more preferably, R 3-1 For H, R 3-2 and R 3-3 Independently methyl; (17) R 3-1-1 It is deuterium; (18)R 3-2 R 3-3 It forms a 3-7 membered monocyclic heterocycle with the N atom attached thereto, wherein the 3-7 membered monocyclic heterocycle contains one heteroatom N, and the 3-7 membered monocyclic heterocycle is optionally surrounded by one or two R atoms. 3a Replacement; preferably, the 3-7 member monocyclic heterocycle is a 4-6 member monocyclic heterocycle, the 4-6 member monocyclic heterocycle contains one heteroatom N, and the 4-6 member monocyclic heterocycle is optionally replaced by one or two R atoms. 3a Replacement; more preferably, the 3-7 member monocyclic heterocycle and the 4-6 member monocyclic heterocycle are saturated monocyclic heterocycles; (19)R 3a It can be a halogen on its own; for example, fluorine. (20) n is 0; or (21) R 1 Located on the aromatic ring.

4. The compound of Formula I as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1) R 1 Independently, it can be deuterium, hydroxyl, methyl, methoxy, fluorine, chlorine, or trifluoromethyl; (2) for , , , , , , , , , , , , , or ;in, For example, or ; For example, or Preferred ; (3) for , , or ; (4) for , , , , , , , , , , , , , , , , , , , , , , , or Preferred , , , , , , , , or For example, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or For example, it is... , , , , , , , , or ; (5) for Preferably, for , , , , , , , , , , , , , , , , , , , , , or For example, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or For example, it is... , , , , , , , , or ; (6) for R 1 Located on the aromatic ring, R 1 Independently for C 1-6 Alkyl, C 1-6 Alkyl or halogen; k is 0, 1, 2, 3 or 4; (7) for , , or Preferred More preferably ; (8) m is 1; L1 is a single bond; in ring A, the C 3-6 The cycloalkylene group is cyclobutylene, cyclohexylene, or bicyclo[1.1.1]pentylene; R 2 Independently deuterium, halogen, or hydroxyl; n is 0; (9) In the middle, R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl; or (10) for , , , , , , , , , , , , , , or Preferred , , , , or .

5. The compound of Formula I as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I satisfies any of the following conditions: Option 1: Ring B is , , or ; X1 is either N or CH; X2 is either N or CH; X3 is CH2, O, or NH, and X4 is a single bond, CH2, -CH2CH2-, or C=O; or, X3 is C=O and X4 is CH2. X5 is either N or CH; X6 represents N=CH, NH, or CH; X7 is either N or C; And when X6 is NH, X5 is N; R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or by one or more R 1-1 Replacement C 1-6 alkyl; R 1-1 Independently halogen or deuterium; k can be 0, 1, 2, 3 or 4; m is 1, 2, or 3; L1 is a single bond or O; Ring A is C 3-6 Cycloalkylene, R 3 for ; Alternatively, ring A is R 3 For H; It can be a single bond or a double bond independently; X8 is NH; X9 is C=O; R 3-1 R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Deuterium is independent of other substances; Or, R 3-2 R 3-3 It forms a 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) with the N atom attached thereto, wherein the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) contains one, two, or three heteroatoms selected from one, two, or three of N, O, and S, and contains at least one N atom; the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) is optionally bounded by one or two R atoms. 3a replace; R 3a Halogens are independent of each other; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; Option 2: Ring B is ; X1 is either N or CH; X2 is either N or CH; X3 is CH2, O, or NH, and X4 is a single bond, CH2, -CH2CH2-, or C=O; or, X3 is C=O and X4 is CH2. R 1 Independently deuterium, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or by one or more R 1-1 Replacement C 1-6 alkyl; R 1-1 It can be either deuterium or a halogen independently; k can be 0, 1, 2, 3 or 4; m is 1 or 2; L1 is a single bond; Ring A is C 3-6 Cycloalkylene, R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Deuterium is independent of other substances; Or, R 3-2 R 3-3 It forms a 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) with the N atom it is attached to, the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) containing one heteroatom selected from the N atom; the 3-7 membered monocyclic heterocycle (e.g., a 3-7 membered saturated monocyclic heterocycle) is optionally surrounded by one or two R atoms. 3a replace; R 3a Halogens are independent of each other; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; Option 3: Ring B is ; X1 is CH; X2 is CH; X3 is CH2; X4 is CH2; R 1 Independent of deuterium and C 1-6 Alkyl, C 1-6 Alkoxy or halogen; k can be 0, 1, 2, 3 or 4; m is 1 or 2; L1 is a single bond; Ring A is C 3-6 Cycloalkylene, R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Deuterium is independent of other substances; Or, R 3-2 R 3-3 It forms a 3-7 membered monocyclic heterocycle (preferably a 3-7 membered monocyclic saturated heterocycle) with the N atom attached thereto, wherein the 3-7 membered monocyclic heterocycle (preferably a 3-7 membered monocyclic saturated heterocycle) contains one heteroatom N (e.g., azirrobutyl or azirropentyl); the 3-7 membered monocyclic heterocycle (preferably a 3-7 membered monocyclic saturated heterocycle, e.g., azirrobutyl or azirropentyl) is optionally surrounded by one or two R atoms. 3a replace; R 3a Halogens are independent of each other; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; Option 4: Ring B is ; X1 is CH; X2 is CH; X3 is CH2; X4 is CH2; R 1 Independently for C 1-3 Alkyl (e.g., methyl), C 1-3 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine or fluorine); k can be 0, 1, 2, 3 or 4; m is 1; L1 is a single bond; Ring A is C 3-6 Cycloalkylene (preferably C14) 3-6 Monocyclic cycloalkylene (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-3 Alkyl groups (e.g., trideuterated methyl groups); Or, R 3-2 R 3-3 It forms a 4-6 membered monocyclic heterocycle (preferably a 4-6 membered monocyclic saturated heterocycle) with the N atom attached thereto, wherein the 4-6 membered monocyclic heterocycle (preferably a 4-6 membered monocyclic saturated heterocycle) contains one heteroatom N (e.g., azirrobutyl or azirropentyl); the 4-6 membered monocyclic heterocycle (preferably a 4-6 membered monocyclic saturated heterocycle, e.g., azirrobutyl or azirropentyl) is optionally surrounded by one or two R atoms. 3a replace; R 3a It can be a halogen (e.g., fluorine) on its own. R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; Option 5: Ring B is ; X1 is CH; X2 is CH; X3 is CH2; X4 is CH2; R 1 Independently halogenated (e.g., chlorine); k is 2; m is 1; L1 is a single bond; Ring A is C 3-6 Monocyclic cycloalkylene (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

6. The compound of Formula I as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula I is any of the following schemes: Scheme 1: The compound shown in Formula I is the same as the compound shown in Formula II. ； Among them, X1, X2, X3, X4, R 1 ,k,m,L1,ring A,R 3 R 2 and n as described in any one of claims 1-5; Scheme 2: The compound shown in Formula I is the same as the compound shown in Formula III. ； Among them, m, L1, ring A, R 3 R 2 and n as described in any one of claims 1-5; Scheme 3: The compound represented by Formula I is the same as the compound represented by Formula IV. in, It can be a single bond or a double bond independently; X5, X6, X7, m, L1, ring A, R 3 R 2 and n as described in any one of claims 1-5; Scheme 4: The compound shown in Formula I is the same as the compound shown in Formula V. Among them, m, L1, ring A, R 3 R 2 and n as described in any one of claims 1-5; Preferably, the compound represented by Formula II is any of the following schemes: Scheme a: The compound shown in Formula II is the same as the compound shown in Formula II-1. in, X3 is CH2 or C=O; R 1 ,k,m,L1,ring A,R 3 R 2 and n as described in any one of claims 1-5; Scheme b: The compound represented by Formula II is the same as the compound represented by Formula II-2. in, X4 is CH2 or -CH2CH2-; X1, X2, R 1 ,k,m,L1,ring A,R 3 R 2 and n as described in any one of claims 1-5; Scheme c: The compound represented by Formula II is the same as the compound represented by Formula II-3. X1 is CH, X2 is N; or, X2 is CH, X1 is N; X4 is CH2 or -CH2CH2-; i and ii are independently 1 or 2; R 1 ,k,m,L1,R 3-1 R 3-2 R 3-3 R 2 and n as described in any one of claims 1-5; Scheme d: The compound represented by Formula II is the compound represented by Formula II-4; in, X4 is CH2, -CH2CH2-, or C=O; X1, X2, R 1 ,k,m,L1,ring A,R 3 R 2 and n as described in any one of claims 1-5; Scheme e: The compound represented by Formula II is the compound represented by Formula II-5; in, R 12 Independently for H and C 1-6 Alkyl or with one or more R 12-1 Replacement C 1-6 alkyl; R 12-1 Independently, it can be deuterium, halogen, or hydroxyl; i and ii are independently 1 or 2; k2 is 0, 1, 2, 3 or 4; R 1 m, L1, R 3-1 R 3-2 R 3-3 R 2 and n as described in any one of claims 1-5; Scheme f: The compound represented by Formula II is the compound represented by Formula II-6; in, It can be a single bond or a double bond independently; X1, X2, X3, X4, R 1 k, m, L1, X8, X9, R 2 And n as described in any one of claims 1-5.

7. The compound of formula I as claimed in claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by Formula II is the same as the compound represented by Formula II-1. In the compound shown in Formula II-1; X3 is CH2 or C=O; R 1 Independent of deuterium and C 1-6 Alkyl, C 1-6 Alkoxy or halogen; k can be 0, 1, 2, 3 or 4; m is 1 or 2; L1 is a single bond; Ring A is C 3-6 Cycloalkylene, R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 3-1-1 Deuterium is independent of other substances; Or, R 3-2 R 3-3 It forms a 3-7 membered monocyclic heterocycle with the N atom attached thereto, the 3-7 membered monocyclic heterocycle containing one heteroatom N; the 3-7 membered monocyclic heterocycle is optionally separated by one or two R atoms. 3a replace; R 3a Halogens are independent of each other; R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; Preferably, in the compound shown in Formula II-1; X3 is CH2; R 1 Independently for C 1-3 Alkyl (e.g., methyl), C 1-3 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine or fluorine); k can be 0, 1, 2, 3 or 4; m is 1; L1 is a single bond; Ring A is C 3-6 Cycloalkylene (preferably C14) 3-6 Monocyclic cycloalkylene (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-3 Alkyl groups (e.g., trideuterated methyl groups); Or, R 3-2 R 3-3 It forms a 4-6 membered monocyclic heterocycle (preferably a 4-6 membered monocyclic saturated heterocycle) with the N atom attached thereto, wherein the 4-6 membered monocyclic heterocycle (preferably a 4-6 membered monocyclic saturated heterocycle) contains one heteroatom N (e.g., azirrobutyl or azirropentyl); the 4-6 membered monocyclic heterocycle (preferably a 4-6 membered monocyclic saturated heterocycle, e.g., azirrobutyl or azirropentyl) is surrounded by one or two R atoms. 3a replace; R 3a It can be a halogen (e.g., fluorine) on its own. R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; More preferably, in the compound shown in Formula II-1; X3 is CH2; R 1 Independently halogenated (e.g., chlorine); k is 2; m is 1; L1 is a single bond; Ring A is C 3-6 Monocyclic cycloalkylene (e.g., cyclobutylene or cyclohexylene), R 3 for ; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0.

8. The compound of Formula I as claimed in claim 6 or 7, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula II-1 is the compound represented by formula II-1-1 (e.g., the compound represented by II-1-1A); (For example ) In the compound shown in II-1-1 (e.g., the compound shown in II-1-1A), X3 can be CH2 or C=O independently; i and ii are independently 1 or 2; R 3-1 R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 Alkyl; for example, R 3-1 For H, R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 1 ,k,m,L1,R 3-1-1 R 2 and n as described in any one of claims 1-7; Preferably, in the compound of formula II-1-1 (e.g., the compound of II-1-1A); X3 is CH2 or C=O; R 1 Independent of deuterium and C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine or fluorine); k can be 0, 1, 2, 3 or 4; m is 1 or 2; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-6 Alkyl groups (e.g., trideuterated methyl groups); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; More preferably, in the compound represented by formula II-1-1 (e.g., the compound represented by II-1-1A); X3 is CH2; R 1 Independently for C 1-3 Alkyl (e.g., methyl), C 1-3 Alkyl groups (e.g., methoxy groups) or halogens (e.g., chlorine or fluorine); k can be 0, 1, 2, 3 or 4; m is 1; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl) or C substituted with one or more deuteriums 1-3 Alkyl groups (e.g., trideuterated methyl groups); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; More preferably, in the compound of formula II-1-1 (e.g., the compound of II-1-1A); X3 is CH2; R 1 Independently halogenated (e.g., chlorine); k is 2; m is 1; L1 is a single bond; i and ii are independently 1 or 2; R 3-1 For H; R 3-2 and R 3-3 Independently for C 1-3 Alkyl (e.g., methyl); R 2 Independently, it can be deuterium, halogen, or hydroxyl; n is 0; Alternatively; the compound shown in Formula II-1 is a compound shown in Formula II-1-2 (e.g., the compound shown in II-1-2A); (For example ) In the compounds shown in II-1-2 (e.g., the compound shown in II-1-2A), X3 is independently CH2; i and ii are independently 1 or 2; Ring P is a 3-7 membered monocyclic heterocycle containing one, two, or three heteroatoms selected from one, two, or three of N, O, and S, and containing at least one N atom; for example, the 3-7 membered monocyclic heterocycle is a saturated monocyclic heterocycle containing one N heteroatom (for example, azirrobutyl or azirropentyl). R 3a Independently, it can be deuterium, halogen, or hydroxyl; iii can be 0, 1, 2, or 3; R 1 ,k,m,L1,R 3-1 R 2 and n as described in any one of claims 1-7; Alternatively, the compound shown in Formula II-1 is a compound shown in Formula II-1-3 (e.g., the compound shown in II-1-3A). (For example ) In the compounds shown in II-1-3 (e.g., the compound shown in II-1-3A), X3 is independently CH2; i is 1 or 2; R 3-1 R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 Alkyl; for example, R 3-1 For H, R 3-2 and R 3-3 Independently for H and C 1-6 Alkyl or with one or more R 3-1-1 Replacement C 1-6 alkyl; R 1 ,k,m,L1,R 3-1-1 R 2 And n as described in any one of claims 1-7.

9. The compound of formula I as claimed in claim 1, characterized in that, The compound represented by Formula I is any of the following compounds: 。 10. A pharmaceutical composition, characterized in that, It comprises (i) a compound of Formula I as described in any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical excipient.

11. The use of a compound of Formula I as described in any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 10, the use comprising (1) as a dopamine D2 receptor partial agonist and / or serotonin 5-HT 1A Receptor agonists and / or serotonin 5-HT 2A (2) In the preparation of treatments and / or prophylaxis with dopamine D2 receptor and / or serotonin 5-HT receptors; 1A receptors and / or 5-HT 2A (2) Application in drugs for diseases related to receptors and / or dopamine D3 receptors, preferably, the disease being schizophrenia; (3) Application in the preparation of drugs for the treatment and / or prevention of diseases, wherein the disease is schizophrenia.

12. A method for preparing the compound of formula II as described in claim 6, characterized in that, It is prepared using any of the following methods: Option 1: Includes the following steps: In an organic solvent and in the presence of an organic base, the compound shown in Formula IIa or its salt undergoes an amidation reaction with the compound shown in Formula IIb to obtain the compound shown in Formula II; ； R 4 It is a halogen; Ring A is C 3-6 Cycloalkylene, R 3 for ; X1, X2, X3, X4, R 1 ,k,m,L1,R 3-1 R 3-2 R 3-3 R 2 and n as described in any one of claims 1-9; Preferably, the salt of the compound represented by formula IIa is a hydrochloride salt or a trifluoroacetate salt of the compound represented by formula IIa, such as a hydrochloride salt of the compound represented by IIa or a trifluoroacetate salt of the compound represented by IIa. Option 2: Includes the following steps: In an organic solvent, the compound shown in Formula IIg or its pharmaceutically acceptable salt undergoes a coupling reaction with the compound shown in Formula IIh to obtain the compound shown in Formula II; ； Y is either -CHO or -CH2-halogen; Ring A is C 3-6 Cycloalkylene, R 3 for ; X1, X2, X3, X4, R 1 ,k,m,L1,R 2 and n as described in any one of claims 1-9; Preferably, the coupling reaction further includes a reducing agent, such as sodium cyanoborohydride.

13. A compound of formula IIa or a salt thereof; ； in, Ring A is C 3-6 Cycloalkylene; X1, X2, X3, X4, R 1 ,k,m,L1,R 3-1 R 2 and n as described in any one of claims 1-9; Preferably, the compound shown in IIa is: or The salt of the compound represented by formula IIa is preferably the trifluoroacetate salt of the compound.

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