Compounds as inhibitors of akt kinases

Abstract

The application belongs to the field of medicinal chemistry, and provides a compound as an Akt kinase inhibitor, and particularly relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and use of the compound in preparation of a medicament for treating an Akt kinase related disease.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180062426.8, filed on September 30, 2021, entitled "A compound as an Akt kinase inhibitor".

[0002] Cross-references to related applications

[0003] This application claims priority and benefit to Chinese patent applications No. 202011057860.0 and No. 202110261605.6, filed with the China National Intellectual Property Administration on September 30, 2020 and March 10, 2021, respectively, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0004] This application belongs to the field of medicinal chemistry and provides a compound as an Akt kinase inhibitor or a pharmaceutically acceptable salt thereof, a method for its preparation, a pharmaceutical composition containing the compound, and relates to its use in the preparation of a medicament for treating Akt kinase-related diseases in patients in need, such as cancer treatment. Background Technology

[0005] Akt, also known as protein kinase B (PKB) or Rac, is a serine / threonine kinase of the AGC family, highly homologous to protein kinase A (PKA) and protein kinase C (PKC). Akt primarily possesses three domains: a pH domain (with an affinity for PIP3, thus crucial for cell membrane binding), a catalytic domain, and a regulatory domain. Studies have shown that human Akt comprises three subtypes: Akt1, Akt2, and Akt3, each with unique functions and expression profiles. Akt1, Akt2, and Akt3 are key mediators of the PI3K / AKT / mTOR signaling pathway, promoting various physiological processes such as proliferation, migration, anti-apoptotic survival, and protein synthesis. Akt1 is widely expressed in tissues and is mainly involved in cell survival pathways and growth control; Akt2 is mainly expressed in muscle and adipocytes and is involved in insulin-mediated glucose metabolism; Akt3 is mainly expressed in the testes and brain and plays an important role in maintaining normal brain volume.

[0006] Akt is one of the most frequently activated protein kinases in human cancers. Overactivation of Akt can induce cell growth, leading to cell proliferation and contributing to resistance to apoptosis. In cancer, Akt activity is often elevated due to oncogenic growth factors, angiogenic factors, cytokines, and genetic alterations, including mutations and / or amplifications of the Akt1, Akt2, and Akt3 genes. Akt signaling can be regulated at various levels; for example, several upstream molecules can regulate the dephosphorylation of PIP3, which can be dephosphorylated to PIP2 via PTEN and SHIP1. Akt can also be dephosphorylated by PPA2 and PHLPP, thus inactivating it. Furthermore, Akt can be positively and negatively regulated through phosphorylation of NF-κB and IRS-1. Studies have shown that Akt is overexpressed in various human tumors, and abnormal Akt function is closely related to the occurrence, development, and resistance to chemotherapy and radiotherapy in these tumors.

[0007] Based on their binding sites, Akt inhibitors can be classified into: PH domain inhibitors, ATP-competitive inhibitors, allosteric inhibitors, and biologics. AstraZeneca's Capivasertib (AZD5363) is a pan-Akt inhibitor; in contrast, ATP-competitive inhibitors and allosteric inhibitors (e.g., MK-2206) have not shown monotherapy activity in many clinical trials. ARQ 092 and ARQ 751 are highly selective allosteric inhibitors that have shown good activity in early studies.

[0008] Akt has become a highly promising anti-tumor target, and highly efficient (active), novel (structural), and highly selective (safe) Akt inhibitors are an important strategy to address current unmet medical needs. Invention Overview

[0009] On the one hand, this application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010]

[0011] in,

[0012] R 1 and R 1’ Each is independently selected from hydrogen or halogen;

[0013] R 2 R 2’ and R 3Each is independently selected from hydrogen, amino, amino-C1-C6 alkyl-, 7-9 membered spiroheterocyclic groups, 10 membered spiroheterocyclic groups with ring atoms composed of nitrogen and carbon atoms, 7-10 membered fused heterocyclic groups, 7-10 membered bridged heterocyclic groups, 5-6 membered heterocyclic groups with ring atoms composed of nitrogen and carbon atoms, and 5-6 membered heterocyclic groups containing silicon or phosphorus atoms in their ring atoms. The amino group or amino-C1-C6 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the cyclic atom, consisting of a 5-6 membered heterocyclic group composed of nitrogen and carbon atoms, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ Instead, the 7-9 spirocyclic group, the 10 spirocyclic group whose ring atoms are composed of nitrogen and carbon atoms, the 7-10 fused heterocyclic group, or the 5-6 fused heterocyclic group whose ring atoms contain silicon or phosphorus atoms are optionally replaced by one or more R 23 Instead, the 7-10 bridging heterocyclic group is replaced by one or more R 24 replace,

[0014] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Substituted morpholino group,

[0015] And R 2 R 2’ and R 3 They are not both hydrogen;

[0016] R 21 Selected from C2-C6 alkenyl-C(O)-, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-optionally substituted by one or more groups selected from: hydroxyl, C1-C6 alkyl or C1-C6 alkylacyl;

[0017] R 22 The group is selected from C2-C6 ynyl-C(O)-, 4-5 membered heterocyclic groups, or 6 membered heterocyclic groups whose ring atoms are composed of nitrogen and sulfur atoms, wherein the 4-5 membered heterocyclic group or the 6 membered heterocyclic group whose ring atoms are composed of nitrogen and sulfur atoms is optionally substituted by one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl;

[0018] R 21’ and R 22’ Each is independently selected from deuterium or C1-C6 alkyl groups;

[0019] R 23 and R 24 Each independently selected C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl or C1-C6 alkylacyl-N(C1-C6 alkyl)-;

[0020] R 25 Selected from C1-C6 alkyl acyl groups;

[0021] R 4 Selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl;

[0022] R 5 Selected from C1-C6 alkyl groups;

[0023] R 5’ Selected from -CD3 or -CH3, and when R 5’ When it is -CH3, R 1 Or R 1’ It is a halogen.

[0024] On the other hand, this application also provides pharmaceutical compositions comprising the above-described compounds of this application or pharmaceutically acceptable salts thereof.

[0025] On the other hand, this application also provides a method for treating diseases mediated by Akt kinase in mammals, comprising administering to a mammal in need of treatment a therapeutically effective amount of the aforementioned compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0026] On the other hand, this application also provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of medicaments for treating Akt kinase-mediated diseases.

[0027] On the other hand, this application also provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the treatment of Akt kinase-mediated diseases.

[0028] On the other hand, this application also provides the above-mentioned compound of this application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating Akt kinase-mediated diseases. Invention Details

[0030] On the one hand, this application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0031]

[0032] in,

[0033] R 1 and R 1’ Each is independently selected from hydrogen or halogen;

[0034] R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, amino-C1-C6 alkyl-, 7-9 membered spiroheterocyclic groups, 10 membered spiroheterocyclic groups with ring atoms composed of nitrogen and carbon atoms, 7-10 membered fused heterocyclic groups, 7-10 membered bridged heterocyclic groups, 5-6 membered heterocyclic groups with ring atoms composed of nitrogen and carbon atoms, and 5-6 membered heterocyclic groups containing silicon or phosphorus atoms in their ring atoms. The amino group or amino-C1-C6 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the cyclic atom, consisting of a 5-6 membered heterocyclic group composed of nitrogen and carbon atoms, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ Instead, the 7-9 spirocyclic group, the 10 spirocyclic group whose ring atoms are composed of nitrogen and carbon atoms, the 7-10 fused heterocyclic group, or the 5-6 fused heterocyclic group whose ring atoms contain silicon or phosphorus atoms are optionally replaced by one or more R 23 Instead, the 7-10 bridging heterocyclic group is replaced by one or more R 24 replace,

[0035] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Substituted morpholino group,

[0036] And R 2 R 2’ and R 3 They are not both hydrogen;

[0037] R 21 Selected from C2-C6 alkenyl-C(O)-, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-optionally substituted by one or more groups selected from: hydroxyl, C1-C6 alkyl or C1-C6 alkylacyl;

[0038] R22 The group is selected from C2-C6 ynyl-C(O)-, 4-5 membered heterocyclic groups, or 6 membered heterocyclic groups whose ring atoms are composed of nitrogen and sulfur atoms, wherein the 4-5 membered heterocyclic group or the 6 membered heterocyclic group whose ring atoms are composed of nitrogen and sulfur atoms is optionally substituted by one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl;

[0039] R 21’ and R 22’ Each is independently selected from deuterium or C1-C6 alkyl groups;

[0040] R 23 and R 24 Each independently selected C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl or C1-C6 alkylacyl-N(C1-C6 alkyl)-;

[0041] R 25 Selected from C1-C6 alkyl acyl groups;

[0042] R 4 Selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl;

[0043] R 5 Selected from C1-C6 alkyl groups;

[0044] R 5’ Selected from -CD3 or -CH3, and when R 5’ When it is -CH3, R 1 Or R 1’ It is a halogen.

[0045] In some embodiments, this application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0046] R 1 and R 1’ Each is independently selected from hydrogen or halogen;

[0047] R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, amino-C1-C6 alkyl-, 7-9 membered spirocyclic groups, 7-10 membered fused heterocyclic groups, 7-10 membered bridged heterocyclic groups, 5-6 membered heterocyclic groups with ring atoms composed of nitrogen and carbon atoms, and 5-6 membered heterocyclic groups with ring atoms containing silicon or phosphorus atoms. The amino group or amino-C1-C6 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’Substitution, wherein the cyclic atom, consisting of a 5-6 membered heterocyclic group composed of nitrogen and carbon atoms, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ Instead, the 7-9 spirocyclic group, 7-10 fused heterocyclic group, or 5-6 cyclic group with silicon or phosphorus atoms in the ring atom is optionally replaced by one or more R 23 Instead, the 7-10 bridging heterocyclic group is replaced by one or more R 24 replace,

[0048] Or, R 3 With R 2 Or R 2’ Together with the carbon atom it is attached to, they form a group that is optionally bounded by one or more R atoms. 25 Substituted morpholino group,

[0049] And R 2 R 2’ and R 3 They are not both hydrogen;

[0050] R 21 Selected from C2-C6 alkenyl-C(O)-, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-optionally substituted by one or more groups selected from: hydroxyl, C1-C6 alkyl or C1-C6 alkylacyl;

[0051] R 22 Selected from C2-C6 ynyl-C(O)- or 4-5 membered heterocyclic groups, wherein the 4-5 membered heterocyclic group is optionally composed of one or more replace;

[0052] R 21’ and R 22’ Each is independently selected from C1-C6 alkyl groups;

[0053] R 23 and R 24 Each independently selected C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl or C1-C6 alkylacyl-N(C1-C6 alkyl)-;

[0054] R 25 Selected from C1-C6 alkyl acyl groups;

[0055] R 4 Selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl;

[0056] R 5 Selected from C1-C6 alkyl groups;

[0057] R 5’ Selected from -CD3 or -CH3, and when R 5’ When it is -CH3, R 1 Or R 1’ It is a halogen.

[0058] In some embodiments, this application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0059] R 1 and R 1’ Each is independently selected from hydrogen or halogen;

[0060] R 2 and R 2’ Each is independently selected from hydrogen, amino, amino-C1-C6 alkyl-, 7-9 membered spiroheterocyclic groups, 10 membered spiroheterocyclic groups with ring atoms composed of nitrogen and carbon atoms, 7-10 membered fused heterocyclic groups, 7-10 membered bridged heterocyclic groups, 5-6 membered heterocyclic groups with ring atoms composed of nitrogen and carbon atoms, and 5-6 membered heterocyclic groups containing silicon or phosphorus atoms in their ring atoms. The amino group or amino-C1-C6 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the cyclic atom, consisting of a 5-6 membered heterocyclic group composed of nitrogen and carbon atoms, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ Instead, the 7-9 spirocyclic group, the 10 spirocyclic group whose ring atoms are composed of nitrogen and carbon atoms, the 7-10 fused heterocyclic group, or the 5-6 fused heterocyclic group whose ring atoms contain silicon or phosphorus atoms are optionally replaced by one or more R 23 Instead, the 7-10 bridging heterocyclic group is replaced by one or more R 24 replace,

[0061] R 3 It is hydrogen;

[0062] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Substituted morpholino group,

[0063] And R 2 and R 2’ They are not both hydrogen;

[0064] R21 Selected from C2-C6 alkenyl-C(O)-, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-optionally substituted by one or more groups selected from: hydroxyl, C1-C6 alkyl or C1-C6 alkylacyl;

[0065] R 22 The group is selected from C2-C6 ynyl-C(O)-, 4-5 membered heterocyclic groups, or 6 membered heterocyclic groups whose ring atoms are composed of nitrogen and sulfur atoms, wherein the 4-5 membered heterocyclic group or the 6 membered heterocyclic group whose ring atoms are composed of nitrogen and sulfur atoms is optionally substituted by one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl;

[0066] R 21’ and R 22’ Each is independently selected from deuterium or C1-C6 alkyl groups;

[0067] R 23 and R 24 Each independently selected C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl or C1-C6 alkylacyl-N(C1-C6 alkyl)-;

[0068] R 25 Selected from C1-C6 alkyl acyl groups;

[0069] R 4 Selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl;

[0070] R 5 Selected from C1-C6 alkyl groups;

[0071] R 5’ Selected from -CD3 or -CH3, and when R 5’ When it is -CH3, R 1 Or R 1’ It is a halogen.

[0072] In some embodiments, this application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0073] R 1 and R 1’ Each is independently selected from hydrogen or halogen;

[0074] R 2 and R 2’One of them is hydrogen, and the other is selected from amino, amino-C1-C6 alkyl-, 7-9 membered spiroheterocyclic groups, 10 membered spiroheterocyclic groups with nitrogen and carbon atoms as ring atoms, 7-10 membered fused heterocyclic groups, 7-10 membered bridged heterocyclic groups, 5-6 membered heterocyclic groups with nitrogen and carbon atoms as ring atoms, and 5-6 membered heterocyclic groups with silicon or phosphorus atoms as ring atoms. The amino group or amino-C1-C6 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the cyclic atom, consisting of a 5-6 membered heterocyclic group composed of nitrogen and carbon atoms, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ Instead, the 7-9 spirocyclic group, the 10 spirocyclic group whose ring atoms are composed of nitrogen and carbon atoms, the 7-10 fused heterocyclic group, or the 5-6 fused heterocyclic group whose ring atoms contain silicon or phosphorus atoms are optionally replaced by one or more R 23 Instead, the 7-10 bridging heterocyclic group is replaced by one or more R 24 Replace, R 3 It is hydrogen;

[0075] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Substituted morpholino group;

[0076] R 21 Selected from C2-C6 alkenyl-C(O)-, C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 Cycloalkyl, 4-12 membered heterocyclic or C1-C6 alkylacylamino-C1-C6 alkyl-optionally substituted by one or more groups selected from: hydroxyl, C1-C6 alkyl or C1-C6 alkylacyl;

[0077] R 22 The group is selected from C2-C6 ynyl-C(O)-, 4-5 membered heterocyclic groups, or 6 membered heterocyclic groups whose ring atoms are composed of nitrogen and sulfur atoms, wherein the 4-5 membered heterocyclic group or the 6 membered heterocyclic group whose ring atoms are composed of nitrogen and sulfur atoms is optionally substituted by one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl;

[0078] R 21’ and R 22’ Each is independently selected from deuterium or C1-C6 alkyl groups;

[0079] R 23 and R 24 Each independently selected C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl or C1-C6 alkylacyl-N(C1-C6 alkyl)-;

[0080] R 25 Selected from C1-C6 alkyl acyl groups;

[0081] R 4 Selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl;

[0082] R 5 Selected from C1-C6 alkyl groups;

[0083] R 5’ Selected from -CD3 or -CH3, and when R 5’ When it is -CH3, R 1 Or R 1’ It is a halogen.

[0084] In some embodiments, the 7-9 spiro-heterocyclic group, the 7-10 fused-heterocyclic group, and the 7-10 bridged-heterocyclic group each independently contain 1-3 heteroatoms selected from N, O, and S.

[0085] In some embodiments, the 7-9 spiro-heterocyclic group, the 7-10 fused-heterocyclic group, and the 7-10 bridged-heterocyclic group each independently contain one or two heteroatoms selected from N, O, and S.

[0086] In some implementations, the 10-membered spirocyclic group, composed of nitrogen and carbon atoms, contains one, two, or three nitrogen atoms.

[0087] In some implementations, the 5-6 membered heterocyclic group, composed of nitrogen and carbon atoms, contains one, two, or three nitrogen atoms.

[0088] In some embodiments, the 5-6 membered heterocyclic group containing silicon or phosphorus atoms in the ring atom contains one silicon atom or one phosphorus atom and one or two heteroatoms selected from N, O and S.

[0089] In some embodiments, the 4-5 membered heterocyclic group and the 4-12 membered heterocyclic group each independently contain 1-3 heteroatoms selected from N, O and S.

[0090] In some implementation schemes, R 1 and R 1’ Each is independently selected from hydrogen or fluorine.

[0091] In some implementation schemes, R 1 and R1’ All are selected from hydrogen.

[0092] In some implementation schemes, R 1 Selected from hydrogen, R 1’ Selected from halogens; or R 1 Selected from halogens, R 1’ Selected from hydrogen.

[0093] In some implementation schemes, R 1 Selected from hydrogen, R 1’ Selected from fluorine; or R 1 Selected from fluorine, R 1’ Selected from hydrogen.

[0094] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, amino-C1-C6 alkyl-, 7-9 membered spirocyclic groups, 7-10 membered fused heterocyclic groups, 7-10 membered bridged heterocyclic groups, 5-6 membered heterocyclic groups with ring atoms composed of nitrogen and carbon atoms, and 5-6 membered heterocyclic groups with ring atoms containing silicon or phosphorus atoms. The amino group or amino-C1-C6 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the cyclic atom, consisting of a 5-6 membered heterocyclic group composed of nitrogen and carbon atoms, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ Instead, the 7-9 spirocyclic group, 7-10 fused heterocyclic group, or 5-6 cyclic group with silicon or phosphorus atoms in the ring atom is optionally replaced by one or more R 23 Instead, the 7-10 bridging heterocyclic group is replaced by one or more R 24 replace,

[0095] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Substituted morpholino group,

[0096] And R 2 R 2’ and R 3 They are not both hydrogen.

[0097] In some implementation schemes, R 2 R 2’ and R 3Each is independently selected from hydrogen, amino, amino-C1-C4 alkyl-, 7-membered, 8-membered or 9-membered spiroheterocyclic groups, 10-membered spiroheterocyclic groups with ring atoms composed of nitrogen and carbon atoms, 7-membered, 8-membered or 9-membered fused heterocyclic groups, 7-membered or 8-membered bridged heterocyclic groups, 5-membered or 6-membered monoheterocyclic groups with ring atoms composed of nitrogen and carbon atoms, and 5-membered or 6-membered monoheterocyclic groups containing silicon or phosphorus atoms. The amino group or amino-C1-C4 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the ring atom is a 5- or 6-membered monoheterocyclic group consisting of nitrogen and carbon atoms, is replaced by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the 7-, 8-, or 9-membered spirocyclic group, the 10-membered spirocyclic group whose ring atoms are composed of nitrogen and carbon atoms, the 7-, 8-, or 9-membered fused heterocyclic group, or the 5- or 6-membered monoheterocyclic group whose ring atoms contain silicon or phosphorus atoms, are optionally replaced by one or more R 23 Instead, the 7- or 8-membered bridged heterocyclic group is replaced by one or more R 24 replace,

[0098] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Substituted morpholino group,

[0099] And R 2 R 2’ and R 3 They are not both hydrogen.

[0100] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, amino-C1-C4 alkyl, 7-membered, 8-membered or 9-membered spirocycloalkyl, 10-membered spirocycloalkyl with ring atoms composed of nitrogen and carbon atoms, 7-membered, 8-membered or 9-membered fused heterocycloalkyl, 7-membered or 8-membered bridged heterocycloalkyl, 5-membered or 6-membered monoheterocycloalkyl with ring atoms composed of nitrogen and carbon atoms, and 5-membered or 6-membered monoheterocycloalkyl with ring atoms containing silicon or phosphorus atoms. The amino group or amino-C1-C4 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the ring atom, consisting of a 5- or 6-membered monoheterocyclic alkyl group composed of a nitrogen atom and a carbon atom, is replaced by one or more R... 22 Replace, and optionally be one or more R22’ The substitution, wherein the 7-, 8-, or 9-membered spirocycloalkyl, the 10-membered spirocycloalkyl whose ring atoms are composed of nitrogen and carbon atoms, the 7-, 8-, or 9-membered cycloalkyl group, or the 5- or 6-membered monoheterocycloalkyl whose ring atoms contain silicon or phosphorus atoms, is optionally replaced by one or more R 23 Replacement, wherein the 7- or 8-membered bridged heterocyclic alkyl group is replaced by one or more R 24 replace,

[0101] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Substituted morpholino group,

[0102] And R 2 R 2’ and R 3 They are not both hydrogen.

[0103] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, amino-C1-C4 alkyl, 7-membered, 8-membered or 9-membered spirocycloalkyl, 10-membered spirocycloalkyl with ring atoms composed of nitrogen and carbon atoms, 5-membered 4-membered heterocycloalkyl, 5-membered 5-membered 5-membered heterocycloalkyl, 5-membered 6-membered heterocycloalkyl, 7-membered or 8-membered bridged heterocycloalkyl, 5-membered or 6-membered mono-heterocycloalkyl with ring atoms composed of nitrogen and carbon atoms, and 6-membered mono-heterocycloalkyl with ring atoms containing silicon or phosphorus atoms. The amino group or amino-C1-C4 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the ring atom, consisting of a 5- or 6-membered monoheterocyclic alkyl group composed of a nitrogen atom and a carbon atom, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ The alternatives, wherein the 7-, 8-, or 9-membered spirocycloalkyl, the 10-membered spirocycloalkyl with a ring atom composed of nitrogen and carbon atoms, the 5- or 4-membered heterocycloalkyl, the 5- or 5-membered heterocycloalkyl, the 5- or 6-membered heterocycloalkyl, or the 6-membered monoheterocycloalkyl with a ring atom containing silicon or phosphorus atoms, are optionally replaced by one or more R 23 Replacement, wherein the 7- or 8-membered bridged heterocyclic alkyl group is replaced by one or more R 24 replace,

[0104] Or, R 3 With R 2 Or R 2’They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Substituted morpholino group,

[0105] And R 2 R 2’ and R 3 They are not both hydrogen.

[0106] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, aminomethyl, Pyrrolidinyl, piperidinyl, piperazineyl, The amino or aminomethyl group is affected by one or more R 21 Replace, and optionally be one or more R 21’ Substitution, wherein the pyrrolidinyl, piperidinyl, or piperazine group is replaced by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the one described Optionally by one or more R 23 Instead, the one described by one or more R 24 replace,

[0107] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Replacement Group,

[0108] And R 2 R 2’ and R 3 They are not both hydrogen.

[0109] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, aminomethyl, The amino or aminomethyl group is affected by one or more R 21 Replace, and optionally be one or more R 21’ Instead, the one described by one or more R 22 Replace, and optionally be one or more R22’ Instead, the one described Optionally by one or more R 23 Instead, the one described by one or more R 24 replace,

[0110] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Replacement Group,

[0111] And R 2 R 2’ and R 3 They are not both hydrogen.

[0112] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, aminomethyl, Pyrrolidinyl, piperidinyl, piperazineyl, The amino and aminomethyl groups are affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the pyrrolidinyl, piperidinyl, or piperazine group is replaced by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the one described Optionally by one or more R 23 Instead, the one described by one or more R 24 replace,

[0113] Or, R 3 With R 2 Or R 2’ Together with the carbon atom it is attached to, they form a group that is optionally bounded by one or more R atoms. 25 Replacement Group,

[0114] And R 2 R 2’ and R 3 They are not both hydrogen.

[0115] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, amino, aminomethyl,

[0116] The amino and aminomethyl groups are affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Instead, the one described by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the one described Optionally by one or more R 23 Instead, the one described by one or more R 24 replace,

[0117] Or, R 3 With R 2 Or R 2’ Together with the carbon atom it is attached to, they form a group that is optionally bounded by one or more R atoms. 25 Replacement Group,

[0118] And R 2 R 2’ and R 3 They are not both hydrogen.

[0119] In some implementation schemes, R 2 and R 2’ One of them is hydrogen, and the other is selected from amino, amino-C1-C6 alkyl-, 7-9 membered spirocyclic group, 7-10 membered fused heterocyclic group, 7-10 membered bridged heterocyclic group, 5-6 membered heterocyclic group with nitrogen and carbon atoms as ring atoms, and 5-6 membered heterocyclic group with silicon or phosphorus atoms as ring atoms. The amino group or amino-C1-C6 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the cyclic atom, consisting of a 5-6 membered heterocyclic group composed of nitrogen and carbon atoms, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ Instead, the 7-9 spirocyclic group, 7-10 fused heterocyclic group, or 5-6 cyclic group with silicon or phosphorus atoms in the ring atom is optionally replaced by one or more R 23 Instead, the 7-10 bridging heterocyclic group is replaced by one or more R 24 replace,

[0120] And R 3 It is hydrogen.

[0121] In some implementation schemes, R 2 and R 2’ One of them is hydrogen, and the other is selected from amino, amino-C1-C4 alkyl-, 7-membered, 8-membered or 9-membered spirocyclic groups, 10-membered spirocyclic groups with ring atoms composed of nitrogen and carbon atoms, 7-membered, 8-membered or 9-membered fused heterocyclic groups, 7-membered or 8-membered bridged heterocyclic groups, 5-membered or 6-membered monocyclic heterocyclic groups with ring atoms composed of nitrogen and carbon atoms, and 5-membered or 6-membered monocyclic heterocyclic groups containing silicon or phosphorus atoms. The amino group or amino-C1-C4 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the ring atom is a 5- or 6-membered monoheterocyclic group consisting of nitrogen and carbon atoms, is replaced by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the 7-, 8-, or 9-membered spirocyclic group, the 10-membered spirocyclic group whose ring atoms are composed of nitrogen and carbon atoms, the 7-, 8-, or 9-membered fused heterocyclic group, or the 5- or 6-membered monoheterocyclic group whose ring atoms contain silicon or phosphorus atoms, are optionally replaced by one or more R 23 Instead, the 7- or 8-membered bridged heterocyclic group is replaced by one or more R 24 replace,

[0122] And R 3 It is hydrogen.

[0123] In some implementation schemes, R 2 and R 2’ One of them is hydrogen, and the other is selected from amino, amino-C1-C4 alkyl, 7-membered, 8-membered or 9-membered spirocycloalkyl, 10-membered spirocycloalkyl with a ring atom composed of nitrogen and carbon atoms, 7-membered, 8-membered or 9-membered fused heterocycloalkyl, 7-membered or 8-membered bridged heterocycloalkyl, 5-membered or 6-membered monoheterocycloalkyl with a ring atom composed of nitrogen and carbon atoms, and 5-membered or 6-membered monoheterocycloalkyl with a ring atom containing silicon or phosphorus atoms. The amino group or amino-C1-C4 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the ring atom, consisting of a 5- or 6-membered monoheterocyclic alkyl group composed of a nitrogen atom and a carbon atom, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ The substitution, wherein the 7-, 8-, or 9-membered spirocycloalkyl, the 10-membered spirocycloalkyl whose ring atoms are composed of nitrogen and carbon atoms, the 7-, 8-, or 9-membered cycloalkyl group, or the 5- or 6-membered monoheterocycloalkyl whose ring atoms contain silicon or phosphorus atoms, is optionally replaced by one or more R 23Replacement, wherein the 7- or 8-membered bridged heterocyclic alkyl group is replaced by one or more R 24 replace,

[0124] And R 3 It is hydrogen.

[0125] In some implementation schemes, R 2 and R 2’ One of them is hydrogen, and the other is selected from amino, amino-C1-C4 alkyl, 7-membered, 8-membered or 9-membered spirocycloalkyl, 10-membered spirocycloalkyl with a ring atom composed of nitrogen and carbon atoms, 5-membered 4-membered heterocycloalkyl, 5-membered 5-membered 5-membered heterocycloalkyl, 5-membered 6-membered heterocycloalkyl, 7-membered or 8-membered bridged heterocycloalkyl, 5-membered or 6-membered mono-heterocycloalkyl with a ring atom composed of nitrogen and carbon atoms, and 6-membered mono-heterocycloalkyl with a ring atom containing silicon or phosphorus atoms. The amino group or amino-C1-C4 alkyl group is affected by one or more R groups. 21 Replace, and optionally be one or more R 21’ Substitution, wherein the ring atom, consisting of a 5- or 6-membered monoheterocyclic alkyl group composed of a nitrogen atom and a carbon atom, is replaced by one or more R... 22 Replace, and optionally be one or more R 22’ The alternatives, wherein the 7-, 8-, or 9-membered spirocycloalkyl, the 10-membered spirocycloalkyl with a ring atom composed of nitrogen and carbon atoms, the 5- or 4-membered heterocycloalkyl, the 5- or 5-membered heterocycloalkyl, the 5- or 6-membered heterocycloalkyl, or the 6-membered monoheterocycloalkyl with a ring atom containing silicon or phosphorus atoms, are optionally replaced by one or more R 23 Replacement, wherein the 7- or 8-membered bridged heterocyclic alkyl group is replaced by one or more R 24 replace,

[0126] And R 3 It is hydrogen.

[0127] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is selected from amino, aminomethyl, ... Pyrrolidinyl, piperidinyl, piperazineyl, The amino or aminomethyl group is affected by one or more R 21 Replace, and optionally be one or more R 21’ Substitution, wherein the pyrrolidinyl, piperidinyl, or piperazine group is replaced by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the one described Optionally by one or more R23 Instead, the one described by one or more R 24 replace,

[0128] And R 3 It is hydrogen;

[0129] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Replacement Group.

[0130] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is selected from amino, aminomethyl, ... The amino or aminomethyl group is affected by one or more R 21 Replace, and optionally be one or more R 21’ Instead, the one described by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the one described Optionally by one or more R 23 Instead, the one described by one or more R 24 replace,

[0131] And R 3 It is hydrogen;

[0132] Or, R 3 With R 2 Or R 2’ They are interconnected, and together with the carbon atoms they are connected to, they form a group optionally bounded by one or more R atoms. 25 Replacement Group.

[0133] In some implementation schemes, R 3 With R 2 Or R 2’ Interconnected, making structural units For optional use by one or more R 25 Replacement

[0134] In some implementation schemes, R 21 Selected from C2-C4 alkenyl-C(O)-, C5-C 10Cycloalkyl, 4-6 membered heterocyclic or C1-C4 alkylacylamino-C1-C4 alkyl-, wherein the C5-C 10 Cycloalkyl, 4-6 membered heterocyclic or C1-C4 alkyl acylamino-C1-C4 alkyl-optionally substituted by one or more groups selected from the following: hydroxyl, C1-C6 alkyl or C1-C4 alkyl acyl.

[0135] In some implementation schemes, R 21 Selected from C2-C3 alkenyl-C(O)-, C7-C 10 Bridged cycloalkyl, 4-6 membered monoheterocyclic alkyl or C1-C3 alkylacylamino-C1-C3 alkyl-, wherein the C7-C 10 Bridged cycloalkyl, 4-6 membered monoheterocyclic alkyl or C1-C3 alkyl acylamino-C1-C3 alkyl-optionally substituted by one or more groups selected from the following: hydroxyl, C1-C4 alkyl or C1-C4 alkyl acyl.

[0136] In some implementation schemes, R 21 Selected from C2-C3 alkenyl-C(O)-, C 10 Bridged cycloalkyl, 5- or 6-membered monoheterocyclic alkyl, or C1-C3 alkylacylamino-C1-C3 alkyl-, wherein the C 10 Bridged cycloalkyl, 5- or 6-membered monoheterocyclic alkyl or C1-C3 alkyl acylamino-C1-C3 alkyl-optionally substituted by one or more groups selected from the following: hydroxyl, C1-C4 alkyl or C1-C4 alkyl acyl.

[0137] In some implementation schemes, R 21 Selected from H2C=CHC(O)-, Or CH3C(O)N(CH3)-CH3CH2-, wherein Optionally substituted with one or more groups selected from the following: hydroxyl or C1-C4 alkyl acyl.

[0138] In some implementation schemes, R 21 Selected from H2C=CHC(O)-, Or CH3C(O)N(CH3)-CH3CH2-.

[0139] In some implementation schemes, R 21 Selected from H2C=CHC(O)-, Or CH3C(O)N(CH3)-CH3CH2-.

[0140] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is an amino group, the amino group being converted by an R group.21 Replace, R 21 Selected from C2-C3 alkenyl-C(O)-, C 10 Bridged cycloalkyl, 5- or 6-membered monoheterocyclic alkyl, or C1-C3 alkylacylamino-C1-C3 alkyl-, wherein the C 10 Bridged cycloalkyl, 5- or 6-membered monoheterocyclic alkyl, or C1-C3 alkylacylamino-C1-C3 alkyl-optionally substituted by one or more groups selected from: hydroxyl, C1-C4 alkyl, or C1-C4 alkylacyl; and / or R 3 It is hydrogen.

[0141] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is an amino group, the amino group being converted by an R group. 21 Replace, R 21 Selected from H2C=CHC(O)-, Or CH3C(O)N(CH3)-CH3CH2-; and / or R 3 It is hydrogen.

[0142] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is amino-C1-C6 alkyl-, wherein the amino-C1-C6 alkyl- is substituted with C2-C3 alkenyl-C(O)-; and / or R 3 It is hydrogen.

[0143] In some implementation schemes, R 22 Selected from C2-C6 ynyl-C(O)- or 4-5 membered heterocyclic groups, wherein the 4-5 membered heterocyclic group is optionally composed of one or more replace.

[0144] In some implementation schemes, R 22 Selected from C2-C3 ynyl-C(O)-, 4- or 5-membered heterocyclic groups, or 6-membered heterocyclic groups whose ring atoms are composed of nitrogen and sulfur atoms, wherein the 4- or 5-membered heterocyclic group or the 6-membered heterocyclic group whose ring atoms are composed of nitrogen and sulfur atoms is optionally substituted by one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl.

[0145] In some implementation schemes, R 22 Selected from C2-C3 ynyl-C(O)- or 4- or 5-membered heterocyclic groups, wherein the 4- or 5-membered heterocyclic group is optionally composed of one or more replace.

[0146] In some implementation schemes, R 22Selected from C2-C3 ynyl-C(O)-, 4- or 5-membered heterocyclic alkyl groups or The 4- or 5-membered heterocyclic alkyl group or Optionally substituted with one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl.

[0147] In some implementation schemes, R 22 Selected from C2-C3 ynyl-C(O)- or 4- or 5-membered heterocyclic alkyl groups, wherein the 4- or 5-membered heterocyclic alkyl group is optionally composed of one or more replace.

[0148] In some implementation schemes, R 22 Selected from H3CC≡CC(O)-,

[0149] In some implementation schemes, R 22 Selected from H3CC≡CC(O)-,

[0150] In some implementation schemes, R 21’ and R 22’ Each is independently selected from deuterium or C1-C4 alkyl groups.

[0151] In some implementation schemes, R 21’ and R 22’ Each is independently selected from deuterium or methyl.

[0152] In some implementation schemes, R 21’ and R 22’ Each is independently selected from C1-C4 alkyl groups.

[0153] In some implementation schemes, R 21’ and R 22’ Each is independently selected from methyl groups.

[0154] In some implementation schemes, R 23 Selected from C1-C4 alkyl, C1-C4 alkylsulfonyl or C1-C4 alkylacyl.

[0155] In some implementation schemes, R 23 Selected from CH3-, CH3S(O)2- or CH3C(O)-.

[0156] In some implementation schemes, R 24 Selected from C1-C4 alkyl acyl-N(C1-C4 alkyl)-.

[0157] In some implementation schemes, R24 Selected from CH3C(O)N(CH3)-.

[0158] In some implementation schemes, R 25 Selected from C1-C4 alkyl acyl groups.

[0159] In some implementation schemes, R 25 Selected from CH3C(O)-.

[0160] In some implementation schemes, R 4 Selected from C1-C4 alkyl acyl or C1-C4 alkyl sulfonyl.

[0161] In some implementation schemes, R 4 Selected from CH3C(O)- or CH3S(O)2-.

[0162] In some implementation schemes, R 5 Selected from C1-C4 alkyl groups.

[0163] In some implementation schemes, R 5 Selected from methyl.

[0164] In some implementation schemes, R 4 Selected from CH3C(O)-; R 5 Selected from methyl.

[0165] In some implementation schemes, R 4 Selected from CH3S(O)2-; R 5 Selected from methyl.

[0166] In some implementation schemes, R 5’ Selected from -CD3 or -CH3, and when R 5’ When it is -CH3, R 1 Or R 1’ It is fluorine.

[0167] In some implementation schemes, R 2 and R 2’ One of them is hydrogen, and the other is selected from a 7-9 membered spiroheterocyclic group, wherein the 7-9 membered spiroheterocyclic group is optionally surrounded by one or two R groups. 23 Replace, R 23 Selected from C1-C4 alkyl, C1-C4 alkylsulfonyl or C1-C4 alkylacyl; and / or R 3 It is hydrogen.

[0168] In some implementation schemes, R 2 and R 2’ One of them is hydrogen, and the other is selected from a 7-9 membered spiroheterocyclic group, wherein the 7-9 membered spiroheterocyclic group is optionally surrounded by one or two R groups. 23 Replace, R23 Selected from CH3-, CH3S(O)2- or CH3C(O)-; and / or R 3 It is hydrogen.

[0169] In some embodiments, the 7-9 membered spiroheterocyclic group is a 7, 8, or 9 membered monospiroheterocyclic ring containing one or two heteroatoms selected from N, O, or S. In some embodiments, the 7-9 membered spiroheterocyclic group is a 7, 8, or 9 membered monospiroheterocyclic ring containing one or two heteroatoms selected from N and O.

[0170] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is a 10-membered spiroheterocyclic group composed of nitrogen and carbon atoms, wherein the 10-membered spiroheterocyclic group is optionally separated by one or two R atoms. 23 Replace, R 23 Selected from C1-C4 alkyl, C1-C4 alkylsulfonyl or C1-C4 alkylacyl; and / or R 3 It is hydrogen.

[0171] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is a 10-membered spiroheterocyclic group composed of nitrogen and carbon atoms, wherein the 10-membered spiroheterocyclic group is optionally separated by one or two R atoms. 23 Replace, R 23 Selected from and C1-C4 alkyl; and / or R 3 It is hydrogen.

[0172] In some embodiments, the 10-membered spiroheterocyclic group contains one or two heteroatoms selected from N.

[0173] In some implementation schemes, R 2 and R 2’ One of them is hydrogen, and the other is selected from 7-10 fused heterocyclic groups, wherein the 7-10 fused heterocyclic group is optionally surrounded by one or two R groups. 23 Replace, R 23 Selected from C1-C4 alkyl, C1-C4 alkylsulfonyl or C1-C4 alkylacyl; and / or R 3 It is hydrogen.

[0174] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is selected from 7-9 membered heterocyclic groups, wherein the 7-9 membered heterocyclic group is optionally surrounded by one Or C1-C4 alkyl acyl substitution; and / or R 3 It is hydrogen.

[0175] In some embodiments, the 7-9 membered heterocyclic group contains one or two heteroatoms selected from N, O, or S. In some embodiments, the 7-9 membered heterocyclic group contains one or two heteroatoms selected from N and O.

[0176] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is selected from a 5-6 membered heterocyclic group whose ring atoms are composed of nitrogen and carbon atoms, said 5-6 membered heterocyclic group being separated by an R 22 Replace, and optionally be an R 22’ Replace; R 22 Selected from C2-C3 ynyl-C(O)-, 4- or 5-membered heterocyclic groups, or 6-membered heterocyclic groups whose cyclic atoms are composed of nitrogen and sulfur atoms, wherein the 4- or 5-membered heterocyclic group or the 6-membered heterocyclic group whose cyclic atoms are composed of nitrogen and sulfur atoms is optionally composed of one, two, or three selected from Halogen, C1-C3 alkyl, or C1-C3 alkyl acyl group substitution; R 22’ Selected from deuterium or C1-C3 alkyl; and / or R 3 It is hydrogen.

[0177] In some embodiments, the cyclic atom is a 5-6 membered heterocyclic group composed of nitrogen and carbon atoms, containing one or two nitrogen atoms.

[0178] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is selected from a 7-10 bridging heterocyclic group, wherein the 7-10 bridging heterocyclic group is separated by one or two R atoms. 24 Replace, R 24 Selected from C1-C4 alkyl acyl-N(C1-C4 alkyl)-; and / or R 3 It is hydrogen.

[0179] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is selected from a 7-10 bridging heterocyclic group, wherein the 7-10 bridging heterocyclic group is substituted with one CH3C(O)N(CH3)-; and / or R 3 It is hydrogen.

[0180] In some embodiments, the 7-10 bridging heterocyclic group contains one or two heteroatoms selected from N, O, or S. In some embodiments, the 7-10 bridging heterocyclic group contains one or two heteroatoms selected from N and O.

[0181] In some implementation schemes, R 2 and R 2’One of them is hydrogen, and the other is selected from a 5-6 membered heterocyclic group containing silicon or phosphorus atoms in the ring atom, wherein the 5-6 membered heterocyclic group is optionally surrounded by one or two R atoms. 23 Replace, R 23 Selected from and C1-C4 alkyl; and / or R 3 It is hydrogen.

[0182] In some embodiments, the 5-6 membered heterocyclic group containing silicon or phosphorus atoms in the ring atom contains one silicon atom or one phosphorus atom, and also contains one heteroatom selected from N, O, or S. In some embodiments, the 5-6 membered heterocyclic group containing silicon or phosphorus atoms in the ring atom contains one silicon atom or one phosphorus atom, and also contains one N atom.

[0183] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, Or, R 3 With R 2 Or R 2’ They connect to each other and together with the carbon atoms they are connected to form a... Group, and R 2 R 2’ and R 3 They are not both hydrogen.

[0184] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is selected from... And R 3 It is hydrogen.

[0185] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, Or, R 3 With R 2 Or R 2’ Together with the carbon atom it is attached to, they form a Group, and R 2 R 2’ and R 3 They are not both hydrogen.

[0186] In some implementation schemes, R2 and R 2’ One is hydrogen, and the other is selected from... And R 3 It is hydrogen.

[0187] In some implementation schemes, R 2 R 2’ and R 3 Each is independently selected from hydrogen, Or R 3 With R 2 Or R 2’ Interconnected, making structural units for And R 2 R 2’ and R 3 They are not both hydrogen.

[0188] In some implementation schemes, R 2 and R 2’ One is hydrogen, and the other is selected from...

[0189] And R 3 For hydrogen. In some implementations, when R 2 R 2’ Or R 3 Each is independently selected from hydrogen or At that time, R 1 Or R 1’ It is fluorine.

[0190] In some implementation schemes, R 2 R 2’ Or R 3 Of these, two are hydrogen.

[0191] In some implementation schemes, R 2 and R 2’ For hydrogen, R 3 It is not hydrogen.

[0192] In some implementation schemes, R 2 Not hydrogen, R 2’ and R 3 It is hydrogen.

[0193] In some implementation schemes, R 2’ Not hydrogen, R 2 and R 3 It is hydrogen.

[0194] In some implementations, this application includes the variables defined above and their implementations, as well as any combination thereof.

[0195] On the other hand, this application provides the following compounds or their pharmaceutically acceptable salts,

[0196]

[0197]

[0198]

[0199] On the other hand, this application also provides pharmaceutical compositions comprising the above-described compounds of this application or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of this application further include pharmaceutically acceptable excipients.

[0200] On the other hand, this application also provides a method for treating diseases mediated by Akt kinase in mammals, comprising administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of the above-mentioned compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0201] On the other hand, this application also provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of medicaments for treating Akt kinase-mediated diseases.

[0202] On the other hand, this application also provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the treatment of Akt kinase-mediated diseases.

[0203] On the other hand, this application also provides the above-mentioned compound of this application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating Akt kinase-mediated diseases.

[0204] In some implementations, the diseases mediated by the Akt kinase are selected from cancers, such as prostate cancer, endometrial cancer, etc.

[0205] The compounds in this application exhibit excellent inhibitory effects on phosphorylation of LNcap cells and AKT1(S473) in LNcap cells, as well as good cellular activity, low toxicity, good pharmacokinetic properties, and strong in vivo tumor inhibitory effects.

[0206] definition

[0207] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0208] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on the aromatic group. Ketone substitution does not exist on the aromatic moiety.

[0209] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0210] C in this article m-n This means that the part has an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0211] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by two Rs, each R has an independent option.

[0212] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0213] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0214] The term "hydroxyl group" refers to the -OH group.

[0215] The term "amino" refers to the -NH2 group.

[0216] The term "alkyl" refers to a compound with the general formula C1. n H2n+1 The alkyl group is a hydrocarbon group, where n is an integer from 1 to 20. The alkyl group can be straight-chain or branched. In this application, the alkyl group can contain 1-10 carbon atoms (C1-C2). 10 Alkyl), 1-6 carbon atoms (C1-C6 alkyl), 1-4 carbon atoms (C1-C4 alkyl), or 1-3 carbon atoms (C1-C3 alkyl). For example, the term "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.

[0217] The term "alkoxy" refers to -O-alkyl.

[0218] The term "aminoalkyl" refers to -alkyl-NH2.

[0219] The term "alkyl acyl" refers to -C(O)-alkyl.

[0220] The term "alkylsulfonyl" refers to -SO2-alkyl.

[0221] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. In this application, the alkenyl group may contain 2-10 carbon atoms (C2-C4). 10 Alkenyl groups are composed of 2-6 carbon atoms (C2-C6 alkenyl) or 2-4 carbon atoms (C2-C4 alkenyl). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0222] The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. In this application, the alkenyl group may contain 2-10 carbon atoms (C2-C4). 10 Alkyne group, consisting of 2-6 carbon atoms (C2-C6 alkynyl) or 2-4 carbon atoms (C2-C4 alkynyl). Non-limiting examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 1,3-butyrylenyl (-C≡CC≡CH), etc.

[0223] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. In this application, cycloalkyl can be a 3-12 membered cycloalkyl, a 3-10 membered cycloalkyl, a 5-10 membered cycloalkyl, a 3-8 membered cycloalkyl, or a 3-6 membered cycloalkyl. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0224] The term "heterocyclic group" refers to a fully saturated or partially unsaturated (but not fully unsaturated) heteroaromatic ring that can exist as a monocyclic, bridged, or spirocyclic ring. In this application, the heterocyclic group can be a 3- to 7-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). In this application, the heterocyclic group can be a 4- to 12-membered, 4- to 8-membered, 5- to 6-membered, 4- to 5-membered, or 6-membered heterocyclic group containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). The "5- or 6-membered monoheterocyclic group whose ring atoms are composed of nitrogen and carbon atoms" in this application can contain 1 or 2 nitrogen atoms. The "5- or 6-membered monoheterocyclic group whose ring atoms contain silicon or phosphorus atoms" in this application can contain 1 silicon atom or 1 phosphorus atom and 1 or 2 heteroatoms selected from N, O, and S. Non-limiting examples of heterocyclic groups include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolyl, N-methylpyrrolyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, and tetrahydrothiophenyl. wait.

[0225] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that can exist as a monocyclic, bridged, or spirocyclic ring. In this application, a heterocyclic alkyl group can be a 3- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen. In this application, a heterocyclic alkyl group can be a 4- to 12-membered, 4- to 8-membered, 5- to 6-membered, 4- to 5-membered, or 6-membered heterocyclic alkyl group containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridinel, oxadiazolyl, and thiobutylcycloyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl. Examples of 7-membered heterocyclic alkyl groups include, but are not limited to, nitrogen-containing heptyl, oxo-containing heptyl, and thio-containing heptyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0226] The term "monohexocyclic group" refers to a fully saturated or partially unsaturated (but not fully saturated) aromatic monocyclic ring having 3 to 10 membered ring atoms, or 4 to 6 membered ring atoms. The monoheterocyclic group in this application can be a 3 to 10 membered ring containing 1 to 3 heteroatoms independently selected from sulfur, silicon, phosphorus, oxygen and / or nitrogen (preferably 1 or 2 heteroatoms). The monoheterocyclic group in this application can be a 3 to 10 membered ring, a 3 to 8 membered ring, a 3 to 7 membered ring, or a 4 to 6 membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen and / or nitrogen (preferably 1 or 2 heteroatoms). Non-limiting examples of monoheterocyclic rings include ethylene oxide rings, tetrahydrofuran rings, dihydrofuran rings, 3,4-dihydrofuran rings, 3,6-dihydrofuran rings, tetrahydropyrrole rings, dihydropyrrole rings, piperidine rings, piperazine rings, morpholine rings, tetrahydropyrazole rings, tetrahydrothiophene rings, etc.

[0227] The term "monohexyl alkyl" refers to a fully saturated monocyclic ring having 3 to 10 membered ring atoms, or 4 to 6 membered ring atoms. In this application, a monoheterocyclic alkyl group can be a 3 to 10 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen. The monoheterocyclic alkyl group in this application can be a 3 to 10 membered ring, a 3 to 8 membered ring, a 3 to 7 membered ring, or a 4 to 6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of monoheterocyclic alkyl groups include ethylene oxide rings, tetrahydrofuran rings, tetrahydropyrrole rings, piperidine rings, piperazine rings, morpholine rings, tetrahydropyrazole rings, tetrahydrothiophene rings, etc.

[0228] The term "spirocyclic group" refers to a polycyclic aromatic ring that is fully saturated or partially unsaturated (but not fully saturated) and shares a single carbon atom (called a spiro atom) among its 5- to 20-membered monocyclic rings. Spirocyclic groups are preferably 6 to 14-membered, more preferably 6 to 10-membered, 7 to 9-membered, or 10-membered. Spirocyclic groups are classified as monospirocyclic, bispirocyclic, or polyspirocyclic based on the number of shared spiro atoms between rings, preferably monospirocyclic or bispirocyclic, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic groups. Non-limiting examples of spirocyclic groups include...

[0229] The term "spirocycloalkyl" refers to a fully saturated spirocycloalkyl group.

[0230] The term "spiroheterocyclic group" refers to a spirocycle in which one or more ring atoms are heteroatoms selected from sulfur, silicon, phosphorus, oxygen and / or nitrogen (preferably one or two heteroatoms, more preferably heteroatoms selected from N, O and / or S), and the remaining ring atoms are carbon. Spiroheterocyclic groups are preferably 6 to 14-membered, more preferably 6 to 10-membered, 7 to 9-membered, or 10-membered. Spiroheterocycles are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups based on the number of shared spiroatoms between rings, preferably monospirocyclic or bispirocyclic, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic, preferably each ring containing one heteroatom selected from N, O and / or S. Non-limiting examples of spirocyclic groups include...

[0231] The term "spiroheteroalkyl" refers to a fully saturated spiroheteroalkyl group.

[0232] The term "bridged ring group" refers to a fully saturated or partially unsaturated (but not fully saturated) aromatic polycyclic aromatic ring having 5 to 20 membered ring atoms, with two rings sharing 3 or more ring atoms. Preferably, it has 6 to 14 members, more preferably 6 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged ring, preferably a bicyclic or tricyclic, more preferably a bicyclic. Non-limiting examples of bridged rings include:

[0233] The term "bridged cycloalkyl" refers to a fully saturated bridged cycloalkyl group.

[0234] The term "bridged heterocyclic group" refers to a bridged ring in which one or more ring atoms are heteroatoms selected from sulfur, silicon, phosphorus, oxygen and / or nitrogen (preferably one or two heteroatoms, preferably heteroatoms selected from N, O and / or S), and the remaining ring atoms are carbon. Bridged heterocyclic groups are preferably 6 to 14-membered, more preferably 6 to 10-membered, 7 to 9-membered, 7-membered, or 8-membered. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic or tricyclic, more preferably bicyclic. Non-limiting examples of bridged heterocyclic groups include...

[0235] The term "bridged heterocyclic alkyl" refers to a fully saturated bridged heterocyclic group.

[0236] The term "fused ring group" refers to a fully saturated or partially unsaturated (but not fully saturated) aromatic polycyclic aromatic ring having 5 to 20 membered ring atoms, with two rings sharing two ring atoms. Preferably, it has 6 to 14 members, more preferably 6 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridging ring, preferably a bicyclic or tricyclic ring, more preferably a bicyclic ring. Non-limiting examples of fused rings include:

[0237] The term "cycloalkyl" refers to a fully saturated cycloalkyl group.

[0238] The term "fused heterocyclic group" refers to a fused ring in which one or more ring atoms are heteroatoms selected from sulfur, silicon, phosphorus, oxygen and / or nitrogen (preferably one or two heteroatoms, preferably heteroatoms selected from N, O and / or S), and the remaining ring atoms are carbon. Fused heterocyclic groups are preferably 6 to 14-membered, more preferably 6 to 10-membered, 7 to 10-membered, 7-membered, 8-membered, or 9-membered. Depending on the number of constituent rings, they can be classified as bicyclic, tricyclic, or polycyclic bridged heterocyclic groups, with bicyclic groups being preferred. Non-limiting examples of fused heterocyclic groups include...

[0239] The term "heterocyclic alkyl" refers to a fully saturated heterocyclic alkyl group.

[0240] Each of the above groups may optionally be substituted by one or more (e.g., 1, 2, or 3) substituents, including but not limited to deuterium, hydroxyl, halogens (F, Cl, Br, or I). C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkyl acyl and C1-C6 alkyl acyl-N(C1-C6 alkyl)-.

[0241] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0242] (i) Suppress the disease or disease state, that is, curb its development;

[0243] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0244] The term "therapeutic effective amount" means (i) the amount of the compound of this application used to treat a particular disease, condition, or disorder, or (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0245] The therapeutic dose of the compound may be determined based on factors such as the specific therapeutic purpose, the method of administration, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compound in the pharmaceutical composition may not be fixed and depends on various factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compound may be provided in a physiologically buffered aqueous solution containing about 0.1–10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on variables such as the type and severity of the disease or condition, the general health status of the specific patient, the relative biological potency of the selected compound, the excipient formulation, and the route of administration. The effective dose can be obtained by extrapolation from dose-response curves derived from in vitro or animal model testing systems.

[0246] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may include, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids.

[0247] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism. The pharmaceutical compositions of this invention can be prepared using conventional methods in the art, for example, by mixing the compounds of this application or salts thereof with one or more pharmaceutically acceptable excipients.

[0248] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0249] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0250] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0251] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36Cl, etc.

[0252] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0253] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from increased metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred in some cases, where deuterium substitution can be partial or complete, with partial deuterium substitution meaning that at least one hydrogen atom is substituted with at least one deuterium atom. For example, all hydrogen atoms in a methyl group are deuterated to form methyl-d3, but this is not a limitation.

[0254] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. For example, the compound structure contains... For (R)- and (S)-enantiomers.

[0255] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0256] Unless otherwise stated, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom in the double bond is attached to two different substituents (in a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered as one of the substituents it is attached to), if the atoms in the double bond and their substituents in the compound are separated by a wavy line... The connection indicates that the compound is a (Z) type isomer, an (E) type isomer, or a mixture of the two isomers.

[0257] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0258] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0259] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0260] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this application to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0261] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0262] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0263] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0264] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0265] An important consideration in synthetic route planning in this field is the selection of appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this application are incorporated herein by reference in their entirety.

[0266] In some embodiments, compounds of general formula (I) of this application can be prepared by those skilled in the art using standard methods in the art via the following route:

[0267]

[0268] in,

[0269] R 1 R 1’ R 2 R 2’ and R 3 The definition is as described above. Detailed Implementation

[0270] For clarity, the present invention is further illustrated by examples, but these examples are not intended to limit the scope of this application. It will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the invention without departing from the spirit and scope thereof. All reagents used in this application are commercially available and can be used without further purification.

[0271] Example 1: Preparation of Compound 1

[0272]

[0273] Step A: Preparation of compound 1A

[0274] Under nitrogen protection at -30°C, N,N-diisopropylethylamine (13.4 g) was slowly added dropwise to a tetrahydrofuran solution of 2,6-dichloro-3-nitropyridine (20.0 g) and tert-butyl(1-(4-aminophenyl)cyclobutyl)carbamate (25.5 g). After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated to give compound 1A (43.4 g).

[0275] MS(ESI, [M+Na)) + )m / z:441.5.

[0276] Step B: Preparation of compound 1B

[0277] At room temperature, compound 1A (40.0 g), zinc powder (31.2 g), ammonium chloride (5.1 g), ethanol (400 mL), and water (40 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction mixture was reacted at 90 °C. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1B (41.0 g).

[0278] MS(ESI, [M+H]) + )m / z:389.3.

[0279] Step C: Preparation of compound 1C

[0280] At room temperature, compound 1B (34.0 g), 2-aminonicotinic acid (11.2 g), sodium perborate (14.3 g), acetic acid (250 mL), and methanol (30 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 55 °C. Once the reaction was complete, the reaction solution was concentrated, ethyl acetate and water were added, and the pH was adjusted to 11-12 with an aqueous sodium hydroxide solution. The mixture was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 50 / 1) to give compound 1C (16.0 g).

[0281] MS(ESI, [M+H]) + )m / z:491.3.

[0282] Step D: Preparation of compound 1D

[0283] 2-Butynic acid (1.00 g), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.97 g), and dichloromethane (50 mL) were added sequentially to a reaction flask. At 0 °C, a dichloromethane (30 mL) solution of N,N-diisopropylethylamine (3.07 g) and 2-(3-bromophenyl)-pyrrolidine (2.96 g) was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, a saturated ammonium chloride aqueous solution was added to the reaction mixture. The phases were separated; the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 1D (3.92 g).

[0284] MS(ESI, [M+H]) + )m / z:292.0.

[0285] Step E: Preparation of compound 1E

[0286] Compound 1D (0.92 g), pinacol diborate (1.20 g), potassium acetate (0.93 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.13 g), and 1,4-dioxane (15 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 2 / 1) yielded compound 1E (0.38 g).

[0287] MS(ESI, [M+H]) + )m / z:340.2.

[0288] Step F: Preparation of compound 1F

[0289] Compound 1E (0.17 g), compound 1C (0.12 g), potassium carbonate (0.11 g), tetrakis(triphenylphosphine)palladium (0.03 g), 1,4-dioxane (3 mL), and water (0.5 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 100 °C for 2 h. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 1F (68 mg).

[0290] MS(ESI, [M+Na)) + )m / z:690.6.

[0291] Step G: Preparation of Compound 1

[0292] Compound 1F (68 mg), methanesulfonic acid (0.1 mL), and dichloromethane (4 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 1 (18 mg).

[0293] HRMS(ESI, [M+H]) + )m / z:568.2823.

[0294] 1 H NMR(500MHz,DMSO-d6)δ8.28(d,J=8.3Hz,1H),8.05-7.95(m,2H),7.94-7.79(m,2H),7.7 1-7.63(m,2H),7.58-7.50(m,2H),7.46-7.38(m,1H),7.31-7.16(m,2H),6.93(d,J=8.5H z,2H),6.46-6.42(m,1H),5.24-5.02(m,1H),3.83(t,J=6.9Hz,1H),3.65-3.54(m,1H),2 .62-2.52(m,2H),2.45-2.30(m,3H),2.18-2.09(m,1H),1.94-1.73(m,4H),1.87(s,3H).

[0295] Example 2: Preparation of Compound 2

[0296]

[0297] Step A: Preparation of compound 2A

[0298] At -10°C, under nitrogen protection, a solution of acryloyl chloride (1.08 g) in tetrahydrofuran (10 mL) was slowly added to a reaction flask containing 3-bromobenzylamine (2.00 g) and N,N-diisopropylethylamine (1.63 g) in tetrahydrofuran (90 mL). After the addition was complete, the mixture was stirred at room temperature until the reaction was complete. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 2A (2.58 g).

[0299] MS(ESI, [M+H]) + )m / z:240.1.

[0300] Step B: Preparation of compound 2B

[0301] Compound 2A (2.00 g), pinacol diborate (3.17 g), potassium acetate (2.45 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.68 g), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was then filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 1 / 1) yielded compound 2B (1.89 g).

[0302] MS(ESI, [M+H]) + )m / z:288.1.

[0303] Step C: Preparation of compound 2C

[0304] Compound 2B (0.14 g), compound 1C (0.12 g), potassium carbonate (0.11 g), tetrakis(triphenylphosphine)palladium (0.028 g), 1,4-dioxane (3 mL), and water (0.5 mL) were added sequentially to a microwave tube. After the additions were complete, nitrogen gas was introduced, and the mixture was microwaved at 100 °C. The reaction was allowed to complete, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 2C (85 mg).

[0305] MS(ESI, [M+H]) + )m / z:616.5.

[0306] 1 H NMR(500MHz,DMSO-d6)δ8.28(d,J=8.3Hz,1H),8.05-7.95(m,2H),7.94-7.79(m,2H),7.71- 7.63(m,2H),7.58-7.50(m,2H),7.42(dt,J=26.0,7.7Hz,1H),7.31-7.16(m,2H),6.93(d,J =8.5Hz,2H),6.46-6.42(m,1H),5.24-5.02(m,1H),3.83(t,J=6.9Hz,1H),3.65-3.54(m,1H ),2.62-2.52(m,2H),2.45-2.30(m,3H),2.18-2.09(m,1H),1.94-1.73(m,4H),1.87(s,3H).

[0307] Step D: Preparation of Compound 2

[0308] Compound 2C (80 mg), methanesulfonic acid (0.1 mL), and dichloromethane (4 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 2 (45 mg).

[0309] HRMS(ESI, [M+H]) + )m / z:516.2516.

[0310] 1 H NMR (500MHz, DMSO-d6) δ8.67(t,J=6.0Hz,1H),8.27(d,J=8.4Hz,1H),8.01(dd,J=4.8,1.8Hz,1H),7.98-7.88(m ,3H),7.67-7.59(m,2H),7.50-7.40(m,3H),7.30(dt,J=7.6,1.3Hz,1H),7.21(dd,J=7.6,1.9Hz,1H),6.94(s,2 H),6.42(dd,J=7.7,4.9Hz,1H),6.31(dd,J=17.1,10.2Hz,1H),6.15(dd,J=17.1,2.2Hz,1H),5.65(dd,J=10.2, 2.2Hz,1H),4.43(d,J=5.9Hz,2H),2.49-2.43(m,2H),2.23-2.13(m,2H),2.11-2.00(m,1H),1.77-1.69(m,1H).

[0311] Example 3: Preparation of Compound 3

[0312]

[0313] Step A: Preparation of compound 3A

[0314] At -10℃, under nitrogen protection, a solution of acryloyl chloride (2.98 g) in tetrahydrofuran (10 mL) was slowly added to a stirred mixture of p-bromoaniline (5.00 g) and N,N-diisopropylethylamine (4.51 g) in tetrahydrofuran (90 mL). After the addition was complete, the mixture was stirred at room temperature until the reaction was complete. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 3A (5.90 g).

[0315] MS(ESI, [M+H]) + )m / z:226.1.

[0316] Step B: Preparation of compound 3B

[0317] Compound 3A (0.5 g), pinacol diborate (0.84 g), potassium acetate (0.65 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.18 g), and 1,4-dioxane (20 mL) were added sequentially to the reaction flask. The mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 2 / 1) yielded compound 3B (0.26 g).

[0318] MS(ESI, [M+H]) + )m / z:274.5.

[0319] Step C: Preparation of compound 3C

[0320] Compound 3B (0.13 g), compound 1C (0.12 g), potassium carbonate (0.11 g), tetrakis(triphenylphosphine)palladium (0.028 g), 1,4-dioxane (3 mL), and water (0.5 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 100 °C for 2 h. The reaction was completed, filtered, and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 3C (78 mg).

[0321] MS(ESI, [M+H]) + )m / z:602.4.

[0322] Step D: Preparation of Compound 3

[0323] Compound 3C (70 mg), methanesulfonic acid (0.1 mL), and dichloromethane (4 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 with 10% sodium hydroxide solution. The mixture was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 3 (34 mg).

[0324] HRMS(ESI, [M+H]) + )m / z:502.2343.

[0325] 1H NMR(500MHz,DMSO-d6)δ10.26(s,1H),8.17(d,J=8.3Hz,1H),7.99-7.91(m,3H),7.88(d,J=8 .4Hz,1H),7.70(d,J=8.5Hz,2H),7.57(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.12(dd,J=7 .7,1.8Hz,1H),6.90(s,2H),6.45-6.30(m,2H),6.21(dd,J=16.9,2.0Hz,1H),5.70(dd,J=10 .0,2.0Hz,1H),2.42-2.36(m,2H),2.15-2.07(m,2H),2.05-1.95(m,1H),1.71-1.62(m,1H).

[0326] Example 4: Preparation of Compound 4

[0327]

[0328] Step A: Preparation of compound 4A

[0329] Under nitrogen protection in an ice-water bath, 3.24 g of 2-chloroacetyl chloride was added dropwise to a reaction solution of 3.60 g of 2-amino-4-bromophenol and 3.22 g of sodium carbonate in 60 mL of tetrahydrofuran. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 4A (3.60 g).

[0330] MS(ESI, [MH]) – m / z: 226.1; MS(ESI, [M+H]) + )m / z:228.0.

[0331] Step B: Preparation of compound 4B

[0332] Under nitrogen protection in an ice-water bath, a 1M borane solution (516 mg) in tetrahydrofuran was slowly added to a tetrahydrofuran solution (10 mL) of compound 4A (452 ​​mg). After the addition was complete, the mixture was stirred at 70 °C. Once the reaction was complete, the reaction was quenched with saturated sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 4B (380 mg).

[0333] MS(ESI, [M+H]) + )m / z:214.3.

[0334] Step C: Preparation of compound 4C

[0335] [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (123 mg), compound 4B (320 mg), pinacol diborate (508 mg), potassium carbonate (294 mg), and dioxane (5 mL) were added sequentially to the reaction flask. The reaction was carried out at 100 °C. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 4C (242 mg).

[0336] MS(ESI, [M+H]) + )m / z:262.4.

[0337] Step D: Preparation of compound 4D

[0338] Compound 4C (200 mg), potassium carbonate (270 mg), tetratetraphenylphosphine palladium (47 mg), compound 1C (320 mg), water (0.5 mL), and dioxane (5 mL) were added sequentially to a reaction flask. After the additions were complete, the reaction mixture was reacted at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 98 / 2) to give compound 4D (260 mg).

[0339] Step E: Preparation of Compound 4

[0340] Compound 4D (260 mg), methanesulfonic acid (0.5 mL), and dichloromethane (5 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the pH of the reaction solution was adjusted to 7-9 with saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 95 / 5) to give compound 4 (135 mg).

[0341] HRMS(ESI, [M+H]) + )m / z:490.2360.

[0342] 1H NMR (500MHz, DMSO-d6): δ8.16(d,J=5.0Hz,1H),7.99(dd,J=5.0Hz,10.0Hz,1H),7.75(d,J=10.0 Hz,1H),7.61(d,J=10.0Hz,1H),7.41(d,J=10.0Hz,1H),7.23(d,J=5.0Hz,1H),7.16-7.14(m,2H ),6.94(s,2H),6.71(d,J=5.0Hz,1H),6.39(q,J=5.0Hz,1H),5.88(s,1H),4.14(t,J=5.0Hz,2H) ,3.30(d,J=10.0Hz,2H),2.46-2.14(m,2H),2.13(br,2H),2.12-2.03(m,3H),1.78-1.72(m,1H).

[0343] Example 5: Preparation of Compound 5

[0344]

[0345] Step A: Preparation of compound 5A

[0346] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (279 mg), tris(dibenzylacetone)dipalladium (274 mg), 1,3-dibromobenzene (705 mg), 4,4-dimethyl-1,4-silzapiperidine (386 mg), sodium tert-butoxide (431 mg), and toluene (10 mL) were added sequentially to the reaction flask. After the additions were complete, the reaction mixture was reacted at 115 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give compound 5A (475 mg). This unpurified compound was used directly in the next reaction step.

[0347] Step B: Preparation of compound 5B

[0348] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (63.9 mg), compound 5A (475 mg), pinacol diboronate (795 mg), potassium acetate (461 mg), and dioxane (8 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction mixture was reacted at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 5B (450 mg).

[0349] MS(ESI, [M+H]) + )m / z:332.5.

[0350] Step C: Preparation of compound 5C

[0351] Under nitrogen protection, compound 5B (311 mg), potassium carbonate (287 mg), compound 1C (340 mg), water (1 mL), and dioxane (10 mL) were added sequentially to a reaction flask. After the additions were complete, the reaction mixture was reacted at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 96 / 4) to give compound 5C (280 mg).

[0352] MS(ESI, [M+H]) + )m / z:660.7.

[0353] Step D: Preparation of Compound 5

[0354] In a reaction flask, methanesulfonic acid (200 mg) was slowly added to a solution of compound 5C (280 mg) in dichloromethane (5 mL). The reaction was allowed to proceed at room temperature until complete. After the reaction was complete, the pH of the reaction solution was adjusted to 7-9 with a saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 95 / 5) to give compound 5 (120 mg).

[0355] MS(ESI, [M+H]) + )m / z:560.6.

[0356] 1 H NMR (500MHz, DMSO-d6): δ8.16(d,J=10.0Hz,1H),7.96-7.95(m,1H),7.85(d,J=5.0Hz,1H),7. 54(d,J=10.0Hz,1H),7.47(s,1H),7.38(d,J=5.0Hz,1H),7.21-7.17(m,3H),6.97(br,2H),6. 82(q,J=5.0Hz,1H),6.37(q,J=5.0Hz,1H),3.63-3.61(m,4H),2.38-2.32(m,2H),2.17(br,2H ),2.09-2.03(m,2H),2.00-1.93(m,1H),1.64-1.61(m,1H),0.67-0.65(m,4H),0.001(s,6H).

[0357] Example 6: Preparation of Compound 6

[0358]

[0359] Step A: Preparation of compound 6A

[0360] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.475 g), tris(dibenzylacetone)dipalladium (0.466 g), 1,3-dibromobenzene (1.200 g), 7-oxa-2-azaspiro[3.5]nonane (0.647 g), sodium tert-butoxide (0.733 g), and toluene (10 mL) were added sequentially to the reaction flask. After the addition was complete, the reaction was carried out at 115 °C. After the reaction was complete, the reaction solution was concentrated and column chromatography (petroleum ether / ethyl acetate = 85 / 15) was performed to give compound 6A (780 mg).

[0361] Step B: Preparation of compound 6B

[0362] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (339 mg), compound 6A (780 mg), pinacol diboronate (1404 mg), potassium acetate (814 mg), and dioxane (8 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction mixture was reacted at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 6B (520 mg).

[0363] MS(ESI, [M+H]) + )m / z:330.5.

[0364] Step C: Preparation of compound 6C

[0365] Under nitrogen protection, compound 6B (520 mg), potassium carbonate (220 mg), tetraphenylphosphine (36 mg), compound 1C (260 mg), water (0.50 mL), and dioxane (10 mL) were added sequentially to a reaction flask. After the additions were complete, the reaction mixture was reacted at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 98 / 2) to give compound 6C (240 mg).

[0366] MS(ESI, [M+H]) + )m / z:658.7.

[0367] Step D: Preparation of Compound 6

[0368] Methanesulfonic acid (331 mg), compound 6C (240 mg), and dichloromethane (5 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the pH of the reaction solution was adjusted to 7-9 with saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 95 / 5) to give compound 6 (140 mg).

[0369] MS(ESI, [M+H]) + )m / z:558.6.

[0370] 1 H NMR (500MHz, DMSO-d6): δ8.45(d,J=5.0Hz,1H),8.22(t,J=5.0Hz,2H),8.11-8.10(m,1H),8 .08(d,J=10.0Hz,1H),8.01(dd,J=5.0Hz,10.0Hz,1H),7.82-7.78(m,2H),7.72-7.70(m,2H ),7.65(t,J=10.0Hz,1H),7.55(dd,J=5.0Hz,10.0Hz,1H),6.98(t,J=10.0Hz,1H),4.34(s, 4H), 3.59-3.57 (m, 4H), 2.66 (t, J = 5.0Hz, 4H), 2.55 (t, J = 5.0Hz, 4H), 1.97 (t, J = 5.0Hz, 4H).

[0371] Example 7: Preparation of Compound 7

[0372]

[0373] Step A: Preparation of compound 7A

[0374] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (367 mg), bis(dibenzylacetone)palladium (270 mg), 1,3-dibromobenzene (695 mg), (R)-3-(methylamine)pyrrole-1-carboxylic acid tert-butyl ester (590 mg), sodium tert-butoxide (566 mg), and dioxane (15 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction mixture was reacted at 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give compound 7A (642 mg).

[0375] MS(ESI, [M-55+H]) + )m / z:299.1.

[0376] Step B: Preparation of compound 7B

[0377] Under nitrogen protection, compound 7A (640 mg), dichloromethane (5 mL), and a 4M dioxane solution (3 mL) of hydrogen chloride were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature until the reaction was complete. The solvent was removed by vacuum distillation to obtain compound 7B (680 mg).

[0378] Step C: Preparation of compound 7C

[0379] Compound 7B (680 mg), tetrahydrofuran (20 mL), N,N-diisopropylethylamine (581 mg), and acetyl chloride (300 mg) were added to the reaction flask. After the additions were complete, the reaction mixture was allowed to react at room temperature. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 7C (430 mg).

[0380] MS(ESI, [M+H]) + )m / z:297.4.

[0381] Step D: Preparation of compound 7D

[0382] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (154 mg), compound 7C (360 mg), pinacol diboronate (478 mg), potassium acetate (370 mg), and dioxane (8 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction was carried out at 110 °C. The reaction was quenched with saturated brine, and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give compound 7D (440 mg).

[0383] MS(ESI, [M+H]) + )m / z:345.6.

[0384] Step E: Preparation of compound 7E

[0385] To a reaction flask, add tetratetraphenylphosphine palladium (99 mg), compound 1C (420 mg), compound 7D (294 mg), potassium carbonate (236 mg), dioxane (5 mL), and water (0.5 mL) sequentially. After the additions are complete, heat the mixture at 120 °C. Once the reactants have reacted completely, concentrate the reaction solution and perform column chromatography (dichloromethane / methanol = 98:2) to give compound 7E (540 mg).

[0386] MS(ESI, [M+H]) + )m / z:673.7.

[0387] Step F: Preparation of Compound 7

[0388] Compound 7E (4901 mg), dichloromethane (6 mL), and methanesulfonic acid (420 mg) were added sequentially to the reaction flask. After addition, the reaction was allowed to proceed at room temperature. Once the reaction was complete, the pH of the reaction solution was adjusted to neutral using sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 96 / 4) to give compound 7 (30 mg).

[0389] MS(ESI, [M+H])+ )m / z:573.4.

[0390] 1 H NMR (500MHz, DMSO-d6): δ8.23(d,J=3.5Hz,1H),8.01-7.96(m,2H),7.62-7.60(m,2H),7.55 (d,J=9.0Hz,1H),7.45(d,J=6.5Hz,1H),7.29-7.22(m,1H),7.01(d,J=7.5Hz,1H),6.92(d,J =7.5Hz,1H),6.42(t,J=6.5Hz,1H),4.58-4.47(m,1H),3.69-3.40(m,3H),3.28-3.25(m,2H ),2.83-2.80(m,3H),2.50(s,3H),2.15-2.08(m,3H),2.06-2.00(m,2H),1.96-1.85(m,3H).

[0391] Example 8: Preparation of Compound 8

[0392]

[0393] Step A: Preparation of compound 8A

[0394] Under nitrogen protection, a solution of 1,2-dichloroethane (25 mL) containing 20.890 g of N,N-diethyl-1,1,1-trifluoro-14-thiamine was slowly added dropwise to a reaction flask containing 4.000 g of tert-butyl 3-oxopyrrolidine-1-carboxylate. After the addition was complete, the reaction mixture was stirred at room temperature. Once the reaction was complete, the reaction mixture was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 8A (2.510 g).

[0395] MS(ESI, [M+H]) + )m / z:208.0.

[0396] Step B: Preparation of compound 8B

[0397] In a reaction flask, compound 8A (1.000 g), a 1,4-dioxane solution (2 mL), and a 1,4-dioxane solution in 4M hydrochloric acid (9.50 mL) were added sequentially. After the additions were complete, the mixture was stirred at room temperature. Once the reaction was complete, the reaction solution was concentrated to give compound 8B (0.512 g).

[0398] Step C: Preparation of compound 8C

[0399] Under nitrogen protection, sodium tert-butoxide (0.928 g), tris(dibenzylacetone)dipalladium (0.442 g), 3,3-difluoropyrrolidine (0.517 g), 1,3-dibromobenzene (2.279 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.451 g), and toluene (30 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give compound 8C (1.199 g).

[0400] Step D: Preparation of compound 8D

[0401] Under nitrogen protection, compound 8C (1.150 g), potassium carbonate (1.227 g), pinacol diborate (1.587 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.170 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.451 g), and N,N-dimethylformamide (30 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was concentrated, and column chromatography (petroleum ether / ethyl acetate = 90 / 10) was performed to give compound 8D (0.779 g).

[0402] MS(ESI, [M+H]) + )m / z:310.2.

[0403] Step E: Preparation of compound 8E

[0404] Under nitrogen protection, compound 8D (0.307 g), potassium carbonate (0.115 g), compound 1C (0.210 g), tetrakis(triphenylphosphine)palladium (0.048 g), 1,4-dioxane (16.00 mL), and water (4.00 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 140 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 98 / 3) to give compound 8E (0.140 g).

[0405] MS(ESI, [M+H]) + )m / z:638.4.

[0406] Step F: Preparation of Compound 8

[0407] Compound 8E (0.140 g), dichloromethane (10 mL), and methanesulfonic acid (0.160 g) were added sequentially to a reaction flask. The mixture was stirred at room temperature after the additions were complete. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 93 / 7) to give compound 8 (98 mg).

[0408] MS(ESI, [M+H]) + )m / z:538.6.

[0409] 1 H NMR (500MHz, DMSO-d6) δ8.24(d,J=8.4Hz,1H),8.00(t,J=7.6Hz,2H),7.64(d,J=8.0Hz,2H),7.46(d ,J=8.0Hz,2H),7.40(d,J=7.7Hz,1H),7.27(dq,J=13.3,7.8Hz,3H),7.02(s,2H),6.66(d,J=8.1Hz,1 H), 6.43 (dd, J = 7.7, 4.7Hz, 1H), 3.74 (t, J = 13.3Hz, 2H), 3.53 (t, J = 7.2Hz, 2H), 2.55 (dd, J = 1.6, 10. 3Hz,2H),2.44(t,J=8.6Hz,2H),2.24–2.10(m,2H),2.11-2.00(m,1H),1.72(dd,J=11.4,6.5Hz,1H).

[0410] Example 9: Preparation of Compound 9

[0411]

[0412] Step A: Preparation of compound 9A

[0413] Under nitrogen protection, hexahydropyrrolo[1,2-A]pyrazin-6-one hydrochloride (0.230 g), 1,3-dibromobenzene (0.774 g), tris(dibenzylacetone)dipalladium (0.150 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.153 g), sodium tert-butoxide (0.552 g), and toluene (7.5 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 6) to give compound 9A (0.100 g).

[0414] MS(ESI, [M+H]) + )m / z:295.4296.3.

[0415] Step B: Preparation of compound 9B

[0416] Under nitrogen protection, potassium carbonate (0.249 g), pinacol diborate (0.332 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.027 g), compound 9A (0.260 g), and N,N-dimethylformamide (20.00 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 70 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 9B (0.112 g).

[0417] MS(ESI, [M+H]) + )m / z:343.5.

[0418] Step C: Preparation of compound 9C

[0419] Under nitrogen protection, compound 9B (0.268 g), compound 1C (0.145 g), potassium carbonate (0.079 g), tetraphenylphosphine palladium (0.033 g), 1,4-dioxane (4 mL), and water (7.5 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 93 / 7) to give compound 9C (0.130 g).

[0420] MS(ESI, [M+H]) + )m / z:671.7.

[0421] Step D: Preparation of Compound 9

[0422] Compound 9C (0.130 g), dichloromethane (10 mL), and methanesulfonic acid (0.149 g) were added sequentially to the reaction flask. The mixture was stirred at room temperature after the addition was complete. The reaction mixture was concentrated and subjected to column chromatography (dichloromethane / methanol = 93 / 7) to give compound 9 (0.047 g).

[0423] MS(ESI, [M+H]) + )m / z:571.5.

[0424] 1H NMR(500MHz,DMSO-d6)δ8.25(d,J=8.4Hz,1H),8.09-7.95(m,2H),7.74-7.60(m,3H),7.53-7.41(m,3H),7.31(t,J=7.9Hz,1H),7.24(dd, J=7.6,1.9Hz,1H),7.14-7.02(m,1H),6.98(s,2H),6.43(dd,J=7.7,4.8Hz,1H),4.55(s,2H),3.95-3.85(m,2H),3.81-3.73(m,1H),3.69( dtd,J=10.8,7.1,3.7Hz,1H),2.93(td,J=12.6,3.8Hz,1H),2.61(td,J=12.2,3.6Hz,1H),2.49-2.42(m,2H),2.35-2.21(m,4H),2.16(td d,J=13.9,7.7,3.8Hz,1H),2.09(ddd,J=11.1,5.2,2.4Hz,1H),1.75(dtt,J=11.0,9.0,6.2Hz,1H),1.69-1.59(m,1H),0.90-0.80(m,1H).

[0425] Example 10: Preparation of Compound 10

[0426]

[0427] Step A: Preparation of Compound 10A

[0428] Under nitrogen protection, 1,3-dibromobenzene (2.356 g), 3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.000 g), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.280 g), tris(dibenzylacetone)dipalladium (0.320 g), sodium tert-butoxide (1.440 g), and toluene (30 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 70 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 10A (0.927 g).

[0429] MS(ESI, [M+H]) + )m / z:355.3.

[0430] Step B: Preparation of compound 10B

[0431] At room temperature, compound 10A (0.494 g), trifluoroacetic acid (6.440 g), 3-oxetane (0.150 g), sodium cyanoborohydride (0.175 g), dichloromethane (2 mL), and methanol (2 mL) were added sequentially to a reaction flask. The mixture was stirred after each addition. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 9:1) to give compound 10B (0.300 g).

[0432] Step C: Preparation of compound 10C

[0433] Under nitrogen protection, compound 10B (0.300 g), potassium carbonate (0.275 g), pinacol diborate (0.356 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.035 g), and N,N-dimethylformamide (34.00 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 70 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 10C (0.403 g).

[0434] MS(ESI, [M+H]) + )m / z:359.5.

[0435] Step D: Preparation of compound 10D

[0436] Under nitrogen protection, compound 10C (0.394 g), tert-butyl(1-(4-((((6-chloro-3-nitropyridin-2-yl)amino)phenyl)cyclobutyl)carbamate (0.522 g), tetrakis(triphenylphosphine)palladium (0.059 g), saturated sodium bicarbonate solution (2.50 mL), ethanol (20 mL), and toluene (20 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 10D (0.579 g).

[0437] MS(ESI, [M+H]) + )m / z:615.6.

[0438] Step E: Preparation of compound 10E

[0439] Under hydrogen protection, compound 10D (0.579 g), palladium / carbon (0.022 g), and tetrahydrofuran (15 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 30 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 10E (0.401 g).

[0440] MS(ESI, [M+H]) + )m / z:585.6.

[0441] Step F: Preparation of compound 10F

[0442] Under nitrogen protection, compound 10E (0.100 g), 2-aminonicotinic acid (0.021 g), sodium perborate tetrahydrate (0.014 g), methanol (5 mL), and acetic acid (2 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 50 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 96 / 4) to give compound 10F (0.078 g).

[0443] MS(ESI, [M+H]) + )m / z:687.5.

[0444] Step G: Preparation of Compound 10

[0445] At room temperature, compound 10F (0.050 g), methanesulfonic acid (0.035 g), and dichloromethane (5 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 99 / 1) to give compound 10 (33 mg).

[0446] MS(ESI, [M+H]) + )m / z:587.5.

[0447] 1 H NMR(500MHz, CDCl3)δ8.07(dd,J=32.5,6.3Hz,2H),7.76(d,J=8.5Hz,1H),7.64–7.47(m,4H),7.38–7.28(m,2H),7. 20(d,J=7.8Hz,1H),6.96(d,J=8.3Hz,2H),6.63(s,2H),6.41(t,J=6.5Hz,1H),4.70(dd,J=15.0,7.8Hz,2H),4.62(d ,J=6.7Hz,1H),3.86(s,2H),3.60-3.41(m,2H),3.28(d,J=11.6Hz,1H),3.18(t,J=10.8Hz,1H),2.63(dt,J=18.5,8. 5Hz, 3H), 2.43 (s, 2H), 2.30 (d, J = 10.9Hz, 3H), 2.15 (p, J = 9.1, 8.7Hz, 1H), 1.88–1.78 (m, 1H), 1.11 (d, J = 6.4Hz, 4H).

[0448] Example 11: Preparation of Compound 11

[0449]

[0450] Step A: Preparation of compound 11A

[0451] Under nitrogen protection, 1,3-dibromobenzene (4.240 g), 1-(oxecyclobut-3-yl)piperazine (1.278 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.420 g), sodium tert-butoxide (2.590 g), tris(dibenzylacetone)dipalladium (0.411 g), and toluene (22 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 70 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 11A (2.032 g).

[0452] MS(ESI, [M+K]) + )m / z:335.4.

[0453] Step B: Preparation of compound 11B

[0454] Under nitrogen protection, compound 11A (2.032 g), potassium tert-butoxide (2.010 g), pinacol diborate (2.600 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.223 g), and N,N-dimethylformamide (34 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 70 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 11B (2.016 g).

[0455] MS(ESI, [M+H]) + )m / z:345.4.

[0456] Step C: Preparation of compound 11C

[0457] Under nitrogen protection, tert-butyl(1-(4-(((6-chloro-3-nitropyridin-2-yl)amino)phenyl)cyclobutyl)carbamate (0.568 g), compound 11B (0.576 g), tetrakis(triphenylphosphine)palladium (0.078 g), ethanol (15 mL), saturated sodium bicarbonate (3 mL), and toluene (15 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C. The reaction was completed, and the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 11C (0.732 g).

[0458] MS(ESI, [M+H]) + )m / z:601.3.

[0459] Step D: Preparation of compound 11D

[0460] Under hydrogen protection, compound 11C (0.037 g) and palladium / carbon (0.001 g) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 30 °C. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 11D (0.013 g).

[0461] MS(ESI, [M+H]) + )m / z:571.5.

[0462] Step E: Preparation of compound 11E

[0463] Under nitrogen protection, compound 11D (0.100 g), 2-aminonicotinic acid (0.022 g), sodium perborate tetrahydrate (0.014 g), methanol (5 mL), and acetic acid (2 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 50 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 99:1) to give compound 11E (50 mg).

[0464] MS(ESI, [M+H]) + )m / z:673.6.

[0465] Step F: Preparation of Compound 11

[0466] At room temperature, compound 11E (50 mg), methanesulfonic acid (35 mg), and dichloromethane (3 mL) were added sequentially to a reaction flask, and the mixture was stirred. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 99 / 1) to give compound 11 (28 mg).

[0467] MS(ESI, [M+H]) + )m / z:573.5.

[0468] 1H NMR (500MHz, CDCl3) δ8.11(d,J=8.3Hz,1H),8.07(tt,J=5.9,3.2Hz,1H),7.77(d,J=8.3Hz,1H),7.61(t,J=2.0Hz,1 H),7.59-7.54(m,2H),7.54-7.46(m,2H),7.45-7.41(m,2H),7.34(t,J=7.8Hz,2H),7.20-7.13(m,1H),6.96(dd,J= 8.3, 2.5Hz, 1H), 6.63 (s, 2H), 6.45-6.36 (m, 1H), 4.69 (dt, J = 19.8, 6.4Hz, 4H), 3.57 (p, J = 6.5Hz, 1H), 3.29 (t, J = 5. 0Hz, 4H), 2.62 (ddd, J=11.9, 8.9, 6.2Hz, 2H), 2.52 (t, J=4.9Hz, 4H), 2.25 (q, J=10.5, 9.1Hz, 2H), 2.18-2.00 (m, 2H).

[0469] Example 12: Preparation of Compound 12

[0470]

[0471] Step A: Preparation of Compound 12A

[0472] Under nitrogen protection, 7-oxa-2-azaspiro[3.5]nonane (0.809 g), 1,4-dibromobenzene (1.500 g), tris(dibenzylacetone)dipalladium (0.582 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.594 g), sodium tert-butoxide (0.917 g), and toluene (20 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 17 / 3) to give compound 12A (1.257 g).

[0473] 1 H NMR (500MHz, DMSO-d6) δ7.27-7.29(m,2H), 6.35-6.37(m,2H), 3.56(s,4H,), 3.53(t,J=5.2Hz,4H), 1.71(t,J=5.2Hz,4H).

[0474] Step B: Preparation of compound 12B

[0475] Under nitrogen protection, potassium acetate (1.263 g), pinacol diborate (2.178 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.525 g), compound 12A (0.452 g), and dioxane (15 mL) were added sequentially to the reaction flask. After the additions were complete, the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 12B (1.500 g).

[0476] MS(ESI, [M+H]) + )m / z:330.5.

[0477] Step C: Preparation of compound 12C

[0478] Under nitrogen protection, compound 12B (0.419 g), compound 1C (0.500 g), potassium carbonate (0.422 g), tetraphenylphosphine palladium (0.058 g), 1,4-dioxane (10 mL), and water (5 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 98:2) to give compound 12C (0.114 g).

[0479] MS(ESI, [M+H]) + )m / z:658.7.

[0480] Step D: Preparation of Compound 12

[0481] Compound 12C (0.114 g), dichloromethane (10 mL), and methanesulfonic acid (0.081 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, a 20% sodium hydroxide aqueous solution was added with stirring in an ice bath to adjust the pH of the solution to 12. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 90:10) to give compound 12 (28 mg).

[0482] MS(ESI, [M+H]) + )m / z:558.6.

[0483] 1H NMR(500MHz,DMSO-d6)δ7.96-7.98(m,2H),7.83-7.85(m,2H),7.61 -7.62(m,1H),7.47-7.48(m,2H),7.33-7.35(m,2H),7.02-7.04(m,1H),6.49(s,2H),6.40-6.42(m,2H),6.30-6.32(m,1H),3 .61(s,4H),3.59(t,J=5.2Hz,4H),3.59(q,J=9.25Hz,2H),2.18(q,J=10.5Hz,2H),2.03-2.11(m,2H),1.76(t,J=5.2Hz,4H).

[0484] Example 13: Preparation of Compound 13

[0485]

[0486] Step A: Preparation of compound 13A

[0487] 2-oxa-6-azaspiro[3,3]heptane (1.00 g), m-dibromobenzene (2.49 g), (tris(dibenzylacetone)dipalladium (0.24 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.16 g), tetrahydrofuran (50 mL), and sodium tert-butoxide (2.03 g) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 80 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 13A (1.24 g).

[0488] MS(ESI, [M+H]) + )m / z:254.3.

[0489] 1 H NMR (500MHz, DMSO-d6): δ7.09(t,J=8.0Hz,1H),6.81(dd,J=1.0,8.0Hz,1H),6.56(t,J=2.0Hz,1H),6.40(dd,J=2.0,8.0Hz,1H),4.70(s,4H),3.97(m,4H).

[0490] Step B: Preparation of compound 13B

[0491] To a reaction flask containing compound 13A (1.13 g), pinacol diboronate (1.69 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.18 g), 1,4-dioxane (50 mL), and potassium acetate (1.30 g) were added sequentially. After the addition was complete, the mixture was stirred at 120 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 13B (1.22 g).

[0492] MS(ESI, [M+H]) + )m / z:302.2.

[0493] 1 H NMR (500MHz, DMSO-d6): δ7.18(t,J=7.5Hz,1H),7.01(d,J=7.0Hz,1H),6.69(d,J =2.5Hz,1H),6.55(d,J=2.0,8.0Hz,1H),4.70(s,4H),3.95(s,4H),1.28(s,12H).

[0494] 13 C NMR (125MHz, DMSO-d6): δ151.34, 128.76, 123.98, 117.41, 115.17, 83.97, 80.38, 61.48, 38.96, 25.12.

[0495] Step C: Preparation of compound 13C

[0496] To a reaction flask containing compound 1C (0.495 g), dichloromethane (20 mL) and methanesulfonic acid (1.480 g) were added sequentially. After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into water, and the pH was adjusted to 9 with a sodium hydroxide aqueous solution (20% w / w). The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13C (0.393 g).

[0497] MS(ESI, [M+H]) + )m / z:391.2.

[0498] Step D: Preparation of Compound 13

[0499] Compound 13B (0.20 g), compound 13C (0.30 g), potassium carbonate (0.28 g), tetra(triphenylphosphine)palladium (0.16 g), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 120 °C for 2 h. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 13 (135 mg).

[0500] MS(ESI, [M+H]) + )m / z:530.7.

[0501] 1 H NMR (500MHz, DMSO-d6): δ8.09(d,J=8.0Hz,1H),7.96(d,J=4.5Hz,1H),7.73(d,J=8.0Hz,1H),7 .55(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),7.36(d,J=7.5Hz,1H),7.34(t,J=8.0Hz,1H),7.12( d,J=7.5Hz,1H),7.01(s,1H),6.46-6.44(m,1H),6.39-6.36(m,1H),4.81(s,4H),4.02(s,4H), 3.43-3.33(m,4H),2.66-2.60(m,2H),2.41-2.36(m,2H),2.22-2.13(m,1H),1.88-1.80(m,1H).

[0502] Example 14: Preparation of Compound 14

[0503]

[0504] Step A: Preparation of Compound 14A

[0505] 0.10 g of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 0.45 g of m-dibromobenzene, 32 mg of tris(dibenzylacetone)dipalladium, 21 mg of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), 20 mL of tetrahydrofuran, and 0.20 g of sodium tert-butoxide were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 80 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 14A (108 mg).

[0506] 1H NMR (500MHz, DMSO-d6): δ7.09(t,J=8.0Hz,1H),6.81(dd,J=1.0,8.0Hz,1H),6.55(t ,J=2.0Hz,1H),6.39(dd,J=2.0,8.0Hz,1H),4.01(s,4H),3.93(s,4H),1.38(s,9H).

[0507] Step B: Preparation of compound 14B

[0508] To a reaction flask containing compound 14A (152 mg), pinacol diboronate (164 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (50 mg), 1,4-dioxane (5 mL), and potassium acetate (127 mg) were added sequentially. After the addition was complete, the mixture was stirred at 120 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 14B (53 mg).

[0509] MS(ESI, [M+H]) + )m / z:401.5.

[0510] Step C: Preparation of compound 14C

[0511] Compound 14B (50 mg), compound 1C (67 mg), potassium carbonate (70 mg), tetra(triphenylphosphine)palladium (40 mg), 1,4-dioxane (4 mL), and water (0.5 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 120 °C for 2 hours. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 10 / 1) yielded compound 14C (80 mg).

[0512] MS(ESI, [M+H]) + )m / z:729.7.

[0513] 1H NMR (500MHz, DMSO-d6): δ8.23(d,J=8.5Hz,1H),8.00(dd,J=1.5,5.0Hz,1H),7.92(d ,J=8.5Hz,1H),7.69-7.54(m,3H),7.46-7.34(m,3H),7.24-7.17(m,2H),7.10-7.07 (m,3H),6.46(dd,J=1.5,7.5Hz,1H),6.33(dd,J=5.0,7.5Hz,1H),4.03(s,4H),3.95 (s,4H),2.46-2.41(m,4H),2.02(brs,1H),1.83(brs,1H),1.39(s,9H),1.36(s,9H).

[0514] Step D: Preparation of Compound 14

[0515] Compound 14C (69 mg), methanesulfonic acid (0.1 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 14 (25 mg).

[0516] HRMS(ESI, [M+H]) + )m / z:529.2814.

[0517] 1 H NMR (500MHz, DMSO-d6): δ8.23(d,J=8.0Hz,1H),8.01(dd,J=2.0,5.0Hz,1H),7.91(d,J=8.5 Hz,1H),7.64(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),7.34(d,J=8.0Hz,1H),7.25-7.21(m,2 H),7.06-7.02(m,3H),6.46-6.44(m,1H),6.43-6.41(m,1H),3.90(s,4H),3.64(s,4H),3.4 3-3.33(m,3H),2.46-2.41(m,2H),2.16-2.11(m,2H),2.07-2.01(m,1H),1.76-1.67(m,1H).

[0518] Example 15: Preparation of Compound 15

[0519]

[0520] Step A: Preparation of Compound 15A

[0521] Under nitrogen protection, (5S,7S)-2-aminoadamantane-1-ol (1.17 g), 1,3-dibromobenzene (1.65 g), tris(dibenzylacetone)dipalladium (0.64 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.65 g), sodium tert-butoxide (1.00 g), and toluene (10 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 15A (1.15 g).

[0522] MS(ESI, [M+H]) + )m / z:322.2.

[0523] Step B: Preparation of compound 15B

[0524] Under nitrogen protection, potassium acetate (0.795 g), pinacol diborate (1.372 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.331 g), compound 15A (1.154 g), and dioxane (30 mL) were added sequentially to the reaction flask. After the additions were complete, the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was concentrated, and column chromatography (petroleum ether / ethyl acetate = 4 / 1) was performed to give compound 15B (0.750 g).

[0525] MS(ESI, [M+H]) + )m / z:370.6.

[0526] Step C: Preparation of compound 15C

[0527] Under nitrogen protection, compound 15B (0.750 g), compound 1C (0.612 g), potassium carbonate (0.495 g), tetrakis(triphenylphosphine)palladium (0.069 g), 1,4-dioxane (20 mL), and water (10 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 3 / 2) to give compound 15C (1.215 g).

[0528] MS(ESI, [M+H]) + )m / z:698.8.

[0529] Step D: Preparation of Compound 15

[0530] Compound 15C (1.215 g), dichloromethane (20 mL), and methanesulfonic acid (0.694 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, a 20% sodium hydroxide aqueous solution was added with stirring in an ice bath to adjust the pH of the solution to 12. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 4 / 1) to give compound 15 (0.388 g).

[0531] MS(ESI, [M+H]) + )m / z:598.7.

[0532] 1 H NMR(500MHz,DMSO-d6)δ8.21(d,1H),7.99-8.00(m,1H),7.83(d,1H),7.62(d,2H),7.43(d,2H),7.28(s,1H),7.19-7.20(m,1H),7.12-7.1 3(m,2H),6.96(s,2H),6.69(d,1H),6.39-6.42(s,1H),5.61(d,1H),2 .41-2.46(m,3H),1.93-2.16(m,9H),1.63-1.77(m,7H),1.30(d,2H).

[0533] Example 16: Preparation of Compound 16

[0534]

[0535] Step A: Preparation of Compound 16A

[0536] Weigh 1.00 g of compound 14A into a reaction flask, add 100 mL of dichloromethane and stir to dissolve. Then add 0.82 g of methanesulfonic acid and stir at room temperature until the reaction is complete. After the reaction is complete, add 2.5 mL of triethylamine to terminate the reaction. Add dichloromethane to adjust the reaction volume to 120 mL to obtain a solution of compound 16A. Do not concentrate the solution; directly add it to the next reaction step.

[0537] Step B: Preparation of compound 16B

[0538] Take 35 mL of a solution of compound 16A, add 169 mg of acetic anhydride, and stir the mixture at room temperature until the reaction is complete. After the reaction is complete, concentrate the reaction solution and perform column chromatography (dichloromethane / methanol = 96 / 4) to give compound 16B (219 mg).

[0539] MS(ESI, [M+H]) + )m / z:295.1.

[0540] 1 H NMR (500MHz, CDCl3): δ7.06 (t, J=8.0Hz, 1H), 6.90-6.88 (m, 1H), 6.57 (d, J=4.0 Hz,1H),6.37-6.34(m,1H),4.29(s,2H),4.16(s,2H),3.99(s,4H),1.88(s,3H).

[0541] Step C: Preparation of compound 16C

[0542] To a reaction flask containing compound 16B (210 mg), pinacol diboron ester (271 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (29 mg), 1,4-dioxane (20 mL), and potassium acetate (209 mg) were added sequentially. After the addition was complete, the mixture was stirred at 120 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 98 / 2) to give compound 16C (185 mg).

[0543] MS(ESI, [M+H]) + )m / z:343.3.

[0544] Step D: Preparation of compound 16D

[0545] Compound 16C (140 mg), compound 1C (276 mg), potassium carbonate (239 mg), tetra(triphenylphosphine)palladium (75 mg), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 120 °C for 2 hours. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 96 / 4) yielded compound 16D (280 mg).

[0546] MS(ESI, [M+H]) + )m / z:671.7.

[0547] Step E: Preparation of Compound 16

[0548] Compound 16D (260 mg), methanesulfonic acid (0.25 mL), and dichloromethane (20 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 16 (125 mg).

[0549] MS(ESI, [M+H]) +)m / z:571.6.

[0550] 1 H NMR(500MHz, CDCl3):8.11-8.04(d,J=8.5Hz,1H),8.06-7.96(dd,J=1.0,4.5Hz,1H),7.76-7.67( d,J=8.5Hz,1H),7.65-7.48(d,J=8.5Hz,2H),7.43-7.35(m,3H),7.26-7.25(m,1H),7.15-6.98(m, 2H),6.61-6.57(m,2H),6.44-6.32(m,1H),6.39-6.25(m,1H),4.29-4.26(m,2H),4.20-4.16(m,2H ),4.05-3.92(m,4H),2.69-2.64(m,2H),2.58-2.52(m,2H),2.46-2.26(m,3H),1.90-1.86(m,4H).

[0551] Example 17: Preparation of Compound 17

[0552]

[0553] Step A: Preparation of compound 17A

[0554] Take 35 mL of a solution of compound 16A, add methanesulfonyl chloride (189 mg), and stir at room temperature after the addition is complete. After the reaction is complete, concentrate the reaction solution and perform column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 17A (227 mg).

[0555] MS(ESI, [M+H]) + )m / z:331.1.

[0556] 1 H NMR (500MHz, CDCl3): δ7.06 (t, J = 3.0 Hz, 1H), 6.90-6.88 (m, 1H), 6.57 (t, J = 2.0 Hz, 1H), 6.36-6.34 (m, 1H), 4.10 (s, 4H), 3.98 (s, 4H), 2.88 (s, 3H).

[0557] Step B: Preparation of compound 17B

[0558] To a reaction flask containing compound 17A (220 mg), pinacol diboronate (253 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (27 mg), 1,4-dioxane (20 mL), and potassium acetate (196 mg) were added sequentially. After the addition was complete, the mixture was stirred at 120 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 17B (157 mg).

[0559] MS(ESI, [M+H]) + )m / z:379.3.

[0560] Step C: Preparation of compound 17C

[0561] Compound 17B (132 mg), compound 1C (223 mg), potassium carbonate (193 mg), tetra(triphenylphosphine)palladium (81 mg), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was purged, and the mixture was microwaved at 120 °C for 2 h. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 98 / 2) to give compound 17C (146 mg).

[0562] MS(ESI, [M+H]) + )m / z:707.7.

[0563] Step D: Preparation of Compound 17

[0564] Compound 17C (150 mg), methanesulfonic acid (0.15 mL), and dichloromethane (15 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding a 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 95 / 5) to give compound 17 (47 mg).

[0565] HRMS(ESI, [M+H]) + )m / z:607.2606.

[0566] 1H NMR(500MHz, CDCl3):8.05-7.91(m,2H),7.69-7.60(m,1H),7.52-7.41(m,2H),7.37-7.26(m,3H),7.23-7.20(m,1H),7.09-6.93(m,2H) ,6.53,6.44(s,2H),6.42-6.18(m,2H),4.04,4.02(s,4H),3.96,3.85(s,4H),2.81,2.80(s,3H),2.58-2.36(m,3H),2.22-2.02(m,3H).

[0567] Example 18: Preparation of Compound 18

[0568]

[0569] Step A: Preparation of Compound 18A

[0570] Under nitrogen protection, hexahydro-1H-furan[3,4-c]pyrrole hydrochloride (0.824 g), 1,3-dibromobenzene (1.300 g), tris(dibenzylacetone)dipalladium (0.505 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.515 g), sodium tert-butoxide (0.794 g), and toluene (10 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 19 / 1) to give compound 18A (0.452 g).

[0571] MS(ESI, [M+H]) + )m / z:268.4.

[0572] Step B: Preparation of compound 18B

[0573] Under nitrogen protection, potassium acetate (0.496 g), pinacol diborate (0.809 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.206 g), compound 18A (0.452 g), and dioxane (20 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 19 / 1) to give compound 18B (0.490 g).

[0574] MS(ESI, [M+H]) + )m / z:316.5.

[0575] Step C: Preparation of compound 18C

[0576] Under nitrogen protection, compound 18B (0.210 g), compound 1C (0.327 g), potassium carbonate (0.276 g), tetraphenylphosphine palladium (0.038 g), 1,4-dioxane (15 mL), and water (7.5 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 1 / 1) to give compound 18C (0.400 g).

[0577] MS(ESI, [M+H]) + )m / z:644.8.

[0578] Step D: Preparation of Compound 18

[0579] Compound 18C (0.400 g), dichloromethane (10 ml), and methanesulfonic acid (0.149 g) were added sequentially to a reaction flask. The mixture was stirred at room temperature after the additions were complete. Once the reaction was complete, a 20% sodium hydroxide aqueous solution was added with stirring in an ice bath to adjust the pH to 12. The phases were separated; the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 7 / 3) to give compound 18 (0.285 g).

[0580] MS(ESI, [M+H]) + )m / z:544.7.

[0581] 1 H NMR(500MHz,DMSO-d6)δ8.43(d,1H),8.11-8.21(m,3H),8.00(d,1H),7.92(d,1H),7.80(d,2H),7.71(d,2H),7.48-7.58(m,2H ),6.98(t,1H),3.70-3.88(m,6H,),3.21(s,2H),2.65-2.68(m,4H),2.21-2.28(m,1H),1.82-1.90(m,1H),1.17-1.29(m,2H).

[0582] Example 19: Preparation of Compound 19

[0583]

[0584] Step A: Preparation of compound 19A

[0585] In a reaction flask under nitrogen protection at 0°C, a solution of 3.24 g of 2-chloroacetyl chloride in tetrahydrofuran (10 mL) was slowly added dropwise to a reaction solution of 3.60 g of 2-amino-4-bromophenol and 3.22 g of sodium carbonate in tetrahydrofuran (60 mL). After the addition was complete, the mixture was stirred at room temperature. Potassium carbonate (5.29 g) was added to the reaction solution, and the mixture was stirred at 66°C. The mixture was filtered, the filtrate was concentrated, and column chromatography (petroleum ether / ethyl acetate = 3 / 1) was performed to give compound 19A (3.4 g).

[0586] MS(ESI, [MH]) - )m / z:226.4.

[0587] Step B: Preparation of compound 19B

[0588] In a reaction flask under nitrogen protection at 0°C, 15 mL of a 2M borane solution in toluene-dimethyl sulfide was slowly added to a 10 mL solution of tetrahydrofuran containing 2.28 g of compound 19A. After the addition was complete, the mixture was stirred at room temperature and reacted at 66°C. The reaction was quenched with saturated sodium hydroxide solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 19B (2.10 g). The product of this step was used directly in the next reaction.

[0589] Step C: Preparation of compound 19C

[0590] In a reaction flask under nitrogen protection at 0°C, acetyl chloride (0.733 g) was slowly added to a tetrahydrofuran (12 mL) solution of compound 19B (2.000 g) and N,N-diisopropylethylamine (1.208 g). After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the reaction mixture was quenched with saturated sodium carbonate solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give compound 19C (2.200 g). The product of this step was used directly in the next reaction.

[0591] Step D: Preparation of compound 19D

[0592] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.702 g), compound 19C (2.200 g), pinacol diboronate (4.360 g), potassium acetate (1.686 g), and dioxane (8 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction was carried out at 110 °C. The reaction was completed, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give compound 19D (2.410 g).

[0593] MS(ESI, [M+H]) + )m / z:304.5.

[0594] Step E: Preparation of compound 19E

[0595] Under nitrogen protection, compound 19D (324 mg), compound 1C (350 mg), potassium carbonate (197 mg), tetraphenylphosphine palladium (82 mg), and dioxane (10 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction was carried out at 110 °C. The reaction was completed, the reaction solution was concentrated, and column chromatography (petroleum ether / ethyl acetate = 95 / 5) was performed to give compound 19E (320 mg).

[0596] MS(ESI, [M+H]) + )m / z:632.7.

[0597] Step F: Preparation of Compound 19

[0598] Compound 19E (320 mg), dichloromethane (10 mL), and methanesulfonic acid (48.7 mg) were added sequentially to a reaction flask, and the mixture was stirred at room temperature. The reaction proceeded completely. The reaction was quenched with saturated sodium carbonate aqueous solution (30 mL), extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 94 / 6) to give compound 19 (120 mg).

[0599] MS(ESI, [M+H]) + )m / z:532.7.

[0600] 1 H NMR (500MHz, DMSO-d6): δ8.22(d,J=8.0Hz,1H),8.00(s,1H),7.87(br,1H),7.63-7.62(m,2H),7.45-7.44(m,2H),7.21(d,J=7.5Hz,1H),7.00-7.69 (m,3H),6.41(t,J=5.0Hz,1H),4.29(s,2H),3.88(s,2H),2.50-2.43(m,2 H),2.24(s,3H),2.19-2.15(m.2H),2.06-2.04(m,1H),1.75-1.72(m,1H).

[0601] Example 20: Preparation of Compound 20

[0602]

[0603] Step A: Preparation of compound 20A

[0604] Under nitrogen protection, 1-bromo-3-iodobenzene (1.180 g), isothiazol-1,1-dioxane (0.720 g), cuprous iodide (0.159 g), potassium carbonate (1.153 g), (1S,2S)-N1,N2-dimethylcyclohexyl-1,2-diamine (0.119 g), and dimethyl sulfoxide (10 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction mixture was reacted at 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give compound 20A (640 mg).

[0605] MS(ESI, [M+H]) + )m / z:276.2.

[0606] Step B: Preparation of compound 20B

[0607] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (151 mg), compound 20A (640 mg), pinacol diborate (1177 mg), potassium acetate (455 mg), and dioxane (8 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction mixture was reacted at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give compound 20B (620 mg).

[0608] MS(ESI, [M+H]) + )m / z:324.5.

[0609] Step C: Preparation of compound 20C

[0610] Tetraphenylphosphine palladium (99 mg), compound 1C (420 mg), compound 20B (415 mg), potassium carbonate (236 mg), dioxane (5 mL), and water (0.5 mL) were added sequentially to a reaction flask, and the mixture was heated to 120 °C. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give compound 20C (380 mg).

[0611] MS(ESI, [M+H]) + )m / z:652.5.

[0612] Step D: Preparation of Compound 20

[0613] Compound 20C (150 mg), dichloromethane (6 mL), and methanesulfonic acid (133 mg) were added sequentially to the reaction flask. The reaction was allowed to proceed at room temperature until complete. The pH of the reaction solution was adjusted to neutral using a saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 97 / 3) to give compound 20 (27 mg).

[0614] MS(ESI, [M+H]) + )m / z:552.5.

[0615] 1 H NMR (500MHz, DMSO-d6): δ8.29 (d, J=8.0Hz, 1H), 8.01 (dd, J=3.0Hz, 6.0Hz, 1H), 7.97 (d, J=8. 5Hz,1H),7.88(s,1H),7.77(d,J=7.5Hz,1H),7.64(d,J=9.0Hz,1H),7.50-7.45(m,3H),7.28 -7.23(m,2H),6.96(br,2H),6.44(q,J=7.5Hz,1H),3.81(t,J=7.5Hz,2H),3.54(t,J=7.5Hz, 2H), 2.43 (t, J = 7.5Hz, 1H), 2.34 (s, 2H), 2.26-2.21 (m, 2H), 2.09 (m, 1H), 1.77-1.75 (m, 1H).

[0616] Example 21: Preparation of compound 21

[0617]

[0618] Step A: Preparation of compound 21A

[0619] Sodium tert-butoxide (0.179 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.040 g), tris(dibenzylacetone)dipalladium (0.039 g), 1,3-dibromobenzene (0.200 g), 1-(piperidin-4-yl)pyrrolidine-2-one hydrochloride (0.174 g), and toluene (10 mL) were added sequentially to a reaction flask. The mixture was stirred at 80 °C under nitrogen protection until complete. The reaction solution was concentrated, and 5 mL of saturated brine was added. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 60 / 1) yielded compound 21A (0.270 g).

[0620] MS(ESI, [M+H]) + )m / z:323.4.

[0621] Step B: Preparation of compound 21B

[0622] Compound 21A (0.270 g), potassium acetate (0.270 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.037 g), pinacol diborate (0.280 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C under nitrogen protection until complete. The reaction solution was concentrated, and saturated brine was added. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 60 / 1) to give compound 21B (0.300 g).

[0623] MS(ESI, [M+H]) + )m / z:371.6.

[0624] Step C: Preparation of compound 21C

[0625] Compound 1C (2.40 g), compound 21B (0.30 g), potassium carbonate (0.17 g), tetrakis(triphenylphosphine)palladium (0.057 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C under nitrogen protection until complete. The reaction solution was concentrated, and saturated brine was added. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 65 / 1) to give compound 21C (0.25 g).

[0626] MS(ESI, M+H) + )m / z:699.8.

[0627] Step D: Preparation of Compound 21

[0628] Compound 21C (0.25 g), dichloromethane (25 mL), and methanesulfonic acid (0.30 g) were added sequentially to a reaction flask. The reaction was stirred at 30 °C until complete. The solution was adjusted to alkaline, saturated brine was added, and the mixture was extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 21 (0.19 g).

[0629] HRMS(ESI, [M+H]) + )m / z:599.3237.

[0630] 1H NMR (500MHz, CDCl3) δ7.99(dd,J=11.1,8.5Hz,1H),7.90(t,J=4.6Hz,1H),7.64(t,J=8.2Hz,1H),7.57(d,J=8.2Hz, 2H),7.48(s,1H),7.47-7.22(m,4H),7.01(t,J=7.6Hz,1H),6.80(dd,J=28.6,9.7Hz,1H),6.55(d,J=15.2Hz,2H),6. 27(ddd,J=58.5,7.7,5.0Hz,1H),4.05(ddd,J=16.5,10.7,3.8Hz,1H),3.65(t,J=16.0Hz,2H),3.28(dt,J=14.1,6.9 Hz,2H),2.76(dt,J=24.5,12.3Hz,2H),2.62-2.46(m,4H),2.44-2.22(m,4H),1.99-1.86(m,3H),1.83-1.65(m,5H).

[0631] Example 22: Preparation of compound 22

[0632]

[0633] Step A: Preparation of compound 22A

[0634] Sodium tert-butoxide (0.180 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.040 g), tris(dibenzylacetone)dipalladium (0.039 g), 1,3-dibromobenzene (0.200 g), 4-methyl-4-oxo-1,4-azaphosphine (0.11 g), and toluene (10 mL) were added sequentially to a reaction flask. The reaction mixture was stirred at 80 °C under nitrogen protection until complete. The reaction solution was concentrated, and saturated brine was added. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 60 / 1) to give compound 22A (0.230 g).

[0635] MS(ESI, [M+H]) + )m / z:288.4.

[0636] Step B: Preparation of compound 22B

[0637] Compound 22A (0.23 g), potassium acetate (0.28 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (39 mg), pinacol diborate (0.29 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to a reaction flask. The reaction mixture was stirred at 100 °C under nitrogen protection until complete. The reaction solution was concentrated, and saturated brine was added. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 60 / 1) to give compound 22B (0.28 g).

[0638] MS(ESI, [M+H]) + )m / z:336.6.

[0639] Step C: Preparation of compound 22C

[0640] Compound 1C (2.30 g), compound 22B (0.28 g), potassium carbonate (0.16 g), tetrakis(triphenylphosphine)palladium (55 mg), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C under nitrogen protection until complete. The reaction solution was concentrated, and saturated brine was added. The mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 65 / 1) to give compound 22C (0.24 g).

[0641] MS(ESI, [M+H]) + )m / z:664.7.

[0642] Step D: Preparation of Compound 22

[0643] Compound 22C (0.24 g), dichloromethane (25 mL), and methanesulfonic acid (0.30 g) were added sequentially to a reaction flask. The reaction was stirred at 30 °C until complete. The solution was adjusted to alkaline, saturated brine was added, and the mixture was extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 22 (0.16 g).

[0644] HRMS(ESI, [M+H]) + )m / z:564.2634.

[0645] 1H NMR (500MHz, DMSO-d6) δ8.24(d,J=8.3Hz,1H),8.02(dd,J=4.7,1.6Hz,1H),7.97(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,2 H),7.61(s,1H),7.49(d,J=8.5Hz,2H),7.38(d,J=7.6Hz,1H),7.30(t,J=7.9Hz,1H),7.26(dd,J=7.6,1.6Hz,1H),7.06 -6.96(m,3H),6.43(dd,J=7.6,4.8Hz,1H),4.48(s,2H),4.03-3.85(m,2H),3.57-3.46(m,2H),2.49-2.43(m,2H),2.28 -2.20(m,2H),2.13-2.03(m,1H),1.88(t,J=13.6Hz,2H),1.75(ddt,J=20.2,14.2,6.4Hz,3H),1.53(d,J=13.0Hz,3H).

[0646] Example 23: Preparation of compound 23

[0647]

[0648] Step A: Preparation of compound 23A

[0649] In a reaction flask under nitrogen protection at 0°C, methanesulfonyl chloride (0.572 g) was added to a solution of (R)-3-(methylamine)pyrrole-1-carboxylic acid tert-butyl ester (1.000 g) and N,N-diisopropylethylamine (0.645 g) in dichloromethane (15 mL). After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated sodium carbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 23A (1.160 g).

[0650] Step B: Preparation of compound 23B

[0651] In a reaction flask, under ice-water bath conditions, 4 mL of a 4M dioxane solution of hydrogen chloride was slowly added to a 10 mL solution of compound 23A (590 mg) in dichloromethane. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the solvent was removed by direct vacuum distillation to obtain compound 23B, which was then used in the next reaction step.

[0652] Step C: Preparation of compound 23C

[0653] 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1320 mg), sodium tert-butoxide (204 mg), 1,3-dibromobenzene (500 mg), and dioxane (10 mL) were added sequentially to a reaction flask containing compound 23B. After the addition was complete, the mixture was stirred at 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give compound 23C (380 mg).

[0654] MS(ESI, [M+H]) + )m / z:333.3.

[0655] Step D: Preparation of compound 23D

[0656] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (93 mg), compound 23C (380 mg), pinacol diboronate (434 mg), potassium acetate (336 mg), and dioxane (8 mL) were added sequentially to a reaction flask. After the additions were complete, the reaction mixture was reacted at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give compound 23D (280 mg).

[0657] MS(ESI, [M+H]) + )m / z:381.3.

[0658] Step E: Preparation of compound 23E

[0659] To a reaction flask, tetrakis(triphenylphosphine)palladium (99 mg), compound 1C (420 mg), compound 23D (325 mg), potassium acetate (236 mg), dioxane (5 mL), and water (0.5 mL) were added sequentially. After the additions were complete, the mixture was stirred at 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give compound 23E (154 mg).

[0660] MS(ESI, [M+H]) + )m / z:709.8.

[0661] Step F: Preparation of compound 23

[0662] Compound 23E (100 mg), dichloromethane (6 mL), and methanesulfonic acid (600 mg) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the pH of the reaction solution was adjusted to neutral with sodium bicarbonate. The reaction solution was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 97 / 3) to give compound 23 (60 mg).

[0663] MS(ESI, [M+H]) +)m / z:609.6.

[0664] 1 H NMR (500MHz, DMSO-d6): δ8.23(d,J=3.5Hz,1H),8.01-7.96(m,2H),7.62(d,J=7.5Hz, 1H),7.44(d,J=7.5Hz,2H),7.32(d,J=7.0Hz,2H),7.27-7.22(m,3H),7.01(s,1H),6.4 3(d,J=7.0Hz,2H),6.42-6.41(m,1H),4.54(t,J=7.5Hz,1H),3.47(q,J=7.5Hz,1H),3 .24(t,J=7.5Hz,1H),2.99(s,3H),2.78(s,3H),2.44-2.42(m,2H),2.22-2.20(s,6H).

[0665] Example 24: Preparation of compound 24

[0666]

[0667] Step A: Preparation of compound 24A

[0668] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (349 mg), bis(dibenzylacetone)palladium (256 mg), (R)-N-methyl-N-(pyrrolo-3-yl)acetamide hydrochloride (500 mg), 1,3-dibromobenzene (660 mg), sodium tert-butoxide (807 mg), and dioxane (15 mL) were added sequentially to the reaction flask. After the addition was complete, the reaction mixture was heated to 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give compound 24A (740 mg).

[0669] MS(ESI, [M+H]) + )m / z:297.4.

[0670] Step B: Preparation of compound 24B

[0671] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (179 mg), compound 24A (650 mg), pinacol diborate (1111 mg), potassium acetate (644 mg), and dioxane (15 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction mixture was reacted at 110 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give compound 24B (740 mg).

[0672] MS(ESI, [M+H]) +)m / z:345.6.

[0673] Step C: Preparation of compound 24C

[0674] Tetraphenylphosphine palladium (208 mg), compound 1C, compound 24B (620 mg), potassium carbonate (498 mg), dioxane (15 mL), and water (0.5 mL) were added sequentially to the reaction flask. After the additions were complete, the mixture was heated to 120 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 98 / 2) to give compound 24C (470 mg).

[0675] MS(ESI, [M+H]) + )m / z:673.6.

[0676] Step D: Preparation of Compound 24

[0677] Compound 24C (420 mg), dichloromethane (6 mL), and methanesulfonic acid (360 mg) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, the pH of the reaction solution was adjusted to neutral using a saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 96:4) to give compound 24 (140 mg).

[0678] MS(ESI, [M+H]) + )m / z:573.7.

[0679] 1 H NMR (500MHz, DMSO-d6): δ8.22 (d,J=8.0Hz, 1H), 8.00 (dd,J=3.5Hz, 7.0Hz, 1H), 7.62 (d,J=7.5Hz,1H),7.44(d,J=7.5Hz,1H),7.30-7.14(m,4H),7.02(s,2H),6.61(br,1H ),6.43-6.41(m,1H),5.20(t,J=7.5Hz,1H),4.68(t,J=7.5Hz,1H),3.49-3.48(m,1H) ,3.37-3.23(m,6H),2.89(s,2H),2.43-2.42(m,2H),2.15-2.12(m,4H),2.03(s,2H).

[0680] Example 25: Preparation of Compound 25

[0681]

[0682] Step A: Preparation of compound 25A

[0683] (S)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (1.60 g), N,N-diisopropylethylamine (1.24 g), and methanesulfonyl chloride (0.91 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated to give compound 25A (2.53 g).

[0684] Step B: Preparation of compound 25B

[0685] A solution of dioxane in hydrochloric acid (6 mL), compound 25A (2.53 g), and dichloromethane (20 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature until complete, and then the reaction solution was concentrated to obtain compound 25B (1.58 g).

[0686] Step C: Preparation of compound 25C

[0687] Under nitrogen protection, compound 25B (0.700 g), 1,3-dibromobenzene (0.949 g), tris(dibenzylacetone)dipalladium (0.368 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.500 g), sodium tert-butoxide (1.500 g), and toluene (20 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 25C (0.456 g).

[0688] MS(ESI, [M+H]) + )m / z:333.3.

[0689] Step D: Preparation of compound 25D

[0690] Under nitrogen protection, potassium acetate (0.385 g), pinacol diboronate (0.627 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.160 g), compound 25C (0.430 g), and dioxane (20 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 110 °C. After the reactants had reacted completely, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 7 / 3) to give compound 25D (0.166 g).

[0691] MS(ESI, [M+H]) + )m / z:381.6.

[0692] Step E: Preparation of compound 25E

[0693] Under nitrogen protection, compound 25D (0.165 g), compound 1C (0.213 g), potassium carbonate (0.180 g), tetraphenylphosphine palladium (0.025 g), 1,4-dioxane (10 mL), and water (5 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 110 °C. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 17 / 3) to give compound 25E (0.075 g).

[0694] MS(ESI, [M+H]) + )m / z:709.7.

[0695] Step F: Preparation of Compound 25

[0696] Compound 25E (0.075 g), dichloromethane (10 mL), and methanesulfonic acid (0.050 g) were added sequentially to a reaction flask. The mixture was stirred at room temperature after the additions were complete. Once the reaction was complete, a 20% sodium hydroxide aqueous solution was added with stirring in an ice bath to adjust the pH to 12. The phases were separated; the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 3 / 7) to give compound 25 (0.040 g).

[0697] MS(ESI, [M+H]) + )m / z:609.7.

[0698] 1 H NMR(500MHz,DMSO-d6)δ8.41(d,1H),8.20(d,1H),7.96(d,1H),7.84(d,1H),7.75(d,2H),7.67(d,2H),7.41-7.45(m,2H),7 .29(m,1H),6.96(m,1H),4.26(s,4H),4.00(m,1H),3.53(d,2H),3.08(t,2H),2.63(s,4H),2.25(t,3H),1.71-2.01(m,7H).

[0699] Example 26: Preparation of Compound 26

[0700]

[0701] Step A: Preparation of compound 26A

[0702] 1,3-Dibromobenzene (0.54 g), 3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester (0.30 g), sodium tert-butoxide (0.29 g), tris(dibenzylacetone)dipalladium (0.14 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.09 g), and 1,4-dioxane (12 mL) were added sequentially to the reaction flask. The reaction was carried out under nitrogen protection and stirred at 100 °C. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 26A (0.51 g).

[0703] MS(ESI, [M-Boc+H]) + )m / z:253.4.

[0704] Step B: Preparation of compound 26B

[0705] Compound 26A (0.46 g) and a 4M dioxane solution (8 mL) of hydrogen chloride were added sequentially to the reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 26B (0.43 g).

[0706] MS(ESI, [M+H]) + )m / z:253.4.

[0707] Step C: Preparation of compound 26C

[0708] At 0°C, under nitrogen protection, acetyl chloride (2.98 g) was slowly added to a dichloromethane (20 mL) solution of compound 26B (0.43 g) and triethylamine (0.69 g). After the addition was complete, the reaction mixture was stirred at room temperature. Once the reaction was complete, saturated sodium bicarbonate aqueous solution (75 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give compound 26C (0.25 g).

[0709] MS(ESI, [M+H]) + )m / z:295.4.

[0710] Step D: Preparation of compound 26D

[0711] To a 100 mL reaction flask, compound 26C (0.25 g), pinacol diborate (0.32 g), potassium acetate (0.25 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.069 g), and 1,4-dioxane (15 mL) were added sequentially. The reaction was carried out under nitrogen protection at 100 °C with stirring. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give compound 26D (0.22 g).

[0712] MS(ESI, [M+H]) + )m / z:343.6.

[0713] Step E: Preparation of compound 26E

[0714] Compound 26D (0.21 g), compound 1C (0.20 g), potassium carbonate (0.17 g), tetra(triphenylphosphine)palladium (0.047 g), 1,4-dioxane (10 mL), and water (1.5 mL) were added sequentially to a 25 mL microwave-safe tube. After the additions were complete, nitrogen gas was introduced, and the mixture was microwaved at 140 °C for 2 h. The reaction was completed, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 26E (0.22 g).

[0715] MS(ESI, [M+H]) + )m / z:671.7.

[0716] Step F: Preparation of Compound 26

[0717] Compound 26E (183 mg), methanesulfonic acid (0.2 mL), and dichloromethane (10 mL) were added sequentially to a 50 mL reaction flask. The reaction mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 26 (106 mg).

[0718] HRMS(ESI, [M+H]) + )m / z:571.2924.

[0719] 1H NMR (500MHz, CDCl3) δ8.11(dd,J=8.3,5.2Hz,1H),8.07(dt,J=4.9,1.7Hz,1H),7.79(dd,J=8.4,3.6Hz,1H),7.60 -7.54(m,2H),7.53-7.41(m,4H),7.36-7.30(m,1H),7.16(ddd,J=14.3,7.8,1.8Hz,1H),6.82-6.76(m,1H),6.62 (s,2H),6.40(dt,J=7.8,5.3Hz,1H),4.94(dd,J=6.9,4.5Hz,1H),4.30-4.10(m,2H),3.98-3.83(m,1H),3.76(dd ,J=22.2,10.2Hz,1H),3.29-3.18(m,1H),3.08-2.88(m,2H),2.68-2.56(m,2H),2.32-2.05(m,4H),1.84(s,3H).

[0720] Example 27: Preparation of Compound 27

[0721]

[0722] Step A: Preparation of compound 27A

[0723] 1,3-Dibromobenzene (4.98 g), 3,6-diazabicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester (2.00 g), sodium tert-butoxide (2.70 g), tris(dibenzylacetone)dipalladium (0.64 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.66 g), and 1,4-dioxane (100 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 27A (2.78 g).

[0724] MS(ESI, [M+H]) + )m / z:297.4.

[0725] Step B: Preparation of compound 27B

[0726] Under nitrogen protection at 0°C, sodium hydride (1.87 g) was slowly added to a tetrahydrofuran (60 mL) solution of compound 27A (2.78 g). After the addition was complete, the mixture was stirred at room temperature for 0.5 h, and then iodomethane (6.64 g) was added to react. Once the reaction was complete, a saturated aqueous solution of ammonium chloride was added to the reaction mixture under ice bath conditions. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 27B (1.91 g).

[0727] MS(ESI, [M+H]) + )m / z:311.4.

[0728] Step C: Preparation of compound 27C

[0729] Compound 27B (1.91 g), pinacol diboronate (2.34 g), potassium acetate (1.81 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.50 g), and 1,4-dioxane (120 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen atmosphere and stirred at 100 °C. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 27C (2.11 g).

[0730] MS(ESI, [M+H]) + )m / z:359.6.

[0731] Step D: Preparation of compound 27D

[0732] In a microwave-safe tube, compound 27C (0.33 g), compound 1C (0.30 g), potassium carbonate (0.25 g), tetra(triphenylphosphine)palladium (71 mg), 1,4-dioxane (14 mL), and water (2 mL) were added sequentially. After the additions were complete, nitrogen gas was introduced, and the mixture was microwaved at 140 °C. Once the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 27D (0.38 g).

[0733] MS(ESI, [M+H]) + )m / z:687.8.

[0734] Step E: Preparation of Compound 27

[0735] Compound 27D (370 mg), methanesulfonic acid (0.3 mL), and dichloromethane (16 mL) were added sequentially to a reaction flask. The reaction was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 27 (157 mg).

[0736] HRMS(ESI, [M+H]) + )m / z:587.3278.

[0737] 1 H NMR (500MHz, CDCl3) δ8.10(dd,J=9.5,8.3Hz,1H),8.06(dd,J=4.8,1.8Hz,1H),7.79(dd,J=8.4,1.3Hz,1H),7.67-7.57(m, 3H),7.48(dt,J=7.8,1.0Hz,1H),7.46-7.41(m,2H),7.31(dt,J=18.8,7.9Hz,1H),7.12(ddd,J=29.3,7.8,1.8Hz,1H),6.9 3(td,J=7.6,2.4Hz,1H),6.60(s,2H),6.39(ddd,J=7.8,5.9,4.8Hz,1H),4.77-4.68(m,1H),3.86-3.72(m,1H),3.72-3.56 (m,1H),2.91(d,J=18.3Hz,3H),2.75-2.56(m,4H),2.47-2.35(m,2H),2.26-2.18(m,1H),2.15(s,3H),1.92-1.70(m,5H).

[0738] Example 28: Preparation of Compound 28

[0739]

[0740] Step A: Preparation of compound 28A

[0741] 0.50 g of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 0.66 g of 1,3-dibromofluorobenzene, 80 mg of tris(dibenzylacetone)dipalladium, 60 mg of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), 50 mL of tetrahydrofuran, and 1.00 g of sodium tert-butoxide were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 80 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 28A (0.51 g).

[0742] Step B: Preparation of compound 28B

[0743] Weigh 0.50 g of compound 28A into a reaction flask, add 10 mL of dichloromethane and stir to dissolve. Then add 0.39 g of methanesulfonic acid. After the addition is complete, stir the mixture at room temperature. After the reaction is complete, add 2 mL of triethylamine to terminate the reaction, giving a solution of compound 28B. Do not concentrate the solution; directly add it to the next reaction step.

[0744] Step C: Preparation of compound 28C

[0745] Take a solution of compound 28B and add acetic anhydride (206 mg). After the addition is complete, stir the mixture at room temperature. Once the reaction is complete, concentrate the reaction solution and perform column chromatography (dichloromethane / methanol = 96:4) to give compound 28C (313 mg).

[0746] MS(ESI, [M+H]) + )m / z:313.79.

[0747] Step D: Preparation of compound 28D

[0748] To a reaction flask containing compound 28C (300 mg), pinacol diboronate (365 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (39 mg), 1,4-dioxane (30 ml), and potassium acetate (282 mg) were added sequentially. After the additions were complete, the mixture was stirred at 120 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 98 / 2) to give compound 28D (278 mg).

[0749] MS(ESI, [M+H]) + )m / z:361.04.

[0750] Step E: Preparation of compound 28E

[0751] Compound 28D (300 mg), compound 1C (409 mg), potassium carbonate (460 mg), tetra(triphenylphosphine)palladium (48 mg), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 120 °C. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 96 / 4) to give compound 28E (252 mg).

[0752] MS(ESI, [M+H]) + )m / z:689.5.

[0753] Step F: Preparation of Compound 28

[0754] Compound 28E (250 mg), methanesulfonic acid (349 mg), and dichloromethane (30 mL) were added sequentially to a reaction flask. The reaction was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 28 (70 mg).

[0755] MS(ESI, [M+H]) + )m / z:589.5.

[0756] 1 H NMR (500MHz, CDCl3): 8.25 (d, J=8.5Hz, 1H), 8.00 (dd, J=2.0, 5.0Hz, 1H), 7.68 (dd, J=2.0, 8.0 Hz,1H),7.60(d,J=8.5Hz,2H),7.42(d,J=8.5Hz,2H),7.20(dd,J=2.0,8.0Hz,1H),7.10-7.44( m,2H),6.94(m,2H),6.61-6.57(m,1H),6.42-6.40(m,1H),4.29(s,2H),4.08(s,4H),4.02(s, 2H),2.44-2.37(m,2H),2.13-2.06(m,2H),2.06-1.98(m,1H),1.75(s,3H),1.73-1.65(m,1H).

[0757] Example 29: Preparation of compound 29

[0758]

[0759] Step A: Preparation of compound 29A

[0760] N-tert-Butoxycarbonyl-N-methylethylenediamine (1.00 g), dichloromethane (30 mL), anhydrous potassium carbonate (1.59 g), and acetic anhydride (0.64 g) were added sequentially to a reaction flask. The mixture was stirred at room temperature after the additions were complete. After the reaction was complete, the mixture was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 29A (1.13 g).

[0761] Step B: Preparation of compound 29B

[0762] To a reaction flask containing compound 29A (1.13 g), a 1,4-dioxane solution (20 mL) of 4 M hydrogen chloride was added, and the mixture was stirred at room temperature after the addition was complete. The reaction was then concentrated to give compound 29B (0.87 g).

[0763] Step C: Preparation of compound 29C

[0764] Compound 29B (0.87 g), 1,3-dibromofluorobenzene (5.42 g), tris(dibenzylacetone)dipalladium (263 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (179 mg), tetrahydrofuran (50 mL), and sodium tert-butoxide (3.31 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 80 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (ethyl acetate) to give compound 29C (0.48 g).

[0765] MS(ESI, [M+H]) + )m / z:271.1.

[0766] Step D: Preparation of compound 29D

[0767] To a reaction flask containing compound 29C (0.48 g), 10 mL of tetrahydrofuran was added and stirred until dissolved. After cooling with ice / ethanol, sodium hydride (0.28 g) was added, and the mixture was stirred for 10 min. Then, 0.76 g of iodomethane was added, and the reaction was stirred at room temperature until complete. The reaction was poured into a saturated aqueous solution of ammonium chloride, stirred, and extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 29D (0.64 g).

[0768] MS(ESI, [M+H]) + )m / z:285.1.

[0769] Step E: Preparation of compound 29E

[0770] To a reaction flask containing compound 29D (509 mg), pinacol diboronate (680 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (73 mg), 1,4-dioxane (20 mL), and potassium acetate (525 mg) were added sequentially. After the additions were complete, the mixture was stirred at 120 °C under nitrogen protection. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 29E (441 mg).

[0771] MS(ESI, [M+H]) + )m / z:333.3.

[0772] Step F: Preparation of compound 29F

[0773] Compound 29E (440 mg), compound 1C (716 mg), potassium carbonate (550 mg), tetra(triphenylphosphine)palladium (77 mg), 1,4-dioxane (10 mL), and water (1 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 120 °C for 2 hours. Once the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 96 / 4) to obtain compound 29F (400 mg).

[0774] MS(ESI, [M+H]) + )m / z:661.39.

[0775] Step G: Preparation of compound 29

[0776] Compound 29F (400 mg), methanesulfonic acid (582 mg), and dichloromethane (30 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding a 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 29 (387 mg).

[0777] MS(ESI, [M+H]) + )m / z:561.34.

[0778] 1 H NMR (500MHz, CDCl3): 8.29 (d, J=8.5Hz, 1H), 8.01 (dd, J=1.5, 5.0Hz, 1H), 7.96 (t, J=8.5Hz, 1H), 7.62 ( d,J=8.0Hz,2H),7.47-7.40(m,3H),7.31-7.22(m,2H),7.01(s,2H),6.79-6.74(m,1H),6.43-6.41(m, 1H),3.56-3.54(m,1H),3.49-3.46(m,1H),3.43-3.33(m,6H),2.94(s,2H),2.90(s,1H),2.78(s,1H), 2.46-2.41(m,2H),2.18-2.13(m,2H),2.08-2.02(m,1H),1.88(s,2H),1.79(s,2H),1.75-1.66(m,1H).

[0779] Example 30: Preparation of compound 30

[0780]

[0781] Step A: Preparation of compound 30A

[0782] Under nitrogen protection, 1-(piperidin-4-yl)pyrrolidine-2-one hydrochloride (0.32 g), 1,3-dibromofluorobenzene (0.40 g), tris(dibenzylacetone)dipalladium (0.07 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.10 g), sodium tert-butoxide (0.33 g), and toluene (20 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C. After the reactants had reacted completely, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 65 / 1) to give compound 30A (0.20 g).

[0783] Step B: Preparation of compound 30B

[0784] Under nitrogen protection, potassium acetate (0.06 g), pinacol diborate (0.10 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg), compound 30A (0.20 g), and dioxane (20 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 110 °C. After the reactants had reacted completely, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 65 / 1) to give compound 30B (0.21 g).

[0785] Step C: Preparation of compound 30C

[0786] Under nitrogen protection, compound 30B (0.21 g), compound 1C (0.11 g), potassium carbonate (0.06 g), tetraphenylphosphine palladium (13 mg), 1,4-dioxane (15 mL), and water (7.5 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 110 °C. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 3 / 7) to give compound 30C (0.16 g).

[0787] MS(ESI, [M+H]) + )m / z:717.8.

[0788] Step D: Preparation of Compound 30

[0789] Compound 30C (0.16 g), dichloromethane (10 mL), and methanesulfonic acid (0.21 g) were added sequentially to a reaction flask. The mixture was stirred at room temperature after the additions were complete. Once the reaction was complete, a 20% sodium hydroxide aqueous solution was added with stirring in an ice bath to adjust the pH to 12. The phases were separated; the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 2 / 3) to give compound 30 (0.08 g).

[0790] MS(ESI, [M+H]) + )m / z:617.7.

[0791] 1 H NMR(500MHz,DMSO-d6)δ8.23(d,1H),7.96-8.02(m,2H),7.63(d,2H),7.4 7(d,2H),7.22-7.33(m,3H),6.98(s,2H),6.62-6.64(m,1H),6.41-6.43(m ,1H),4.51-4.57(m,1H),3.47(q,2H),3.24(q,2H),2.99(s,3H),2.78(s,3 H),2.44-2.48(m,2H),2.02-2.25(m,5H),1.69-1.77(m,1H),1.23(s,2H).

[0792] Example 31: Preparation of compound 31

[0793]

[0794] Step A: Preparation of compound 31A

[0795] Under nitrogen protection, 1-(piperidin-4-yl)pyrrolidine-2-one hydrochloride (0.61 g), 1,3-dibromobenzene (0.80 g), tris(dibenzylacetone)dipalladium (0.31 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.32 g), sodium tert-butoxide (0.49 g), and toluene (10 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C. After the reactants had reacted completely, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 31A (0.50 g).

[0796] MS(ESI, [M+H]) + )m / z:297.1.

[0797] Step B: Preparation of compound 31B

[0798] Under nitrogen protection, potassium acetate (0.489 g), pinacol diboronate (0.811 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.207 g), compound 31A (0.502 g), and dioxane (20 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 110 °C. After the reactants had reacted completely, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 7 / 3) to give compound 31B (0.293 g).

[0799] MS(ESI, [M+H]) + )m / z:345.6.

[0800] Step C: Preparation of compound 31C

[0801] Under nitrogen protection, compound 31B (0.293 g), compound 1C (0.320 g), potassium carbonate (0.270 g), tetraphenylphosphine palladium (0.040 g), 1,4-dioxane (15 mL), and water (7.5 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 110 °C. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 7 / 3) to give compound 31C (0.294 g).

[0802] MS(ESI, [M+H]) + )m / z:673.4.

[0803] Step D: Preparation of compound 31

[0804] Compound 31C (0.294 g), dichloromethane (10 mL), and methanesulfonic acid (0.210 g) were added sequentially to a reaction flask. The mixture was stirred at room temperature after the additions were complete. Once the reaction was complete, a 20% sodium hydroxide aqueous solution was added with stirring in an ice bath to adjust the pH to 12. The phases were separated; the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 2 / 3) to give compound 31 (0.183 g).

[0805] MS(ESI, [M+H]) + )m / z:573.7.

[0806] 1 H NMR(500MHz,DMSO-d6)δ8.21(d,1H),7.95-8.01(m,2H),7.62(d,2H),7.44(d,2H),7.23-7.32(m,4H),7.02(s,2H),6.60(d,1 H),6.41-6.43(m,1H),3.36-3.49(m,1H),3.21-3.35(m,4H),2.89(s,3H),2.42-2.43(m,2H),2.03-2.20(m,8H),1.7(m,1H).

[0807] Example 32: Preparation of compound 32

[0808]

[0809] Step A: Preparation of compound 32A

[0810] To a 100 mL single-necked flask, 1.8 g of 4-(N-methylmethanesulfonamide)piperidine-1-carbamate tert-butyl ester, 5 mL of dichloromethane, and 2 mL of a 4M solution of dioxane (4M hydrogen chloride) were added sequentially. After the addition was complete, the mixture was stirred at room temperature. Once the reaction was complete, compound 32A (1.26 g) was obtained by vacuum distillation and used directly in the next reaction step.

[0811] Step B: Preparation of compound 32B

[0812] Under nitrogen protection, 2,2'-(3,3'-dichloro-1,1'-biphenyl-4,4'-diazo)bis(N-phenyl-3-oxo-butyramide) (0.491 g), bis(dibenzylacetone)palladium (0.361 g), 1,3-dibromo-2-fluorobenzene (1 g), compound 32A (1.2 g), sodium tert-butoxide (0.757 g), and dioxane (15 mL) were added sequentially to a 100 mL single-necked flask. The mixture was heated to 120 °C to react. After the reaction was complete, the solvent was removed by vacuum distillation, and the concentrate was concentrated and then subjected to column chromatography (petroleum ether: ethyl acetate = 85:15) to give compound 32B (680 mg).

[0813] MS(ESI, [M+H]) + )m / z:365.1.

[0814] Step C: Preparation of compound 32C

[0815] To a 100 mL single-necked flask, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (139 mg), compound 32B (620 mg), pinacol diborate (862 mg), potassium acetate (333 mg), and dioxane (15 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 120 °C for reaction. After the reaction was complete, the mixture was concentrated and subjected to column chromatography (petroleum ether: ethyl acetate = 75:25) to give compound 32C (420 mg).

[0816] MS(ESI, [M+H]) + )m / z:413.3.

[0817] Step D: Preparation of compound 32D

[0818] To a 100 mL single-necked flask, tetraphenylphosphine palladium (51.8 mg), compound 32C (220 mg), compound 1C (220 mg), potassium carbonate (124 mg), dioxane (5 mL), and water (0.5 mL) were added sequentially. After the addition was complete, the mixture was transferred to an oil bath at 100 °C and heated to react. After the reaction was complete, the mixture was concentrated and subjected to column chromatography (dichloromethane:methanol = 94:6) to give 32D (180 mg).

[0819] MS(ESI, [M+H])+ )m / z:741.4.

[0820] Step E: Preparation of Compound 32

[0821] To a 50 mL single-necked flask, compound 32D (180 mg), dichloromethane (10 mL), and methanesulfonic acid (46.7 mg) were added sequentially. The mixture was stirred at room temperature after the addition was complete. Once the reactants had reacted completely, the pH of the reaction solution was adjusted to neutral using a saturated sodium carbonate aqueous solution. The solution was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane:methanol = 96:4) to obtain compound 32 (120 mg).

[0822] MS(ESI, [M+H]) + )m / z:641.7.

[0823] 1 H NMR (500MHz, CDCl3): δ8.12(d,J=7.5Hz,1H),8.07(dd,J=5.0,10.0Hz,1H),7.80(dd,J=5.0,10.0 Hz,1H),7.56-7.51(m,3H),7.40(d,J=10.0Hz,1H),7.12(q,J=10.0Hz,1H),6.99(t,J=7.5Hz,1H), 6.59(br,2H),6.39(q,J=8.0Hz,1H),3.93-3.91(m,1H),3.51(d,J=10.0Hz,2H),2.88-2.87(m,6H ),2.81(t,J=10.0Hz,2H),2.63-2.58(m,2H),2.24-2.19(m,1H),2.12-2.06(m,2H),1.83(br,6H).

[0824] Example 33: Preparation of compound 33

[0825]

[0826] Step A: Preparation of compound 33A

[0827] At 0°C, trifluoroacetic acid (2 mL) was slowly added dropwise to a reaction solution of 0.5 g of tert-butyl 7-oxo-2,6-diazaspiro[3,4]octane-2-carboxylate in 10 mL of dichloromethane. After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated to give compound 33A (0.78 g).

[0828] MS(ESI, [M+H]) + )m / z:127.4.

[0829] Step B: Preparation of compound 33B

[0830] Compound 33A (0.5 g), 1,3-dibromobenzene (0.74 g), (tris(dibenzylacetone)dipalladium) (0.19 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.13 g), sodium tert-butoxide (1 g), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 50 / 1) to give compound 33B (0.54 g).

[0831] MS(ESI, [M+H]) + )m / z:281.4.

[0832] Step C: Preparation of compound 33C

[0833] At 0°C under nitrogen protection, sodium hydride (0.37 g) was slowly added to a tetrahydrofuran (30 mL) solution of compound 33B (0.52 g). After the addition was complete, the reaction mixture was transferred to room temperature and stirred for 0.5 h. Iodomethane (1.32 g) was then added to the reaction mixture. After the reaction was complete, saturated ammonium chloride aqueous solution (75 mL) was added to the reaction mixture under ice bath conditions. The mixture was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride aqueous solution (100 mL), dried, filtered, and concentrated to obtain compound 33C (0.50 g).

[0834] MS(ESI, [M+H]) + )m / z:295.4.

[0835] Step D: Preparation of compound 33D

[0836] Compound 33C (0.50 g), pinacol diborate (0.65 g), potassium acetate (0.50 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.14 g), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection and stirred at 100 °C. After the reaction was complete, the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 33D (0.12 g).

[0837] MS(ESI, [M+H]) + )m / z:343.5.

[0838] Step E: Preparation of compound 33E

[0839] Compound 33D (0.12 g), compound 1C (0.14 g), potassium carbonate (0.12 g), tetrakis(triphenylphosphine)palladium (0.03 g), 1,4-dioxane (4 mL), and water (0.5 mL) were added sequentially to a microwave tube. After the additions were complete, nitrogen gas was introduced, and the reaction was carried out in a microwave oven at 100 °C. The reaction was completed, the reaction solution was filtered, and the solution was concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 33E (0.18 g).

[0840] MS(ESI, [M+H]) + )m / z:671.4.

[0841] Step F: Preparation of compound 33

[0842] Compound 33E (176 mg), methanesulfonic acid (0.15 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding a 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 33 (69 mg).

[0843] MS(ESI, [M+H]) + )m / z:571.6.

[0844] 1 H NMR (500MHz, CDCl3) δ8.14 (dd, J=8.4, 2.8Hz, 1H), 8.02 (dd, J=5.0, 1.9Hz, 1H), 7.78 (dd, J=8.5, 2.7Hz, 1 H),7.60-7.55(m,2H),7.48-7.42(m,3H),7.30(t,J=7.9Hz,1H),7.17(dt,J=7.8,1.8Hz,1H),7.09(d,J= 2.2Hz,1H),6.52(dd,J=7.9,2.4Hz,1H),6.42(dd,J=7.7,4.8Hz,1H),3.91(s,4H),3.69(d,J=2.6Hz,2H) ,2.89(s,3H),2.72(s,2H),2.68-2.61(m,2H),2.35-2.28(m,2H),2.20-2.02(m,1H),1.90-1.80(m,1H).

[0845] Example 34: Preparation of compound 34

[0846]

[0847] Step A: Preparation of compound 34A

[0848] Ethyl 2,2-difluoro-2-iodoacetate (10 g), vinyltrimethylsilane (8.9 g), copper powder (0.13 g), and acetonitrile (50 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 65 °C. The reaction proceeded to completion, the solvent was removed by vacuum distillation, and the mixture was concentrated to give compound 34A (8.34 g).

[0849] MS(ESI, [M+H]) + )m / z:351.0.

[0850] Step B: Preparation of compound 34B

[0851] Compound 34A (3.0 g), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (1.1 g), and ethanol (20 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 8 / 2) to give compound 34B (1.0 g).

[0852] MS(ESI, [M+K]) + )m / z:415.4.

[0853] Step C: Preparation of compound 34C

[0854] Compound 34B (1.0 g), potassium fluoride (1.0 g), and dimethyl sulfoxide (20 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 34C (0.76 g).

[0855] MS(ESI, [M+H]) + )m / z:305.4.

[0856] Step D: Preparation of compound 34D

[0857] Compound 34C (3.0 g), a 4M hydrochloric acid solution of dioxane (6.2 mL), and dichloromethane (20 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the solution was concentrated to give compound 34D (0.63 g).

[0858] MS(ESI, [M+H]) + )m / z:205.4.

[0859] Step E: Preparation of compound 34E

[0860] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.33 g), tris(dibenzylacetone)dipalladium (0.37 g), 1,3-dibromo-2-fluorobenzene (4.5 g), compound 34D (0.63 g), sodium tert-butoxide (0.28 g), and dioxane (20 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was concentrated, and column chromatography (petroleum ether / ethyl acetate = 9 / 1) was performed to give compound 34E (0.23 g).

[0861] MS(ESI, [M+H]) + )m / z:359.0.

[0862] Step F: Preparation of compound 34F

[0863] Compound 34E (0.43 g), pinacol diborate (0.25 g), potassium acetate (0.19 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.10 g), and 1,4-dioxane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 34F (0.17 g).

[0864] MS(ESI, [M+H]) + )m / z:407.12.

[0865] Step G: Preparation of compound 34G

[0866] Compound 34F (0.17 g), compound 1C (0.12 g), potassium carbonate (0.090 g), tetra(triphenylphosphine)palladium (0.077 g), 1,4-dioxane (10 mL), and water (10 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 34G (0.20 g).

[0867] MS(ESI, [M+H]) + )m / z:735.7.

[0868] Step H: Preparation of compound 34

[0869] Compound 34G (0.21 g), methanesulfonic acid (0.13 g), and dichloromethane (15 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 34 (0.041 g).

[0870] MS(ESI, [M+H]) + )m / z:635.5.

[0871] 1 H NMR (500MHz, CDCl3) δ8.48(d,J=8.6Hz,1H),8.31(d,J=5.1Hz,1H),8.14(d,J=8.5Hz,1H),7.97(d,J=8.2Hz,2H),7.92-7 .83(m,3H),7.80(d,J=7.8Hz,1H),7.64(t,J=8.0Hz,1H),7.53(d,J=7.7Hz,1H),7.33(d,J=8.4Hz,1H),6.77(t,J=6.4Hz ,1H),4.46-4.33(m,1H),4.14(d,J=12.3Hz,2H),3.82(t,J=6.7Hz,2H),3.21(t,J=12.2Hz,2H),3.13-3.02(m,2H),2.94 (q,J=10.3,9.6Hz,2H),2.86(dd,J=14.7,7.7Hz,2H),2.32-2.24(m,2H),2.18(d,J=13.6Hz,2H),1.59(d,J=17.5Hz,2H).

[0872] Example 35: Preparation of compound 35

[0873]

[0874] Step A: Preparation of compound 35A

[0875] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.21 g), tris(dibenzylacetone)dipalladium (0.20 g), 1,3-dibromo-2-fluorobenzene (1.68 g), 2,7-diazaspiro[3.5]nonane-7-carbonate tert-butyl ester (1.00 g), sodium tert-butoxide (1.70 g), and tetrahydrofuran (25 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 85 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 35A (1.51 g).

[0876] MS(ESI, [M-100+H]) + )m / z:299.4.

[0877] Step B: Preparation of compound 35B

[0878] Compound 35A (1.51 g), methanesulfonic acid (3.62 g), and dichloromethane (60 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to obtain compound 35B (1.32 g).

[0879] MS(ESI, [M+H]) + )m / z:299.4.

[0880] Step C: Preparation of compound 35C

[0881] Compound 35B (1.32 g), acetic anhydride (0.67 g), triethylamine (1.32 g), and dichloromethane (50 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, water and dichloromethane were added to the reaction solution for extraction, followed by washing with saturated brine and drying over anhydrous sodium sulfate. The solution was filtered and concentrated to obtain compound 35C (1.32 g).

[0882] MS(ESI, [M+H]) + )m / z:341.4.

[0883] Step D: Preparation of compound 35D

[0884] Compound 35C (1.32 g), pinacol diborate (1.47 g), potassium acetate (1.14 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.32 g), and 1,4-dioxane (50 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 35D (1.27 g).

[0885] MS(ESI, [M+H]) + )m / z:389.6.

[0886] Step E: Preparation of compound 35E

[0887] Compound 35D (0.59 g), compound 1C (0.5 g), potassium carbonate (0.42 g), tetra(triphenylphosphine)palladium (0.12 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 35E (0.64 g).

[0888] MS(ESI, [M+H]) + )m / z:717.8.

[0889] Step F: Preparation of compound 35

[0890] Compound 35E (0.63 g), methanesulfonic acid (0.84 g), and dichloromethane (30 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 35 (0.32 g).

[0891] MS(ESI, [M+H]) + )m / z:617.7.

[0892] 1 H NMR (500MHz, CDCl3) δ8.09(d,J=8.3Hz,1H),8.05(dd,J=4.8,1.5Hz,1H),7.76(dd,J=8.3,2.0Hz,1H),7.53(d,J=8.4Hz,2 H),7.38(d,J=8.4Hz,2H),7.24(t,J=6.7Hz,1H),7.09(dd,J=7.8,1.6Hz,1H),7.03(t,J=7.8Hz,1H),6.59(s,2H),6.46(t, J=8.1Hz,1H),6.36(dd,J=7.8,4.9Hz,1H),3.77(s,4H),3.60-3.54(m,2H),3.44-3.38(m,2H),2.59(ddd,J=11.8,8.9,6.6 Hz,2H),2.19(ddd,J=11.5,9.1,6.0Hz,2H),2.09(s,4H),2.03(s,1H),1.92(s,2H),1.87-1.83(m,2H),1.81-1.77(m,2H).

[0893] Example 36: Preparation of compound 36

[0894]

[0895] Step A: Preparation of compound 36A

[0896] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.088 g), tris(dibenzylacetone)dipalladium (0.086 g), 1,3-dibromo-2-fluorobenzene (0.72 g), 2,6-diaza-spiro[3,4]octane-2-carbonate tert-butyl ester (0.40 g), sodium tert-butoxide (0.72 g), and tetrahydrofuran (25 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 85 °C. Once the reaction was complete, the reaction solution was concentrated, and column chromatography (petroleum ether / ethyl acetate = 9 / 1) was performed to give compound 36A (620 mg).

[0897] MS(ESI, [M+H]) + )m / z:385.4.

[0898] Step B: Preparation of compound 36B

[0899] Compound 36A (600 mg), methanesulfonic acid (1.55 g), and dichloromethane (30 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 36B (420 mg).

[0900] MS(ESI, [M+H]) + )m / z:285.3.

[0901] Step C: Preparation of compound 36C

[0902] Compound 36B (0.42 g), acetic anhydride (0.23 g), triethylamine (0.45 g), and dichloromethane (20 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, water and dichloromethane were added to the reaction solution for extraction, followed by washing with saturated brine and drying over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 36C (440 mg).

[0903] MS(ESI, [M+H]) + )m / z:327.4.

[0904] Step D: Preparation of compound 36D

[0905] Compound 36C (0.44 g), pinacol diborate (0.51 g), potassium acetate (0.40 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.11 g), and 1,4-dioxane (30 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 40 / 1) yielded compound 36D (0.63 g).

[0906] MS(ESI, [M+H]) + )m / z:375.5.

[0907] Step E: Preparation of compound 36E

[0908] Compound 36D (0.74 g), compound 1C (0.5 g), potassium carbonate (0.42 g), tetra(triphenylphosphine)palladium (0.12 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 36E (500 mg).

[0909] MS(ESI, [M+H]) + )m / z:703.4.

[0910] Step F: Preparation of compound 36

[0911] Compound 36E (500 mg), methanesulfonic acid (0.7 g), and dichloromethane (20 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 with 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 36 (190 mg).

[0912] MS(ESI, [M+H]) + )m / z:603.6.

[0913] 1H NMR (500MHz, CDCl3) δ8.12(d,J=8.3Hz,1H),8.06(dd,J=4.8,1.7Hz,1H),7.76(dd,J=8.3,2.4Hz,1H),7.54(d,J=8.4Hz,2H),7 .40(d,J=8.4Hz,2H),7.27-7.18(m,1H),7.10(dd,J=7.8,1.6Hz,1H),7.06(t,J=7.9Hz,1H),6.78-6.64(m,1H),6.59(s,2H),6. 38(dd,J=7.8,4.9Hz,1H),4.11(d,J=8.4Hz,1H),4.05(d,J=8.4Hz,1H),4.01(d,J=9.9Hz,1H),3.96(d,J=9.9Hz,1H),3.60(qd ,J=9.8,2.0Hz,2H),3.49(ddq,J=14.4,9.5,7.3Hz,2H),2.66-2.54(m,2H),2.27-2.17(m,4H),2.16-1.94(m,4H),1.89(s,3H).

[0914] Example 37: Preparation of compound 37

[0915]

[0916] Step A: Preparation of compound 37A

[0917] 2,6-diaza-spiro[3,4]octane-2-tert-butyl carbonate (0.60 g), acetic anhydride (0.44 g), triethylamine (0.86 g), and dichloromethane (40 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was complete, water and dichloromethane were added to the reaction solution for extraction, followed by washing with saturated brine and drying over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 37A (0.82 g).

[0918] MS(ESI, [M+H]) + )m / z:255.4.

[0919] Step B: Preparation of compound 37B

[0920] Compound 37A (0.82 g), trifluoroacetic acid (6.14 g), and dichloromethane (50 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 37B (1.68 g).

[0921] MS(ESI, [M+H]) + )m / z:155.4.

[0922] Step C: Preparation of compound 37C

[0923] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.22 g), tris(dibenzylacetone)dipalladium (0.22 g), 1,3-dibromo-2-fluorobenzene (1.68 g), compound 37B (1.20 g), sodium tert-butoxide (0.88 g), and tetrahydrofuran (100 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 85 °C. The reaction was completed, the reaction solution was concentrated, and column chromatography (petroleum ether / ethyl acetate = 9 / 1) was performed to give compound 37C (960 mg).

[0924] MS(ESI, [M+H]) + )m / z:327.4.

[0925] Step D: Preparation of compound 37D

[0926] Compound 37C (0.78 g), pinacol diborate (0.92 g), potassium acetate (0.80 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.19 g), and 1,4-dioxane (60 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 37D (0.64 g).

[0927] MS(ESI, [M+H]) + )m / z:375.5.

[0928] Step E: Preparation of compound 37E

[0929] Compound 37D (0.53 g), compound 1C (0.32 g), potassium carbonate (0.27 g), tetra(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction proceeded to completion, and the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 37E (0.43 g).

[0930] MS(ESI, [M+H]) + )m / z:703.7.

[0931] Step F: Preparation of compound 37

[0932] Compound 37E (0.43 g), methanesulfonic acid (0.58 g), and dichloromethane (25 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 37 (0.10 g).

[0933] MS(ESI, [M+H]) + )m / z:603.6.

[0934] 1 H NMR (500MHz, CDCl3) δ8.26 -7.99(m,2H),7.76(d,J=8.1Hz,1H),7.54(d,J=6.2Hz,2H),7.39(d,J=7.5Hz,2H),7.33-7.26(m,1H),7.22-6.9 3(m,2H),6.59(s,2H),6.48(dd,J=13.6,6.9Hz,1H),6.38(dd,J=7.1,5.1Hz,1H),3.93(s,3H),3.66(d,J=10.6H z, 2H), 3.54 (dt, J = 10.4, 6.9 Hz, 2H), 2.60 (dd, J = 17.4, 8.9 Hz, 2H), 2.27 (t, J = 6.7 Hz, 1H), 2.21 (dd, J = 15.6, 10.0 Hz, 2H), 2.12 (dd, J = 14.1, 7.5 Hz, 2H), 2.05 (t, J = 6.6 Hz, 3H), 1.98 (s, 3H), 1.87-1.75 (m, 1H). Example 38: Preparation of compound 38

[0935]

[0936] Step A: Preparation of compound 38A

[0937] At 0°C, dilute hydrochloric acid (0.433 g) was added dropwise to 1-(piperidin-4-yl)pyrrolidone-2-one (1 g) and water (10 mL). After the addition was complete, an aqueous solution of sodium nitrite (0.533 g) was slowly added dropwise. The mixture was stirred at room temperature after the addition was complete. After the reaction was complete, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the compound 38A (0.7 g) was concentrated.

[0938] MS(ESI, [M+H]) + )m / z:198.4.

[0939] Step B: Preparation of compound 38B

[0940] Under nitrogen protection, heavy water (8 mL) was slowly added to compound 38A (0.7 g) and sodium methoxide (0.553 g). After the addition was complete, the mixture was stirred at 80 °C. Deuterated ethanol (5 mL) was then slowly added to the reaction flask, and the mixture was stirred at 80 °C again. After the reaction was complete, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 38B (0.45 g).

[0941] 1 H NMR (500MHz, CDCl3) δ4.40-4.29 (m, 1H), 3.33-3.21 (m, 2H), 2.00 (t, J = 7.0Hz, 2H), 1.97-1. 92(m,1H),1.82-1.71(m,2H),1.44(tt,J=14.8,7.3Hz,1H),1.23(s,1H),0.92-0.75(m,1H).

[0942] Step C: Preparation of compound 38C

[0943] At room temperature, sodium methoxide (0.362 g) was added to a solution of compound 38B (0.45 g) in deuterated ethanol (2.5 mL) and heavy water (5.00 mL). After the addition was complete, nickel-aluminum alloy (1.35 g) was added to the reaction flask, and the temperature was controlled at 30-40 °C. After the addition was complete, the mixture was stirred at 35 °C. After the reaction was complete, the mixture was filtered, concentrated, and the residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 38C (0.23 g).

[0944] MS(ESI, [M+H]) + )m / z:173.5.

[0945] Step D: Preparation of compound 38D

[0946] Sodium tert-butoxide (0.352 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.152 g), tris(dibenzylacetone)dipalladium (0.224 g), 1,3-dibromo-2-fluorobenzene (0.31 g), compound 38C, and 1,4-dioxane (10 mL) were added sequentially to a microwave tube. The mixture was stirred at 100 °C under nitrogen protection until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 40 / 1) yielded compound 38D (0.14 g).

[0947] MS(ESI, [M+H]) + )m / z:345.3.

[0948] Step E: Preparation of compound 38E

[0949] Compound 38D (0.14 g), pinacol diborate (0.21 g), potassium acetate (0.12 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.066 g), and 1,4-dioxane (15 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection and stirred at 100 °C. After the reaction was complete, the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 40 / 1) yielded compound 38E (0.13 g).

[0950] MS(ESI, [M+H]) + )m / z:393.4.

[0951] Step F: Preparation of compound 38F

[0952] Compound 38E (0.13 g), compound 1C (0.1 g), potassium carbonate (0.056 g), tetra(triphenylphosphine)palladium (0.047 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 30 / 1) yielded compound 38F (0.03 g).

[0953] MS(ESI, [M+H]) + )m / z:721.4.

[0954] Step G: Preparation of compound 38

[0955] Compound 38F (0.028 g), methanesulfonic acid (0.019 g), and dichloromethane (20 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding a 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 38 (0.013 g).

[0956] MS(ESI, [M+H]) + )m / z:621.5.

[0957] 1H NMR (500MHz, CDCl3) δ8.11(d,J=8.3Hz,1H),8.06(d,J=3.6Hz,1H),7.81(d,J=6.9Hz,1H),7.55(d,J=8.2Hz,2H),7.51(t, J=7.1Hz,1H),7.40(d,J=8.2Hz,2H),7.12(dd,J=12.9,7.2Hz,2H),7.00(t,J=7.6Hz,1H),6.57(s,2H),6.39(dd,J=7.5,4 .9Hz,1H),4.15(t,J=12.1Hz,1H),3.48(s,1H),3.41(t,J=6.9Hz,2H),2.65-2.57(m,2H),2.41(dd,J=16.7,8.4Hz,1H),2 .28-2.21(m,2H),2.20-2.09(m,2H),2.03(dd,J=13.9,7.0Hz,2H),1.93(dd,J=16.1,7.5Hz,2H),1.78(d,J=12.3Hz,2H).

[0958] Example 39: Preparation of compound 39

[0959]

[0960] Step A: Preparation of compound 39A

[0961] At room temperature, 0.914 g of dilute hydrochloric acid was slowly added to a 20 mL solution of 1 g of tert-butyl 4-oxopiridine-1-carboxylic acid. After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the solution was concentrated to give compound 39A (0.7 g).

[0962] MS(ESI, [M+H]) + )m / z:100.1.

[0963] Step B: Preparation of compound 39B

[0964] Compound 39A (0.7 g), 1-bromo-3-iodobenzene (1.461 g), potassium carbonate (2.85 g), cuprous iodide (0.098 g), L-alanine (0.119 g), and dimethyl sulfoxide (10 mL) were added sequentially to a reaction flask under nitrogen protection and stirred at 100 °C. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 39B (0.088 g).

[0965] MS(ESI, [M+H]) + )m / z:254.1.

[0966] Step C: Preparation of compound 39C

[0967] Compound 39B (0.3 g), 2-aminopropane-1-ol (0.177 g), acetic acid (0.142 g), and methanol (10 mL) were added sequentially to a reaction flask under nitrogen protection and stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.148 g) was then added to the reaction flask and stirred at room temperature. After the reaction was complete, the mixture was concentrated and subjected to column chromatography (dichloromethane / methanol = 25 / 1) to give compound 39C (0.23 g).

[0968] MS(ESI, [M+H]) + )m / z:313.4.

[0969] Step D: Preparation of compound 39D

[0970] N,N-carbonyldiimidazole (0.179 g), compound 39C (0.23 g), and toluene (10 mL) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was stirred at room temperature for 1 hour, then stirred at 110 °C. After the reaction was complete, the mixture was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 39D (0.16 g).

[0971] MS(ESI, [M+H]) + )m / z:339.1.

[0972] Step E: Preparation of compound 39E

[0973] Compound 39D (0.16 g), pinacol diborate (0.24 g), potassium acetate (0.14 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.039 g), and 1,4-dioxane (20 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 50 / 1) yielded compound 39E (0.06 g).

[0974] MS(ESI, [M+H]) + )m / z:387.6.

[0975] Step F: Preparation of compound 39F

[0976] Compound 39E (0.06 g), compound 1C (0.08 g), potassium carbonate (0.045 g), tetra(triphenylphosphine)palladium (0.038 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 30 / 1) yielded compound 39F (65 mg).

[0977] MS(ESI, [M+H]) + )m / z:715.5.

[0978] Step G: Preparation of compound 39

[0979] Compound 39F (0.065 g), methanesulfonic acid (0.051 g), and dichloromethane (20 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding a 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 39 (0.032 g).

[0980] MS(ESI, [M+H]) + )m / z:615.7.

[0981] 1 H NMR (500MHz, CDCl3) δ8.05(d,J=8.3Hz,1H),7.91(d,J=4.0Hz,1H),7.71(d,J=8.4Hz,1H),7.66(d,J=8.2Hz,2H),7.49(s,1H),7.45(d ,J=7.6Hz,1H),7.40(d,J=8.2Hz,2H),7.24(d,J=7.9Hz,1H),7.09(d,J=7.5Hz,1H),6.88(d,J=7.9Hz,3H),6.41(dd,J=7.2,5.3Hz,1H ),4.35(t,J=8.3Hz,1H),4.00-3.90(m,1H),3.82(dd,J=8.2,5.6Hz,1H),3.77-3.65(m,3H),2.86-2.72(m,4H),2.68(s,4H),2.37(d, J=7.5Hz,1H),2.07(qd,J=12.1,3.7Hz,1H),1.99-1.92(m,2H),1.88(d,J=7.1Hz,1H),1.81(d,J=10.8Hz,1H),1.32(d,J=6.1Hz,3H).

[0982] Example 40: Preparation of Compound 40

[0983]

[0984] Step A: Preparation of compound 40A

[0985] To a reaction flask, cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (250 mg), 1,3-dibromo-2-fluorobenzene (448 mg), tris(dibenzylacetone)dipalladium (55 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (40 mg), tetrahydrofuran (30 mL), and sodium tert-butoxide (509 mg) were added sequentially. After the addition was complete, the mixture was stirred at 80 °C under nitrogen protection. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 40A (164 mg).

[0986] MS(ESI, [M+H]) + )m / z:385.0.

[0987] Step B: Preparation of compound 40B

[0988] To a reaction flask containing compound 40A (164 mg), dichloromethane (15 mL) and methanesulfonic acid (130 mg) were added sequentially. After the addition was complete, the mixture was stirred at room temperature. The reaction was allowed to proceed to the next step without further processing.

[0989] Step C: Preparation of compound 40C

[0990] Triethylamine (42.9 mg) and acetic anhydride (43.3 mg) were added to the reaction solution containing compound 40B, and the mixture was stirred at room temperature after the addition was complete. After the reaction was complete, the mixture was washed twice with water and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated to give compound 40C (142 mg).

[0991] MS(ESI, [M+H]) + )m / z:327.4.

[0992] Step D: Preparation of compound 40D

[0993] Compound 40C (142 mg), pinacol diborate (164 mg), potassium acetate (127 mg), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (50 mg), and 1,4-dioxane (10 mL) were added sequentially to the reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was then filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 5 / 1) yielded compound 40D (101 mg).

[0994] MS(ESI, [M+H]) + )m / z:375.4.

[0995] Step E: Preparation of compound 40E

[0996] Compound 40D (100 mg), compound 1C (135 mg), potassium carbonate (150 mg), tetra(triphenylphosphine)palladium (20 mg), 1,4-dioxane (3 mL), and water (0.3 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 120 °C. The reaction was completed, filtered, and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 40E (101 mg).

[0997] MS(ESI, [M+H]) + )m / z:703.5.

[0998] Step F: Preparation of Compound 40

[0999] Compound 40E (101 mg), methanesulfonic acid (138 mg), and dichloromethane (10 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature after the addition was complete. After the reaction was complete, the pH of the reaction solution was adjusted to 9 with a saturated sodium carbonate aqueous solution, and the mixture was extracted with water and dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 40 (42 mg).

[1000] MS(ESI, [M+H]) + )m / z:603.7.

[1001] 1 H NMR (500MHz, CDCl3) δ8.12(d,J=8.5Hz,1H),8.05(d,J=1.0Hz,1H),7.76(d,J=7.0Hz,1H),7.54(d,J=8.0Hz,2H),7.40(d,J=8.0 Hz,2H),7.26-7.24(m,1H),7.10(d,J=7.5Hz,1H),7.06(t,J=8.0Hz,1H),6.71(t,J=8.0Hz,1H),6.58(s,2H),6.39(dd,J=5.0,7 .5Hz,1H),3.80-3.75(m,2H),3.61-3.56(m,2H),3.54-3.51(m,1H),3.43-3.40(m,1H),3.37-3.32(m,2H),3.10-3.04(m,1H),3 .02-2.96(m,1H),2.63-2.58(m,2H),2.27-2.24(m,2H),2.17-2.12(m,2H),2.06(s,3H),2.06-2.04(m,1H),1.86-1.78(m,1H).

[1002] Example 41: Preparation of compound 41

[1003]

[1004] Step A: Preparation of compound 41A

[1005] 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.94 g), bis(diphenylmethyl ethyl acetone)palladium (2.164 g), 1,3-dibromo-2-fluorobenzene (6 g), tert-butylpiperidin-4-ylcarbamate (4.73 g), sodium tert-butoxide (4.54 g), and dioxane (20 mL) were added sequentially to a reaction flask. The mixture was stirred overnight at 100°C under nitrogen protection. After the reaction was complete, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 50 / 1) to give compound 41A (2.6 g).

[1006] MS(ESI, [M+H]) + )m / z:373.2.

[1007] Step B: Preparation of compound 41B

[1008] Compound 41A (2.6 g), dichloromethane (30 mL), and a dioxane solution (7.37 mL) in hydrochloric acid were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and compound 41B (2 g) was obtained.

[1009] MS(ESI, [M+H]) + )m / z:273.3.

[1010] Step C: Preparation of compound 41C

[1011] Under ice-water bath conditions, 0.611 g of 4-chlorobutane-1-sulfonyl chloride was slowly added to a 15 mL solution of N,N-dimethylformamide containing 0.873 g of compound 41B. After the addition was complete, the reaction mixture was slowly heated to room temperature with stirring. After the reaction was complete, the reaction mixture was added to 30 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 0.826 g of compound 41C.

[1012] MS(ESI, [M+H]) + )m / z:427.4.

[1013] Step D: Preparation of compound 41D

[1014] Compound 41C (0.826 g) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydrogen hydride (153 mg) was added under ice bath conditions. After the addition was complete, the mixture was refluxed at 80 °C overnight. After the reaction was complete, the reaction solution was poured into 30 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 41D (0.3 g).

[1015] MS(ESI, [M+H]) + )m / z:391.6.

[1016] Step E: Preparation of compound 41E

[1017] Compound 41D (0.3 g), pinacol diborate (0.389 g), potassium acetate (0.15 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.125 g), and 1,4-dioxane (15 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection and stirred at 100 °C. After the reaction was complete, the mixture was filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 7 / 3) yielded compound 41E (0.265 g).

[1018] MS(ESI, [M+H]) + )m / z:439.5.

[1019] Step F: Preparation of compound 41F

[1020] Compound 41E (0.265 g), compound 1C (0.187 g), potassium carbonate (0.105 g), tetra(triphenylphosphine)palladium (0.088 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / 10% methanol = 4 / 1) yielded compound 41F (184 mg).

[1021] MS(ESI, [M+H]) + )m / z:767.7.

[1022] Step G: Preparation of compound 41

[1023] Compound 41F (171 mg), methanesulfonic acid (0.142 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / 10% methanol = 1 / 1) to give compound 41 (80 mg).

[1024] MS(ESI, [M+H]) + )m / z:667.6.

[1025] 1 H NMR(500MHz,DMSO-d6)δ8.26(d,1H),8.00(s,1H),7.73(s,1H),7.60(s,2 H),7.44(s,2H),7.29(s,1H),7.09-7.19(m,3H),6.94(s,2H),6.41(s,1H ),3.86(s,1H),3.56(s,2H),3.42(s,2H),3.06(s,2H),2.77(s,2H),2.43 (s,2H),2.17(s,2H),2.04(s,3H),1.89(d,2H),1.72(s,2H),1.60(s,2H).

[1026] Example 42: Preparation of compound 42

[1027]

[1028] Step A: Preparation of compound 42A

[1029] Under ice-water bath conditions, 0.538 g of 3-chloropropane-1-sulfonyl chloride was slowly added to a 15 mL solution of N,N-dimethylformamide containing 0.83 g of compound 41B. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred. After the reaction was complete, the reaction mixture was added to 30 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 13 / 7) to give compound 42A (0.212 g).

[1030] MS(ESI, [M+H]) + )m / z:413.4.

[1031] Step B: Preparation of compound 42B

[1032] Compound 42A (0.212 g) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydrogen hydride (146 mg) was added under ice bath conditions. After the addition was complete, the mixture was refluxed at 80 °C overnight. After the reaction was complete, the reaction solution was poured into 30 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain compound 42B (0.249 g).

[1033] MS(ESI, [M+H]) + )m / z:377.3.

[1034] Step C: Preparation of compound 42C

[1035] Compound 42B (0.249 g), pinacol diborate (0.335 g), potassium acetate (0.13 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.054 g), and 1,4-dioxane (15 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 1 / 1) yielded compound 42C (0.21 g).

[1036] MS(ESI, [M+H]) + )m / z:425.3.

[1037] Step D: Preparation of compound 42D

[1038] Compound 42C (0.21 g), compound 1C (0.243 g), potassium carbonate (0.137 g), tetra(triphenylphosphine)palladium (0.057 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 110 °C. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / 10% methanol = 3 / 7) yielded compound 42D (185 mg).

[1039] MS(ESI) m / z: 753.7 [M+H] + .

[1040] Step E: Preparation of Compound 42

[1041] Compound 42D (185 mg), methanesulfonic acid (0.16 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / 10% methanol = 2 / 3) to give compound 42 (40 mg).

[1042] MS(ESI, [M+H]) + )m / z:653.6.

[1043] 1H NMR(500MHz,DMSO-d6)δ8.26(d,1H),8.00(d,1H),7.7(d,1H),7.59(d,2H),7.42(d,2H),7.28(t,1H),7.08-7.20(m,3H),6.90(s,2H), 6.41(t,1H),3.4(d,2H),3.28(t,3H),3.19(t,2H),2.8(m,2H),2.42(q,2H),2.2(m,2H),2.02-2.13(m,3H),1.88(s,4H),1.70(m,1H).

[1044] Example 43: Preparation of compound 43

[1045]

[1046] Step A: Preparation of compound 43A

[1047] To a reaction flask, tert-butyl octane-3-ylcarbamate (0.5 g), 1-bromo-3-iodobenzene (0.75 g), potassium carbonate (0.92 g), cuprous iodide (0.05 g), L-proline (0.02 g), and dimethyl sulfoxide (10 mL) were added sequentially. After the additions were complete, the mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 43A (0.14 g).

[1048] MS(ESI, [M+H]) + )m / z:381.5.

[1049] Step B: Preparation of compound 43B

[1050] Compound 43A (0.14 g) and a 4M dioxane solution (4 mL) of hydrogen chloride were added sequentially to the reaction flask and stirred at room temperature. The reaction was completed, and the mixture was concentrated to give compound 43B (0.15 g).

[1051] MS(ESI, [M+H]) + )m / z:281.8.

[1052] Step C: Preparation of compound 43C

[1053] At 0°C, acetic anhydride (0.07 g) was slowly added to a reaction solution of compound 43B (0.15 g) and triethylamine (0.24 g) in dichloromethane (6 mL). After the addition was complete, the reaction solution was transferred to room temperature and stirred. Once the reaction was complete, saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), and dried. The mixture was filtered and concentrated to obtain compound 43C (0.11 g).

[1054] MS(ESI, [M+H]) + )m / z:323.4.

[1055] Step D: Preparation of compound 43D

[1056] At 0°C under nitrogen protection, sodium hydride (0.07 g) was slowly added to a tetrahydrofuran (12 mL) reaction solution of compound 43C (0.22 g). After the addition was complete, the reaction solution was transferred to room temperature and stirred for 0.5 h. Iodomethane (0.48 g) was then added to the reaction solution. After the reaction was complete, saturated ammonium chloride aqueous solution (50 mL) was added to the reaction solution under ice bath conditions. The solution was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), and dried. The solution was filtered and concentrated to obtain compound 43D (0.22 g).

[1057] MS(ESI, [M+H]) + )m / z:336.8.

[1058] Step E: Preparation of compound 43E

[1059] Compound 43D (0.22 g), pinacol diborate (0.25 g), potassium acetate (0.20 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.05 g), and 1,4-dioxane (10 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 43E (0.1 g).

[1060] MS(ESI, [M+H]) + )m / z:385.6.

[1061] Step F: Preparation of compound 43F

[1062] Compound 43E (0.10 g), compound 1C (0.11 g), potassium carbonate (0.09 g), tetra(triphenylphosphine)palladium (0.03 g), 1,4-dioxane (4 mL), and water (0.5 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 100 °C. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 43F (0.10 g).

[1063] MS(ESI, [M+H]) + )m / z:713.7.

[1064] Step F: Preparation of compound 43

[1065] Compound 43F (100 mg), methanesulfonic acid (0.10 mL), and dichloromethane (6 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 43 (26 mg).

[1066] MS(ESI, [M+H]) + )m / z:613.7.

[1067] 1 H NMR (500MHz, CDCl3) δ8.06 (dt, J=36.6, 6.5Hz, 2H), 7.76 (q, J=6.6, 5.8Hz, 1H), 7.58 (t, J=7.4H z,2H),7.53-7.39(m,3H),7.39-7.24(m,2H),7.15(q,J=6.9Hz,1H),6.79(t,J=7.5Hz,1H),6.6 1(s,2H),6.39(q,J=6.4Hz,1H),5.18(dq,J=12.7,6.5Hz,1H),4.35(d,J=14.0Hz,2H),2.61(q, J=9.4,8.6Hz,3H),2.55-2.30(m,6H),2.25-2.05(m,4H),2.05-1.77(m,6H),1.53-1.20(m,3H).

[1068] Example 44: Preparation of compound 44

[1069]

[1070] Step A: Preparation of compound 44A

[1071] At 0°C, acetic anhydride (0.68 g) was slowly added to a reaction solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1 g) and triethylamine (2.24 g) in dichloromethane (20 mL). After the addition was complete, the reaction solution was transferred to room temperature and stirred. After the reaction was complete, the solution was extracted with saturated sodium bicarbonate aqueous solution and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to obtain compound 44A (1.18 g).

[1072] MS(ESI, [M+H]) + )m / z:269.5.

[1073] Step B: Preparation of compound 44B

[1074] At 0°C, 2 mL of trifluoroacetic acid was slowly added dropwise to a reaction solution of 0.5 g of compound 44A in 10 mL of dichloromethane. After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain 0.85 g of compound 44B.

[1075] MS(ESI, [M+H]) + )m / z:169.4.

[1076] Step C: Preparation of compound 44C

[1077] Compound 44B (0.5 g), 1,3-dibromofluorobenzene (0.68 g), (tris(dibenzylacetone)dipalladium) (0.16 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.11 g), sodium tert-butoxide (0.85 g), and 1,4-dioxane (25 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 50 / 1) to give compound 44C (0.22 g).

[1078] MS(ESI, [M+H]) + )m / z:341.4.

[1079] Step D: Preparation of compound 44D

[1080] Compound 44C (0.22 g), pinacol diborate (0.24 g), potassium acetate (0.19 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.05 g), and 1,4-dioxane (20 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 44D (98 mg).

[1081] MS(ESI, [M+H]) +)m / z:389.5.

[1082] Step E: Preparation of compound 44E

[1083] Compound 44D (98 mg), compound 1C (103 mg), potassium carbonate (87 mg), tetra(triphenylphosphine)palladium (24 mg), 1,4-dioxane (4 mL), and water (0.5 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 100 °C. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 44E (84 mg).

[1084] MS(ESI, [M+H]) + )m / z:717.4.

[1085] Step F: Preparation of compound 44

[1086] Compound 44E (84 mg), methanesulfonic acid (0.10 mL), and dichloromethane (6 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 44 (37 mg).

[1087] MS(ESI, [M+H]) + )m / z:617.6.

[1088] 1 H NMR(500MHz, CDCl3)δ8.11(d,J=8.3Hz,1H),8.05-7.99(m,1H),7.79(dd,J=8.4,2.1Hz, 1H),7.56(d,J=8.0Hz,2H),7.49(t,J=7.3Hz,1H),7.38(d,J=8.0Hz,2H),7.14-7.06(m, 2H),6.95(t,J=7.9Hz,1H),6.59(s,2H),6.39(dd,J=7.7,4.8Hz,1H),3.80(d,J=49.5Hz ,4H),3.06-2.92(m,4H),2.64-2.58(m,2H),2.40-2.32(m,2H),2.24-2.14(m,1H),1.98 -1.92(m,4H),1.89(s,3H),1.85-1.80(m,1H).

[1089] Example 45: Preparation of compound 45

[1090]

[1091] Step A: Preparation of compound 45A

[1092] At 0°C, under nitrogen protection, sodium hydride (7.9 g) was slowly added to a tetrahydrofuran solution of 10 g of 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, and the mixture was stirred at room temperature for 1 hour. Iodomethane (27.9 g) was then added dropwise to the reaction flask at 0°C, and the mixture was stirred at room temperature after the addition was complete. After the reaction was complete, the reaction was quenched with an aqueous solution of ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 45A (13.0 g).

[1093] MS(ESI, [M+H]) + )m / z:269.5.

[1094] Step B: Preparation of compound 45B

[1095] Compound 45A (13.0 g), dichloromethane (260 mL), and dilute hydrochloric acid (12.4 g) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the mixture was filtered and dried to obtain compound 45B (8.9 g).

[1096] MS(ESI, [M+H]) + )m / z:169.4.

[1097] Step C: Preparation of compound 45C

[1098] Sodium tert-butoxide (11.3 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (1.8 g), tris(dibenzylacetone)dipalladium (2.7 g), 1,3-dibromo-2-fluorobenzene (11.2 g), compound 45B (8.9 g), and 1,4-dioxane (100 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C under nitrogen protection until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 100 / 1) yielded compound 45C (4.8 g).

[1099] MS(ESI, [M+H]) + )m / z:341.4.

[1100] Step D: Preparation of compound 45D

[1101] Compound 45C (3.0 g), pinacol diborate (3.4 g), potassium acetate (2.6 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (1.4 g), and 1,4-dioxane (100 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 100 / 1) yielded compound 45D (3.0 g).

[1102] MS(ESI, [M+H]) + )m / z:389.5.

[1103] Step E: Preparation of compound 45E

[1104] Compound 45D (2.8 g), compound 1C (2.3 g), potassium carbonate (1.3 g), tetra(triphenylphosphine)palladium (1.1 g), 1,4-dioxane (50 mL), and water (10 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 45E (2.1 g).

[1105] MS(ESI, [M+H]) + )m / z:717.5.

[1106] Step F: Preparation of compound 45

[1107] Compound 45E (2.1 g), methanesulfonic acid (2.3 g), and dichloromethane (80 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding a 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 45 (0.43 g).

[1108] MS(ESI, [M+H]) + )m / z:617.6.

[1109] 1H NMR (500MHz, CDCl3) δ8.19-7.88(m,2H),7.73(d,J=8.5Hz,1H),7.60-7.26(m, 5H),7.05(s,2H),6.94(d,J=8.8Hz,1H),6.53(d,J=10.6Hz,1H),6.33(s,1H), 3.19(s,2H),3.02(s,4H),2.94(d,J=9.5Hz,2H),2.79(s,3H),2.60-2.52(m,1 H),2.27(d,J=14.2Hz,3H),2.10(s,1H),1.75(s,4H),1.19(d,J=14.4Hz,1H).

[1110] Example 46: Preparation of Compound 46

[1111]

[1112] Step A: Preparation of compound 46A

[1113] 1.4 g of tert-butyl oxalate 4-amino-3-methylpiperidin-1-carboxylate, 0.93 g of triethylamine, 0.93 g of 4-bromobutyryl chloride, and 25 mL of tetrahydrofuran were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature. The reaction proceeded to completion, the solvent was removed by vacuum distillation, and the mixture was concentrated to give compound 46A (0.84 g).

[1114] MS(ESI, [M+H]) + )m / z:363.1.

[1115] Step B: Preparation of compound 46B

[1116] Compound 46A (3.0 g), sodium hydride (0.088 g), and tetrahydrofuran (25 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 46B (0.18 g).

[1117] MS(ESI, [M+H]) + )m / z:283.5.

[1118] Step C: Preparation of compound 46C

[1119] Compound 46B (1.0 g), a 4M hydrochloric acid solution of 1,4-dioxane (3.7 mL), and a 1,4-dioxane solution (20 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the solution was concentrated to give compound 46C (0.83 g).

[1120] MS(ESI, [M+H]) + )m / z:183.5.

[1121] Step D: Preparation of compound 46D

[1122] Compound 46C (3.0 g), cesium carbonate (2.3 g), tris(dibenzylacetone)dipalladium-chloroform adduct (0.21 g), 1-(3-methylpiperidin-4-yl)pyrrolidine-2-one hydrochloride (0.51 g), 1,3-dibromo-m-fluorobenzene (0.89 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.14 g), and dioxane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C. After the reaction was complete, the mixture was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 46D (0.38 g).

[1123] MS(ESI, [M+H]) + )m / z:355.4.

[1124] Step E: Preparation of compound 46E

[1125] Under nitrogen protection, 0.38 g of 46D, 0.21 g of potassium carbonate, 0.41 g of pinacol diborate, 0.17 g of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and 20 mL of dioxane were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 46E (0.16 g).

[1126] MS(ESI, [M+H]) + )m / z:403.6.

[1127] Step F: Preparation of compound 46F

[1128] Compound 46E (0.16 g), compound 1C (0.18 g), potassium carbonate (0.087 g), tetra(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (10 mL), and water (2.0 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 46F (0.20 g).

[1129] MS(ESI, [M+H]) + )m / z:731.8.

[1130] Step G: Preparation of Compound 46

[1131] Compound 46F (0.20 g), methanesulfonic acid (0.16 g), and dichloromethane (15 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 with 10% sodium hydroxide solution. The mixture was extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 46 (0.078 g).

[1132] MS(ESI, [M+H]) + )m / z:631.7.

[1133] 1 H NMR (500MHz, CDCl3) δ8.10-8.04 (m, 1H), 7.94 (dd, J = 5.0, 2.3Hz, 1H), 7.74 ( dq,J=8.1,2.7Hz,1H),7.56-7.47(m,2H),7.43-7.33(m,3H),7.05(tt,J=11 .9,3.0Hz,2H),6.95(t,J=8.0Hz,1H),6.34(ddd,J=7.4,4.9,2.1Hz,1H),3. 71(td,J=12.1,4.2Hz,1H),3.46-3.32(m,3H),3.32-3.26(m,1H),2.76(td, J=11.9,2.9Hz,1H),2.59(dddd,J=11.9,9.0,6.3,2.3Hz,2H),2.47-2.41(m ,1H),2.37(dtt,J=11.7,5.8,2.6Hz,4H),2.15(ddtt,J=15.9,9.6,6.7,3.4 Hz,1H),1.98(dp,J=12.3,5.2,4.0Hz,3H),1.81(ddtq,J=12.4,9.3,6.3,3. 7,2.9Hz,1H),1.72-1.60(m,1H),1.34(d,J=2.3Hz,1H),1.26-1.14(m,3H).

[1134] Example 47: Preparation of Compound 47

[1135]

[1136] Step A: Preparation of compound 47A

[1137] 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (2.5 g), acetic anhydride (1.93 g), triethylamine (6.3 g), and dichloromethane (40 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, water and dichloromethane were added to the reaction solution for extraction, followed by washing with saturated brine and drying over anhydrous sodium sulfate. The mixture was filtered, concentrated, and compound 47A (3.0 g) was obtained.

[1138] MS(ESI, [M+Na)) + )m / z:241.1.

[1139] Step B: Preparation of compound 47B

[1140] Compound 47A (3.01 g), trifluoroacetic acid (2.2 g), and dichloromethane (50 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 47B (2.3 g).

[1141] MS(ESI, [M+H]) + )m / z:141.1.

[1142] Step C: Preparation of compound 47C

[1143] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.73 g), tris(dibenzylacetone)dipalladium (0.26 g), 1,3-dibromo-2-fluorobenzene (4.5 g), compound 47B (1.6 g), sodium tert-butoxide (11 g), and dioxane (20 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 85 °C. Once the reaction was complete, the reaction solution was concentrated, and column chromatography (petroleum ether / ethyl acetate = 9 / 1) was performed to give compound 47C (0.43 g).

[1144] MS(ESI, [M+H]) + )m / z:312.9.

[1145] Step D: Preparation of compound 47D

[1146] Compound 47C (0.43 g), pinacol diborate (0.52 g), potassium acetate (0.22 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.270 g), and 1,4-dioxane (60 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 47D (0.13 g).

[1147] MS(ESI, [M+H]) + )m / z:361.6.

[1148] Step E: Preparation of compound 47E

[1149] Compound 47D (0.13 g), compound 1C (0.12 g), potassium carbonate (0.068 g), tetra(triphenylphosphine)palladium (0.057 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 47E (0.21 g).

[1150] MS(ESI, [M+H]) + )m / z:689.44.

[1151] Step F: Preparation of Compound 47

[1152] Compound 47E (0.21 g), methanesulfonic acid (0.58 g), and dichloromethane (25 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 47 (0.11 g).

[1153] MS(ESI, [M+H]) + )m / z:589.6.

[1154] 1 H NMR (500MHz, CDCl3) δ8.07-7.89(m,2H),7.61(d,J=8.4Hz,1H),7.46(dd,J=17.7,8.1Hz,2H),7.28(t,J=12.7Hz,2H), 7.15(t,J=7.4Hz,1H),7.05(d,J=7.8Hz,1H),6.97(q,J=7.7Hz,1H),6.48(dt,J=26.1,8.2Hz,2H),6.33(dd,J=7.8,4.8 Hz,1H),4.46-4.25(m,2H),3.86(dd,J=18.6,12.8Hz,2H),3.53(d,J=13.7Hz,1H),3.47-3.28(m,1H),2.78(q,J=6.9H z,1H),2.48(dq,J=53.9,11.6,10.3Hz,4H),2.28-2.09(m,1H),1.91-1.79(m,3H),1.54(d,J=8.6Hz,1H),1.35(s,1H).

[1155] Example 48: Preparation of compound 48

[1156]

[1157] Step A: Preparation of compound 48A

[1158] 3.5 g of 4-amino-3-methylpiperidin-1-carboxylic acid tert-butyl oxalate, 2.9 g of triethylamine, 3.3 g of 4-bromobutyryl chloride, and 25 ml of tetrahydrofuran were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature. The reaction proceeded to completion, the solvent was removed by vacuum distillation, and the mixture was concentrated to give compound 48A (0.78 g).

[1159] MS(ESI, [M+H]) + )m / z:363.1.

[1160] Step B: Preparation of compound 48B

[1161] Compound 48A (1.4 g), sodium hydride (0.088 g), and tetrahydrofuran (25 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 48B (0.52 g).

[1162] MS(ESI, [M+H]) + )m / z:283.5.

[1163] Step C: Preparation of compound 48C

[1164] Compound 48B (0.52 g), a 1,4-dioxane solution in 4M hydrochloric acid (0.34 mL), and a 1,4-dioxane solution (20 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the solution was concentrated to give compound 48C (0.41 g).

[1165] MS(ESI, [M+H]) + )m / z:183.5.

[1166] Step D: Preparation of compound 48D

[1167] Compound 48C (0.41 g), cesium carbonate (2.2 g), tris(dibenzylacetone)dipalladium-chloroform adduct (0.21 g), 1-(3-methylpiperidin-4-yl)pyrrolidine-2-one hydrochloride (0.51 g), 1,3-dibromo-m-fluorobenzene (0.89 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.14 g), and dioxane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at 100 °C. After the reaction was complete, the mixture was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 48D (0.28 g).

[1168] MS(ESI, [M+H]) +)m / z:337.1.

[1169] Step E: Preparation of compound 48E

[1170] Under nitrogen protection, 48D (0.28 g), potassium carbonate (0.24 g), pinacol diborate (0.32 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.138 g), and dioxane (20 mL) were added sequentially to the reaction flask. After the additions were complete, the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 48E (0.087 g).

[1171] MS(ESI, [M+H]) + )m / z:385.3.

[1172] Step F: Preparation of compound 48F

[1173] Compound 48E (0.087 g), compound 1C (0.075 g), potassium carbonate (0.087 g), tetra(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 48F (0.080 g).

[1174] MS(ESI, [M+H]) + )m / z:713.1.

[1175] Step G: Preparation of compound 48

[1176] Compound 48F (0.080 g), methanesulfonic acid (0.16 g), and dichloromethane (15 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 with 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 48 (0.021 g).

[1177] MS(ESI, [M+H]) + )m / z:613.1.

[1178] 1H NMR (500MHz, CDCl3) δ8.09-7.94(m,2H),7.70(d,J=8.5Hz,1H),7.48(h,J=9.0,8.5Hz,3H),7.36(d,J=7.8Hz,2H),7.23(t,J=7.9Hz,1H),7.09 (d,J=7.7Hz,1H),6.84(dd,J=8.2,2.4Hz,1H),6.59(d,J=20.1Hz,2H),6.33(dd,J=7.8,4.8Hz,1H),4.39(ddt,J=12.9,9.3,4.6Hz,1H),4.26(d t, J = 22.0, 11.0 Hz, 1H), 3.47 (dt, J = 12.6, 3.7 Hz, 1H), 3.29 (t, J = 7.0 Hz, 2H), 3.16-3.03 (m, 1H), 2.54 (dt, J = 12.0, 8.5 Hz, 3H), 2.35 (t, J = 8.1 Hz, 3H), 2.16 (tt, J = 9.0, 4.5 Hz, 3H), 1.72 (dtd, J = 24.1, 12.1, 11.6, 6.7 Hz, 4H), 1.60 (d, J = 12.3 Hz, 2H), 1.07 (d, J = 6.9 Hz, 3H). Example 49: Preparation of compound 49

[1179]

[1180] Step A: Preparation of compound 49A

[1181] 33A (0.52 g), 1,3-dibromofluorobenzene (0.83 g), tris(dibenzylacetone)dipalladium (0.20 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.14 g), sodium tert-butoxide (1.04 g), and 1,4-dioxane (30 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 50 / 1) to give compound 49A (0.22 g).

[1182] MS(ESI, [M+H]) + )m / z:299.3.

[1183] Step B: Preparation of compound 49B

[1184] At 0°C under nitrogen protection, sodium hydride (0.11 g) was slowly added to a tetrahydrofuran (10 mL) reaction solution of compound 49A (0.16 g). After the addition was complete, the reaction solution was transferred to room temperature and stirred for 0.5 h. Iodomethane (0.23 g) was then added to continue the reaction. After the reaction was complete, saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction solution under ice bath for extraction. The solution was washed with saturated brine and dried. After filtration, the solution was concentrated to obtain compound 49B (0.18 g).

[1185] MS(ESI, [M+H]) + )m / z:313.3.

[1186] Step C: Preparation of compound 49C

[1187] Compound 49B (0.17 g), pinacol diborate (0.20 g), potassium acetate (0.16 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.04 g), and 1,4-dioxane (10 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 49C (0.19 g).

[1188] MS(ESI, [M+H]) + )m / z:361.5.

[1189] Step D: Preparation of compound 49D

[1190] Compound 49C (0.14 g), compound 1C (0.16 g), potassium carbonate (0.14 g), tetrakis(triphenylphosphine)palladium (0.04 g), 1,4-dioxane (4 mL), and water (0.5 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was introduced, and the mixture was microwaved at 100 °C. Once the reaction was complete, the reaction solution was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 49D (0.14 g).

[1191] MS(ESI, [M+H]) + )m / z:689.7.

[1192] Step E: Preparation of Compound 49

[1193] Compound 49D (135 mg), methanesulfonic acid (0.10 mL), and dichloromethane (6 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 49 (49 mg).

[1194] MS(ESI, [M+H]) + )m / z:589.4.

[1195] 1 H NMR (500MHz, CDCl3) δ8.14 (dd, J=8.5, 3.4Hz, 1H), 8.02 (dt, J=4.9, 2.5Hz, 1H), 7.83

[1196] -7.75(m,1H),7.55(dt,J=8.4,2.4Hz,2H),7.42(dt,J=8.3,2.4Hz,2H),7.32-7.26(m,1H),7.17

[1197] -7.13(m,1H),7.07(dd,J=9.5,6.0Hz,1H),6.57-6.49(m,1H),6.45-6.39(m,1H),4.10-3.96(m,4H),3.71(d,J=3.3Hz,2H) ,2.89(d,J=3.5Hz,3H),2.72(d,J=3.5Hz,2H),2.70-2.60(m,2H),2.37-2.22(m,2H),2.20-2.08(m,1H),1.90-1.80(m,1H).

[1198] Example 50: Preparation of Compound 50

[1199]

[1200] Step A: Preparation of compound 50A

[1201] Compound 39B (1.7 g), L-proline benzyl hydrochloride (2.4 g), acetic acid (0.8 g), and methanol (20 mL) were added sequentially to a reaction flask under nitrogen protection and stirred at room temperature. Sodium cyanoborohydride (0.84 g) was then added, and the mixture was stirred at room temperature after the addition was complete. After the reaction was complete, saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and the mixture was concentrated. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 50A (1.3 g).

[1202] MS(ESI,[M+H) + )m / z:443.4.

[1203] Step B: Preparation of compound 50B

[1204] Compound 50A (1.3 g), sodium hydroxide (0.35 g), tetrahydrofuran (30 mL), and water (10 mL) were added sequentially to a reaction flask, and the mixture was stirred at 70 °C. After the reaction was complete, the mixture was concentrated, and the residue was extracted with ethyl acetate. The aqueous phase was adjusted to pH 4-5 with 1 M dilute hydrochloric acid, concentrated, dissolved in methanol (30 mL), filtered through an organic membrane, and concentrated to obtain compound 50B (1.0 g).

[1205] Step C: Preparation of compound 50C

[1206] Compound 50B (1.0 g), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.2 g), and dichloromethane (20 mL) were added sequentially to a reaction flask under nitrogen protection and stirred at room temperature. N,N-diisopropylethylamine (1.5 g) and N,O-dimethylhydroxylamine hydrochloride (0.4 g) were then added, and the mixture was stirred at room temperature after the addition was complete. After the reaction was complete, the mixture was concentrated and subjected to column chromatography (dichloromethane / methanol = 100 / 1) to give compound 50C (1.0 g).

[1207] MS(ESI,[M+H) + )m / z:396.2.

[1208] Step D: Preparation of compound 50D

[1209] At -15°C, under nitrogen protection, methyl magnesium bromide (1.5 g) was added dropwise to a tetrahydrofuran (20 mL) solution of compound 50C (1.0 g). After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, 50 mL of saturated ammonium chloride aqueous solution was added to the reaction flask, and the mixture was extracted with ethyl acetate and concentrated. Column chromatography (dichloromethane / methanol = 40 / 1) yielded compound 50D (0.23 g).

[1210] MS(ESI,[M+H) + )m / z:351.1.

[1211] Step E: Preparation of compound 50E

[1212] Compound 50D (0.23 g), pinacol diborate (0.33 g), potassium acetate (0.2 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.053 g), and 1,4-dioxane (20 mL) were added sequentially to a reaction flask. Under nitrogen protection, the reaction was stirred at 100 °C until complete. The mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 40 / 1) to give compound 50E (0.054 g).

[1213] MS(ESI,[M+H) + )m / z:399.4.

[1214] Step F: Preparation of compound 50F

[1215] Compound 50E (0.054 g), compound 1C (0.06 g), potassium carbonate (0.051 g), tetra(triphenylphosphine)palladium (0.014 g), 1,4-dioxane (5 mL), and water (1 mL) were added sequentially to a reaction flask. After the additions were complete, the mixture was stirred at 100 °C under nitrogen protection. Once the reaction was complete, the mixture was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 50F (0.050 g).

[1216] MS(ESI,[M+H) + )m / z:727.4.

[1217] Step F: Preparation of Compound 50

[1218] Compound 50F (0.05 g), methanesulfonic acid (0.066 g), and dichloromethane (6 mL) were added sequentially to a reaction flask and stirred at room temperature. After the reaction was complete, the pH was adjusted to 13 by adding a 10% sodium hydroxide aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 50 (0.0050 g).

[1219] MS(ESI, [M+H]) + )m / z:627.7.

[1220] 1 H NMR (500MHz, DMSO) δ9.36(d,J=41.5Hz,1H),8.99(s,1H),8.34-8.26(m,1H),8.08(d,J=6.1Hz,1H),8.03(d,J=8.4Hz,1 H),7.74(dd,J=33.2,8.5Hz,2H),7.66-7.57(m,3H),7.48(d,J=7.1Hz,3H),7.31(t,J=7.9Hz,1H),7.02(d,J=6.5Hz,1H) ,6.61(s,1H),4.88(d,J=26.5Hz,1H),3.90(dd,J=20.9,9.0Hz,2H),3.55(d,J=34.7Hz,2H),2.72(s,3H),2.63(t,J=7.8 Hz,4H),2.37(d,J=9.4Hz,3H),2.28-2.09(m,3H),2.07-1.96(m,3H),1.88-1.80(m,2H),1.62(dd,J=71.1,14.4Hz,3H).

[1221] Example 51: Preparation of compound 51

[1222]

[1223] Step A: Preparation of compound 51A

[1224] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.22 g), tris(dibenzylacetone)dipalladium (0.32 g), 1,3-dibromo-2-fluorobenzene (0.89 g), 2,7-diazaspiro[3.5]nonane-7-carbonate tert-butyl ester (0.70 g), sodium tert-butoxide (1.0 g), and tetrahydrofuran (25 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 85 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 51A (0.37 g).

[1225] MS(ESI, [M+H]) + )m / z:371.3.

[1226] Step B: Preparation of compound 51B

[1227] Compound 51A (0.37 g), methanesulfonic acid (0.28 g), and dichloromethane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to obtain compound 51B (0.23 g).

[1228] MS(ESI, [M+H]) + )m / z:271.3.

[1229] Step C: Preparation of compound 51C

[1230] Compound 51B (0.23 g), acetic anhydride (0.13 g), triethylamine (0.87 g), and dichloromethane (50 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, water and dichloromethane were added to the reaction solution for extraction, followed by washing with saturated brine and drying over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 51C (0.34 g).

[1231] MS(ESI, [M+H]) + )m / z:313.0.

[1232] Step D: Preparation of compound 51D

[1233] Compound 51C (0.34 g), pinacol diborate (0.42 g), potassium acetate (0.21 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.18 g), and 1,4-dioxane (50 mL) were added sequentially to a reaction flask. Under nitrogen protection, the mixture was stirred at 100 °C until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 51D (0.17 g).

[1234] MS(ESI, [M+H]) + )m / z:361.5.

[1235] Step E: Preparation of compound 51E

[1236] Compound 51D (0.17 g), compound 1C (0.16 g), potassium carbonate (0.89 g), tetra(triphenylphosphine)palladium (0.74 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to the reaction flask. After the addition was complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 51E (0.15 g).

[1237] MS(ESI, [M+H]) + )m / z:689.6.

[1238] Step F: Preparation of compound 51

[1239] Compound 51E (0.15 g), methanesulfonic acid (0.21 g), and dichloromethane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 51 (0.089 g).

[1240] HRMS(ESI, [M+H]) + )m / z:589.2825.

[1241] 1H NMR (500MHz, CDCl3) δ8.09-7.94(m,2H),7.66(d,J=8.5Hz,1H),7.48(d,J=7.9Hz,2H),7.32(d,J=7.8 Hz,2H),7.09-7.02(m,1H),6.98(t,J=7.8Hz,1H),6.59-6.47(m,2H),6.32(m,1H),4.39(d,J=6.0Hz,2 H),3.88(dd,J=20.6,12.8Hz,2H),3.54(d,J=13.7Hz,1H),3.41(d,J=11.6Hz,1H),2.80(q,J=7.0Hz,1 H),2.54(q,J=9.1Hz,3H),2.21(m,2H),2.10(dt,J=19.0,9.3Hz,1H),1.89(s,3H),1.82-1.70(m,1H).

[1242] Example 52: Preparation of compound 52

[1243]

[1244] Step A: Preparation of compound 52A

[1245] To a reaction flask, 1-tert-butoxycarbonyl-4-methylaminopiperidine (2.00 g), 1,3-dibromobenzene (3.30 g), tris(dibenzylacetone)dipalladium (0.43 g), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.44 g), 1,4-dioxane (100 mL), and sodium tert-butoxide (1.79 g) were added sequentially. After the addition was complete, the mixture was stirred at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 52A (1.16 g).

[1246] MS(ESI, [Mt-Bu+H]) + )m / z:313.4.

[1247] Step B: Preparation of compound 52B

[1248] To a reaction flask containing compound 52A (1.15 g), dichloromethane (10 mL) and a 4M dioxane solution (15 mL) containing hydrogen chloride were added sequentially. The mixture was stirred at room temperature after the addition was complete. The reaction was then concentrated to give compound 52B (1.17 g).

[1249] MS(ESI, [M+H]) + )m / z:269.5.

[1250] Step C: Preparation of compound 52C

[1251] To a reaction flask containing compound 52B (1.17 g), triethylamine (1.16 g), acetic anhydride (0.78 g), and dichloromethane (40 mL) were added sequentially, and the mixture was stirred at room temperature after the addition was complete. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 52C (0.90 g).

[1252] MS(ESI, [M+H]) + )m / z:311.4.

[1253] Step D: Preparation of compound 52D

[1254] Compound 52C (0.88 g), pinacol diborate (1.08 g), potassium acetate (0.83 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.23 g), and 1,4-dioxane (50 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was filtered and concentrated. Column chromatography (petroleum ether / ethyl acetate = 1 / 2) yielded compound 52D (0.90 g).

[1255] MS(ESI, [M+H]) + )m / z:359.6.

[1256] Step E: Preparation of compound 52E

[1257] Compound 52D (200 mg), compound 1C (219 mg), potassium carbonate (169 mg), tetra(triphenylphosphine)palladium (47 mg), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to a microwave tube. After the addition was complete, nitrogen gas was purged, and the mixture was microwaved at 140 °C. Once the reaction was complete, the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 52E (216 mg).

[1258] MS(ESI, [M+H]) + )m / z:687.8.

[1259] Step F: Preparation of compound 52

[1260] Compound 52E (206 mg), methanesulfonic acid (0.2 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature after the addition was complete. After the reaction was complete, the pH of the reaction solution was adjusted to 9 with a saturated sodium carbonate aqueous solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 52 (145 mg).

[1261] MS(ESI, [M+H]) +)m / z:587.7.

[1262] 1 H NMR (500MHz, CDCl3) δ8.07(d,J=8.4Hz,1H),7.90(dd,J=5.2,1.7Hz,1H),7.72(d,J=8.4Hz,1H),7.68–7.62(m,2H),7.48–7.4 3(m,2H),7.39(s,1H),7.29(d,J=7.7Hz,1H),7.26–7.21(m,1H),7.15(dd,J=7.8,1.7Hz,1H),6.82(dd,J=8.1,2.5Hz,1H),6. 44(dd,J=7.7,5.2Hz,1H),4.65–4.57(m,1H),3.89–3.81(m,1H),3.78–3.70(m,1H),3.10–3.02(m,1H),2.81–2.71(m,5H),2. 70–2.59(m,2H),2.55–2.47(m,1H),2.38–2.29(m,1H),2.04(s,3H),1.93–1.84(m,1H),1.81–1.71(m,2H),1.66–1.51(m,2H).

[1263] Example 53: Preparation of compound 53

[1264]

[1265] Step A: Preparation of compound 53A

[1266] Add 0.35 g of 3,6-diazacyclic [3.2.0]heptane-6-carboxylic acid tert-butyl ester, 0.28 g of acetyl chloride, 0.54 g of triethylamine, and 15 mL of dichloromethane to the reaction flask in sequence. Stir at room temperature. After the reaction is complete, extract the reaction solution with water and dichloromethane, wash with saturated brine, and dry with anhydrous sodium sulfate. Filter and concentrate to give compound 53A (0.45 g).

[1267] MS(ESI, [M+H]) + )m / z:241.1.

[1268] Step B: Preparation of compound 53B

[1269] Compound 53A (0.42 g), hydrochloric acid (3.06 g), and dichloromethane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 53B (0.4 g).

[1270] MS(ESI, [M+H]) +)m / z:141.1.

[1271] Step C: Preparation of compound 53C

[1272] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.20 g), tris(dibenzylacetone)dipalladium (0.30 g), 1,3-dibromobenzene (0.43 g), compound 53B (0.29 g), sodium tert-butoxide (0.47 g), and dioxane (30 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was concentrated, and column chromatography (dichloromethane / methanol = 50 / 1) was performed to give compound 53C (0.07 g).

[1273] MS(ESI, [M+H]) + )m / z:295.4.

[1274] Step D: Preparation of compound 53D

[1275] Compound 53C (0.12 g), pinacol diborate (0.21 g), potassium acetate (0.12 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.066 g), and 1,4-dioxane (20 mL) were added sequentially to a reaction flask. Under nitrogen protection, the mixture was stirred at 100 °C until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 40 / 1) yielded compound 53D (0.09 g).

[1276] MS(ESI, [M+H]) + )m / z:343.6.

[1277] Step E: Preparation of compound 53E

[1278] Compound 53D (0.088 g), compound 1C (0.075 g), potassium carbonate (0.042 g), tetra(triphenylphosphine)palladium (0.035 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction proceeded to completion, and the mixture was filtered and concentrated. Column chromatography (dichloromethane / methanol = 40 / 1) yielded compound 53E (0.054 g).

[1279] MS(ESI, [M+H]) + )m / z:671.8.

[1280] Step F: Preparation of compound 53

[1281] Compound 53E (0.050 g), methanesulfonic acid (0.072 g), and dichloromethane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 40 / 1) to give compound 53 (0.020 g).

[1282] HRMS(ESI, [M+H]) + )m / z:571.2924.

[1283] 1 H NMR (500MHz, CDCl3) δ8.08(t,J=8.4Hz,1H),8.02(dd,J=8.7,4.4Hz,1H),7.73(d,J=8.3Hz,1H),7.68(d,J=8.2Hz,1H),7.61(d,J=8.2Hz,1H ),7.41(t,J=8.5Hz,2H),7.34(d,J=7.7Hz,1H),7.23(dd,J=14.2,7.0Hz,2H),7.13-7.07(m,1H),6.62(d,J=9.8Hz,2H),6.37(dd,J=14.0,8 .0Hz,2H),4.67-4.50(m,1H),4.18(dd,J=19.0,11.7Hz,1H),3.95-3.76(m,3H),3.67-3.60(m,1H),3.58(d,J=6.1Hz,1H),3.34(dd,J=14.7 ,6.2Hz,1H),3.31-3.23(m,1H),3.17(s,1H),2.65(dd,J=39.8,30.3Hz,4H),2.45(d,J=39.0Hz,2H),2.12(s,1H),2.00(s,1H),1.85(s,1H).

[1284] Example 54: Preparation of compound 54

[1285]

[1286] Step A: Preparation of compound 54A

[1287] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (3.3 g), tris(dibenzylacetone)dipalladium (4.9 g), 1,3-dibromo-2-fluorobenzene (2.6 g), 4-acetylaminopiperidine hydrochloride (3.0 g), sodium tert-butoxide (3.6 g), and dioxane (30 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C. Once the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 54A (0.90 g).

[1288] MS(ESI, [M+H]) + )m / z:297.1.

[1289] Step B: Preparation of compound 54B

[1290] Compound 54A (0.90 g), sodium hydride (1.2 g), deuterated iodomethane (3.1 g), and tetrahydrofuran (20 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction solution, followed by extraction with water and ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 54B (1.5 g).

[1291] MS(ESI, [M+H]) + )m / z:314.5.

[1292] Step C: Preparation of compound 54C

[1293] Compound 54B (1.5 g), pinacol diborate (2.4 g), potassium acetate (1.4 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.57 g), and 1,4-dioxane (50 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 54C (0.62 g).

[1294] MS(ESI, [M+H]) + )m / z:362.1.

[1295] Step D: Preparation of compound 54D

[1296] Compound 54C (0.33 g), compound 1C (0.30 g), potassium carbonate (0.17 g), tetra(triphenylphosphine)palladium (0.21 g), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 54D (0.28 g).

[1297] MS(ESI, [M+H]) + )m / z:690.8.

[1298] Step E: Preparation of Compound 54

[1299] Compound 54D (0.28 g), methanesulfonic acid (0.19 g), and dichloromethane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 54 (0.14 g).

[1300] HRMS(ESI, [M+H]) + )m / z:590.3460.

[1301] 1 H NMR(500MHz, CDCl3)δ8.08-7.96(m,2H),7.70(dd,J=8.4,2.1Hz,1H),7.55(m,1H),7.49(dd,J=8.2,5.9Hz,2H) ,7.43(dd,J=15.3,7.7Hz,1H),7.40-7.32(m,2H),7.25(q,J=8.1Hz,1H),7.08(dd,J=7.8,1.8Hz,1H),6.89(dd, J=8.2,2.6Hz,1H),6.56(s,2H),6.32(dd,J=7.8,4.8Hz,1H),4.59(tt,J=12.2,4.1Hz,1H),3.84-3.66(m,2H), 2.80(m,2H),2.54(m,2H),2.17(m,2H),2.10(s,1H),2.04(s,2H),1.97(s,3H),1.75(m,2H),1.66-1.59(m,1H).

[1302] Example 55: Preparation of compound 55

[1303]

[1304] Step A: Preparation of compound 55A

[1305] Under nitrogen protection, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (3.1 g), tris(dibenzylacetone)dipalladium (2.3 g), 1,3-dibromo-2-fluorobenzene (5.1 g), 4-acetylaminopiperidine hydrochloride (3.0 g), sodium tert-butoxide (3.6 g), and tetrahydrofuran (30 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at 100 °C. The reaction was completed, and the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 55A (1.0 g).

[1306] MS(ESI, [M+H]) + )m / z:315.4.

[1307] Step B: Preparation of compound 55B

[1308] Compound 55A (1.0 g), sodium hydride (1.1 g), deuterated iodomethane (1.1 g), and tetrahydrofuran (10 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, a saturated ammonium chloride solution was added to the reaction solution, followed by extraction with water and ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give compound 55B (1.4 g).

[1309] MS(ESI, [M+H]) + )m / z:332.4.

[1310] Step C: Preparation of compound 55C

[1311] Compound 55B (1.4 g), pinacol diborate (2.0 g), potassium acetate (1.2 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.5 g), and 1,4-dioxane (50 mL) were added sequentially to a reaction flask. The reaction was carried out under nitrogen protection at 100 °C with stirring until complete. The mixture was then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 55C (0.75 g).

[1312] MS(ESI, [M+H]) + )m / z:380.1.

[1313] Step D: Preparation of compound 55D

[1314] Compound 55C (0.35 g), compound 1C (0.30 g), potassium carbonate (0.17 g), tetra(triphenylphosphine)palladium (0.21 g), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially to the reaction flask. After the additions were complete, nitrogen gas was introduced, and the mixture was stirred at 100 °C. The reaction was allowed to proceed to completion, then filtered and concentrated. Column chromatography (dichloromethane / methanol = 20 / 1) yielded compound 55D (0.28 g).

[1315] MS(ESI, [M+H]) + )m / z:708.5.

[1316] Step E: Preparation of Compound 55

[1317] Compound 55D (0.28 g), methanesulfonic acid (0.19 g), and dichloromethane (10 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was complete, the pH of the reaction solution was adjusted to 13 by adding 10% sodium hydroxide solution. The mixture was then extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 10 / 1) to give compound 55 (0.11 g).

[1318] HRMS(ESI, [M+H]) + )m / z:608.3345.

[1319] 1 H NMR (500MHz, CDCl3) δ8.05(dd,J=8.3,5.6Hz,1H),7.99(dd,J=4.8,1.9Hz,1H),7.74(dd,J=8.4,2.3Hz,1H),7.48(d d,J=8.5,2.5Hz,2H),7.46-7.40(m,1H),7.33(dd,J=8.4,2.2Hz,2H),7.09-7.00(m,2H),6.98-6.89(m,1H),6.54(s ,2H),6.31(dd,J=7.8,4.9Hz,1H),4.57(tt,J=12.3,4.2Hz,1H),3.53-3.36(m,2H),2.86-2.66(m,2H),2.53(dddd, J=12.1,9.5,6.2,2.9Hz,2H),2.20-2.14(m,3H),2.09(s,2H),2.04(s,3H),1.86(m,2H),1.74(m,1H),1.66(m,2H).

[1320] Inhibitory effect of compound 1 on the proliferation of LNcap cells

[1321] Take one dish of LNcap cells (PTEN-deficient human prostate cancer cells) in the exponential growth phase, digest with 1 mL of trypsin for 3 min, then add 4 mL of complete culture medium to stop the digestion and collect the cells into a centrifuge tube. Take 20 μl for counting, aspirate the required number of cells (mL), centrifuge at 1200 rpm for 5 min, discard the supernatant, add an appropriate amount of seeding medium (RPMI medium + 5% FBS + 1% sodium pyruvate + 1% glutamine) to adjust the cell density to 3*10⁻⁶ cells / mL. 4Cells / mL. 100 μL / well was seeded into 96-well plates using a pipette and incubated at 37°C in a humidified incubator with 5% CO2. After overnight incubation, the compound was added using a nanoparticle pipette, with two replicates for each concentration. Cells without the compound served as a negative control. After 72 hours, CCK-8 was added at 10 μL / well. The absorbance was measured at 450 nm using an Envision microplate reader after 4 hours. The inhibition rate was calculated as follows: Inhibition rate (%) = (Negative control average - Experimental group average) / (Negative control average - Blank group average) × 100%. A four-parameter analysis was performed, with the logarithm of compound concentration on the x-axis and the inhibition rate on the y-axis. A dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 1.

[1322] Table 1

[1323]

[1324]

[1325] Example 2: Inhibition of AKT1 (S473) phosphorylation in LNcap cells by compound

[1326] Logarithmic-phase LNcap AKT1 (S473) cells were digested with 1 mL of trypsin for 3 min, and the digestion was terminated by adding 4 mL of complete culture medium. The cells were collected into centrifuge tubes. 20 μl of the collected cells were counted, and the desired number (mL) was centrifuged at 1200 rpm for 5 min. The cells were then added to seeding medium (2% FBS + phenol red-free 1640 basal medium + 1% sodium pyruvate + 1% glutamine) to adjust the cell density to approximately 1*10E6 cells / mL. The cells were seeded into 96-well plates at the above cell density (100 μL / well) and cultured overnight in a cell culture incubator at 37°C and 5% CO2. The next day, the appropriate compound was sprayed into the cells using a nanoparticle dispenser according to the plate distribution and incubated for 1 h in a cell culture incubator at 37°C and 5% CO2. The supernatant was discarded, and 40 μl of lysis buffer (1X) with blocking solution was added. The cells were then incubated with shaking at room temperature for 30 min. After mixing, transfer 16 μL of the lysate to a 384-well white plate. Add 4 μL of pre-mixed antibody (v / v) prepared with detection buffer, cover the plate, centrifuge to mix thoroughly, and incubate overnight at room temperature. Detect the 665 nm / 620 nm signal values ​​using a PEEnvision multi-function plate reader, and calculate the IC50 using four-parameter fitting. 50 .

[1327] The results of the inhibitory effects of the compounds on LNcap cells and AKT1(S473) phosphorylation are shown in Table 2.

[1328] Table 2

[1329]

[1330]

[1331] Pharmacokinetic evaluation of compound in mice in Experiment Example 3

[1332] ICR mice, weighing 18–22 g, were randomly divided into 4 groups of 9 mice each after acclimatization for 3–5 days. Compound 28 and Compound 30 were administered by gavage (IG) at a dose of 10 mg / kg, and Compound 28 and Compound 30 were administered by intravenous injection (IV) at a dose of 1 mg / kg, respectively.

[1333] The test animals (ICR mice) were fasted for 12 hours before administration and given food 4 hours after administration. They had free access to water before, during, and after the experiment.

[1334] Following oral administration, approximately 0.1 mL of blood was collected from the orbital sinus at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h. Following intravenous administration, approximately 0.1 mL of blood was collected from the orbital sinus at 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h. Blood was collected from each mouse at 3–4 time points, with 3 mice at each time point. Whole blood was collected and placed in centrifuge tubes containing EDTA-K2, stored at 4°C, and centrifuged at 4°C and 4000 rpm for 10 min within 1 hour to separate plasma. All collected plasma was immediately stored at -20°C for analysis.

[1335] Take 30 μL of the plasma sample to be tested and the standard sample, add 300 μL of acetonitrile solution containing internal standard (diazepam 20 ng / mL), shake and mix for 5 min, centrifuge at 13000 rpm for 10 min, take 80 μL of supernatant, add 80 μL of ultrapure water to dilute, mix well, take 2 μL for liquid chromatography-mass spectrometry determination, and record the chromatogram.

[1336] The oral and intravenous exposures of the compounds in this application were evaluated using in vivo pharmacokinetic experiments in mice. The results are shown in Table 3 below.

[1337] Table 3. Pharmacokinetic parameters of the compounds in mice.

[1338]

[1339]

[1340]

[1341] Pharmacokinetic evaluation of compound in rats in Experiment Example 4

[1342] SD rats, weighing 180-220g, were randomly divided into 4 groups of 3 rats each after 7 days of acclimatization. Compound 28 and Compound 30 were administered by gavage (IG) at a dose of 10mg / kg, and Compound 28 and Compound 30 were administered by intravenous injection (IV) at a dose of 1mg / kg, respectively.

[1343] The test animals (SD rats) were fasted for 12 hours before administration and given food 4 hours after administration. They had free access to water before, during, and after the experiment.

[1344] Blood samples of approximately 0.1 mL were collected from the orbital sinus at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h after gavage administration. Similarly, blood samples of approximately 0.1 mL were collected from the orbital sinus at 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after intravenous administration. Three rats were involved at each time point. Whole blood was collected and placed in centrifuge tubes containing EDTA-K2, stored at 4°C, and centrifuged at 4°C and 4000 rpm for 10 min within 1 hour to separate plasma. All collected plasma was immediately stored at -20°C for analysis.

[1345] Take 30 μL of the plasma sample to be tested and the standard sample, add 300 μL of acetonitrile solution containing internal standard (diazepam 20 ng / mL), shake and mix for 5 min, centrifuge at 13000 rpm for 10 min, take 80 μL of supernatant, add 80 μL of ultrapure water to dilute, mix well, take 2 μL for liquid chromatography-mass spectrometry determination, and record the chromatogram.

[1346] The oral and intravenous exposures of the compounds of this invention were evaluated using in vivo pharmacokinetic experiments in rats. The results are shown in Table 4 below.

[1347] Table 4. Pharmacokinetic parameters of the compounds in rats.

[1348]

[1349] Pharmacodynamic evaluation of compound 5 in a nude mouse subcutaneous xenograft model of AN3CA human endometrial cancer cells.

[1350] SPF-grade female BALB / c nude mice (source: Changzhou Cavens Laboratory Animal Co., Ltd.) were subcutaneously injected with 5×10 [units of something] into the right axilla. 6 AN3CA cells (source: Nanjing Kebai Biotechnology Co., Ltd.). When the average tumor volume reaches 130 mm². 3 At approximately 10:00 AM, the animals were divided into 3 groups of 6 animals each, and the medication was administered as shown in Table 5:

[1351] Table 5 Dosing Regimen

[1352]

[1353] Note: ig means gavage; qd means once daily administration.

[1354] Day 0 was designated as the day of grouping. Administration of the drug via gavage began on this day, with a volume of 10 mL / kg. The solvent was D5W (5% glucose solution). Tumor volume was measured 2-3 times per week, and mouse weight was recorded. General mouse behavior was observed and recorded daily. At the end of the experiment, the tumors were removed, weighed, and photographed.

[1355] Formula for calculating tumor volume: Tumor volume (mm) 3 )=1 / 2×(a×b 2 (where a represents the major axis and b represents the minor axis).

[1356] The relative tumor proliferation rate, T / C%, is the percentage of tumor volume in the treatment group and the control group at a given time point. The calculation formula is as follows: T / C% = T RTV / C RTV ×100% (T) RTV : Mean RTV in the treatment group; C RTV Mean RTV of solvent control group; relative tumor volume RTV = TV t / TV0, where TV0 is the tumor volume of the animal at the time of grouping, TV t (This refers to the tumor volume in the animal after treatment).

[1357] The relative tumor inhibition rate, TGI (%), is calculated using the following formula: TGI% = (1 - tumor weight in the treatment group / tumor weight in the control group) × 100%.

[1358] Weight change rate (WCR) (%) is calculated using the formula: WCR = (Wt) / (Wt) t -Wt0) / Wt0×100%, where Wt0 is the animal's body weight at the time of grouping (i.e., day d0), Wt t The animal's weight at the time of each measurement.

[1359] All experimental results are expressed as mean ± SD. A t-test was used to compare the relative tumor volume between the treatment group and the control group; p < 0.01 was considered highly significant.

[1360] The results are shown in Table 6. The in vivo efficacy results showed that both compound 28 and compound 30 had strong in vivo tumor inhibition effects.

[1361] Table 6. Effects of AKT inhibitors on subcutaneous xenografts of AN3CA human endometrial cancer cells.

[1362]

[1363]

[1364] Note: Compared with the control group, **p<0.01.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, （I） in, R 1 and R 1’ Each is independently selected from hydrogen or halogen; R 2 R 2’ and R 3 Each is independently selected from hydrogen, 7-9 membered spiroheterocyclic groups, 10 membered spiroheterocyclic groups with cyclic atoms composed of nitrogen and carbon atoms, and 5-6 membered heterocyclic groups with cyclic atoms composed of nitrogen and carbon atoms, wherein the 5-6 membered heterocyclic group with cyclic atoms composed of nitrogen and carbon atoms is affected by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the 7-9 spiroheterocyclic group, or the 10 spiroheterocyclic group whose ring atoms are composed of nitrogen and carbon atoms, is optionally replaced by one or more R... 23 replace, And R 2 R 2’ and R 3 They are not both hydrogen; R 22 Selected from 4-5 membered heterocyclic groups or 6-membered heterocyclic groups whose cyclic atoms are composed of nitrogen and sulfur atoms, wherein the 4-5 membered heterocyclic group or the 6-membered heterocyclic group whose cyclic atoms are composed of nitrogen and sulfur atoms is optionally substituted by one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl; R 22’ Each is independently selected from deuterium or C1-C6 alkyl groups; R 23 Each independently selected C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkyl acyl or C1-C6 alkyl acyl-N (C1-C6 alkyl)-.

2. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1’ Each is independently selected from hydrogen or fluorine.

3. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 R 2’ and R 3 Each is independently selected from hydrogen, 7-membered, 8-membered, or 9-membered spiroheterocyclic groups, 10-membered spiroheterocyclic groups with cyclic atoms composed of nitrogen and carbon atoms, or 5-membered or 6-membered monoheterocyclic groups with cyclic atoms composed of nitrogen and carbon atoms, wherein the 5-membered or 6-membered monoheterocyclic group with cyclic atoms composed of nitrogen and carbon atoms is affected by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the 7-, 8-, or 9-membered spiroheterocyclic group, or the 10-membered spiroheterocyclic group whose ring atoms are composed of nitrogen and carbon atoms, is optionally replaced by one or more R... 23 replace, And R 2 R 2’ and R 3 They are not both hydrogen.

4. The compound of formula (I) as claimed in claim 3, or a pharmaceutically acceptable salt thereof, wherein R 2 R 2’ and R 3 Each is independently selected from hydrogen, 7-membered, 8-membered, or 9-membered spiroheterocyclic alkyl, 10-membered spiroheterocyclic alkyl with cyclic atoms composed of nitrogen and carbon atoms, or 5-membered or 6-membered monoheterocyclic alkyl with cyclic atoms composed of nitrogen and carbon atoms, wherein the 5-membered or 6-membered monoheterocyclic alkyl with cyclic atoms composed of nitrogen and carbon atoms is affected by one or more R 22 Replace, and optionally be one or more R 22’ The substitution, wherein the 7-, 8-, or 9-membered spiroheteroalkyl group, or the 10-membered spiroheteroalkyl group whose cyclic atoms are composed of nitrogen and carbon atoms, is optionally replaced by one or more R 23 replace, And R 2 R 2’ and R 3 They are not both hydrogen.

5. The compound of formula (I) as claimed in claim 3, or a pharmaceutically acceptable salt thereof, wherein R 2 R 2’ and R 3 Each is independently selected from hydrogen, , , , , , pyrroloalkyl, piperidinyl, or piperazine, wherein the pyrroloalkyl, piperidinyl, or piperazine is oxidized by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the one described , , , , , Optionally by one or more R 23 replace, And R 2 R 2’ and R 3 They are not both hydrogen.

6. The compound of formula (I) as claimed in claim 3, or a pharmaceutically acceptable salt thereof, wherein R 2 R 2’ and R 3 Each is independently selected from hydrogen, , , , , , , , , , , ,or , wherein , or by one or more R 22 Replace, and optionally be one or more R 22’ Instead, the one described , , , , , , , ,or Optionally by one or more R 23 replace, And R 2 R 2’ and R 3 They are not both hydrogen.

7. The compound of formula (I) as claimed in claim 3, or a pharmaceutically acceptable salt thereof, wherein R 2 R 2’ and R 3 Each is independently selected from hydrogen, , , , , , , , , , , , , , , , , , , , , , ,or And R 2 R 2’ and R 3 They are not both hydrogen.

8. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein R 22 Selected from 4- or 5-membered heterocyclic groups, wherein the 4- or 5-membered heterocyclic group is optionally composed of one or more... replace.

9. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein R 22 Selected from 4- or 5-membered heterocyclic groups or 6-membered heterocyclic groups whose ring atoms are composed of nitrogen and sulfur atoms, wherein the 4- or 5-membered heterocyclic group or the 6-membered heterocyclic group whose ring atoms are composed of nitrogen and sulfur atoms is optionally substituted by one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl.

10. The compound of formula (I) as claimed in claim 9, or a pharmaceutically acceptable salt thereof, wherein R 22 Selected from 4- or 5-membered heterocyclic alkyl groups or The 4- or 5-membered heterocyclic alkyl or Optionally substituted with one or more groups selected from the following: Halogen, C1-C3 alkyl or C1-C6 alkyl acyl.

11. The compound of formula (I) as claimed in claim 9, or a pharmaceutically acceptable salt thereof, wherein R 22 Selected from , , , , , , or .

12. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein R 23 Selected from C1-C4 alkyl, C1-C4 alkylsulfonyl or C1-C4 alkylacyl.

13. The compound of formula (I) as claimed in claim 12, or a pharmaceutically acceptable salt thereof, wherein R 23 Selected from , CH3-, CH3S(O)2- or CH3C(O)-.

14. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein R 22’ Each is independently selected from deuterium or C1-C4 alkyl groups.

15. The compound of formula (I) as claimed in claim 14, or a pharmaceutically acceptable salt thereof, wherein R 22’ Each is independently selected from deuterium or methyl.

16. The following compounds or their pharmaceutically acceptable salts, 。 17. Use of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Akt kinase-mediated diseases, wherein, The diseases mediated by the Akt kinase are selected from prostate cancer or endometrial cancer.

Images