Compounds as Akt kinase inhibitors

Abstract

The present invention belongs to the field of medicinal chemistry and provides compounds as Akt kinase inhibitors, specifically relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a process for preparing the same, a pharmaceutical composition containing the compound, and its use in the manufacture of a medicament for treating an Akt kinase-related disease. JPEG2023542969000222.jpg47170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to and benefits from Chinese patent application No. 202011057860.0 filed with the State Intellectual Property Office of China on September 30, 2020, and Chinese patent application No. 202110261605.6 filed with the State Intellectual Property Office of China on March 10, 2021, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present invention belongs to the field of medicinal chemistry and provides compounds or pharmaceutically acceptable salts thereof as Akt kinase inhibitors, methods for preparing the same, and pharmaceutical compositions containing the compounds, and relates to their use in the manufacture of medicaments for the treatment of Akt kinase-related diseases, such as cancer, in patients in need thereof. [Background technology]

[0003] Akt, also known as protein kinase B (PKB) or Rac, is a serine / threonine kinase of the AGC family and shares high homology with protein kinase A (PKA) and protein kinase C (PKC). Akt has three main domains: a PH domain (which has affinity for PIP3 and is crucial for cell membrane binding), a catalytic domain, and a regulatory domain. Studies have shown that human Akt contains three subtypes, Akt1, Akt2, and Akt3, each with a unique function and expression map. Akt1, Akt2, and Akt3 are key mediators of the PI3K / AKT / mTOR signaling pathway and promote various physiological processes, including proliferation, migration, anti-apoptotic survival, and protein synthesis. Akt1 is widely expressed in tissues and is primarily involved in cell survival and growth regulation. Akt2 is primarily expressed in muscle and adipocytes and is involved in insulin-mediated glucose metabolism. Akt3 is mainly expressed in the testis and brain and plays an important role in maintaining normal brain volume.

[0004] Akt is one of the most commonly activated protein kinases in human cancers. Overactivation of Akt induces cell proliferation, causing cell growth and helping to resist cell apoptosis. In cancer, Akt activity is often elevated by 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 by PTEN and SHIP1. Akt can also be inactivated by dephosphorylation by PPA2 and PHLPP. Furthermore, phosphorylation of NFkB and IRS-1 can regulate Akt through positive and negative feedback. Studies have shown that Akt is overexpressed in various human tumors, and abnormal Akt function is closely associated with the development, progression, and resistance to chemotherapy and radiation therapy.

[0005] Akt inhibitors are classified into PH domain inhibitors, ATP-competitive inhibitors, allosteric inhibitors, and biologics based on their binding sites. While Capivasertib (AZD5363), developed by Azrican, is a pan-Akt inhibitor, ATP-competitive inhibitors and allosteric inhibitors (e.g., MK-2206) have not demonstrated single-agent activity in many clinical trials. ARQ 092 and ARQ 751 are highly selective allosteric inhibitors, and both have demonstrated favorable activity in early studies.

[0006] Akt has become an anti-tumor target with extremely profound development prospects, and highly efficient (activity), novel (structure) and highly selective (safety) Akt inhibitors are an important strategy to solve hitherto unmet medical needs. Summary of the Invention [Problem to be solved by the invention]

[0007] According to one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 and R 1’ are each independently selected from hydrogen or halogen; R 2 , R 2’ and R 3 each independently represents hydrogen, amino, amino-C1-C6 alkyl-, a 7- to 9-membered spiroheterocyclyl, a 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, a 7- to 10-membered fused heterocyclyl, a 7- to 10-membered bridged heterocyclyl, a 5- to 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, a 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom, [ka] wherein the amino or amino-C1-C6 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- to 6-membered heterocyclyl having a nitrogen atom and a carbon atom as ring atoms is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7- to 9-membered spiroheterocyclyl, the 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, the 7- to 10-membered fused heterocyclyl, or the 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom may optionally be substituted with one or more R 23 wherein said 7- to 10-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25forming a morpholinyl substituted with And R 2 , R 2’ and R 3 does not simultaneously become hydrogen, R 21 is C2-C6 alkenyl-C(O)-, C3-C 12 cycloalkyl, 4- to 12-membered heterocyclyl, and C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 cycloalkyl, 4-12 membered heterocyclyl or C1-C6 alkylacylamino-C1-C6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C6 alkylacyl; R 22 is selected from the group consisting of C2-C6 alkynyl-C(O)-, 4- to 5-membered heterocyclyl, and 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom, wherein the 4- to 5-membered heterocyclyl or the 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom is optionally [ka] substituted with one or more groups selected from the group consisting of halogen, C1-C3 alkyl, and C1-C6 alkyl acyl; R 21’ and R 22’ are each independently selected from deuterium or C1-C6 alkyl; R 23 and R 24 are each independently [ka] selected from the group consisting of C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, and C1-C6 alkylacyl-N(C1-C6 alkyl)-; R 25 is selected from C1 to C6 alkyl acyls, R 4is selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl, R 5 is selected from C1 to C6 alkyl, R 5’ is selected from -CD3 or -CH3, and R 5’ is -CH3, R 1 or R 1’ is a halogen.]

[0008] In another aspect, the present invention further provides a pharmaceutical composition comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof. According to another aspect, the present invention further provides a method for treating an Akt kinase-mediated disease in a mammal, comprising administering a therapeutically effective amount of the above-described compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal in need of such treatment. According to another aspect, the present invention further provides the use of the above compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating an Akt kinase-mediated disease.

[0009] According to another aspect, the present invention further provides the use of the above compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of an Akt kinase-mediated disease. In another aspect, the present invention further provides the above-described compound according to the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating an Akt kinase-mediated disease. [Means for solving the problem]

[0010] According to one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 and R 1’ are each independently selected from hydrogen or halogen; R 2 , R 2’ and R 3 each independently represents hydrogen, amino, amino-C1-C6 alkyl-, a 7- to 9-membered spiroheterocyclyl, a 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, a 7- to 10-membered fused heterocyclyl, a 7- to 10-membered bridged heterocyclyl, a 5- to 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, a 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom, [ka] wherein the amino or amino-C1-C6 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- to 6-membered heterocyclyl having a nitrogen atom and a carbon atom as ring atoms is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7- to 9-membered spiroheterocyclyl, the 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, the 7- to 10-membered fused heterocyclyl, or the 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom may optionally be substituted with one or more R 23 wherein said 7- to 10-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 forming a morpholinyl substituted with And R 2 , R 2’ and R 3 does not simultaneously become hydrogen, R 21 is C2-C6 alkenyl-C(O)-, C3-C 12cycloalkyl, 4- to 12-membered heterocyclyl, and C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 cycloalkyl, 4-12 membered heterocyclyl or C1-C6 alkylacylamino-C1-C6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C6 alkylacyl; R 22 is selected from the group consisting of C2-C6 alkynyl-C(O)-, 4- to 5-membered heterocyclyl, and 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom, wherein the 4- to 5-membered heterocyclyl or the 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom is optionally [ka] substituted with one or more groups selected from the group consisting of halogen, C1-C3 alkyl, and C1-C6 alkyl acyl; R 21’ and R 22’ are each independently selected from deuterium or C1-C6 alkyl; R 23 and R 24 are each independently [ka] selected from the group consisting of C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, and C1-C6 alkylacyl-N(C1-C6 alkyl)-; R 25 is selected from C1 to C6 alkyl acyls, R 4 is selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl, R 5 is selected from C1 to C6 alkyl, R 5’ is selected from -CD3 or -CH3, and R 5’ is -CH3, R 1 or R1’ is a halogen.

[0011] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [In the formula, R 1 and R 1’ are each independently selected from hydrogen or halogen; R 2 , R 2’ and R 3 each independently represents hydrogen, amino, amino-C1-C6 alkyl-, a 7- to 9-membered spiroheterocyclyl, a 7- to 10-membered fused heterocyclyl, a 7- to 10-membered bridged heterocyclyl, a 5- to 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, a 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom, [ka] wherein the amino or amino-C1-C6 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- to 6-membered heterocyclyl having a nitrogen atom and a carbon atom as ring atoms is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7- to 9-membered spiroheterocyclyl, 7- to 10-membered fused heterocyclyl, or 5- to 6-membered heterocyclyl containing a silicon atom or a phosphorus atom in the ring atom may optionally be substituted with one or more R 23 wherein said 7- to 10-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 forming a morpholinyl substituted with And R 2 , R 2’ and R3 does not simultaneously become hydrogen, R 21 is C2-C6 alkenyl-C(O)-, C3-C 12 cycloalkyl, 4- to 12-membered heterocyclyl, and C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 cycloalkyl, 4-12 membered heterocyclyl or C1-C6 alkylacylamino-C1-C6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C6 alkylacyl; R 22 is selected from the group consisting of C2-C6 alkynyl-C(O)-, and 4- to 5-membered heterocyclyl, wherein said 4- to 5-membered heterocyclyl optionally includes one or more [ka] is replaced by R 21’ and R 22’ are each independently selected from C1 to C6 alkyl, R 23 and R 24 are each independently [ka] selected from the group consisting of C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, and C1-C6 alkylacyl-N(C1-C6 alkyl)-; R 25 is selected from C1 to C6 alkyl acyls, R 4 is selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl, R 5 is selected from C1 to C6 alkyl, R 5’ is selected from -CD3 or -CH3, and R 5’ is -CH3, R 1 or R 1’ is a halogen.

[0012] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [In the formula, R 1 and R 1’ are each independently selected from hydrogen or halogen; R 2 and R 2’ each independently represents hydrogen, amino, amino-C1-C6 alkyl-, a 7- to 9-membered spiroheterocyclyl, a 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, a 7- to 10-membered fused heterocyclyl, a 7- to 10-membered bridged heterocyclyl, a 5- to 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, a 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom, [ka] wherein the amino or amino-C1-C6 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- to 6-membered heterocyclyl having a nitrogen atom and a carbon atom as ring atoms is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7- to 9-membered spiroheterocyclyl, the 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, the 7- to 10-membered fused heterocyclyl, or the 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom may optionally be substituted with one or more R 23 wherein said 7- to 10-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by R 3 is hydrogen, Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25forming a morpholinyl substituted with And R 2 and R 2’ does not simultaneously become hydrogen, R 21 is C2-C6 alkenyl-C(O)-, C3-C 12 cycloalkyl, 4- to 12-membered heterocyclyl, and C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 cycloalkyl, 4-12 membered heterocyclyl or C1-C6 alkylacylamino-C1-C6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C6 alkylacyl; R 22 is selected from the group consisting of C2-C6 alkynyl-C(O)-, 4- to 5-membered heterocyclyl, and 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom, wherein the 4- to 5-membered heterocyclyl or the 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom is optionally [ka] substituted with one or more groups selected from the group consisting of halogen, C1-C3 alkyl, and C1-C6 alkyl acyl; R 21’ and R 22’ are each independently selected from deuterium or C1-C6 alkyl; R 23 and R 24 are each independently [ka] selected from the group consisting of C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, and C1-C6 alkylacyl-N(C1-C6 alkyl)-; R 25 is selected from C1 to C6 alkyl acyls, R 4is selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl, R 5 is selected from C1 to C6 alkyl, R 5’ is selected from -CD3 or -CH3, and R 5’ is -CH3, R 1 or R 1’ is a halogen.

[0013] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [In the formula, R 1 and R 1’ are each independently selected from hydrogen or halogen; R 2 and R 2’ Among these, one is hydrogen and the other is amino, amino-C1-C6 alkyl-, 7- to 9-membered spiroheterocyclyl, 10-membered spiroheterocyclyl whose ring atoms are composed of a nitrogen atom and a carbon atom, 7- to 10-membered fused heterocyclyl, 7- to 10-membered bridged heterocyclyl, 5- to 6-membered heterocyclyl whose ring atoms are composed of a nitrogen atom and a carbon atom, 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom, [ka] wherein the amino or amino-C1-C6 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- to 6-membered heterocyclyl having a nitrogen atom and a carbon atom as ring atoms is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7- to 9-membered spiroheterocyclyl, the 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, the 7- to 10-membered fused heterocyclyl, or the 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom may optionally be substituted with one or more R 23wherein said 7- to 10-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by R 3 is hydrogen, Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 forming a morpholinyl substituted with R 21 is C2-C6 alkenyl-C(O)-, C3-C 12 cycloalkyl, 4- to 12-membered heterocyclyl, and C1-C6 alkylacylamino-C1-C6 alkyl-, wherein the C3-C 12 cycloalkyl, 4-12 membered heterocyclyl or C1-C6 alkylacylamino-C1-C6 alkyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C6 alkylacyl; R 22 is selected from the group consisting of C2-C6 alkynyl-C(O)-, 4- to 5-membered heterocyclyl, and 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom, wherein the 4- to 5-membered heterocyclyl or the 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom is optionally [ka] substituted with one or more groups selected from the group consisting of halogen, C1-C3 alkyl, and C1-C6 alkyl acyl; R 21’ and R 22’ are each independently selected from deuterium or C1-C6 alkyl; R 23 and R 24 are each independently [ka] selected from the group consisting of C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, and C1-C6 alkylacyl-N(C1-C6 alkyl)-; R 25 is selected from C1 to C6 alkyl acyls, R 4 is selected from C1-C6 alkyl acyl or C1-C6 alkyl sulfonyl, R 5 is selected from C1 to C6 alkyl, R 5’ is selected from -CD3 or -CH3, and R 5’ is -CH3, R 1 or R 1’ is a halogen.

[0014] In some embodiments, the 7-9 membered spiroheterocyclyl, the 7-10 membered fused heterocyclyl, and the 7-10 membered bridged heterocyclyl each independently contain 1-3 heteroatoms selected from N, O, and S. In some embodiments, the 7-9 membered spiroheterocyclyl, the 7-10 membered fused heterocyclyl, and the 7-10 membered bridged heterocyclyl each contain 1 or 2 heteroatoms independently selected from N, O, and S. In some embodiments, a 10-membered spiroheterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom contains 1, 2, or 3 nitrogen atoms.

[0015] In some embodiments, a 5-6 membered heterocyclyl consisting of nitrogen and carbon atoms in the ring is 1, 2, or 3 nitrogen atoms. In some embodiments, a 5- to 6-membered heterocyclyl containing a silicon or phosphorus ring atom contains one silicon atom or one phosphorus atom and one or two heteroatoms selected from N, O, or S. In some embodiments, the 4-5 membered heterocyclyl and the 4-12 membered heterocyclyl each independently contain 1-3 heteroatoms selected from N, O, or S.

[0016] In some embodiments, R 1 and R 1’ are each independently selected from hydrogen or fluorine. In some embodiments, R 1 and R 1’ are all selected from hydrogen. In some embodiments, R 1 is selected from hydrogen, and R 1’ is selected from halogens, or R 1 is selected from halogens, and R 1’ is selected from hydrogen. In some embodiments, R 1 is selected from hydrogen, and R 1’ is selected from fluorine, or R 1 is selected from fluorine, and R 1’ is selected from hydrogen. In some embodiments, R 2 , R 2’ and R 3 each independently represents hydrogen, amino, amino-C1-C6 alkyl-, a 7- to 9-membered spiroheterocyclyl, a 7- to 10-membered fused heterocyclyl, a 7- to 10-membered bridged heterocyclyl, a 5- to 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, a 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom, [ka] wherein the amino or amino-C1-C6 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- to 6-membered heterocyclyl having a nitrogen atom and a carbon atom as ring atoms is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7- to 9-membered spiroheterocyclyl, 7- to 10-membered fused heterocyclyl, or 5- to 6-membered heterocyclyl containing a silicon atom or a phosphorus atom in the ring atom may optionally be substituted with one or more R23 wherein said 7- to 10-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 forming a morpholinyl substituted with And R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0017] In some embodiments, R 2 , R 2’ and R 3 each independently represents hydrogen, amino, amino-C1-C4 alkyl, a 7-, 8-, or 9-membered spiroheterocyclyl, a 10-membered spiroheterocyclyl consisting of a nitrogen atom and a carbon atom as ring atoms, a 7-, 8-, or 9-membered fused heterocyclyl, a 7-, or 8-membered bridged heterocyclyl, a 5-, or 6-membered monoheterocyclyl consisting of a nitrogen atom and a carbon atom as ring atoms, a 5-, or 6-membered monoheterocyclyl consisting of a silicon atom or a phosphorus atom as ring atoms, [ka] wherein said amino or amino-C1-C4 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- or 6-membered monoheterocyclyl, the ring atoms of which are nitrogen and carbon atoms, is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7-, 8-, or 9-membered spiroheterocyclyl, the 10-membered spiroheterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, the 7-, 8-, or 9-membered fused heterocyclyl, or the 5- or 6-membered monoheterocyclyl whose ring atoms include a silicon atom or a phosphorus atom may optionally be substituted with one or more R23 wherein said 7- or 8-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 forming a morpholinyl substituted with And R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0018] In some embodiments, R 2 , R 2’ and R 3 each independently represents hydrogen, amino, amino-C1-C4 alkyl, a 7-, 8-, or 9-membered spiroheterocycloalkyl, a 10-membered spiroheterocycloalkyl whose ring atoms are a nitrogen atom and a carbon atom, a 7-, 8-, or 9-membered fused heterocycloalkyl, a 7-, or 8-membered bridged heterocycloalkyl, a 5-, or 6-membered monoheterocycloalkyl whose ring atoms are a nitrogen atom and a carbon atom, a 5-, or 6-membered monoheterocycloalkyl whose ring atoms include a silicon atom or a phosphorus atom, [ka] wherein said amino or amino-C1-C4 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- or 6-membered monoheterocycloalkyl, the ring atoms of which are nitrogen and carbon atoms, is substituted with one or more R 22 and optionally one or more R 22’wherein said 7-, 8-, or 9-membered spiroheterocycloalkyl, 10-membered spiroheterocycloalkyl whose ring atoms consist of nitrogen and carbon atoms, 7-, 8-, or 9-membered fused heterocycloalkyl, or 5- or 6-membered monoheterocycloalkyl whose ring atoms include silicon or phosphorus atoms, optionally substituted with one or more R 23 wherein said 7- or 8-membered bridged heterocycloalkyl is substituted with one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 forming a morpholinyl substituted with And R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0019] In some embodiments, R 2 , R 2’ and R 3 each independently represents hydrogen, amino, amino-C1-C4 alkyl, 7-, 8-, or 9-membered spiroheterocycloalkyl, 10-membered spiroheterocycloalkyl whose ring atoms are nitrogen and carbon atoms, 5- to 4-membered fused heterocycloalkyl, 5- to 5-membered fused heterocycloalkyl, 5- to 6-membered fused heterocycloalkyl, 7- or 8-membered bridged heterocycloalkyl, 5- or 6-membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms, 6-membered monoheterocycloalkyl whose ring atoms include a silicon atom or a phosphorus atom, [ka] wherein said amino or amino-C1-C4 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’wherein the 5- or 6-membered monoheterocycloalkyl, the ring atoms of which are nitrogen and carbon atoms, is substituted with one or more R 22 and optionally one or more R 22’ wherein said 7-, 8-, or 9-membered spiroheterocycloalkyl, 10-membered spiroheterocycloalkyl whose ring atoms consist of nitrogen and carbon atoms, 5-4-membered fused heterocycloalkyl, 5-5-membered fused heterocycloalkyl, 5-6-membered fused heterocycloalkyl, or 6-membered monoheterocycloalkyl whose ring atoms include silicon or phosphorus atoms, optionally substituted with one or more R 23 wherein said 7- or 8-membered bridged heterocycloalkyl is substituted with one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 forming a morpholinyl substituted with And R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0020] In some embodiments, R 2 , R 2’ and R 3 are each independently hydrogen, amino, aminomethyl, [ka] pyrrolidinyl, piperidinyl, piperazinyl, [ka] wherein said amino or aminomethyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein said pyrrolidinyl, piperidinyl or piperazinyl is substituted with one or more R 22and optionally one or more R 22’ wherein said [ka] optionally one or more R 23 wherein said [ka] is one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 is replaced by [ka] It forms the base, And R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0021] In some embodiments, R 2 , R 2’ and R 3 are each independently hydrogen, amino, aminomethyl, [ka] wherein said amino or aminomethyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein said [ka] is one or more R 22 and optionally one or more R 22’ wherein said [ka] optionally one or more R 23 wherein said [ka] is one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 is replaced by [ka] It forms the base, And R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0022] In some embodiments, R 2 , R 2’ and R 3 are each independently hydrogen, amino, aminomethyl, [ka] pyrrolidinyl, piperidinyl, piperazinyl, [ka] wherein said amino and aminomethyl are selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein said pyrrolidinyl, piperidinyl or piperazinyl is substituted with one or more R 22 and optionally one or more R 22’ wherein said [ka] optionally one or more R 23wherein said [ka] is one or more R 24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 is replaced by [ka] It forms the base, And R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0023] In some embodiments, R 2 , R 2’ and R 3 are each independently hydrogen, amino, aminomethyl, [ka] wherein said amino and aminomethyl are selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein said [ka] is one or more R 22 and optionally one or more R 22’ wherein said [ka] optionally one or more R 23 wherein said [ka] is one or more R24 is replaced by Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 is replaced by [ka] It forms the base, And R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0024] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is amino, amino-C1-C6 alkyl-, 7- to 9-membered spiroheterocyclyl, 7- to 10-membered fused heterocyclyl, 7- to 10-membered bridged heterocyclyl, 5- to 6-membered heterocyclyl whose ring atoms are composed of a nitrogen atom and a carbon atom, 5- to 6-membered heterocyclyl whose ring atom contains a silicon atom or a phosphorus atom, [ka] wherein the amino or amino-C1-C6 alkyl is selected from one or more R 21 and optionally one or more R 21’ wherein the 5- to 6-membered heterocyclyl having a nitrogen atom and a carbon atom as ring atoms is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7- to 9-membered spiroheterocyclyl, 7- to 10-membered fused heterocyclyl, or 5- to 6-membered heterocyclyl containing a silicon atom or a phosphorus atom in the ring atom may optionally be substituted with one or more R 23 wherein said 7- to 10-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by And R 3 It is hydrogen.

[0025] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is amino, amino-C1-C4 alkyl, 7-, 8-, or 9-membered spiroheterocyclyl, 10-membered spiroheterocyclyl whose ring atoms are nitrogen and carbon atoms, 7-, 8-, or 9-membered fused heterocyclyl, 7-, or 8-membered bridged heterocyclyl, 5-, or 6-membered monoheterocyclyl whose ring atoms are nitrogen and carbon atoms, 5-, or 6-membered monoheterocyclyl whose ring atoms include a silicon atom or a phosphorus atom, [ka] wherein said amino or amino-C1-C4 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- or 6-membered monoheterocyclyl, the ring atoms of which are nitrogen and carbon atoms, is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7-, 8-, or 9-membered spiroheterocyclyl, the 10-membered spiroheterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, the 7-, 8-, or 9-membered fused heterocyclyl, or the 5- or 6-membered monoheterocyclyl whose ring atoms include a silicon atom or a phosphorus atom may optionally be substituted with one or more R 23 wherein said 7- or 8-membered bridged heterocyclyl is substituted with one or more R 24 is replaced by And R 3 It is hydrogen.

[0026] In some embodiments, R 2 and R 2’one of which is hydrogen and the other is amino, amino-C1-C4 alkyl, 7-, 8-, or 9-membered spiroheterocycloalkyl, 10-membered spiroheterocycloalkyl whose ring atoms are nitrogen and carbon atoms, 7-, 8-, or 9-membered fused heterocycloalkyl, 7-, or 8-membered bridged heterocycloalkyl, 5-, or 6-membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms, 5-, or 6-membered monoheterocycloalkyl whose ring atoms include a silicon atom or a phosphorus atom; [ka] wherein said amino or amino-C1-C4 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- or 6-membered monoheterocycloalkyl, the ring atoms of which are nitrogen and carbon atoms, is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7-, 8-, or 9-membered spiroheterocycloalkyl, 10-membered spiroheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7-, 8-, or 9-membered fused heterocycloalkyl, or 5- or 6-membered monoheterocycloalkyl whose ring atoms include a silicon atom or a phosphorus atom may optionally be substituted with one or more R 23 wherein said 7- or 8-membered bridged heterocycloalkyl is substituted with one or more R 24 is replaced by And R 3 It is hydrogen.

[0027] In some embodiments, R 2 and R 2’wherein one is hydrogen and the other is amino, amino-C1-C4 alkyl, 7-, 8-, or 9-membered spiroheterocycloalkyl, 10-membered spiroheterocycloalkyl whose ring atoms are nitrogen and carbon atoms, 5-4-membered fused heterocycloalkyl, 5-5-membered fused heterocycloalkyl, 5-6-membered fused heterocycloalkyl, 7- or 8-membered bridged heterocycloalkyl, 5- or 6-membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms, 6-membered monoheterocycloalkyl whose ring atoms include a silicon atom or a phosphorus atom; [ka] wherein said amino or amino-C1-C4 alkyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein the 5- or 6-membered monoheterocycloalkyl, the ring atoms of which are nitrogen and carbon atoms, is substituted with one or more R 22 and optionally one or more R 22’ wherein the 7-, 8-, or 9-membered spiroheterocycloalkyl, 10-membered spiroheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5-4-membered fused heterocycloalkyl, 5-5-membered fused heterocycloalkyl, 5-6-membered fused heterocycloalkyl, or 6-membered monoheterocycloalkyl whose ring atoms include a silicon atom or a phosphorus atom may optionally be substituted with one or more R 23 wherein said 7- or 8-membered bridged heterocycloalkyl is substituted with one or more R 24 is replaced by And R 3 It is hydrogen.

[0028] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is amino, aminomethyl, [ka] pyrrolidinyl, piperidinyl, piperazinyl, [ka] wherein said amino or aminomethyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein said pyrrolidinyl, piperidinyl or piperazinyl is substituted with one or more R 22 and optionally one or more R 22’ wherein said [ka] optionally one or more R 23 wherein said [ka] is one or more R 24 is replaced by And R 3 is hydrogen, Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 is replaced by [ka] It forms the base.

[0029] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is amino, aminomethyl, [ka] wherein said amino or aminomethyl is selected from the group consisting of one or more R 21 and optionally one or more R 21’ wherein said [ka] is one or more R 22 and optionally one or more R 22’ wherein said [ka] optionally one or more R 23 wherein said [ka] is one or more R 24 is replaced by And R 3 is hydrogen, Alternatively, R 3 is R 2 or R 2’ and are bonded to each other and, together with the carbon atoms bonded thereto, optionally form one or more R 25 is replaced by [ka] It forms the base.

[0030] In some embodiments, R 3 is R 2 or R 2’ and are bonded to each other, forming the structural unit [ka] optionally one or more R 25 is replaced by [ka] Make it so that it becomes like this.

[0031] In some embodiments, R 21 C2-C4 alkenyl-C(O)-, C5-C 10cycloalkyl, 4- to 6-membered heterocyclyl, and C1-C4 alkylacylamino-C1-C4 alkyl-, wherein the C5-C 10 The cycloalkyl, 4- to 6-membered heterocyclyl, or C1-C4 alkylacylamino-C1-C4 alkyl- is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C4 alkylacyl.

[0032] In some embodiments, R 21 C2-C3 alkenyl-C(O)-, C7-C 10 selected from the group consisting of bridged cycloalkyl, 4-6 membered monoheterocycloalkyl, and C1-C3 alkylacylamino-C1-C3 alkyl-, wherein the C7-C 10 The bridged cycloalkyl, 4-6 membered monoheterocycloalkyl or C1-C3 alkylacylamino-C1-C3 alkyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C4 alkyl, and C1-C4 alkylacyl.

[0033] In some embodiments, R 21 is C2-C3 alkenyl-C(O)-, C 10 is selected from the group consisting of bridged cycloalkyl, 5- or 6-membered monoheterocycloalkyl, and C1-C3 alkylacylamino-C1-C3 alkyl-, wherein said C 10 The bridged cycloalkyl, 5- or 6-membered monoheterocycloalkyl, or C1-C3 alkylacylamino-C1-C3 alkyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C4 alkyl, and C1-C4 alkylacyl.

[0034] In some embodiments, R 21 is H2C=CHC(O)-, [ka] and CH3C(O)N(CH3)-CH3CH2-, wherein said [ka] is optionally substituted with one or more groups selected from the group consisting of hydroxy and C1-C4 alkyl acyl.

[0035] In some embodiments, R 21 is H2C=CHC(O)-, [ka] and CH3C(O)N(CH3)-CH3CH2-.

[0036] In some embodiments, R 21 is H2C=CHC(O)-, [ka] and CH3C(O)N(CH3)-CH3CH2-.

[0037] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is amino, and the amino is one R 21 is replaced by R 21 is C2-C3 alkenyl-C(O)-, C 10 is selected from the group consisting of bridged cycloalkyl, 5- or 6-membered monoheterocycloalkyl, and C1-C3 alkylacylamino-C1-C3 alkyl-, wherein said C 10 The bridged cycloalkyl, 5- or 6-membered monoheterocycloalkyl, or C1-C3 alkylacylamino-C1-C3 alkyl is optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C4 alkyl, and C1-C4 alkylacyl, and / or R 3 It is hydrogen.

[0038] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is amino, and the amino is one R 21 is replaced by R 21 is H2C=CHC(O)-, [ka] and CHC(O)N(CH)—CHCH—, and / or R 3 It is hydrogen.

[0039] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is amino-C1-C6 alkyl, said amino-C1-C6 alkyl being substituted with C2-C3 alkenyl-C(O)-; and / or R 3 It is hydrogen. In some embodiments, R 22 is selected from the group consisting of C2-C6 alkynyl-C(O)-, and 4- to 5-membered heterocyclyl, wherein said 4- to 5-membered heterocyclyl optionally includes one or more [ka] is replaced by . In some embodiments, R 22 is selected from the group consisting of C2-C3 alkynyl-C(O)-, a 4- or 5-membered heterocyclyl, and a 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom, wherein the 4- or 5-membered heterocyclyl or the 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom is optionally [ka] It is substituted with one or more groups selected from the group consisting of halogen, C1-C3 alkyl, and C1-C6 alkyl acyl.

[0040] In some embodiments, R22 is selected from the group consisting of C2-C3 alkynyl-C(O)-, and 4- or 5-membered heterocyclyl, wherein said 4- or 5-membered heterocyclyl optionally comprises one or more [ka] is replaced by .

[0041] In some embodiments, R 22 is C2-C3 alkynyl-C(O)-, 4- or 5-membered heterocycloalkyl, and [ka] wherein said 4- or 5-membered heterocycloalkyl or [ka] is optionally [ka] It is substituted with one or more groups selected from the group consisting of halogen, C1-C3 alkyl, and C1-C6 alkyl acyl.

[0042] In some embodiments, R 22 is selected from the group consisting of C2-C3 alkynyl-C(O)-, and 4- or 5-membered heterocycloalkyl, wherein said 4- or 5-membered heterocycloalkyl optionally comprises one or more [ka] is replaced by .

[0043] In some embodiments, R 22 is H3CC≡CC(O)-, [ka] is selected from the group consisting of:

[0044] In some embodiments, R 22 is H3CC≡CC(O)-, [ka] is selected from the group consisting of: In some embodiments, R 21’ and R 22’ are each independently selected from deuterium or C1-C4 alkyl. In some embodiments, R 21’ and R 22’ are each independently selected from deuterium or methyl.

[0045] In some embodiments, R 21’ and R 22’ are each independently selected from C1 to C4 alkyl. In some embodiments, R 21’ and R 22’ are each independently selected from methyl. In some embodiments, R 23 teeth [ka] It is selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, and C1-C4 alkylacyl. In some embodiments, R 23 teeth [ka] Selected from the group consisting of CH3-, CH3S(O)2-, and CH3C(O)-. In some embodiments, R 24 is selected from C1-C4 alkyl acyl-N(C1-C4 alkyl)-.

[0046] In some embodiments, R 24 is selected from CH3C(O)N(CH3)-. In some embodiments, R 25 is selected from C1-C4 alkyl acyls. In some embodiments, R 25 is selected from CH3C(O)-. In some embodiments, R 4 is selected from C1-C4 alkyl acyl or C1-C4 alkyl sulfonyl. In some embodiments, R 4 is selected from CH3C(O)- or CH3S(O)2-.

[0047] In some embodiments, R 5 is selected from C1 to C4 alkyl. In some embodiments, R 5 is selected from methyl. In some embodiments, R 4 is selected from CH3C(O)-, and R 5 is selected from methyl. In some embodiments, R 4 is selected from CH3S(O)2-, and R 5 is selected from methyl. In some embodiments, R 5’ is selected from -CD3 or -CH3, and R 5’ is -CH3, R 1 or R 1’ is fluorine.

[0048] In some embodiments, R 2 and R 2’ wherein one is hydrogen and the other is selected from 7- to 9-membered spiroheterocyclyl, and said 7- to 9-membered spiroheterocyclyl optionally has one or two R 23 is replaced by R 23 teeth [ka] selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, and C1-C4 alkylacyl, and / or R3 It is hydrogen.

[0049] In some embodiments, R 2 and R 2’ wherein one is hydrogen and the other is selected from 7- to 9-membered spiroheterocyclyl, and the 7- to 9-membered spiroheterocyclyl optionally has one or two R 23 is replaced by R 23 teeth [ka] selected from the group consisting of CH3-, CH3S(O)2-, and CH3C(O)-, and / or R 3 It is hydrogen.

[0050] In some embodiments, the 7- to 9-membered spiroheterocyclyl is a 7-, 8-, or 9-membered monospiroheterocycle containing one or two heteroatoms selected from N, O, or S. In some embodiments, the 7- to 9-membered spiroheterocyclyl is a 7-, 8-, or 9-membered monospiroheterocycle containing one or two heteroatoms selected from N and O.

[0051] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is a 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, and said 10-membered spiroheterocyclyl optionally contains one or two R 23 is replaced by R 23 teeth [ka] selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, and C1-C4 alkylacyl, and / or R 3 It is hydrogen.

[0052] In some embodiments, R 2 and R 2’one of which is hydrogen and the other is a 10-membered spiroheterocyclyl whose ring atoms are a nitrogen atom and a carbon atom, and said 10-membered spiroheterocyclyl optionally contains one or two R 23 is replaced by R 23 teeth [ka] and C1-C4 alkyl, and / or R 3 It is hydrogen.

[0053] In some embodiments, the 10-membered spiroheterocyclyl contains 1 or 2 heteroatoms selected from N. In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is selected from a 7- to 10-membered fused heterocyclyl, and the 7- to 10-membered fused heterocyclyl optionally has one or two R 23 is replaced by R 23 teeth [ka] selected from the group consisting of C1-C4 alkyl, C1-C4 alkylsulfonyl, and C1-C4 alkylacyl, and / or R 3 It is hydrogen. In some embodiments, R 2 and R 2’ wherein one is hydrogen and the other is selected from 7- to 9-membered fused heterocyclyl, and the 7- to 9-membered fused heterocyclyl optionally has one [ka] or C1-C4 alkyl acyl, and / or R 3 It is hydrogen.

[0054] In some embodiments, the 7- to 9-membered fused heterocyclyl contains 1 or 2 heteroatoms selected from N, O, or S. In some embodiments, the 7- to 9-membered fused heterocyclyl contains 1 or 2 heteroatoms selected from N and O.

[0055] In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is selected from 5- to 6-membered heterocyclyls whose ring atoms are a nitrogen atom and a carbon atom, and the 5- to 6-membered heterocyclyl is selected from one R 22 and optionally one R 22’ is replaced by R 22 is selected from the group consisting of C2-C3 alkynyl-C(O)-, a 4- or 5-membered heterocyclyl, and a 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom, wherein the 4- or 5-membered heterocyclyl or the 6-membered heterocyclyl whose ring atoms are a nitrogen atom and a sulfur atom is optionally [ka] substituted with one, two, or three groups selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 alkyl acyl; R 22’ is selected from deuterium or C1-C3 alkyl, and / or R 3 It is hydrogen.

[0056] In some embodiments, the 5- to 6-membered heterocyclyl, whose ring atoms are a nitrogen atom and a carbon atom, contains 1 or 2 nitrogen atoms. In some embodiments, R 2 and R 2’ one of which is hydrogen and the other is selected from 7- to 10-membered bridged heterocyclyl, and the 7- to 10-membered bridged heterocyclyl is selected from one or two R 24 is replaced by R 24 is selected from C1-C4 alkyl acyl-N(C1-C4 alkyl)-, and / or R 3 It is hydrogen. In some embodiments, R 2 and R 2’ wherein one is hydrogen and the other is selected from a 7- to 10-membered bridged heterocyclyl, wherein the 7- to 10-membered bridged heterocyclyl is substituted with one CHC(O)N(CH)-, and / or R 3 It is hydrogen.

[0057] In some embodiments, the 7- to 10-membered bridged heterocyclyl contains 1 or 2 heteroatoms selected from N, O, or S. In some embodiments, the 7- to 10-membered bridged heterocyclyl contains 1 or 2 heteroatoms selected from N and O. In some embodiments, R 2 and R 2’ one of which is hydrogen, and the other is selected from 5- to 6-membered heterocyclyls containing a silicon atom or a phosphorus atom as a ring atom, and the 5- to 6-membered heterocyclyl optionally contains one or two R 23 is replaced by R 23 teeth [ka] and C1-C4 alkyl, and / or R 3 It is hydrogen.

[0058] In some embodiments, the 5- to 6-membered heterocyclyl containing a silicon or phosphorus ring atom contains one silicon atom or one phosphorus atom and further contains one heteroatom selected from N, O, or S. In some embodiments, the 5- to 6-membered heterocyclyl containing a silicon or phosphorus ring atom contains one silicon atom or one phosphorus atom and further contains one N atom.

[0059] In some embodiments, R 2 , R 2’ and R 3 are each independently hydrogen, [ka] or R 3 is R 2 or R 2’ and bond to each other, and together with the carbon atoms bonded to them form a single [ka] group and R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0060] In some embodiments, R 2 and R 2’ One of them is hydrogen and the other is [ka] and R 3 is hydrogen.

[0061] In some embodiments, R 2 , R 2’ and R 3 are each independently hydrogen, [ka] [ka] or R 3 is R 2 or R 2’ and bond to each other, and together with the carbon atoms bonded to them form a single [ka] group and R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0062] In some embodiments, R 2and R 2’ One of them is hydrogen and the other is [ka] and R 3 is hydrogen.

[0063] In some embodiments, R 2 , R 2’ and R 3 are each independently hydrogen, [ka] [ka] or R 3 is R 2 or R 2’ and are bonded to each other, forming the structural unit [ka] but [ka] and R 2 , R 2’ and R 3 does not simultaneously become hydrogen.

[0064] In some embodiments, R 2 and R 2’ One of them is hydrogen and the other is [ka] [ka] and R 3 is hydrogen. In some embodiments, R 2 , R 2’ or R 3 are each independently hydrogen or [ka] If R 1 or R 1’ is fluorine.

[0065] In some embodiments, R 2 , R 2’ or R 3 Two of them are hydrogen. In some embodiments, R 2 and R 2’ is hydrogen and R 3 is not hydrogen. In some embodiments, R 2 is not hydrogen, but R 2’ and R 3 It is hydrogen. In some embodiments, R 2’ is not hydrogen, but R 2 and R 3 It is hydrogen. In some embodiments, the present invention includes the above-defined variables and embodiments thereof, and any combination thereof.

[0066] In another aspect, the present invention provides the following compound or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka] [ka]

[0067] In another aspect, the present invention further provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant. According to another aspect, the present invention further provides a method for treating an Akt kinase-mediated disease in a mammal, comprising administering a therapeutically effective amount of the above-described compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment.

[0068] According to another aspect, the present invention further provides the use of the above compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating an Akt kinase-mediated disease. According to another aspect, the present invention further provides the use of the above compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of an Akt kinase-mediated disease.

[0069] In another aspect, the present invention further provides the above compound according to the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating an Akt kinase-mediated disease. In some embodiments, the Akt kinase-mediated disease is a cancer selected from, for example, prostate cancer, endometrial cancer, and the like.

[0070] The compounds of the present invention have good inhibitory effects on the phosphorylation of LNcap cells and LNcap cell AKT1 (S473), respectively, and have good cellular activity, low toxicity, good pharmacokinetic properties, and strong tumor-suppressing effects in vivo.

[0071] [Definition] Unless otherwise specified, the following terms used herein have the following meanings. Unless otherwise defined, a particular term should not be considered indefinite or unclear, but should be understood as having the general meaning in the art. When a trade name is mentioned herein, it refers to the corresponding product or its active ingredient.

[0072] The term "substituted / substituted / substituted" means that any one or more hydrogen atoms at a specified atom may be replaced with a substituent, provided that the valence state of the specified atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =0), it means that two hydrogen atoms are replaced with oxo, and that the oxo group does not occur on an aryl group. There are no keto substituents on aromatic moieties.

[0073] The term "optionally" or "optionally / as needed" means that the following circumstances or conditions may or may not occur, and the description includes both cases where the circumstances or conditions occur and cases where they do not occur. For example, "optionally" ethyl being substituted with a halogen means that the ethyl may be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3) with a halogen. It should be understood by those skilled in the art that any group containing one or more substituents does not introduce any spatially impossible and / or synthetically impossible substitutions or substitution modes.

[0074] C as described herein m-n means that the moiety 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.

[0075] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition at each occurrence is independent. So, for example, when a group is substituted with two R, each R is an independent option.

[0076] When a bond of a substituent crosses two atoms in a ring, the substituent can be bonded to any atom in the ring. For example, [ka] indicates that the cyclohexyl group may be substituted at any position in the cyclohexadiene group.

[0077] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine (fluoro, chloro, bromo, and iodo). The term "hydroxy" refers to the group --OH. The term "amino" refers to the group --NH.sub.2.

[0078] The term "alkyl" refers to a group having the general formula C n H 2n+1 where n is an integer from 1 to 20. The alkyl may be linear or branched. As used herein, alkyl refers to a hydrocarbon group having 1 to 10 carbon atoms (C1 to C 10 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), or 1 to 3 carbon atoms (C1-C3 alkyl). For example, the term "C 1-6 "Alkyl" means alkyl having 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) in alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio is defined as above.

[0079] The term "alkoxy" refers to --O-alkyl. The term "aminoalkyl" refers to the group -alkyl-NH2. The term "alkyl acyl" refers to -C(O)-alkyl. The term "alkylsulfonyl" refers to -SO2-alkyl.

[0080] The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond. As used herein, alkenyl refers to an alkyl group having 2 to 10 carbon atoms (C2 to C6). 10 Alkenyl may contain 2 to 6 carbon atoms (C-C alkenyl), 2 to 6 carbon atoms (C-C alkenyl), or 2 to 4 carbon atoms (C-C alkenyl). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0081] The term "alkynyl" refers to a straight or branched chain, unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. As used herein, alkynyl refers to an alkyl group having 2 to 10 carbon atoms (C2 to C6). 10 The alkynyl group can contain 2 to 6 carbon atoms (C2-C6 alkynyl), 2 to 6 carbon atoms (C2-C4 alkynyl), or 2 to 4 carbon atoms (C2-C4 alkynyl). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl (prop-1-ynyl), 2-propynyl (prop-2-ynyl), 1,3-butadiynyl (-C≡CC≡CH), and the like.

[0082] The term "cycloalkyl" means a carbocycle that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Examples of cycloalkyls described herein include 3- to 12-membered cycloalkyls, 3- to 10-membered cycloalkyls, 5- to 10-membered cycloalkyls, 3- to 8-membered cycloalkyls, and 3- to 6-membered cycloalkyls. Non-limiting examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0083] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic), and may exist as a monocyclic, bridged, or spirocyclic ring. A heterocyclyl as described herein may be a 3- to 7-membered ring, typically containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen. The heterocyclyl described herein may be a 4- to 12-membered heterocyclyl, a 4- to 8-membered heterocyclyl, a 5- to 6-membered heterocyclyl, a 4- to 5-membered heterocyclyl, or a 6-membered heterocyclyl, typically containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. A "5- or 6-membered monoheterocyclyl (single heterocyclic group) whose ring atoms are composed of a nitrogen atom and a carbon atom" described herein may contain one or two nitrogen atoms. A "5- or 6-membered monoheterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom" described herein may contain one silicon atom or one phosphorus atom and one or two heteroatoms selected from N, O, and S. Non-limiting examples of heterocyclyl include oxiranyl (also known as ethylene oxide), tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, [ka] These include, but are not limited to:

[0084] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Heterocycloalkyls described herein can be 3- to 7-membered rings, typically containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen. Heterocycloalkyls described herein can be 4- to 12-membered heterocycloalkyls, 4- to 8-membered heterocycloalkyls, 5- to 6-membered heterocycloalkyls, 4- to 5-membered heterocycloalkyls, or 6-membered heterocycloalkyls, containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxiranyl (also known as an ethylene oxide group), ethylene sulfide, and azirdinyl (also known as an azirane group). Non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocycloalkyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyls include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and the like. [ka] Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferred are monocyclic heterocycloalkyls having 5 or 6 ring atoms.

[0085] The term "monoheterocyclyl" refers to a fully saturated or partially unsaturated (not fully saturated aromatic) single ring (monocyclic ring) having 3 to 10 ring atoms or 4 to 6 ring atoms. A monoheterocyclyl described herein may 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. A monoheterocyclyl described herein may 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 monoheterocycles include an oxirane ring, a tetrahydrofuran ring, a dihydrofuran ring, a 3,4-dihydrofuran ring, a 3,6-dihydrofuran ring, a pyrrolidine ring, a dihydropyrrole ring, a piperidine ring, a piperazine ring, a morpholine ring, a tetrahydropyrazole ring, and a tetrahydrothiophene ring.

[0086] The term "monoheterocycloalkyl" refers to a fully saturated monocyclic ring having 3 to 10 ring atoms or 4 to 6 ring atoms. The monoheterocycloalkyls described herein may be 3 to 10-membered rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, silicon, phosphorus, oxygen, and / or nitrogen. The monoheterocycloalkyls described herein may be 3 to 10-membered, 3 to 8-membered, 3 to 7-membered, or 4 to 6-membered rings containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of monoheterocycloalkyls include oxirane rings, tetrahydrofuran rings, pyrrolidine rings, piperidine rings, piperazine rings, morpholine rings, tetrahydropyrazole rings, tetrahydrothiophene rings, and the like.

[0087] The term "spirocyclic group" refers to a polycyclic ring (a polycyclic ring) in which one carbon atom (called a spiro atom) is shared between 5- to 20-membered monocyclic rings (monocyclic rings) that are fully saturated or partially unsaturated (not fully saturated aromatic). Spirocyclic groups are preferably 6- to 14-membered, more preferably 6- to 10-membered, 7- to 9-membered, or 10-membered. Spiro rings are classified as monospiro rings, disspiro rings, or polyspiro rings depending on the number of spiro atoms shared between the rings, and are preferably monospiro rings or disspiro rings, and more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiro rings. Non-limiting examples of spiro rings include: [ka] Examples include:

[0088] The term "spirocycloalkyl" means a fully saturated spirocyclic group. The term "spiroheterocyclyl" means that one or more ring atoms in the spiro ring 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. Spiroheterocyclyls are preferably 6-14 membered, more preferably 6-10 membered, 7-9 membered, or 10 membered. Spiroheterocycles are classified into monospiroheterocycles, dispiroheterocycles, or polyspiroheterocycles depending on the number of spiro atoms shared between rings, and are preferably monospiroheterocycles or dispiroheterocycles, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocycles, each of which preferably contains one heteroatom selected from N, O, and / or S. Non-limiting examples of spiroheterocycles include: [ka] Examples include:

[0089] The term "spiroheterocycloalkyl" means a fully saturated spiroheterocyclyl. The term "bridged ring group" refers to a fully saturated or partially unsaturated (not fully saturated aromatic) all-carbon polycyclic ring having 5 to 20 ring atoms, with two rings sharing three or more ring atoms. It is preferably 6 to 14-membered, more preferably 6 to 10-membered. Depending on the number of rings, bridged rings can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, with bicyclic or tricyclic being preferred, and bicyclic being more preferred. Non-limiting examples of bridged rings include: [ka] Examples include:

[0090] The term "bridged cycloalkyl" means a fully saturated bridged ring group. The term "bridged heterocyclyl" means that one or more ring atoms in the bridged ring 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. The bridged heterocyclyl (bridged heterocyclic group) is 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 constituting the heterocycle, the bridged heterocycle (bridged heterocycle) can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic, with bicyclic or tricyclic being preferred, and bicyclic being more preferred. Non-limiting examples of bridged heterocycles include: [ka] Examples include:

[0091] The term "bridged heterocycloalkyl" means a fully saturated bridged heterocyclyl. The term "fused ring group" means a fully saturated or partially unsaturated (not fully saturated aromatic) all-carbon polycyclic ring having 5 to 20 ring atoms, with two rings sharing two ring atoms. Preferably, it has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms. Depending on the number of rings, it may be bicyclic, tricyclic, tetracyclic, or polycyclic. condensationThe fused rings are preferably bicyclic or tricyclic, and more preferably bicyclic. [ka] Examples include:

[0092] The term "fused cycloalkyl" means a fully saturated fused ring group. The term "fused heterocyclyl (fused heterocyclic group)" means that one or more ring atoms in the fused ring 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. The fused heterocyclyl (fused heterocyclic group) is preferably a 6- to 14-membered ring, more preferably a 6- to 10-membered ring, a 7- to 10-membered ring, a 7-membered ring, an 8-membered ring or a 9-membered ring. Depending on the number of rings constituting the fused heterocyclyl (fused heterocyclic group), it may be bicyclic, tricyclic or polycyclic. condensation Although heterocycles are classified into heterocycles, bicycles are preferred. Non-limiting examples of fused heterocycles include: [ka] Examples include:

[0093] The term "fused heterocycloalkyl" means a fully saturated fused heterocyclyl (fused heterocyclic group). Each of the above groups may be optionally substituted with one or more (e.g., 1, 2, or 3) substituents, such as deuterium, hydroxy, halogen (F, Cl, Br, or I), [ka] , C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl and C1-C6 alkylacyl-N(C1-C6 alkyl)-.

[0094] The term "treatment" means administering a compound or formulation according to the present invention to alleviate or eliminate a disease or one or more symptoms associated with said disease, and includes the following: (i) inhibiting the disease or disease state, i.e., inhibiting its onset or progression, and (ii) alleviating the disease or disease state, i.e., reducing the disease or disease state.

[0095] The term "therapeutically effective amount" refers to a dose of a compound according to the present invention to (i) treat a specific disease, condition, or disorder, or (ii) improve or eliminate one or more symptoms of a specific disease, condition, or disorder. The amount of a compound according to the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the administration form, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and the contents disclosed in the present invention.

[0096] The therapeutic amount of a compound of the present invention will be determined based, for example, on the specific therapeutic use, the form of the compound administered, the patient's health condition, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present invention in a pharmaceutical composition will vary and will depend on several factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, a compound of the present invention may be provided for parenteral administration in an aqueous physiological buffer solution containing about 0.1-10% w / v of the compound. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. Dosage may depend on variables such as the category and progression of the disease or condition, the general health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. Effective dosages are obtained by extrapolating dose-response curves derived from in vitro or animal model test systems.

[0097] The term "pharmaceutically acceptable" means that such compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problem or complication, commensurate with a reasonable benefit-risk ratio. Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc.

[0098] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or salts thereof with pharmaceutically acceptable adjuvants. Pharmaceutical compositions are intended to be advantageous for administering the compounds of the present invention to an organism. The pharmaceutical compositions of the present invention can be prepared by conventional methods in the art, for example, by mixing the compounds of the present invention or salts thereof with one or more pharmaceutically acceptable adjuvants.

[0099] The term "pharmaceutically acceptable adjuvant" means an adjuvant that does not have a significant irritating effect on the living body and does not impair the biological activity or performance of the active compound. Suitable adjuvants 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.

[0100] The term "comprise" and its English variants (e.g., "comprises" and "comprising") are to be construed in an open-ended, inclusive sense, i.e., "including, but not limited to," etc.

[0101] The compounds and intermediates according to the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogen atoms. Valence tautomers include interconversions via reorganization of some bonding electrons.

[0102] The present invention also includes isotope-labeled compounds of the present invention that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, e.g., 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 36 Cl, etc.

[0103] Some isotopically labeled compounds of the invention (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred for their ease of preparation and detectability.15 O. 13 N, 11 C and 18 Positron-emitting isotopes, such as F, are useful in positron emission tomography (PET) studies to examine substrate occupancy. Isotopically labeled compounds of the invention can generally be prepared following procedures analogous to those disclosed in the following schemes and / or examples by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0104] Additionally, heavy isotopes (e.g., deuterium, i.e. 2 H) may be preferred in some circumstances due to certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), where deuterium substitution can be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium. For example, but not limited to, all methyl hydrogens are deuterated to form methyl-d3.

[0105] The compounds of the present invention may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise specified, all stereoisomers, e.g., optical isomers and diastereomers, are included. The compounds of the present invention containing asymmetric carbon atoms can be separated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral materials or chiral reagents. For example, the compounds included in the compound structure [ka] are the (R)- and (S)-enantiomers.

[0106] Unless otherwise specified, the absolute configuration of one stereocenter is represented by a solid wedge bond. [ka] and dotted wedge bonds [ka] The relative configuration of the stereocenters is represented by a straight solid bond. [ka] and a straight dotted bond [ka] and the solid wedge connection [ka] or wedge-shaped dotted bond [ka] is a wavy line [ka] or a straight solid line combination [ka] or a straight dotted bond [ka] is a wavy line [ka] It is expressed as:

[0107] Unless otherwise specified, 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 two different substituents are bonded to each atom on the double bond (in a double bond containing a nitrogen atom, a pair of lone electron pairs on the nitrogen atom is considered to be one substituent of that bond), the atom on the double bond in the compound and the substituent are separated by a wavy line. [ka] When connected by , it refers to the (Z) isomer, the (E) isomer, or a mixture of the two isomers of the compound.

[0108] The pharmaceutical compositions of the present invention can be manufactured by combining the compounds of the present invention with suitable pharmaceutically acceptable auxiliaries, and can be prepared as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, creams, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0109] Typical routes of administration of the compound according to the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral administration, rectal administration, topical administration, inhalation administration, parenteral administration, sublingual administration, intravaginal administration, intranasal administration, intraocular administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, and intravenous administration.

[0110] The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, sugar-coated tableting, pulverizing, emulsifying, and lyophilizing methods.

[0111] In some embodiments, the pharmaceutical composition is in an oral dosage form. For oral administration, the pharmaceutical composition may be prepared by mixing the active compound with pharmaceutically acceptable adjuvants known in the art. These adjuvants may be used to formulate the compounds of the present invention into tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, suspensions, etc., for oral administration to patients.

[0112] Oral solid compositions can be prepared by conventional blending, filling, or tableting methods. For example, they can be prepared by blending the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain tablets or sugar-coated cores. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0113] The pharmaceutical compositions may further be adapted for parenteral administration in sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0114] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments described below in combination with other chemical synthetic methods, and equivalents well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0115] The chemical reactions of specific embodiments of the present invention are accomplished in suitable solvents, which must be compatible with the chemical transformations of the present invention and the desired reagents and materials. Those skilled in the art may need to modify or select synthetic procedures or reaction schemes based on existing embodiments to obtain compounds of the present invention.

[0116] One of the important considerations in planning any synthetic route in the art is the selection of appropriate protecting groups for reactive functional groups (such as the amino groups described herein); see, for example, Greene's Protective Groups in Organic Synthesis (4th Ed.). Hoboken, New Jersey: John Wiley & Sons, Inc., all references cited therein are incorporated herein in their entirety.

[0117] In some embodiments, the compounds of general formula (I) according to the present invention can be prepared by one skilled in the art of organic synthesis via the following schemes using standard methods in the art. [ka] [In the formula, R 1 , R 1’ , R 2 , R 2’ and R 3is as above.] DETAILED DESCRIPTION OF THE INVENTION

[0118] For clarity, the present invention is further described using the following examples, but these examples are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in the present invention are commercially available products and can be used without the need for further purification.

[0119] Example 1: Preparation of Compound 1 [ka]

[0120] Step A: Preparation of Compound 1A At -30°C under nitrogen gas protection, N,N-diisopropylethylamine (13.4 g) was slowly added dropwise to a tetrahydrofuran solution of 2,6-3-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 completed, the reaction solution was concentrated to obtain compound 1A (43.4 g). MS (ESI, [M+Na] + ) m / z: 441.5.

[0121] Step B: Preparation of Compound 1B Compound 1A (40.0 g), zinc powder (31.2 g), ammonium chloride (5.1 g), ethanol (400 mL), and water (40 mL) were sequentially added to a reaction flask at room temperature. After the addition was completed, the reaction was carried out at 90°C. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1B (41.0 g). MS (ESI, [M+H] + ) m / z:389.3.

[0122] Step C: Preparation of Compound 1C Compound 1B (34.0 g), 2-aminonicotinaldehyde (11.2 g), sodium perborate (14.3 g), acetic acid (250 mL), and methanol (30 mL) were sequentially added to a reaction flask at room temperature. After the addition was complete, the mixture was stirred at 55°C. After the reaction was complete, the reaction solution was concentrated, and ethyl acetate and water were added. The pH was then adjusted to 11-12 with aqueous sodium hydroxide. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 50 / 1) to obtain compound 1C (16.0 g). MS (ESI, [M+H] + ) m / z:491.3.

[0123] Step D: Preparation of Compound 1D 2-Butynoic acid (1.00 g), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.97 g), and dichloromethane (50 mL) were added sequentially to a reaction flask. At 0 °C, a solution of N,N-diisopropylethylamine (3.07 g) and 2-(3-bromophenyl)-pyrrolidine (2.96 g) in dichloromethane (30 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, saturated aqueous ammonium chloride solution was added to the reaction mixture to separate the phases. The aqueous phase was extracted with dichloromethane, and the combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 1D (3.92 g). MS (ESI, [M+H] + ) m / z: 292.0.

[0124] Step E: Preparation of Compound 1E Compound 1D (0.92 g), bis(pinacolato)diboron (1.20 g), potassium acetate (0.93 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.13 g), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask. The mixture was stirred at 100 °C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 1E (0.38 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 2 / 1). MS (ESI, [M+H] + ) m / z: 340.2.

[0125] Step F: Preparation of Compound 1F 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 sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 100°C for 2 hours. After the reaction was complete, the reaction mixture was filtered and concentrated. Compound 1F (68 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+Na] + ) m / z: 690.6.

[0126] Step G: Preparation of Compound 1 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 1 (18 mg). HRMS (ESI, [M+H] + ) m / z: 568.2823.

[0127] 1H NMR (500MHz, DMSO-d6) δ 8.28 (d, J = 8.3 Hz, 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), 7.46 - 7.38 (m, 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 = 6.9 Hz, 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).

[0128] Example 2: Preparation of Compound 2 [ka] Step A: Preparation of Compound 2A Under a nitrogen atmosphere, a solution of acryloyl chloride (1.08 g) in tetrahydrofuran (10 mL) was slowly added to a reaction solution of 3-bromobenzylamine (2.00 g) and N,N-diisopropylethylamine (1.63 g) in tetrahydrofuran (90 mL) in a reaction flask at -10°C. After the addition was complete, the mixture was stirred at room temperature to allow the reaction to complete. A saturated aqueous solution of ammonium chloride was added to the reaction solution, which was then extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 2A (2.58 g). MS (ESI, [M+H] + ) m / z: 240.1.

[0129] Step B: Preparation of Compound 2B Compound 2A (2.00 g), bis(pinacolato)diboron (3.17 g), potassium acetate (2.45 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.68 g), and 1,4-dioxane (30 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 2B (1.89 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 1 / 1). MS (ESI, [M+H] + ) m / z: 288.1.

[0130] Step C: Preparation of Compound 2C 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 sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 100 °C. After the reaction was complete, the mixture was filtered and concentrated. Compound 2C (85 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 616.5.

[0131] 1H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J = 8.3 Hz, 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, 7.7 Hz, 1H), 7.31 - 7.16 (m, 2H), 6.93 (d, J = 8.5 Hz, 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). Step D: Preparation of Compound 2 Compound 2C (80 mg), methanesulfonic acid (0.1 mL), and dichloromethane (4 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 2 (45 mg). HRMS (ESI, [M+H] + ) m / z: 516.2516.

[0132] 1H NMR (500 MHz, DMSO-d6) δ 8.67 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 4.8, 1.8 Hz, 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, 1.3 Hz, 1H), 7.21 (dd, J = 7.6, 1.9 Hz, 1H), 6.94 (s, 2H), 6.42 (dd, J = 7.7, 4.9 Hz, 1H), 6.31 (dd, J = 17.1, 10.2 Hz, 1H), 6.15 (dd, J = 17.1, 2.2 Hz, 1H), 5.65 (dd, J = 10.2, 2.2 Hz, 1H), 4.43 (d, J = 5.9 Hz, 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).

[0133] Example 3: Preparation of Compound 3 [ka]

[0134] Step A: Preparation of Compound 3A Under a nitrogen atmosphere, a solution of acryloyl chloride (2.98 g) in tetrahydrofuran (10 mL) was slowly added to a stirred solution of p-bromoaniline (5.00 g) and N,N-diisopropylethylamine (4.51 g) in tetrahydrofuran (90 mL) in a reaction flask at -10°C. After the addition was complete, the mixture was stirred at room temperature to allow the reaction to complete. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 3A (5.90 g). MS (ESI, [M+H] + ) m / z: 226.1.

[0135] Step B: Preparation of Compound 3B Compound 3A (0.5 g), bis(pinacolato)diboron (0.84 g), potassium acetate (0.65 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.18 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated. Compound 3B (0.26 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 2 / 1). MS (ESI, [M+H] + ) m / z: 274.5.

[0136] Step C: Preparation of Compound 3C 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, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 100°C for 2 hours. After the reaction was complete, the mixture was filtered and concentrated. Compound 3C (78 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 602.4.

[0137] Step D: Preparation of Compound 3 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 3 (34 mg).

[0138] HRMS (ESI, [M+H] + ) m / z: 502.2343. 1 H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.99 - 7.91 (m, 3H), 7.88 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.12 (dd, J = 7.7, 1.8 Hz, 1H), 6.90 (s, 2H), 6.45 - 6.30 (m, 2H), 6.21 (dd, J = 16.9, 2.0 Hz, 1H), 5.70 (dd, J = 10.0, 2.0 Hz, 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).

[0139] Example 4: Preparation of Compound 4 [ka]

[0140] Step A: Preparation of Compound 4A Under a nitrogen atmosphere and an ice-water bath, 2-chloroacetyl chloride (3.24 g) was added dropwise to a reaction solution of 2-amino-4-bromophenol (3.60 g) and sodium carbonate (3.22 g) in tetrahydrofuran (60 mL). After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 4A (3.60 g). MS (ESI, [MH] - ) m / z: 226.1; MS (ESI, [M+H] + ) m / z: 228.0.

[0141] Step B: Preparation of Compound 4B In an ice-water bath and under a nitrogen atmosphere, a 1 M borane solution (516 mg) in tetrahydrofuran was slowly added to a solution of compound 4A (452 ​​mg) in tetrahydrofuran (10 mL). After the addition was complete, the mixture was stirred at 70°C and allowed to react. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate, and the reaction solution was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 4B (380 mg). MS (ESI, [M+H] + ) m / z: 214.3.

[0142] Step C: Preparation of Compound 4C In a reaction flask, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (123 mg), compound 4B (320 mg), bis(pinacolato)diboron (508 mg), potassium carbonate (294 mg), and dioxane (5 mL) were sequentially added. The reaction was carried out at 100°C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 4C (242 mg). MS (ESI, [M+H] + ) m / z: 262.4.

[0143] Step D: Preparation of Compound 4D Compound 4C (200 mg), potassium carbonate (270 mg), tetrakis(triphenylphosphine)palladium (47 mg), compound 1C (320 mg), water (0.5 mL), and dioxane (5 mL) were sequentially added to a reaction flask. After the addition was complete, the reaction was carried out at 110°C. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 98 / 2) to obtain compound 4D (260 mg).

[0144] Step E: Preparation of Compound 4 Compound 4D (260 mg), methanesulfonic acid (0.5 mL), and dichloromethane (5 mL) 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 adjusted to pH 7-9 with saturated aqueous sodium bicarbonate solution, and the reaction solution was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 95 / 5) to obtain compound 4 (135 mg). HRMS (ESI, [M+H] + ) m / z: 490.2360.

[0145] 1 H NMR (500 MHz, DMSO-d6): δ 8.16(d, J = 5.0 Hz,1H),7.99 (dd, J = 5.0 Hz,10.0Hz, 1H), 7.75(d, J = 10.0 Hz,1H), 7.61(d, J = 10.0 Hz,1H), 7.41(d, J = 10.0 Hz,1H), 7.23(d, J = 5.0 Hz,1H), 7.16 - 7.14(m,2H), 6.94(s, 2H), 6.71(d, J = 5.0 Hz,1H), 6.39(q, J = 5.0 Hz,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).

[0146] Example 5: Preparation of Compound 5 [ka]

[0147] Step A: Preparation of Compound 5A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (279 mg), tris(dibenzylideneacetone)dipalladium (274 mg), 1,3-dibromobenzene (705 mg), 4,4-dimethyl-1,4-silapiperidine (386 mg), sodium tert-butoxide (431 mg), and toluene (10 mL) were sequentially added to a 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 purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain compound 5A (475 mg). This crude product was used directly in the next step.

[0148] Step B: Preparation of Compound 5B Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (63.9 mg), compound 5A (475 mg), bis(pinacolato)diboron (795 mg), potassium acetate (461 mg), and dioxane (8 mL) were sequentially added to a reaction flask. After the addition was complete, the reaction was carried out at 110°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 5B (450 mg). MS (ESI, [M+H] + ) m / z: 332.5.

[0149] Step C: Preparation of Compound 5C Under a nitrogen atmosphere, compound 5B (311 mg), potassium carbonate (287 mg), compound 1C (340 mg), water (1 mL), and dioxane (10 mL) were sequentially added to a reaction flask. After the addition was completed, the reaction was carried out at 110°C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 96 / 4) to obtain compound 5C (280 mg). MS (ESI, [M+H] + ) m / z: 660.7.

[0150] Step D: Preparation of Compound 5 In a reaction flask, methanesulfonic acid (200 mg) was gradually added to a solution of compound 5C (280 mg) in dichloromethane (5 mL). After the addition was complete, the reaction was allowed to proceed at room temperature. After the reaction was complete, the reaction solution was adjusted to pH 7-9 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 95 / 5) to give compound 5 (120 mg). MS (ESI, [M+H] + ) m / z: 560.6.

[0151] 1 H NMR (500 MHz, DMSO-d6): δ 8.16 (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).

[0152] Example 6: Preparation of Compound 6 [ka]

[0153] Step A: Preparation of Compound 6A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.475 g), tris(dibenzylideneacetone)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 sequentially added to a 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 purified by column chromatography (petroleum ether / ethyl acetate = 85 / 15) to obtain compound 6A (780 mg).

[0154] Step B: Preparation of Compound 6B Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (339 mg), compound 6A (780 mg), bis(pinacolato)diboron (1404 mg), potassium acetate (814 mg), and dioxane (8 mL) were sequentially added to a reaction flask. After the addition was complete, the reaction was carried out at 110°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 6B (520 mg). MS (ESI, [M+H] + ) m / z: 330.5.

[0155] Step C: Preparation of Compound 6C Under a nitrogen atmosphere, compound 6B (520 mg), potassium carbonate (220 mg), tetratriphenylphosphine (36 mg), compound 1C (260 mg), water (0.50 mL), and dioxane (10 mL) were sequentially added to a reaction flask. After the addition was completed, the reaction was carried out at 110°C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 98 / 2) to obtain compound 6C (240 mg). MS (ESI, [M+H] + ) m / z: 658.7.

[0156] Step D: Preparation of Compound 6 Methanesulfonic acid (331 mg), compound 6C (240 mg), and dichloromethane (5 mL) 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 mixture was adjusted to pH 7-9 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 95 / 5) to give compound 6 (140 mg). MS (ESI, [M+H] + ) m / z: 558.6. 1 H NMR (500 MHz, DMSO-d6): δ 8.45 (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).

[0157] Example 7: Preparation of Compound 7 [ka] Step A: Preparation of Compound 7A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (367 mg), bis(dibenzylideneacetone)palladium (270 mg), 1,3-dibromobenzene (695 mg), (R)-3-(methylamine)pyrrole-1-carboxylate tert-butyl (590 mg), sodium tert-butoxide (566 mg), and dioxane (15 mL) were sequentially added to a reaction flask. After the addition was complete, the reaction was carried out at 120°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain compound 7A (642 mg). MS (ESI, [M-55+H] + ) m / z: 299.1.

[0158] Step B: Preparation of Compound 7B In a nitrogen atmosphere, compound 7A (640 mg), dichloromethane (5 mL), and a 4 M solution of hydrogen chloride in dioxane (3 mL) were sequentially added to a reaction flask. After the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, the solvent was evaporated under reduced pressure to give compound 7B (680 mg).

[0159] Step C: Preparation of Compound 7C Compound 7B (680 mg), tetrahydrofuran (20 mL), N,N-diisopropylethylamine (581 mg), and acetyl chloride (300 mg) were added to a reaction flask. After the addition was completed, the mixture was allowed to react at room temperature. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 7C (430 mg). MS (ESI, [M+H] + ) m / z: 297.4.

[0160] Step D: Preparation of Compound 7D Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (154 mg), compound 7C (360 mg), bis(pinacolato)diboron (478 mg), potassium acetate (370 mg), and dioxane (8 mL) were sequentially added to a reaction flask. After the addition was complete, the reaction was allowed to proceed at 110°C. After the reaction was complete, the reaction was quenched with saturated brine, extracted with ethyl acetate, and the combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give compound 7D (440 mg). MS (ESI, [M+H] + ) m / z: 345.6.

[0161] Step E: Preparation of Compound 7E In a reaction flask, tetrakis(triphenylphosphine)palladium (99 mg), compound 1C (420 mg), compound 7D (294 mg), potassium carbonate (236 mg), dioxane (5 mL), and water (0.5 mL) were sequentially added. After the addition was complete, the mixture was heated to 120°C for reaction. After the reaction of the raw materials was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 98:2) to obtain compound 7E (540 mg). MS (ESI, [M+H] + ) m / z: 673.7.

[0162] Step F: Preparation of Compound 7 In a reaction flask, compound 7E (49 0m g), dichloromethane (6 mL), and methanesulfonic acid (420 mg) were added sequentially. After the addition was complete, the reaction was allowed to proceed at room temperature. After the reaction was complete, the pH of the reaction mixture was adjusted to neutral with sodium bicarbonate, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 96 / 4) to obtain compound 7 (30 mg). MS (ESI, [M+H] + ) m / z: 573.4.

[0163] 1 H NMR (500 MHz, DMSO-d6): δ 8.23 ​​(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).

[0164] Example 8: Preparation of Compound 8 [ka] Step A: Preparation of Compound 8A Under a nitrogen atmosphere, a solution of N,N-diethyl-1,1,1-trifluoro-14-thiamine (20.890 g) in 1,2-dichloroethane (25 mL) was slowly added dropwise to a reaction flask containing tert-butyl 3-oxopyrrolidine-1-carboxylate (4.000 g). After the addition was complete, the reaction mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 8A (2.510 g). MS (ESI, [M+H] + ) m / z: 208.0.

[0165] Step B: Preparation of Compound 8B In a reaction flask, compound 8A (1.000 g), a 1,4-dioxane solution (2 mL), and a 4 M solution of hydrochloric acid in 1,4-dioxane (9.50 mL) were added sequentially. After the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, the reaction solution was concentrated to give compound 8B (0.512 g).

[0166] Step C: Preparation of Compound 8C Under a nitrogen atmosphere, sodium tert-butoxide (0.928 g), tris(dibenzylideneacetone)dipalladium (0.442 g), 3,3-difluoropyrrolidine (0.517 g), 1,3-dibromobenzene (2.279 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.451 g), and toluene (30 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110 °C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5) to obtain compound 8C (1.199 g).

[0167] Step D: Preparation of Compound 8D Under a nitrogen atmosphere, compound 8C (1.150 g), potassium carbonate (1.227 g), bis(pinacolato)diboron (1.587 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.170 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.451 g), and N,N-dimethylformamide (30 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110 °C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain compound 8D (0.779 g). MS (ESI, [M+H] + ) m / z: 310.2.

[0168] Step E: Preparation of Compound 8E Under a nitrogen atmosphere, 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 sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 140°C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 98 / 3) to give compound 8E (0.140 g). MS (ESI, [M+H] + ) m / z: 638.4.

[0169] Step F: Preparation of Compound 8 Compound 8E (0.140 g), dichloromethane (10 mL), and methanesulfonic acid (0.160 g) were added sequentially to a reaction flask. After the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 93 / 7) to obtain compound 8 (98 mg). MS (ESI, [M+H] + ) m / z: 538.6.

[0170] 1H NMR (500 MHz, DMSO-d6) δ 8.24 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 7.6 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.7 Hz, 1H), 7.27 (dq, J = 13.3, 7.8 Hz, 3H), 7.02 (s, 2H), 6.66 (d, J = 8.1 Hz, 1H), 6.43 (dd, J = 7.7, 4.7 Hz, 1H), 3.74 (t, J = 13.3 Hz, 2H), 3.53 (t, J = 7.2 Hz, 2H), 2.55 (dd, J = 1.6, 10.3 Hz, 2H), 2.44 (t, J = 8.6 Hz, 2H), 2.24 - 2.10 (m, 2H), 2.11 - 2.00 (m, 1H), 1.72 (dd, J = 11.4, 6.5Hz, 1H).

[0171] Example 9: Preparation of Compound 9 [ka]

[0172] Step A: Preparation of Compound 9A Under a nitrogen atmosphere, hexahydropyrrolo[1,2-α]pyrazin-6-one hydrochloride (0.230 g), 1,3-dibromobenzene (0.774 g), tris(dibenzylideneacetone)dipalladium (0.150 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.153 g), sodium tert-butoxide (0.552 g), and toluene (7.5 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 6) to obtain compound 9A (0.100 g). MS (ESI, [M+H] + ) m / z: 295.4296.3.

[0173] Step B: Preparation of Compound 9B Under a nitrogen atmosphere, potassium carbonate (0.249 g), bis(pinacolato)diboron (0.332 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.027 g), compound 9A (0.260 g), and N,N-dimethylformamide (20.00 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 70°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 9B (0.112 g). MS (ESI, [M+H] + ) m / z: 343.5.

[0174] Step C: Preparation of Compound 9C Under a nitrogen atmosphere, compound 9B (0.268 g), compound 1C (0.145 g), potassium carbonate (0.079 g), tetrakis(triphenylphosphine)palladium (0.033 g), 1,4-dioxane (4 mL), and water (7.5 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 93 / 7) to obtain compound 9C (0.130 g). MS (ESI, [M+H] + ) m / z: 671.7.

[0175] Step D: Preparation of Compound 9 Compound 9C (0.130 g), dichloromethane (10 mL), and methanesulfonic acid (0.149 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 and purified by column chromatography (dichloromethane / methanol = 93 / 7) to obtain compound 9 (0.047 g). MS (ESI, [M+H] + ) m / z: 571.5.

[0176] 1H NMR (500 MHz, DMSO-d6)δ 8.25 (d, J = 8.4 Hz, 1H), 8.09 - 7.95 (m, 2H), 7.74 - 7.60 (m, 3H), 7.53 - 7.41 (m, 3H), 7.31 (t, J = 7.9 Hz, 1H), 7.24 (dd, J = 7.6, 1.9 Hz, 1H), 7.14 - 7.02 (m, 1H), 6.98 (s, 2H), 6.43 (dd, J = 7.7, 4.8 Hz, 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, 3.7 Hz, 1H), 2.93 (td, J = 12.6, 3.8 Hz, 1H), 2.61 (td, J = 12.2, 3.6 Hz, 1H), 2.49 - 2.42 (m, 2H), 2.35 - 2.21 (m, 4H), 2.16 (tdd, J = 13.9, 7.7, 3.8 Hz, 1H), 2.09 (ddd, J = 11.1, 5.2, 2.4 Hz, 1H), 1.75 (dtt, J = 11.0, 9.0, 6.2 Hz, 1H), 1.69 - 1.59 (m, 1H), 0.90 - 0.80 (m, 1H).

[0177] Example 10: Production of Compound 10

change

[0178] Step B: Preparation of Compound 10B Compound 10A (0.494 g), trifluoroacetic acid (6.440 g), 3-oxetanone (0.150 g), sodium cyanoborohydride (0.175 g), dichloromethane (2 mL), and methanol (2 mL) were sequentially added to a reaction flask at room temperature. After the addition was complete, the mixture was stirred and allowed to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 9:1) to obtain compound 10B (0.300 g).

[0179] Step C: Preparation of Compound 10C Under a nitrogen atmosphere, compound 10B (0.300 g), potassium carbonate (0.275 g), bis(pinacolato)diboron (0.356 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.035 g), and N,N-dimethylformamide (34.00 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 70 °C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 10C (0.403 g). MS (ESI, [M+H] + ) m / z:359.5.

[0180] Step D: Preparation of Compound 10D Under a nitrogen atmosphere, 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 sequentially added to a reaction flask. After the addition was completed, the mixture was stirred at 100°C. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 10D (0.579 g). MS (ESI, [M+H] + ) m / z:615.6.

[0181] Step E: Preparation of Compound 10E Under a hydrogen atmosphere, compound 10D (0.579 g), palladium / carbon (0.022 g), and tetrahydrofuran (15 mL) were sequentially added to a reaction flask. After the addition was completed, the mixture was stirred at 30°C to react. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound 10E (0.401 g). MS (ESI, [M+H] + ) m / z: 585.6.

[0182] Step F: Preparation of Compound 10F Under a nitrogen atmosphere, compound 10E (0.100 g), 2-aminonicotine (0.021 g), sodium perborate tetrahydrate (0.014 g), methanol (5 mL), and acetic acid (2 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 50°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 96 / 4) to obtain compound 10F (0.078 g). MS (ESI, [M+H] + ) m / z: 687.5.

[0183] Step G: Preparation of Compound 10 Compound 10F (0.050 g), methanesulfonic acid (0.035 g), and dichloromethane (5 mL) were added sequentially to a reaction flask at room temperature. After the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 99 / 1) to obtain compound 10 (33 mg). MS (ESI, [M+H] + ) m / z: 587.5.

[0184] 1 H NMR (500 MHz, CDCl3) δ 8.07 (dd, J = 32.5, 6.3 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.64 - 7.47 (m, 4H), 7.38 - 7.28 (m, 2H), 7.20 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 2H), 6.63 (s, 2H), 6.41 (t, J = 6.5 Hz, 1H), 4.70 (dd, J = 15.0, 7.8 Hz, 2H), 4.62 (d, J = 6.7 Hz, 1H), 3.86 (s, 2H), 3.60 - 3.41 (m, 2H), 3.28 (d, J = 11.6 Hz, 1H), 3.18 (t, J = 10.8 Hz, 1H), 2.63 (dt, J = 18.5, 8.5 Hz, 3H), 2.43 (s, 2H), 2.30 (d, J = 10.9 Hz, 3H), 2.15 (p, J =9.1, 8.7 Hz, 1H), 1.88 - 1.78 (m, 1H), 1.11 (d, J = 6.4 Hz, 4H).

[0185] Example 11: Preparation of Compound 11 [ka]

[0186] Step A: Preparation of Compound 11A Under a nitrogen atmosphere, 1,3-dibromobenzene (4.240 g), 1-(oxetan-3-yl)piperazine (1.278 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.420 g), sodium tert-butoxide (2.590 g), tris(dibenzylideneacetone)dipalladium (0.411 g), and toluene (22 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 70 °C to allow the reaction to proceed. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 11A (2.032 g). MS (ESI, [M+K] + ) m / z: 335.4.

[0187] Step B: Preparation of Compound 11B Under a nitrogen atmosphere, compound 11A (2.032 g), potassium tert-butoxide (2.010 g), bis(pinacolato)diboron (2.600 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.223 g), and N,N-dimethylformamide (34 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 70 °C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 11B (2.016 g). MS (ESI, [M+H] + ) m / z: 345.4.

[0188] Step C: Preparation of Compound 11C Under a nitrogen atmosphere, (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 completed, the mixture was stirred at 100°C. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 11C (0.732 g). MS (ESI, [M+H] + ) m / z: 601.3.

[0189] Step D: Preparation of Compound 11D Under a hydrogen atmosphere, compound 11C (0.037 g) and palladium / carbon (0.001 g) were added sequentially to a reaction flask. After the addition was completed, the mixture was stirred at 30°C to react. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 11D (0.013 g). MS (ESI, [M+H] + ) m / z: 571.5.

[0190] Step E: Preparation of Compound 11E Under a nitrogen atmosphere, compound 11D (0.100 g), 2-aminonicotine (0.022 g), sodium perborate tetrahydrate (0.014 g), methanol (5 mL), and acetic acid (2 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 50°C to react. After the reaction was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 99:1) to obtain compound 11E (50 mg). MS (ESI, [M+H] + ) m / z: 673.6.

[0191] Step F: Preparation of Compound 11 Compound 11E (50 mg), methanesulfonic acid (35 mg), and dichloromethane (3 mL) were added sequentially to a reaction flask at room temperature, and the mixture was stirred and reacted. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 99 / 1) to give Compound 11 (28 mg). MS (ESI, [M+H] + ) m / z: 573.5.

[0192] 1 H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8.3 Hz, 1H), 8.07 (tt, J = 5.9, 3.2 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.61 (t, J = 2.0 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.54 - 7.46 (m, 2H), 7.45 - 7.41 (m, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.20 - 7.13 (m, 1H), 6.96 (dd, J = 8.3, 2.5 Hz, 1H), 6.63 (s, 2H), 6.45 - 6.36 (m, 1H), 4.69 (dt, J = 19.8, 6.4 Hz, 4H), 3.57 (p, J = 6.5 Hz, 1H), 3.29 (t, J = 5.0 Hz, 4H), 2.62 (ddd, J = 11.9, 8.9, 6.2 Hz, 2H), 2.52 (t, J = 4.9 Hz, 4H), 2.25 (q, J = 10.5, 9.1 Hz, 2H), 2.18 - 2.00 (m, 2H).

[0193] Example 12: Preparation of Compound 12 [ka]

[0194] Step A: Preparation of Compound 12A Under a nitrogen atmosphere, 7-oxa-2-azaspiro[3.5]nonane (0.809 g), 1,4-dibromobenzene (1.500 g), tris(dibenzylideneacetone)dipalladium (0.582 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.594 g), sodium tert-butoxide (0.917 g), and toluene (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 17 / 3) to obtain compound 12A (1.257 g). 1 H NMR (500 MHz, DMSO-d6) δ 7.27 - 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).

[0195] Step B: Preparation of Compound 12B Under a nitrogen atmosphere, potassium acetate (1.263 g), bis(pinacolato)diboron (2.178 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.525 g), compound 12A (0.452 g), and dioxane (15 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 12B (1.500 g). MS (ESI, [M+H] + ) m / z: 330.5.

[0196] Step C: Preparation of Compound 12C Under a nitrogen atmosphere, compound 12B (0.419 g), compound 1C (0.500 g), potassium carbonate (0.422 g), tetrakis(triphenylphosphine)palladium (0.058 g), 1,4-dioxane (10 mL), and water (5 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 98:2) to obtain compound 12C (0.114 g). MS (ESI, [M+H] + ) m / z: 658.7.

[0197] Step D: Preparation of Compound 12 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 and allowed to react. After the reaction was complete, 20% aqueous sodium hydroxide solution was added while stirring in an ice bath, the solution was adjusted to pH 12, and 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 purified by column chromatography (dichloromethane / methanol = 90:10) to give compound 12 (28 mg). MS (ESI, [M+H] + ) m / z: 558.6.

[0198] 1 H NMR (500 MHz, 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).

[0199] Example 13: Preparation of Compound 13 [ka]

[0200] Step A: Preparation of Compound 13A In a reaction flask, 2-oxa-6-azaspiro[3,3]heptane (1.00 g), m-dibromobenzene (2.49 g), (tris(dibenzylideneacetone)dipalladium (0.24 g ), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.16 g), tetrahydrofuran (50 mL), and sodium tert-butoxide (2.03 g) were added sequentially, and after the addition was completed, the mixture was stirred at 80°C under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain Compound 13A (1.24 g). MS (ESI, [M+H] + ) m / z: 254.3.

[0201] 1 H NMR (500 MHz, DMSO-d6): δ 7.09 (t, J = 8.0 Hz, 1H), 6.81 (dd, J = 1.0, 8.0 Hz, 1H), 6.56 (t, J = 2.0 Hz, 1H), 6.40 (dd, J = 2.0, 8.0 Hz, 1H), 4.70 (s, 4H), 3.97 (m, 4H).

[0202] Step B: Preparation of Compound 13B To a reaction flask containing compound 13A (1.13 g), bis(pinacolato)diboron (1.69 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.18 g), 1,4-dioxane (50 mL), and potassium acetate (1.30 g) were added sequentially. After the addition was completed, the mixture was stirred at 120°C under a nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 13B (1.22 g). MS (ESI, [M+H] + ) m / z: 302.2.

[0203] 1 H NMR (500 MHz, DMSO-d6): δ 7.18 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.55 (d, J = 2.0, 8.0 Hz, 1H), 4.70 (s, 4H), 3.95 (s, 4H), 1.28 (s, 12H). 13 C NMR (125 MHz, DMSO-d6): δ 151.34, 128.76, 123.98, 117.41, 115.17, 83.97, 80.38, 61.48, 38.96, 25.12.

[0204] Step C: Preparation of Compound 13C To a reaction flask containing compound 1C (0.495 g), dichloromethane (20 mL) and methanesulfonic acid (1.480 g) were added sequentially, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was poured into water, adjusted to pH 9 with aqueous sodium hydroxide (20% w / w), extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 13C (0.393 g). MS (ESI, [M+H] + ) m / z: 391.2.

[0205] Step D: Preparation of Compound 13 Compound 13B (0.20 g), compound 13C (0.30 g), potassium carbonate (0.28 g), tetrakis(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, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered and concentrated. Compound 13 (135 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 530.7.

[0206] 1 H NMR (500 MHz, DMSO-d6): δ 8.09 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 4.5 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 7.5 Hz, 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).

[0207] Example 14: Preparation of Compound 14 [ka]

[0208] Step A: Preparation of Compound 14A In a reaction flask, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.10 g), m-dibromobenzene (0.45 g), (tris(dibenzylideneacetone)dipalladium (32 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (21 mg), tetrahydrofuran (20 mL), and sodium tert-butoxide (0.20 g) were added sequentially. After the addition was completed, the mixture was stirred at 80°C under a nitrogen atmosphere to react. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain Compound 14A (108 mg). 1 H NMR (500 MHz, DMSO-d6): δ 7.09 (t, J = 8.0 Hz, 1H), 6.81 (dd, J = 1.0, 8.0 Hz, 1H), 6.55 (t, J = 2.0 Hz, 1H), 6.39 (dd, J = 2.0, 8.0 Hz, 1H), 4.01 (s, 4H), 3.93 (s, 4H), 1.38 (s, 9H).

[0209] Step B: Preparation of Compound 14B To a reaction flask containing compound 14A (152 mg), bis(pinacolato)diboron (164 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium 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 a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 14B (53 mg). MS (ESI, [M+H] + ) m / z: 401.5.

[0210] Step C: Preparation of Compound 14C Compound 14B (50 mg), compound 1C (67 mg), potassium carbonate (70 mg), tetrakis(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, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered and concentrated. Compound 14C (80 mg) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 729.7.

[0211] 1 H NMR (500 MHz, DMSO-d6): δ 8.23 ​​(d, J = 8.5 Hz, 1H), 8.00 (dd, J = 1.5, 5.0 Hz, 1H), 7.92 (d, J = 8.5 Hz, 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, 7.5 Hz, 1H), 6.33 (dd, J = 5.0, 7.5 Hz, 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).

[0212] Step D: Preparation of Compound 14 Compound 14C (69 mg), methanesulfonic acid (0.1 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask and stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 14 (25 mg). HRMS (ESI, [M+H] +) m / z: 529.2814.

[0213] 1 H NMR (500 MHz, DMSO-d6): δ 8.23 ​​(d, J = 8.0 Hz, 1H), 8.01 (dd, J = 2.0, 5.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.25 - 7.21 (m, 2H), 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), 3.43 - 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).

[0214] Example 15: Preparation of Compound 15 [ka]

[0215] Step A: Preparation of Compound 15A Under a nitrogen atmosphere, (5S,7S)-2-aminoadamantan-1-ol (1.17 g), 1,3-dibromobenzene (1.65 g), tris(dibenzylideneacetone)dipalladium (0.64 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.65 g), sodium tert-butoxide (1.00 g), and toluene (10 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C to allow the reaction to proceed. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 15A (1.15 g). MS (ESI, [M+H] + ) m / z: 322.2.

[0216] Step B: Preparation of Compound 15B Under a nitrogen atmosphere, potassium acetate (0.795 g), bis(pinacolato)diboron (1.372 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.331 g), compound 15A (1.154 g), and dioxane (30 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 15B (0.750 g). MS (ESI, [M+H] + ) m / z: 370.6.

[0217] Step C: Preparation of Compound 15C Under a nitrogen atmosphere, 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 sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 3 / 2) to obtain compound 15C (1.215 g). MS (ESI, [M+H] + ) m / z: 698.8.

[0218] Step D: Preparation of Compound 15 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 and allowed to react. After the reaction was complete, 20% aqueous sodium hydroxide solution was added while stirring in an ice bath, the solution was adjusted to pH 12, and 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 purified by column chromatography (dichloromethane / methanol = 4 / 1) to give compound 15 (0.388 g). MS (ESI, [M+H] +) m / z: 598.7.

[0219] 1 H NMR (500 MHz, DMSO-d6) δ 8.21(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 - 7.13(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).

[0220] Example 16: Preparation of Compound 16 [ka]

[0221] Step A: Preparation of Compound 16A Compound 14A (1.00 g) was weighed and added to a reaction flask, and dichloromethane (100 mL) was added and stirred to dissolve. Then, methanesulfonic acid (0.82 g) was added, and after the addition was complete, the mixture was stirred at room temperature to react. After the reaction was complete, triethylamine (2.5 mL) was added to quench the reaction. Dichloromethane was added to adjust the volume of the reaction solution to 120 mL to obtain a solution of compound 16A. This solution was used directly in the next step of the reaction without concentrating it.

[0222] Step B: Preparation of Compound 16B To the solution of compound 16A (35 mL), acetic anhydride (169 mg) was added, and after the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 96 / 4) to give compound 16B (219 mg). MS (ESI, [M+H] + ) m / z: 295.1.

[0223] 1 H NMR (500 MHz, CDCl3): δ 7.06 (t, J = 8.0 Hz, 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).

[0224] Step C: Preparation of Compound 16C To a reaction flask containing compound 16B (210 mg), bis(pinacolato)diboron (271 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium 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 under a nitrogen atmosphere at 120°C to react. After the reaction was complete, the reaction solution was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 98 / 2) to give compound 16C (185 mg). MS (ESI, [M+H] + ) m / z: 343.3.

[0225] Step D: Preparation of Compound 16D Compound 16C (140 mg), compound 1C (276 mg), potassium carbonate (239 mg), tetrakis(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, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered and concentrated. Compound 16D (280 mg) was obtained by column chromatography (dichloromethane / methanol = 96 / 4). MS (ESI, [M+H] + ) m / z: 671.7.

[0226] Step E: Preparation of Compound 16 Compound 16D (260 mg), methanesulfonic acid (0.25 mL), and dichloromethane (20 mL) were added sequentially to a reaction flask and stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 16 (125 mg). MS (ESI, [M+H] + ) m / z: 571.6.

[0227] 1 H NMR (500 MHz, CDCl3): 8.11-8.04 (d, J = 8.5 Hz, 1H), 8.06 - 7.96 (dd, J = 1.0, 4.5 Hz, 1H), 7.76 - 7.67 (d, J = 8.5 Hz, 1H), 7.65 - 7.48 (d, J = 8.5 Hz, 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).

[0228] Example 17: Preparation of Compound 17 [ka]

[0229] Step A: Preparation of Compound 17A To the solution of compound 16A (35 mL), methanesulfonyl chloride (189 mg) was added, and after the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 17A (227 mg). MS (ESI, [M+H] + ) m / z: 331.1.

[0230] 1 H NMR (500 MHz, CDCl3): δ 7.06 (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).

[0231] Step B: Preparation of Compound 17B To a reaction flask containing compound 17A (220 mg), bis(pinacolato)diboron (253 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium 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 a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 17B (157 mg). MS (ESI, [M+H] + ) m / z: 379.3.

[0232] Step C: Preparation of Compound 17C Compound 17B (132 mg), compound 1C (223 mg), potassium carbonate (193 mg), tetrakis(triphenylphosphine)palladium (81 mg), 1,4-dioxane (10 mL), and water (1 mL) were sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 98 / 2) to give compound 17C (146 mg). MS (ESI, [M+H] + ) m / z: 707.7.

[0233] Step D: Preparation of Compound 17 Compound 17C (150 mg), methanesulfonic acid (0.15 mL), and dichloromethane (15 mL) were added sequentially to a reaction flask and stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 95 / 5) to give compound 17 (47 mg). HRMS (ESI, [M+H] + ) m / z: 607.2606.

[0234] 1 H NMR (500 MHz, 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).

[0235] Example 18: Preparation of Compound 18 [ka] Step A: Preparation of Compound 18A Under a nitrogen atmosphere, hexahydro-1H-furan[3,4-c]pyrrole hydrochloride (0.824 g), 1,3-dibromobenzene (1.300 g), tris(dibenzylideneacetone)dipalladium (0.505 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.515 g), sodium tert-butoxide (0.794 g), and toluene (10 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C to allow the reaction to proceed. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 19 / 1) to obtain compound 18A (0.452 g). MS (ESI, [M+H] + ) m / z: 268.4.

[0236] Step B: Preparation of Compound 18B Under a nitrogen atmosphere, potassium acetate (0.496 g), bis(pinacolato)diboron (0.809 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.206 g), compound 18A (0.452 g), and dioxane (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 19 / 1) to obtain compound 18B (0.490 g). MS (ESI, [M+H] + ) m / z: 316.5.

[0237] Step C: Preparation of Compound 18C Under a nitrogen atmosphere, compound 18B (0.210 g), compound 1C (0.327 g), potassium carbonate (0.276 g), tetrakis(triphenylphosphine)palladium (0.038 g), 1,4-dioxane (15 mL), and water (7.5 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 1 / 1) to obtain compound 18C (0.400 g). MS (ESI, [M+H] + ) m / z: 644.8.

[0238] Step D: Preparation of Compound 18 Compound 18C (0.400 g), dichloromethane (10 mL), and methanesulfonic acid (0.149 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, 20% aqueous sodium hydroxide was added while stirring in an ice bath, the solution was adjusted to pH 12, and 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 purified by column chromatography (dichloromethane / methanol = 7 / 3) to give compound 18 (0.285 g). MS (ESI, [M+H] + ) m / z: 544.7.

[0239] 1 H NMR (500 MHz, DMSO-d6) δ 8.43(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).

[0240] Example 19: Preparation of Compound 19 [ka]

[0241] Step A: Preparation of Compound 19A In a reaction flask, at 0°C under a nitrogen atmosphere, a solution of 2-chloroacetyl chloride (3.24 g) in tetrahydrofuran (10 mL) was slowly added dropwise to a reaction solution of 2-amino-4-bromophenol (3.60 g) and sodium carbonate (3.22 g) 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 then filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 19A (3.4 g). MS (ESI, [MH] - ) m / z: 226.4.

[0242] Step B: Preparation of Compound 19B In a reaction flask, at 0°C under a nitrogen atmosphere, a 2M borane solution in toluene-dimethyl sulfide (15 mL) was slowly added to a solution of compound 19A (2.28 g) in tetrahydrofuran (10 mL). After the addition was complete, the mixture was stirred at room temperature and allowed to react at 66°C. After the reaction was complete, the reaction was quenched with saturated aqueous sodium hydroxide, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 19B (2.10 g). The reaction product of this step was used directly in the next step.

[0243] Step C: Preparation of Compound 19C In a reaction flask, acetyl chloride (0.733 g) was slowly added to a solution of compound 19B (2.000 g) and N,N-diisopropylethylamine (1.208 g) in tetrahydrofuran (12 mL) at 0°C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the reaction mixture was quenched with saturated sodium carbonate solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give compound 19C (2.200 g). The reaction product of this step was used directly in the next step.

[0244] Step D: Preparation of Compound 19D Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.702 g), compound 19C (2.200 g), bis(pinacolato)diboron (4.360 g), potassium acetate (1.686 g), and dioxane (8 mL) were added sequentially to a reaction flask. After the addition was completed, the mixture was reacted at 110° C. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give compound 19D (2.410 g). MS (ESI, [M+H] + ) m / z: 304.5.

[0245] Step E: Preparation of Compound 19E Under a nitrogen atmosphere, compound 19D (324 mg), compound 1C (350 mg), potassium carbonate (197 mg), tetrakis(triphenylphosphine)palladium (82 mg), and dioxane (10 mL) were sequentially added to a reaction flask, and after the addition was completed, the reaction was carried out at 110° C. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate=95 / 5) to give compound 19E (320 mg). MS (ESI, [M+H] + ) m / z: 632.7.

[0246] Step F: Preparation of Compound 19 Compound 19E (320 mg), dichloromethane (10 mL), and methanesulfonic acid (48.7 mg) were added sequentially to a reaction flask and stirred at room temperature. The raw materials were allowed to react completely. The reaction was quenched with saturated aqueous sodium carbonate (30 mL), extracted with dichloromethane, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 94 / 6) to give compound 19 (120 mg). MS (ESI, [M+H] + ) m / z: 532.7.

[0247] 1 H NMR (500 MHz, DMSO-d6): δ 8.22 (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, 2H), 2.24 (s, 3H), 2.19 - 2.15 (m.2H), 2.06 - 2.04 (m, 1H), 1.75 - 1.72 (m, 1H).

[0248] Example 20: Preparation of Compound 20 [ka]

[0249] Step A: Preparation of Compound 20A Under a nitrogen atmosphere, 1-bromo-3-iodobenzene (1.180 g), isothiazole-1,1-dioxide (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, and the mixture was reacted at 120° C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 90 / 10) to obtain compound 20A (640 mg). MS (ESI, [M+H] + ) m / z: 276.2.

[0250] Step B: Preparation of Compound 20B Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (151 mg), compound 20A (640 mg), bis(pinacolato)diboron (1177 mg), potassium acetate (455 mg), and dioxane (8 mL) were added sequentially to a reaction flask, and after the addition was completed, the reaction was carried out at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound 20B (620 mg). MS (ESI, [M+H] + ) m / z: 324.5.

[0251] Step C: Preparation of Compound 20C Tetrakis(triphenylphosphine)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 completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate=60 / 40) to give compound 20C (380 mg). MS (ESI, [M+H] + ) m / z: 652.5.

[0252] Step D: Preparation of Compound 20 Compound 20C (150 mg), dichloromethane (6 mL), and methanesulfonic acid (133 mg) were added sequentially to a reaction flask. After the addition was complete, the reaction was allowed to proceed at room temperature. After the reaction was complete, the pH of the reaction mixture was adjusted to neutral with saturated aqueous sodium bicarbonate, and the reaction mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 97 / 3) to give compound 20 (27 mg). MS (ESI, [M+H] + ) m / z: 552.5.

[0253] 1 H NMR (500 MHz, DMSO-d6): δ 8.29 (d, J = 8.0 Hz, 1H), 8.01 (dd, J = 3.0 Hz, 6.0Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.88 (s, 1H) , 7.77(d, J = 7.5 Hz, 1H), 7.64(d, J =9.0 Hz, 1H), 7.50-7.45(m, 3H), 7.28 - 7.23(m, 2H), 6.96(br, 2H), 6.44(q, J = 7.5 Hz, 1H), 3.81(t, J = 7.5 Hz, 2H), 3.54(t, J = 7.5 Hz, 2H), 2.43(t, J = 7.5 Hz, 1H), 2.34(s, 2H), 2.26 - 2.21(m, 2H), 2.09(m, 1H), 1.77 - 1.75(m, 1H).

[0254] Example 21: Preparation of Compound 21 [ka]

[0255] Step A: Preparation of Compound 21A Sodium tert-butoxide (0.179 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.040 g), tris(dibenzylideneacetone)dipalladium (0.039 g), 1,3-dibromobenzene (0.200 g), 1-(piperidin-4-yl)pyrrolidin-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 a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated, 5 mL of saturated brine was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 21A (0.270 g) was obtained by column chromatography (dichloromethane / methanol = 60 / 1). MS (ESI, [M+H] + ) m / z: 323.4.

[0256] Step B: Preparation of Compound 21B In a reaction flask, compound 21A (0.270 g), potassium acetate (0.270 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.037 g), bis(pinacolato)diboron (0.280 g), 1,4-dioxane (25 mL), and water (5 mL) were sequentially added and reacted under a nitrogen atmosphere at 100 °C with stirring. After the reaction was completed, the reaction solution was concentrated, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 60 / 1) to obtain compound 21B (0.300 g). MS (ESI, [M+H] + ) m / z: 371.6.

[0257] Step C: Preparation of Compound 21C In a reaction flask, 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 sequentially added, and the mixture was stirred under a nitrogen atmosphere at 100 ° C. After the reaction was completed, the reaction solution was concentrated, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 65 / 1) to obtain compound 21C (0.25 g). MS (ESI, M+H) + ) m / z: 699.8.

[0258] Step D: Preparation of Compound 21 Compound 21C (0.25 g), dichloromethane (25 mL), and methanesulfonic acid (0.30 g) were added sequentially to a reaction flask. The mixture was stirred at 30°C and allowed to react. After the reaction was completed, 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 purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 21 (0.19 g). HRMS (ESI, [M+H] + ) m / z: 599.3237.

[0259] 1H NMR (500 MHz, CDCl3) δ 7.99 (dd, J = 11.1, 8.5 Hz, 1H), 7.90 (t, J = 4.6 Hz, 1H), 7.64 (t, J = 8.2 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.48 (s, 1H), 7.47 - 7.22 (m, 4H), 7.01 (t, J = 7.6 Hz, 1H), 6.80 (dd, J = 28.6, 9.7 Hz, 1H), 6.55 (d, J = 15.2 Hz, 2H), 6.27 (ddd, J = 58.5, 7.7, 5.0 Hz, 1H), 4.05 (ddd, J = 16.5, 10.7, 3.8 Hz, 1H), 3.65 (t, J = 16.0 Hz, 2H), 3.28 (dt, J = 14.1, 6.9 Hz, 2H), 2.76 (dt, J = 24.5, 12.3 Hz, 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).

[0260] Example 22: Production of Compound 22

change

[0261] ステップA: Manufacture of compound 22A Sodium tert-butoxide (0.180 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.040 g), tris(dibenzylideneacetone)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 sequentially added to a reaction flask. The mixture was stirred at 80 °C under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated, saturated brine was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 60 / 1) to give compound 22A (0.230 g). MS (ESI, [M+H] + ) m / z: 288.4.

[0262] Step B: Preparation of Compound 22B Compound 22A (0.23 g), potassium acetate (0.28 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (39 mg), bis(pinacolato)diboron (0.29 g), 1,4-dioxane (25 mL), and water (5 mL) were sequentially added to a reaction flask. The mixture was stirred at 100 °C under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 60 / 1) to obtain compound 22B (0.28 g). MS (ESI, [M+H] + ) m / z: 336.6.

[0263] Step C: Preparation of Compound 22C In a reaction flask, 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 sequentially added, and the mixture was stirred under a nitrogen atmosphere at 100 ° C. After the reaction was completed, the reaction solution was concentrated, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 65 / 1) to obtain compound 22C (0.24 g). MS (ESI, [M+H] + ) m / z: 664.7.

[0264] Step D: Preparation of Compound 22 Compound 22C (0.24 g), dichloromethane (25 mL), and methanesulfonic acid (0.30 g) were added sequentially to a reaction flask. The mixture was stirred at 30°C and allowed to react. After the reaction was completed, 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 purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 22 (0.16 g). HRMS (ESI, [M+H] + ) m / z: 564.2634.

[0265] 1H NMR (500 MHz, DMSO-d6) δ 8.24 (d, J = 8.3 Hz, 1H), 8.02 (dd, J = 4.7, 1.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.6, 1.6 Hz, 1H), 7.06 - 6.96 (m, 3H), 6.43 (dd, J = 7.6, 4.8 Hz, 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 = 13.6 Hz, 2H), 1.75 (ddt, J = 20.2, 14.2, 6.4 Hz, 3H), 1.53 (d, J = 13.0 Hz, 3H).

[0266] Example 23: Preparation of Compound 23 [ka]

[0267] Step A: Preparation of Compound 23A In a reaction flask, tert-butyl (R)-3-(methylamine)pyrrole-1-carboxylate (1.000 g) and N,N-diisopropylethylamine (0.645 g) were added to a dichloromethane (15 mL) solution of methanesulfonyl chloride (0.572 g) at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with saturated aqueous sodium carbonate solution and extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 23A (1.160 g).

[0268] Step B: Preparation of Compound 23B In a reaction flask, a 4 M solution of hydrogen chloride in dioxane (4 mL) was slowly added to a solution of compound 23A (590 mg) in dichloromethane (10 mL) in an ice-water bath. After the addition was complete, the mixture was stirred at room temperature to react. After the reaction was complete, the solvent was directly distilled off under reduced pressure to obtain compound 23B, which was directly used in the next step. Step C: Preparation of Compound 23C To a reaction flask containing compound 23B, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1320 mg), sodium tert-butoxide (204 mg), 1,3-dibromobenzene (500 mg), and dioxane (10 mL) were added sequentially. After the addition was complete, the mixture was stirred at 120°C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound 23C (380 mg). MS (ESI, [M+H] + ) m / z: 333.3.

[0269] Step D: Preparation of Compound 23D Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (93 mg), compound 23C (380 mg), bis(pinacolato)diboron (434 mg), potassium acetate (336 mg), and dioxane (8 mL) were sequentially added to a reaction flask. After the addition was complete, the reaction was carried out at 110°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound 23D (280 mg). MS (ESI, [M+H] + ) m / z: 381.3.

[0270] Step E: Preparation of Compound 23E In 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 addition was completed, the mixture was stirred at 120°C to react. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give compound 23E (154 mg). MS (ESI, [M+H] + ) m / z: 709.8.

[0271] Step F: Preparation of Compound 23 Compound 23E (100 mg), dichloromethane (6 mL), and methanesulfonic acid (600 mg) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, the pH of the reaction mixture was adjusted to neutral with sodium bicarbonate, and the reaction mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 97 / 3) to give compound 23 (60 mg). MS (ESI, [M+H] + ) m / z: 609.6.

[0272] 1 H NMR (500 MHz, DMSO-d6): δ 8.23 ​​(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), 6.43(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). Example 24: Preparation of Compound 24 [ka] Step A: Preparation of Compound 24A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (349 mg), bis(dibenzylideneacetone)palladium (256 mg), (R)-N-methyl-N-(pyrrol-3-yl)acetamide hydrochloride (500 mg), 1,3-dibromobenzene (660 mg), sodium tert-butoxide (807 mg), and dioxane (15 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was heated to 120 °C and reacted. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 60 / 40) to obtain compound 24A (740 mg). MS (ESI, [M+H] + ) m / z: 297.4.

[0273] Step B: Preparation of Compound 24B Under a nitrogen atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (179 mg), compound 24A (650 mg), bis(pinacolato)diboron (1111 mg), potassium acetate (644 mg), and dioxane (15 mL) were added sequentially to a reaction flask, and after the addition was completed, the reaction was carried out at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 80 / 20) to obtain compound 24B (740 mg). MS (ESI, [M+H] + ) m / z: 345.6.

[0274] Step C: Preparation of Compound 24C In a reaction flask, tetrakis(triphenylphosphine)palladium (208 mg), compound 1C, compound 24B (620 mg), potassium carbonate (498 mg), dioxane (15 mL), and water (0.5 mL) were sequentially added. After the addition was complete, the mixture was heated to 120°C for reaction. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 98 / 2) to give compound 24C (470 mg). MS (ESI, [M+H] + ) m / z: 673.6.

[0275] Step D: Preparation of Compound 24 Compound 24C (420 mg), dichloromethane (6 mL), and methanesulfonic acid (360 mg) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, the pH of the reaction mixture was adjusted to neutral with saturated aqueous sodium bicarbonate, and the reaction mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 96:4) to give compound 24 (140 mg). MS (ESI, [M+H] + ) m / z: 573.7.

[0276] 1 H NMR (500 MHz, DMSO-d6): δ 8.22 (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).

[0277] Example 25: Preparation of Compound 25 [ka]

[0278] Step A: Preparation of Compound 25A In a reaction flask, (S)-tert-butyl 3-((methylamino))pyrrolidine-1-carboxylate (1.60 g), N,N-diisopropylethylamine (1.24 g), and methanesulfonyl chloride (0.91 g) were added sequentially. After the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, the reaction solution was concentrated to obtain Compound 25A (2.53 g).

[0279] Step B: Preparation of Compound 25B A solution of hydrochloric acid in dioxane (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 to react, and after completion of the reaction, the reaction solution was concentrated to give compound 25B (1.58 g).

[0280] Step C: Preparation of Compound 25C Under a nitrogen atmosphere, compound 25B (0.700 g), 1,3-dibromobenzene (0.949 g), tris(dibenzylideneacetone)dipalladium (0.368 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.500 g), sodium tert-butoxide (1.500 g), and toluene (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C to allow the reaction to proceed. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 25C (0.456 g). MS (ESI, [M+H] + ) m / z: 333.3.

[0281] Step D: Preparation of Compound 25D Under a nitrogen atmosphere, potassium acetate (0.385 g), bis(pinacolato)diboron (0.627 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.160 g), compound 25C (0.430 g), and dioxane (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction of the raw materials was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 7 / 3) to obtain compound 25D (0.166 g). MS (ESI, [M+H] + ) m / z: 381.6.

[0282] Step E: Preparation of Compound 25E Under a nitrogen atmosphere, compound 25D (0.165 g), compound 1C (0.213 g), potassium carbonate (0.180 g), tetrakis(triphenylphosphine)palladium (0.025 g), 1,4-dioxane (10 mL), and water (5 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 17 / 3) to give compound 25E (0.075 g). MS (ESI, [M+H] + ) m / z: 709.7.

[0283] Step F: Preparation of Compound 25 Compound 25E (0.075 g), dichloromethane (10 mL), and methanesulfonic acid (0.050 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, 20% aqueous sodium hydroxide solution was added while stirring in an ice bath to adjust the solution to pH 12, and 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 purified by column chromatography (dichloromethane / methanol = 3 / 7) to give compound 25 (0.040 g). MS (ESI, [M+H] + ) m / z: 609.7.

[0284] 1 H NMR (500 MHz, 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).

[0285] Example 26: Preparation of Compound 26 [ka]

[0286] Step A: Preparation of Compound 26A In a reaction flask, 1,3-dibromobenzene (0.54 g), tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (0.30 g), sodium tert-butoxide (0.29 g), tris(dibenzylideneacetone)dipalladium (0.14 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.09 g), and 1,4-dioxane (12 mL) were sequentially added. The mixture was stirred at 100 °C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 26A (0.51 g). MS (ESI, [M-Boc+H] + ) m / z: 253.4.

[0287] Step B: Preparation of Compound 26B Compound 26A (0.46 g) and a 4 M solution of hydrogen chloride in dioxane (8 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature to react. After completion of the reaction, the reaction solution was concentrated to give Compound 26B (0.43 g). MS (ESI, [M+H] +) m / z: 253.4.

[0288] Step C: Preparation of Compound 26C At 0°C under a nitrogen atmosphere, acetyl chloride (2.98 g) was slowly added to a solution of compound 26B (0.43 g) and triethylamine (0.69 g) in dichloromethane (20 mL) in a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, saturated aqueous sodium bicarbonate solution (75 mL) was added to the reaction mixture, which was then 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 purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give compound 26C (0.25 g). MS (ESI, [M+H] + ) m / z: 295.4.

[0289] Step D: Preparation of Compound 26D In a 100 mL reaction flask, compound 26C (0.25 g), bis(pinacolato)diboron (0.32 g), potassium acetate (0.25 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.069 g), and 1,4-dioxane (15 mL) were sequentially added. The mixture was stirred at 100 °C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4) to give compound 26D (0.22 g). MS (ESI, [M+H] + ) m / z: 343.6.

[0290] Step E: Preparation of Compound 26E In a 25 mL microwave tube, compound 26D (0.21 g), compound 1C (0.20 g), potassium carbonate (0.17 g), tetrakis(triphenylphosphine)palladium (0.047 g), 1,4-dioxane (10 mL), and water (1.5 mL) were sequentially added. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 140 °C for 2 hours. After the reaction was complete, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 26E (0.22 g). MS (ESI, [M+H] + ) m / z: 671.7.

[0291] Step F: Preparation of Compound 26 Compound 26E (183 mg), methanesulfonic acid (0.2 mL), and dichloromethane (10 mL) were added sequentially to a 50 mL reaction flask. The mixture was stirred at room temperature and allowed to react. After completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 26 (106 mg). HRMS (ESI, [M+H] + ) m / z: 571.2924.

[0292] 1H NMR (500 MHz, CDCl3) δ 8.11 (dd, J = 8.3, 5.2 Hz, 1H), 8.07 (dt, J = 4.9, 1.7 Hz, 1H), 7.79 (dd, J = 8.4, 3.6 Hz, 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, 1.8 Hz, 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, 4.5 Hz, 1H), 4.30 - 4.10 (m, 2H), 3.98 - 3.83 (m, 1H), 3.76 (dd, J = 22.2, 10.2 Hz, 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).

[0293] Example 27: Preparation of Compound 27 [ka]

[0294] Step A: Preparation of Compound 27A In a reaction flask, 1,3-dibromobenzene (4.98 g), tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (2.00 g), sodium tert-butoxide (2.70 g), tris(dibenzylideneacetone)dipalladium (0.64 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.66 g), and 1,4-dioxane (100 mL) were sequentially added. The mixture was stirred under a nitrogen atmosphere at 100°C. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 27A (2.78 g). MS (ESI, [M+H] +) m / z: 297.4.

[0295] Step B: Preparation of Compound 27B Sodium hydride (1.87 g) was slowly added to a solution of compound 27A (2.78 g) in tetrahydrofuran (60 mL) in a reaction flask at 0°C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at room temperature for 0.5 hours, and then iodomethane (6.64 g) was added and reacted. After the reaction was complete, saturated aqueous ammonium chloride solution was added to the reaction mixture in an ice bath, followed by extraction with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 27B (1.91 g). MS (ESI, [M+H] + ) m / z: 311.4.

[0296] Step C: Preparation of Compound 27C Compound 27B (1.91 g), bis(pinacolato)diboron (2.34 g), potassium acetate (1.81 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.50 g), and 1,4-dioxane (120 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 27C (2.11 g). MS (ESI, [M+H] + ) m / z: 359.6.

[0297] Step D: Preparation of Compound 27D Compound 27C (0.33 g), compound 1C (0.30 g), potassium carbonate (0.25 g), tetrakis(triphenylphosphine)palladium (71 mg), 1,4-dioxane (14 mL), and water (2 mL) were added sequentially to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 140 °C. After the reaction was complete, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 27D (0.38 g). MS (ESI, [M+H] + ) m / z: 687.8.

[0298] Step E: Preparation of Compound 27 Compound 27D (370 mg), methanesulfonic acid (0.3 mL), and dichloromethane (16 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature and allowed to react. After the reaction was completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 27 (157 mg). HRMS (ESI, [M+H] + ) m / z: 587.3278.

[0299] 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J =9.5, 8.3 Hz, 1H), 8.06 (dd, J = 4.8, 1.8 Hz, 1H), 7.79 (dd, J = 8.4, 1.3 Hz, 1H), 7.67 - 7.57 (m, 3H), 7.48 (dt, J = 7.8, 1.0 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.31 (dt, J = 18.8, 7.9 Hz, 1H), 7.12 (ddd, J = 29.3, 7.8, 1.8 Hz, 1H), 6.93 (td, J = 7.6, 2.4 Hz, 1H), 6.60 (s, 2H), 6.39 (ddd, J = 7.8, 5.9, 4.8 Hz, 1H), 4.77 - 4.68 (m, 1H), 3.86 - 3.72 (m, 1H), 3.72 - 3.56 (m, 1H), 2.91 (d, J = 18.3 Hz, 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).

[0300] Example 28: Production of Compound 28

change

[0301] ステップA: Manufacturing of Compound 28A In a reaction flask, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.50 g), 1,3-dibromofluorobenzene (0.66 g), (tris(dibenzylideneacetone)dipalladium (80 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (60 mg), tetrahydrofuran (50 mL), and sodium tert-butoxide (1.00 g) were added sequentially. After the addition was completed, the mixture was stirred at 80°C under a nitrogen atmosphere to react. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 28A (0.51 g).

[0302] Step B: Preparation of Compound 28B Compound 28A (0.50 g) was weighed and added to a reaction flask, and dichloromethane (10 mL) was added and stirred to dissolve. Then, methanesulfonic acid (0.39 g) was added, and after the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, triethylamine (2 mL) was added to stop the reaction, and a solution of compound 28B was obtained. This was used directly in the next step of the reaction without concentration.

[0303] Step C: Preparation of Compound 28C The above compound 28B solution was taken and acetic anhydride (206 mg) was added. After the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 96:4) to obtain compound 28C (313 mg). MS (ESI, [M+H] + ) m / z: 313.79.

[0304] Step D: Preparation of Compound 28D To a reaction flask containing compound 28C (300 mg), bis(pinacolato)diboron (365 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (39 mg), 1,4-dioxane (30 mL), and potassium acetate (282 mg) were added sequentially. After the addition was complete, the mixture was stirred at 120°C under a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 98 / 2) to give compound 28D (278 mg). MS (ESI, [M+H] + ) m / z: 361.04.

[0305] Step E: Preparation of Compound 28E Compound 28D (300 mg), compound 1C (409 mg), potassium carbonate (460 mg), tetrakis(triphenylphosphine)palladium (48 mg), 1,4-dioxane (10 mL), and water (1 mL) were sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen, and the reaction was carried out in a microwave oven at 120 °C. After the reaction was complete, the reaction mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 96 / 4) to give compound 28E (252 mg). MS (ESI, [M+H] + ) m / z: 689.5.

[0306] Step F: Preparation of Compound 28 Compound 28E (250 mg), methanesulfonic acid (349 mg), and dichloromethane (30 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature and allowed to react. After the reaction was completed, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 28 (70 mg). MS (ESI, [M+H] + ) m / z: 589.5.

[0307] 1 H NMR (500 MHz, CDCl3): 8.25 (d, J = 8.5 Hz, 1H), 8.00 (dd, J = 2.0, 5.0 Hz, 1H), 7.68 (dd, J = 2.0, 8.0 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.20 (dd, J = 2.0, 8.0 Hz, 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).

[0308] Example 29: Preparation of Compound 29 [ka] Step A: Preparation of Compound 29A 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. After the addition was complete, the mixture was stirred at room temperature to react. After the reaction was complete, the mixture was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave compound 29A (1.13 g).

[0309] Step B: Preparation of Compound 29B To a reaction flask containing compound 29A (1.13 g), a 1,4-dioxane solution (20 mL) of hydrogen chloride (4 M) was added, and after the addition was completed, the mixture was stirred at room temperature to react. After the reaction was completed, the reaction solution was concentrated to give compound 29B (0.87 g).

[0310] Step C: Preparation of Compound 29C Compound 29B (0.87 g), 1,3-dibromofluorobenzene (5.42 g), (tris(dibenzylideneacetone)dipalladium (263 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (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 a nitrogen atmosphere to allow the reaction to proceed. After the reaction was complete, the mixture was filtered, concentrated, and purified by column chromatography (ethyl acetate) to give compound 29C (0.48 g). MS (ESI, [M+H] + ) m / z: 271.1.

[0311] Step D: Preparation of Compound 29D In a reaction flask containing compound 29C (0.48 g), tetrahydrofuran (10 mL) was added and stirred to dissolve. After cooling with ice / ethanol, sodium hydride (0.28 g) was added. After the addition was complete, the mixture was stirred for 10 minutes. After the addition was complete, iodomethane (0.76 g) was added. After the addition was complete, the mixture was stirred at room temperature and allowed to react. The reaction was allowed to complete. The mixture was poured into saturated aqueous ammonium chloride solution, stirred, extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 29D (0.64 g). MS (ESI, [M+H] + ) m / z: 285.1.

[0312] Step E: Preparation of Compound 29E To a reaction flask containing compound 29D (509 mg), bis(pinacolato)diboron (680 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (73 mg), 1,4-dioxane (20 mL), and potassium acetate (525 mg) were added sequentially. After the addition was complete, the mixture was stirred at 120°C under a nitrogen atmosphere. After the reaction was complete, the reaction solution was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 29E (441 mg). MS (ESI, [M+H] +) m / z: 333.3.

[0313] Step F: Preparation of Compound 29F Compound 29E (440 mg), compound 1C (716 mg), potassium carbonate (550 mg), tetrakis(triphenylphosphine)palladium (77 mg), 1,4-dioxane (10 mL), and water (1 mL) were sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 96 / 4) to give compound 29F (400 mg). MS (ESI, [M+H] + ) m / z: 661.39.

[0314] Step G: Preparation of Compound 29 Compound 29F (400 mg), methanesulfonic acid (582 mg), and dichloromethane (30 mL) were added sequentially to a reaction flask and stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 29 (387 mg). MS (ESI, [M+H] + ) m / z: 561.34.

[0315] 1H NMR (500 MHz, CDCl3): 8.29 (d, J = 8.5 Hz, 1H), 8.01 (dd, J = 1.5, 5.0 Hz, 1H), 7.96 (t, J =8.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 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).

[0316] Example 30: Preparation of Compound 30 [ka]

[0317] Step A: Preparation of Compound 30A Under a nitrogen atmosphere, 1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (0.32 g), 1,3-dibromofluorobenzene (0.40 g), tris(dibenzylideneacetone)dipalladium (0.07 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.10 g), sodium tert-butoxide (0.33 g), and toluene (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C to allow the reaction to proceed. After the reaction of the raw materials was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 65 / 1) to obtain compound 30A (0.20 g).

[0318] Step B: Preparation of Compound 30B Under a nitrogen atmosphere, potassium acetate (0.06 g), bis(pinacolato)diboron (0.10 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (25 mg), compound 30A (0.20 g), and dioxane (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction of the raw materials was complete, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 65 / 1) to obtain compound 30B (0.21 g).

[0319] Step C: Preparation of Compound 30C Under a nitrogen atmosphere, compound 30B (0.21 g), compound 1C (0.11 g), potassium carbonate (0.06 g), tetrakis(triphenylphosphine)palladium (13 mg), 1,4-dioxane (15 mL), and water (7.5 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 3 / 7) to obtain compound 30C (0.16 g). MS (ESI, [M+H] + ) m / z: 717.8.

[0320] Step D: Preparation of Compound 30 Compound 30C (0.16 g), dichloromethane (10 mL), and methanesulfonic acid (0.21 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, 20% aqueous sodium hydroxide solution was added while stirring in an ice bath to adjust the solution to pH 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 purified by column chromatography (dichloromethane / methanol = 2 / 3) to give compound 30 (0.08 g). MS (ESI, [M+H] + ) m / z: 617.7.

[0321] 1H NMR (500 MHz, DMSO-d6) δ 8.23 ​​(d, 1H), 7.96 - 8.02 (m, 2H), 7.63 (d, 2H), 7.47 (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, 3H), 2.44 - 2.48 (m, 2H), 2.02 - 2.25 (m, 5H), 1.69 - 1.77 (m, 1H), 1.23 (s, 2H).

[0322] Example 31: Preparation of Compound 31 [ka]

[0323] Step A: Preparation of Compound 31A Under a nitrogen atmosphere, 1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (0.61 g), 1,3-dibromobenzene (0.80 g), tris(dibenzylideneacetone)dipalladium (0.31 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.32 g), sodium tert-butoxide (0.49 g), and toluene (10 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 120 °C to allow the reaction to proceed. After the reaction of the raw materials was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain compound 31A (0.50 g). MS (ESI, [M+H] + ) m / z: 297.1.

[0324] Step B: Preparation of Compound 31B Under a nitrogen atmosphere, potassium acetate (0.489 g), bis(pinacolato)diboron (0.811 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.207 g), compound 31A (0.502 g), and dioxane (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction of the raw materials was complete, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 7 / 3) to obtain compound 31B (0.293 g). MS (ESI, [M+H] + ) m / z: 345.6.

[0325] Step C: Preparation of Compound 31C Under a nitrogen atmosphere, compound 31B (0.293 g), compound 1C (0.320 g), potassium carbonate (0.270 g), tetrakis(triphenylphosphine)palladium (0.040 g), 1,4-dioxane (15 mL), and water (7.5 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 110°C to react. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 7 / 3) to obtain compound 31C (0.294 g). MS (ESI, [M+H] + ) m / z: 673.4.

[0326] Step D: Preparation of Compound 31 Compound 31C (0.294 g), dichloromethane (10 mL), and methanesulfonic acid (0.210 g) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, 20% aqueous sodium hydroxide solution was added while stirring in an ice bath, the solution was adjusted to pH 12, and 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 purified by column chromatography (dichloromethane / methanol = 2 / 3) to give compound 31 (0.183 g). MS (ESI, [M+H] + ) m / z: 573.7.

[0327] 1 H NMR (500 MHz, DMSO-d6) δ 8.21(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, 1H), 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).

[0328] Example 32: Preparation of Compound 32 [ka]

[0329] Step A: Preparation of Compound 32A In a 100 mL single-neck flask, tert-butyl 4-(N-methylmethanesulfonamido)piperidine-1-carbamate (1.8 g), dichloromethane (5 mL), and a 4 M solution of hydrogen chloride in dioxane (2 mL) were added sequentially. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, the mixture was distilled under reduced pressure to obtain compound 32A (1.26 g), which was used directly in the next step.

[0330] Step B: Preparation of Compound 32B Under a nitrogen atmosphere, 2,2'-(3,3'-dichloro-1,1'-biphenyl-4,4'-diazo)bis(N-phenyl-3-oxo-butyramide) (0.491 g), bis(dibenzylideneacetone)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 sequentially added to a 100 mL single-neck flask, and the mixture was heated to 120 °C. After completion of the reaction, the solvent was distilled off under reduced pressure, and the mixture was concentrated. Compound 32B (680 mg) was obtained by column chromatography (petroleum ether:ethyl acetate = 85:15). MS (ESI, [M+H] + ) m / z: 365.1.

[0331] Step C: Preparation of Compound 32C In a 100 mL single-neck flask, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (139 mg), compound 32B (620 mg), bis(pinacolato)diboron (862 mg), potassium acetate (333 mg), and dioxane (15 mL) were sequentially added, and the mixture was heated to 120°C under a nitrogen atmosphere. After completion of the reaction, the mixture was concentrated and then purified by column chromatography (petroleum ether:ethyl acetate = 75:25) to obtain compound 32C (420 mg). MS (ESI, [M+H] + ) m / z: 413.3.

[0332] Step D: Preparation of Compound 32D In a 100 mL single-neck flask, tetrakis(triphenylphosphine)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 then purified by column chromatography (dichloromethane:methanol = 94:6) to obtain compound 32D (180 mg). MS (ESI, [M+H] + ) m / z: 741.4.

[0333] Step E: Preparation of Compound 32 In a 50 mL single-neck flask, compound 32D (180 mg), dichloromethane (10 mL), and methanesulfonic acid (46.7 mg) were added sequentially. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction of the raw materials was complete, the pH of the reaction mixture was adjusted to neutral with saturated aqueous sodium carbonate, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane:methanol = 96:4) to give compound 32 (120 mg). MS (ESI, [M+H] + ) m / z: 641.7.

[0334] 1 H NMR (500 MHz, CDCl3): δ 8.12 (d, J = 7.5 Hz, 1H), 8.07 (dd, J = 5.0, 10.0 Hz, 1H), 7.80 (dd, J = 5.0, 10.0 Hz, 1H), 7.56 - 7.51 (m, 3H), 7.40 (d, J = 10.0 Hz, 1H), 7.12 (q, J = 10.0 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.59 (br, 2H), 6.39 (q, J = 8.0 Hz, 1H), 3.93 - 3.91 (m, 1H), 3.51 (d, J = 10.0 Hz, 2H), 2.88 - 2.87 (m, 6H), 2.81 (t, J = 10.0 Hz, 2H), 2.63 - 2.58(m, 2H), 2.24 - 2.19 (m, 1H), 2.12 - 2.06 (m, 2H), 1.83 (br, 6H).

[0335] Example 33: Preparation of Compound 33 [ka]

[0336] Step A: Preparation of Compound 33A Trifluoroacetic acid (2 mL) was slowly added dropwise to a reaction solution of tert-butyl 7-oxo-2,6-diazaspiro[3,4]octane-2-carboxylate (0.5 g) in dichloromethane (10 mL) at 0 °C. After the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain compound 33A (0.78 g). MS (ESI, [M+H] + ) m / z: 127.4.

[0337] Step B: Preparation of Compound 33B Compound 33A (0.5 g), 1,3-dibromobenzene (0.74 g), (tris(dibenzylideneacetone)dipalladium (0.19 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (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 completed, the mixture was stirred at 100°C under a nitrogen atmosphere to allow the reaction to proceed. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 50 / 1) to obtain Compound 33B (0.54 g). MS (ESI, [M+H] + ) m / z: 281.4.

[0338] Step C: Preparation of Compound 33C Sodium hydride (0.37 g) was slowly added to a solution of compound 33B (0.52 g) in tetrahydrofuran (30 mL) under a nitrogen atmosphere at 0°C. After the addition was complete, the reaction mixture was transferred to room temperature and stirred for 0.5 hours. Subsequently, iodomethane (1.32 g) was added and the reaction mixture was reacted. After the reaction was complete, saturated aqueous ammonium chloride solution (75 mL) was added to the reaction mixture in an ice bath, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (100 mL), dried, filtered, and concentrated to give compound 33C (0.50 g). MS (ESI, [M+H] + ) m / z: 295.4.

[0339] Step D: Preparation of Compound 33D Compound 33C (0.50 g), bis(pinacolato)diboron (0.65 g), potassium acetate (0.50 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.14 g), and 1,4-dioxane (30 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 33D (0.12 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 343.5.

[0340] Step E: Preparation of Compound 33E 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 sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 100 °C. After the reaction was complete, the reaction mixture was filtered and concentrated. Compound 33E (0.18 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 671.4.

[0341] Step F: Preparation of Compound 33 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 33 (69 mg). MS (ESI, [M+H] + ) m / z: 571.6.

[0342] 1H NMR (500 MHz, CDCl3) δ 8.14 (dd, J = 8.4, 2.8 Hz, 1H), 8.02 (dd, J = 5.0, 1.9 Hz, 1H), 7.78 (dd, J = 8.5, 2.7 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.48 - 7.42 (m, 3H), 7.30 (t, J = 7.9 Hz, 1H), 7.17 (dt, J = 7.8, 1.8 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.52 (dd, J = 7.9, 2.4 Hz, 1H), 6.42 (dd, J = 7.7, 4.8 Hz, 1H), 3.91 (s, 4H), 3.69 (d, J = 2.6 Hz, 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).

[0343] Example 34: Preparation of Compound 34 [ka]

[0344] Step A: Preparation of Compound 34A 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 a reaction flask. After the addition was complete, the mixture was stirred at 65°C. After the reaction was complete, the solvent was removed under reduced pressure and the mixture was concentrated to give Compound 34A (8.34 g). MS (ESI, [M+H] + ) m / z: 351.0.

[0345] Step B: Preparation of Compound 34B Compound 34A (3.0 g), tert-butyl 4-aminopiperidine-1-carboxylate (1.1 g), and ethanol (20 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 8 / 2) to give Compound 34B (1.0 g). MS (ESI, [M+K] + ) m / z: 415.4.

[0346] Step C: Preparation of Compound 34C Compound 34B (1.0 g), potassium fluoride (1.0 g), and dimethyl sulfoxide (20 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 34C (0.76 g). MS (ESI, [M+H] + ) m / z: 305.4.

[0347] Step D: Preparation of Compound 34D Compound 34C (3.0 g), a 4 M solution of hydrochloric acid in dioxane (6.2 mL), and dichloromethane (20 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 34D (0.63 g). MS (ESI, [M+H] + ) m / z: 205.4.

[0348] Step E: Preparation of Compound 34E Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.33 g), tris(dibenzylideneacetone)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 sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 34E (0.23 g). MS (ESI, [M+H] +) m / z: 359.0.

[0349] Step F: Preparation of Compound 34F Compound 34E (0.43 g), bis(pinacolato)diboron (0.25 g), potassium acetate (0.19 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.10 g), and 1,4-dioxane (10 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated. Compound 34F (0.17 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 407.12.

[0350] Step G: Preparation of Compound 34G Compound 34F (0.17 g), compound 1C (0.12 g), potassium carbonate (0.090 g), tetrakis(triphenylphosphine)palladium (0.077 g), 1,4-dioxane (10 mL), and water (10 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 34G (0.20 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 735.7.

[0351] Step H: Preparation of Compound 34 Compound 34G (0.21 g), methanesulfonic acid (0.13 g), and dichloromethane (15 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 34 (0.041 g). MS (ESI, [M+H] +m / z: 635.5.

[0352] 1 H NMR (500 MHz, CDCl3) δ 8.48 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 5.1 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.92 - 7.83 (m, 3H), 7.80 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.77 (t, J = 6.4 Hz, 1H), 4.46 - 4.33 (m, 1H), 4.14 (d, J = 12.3 Hz, 2H), 3.82 (t, J = 6.7 Hz, 2H), 3.21 (t, J = 12.2 Hz, 2H), 3.13 - 3.02 (m, 2H), 2.94 (q, J = 10.3, 9.6 Hz, 2H), 2.86 (dd, J = 14.7, 7.7 Hz, 2H), 2.32 - 2.24 (m, 2H), 2.18 (d, J = 13.6 Hz, 2H), 1.59 (d, J = 17.5 Hz, 2H).

[0353] Example 35: Production of Compound 35

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[0354] ステップA: Manufacturing of Compound 35A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.21 g), tris(dibenzylideneacetone)dipalladium (0.20 g), 1,3-dibromo-2-fluorobenzene (1.68 g), 2,7-diazaspiro[3.5]nonane-7-tert-butyl carbonate (1.00 g), sodium tert-butoxide (1.70 g), and tetrahydrofuran (25 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 85°C. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 35A (1.51 g). MS (ESI, [M-100+H] + ) m / z: 299.4.

[0355] Step B: Preparation of Compound 35B 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 35B (1.32 g). MS (ESI, [M+H] + ) m / z: 299.4.

[0356] Step C: Preparation of Compound 35C 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 completed, the reaction mixture was extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 35C (1.32 g). MS (ESI, [M+H] + ) m / z: 341.4.

[0357] Step D: Preparation of Compound 35D Compound 35C (1.32 g), bis(pinacolato)diboron (1.47 g), potassium acetate (1.14 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.32 g), and 1,4-dioxane (50 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 35D (1.27 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 389.6.

[0358] Step E: Preparation of Compound 35E Compound 35D (0.59 g), compound 1C (0.5 g), potassium carbonate (0.42 g), tetrakis(triphenylphosphine)palladium (0.12 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 35E (0.64 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 717.8.

[0359] Step F: Preparation of Compound 35 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 35 (0.32 g). MS (ESI, [M+H] + ) m / z: 617.7.

[0360] 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.3 Hz, 1H), 8.05 (dd, J = 4.8, 1.5 Hz, 1H), 7.76 (dd, J = 8.3, 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 6.7 Hz, 1H), 7.09 (dd, J = 7.8, 1.6 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.59 (s, 2H), 6.46 (t, J = 8.1 Hz, 1H), 6.36 (dd, J = 7.8, 4.9 Hz, 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, 6.0 Hz, 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).

[0361] Example 36: Production of Compound 36

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[0362] ステップA: Manufacturing of Compound 36A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.088 g), tris(dibenzylideneacetone)dipalladium (0.086 g), 1,3-dibromo-2-fluorobenzene (0.72 g), 2,6-diaza-spiro[3.4]octane-2-tert-butyl carbonate (0.40 g), sodium tert-butoxide (0.72 g), and tetrahydrofuran (25 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 85 °C. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 36A (620 mg). MS (ESI, [M+H] + ) m / z: 385.4.

[0363] Step B: Preparation of Compound 36B 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 36B (420 mg). MS (ESI, [M+H] + ) m / z: 285.3.

[0364] Step C: Preparation of Compound 36C 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 completed, the reaction mixture was extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 36C (440 mg). MS (ESI, [M+H] + ) m / z: 327.4.

[0365] Step D: Preparation of Compound 36D Compound 36C (0.44 g), bis(pinacolato)diboron (0.51 g), potassium acetate (0.40 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.11 g), and 1,4-dioxane (30 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated. Compound 36D (0.63 g) was obtained by column chromatography (dichloromethane / methanol = 40 / 1). MS (ESI, [M+H] + ) m / z: 375.5.

[0366] Step E: Preparation of Compound 36E Compound 36D (0.74 g), compound 1C (0.5 g), potassium carbonate (0.42 g), tetrakis(triphenylphosphine)palladium (0.12 g), 1,4-dioxane (25 mL), and water (5 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 36E (500 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 703.4.

[0367] Step F: Preparation of Compound 36 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 36 (190 mg). MS (ESI, [M+H] + ) m / z: 603.6.

[0368] 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.3 Hz, 1H), 8.06 (dd, J = 4.8, 1.7 Hz, 1H), 7.76 (dd, J = 8.3, 2.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.27 - 7.18 (m, 1H), 7.10 (dd, J = 7.8, 1.6 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.78 - 6.64 (m, 1H), 6.59 (s, 2H), 6.38 (dd, J = 7.8, 4.9 Hz, 1H), 4.11 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 8.4 Hz, 1H), 4.01 (d, J = 9.9 Hz, 1H), 3.96 (d, J = 9.9 Hz, 1H), 3.60 (qd, J = 9.8, 2.0 Hz, 2H), 3.49 (ddq, J = 14.4, 9.5, 7.3 Hz, 2H), 2.66 - 2.54 (m, 2H), 2.27 - 2.17 (m, 4H), 2.16 - 1.94 (m, 4H), 1.89 (s, 3H).

[0369] Example 37: Preparation of Compound 37 [ka]

[0370] Step A: Preparation of Compound 37A In a reaction flask, 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. The mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 37A (0.82 g). MS (ESI, [M+H] + ) m / z: 255.4.

[0371] Step B: Preparation of Compound 37B In a reaction flask, compound 37A (0.82 g), trifluoroacetic acid (6.14 g), and dichloromethane (50 mL) were added sequentially. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 37B (1.68 g). MS (ESI, [M+H] + ) m / z: 155.4.

[0372] Step C: Preparation of Compound 37C Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.22 g), tris(dibenzylideneacetone)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 sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 85°C. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 37C (960 mg). MS (ESI, [M+H] + ) m / z: 327.4.

[0373] Step D: Preparation of Compound 37D Compound 37C (0.78 g), bis(pinacolato)diboron (0.92 g), potassium acetate (0.80 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.19 g), and 1,4-dioxane (60 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated. Compound 37D (0.64 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 375.5.

[0374] Step E: Preparation of Compound 37E Compound 37D (0.53 g), compound 1C (0.32 g), potassium carbonate (0.27 g), tetrakis(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (25 mL), and water (5 mL) were added sequentially to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 37E (0.43 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 703.7.

[0375] Step F: Preparation of Compound 37 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 37 (0.10 g). MS (ESI, [M+H] + ) m / z: 603.6.

[0376] 1H NMR (500 MHz, CDCl3) δ 8.26 -7.99 (m, 2H), 7.76 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 6.2 Hz, 2H), 7.39 (d, J = 7.5 Hz, 2H), 7.33 - 7.26 (m, 1H), 7.22 - 6.93 (m, 2H), 6.59 (s, 2H), 6.48 (dd, J = 13.6, 6.9 Hz, 1H), 6.38 (dd, J = 7.1, 5.1 Hz, 1H), 3.93 (s, 3H), 3.66 (d, J = 10.6 Hz, 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).

[0377] Example 38: Preparation of Compound 38 [ka]

[0378] Step A: Preparation of Compound 38A Dilute hydrochloric acid (0.433 g) was added dropwise to 1-(piperidin-4-yl)pyrrolidin-2-one (1 g) and water (10 mL) at 0 ° C. After the addition, an aqueous solution of sodium nitrite (0.533 g) was slowly added dropwise, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 38A (0.7 g). MS (ESI, [M+H] + ) m / z: 198.4.

[0379] Step B: Preparation of Compound 38B Under a nitrogen atmosphere, deuterium oxide (8 mL) was slowly added to compound 38A (0.7 g) and sodium methoxide (0.553 g), and after the addition was completed, the mixture was stirred at 80° C. Deuterated ethanol (5 mL) was slowly added to the reaction flask, and the mixture was continued to stir at 80° C. After the reaction was completed, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, suction filtered, and concentrated to give compound 38B (0.45 g). 1 H NMR (500 MHz, CDCl3) δ 4.40 - 4.29 (m, 1H), 3.33 - 3.21 (m, 2H), 2.00 (t, J = 7.0 Hz, 2H), 1.97 - 1.92 (m, 1H), 1.82 - 1.71 (m, 2H), 1.44 (tt, J = 14.8, 7.3 Hz, 1H), 1.23 (s, 1H), 0.92 - 0.75 (m, 1H).

[0380] Step C: Preparation of Compound 38C 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) at room temperature. 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 completed, the mixture was filtered and concentrated. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 38C (0.23 g). MS (ESI, [M+H] + ) m / z: 173.5.

[0381] Step D: Preparation of Compound 38D Sodium tert-butoxide (0.352 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.152 g), tris(dibenzylideneacetone)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, and the mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 38D (0.14 g) was obtained by column chromatography (dichloromethane / methanol = 40 / 1). MS (ESI, [M+H] + ) m / z: 345.3.

[0382] Step E: Preparation of Compound 38E Compound 38D (0.14 g), bis(pinacolato)diboron (0.21 g), potassium acetate (0.12 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.066 g), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere and reacted. After completion of the reaction, the mixture was filtered and concentrated. Compound 38E (0.13 g) was obtained by column chromatography (dichloromethane / methanol = 40 / 1). MS (ESI, [M+H] + ) m / z: 393.4.

[0383] Step F: Preparation of Compound 38F Compound 38E (0.13 g), compound 1C (0.1 g), potassium carbonate (0.056 g), tetrakis(triphenylphosphine)palladium (0.047 g), 1,4-dioxane (10 mL), and water (2 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen, and the reaction was stirred at 100°C. After the reaction was complete, the reaction solution was filtered and concentrated. Compound 38F (0.03 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 721.4.

[0384] Step G: Preparation of Compound 38 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 38 (0.013 g). MS (ESI, [M+H] + ) m / z: 621.5.

[0385] 1 H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 3.6 Hz, 1H), 7.81 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.51 (t, J = 7.1 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.12 (dd, J = 12.9, 7.2 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.57 (s, 2H), 6.39 (dd, J = 7.5, 4.9 Hz, 1H), 4.15 (t, J = 12.1 Hz, 1H), 3.48 (s, 1H), 3.41 (t, J = 6.9 Hz, 2H), 2.65 - 2.57 (m, 2H), 2.41 (dd, J = 16.7, 8.4 Hz, 1H), 2.28 - 2.21 (m, 2H), 2.20 - 2.09 (m, 2H), 2.03 (dd, J = 13.9, 7.0 Hz, 2H), 1.93 (dd, J = 16.1, 7.5 Hz, 2H), 1.78 (d, J = 12.3 Hz, 2H).

[0386] Example 39: Preparation of Compound 39 [ka]

[0387] Step A: Preparation of Compound 39A Dilute hydrochloric acid (0.914 g) was slowly added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1 g) in dichloromethane (20 mL) at room temperature, and after the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 39A (0.7 g). MS (ESI, [M+H] + ) m / z: 100.1.

[0388] Step B: Preparation of Compound 39B 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, and the mixture was stirred under a nitrogen atmosphere at 100° C. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 39B (0.088 g). MS (ESI, [M+H] + ) m / z: 254.1.

[0389] Step C: Preparation of Compound 39C Compound 39B (0.3 g), 2-aminopropan-1-ol (0.177 g), acetic acid (0.142 g), and methanol (10 mL) were added to a reaction flask in this order and stirred at room temperature under a nitrogen atmosphere for 1 hour. Sodium cyanoborohydride (0.148 g) was added to the reaction flask and stirred at room temperature. After the reaction was completed, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 25 / 1) to obtain compound 39C (0.23 g). MS (ESI, [M+H] + ) m / z: 313.4.

[0390] Step D: Preparation of Compound 39D In a reaction flask, N,N-carbonyldiimidazole (0.179 g), compound 39C (0.23 g), and toluene (10 mL) were added in that order, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, and then at 110°C. After the reaction was completed, the mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 39D (0.16 g). MS (ESI, [M+H] + ) m / z: 339.1.

[0391] Step E: Preparation of Compound 39E Compound 39D (0.16 g), bis(pinacolato)diboron (0.24 g), potassium acetate (0.14 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.039 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere, and after completion of the reaction, the mixture was filtered and concentrated. Compound 39E (0.06 g) was obtained by column chromatography (dichloromethane / methanol = 50 / 1). MS (ESI, [M+H] + ) m / z: 387.6.

[0392] Step F: Preparation of Compound 39F Compound 39E (0.06 g), compound 1C (0.08 g), potassium carbonate (0.045 g), tetrakis(triphenylphosphine)palladium (0.038 g), 1,4-dioxane (10 mL), and water (2 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen, and the reaction was stirred at 100°C. After the reaction was complete, the reaction solution was filtered and concentrated. Compound 39F (65 mg) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 715.5.

[0393] Step G: Preparation of Compound 39 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 39 (0.032 g). MS (ESI, [M+H] + ) m / z: 615.7.

[0394] 1 H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 4.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.49 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 7.9 Hz, 3H), 6.41 (dd, J = 7.2, 5.3 Hz, 1H), 4.35 (t, J = 8.3 Hz, 1H), 4.00 - 3.90 (m, 1H), 3.82 (dd, J = 8.2, 5.6 Hz, 1H), 3.77 - 3.65 (m, 3H), 2.86 - 2.72 (m, 4H), 2.68 (s, 4H), 2.37 (d, J = 7.5 Hz, 1H), 2.07 (qd, J = 12.1, 3.7 Hz, 1H), 1.99 - 1.92 (m, 2H), 1.88 (d, J = 7.1 Hz, 1H), 1.81 (d, J = 10.8 Hz, 1H), 1.32 (d, J = 6.1 Hz, 3H).

[0395] Example 40: Preparation of Compound 40 [ka]

[0396] Step A: Preparation of Compound 40A In a reaction flask, cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (250 mg), 1,3-dibromo-2-fluorobenzene (448 mg), tris(dibenzylideneacetone)dipalladium (55 mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (40 mg), tetrahydrofuran (30 mL), and sodium tert-butoxide (509 mg) were added sequentially. After the addition was completed, the mixture was stirred at 80°C under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 40A (164 mg). MS (ESI, [M+H] + ) m / z: 385.0.

[0397] Step B: Preparation of Compound 40B To a reaction flask containing Compound 40A (164 mg), dichloromethane (15 mL) and methanesulfonic acid (130 mg) were added in that order, and after the addition was completed, the mixture was stirred at room temperature and reacted. After the reaction was completed, the mixture was directly subjected to the next step without further treatment.

[0398] Step C: Preparation of Compound 40C To the reaction mixture containing compound 40B, triethylamine (42.9 mg) and acetic anhydride (43.3 mg) were added, and after the addition was completed, the mixture was stirred at room temperature and allowed to react. After the reaction was completed, the mixture was washed with water twice and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give compound 40C (142 mg). MS (ESI, [M+H] + ) m / z: 327.4.

[0399] Step D: Preparation of Compound 40D Compound 40C (142 mg), bis(pinacolato)diboron (164 mg), potassium acetate (127 mg), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (50 mg), and 1,4-dioxane (10 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere, and after completion of the reaction, the mixture was filtered and concentrated. Compound 40D (101 mg) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 375.4.

[0400] Step E: Preparation of Compound 40E Compound 40D (100 mg), compound 1C (135 mg), potassium carbonate (150 mg), tetrakis(triphenylphosphine)palladium (20 mg), 1,4-dioxane (3 mL), and water (0.3 mL) were sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 120 °C. After the reaction was complete, the mixture was filtered and concentrated. Compound 40E (101 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 703.5. Step F: Preparation of Compound 40 Compound 40E (101 mg), methanesulfonic acid (138 mg), and dichloromethane (10 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, the reaction solution was adjusted to pH 9 with saturated aqueous sodium carbonate, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 40 (42 mg). MS (ESI, [M+H] + ) m / z: 603.7.

[0401] 1H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.26-7.24 (m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.71 (t, J = 8.0 Hz, 1H), 6.58 (s, 2H), 6.39 (dd, J = 5.0, 7.5 Hz, 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).

[0402] Example 41: Preparation of Compound 41 [ka]

[0403] Step A: Preparation of Compound 41A In a reaction flask, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.94 g), bis(dibenzylideneacetone)palladium (2.164 g), 1,3-dibromo-2-fluorobenzene (6 g), (tert-butyl)piperidin-4-ylcarbamate (4.73 g), sodium tert-butoxide (4.54 g), and dioxane (20 mL) were sequentially added, and the mixture was stirred overnight at 100°C under a nitrogen atmosphere. After completion of the reaction, the reaction solution was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 50 / 1) to obtain compound 41A (2.6 g). MS (ESI, [M+H] + ) m / z: 373.2.

[0404] Step B: Preparation of Compound 41B Compound 41A (2.6 g), dichloromethane (30 mL), and a solution of hydrochloric acid in dioxane (7.37 mL) were added sequentially to a reaction flask and stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 41B (2 g). MS (ESI, [M+H] + ) m / z: 273.3.

[0405] Step C: Preparation of Compound 41C In an ice-water bath, 4-chlorobutane-1-sulfonyl chloride (0.611 g) was gradually added to a solution of compound 41B (0.873 g) in N,N-dimethylformamide (15 mL). After the addition was complete, the reaction mixture was gradually warmed 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 purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 41C (0.826 g). MS (ESI, [M+H] + ) m / z: 427.4.

[0406] Step D: Preparation of Compound 41D Compound 41C (0.826 g) was dissolved in N,N-dimethylformamide (15 mL), and then sodium hydrogen (153 mg) was added in an ice bath. After the addition was completed, the mixture was refluxed at 80° C. overnight. After the reaction was completed, 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 purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 41D (0.3 g). MS (ESI, [M+H] +) m / z: 391.6.

[0407] Step E: Preparation of Compound 41E Compound 41D (0.3 g), bis(pinacolato)diboron (0.389 g), potassium acetate (0.15 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.125 g), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 41E (0.265 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 7 / 3). MS (ESI, [M+H] + ) m / z: 439.5.

[0408] Step F: Preparation of Compound 41F Compound 41E (0.265 g), compound 1C (0.187 g), potassium carbonate (0.105 g), tetrakis(triphenylphosphine)palladium (0.088 g), 1,4-dioxane (10 mL), and water (2 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen, and the reaction was carried out with stirring at 110°C. After the reaction was complete, the reaction solution was filtered and concentrated. Compound 41F (184 mg) was obtained by column chromatography (dichloromethane / 10% methanol = 4 / 1). MS (ESI, [M+H] + ) m / z: 767.7.

[0409] Step G: Preparation of Compound 41 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / 10% methanol = 1 / 1) to give compound 41 (80 mg). MS (ESI, [M+H]+ ) m / z: 667.6.

[0410] 1 H NMR (500 MHz, DMSO-d6) δ 8.26 (d, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.60 (s, 2H), 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).

[0411] Example 42: Preparation of Compound 42 [ka]

[0412] Step A: Preparation of Compound 42A In an ice-water bath, 3-chloropropane-1-sulfonyl chloride (0.538 g) was gradually added to a solution of compound 41B (0.83 g) in N,N-dimethylformamide (15 mL). After the addition was complete, the reaction mixture was gradually warmed 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 purified by column chromatography (petroleum ether / ethyl acetate = 13 / 7) to give compound 42A (0.212 g). MS (ESI, [M+H] + ) m / z: 413.4.

[0413] Step B: Preparation of Compound 42B Compound 42A (0.212 g) was dissolved in N,N-dimethylformamide (15 mL), and then sodium hydrogen (146 mg) was added under ice bath conditions. After the addition was completed, the mixture was refluxed at 80°C overnight to react. After the reaction was completed, 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). MS (ESI, [M+H] + ) m / z: 377.3.

[0414] Step C: Preparation of Compound 42C Compound 42B (0.249 g), bis(pinacolato)diboron (0.335 g), potassium acetate (0.13 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.054 g), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask. The mixture was stirred at 100 °C under a nitrogen atmosphere, and after completion of the reaction, the mixture was filtered and concentrated. Compound 42C (0.21 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 1 / 1). MS (ESI, [M+H] + ) m / z: 425.3.

[0415] Step D: Preparation of Compound 42D Compound 42C (0.21 g), compound 1C (0.243 g), potassium carbonate (0.137 g), tetrakis(triphenylphosphine)palladium (0.057 g), 1,4-dioxane (10 mL), and water (2 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen, and the reaction was stirred at 110°C. After the reaction was complete, the reaction solution was filtered and concentrated. Compound 42D (185 mg) was obtained by column chromatography (dichloromethane / 10% methanol = 3 / 7). MS (ESI) m / z: 753.7 [M+H] + .

[0416] Step E: Preparation of Compound 42 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / 10% methanol = 2 / 3) to give compound 42 (40 mg). MS (ESI, [M+H] + ) m / z: 653.6.

[0417] 1 H NMR (500 MHz, DMSO-d6) δ 8.26 (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).

[0418] Example 43: Preparation of Compound 43 [ka]

[0419] Step A: Preparation of Compound 43A In a reaction flask, tert-butyl exo-8-azabicyclo[3.2.1]octan-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 sequentially added. After the addition was complete, the mixture was stirred at 100 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 43A (0.14 g). MS (ESI, [M+H] + ) m / z: 381.5.

[0420] Step B: Preparation of Compound 43B Compound 43A (0.14 g) and a 4 M solution of hydrogen chloride in dioxane (4 mL) were added sequentially to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give Compound 43B (0.15 g). MS (ESI, [M+H] + ) m / z: 281.8.

[0421] Step C: Preparation of Compound 43C 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) at 0 °C. After the addition was complete, the reaction solution was brought to room temperature and stirred. After the reaction was complete, saturated aqueous sodium bicarbonate 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 aqueous sodium chloride solution (50 mL), and dried. The mixture was filtered and concentrated to give compound 43C (0.11 g). MS (ESI, [M+H] + ) m / z: 323.4.

[0422] Step D: Preparation of Compound 43D At 0 °C under a nitrogen atmosphere, sodium hydride (0.07 g) was slowly added to a reaction solution of compound 43C (0.22 g) in tetrahydrofuran (12 mL). After the addition was complete, the reaction solution was transferred to room temperature and stirred for 0.5 hours. Subsequently, iodomethane (0.48 g) was added and the reaction was continued. After the reaction was complete, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution in an ice bath, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (100 mL), and dried. The mixture was filtered and concentrated to give compound 43D (0.22 g). MS (ESI, [M+H] + ) m / z: 336.8.

[0423] Step E: Preparation of Compound 43E Compound 43D (0.22 g), bis(pinacolato)diboron (0.25 g), potassium acetate (0.20 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.05 g), and 1,4-dioxane (10 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere, and after completion of the reaction, the mixture was filtered and concentrated. Compound 43E (0.1 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 385.6.

[0424] Step F: Preparation of Compound 43F Compound 43E (0.10 g), compound 1C (0.11 g), potassium carbonate (0.09 g), tetrakis(triphenylphosphine)palladium (0.03 g), 1,4-dioxane (4 mL), and water (0.5 mL) were sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 100 °C. After the reaction was complete, the reaction mixture was filtered and concentrated. Compound 43F (0.10 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 713.7.

[0425] Step F: Preparation of Compound 43 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 43 (26 mg). MS (ESI, [M+H] + ) m / z: 613.7.

[0426] 1 H NMR (500 MHz, CDCl3) δ 8.06 (dt, J = 36.6, 6.5 Hz, 2H), 7.76 (q, J = 6.6, 5.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.53 - 7.39 (m, 3H), 7.39 - 7.24 (m, 2H), 7.15 (q, J = 6.9 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.61 (s, 2H), 6.39 (q, J = 6.4 Hz, 1H), 5.18 (dq, J = 12.7, 6.5 Hz, 1H), 4.35 (d, J = 14.0 Hz, 2H), 2.61 (q, J = 9.4, 8.6 Hz, 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).

[0427] Example 44: Preparation of Compound 44 [ka]

[0428] Step A: Preparation of Compound 44A 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) at 0 °C. After the addition was complete, the reaction solution was brought to room temperature and stirred. After the reaction was complete, the reaction solution was extracted with saturated aqueous sodium bicarbonate and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 44A (1.18 g). MS (ESI, [M+H] + ) m / z: 269.5.

[0429] Step B: Preparation of Compound 44B Trifluoroacetic acid (2 mL) was slowly added dropwise to a reaction solution of compound 44A (0.5 g) in dichloromethane (10 mL) at 0°C. After the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 44B (0.85 g). MS (ESI, [M+H] + ) m / z: 169.4.

[0430] Step C: Preparation of Compound 44C Compound 44B (0.5 g), 1,3-dibromofluorobenzene (0.68 g), (tris(dibenzylideneacetone)dipalladium (0.16 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (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 completed, the mixture was stirred at 100°C under a nitrogen atmosphere to react. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 50 / 1) to obtain compound 44C (0.22 g). MS (ESI, [M+H] + ) m / z: 341.4.

[0431] Step D: Preparation of Compound 44D Compound 44C (0.22 g), bis(pinacolato)diboron (0.24 g), potassium acetate (0.19 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.05 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask. The mixture was stirred at 100 °C under a nitrogen atmosphere, and after completion of the reaction, the mixture was filtered and concentrated. Compound 44D (98 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 389.5.

[0432] Step E: Preparation of Compound 44E Compound 44D (98 mg), compound 1C (103 mg), potassium carbonate (87 mg), tetrakis(triphenylphosphine)palladium (24 mg), 1,4-dioxane (4 mL), and water (0.5 mL) were sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 100 °C. After the reaction was complete, the reaction mixture was filtered and concentrated. Compound 44E (84 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 717.4.

[0433] Step F: Preparation of Compound 44 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 44 (37 mg). MS (ESI, [M+H] + ) m / z: 617.6.

[0434] 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8.3 Hz, 1H), 8.05 - 7.99 (m, 1H), 7.79 (dd, J = 8.4, 2.1 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.14 - 7.06 (m, 2H), 6.95 (t, J = 7.9 Hz, 1H), 6.59 (s, 2H), 6.39 (dd, J = 7.7, 4.8 Hz, 1H), 3.80 (d, J = 49.5 Hz, 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).

[0435] Example 45: Preparation of Compound 45 [ka]

[0436] Step A: Preparation of Compound 45A At 0°C under a nitrogen atmosphere, sodium hydride (7.9 g) was slowly added to a tetrahydrofuran solution of tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (10 g) and stirred at room temperature for 1 hour. Iodomethane (27.9 g) was added dropwise to the reaction flask at 0°C, and after the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the reaction was quenched with aqueous ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 45A (13.0 g). MS (ESI, [M+H] + ) m / z: 269.5.

[0437] Step B: Preparation of Compound 45B In a reaction flask, compound 45A (13.0 g), dichloromethane (260 mL), and dilute hydrochloric acid (12.4 g) were added in that order and stirred at room temperature. After the reaction was completed, the mixture was filtered and dried to obtain compound 45B (8.9 g). MS (ESI, [M+H] + ) m / z: 169.4.

[0438] Step C: Preparation of Compound 45C Sodium tert-butoxide (11.3 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (1.8 g), tris(dibenzylideneacetone)dipalladium (2.7 g), 1,3-dibromo-2-fluorobenzene (11.2 g), compound 45B (8.9 g), and 1,4-dioxane (100 mL) were sequentially added to a reaction flask and stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 45C (4.8 g) was obtained by column chromatography (dichloromethane / methanol = 100 / 1). MS (ESI, [M+H] + ) m / z: 341.4.

[0439] Step D: Preparation of Compound 45D Compound 45C (3.0 g), bis(pinacolato)diboron (3.4 g), potassium acetate (2.6 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (1.4 g), and 1,4-dioxane (100 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere, and after completion of the reaction, the mixture was filtered and concentrated. Compound 45D (3.0 g) was obtained by column chromatography (dichloromethane / methanol = 100 / 1). MS (ESI, [M+H] + ) m / z: 389.5.

[0440] Step E: Preparation of Compound 45E Compound 45D (2.8 g), compound 1C (2.3 g), potassium carbonate (1.3 g), tetrakis(triphenylphosphine)palladium (1.1 g), 1,4-dioxane (50 mL), and water (10 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen, and the reaction was carried out with stirring at 100°C. After the reaction was complete, the reaction solution was filtered and concentrated. Compound 45E (2.1 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 717.5.

[0441] Step F: Preparation of Compound 45 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 45 (0.43 g). MS (ESI, [M+H] + ) m / z: 617.6.

[0442] 1 H NMR (500 MHz,CDCl3) δ 8.19 - 7.88 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.60 - 7.26 (m, 5H), 7.05 (s, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 10.6 Hz, 1H), 6.33 (s, 1H), 3.19 (s, 2H), 3.02 (s, 4H), 2.94 (d, J = 9.5 Hz, 2H), 2.79 (s, 3H), 2.60 - 2.52 (m, 1H), 2.27 (d, J = 14.2 Hz, 3H), 2.10 (s, 1H), 1.75 (s, 4H), 1.19 (d, J = 14.4 Hz, 1H).

[0443] Example 46: Preparation of Compound 46 [ka]

[0444] Step A: Preparation of Compound 46A In a reaction flask, 4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl oxalate (1.4 g), triethylamine (0.93 g), 4-bromobutyryl chloride (0.93 g), and tetrahydrofuran (25 mL) were added sequentially. After the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure and concentrated to give compound 46A (0.84 g). MS (ESI, [M + H] + ) m / z: 363.1.

[0445] Step B: Preparation of Compound 46B 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). MS (ESI, [M+H] + ) m / z: 283.5.

[0446] Step C: Preparation of Compound 46C Compound 46B (1.0 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (3.7 mL), and a solution of 1,4-dioxane (20 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 46C (0.83 g). MS (ESI, [M+H] + ) m / z: 183.5.

[0447] Step D: Preparation of Compound 46D Compound 46C (3.0 g), cesium carbonate (2.3 g), tris(dibenzylideneacetone)dipalladium-chloroform adduct (0.21 g), 1-(3-methylpiperidin-4-yl)pyrrolidin-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 sequentially added to a reaction flask. The mixture was stirred at 100 °C. After completion of the reaction, the mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 46D (0.38 g). MS (ESI, [M+H] + ) m / z: 355.4.

[0448] Step E: Preparation of Compound 46E Under a nitrogen atmosphere, compound 46D (0.38 g), potassium carbonate (0.21 g), bis(pinacolato)diboron (0.41 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.17 g), and dioxane (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 46E (0.16 g). MS (ESI, [M+H] + ) m / z: 403.6.

[0449] Step F: Preparation of Compound 46F Compound 46E (0.16 g), compound 1C (0.18 g), potassium carbonate (0.087 g), tetrakis(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (10 mL), and water (2.0 mL) were added sequentially to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 46F (0.20 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 731.8.

[0450] Step G: Preparation of Compound 46 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 46 (0.078 g). MS (ESI, [M+H] + ) m / z: 631.7.

[0451] 1H NMR (500 MHz, CDCl3) δ 8.10 - 8.04 (m, 1H), 7.94 (dd, J = 5.0, 2.3 Hz, 1H), 7.74 (dq, J = 8.1, 2.7 Hz, 1H), 7.56 - 7.47 (m, 2H), 7.43 - 7.33 (m, 3H), 7.05 (tt, J = 11.9, 3.0 Hz, 2H), 6.95 (t, J = 8.0 Hz, 1H), 6.34 (ddd, J = 7.4, 4.9, 2.1 Hz, 1H), 3.71 (td, J = 12.1, 4.2 Hz, 1H), 3.46 - 3.32 (m, 3H), 3.32 - 3.26 (m, 1H), 2.76 (td, J = 11.9, 2.9 Hz, 1H), 2.59 (dddd, J = 11.9, 9.0, 6.3, 2.3 Hz, 2H), 2.47 - 2.41 (m, 1H), 2.37 (dtt, J = 11.7, 5.8, 2.6 Hz, 4H), 2.15 (ddtt, J = 15.9, 9.6, 6.7, 3.4 Hz, 1H), 1.98 (dp, J = 12.3, 5.2, 4.0 Hz, 3H), 1.81 (ddtq, J = 12.4, 9.3, 6.3, 3.7, 2.9 Hz, 1H), 1.72 - 1.60 (m, 1H), 1.34 (d, J = 2.3 Hz, 1H), 1.26 - 1.14 (m, 3H).

[0452] Example 47: Production of Compound 47

change

[0453] ステップA: Manufacture of compound 47A In a reaction flask, tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (2.5 g), acetic anhydride (1.93 g), triethylamine (6.3 g), and dichloromethane (40 mL) were added sequentially. The mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 47A (3.0 g). MS (ESI, [M+Na] + ) m / z: 241.1.

[0454] Step B: Preparation of Compound 47B In a reaction flask, compound 47A (3.01 g), trifluoroacetic acid (2.2 g), and dichloromethane (50 mL) were added sequentially. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 47B (2.3 g). MS (ESI, [M+H] + ) m / z: 141.1.

[0455] Step C: Preparation of Compound 47C Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.73 g), tris(dibenzylideneacetone)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 sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 85°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 47C (0.43 g). MS (ESI, [M+H] + ) m / z: 312.9.

[0456] Step D: Preparation of Compound 47D Compound 47C (0.43 g), bis(pinacolato)diboron (0.52 g), potassium acetate (0.22 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.270 g), and 1,4-dioxane (60 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 47D (0.13 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 361.6.

[0457] Step E: Preparation of Compound 47E Compound 47D (0.13 g), compound 1C (0.12 g), potassium carbonate (0.068 g), tetrakis(triphenylphosphine)palladium (0.057 g), 1,4-dioxane (25 mL), and water (5 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 47E (0.21 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 689.44.

[0458] Step F: Preparation of Compound 47 Compound 47E (0.21 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 47 (0.11 g). MS (ESI, [M+H] + ) m / z: 589.6.

[0459] 1H NMR (500 MHz, CDCl3) δ 8.07 - 7.89 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 17.7, 8.1 Hz, 2H), 7.28 (t, J = 12.7 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.97 (q, J = 7.7 Hz, 1H), 6.48 (dt, J = 26.1, 8.2 Hz, 2H), 6.33 (dd, J = 7.8, 4.8 Hz, 1H), 4.46 - 4.25 (m, 2H), 3.86 (dd, J = 18.6, 12.8 Hz, 2H), 3.53 (d, J = 13.7 Hz, 1H), 3.47 - 3.28 (m, 1H), 2.78 (q, J = 6.9 Hz, 1H), 2.48 (dq, J = 53.9, 11.6, 10.3 Hz, 4H), 2.28 - 2.09 (m, 1H), 1.91 - 1.79 (m, 3H), 1.54 (d, J = 8.6 Hz, 1H), 1.35 (s, 1H).

[0460] Example 48: Preparation of Compound 48 [ka]

[0461] Step A: Preparation of Compound 48A In a reaction flask, 4-amino-3-methylpiperidine-1-carboxylic acid tert-butyl oxalate (3.5 g), triethylamine (2.9 g), 4-bromobutyryl chloride (3.3 g), and tetrahydrofuran (25 mL) were added sequentially. After the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure and concentrated to give compound 48A (0.78 g). MS (ESI, [M+H] + ) m / z: 363.1.

[0462] Step B: Preparation of Compound 48B Compound 48A (1.4 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 48B (0.52 g). MS (ESI, [M+H] + ) m / z: 283.5.

[0463] Step C: Preparation of Compound 48C Compound 48B (0.52 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (0.34 mL), and a solution of 1,4-dioxane (20 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 48C (0.41 g). MS (ESI, [M + H] + ) m / z: 183.5.

[0464] Step D: Preparation of Compound 48D Compound 48C (0.41 g), cesium carbonate (2.2 g), tris(dibenzylideneacetone)dipalladium-chloroform adduct (0.21 g), 1-(3-methylpiperidin-4-yl)pyrrolidin-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 sequentially added to a reaction flask. The mixture was stirred at 100 °C. After completion of the reaction, the mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 48D (0.28 g). MS (ESI, [M+H] + ) m / z: 337.1.

[0465] Step E: Preparation of Compound 48E Under a nitrogen atmosphere, compound 48D (0.28 g), potassium carbonate (0.24 g), bis(pinacolato)diboron (0.32 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.138 g), and dioxane (20 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 48E (0.087 g). MS (ESI, [M+H] + ) m / z: 385.3.

[0466] Step F: Preparation of Compound 48F Compound 48E (0.087 g), compound 1C (0.075 g), potassium carbonate (0.087 g), tetrakis(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 48F (0.080 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 713.1.

[0467] Step G: Preparation of Compound 48 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 48 (0.021 g). MS (ESI, [M+H] + ) m / z: 613.1.

[0468] 1H NMR (500 MHz, CDCl3) δ 8.09 - 7.94 (m, 2H), 7.70 (d, J = 8.5 Hz, 1H), 7.48 (h, J = 9.0, 8.5 Hz, 3H), 7.36 (d, J = 7.8 Hz, 2H), 7.23 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.84 (dd, J = 8.2, 2.4 Hz, 1H), 6.59 (d, J = 20.1 Hz, 2H), 6.33 (dd, J = 7.8, 4.8 Hz, 1H), 4.39 (ddt, J = 12.9, 9.3, 4.6 Hz, 1H), 4.26 (dt, 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, 1.60 (d, J = 12.3 Hz, 2H), 1.07 (d, J = 6.9 Hz, 3H).

[0469] Example 49: Production of Compound 49

change

[0470] ステップA: Manufacture of compound 49A In a reaction flask, 33A (0.52 g), 1,3-dibromofluorobenzene (0.83 g), (tris(dibenzylideneacetone)dipalladium (0.20 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.14 g), sodium tert-butoxide (1.04 g), and 1,4-dioxane (30 mL) were added sequentially. After the addition was completed, the mixture was stirred at 100°C under a nitrogen atmosphere to react. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 50 / 1) to obtain compound 49A (0.22 g). MS (ESI, [M+H] + ) m / z: 299.3.

[0471] Step B: Preparation of Compound 49B Sodium hydride (0.11 g) was slowly added to a reaction solution of compound 49A (0.16 g) in tetrahydrofuran (10 mL) at 0°C under a nitrogen atmosphere. After the addition was complete, the reaction solution was brought to room temperature and stirred for 0.5 hours. Subsequently, iodomethane (0.23 g) was added and the reaction was continued. After the reaction was complete, saturated aqueous ammonium chloride solution was added to the reaction solution in an ice bath, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried. The mixture was filtered and concentrated to give compound 49B (0.18 g). MS (ESI, [M+H] + ) m / z: 313.3.

[0472] Step C: Preparation of Compound 49C Compound 49B (0.17 g), bis(pinacolato)diboron (0.20 g), potassium acetate (0.16 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.04 g), and 1,4-dioxane (10 mL) were sequentially added to a reaction flask. The mixture was stirred under a nitrogen atmosphere at 100 °C. After completion of the reaction, the mixture was filtered and concentrated. Compound 49C (0.19 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 361.5.

[0473] Step D: Preparation of Compound 49D 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 sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 100 °C. After the reaction was complete, the reaction mixture was filtered and concentrated. Compound 49D (0.14 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 689.7.

[0474] Step E: Preparation of Compound 49 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 completion of the reaction, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 49 (49 mg). MS (ESI, [M+H] + ) m / z: 589.4.

[0475] 1H NMR (500 MHz, CDCl3) δ 8.14 (dd, J = 8.5, 3.4 Hz, 1H), 8.02 (dt, J = 4.9, 2.5 Hz, 1H), 7.83 - 7.75 (m, 1H), 7.55 (dt, J = 8.4, 2.4 Hz, 2H), 7.42 (dt, J = 8.3, 2.4 Hz, 2H), 7.32 - 7.26 (m, 1H), 7.17 - 7.13 (m, 1H), 7.07 (dd, J = 9.5, 6.0 Hz, 1H), 6.57 - 6.49 (m, 1H), 6.45 - 6.39 (m, 1H), 4.10 - 3.96 (m, 4H), 3.71 (d, J = 3.3 Hz, 2H), 2.89 (d, J = 3.5 Hz, 3H), 2.72 (d, J = 3.5 Hz, 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).

[0476] Example 50: Preparation of Compound 50 [ka]

[0477] Step A: Preparation of Compound 50A 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 and stirred at room temperature under a nitrogen atmosphere. Sodium cyanoborohydride (0.84 g) was added, and after the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, saturated aqueous sodium bicarbonate (50 mL) was added to the reaction mixture, which was then concentrated. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 50A (1.3 g). MS (ESI, [M+H] + ) m / z: 443.4.

[0478] Step B: Preparation of Compound 50B 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 and reacted at 70° C. After completion of the reaction, the mixture was concentrated, and the residue was extracted with ethyl acetate. The aqueous phase was adjusted to pH 4-5 with 1 M diluted hydrochloric acid, concentrated, dissolved in methanol (30 mL), filtered through an organic membrane, and concentrated to obtain compound 50B (1.0 g).

[0479] Step C: Preparation of Compound 50C Compound 50B (1.0 g), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.2 g), and dichloromethane (20 mL) were added sequentially to a reaction flask and stirred at room temperature under a nitrogen atmosphere. N,N-Diisopropylethylamine (1.5 g) and N,O-dimethylhydroxyamine hydrochloride (0.4 g) were added, and after the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 100 / 1) to obtain compound 50C (1.0 g). MS (ESI, [M+H] + ) m / z: 396.2.

[0480] Step D: Preparation of Compound 50D Methylmagnesium bromide (1.5 g) was added dropwise to a solution of compound 50C (1.0 g) in tetrahydrofuran (20 mL) at -15°C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at room temperature. After the reaction was complete, 50 mL of saturated aqueous ammonium chloride solution was added to the reaction flask, and the mixture was extracted with ethyl acetate and concentrated. Compound 50D (0.23 g) was obtained by column chromatography (dichloromethane / methanol = 40 / 1). MS (ESI, [M+H] + ) m / z: 351.1.

[0481] Step E: Preparation of Compound 50E Compound 50D (0.23 g), bis(pinacolato)diboron (0.33 g), potassium acetate (0.2 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.053 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 40 / 1) to give compound 50E (0.054 g). MS (ESI, [M+H] + ) m / z: 399.4.

[0482] Step F: Preparation of Compound 50F Compound 50E (0.054 g), compound 1C (0.06 g), potassium carbonate (0.051 g), tetrakis(triphenylphosphine)palladium (0.014 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100°C under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 50F (0.050 g). MS (ESI, [M+H] + ) m / z: 727.4.

[0483] Step F: Preparation of Compound 50 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 completed, the reaction mixture was adjusted to pH 13 with 10% aqueous sodium hydroxide, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 50 (0.0050 g). MS (ESI, [M+H] + ) m / z: 627.7.

[0484] 1H NMR (500 MHz, DMSO) δ 9.36 (d, J = 41.5 Hz, 1H), 8.99 (s, 1H), 8.34 - 8.26 (m, 1H), 8.08 (d, J = 6.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 33.2, 8.5 Hz, 2H), 7.66 - 7.57 (m, 3H), 7.48 (d, J = 7.1 Hz, 3H), 7.31 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 6.5 Hz, 1H), 6.61 (s, 1H), 4.88 (d, J = 26.5 Hz, 1H), 3.90 (dd, J = 20.9, 9.0 Hz, 2H), 3.55 (d, J = 34.7 Hz, 2H), 2.72 (s, 3H), 2.63 (t, J = 7.8 Hz, 4H), 2.37 (d, J = 9.4 Hz, 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, 14.4 Hz, 3H).

[0485] Example 51: Preparation of Compound 51 [ka]

[0486] Step A: Preparation of Compound 51A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.22 g), tris(dibenzylideneacetone)dipalladium (0.32 g), 1,3-dibromo-2-fluorobenzene (0.89 g), 2,7-diazaspiro[3.5]nonane-7-tert-butyl carbonate (0.70 g), sodium tert-butoxide (1.0 g), and tetrahydrofuran (25 mL) were sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 85°C. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 51A (0.37 g). MS (ESI, [M + H] + ) m / z: 371.3.

[0487] Step B: Preparation of Compound 51B 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 51B (0.23 g). MS (ESI, [M+H] + ) m / z: 271.3.

[0488] Step C: Preparation of Compound 51C 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 completed, the reaction mixture was extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 51C (0.34 g). MS (ESI, [M+H] + ) m / z: 313.0.

[0489] Step D: Preparation of Compound 51D Compound 51C (0.34 g), bis(pinacolato)diboron (0.42 g), potassium acetate (0.21 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.18 g), and 1,4-dioxane (50 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated. Compound 51D (0.17 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 361.5.

[0490] Step E: Preparation of Compound 51E Compound 51D (0.17 g), compound 1C (0.16 g), potassium carbonate (0.89 g), tetrakis(triphenylphosphine)palladium (0.74 g), 1,4-dioxane (25 mL), and water (5 mL) were sequentially added to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 51E (0.15 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 689.6.

[0491] Step F: Preparation of Compound 51 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 51 (0.089 g). HRMS (ESI, [M+H] + ) m / z: 589.2825.

[0492] 1H NMR (500 MHz, CDCl3) δ 8.09 - 7.94 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.09 - 7.02 (m, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.59 - 6.47 (m, 2H), 6.32 (m, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.88 (dd, J = 20.6, 12.8 Hz, 2H), 3.54 (d, J = 13.7 Hz, 1H), 3.41 (d, J = 11.6 Hz, 1H), 2.80 (q, J = 7.0 Hz, 1H), 2.54 (q, J = 9.1 Hz, 3H), 2.21 (m, 2H), 2.10 (dt, J = 19.0, 9.3 Hz, 1H), 1.89 (s, 3H), 1.82 - 1.70 (m, 1H).

[0493] Example 52: Preparation of Compound 52 [ka]

[0494] Step A: Preparation of Compound 52A In a reaction flask, 1-tert-butoxycarbonyl-4-(methylamino)piperidine (2.00 g), 1,3-dibromobenzene (3.30 g), tris(dibenzylideneacetone)dipalladium (0.43 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.44 g), 1,4-dioxane (100 mL), and sodium tert-butoxide (1.79 g) were added sequentially. After the addition was completed, the mixture was stirred under a nitrogen atmosphere at 100°C to react. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 52A (1.16 g). MS (ESI, [Mt-Bu+H] + ) m / z: 313.4.

[0495] Step B: Preparation of Compound 52B To a reaction flask containing compound 52A (1.15 g), dichloromethane (10 mL) and a 4 M solution of hydrogen chloride in dioxane (15 mL) were added sequentially. After the addition was completed, the mixture was stirred at room temperature and allowed to react. After the reaction was completed, the reaction solution was concentrated to give compound 52B (1.17 g). MS (ESI, [M+H] + ) m / z: 269.5.

[0496] Step C: Preparation of Compound 52C 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. After the addition was completed, the mixture was stirred at room temperature and allowed to react. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 52C (0.90 g). MS (ESI, [M+H] + ) m / z: 311.4.

[0497] Step D: Preparation of Compound 52D Compound 52C (0.88 g), bis(pinacolato)diboron (1.08 g), potassium acetate (0.83 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.23 g), and 1,4-dioxane (50 mL) were sequentially added to a reaction flask. The mixture was stirred under a nitrogen atmosphere at 100 °C. After completion of the reaction, the mixture was filtered and concentrated. Compound 52D (0.90 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 1 / 2). MS (ESI, [M+H] + ) m / z: 359.6.

[0498] Step E: Preparation of Compound 52E Compound 52D (200 mg), compound 1C (219 mg), potassium carbonate (169 mg), tetrakis(triphenylphosphine)palladium (47 mg), 1,4-dioxane (10 mL), and water (2 mL) were sequentially added to a microwave tube. After the addition was complete, the atmosphere was replaced with nitrogen and the reaction was carried out in a microwave oven at 140 °C. After the reaction was complete, the mixture was filtered and concentrated. Compound 52E (216 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 687.8.

[0499] Step F: Preparation of Compound 52 Compound 52E (206 mg), methanesulfonic acid (0.2 mL), and dichloromethane (10 mL) were added sequentially to a reaction flask. After the addition was complete, the mixture was stirred at room temperature and allowed to react. After the reaction was complete, the reaction solution was adjusted to pH 9 with saturated aqueous sodium carbonate, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 52 (145 mg). MS (ESI, [M+H] + ) m / z: 587.7.

[0500] 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 5.2, 1.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.48 - 7.43 (m, 2H), 7.39 (s, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.15 (dd, J = 7.8, 1.7 Hz, 1H), 6.82 (dd, J = 8.1, 2.5 Hz, 1H), 6.44 (dd, J = 7.7, 5.2 Hz, 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).

[0501] Example 53: Preparation of Compound 53 [ka]

[0502] Step A: Preparation of Compound 53A In a reaction flask, tert-butyl 3,6-diazacyclo[3.2.0]heptane-6-carboxylate (0.35 g), acetyl chloride (0.28 g), triethylamine (0.54 g), and dichloromethane (15 mL) were added sequentially. The mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 53A (0.45 g). MS (ESI, [M+H] + ) m / z: 241.1.

[0503] Step B: Preparation of Compound 53B In a reaction flask, compound 53A (0.42 g), hydrochloric acid (3.06 g), and dichloromethane (10 mL) were added sequentially. The mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated to give compound 53B (0.4 g). MS (ESI, [M+H] + ) m / z: 141.1.

[0504] Step C: Preparation of Compound 53C Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.20 g), tris(dibenzylideneacetone)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 sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100 °C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 50 / 1) to obtain compound 53C (0.07 g). MS (ESI, [M + H] + ) m / z: 295.4.

[0505] Step D: Preparation of Compound 53D Compound 53C (0.12 g), bis(pinacolato)diboron (0.21 g), potassium acetate (0.12 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.066 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 53D (0.09 g) was obtained by column chromatography (dichloromethane / methanol = 40 / 1). MS (ESI, [M+H] + ) m / z: 343.6.

[0506] Step E: Preparation of Compound 53E Compound 53D (0.088 g), compound 1C (0.075 g), potassium carbonate (0.042 g), tetrakis(triphenylphosphine)palladium (0.035 g), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 53E (0.054 g) was obtained by column chromatography (dichloromethane / methanol = 40 / 1). MS (ESI, [M+H] + ) m / z: 671.8.

[0507] Step F: Preparation of Compound 53 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 40 / 1) to give compound 53 (0.020 g). HRMS (ESI, [M+H] + ) m / z: 571.2924.

[0508] 1H NMR (500 MHz, CDCl3) δ 8.08 (t, J = 8.4 Hz, 1H), 8.02 (dd, J = 8.7, 4.4 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 8.5 Hz, 2H), 7.34 (d, J = 7.7 Hz, 1H), 7.23 (dd, J = 14.2, 7.0 Hz, 2H), 7.13 - 7.07 (m, 1H), 6.62 (d, J = 9.8 Hz, 2H), 6.37 (dd, J = 14.0, 8.0 Hz, 2H), 4.67 - 4.50 (m, 1H), 4.18 (dd, J = 19.0, 11.7 Hz, 1H), 3.95 - 3.76 (m, 3H), 3.67 - 3.60 (m, 1H), 3.58 (d,J = 6.1 Hz, 1H), 3.34 (dd, J = 14.7, 6.2 Hz, 1H), 3.31 - 3.23 (m, 1H), 3.17 (s, 1H), 2.65 (dd, J = 39.8, 30.3 Hz, 4H), 2.45 (d, J = 39.0 Hz, 2H), 2.12 (s, 1H), 2.00 (s, 1H), 1.85 (s, 1H).

[0509] Example 54: Production of Compound 54

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[0510] ステップA: Manufacturing of Compound 54A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (3.3 g), tris(dibenzylideneacetone)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 sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 54A (0.90 g). MS (ESI, [M + H] + ) m / z: 297.1.

[0511] Step B: Preparation of Compound 54B 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 completed, saturated ammonium chloride solution was added to the reaction mixture, which was then extracted with water and ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 54B (1.5 g). MS (ESI, [M+H] + ) m / z: 314.5.

[0512] Step C: Preparation of Compound 54C Compound 54B (1.5 g), bis(pinacolato)diboron (2.4 g), potassium acetate (1.4 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.57 g), and 1,4-dioxane (50 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 54C (0.62 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 362.1.

[0513] Step D: Preparation of Compound 54D Compound 54C (0.33 g), compound 1C (0.30 g), potassium carbonate (0.17 g), tetrakis(triphenylphosphine)palladium (0.21 g), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 54D (0.28 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 690.8.

[0514] Step E: Preparation of Compound 54 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 54 (0.14 g). HRMS (ESI, [M+H] + ) m / z: 590.3460.

[0515] 1H NMR (500 MHz, CDCl3) δ 8.08 - 7.96 (m, 2H), 7.70 (dd, J = 8.4, 2.1 Hz, 1H), 7.55 (m, 1H), 7.49 (dd, J = 8.2, 5.9 Hz, 2H), 7.43 (dd, J = 15.3, 7.7 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.25 (q, J = 8.1 Hz, 1H), 7.08 (dd, J = 7.8, 1.8 Hz, 1H), 6.89 (dd, J = 8.2, 2.6 Hz, 1H), 6.56 (s, 2H), 6.32 (dd, J = 7.8, 4.8 Hz, 1H), 4.59 (tt, J = 12.2, 4.1 Hz, 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).

[0516] Example 55: Preparation of Compound 55 [ka]

[0517] Step A: Preparation of Compound 55A Under a nitrogen atmosphere, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (3.1 g), tris(dibenzylideneacetone)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 sequentially added to a reaction flask. After the addition was complete, the mixture was stirred at 100°C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 55A (1.0 g). MS (ESI, [M + H] + ) m / z: 315.4.

[0518] Step B: Preparation of Compound 55B 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 completed, saturated ammonium chloride solution was added to the reaction mixture, which was then extracted with water and ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give compound 55B (1.4 g). MS (ESI, [M+H] + ) m / z: 332.4.

[0519] Step C: Preparation of Compound 55C Compound 55B (1.4 g), bis(pinacolato)diboron (2.0 g), potassium acetate (1.2 g), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (0.5 g), and 1,4-dioxane (50 mL) were sequentially added to a reaction flask. The mixture was stirred at 100°C under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and concentrated. Compound 55C (0.75 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 380.1.

[0520] Step D: Preparation of Compound 55D Compound 55C (0.35 g), compound 1C (0.30 g), potassium carbonate (0.17 g), tetrakis(triphenylphosphine)palladium (0.21 g), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially to a reaction flask. After the addition was complete, the atmosphere was replaced with nitrogen and the mixture was stirred at 100°C. After the reaction was complete, the mixture was filtered and concentrated. Compound 55D (0.28 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 708.5.

[0521] Step E: Preparation of Compound 55 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 completed, the reaction mixture was adjusted to pH 13 with 10% sodium hydroxide solution, extracted with water and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 55 (0.11 g). HRMS (ESI, [M+H] + ) m / z: 608.3345.

[0522] 1 H NMR (500 MHz, CDCl3) δ 8.05 (dd, J = 8.3, 5.6 Hz, 1H), 7.99 (dd, J = 4.8, 1.9 Hz, 1H), 7.74 (dd, J = 8.4, 2.3 Hz, 1H), 7.48 (dd, J = 8.5, 2.5 Hz, 2H), 7.46 - 7.40 (m, 1H), 7.33 (dd, J = 8.4, 2.2 Hz, 2H), 7.09 - 7.00 (m, 2H), 6.98 - 6.89 (m, 1H), 6.54 (s, 2H), 6.31 (dd, J = 7.8, 4.9 Hz, 1H), 4.57 (tt, J = 12.3, 4.2 Hz, 1H), 3.53 - 3.36 (m, 2H), 2.86 - 2.66 (m, 2H), 2.53 (dddd, J = 12.1, 9.5, 6.2, 2.9 Hz, 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).

[0523] [Test Example 1] Growth inhibitory effect of compounds on LNcap cells One plate of LNcap cells (PTEN-deficient human prostate cancer cells) in good exponential growth phase was taken and digested with 1 mL of trypsin for 3 minutes. 4 mL of complete medium was added to terminate the digestion, and the cells were collected in a centrifuge tube. 20 μL of the cells were counted, and the required number of cells (mL) was aspirated and centrifuged at 1,200 rpm for 5 minutes. The supernatant was discarded, and an appropriate amount of inoculation medium (plating medium) (RPMI medium + 5% FBS + 1% sodium pyruvate + 1% glutamine) was added to adjust the cell density to 3 × 10 4 The concentration of cells was adjusted to 1 / mL. Using a multichannel pipette, 100 μL per well was inoculated into a 96-well plate and cultured in a cell incubator at 37°C with 5% CO2 and saturated humidity. After overnight culture, compounds were added using a nolitre sampler. Two duplicate wells were set up for each concentration. Cells without compound were used as negative controls. After 72 hours, 10 μL of CCK-8 was added per well. After 4 hours, the absorbance was measured at 450 nm using an Envision microplate reader. The inhibition rate was calculated as follows: Inhibition rate (%) = (mean value of negative control group - mean value of experimental group) / (mean value of negative control group - mean value of blank group) × 100%. A four-parameter analysis was performed using the abscissa as the logarithm of the compound concentration and the ordinate as the inhibition rate, and a dose-response curve was fitted to determine the IC. 50 The experimental results are shown in Table 1.

[0524] [Table 1]

[0525] [Test Example 2] Inhibitory effect of compounds on AKT1 (S473) phosphorylation in LNcap cells LNcap cells AKT1 (S473) grown in logarithmic growth phase were harvested and digested with 1 mL of trypsin for 3 minutes. 4 mL of complete medium was added to terminate the digestion, and the cells were collected in a centrifuge tube. 20 μL of the cells were counted to obtain the required number of cells (mL). The cells were centrifuged at 1,200 rpm for 5 minutes and inoculated with inoculation medium (2% FBS + phenol red-free 1640 basal medium + 1% sodium pyruvate + 1% glutamine) to a cell density of 1 × 10. 6The cells were seeded at the above cell density into a 96-well plate at 100 μL per well and incubated overnight at 37°C in a 5% CO2 cell incubator. The next day, the corresponding compound was sprayed onto the plate using a Nolitre sampler according to the plate distribution and incubated for 1 hour at 37°C in a 5% CO2 cell incubator. The supernatant was aspirated and discarded, and 40 μL of lysis solution (1X) containing blocking solution was added and incubated at room temperature for 30 minutes with shaking. After uniform mixing, 16 μL of the lysate was transferred to a 384-well small-volume whiteboard. 4 μL (v / v) of premixed antibody prepared in detection buffer was added, the plate was covered, centrifuged to mix uniformly, and incubated overnight at room temperature. Signal values ​​at 665 nm and 620 nm were detected using a PE Envision multifunction microplate reader, and IC was calculated using a four-parameter fitting. 50 was calculated. The results of the inhibitory effects of compounds on LNcap cells and on the phosphorylation of AKT1 (S473) are shown in Table 2.

[0526] [Table 2]

[0527] [Test Example 3] Pharmacokinetic evaluation of compounds in mice ICR mice weighing 8 to 22 g were adapted for 3 to 5 days and then randomly divided into groups of 9 mice each. Compound 28 and Compound 30 were administered intragastrically (IG) at a dose of 10 mg / kg, and Compound 28 and Compound 30 were administered intravenously (IV) at a dose of 1 mg / kg. The test animals (ICR mice) were fasted for 12 hours before administration, fed starting 4 hours after administration, and allowed to drink water ad libitum before, during, and after the experiment.

[0528] Approximately 0.1 mL of blood was collected via the orbit at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after intravenous administration. Approximately 0.1 mL of blood was collected via the orbit at 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 24 hours after intravenous administration. Each mouse received 3-4 blood samples. Whole blood was collected from three mice at each time point, placed in EDTA-K2-containing centrifuge tubes, and stored at 4°C. Plasma was collected within 1 hour by centrifugation at 4,000 rpm for 10 minutes at 4°C. All plasma samples were stored at -20°C immediately after collection and then prepared for analysis.

[0529] 30 μL of the test plasma sample and the calibration curve sample were aspirated with a pipette, and 300 μL of an acetonitrile solution containing the internal standard (diazepam: 20 ng / mL) was added. The resulting mixture was shaken for 5 minutes to mix uniformly, and then centrifuged at 13,000 rpm for 10 minutes. 80 μL of the supernatant was taken, diluted with 80 μL of ultrapure water, and mixed uniformly. 2 μL of the resulting solution was aspirated with a pipette and used for liquid phase chromatography-mass spectrometry, and the chromatogram was recorded. The exposure dose of the compound of the present invention after oral administration and intravenous injection was evaluated by a pharmacokinetic study in mice, and the results are shown in Table 3 below.

[0530] [Table 3]

[0531] [Test Example 4] Pharmacokinetic evaluation of compounds in rats SD rats weighing 180-220 g were subjected to 7 days of adaptation feeding and then randomly divided into groups of 3 rats. Compound 28 and Compound 30 were administered intragastrically (IG) at a dose of 10 mg / kg, respectively, and Compound 28 and Compound 30 were administered intravenously (IV) at a dose of 1 mg / kg, respectively. The test animals (SD rats) were fasted for 12 hours before administration, fed starting 4 hours after administration, and allowed to drink water ad libitum before, during, and after the experiment.

[0532] Approximately 0.1 mL of blood was collected from the orbit at 15, 30, 1, 2, 3, 4, 6, 8, 10, and 24 hours after intravenous administration. Approximately 0.1 mL of blood was collected from the orbit at 5, 10, 30, 1, 2, 4, 6, 8, 10, and 24 hours after intravenous administration. Whole blood was collected from three mice at each time point, placed in EDTA-K2-containing centrifuge tubes, and stored at 4°C. Plasma was collected within 1 hour by centrifugation at 4°C and 4000 rpm for 10 minutes. All plasma samples were stored at -20°C immediately after collection and then prepared for analysis.

[0533] 30 μL of the test plasma sample and the calibration curve sample were aspirated with a pipette, and 300 μL of an acetonitrile solution containing the internal standard (diazepam: 20 ng / mL) was added. The resulting mixture was shaken for 5 minutes to mix uniformly, and then centrifuged at 13,000 rpm for 10 minutes. 80 μL of the supernatant was taken, diluted with 80 μL of ultrapure water, and mixed uniformly. 2 μL of the resulting solution was aspirated with a pipette and used for liquid phase chromatography-mass spectrometry, and the chromatogram was recorded.

[0534] The oral and intravenous exposure of the compound of the present invention was evaluated in a pharmacokinetic study in rats, and the results are shown in Table 4 below.

[0535] [Table 4]

[0536] [Test Example 5] Pharmacological evaluation of compounds in a nude mouse subcutaneously transplanted tumor model of AN3CA human endometrial cancer cells 5 × 10 SPF female BALB / C nude mice (source: Changzhou Changzhou Animal Laboratory Co., Ltd.) were injected subcutaneously into the right axilla of 6 AN3CA cells (source: Nanjing Kebai Biotechnology Co., Ltd.) were inoculated into the mice. The average tumor volume was 130 mm 3 When this level was reached, the animals were divided into three groups of six and dosed as shown in Table 5.

[0537] [Table 5]

[0538] The day of group allocation was designated as day 0. On the day of group allocation, intragastric administration began, with the administration volume being 10 mL / kg. The vehicle was D5W (5% glucose solution). Tumor volume was measured two to three times a week, and mice were weighed and recorded. The general condition of the animals was observed and recorded daily. After the experiment, tumors were removed, weighed, and photographed.

[0539] Tumor volume calculation formula: Tumor volume (mm 3 )=1 / 2×(a×b 2 ) (where a represents the major axis and b represents the minor axis). The relative tumor growth rate is T / C%, i.e., the percentage value of the relative tumor volume between the treatment group and the control group at a certain time point. The calculation formula is as follows: T / C%=T RTV / C RTV ×100%(T RTV :Treatment group mean RTV, C RTV : Mean RTV of the vehicle control group, relative tumor volume...

Claims

1. The following formula (I): 【Chemistry 1】 [In the formula, R １ and R １’ are each independently selected from hydrogen or halogen; R ２ , R ２’ and R ３ are each independently hydrogen, 【Chemistry 2】 7- to 10-membered fused heterocyclyl, 7- to 10-membered bridged heterocyclyl whose ring atoms are nitrogen and carbon atoms, and 5- to 6-membered heterocyclyl whose ring atoms are nitrogen and carbon atoms, wherein the 5- to 6-membered heterocyclyl whose ring atoms are nitrogen and carbon atoms is selected from the group consisting of one or more R ２２ and optionally one or more R ２２’ where: 【Transformation 3】 or a 7- to 10-membered fused heterocyclyl optionally having one or more R ２３ wherein said 7- to 10-membered bridged heterocyclyl consisting of a nitrogen atom and a carbon atom is substituted with one or more R ２４ is replaced by And R ２ , R ２’ and R ３ does not simultaneously become hydrogen, R ２２ is a 4- to 5-membered heterocyclyl, and 【Chemistry 4】 wherein said 4- to 5-membered heterocyclyl or 【Transformation 5】 is optionally 【Transformation 6】 Halogen, C １ ~C ３ Alkyl, and C １ ~C ６ substituted with one or more groups selected from the group consisting of alkyl acyl; R ２２’ are each independently deuterium or C １ ~C ６ selected from alkyl, R ２３ and R ２４ are each independently 【Transformation 7】 C １ ~C ６ Alkyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkyl acyl, and C １ ~C ６ Alkyl acyl-N(C １ ~C ６ alkyl)- ], A compound of formula (I) or a pharmaceutically acceptable salt thereof:

2. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, During the ceremony, R ２ , R ２’ and R ３ are each independently hydrogen, 【Transformation 8】 7-10 membered fused heterocyclyl, 7-10 membered bridged heterocyclyl whose ring atoms are nitrogen and carbon atoms, and 5-6 membered heterocyclyl whose ring atoms are nitrogen and carbon atoms, wherein the 5-6 membered heterocyclyl whose ring atoms are nitrogen and carbon atoms is selected from the group consisting of one or more R ２２ and optionally one or more R ２２’ where: 【Chemistry 9】 or a 7- to 10-membered fused heterocyclyl optionally has one or more R ２３ wherein said 7- to 10-membered bridged heterocyclyl consisting of a nitrogen atom and a carbon atom is substituted with one or more R ２４ is replaced by And R ２ , R ２’ and R ３ does not simultaneously become hydrogen, R ２２ is selected from the group consisting of 4- to 5-membered heterocyclyl, wherein said 4- to 5-membered heterocyclyl optionally includes one or more 【Chemistry 10】 is replaced by R ２２’ is C １ ~C ６ A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from alkyl.

3. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２ , R ２’ and R ３ are each independently hydrogen, 【Chemistry 11】 and 5-6 membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms, wherein the 5-6 membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms is selected from the group consisting of 7-, 8-, or 9-membered fused heterocycloalkyl, 8-membered bridged heterocycloalkyl whose ring atoms are nitrogen and carbon atoms, and wherein the 5-6 membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms is selected from the group consisting of one or more R ２２ and optionally one or more R ２２’ where: 【Chemistry 12】 or a 7-, 8-, or 9-membered fused heterocycloalkyl optionally having one or more R ２３ wherein said 8-membered bridged heterocycloalkyl, whose ring atoms are nitrogen and carbon atoms, is substituted with one or more R ２４ is replaced by And R ２ , R ２’ and R ３ is not simultaneously hydrogen, or a pharmaceutically acceptable salt thereof.

4. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２２’ is C １ ~C ４ alkyl; or R ２２’ are each independently selected from methyl; A compound of formula (I) or a pharmaceutically acceptable salt thereof:

5. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R １ and R １’ are each independently selected from hydrogen or fluorine, Or, R １ and R １’ are all selected from hydrogen, Or, R １ is selected from hydrogen, and R １’ is selected from fluorine, Or, R １ is selected from fluorine, and R １’ is selected from hydrogen, A compound of formula (I) or a pharmaceutically acceptable salt thereof:

6. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２ , R ２’ and R ３ are each independently hydrogen, 【Chemistry 13】 and 5- or 6-membered monoheterocyclyl whose ring atoms are nitrogen and carbon atoms, wherein the 5- or 6-membered monoheterocyclyl whose ring atoms are nitrogen and carbon atoms is selected from the group consisting of 7-, 8-, or 9-membered fused heterocyclyl, 7- or 8-membered bridged heterocyclyl whose ring atoms are nitrogen and carbon atoms, wherein the 5- or 6-membered monoheterocyclyl whose ring atoms are nitrogen and carbon atoms is selected from the group consisting of one or more R ２２ and optionally one or more R ２２’ where: 【Chemistry 14】 or a 7-, 8-, or 9-membered fused heterocyclyl optionally has one or more R ２３ wherein said 7- or 8-membered bridged heterocyclyl, whose ring atoms are a nitrogen atom and a carbon atom, is substituted with one or more R ２４ is replaced by And R ２ , R ２’ and R ３ does not simultaneously become hydrogen, Or, R ２ , R ２’ and R ３ are each independently hydrogen, 【Chemistry 15】 and 5- or 6-membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms, wherein the 5- or 6-membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms is selected from the group consisting of 7-, 8-, or 9-membered fused heterocycloalkyl, 7- or 8-membered bridged heterocycloalkyl whose ring atoms are nitrogen and carbon atoms, wherein the 5- or 6-membered monoheterocycloalkyl whose ring atoms are nitrogen and carbon atoms is selected from the group consisting of one or more R ２２ and optionally one or more R ２２’ where: 【Chemistry 16】 or a 7-, 8-, or 9-membered fused heterocycloalkyl optionally having one or more R ２３ wherein said 7- or 8-membered bridged heterocycloalkyl, whose ring atoms are nitrogen and carbon atoms, is substituted with one or more R ２４ is replaced by And R ２ , R ２’ and R ３ does not simultaneously become hydrogen, Or, R ２ , R ２’ and R ３ are each independently hydrogen, 【Chemistry 17】 Pyrrolidinyl, piperidinyl, and piperazinyl wherein said pyrrolidinyl, piperidinyl or piperazinyl is selected from the group consisting of one or more R ２２ and optionally one or more R ２２’ wherein said [Chemistry 18] is one or more R ２３ wherein said 【Chemistry 19】 is one or more R ２４ is replaced by And R ２ , R ２’ and R ３ does not simultaneously become hydrogen, Or, R ２ , R ２’ and R ３ are each independently hydrogen, 【Chemistry 20】 wherein said 【Chemistry 21】 is one or more R ２２ and optionally one or more R ２２’ wherein said 【Chemistry 22】 optionally one or more R ２３ wherein said 【Chemistry 23】 is one or more R ２４ is replaced by And R ２ , R ２’ and R ３ does not become hydrogen at the same time, A compound of formula (I) or a pharmaceutically acceptable salt thereof:

7. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２ , R ２’ and R ３ are each independently hydrogen, 【Chemistry 24】 【Chemistry 25】 and R ２ , R ２’ and R ３ does not become hydrogen at the same time, A compound of formula (I) or a pharmaceutically acceptable salt thereof:

8. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２２ is selected from the group consisting of 4- or 5-membered heterocyclyl, wherein said 4- or 5-membered heterocyclyl optionally comprises one or more 【Chemistry 26】 is replaced by Or, R ２２ is selected from 4- or 5-membered heterocycloalkyl, wherein said 4- or 5-membered heterocycloalkyl optionally comprises one or more 【Chemistry 27】 is replaced by Or, R ２２ teeth 【Chemistry 28】 Selected from the group consisting of: A compound of formula (I) or a pharmaceutically acceptable salt thereof:

9. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２２ teeth 【Chemistry 29】 Selected from the group consisting of: A compound of formula (I) or a pharmaceutically acceptable salt thereof:

10. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２２’ is deuterium or C １ ~C ４ selected from the group consisting of alkyl, Or, R ２２’ is selected from deuterium or methyl; A compound of formula (I) or a pharmaceutically acceptable salt thereof:

11. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２３ teeth 【Transformation 30】 C １ ~C ４ Alkyl, C １ ~C ４ Alkylsulfonyl, and C １ ~C ４ alkyl acyls, Or, R ２３ teeth 【Chemistry 31】 CH ３ -, CH ３ S (O) ２ -, and CH ３ C(O)—, A compound of formula (I) or a pharmaceutically acceptable salt thereof:

12. 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, R ２４ is C １ ~C ４ Alkyl acyl-N(C １ ~C ４ alkyl)-, Or, R ２４ is CH ３ C(O)N(CH ３ ) - selected from A compound of formula (I) or a pharmaceutically acceptable salt thereof:

13. A compound or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 Selected from the group consisting of: A compound or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for treating an Akt kinase-mediated disease.

16. 16. The compound or a pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 15, wherein the Akt kinase-mediated disease is selected from cancer.

17. The Akt kinase-mediated disease is selected from prostate cancer or endometrial cancer; 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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