Nitrogen-containing heterocyclic compounds with Nrf2 activating effect and their uses

Abstract

Provide a compound of formula (1) having an Nrf2 activation energy, or a salt thereof or a solvate thereof. In the formula, Xa1 is CRa1 or N, Xa3 is CRa3 or N, Ra1, Ra2 and Ra3 are each independently selected from the group consisting of hydrogen, halogen and C1-C6 alkoxy, Xb1, Xb2 and Xb3 are each independently selected from the group consisting of CH2, O, NH, S and C=O, Y is a C6-C10 aryl group that may also have substituents or a 5-10 heteroaryl group that may also have substituents, and Z is a C6-C10 aryl group that may also have substituents, a 5-10 heteroaryl group that may also have substituents or a C1-C6 alkyl group that may also have substituents.

Description

Technical Field

[0001] This invention relates to nitrogen-containing heterocyclic compounds or their salts or solvates having Nrf2 activating properties, and their uses. Furthermore, it relates to pharmaceuticals and pharmaceutical compositions containing these as active ingredients. Prior Technology

[0002] Nrf2 is a regulator of a wide variety of biological defense genes and a transcription factor activated in response to oxidative stress. Under normal conditions, Nrf2 binds to Keap1 and is ubiquitinated and broken down via the protease pathway. However, under stress, it is released from Keap1, escapes degradation, and migrates into the cell nucleus. Subsequently, Nrf2 forms a heterodimer with small Maf factors, binding to antioxidant response elements (AREs) and inducing the transcription of downstream molecules.

[0003] In addition to its antioxidant effects, Nrf2 activation has demonstrated a wide range of pharmacological effects, including anti-inflammatory, anti-fibrotic, and anti-apoptosis effects, suggesting a protective effect against a variety of diseases. Specific examples of these diseases include: neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's dyskinesia, and amyotrophic lateral sclerosis; lung diseases such as acute pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary hypertension, and asthma; kidney diseases such as chronic nephropathy and acute nephropathy; ophthalmological diseases such as uveitis, glaucoma, and age-related macular degeneration; liver diseases such as non-alcoholic steatohepatitis; and immune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and ulcerative colitis (Non-Patent Literature 3-7). In fact, bardoxolone methyl (CDDO-Me, Patent Document 1), a compound with Nrf2 activation induction activity, has been used in clinical trials for various chronic kidney diseases, and RTA-408 (omaveloxolone, Patent Document 2) has been used for Friedreich's ataxia. Dimethyl fumarate (Patent Document 3) has been used as a treatment for multiple sclerosis. However, these compounds are covalently bonded to Keap1. There have been reports of a risk of heart failure arising from interactions between the covalently bonded sites of bardoxolone and non-target proteins (Non-Patent Document 8).

[0004] To date, compounds described in Patent Document 4 and others have been reported as Nrf2 activators. However, they have not yet reached the stage of clinical development, and there is a desire to develop non-covalently bonded Nrf2 activators that can reduce interactions with non-target proteins (Non-Patent Documents 1-3). [Preliminary Technology Documents] [Patent Literature]

[0005] [Patent Document 1] International Publication No. 1999 / 065478 [Patent Document 2] International Publication No. 2014 / 176415 [Patent Document 3] International Publication No. 2016 / 090154 [Patent Document 4] International Publication No. 2020 / 165776 [Non-patent literature]

[0006] [Non-patent literature 1] Med Chem Commun, 2017, 8, 286-294. [Non-Patent Literature 2] Medicinal Chemistry Research, 2020, 29, 846-867. [Non-patent literature 3] Nature Reviews Drug Discovery, 2019, 18, 295-317. [Non-Patent Literature 4] Oxydative Medicine and Cellular Longevity, 2019, Article ID 9372182, 1-20. [Non-Patent Literature 5] Neurodegenr Dis Manag, 2017, 7, 97-100. [Non-Patent Literature 6] Oxydative Medicine and Cellular Longevity, 2019, Article ID 7090534, 1-17. [Non-Patent Literature 7] Oxydative Medicine and Cellular Longevity, 2020, Article ID 9410952, 1-22. [Non-Patent Literature 8] Am J Nephrol, 2014, 39, 499-508 Summary of the Invention

[0007] [The problem the invention aims to solve]

[0008] The object of this invention is to provide low-molecular-weight compounds or their salts or solvates that have an activation energy of Nrf2 and reduce interactions between covalently bonded and non-target proteins. Furthermore, it is possible to provide preventative or therapeutic agents for various diseases, such as neurodegenerative diseases, lung diseases, and kidney diseases, containing these as active ingredients. [Technical methods used to solve the problem]

[0009] In order to solve this problem, the inventors have conducted intensive research and discovered that compounds having a basic skeleton as shown in formula (I), which are chemically significantly different from well-known Nrf2 activators, or their pharmacologically permissible salts or solvates, have excellent Nrf2 activating effects, thus completing the present invention.

[0010] That is, one aspect of the present invention provides the following invention. [1] A compound of formula (1) or a salt thereof or a solvate thereof, formula (1): [Chemistry 1] [In the formula, X a1 is either CR a1 or N, X a3 is either CR a3 or N. Ra1, Ra2, and Ra3 each independently choose from groups consisting of free hydrogen, halogens, and C1-C6 alkoxy groups. Xb1, Xb2, and Xb3 each independently choose a group composed of CH2, O, NH, S, and C=O. Y is a C6-C10 aryl or a 5-10 heteroaryl group, wherein the aforementioned C6-C10 aryl and 5-10 heteroaryl groups may also be substituted by one or more groups selected from the group consisting of Ry1, Ry2, Ry3, Ry4 and Ry5. The aforementioned Ry1, Ry2, Ry3, Ry4, and Ry5 are each independently chosen from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4-10 member heterocyclic C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4-10 member heterocyclic oxy, C1-C6 alkylamino C1-C6 alkoxy, 5-10 member heteroaryloxy, C1-C6 alkylthio, 4-10 member saturated heterocyclic groups with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic groups with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member heteroaryl groups and C1-C6 alkyl (C1-C6 alkoxy C ... The group consisting of 6-alkyl)amino groups, Z is a C6-C10 aryl, 5-10 heteroaryl, or C1-C6 alkyl group. The aforementioned C6-C10 aryl, 5-10 heteroaryl, and C1-C6 alkyl groups may also be substituted by Rz3, and may also be substituted by one or more groups selected from the group consisting of Rz1, Rz2, Rz4, and Rz5. R z3 is a base selected from the following substituent group A: [Chemistry 2] In the formula, The wavy line represents the bond points with the aforementioned C6-C10 aryl, 5-10 heteroaryl, or C1-C6 alkyl groups. R5 is a hydroxyl group, a C1-C6 alkoxy group, a mono- or di-C1-C6 alkylamino group, or a C1-C6 alkylsulfonylamino group. n is 1 or 2, R z1, R z2, R z4 and R z5 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl (5-10 member heteroaryl C1-C6 alkyl) amino group (4-10 member heterocyclic) amino group (4-8 member cyclic) amino group (4-8 member cyclic) amino group (4-8 member cyclic) amino group (4-10 ...5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group ( [2] The compound described in [1] or its salt or solvate thereof, wherein Xb1 is CH2, Xb2 is CH2, O, NH or C=O, and Xb3 is CH2, O, NH, S or C=O. [3] The compounds described in [1] or [2], or their salts or solvates, Xb1 and Xb2 are CH2, Xb3 is O, or Xb1 and Xb3 are CH2, Xb2 is O, or Xb1 and Xb2 are CH2, Xb3 is S, or X b1 is CH 2, X b2 is NH, X b3 is C=O, or Xb1 and Xb2 are CH2, Xb3 is NH, or X b1 is CH 2, X b2 is C=O, X b3 is NH, or Xb1 and Xb3 are CH2, Xb2 is NH, or Xb1, Xb2 and Xb3 are CH2. [4] The compound described in any of [1] to [3] or its salt or solvate, X a1 is CR a1, X a3 is CR a3 or N. [5] The compound described in any of [1] to [4], or its salt or solvate, wherein Z is phenyl, pyridyl or C2-C5 alkyl, and the aforementioned phenyl, pyridyl or C2-C5 alkyl may also be substituted by Rz3, and may be substituted by one or more groups selected from the group consisting of Rz1, Rz2, Rz4 and Rz5. R z3 is a base selected from the following substituent group B: [Chemistry 3] In the formula, The wavy line represents the bond point with the aforementioned phenyl, pyridyl, or C2-C5 alkyl groups. R5 is a hydroxyl, C1-C6 alkoxy, mono-C1-C6 alkylamine, or C1-C6 alkylsulfonylamine group. R z1, R z2, R z4 and R z5 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl (5-10 member heteroaryl C1-C6 alkyl) amino group (4-10 member heterocyclic) amino group (4-8 member cyclic) amino group (4-8 member cyclic) amino group (4-8 member cyclic) amino group (4-10 ...5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group (4-10 member cyclic) amino group (5-10 member cyclic) amino group ( [6] The compounds described in any of [1] to [5], or their salts or solvates, wherein Rz1, Rz2 and Rz5 are each independently chosen from the group consisting of hydrogen, halogens and C1-C6 alkyl groups. R z4 may be a C1-C6 alkyl (5-10 member heteroaryl C1-C2 alkyl) amino group, a C1-C6 alkyl (4-10 member heterocyclic) amino group, or a 4-8 member cyclic amino group, which may also have substituents. [7] The compound described in any of [1] to [6], or its salt or solvate, wherein Y is phenyl or 6-10 heteroaryl, and the aforementioned phenyl and 6-10 heteroaryl groups may also be substituted by one or more groups selected from the group consisting of Ry1, Ry2, Ry3, Ry4 and Ry5. The aforementioned Ry1, Ry2, Ry3, Ry4, and Ry5 are each independently chosen to be free of hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, 5-6 member saturated heterocyclic groups with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic groups with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member heteroaryl groups and C1-C3 alkyl (C1-C3 alkoxy C1-C6) A group consisting of 2-alkyl)amino groups. [8] The compound described in any of [1] to [7], or its salt or solvate, wherein Y is phenyl or 6-10 heteroaryl, and the aforementioned phenyl and 6-10 heteroaryl groups may be substituted with Ry3 by a group other than hydrogen, and may also be substituted with one or more groups selected from the group consisting of Ry1, Ry2, Ry4 and Ry5. The aforementioned Ry1, Ry2, Ry4, and Ry5 are each independently chosen from the group consisting of hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, and C1-C3 alkoxy. The aforementioned R y3 is a 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, a 5-6 member saturated heterocyclic group with a bonding hand on the carbon atom of the ring and may also have a substituent, a 4-10 member saturated heterocyclic group with a bonding hand on the nitrogen atom of the ring and may also have a substituent, or a 5-10 member heteroaryl or C1-C3 alkyl (C1-C3 alkoxy C1-C2 alkyl)amino group that may also have a substituent. [9] For any of the compounds described in [1] to [8], or their salts or solvates, Z is a base represented by the following formula (2): [Chemistry 4] [In the formula, The wavy line represents the Z-bonded nodes. R z3 is a base selected from the following substituent group B: [Chemistry 5] (in the formula, The wavy line represents a key node. R5 can be a hydroxyl group, a C1-C6 alkoxy group, a mono-C1-C6 alkylamino group, or a C1-C6 alkylsulfonylamino group. X z is CR z5 or N. Rz1, Rz2, and Rz5 are each independently selected from groups consisting of free hydrogen, halogens, and C1-C6 alkyl groups. R z4 can be a C1-C6 alkyl (5-10 member heteroaryl C1-C2 alkyl) amino group, a C1-C6 alkyl (4-10 member heterocyclic) amino group, or a 4-8 member cyclic amino group, which may also have substituents.

[10] For any of the compounds described in [1] to [9], or their salts or solvates, Y is a base represented by the following formula (3): [Chemistry 6] [In the formula, The wavy line represents the Y-bond nodes. X y1 is CR y3 or N, X y2 is CR y4 or N, X y3 is CR y5 or N, Ry1 and Ry5 are each independently selected from the group consisting of hydrogen, halogen, cyano, and C1-C3 alkyl groups. Ry2 and Ry4 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, and C1-C3 alkoxy. R y3 can be a 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, a 5-6 member saturated heterocyclic group with a bonding hand on the carbon atom of the ring and may also have substituents, a 4-10 member saturated heterocyclic group with a bonding hand on the nitrogen atom of the ring and may also have substituents, or a 5-10 member heteroaryl or C1-C3 alkyl (C1-C3 alkoxy C1-C2 alkyl)amino group, or a 5-6 member heteroaryl group, or a C1-C3 alkyl (C1-C3 alkoxy C1-C2 alkyl)amino group, When Xy1 is CRy3, Ry2 and Ry3 can also form 5- or 6-membered heteroaryl rings together with the bonded carbon atoms. When Xy1 is CRy3 and Xy2 is CRy4, Ry3 and Ry4 can also form 5- or 6-membered heteroaromatic rings together with the bonded carbon atoms. When Xy2 is CRy4 and Xy3 is CRy5, Ry4 and Ry5 can also form 5- or 6-membered heteroaromatic rings together with the bonded carbon atoms.

[11] The compound described in any of [1] to

[10] , or its salt or solvate, is a base represented by formula (4): [Chemistry 7] [In the formula, X a3 is either CR a3 or N. Ra1, Ra2, and Ra3 each independently choose from groups consisting of hydrogen, halogens, and C1-C6 alkoxy groups. Xb1 and Xb2 are CH2, Xb3 is O, or Xb1 and Xb3 are CH2, Xb2 is O, or Xb1 and Xb2 are CH2, Xb3 is S, or X b1 is CH 2, X b2 is NH, X b3 is C=O, or Xb1 and Xb2 are CH2, Xb3 is NH, or X b1 is CH 2, X b2 is C=O, X b3 is NH, or Xb1 and Xb3 are CH2, Xb2 is NH, or Xb1, Xb2, and Xb3 are CH2. X y1 is CR y3 or N, X y2 is CR y4 or N, X y3 is CR y5 or N, Ry1 and Ry5 are each independently selected from the group consisting of hydrogen, halogen, cyano, and C1-C3 alkyl groups. Ry2 and Ry4 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, and C1-C3 alkoxy. R y3 is selected from the group consisting of 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, 5-6 member saturated heterocycles with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic groups with a bonding hand on the nitrogen atom of the ring and may also have substituents, and 5-10 member heteroaryl or C1-C3 alkyl (C1-C3 alkoxy C1-C2 alkyl)amino groups that may also have substituents. When Xy1 is CRy3, Ry2 and Ry3 can also form 5- or 6-membered heteroaromatic rings together with the bonded carbon atoms. When Xy1 is CRy3 and Xy2 is CRy4, Ry3 and Ry4 can also form 5- or 6-membered heteroaromatic rings together with the bonded carbon atoms. When Xy2 is CRy4 and Xy3 is CRy5, Ry4 and Ry5 can also form 5- or 6-membered heteroaromatic rings together with the bonded carbon atoms. R z3 represents the following substituent group B: [Chemistry 8] (in the formula, The wavy line represents the bond node of the loop with the aforementioned Rz3 and Rz3 bonds. R5 can be a hydroxyl group, a C1-C6 alkoxy group, a mono-C1-C6 alkylamino group, or a C1-C6 alkylsulfonylamino group. X z is CR z5 or N. Rz1, Rz2, and Rz5 are each independently selected from groups consisting of free hydrogen, halogens, and C1-C6 alkyl groups. R z4 can be a C1-C6 alkyl (5-10 member heteroaryl C1-C2 alkyl) amino group, a C1-C6 alkyl (4-10 member heterocyclic) amino group, or a 4-8 member cyclic amino group, which may also have substituents.

[12] The compound described in any of [1] to

[11] or its salt or solvate thereof, wherein Xb1 and Xb2 are CH2 and Xb3 is O.

[13] The compound described in any of [1] to

[12] or its salt or solvate, wherein R5 is a hydroxyl group or a C1-C6 alkylsulfonylamine group.

[14] The compound described in any of [1] to

[13] or its salt or solvate thereof, wherein X z is CR z5, and R z1, R z2 and R z5 are each independently chosen from the group consisting of hydrogen, fluorine, chlorine, methyl and ethyl.

[15] The compound described in any of [1] to

[14] or its salt or solvate, Rz4 may be a 4-6 member cyclic amine group having one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 alkoxy, or a 4-6 member cyclic amine group having a crosslinking group on the ring selected from the group consisting of C1-C2 alkyl and C1-C2 alkyl containing one oxygen atom.

[16] The compound described in any of [1] to

[14] or its salt or solvate, R z4 may be a C1-C3 alkyl (5-6 member heteroaryl C1-C2 alkyl) amino group having a substituent selected from the group consisting of hydrogen, halogen and C1-C6 alkyl, or a C1-C3 alkyl (4-6 member heterocyclic) amino group having a substituent selected from the group consisting of hydrogen, halogen and C1-C6 alkyl.

[17] The compound described in any of [1] to

[16] or its salt or solvate, wherein Ry1 is chlorine, Xy1 is CRy3, Xy2 is CRy4, Xy3 is CRy5, Ry3 is a 4-10 member saturated heterocyclic group with a bonding chirp on the nitrogen atom of the ring and may also have substituents or a 5-10 member heteroaryl group, and Ry2, Ry4 and Ry5 are hydrogen.

[18] The compound described in any of [1] to

[17] or its salt or solvate, Ra1 is hydrogen or fluorine, Ra2 is hydrogen or methoxy, and Ra3 is hydrogen or fluorine.

[19] The compound described in any of [1] to

[18] , or a salt thereof or a solvate thereof, wherein R z4 is 3-oxa-8-azabicyclo[3.2.1]oct-8-yl, morpholine-4-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, (2S,3S)-3-methoxy-2-methylazetidine-1-yl, 1,3,3a,4,6,6a-hexahydrofuro. [3,4-c]pyrrolo-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolodin-1-yl, piperin-1-yl, methyl(1,2-oxazole-3-ylmethyl)amino, methyl(oxetane-3-yl)amino, methyl-[(3R)-oxolane-3-yl]amino or methyl-(3-methyloxetane-3-yl)amino.

[20] The compound described in any of [1] to

[19] , or its salt or solvate, R y3 is 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl, 4-methylpiperyl, (2R)-2,4-dimethylpiperyl, 6-methoxy-2-azaspiro[3.3]hept-2-yl, 4-(2-methoxyethyl)piperyl, 3-methoxyacetyl-1-yl, 4-(oxacyclobutane-3-yl)piperyl, 2-oxa-6-azaspiro[3.3]hept-6-yl, (2R,5R)-2,4,5-trimethylpiperyl, 4-(2-hydroxy-2-methylpropyl)piperyl or mofolin-4-yl.

[21] A compound or a salt thereof or a solvate thereof, selected from the following compounds: compound 17-1, compound 17-2, compound 17-3, compound 17-4, compound 17-5, compound 17-8, compound 17-9, compound 17-10, compound 17-15, compound 17-16, compound 17-23, compound 1-1, compound 1-2, compound 1-3, compound 1-4, compound 1-5, compound 1-6, compound 1-7, compound 1-8, compound 1-9, compound 1-10, compound 1-11, compound 1-12, compound 1-13, compound 1-14, compound 1-15, compound 1-16, compound 1-1 7. Compounds 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-30, 1-31, 1-32, 1-33, 1-34, 1-35, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45, 1-46, 1-47, 1-48, 1-49, 1-50 Compounds 1-51, 1-52, 1-53, 1-54, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70, 1-71, 1-72, 1-73, 1-74, 1-75, 1-76, 1-77, 1-78, 1-79, 1-80, 1-81 Compounds 1-82, 1-83, 1-84, 1-85, 1-86, 1-87, 1-88, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20Compounds 3-21, 3-22, 3-23, 3-24, 3-25, 3-26, 3-27, 3-28, 4-1, 4-2, 4-3, 4-4, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19, 4-20, 4-21, 4-22, 4-23, 4-24, and other compounds. Compounds 4-25, 4-26, 4-27, 4-28, 4-29, 4-30, 4-31, 4-32, 4-33, 4-34, 4-35, 4-36, 4-37, 4-38, 4-39, 4-40, 4-41, 4-42, 4-43, 4-44, 4-45, 4-46, 4-47, 4-48, 4-49, 4-50, 4-51, 4-52, 4-53, 4-54, and 4-55. Compounds 4-56, 4-57, 4-58, 4-59, 4-60, 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-14, 5-15, 5-16, 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-1 3. Compounds 7-1, 7-2, 7-3, 7-4, 7-5, 7-6, 7-7, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-14, 7-15, 7-16, 7-17, 7-18, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-9, 9-1, 9-2, 9-3, 9-4, 9-5, 9-6, 9-7.Compounds 9-8, 9-9, 9-10, 9-11, 9-12, 9-13, 9-14, 9-15, 9-16, 9-17, 9-18, 9-19, 9-20, 9-21, 9-22, 9-23, 9-24, 9-25, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 10-7, 10-8, 10-9, 10-10, 10-11, 10-12, 10-13 Compounds 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 11-8, 11-9, 11-10, 12-1, 12-2, 12-3, 12-4, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-7, 13-8, 13-9, 13-10, 13-11, 13-12, 13-13, 13-14, 13-15, 13-16, and others. Compounds 13-17, 13-18, 13-19, 13-20, 13-21, 14-1, 14-2, 14-3, 14-4, 14-5, 14-6, 14-7, 14-8, 14-9, 15-1, 15-2, 15-3, 15-4, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-7, 16-8, 16-9, 16-10, 16-11, 16-12, and 16-16. Compounds 16-13, 16-14, 16-15, 16-16, 16-17, 17-18, 17-21, 18-1, 18-2, 18-3, 18-4, 18-5, 18-6, 18-7, 18-8, 18-9, 18-10, 18-11, 18-12, 19-2, 19-3, 19-4, 19-5, 19-6, 19-7, 19-8, 19-9, 19-10, 19-11, 19-12Compounds 19-13, 19-14, 19-15, 19-16, 19-17, 19-18, and 19-19.

[22] A compound or a salt thereof or a solvate thereof, selected from the following compounds: Compounds 1-4, 1-18, 1-21, 1-33, 1-54, 1-83, 1-88, 2-2, 4-8, 4-37, 5-1, 5-2, 5-7, 5-9, 5-10, 5-16, 7-2, 13-16, 13-21, 14-1, 19-9, and 19-15.

[23] A pharmaceutical composition comprising any of the compounds described in [1] to

[22] , or salts thereof, or solvates thereof.

[24] The pharmaceutical composition described in

[23] is used for the prevention and / or treatment of neurodegenerative diseases, lung diseases, or kidney diseases.

[25] A method for the prevention and / or treatment of a neurodegenerative disease, a lung disease, or a kidney disease, comprising administering an effective amount of any of the compounds described in [1] to

[22] or a salt thereof or a solvate thereof to the subject.

[26] Use of a compound described in any of [1] to

[22] or a salt thereof or a solvate thereof for the prevention and / or treatment of neurodegenerative diseases, lung diseases or kidney diseases.

[27] Use of a compound described in any of [1] to

[22] or a salt thereof or a solvate thereof for the preparation of a pharmaceutical composition for the prevention and / or treatment of neurodegenerative diseases, lung diseases or kidney diseases.

[28] 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylacetyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[29] 4-[3-[2,6-dichloro-4-(7-oxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[30] 4-[3-[2,6-dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl]benzoic acid or a salt thereof, or a solvate thereof.

[31] 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl]benzoyl]-2,4-dihydro-1,3-benzoyl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[32] 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl]-5-fluoro-2-morphofolin-4-ylbenzoic acid or a salt thereof, or a solvate thereof.

[33] 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid or a salt thereof, or a solvate thereof.

[34] 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[35] 4-[3-[2,6-dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[36] 4-[3-[2,6-dichloro-4-(4-ethylpiperyl-1-yl)benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[37] 4-[3-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[38] 4-[3-[2,6-dichloro-4-(3,3-dimethoxyacryl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[39] 4-[3-[2,6-dichloro-4-(5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[40] 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[41] 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[42] 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azabispiro[3.1.56.14]dodec-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[43] 4-[3-[2,6-dichloro-4-(3,3-dimethoxyacryl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[44] 4-[3-[2,6-dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid or a salt thereof, or a solvate thereof.

[44] 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid or a salt thereof, or a solvate thereof.

[45] 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[46] 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoyl]-2-morphofolin-4-ylbenzoic acid or a salt thereof, or a solvate thereof.

[47] 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)-2-methylpyridin-3-carbonyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[48] ​​4-[3-[5-chloro-7-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

[49] 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylacet-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-2-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[50] 4-[3-[2,6-dichloro-4-(7-oxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[51] 4-[3-[2,6-dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl]benzoic acid.

[52] 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[53] 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid.

[54] 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[55] 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[56] 4-[3-[2,6-dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[57] 4-[3-[2,6-dichloro-4-(4-ethylpiperyl-1-yl)benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[58] 4-[3-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzo[3-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[59] 4-[3-[2,6-dichloro-4-(3,3-dimethoxyacryl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[60] 4-[3-[2,6-dichloro-4-(5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[61] 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[62] 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[63] 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azabispiro[3.1.56.14]dodec-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[64] 4-[3-[2,6-dichloro-4-(3,3-dimethoxyacryl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[65] 4-[3-[2,6-dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid.

[66] 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[67] 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[68] 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoyl]-2-morpholin-4-ylbenzoic acid.

[69] 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)-2-methylpyridin-3-carbonyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[70] 4-[3-[5-chloro-7-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

[71] 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylacetyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[72] 4-[3-[2,6-dichloro-4-(7-oxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[73] 4-[3-[2,6-dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[74] 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[75] 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid hydrate.

[76] 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[77] 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[78] 4-[3-[2,6-dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[79] 4-[3-[2,6-dichloro-4-(4-ethylpiperyl-1-yl)benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[80] 4-[3-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[81] 4-[3-[2,6-dichloro-4-(3,3-dimethoxyacryl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[82] 4-[3-[2,6-dichloro-4-(5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[83] 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[84] 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl] hydrate of benzoic acid.

[85] 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azabispiro[3.1.56.14]dodec-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[86] 4-[3-[2,6-dichloro-4-(3,3-dimethoxyacryl-1-yl)benzoyl]-2,4-dihydro-1,3-benzoyl]-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[87] 4-[3-[2,6-dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[88] 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[89] 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate.

[90] 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoyl]-2-morpholin-4-ylbenzoic acid hydrate.

[91] 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)-2-methylpyridin-3-carbonyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a hydrate thereof.

[92] 4-[3-[5-chloro-7-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzo[3-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid hydrate. [Invention Effects]

[0011] According to the compounds of the present invention or their pharmacologically permissible salts or solvates thereof, preventive or therapeutic agents are provided for various diseases, such as neurodegenerative diseases, lung diseases, and kidney diseases, which have Nrf2 activating activity. Simple Explanation of the Diagram

[0012] none. Implementation

[0013] The following shows the definitions of symbols, terms, etc., recorded in this specification, the embodiments of the present invention, etc., and describes the present invention in detail.

[0014] Examples of "halogens" in this specification include F, Cl, Br, or I.

[0015] In this specification, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing one arbitrary hydrogen atom, whose skeleton does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds, and which has a hydrocarbon group (hydrocarbyl) or hydrocarbon group structure containing hydrogen and carbon atoms. Alkyl groups can be straight-chain or branched-chain. As alkyl groups, those with 1 to 20 carbon atoms (C1 to C20, hereinafter "CpCq" means p to q carbon atoms) are preferred, C1 to C10 alkyl groups are more preferred, and C1 to C6 alkyl groups are even more preferred. Specifically, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, tributyl, isobutyl (2-methylpropyl), n-pentyl, dipentyl (1-methylbutyl), tripentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, etc.

[0016] In this specification, "alkenyl" refers to a monovalent group having at least one double bond (two adjacent sp 2 carbon atoms). Depending on the configuration of the double bond and substitutions (where present), the geometry of the double bond can be trans-sideways (E) or unilateral (Z), cis- or trans-. Alkenyl groups can be linear or branched. C2-C10 alkenyl groups are preferred, and C2-C6 alkenyl groups are more preferred. Specific examples include, for instance, ethylene, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, etc.

[0017] In this specification, "alkynyl" refers to a monovalent group having at least one tandem bond (two adjacent sp carbon atoms). Alynyl groups are not only linear but also branched. C2-C10 alkynyl groups are preferred examples, and C2-C6 alkynyl groups are more preferred. Specific examples include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentyynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0018] In this specification, "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic groups. C3-C8 cycloalkyl groups are preferred examples. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclic [2.2.1]heptyl, spiro [3.3]heptyl, etc.

[0019] In this specification, "cycloalkylalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are replaced by the aforementioned "cycloalkyl". Preferably, the cycloalkylalkyl group is a C3-C8 cycloalkyl or a C1-C6 cycloalkyl group, and more preferably a C3-C6 cycloalkyl or a C1-C2 cycloalkyl group. Specific examples of cycloalkylalkyl groups include, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0020] In this specification, "aminoalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are replaced by an "amino" group as defined below. Preferably, the aminoalkyl group is an amino C1-C6 alkyl group. Examples of aminoalkyl groups include, for instance, 1-pyridylmethyl, 2-(1-piperidinyl)ethyl, 3-(1-piperidinyl)propyl, and 4-aminobutyl.

[0021] In this specification, "protected aminoalkyl" refers to a group in which the amino group contained in the aforementioned definition of "aminoalkyl" is protected by any protecting group. Specific examples of protecting groups for the amino group include Fmoc, Boc, Cbz, Alloc, Teoc, trifluoroacetyl, pentafluoropropionic acid, phthalyl, tosyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, and 2,4-dinitrobenzenesulfonyl.

[0022] In this specification, "hydroxyalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are replaced by hydroxyl groups. Preferably, hydroxy C1-C6 alkyl groups are listed as hydroxyalkyl groups. Specific examples of hydroxyalkyl groups include, for instance, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 5-hydroxypentyl, etc.

[0023] In this specification, "haloalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are substituted with halogens. Preferably, C1-C6 haloalkyl, and more preferably C1-C6 fluoroalkyl. Specific examples of haloalkyl groups include, for instance, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, and 5,5-difluoropentyl.

[0024] In this specification, "carboxyalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are replaced by a carboxyl group. C1-C6 carboxyalkyl groups are preferred examples. Carboxymethyl groups are specifically examples of carboxyalkyl groups.

[0025] In this specification, "aryl" refers to a monovalent aromatic hydrocarbon ring and an aromatic hydrocarbon cyclic group. Preferably, C6-C10 aryl groups are listed. Specifically, examples include phenyl and naphthyl (e.g., 1-naphthyl, 2-naphthyl).

[0026] In this specification, "heterocyclic group" refers to a non-aromatic, cyclic, monovalent group containing 1 to 5 heteroatoms in addition to a carbon atom. The heterocyclic group may have double bonds and / or triple bonds in the ring, and the carbon atom in the ring may be oxidized to form a carbonyl group. It can be a monocyclic or condensed ring. In the case of a condensed ring, it can also form a condensed ring with aromatic rings such as benzene, pyridine, and pyrimidine. It can also form a condensed ring with saturated alicyclic rings such as cyclopentane and cyclohexane, tetrahydropiperanone, dialkyl, and pyrrolidine rings. The number of atoms in the ring constituting the heterocyclic group is preferably 4 to 10 (4 to 10-membered heterocyclic group), more preferably 4 to 7 (4 to 7-membered heterocyclic group).As heterocyclic groups, specific examples include, for instance, azetidinyl, ethoxylated azetidinyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropiperanyl, tetrahydropiperanyl, tetrahydropyridyl, tetrahydropyrimidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, ethoxylated pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, and isotetrahydrothiazolidinyl. isothiazolidinyl, 1,2-thiazinane, thiadiazolidinyl, oxazolidonyl, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo[1,2-c]imidazolyl, thietanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octyl [3.2.1]octanyl), 2,4,5-trimethylpiperyl-1-yl, sultam, 2-oxaspiro[3.3]heptyl, 6,7-dihydropyrrolo[1,2-a]imidazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, azepanyl, dioxepanyl, 5,9-dioxaspiro[3.5]nonyl, etc.

[0027] In this specification, "heteroaryl" refers to an aromatic cyclic monovalent group, or an aromatic heterocyclic group, containing 1 to 5 heteroatoms in addition to a carbon atom. The ring can be monocyclic, condensed with other rings, or partially saturated. The number of atoms in the ring constituting the heteroaryl is preferably 5 to 10 (5 to 10-membered heteroaryl), more preferably 5 to 7 (5 to 7-membered heteroaryl). As heteroaryl groups, specific examples include, for instance, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, and benzothiazolyl. (benzothiazolyl), benzoxazolyl, benzoxadiazolyl, benzoimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, pyrrolopyridyl, furopyridinyl, etc.

[0028] In this specification, "arylalkyl" refers to a group in which at least one hydrogen atom of the aforementioned "alkyl" is replaced by the aforementioned "aryl". Preferably, the arylalkyl group is a C7-C14 arylalkyl group, and more preferably a C7-C10 arylalkyl group. Specific examples of arylalkyl groups include, for example, benzyl, phenethyl, and 3-phenylpropyl.

[0029] In this specification, "heteroarylalkyl" refers to a group in which at least one hydrogen atom of the aforementioned "alkyl" is replaced by the aforementioned "heteroaryl". Preferably, it is a 5- to 10-membered heteroaryl C1-C6 alkyl, more preferably a 5- to 10-membered heteroaryl C1-C2 alkyl. Specific examples of heteroarylalkyl groups include, for instance, 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolinyl)ethyl, 2-(7-quinolinyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0030] In this specification, "heterocyclic alkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are replaced by the aforementioned "heterocyclic group". Preferably, the heterocyclic alkyl group is a 4- to 7-membered heterocyclic C1-C6 alkyl group, more preferably a 4- to 7-membered heterocyclic C1-C2 alkyl group. Specific examples of heterocyclic alkyl groups include, for instance, 2-(tetrahydro-2H-piperan-4-yl)ethyl, 2-(acet-3-yl)ethyl, and 4-(oxacyclopentan-2-ylmethyl)piperyl-1-yl.

[0031] In this specification, "saturated heterocyclic group" refers to a non-aromatic, cyclic, monovalent group containing 1 to 5 heteroatoms in addition to a carbon atom. Saturated heterocyclic groups may have double bonds and / or triple bonds in the ring, and the carbon atoms in the ring may be oxidized to form a carbonyl group. Saturated heterocyclic groups can be monocyclic or can form condensation rings with other rings, such as aromatic rings (e.g., benzene rings, pyridine rings, pyrimidine rings), saturated alicyclic rings (e.g., cyclopentane rings, cyclohexane rings), tetrahydropiperanane rings, dialkyl rings, pyrrolidine rings, etc. Preferably, 4- to 10-membered saturated heterocyclic groups are listed as examples. As saturated heterocyclic groups, specific examples include acrylyl, septyl-acrylyl, oxobutyryl, tetrahydrofuranyl, tetrahydropiperanyl, morphofolinyl, thiomorphofolinyl, pyrrolidyl, 2-septyl-pyrrolidyl, 4-septyl-pyrrolidyl, piperidinyl, 4-septyl-piperidinyl, piperidyl, pyrazolidyl, imidazodinyl, azolidinyl, isozolidyl, tetrahydrothiazolyl, and isotetrahydrothiazolyl. yl, thiadiazolyl, acezolidinone, dioxacyclopentyl, diaceyl, thiohexacyclobutyl, octahydroindolyl, indolinyl, 5,9-dioxaspiro[3.5]nonyl, 3-oxa-8-azabicyclo[3.2.1]oct-8-yl, mofolin-4-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 3-methoxy-2-methyl 1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrolo-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolo-1-yl, piperidin-1-yl, 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3,5]non-2-yl, 4-methylpiperidin-1-yl, 2,4-dimethylpiperidin-1 - yl, 6-methoxy-2-azaspiro[3.3]hept-2-yl, 4-(2-methoxyethyl)piperyl-1-yl, 3-methoxyazido-1-yl, 4-(oxacyclobutane-3-yl)piperyl-1-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2,4,5-trimethylpiperyl-1-yl, 4-(2-hydroxy-2-methylpropyl)piperyl-1-yl, etc.

[0032] In this specification, "alkoxy" refers to an alkyl-bonded alkoxy group as defined above. Preferably, C1-C6 alkoxy groups are listed. Specific examples of alkoxy groups include, for instance, methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, secondary butoxy, tertiary butoxy, pentyloxy, and 3-methylbutoxy.

[0033] In this specification, "haloalkoxy" refers to a group in which one or more hydrogen atoms of the aforementioned "alkoxy" are substituted with halogens. Preferably, C1-C6 haloalkoxy, and more preferably C1-C6 fluoroalkoxy, are examples of haloalkoxy compounds such as difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0034] In this specification, "cycloalkoxy" refers to the "cycloalkyl" bonded oxygen group as defined above. C3-C8 cycloalkoxy groups are preferred examples. Specific examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, and cyclopentyloxy.

[0035] In this specification, "alkoxyalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are substituted by the aforementioned "alkoxy". Preferably, the alkoxyalkyl group is a C1-C6 alkoxy-C1-C6 alkyl, and more preferably a C1-C6 alkoxy-C1-C2 alkyl. Specific examples of alkoxyalkyl groups include, for instance, methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, secondary butoxymethyl, tertiary butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, etc.

[0036] In this specification, "cycloalkoxyalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are substituted by the aforementioned "cycloalkoxy". Preferably, the cycloalkoxyalkyl group is a C3-C8 cycloalkoxy C1-C6 alkyl group, and more preferably a C3-C6 cycloalkoxy C1-C2 alkyl group. Specific examples of cycloalkoxyalkyl groups include, for example, cyclopropoxymethyl and cyclobutoxymethyl.

[0037] In this specification, "aryloxy group" refers to the "aryl" bonded oxygen group as defined above. Preferably, C6-C10 aryloxy groups are cited as examples. Specific examples of aryloxy groups include, for instance, phenoxy, 1-naphthyloxy, and 2-naphthyloxy groups.

[0038] In this specification, "heterocyclic oxy group" refers to the "heterocyclic" bonded oxy group as defined above. The ring constituting the heterocyclic oxy group preferably has 4 to 10 atoms (4 to 10-membered heterocyclic oxy group), more preferably 4 to 7 (4 to 7-membered heterocyclic oxy group). Specific examples of heterocyclic oxy groups include, for example, acryloxy, ethylene oxide oxy, oxobutyryloxy, acryloxy, dihydrofuranyloxy, tetrahydrofuranyloxy, dihydropiperanyloxy, tetrahydropiperanyloxy, tetrahydropyridyloxy, tetrahydropyrimidinyloxy, mofolinyloxy, thiomofolinyloxy, pyrrolidinyloxy, piperidinyloxy, piperidinyloxy, pyrazolidinyloxy, imidazolinyloxy, imidazolinyloxy, succinyloxy, isozyzolidinyloxy, tetrahydrothiazolinyloxy, isotetrahydrothiazolinyloxy, 1 ,2-thiazinyloxy, thiadiazolyloxy, oxazolidone oxy, benzodialkyloxy, benzodiazolyloxy, dioxacyclopentyloxy, dialkyloxy, tetrahydropyrrolo[1,2-c]imidazoloxy, thiocyclobutyloxy, 3,6-diazabicyclo[3.1.1]heptyloxy, 2,5-diazabicyclo[2.2.1]heptyloxy, 3-oxa-8-azabicyclo[3.2.1]octyloxy, sulopentamethoxy, 2-oxaspiro[3.3]heptyloxy, etc.

[0039] In this specification, "heteroaryloxy" refers to the "heteroaryl" bonded oxygen group as defined above. The ring containing the heteroaryloxy group preferably has 5 to 10 atoms (5 to 10 members of the heteroaryloxy group), more preferably 5 to 7 (5 to 7 members of the heteroaryloxy group). Specific examples of heteroaryloxy groups include, for instance, furanyloxy, thiophenyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, thiazolyloxy, isothiazolyloxy, succinyloxy, isosuccinyloxy, succinyldiazolyloxy, thiazolyloxy, triazolyloxy, tetrazolyloxy, pyridyloxy, pyrimidinyloxy, pyrimidinyloxy, pyrazolyloxy, triazolyloxy, and benzofuran. Benzyloxy, benzothiophenyloxy, benzothiadiazoleyloxy, benzothiazolyloxy, benzoimidazolyloxy, benzoimidazolyloxy, indoleyloxy, isoindoleyloxy, indazoleyloxy, quinolinyloxy, isoquinolinyloxy, inlinyloxy, quinazolinyloxy, quinazolinyloxy, benzodioxanepentenyloxy, indoleyloxy, imidazopyridyloxy, etc.

[0040] In this specification, "arylalkyloxy" refers to the "aryl" bonded alkyl group as defined above. Preferably, it is a C7-C14 arylalkyloxy group, and more preferably a C7-C10 arylalkyloxy group. Specific examples of arylalkyloxy groups include, for example, benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[0041] In this specification, "heteroarylalkoxy" refers to the "heteroarylalkyl" bonded oxygen group as defined above. Preferably, it is a 5- to 10-membered heteroaryl C1-C6 alkoxy, and more preferably a 5- to 10-membered heteroaryl C1-C2 alkoxy. Specific examples of heteroarylalkoxy include, for instance, 3-thienylmethoxy and 3-pyridylmethoxy.

[0042] In this specification, "arylalkyloxyalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are substituted by the aforementioned "arylalkyloxy". Preferably, it is a C7-C14 arylalkyloxyC1-C6 alkyl, and more preferably a C7-C14 arylalkyloxyC1-C2 alkyl. Specific examples of arylalkyloxyalkyl include, for instance, benzyloxymethyl and 1-(benzyloxy)ethyl.

[0043] In this specification, "heteroarylalkoxyalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are substituted by the aforementioned "heteroarylalkoxy". Preferably, it is a 5- to 10-membered heteroaryl C1-C6 alkoxy C1-C6 alkyl, more preferably a 5- to 10-membered heteroaryl C1-C2 alkoxy C1-C2 alkyl. Specific examples of heteroarylalkoxyalkyl include, for instance, 3-pyridylmethoxymethyl.

[0044] In this specification, "heterocyclic alkoxy" refers to an oxygen group in which an alkyl group is bonded to a heterocyclic group as defined above. The ring constituting the heterocyclic group preferably has 4 to 10 atoms (4 to 10-membered heterocyclic group), more preferably 4 to 7 (4 to 7-membered heterocyclic group), and the alkyl group is preferably C1-C6 alkyl, more preferably C1-C4 alkyl. The preferred heterocyclic alkoxy group is a 4 to 10-membered heterocyclic C1-C6 alkoxy group, more preferably a 4 to 7-membered heterocyclic C1-C2 alkoxy group. Specific examples of heterocyclic alkoxy groups include oxepane-2-ylmethoxy, oxepane-3-ylmethoxy, oxepane-4-ylmethoxy, 1,4-dialkyl-2-ylmethoxy, (1-methylpiperidin-4-yl)methoxy, and 3-morphofolin-4-ylpropoxy.

[0045] In this specification, "hydroxyalkoxy" refers to a group in which a "hydroxyl group" is bonded to an "alkoxy" group as defined above. Preferably, the hydroxyalkoxy group is a hydroxy C2-C6 alkoxy group, and more preferably a hydroxy C3-C6 alkoxy group. Specific examples of hydroxyalkoxy groups include 3-hydroxy-3-methylbutoxy and 4-hydroxybutoxy.

[0046] In this specification, "alkoxyalkoxy" refers to an "alkoxy" group bonded to an "alkoxy" group as defined above. Preferably, it is a C1-C6 alkoxy, more preferably a C1-C3 alkoxy, or C1-C2 alkoxy. Specific examples of alkoxyalkoxy groups include 2-methoxyethoxy.

[0047] In this specification, "alkylaminoalkoxy" refers to a group in which an "alkylamino group" is bonded to an "alkoxy group" as defined above. Preferably, the alkylaminoalkoxy group is a bis(C1-C6 alkyl)aminoC1-C6 alkoxy group, and more preferably a bis(C1-C4 alkyl)aminoC1-C3 alkoxy group. Specific examples of alkylaminoalkoxy groups include 2-(dimethylamino)ethoxy.

[0048] In this specification, "aryloxyalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are substituted by the aforementioned "aryloxy" group. Preferably, the aryloxyalkyl group is a C6-C10 aryloxyC1-C6 alkyl group, and more preferably a C6-C10 aryloxyC1-C2 alkyl group. Specific examples of aryloxyalkyl groups include, for example, phenoxymethyl and 2-phenoxyethyl.

[0049] In this specification, "amine group" refers narrowly to -NH2 and broadly to -NRR', where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, or R and R' together with the nitrogen atom to which they are bonded form a ring. Preferably, -NH2, mono-C1-C6 alkylamine, di-C1-C6 alkylamine, and 4- to 8-membered cyclic amine groups are included.

[0050] In this specification, "monoalkylamine" refers to an "amine group" as defined above, where R is hydrogen and R' is an "alkyl" group as defined above. Monoalkylamine groups are preferably C1-C6 alkylamine groups. Specific examples of monoalkylamine groups include, for instance, methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, secondary butylamino, and tertiary butylamino.

[0051] In this specification, "dialkylamino" refers to an amino group in which R and R' are independently an alkyl group as defined above. Preferably, diC1-C6 alkylamino groups are listed. Specifically, examples of dialkylamino groups include, for example, dimethylamino and diethylamino.

[0052] In this specification, "cyclic amino group" refers to the group in which R and R' of the aforementioned "amino group" form a ring together with the nitrogen atom to which they are bonded. Preferably, 4 to 8 cyclic amino groups can be listed. Specific examples of cyclic amino groups include, for example, 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, and 3-oxa-8-azabicyclo[3.2.1]oct-8-yl.

[0053] In this specification, "aminocarbonyl" refers to the "amino" bonded carbonyl group as defined above. Examples of aminocarbonyl groups include -CONH2, mono-C1-C6 alkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl. Specific examples of aminocarbonyl groups include -CONH2, dimethylaminocarbonyl, 1-acetylcarbonyl, 1-pyrrolidylcarbonyl, 1-piperidinylcarbonyl, 1-piperidylcarbonyl, 4-morphofolinylcarbonyl, 3-azolidinylcarbonyl, 1,1-thiodimorphofolinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]oct-8-ylcarbonyl.

[0054] In this specification, "aminocarbonyl alkyl" means a group in which one or more hydrogen atoms of the aforementioned "alkyl" are replaced by the aforementioned "aminocarbonyl" group. Preferably, the aminocarbonyl alkyl group is an aminocarbonyl C1-C6 alkyl group, and more preferably an aminocarbonyl C1-C4 alkyl group. As an aminocarbonyl alkyl group, specific examples include, for example, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, tributylaminocarbonylmethyl, 1-acetylcarbonylmethyl, 1-pyrrolidylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morphofolinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-acetylcarbonyl)ethyl, 2-(1-pyrrolidylcarbonyl)ethyl, 2-(4-morphofolinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, 4-(dimethylaminocarbonyl)butyl, etc.

[0055] In this specification, "alkylsulfonyl" refers to an alkyl-bonded sulfonyl group as defined above. C1-C6 alkylsulfonyl groups are preferably included. Specific examples of alkylsulfonyl groups include, for example, methylsulfonyl and ethylsulfonyl.

[0056] In this specification, "alkylsulfonylamino" refers to a group in which a sulfonyl group is bonded to an amino group as defined above. Preferably, examples include C1-C6 alkylsulfonyl-NH-, (C1-C6 alkylsulfonyl-)2N-, etc. Specific examples of aminoalkylsulfonyl groups include, for instance, methylsulfonylamino, ethylsulfonylamino, bis(methylsulfonyl)amino, bis(ethylsulfonyl)amino, etc.

[0057] In this specification, "alkylsulfonylalkyl" refers to a group in which one or more hydrogen atoms of the aforementioned "alkyl" are replaced by the aforementioned "alkylsulfonyl". Preferably, the alkylsulfonylalkyl group is a C1-C6 alkylsulfonyl C1-C6 alkyl, and more preferably a C1-C6 alkylsulfonyl C1-C2 alkyl. Specific examples of alkylsulfonylalkyl groups include, for example, methylsulfonylmethane, 2-(methylsulfonylmethane)ethyl, etc.

[0058] In this specification, "alkyl thio" refers to the thio group with an alkyl bond as defined above, and preferably includes C1-C6 alkyl thio groups. Specific examples of alkyl thio groups include, for example, methyl thio, ethyl thio, 1-propyl thio, 2-propyl thio, n-butyl thio, i-butyl thio, secondary butyl thio, tertiary butyl thio, etc.

[0059] In this specification, "acyl" (alkanoyl) refers to a carbonyl group bonded to hydrogen or the aforementioned "alkyl" group. Preferably, C1-C6 acyl groups are listed, more preferably C2-C4 acyl groups. Specific examples of acyl groups include methyl, acetyl, propionic, and butyl groups.

[0060] In this specification, "haloalkanoyl" refers to a carbonyl group bonded to the aforementioned "haloalkyl" group. C2-C6 haloalkanoyl groups are preferred examples, and C2-C4 haloalkanoyl groups are even more preferred. Specific examples of haloalkanoyl groups include trifluoroacetyl, trichloroacetyl, pentafluoropropionic acid, 2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionic acid, and 3,3,3-trifluoro-2-(trifluoromethyl)propionic acid.

[0061] In this specification, "alkylene" refers to a divalent group derived from the aforementioned "alkyl" by further removing one arbitrary hydrogen atom, preferably a C1-C8 alkylene, and more preferably a C4-C8 alkylene. As alkyl groups, specific examples include -CH 2-, -(CH 2) 2-, -(CH 2) 3-, -CH(CH 3)CH 2-, -C(CH 3) 2-, -(CH 2) 4-, -CH(CH 3)CH 2CH 2-, -C(CH 3) 2CH 2-, -CH 2CH(CH 3)CH 2-, -CH 2C(CH 3) 2-, -CH 2CH 2CH(CH 3)-, -CH 2CH(CH 2CH 3)-, -(CH 2) 5-, -CH(CH 3)CH(CH 2CH 3)-, -(CH 2) 6-, -(CH 2) 7-, -(CH 2) 8-, etc.

[0062] In this specification, "arylene" refers to a divalent group derived from the aforementioned "aryl" group by further removing one arbitrary hydrogen atom. The arylene group can be a monocyclic or condensed ring. The number of atoms in the ring constituting the arylene group is not particularly limited, but is preferably 6 to 10 (C 6 to C 10 arylene). Specific examples of arylene groups include, for example, 1,2-arylene-phenyl, 1,3-arylene-phenyl, 1,4-arylene-phenyl, 1,2-arylephrine, 1,3-arylephrine, and 1,4-arylephrine.

[0063] In this specification, "aromatic hydrocarbon ring" refers to a hydrocarbon ring consisting of a single ring or a condensed ring that exhibits aromaticity. Preferably, 6 to 10 aromatic hydrocarbon rings can be listed. Specific examples of aromatic hydrocarbon rings include, for instance, benzene rings and naphthalene rings.

[0064] In this specification, "aromatic heterocycle" refers to a cyclic compound consisting of a monocyclic or condensed ring and containing one or more heteroatoms, exhibiting aromaticity. Preferably, 5 to 10 aromatic heterocycles are listed. As aromatic heterocycles, specific examples include, for example, furan rings, thiophene rings, pyrrole rings, imidazole rings, pyrazole rings, thiazole rings, isothiazole rings, oxazole rings, isothiazole rings, oxadiazole rings, thiadiazole rings, triazole rings, tetraazole rings, pyridine rings, pyrimidine rings, pyridazine rings, pyrazine rings, triazine rings, benzofuran rings, benzothiophene rings, benzothiadiazoline rings, benzothiazoline rings, and benzoxazoline rings. [)] cyclic, benzo[a]diazolin (benz) [o]xadiazoline [ ] ring, benzimidazole ring, benzotriazole ring, indole ring, isoindole ring, indazole ring, azaindole ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring, benzodioxole ring, indolizine ring, imidazopyridine ring, pyrazolopyridine ring, imidazopyridine ring, triazolopyridine ring, pyrrolopyridine ring, furopyridine ring, etc.

[0065] In this specification, "alicyclic ring" refers to a non-aromatic hydrocarbon ring. Alicyclic rings may also have unsaturated bonds within the ring, or they may be polycyclic rings with two or more rings. Furthermore, the carbon atoms constituting the ring may be oxidized to form a carbonyl group. Preferably, 3 to 8-membered alicyclic rings are listed. Specific examples of alicyclic rings include, for instance, cyclopropane rings, cyclobutane rings, cyclopentane rings, cyclohexane rings, cycloheptane rings, cyclooctane rings, and bicyclic [2.2.1]heptane rings.

[0066] In this specification, "saturated heterocycle" refers to a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms, and which does not contain double bonds and / or triple bonds. Saturated heterocycles can be monocyclic or form condensation rings with other rings, such as aromatic rings like benzene rings. Preferably, 4 to 10 saturated heterocycles are listed. As saturated heterocycles, specific examples include, for instance, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydropyran rings, morpholine rings, thiomorpholine rings, pyrrolidine rings, 2-oxopyrrolidine rings, 4-oxopyrrolidine rings, piperidine rings, 4-oxopiperidine rings, piperazine rings, and pyrazolidine rings. [)] ring, imidazolidine ring, oxazolidine ring, isozolidine ring, thiazolidine ring, isotetrahydrothiazolidine ring, thiadiazolidine ring, oxazolidinone ring, dioxolane ring, dioxan ring, thietane ring, octahydroindole ring, indoline ring, azepane ring, dioxepane ring, 5,9-dioxaspiro[3.5]nonane ring, etc.

[0067] In this specification, "heterocyclic ring" refers to a non-aromatic heterocyclic ring containing preferably 1 to 5, more preferably 1 to 3, heteroatoms in the ring. The heterocyclic ring may have double bonds and / or triple bonds, and the carbon atoms in the ring may be oxidized to form carbonyl groups. It can be a monocyclic, condensed, or spirocyclic ring. The number of atoms in the ring constituting the heterocyclic ring is preferably 3 to 12 (3 to 12-membered heterocyclic ring), more preferably 4 to 10 (4 to 10-membered heterocyclic ring). As heterocycles, specific examples include, for instance, acrylonitrile rings, oxacyclobutane rings, tetrahydrofuran rings, tetrahydropiperanane rings, mofolin rings, thiomofolin rings, pyrrolidine rings, 4-side-oxypyrrolidine rings, piperidine rings, 4-side-oxypiperidine rings, piperidine rings, pyrazolidine rings, imidazoline rings, oxazolidine rings, isozolidine rings, tetrahydrothiazole rings, isotetrahydrothiazole rings, thiazoline rings, oxazolidine rings, dioxacyclopentane rings, and dioxacyclobutane rings. Alkane rings, thioheterocyclic butane rings, octahydroindole rings, 6,7-dihydro-pyrrolo[1,2-a]imidazolium rings, or azacyclic octane rings, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine rings, azacyclic heptane rings, dioxoheptane rings, 5,9-dioxaspiro[3,5]nonane rings, or rings in which one or more single bonds of such saturated heterocycles are replaced by double or triple bonds, etc.

[0068] The term "carboxyl protecting group" in this specification can include alkyl ester protecting groups, benzyl ester protecting groups, substituted alkyl ester protecting groups, etc.

[0069] The term "protecting group of amine" in this specification can include carbamate-type protecting groups, amide-type protecting groups, arylsulfonamide-type protecting groups, alkylamine-type protecting groups, imine-type protecting groups, etc.

[0070] The term "protecting group of hydroxyl group" in this specification can include alkyl ether type protecting groups, aralkyl ether type protecting groups, silicone ether type protecting groups, carbonate type protecting groups, etc.

[0071] Examples of "halogen-derived substituents" in this specification include fluorine (-F), chlorine (-Cl), bromo (-Br), and iodo (-I).

[0072] Examples of "substituents derived from oxygen atoms" in the specification include hydroxyl (-OH), oxy group (-OR), carbonyl group (-C(=O)-R), carboxyl group (-CO 2H), oxycarbonyl group (-C(=O)-OR), carbonyloxy group (-OC(=O)-R), thiocarbonyl group (-C(=O)-SR), carbonylthio group (-SC(=O)-R), aminocarbonyl group (-C(=O)-NHR), carbonylamino group (-NH-C(=O)-R), oxycarbonylamino group (-NH-C(=O)-OR), sulfonylamino group (-NH-SO 2-R), aminosulfonyl group (-SO 2-NHR), sulfamoylamino group (-NH-SO 2-NHR), thiocarboxyl group (-C(=O)-SH), and carboxylcarbonyl group (-C(=O)-CO 2H).

[0073] Examples of "substituents derived from nitrogen atoms" in this specification include azide (-N 3, also known as "azido group"), cyano (-CN), primary amino (-NH 2), secondary amino (-NH-R), tertiary amino (-NR(R')), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R''), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R''), and aminocarbonylamino (-NR-CO-NR'R'').

[0074] Examples of "substituents derived from sulfur atoms" in this specification include thiol (-SH), thio (-SR), sulfinyl (-S(=O)-R), sulfonyl (-S(=O) 2-R), sulfo (-SO 3H), and pentafluorohydrosulfonyl (-SF 5).

[0075] Examples of "substituents derived from boron atoms" in this specification include boryl (-BR(R')), dioxyboryl (-B(OR)(OR')), and trifluoroborate (-BF3-). Specifically, examples of these substituents R and R' are each independently a "boryl-derived substituent" selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or the two substituents R and R' are "boryl-derived substituents" in which R and R' together with their respective bonded atoms form a ring, i.e., cyclic boryl. A preferred example of a "boryl-derived substituent" is a cyclic boryl. More specifically, examples of cyclic oxoboroyl groups include pinacolato oxoboroyl, neoopentadiolate oxoboroyl, catecholato oxoboroyl, and 9-boronbicyclo[3.3.1]non-9-yl.

[0076] Examples of "zinc-derived groups" in this specification include alkyl zinc groups (-Zn-(C1-C6 alkyl)) or zinc halide groups (-Zn-X). Preferred examples of "zinc-derived groups" include -ZnMe, -ZnEt, -ZnPr, -ZnCl, -ZnBr, and -ZnI. Compounds having these "zinc-derived groups" can be prepared with reference to March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th edition, John Wiley & Sons, Inc. 2019) or RC Laroch's Comprehensive Organic Transformations (3rd edition, John Wiley & Sons, Inc. 2018).

[0077] In this specification, "may also be substituted" means that a certain group can be substituted by any substituent. Furthermore, each of these groups can also be given substituents, and there are no restrictions on these substituents. For example, one or more substituents can be independently and freely selected from any substituents containing halogen atoms, oxygen atoms, sulfur atoms, nitrogen atoms, boron atoms, silicon atoms, or phosphorus atoms.

[0078] In this specification, "can also be protected" means that a base can also be protected by any protecting base.

[0079] In this specification, "one or more" means one or more numbers. When "one or more" is used in context relating to substituents of a base, this term means a number from one up to the maximum number of substituents allowed for that base.

[0080] In this specification, the "~" sign indicating a numerical range includes both ends of the range. For example, "A~B" means a range of values ​​above A and below B.

[0081] When the term "approximately" is used in combination with numerical values ​​in this manual, it means a range of values ​​within +10% and -10% of that value.

[0082] The term "and / or" in this specification includes any combination of "and" and "or" appropriately. Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.

[0083] One embodiment of the present invention is a compound represented by general formula (1) (hereinafter also referred to as "compound (1)") or a salt thereof or a solvate thereof.

[0084] In compound (1), X a1 is either CR a1 or N. CR a1 is preferred as X a1.

[0085] In compound (1), X a3 is either CR a3 or N. CR a3 is preferred as X a3.

[0086] In compound (1), Ra1 is hydrogen, halogen, or C1-C6 alkoxy. Hydrogen or fluorine is preferred as Ra1.

[0087] In compound (1), Ra2 is hydrogen, halogen, or C1-C6 alkoxy. Hydrogen or methoxy is preferred as Ra2.

[0088] In compound (1), Ra3 is hydrogen, halogen, or C1-C6 alkoxy. Hydrogen or fluorine is preferred as Ra3.

[0089] In compound (1), Xb1 is CH2, O, NH, S or C=O. CH2 is preferred as Xb1.

[0090] In compound (1), Xb2 is CH2, O, NH, S or C=O. Preferably, Xb2 is CH2, O, NH or C=O, and more preferably CH2.

[0091] In compound (1), Xb3 is CH2, O, NH, S or C=O. Preferably, Xb3 is CH2, O, NH, S or C=O, and more preferably O.

[0092] For the combination of X b1, X b2, and X b3, it is preferable that X b1 is CH2, X b2 is CH2, O, NH, or C=O, and X b3 is CH2, O, NH, S, or C=O. Alternatively, X b1 and X b2 can be CH2 and X b3 can be O, or X b1 and X b3 can be CH2 and X b2 can be O, or X b1 and X b2 can be CH2 and X b3 can be S, or X b1 can be CH2, X b2 can be NH and X b3 can be C=O, or X b1 and X b2 can be CH2 and X b3 can be NH, or X b1 can be CH2, X b2 can be C=O and X b3 can be NH, or X b1 and X b3 can be CH2 and X b2 can be NH, or X b1, X b2, and X b3 can be CH2. The best combination is X b1 and X b2 can be CH2 and X b3 can be O.

[0093] In compound (1), Z is a C6-C10 aryl, a 5-10 member heteroaryl, or a C1-C6 alkyl. The C6-C10 aryl, 5-10 member heteroaryl, and C1-C6 alkyl may also be substituted by Rz3, and may also be substituted by one or more groups selected from the group consisting of Rz1, Rz2, Rz4, and Rz5. Preferably, Z is also substituted by Rz3, and may also be substituted by one or more groups selected from the group consisting of Rz1, Rz2, Rz4, and Rz5, such as phenyl, pyridyl, or C2-C5 alkyl.

[0094] In compound (1), Z is preferably the group shown in formula (2): [Chemistry 9] [In the formula, the wavy line represents the bond node of Z, and Xz is CR z5 or N]. In formula (2), it is preferred that Xz is CR z5.

[0095] In compound (1), R z1, R z2, and R z5 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl (5-10 member heteroaryl C1-C6 alkyl) amino, C1-C6 alkyl (4-10 member heterocyclic) amino, and 4-8 member cyclic amino. R z1, R z2, and R z5 are preferably each independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl, and more preferably each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl, and ethyl.

[0096] In compound (1), Rz4 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkyl (5-10 member heteroaryl C1-C6 alkyl) amine with substituents, or C1-C6 alkyl (4-10 member heterocyclic) amine with substituents, or 4-8 member cyclic amine with substituents. Rz4 is preferably a C1-C6 alkyl (5-10 member heteroaryl C1-C2 alkyl) amino group, a C1-C6 alkyl (4-10 member heterocyclic) amino group, or a 4-8 member cyclic amino group, which may also have substituents. More preferably, it is a 4-6 member cyclic amino group that may also have one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy; a 4-6 member cyclic amino group with a crosslinking group selected from the group consisting of C1-C2 alkyl and C1-C2 alkyl containing one oxygen atom; a C1-C3 alkyl (5-6 member heteroaryl C1-C2 alkyl) amino group that may also have substituents selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; or a C1-C3 alkyl (5-6 member heteroaryl C1-C2 alkyl) amino group that may also have substituents selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl. The C1-C group consisting of substituents of 1-C 6 alkyl groups 3-alkyl(4-6-membered heterocyclic)amino, preferably 3-oxa-8-azabicyclo[3.2.1]oct-8-yl, mofolin-4-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, (2S,3S)-3-methoxy-2-methylacet-1-yl, 1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrolo-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolodin-1-yl, piperidin-1-yl, methyl(1,2-azol-3-ylmethyl)amino, methyl(oxecyclobutane-3-yl)amino, methyl-[(3R)-oxecyclopentane-3-yl]amino or methyl-(3-methyloxecyclobutane-3-yl)amino.

[0097] In compound (1), R z3 is a carboxyl group or its biological equivalent. A biological equivalent is, for example, a functional group described by Matsuoka et al. (Farumashia, 2010, 46(3), 215-222) and Thornber et al. (Chem. Soc. Rev., 1979, 8, 563-580) that, although chemically different, exhibit the same biological effects. Examples of carboxyl equivalents include functional groups with acidic protons. R z3 may also contain compounds that, upon application to a target, can be converted into a carboxyl group or its biological equivalent, such as prodrugs.

[0098] In compound (1), R z3 is a group specifically selected from substituent group A: [Chemistry 10] (In the formula, the wavy line represents the bond node, R5 is a hydroxyl group, a C1-C6 alkoxy group, a mono- or di-C1-C6 alkylamino group, or a C1-C6 alkylsulfonylamino group, and n is 1 or 2.) Rz3 is preferably a group selected from the following substituent group B: [Chemistry 11] (In the formula, the wavy line represents the bond node, and R5 is a hydroxyl group, a C1-C6 alkoxy group, a mono-C1-C6 alkylamine group, or a C1-C6 alkylsulfonylamine group.) Furthermore, R5 is preferably a hydroxyl group or a C1-C6 alkylsulfonylamine group.

[0099] In compound (1), Y is a C6-C10 aryl or a 5-10 heteroaryl, wherein the C6-C10 aryl or the 5-10 heteroaryl may be substituted by one or more groups selected from the group consisting of Ry1, Ry2, Ry3, Ry4 and Ry5. Preferably, Y is a phenyl or a 6-10 heteroaryl that may also be substituted by one or more groups selected from the group consisting of Ry1, Ry2, Ry3, Ry4 and Ry5, more preferably a phenyl or a 6-10 heteroaryl that may also be substituted by Ry3 and may also be substituted by one or more groups selected from the group consisting of Ry1, Ry2, Ry4 and Ry5.

[0100] In compound (1), Y is preferably the base shown in formula (3): [Chemistry 12] [In the formula, the wavy line represents the bond node of Y, Xy1 is CRy3 or N, Xy2 is CRy4 or N, and Xy3 is CRy5 or N]. In formula (3), preferably Xy1 is CRy3, Xy2 is CRy4, and Xy3 is CRy5.

[0101] In compound (1), Ry1 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4-10 member heterocyclic C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4-10 member heterocyclic oxy, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 alkylamino C1-C6 alkoxy, 5-10 member heteroaryloxy, C1-C6 alkylthio, 4-10 member saturated heterocyclic group with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic group with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member aromatic heterocyclic group or C1-C6 alkyl (C 1-C 6 alkoxy (C 1-C 6 alkyl)amine. Preferred components of Ry1 include hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C3 alkoxy-C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, 5-6 member saturated heterocyclic groups with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic groups with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member aromatic heterocyclic groups or C1-C3 alkyl (C1-C2) alkylyloxy, alkylylyloxy, alkylylylthio, alkylyl ... 3-alkoxy (C1-C2 alkyl)amino, more preferably hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl or C1-C3 alkoxy, more preferably hydrogen, halogen, cyano or C1-C3 alkyl, particularly preferably chlorine.

[0102] In compound (1), Ry2 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4-10 member heterocyclic C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4-10 member heterocyclic oxy, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 alkylamino C1-C6 alkoxy, 5-10 member heteroaryloxy, C1-C6 alkylthio, 4-10 member saturated heterocyclic group with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic group with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member aromatic heterocyclic group or C1-C6 alkyl (C 1-C 6 alkoxy (C 1-C 6 alkyl)amine. Ry2 is preferably hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C3 alkoxy-C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, 5-6 member saturated heterocyclic groups with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic groups with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member aromatic heterocyclic groups or C1-C3 alkyl (C1-C2) The 3-alkoxy (C1-C2 alkyl)amino group, more preferably hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl or C1-C3 alkoxy, and even more preferably hydrogen.

[0103] In compound (1), R y3 is hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4-10 member heterocyclic C1-C6 alkoxy, hydroxy C2-C6 alkoxy, 4-10 member heterocyclic oxy, C1-C6 alkoxy C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 alkylamino C1-C6 alkoxy, 5-10 member heteroaryloxy, C1-C6 alkylthio, 4-10 member saturated heterocyclic group with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic group with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member heteroaryl or C1-C6 alkyl (C 1-C 6 alkoxy (C 1-C 6 alkyl)amine.Preferred components of Ry3 include hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C3 alkoxy-C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, 5-6 member saturated heterocyclic groups with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic groups with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member heteroaryl groups or C1-C3 alkyl (C1-C3 alkoxy C ... 1-C2 alkyl)amino, preferably 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C3 alkoxy C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, 5-6 member saturated heterocycles with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocycles with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member heteroaryl or C1-C3 alkyl (C1-C3 alkoxy C1-C) 2-alkyl)amino, preferably a 4-10 member saturated heterocyclic group with a bonding hand on the nitrogen atom of the ring and may also have substituents, or a 5-10 member heteroaryl group with substituents, particularly 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl, 4-methylpiperyl-1-yl, (2R)-2,4-dimethylpiperyl-1-yl, 6-methoxy -2-azaspiro[3.3]hept-2-yl, 4-(2-methoxyethyl)piperyl-1-yl, 3-methoxyacetyl-1-yl, 4-(oxacyclobutane-3-yl)piperyl-1-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, (2R,5R)-2,4,5-trimethylpiperyl-1-yl, 4-(2-hydroxy-2-methylpropyl)piperyl-1-yl or morpholin-4-yl.

[0104] In compound (1), Ry4 and Ry5 are each independently chosen from hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkoxy, 4-10 member heterocyclic C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 alkylamino C1-C6 alkoxy, 5-10 member heteroaryloxy, C1-C6 thio, 4-10 member saturated heterocyclic groups with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic groups with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member aromatic heterocyclic groups and C1 The group consisting of 1-C 6 alkyl (C 1-C 6 alkoxy C 1-C 6 alkyl) amino groups. Ry4 and Ry5 are preferably independently selected from hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, 5-6 member heterocyclic C1-C4 alkoxy, hydroxy C3-C6 alkoxy, 5-6 member heterocyclic oxy, C1-C3 alkoxy-C1-C2 alkoxy, C1-C3 alkoxy, C1-C4 alkylamino C1-C3 alkoxy, 5-6 member heteroaryloxy, C1-C4 alkylthio, 5-6 member saturated heterocyclic groups with a bonding hand on the carbon atom of the ring and may also have substituents, 4-10 member saturated heterocyclic groups with a bonding hand on the nitrogen atom of the ring and may also have substituents, 5-10 member aromatic heterocyclic groups and C1-C5 alkylthio groups. The group consisting of 3 alkyl (C1-C3 alkoxy C1-C2 alkyl) amino groups is more preferably the group consisting of hydrogen, halogen, cyano, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl and C1-C3 alkoxy groups, and even more preferably the group consisting of hydrogen, halogen, cyano and C1-C3 alkyl groups, with hydrogen being particularly preferred.

[0105] In compound (1), when Xy1 is CRy3, Ry2 and Ry3 can also form a 5- or 6-membered heteroaromatic ring together with the bonded carbon atom. When Xy1 is CRy3 and Xy2 is CRy4, Ry3 and Ry4 can also form a 5- or 6-membered heteroaromatic ring together with the bonded carbon atom. When Xy2 is CRy4 and Xy3 is CRy5, Ry4 and Ry5 can also form a 5- or 6-membered heteroaromatic ring together with the bonded carbon atom.

[0106] Other embodiments of the present invention are compounds (hereinafter also referred to as "compound (4)") or salts or solvates of the general formula (4). In compound (4), Xa3, Ra1, Ra2, Xb1, Xb2, Xb3, Ry1, Ry2, Xy1, Xy2, Xy3, Rz1, Rz2, Rz3, Rz4 and Xz are synonyms of Xa3, Ra1, Ra2, Xb1, Xb2, Xb3, Ry1, Ry2, Xy1, Xy2, Xy3, Rz1, Rz2, Rz3, Rz4 and Xz in the above compound (1).

[0107] The compounds described in this specification may be their salts or solvates. Salts of the compounds include, for example, hydrochlorides; hydrobromides; hydroiodates; phosphates; phosphonates; sulfates; sulfonates such as methanesulfonates and p-toluenesulfonates; carboxylates such as acetates, citrates, malates, tartrates, succinates, and salicylates; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts can be produced, for example, by contacting the compound with an acid or base. A solvate in this specification refers to a molecular group formed by the compound and a solvent, and there are no particular limitations as long as it is a solvate formed by a solvent permitted for ingestion during pharmaceutical administration. Examples of this include not only solvates of hydrates, alcohols (ethanol compounds, methanol compounds, 1-propanol compounds, 2-propanol compounds, etc.), dimethyl sulfoxide, etc., with a single solvent, but also solvates formed with one molecule of the compound and multiple solvents, or solvates formed with one molecule of the compound and multiple types of solvents. When the solvent is water, it is called a hydrate. The solvate of the compound of the present invention is preferably a hydrate, and specifically, one to ten hydrates, more preferably one to five hydrates, and even more preferably one to three hydrates can be listed.

[0108] When the compound according to the invention is obtained as a free form, the compound can be converted by conventional methods into a state in which the compound can also form salts or hydrates or solvates. Examples include hydrates, ethanolates, etc., of the compound shown in formula (1) or its salts. Specifically, examples include hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, pentahydrates, hexahydrates, heptahydrates, octahydrates, nonahydrates, decahydrates, or monoethanolates of the compound shown in formula (1), or hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, pentahydrates, hexahydrates, heptahydrates, octahydrates, nonahydrates, decahydrates, or monoethanolates of the sodium salt of the compound shown in formula (1), or hydrates or ethanolates of the hydrochloride salt of the compound shown in formula (1), but are not limited thereto. The hydrates or solvates can be manufactured in crystalline or amorphous forms, and in the case of crystalline forms, they can be crystalline polymorphs. As a method for manufacturing hydrates or solvates, for example, the compound shown in formula (1) is added to a solvent such as ethanol and / or water, and stirred, cooled, concentrated, and / or dried, etc., to obtain hydrates or solvates by conventional methods.

[0109] Furthermore, when the compound according to the invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted to its free form by conventional methods.

[0110] The compounds described in this specification may contain one or more isotopic atoms in proportions other than those naturally occurring. Compounds labeled with isotopic atoms are also included in this invention, where any atom in the compound is replaced by another isotopic atom with the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons), or where the substitution is achieved by an isotope with a different proportion than that found in naturally occurring isotopes. Examples of isotopic elements included in the compounds described in this specification are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms, respectively containing 2H, 3H, 13C, 14C, 15N, 17O, 18O, 32P, 35S, 18F, and 36Cl. Compounds labeled with isotopic atoms are useful as therapeutic or preventative agents, research reagents (e.g., analytical reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds contained in this specification in all proportions of radioactive or non-radioactive isotopic elements are included within the scope of this invention. Compounds labeled with isotopic atoms can be manufactured using the same method as that used to manufacture unlabeled compounds, employing reagents, solvents, etc., containing the corresponding isotopic atoms.

[0111] The compounds, their salts, or solvates described in this specification include all such stereoisomers (e.g., enantiomers, diastereomers (including cis and trans geometric isomers), racemic mixtures of the aforementioned isomers, and other mixtures. For example, the compounds of the present invention may also have one or more asymmetric points, and the present invention includes racemic mixtures, diastereomer mixtures, and enantiomers of such compounds.

[0112] <General Manufacturing Method> Examples of methods for manufacturing compounds of formula (1) or their salts or solvates are illustrated by the following flowchart group. The compounds of the present invention can be synthesized by various methods, the following manufacturing methods being examples. The present invention is not limited to the specified chemical reactions and conditions. In the following flowcharts of the manufacturing methods, some substituents are excluded for clarity, but this is not intended to limit the disclosure of the flowcharts. Representative compounds of the present invention can be synthesized using suitable intermediates, known compounds, and reagents. The variable groups represented by R1, R2, etc., and the variables represented by n, etc., in the following general synthetic methods are synonymous with the variable groups represented by R1, R2, etc., and the variables represented by n, etc., in the compounds represented by the general formulas defined in this specification. Furthermore, when the starting material or target product of a certain step undergoes an undesirable chemical transformation under the reaction conditions of that step, the target product of that step can be obtained by, for example, protection and deprotection of functional groups. For information on the selection of protecting groups, and the methods of protection and deprotection, please refer to, for example, TW Greene, PGM Wuts, Protective Groups in Organic Synthesis (5th edition, John Wiley & Sons 2014). A portion of the protection and deprotection of functional groups is also described in the flowchart below.

[0113] The compounds of the present invention can be synthesized by, for example, the manufacturing methods shown below.

[0114] General manufacturing method A [Chemistry 13] In the formula, PG 1 represents the protecting group of the amino group, L 1 and L 2 each independently represent the dissociating group, and X a1, X a3, Ra2, X b1, X b2, X b3, Y and Z are synonyms with the definitions in [1] above.

[0115] Protecting groups (PG 1) for amino groups can include methyl, C1-C6 alkyl carbonyl (acetyl, propionic, butyl, isobutyl, pentayl, isopentyl, trimethylacetyl, etc.), carbamoyl, C1-C6 alkoxy carbonyl (methoxy carbonyl, ethoxy carbonyl, isopropyloxy carbonyl, secondary butoxy carbonyl, tertiary butoxy carbonyl, etc.), substituted silyl (trimethylsilyl, triethylsilyl, triisopropylsilyl, tributyldimethylsilyl, tributyldiphenylsilyl, etc.), aralkyloxy carbonyl (benzyloxy carbonyl, 9-fluorenyl methyloxy carbonyl, etc.), allyl, aralkyl (benzyl, cumyl, etc.), etc.

[0116] In general preparation method A, the detached radicals (L1 and L2) can include halogen atoms, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, acetoxy, trifluoroacetoxy, methanesulfonyloxy, p-toluenesulfonyloxy, boron-derived radicals (4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane, 9-BBN, etc.), zinc-derived radicals, etc.

[0117] Step 1 Compound (A-3) can be prepared by coupling a compound (A-1) having a release group L1 and a compound (A-2) having a release group L2 in the presence of a palladium catalyst, a coordinating group, and a base. Examples of compounds having a release group L1 and L2 include compounds having a halogen atom as a release group, compounds having a release group derived from sulfonic acid, compounds having a release group derived from a boron atom, and compounds having a zinc-derived group. This is a method well known to those skilled in the art, and can be prepared using methods described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition (RC Larock), or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (MB Smith, J. March), and can be used in coupling reactions. The coupling reaction can be carried out by referring to the methods of Suzuki et al. (Chem. Rev. 1995, 95, 2457-2483) or Negishi et al. (J.Org. Chem. 1977, 42, 1821-1823).

[0118] The palladium catalyst used in the coupling reaction can be a product that can be purchased from commercial suppliers. Examples include the 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex, the 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex, the bis(triphenylphosphine)palladium(II) dichlorobis(tricyclohexylphosphine)palladium(II), the [1,3-bis(2,6-diisopropylphenyl)imidazolidene-2-yl](3-chloropyridyl)palladium(II), the (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II), or the [1,3-bis(2,6-di-3-pentylphenyl)imidazolidene-2-yl](3-chloropyridyl)palladium(II), or Org. Lett. 2014, 16, 4638-4641, or J. Am. Chem. Catalysts described in Soc., 2014, 136, 14027-14030, such as SPhos Pd G3, XPhos Pd G3, CPhos Pd G3, or XantPhos Pd G3, are available from Buchwald et al. Furthermore, they can be used in combination with palladium and ligands. Suitable combinations include palladium such as palladium acetate, allyl palladium(II) chloride (dimer), or Pd2(dba)3, which are commercially available, and ligands such as dppf, SPhos, or Xantphos, which are commercially available.

[0119] The base used in the coupling reaction can be, for example, a tertiary amine (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), an inorganic base such as a carbonate or phosphate (sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc.), or a metal alkoxide (sodium methoxide). [)], Sodium tert-butoxide [)], sodium tert-pentoxide [)], potassium tert-butoxide, potassium tert-pentoxide, etc.), preferably inorganic bases such as cesium carbonate.

[0120] The solvent used in the coupling reaction may be, for example, an ether solvent (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), an acetylamine solvent (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidone-2-one, etc.), or acetonitrile, with 2-methyltetrahydrofuran and 1-methylpyrrolidone-2-one being preferred examples.

[0121] The appropriate reaction temperature for the coupling reaction is typically 0°C to near the boiling point of the solvent, preferably 10°C to 120°C. The reaction time is typically 30 minutes to 24 hours, preferably 1 hour to 12 hours. The obtained target compound (A-3) is separated using common techniques and, if necessary, purified by crystallization or chromatography.

[0122] Step 2 Compound (A-4) can be prepared by deprotecting the protecting group of compound (A-3). When the protecting group PG1 is a C1-C6 alkoxycarbonyl group such as a tertiary butoxycarbonyl group, an acid is preferably used for the deprotection reaction. Examples of acids used in the deprotection reaction include inorganic acids (hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), and carboxylic acids (formic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, succinic acid, malonic acid, gluconic acid, mandelic acid, benzoic acid, salicylic acid, fluoroacetic acid, trifluoroacetic acid, tartaric acid, propionic acid, glutaric acid, etc.), with preferred examples being hydrogen chloride, methanesulfonic acid, and trifluoroacetic acid.

[0123] Solvents used in deprotection reactions include, for example, ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), acetylamine solvents (N,N-dimethylmethoxyamine, N,N-dimethylacetylamine, 1-methylpyrrolidone, 2-one, etc.), and ester solvents (ethyl acetate, isopropyl acetate, etc.), with 1,4-dimethylethane and ethyl acetate being preferred examples.

[0124] The appropriate reaction temperature for the deprotection reaction is typically, for example, the temperature range of 0°C to near the boiling point of the solvent, preferably 10°C to 100°C. The appropriate reaction time for the deprotection reaction is typically, for example, the range of 30 minutes to 12 hours, preferably 1 hour to 6 hours. The obtained compound (A-4) is separated using common techniques, and may also be purified by crystallization or chromatography if necessary. Furthermore, compound (A-4) can be obtained as a salt of the acid used in the reaction, and this salt can also be used in the next step.

[0125] Step 3 Compound (A-6) can be produced by converting compound (A-5) into an acid chloride, followed by a acetylation reaction in the presence of compound (A-4) and a base. Examples of reagents that convert compound (A-5) into an acid chloride include thionyl chloride, xylene chloride, and Ghosez's reagent. Examples of bases used in amination reactions include tertiary amines (triethylamine, 4-methylmorphofolin, N,N-diisopropylethylamine, DBU, DABCO, etc.), diamines (N,N,N',N'-tetramethylethylenediamine, etc.), guanidines (guanidine, tetramethylguanidine, etc.), and pyridines (pyridine, 2,6-dimethylpyridine (2,6-lutidine), 2,4,6-trimethylpyridine (2,4,6-collidine), 4-dimethylaminopyridine, etc.), with preferred examples being tertiary amines such as N,N-diisopropylethylamine and 4-methylmorphofolin.

[0126] Solvents used in acetylation reactions include, for example, ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), halogen solvents (dichloromethane, dichloroethane, chloroform, etc.), acetylation solvents (N,N-dimethylmethoxymethane, N,N-dimethylacetamide, 1-methylpyrrolidone-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), acetonitrile, and water, with dichloromethane and acetonitrile being preferred examples.

[0127] The appropriate reaction temperature for the amination reaction is, for example, the temperature range of 0°C to near the boiling point of the solvent, preferably 20°C to 60°C. The appropriate reaction time for the deprotection reaction is, for example, the range of 10 minutes to 24 hours, preferably 30 minutes to 12 hours.

[0128] In addition to the acid chloride method, compound (A-6) can also be produced by, for example, acetylation of compound (A-4) and compound (A-5) in the presence of a base using a condensing agent. Examples of condensing agents used in amination reactions include benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris(pyrrolidino))phosphonium hexafluorophosphate (PyBOP (registered trademark)), PyAOP, BroP, PyCloP, PyBroP (registered trademark), BOP-based condensing agents such as DEPBT, 4-(4,6-dimethoxy-1,3,5-tris(2-yl)-4-methylmorphoformin chloride n-hydrate (DMT-MM), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureaium (uranium) [)]Tetrafluoroborate (TBTU), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethylaminoonium (aminium)hexafluorophosphate (HATU), ethyl (hydroxyimino)cyanoacetate (Oxyma), T3P, etc., with HATU being a preferred example.

[0129] The base used in the amination reaction via the condensing agent includes, for example, tertiary amines (triethylamine, 4-methylmorphofolin, N,N-diisopropylethylamine, DBU, DABCO, etc.) and pyridines (pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, etc.), with preferred examples being tertiary amines such as N,N-diisopropylethylamine and 4-methylmorphofolin.

[0130] Solvents used in the acetylation reaction via condensing agents include, for example, ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), halogen solvents (dichloromethane, dichloroethane, chloroform, etc.), acetylation solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidone-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), and acetonitrile, with dichloromethane and N,N-dimethylformamide being preferred examples.

[0131] The appropriate reaction temperature for acetylation via a condensing agent is, for example, the temperature range of 0°C to near the boiling point of the solvent, preferably 20°C to 60°C. The appropriate reaction time for acetylation via a condensing agent is, for example, the range of 1 minute to 24 hours, preferably 30 minutes to 12 hours. The obtained compound (A-6) is separated using conventional techniques and, if necessary, purified by crystallization or chromatography.

[0132] General Method B [Chemistry 14] In the formula, L3 represents a detached group, RA represents a C1-C6 alkyl group, RB1 represents pinacolyl, neopentyl glycolyl, catecholyl, or bicyclo[3.3.1]non-9-yl, Xa1, Xa3, Xb1, Xb2, Xb3, Y, and Z are synonymous with the definitions in [1] above. Examples of detached groups L3 in general preparation method B include halogen atoms, acetoxy groups, trifluoroacetoxy groups, methanesulfonyloxy groups, p-toluenesulfonyloxy groups, trifluoromethanesulfonyl groups, and nonafluorobutanesulfonyl groups.

[0133] Step 1 Compound (B-2) can be prepared by borylation of compound (B-1) with various diborane reagents in the presence of an iridium catalyst and a ligand. The borylation reaction can be carried out, for example, according to Angew. Chem. Int. Ed., 2021, 60, 2796-2821. Examples of iridium catalysts and ligands used in the borylation reaction include bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I) and 4,4'-bis(tributyl)-2,2'-bipyridine.

[0134] Solvents used in the borylation reaction include, for example, ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethyl ethane, etc.) and hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), with tetrahydrofuran or hexane being preferred examples.

[0135] The appropriate reaction temperature for the borylation reaction is, for example, typically 0°C to the temperature range near the boiling point of the solvent, preferably 10°C to 120°C. The reaction time is typically 30 minutes to 48 hours, preferably 1 hour to 24 hours. The obtained compound (B-2) is separated using common techniques and, if necessary, purified by crystallization or chromatography.

[0136] Step 2 Compound (B-3) can be produced by providing an oxidizing agent, such as hydrogen peroxide, to compound (B-2) in an oxidation reaction.

[0137] Solvents used in oxidation reactions include, for example, ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethyl ether, etc.) and alcohol solvents (methanol, ethanol, isopropanol, butanol, etc.), with methanol being a preferred example.

[0138] The appropriate reaction temperature for the oxidation reaction is typically 0°C to near the boiling point of the solvent, preferably 10°C to 60°C. The reaction time is typically 30 minutes to 24 hours, preferably 1 hour to 12 hours. The obtained compound (B-3) is separated using common techniques and, if necessary, purified by crystallization or chromatography.

[0139] Step 3 Compound (B-5) can be prepared by etherification of compound (B-3) and compound (B-4) having the detachable group L3 in the presence of a base. The etherification reaction can be carried out according to the method of Williamson (Liebigs Ann. Chem. 1851, 77, 37-49).

[0140] The bases used in etherification reactions include, for example, tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.) and inorganic bases (sodium carbonate, potassium carbonate, cesium carbonate, etc.), with potassium carbonate being a preferred example of an inorganic base.

[0141] Solvents used in etherification reactions include, for example, ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), acetamide solvents (N,N-dimethylmethoxyamine, N,N-dimethylacetamide, 1-methylpyrrolidone-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), and acetonitrile, with acetamide solvents such as 1-methylpyrrolidone-2-one being a preferred example.

[0142] The appropriate reaction temperature for etherification is typically 0°C to near the boiling point of the solvent, preferably 10°C to 60°C. The appropriate reaction time for etherification is typically 30 minutes to 24 hours, preferably 1 hour to 12 hours. The obtained compound (B-5) is separated using common techniques and, if necessary, purified by crystallization or chromatography.

[0143] General manufacturing method C [Chemistry 15] In the formula, PG 2 represents the protecting group of the carboxyl group, Z 1 represents a group that can have any substituents and is selected from the group consisting of aryl, heteroaryl, and alkyl groups, and X a1, X a3, Ra2, X b1, X b2, X b3, and Y are synonyms with the definitions in [1] above. Examples of protecting groups of the carboxyl group include C1-6 alkyl esters (methyl ester, ethyl ester, propyl ester, butyl ester, etc.), benzyl esters, aryl esters, etc. In addition to the protecting groups of these examples, the selection of protecting groups, as well as the methods of protection and deprotection, can be selected, for example, see TW Greene, PGM Wuts, Protective Groups in Organic Synthesis (5th edition, John Wiley & Sons 2014).

[0144] Step 1 Compound (C-2) can be produced by subjecting compound (C-1) to a deprotection reaction. When the protecting group PG2 is an alkyl ester such as a methyl ester, a base is preferably used for deprotection. Examples of bases used in the deprotection reaction include inorganic bases (sodium hydroxide, potassium hydroxide, barium hydroxide, potassium trimethylsilanolate, etc.) or metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-amyloxide, potassium tert-butoxide, potassium tert-amyloxide, etc.), with inorganic bases such as potassium hydroxide being preferred. Solvents used in deprotection reactions include, for example, ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), alcohol solvents (methanol, ethanol, isopropanol, butanol, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidone-2-one, etc.), and water. Preferred examples include tetrahydrofuran, methanol, or water, or solvents mixed in any ratio.

[0145] The appropriate reaction temperature for the deprotection reaction is, for example, typically 0°C to the temperature range near the boiling point of the solvent, preferably 20°C to 120°C. The appropriate reaction time for the deprotection reaction is, for example, typically 30 minutes to 24 hours, preferably 1 hour to 6 hours. The obtained compound (C-2) is separated using common techniques, and may also be purified by crystallization or chromatography if necessary.

[0146] General manufacturing method D [Chemistry 16] In the formula, L4 represents the detached group, Y1 represents the group consisting of aryl, heteroaryl, and alkyl groups that are freely chosen and may have substituents, and Xa1, Xa3, Ra2, Xb1, Xb2, Xb3, and Z are synonyms with the definitions in [1] above. Examples of detached groups L4 in general preparation method D include halogen atoms, trifluoromethanesulfonyl, and nonafluorobutanesulfonyl.

[0147] Step 1 Compound (D-2) can be produced by coupling a compound (D-1) with an L4 detachment group to various nucleophiles in the presence of a palladium catalyst, a ligand, and a base. Examples of compounds (D-1) with an L4 detachment group include compounds with a halogen atom as a detachment group and compounds with a sulfonic acid-derived detachment group. These compounds can be produced using methods known to those skilled in the art, such as those described in *Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition* (RC Larock) or *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 7th Edition (MB Smith, J. March), and can be used in coupling reactions. Examples of nucleophiles used in coupling reactions are amine compounds, alcohol compounds, and compounds with boron-derived groups, which form CN, CO, and CC bonds, respectively, to produce the target compound. These coupling reactions can be performed using the methods of Buchwald et al. (Org. Synth., 2002, 78, 23), Suzuki et al. (Chem. Rev. 1995, 95, 2457-2483), and Buchwald et al. (J. Am. Chem. Soc. 2001, 123, 12202-12206).

[0148] The palladium catalyst and ligand used in the coupling reaction can be combined with commercially available palladium catalysts such as allyl palladium(II) chloride (dimer), palladium acetate, or Pd₂(dba)₃, and commercially available ligands such as rac-BINAP, dppf, SPhos, or Xantphos, or preferably complexes of palladium and ligands such as SPhos Pd G₃ or rac-BINAP Pd G₄. The base used in the coupling reaction can be, for example, tertiary amines (triethylamine, 4-methylmorphofolin, N,N-diisopropylethylamine, DBU, DABCO, etc.), inorganic bases such as carbonates or phosphates (sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc.), or metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-amyloxide, potassium tert-butoxide, potassium tert-amyloxide, etc.), preferably inorganic bases such as cesium carbonate.

[0149] Solvents used in the coupling reaction include, for example, ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), acetonitrile solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidone-2-one, etc.), and preferred examples are methyltetrahydrofuran and 1-methylpyrrolidone-2-one.

[0150] The appropriate reaction temperature for the coupling reaction is, for example, typically 0°C to the temperature range near the boiling point of the solvent, preferably 10°C to 120°C. The appropriate reaction time for the coupling reaction is, for example, typically 30 minutes to 24 hours, preferably 1 hour to 12 hours. The obtained compound (D-2) is separated using common techniques, and may also be purified by crystallization or chromatography if necessary.

[0151] Furthermore, when the dissociation group L4 of compound (D-1) is a fluorine atom, compound (D-2) can be produced by reacting compound (D-1) with various nucleophiles in the presence of a base via an SNAr reaction. Examples of bases used in SNAr reactions include tertiary amines (triethylamine, 4-methylmorphofolin, N,N-diisopropylethylamine, DBU, DABCO, etc.), inorganic bases (sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, etc.), and metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-amyloxide, potassium tert-butoxide, potassium tert-amyloxide, etc.), with preferred examples being DBU, sodium hydride, potassium carbonate, or potassium tert-butoxide.

[0152] Solvents used in SNAr reactions include, for example, ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), hydrocarbon solvents (benzene, toluene, etc.), and amide solvents (N,N-dimethylmethoxyamine, N,N-dimethylacetamide, 1-methylpyrrolidone-2-one, etc.). Preferred examples include hydrocarbon solvents such as toluene, or amide solvents such as 1-methylpyrrolidone-2-one.

[0153] The appropriate reaction temperature for the SNAr reaction is typically in the range of 0°C to near the boiling point of the solvent, preferably in the range of 20°C to 120°C. The appropriate reaction time for the SNAr reaction is typically in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The obtained compound (D-2) is separated using common techniques and, if necessary, purified by crystallization or chromatography.

[0154] General manufacturing method E [Chemistry 17] In the formula, L5 and L6 each independently represent the detaching radical, and Xa1, Xa3, Ra2, Xb1, Xb2, Xb3, Y, and Z are synonymous with the definitions in [1] above. Examples of detaching radicals L5 and L6 in general preparation E include halogen atoms, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, acetoxy, trifluoroacetoxy, methanesulfonyloxy, p-toluenesulfonyloxy, boron-derived radicals (4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane, 9-BBN, etc.), zinc-derived radicals, etc.

[0155] Step 1 Compound (E-3) can be prepared by coupling compound (E-1) having a detachable group L5 and compound (E-2) having a detachable group L6 in the presence of a palladium catalyst, a coordinating group, and a base. When the detachable group L5 of compound (E-1) is a halogen atom, L5 can also be replaced with other detachable groups, such as those derived from boron or zinc, before the coupling reaction. Compounds having such detachable groups can be prepared using methods well known to those skilled in the art, such as those described in *Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition* (RC Larock) or *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 7th Edition (MB Smith, J. March), for use in coupling reactions. The coupling reaction can be carried out according to the method of Suzuki et al. (Chem. Rev. 1995, 95, 2457-2483) or the method of Negishi et al. (J.Org. Chem. 1977, 42, 1821-1823).

[0156] The palladium catalyst used in the coupling reaction can be a product that can be purchased from commercial suppliers. For example, palladium and its ligands form complexes such as the 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex, the 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex, the bis(triphenylphosphine)palladium(II) dichlorobis(tricyclohexylphosphine)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl](3-chloropyridyl)palladium(II), (1,3-bis(2,6-diisopropylphenyl)imidazolinidine)(3-chloropyridyl)palladium(II), or [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-yl](3-chloropyridyl)palladium(II), or Org. Lett. 2014, 16, 4638-4641, or J. Am. Chem. Soc., Catalysts described in Buchwald et al., such as SPhos Pd G3, XPhos Pd G3, CPhos Pd G3, or XantPhos Pd G3, as recorded in 2014, 136, 14027-14030, are also available. Furthermore, palladium and ligands can be used in combination. Commercially available palladium, such as palladium acetate, allyl palladium(II) chloride (dimer), or Pd2(dba)3, can be appropriately combined with commercially available ligands such as dppf, SPhos, or Xantphos.

[0157] The base used in the coupling reaction is, for example, a tertiary amine (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), an inorganic base such as a carbonate or phosphate (sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, etc.), or a metal alkoxide (sodium methoxide, sodium tert-butoxide, sodium tert-amyloxide, potassium tert-butoxide, potassium tert-amyloxide, etc.), preferably an inorganic base such as cesium carbonate.

[0158] The solvent used in the coupling reaction may be, for example, an ether solvent (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dimethylethane, etc.), an acetylamine solvent (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidone-2-one, etc.), or acetonitrile, with 2-methyltetrahydrofuran and 1-methylpyrrolidone being preferred examples.

[0159] The appropriate reaction temperature for the coupling reaction is typically 0°C to near the boiling point of the solvent, preferably 10°C to 120°C. The reaction time is typically 30 minutes to 24 hours, preferably 1 hour to 12 hours. The obtained target compound (E-3) is separated using common techniques and, if necessary, purified by crystallization or chromatography.

[0160] <Pharmaceutical Compositions> The present invention provides pharmaceutical compositions containing compounds represented by formula (1) of the present invention. The pharmaceutical composition of the present invention, in addition to the compound represented by formula (1), salts of the compound represented by formula (1), or solvates thereof, can be introduced into a pharmaceutically acceptable carrier and formulated by known methods. Regarding formulation, commonly used excipients, binders, lubricants, colorants, flavoring and odor-correcting agents, etc., or, as needed, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc., can be used to formulate the components used as raw materials in general pharmaceutical preparations, and the formulation can be carried out according to conventional methods. Formulation refers to the process, through well-known methods, of shaping the active ingredients of pharmaceutical products into the most suitable form or property, i.e., dosage form, according to the method of use and purpose. Commonly used dosage forms include, for example, liquid pharmaceutical preparations (liquids), such as injections, suspensions, emulsions, and eye drops; tablets, powders, granules, pellets, coated tablets, capsules, and dry syrups. [)], throat lozenges, suppositories, and other solid pharmaceutical preparations (solid preparations), but not limited to these.

[0161] For example, a liquid formulation can be prepared by adding a compound of formula (1) of the present invention, or a salt thereof, or a solvate thereof, in appropriate combination with pharmaceutically acceptable additives commonly used in the pharmaceutical preparation field, such as sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., and then mixing them in the unit dosage form required by generally accepted pharmaceutical practices. Alternatively, a solid formulation prepared as a liquid can be dissolved in an appropriate solvent, such as sterile water or physiological saline, before administration, and then provided for administration.

[0162] This type of liquid can also be used, for example, in the form of a sterile solution or suspension for non-oral administration, in combination with pharmaceutically acceptable solutions such as water or other similar solutions. For example, it can be formulated by mixing with a pharmacologically acceptable carrier or solvent, specifically sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., in the unit dosage form required by generally accepted pharmaceutical practices. Specifically, examples include light anhydrous silica, lactose, crystalline cellulose, mannitol, starch, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylamino acetate, polyvinylpyrrolidone, gelatin, medium-chain triglycerides, polyoxyethylene cured castor oil 60, powdered sugar, carboxymethyl cellulose, corn starch, and inorganic salts as carriers. The amount of active ingredient in these formulations is set in a manner that allows for an appropriate volume to achieve the indicated range. The sterile composition for injection uses a carrier such as distilled water for injection and can be formulated according to the usual formulation implementation.

[0163] As an aqueous solution for injection, examples include isotonic solutions containing physiological saline, other adjuvants such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and appropriate dissolving agents such as alcohols, specifically ethanol, polyols such as propylene glycol and polyethylene glycol, and nonionic surfactants such as polysorbate 80 (registered trademark) and HCO-50.

[0164] Examples of oily solutions include sesame oil and soybean oil, and they can also be used in combination with benzyl benzoate and benzyl alcohol as dissolving agents. Furthermore, they can be formulated with buffers such as phosphate buffer and sodium acetate buffer, analgesics such as procaine hydrochloride, stabilizers such as benzyl alcohol and phenol, and antioxidants. The formulated injection solution is typically filled into appropriate ampoules.

[0165] For example, in the manufacture of solid preparations, the compound represented by formula (1) of the present invention, or its salt, or a solvate thereof, is appropriately combined with excipients, and further, as needed, binders, disintegrants, moisturizers, colorants, flavoring agents, odorants, etc., which are pharmaceutically acceptable additives commonly used in the pharmaceutical preparation field, and then, by conventional methods, is prepared as tablets, powders, granules, pellets, coated tablets, capsules, dry syrups, throat lozenges, suppositories, etc.

[0166] Pharmaceutically acceptable additives used in this type of solid preparation include, for example, vegetable and animal oils such as soybean oil, tallow, and synthetic glycerides; hydrocarbons such as flowing paraffin, squalane, and solid paraffin; ester oils such as octyl dodecyl myristate and isopropyl myristate; higher alcohols such as cetearyl alcohol and docosyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hardened castor oil, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyethylene polymers, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyvalent alcohols such as glycerol, propylene glycol, dipropylene glycol, and sorbitol; sugars such as lactose, lactose hydrate, fructose, and sucrose; and anhydrous silicic acid. Inorganic powders such as aluminum silicate, magnesium aluminum silicate, and aluminum silicate, as well as pure water.

[0167] Examples of excipients include sugars (e.g., lactose, lactose hydrate, fructose, sucrose, etc.), sugar alcohols (e.g., mannitol, etc.), starches (corn starch, potato starch, wheat starch, rice starch, partially pregelatinized (alpha) starch, pregelatinized starch, etc.), cellulose (e.g., crystalline cellulose), and inorganic salts (e.g., calcium silicate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc.).

[0168] Examples of binders include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol, polyoxyethylene, and block polymers.

[0169] Examples of disintegrants include croscarmellose sodium, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose, crystalline cellulose, sodium lauryl sulfate, povidone, or polysorbate.

[0170] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate, and hardened oils.

[0171] As a coloring agent, it is a permissible addition to pharmaceuticals. As a flavoring and odor-correcting agent, it can be cocoa powder, menthol, spices, peppermint oil, borneol, cinnamon bark powder, etc.

[0172] These tablets and granules may also be appropriately coated with sugar or other suitable substances. Furthermore, when manufacturing liquid formulations such as syrups and injectable preparations, pH adjusters, solubilizers, isotonic agents, and solubilizers and stabilizers as needed may be added to the compounds of the present invention or their pharmacologically permissible salts, and the formulation may be carried out by conventional methods.

[0173] Administration is preferably non-oral, but the method of administration is not limited to non-oral administration. Specific examples of non-oral administration include injectable formulations, nasal formulations, pulmonary formulations, and transdermal formulations. Examples of injectable formulations include systemic or local administration via intravenous injection, intramuscular injection, intraperitoneal injection, and subcutaneous injection.

[0174] Furthermore, an appropriate administration method can be selected based on the patient's age and symptoms. As for the dosage of a pharmaceutical composition containing the compound of formula (1) of the present invention, or its salt, or a solvate thereof, manufactured by the method of the present invention, for example, a range from 0.0001 mg to 1000 mg per kg of body weight per dose can be selected. Alternatively, a dosage range from 0.001 to 100000 mg / body per patient can be selected, but it is not necessarily limited to these values. The dosage and administration method vary depending on the patient's weight, age, symptoms, etc., but can be appropriately selected by those skilled in the art to which this invention pertains.

[0175] In one state, the compounds of the present invention can be used for Nrf2 activation, or for Keap1 inhibition and Nrf2 activation.

[0176] In one embodiment, the pharmaceutical composition of the present invention can be used for the treatment or prevention of diseases, such as those described in Nature Reviews Drug Discovery, 2019, 18, pp. 295-317, more specifically, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis; lung diseases such as acute pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary hypertension, and asthma; kidney diseases such as chronic kidney disease and acute kidney disease; and uveitis and glaucoma. Ophthalmic diseases such as age-related macular degeneration; liver diseases such as non-alcoholic steatohepatitis; immune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and ulcerative colitis; head and neck cancers (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, stomach cancer, colorectal cancers (cecal cancer, colon cancer, rectal cancer, etc.), lung cancers (small cell carcinoma, non-small cell carcinoma, etc.), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, and uterine cancers (endometrial cancer, cervical cancer, etc.). Solid cancers such as testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis and ureter cancer, malignant melanoma, and skin cancer; leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphoblastic leukemia, etc.); malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.); multiple myeloma; and myelodysplastic syndrome are examples of proliferative diseases of the blood and lymphatic system.

[0177] The term "object" in this specification includes mammals, with humans being a preferred mammal. [Example]

[0178] The invention is further illustrated by the following examples and references. All starting materials and reagents were purchased from commercial suppliers or synthesized using well-known methods. Room temperature (rt) refers to 5–35°C. HPLC purification of the compounds was performed using an AutoPurification HPLC / MS System (Waters) and Trilution (Gilson). ¹H-NMR spectroscopy was performed using Me₄Si as an internal standard, or without it, using an MR400 OneNMR probe (400 MHz, Agilent Technology), an AVANCE III HD 400 SMART-BBFO probe (400 MHz, Bruker), an ECP400 (400 MHz, JEOL), an AVANCE III HD 400 SMART-BBFO probe (400 MHz, Bruker), an MR400 OneNMR probe (400 MHz, Agilent Technology), or an AVANCE NEO 400 iProbe (400 MHz, Bruker). Measurements were performed using the following parameters: s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double doublet, dt = double triplet. triplet, td = triple doublet, m = multiplet. NMR data are expressed in ppm (parts per million, δ). Mass spectrometry data were obtained using a Shimadzu LCMS-2020 single quadrupole mass spectrometer with ultra-high-speed liquid chromatography (Nexera UC or Nexera) or a Waters SQD or SQD2 single quadrupole mass spectrometer with Acquity ultra-high-speed liquid chromatography (UPLC or UPLC I-Class). Two points regarding retention time are recorded, showing the retention time of its rotational isomers. Microwave irradiation was performed using an Initiator™ (Biotage).

[0179] Analysis condition A Installation:Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition B Device: Nexera UC / 2020 Column used: XSelect CSH C18 2.1mm I.D. × 50mm L, 2.5μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.75 min) → 100 / 0 (1.25 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition C Device:Nexera 2020 Column used: Meteoric Core C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition D Device:Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition E Device:Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 40 / 60 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition F Device:Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 5μm Column temperature: 35℃ Mobile phase and gradient: A) MeOH, B) 10 mM AA, H₂O, A / B = 5 / 95 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 0.9 mL / min Test wavelength (PDA total): 210-400nm Analysis condition G Installation:Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition H Installation:Nexera / 2020 Column used: Meteoric Core C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis Condition I Installation:Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 50 / 50 → 100 / 0 (1.0 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition J Installation:Nexera / 2020 Column used: Meteoric Core C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 50 / 50 → 100 / 0 (1.0 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition K Installation:Acquity SQD Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition L Installation:Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.7 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition M Installation:Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 5μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (4.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition N Installation:Nexera / 2020 Column used: Speed ​​Core C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition O Installation:Acquity SQD Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.05% FA, CH3CN; B) 0.05% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.0 min) → 100 / 0 (0.4 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition P Installation:Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 50 / 50 → 100 / 0 (1.0 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition Q Installation:Nexera / 2020 Column used: Kinetex 1.7u C18 2.1mm I.D. × 50mm L, 1.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 0 / 100 (1.5 min) → 0 / 100 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis condition R Device: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 3.0mmD × 50mm.L, 2.2μm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 95 / 5 (2.0 min) → 95 / 5 (0.7 min) Flow rate: 1.2 mL / min Test wavelength (PDA total): 190-400nm Analysis condition S Device: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 2.1mmD × 50mm.L, 2.6μm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 95 / 5 (2.0 min) → 95 / 5 (0.7 min) Flow rate: 1 mL / min Test wavelength (PDA total): 190-400nm Analysis condition T Device: Shimadzu LCMS-2020 String used: Halo C18 2.1mmD × 30mm.L, 2.0μm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (0.7 min) → 100 / 0 (0.25 min) Flow rate: 0.8 mL / min Test wavelength (PDA total): 190-400nm Analysis condition U Device: Shimadzu LCMS-2020 Column used: InertCore C18 2.1mmD × 50mm.L, 2.6μm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (L min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 190-400nm Analysis condition V Device: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 3.0mmD × 50mm.L, 2.2μm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (1.1 min) → 100 / 0 (0.6 min) Flow rate: 1.2 mL / min Test wavelength (PDA total): 190-400nm Analysis condition W Device: Shimadzu LCMS-2020 Tube string used: XSelect HSS T3 3.0mmD × 50mm.L, 2.5μm Column temperature: 40℃ Moving phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% TFA, H2O; A / B = 5 / 95 → 95 / 5 (1.1 min) → 95 / 5 (0.6 min) Flow rate: 1.2 mL / min Test wavelength (PDA total): 190-400nm Analysis condition X Device: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 3.0mmD × 50mm.L, 2.2μm Column temperature: 40℃ Moving phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 95 / 5 (1.1 min) → 95 / 5 (0.6 min) Flow rate: 1.2 mL / min Test wavelength (PDA total): 190-400nm Analysis of condition Y Device: Shimadzu LCMS-2020 Tubing used: CORTECS C18 2.1mmD × 50mm.L, 2.7μm Column temperature: 40℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.2 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 190-400nm Analysis condition Z Device: Shimadzu LCMS-2020 Column used: Kinetex EVO C18 2.1mmD × 50mm.L, 2.6μm Column temperature: 40℃ The moving phase and gradient: A) CH3CN, B) 6.5mM NH4HCO3, H2O, A / B = 10 / 90 → 95 / 5 (1.1 min) → 95 / 5 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 190-400nm Analysis conditions AA Device: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 3.0mmD × 50mm.L, 2.2μm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 30 / 70 → 80 / 20 (3.8 min) → 80 / 20 to 100 / 0 (0.3 min) → 100 / 0 (0.5 min) Flow rate: 1.2 mL / min Test wavelength (PDA total): 190-400nm Analysis conditions AB Device: Shimadzu LCMS-2020 Tubing used: Waters T3 4.6mmD × 100mm.L, 3.0μm Column temperature: 40℃ Moving phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.2 min) → 100 / 0 (1.8 min) Flow rate: 1.2 mL / min Test wavelength (PDA total): 190-400nm Analysis conditions AC Device: Shimadzu LCMS-2020 Column used: Kinetex XB-C18 3.0mmD × 30mm.L, 1.7μm Column temperature: 40℃ Moving phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.2 min) → 100 / 0 (1.8 min) Flow rate: 1.2 mL / min Test wavelength (PDA total): 190-400nm Analysis conditions AD Device: Shimadzu LCMS-2020 Column used: halo-C18 3.0mmD × 30mm.L, 2.0μm Column temperature: 40℃ Moving phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (1.5 min) Flow rate: 1.5 mL / min Test wavelength (PDA total): 190-400nm Analysis conditions AE Device: Shimadzu LCMS-2020 String used: Halo 90A C18 3.0mmD × 30mm.L, 2.0μm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (1.5 min) → 100 / 0 (1.5 min) Flow rate: 1.5 mL / min Test wavelength (PDA total): 190-400nm Analysis conditions AF Installation:Nexera / 2020 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 5μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (4.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis conditions AG Device:Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1mm I.D. × 50mm L, 2.7μm Column temperature: 35℃ Shifting phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = 5 / 95 → 100 / 0 (4.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Test wavelength (PDA total): 210-400nm Analysis conditions AH Device: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 3mm × 5cm, 2.2μm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (2.2 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Test wavelength (PDA total): 220±4nm Analysis Condition AI Device: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 2.2μm 3mm × 5cm Column temperature: 40℃ Moving phase and gradient: A) 0.05% TFA, CH3CN; B) 0.05% TFA, H2O; A / B = 5 / 95 → 100 / 0 (1.2 min) → 100 / 0 (1.0 min) Flow rate: 1 mL / min Test wavelength (PDA total): 254±4nm

[0180] Compounds 1-7 4-[3-[2,6-dichloro-4-(2,2-difluoro-5-azaspiro[2.3]hexane-5-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound A9 N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate tributyl ester [Chemistry 18] A solution of 3-bromo-2-hydroxybenzaldehyde (5.00 g, 24.9 mmol) and tributyl carbamate (8.74 g, 74.6 mmol) in acetonitrile (35.0 mL) was cooled to 0 °C. Triethylsilane (11.9 mL, 74.6 mmol) and trifluoroacetic acid (3.81 mL, 49.7 mmol) were added to the reaction solution. After stirring at 35 °C for 5 hours, the mixture was cooled to room temperature. After stirring at room temperature for 15 hours, water was added to the reaction solution and stirred for 1 hour. Water was added again, and the mixture was stirred for 30 minutes. The reaction solution was filtered, and the obtained solid was washed with acetonitrile / water (1 / 2). The solid was then washed with heptane and dried under reduced pressure to give the title compound (88%, 6.60 g). LCMS:m / z 300[MH] - HPLC retention time: 1.16 minutes (analytical condition G)

[0181] Second step Compound A10 8-Bromo-2,4-dihydro-1,3-benzo[3]-3-carboxylic acid tributyl ester (tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate) [Chemistry 19] In a solution of N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate tributyl ester (5.00 g, 16.6 mol) in acetonitrile (30.0 mL), 36% formaldehyde aqueous solution (5.06 mL, 66.2 mmol) and formic acid (5.08 mL, 132 mmol) were added, and the mixture was stirred at 56 °C for 7 hours. The reaction solution was cooled to 25 °C, water was added, and the mixture was stirred for 30 minutes. Water was added again, and the mixture was stirred for another 30 minutes. The reaction solution was filtered, and the obtained solid was washed with acetonitrile / water (1 / 2). The solid was dried under reduced pressure to give the title compound (81%, 4.20 g). LCMS:m / z 214[M-Boc+H] + HPLC retention time: 1.31 minutes (analytical condition G)

[0182] Third step Compound A4 4-Bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 20] A suspension of 4-bromo-2,5-difluorobenzoic acid (3.00 g, 12.7 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (2.46 g, 16.5 mmol) in tetrahydrofuran (6.00 mL) was added to a 1M solution of (bis(trimethylsilyl)aminolithium) in tetrahydrofuran (50.6 mL, 50.6 mmol) at room temperature for 12 minutes. The reaction mixture was stirred at room temperature for 5.5 hours and then allowed to stand at room temperature for 15 hours. 2M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the two organic layers were combined and washed with 20% ammonium chloride aqueous solution and 15% sodium chloride aqueous solution. The crude product of the title compound was obtained by concentrating the washed organic layer. LCMS:m / z 330[M+H] + HPLC retention time: 0.61 minutes (analytical condition D)

[0183] Fourth step Compound A5 Methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 21] A solution of 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid (4.18 g, 12.7 mmol) in N,N-dimethylformamide (21.0 mL) was added, along with potassium carbonate (2.10 g, 15.2 mmol) and methyl iodoforme (1.58 mL, 25.3 mmol), and the mixture was stirred at room temperature for 30 minutes. A 20% aqueous solution of ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 20% aqueous solution of ammonium chloride and concentrated. Methanol was added to the crude product, and the mixture was heated to 60°C, cooled to room temperature, and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was stirred for 1 hour, followed by another 30 minutes of stirring. The reaction mixture was filtered, and the resulting solid was washed with methanol / water (1 / 1) and dried under reduced pressure to obtain the title compound (55%, 2.38 g). LCMS:m / z 344[M+H] + HPLC retention time: 1.18 minutes (analytical condition G)

[0184] Fifth step Compound A6 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3]3-carboxylic acid tributyl ester [Chemistry 22] A solution of methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate (1.21 g, 3.50 mmol) in tetrahydrofuran (5.30 mL) was cooled to -10 °C. A 2M solution of magnesium isopropyl chloride in tetrahydrofuran (1.91 mL, 3.82 mmol) was added, and the mixture was stirred for 1 hour. A 2M solution of zinc(II)-2-methyltetrahydrofuran (0.955 mL, 1.91 mmol) was added to the reaction mixture. A terbutyl ester of 8-bromo-2,4-dihydro-1,3-benzo[3]3-carboxylic acid (1.00 g, 3.18 mmol) and SPhos Pd G3 (0.0250 g, 0.0320 mmol) were added to the reaction mixture, and the mixture was heated to 45 °C and stirred for 90 minutes. The reaction solution was cooled to room temperature, and ethyl acetate and ammonium chloride aqueous solution were added. Extraction was performed with ethyl acetate. The organic layer was washed with aqueous N-acetylcysteine ​​and sodium chloride solution, and concentrated to obtain the crude product. Ethanol was added to the crude product, and the mixture was heated to 80°C to dissolve it, then cooled to room temperature. Heptane was added to the obtained solution, and the mixture was cooled to 0°C. The filtered solid was washed with ethanol / heptane (1 / 2) and dried under reduced pressure to give the title compound (73%, 1.16 g). LCMS:m / z 499[M+H] + HPLC retention time: 1.40 min (analytical condition G)

[0185] Step Six Compound A7 4-(3,4-dihydro-2H-1,3-benzo[3,4]3-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate dihydrochloride [Chemistry 23] A solution of 4M ethyl acetate hydrochloride (25.1 mL, 100 mmol) was added to 100 mL of acetonitrile containing 10.0 g (20.1 mmol) of tributyl 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-]-3-carboxylic acid. The mixture was stirred at room temperature for 2 hours. The solid obtained was filtered to yield crystals of the title compound (76%, 7.16 g). LCMS:m / z 399[M+H] + HPLC retention time: 0.75 minutes (analytical condition G)

[0186] Step 7 Compound A2 4-Bromo-2,6-dichlorobenzoic acid [Chemistry 24] A solution of 4-bromo-2,6-dichlorobenzoic acid (45.5 g, 169 mmol) in toluene (241 mL) was added, along with thionyl chloride (24.5 mL, 337 mmol) and N,N-dimethylformamide (0.261 mL, 3.37 mmol), and stirred at 70 °C for 7 hours. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (99%, 48.0 g). HPLC retention time: 1.48 minutes (analytical condition G) 1H-NMR (400 MHz, CDCl 3) δ 7.56 (s, 2H)

[0187] Step 8 Compound A Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[8-]]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 25] A solution of methyl 4-(3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-dihydro-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3,2.1]oct-8-yl)benzoate dihydrochloride (9.22 g, 19.6 mmol)) in toluene (92.0 mL) was added, along with 4-bromo-2,6-dichlorobenzoyl chloride (7.33 g, 25.4 mmol) and pyridine (11.1 mL, 137 mmol). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was extracted with ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with 50% saturated sodium bicarbonate aqueous solution and 50% saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After filtration through the drying agent, the filtrate was concentrated, and the residue was triturated with hexane to give the title compound (48%, 6.06 g). LCMS:m / z 649[M+H] + HPLC retention time: 1.42 minutes (analytical condition G)

[0188] Step 9 Compounds 1-7 4-[3-[2,6-dichloro-4-(2,2-difluoro-5-azaspiro[2.3]hex-5-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 26] A suspension of compound A (30.0 mg, 0.0460 mmol), 2,2-difluoro-5-azaspiro[2.3]hexane hydrochloride (14.4 mg, 0.0920 mmol), rac-BINAP Pd G4 (2.32 mg, 0.00231 mmol), and cesium carbonate (45.1 mg, 0.138 mmol) in 1,4-dioxane (0.231 mL) was stirred at 110 °C for 1.5 h. The reaction mixture was cooled to room temperature, and methanol (0.230 mL) and 8M potassium hydroxide aqueous solution (0.0575 mL, 0.460 mmol) were added. After stirring at room temperature for 1 h, the mixture was stirred at 50 °C for 1 h. Formic acid aqueous solution was added to the reaction mixture, and the mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (83%, 25.7 mg). LCMS:m / z 674[M+H] + HPLC retention time: 1.61 min, 1.64 min (analytical condition B)

[0189] Compounds 1-33 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3,2.1]oct-8-yl]benzoic acid First step Compound CP5 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl benzoate [Chemistry 27] A solution of compound A (20.2 g, 31.1 mmol), (3R)-1,3-dimethylpiperazine (4.61 g, 40.4 mmol), rac-BINAP Pd G4 (938 mg, 0.932 mmol), and cesium carbonate (30.4 g, 93.0 mmol) in 1,4-dimethylpiperazine (202 mL) was stirred at 80 °C for 7.5 h. Then, (3R)-1,3-dimethylpiperazine (2.48 g, 21.7 mmol) was added, and the reaction mixture was stirred at 100 °C for 49 h. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was washed with 15% sodium chloride aqueous solution, and the residue obtained by concentrating the organic layer was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to give the title compound (75%, 15.9 g). LCMS:m / z 683[M+H] + HPLC retention time: 0.89 minutes (analytical condition G)

[0190] Second step Compounds 1-33 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3,2.1]oct-8-yl]benzoic acid [Chemistry 28] A solution of methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl]benzoate (18.6 g, 27.2 mmol) in 1-methylpyrrolidine-2-one (186 mL) was added to an 8M aqueous solution of potassium hydroxide (11.9 mL, 95.0 mmol), and the mixture was stirred at 60 °C for 2 hours. An aqueous solution of formic acid was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (85%, 15.4 g). LCMS:m / z 669[M+H] + HPLC retention time: 0.99 min, 1.04 min (analytical condition B)

[0191] Using amines and compound A listed in Table 1-2 that are known in the literature or commercially available, the compounds shown in Table 1-1 were synthesized via the same procedure as step nine of compounds 1-7. However, in the synthesis of compounds 1-1, 1-5, 1-34, 1-41, and 1-42, toluene solution was used instead of 1,4-dimethylolpropane solution; in the synthesis of compounds 1-6, 1-16, 1-17, 1-43, and 1-45, 1-methylpyrrolidone solution was used; and in the synthesis of compounds 1-19, 1-20, and 1-44, a solution of 1-methylpyrrolidone:water = 10:1 was used. Furthermore, in the synthesis of compounds 1-32 and 1-46, Xantphos Pd G4 was used instead of rac-BINAP Pd G4.

[0192] [Table 1-1]

[0193] [Table 1-2]

[0194] Compounds 1-4 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylacetyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step compound a1 (2R,3R)-3-methoxy-2-methylacetyl-1-carboxylic acid benzyl ester [Chemistry 29] A solution of (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylic acid benzyl ester (267 mg, 1.21 mmol) and iodomethane (343 mg, 2.41 mmol) in tetrahydrofuran (3.02 mL) was cooled to 0 °C. 60% sodium hydride (72.4 mg, 1.81 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. An aqueous formic acid solution was added to the reaction mixture, and the reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (92%, 261 mg). LCMS:m / z 236[M+H] + HPLC retention time: 0.71 minutes (analytical condition D)

[0195] Second step Compounds 1-4 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylacetyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 30] A 10% palladium / carbon solution (353 mg, 0.332 mmol) was added to a methanol (4.42 mL) solution of (2R,3R)-3-methoxy-2-methylacetate-1-carboxylic acid benzyl ester (260 mg, 1.11 mmol). The mixture was stirred at room temperature for 2 hours under hydrogen conditions. The reaction solution was filtered through diatomaceous earth, and a methanol solution of hydrochloric acid was added to the filtrate. The reaction solution was concentrated to obtain a crude product of (2R,3R)-3-methoxy-2-methylacetate hydrochloride. Using the obtained crude product and compound A, the title compound was obtained by the same procedure as in step nine of compounds 1-7. LCMS:m / z 656[M+H] + HPLC retention time: 1.57 min, 1.60 min (analytical condition B)

[0196] Compounds 1-9 4-[3-[2,6-dichloro-4-(3-methoxy-2,2-dimethylacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2,1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound b1 1-Diphenylmethyl-3-methoxy-2,2-dimethylacetate [Chemistry 31] A solution of 1-benzhydryl-2,2-dimethylacetate-3-ol (50.0 mg, 0.187 mmol) and methyl iodoform (53.1 mg, 0.374 mmol) in tetrahydrofuran (0.468 mL) was cooled to 0 °C. 60% sodium hydride (11.2 mg, 0.281 mmol) was added, and the mixture was stirred at room temperature for 2 hours. An aqueous formic acid solution was added to the reaction mixture, and the solution was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (94%, 49.7 mg). LCMS:m / z 282[M+H] + HPLC retention time: 0.54 minutes (analytical condition D)

[0197] Second step Compounds 1-9 4-[3-[2,6-dichloro-4-(3-methoxy-2,2-dimethylacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2,1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 32] 20% palladium hydroxide / carbon (122 mg, 0.174 mmol) was added to methanol (0.871 mL) containing 49.0 mg (0.174 mmol). The mixture was stirred at room temperature for 2 hours under hydrogen conditions. The reaction solution was filtered through diatomaceous earth, and hydrochloric acid-methanol solution was added to the filtrate. The reaction solution was concentrated to obtain a crude product of 3-methoxy-2,2-dimethylacetate hydrochloride. Using the obtained crude product and compound A, the title compound was obtained by the same procedure as in step nine of compounds 1-7. LCMS:m / z 670[M+H] + HPLC retention time: 1.61 min, 1.65 min (analytical condition B)

[0198] Compounds 1-84 4-[3-[2,6-dichloro-4-[(2R,3S)-2-methyl-3-morpholin-4-ylacet-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound C1 (2R,3S)-2-methyl-3-morpholine-4-ylacetyl-1-carboxylic acid benzyl ester [Chemistry 33] A solution of (2R,3R)-3-hydroxy-2-methylacetate-1-carboxylic acid benzyl ester (36.0 mg, 0.163 mmol) and N,N-diisopropylethylamine (0.0425 mL, 0.244 mmol) in dichloromethane (1.63 mL) was cooled to -78 °C. Trifluoromethanesulfonic anhydride (0.0401 mL, 0.244 mmol) was added, and the mixture was stirred at -78 °C for 1 hour. Morphine (0.142 mL, 1.63 mmol) was added, and the mixture was stirred overnight at room temperature. After stirring overnight at room temperature, the mixture was stirred at 40 °C for 4 hours. The reaction mixture was concentrated with methanol, and the residue was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (57%, 27.0 mg). LCMS:m / z 291[M+H] + HPLC retention time: 0.84 minutes (analytical condition F)

[0199] Second step Compounds 1-84 4-[3-[2,6-dichloro-4-[(2R,3S)-2-methyl-3-morpholin-4-ylacet-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 34] A 10% palladium / carbon solution (27.5 mg, 0.0260 mmol) was added to a methanol (0.344 mL) solution of (2R,3S)-2-methyl-3-morphofolin-4-ylacetate-1-carboxylic acid benzyl ester (25.0 mg, 0.0860 mmol). The mixture was stirred at room temperature for 1 hour under hydrogen conditions. The reaction solution was filtered through diatomaceous earth, and a methanol solution of hydrochloric acid was added to the filtrate. The reaction solution was concentrated to obtain a crude product of 4-[(2R,3S)-2-methylacetate-3-yl]morphofolin hydrochloride. Using the obtained crude product and compound A, the title compound was obtained by the same procedure as in step nine of compounds 1-7. LCMS:m / z 711[M+H] + HPLC retention time: 1.14 minutes (analytical condition B)

[0200] Compounds 1-85 4-[3-[2,6-dichloro-4-[(2R,3R)-2-methyl-3-morpholin-4-ylazido-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step compound C2 (2R,3R)-2-methyl-3-morpholin-4-ylacetyl-1-carboxylic acid benzyl ester [Chemistry 35] A solution of (2R)-2-methyl-3-sideoxyacetate-1-carboxylic acid benzyl ester (60.0 mg, 0.274 mmol) and morpholin (0.0265 mL, 0.301 mmol) in dichloromethane (0.684 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (69.6 mL, 0.328 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Dichloromethane was added to the reaction mixture, and the solution was washed with a saturated aqueous sodium bicarbonate solution. The organic layer was concentrated, and the residue was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (45%, 36.0 mg). LCMS:m / z 291[M+H] + HPLC retention time: 0.87 minutes (analytical condition F)

[0201] Second step Compounds 1-85 4-[3-[2,6-dichloro-4-[(2R,3R)-2-methyl-3-morpholin-4-ylazido-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 36] A 10% palladium / carbon solution (35.2 mg, 0.0330 mmol) was added to a methanol (0.411 mL) solution of (2R,3R)-2-methyl-3-morphofolin-4-ylacetate-1-carboxylic acid benzyl ester (32.0 mg, 0.110 mmol). The mixture was stirred at room temperature for 1 hour under hydrogen conditions. The reaction solution was filtered through diatomaceous earth, and a methanol solution of hydrochloric acid was added to the filtrate. The reaction solution was concentrated to obtain a crude product of 4-[(2R,3R)-2-methylacetate-3-yl]morphofolin hydrochloride. Using the obtained crude product and compound A, the title compound was obtained by the same procedure as in step nine of compounds 1-7. LCMS:m / z 711[M+H] + HPLC retention time: 1.16 minutes (analytical condition B)

[0202] Compounds 1-22 4-[3-[2,6-dichloro-4-[(7S)-7-methoxy-5-oxa-2-azaspiro[3.4]oct-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Chemistry 37] A solution of (7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octyl-2-carboxylic acid tributyl ester (54.6 mg, 0.238 mmol) in tetrahydrofuran (2.38 mL) was cooled to 0 °C. 60% sodium hydride (23.8 mg, 0.595 mmol) was added, and the mixture was stirred at 0 °C for 5 minutes. Iodomethane (67.6 mg, 0.476 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. 60% sodium hydride (23.8 mg, 0.595 mmol) and iodomethane (67.6 mg, 0.476 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. 1-Methylpyrrolidone (0.238 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product of tributyl (7S)-7-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid. Trifluoroacetic acid (0.501 mL, 6.54 mmol) was added to a dichloromethane (1.50 mL) solution of the obtained crude product, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain a crude product of (7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octane trifluoroacetate. Using the obtained crude product and compound A, the title compound was obtained by the same procedure as in step nine of compounds 1-7. However, toluene was used instead of 1,4-dimethylamine as the solvent. LCMS:m / z 698[M+H] + HPLC retention time: 1.63 min, 1.64 min (analytical condition B)

[0203] Compounds 1-23 4-[3-[2,6-dichloro-4-[(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]oct-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Chemistry 38] The title compound was obtained by using (7R)-7-hydroxy-5-oxa-2-azaspiro[3.4]octyl-2-carboxylic acid tributyl ester via the same procedure as that used for compounds 1-22. LCMS:m / z 698[M+H] + HPLC retention time: 1.62 min, 1.63 min (analytical condition B)

[0204] Compounds 1-31 4-[3-[2,6-dichloro-4-[(8S)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid First step compound e1 (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid tributyl ester [Chemistry 39] compound e2 (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid tributyl ester [Chemistry 40] A 10% palladium / carbon (6.76 mg, 0.0640 mmol) solution of 33.8 mg (0.140 mmol) of tributyl 8-methoxy-5-oxa-2-azaspiro[3.4]oct-7-en-2-carboxylic acid was added to a methanol (2.8 mL) solution. The mixture was stirred at room temperature for 15 hours under hydrogen conditions. The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a racemic mixture of 8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid tributyl ester. The obtained racemic mixture was purified by SFC (CHIRALPAKIG, supercritical carbon dioxide / ethanol / methyl tributyl ether) to obtain tributyl (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid (31%, 10.7 mg) and (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid (25%, 8.40 mg).

[0205] compound e1 (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid tributyl ester [Chemistry 41] LCMS:m / z 244[M+H] + SFC retention time: 4.72 min (analytical conditions: CHIRALPAK IG 4.6 mm I.D. x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / methyl tributyl ether = 1 / 1] = 90 / 10 (10 min), 40 °C, 210 nm)

[0206] compound e2 (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid tributyl ester [Chemistry 42] LCMS:m / z 244[M+H] + SFC retention time: 5.37 min (analytical conditions: CHIRALPAK IG 4.6 mm IDx250 mm, 5 μm, supercritical carbon dioxide / [ethanol / methyl tributyl ether=1 / 1]=90 / 10 (10 min), 40 °C, 210 nm)

[0207] Second step Compounds 1-31 4-[3-[2,6-dichloro-4-[(8S)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Chemistry 43] A solution of (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octyl-2-carboxylic acid tributyl ester (10.7 mg, 0.0440 mmol) in dichloromethane (0.750 mL) was added to trifluoroacetic acid (0.250 mL, 3.26 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the obtained crude product and compound A were used to obtain the title compound by the same procedure as step nine of compounds 1-7. However, toluene was used instead of 1,4-dimethylamine as the solvent. LCMS:m / z 698[M+H] + HPLC retention time: 1.67 min, 1.68 min (analytical condition B)

[0208] Compounds 1-30 4-[3-[2,6-dichloro-4-[(8R)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Chemistry 44] The title compound was obtained by using the same procedure as that used in the preparation of compound 1-31, and the tributyl (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]oct-2-carboxylic acid obtained in the first step. LCMS:m / z 698[M+H] + HPLC retention time: 1.67 min, 1.68 min (analytical condition B)

[0209] Compounds 1-24 4-[3-[2,6-dichloro-4-[(1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid First step Compound f1 6-Methoxy-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (O-tert butyl 6-methoxy-2-azaspiro[3.3]heptane-2-carbothioate) [Chemistry 45] A solution of 2M sodium tert-butoxide in tetrahydrofuran (1.00 mL) was added to a solution of carbon disulfide (0.0280 mL, 0.458 mmol) in tetrahydrofuran (0.489 mL, 0.978 mmol), and stirred at room temperature for 30 minutes. Iodomethane (0.0267 mL, 0.428 mL) was added, and stirred at room temperature for 15 minutes. The reaction solution was cooled to 0°C, and 6-methoxy-1-methyl-2-azaspiro[3.3]heptane hydrochloride (50.0 mg, 0.306 mmol) and triethylamine (0.0639 mL, 0.458 mmol) were added, and stirred at 0°C for 1 hour. A 1M aqueous solution of potassium hydroxide was added to the reaction solution, and the mixture was extracted with diethyl ether and passed through a phase separator. After concentrating the organic layer, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (85%, 63.3 mg). LCMS:m / z 188[M-tBu+H] + HPLC retention time: 0.93 minutes (analytical condition D)

[0210] Second step Compound F2 (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 46] Compound F3 (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 47] A solution of 6-methoxy-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (63.3 mg, 0.260 mmol) in tetrahydrofuran (1.30 mL) was cooled to -78 °C. Tetramethylethylenediamine (0.118 mL, 0.780 mmol) and a 1.05 M butyllithium cyclohexane-hexane solution (0.495 mL, 0.520 mmol) were added, and the mixture was stirred at -78 °C for 35 min. Iodomethane (0.0650 mL, 1.04 mmol) was added, and the mixture was stirred at -78 °C for 10 min, followed by stirring at room temperature for 40 min. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether and passed through a phase separator. After concentrating the organic layer, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a non-diastereo mixture of 6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (61%, 40.7 mg). The non-mirror image mixture (40.7 mg, 0.158 mmol) was purified by HPLC (CHIRALPAK IE, hexane / 2-propanol) to obtain a racemic mixture of (4S,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (47%, 19.0 mg) and (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (34%, 14.0 mg).

[0211] Compound F2 (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate O-tert-butyl(4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate [Chemistry 48] LCMS:m / z 202[M-tBu+H] + SFC retention time: 4.16 min, 5.18 min (analytical conditions: CHIRALPAK IC 4.6 mm IDx250 mm, 5 μm, supercritical carbon dioxide / [ethanol / methyl tributyl ether = 1 / 1] = 90 / 10 (10 min), 40 °C, 254 nm)

[0212] Compound F3 (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 49] LCMS:m / z 202[M-tBu+H] + SFC retention time: 4.79 min, 5.88 min (analytical conditions: CHIRALPAK IC 4.6 mm IDx250 mm, 5 μm, supercritical carbon dioxide / [ethanol / methyl tributyl ether = 1 / 1] = 90 / 10 (10 min), 40 °C, 254 nm)

[0213] Third step Compound F4 (1S,4S,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hepta-2-thiocarboxylic acid O-tert-butyl ester [Transformation 50] Compound F5 (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 51] Compound F6 (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 52] Compound F7 (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 53] A racemic mixture of (4S,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (19.0 mg, 0.0740 mmol) was purified by HPLC (CHIRALPAKIC, hexane / 2-propanol) to obtain (1S,4S,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (41%, 7.70 mg) and (1R,4S,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (39%, 7.40 mg).

[0214] Compound F4 (1S,4S,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hepta-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 54] LCMS:m / z 202[M-tBu+H]+ SFC retention time: 4.09 min (analytical conditions: CHIRALPAK IC 4.6 mm IDx250 mm, 5 μm, supercritical carbon dioxide / [ethanol / methyl tributyl ether = 1 / 1] = 90 / 10 (10 min), 40 °C, 254 nm)

[0215] Compound F5 (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 55] LCMS:m / z 202[M-tBu+H] + SFC retention time: 5.09 min (analytical conditions: CHIRALPAK IC 4.6 mm IDx250 mm, 5 μm, supercritical carbon dioxide / [ethanol / methyl tributyl ether = 1 / 1] = 90 / 10 (10 min), 40 °C, 254 nm)

[0216] A racemic mixture of (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (14.0 mg, 0.0540 mmol) was purified by HPLC (CHIRALPAKIC, hexane / 2-propanol) to obtain (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (36%, 5.10 mg) and (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (40%, 5.60 mg).

[0217] Compound F6 (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 56] LCMS:m / z 202[M-tBu+H]+ SFC retention time: 4.73 min (analytical conditions: CHIRALPAK IC 4.6 mm IDx250 mm, 5 μm, supercritical carbon dioxide / [ethanol / methyl tributyl ether = 1 / 1] = 90 / 10 (10 min), 40 °C, 254 nm)

[0218] Compound F7 (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester [Chemistry 57] LCMS:m / z 202[M-tBu+H] + SFC retention time: 5.81 min (analytical conditions: CHIRALPAK IC 4.6 mm IDx250 mm, 5 μm, supercritical carbon dioxide / [ethanol / methyl tributyl ether = 1 / 1] = 90 / 10 (10 min), 40 °C, 254 nm)

[0219] Fourth step Compounds 1-24 4-[3-[2,6-dichloro-4-[(1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Chem.58] A solution of (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester (5.60 mg, 0.0220 mmol) in dichloromethane (0.218 mL) was added to trifluoroacetic acid (0.00335 mL, 0.0440 mmol), and the mixture was stirred overnight at room temperature. Trifluoroacetic acid (0.0335 mL, 0.0440 mmol) was then added, and the mixture was stirred for another 1 hour at room temperature. The reaction mixture was concentrated, and the obtained crude product and compound A were used to obtain the title compound via the same procedure as step nine of compounds 1-7. LCMS:m / z 696[M+H] + HPLC retention time: 1.75 min, 1.78 min (analytical condition B)

[0220] Compounds 1-25 4-[3-[2,6-dichloro-4-[(1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Chemistry 59] The title compound was obtained using (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester via the same procedure as in the fourth step of compounds 1-24. LCMS:m / z 696[M+H] + HPLC retention time: 1.75 min, 1.78 min (analytical condition B)

[0221] Compounds 1-26 4-[3-[2,6-dichloro-4-[(1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Transformation 60] The title compound was obtained using (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester via the same procedure as in the fourth step of compounds 1-24. LCMS:m / z 696[M+H] + HPLC retention time: 1.75 min, 1.78 min (analytical condition B)

[0222] Compounds 1-27 4-[3-[2,6-dichloro-4-[(1S,4S,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Chemistry 61] The title compound was obtained using (1S,4S,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]hept-2-thiocarboxylic acid O-tert-butyl ester via the same procedure as in the fourth step of compounds 1-24. LCMS:m / z 696[M+H] + HPLC retention time: 1.74 min, 1.78 min (analytical condition B)

[0223] Compounds 1-86 4-[3-[2,6-dichloro-4-[rel-(6R,7R)-6-methoxy-7-methyl-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid First step Compound g1 6-(dimethylhydrazine)-2-azaspiro[3.3]hept-2-carboxylic acid tributyl ester [Chemistry 62] A solution of tributyl 6-sidekto-2-azaspiro[3.3]hept-2-carboxylic acid (100 mg, 0.473 mmol), 1,1-dimethylhydrazine (0.0470 mL, 0.615 mmol), and acetic acid (0.0310 mL, 0.544 mL) in tetrahydrofuran (2.00 mL) was stirred at 60 °C for 2 hours. After distilling off the tetrahydrofuran, 1M sodium hydroxide aqueous solution was added. The reaction solution was extracted with ethyl acetate and passed through a phase separator. After concentrating the organic layer, the residue was purified by silica gel column chromatography (hexane / ethyl acetate, then ethyl acetate / methanol) to give the title compound (93%, 111 mg). LCMS:m / z 254[M+H] + HPLC retention time: 0.83 minutes (analytical condition F)

[0224] Second step compound g2 rac-(5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]hepta-2-carboxylic acid tributyl ester (rac-tert butyl (5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate) [Chemistry 63] Compound g3 rac-(5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]hepta-2-carboxylic acid tributyl ester [Chemistry 64] A solution of 6-(dimethylhydrazinyl)-2-azaspiro[3.3]hept-2-carboxylic acid tributyl ester (89.5 mg, 0.353 mmol) in tetrahydrofuran (3.60 mL) was cooled to -78 °C, and a 1.5 M solution of lithium diisopropylamide tetrahydrofuran in ethylphenylheptane (0.283 mL, 0.424 mmol) was added. The reaction mixture was stirred at 0 °C for 30 minutes and then cooled to -78 °C. Iodomethane (0.0660 mL, 1.06 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated, and saturated oxalic acid aqueous solution (1.80 mL) and ethyl acetate (1.80 mL) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and passed through a phase separator. After concentrating the organic layer, crude product of 5-methyl-6-sideoxy-2-azaspiro[3.3]hept-2-carboxylic acid tributyl ester was obtained. The obtained crude product was cooled to 0°C in a solution of dichloromethane (3.00 mL) and methanol (3.00 mL), and sodium borohydride (26.5 mg, 0.700 mmol) was added. The reaction mixture was stirred at 0°C for 35 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and passed through a phase separator. After concentrating the organic layer, a non-mirror image mixture of 6-hydroxy-5-methyl-2-azaspiro[3.3]hept-2-carboxylic acid tributyl ester (84%, 67.0 mg) was obtained. The non-mirror image mixture (59.0 mg, 0.260 mmol) was purified by HPLC (CHIRALPAK IE, acetonitrile / water) to obtain rac-(5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]hept-2-carboxylic acid tributyl ester (53%, 31.3 mg) and rac-(5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]hept-2-carboxylic acid tributyl ester (28%, 16.5 mg).

[0225] compound g2 rac-(5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]hepta-2-carboxylic acid tributyl ester [Chemistry 65] LCMS:m / z 228[M+H] + 1H-NMR (400 MHz, CDCl 3) δ: 4.03 (1H, d, J = 8.7 Hz), 3.83 (2H, d, J = 8.9 Hz), 3.79 (2H, d, J = 8.9 Hz), 3.64-3.56 (1H, m), 3.63 (1H, d, J) = 8.7 Hz), 2.49 (1H, dd, J = 11.5, 6.9 Hz), 2.13-2.06 (1H, m), 1.92 (1H, dd, J = 11.5, 8.1 Hz), 1.43 (9H, s), 1.14 (3H, d, J = 6.9 Hz).

[0226] Compound g3 rac-(5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]hepta-2-carboxylic acid tributyl ester [Chemistry 66] LCMS:m / z 228[M+H] + 1H-NMR (400 MHz, CDCl 3) δ: 4.32-4.25 (1H, m), 4.01 (1H, d, J = 9.0 Hz), 3.88 (1H, d, J = 8.6 Hz), 3.84 (1H, d, J = 8.6 Hz), 3.66 (1H, d, J = 9.0 Hz), 2.56-2.46 (2H, m), 2.11 (1H, dd, J = 13.10, 6.92 Hz), 1.43 (9H, s), 1.07 (3H, d, J = 7.25 Hz).

[0227] Third step Compounds 1-86 4-[3-[2,6-dichloro-4-[rac-(6R,7R)-6-methoxy-7-methyl-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]benzoic acid [Chemistry 67] The title compound was obtained using rac-(5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]hept-2-carboxylic acid tributyl ester and compound A, by the same procedure as that used for compounds 1-22. LCMS:m / z 696[M+H] + HPLC retention time: 1.74 min, 1.78 min (analytical condition B)

[0228] Compounds 1-87 4-[3-[2,6-dichloro-4-[rac-(6R,7S)-6-methoxy-7-methyl-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl]benzoic acid [Chemistry 68] The title compound was obtained using rac-(5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]hept-2-carboxylic acid tributyl ester and compound A, by the same procedure as that used for compounds 1-22. LCMS:m / z 696[M+H] + HPLC retention time: 1.78 min, 1.81 min (analytical condition B)

[0229] Compounds 1-47 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound CP1 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl benzoate [Chemistry 69] A suspension of compound A (35.5 mg, 0.0550 mmol), 2-azaspiro[3.3]hepta-6-carboxynitrile (13.3 mg, 0.109 mmol), rac-BINAP Pd G4 (5.49 mg, 0.00546 mmol), and cesium carbonate (53.4 mg, 0.164 mmol) in 1,4-dimethylamine (0.550 mL) was stirred at 100 °C for 30 min. An aqueous formic acid solution was added to the reaction mixture, and the solution was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (78%, 29.6 mg). LCMS:m / z 691[M+H] + HPLC retention time: 0.96 minutes (analytical condition D)

[0230] Second step Compounds 1-47 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 70] A solution of methyl 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate (29.6 mg, 0.0430 mmol) and trimethyltin hydroxide (77.0 mg, 0.428 mmol) in chlorobenzene (0.940 mL) was stirred at 135 °C for 14 hours. An aqueous formic acid solution was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (98%, 4.50 mg). LCMS:m / z 677[M+H] + HPLC retention time: 1.62 minutes (analytical condition B)

[0231] Compounds 1-15 4-[3-[2,6-dichloro-4-(3-cyano-3-methylacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound CP2 4-[3-[2,6-dichloro-4-(3-cyano-3-methylacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl benzoate [Chemistry 71] The title compound was synthesized using 3-methylacetate-3-carboxynitrile hydrochloride and compound A, following the same procedure as in the first step of compounds 1-47. However, 1-methylpyrrolidin-2-one was used as the solvent instead of 1,4-dimethylacetate. LCMS:m / z 665[M+H] + HPLC retention time: 0.95 minutes (analytical condition D)

[0232] Second step Compounds 1-15 4-[3-[2,6-dichloro-4-(3-cyano-3-methylacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 72] The title compound was synthesized using methyl 4-[3-[2,6-dichloro-4-(3-cyano-3-methylacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate via the same procedure as in the second step of compounds 1-47. LCMS:m / z 651[M+H] + HPLC retention time: 1.50 min (analytical condition B)

[0233] In the following synthesis, the intermediates shown in Table 1-3 are used.

[0234] [Table 1-3]

[0235] Compound B 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester First step Compound B1 4-Bromo-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 73] Mofolin (6.98 g, 80.0 mmol) was added to 4-bromo-2,5-difluorobenzoic acid (950 mg, 4.01 mmol), and the mixture was stirred at 100 °C for 24 hours. Ethyl acetate and hydrochloric acid were added to the reaction mixture, and the mixture was extracted and washed with saturated brine. The organic layer was concentrated to give the title compound (98%, 1.20 g). LCMS:m / z 304[M+H] + HPLC retention time: 0.77 minutes (analytical condition N)

[0236] Second step Compound B2 methyl 4-bromo-5-fluoro-2-morphofolin-4-ylbenzoate [Chemistry 74] A solution of 4-bromo-5-fluoro-2-morphofolin-4-ylbenzoic acid (400 mg, 1.32 mmol) in dichloromethane (5.00 mL)-methanol (1.00 mL) was added to a 2M solution of trimethylsilyldiazomethane-hexane (1.32 mL, 2.63 mmol), and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture, and the mixture was concentrated. The reaction mixture was then purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (81%, 341 mg). LCMS:m / z 318[M+H] + HPLC retention time: 1.10 min (analytical condition N)

[0237] Third step Compound B3 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid tributyl ester [Chemistry 75] A solution of methyl 4-bromo-5-fluoro-2-morphofolin-4-ylbenzoate (2.95 g, 9.28 mmol), bis(pinacolato)diboron (2.78 g, 11.0 mmol), potassium acetate (2.48 g, 25.3 mmol), and 1,1'-bis(diphenylphosphine)ferrocene-palladium(II)dichloromethane complex (0.344 g, 0.422 mmol) in 1,4-dimethylbenzene (16.9 mL) was stirred at 90 °C for 5 hours. The reaction mixture was cooled to room temperature, and 8-bromo-2,4-dihydro-1,3-benzo[a]3-carboxylic acid tributyl ester (2.65 g, 8.43 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (0.344 g, 0.422 mmol), potassium carbonate (3.50 g, 25.3 mmol), and water (4.22 mL) were added. The mixture was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The mixture was filtered through diatomaceous earth. The organic layer was washed with brine, dried, and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (91%, 3.63 g). LCMS:m / z 473[M+H] + HPLC retention time: 1.34 minutes (analytical condition G)

[0238] Fourth step Compound B4 4-(3,4-dihydro-2H-1,3-benzo[a]-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate dihydrochloride [Chemistry 76] A solution of 100 mg (0.212 mmol) of tributyl 8-(2-fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid in dichloromethane (1.058 mL) was added to a solution of 4M 1,4-dimethylhydrochloride (0.794 mL, 3.17 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the crude product of the title compound. LCMS:m / z 373[M+H] + HPLC retention time: 0.49 minutes (analytical condition D)

[0239] Fifth step Compound B 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester [Chemistry 77] A solution of methyl 4-(3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-benzo[3,4-dihydro-2H-1,3-dihydro-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3,2,1]oct-8-yl)benzoate dihydrochloride (141 mg, 0.317 mmol) and 4-bromo-2,6-dichlorobenzoyl chloride (137 mg, 0.476 mmol) in dichloromethane (1.585 mL) was cooled to 0 °C. N,N-diisopropylethylamine (0.166 mL, 0.951 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Ethanolamine was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (56%, 110 mg). LCMS:m / z 623[M+H] + HPLC retention time: 1.37 minutes (analytical condition G)

[0240] Compound C 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[a]-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 78] Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[3-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate (16.0 mg, 0.0260 mmol) was added to tetrahydrofuran (0.0641 mL) and methanol (0.0641 mL), followed by the addition of 5M sodium hydroxide aqueous solution (0.0513 mL, 0.256 mmol). The mixture was stirred at 60 °C for 15 minutes. 1M hydrochloric acid was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic layer was concentrated to give the title compound (91%, 14.3 mg). LCMS:m / z 609[M+H] + HPLC retention time: 1.15 min, 1.16 min (analytical condition G)

[0241] Compound D Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[4-]-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate First step Compound D2 4-Bromo-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 79] A solution of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (615 mg, 4.11 mmol) in 1-methylpyrrolidone-2-one (3.43 mL) was added to potassium tert-butoxide (584 mg, 5.21 mmol), and the mixture was stirred at room temperature for 5 hours. Then, 4-bromo-2-fluorobenzoic acid (300 mg, 1.37 mmol) was added, and the mixture was stirred at 150 °C for 21 hours. Methanol was added to the reaction mixture, and the reaction mixture was purified by reverse-phase silica gel chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (94%, 400 mg). LCMS:m / z 312[M+H] + HPLC retention time: 0.64 minutes (analytical condition F)

[0242] Second step Compound D3 Methyl 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 80] The title compound was obtained using 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid via the same procedure as in the second step of compound B. LCMS:m / z 326[M+H] + HPLC retention time: 0.82 minutes (analytical condition D)

[0243] Third step Compound D4 8-[4-methoxycarbonyl-3-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3]3-carboxylic acid tributyl ester [Chemistry 81] The title compound was obtained by using methyl 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate via the same procedure as in the third step of compound B. LCMS:m / z 481[M+H] + HPLC retention time: 0.98 minutes (analytical condition D)

[0244] Fourth step Compound D5 4-(3,4-dihydro-2H-1,3-benzo[3,4]2-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate dihydrochloride [Chemistry 82] The title compound was obtained by using 8-[4-methoxycarbonyl-3-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3]3-carboxylic acid tributyl ester via the same procedure as in the fourth step of compound B. LCMS:m / z 381[M+H] + HPLC retention time: 0.52 minutes (analytical condition D)

[0245] Fifth step Compound D Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[4-]-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 83] The title compound was obtained by the same procedure as in step 5 of compound B, of methyl 4-(3,4-dihydro-2H-1,3-benzoyl-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate dihydrochloride. LCMS:m / z 631[M+H] + HPLC retention time: 1.00 min (analytical condition D)

[0246] Compound E 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-2-morphofolin-4-ylbenzoate First step Compound E1 4-Bromo-2-morphofolin-4-ylbenzoic acid [Chemistry 84] Mofolin (5.76 mL, 66.1 mmol) was added to a solution of 4-bromo-2-fluorobenzoic acid (672 mg, 3.07 mmol) in 1-methylpyrrolidone (3.07 mL), and the mixture was stirred at 150 °C for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (77%, 672 mg). LCMS:m / z 286[M+H] + HPLC retention time: 0.75 minutes (analytical condition G)

[0247] Second step Compound E2 Methyl 4-bromo-2-morphofolin-4-ylbenzoate [Chemistry 85] The title compound was obtained using 4-bromo-2-morphofolin-4-ylbenzoic acid via the same procedure as in the second step of compound B. LCMS:m / z 300[M+H] + HPLC retention time: 1.10 min (analytical condition G)

[0248] Third step Compound E3 8-(4-methoxycarbonyl-3-morpholino-4-ylphenyl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid tributyl ester [Chemistry 86] The title compound was obtained by using methyl 4-bromo-2-morphofolin-4-ylbenzoate via the same procedure as in the third step of compound B. LCMS:m / z 455[M+H] + HPLC retention time: 1.31 minutes (analytical condition G)

[0249] Fourth step Compound E4 4-(3,4-dihydro-2H-1,3-benzo[a]-8-yl]-2-morphofolin-4-ylbenzoate dihydrochloride [Chemistry 87] The title compound was obtained by using terbutyl 8-(4-methoxycarbonyl-3-mofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[3-]-3-carboxylic acid, via the same procedure as in step four of compound B. LCMS:m / z 355[M+H] + HPLC retention time: 0.67 minutes (analytical condition G)

[0250] Fifth step Compound E 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-2-morphofolin-4-ylbenzoate [Chemistry 88] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzoyl-8-yl)-2-morphofolin-4-ylbenzoate dihydrochloride via the same procedure as in step 5 of compound B. LCMS:m / z 605[M+H] + HPLC retention time: 1.35 minutes (analytical condition G)

[0251] Compound F 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[a]-8-yl]-2-morpholin-4-ylbenzoic acid [Chemistry 89] The title compound was obtained using methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-2-morphofolin-4-ylbenzoate via the same procedure as that used in the preparation of compound C. LCMS:m / z 591[M+H] + HPLC retention time: 1.13 min, 1.15 min (analytical condition G)

[0252] Compound G 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzothiazolyl]-5-fluoro-2-morphofolin-4-ylbenzoate First step Compound G2 2-Ethylhexyl 3-(2-bromo-6-cyanophenyl)hydrothiopropionic acid [Chemistry 90] Potassium carbonate (4.15 g, 30.0 mmol) was added to a solution of 3-bromo-2-fluorobenzonitrile (2.00 g, 10.0 mmol), 2-ethylhexyl 3-sulfanyl propionate (2.49 mL, 11.0 mmol), and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (97%, 3.87 g). LCMS:m / z 398[M+H] + HPLC retention time: 1.60 min (analytical condition G)

[0253] Second step Compound G4 2-Ethylhexyl 3-[2-bromo-6-[[(2-methylpropane-2-yl)oxycarbonylamino]methyl]phenyl]hydrothiopropionic acid ester [Chemistry 91] Sodium borohydride (567 mg, 15.0 mmol) was added dropwise to a methanol (25.0 mL) solution of 2-ethylhexyl 3-(2-bromo-6-cyanophenyl)hydrothiopropionate (1.99 g, 5.00 mmol) and cobalt(II) chloride hexahydrate (2.38 g, 10.0 mmol) and stirred at room temperature for 2 hours. Di-tert-butyl dicarbonate (2.32 mL, 10.0 mmol) was added, and the mixture was stirred at room temperature for another 1 hour. The reaction mixture was cooled to 0 °C, and 1 M hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions. After passing through a phase separator, the organic layer was concentrated, and the residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (95%, 965 mg). LCMS: m / z 524[M+Na] + HPLC retention time: 1.73 minutes (analytical condition G)

[0254] Third step Compound G5 N-[(3-bromo-2-hydrothiophenyl)methyl]carbamate tributyl ester (tert-butyl N-[(3-bromo-2-sulfanylphenyl)methyl]carbamate) [Chemistry 92] A solution of 2-ethylhexyl 3-[2-bromo-6-[[(2-methylpropane-2-yl)oxycarbonylamino]methyl]phenyl]hydrothiopropionic acid 2-ethylhexyl ester (950 mg, 1.89 mmol) in tetrahydrofuran (12.6 mL) was cooled to -78 °C, and 1.7 M potassium tert-pentoxide in toluene solution (2.22 mL, 3.78 mmol) was added dropwise, while stirring at -78 °C for 30 min. Extraction with ethyl acetate was performed after adding 1 M hydrochloric acid. The organic layer was washed with saturated sodium chloride aqueous solution, and concentrated using a phase separator to obtain the crude product of the title compound. LCMS:m / z 262[M-tBu+H] + HPLC retention time: 1.27 minutes (analytical condition G)

[0255] Fourth step Compound G6 8-Bromo-2,4-dihydro-1,3-benzothia®-3-carboxylic acid tributyl ester [Chemistry 93] A solution of N-[(3-bromo-2-hydrothiophenyl)methyl]carbamate tributyl ester (602 mg, 1.89 mmol), paraformaldehyde (568 mg, 18.9 mmol), and p-toluenesulfonic acid (3.60 mg, 0.0190 mmol) in toluene (0.200 mL) was stirred at 90 °C for 1 hour. The reaction mixture was injected into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and concentrated using a phase separator. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (99%, 620 mg). LCMS:m / z 274[M-tBu+H] + HPLC retention time: 1.37 minutes (analytical condition G)

[0256] Fifth step Compound G7 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzothia®-3-carboxylic acid tributyl ester [Chemistry 94] The title compound was obtained by using 8-bromo-2,4-dihydro-1,3-benzothia®-3-carboxylic acid tributyl ester and methyl 4-bromo-5-fluoro-2-morphofolin-4-ylbenzoate via the same procedure as in the third step of compound B. LCMS:m / z 489[M+H] + HPLC retention time: 1.34 minutes (analytical condition G)

[0257] Step Six Compound G8 4-(3,4-dihydro-2H-1,3-benzothia-8-yl)-5-fluoro-2-morphofolin-4-ylbenzoate methyl hydrochloride [Chem. 95] The title compound was synthesized using terbutyl 8-(2-fluoro-4-methoxycarbonyl-5-mofolin-4-ylphenyl)-2,4-dihydro-1,3-benzothia®-3-carboxylic acid, via the same procedure as in step four of compound B. LCMS:m / z 389[M+H] + HPLC retention time: 0.69 minutes (analytical condition G)

[0258] Step 7 Compound G 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzothiazyne-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate [Chemistry 96] The title compound was obtained using methyl 4-(3,4-dihydro-2H-1,3-benzothia-8-yl)-5-fluoro-2-morphofolin-4-ylbenzoate dihydrochloride via the same procedure as in step five of compound B. However, N,N-diisopropylethylamine was substituted with triethylamine. LCMS:m / z 639[M+H] + HPLC retention time: 1.37 min, 1.39 min (analytical condition G)

[0259] Compound H Methyl 4-[3-(4-bromo-2-chlorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[8-]]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 97] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzo[ ... LCMS:m / z 615[M+H] + HPLC retention time: 0.97 minutes (analytical condition N)

[0260] Compound I 4-[3-(4-bromo-2-chlorobenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester [Chem. 98] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate dihydrochloride and 4-bromo-2-chlorobenzoyl chloride, following the same procedure as in step 5 of compound B. LCMS:m / z 589[M+H] + HPLC retention time: 1.32 minutes (analytical condition N)

[0261] Compound J 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester First step Compound J2 methyl 4-bromo-2-chloro-5-methylbenzoate [Chemistry 99] N-chlorosuccinimide (350 mg, 2.62 mmol), palladium(II) acetate (24.5 mg, 0.109 mmol), sodium peroxydisulfate (1.04 g, 4.37 mmol), and trifluoromethanesulfonic acid (0.579 mL, 6.55 mmol) were added to a solution of methyl 4-bromo-3-methylbenzoate (500 mg, 2.18 mmol) in dichloromethane (5.46 mL), and the mixture was stirred at 60 °C for 7 hours. The solution was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (62%, 430 mg). LCMS:m / z 263[M+H] + HPLC retention time: 0.94 minutes (analytical condition D)

[0262] Second step Compound J3 4-Bromo-2-chloro-5-methylbenzoic acid [Chemistry 100] Lithium hydroxide (117 mg, 4.88 mmol) was added to a solution of methyl 4-bromo-2-chloro-5-methylbenzoate (429 mg, 1.63 mmol) in 1,4-dimethyl benzoate (3.50 mL) / water (1.75 mL), and the mixture was stirred at room temperature for 1 hour. 5M hydrochloric acid (1.63 mL, 8.13 mmol) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated to obtain the crude product of the title compound. LCMS:m / z 247[MH] - HPLC retention time: 0.72 minutes (analytical condition D)

[0263] Third step Compound J4 4-Bromo-2-chloro-5-methylbenzyl chloride [Chemistry 101] A solution of 4-bromo-2-chloro-5-methylbenzoic acid (250 mg, 1.00 mmol) and xylene chloride (0.175 mL, 2.00 mmol) in dichloromethane (5.01 mL) was cooled to 0 °C. N,N-dimethylformamide (0.000776 mL, 0.0100 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the crude product of the title compound.

[0264] Fourth step Compound J 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester [Chemistry 102] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate dihydrochloride and 4-bromo-2-chloro-5-methylbenzoyl chloride, following the same procedure as in step 5 of compound B. LCMS:m / z 629[M+H] + HPLC retention time: 1.02 minutes (analytical condition D)

[0265] compound K 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester First step compound K2 Methyl 4-bromo-2-chloro-5-methoxybenzoate [Chemistry 103] The title compound was obtained using methyl 4-bromo-3-methoxybenzoate via the same procedure as in the first step of compound J. LCMS:m / z 279[M+H] + HPLC retention time: 1.20 min (analytical condition G)

[0266] Second step compound K3 4-Bromo-2-chloro-5-methoxybenzoic acid [Chemistry 104] The title compound was obtained using methyl 4-bromo-2-chloro-5-methoxybenzoate via the same method as in the second step of compound J. LCMS:m / z 263[MH] - HPLC retention time: 0.69 minutes (analytical condition D)

[0267] Third step Compound K4 4-Bromo-2-chloro-5-methoxybenzyl chloride [Chemistry 105] The crude product of the title compound was obtained using 4-bromo-2-chloro-5-methoxybenzoic acid via the same procedure as in the third step of compound J.

[0268] Fourth step compound K 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester [Chemistry 106] The title compound was synthesized using methyl 4-(3,4-dihydro-2H-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate dihydrochloride and 4-bromo-2-chloro-5-methoxybenzoyl chloride, following the same procedure as in step 5 of compound B. LCMS:m / z 619[M+H] + HPLC retention time: 0.95 minutes (analytical condition D)

[0269] Compound L 4-[2-(4-bromo-2,6-dichlorobenzoyl)-4-sideoxy-1,3-dihydrophthalazine-5-yl]-2-morphofolin-4-ylbenzoate First step Compound L4 2-Bromo-6-[[(2-methylpropane-2-yl)oxycarbonyl-[(2-methylpropane-2-yl)oxycarbonylamino]amino]methyl]methyl benzoate [Chemistry 107] A solution of methyl 2-bromo-6-(bromomethyl)benzoate (6.80 g, 22.1 mmol) in N,N-dimethylformamide (100 mL) was cooled to 0 °C, and di(tert-butyl) dihydrazo dicarboxylic acid (20.5 g, 88.0 mmol) and cesium carbonate (14.4 g, 44.2 mmol) were added. The mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the solution was extracted with ethyl acetate. The organic layer was concentrated and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (55%, 5.62 g). LCMS:m / z 481[M+Na] + HPLC retention time: 1.34 minutes (analytical condition G)

[0270] Second step Compound L5 5-Bromo-4-Syne-1,3-Dihydrotetramethyl-2-carboxylic acid tributyl ester [Chemistry 108] A solution of methyl 2-bromo-6-[[(2-methylpropane-2-yl)oxycarbonyl-[(2-methylpropane-2-yl)oxycarbonylamino]amino]methyl]benzoate (5.61 g, 12.2 mmol) in tetrahydrofuran (150 mL) was added to a 1M solution of lithium bis(trimethylsilyl)amide (15.9 mL, 15.9 mmol), and the mixture was stirred at 60 °C for 12 h. An aqueous formic acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was concentrated and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (64%, 2.55 g). LCMS: m / z 349[M+Na] + HPLC retention time: 0.97 minutes (analytical condition G)

[0271] Third step Compound L6 5-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-4-sideoxy-1,3-dihydro-2-carboxylic acid tributyl ester [Chemistry 109] The title compound was synthesized using 5-bromo-4-semi-oxy-1,3-dihydro-2-carboxylic acid tributyl ester and methyl 4-bromo-2-morphofolin-4-ylbenzoate via the same procedure as in the third step of compound B. LCMS:m / z 468[M+H] + HPLC retention time: 1.07 minutes (analytical condition G)

[0272] Fourth step Compound L 4-[2-(4-bromo-2,6-dichlorobenzoyl)-4-sideoxy-1,3-dihydro-5-yl]-2-morpholin-4-ylbenzoate [Chemical 110] 5-(4-methoxycarbonyl-3-morphofolin-4-ylphenyl)-4-sideoxy-1,3-dihydro-2-carboxylic acid tributyl ester (50 mg, 0.107 mmol) was added to a 4M solution of 1,4-dimethylhydrochloride (0.535 mL, 2.14 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and dichloromethane (1.00 mL) was added, followed by cooling to 0°C. 4-bromo-2,6-dichlorobenzyl chloride (40.1 mg, 0.139 mmol) and N,N-diisopropylethylamine (0.0960 mL, 0.535 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (73%, 48.0 mg). LCMS:m / z 618[M+H] + HPLC retention time: 1.19 minutes (analytical condition G)

[0273] Compound M 4-[3-(4-bromo-2,6-dichlorobenzoyl)-5-fluoro-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester First step Compound M2 N-[(2-fluoro-6-hydroxyphenyl)methyl]carbamate tributyl ester [Chemistry 111] A solution of 2-bromo-3-fluorophenol (500 mg, 2.62 mmol) in 1,4-dimethylamine (10.0 mL)-water (2.00 mL) was mixed with cataCXium (trademark) A Pd G3 (28.6 mg, 0.0390 mmol), potassium carbonate (1.09 mg, 7.85 mmol), and potassium [[(tributoxycarbonyl)amino]methyl]trifluoroborate (1.24 g, 5.24 mmol). The mixture was stirred in a microwave oven at 130 °C for 20 min. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (89%, 563 mg). LCMS:m / z 186[M-tBu+H] + HPLC retention time: 1.05 minutes (analytical condition G)

[0274] Second step Compound M3 N-[(3-bromo-6-fluoro-2-hydroxyphenyl)methyl]carbamate tributyl ester [Chemistry 112] A solution of N-[(2-fluoro-6-hydroxyphenyl)methyl]carbamate tributyl ester (560 mg, 2.32 mmol) and N,N-diisopropylethylamine (0.992 mL, 6.96 mmol) in dichloromethane (40.0 mL) was cooled to 0 °C, and a solution of N-bromosuccinimide (413 mg, 2.32 mmol) in dichloromethane (40.0 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (96%, 715 mg). LCMS:m / z 264[M-tBu+H] + HPLC retention time: 1.23 minutes (analytical condition G)

[0275] Third step Compound M4 8-Bromo-5-fluoro-2,4-dihydro-1,3-benzo[3-]-3-carboxylic acid tributyl ester [Chemistry 113] A solution of N-[(3-bromo-6-fluoro-2-hydroxyphenyl)methyl]carbamate tributyl ester (600 mg, 1.87 mmol) in dichloroethane (30.0 mL) was mixed with p-toluenesulfonic acid (35.6 mg, 0.187 mmol) and 90% paraformaldehyde (625 mg, 18.7 mmol) and stirred overnight at 90 °C. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (64%, 399 mg). LCMS:m / z 332[M+H] + HPLC retention time: 1.34 minutes (analytical condition G)

[0276] Fourth step Compound Z6 (2-Fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)boronic acid [Chemistry 114] A solution of methyl 4-bromo-5-fluoro-2-morphofolin-4-ylbenzoate (96.0 mg, 0.302 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride (11.0 mg, 0.0150 mmol), potassium acetate (44.4 mg, 0.453 mmol), and bis-pinacolborate (77.0 mg, 0.302 mol) in 1,4-dimethylbenzane (1.51 mL) was stirred at 100 °C for 3 hours. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (53%, 44.8 mg). LCMS:m / z 284[M+H] + HPLC retention time: 0.63 minutes (analytical condition G)

[0277] Fifth step Compound M5 5-Fluoro-8-(2-Fluoro-4-methoxycarbonyl-5-morpholino-4-ylphenyl)-2,4-dihydro-1,3-benzo[3-]carboxylic acid tributyl ester [Chemistry 115] A solution of 8-bromo-5-fluoro-2,4-dihydro-1,3-benzo[3-]-3-carboxylic acid tributyl ester (200 mg, 0.602 mmol) in 1,4-dimethyl ether (2.40 mL)-water (0.600 mL) was added, along with (2-fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)boronic acid (205 mg, 0.723 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride (22.0 mg, 0.0300 mmol), and potassium carbonate (250 mg, 1.81 mmol). The mixture was stirred at 90 °C for 3 hours. Then, 2-fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)boronic acid (205 mg, 0.723 mmol) was added to the reaction mixture, and the mixture was stirred at 90 °C overnight. 2-Fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)boronic acid (205 mg, 0.723 mmol) and 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride (22.0 mg, 0.0300 mmol) were added to the reaction solution, and the mixture was stirred at 90 °C for 3 hours. An aqueous formic acid solution was added to the reaction solution, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (69%, 205 mg). LCMS:m / z 491[M+H] + HPLC retention time: 1.36 minutes (analytical condition G)

[0278] Step Six Compound M6 5-Fluoro-4-(5-Fluoro-3,4-dihydro-2H-1,3-benzo[a]-8-yl)-2-morphofolin-4-ylbenzoate dihydrochloride [Chemistry 116] The title compound was obtained by using 5-fluoro-8-(2-fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[3-]-carboxylic acid tributyl ester via the same procedure as in step four of compound B. LCMS: m / z 362[M-CH2+H]+ HPLC retention time: 0.69 minutes (analytical condition N) 1H-NMR (400 MHz, DMSO-D 6) δ: 7.52 (1H, d, J = 9.7 Hz), 7.41-7.39 (1H, m), 7.07 (2H, d, J = 7.0 Hz), 5.16 (2H, s), 4.38 (2H, s), 3.85 (3H, s), 3.71 (4H, s), 2.96 (4H, s).

[0279] Step 7 Compound M 4-[3-(4-bromo-2,6-dichlorobenzoyl)-5-fluoro-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester [Chemistry 117] The title compound was obtained by using methyl 5-fluoro-4-(5-fluoro-3,4-dihydro-2H-1,3-benzo[8-yl]-2-morphofolin-4-ylbenzoate dihydrochloride and 4-bromo-2,6-dichlorobenzoyl chloride, following the same procedure as in step 5 of compound B. LCMS:m / z 641[M+H] + HPLC retention time: 1.40 min (analytical condition N)

[0280] Compound N 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoyl-8-yl]-2-morphofolin-4-ylbenzoate First step Compound N3 N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate tributyl ester [Chemistry 118] A solution of 3-bromo-4-fluoro-2-hydroxybenzonitrile (970 mg, 4.49 mmol) in tetrahydrofuran (20.0 mL) was reacted with 1.2 M borane·tetrahydrofuran complex (9.36 mL, 11.2 mmol). The reaction mixture was stirred at 60 °C for 15 hours. Methanol was added to the reaction mixture for concentration. Tetrahydrofuran (10.0 mL) and 2 M hydrochloric acid (5.61 mL, 11.2 mmol) were added, and the mixture was heated at 60 °C for 3 hours. The reaction mixture was cooled to 0 °C, and saturated sodium bicarbonate aqueous solution was added, followed by di(tert-butyl dicarbonate) (1.96 g, 8.98 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated ammonium chloride aqueous solution, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (79%, 1.13 g). LCMS:m / z 318[MH] - HPLC retention time: 1.18 minutes (analytical condition N)

[0281] Second step Compound N4 8-Bromo-7-fluoro-2,4-dihydro-1,3-benzo[3]-3-carboxylic acid tributyl ester [Chemistry 119] A solution of N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate tributyl ester (600 mg, 1.87 mmol) in toluene (5.00 mL) was mixed with p-toluenesulfonic acid monohydrate (1.78 mg, 0.00937 mmol) and paraformaldehyde (281 mg, 9.37 mmol) and stirred at 100 °C for 3 hours. The reaction mixture was then stirred at 90 °C for 20 hours. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (24%, 152 mg). LCMS:m / z 332[M+H] + HPLC retention time: 1.30 min (analytical condition G)

[0282] Third step Compound N7 Methyl 2-Mofolin-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)benzoate (Methyl 2-morpholine-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) benzoate) [Chemistry 120] A solution of methyl 4-bromo-2-morphofolin-4-ylbenzoate (1.60 g, 5.33 mmol), bis-pinacolborate (2.71 g, 10.7 mmol), palladium(II) acetate (0.0600 g, 0.267 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.254 g, 0.533 mmol), and potassium acetate (1.31 g, 13.3 mmol) in 1,4-dimethylbenzene (10.0 mL) was stirred at 85 °C for 2 hours. An ethyl acetate / hexane 1 / 1 solution was added to the reaction mixture, and the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (89%, 2.05 g). LCMS:m / z 348[M+H] + HPLC retention time: 1.21 minutes (analytical condition G)

[0283] Fourth step Compound N5 7-Fluoro-8-(4-methoxycarbonyl-3-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid tributyl ester [Chemistry 121] A solution of methyl 2-morpholino-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)benzoate (85.0 mg, 0.246 mmol), tributyl 8-bromo-7-fluoro-2,4-dihydro-1,3-benzo[3]-carboxylic acid (68.0 mg, 0.205 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride (15.0 mg, 0.0200 mmol), and 2M sodium carbonate aqueous solution (0.307 mL, 0.614 mmol) in 1,4-dimethylalkyl (1.00 mL) was stirred at 90 °C for 1.5 hours. The reaction solution was mixed with another compound obtained by the same method as described above, and an aqueous formic acid solution was added. The mixture was then purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (71.0 mg). LCMS:m / z 473[M+H] + HPLC retention time: 1.30 min (analytical condition G)

[0284] Fifth step Compound N 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoyl-8-yl]-2-morphofolin-4-ylbenzoate [Chemistry 122] 7-fluoro-8-(4-methoxycarbonyl-3-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid tributyl ester (344 mg, 0.728 mmol) was added to a 4M solution of 1,4-dimethylhydrochloride (3.64 mL, 14.6 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting residue was added to dichloromethane (5.00 mL), 4-bromo-2,6-dichlorobenzoyl chloride (273 mg, 0.946 mmol), and N,N-diisopropylethylamine (0.634 mL, 3.64 mmol), and stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (51%, 231 mg). LCMS:m / z 623[M+H] + HPLC retention time: 0.98 minutes (analytical conditions O)

[0285] Compound O Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzoyl]-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate First step Compound O1 2,6-Dichloro-4-fluorobenzoic acid [Chemistry 123] The crude product of the title compound was obtained using 2,6-dichloro-4-fluorobenzoic acid via the same procedure as in the third step of compound J.

[0286] Second step Compound O Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzoyl]-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 124] The title compound was obtained using methyl 4-(3,4-dihydro-2H-1,3-benzo[ ... LCMS:m / z 589[M+H] + HPLC retention time: 0.96 minutes (analytical condition D)

[0287] Compound P 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[4-]-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 125] A solution of methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[4-]-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate (100 mg, 0.170 mmol) in 1-methylpyrrolidone (1.70 mL) was added to a 2M aqueous solution of lithium hydroxide (0.424 mL, 0.848 mmol), and the mixture was stirred at room temperature for 14 hours. Then, 1-methylpyrrolidone (1.70 mL) and 2M aqueous solution of lithium hydroxide (0.424 mL, 0.848 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. An aqueous formic acid solution was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (63%, 61.9 mg). LCMS:m / z 575[M+H] + HPLC retention time: 0.77 minutes (analytical condition D)

[0288] Compound Q 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-2-morpholin-4-ylbenzoate First step Compound Q1 ethyl 4-bromo-2-morphofolin-4-ylbenzoate [Chemistry 126] A solution of 4-bromo-2-morphofolin-4-ylbenzoic acid (1.50 g, 5.24 mmol) in N,N-dimethylformamide (26.2 mL) was mixed with potassium carbonate (2.17 g, 15.7 mmol) and iodoethane (0.632 mL, 7.86 mmol) and stirred at 25 °C for 2.5 h. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (99%, 1.63 g). LCMS:m / z 314[M+H] + HPLC retention time: 0.86 minutes (analytical conditions O)

[0289] Second step Compound Q4 8-(4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid tributyl ester [Chemistry 127] A solution of 1,4-dimethyl 8-bromo-2,4-dihydro-1,3-benzo[3]3-carboxylic acid tributyl ester (3.40 g, 10.8 mmol), bis-pinacolborate ester (5.50 g, 21.6 mmol), potassium acetate (4.25 g, 43.3 mmol), and a 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (0.792 g, 1.08 mmol) in 1,4-dimethyl ... LCMS:m / z 362[M+H] + HPLC retention time: 1.36 minutes (analytical condition G)

[0290] Third step Compound Q2 8-(4-ethoxycarbonyl-3-morpholino-4-ylphenyl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid tributyl ester [Chemistry 128] A solution of ethyl 4-bromo-2-morphofolin-4-ylbenzoate (1.30 g, 3.76 mmol) and 8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,4-dihydro-1,3-benzo[3-]-carboxylic acid tributyl ester (1.36 g, 4.14 mmol) in 1,4-dimethylalkyl (11.4 mL) / water (1.14 mL) was added, along with a 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (0.275 g, 0.376 mmol) and potassium carbonate (1.56 g, 11.3 mmol). The mixture was stirred at 90 °C for 2 hours. The reaction solution was concentrated, extracted with ethyl acetate, and the organic layer was washed with water. After concentration, the residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (81%, 1.43 g). LCMS:m / z 469[M+H] + HPLC retention time: 1.38 minutes (analytical condition G)

[0291] Fourth step Compound Q3 4-(3,4-dihydro-2H-1,3-benzo[a]-8-yl]-2-morphofolin-4-ylbenzoate ethyl hydrochloride [Chemistry 129] The title compound was obtained by using terbutyl 8-(4-ethoxycarbonyl-3-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[3-]-3-carboxylic acid, via the same procedure as in step four of compound B. LCMS:m / z 369[M+H] + HPLC retention time: 0.74 minutes (analytical condition G)

[0292] Fifth step Compound Q 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-2-morpholin-4-ylbenzoate [Chemistry 130] The title compound was obtained using ethyl 4-(3,4-dihydro-2H-1,3-benzo[8-yl]-2-morphofolin-4-ylbenzoate hydrochloride and 2,6-dichloro-4-fluorobenzoyl chloride, in the same manner as in step 5 of compound B. LCMS:m / z 559[M+H] + HPLC retention time: 1.33 minutes (analytical condition G)

[0293] Compound R 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-2-morphofolin-4-ylbenzoate [Chemistry 131] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzo[8-yl]-2-morphofolin-4-ylbenzoate dihydrochloride and 2,6-dichloro-4-fluorobenzoyl chloride, following the same procedure as in step 5 of compound B. LCMS:m / z 545[M+H] + HPLC retention time: 1.26 minutes (analytical condition G)

[0294] Compound S 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate [Chemistry 132] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate dihydrochloride and 2,6-dichloro-4-fluorobenzoyl chloride, following the same procedure as in step 5 of compound B. LCMS:m / z 563[M+H] + HPLC retention time: 0.91 minutes (analytical condition D)

[0295] Compound T 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-2-methyl-6-morphofolin-4-ylbenzoate First step Compound T1 4-Bromo-2-methyl-6-morphofolin-4-ylbenzoic acid [Chemistry 133] The title compound was obtained using 4-bromo-2-fluoro-6-methylbenzoic acid via the same procedure as in the first step of compound B. LCMS:m / z 300[M+H] + HPLC retention time: 0.89 minutes (analytical condition N)

[0296] Second step Compound T2 methyl 4-bromo-2-methyl-6-morphofolin-4-ylbenzoate [Chemistry 134] The title compound was obtained using 4-bromo-2-methyl-6-morphofolin-4-ylbenzoic acid via the same procedure as in the second step of compound B. LCMS:m / z 314[M+H] + HPLC retention time: 0.91 minutes (analytical condition D)

[0297] Third step Compound T3 8-(4-methoxycarbonyl-3-methyl-5-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid tributyl ester [Chemistry 135] The title compound was obtained by using methyl 4-bromo-2-methyl-6-mofolin-4-ylbenzoate and terbutyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,4-dihydro-1,3-benzo[a]-3-carboxylic acid, via the same procedure as in the third step of compound Q. LCMS:m / z 469[M+H] + HPLC retention time: 1.06 minutes (analytical condition D)

[0298] Fourth step Compound T4 4-(3,4-dihydro-2H-1,3-benzo[a]-8-yl]-2-methyl-6-morphofolin-4-ylbenzoate dihydrochloride [Chemistry 136] The title compound was obtained by using terbutyl 8-(4-methoxycarbonyl-3-methyl-5-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[3-]-carboxylic acid, via the same procedure as in step four of compound B. LCMS:m / z 369[M+H] + HPLC retention time: 0.79 minutes (analytical condition N)

[0299] Fifth step Compound T 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-2-methyl-6-morphofolin-4-ylbenzoate [Chemistry 137] A catalytic amount of N,N-dimethylformamide was added to a solution of 2,6-dichloro-4-fluorobenzoic acid (24.9 mg, 0.119 mmol) and xylene chloride (0.0109 mL, 0.125 mmol) in dichloromethane (0.566 mL), and the mixture was stirred at room temperature for 45 minutes. Methyl 4-(3,4-dihydro-2H-1,3-benzo[a]-8-yl]-2-methyl-6-morphofolin-4-ylbenzoate dihydrochloride (50.0 mg, 0.113 mmol) was added to the reaction mixture. The mixture was cooled to 0 °C, and N,N-diisopropylethylamine (0.0990 mL, 0.566 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (71%, 44.7 mg). LCMS:m / z 559[M+H] + HPLC retention time: 1.02 minutes (analytical condition D)

[0300] Compound U 4-[3-(2-chloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate First step Compound U2 2-Chloro-4-fluorobenzoic acid [Chemistry 138] Using 2-chloro-4-fluorobenzoic acid, the crude product of the title compound was obtained through the same procedure as in the third step of compound J.

[0301] Second step Compound U 4-[3-(2-chloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate [Chemistry 139] The title compound was obtained by using 2-chloro-4-fluorobenzoyl chloride and methyl 4-(3,4-dihydro-2H-1,3-benzo[8-]yl]-5-fluoro-2-morphofolin-4-ylbenzoate dihydrochloride, following the same procedure as in step 5 of compound B. LCMS:m / z 529[M+H] + HPLC retention time: 1.23 minutes (analytical condition G)

[0302] Compound V 4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid First step Compound V2 methyl 2-chloro-4-fluoro-5-methoxybenzoate [Chemistry 140] The title compound was obtained using methyl 4-fluoro-3-methoxybenzoate via the same procedure as in the first step of compound J. LCMS:m / z 219[M+H] + HPLC retention time: 1.08 minutes (analytical condition G)

[0303] Second step Compound V3 2-Chloro-4-fluoro-5-methoxybenzoic acid [Chemistry 141] A solution of methyl 2-chloro-4-fluoro-5-methoxybenzoate (240 mg, 1.10 mmol) and lithium hydroxide (79.0 mg, 3.29 mmol) in 1,4-dimethyl alkylene (2.61 mL)-water (1.31 mL) was stirred at room temperature for 2 hours. After adding hydrochloric acid, the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The organic layer was then concentrated using a phase separator to obtain the crude product of the title compound. LCMS:m / z 205[M+H] + HPLC retention time: 0.59 minutes (analytical condition D)

[0304] Third step Compound V4 2-Chloro-4-fluoro-5-methoxybenzyl chloride [Chemistry 142] The crude product of the title compound was obtained by using 2-chloro-4-fluoro-5-methoxybenzoic acid via the same procedure as in the third step of compound J.

[0305] Fourth step Compound V5 4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester [Chemistry 143] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate dihydrochloride and 2-chloro-4-fluoro-5-methoxybenzoyl chloride, following the same procedure as in step 5 of compound B. LCMS:m / z 558[M+H] + HPLC retention time: 0.88 minutes (analytical condition D)

[0306] Fifth step Compound V 4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 144] The title compound was obtained using methyl 4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoyl]-5-fluoro-2-morphofolin-4-ylbenzoate via the same procedure as that used in the preparation of compound P. LCMS:m / z 545[M+H] + HPLC retention time: 0.72 minutes (analytical condition D)

[0307] Compound W Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[3,4-dihydro-1,3-benzo[3,4-dihydro-8-yl]-5-fluoro-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)benzoate First step Compound X7 2-(aminomethyl)-6-bromophenol hydrochloride [Chemistry 145] A solution of 4 M 1,4-dimethyl methylcarbamate (4.14 mL, 16.6 mmol) was added to a solution of N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate (500 mg, 1.66 mmol) in 1,4-dimethyl methyl methyl carbamate (4.14 mL), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated to obtain the crude product of the title compound. LCMS:m / z 202[M+H] + HPLC retention time: 0.28 minutes (analytical condition D)

[0308] Second step Compound W1 N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-fluorobenzoamide [Chemistry 146] N,N-diisopropylethylamine (9.59 g, 74.2 mmol) and HATU (9.41 g, 24.7 mmol) were added to a solution of 2,6-dichloro-4-fluorobenzoic acid (5.17 g, 24.7 mmol) in N,N-dimethylformamide (60.0 mL), and the mixture was stirred at room temperature for 1 hour. For the reaction mixture, 2-(aminomethyl)-6-bromophenol hydrochloride (5.90 g, 24.7 mmol) and N,N-diisopropylethylamine (6.39 g, 49.5 mmol) in N,N-dimethylformamide (70.0 mL) were added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of the title compound. LCMS:m / z 392[M+H] + HPLC retention time: 0.80 min (analytical condition Z)

[0309] Third step Compound W2 (8-Bromo-2,4-dihydro-1,3-benzo[3-yl]-(2,6-dichloro-4-fluorophenyl)methyl ketone ((8-bromo-2,4-dihydro-1,3-benzoxazine-3-yl)-(2,6-dichloro-4-fluorophenyl) methanone) [Chemistry 147] p-Toluenesulfonic acid (6.43 g, 33.8 mmol) and paraformaldehyde (19.6 g, 677 mmol) were added to a solution of N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-fluorobenzylamine (13.3 g, 33.8 mmol) in toluene (33.0 mL) / 1,4-dimethylethane (33.0 mL), and the mixture was stirred at 90 °C for 5 hours. Ethyl acetate and a saturated aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. This mixture was then mixed with another compound obtained by the same method described above, and ethanol was added to obtain the title compound (8.52 g) by preparation. LCMS:m / z 404[M+H] + HPLC retention time: 1.46 minutes (analytical condition S)

[0310] Fourth step Compound W9 Methyl 5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)benzoate [Chemistry 148] A solution of methyl 4-bromo-5-fluoro-2-hydroxybenzoate (16.1 g, 64.7 mmol) in 220 mL of 1,4-dimethylbenzyl ether was added, along with bis(diphenylphosphine)ferrocene-palladium(II)dichloromethane complex (2.64 g, 3.23 mmol), and stirred at 100 °C for 16 hours. The crude product was used in subsequent reactions. LCMS:m / z 297[M+H] + HPLC retention time: 0.96 minutes (analytical condition D)

[0311] Fifth step Compound W3 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-hydroxybenzoate [Chemistry 149] A solution of methyl 5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate (15.4 g, 51.8 mmol) and (8-bromo-2,4-dihydro-1,3-benzo[3-yl]-(2,6-dichloro-4-fluorophenyl) ketone (21.0 g, 51.8 mmol) in 1,4-dimethyl alkyl (210 mL) / water (21.0 mL) was prepared, and 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (1.90 g, 2.59 mmol) and potassium carbonate (14.3 g, 104 mmol) were added and stirred at 100 °C for 16 hours. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (99%, 25.4 g). LCMS:m / z 494[M+H] + HPLC retention time: 0.99 minutes (analytical condition D)

[0312] Step Six Compound W4 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate [Chemistry 150] A solution of methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[8-]-5-fluoro-2-hydroxybenzoate (45.4 mg, 0.0920 mmol) in N,N-dimethylformamide (0.919 mL) was added, followed by the addition of N,N-diisopropylethylamine (0.0320 mL, 0.184 mmol) and N-phenylbis(trifluoromethanesulfonylimide) (49.2 mg, 0.138 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (92%, 53.2 mg). LCMS:m / z 626[M+H] + HPLC retention time: 1.04 minutes (analytical condition D)

[0313] Step 7 Compound W5 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate [Chemistry 151] A solution of methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[8-]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate (17.9 g, 28.6 mmol) in 1,4-dimethyl benzoate (178 mL) was added to bis(pinacolborate) 14.5 g, 57.1 mmol, 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (1.05 g, 1.43 mmol) and potassium acetate (8.41 g, 85.7 mmol), and stirred at 100 °C for 16 hours. LCMS:m / z 604[M+H] + HPLC retention time: 0.89 minutes (analytical condition T)

[0314] Step 8 Compound W6 2-Bromo-4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[8-]-5-fluorobenzoate methyl ester [Chemistry 152] A solution of methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[-8-yl]-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate (200 mg, 0.331 mmol), copper(II) bromide (222 mg, 0.993 mmol), and N,N-dimethylformamide (3.00 mL)-water (1.00 mL) was stirred at 80 °C for 1 hour. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.5% trifluoroacetic acid) to give the title compound (63%, 4.39 g). LCMS:m / z 556[M+H] + HPLC retention time: 3.58 minutes (analytical conditions AA)

[0315] Step 9 Compound W Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[3,4-dihydro-1,3-benzo[3,4-dihydro-8-yl]-5-fluoro-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)benzoate [Chemistry 153] A solution of methyl 2-bromo-4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzo[3,4-dichloro-8-yl]-5-fluorobenzoate (400 mg, 0.718 mmol), 3-oxa-8-azabicyclo[3.2.1]octane (122 mg, 1.08 mmol), Xantphos Pd G4 (69.1 mg, 0.0720 mmol), and cesium carbonate (702 mg, 2.15 mmol) in toluene (4.79 mL) was stirred overnight at 100 °C. 1-Methylpyrrolidone and an aqueous formic acid solution were added to the reaction mixture, and the solution was purified by HPLC (acetonitrile / water, 0.5% trifluoroacetic acid) to obtain the title compound (26%, 110 mg). LCMS:m / z 589[M+H] + HPLC retention time: 0.96 minutes (analytical condition D)

[0316] Compound X 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate methyl benzoate First step Compound X2 Methyl 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoate [Chemistry 154] A solution of methyl 4-bromo-2,6-dichlorobenzoate (523 mg, 1.842 mmol) and (1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazole (460 mg, 2.21 mmol) in 1,4-dimethylalkyl (8.37 mL)-water (0.837 mL) was added to a 1,1'-bis(diphenylphosphine)ferrocene-palladium(II)dichloromethane complex (135 mg, 0.184 mmol) and potassium carbonate (764 mg, 5.53 mmol), and stirred at 100 °C for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.5% formic acid) to obtain a quantitative amount of the title compound (581 mg). LCMS:m / z 285[M+H] + HPLC retention time: 0.74 minutes (analytical condition D)

[0317] Second step Compound X3 2,6-Dichloro-4-(1-methylpyrazol-4-yl)benzoic acid [Chemistry 155] A solution of methyl 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoate (582 mg, 2.04 mmol) in dimethyl sulfoxide (3.06 mL)-water (1.02 mL) was added to a 5M sodium hydroxide aqueous solution (2.04 mL, 10.2 mmol), and the mixture was stirred at 60 °C for 3 hours. An aqueous formic acid solution was added to the reaction mixture, and the solution was purified by reverse-phase column chromatography (acetonitrile / water, 0.5% formic acid) to give the title compound (86%, 477 mg). LCMS:m / z 271[M+H] + HPLC retention time: 0.56 minutes (analytical condition K)

[0318] Third step Compound X4 N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-(1-methylpyrazol-4-yl)benzamide [Chemistry 156] A solution of 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoic acid (477 mg, 1.76 mmol) in N,N-dimethylformamide (8.20 mL) was added, along with HATU (656 mg, 1.73 mmol), 2-(aminomethyl)-6-bromophenol hydrochloride (392 mg, 1.64 mmol), and N,N-diisopropylethylamine (1.15 mL, 6.57 mmol). The mixture was stirred at room temperature for 5 hours. The reaction solution was filtered and purified by reverse-phase column chromatography (acetonitrile / water, 0.5% formic acid) to give the title compound (90%, 198 mg). LCMS:m / z 454[M+H] + HPLC retention time: 0.74 minutes (analytical condition D)

[0319] Fourth step Compound X5 (8-Bromo-2,4-dihydro-1,3-benzo[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl] ketone [Chemistry 157] The title compound was obtained using N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-(1-methylpyrazol-4-yl)benzamide via the same procedure as in the third step of compound W. LCMS:m / z 466[M+H] + HPLC retention time: 0.85 minutes (analytical condition D)

[0320] Fifth step Compound X6 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-5-fluoro-2-hydroxybenzoate [Chemistry 158] The title compound was obtained using (8-bromo-2,4-dihydro-1,3-benzo[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl] ketone and methyl 4-bromo-5-fluoro-2-hydroxybenzoate, via the same procedure as in the third step of compound B. LCMS:m / z 556[M+H] + HPLC retention time: 0.93 minutes (analytical condition D)

[0321] Step Six Compound X 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate methyl benzoate [Chemistry 159] A solution of methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-5-fluoro-2-hydroxybenzoate (66.6 mg, 0.120 mmol) in N,N-dimethylformamide (1.20 mL) was added, along with N,N-diisopropylethylamine (0.0417 mL, 0.239 mmol) and N-phenylbis(trifluoromethanesulfonylimide) (64.1 mg, 0.180 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was injected with 1 M hydrochloric acid and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (97%, 79.7 mg). LCMS:m / z 688[M+H] + HPLC retention time: 0.99 minutes (analytical condition D)

[0322] compound Y 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl]benzoyl]-2,4-dihydro-1,3-benzoyl]-5-fluoro-2-(trifluoromethylsulfonyluoxy)methyl benzoate First step compound Y1 (8-Bromo-2,4-dihydro-1,3-benzo[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl]phenyl]methyl ketone [Chemistry 160] A solution of (8-bromo-2,4-dihydro-1,3-benzo[3]-3-yl]-(2,6-dichloro-4-fluorophenyl) methyl ketone (500 mg, 1.23 mmol) in 1-methylpyrrolidone (2.15 mL) was mixed with (3R)-1,3-dimethylpiperidine (705 mg, 6.17 mmol) and N,N-diisopropylethylamine (0.00215 mL, 12.3 mmol). The mixture was stirred in a microwave at 200 °C for 1.5 hours, followed by stirring at 220 °C for 1.5 hours. An aqueous formic acid solution was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.5% formic acid) to give the title compound (66%, 406 mg). LCMS:m / z 498[M+H] + HPLC retention time: 0.56 minutes (analytical condition D)

[0323] Second step compound Y2 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-hydroxybenzoate methyl ester [Chemistry 161] The title compound was obtained by using (8-bromo-2,4-dihydro-1,3-benzo[2,6-dichloro-4-[(2R)-2,4-dimethylpiper[-1-yl]phenyl] ketone and methyl 4-bromo-5-fluoro-2-hydroxybenzoate, via the same procedure as in the third step of compound B. LCMS:m / z 588[M+H] + HPLC retention time: 0.71 minutes (analytical condition T)

[0324] Third step compound Y 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl]benzoyl]-2,4-dihydro-1,3-benzoyl]-5-fluoro-2-(trifluoromethylsulfonyluoxy)methyl benzoate [Chemistry 162] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl]benzoyl]-2,4-dihydro-1,3-benzo[8-]-5-fluoro-2-hydroxybenzoate via the same procedure as in step six of compound W. However, N,N-diisopropylethylamine was substituted with triethylamine. LCMS:m / z 720[M+H] + HPLC retention time: 0.68 minutes (analytical condition D)

[0325] Compound Z 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzo[3-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester First step Compound Z2 N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate tributyl ester [Chemistry 163] A solution of 3-bromo-4-fluoro-2-hydroxybenzonitrile (176 mg, 0.813 mmol) in tetrahydrofuran (1.63 mL) was cooled to 0 °C, and a 1 M borane-tetrahydrofuran complex (1.63 mL, 1.63 mmol) was added. The mixture was stirred at 60 °C for 2.5 h. The reaction mixture was then cooled to 0 °C, and 5 M hydrochloric acid (0.358 mL, 1.79 mmol) was added. The mixture was stirred at 60 °C for 2 h. The reaction mixture was then cooled to 0 °C, and 6 M sodium hydroxide aqueous solution (0.298 mL, 1.79 mmol) and di(tert-butyl dicarbonate) (0.266 mL, 0.976 mmol) were added. The mixture was stirred at room temperature for 30 min. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium bichloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (60%, 156 mg). LCMS:m / z 264[M-tBu+H] + HPLC retention time: 0.86 minutes (analytical conditions O)

[0326] Second step Compound Z3 8-Bromo-7-fluoro-2,4-dihydro-1,3-benzo[3]-3-carboxylic acid tributyl ester [Chemistry 164] The title compound was obtained using N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate tributyl ester via the same method as in the third step of compound W. LCMS:m / z 332[M+H] + HPLC retention time: 0.95 minutes (analytical conditions O)

[0327] Third step Compound Z4 7-Fluoro-8-(2-Fluoro-4-methoxycarbonyl-5-morpholino-4-ylphenyl)-2,4-dihydro-1,3-benzo[3-]-carboxylic acid tributyl ester [Chemistry 165] A solution of 8-bromo-7-fluoro-2,4-dihydro-1,3-benzo[3-]-carboxylic acid tributyl ester (400 mg, 1.20 mmol) and (2-fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)boronic acid (639 mg, 1.81 mmol) in 1,4-dimethylalkylene (5.02 mL)-water (1.00 mL) was added, along with potassium phosphate (1.28 g, 6.02 mmol) and XPhos Pd G3 (51.0 mg, 0.0600 mmol), and stirred at 50 °C for 4.5 h. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated sodium bichloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (92%, 544 mg). LCMS:m / z 491[M+H] + HPLC retention time: 0.96 minutes (analytical conditions O)

[0328] Fourth step Compound Z5 5-Fluoro-4-(7-Fluoro-3,4-dihydro-2H-1,3-benzo[a]-8-yl)-2-morphofolin-4-ylbenzoate methyl hydrochloride [Chemistry 166] The title compound was obtained by using 7-fluoro-8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzo[3-]-3-carboxylic acid tributyl ester via the same procedure as in step four of compound B. LCMS:m / z 391[M+H] + HPLC retention time: 0.49 minutes (analytical conditions O)

[0329] Fifth step Compound Z 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzo[3-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester [Chemistry 167] The title compound was obtained by using methyl 5-fluoro-4-(7-fluoro-3,4-dihydro-2H-1,3-benzo[a]-8-yl]-2-morphofolin-4-ylbenzoate hydrochloride and 4-bromo-2,6-dichlorobenzoyl chloride, following the same procedure as in step five of compound B. However, N,N-diisopropylethylamine was substituted with diisopropylamine. LCMS:m / z 641[M+H] + HPLC retention time: 0.99 minutes (analytical conditions O)

[0330] Compounds 1-61 4-[3-[2,6-dichloro-4-(5-oxa-2-azaspiro[3.4]oct-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 168] The title compound was obtained by using compound D and 2,2,2-trifluoroacetate of 5-oxa-2-azaspiro[3.4]octane via the same procedure as in step nine of compounds 1-7. LCMS:m / z 650[M+H] + HPLC retention time: 1.65 min, 1.68 min (analytical condition B)

[0331] Compounds 1-71 4-[3-[2-chloro-4-(3-methoxyazido-1-yl)-5-methylbenzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound CP8 Methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[8-]]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 169] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzo[ ... LCMS:m / z 629[M+H] + HPLC retention time: 1.02 minutes (analytical condition D)

[0332] Second step Compounds 1-71 4-[3-[2-chloro-4-(3-methoxyazido-1-yl)-5-methylbenzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 170] The title compound was obtained using methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[8-]]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate and 3-methoxyacetate hydrochloride, via the same procedure as in step nine of compounds 1-7. LCMS:m / z 622[M+H] + HPLC retention time: 1.48 minutes (analytical condition B)

[0333] Compounds 1-74 4-[3-[2-chloro-5-methoxy-4-(3-methoxyazido-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound CP9 Methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[8-]]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 171] The title compound was obtained by using methyl 4-(3,4-dihydro-2H-1,3-benzo[ ... LCMS:m / z 645[M+H] + HPLC retention time: 0.97 minutes (analytical condition D)

[0334] Second step Compounds 1-74 4-[3-[2-chloro-5-methoxy-4-(3-methoxyazido-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 172] The title compound was obtained using methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[4-]-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate and 3-methoxyazinon hydrochloride, via the same procedure as in step nine of compounds 1-7. LCMS:m / z 638[M+H] + HPLC retention time: 1.47 minutes (analytical condition B)

[0335] Compounds 1-55 4-[3-[2,6-dichloro-4-[4-(oxocyclobutane-3-yl)piperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 173] A solution of compound B (12.0 mg, 0.0190 mmol) and 1-(oxetane-3-yl)piperidine (5.47 mg, 0.0380 mmol), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dichloropalladium(II) (1.54 mg, 0.00192 mmol), and cesium carbonate (18.8 mg, 0.0580 mmol) in toluene (0.192 mL) was heated at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was concentrated. Methanol (0.0950 mL), tetrahydrofuran (0.095 mL), and 5M sodium hydroxide aqueous solution (0.0380 mL, 0.190 mmol) were added, and the mixture was stirred at 60 °C for 30 minutes. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (64%, 8.20 mg). LCMS:m / z 671[M+H] + HPLC retention time: 0.75 min, 0.80 min (analytical condition A)

[0336] Compounds 1-54 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 174] A solution of compound B (1.72 g, 2.76 mmol) and 1-(2-methoxyethyl)piperidine (0.818 mL, 5.51 mmol), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dichloropalladium(II) (65.0 mg, 0.0810 mmol), and cesium carbonate (2.69 g, 8.27 mmol) in toluene (15.0 mL) was heated at 95 °C for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was concentrated. Dimethyl sulfoxide (5.00 mL), 1,4-dimethylamine (5.00 mL), and 5M sodium hydroxide aqueous solution (2.76 mL, 13.8 mmol) were added, and the mixture was stirred at 90 °C for 1 hour. The reaction solution was concentrated, 1,4-dimethylamine was removed, formic acid was added, and the reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (67%, 1.24 g). LCMS:m / z 673[M+H] + HPLC retention time: 0.77 min, 0.82 min (analytical condition A)

[0337] Compounds 1-88 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound CP6 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl benzoate [Chemistry 175] A solution of compound H (3.46 g, 5.62 mmol) and 6-methoxy-2-azaspiro[3.3]heptane hydrochloride (1.84 g, 11.2 mmol), rac-BINAP Pd G4 (170 mg, 0.169 mmol), and cesium carbonate (9.15 g, 28.1 mmol) in 1,4-dimethylamine (34.6 mL) was heated at 100 °C for 2 hours. The reaction solution was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was washed with 15% sodium chloride aqueous solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (86%, 3.20 g). LCMS:m / z 662[M+H] + HPLC retention time: 3.1 minutes (analytical conditions AF)

[0338] Second step Compounds 1-88 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 176] A solution of methyl 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-dihydro-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate (3.17 g, 4.79 mmol) in tetrahydrofuran (7.61 mL) was added to ethanol (7.61 mL) and 8M potassium hydroxide aqueous solution (2.99 mL, 23.9 mmol), and the mixture was heated at 60 °C for 35 min. The reaction mixture was cooled to 0 °C and 0.5M hydrochloric acid was added. The resulting solid was filtered and washed with ethanol / water to give the title compound (97%, 3.01 g). LCMS:m / z 648[M+H] + HPLC retention time: 1.64 minutes (analytical condition B)

[0339] Compounds 1-83 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound CP7 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[4-]-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 177] A solution of compound D (24.0 g, 38.0 mmol) in 1,3-dimethyl-2-imidazolidinone (120 mL) was added to an 8M aqueous solution of potassium hydroxide (23.7 mL, 190 mmol), and the mixture was stirred at 60 °C for 3 hours. The reaction mixture was cooled to room temperature, and 2M hydrochloric acid and water were added. The mixture was stirred at room temperature for 30 minutes. The resulting solid was filtered and washed with water to give the title compound (90%, 21.0 g). LCMS:m / z 617[M+H] + HPLC retention times: 1.17 and 1.21 minutes (analytical condition G)

[0340] Second step Compounds 1-83 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 178] 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[4-]-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid (21.0 g, 34.0 mmol), 6-methoxy-2-azaspiro[3.3]heptane hydrochloride (8.34 g, 50.9 mmol), allyl palladium(II) chloride (dimer) (621 mg, 1.70 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (983 mg, 1.70 mmol), and dibenzylideneacetone (398 mg, 1.70 mmol). A solution of tetrahydrofuran (679 mL) containing 1 mmol was added, and sodium tert-butoxide (13.1 g, 136 mmol) was added. The mixture was stirred at 30 °C for 3 hours. A 0.5 M potassium hydrogen sulfate aqueous solution, ethyl acetate, N-acetylcysteine, and water were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution. The residue was dried over magnesium sulfate, filtered, and concentrated. Acetonitrile was added to the residue, and the mixture was stirred at 50 °C for 15 minutes. The mixture was cooled to room temperature, water was added, and the mixture was stirred at 25 °C for 30 minutes. The obtained solid was filtered and washed with acetonitrile / water (1 / 2) to give the title compound (70%, 15.8 g). LCMS:m / z 664[M+H] + HPLC retention time: 1.67, 1.70 minutes (analytical condition B)

[0341] Using the corresponding intermediates and the commercially available amine reagents shown in Tables 1-5, the compounds shown in Tables 1-4 were obtained by the same procedure as that used for compounds 1-55. However, in the synthesis of compounds 1-59, a 1,4-dimethyl alkyl solution was used instead of a toluene solution.

[0342] [Table 1-4]

[0343] [Table 1-5]

[0344] Compounds 1-73 4-[3-[2-chloro-5-methoxy-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzoyl]-2,4-dihydro-1,3-benzo[3]-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 179] A solution of compound K (60.0 mg, 0.0970 mmol), 2-oxalate (27.5 mg, 0.145 mmol), cesium carbonate (158 mg, 0.484 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (12.1 mg, 0.0190 mmol), and tris(dibenzylideneacetone)dipalladium(O)-chloroform adduct (10.0 mg, 0.00968 mmol) in 1-methylpyrrolidone-2-one (0.960 mL) was stirred at 100 °C for 2 hours. After cooling the reaction solution to room temperature, 0.121 mL (0.970 mmol) of 8M potassium hydroxide aqueous solution was added, and the mixture was stirred at 60 °C for 30 minutes. An aqueous formic acid solution was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (55%, 33.2 mg). LCMS:m / z 624[M+H] + HPLC retention time: 1.34 minutes (analytical condition B)

[0345] Using the corresponding intermediates and the amine reagents shown in Tables 1-7, the compounds shown in Tables 1-6 were obtained by the same procedure as that used for compounds 1-73. However, in compounds 1-57, 1-67, and 1-76, palladium(II) acetate was used instead of the tris(dibenzylacetone)dipalladium(O)-chloroform adduct. Furthermore, in compounds 1-57, 1-60, 1-65, 1-66, 1-67, 1-76, 1-79, 1-80, 1-81, 1-82, and 1-35, toluene solvent was used instead of the 1-methylpyrrolidone solvent.

[0346] [Table 1-6]

[0347] [Table 1-7]

[0348] Compounds 1-64 4-[3-[2,6-dichloro-4-(4-methylpiperyl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[8-yl]-2-morpholin-4-ylbenzoic acid [Chemistry 180] A solution of compound F (10.0 mg, 0.0170 mmol) and 1-methylpiperidine (0.00376 mL, 0.0340 mmol), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dichloropalladium(II) (1.35 mg, 0.00169 mmol), and cesium carbonate (16.5 mg, 0.0510 mmol) in toluene (0.150 mL) was heated at 100 °C for 45 minutes. The reaction solution was cooled to room temperature, and 1-methylpiperidine (0.00376 mL, 0.0340 mmol), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dichloropalladium(II) (1.35 mg, 0.00169 mmol), and 1-methylpyrrolidin-2-one (0.100 mL) were added, and the mixture was heated at 100 °C for 45 minutes. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (35%, 3.60 mg). LCMS:m / z 611[M+H] + HPLC retention time: 0.74 min, 0.80 min (analytical condition A)

[0349] Compounds 1-51 4-[3-[2,6-dichloro-4-(2-sideoxy-1,3-azolidin-3-yl)benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 181] A solution of compound B (50.0 mg, 0.080 mmol), 1,3-oxazolidin-2-one (14.0 mg, 0.160 mmol), sodium tert-butoxide (15.4 mg, 0.160 mmol), and XantPhos Pd G4 (7.71 mg, 0.00801 mmol) in 1-methylpyrrolidone (1.00 mL) was stirred at 100 °C for 15 hours. An aqueous formic acid solution was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (96%, 4.80 mg). LCMS:m / z 616[M+H] + HPLC retention time: 1.32 min, 1.35 min (analytical condition B)

[0350] Compounds 1-52 4-[3-[2,6-dichloro-4-(2-sideoxypyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid First step compound CP3 4-[3-[2,6-dichloro-4-(2-sideoxypyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate [Chemistry 182] A solution of compound B (60.0 mg, 0.0960 mmol), pyrrolidone-2-one (16.4 mg, 0.192 mmol), potassium carbonate (39.8 mg, 0.288 mmol), copper iodide (I) (9.15 mg, 0.0480 mmol), and (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (13.7 mg, 0.0960 mmol) in 1-methylpyrrolidone-2-one (0.960 mL) was stirred at 100 °C for 4.5 hours. The reaction mixture was cooled to room temperature, and pyrrolidone-2-one (8.18 mg, 0.0960 mmol), potassium carbonate (39.8 mg, 0.288 mmol), copper iodide (I) (3.66 mg, 0.0190 mmol), and (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (4.10 mg, 0.0290 mmol) were added. The mixture was stirred at 100 °C for 4.5 h. Formic acid aqueous solution was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (44%, 26.5 mg). LCMS:m / z 628[M+H] + HPLC retention time: 0.99 minutes (analytical condition D)

[0351] Second step Compounds 1-52 4-[3-[2,6-dichloro-4-(2-sideoxypyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 183] A solution of methyl 4-[3-[2,6-dichloro-4-(2-sideoxypyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate (26.3 mg, 0.0420 mmol) and trimethylstannanol (30.3 mg, 0.167 mmol) in chlorobenzene (0.140 mL) was stirred in a microwave oven at 200 °C for 0.75 h. An aqueous formic acid solution was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (97%, 24.9 mg). LCMS:m / z 614[M+H] + HPLC retention time: 1.35 min, 1.36 min (analytical condition B)

[0352] Compounds 1-50 4-[3-[2,6-dichloro-4-(2-sideoxy-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 184] A solution of compound C (40.0 mg, 0.0660 mmol), acrylonitrile-2-one (14.0 mg, 0.197 mmol), cesium carbonate (64.1 mg, 0.197 mmol), and XantPhos Pd G4 (6.31 mg, 0.00655 mmol) in 1,4-dimethyl ether (0.800 mL) was stirred at 100 °C for 2 hours. An aqueous formic acid solution was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (52%, 20.3 mg). LCMS:m / z 600[M+H] + HPLC retention time: 1.34 min, 1.36 min (analytical condition D)

[0353] Compounds 2-6 4-[3-[2-chloro-5-methoxy-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemistry 185] A solution of compound K (52.0 mg, 0.0840 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (22.7 mg, 0.109 mmol), potassium carbonate (34.8 mg, 0.252 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (6.14 mg, 0.00839 mmol) in 1,4-dimethylalkane (0.400 mL) and water (0.0400 mL) was stirred at 100 °C for 2 hours. The reaction mixture was filtered, concentrated, and the residue was added to a 5M aqueous solution of sodium hydroxide (0.0503 mL, 0.252 mmol) and 1,4-dimethylalkane (0.500 mL), and stirred at 60 °C for 1 hour. After adding aqueous formic acid and dimethyl sulfoxide to the reaction mixture, the mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (69%, 35.0 mg). LCMS:m / z 607[M+H] + HPLC retention time: 0.98 minutes (analytical condition A)

[0354] The compounds shown in Table 2-1 were synthesized using various boric acids or boronic esters known in the literature or commercially available, or the boric acids or boronic esters shown in Table 2-2, via the same procedures as those used in the preparation of compounds 2-6. However, in the synthesis of compounds 2-4, palladium(II) dichloride was replaced with tetra(triphenylphosphine)palladium, and in the synthesis of compounds 2-5, toluene was replaced with 1,4-dimethylamine / water.

[0355] [Table 2-1]

[0356] [Table 2-2]

[0357] Compound 3-2 4-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyr-3-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step compound BRO4 [3,5-Dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-]-3-carbonyl]phenyl]boronic acid [Chemistry 186] A solution of compound A (1.00 g, 1.54 mmol), bis-pinacolborate (0.781 g, 3.08 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex (0.126 g, 0.154 mmol), and potassium acetate (0.453 g, 4.61 mmol) in 1,4-dimethylamine (5.13 mL) was stirred at 100 °C for 2 hours. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through diatomaceous earth. Water was added to the filtrate, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. A solution of periodic acid (0.526 g, 2.06 mmol) in water (1.40 mL) was added to the residue in ethanol (14.0 mL). The reaction mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (89%, 0.845 g). LCMS:m / z 615[M+H] + HPLC retention time: 0.82 min, 0.85 min (analytical condition D)

[0358] Second step Compound 3-2a 4-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyr-3-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 187] A solution of [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-oxo]phenyl]boronic acid (48.1 mg, 0.0780 mmol), 3-bromo-5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyridine (13.0 mg, 0.0600 mmol), APos Pd G3 (3.82 mg, 0.00602 mmol), and potassium carbonate (33.3 mg, 0.241 mmol) in 1,4-diane (0.540 mL) and water (0.00540 mL) was stirred at 60 °C for 1 hour. An aqueous formic acid solution was added to the reaction solution, and the mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (92%, 38.9 mg). LCMS:m / z 706[M+H] + HPLC retention time: 0.70 minutes (analytical condition D)

[0359] Third step Compound 3-2 4-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyr-3-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 188] A solution of methyl 4-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyryl-3-yl)benzoyl]-2,4-dihydro-1,3-benzoyl-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate (38.9 mg, 0.0550 mmol) in 1-methylpyrrolidone (0.550 mL) was added to an 8M aqueous solution of potassium hydroxide (0.0688 mL, 0.551 mmol). The reaction mixture was stirred at 60 °C for 1 hour. An aqueous solution of formic acid was added to the reaction mixture, and the mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (64%, 24.3 mg). LCMS:m / z 692[M+H] + HPLC retention time: 1.14 min, 1.18 min (analytical condition B)

[0360] Compounds 3-6 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound H6 7-Bromo-2-methylpyrazolo[4,3-c]pyridine [Chemistry 189] A solution of 7-bromo-1H-pyrazolo[4,3-c]pyridine (80.0 mg, 0.404 mmol) in N,N-dimethylformamide (2.02 mL) was mixed with 1 M bis(trimethylsilyl)acetamide sodium tetrahydrofuran solution (0.606 mL, 0.606 mmol) and iodomethane (0.0760 mL, 1.21 mmol), and stirred at room temperature for 15 minutes. An aqueous formic acid solution was added to the reaction mixture, and the solution was purified by reverse-phase column chromatography (methanol / water, 0.01 M ammonium acetate) to give the title compound (12%, 10.4 mg). 1H-NMR (400 MHz, CDCl 3) δ: 9.05 (1H, s), 8.44 (1H, s), 8.19 (1H, d, J = 0.34 Hz), 4.32 (3H, d, J = 0.34 Hz).

[0361] Second step Compounds 3-6a 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 190] The title compound was obtained using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-2-]phenyl]boronic acid and 7-bromo-2-methylpyrazolo[4,3-c]pyridine, via the same procedure as in the second step of compound 3-2. LCMS:m / z 702[M+H] + HPLC retention time: 0.69 min, 0.72 min (analytical condition D)

[0362] Third step Compounds 3-6 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 191] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate via the same procedure as in the third step of compound 3-2. LCMS:m / z 688[M+H] + HPLC retention time: 1.15 min, 1.19 min (analytical condition B)

[0363] Compound 3-10 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2,1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound H10 7-bromo-2-methyltriazolo[4,5-c]pyridine [Chemistry 192] A solution of 7-bromo-3H-triazolo[4,5-c]pyridine (199 mg, 1.00 mmol) in N,N-dimethylformamide (5.00 mL) was mixed with 1 M bis(trimethylsilyl)amide sodium tetrahydrofuran solution (1.50 mL, 1.50 mmol) and iodomethane (0.188 mL, 3.00 mmol) and stirred at room temperature for 30 minutes. An aqueous formic acid solution was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (33%, 69.2 mg). LCMS:m / z 213[M+H] + HPLC retention time: 0.50 min (analytical condition D)

[0364] Second step Compound 3-10a 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-dichloro-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 193] The title compound was obtained using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-2-]phenyl]boronic acid and 7-bromo-2-methyltriazolo[4,5-c]pyridine, via the same procedure as in the second step of compound 3-2. LCMS:m / z 703[M+H] + HPLC retention time: 0.91 min, 0.94 min (analytical condition D)

[0365] Third step Compound 3-10 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2,1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 194] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate via the same procedure as in the third step of compound 3-2. LCMS:m / z 689[M+H] + HPLC retention time: 1.43 min, 1.45 min (analytical condition B)

[0366] Compound 3-17 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2,1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound 3-17a 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2,1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 195] Compound 3-19a 4-[3-[2,6-dichloro-4-(3-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-dichloro-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemistry 196] A solution of 7-bromo-3H-triazolo[4,5-b]pyridine (100 mg, 0.502 mmol) in tetrahydrofuran (2.51 mL) was mixed with 1M bis(trimethylsilyl)acetic acid sodium tetrahydrofuran solution (0.754 mL, 0.754 mmol) and iodomethane (0.0940 mL, 1.51 mmol), and stirred at room temperature for 18 hours. Then, 1M bis(trimethylsilyl)acetic acid sodium tetrahydrofuran solution (0.754 mL, 0.754 mmol) was added, and stirred at room temperature for 1 hour. Finally, 1M bis(trimethylsilyl)acetic acid sodium tetrahydrofuran solution (0.754 mL, 0.754 mmol) and iodomethane (0.094 mL, 1.51 mmol) were added, and stirred at room temperature for 1 hour. An aqueous formic acid solution was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (methanol / water, 0.01 M ammonium acetate) to obtain a mixture (25%, 27.0 mg) of 7-bromo-2-methyltriazolo[4,5-b]pyridine and 7-bromo-3-methyltriazolo[4,5-b]pyridine. Using the obtained mixture and [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-2-]phenyl]boronic acid, the title compounds 3-17a and 3-19a were obtained by the same procedure as in the second step of compound 3-2. However, purification was performed using reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) followed by SFC (ACQUITY UPC2 Torus 1-AA, supercritical carbon dioxide / methanol). Compound 3-17a LCMS:m / z 703[M+H] + SFC residence time: 3.18 minutes (analytical conditions: ACQUITY UPC2 Torus 1-AA 4.6 mm IDx50 mm, 5 μm, supercritical carbon dioxide / methanol = 70 / 30 (10 minutes), 40℃, 270 nm) Compound 3-19a LCMS:m / z 703[M+H] + SFC residence time: 2.44 minutes (analytical conditions: ACQUITY UPC2 Torus 1-AA 4.6 mm IDx50 mm, 5 μm, supercritical carbon dioxide / methanol = 70 / 30 (10 minutes), 40℃, 270 nm)

[0367] Second step Compound 3-17 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2,1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 197] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate via the same procedure as the third step of compound 3-2. LCMS:m / z 689[M+H] + HPLC retention time: 1.52 min, 1.56 min (analytical condition B)

[0368] Compound 3-19 4-[3-[2,6-dichloro-4-(3-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3,2,1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 198] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-(3-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate via the same procedure as the third step of compound 3-2. LCMS:m / z 689[M+H] + HPLC retention time: 1.57 min, 1.58 min (analytical condition B)

[0369] Compound 3-26 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound H26 7-Bromo-4-methoxy-2-methyltriazolo[4,5-c]pyridine [Chemistry 199] Compound H27 7-Bromo-4-methoxy-3-methyltriazolo[4,5-c]pyridine [Chemistry 200] A solution of 7-bromo-4-methoxy-3H-triazolo[4,5-c]pyridine (40.0 mg, 0.175 mmol) in tetrahydrofuran (0.900 mL) was mixed with 2.4 M lithium bis(trimethylsilyl)acetamide tetrahydrofuran solution (0.109 mL, 0.262 mmol) and iodomethane (0.0660 mL, 1.05 mmol) and stirred at room temperature for 68 hours. Formic acid aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give title compound h26 (5.0%, 2.10 mg) and title compound h27 (42%, 17.8 mg). Compound H26 LCMS:m / z 243[M+H] + HPLC retention time: 0.66 minutes (analytical condition D) Compound H27 LCMS:m / z 243[M+H] + HPLC retention time: 0.61 minutes (analytical condition D)

[0370] Second step Compound 3-26a 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemical Engineering 201] The title compound was obtained using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-2-]phenyl]boronic acid and 7-bromo-4-methoxy-2-methyltriazolo[4,5-c]pyridine, via the same procedure as in the second step of compound 3-2. LCMS:m / z 733[M+H] + HPLC retention time: 1.07 min, 1.10 min (analytical condition K)

[0371] Third step Compound 3-26 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemical Engineering 202] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate via the same procedure as the third step of compound 3-2. LCMS:m / z 719[M+H] + HPLC retention time: 1.70 min, 1.71 min (analytical condition B)

[0372] Compound 3-27 4-[3-[2,6-dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid First step Compound 3-27a 4-[3-[2,6-dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate [Chemical Engineering 203] The title compound was obtained using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-2]-3-carbonyl]phenyl]boronic acid, compound 3-26, and 7-bromo-4-methoxy-3-methyltriazolo[4,5-c]pyridine obtained in the first step, via the same procedure as in the second step of compound 3-2. LCMS:m / z 733[M+H] + HPLC retention time: 1.08 minutes (analytical condition K)

[0373] Second step Compound 3-27 4-[3-[2,6-dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemical 204] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate via the same procedure as in the third step of compound 3-2. LCMS:m / z 719[M+H] + HPLC retention time: 1.69 minutes (analytical condition B)

[0374] First step The compounds shown in Table 3-1 were synthesized using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)phenyl]-2,4-dihydro-1,3-benzo[3-]phenyl]boronic acid and the brominated aryl group listed in Table 3-1, via the same procedure as the second step of compound 3-2. However, in the synthesis of compounds 3-14a, 3-15a, and 3-18a, triphenylphosphine palladium (0) was used to replace APhos Pd G3, and sodium carbonate was used to replace potassium carbonate.

[0375] [Table 3-1]

[0376] Second step Using the esters listed in Table 3-1 obtained in the first step, the compounds shown in Table 3-2 were synthesized via the same procedure as in the second step of compound 3-2.

[0377] [Table 3-2]

[0378] Compound 3-1 4-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropane-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid First step compound BRO1 [3,5-Dichloro-4-[8-(2-fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[-3-carbonyl]phenyl]boronic acid [Chemical Engineering 205] A solution of compound B (300 mg, 0.481 mmol), bis(pinacolborate) (244 mg, 0.961 mmol), and potassium acetate (141 mg, 1.44 mmol) in 1,4-dimethylamine (2.40 mL) was mixed with 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride (35.2 mg, 0.0480 mmol). The reaction mixture was stirred at 100 °C for 1 hour. After concentration, the residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (100%, 284 mg). LCMS:m / z 589[M+H] + HPLC retention time: 0.76 min, 0.79 min (analytical condition D)

[0379] Second step Compound 3-1a 4-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropane-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoate methyl ester [Chemical Engineering 206] A solution of [3,5-dichloro-4-[8-(2-fluoro-4-methoxycarbonyl-5-morphofolin-4-ylphenyl)-2,4-dihydro-1,3-benzo[-3-carbonyl]phenyl]boronic acid (30.0 mg, 0.0510 mmol), 2-(4-bromopyrazol-1-yl)-2-methylpropane-1-ol (16.7 mg, 0.0760 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride (3.73 mg, 0.00509 mmol), and potassium carbonate (21.1 mg, 0.153 mmol) in 1,4-dimethylalkanes (0.191 mL) and water (0.0636 mL) was stirred at 100 °C for 1 hour. The reaction solution was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (66%, 22.9 mg). LCMS:m / z 683[M+H] + HPLC retention time: 0.85 min, 0.86 min (analytical condition D)

[0380] Third step Compound 3-1 4-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropane-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzo[8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid [Chemical 207] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropane-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoyl]-5-fluoro-2-morphofolin-4-ylbenzoate via the same procedure as in the third step of compound 3-2. LCMS:m / z 669[M+H] + HPLC retention time: 1.01 min, 1.04 min (analytical condition A)

[0381] Compound 3-28 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-2-morpholin-4-ylbenzoic acid First step compound BRO2 [3,5-Dichloro-4-[8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzo[-3-carbonyl]phenyl]boronic acid [Chemical Engineering 208] A solution of compound E (175 mg, 0.289 mmol), bis(pinacolborate) (147 mg, 0.579 mmol), and potassium acetate (85.0 mg, 0.868 mmol) in 1,4-dimethylamine (3.00 mL) was reacted with 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) chloride (21.2 mg, 0.0290 mmol). The reaction mixture was stirred at 90 °C for 1 hour. An aqueous formic acid solution was added to the reaction mixture, and the reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (77%, 127 mg). LCMS:m / z 571[M+H] + HPLC retention time: 1.11 minutes (analytical condition G)

[0382] Second step Compound 3-28a 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-2-morphofolin-4-ylbenzoate [Chemical Engineering 209] The title compound was obtained using [3,5-dichloro-4-[8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzo[-3-carbonyl]phenyl]boronic acid and 4-bromo-1-(2-methoxyethyl)pyrazole via the same method as in compound 3-1 and step two. LCMS:m / z 651[M+H] + HPLC retention time: 1.22 min, 1.24 min (analytical condition G)

[0383] Third step Compound 3-28 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzo[-8-yl]-2-morpholin-4-ylbenzoic acid [Chemical 210] The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoyl]-2-morphofolin-4-ylbenzoate via the same procedure as in the third step of compound 3-2. LCMS:m / z 637[M+H] + HPLC retention time: 1.01 min, 1.04 min (analytical condition A)

[0384] Compound 4-2 4-[3-[2,6-dichloro-4-(3-ethoxy-3-methylacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 211] 1-Methylpyrrolidone-2-one (0.600 mL) was added to 3-ethoxy-3-methylacetate hydrochloride (27.0 mg, 0.178 mmol) and potassium carbonate (23.0 mg, 0.166 mmol), and the mixture was stirred at room temperature for 10 minutes. Compound O (35.0 mg, 0.0590 mmol) was added to the reaction mixture, and the mixture was stirred at 100 °C for 14 hours. After cooling the reaction mixture, 8M potassium hydroxide aqueous solution (0.0742 mL, 0.594 mmol) was added, and the mixture was stirred at 60 °C for 1 hour. After neutralizing the reaction mixture with formic acid aqueous solution, the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (82%, 32.7 mg). LCMS:m / z 670[M+H] + HPLC retention time: 1.62 min, 1.66 min (analytical condition B)

[0385] Using the amines listed in Table 4-2, which are known in the literature or commercially available, the compounds shown in Table 4-1 were synthesized by the same procedure as that used in the synthesis of compound 4-2. However, in the synthesis of compounds 4-18, 4-7, and 4-17, potassium tert-butoxide was used instead of potassium carbonate, and in the synthesis of compounds 4-20, 4-22, 4-23, 4-24, 4-25, 4-27, 4-28, and 4-29, triethylamine was used.

[0386] [Table 4-1]

[0387] [Table 4-2]

[0388] Compound 4-12 4-[3-[2,6-dichloro-4-(4-cyclopropylpiperyl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-dichloro-1-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 212] 1-Methylpyrrolidone-2-one (0.106 mL), compound O (25.0 mg, 0.0420 mmol), and 1-cyclopropylpiperidine (16.1 mg, 0.127 mmol) were stirred at 130 °C for 6 hours. After cooling, 0.0265 mL (0.212 mmol) of 8M potassium hydroxide aqueous solution was added, and the mixture was stirred at 60 °C for 30 minutes. The reaction mixture was neutralized with formic acid aqueous solution, and then purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (73%, 21.1 mg). LCMS:m / z 681[M+H] + HPLC retention time: 1.03, 1.06 minutes (analytical condition B)

[0389] Using the amines shown in Table 4-4 that are known in the literature or commercially available, the compounds shown in Table 4-3 were synthesized by the same procedure as that used for compound 4-12.

[0390] [Table 4-3]

[0391] [Table 4-4]

[0392] Compound 4-13 4-[3-[4-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]e-8-yl]-2,6-dichlorobenzoyl]-2,4-dihydro-1,3-benzoe-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 213] In 1-methylpyrrolidin-2-one (0.0870 mL), (9aS)-1,3,4,6,7,8,9,9a-octahydropyrro[2,1-c][1,4]e-dihydrochloride (37.4 mg, 0.174 mmol) and potassium tert-butoxide (42 mg, 0.375 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Compound P (20.0 mg, 0.0350 mmol) was added to the reaction mixture, and the mixture was stirred at 130 °C for 4 hours. The reaction mixture was cooled, diluted with methanol, and neutralized with aqueous formic acid. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (40%, 9.70 mg). LCMS:m / z 697[M+H] + HPLC retention time: 1.03 min, 1.06 min (analytical condition B)

[0393] Compound 4-14 4-[3-[4-[(9aR)-3,4,6,7,9,9a-hexahydro-1H-pyrro[2,1-c][1,4]e-8-yl]-2,6-dichlorobenzoyl]-2,4-dihydro-1,3-benzoe-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 214] The title compound was synthesized using compound P and (9aR)-1,3,4,6,7,8,9,9a-octahydropyridine[2,1-c][1,4]dihydrochloride via the same procedure as that used for compounds 4-13. LCMS:m / z 697[M+H] + HPLC retention time: 1.03 min, 1.06 min (analytical condition B)

[0394] Compound 4-15 4-[3-[2,6-dichloro-4-[4-(2-hydroxy-2-methylpropyl)piperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo[3-2-ethyl]-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemical 215] 1-Methylpyrrolidone-2-one (0.174 mL), N,N-diisopropylethylamine (35.9 mg, 0.278 mmol), compound P (20.0 mg, 0.0350 mmol), and 2-methyl-1-piperylpropane-2-ol dihydrochloride (24.1 mg, 0.104 mmol) were stirred at 130 °C for 2 hours. The reaction mixture was cooled and neutralized with aqueous formic acid. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (34%, 8.30 mg). LCMS:m / z 713[M+H] + HPLC retention time: 1.00 min, 1.04 min (analytical condition B)

[0395] Compound 4-19 4-[3-(2,6-dichloro-4-morphofolin-4-ylbenzoyl)-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 216] 1-Methylpyrrolidone-2-one (0.0870 mL), compound P (20.0 mg, 0.0340 mmol), and mofoolin (15.2 mg, 0.174 mmol) were stirred at 130 °C for 4 hours. After cooling, the reaction mixture was diluted with methanol and neutralized with aqueous formic acid. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (65%, 14.5 mg). LCMS:m / z 642[M+H] + HPLC retention time: 1.45 minutes (analytical condition B)

[0396] Using the amines listed in Table 4-6 that are known in the literature or commercially available, the compounds shown in Table 4-5 were synthesized by the same procedure as that used in the preparation of compound 4-19.

[0397] [Table 4-5]

[0398] [Table 4-6]

[0399] Compound 4-42 4-[3-[2,6-dichloro-4-[[(2S)-1,4-dialkyl-2-yl]methoxy]benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl]benzoic acid [Chemistry 217] 1-Methylpyrrolidone (0.254 mL) was added to [(2R)-1,4-dialkyl-2-yl]methanol (0.0273 mL, 0.254 mmol) and potassium tert-butoxide (27.4 mg, 0.244 mmol), and the mixture was stirred at room temperature for 10 minutes. Compound O (30.0 mg, 0.0510 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After neutralizing the reaction mixture with aqueous formic acid, the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (69%, 23.8 mg). LCMS:m / z 673[M+H] + HPLC retention time: 1.43 minutes (analytical condition B)

[0400] Using alcohols known in the literature or commercially available as shown in Table 4-8, the compounds shown in Table 4-7 were synthesized via the same procedure as that used for compound 4-42. In the synthesis of compounds 4-43, 4-44, and 4-45, sodium tert-butoxide was used instead of potassium tert-butoxide; in the synthesis of compound 4-46, sodium hydride was used. Furthermore, compound 4-43 used an ethyl ester intermediate, while compounds 4-44, 4-45, 4-46, and 4-47 used a methyl ester intermediate; the ester hydrolysis reaction was also carried out simultaneously. Furthermore, for compounds 4-48, 4-49, 4-50, 4-51, 4-52, and 4-53, after the aromatic nucleophilic substitution reaction, an 8M potassium hydroxide aqueous solution was added, and the mixture was stirred at 60°C for 30 minutes to carry out the hydrolysis reaction.

[0401] [Table 4-7]

[0402] [Table 4-8]

[0403] Compound 4-40 4-[3-(2,6-dichloro-4-methoxybenzoyl)-2,4-dihydro-1,3-benzo[3-benzo[4-]-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 218] Compound 4-41 4-[3-[2,6-dichloro-4-(oxane)-4-ylmethoxy)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 219] Using compound O and oxacyclohexane-4-ylmethanol, 4-[3-(2,6-dichloro-4-methoxybenzoyl)-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid and 4-[3-[2,6-dichloro-4-(oxacyclohexane-4-ylmethoxy)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid were obtained by the same procedure as that used in the preparation of compound 42. Compound 4-40 LCMS:m / z 587[M+H] + HPLC retention time: 1.47, 1.49 minutes (analytical condition B) Compound 4-41 LCMS:m / z 671[M+H] + HPLC retention time: 1.54, 1.55 minutes (analytical condition B)

[0404] Compounds 5-7 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid Synthesis Method A First step Compound AZ1 4-[3-[2,6-dichloro-4-(3-hydroxyacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl benzoate [Chem.220] A suspension of compound A (2.00 g, 3.08 mmol), acrylonitrile-3-ol hydrochloride (674 mg, 6.15 mmol), rac-BINAP Pd G4 (217 mg, 0.215 mmol), and cesium carbonate (4.01 g, 12.3 mmol) in 1-methylpyrrolidone-2-one (28.0 mL) and water (2.80 mL) was stirred at 100 °C for 4 hours. An aqueous formic acid solution was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (83%, 1.64 g). LCMS:m / z 642[M+H] + HPLC retention time: 0.85 minutes (analytical condition D)

[0405] Second step Compound AZ2 4-[3-[2,6-dichloro-4-(3-sideoxy-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-2-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl benzoate [Chemistry 221] Methyl 4-[3-[2,6-dichloro-4-(3-hydroxyacetyl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azadicyclo[3.2.1]oct-8-yl)benzoate (1.64 g, 2.55 mmol) and Dess-Martin Periodinane (1.08 g, 2.55 mmol) in dichloromethane (25.5 mL) were stirred at room temperature for 1 hour. Dess-Martin Periodinane (0.866 g, 2.04 mmol) was added, and the mixture was stirred at room temperature for another 2 hours. Dichloromethane and an aqueous solution of sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and sodium chloride aqueous solutions, and then concentrated after passing through a phase separator. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (81%, 1.33 g). LCMS:m / z 640[M+H] + HPLC retention time: 0.91 minutes (analytical condition D)

[0406] Third step Compounds 5-7 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 222] In a solution of methyl 4-[3-[2,6-dichloro-4-(3-sideoxyacetyl-1-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate (25.0 mg, 0.0390 mmol) and 2-methyl-1,3-propanediol (0.00693 ml, 0.0780 mmol) in acetonitrile (0.195 ml), trimethylsilyl trifluoromethanesulfonate (0.00377 ml, 0.0200 mmol) was added. After stirring at room temperature for 1 hour, the mixture was stirred at 70°C for 4 hours. Tetrahydrofuran (0.0980 ml) and methanol (0.0980 ml) were added to the reaction mixture, followed by 8M potassium hydroxide aqueous solution (0.0980 ml, 0.780 mmol). The mixture was stirred at 60°C for 30 minutes. Formic acid aqueous solution was added to the reaction mixture, and the solution was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (75%, 20.3 mg). LCMS:m / z 698[M+H] + HPLC retention time: 1.60, 1.63 minutes (analytical condition B)

[0407] Compounds 5-7 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid Synthesis Method B First step Compound ACP2 7-Methyl-5,9-dioxa-2-azaspiro[3.5]non-2-carboxylic acid benzyl ester (benzyl 7-methyl-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate) [Chemistry 223] A solution of 3-side-oxy-acetyl-1-carboxylic acid benzyl ester (15.0 g, 73.1 mmol) in acetonitrile (300 mL) was mixed with 2-methyl-1,3-propanediol (13.0 mL, 146 mmol) and trimethylsilyl trifluoromethanesulfonate (6.60 mL, 36.5 mmol) and stirred at 70 °C for 4.5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with 5% sodium bicarbonate aqueous solution and 15% sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (84%, 17.0 g). LCMS:m / z 278[M+H] + HPLC retention time: 1.06 minutes (analytical condition G)

[0408] Second step Compound ACP3 7-Methyl-5,9-dioxa-2-azaspiro[3,5]nonane [Chemistry 224] A solution of 1,4-dimethylbenzyl 7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-carboxylic acid (13.5 g, 48.7 mmol) in 1,4-dimethylalkane (135 mL) was mixed with 20% palladium hydroxide-activated carbon (containing water) (1.20 g, 1.70 mmol) and stirred for 16 hours under hydrogen conditions. The reaction solution was filtered through diatomaceous earth and washed with 1,4-dimethylalkane to obtain the crude product of the title compound in 1,4-dimethylalkane.

[0409] Third step Compound AC7 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl benzoate [Chemistry 225] Compound A (15.6 g, 24.0 mmol), a 3.05 wt% solution of 7-methyl-5,9-dioxa-2-azaspiro[3.5]non-1,4-dioxane (146 g, 31.2 mmol), cesium carbonate (23.5 g, 72.0 mmol), and a 1,4-dioxane solution of rac-BINAP Pd G4 (724 mg, 0.720 mmol) (109 mL) were stirred at 60 °C for 16 hours. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. A 5% aqueous solution of N-acetycysteine ​​was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes for extraction. The organic layer was concentrated by drying with sodium sulfate in a 15% aqueous solution of sodium chloride. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give a mixture of the title compound (20.3 g) and ethyl acetate. LCMS:m / z 712[M+H] + HPLC retention time: 3.22 minutes (analytical conditions AF)

[0410] Fourth step Compounds 5-7 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3.2.1]oct-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid [Chemistry 226] A solution of methyl 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo[3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoate (17.1 g, 24.0 mmol) in tetrahydrofuran (42.7 mL) and methanol (42.7 mL) was added, followed by the addition of 8M potassium hydroxide aqueous solution (9.00 mL, ...

Claims

1. A compound or a salt thereof or a hydrate thereof, selected from the following compounds: 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylacetyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7-oxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperyl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piper-1-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-morphofolin-4-ylbenzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(4-ethylpiper-1-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.1] Oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazido-1-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azabispiro[3.1.56.14]dodec-2-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(3,3-dimethoxyacet-1-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]hept-2-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]hept-2-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2]1] Oct-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-2-morphofolin-4-ylbenzoic acid, 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]non-2-yl)-2-methylpyridin-3-carbonyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid, and 4-[3-[5-chloro-7-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

2. A 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid or a salt thereof, or a hydrate thereof.

3. A 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

4. A salt of 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

5. A hydrate of 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperyl-1-yl]benzoyl]-2,4-dihydro-1,3-benzo-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)benzoic acid.

6. A pharmaceutical composition comprising any one of claims 1 to 5, a compound or a salt thereof, or a hydrate thereof.

7. A pharmaceutical composition comprising, as any one of claims 1 to 5, a compound or its salt or hydrate thereof as an active ingredient.

8. The pharmaceutical composition as claimed in claim 6, for the treatment of neurodegenerative diseases, acute pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary hypertension, asthma, chronic kidney disease, or acute kidney disease.

9. Use of any compound as claimed in claims 1 to 5, or a salt thereof or a hydrate thereof, for the preparation of a pharmaceutical composition for the treatment of neurodegenerative diseases, acute pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary hypertension, asthma, chronic kidney disease, or acute kidney disease.