Nitrogen-containing heterocyclic compound having nrf2 activation effect

Abstract

Provided is a compound able to activate Nrf2 and represented by formula (1), a salt thereof, or a solvate of these.　Formula (1) (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, halogens, and C1–C6 alkoxy groups, Xb1, Xb2, and Xb3 are each independently selected from the group consisting of CH2, O, NH, S, and C=O, Y is an optionally substituted C6–C10 aryl or an optionally substituted 5– to 10-member heteroaryl, and Z is an optionally substituted C6–C10 aryl, an optionally substituted 5– to 10-member heteroaryl, or an optionally substituted C1–C6 alkyl.)

Description

Nitrogen-containing heterocyclic compounds with Nrf2 activation activity

[0001] The present invention relates to a nitrogen-containing heterocyclic compound, a salt thereof, or a solvate thereof having Nrf2 activation activity, and uses thereof. It also relates to a medicament and a pharmaceutical composition containing the compound or salt as an active ingredient.

[0002] Nrf2 is a regulatory factor for genes involved in various biological defenses and a transcription factor that is activated in response to oxidative stress. Under normal conditions, Nrf2 binds to Keap1, undergoes ubiquitination, and is degraded via the proteasome pathway. However, under stressful conditions, it is released from Keap1, avoiding degradation and translocating into the nucleus. Nrf2 then forms a heterodimer with a small Maf group factor and induces the transcription of downstream molecules by binding to antioxidant response elements (AREs).

[0003] Activation of Nrf2 exhibits a wide range of pharmacological effects, including antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects, and is thought to have a protective effect against various diseases. Specific examples of diseases include neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis; pulmonary diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary arterial hypertension, and asthma; renal diseases such as chronic kidney disease and acute kidney injury; ophthalmological diseases such as uveitis, glaucoma, and age-related macular degeneration; liver diseases such as non-alcoholic steatohepatitis; and immune / inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and ulcerative colitis (Non-Patent Documents 3 to 7). Clinical trials are currently being conducted on compounds that actually induce Nrf2 activation, such as bardoxolone methyl (CDDO-Me, Patent Document 1) for various chronic kidney diseases, and RTA-408 (omaveloxolone, Patent Document 2) for Friedreich's ataxia. Dimethyl fumarate (Patent Document 3) is used as a therapeutic agent for multiple sclerosis. However, these compounds covalently bind to Keap1. Concerns have been raised about the risk of heart failure due to interactions between the covalent binding site of bardoxolone methyl and non-target proteins (Non-Patent Document 8).

[0004] To date, compounds such as those described in Patent Document 4 have been reported as Nrf2 activators. However, they have not yet reached clinical development, and there is a need for the development of non-covalent Nrf2 activators that are expected to reduce interactions with non-target proteins (Non-Patent Documents 1 to 3).

[0005] International Publication No. WO 1999 / 065478 International Publication No. WO 2014 / 176415 International Publication No. WO 2016 / 090154 International Publication No. WO 2020 / 165776

[0006] Med Chem Commun, 2017, 8, 286-294. Medicinal Chemistry Research, 2020, 29, 846-867. Nature Reviews Drug Discovery, 2019, 18, 295-317. Oxydative Medicine and Cellular Longevity, 2019, Article ID9372182, 1-20. Neurodegenr Dis Manag, 2017, 7, 97-100. Oxydative Medicine and Cellular Longevity, 2019, Article ID7090534, 1-17. Oxydative Medicine and Cellular Longevity, 2020, Article ID9410952, 1-22. Am J Nephrol, 2014, 39, 499-508

[0007] An object of the present invention is to provide a low molecular weight compound, a salt thereof, or a solvate thereof that has the ability to activate Nrf2 and exhibits reduced interaction with non-target proteins due to covalent bonding, and to provide a preventive or therapeutic agent for various diseases, such as neurodegenerative diseases, pulmonary diseases, and renal diseases, containing the compound or salt as an active ingredient.

[0008] The present inventors have conducted extensive research to solve these problems and have found that compounds having a basic skeleton represented by formula (I), or pharmacologically acceptable salts thereof, or solvates thereof, which have a chemical structure significantly different from that of known Nrf2 activators, have excellent Nrf2 activating activity, thereby completing the present invention.

[0009] That is, in one aspect of the present invention, the following invention is provided: [1] Formula (1): [In the formula, X ａ１ is CR ａ１ or N, X ａ３ is CR ａ３ or N, R ａ１ , R ａ２ and R ａ３ are each independently hydrogen, halogen, and C １ -C６ alkoxy; ｂ１ , X ｂ２ and X ｂ３ are each independently CH ２ , O, NH, S and C═O, and Y is C ６ -C １０ aryl or 5- to 10-membered heteroaryl, ６ -C １０ Aryl and 5- to 10-membered heteroaryl are R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ and wherein said R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, hydroxy C ２ -C ６ Alkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Alkylamino C １ -C ６ Alkoxy, 5-10 membered heteroaryloxy, C １ -C ６ alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, and C １ -C ６ Alkyl (C １ -C ６ Alkoxy C １-C ６ Z is selected from the group consisting of C ６ -C １０ Aryl, 5- to 10-membered heteroaryl or C １ -C ６ alkyl, ６ -C １０ Aryl, 5- to 10-membered heteroaryl and C １ -C ６ Alkyl is R ｚ３ and R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ and R ｚ３ is the following substituent group A: (wherein the wavy line represents the C ６ -C １０ Aryl, 5- to 10-membered heteroaryl or C １ -C ６ represents the point of attachment to the alkyl, R ５ is hydroxy, C １ -C ６ Alkoxy, mono or di C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino, and n is 1 or 2; ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ are each independently hydrogen, halogen, or C １ -C ６ alkyl, optionally substituted C １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ６ alkyl)amino, optionally substituted C １ -C ６ [2] A compound represented by the formula (I) or a salt thereof, or a solvate thereof, wherein X is selected from the group consisting of alkyl(4- to 10-membered heterocyclyl)amino and optionally substituted 4- to 8-membered cyclic amino. ｂ１is CH ２ and X ｂ２ is CH ２ , O, NH or C═O, and X ｂ３ is CH ２ [3] The compound according to [1], or a salt thereof, or a solvate thereof, wherein X is O, NH, S, or C=O. ｂ１ and X ｂ２ is CH ２ and X ｂ３ is O or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is S or X ｂ１ is CH ２ and X ｂ２ is NH, and X ｂ３ is C=O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is NH or X ｂ１ is CH ２ and X ｂ２ is C=O, and X ｂ３ is NH or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is NH or X ｂ１ , X ｂ２ and X ｂ３ is CH ２ [4] The compound according to [1] or [2], or a salt thereof, or a solvate thereof, wherein X ａ１ is CR ａ１ and X ａ３ is CR ａ３ [5] The compound according to any one of [1] to [3], or a salt thereof, or a solvate thereof, wherein Z is phenyl, pyridyl, or C ２ -C ５ alkyl, and the phenyl, pyridyl and C ２ -C ５ Alkyl is Rｚ３ and R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ and R ｚ３ The following substituent group B: wherein the wavy line represents the phenyl, pyridyl or C ２ -C ５ represents the point of attachment to the alkyl, R ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino, R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ are each independently hydrogen, halogen, C １ -C ６ alkyl, optionally substituted C １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ６ alkyl)amino, optionally substituted C １ -C ６ [6] The compound according to any one of [1] to [4], wherein R is selected from the group consisting of alkyl(4- to 10-membered heterocyclyl)amino and optionally substituted 4- to 8-membered cyclic amino, or a salt thereof, or a solvate thereof. ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, and C １ -C ６ alkyl; R ｚ４ C which may have a substituent １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ２ alkyl)amino, optionally substituted C １ -C ６The compound according to any one of [1] to [5], or a salt thereof, or a solvate thereof, wherein Y is alkyl(4- to 10-membered heterocyclyl)amino or optionally substituted 4- to 8-membered cyclic amino. [7] The compound according to any one of [1] to [5], or a salt thereof, or a solvate thereof, wherein Y is phenyl or 6- to 10-membered heteroaryl, and the phenyl and 6- to 10-membered heteroaryl are each independently selected from the group consisting of R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ and wherein said R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl, C １ -C ３ Alkoxy, 5- to 6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, and C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２[8] The compound according to any one of [1] to [6], or a salt thereof, or a solvate thereof, wherein Y is phenyl or 6- to 10-membered heteroaryl, and the phenyl and 6- to 10-membered heteroaryl are selected from the group consisting of R ｙ３ is substituted with a group other than hydrogen, and R ｙ１ , R ｙ２ , R ｙ４ and R ｙ５ and wherein said R ｙ１ , R ｙ２ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy, wherein R ｙ３ 5-6 membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２[9] The compound according to any one of [1] to [7], or a salt thereof, or a solvate of the compound or the salt, wherein Z is a group represented by the following formula (2): wherein the wavy line represents the attachment point of Z; ｚ３ is the following substituent group B: wherein the wavy line represents the point of attachment; ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino.), X ｚ is CR ｚ５ or N, R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, and C １ -C ６ alkyl; R ｚ４ C which may have a substituent １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ２ alkyl)amino, optionally substituted C １ -C ６

[10] The compound according to any one of [1] to [8], wherein Y is a group represented by the following formula (3): wherein the wavy line represents the attachment point of Y; ｙ１ is CR ｙ３ or N, X ｙ２ is CR ｙ４ or N, X ｙ３ is CR ｙ５ or N, R ｙ１ and R ｙ５ are each independently hydrogen, halogen, cyano, and C １ -C ３ alkyl; Rｙ２ and R ｙ４ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy; R ｙ３ 5-6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ X is an alkyl)amino; ｙ１ is CR ｙ３ If R ｙ２ and R ｙ３ may be taken together with the carbon atom to which X is attached to form a 5- or 6-membered heteroaryl ring; ｙ１ is CR ｙ３ and X ｙ２ is CR ｙ４ If R ｙ３ and R ｙ４ may be taken together with the carbon atom to which X is attached to form a 5- or 6-membered heteroaryl ring; ｙ２ is CR ｙ４ and X ｙ３is CR ｙ５ If R ｙ４ and R ｙ５ may be taken together with the carbon atom to which it is bonded to form a 5- or 6-membered heteroaryl ring.]

[11] The compound according to any one of [1] to [9], or a salt thereof, or a solvate of the compound or the salt, represented by formula (4): [In the formula, X ａ３ is CR ａ３ or N, R ａ１ , R ａ２、 and R ａ３ are each independently hydrogen, halogen, and C １ -C ６ alkoxy; ｂ１ and X ｂ２ is CH ２ and X ｂ３ is O or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is S or X ｂ１ is CH ２ and X ｂ２ is NH, and X ｂ３ is C=O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is NH or X ｂ１ is CH ２ and X ｂ２ is C=O, and X ｂ３ is NH or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is NH or X ｂ１ , X ｂ２ and X ｂ３ is CH ２ and X ｙ１ is CR ｙ３ or N, X ｙ２ is CR ｙ４or N, X ｙ３ is CR ｙ５ or N, R ｙ１ and R ｙ５ are each independently hydrogen, halogen, cyano, and C １ -C ３ alkyl; R ｙ２ and R ｙ４ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy; R ｙ３ 5-6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic ring having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic ring having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl group optionally having a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ X is selected from the group consisting of (alkyl)amino; ｙ１ is CR ｙ３ If R ｙ２ and R ｙ３ may be taken together with the carbon atom to which X is attached to form a 5- or 6-membered heteroaryl ring; ｙ１ is CR ｙ３and X ｙ２ is CR ｙ４ If R ｙ３ and R ｙ４ may be taken together with the carbon atom to which X is attached to form a 5- or 6-membered heteroaryl ring; ｙ２ is CR ｙ４ and X ｙ３ is CR ｙ５ If R ｙ４ and R ｙ５ may be taken together with the carbon atom to which R is attached to form a 5- or 6-membered heteroaryl ring, ｚ３ is the following substituent group B: (Wherein, the wavy line represents the R ｚ３ and R ｚ３ represents the point of attachment to the ring to which R is attached; ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino.), X ｚ is CR ｚ５ or N, R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, and C １ -C ６ alkyl; R ｚ４ C which may have a substituent １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ２ alkyl)amino, optionally substituted C １ -C ６

[12] The compound according to any one of [1] to

[10] , wherein X is a group represented by the formula: ｂ１ and X ｂ２ is CH ２ and X ｂ３

[13] The compound according to any one of [1] to

[11] , or a salt thereof, or a solvate thereof, wherein R ５ is hydroxy or C １ -C ６ The compound according to any one of [1] to

[12] , or a salt thereof, or a solvate thereof, wherein X is alkylsulfonylamino. ｚ is CR ｚ５ and R ｚ１ , R ｚ２ and R ｚ５

[15] The compound according to any one of [1] to

[13] , or a salt thereof, or a solvate thereof, wherein R ｚ４ is hydrogen, halogen, C １ -C ６ Alkyl and C １ -C ６ 4- to 6-membered cyclic amino optionally having one or more substituents selected from the group consisting of alkoxy, or C １ -C ２ Alkylene and C containing one oxygen atom １ -C ２

[16] The compound according to any one of [1] to

[14] , or a salt thereof, or a solvate of the compound or the salt, wherein R is a 4- to 6-membered cyclic amino having a bridging group selected from the group consisting of alkylene. ｚ４ is hydrogen, halogen and C １ -C ６ C optionally having a substituent selected from the group consisting of alkyl １ -C ３ Alkyl (5-6 membered heteroaryl C １ -C ２ alkyl)amino or hydrogen, halogen and C １ -C ６ C optionally having a substituent selected from the group consisting of alkyl １ -C ３

[17] The compound according to any one of [1] to

[14] , or a salt thereof, or a solvate thereof, wherein R is alkyl(4- to 6-membered heterocyclyl)amino. ｙ１ is chlorine, and X ｙ１ is CRｙ３ and X ｙ２ is CR ｙ４ and X ｙ３ is CR ｙ５ and R ｙ３ is a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, or a 5- to 10-membered heteroaryl which may have a substituent, and R ｙ２ , R ｙ４ and R ｙ５

[18] The compound according to any one of [1] to

[16] , a salt thereof, or a solvate thereof, wherein R is hydrogen. ａ１ is hydrogen or fluorine, and R ａ２ is hydrogen or methoxy, and R ａ３

[19] The compound according to any one of [1] to

[17] , a salt thereof, or a solvate thereof, wherein R is hydrogen or fluorine. ｚ４

[20] The compound according to any one of [1] to

[18] , wherein R is 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, morpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, (2S,3S)-3-methoxy-2-methylazetidin-1-yl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, methyl(1,2-oxazol-3-ylmethyl)amino, methyl(oxetan-3-yl)amino, methyl-[(3R)-oxolan-3-yl]amino, or methyl-(3-methyloxetan-3-yl)amino, or a salt thereof, or a solvate thereof. ｙ３

[0010] The compound according to the present invention, or a pharmacologically acceptable salt thereof, or a solvate thereof has an Nrf2 activating effect, and provides a preventive or therapeutic agent for various diseases, such as neurodegenerative diseases, pulmonary diseases, and renal diseases.

[0011] The present invention will be described in detail below by showing definitions of symbols, terms, etc. used in this specification, and embodiments of the present invention.

[0012] As used herein, "halogen" is exemplified by F, Cl, Br, or I.

[0013] As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chain alkyls. Alkyl preferably has 1 to 20 carbon atoms (C １ -C ２０ , hereinafter referred to as “C ｐ -C ｑ " means that the number of carbon atoms is p to q), and more preferably C １ -C １０ Alkyl, more preferably C １ -C ６Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (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, and 2-ethylbutyl.

[0014] As used herein, "alkenyl" refers to an alkyl group having at least one double bond (two adjacent sp ２ It is a monovalent group having 1 carbon atom. Depending on the configuration of the double bond and the substituents (if any), the geometry of the double bond can be in the Entgegen (E) or Zusammen (Z), cis or trans configuration. Alkenyl includes not only straight chains but also branched chains. C is preferred as alkenyl. ２ -C １０ alkenyl, more preferably C ２ -C ６ Specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

[0015] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight chain but also branched chain. C ２ -C １０ Alkynyl, more preferably C ２ -C ６Specific examples include alkynyl, ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, 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.

[0016] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. ３ -C ８ Specific examples include cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

[0017] As used herein, "cycloalkylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with a "cycloalkyl" as defined above. ３ -C ８ Cycloalkyl C １ -C ６ Alkyl is preferred, C ３ -C ６ Cycloalkyl C １ -C ２ Alkyl is more preferred. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0018] As used herein, "aminoalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "amino" defined below. １ -C ６ Alkyl is preferred. Specific examples of aminoalkyl include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, and 4-aminobutyl.

[0019] As used herein, the term "protected aminoalkyl" refers to a group in which the amino group included in the above-defined "aminoalkyl" is protected with any protecting group. Specific examples of the amino-protecting group include Fmoc, Boc, Cbz, Alloc, Teoc, trifluoroacetyl, pentafluoropropionyl, phthaloyl, tosyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, and 2,4-dinitrobenzenesulfonyl.

[0020] As used herein, "hydroxyalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above have been replaced with a hydroxyl group. １ -C ６ Specific examples of hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

[0021] As used herein, "haloalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above are substituted with halogen. １ -C ６ Alkyl is preferred, C １ -C ６ Fluoroalkyl is more preferred. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, and 5,5-difluoropentyl.

[0022] As used herein, "carboxyalkyl" refers to a group in which one or more hydrogen atoms of the "alkyl" defined above are replaced by carboxy. As the carboxyalkyl, carboxy C １ -C ６ Specific examples of carboxyalkyl include carboxymethyl.

[0023] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring or aromatic hydrocarbon ring group. Preferred examples of aryl include C ６ -C １０ Specific examples include phenyl and naphthyl (for example, 1-naphthyl and 2-naphthyl).

[0024] As used herein, "heterocyclyl" refers to a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. A heterocyclyl may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl. The heterocyclyl may be a monocyclic or fused ring. In the case of a fused ring, the fused ring may be formed with an aromatic ring such as a benzene ring, a pyridine ring, or a pyrimidine ring. The fused ring may be formed with a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, or a saturated heterocyclic ring such as a tetrahydropyran ring, a dioxane ring, or a pyrrolidine ring. The number of atoms constituting the heterocyclyl ring is preferably 4 to 10 (4- to 10-membered heterocyclyl), more preferably 4 to 7 (4- to 7-membered heterocyclyl). Specific examples of heterocyclyl include azetidinyl, oxoazetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxopyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-thiazinane, thiadiazolidinyl, oxazolidonyl, benzodioxanyl, benzophenone ... oxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo[1,2-c]imidazole, thietanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2,4,5-trimethylpiperazin-1-yl, sultam, 2-oxaspiro[3.3]heptyl, 6,7-dihydro-pyrrolo[1,2-a]imidazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, azepanyl, dioxepanyl, 5,9-dioxaspiro[3.5]nonanyl, and the like.

[0025] As used herein, the term "heteroaryl" refers to an aromatic cyclic monovalent group or aromatic heterocyclic group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring may be a monocyclic ring or a condensed ring with another ring, and may be partially saturated. The number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5- to 10-membered heteroaryl), and more preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl.

[0026] As used herein, "aralkyl (arylalkyl)" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with an "aryl" as defined above. ７ -C １４ Aralkyl is preferred, C ７ -C １０ Aralkyl is more preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0027] As used herein, "heteroarylalkyl" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with a "heteroaryl" as defined above. Heteroarylalkyl includes 5- to 10-membered heteroaryl C １ -C ６ Alkyl is preferred, and 5- to 10-membered heteroaryl C １ -C ２Specific examples of heteroarylalkyl include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0028] As used herein, "heterocyclylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are replaced with a "heterocyclyl" defined above. The heterocyclylalkyl includes 4- to 7-membered heterocyclyl C １ -C ６ Alkyl is preferred, and 4- to 7-membered heterocyclyl C １ -C ２ Specific examples of heterocyclylalkyl include 2-(tetrahydro-2H-pyran-4-yl)ethyl, 2-(azetidin-3-yl)ethyl, and 4-(oxolan-2-ylmethyl)piperazin-1-yl.

[0029] As used herein, the term "saturated heterocyclic group" refers to a non-aromatic, cyclic, monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. The saturated heterocyclic group may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl. The saturated heterocyclic group may be a monocyclic group, or may form a condensed ring with another ring, for example, an aromatic ring such as a benzene ring, a pyridine ring, or a pyrimidine ring, a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, or a saturated heterocyclic ring such as a tetrahydropyran ring, a dioxane ring, or a pyrrolidine ring. Preferred examples of the saturated heterocyclic group include 4- to 10-membered saturated heterocyclic groups. Specific examples of the saturated heterocyclic group include azetidinyl, oxoazetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 4-oxopyrrolidinyl, piperidinyl, 4-oxopiperidinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, and the like. nyl, isothiazolidinyl, thiadiazolidinyl, oxazolidonyl, dioxolanyl, dioxanyl, thietanyl, octahydroindolyl, indolinyl, 5,9-dioxaspiro[3.5]nonanyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, morpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 3-methoxy-2-methylazetidinyl 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl, 4-methylpiperazin-1-yl, 2,4-dimethylpiperazin-1-yl, 6-methyl- oxetan-3-yl)piperazin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2,4,5-trimethylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, and the like.

[0030] As used herein, "alkoxy" refers to an oxy group to which the above-defined "alkyl" is bonded. １ -C ６ Specific examples of the alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.

[0031] As used herein, "haloalkoxy" refers to a group in which one or more hydrogen atoms of the "alkoxy" defined above are substituted with halogen. １ -C ６ Haloalkoxy is preferred, C １ -C ６ Fluoroalkoxy is more preferred. Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0032] As used herein, "cycloalkoxy" refers to an oxy group to which the above-defined "cycloalkyl" is bonded. As the cycloalkoxy, C ３ -C ８ Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, cyclopentyloxy, etc.

[0033] As used herein, "alkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "alkoxy" as defined above. １ -C ６ Alkoxy C １ -C ６ Alkyl is preferred, C １ -C ６ Alkoxy C １ -C ２Alkyl is more preferred. Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

[0034] As used herein, "cycloalkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with a "cycloalkoxy" as defined above. ３ -C ８ Cycloalkoxy C １ -C ６ Alkyl is preferred, C ３ -C ６ Cycloalkoxy C １ -C ２ Alkyl is more preferred. Specific examples of cycloalkoxyalkyl include cyclopropoxymethyl and cyclobutoxymethyl.

[0035] As used herein, "aryloxy" refers to an oxy group to which the above-defined "aryl" is bonded. ６ -C １０ Specific examples of the aryloxy include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

[0036] As used herein, "heterocyclyloxy" refers to an oxy group bonded to a "heterocyclyl" as defined above. The number of atoms constituting the ring of the heterocyclyloxy is preferably 4 to 10 (4- to 10-membered heterocyclyloxy), more preferably 4 to 7 (4- to 7-membered heterocyclyloxy). Specific examples of heterocyclyloxy include azetidinyloxy, oxiranyloxy, oxetanyloxy, azetidinyloxy, dihydrofuryloxy, tetrahydrofuryloxy, dihydropyranyloxy, tetrahydropyranyloxy, tetrahydropyridyloxy, tetrahydropyrimidyloxy, morpholinyloxy, thiomorpholinyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, pyrazolidinyloxy, imidazolinyloxy, imidazolidinyloxy, oxazolidinyloxy, isoxazolidinyloxy, thiazolinyloxy, and the like. diazabicyclo[3.1.1]heptanyloxy, 2,5-diazabicyclo[2.2.1]heptanyloxy, 3-oxa-8-azabicyclo[3.2.1]octanyloxy, sultamoxy, 2-oxaspiro[3.3]heptyloxy, and the like.

[0037] As used herein, "heteroaryloxy" refers to an oxy group bonded to a "heteroaryl" as defined above. The number of atoms constituting the ring of the heteroaryloxy is preferably 5 to 10 (5- to 10-membered heteroaryloxy), more preferably 5 to 7 (5- to 7-membered heteroaryloxy). Specific examples of heteroaryloxy include furyloxy, thienyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, thiazolyloxy, isothiazolyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, triazolyloxy, tetrazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinyloxy, pyrazinyloxy, triazinyloxy, benzofuranyloxy, benzothienyloxy, benzothiadiazolyloxy, benzothiazolyloxy, benzoxazolyloxy, benzoxadiazolyloxy, benzimidazolyloxy, indolyloxy, isoindolyloxy, indazolyloxy, quinolyloxy, isoquinolyloxy, cinnolinyloxy, quinazolinyloxy, quinoxalinyloxy, benzodioxolyloxy, indolizinyloxy, and imidazopyridyloxy.

[0038] As used herein, "aralkoxy" refers to an oxy group to which the above-defined "aralkyl" is bonded. ７ -C １４ Aralkoxy is preferred, C ７ -C １０ Aralkoxy is more preferred. Specific examples of aralkoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[0039] As used herein, "heteroarylalkoxy" refers to an oxy group to which the above-defined "heteroarylalkyl" is bonded. Heteroarylalkoxy includes 5- to 10-membered heteroaryl C １ -C ６ Alkoxy is preferred, and 5- to 10-membered heteroaryl C １ -C ２Alkoxy is more preferred. Specific examples of heteroarylalkoxy include 3-thienylmethoxy and 3-pyridylmethoxy.

[0040] As used herein, "aralkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "aralkoxy" as defined above. ７ -C １４ Aralkoxy C １ -C ６ Alkyl is preferred, C ７ -C １４ Aralkoxy C １ -C ２ Alkyl is more preferred. Specific examples of aralkoxyalkyl include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0041] As used herein, "heteroarylalkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with a "heteroarylalkoxy" defined above. Heteroarylalkoxyalkyl includes 5- to 10-membered heteroaryl C １ -C ６ Alkoxy C １ -C ６ Alkyl is preferred, and 5- to 10-membered heteroaryl C １ -C ２ Alkoxy C １ -C ２ Alkyl is more preferred. Specific examples of heteroarylalkoxyalkyl include 3-pyridylmethoxymethyl.

[0042] As used herein, "heterocyclylalkoxy" refers to an oxy group in which an "alkyl" is bonded to a "heterocyclyl" as defined above. The number of atoms constituting the heterocyclyl ring is preferably 4 to 10 (4- to 10-membered heterocyclyl), more preferably 4 to 7 (4- to 7-membered heterocyclyl), and the alkyl is preferably C １ -C ６ Alkyl is preferred, and C １ -C ４Preferred heterocyclylalkoxy is 4- to 10-membered heterocyclylC １ -C ６ Alkoxy, more preferably 4- to 7-membered heterocyclyl C １ -C ２ Specific examples of heterocyclylalkoxy include oxolan-2-ylmethoxy, oxolan-3-ylmethoxy, oxan-4-ylmethoxy, 1,4-dioxan-2-ylmethoxy, (1-methylpiperidin-4-yl)methoxy, and 3-morpholin-4-ylpropoxy.

[0043] As used herein, "hydroxyalkoxy" refers to a group in which "hydroxy" is bonded to the "alkoxy" defined above. Preferred examples of hydroxyalkoxy include hydroxy C ２ -C ６ Alkoxy, more preferably hydroxy C ３ -C ６ Specific examples of hydroxyalkoxy include 3-hydroxy-3-methylbutoxy and 4-hydroxybutoxy.

[0044] As used herein, "alkoxyalkoxy" refers to a group in which an "alkoxy" is bonded to the "alkoxy" defined above. Preferred examples of alkoxyalkoxy include C １ -C ６ Alkoxy C １ -C ６ Alkoxy, more preferably C １ -C ３ Alkoxy C １ -C ２ Alkoxy. Specific examples of alkoxyalkoxy include 2-methoxyethoxy.

[0045] As used herein, "alkylaminoalkoxy" refers to a group in which "alkylamino" is bonded to the "alkoxy" defined above. Preferred examples of alkylaminoalkoxy include bis(C １ -C ６ Alkyl)amino C １ -C ６Alkoxy, more preferably bis(C １ -C ４ Alkyl)amino C １ -C ３ Alkylaminoalkoxy is exemplified by 2-(dimethylamino)ethoxy.

[0046] As used herein, "aryloxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "aryloxy" as defined above. ６ -C １０ Aryloxy C １ -C ６ Alkyl is preferred, C ６ -C １０ Aryloxy C １ -C ２ Alkyl is more preferred. Specific examples of aryloxyalkyl include phenoxymethyl and 2-phenoxyethyl.

[0047] In the present specification, "amino" means, in a narrow sense, -NH ２ and broadly, -NRR', where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R' together with the nitrogen atom to which they are attached form a ring. ２ , Mono C １ -C ６ Alkylamino, DiC １ -C ６ Examples thereof include alkylamino and 4- to 8-membered cyclic amino.

[0048] As used herein, "monoalkylamino" refers to a group in which R is hydrogen and R' is an "alkyl" as defined above, among the "amino" groups defined above. As the monoalkylamino, a monoC １ -C ６Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0049] As used herein, "dialkylamino" refers to a group in which R and R' are independently "alkyl" as defined above, among the "amino" groups defined above. As dialkylamino, diC １ -C ６ Specific examples of dialkylamino include dimethylamino and diethylamino.

[0050] As used herein, "cyclic amino" refers to a group in which R and R' form a ring together with the nitrogen atom to which they are attached in the above-defined "amino." Preferred examples of the cyclic amino include 4- to 8-membered cyclic amino. Specific examples of the cyclic amino include 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, and the like.

[0051] As used herein, "aminocarbonyl" refers to a carbonyl group to which the above-defined "amino" is bonded. As the aminocarbonyl, -CONH is preferable. ２ , Mono C １ -C ６ Alkylaminocarbonyl, diC １ -C ６ Examples of the aminocarbonyl include alkylaminocarbonyl and 4- to 8-membered cyclic aminocarbonyl. ２, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, and the like.

[0052] As used herein, "aminocarbonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with an "aminocarbonyl" as defined above. As the aminocarbonylalkyl, an aminocarbonyl C １ -C ６ Alkyl is preferred, and aminocarbonyl C １ -C ４ Specific examples of aminocarbonylalkyl include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, and 4-(dimethylaminocarbonyl)butyl.

[0053] As used herein, "alkylsulfonyl" refers to a sulfonyl group having an "alkyl" as defined above bonded thereto. As the alkylsulfonyl, C １ -C ６ Specific examples of alkylsulfonyl include methylsulfonyl and ethylsulfonyl.

[0054] As used herein, "alkylsulfonylamino" refers to a group in which a sulfonyl group is bonded to the "amino" defined above. １ -C ６Alkylsulfonyl-NH-, (C １ -C ６ Alkylsulfonyl-) ２ N-, etc. Specific examples of the aminoalkylsulfonyl include methylsulfonylamino, ethylsulfonylamino, bis(methylsulfonyl)amino, bis(ethylsulfonyl)amino, etc.

[0055] As used herein, "alkylsulfonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" defined above are substituted with an "alkylsulfonyl" defined above. As the alkylsulfonylalkyl, C １ -C ６ Alkylsulfonyl C １ -C ６ Alkyl is preferred, C １ -C ６ Alkylsulfonyl C １ -C ２ Alkyl is more preferred. Specific examples of alkylsulfonylalkyl include methylsulfonylmethyl and 2-(methylsulfonyl)ethyl.

[0056] As used herein, "alkylthio" refers to a thio group having an "alkyl" bonded thereto, as defined above, and preferably C １ -C ６ Specific examples of alkylthio include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, i-butylthio, s-butylthio, and t-butylthio.

[0057] As used herein, "acyl (alkanoyl)" refers to a group in which a carbonyl group is bonded to hydrogen or the above-mentioned "alkyl." Preferred examples of acyl include C １ -C ６ Acyl, more preferably C ２ -C ４ Specific examples of acyl include formyl, acetyl, propionyl, and butanoyl.

[0058] As used herein, "haloacyl (haloalkanoyl)" refers to a group in which a carbonyl group is bonded to the "haloalkyl". Preferred examples of haloacyl include C ２ -C ６ Haloacyl, more preferably C ２ -C ４ Specific examples of haloacyls include trifluoroacetyl, trichloroacetyl, pentafluoropropionyl, 2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionyl, and 3,3,3-trifluoro-2-(trifluoromethyl)propionyl.

[0059] As used herein, "alkylene" refers to a divalent group derived from the "alkyl" by further removing one optional hydrogen atom, and C １ -C ８ Alkylene is preferred, C ４ -C ８ Alkylene is more preferred. Specific examples of alkylene 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 ２ CH ２ -, -C(CH ３ ) ２ CH ２ -, -CH ２ CH (CH ３ ) CH ２ -, -CH ２ C(CH ３ ) ２ -, -CH ２ CH ２ CH (CH ３ ) -, -CH ２ CH (CH ２ CH ３ ) -, -(CH ２ ) ５-, -CH(CH ３ ) CH(CH ２ CH ３ ) -, -(CH ２ ) ６ -, -(CH ２ ) ７ -, -(CH ２ ) ８ - and others.

[0060] In this specification, "arylene" means a divalent group derived from the above-mentioned "aryl" by further removing one arbitrary hydrogen atom. The arylene may be a single ring or a condensed ring. The number of atoms constituting the ring of the arylene is not particularly limited, but is preferably 6 to 10 (C ６ ~C １０ Arylene. Specific examples of arylene include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, 1,3-naphthylene, and 1,4-naphthylene.

[0061] As used herein, the term "aromatic hydrocarbon ring" refers to a hydrocarbon ring composed of a single ring or fused rings that exhibits aromaticity. Preferred examples of the aromatic hydrocarbon ring include 6- to 10-membered aromatic hydrocarbon rings. Specific examples of the aromatic hydrocarbon ring include a benzene ring and a naphthalene ring.

[0062] As used herein, the term "aromatic heterocycle" refers to a cyclic compound consisting of a single ring or fused rings containing one or more heteroatoms and exhibiting aromaticity. Preferred examples of aromatic heterocycles include 5- to 10-membered aromatic heterocycles. Specific examples of the aromatic heterocycle include a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a triazine ring, a benzofuran ring, a benzothiophene ring, a benzothiadiazoline ring, a benzothiazoline ring, a benzoxazoline ring, a benzoxadiazoline ring, a benzimidazole ring, a benzotriazole ring, an indole ring, an isoindole ring, an indazole ring, an azaindole ring, a quinoline ring, an isoquinoline ring, a cinnoline ring, a quinazoline ring, a quinoxaline ring, a benzodioxole ring, an indolizine ring, an imidazopyridine ring, a pyrazolopyridine ring, an imidazopyridine ring, a triazolopyridine ring, a pyrrolopyrazine ring, and a furopyridine ring.

[0063] As used herein, "alicyclic ring" refers to a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond within the ring, or may be a polycyclic ring having two or more rings. Furthermore, the carbon atoms constituting the ring may be oxidized to form a carbonyl. Preferred examples of the alicyclic ring include 3- to 8-membered alicyclic rings. Specific examples of the alicyclic ring include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.

[0064] As used herein, the term "saturated heterocycle" refers to a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and containing no double and / or triple bonds within the ring. The saturated heterocycle may be a monocycle or may form a condensed ring with another ring, for example, an aromatic ring such as a benzene ring. Preferred examples of the saturated heterocycle include 4- to 10-membered saturated heterocycles. Specific examples of the saturated heterocycle include an azetidine ring, an oxoazetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 2-oxopyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, an indoline ring, an azepane ring, a dioxepane ring, and a 5,9-dioxaspiro[3.5]nonane ring.

[0065] As used herein, the term "heterocycle" refers to a non-aromatic heterocycle containing preferably 1 to 5, more preferably 1 to 3, heteroatoms among the atoms constituting the ring. The heterocycle may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl. The heterocycle may be a monocyclic, fused ring, or spiro ring. The number of atoms constituting the ring of the heterocycle is preferably 3 to 12 (3- to 12-membered heterocycle), more preferably 4 to 10 (4- to 10-membered heterocycle). Specific examples of the heterocyclic ring include an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a diphenyl ring, a ... Examples thereof include an oxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, a 6,7-dihydro-pyrrolo[1,2-a]imidazole ring, an azocane ring, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine ring, an azepane ring, a dioxepane ring, a 5,9-dioxaspiro[3.5]nonane ring, and rings in which one or more single bonds in these saturated heterocycles are replaced with double bonds or triple bonds.

[0066] As used herein, the term "carboxyl-protecting group" includes alkyl ester-type protecting groups, benzyl ester-type protecting groups, substituted alkyl ester-type protecting groups, and the like.

[0067] As used herein, the term "amino-protecting group" includes carbamate-type protecting groups, amide-type protecting groups, arylsulfonamide-type protecting groups, alkylamine-type protecting groups, imide-type protecting groups, and the like.

[0068] As used herein, the term "hydroxy-protecting group" includes alkyl ether-type protecting groups, aralkyl ether-type protecting groups, silyl ether-type protecting groups, carbonate-type protecting groups, and the like.

[0069] As used herein, the term "substituent derived from halogen" includes fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), and the like.

[0070] As used herein, examples of an "oxygen atom-derived substituent" include hydroxy (-OH), oxy (-OR), carbonyl (-C(=O)-R), carboxyl (-COH), oxycarbonyl (-C(=O)-OR), carbonyloxy (-OC(=O)-R), thiocarbonyl (-C(=O)-SR), carbonylthio group (-SC(=O)-R), aminocarbonyl (-C(=O)-NHR), carbonylamino (-NH-C(=O)-R), oxycarbonylamino (-NH-C(=O)-OR), sulfonylamino (-NH-SO2-R), aminosulfonyl (-SO2-NHR), sulfamoylamino (-NH-SO2-NHR), thiocarboxyl (-C(=O)-SH), and carboxylcarbonyl (-C(=O)-CO2H).

[0071] As used herein, examples of a "nitrogen atom-derived substituent" include azide (-N3, also referred to as an "azido group"), cyano (-CN), primary amino (-NH2), 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'').

[0072] As used herein, examples of a "sulfur atom-derived substituent" include thiol (-SH), thio (-SR), sulfinyl (-S(=O)-R), sulfonyl (-S(=O)2-R), sulfo (-SO3H), and pentafluorosulfanyl (-SF5).

[0073] As used herein, examples of the "boron atom-derived substituent" include boryl (-BR(R')), dioxyboryl (-B(OR)(OR')), and trifluoroborate (-BF3-). Specific examples include "boron atom-derived substituents" in which the two substituents R and R' are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and the like, or "boron atom-derived substituents" in which the two substituents R and R' form a ring together with the atoms to which R and R' are bonded, i.e., a cyclic boryl group. A preferred "boron atom-derived substituent" is a cyclic boryl group. More specific examples of the cyclic boryl group include a pinacolatoboryl group, a neopentanediolateboryl group, a catecholatoboryl group, and a 9-borabicyclo[3.3.1]nonan-9-yl group.

[0074] Examples of the "zinc-derived group" herein include an alkyl zinc group (-Zn-(C1-C6 alkyl)) and a zinc halide group (-Zn-X). Preferred examples of the "zinc-derived group" include -ZnMe, -ZnEt, -ZnPr, -ZnCl, -ZnBr, and -ZnI. Compounds having these "zinc-derived groups" can be produced by referring to March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th Edition, John Wiley & Sons, Inc., 2019) or R.C. Laroch, Comprehensive Organic Transformations (3rd Edition, John Wiley & Sons, Inc., 2018).

[0075] In this specification, the term "optionally substituted" means that a group may be substituted with any substituent. Furthermore, each of these may be given a substituent, and the substituents are not limited, and may be independently selected from any substituents containing, for example, a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom.

[0076] As used herein, the term "optionally protected" means that a group may be protected by any protecting group.

[0077] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means a number from one to the maximum number of substituents permitted by the group.

[0078] In this specification, the term "to" indicating a numerical range includes both ends of the range. For example, "A to B" means a numerical range that is equal to or greater than A and equal to or less than B.

[0079] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

[0080] As used herein, the term "and / or" includes any combination of "and" and "or" as appropriate. 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, and (vii) A, B, and C.

[0081] One embodiment of the present invention is a compound represented by general formula (1) (hereinafter also referred to as "compound (1)"), a salt thereof, or a solvate thereof.

[0082] In compound (1), X ａ１ is CR ａ１ Or N. X ａ１ Preferably, CR ａ１ is.

[0083] In compound (1), X ａ３ is CR ａ３ Or N. X ａ３ Preferably, CR ａ３ is

[0084] In compound (1), R ａ１ is hydrogen, halogen or C １ -C６ Alkoxy. ａ１ is preferably hydrogen or fluorine.

[0085] In compound (1), R ａ２ is hydrogen, halogen or C １ -C ６ Alkoxy. ａ２ is preferably hydrogen or methoxy.

[0086] In compound (1), R ａ３ is hydrogen, halogen or C １ -C ６ Alkoxy. ａ３ is preferably hydrogen or fluorine.

[0087] In compound (1), X ｂ１ is CH ２ , O, NH, S or C═O. X ｂ１ Preferably, CH ２ is.

[0088] In compound (1), X ｂ２ is CH ２ , O, NH, S or C═O. X ｂ２ Preferably, CH ２ , O, NH or C═O, more preferably CH ２ is.

[0089] In compound (1), X ｂ３ is CH ２ , O, NH, S or C═O. X ｂ３ Preferably, CH ２ , O, NH, S or C═O, more preferably O.

[0090] X ｂ１ , X ｂ２ and X ｂ３ The combination of X ｂ１ is CH ２ and X ｂ２ is CH ２ , O, NH or C═O, and X ｂ３ is CH ２ , O, NH, S or C═O, and Xｂ１ and X ｂ２ is CH ２ and X ｂ３ is O or X ｂ１ and X ｂ３ is CH ２ and Xb ２ is O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is S or Xb １ is CH ２ and X ｂ２ is NH, and X ｂ３ is C=O or X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is NH or X ｂ１ is CH ２ and X ｂ２ is C=O, and X ｂ３ is NH or X ｂ１ and X ｂ３ is CH ２ and X ｂ２ is NH or X ｂ１ , X ｂ２ and X ｂ３ is CH ２ More preferably, X ｂ１ and X ｂ２ is CH ２ and X ｂ３ is most preferably O.

[0091] In compound (1), Z is C ６ -C １０ Aryl, 5- to 10-membered heteroaryl or C １ -C ６ alkyl, and ６ -C １０ Aryl, 5- to 10-membered heteroaryl and C １ -C ６ Alkyl is R ｚ３ and R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５Z is preferably R ｚ３ and R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ phenyl, pyridyl or C optionally substituted with one or more groups selected from the group consisting of ２ -C ５ It is alkyl.

[0092] In compound (1), Z is preferably a group represented by formula (2): [wherein the wavy line represents the attachment point of Z, and X ｚ is CR ｚ５ or N. In formula (2), preferably, X ｚ is CR ｚ５ is.

[0093] In compound (1), R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, or C １ -C ６ alkyl, optionally substituted C １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ６ alkyl)amino, optionally substituted C １ -C ６ R is selected from the group consisting of alkyl(4- to 10-membered heterocyclyl)amino and optionally substituted 4- to 8-membered cyclic amino. ｚ１ , R ｚ２ and R ｚ５ are preferably each independently hydrogen, halogen, or C １ -C ６ alkyl, and more preferably each independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl and ethyl.

[0094] In compound (1), R ｚ４ is hydrogen, halogen, C １ -C ６ alkyl, optionally substituted C１ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ６ alkyl)amino, optionally substituted C １ -C ６ R is alkyl(4- to 10-membered heterocyclyl)amino or an optionally substituted 4- to 8-membered cyclic amino. ｚ４ Preferably, C which may have a substituent １ -C ６ Alkyl (5- to 10-membered heteroaryl C １ -C ２ alkyl)amino, optionally substituted C １ -C ６ alkyl(4- to 10-membered heterocyclyl)amino or 4- to 8-membered cyclic amino optionally having a substituent, more preferably hydrogen, halogen, C １ -C ６ Alkyl and C １ -C ６ 4- to 6-membered cyclic amino optionally having one or more substituents selected from the group consisting of alkoxy; １ -C ２ Alkylene and C containing one oxygen atom １ -C ２ 4-6 membered cyclic amino having a bridging group selected from the group consisting of alkylene; hydrogen, halogen and C １ -C ６ C optionally having a substituent selected from the group consisting of alkyl １ -C ３ Alkyl (5-6 membered heteroaryl C １ -C ２ alkyl)amino; hydrogen, halogen and C １ -C ６ C optionally having a substituent selected from the group consisting of alkyl １ -C ３Alkyl(4- to 6-membered heterocyclyl)amino is particularly preferred, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, morpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, (2S,3S)-3-methoxy-2-methylazetidin-1-yl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, methyl(1,2-oxazol-3-ylmethyl)amino, methyl(oxetan-3-yl)amino, methyl-[(3R)-oxolan-3-yl]amino or methyl-(3-methyloxetan-3-yl)amino is particularly preferred.

[0095] In compound (1), R ｚ３ is a carboxyl group or a biological equivalent thereof. Examples of biological equivalents include functional groups that have different chemical structures but can exhibit similar biological effects, as described by Matsuoka et al. (Pharmacia, 2010, 46(3), 215-222) and Thornber et al. (Chem. Soc. Rev., 1979, 8, 563-580). Examples of equivalents of a carboxyl group include functional groups with an acidic proton. ｚ３ The compounds may also include compounds that can be converted into a carboxyl group or a biological equivalent thereof after administration to a subject, such as prodrugs thereof.

[0096] In compound (1), R ｚ３ Specifically, the following substituent group A: wherein the wavy line represents the point of attachment and R ５ is hydroxy, C １ -C ６ Alkoxy, mono or di C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino, and n is 1 or 2. ｚ３ As the substituents, the following group B is preferred: wherein the wavy line represents the point of attachment and R ５ is hydroxy, C１ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino. ５ is preferably hydroxy or C １ -C ６ It is alkylsulfonylamino.

[0097] In compound (1), Y is C ６ -C １０ aryl or 5- to 10-membered heteroaryl, ６ -C １０ Aryl and 5- to 10-membered heteroaryl are R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ Y is preferably R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ and more preferably, R ｙ３ and R ｙ１ , R ｙ２ , R ｙ４ and R ｙ５ and n is 0, 1, 2, 3, 4, 5, 6, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69

[0098] In compound (1), Y is preferably a group represented by formula (3): [wherein the wavy line represents the attachment point of Y, and X ｙ１ is CR ｙ３ or N, and X ｙ２ is CR ｙ４ or N, and X ｙ３ is CR ｙ５ or N. In formula (3), preferably, X ｙ１ is CR ｙ３ and Xｙ２ is CR ｙ４ and X ｙ３ is CR ｙ５ is.

[0099] In compound (1), R ｙ１ is hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, hydroxy C ２ -C ６ Alkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C １ -C ６ Alkoxy, C １ -C ６ Alkylamino C １ -C ６ Alkoxy, 5-10 membered heteroaryloxy, C １ -C ６ alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered aromatic heterocyclic group optionally having a substituent, or C １ -C ６ Alkyl (C １ -C ６ Alkoxy C １ -C ６ alkyl)amino. ｙ１ is preferably hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl, C １ -C ３Alkoxy, 5- to 6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy-C １ -C ２ Alkoxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, an optionally substituted 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring, an optionally substituted 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring, an optionally substituted 5- to 10-membered aromatic heterocyclic group, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ alkyl)amino, more preferably hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl or C １ -C ３ Alkoxy, more preferably hydrogen, halogen, cyano or C １ -C ３ It is preferably alkyl, and particularly preferably chlorine.

[0100] In compound (1), R ｙ２ is hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C １ -C ６Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, hydroxy C ２ -C ６ Alkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C １ -C ６ Alkoxy, C １ -C ６ Alkylamino C １ -C ６ Alkoxy, 5-10 membered heteroaryloxy, C １ -C ６ alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered aromatic heterocyclic group optionally having a substituent, or C １ -C ６ Alkyl (C １ -C ６ Alkoxy C １ -C ６ alkyl)amino. ｙ２ is preferably hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl, C １ -C ３ Alkoxy, 5- to 6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy-C １ -C ２ Alkoxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, an optionally substituted 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring, an optionally substituted 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring, an optionally substituted 5- to 10-membered aromatic heterocyclic group, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ alkyl)amino, more preferably hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl or C １ -C ３ It is preferably alkoxy, and more preferably hydrogen.

[0101] In compound (1), R ｙ３ is hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, hydroxy C ２ -C ６ Alkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C １ -C ６ Alkoxy, C １ -C ６ Alkylamino C １ -C ６ Alkoxy, 5-10 membered heteroaryloxy, C １ -C ６alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, or C １ -C ６ Alkyl (C １ -C ６ Alkoxy C １ -C ６ alkyl)amino. ｙ３ is preferably hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl, C １ -C ３ Alkoxy, 5- to 6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy-C １ -C ２ Alkoxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ alkyl)amino, more preferably 5- to 6-membered heterocyclylC １ -C ４ Alkoxy, hydroxy C３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy C １ -C ２ Alkoxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic ring having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic ring having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl group optionally having a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ and (2R)-2,4-dimethylpiperazin-1-yl, 6-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl, 4-methylpiperazin-1-yl, ... 2-oxa-6-azaspiro[3.3]heptan-6-yl, (2R,5R)-2,4,5-trimethylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, or morpholin-4-yl.

[0102] In compound (1), R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ６ Alkyl, C２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, hydroxy C ２ -C ６ Alkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C １ -C ６ Alkoxy, C １ -C ６ Alkylamino C １ -C ６ Alkoxy, 5-10 membered heteroaryloxy, C １ -C ６ alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered aromatic heterocyclic group optionally having a substituent, and C １ -C ６ Alkyl (C １ -C ６ Alkoxy C １ -C ６ R is selected from the group consisting of (alkyl)amino. ｙ4 and R ｙ5 are preferably each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl, C １ -C ３ Alkoxy, 5- to 6-membered heterocyclyl C １ -C ４ Alkoxy, hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy-C１ -C ２ Alkoxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered aromatic heterocyclic group optionally having a substituent, and C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ more preferably, each independently selected from the group consisting of hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy, more preferably each independently selected from the group consisting of hydrogen, halogen, cyano and C １ -C ３ It is preferably selected from the group consisting of alkyl, and particularly preferably hydrogen.

[0103] In compound (1), X ｙ１ is CR ｙ３ If R ｙ２ and R ｙ３ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring, ｙ１ is CR ｙ３ and X ｙ２ is CR ｙ４ If R ｙ３ and R ｙ４ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring, ｙ２ is CR ｙ４and X ｙ３ is CR ｙ５ If R ｙ４ and R ｙ５ together with the carbon atom to which it is attached may form a 5- or 6-membered heteroaryl ring.

[0104] Another embodiment of the present invention is a compound represented by general formula (4) (hereinafter also referred to as "compound (4)"), a salt thereof, or a solvate thereof. X in compound (4) ａ３ , R ａ１ , R ａ２、 X ｂ１ , X ｂ２ , X ｂ３ , R ｙ１ , R ｙ２ , X ｙ１ , X ｙ２ , X ｙ３ , R ｚ１ , R ｚ２ , R ｚ３ , R ｚ４ and X ｚ represents X in the above-mentioned compound (1). ａ３ , R ａ１ , R ａ２、 X ｂ１ , X ｂ２ , X ｂ３ , R ｙ１ , R ｙ２ , X ｙ１ , X ｙ２ , X ｙ３ , R ｚ１ , R ｚ２ , R ｚ３ , R ｚ４ and X ｚ is synonymous with.

[0105] The compounds described herein may be salts or solvates thereof. Salts of the compounds include, for example, hydrochlorides; hydrobromides; hydroiodides; phosphates; phosphonates; sulfates; sulfonates such as methanesulfonate and p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, and salicylate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. These salts are produced, for example, by contacting the compound with an acid or a base. As used herein, the term "solvate" refers to a compound that forms a molecular group together with a solvent, and is not particularly limited as long as it is a solvate formed with a solvent that is acceptable for ingestion accompanying pharmaceutical administration. Examples of solvates include hydrates, alcoholates (ethanol solvates, methanol solvates, 1-propanol solvates, 2-propanol solvates, etc.), and solvates with a single solvent such as dimethyl sulfoxide, as well as solvates formed with multiple solvents per molecule of the compound, or solvates formed with multiple types of solvents per molecule of the compound. A solvate formed when the solvent is water is called a hydrate. As the solvate of the compound of the present invention, hydrates are preferred, and specific examples of such hydrates include mono- to decahydrates, preferably mono- to pentahydrates, and more preferably mono- to trihydrates.

[0106] When the compound according to the present invention is obtained in a free form, the compound can be converted into a salt thereof or a hydrate or solvate thereof according to a conventional method. Examples include hydrates and ethanolates of the compound represented by formula (1) or its salts. Specific examples include, but are not limited to, the hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nodahydrate, decahydrate, or monoethanolate of the compound represented by formula (1), or the hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nodahydrate, decahydrate, or monoethanolate of the sodium salt of the compound represented by formula (1), or the hydrate or ethanolate of the hydrochloride of the compound represented by formula (1). The hydrate or solvate may be produced in a crystalline or amorphous form, and in the case of a crystalline form, it may take the form of a crystalline polymorph. As a method for producing the hydrate or solvate, for example, a solvent such as ethanol and / or water is added to the compound represented by formula (1), and the hydrate or solvate can be obtained by a conventional method, such as stirring, cooling, concentrating, and / or drying.

[0107] Furthermore, when the compound according to the present invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted into its free form by a conventional method.

[0108] The compounds described herein may contain unnatural proportions of isotope atoms in one or more atoms constituting such compounds. The present invention also includes compounds in which any atom in a compound is substituted with another isotope atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons), thereby substituting isotopes with an abundance ratio different from the abundance ratio of isotopes in nature, i.e., compounds labeled with isotope atoms. Examples of isotope elements contained in the compounds of the present specification include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, etc., and each of these isotopes is 2 H, 3 H, 13 C. 14 C. 15 N, 17 O.18 O. 32 P, 35 S, 18 F, 36 Isotopically labeled compounds include Cl and the like. Compounds labeled with isotope atoms are useful as therapeutic or preventive agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds herein containing radioactive or non-radioactive isotopes in all proportions are encompassed within the scope of the present invention. Compounds labeled with isotope atoms can be produced using reagents and solvents containing the corresponding isotope atoms in the same manner as for producing unlabeled compounds.

[0109] The compounds described herein, their salts, or solvates thereof include all stereoisomers thereof (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates, and other mixtures of such isomers. For example, the compounds of the present invention may have one or more asymmetric centers, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

[0110] <General Manufacturing Method> Examples of manufacturing methods for the compound represented by formula (1) or a salt thereof, or a solvate thereof are explained using the following group of schemes. The compounds of the present invention can be synthesized by various methods, and the manufacturing methods below are illustrative, and the present invention is not limited to the chemical reactions and conditions explicitly stated. In the manufacturing schemes below, some substituents are omitted for clarity, but these are not intended to limit the disclosure of the schemes. Representative compounds of the present invention can be synthesized using appropriate intermediates, known compounds, and reagents. In the formulas in the following general synthesis methods, R １ , R ２ and variables such as n are used in compounds represented by the general formulas defined herein. １ , R ２and variables represented by n, etc. In addition, when the starting material or target product of a certain process undergoes an undesired chemical transformation under the reaction conditions of that process, the target product of that process can be obtained, for example, by protecting and deprotecting functional groups. Regarding the selection of protecting groups and the selection of protection and deprotection methods, reference can be made to, for example, TW Greene, PGM Wuts, Protective Groups in Organic Synthesis (5th Edition, John Wiley & Sons 2014). Some of the protection and deprotection of functional groups are also described in the following schemes.

[0111] The compounds of the present invention can be synthesized, for example, by the following production methods.

[0112] General manufacturing method A In the formula, P.G. １ represents an amino protecting group, L １ and L ２ each independently represents a leaving group; X ａ１ , X ａ３ , R ａ２ , X ｂ１ , X ｂ２ , X ｂ３ , Y and Z are as defined in [1] above.

[0113] Amino protecting group (PG １ ) is a formyl group, C １ -C ６ Alkylcarbonyl groups (acetyl groups, propionyl groups, butyryl groups, isobutyryl groups, valeryl groups, isovaleryl groups, pivaloyl groups, etc.), carbamoyl groups, C １ -C ６Examples include alkoxycarbonyl groups (methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl group, sec-butoxycarbonyl group, t-butoxycarbonyl group, etc.), substituted silyl groups (trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc.), aralkyloxycarbonyl groups (benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc.), allyl groups, and aralkyl groups (benzyl group, cumyl group, etc.).

[0114] The leaving group (L １ and L ２ ) includes a halogen atom, a trifluoromethanesulfonyl group, a nonafluorobutanesulfonyl group, acetyloxy, a trifluoroacetyloxy group, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a group derived from a boron atom (4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 9-BBN, etc.), a group derived from zinc, and the like.

[0115] Step 1: Compound (A-3) is prepared by removing a leaving group L １ and a compound (A-1) having a leaving group L ２ and a compound (A-2) having the following formula: １ and compounds having L ２Examples of compounds having the formula (I) include compounds having a halogen atom as a leaving group, compounds having a sulfonic acid-derived leaving group, compounds having a boron atom-derived leaving group, and compounds having a zinc-derived group. These can be prepared by 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" (by R.C. Larock) or "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition" (by M.B. Smith and J. March), and can be used in coupling reactions. The coupling reaction can be carried out by referring 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).

[0116] The palladium catalyst used in the coupling reaction can be one available from a commercial supplier. Palladium and a ligand complex, such as 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, bis(triphenylphosphine)palladium(II) dichloride, dichlorobis(tricyclohexylphosphine)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, or [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, or Org. Examples of catalysts include those by Buchwald et al., such as SPhos Pd G3, XPhos Pd G3, CPhos Pd G3, or XantPhos Pd G3, as described in J. Am. Chem. Soc., 2014, 136, 14027-14030. Palladium can also be used in combination with a ligand. Palladium can be obtained from commercial suppliers, such as palladium acetate, allylpalladium(II) chloride (dimer), or Pd2(dba)3. Ligands can be obtained from commercial suppliers, such as dppf, SPhos, or Xantphos, and can be used in appropriate combinations.

[0117] Examples of the base used in the coupling reaction include tertiary amines (triethylamine, 4-methylmorpholine, 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-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), and preferably inorganic bases such as cesium carbonate.

[0118] Examples of the solvent used in the coupling reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), and acetonitrile, and preferred examples include 2-methyltetrahydrofuran and 1-methylpyrrolidin-2-one.

[0119] The optimum reaction temperature for the coupling reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, preferably in the range of 10°C to 120°C. The reaction time is typically in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The obtained target compound (A-3) may be isolated by a conventional technique and, if necessary, purified by crystallization or chromatography.

[0120] Step 2 Compound (A-4) can be produced by deprotecting the protecting group of compound (A-3). １ C such as t-butoxycarbonyl １ -C ６In the case of an alkoxycarbonyl group, the deprotection reaction is preferably carried out using an acid. Examples of the acid 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.), and preferred examples include hydrogen chloride, methanesulfonic acid, and trifluoroacetic acid.

[0121] Examples of the solvent used in the deprotection reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), and ester solvents (ethyl acetate, isopropyl acetate, etc.), and preferably 1,4-dioxane or ethyl acetate.

[0122] The optimal reaction temperature for the deprotection reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, preferably in the range of 10°C to 100°C. The optimal reaction time for the deprotection reaction is typically in the range of 30 minutes to 12 hours, preferably in the range of 1 hour to 6 hours. The obtained compound (A-4) may be isolated by a general technique and, if necessary, purified by crystallization or chromatography. Note that compound (A-4) may be obtained as a salt with the acid used in the reaction, and such a salt may also be subjected to the next step.

[0123] Step 3 Compound (A-6) can be produced by converting compound (A-5) to an acid chloride, followed by amidation reaction with compound (A-4) in the presence of a base. Examples of reagents for converting compound (A-5) to an acid chloride include thionyl chloride, oxalyl chloride, and Ghosez reagent. Examples of bases used in the amidation reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), diamines (N,N,N',N'-tetramethylethylenediamine, etc.), guanidines (guanidine, tetramethylguanidine, etc.), and pyridines (pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, etc.), and preferred examples include tertiary amines such as N,N-diisopropylethylamine and 4-methylmorpholine.

[0124] Examples of the solvent used in the amidation reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), halogen-based solvents (dichloromethane, dichloroethane, chloroform, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), acetonitrile, and water, and preferably, dichloromethane or acetonitrile.

[0125] The optimum reaction temperature for the amidation reaction is, for example, in the range of 0° C. to a temperature near the boiling point of the solvent, preferably in the range of 20° C. to 60° C. The optimum reaction time for the deprotection reaction is, for example, in the range of 10 minutes to 24 hours, preferably in the range of 30 minutes to 12 hours.

[0126] In addition to the method via an acid chloride, compound (A-6) can also be produced, for example, by subjecting compound (A-4) and compound (A-5) to an amidation reaction using a condensing agent in the presence of a base. Condensing agents used in the amidation reaction include BOP-based condensing agents such as benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP (registered trademark)), PyAOP, BroP, PyCloP, PyBroP (registered trademark), and DEPBT, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Examples include hexafluorophosphate (HATU), ethyl (hydroxyimino) cyanoacetate (Oxyma), T3P, etc., and preferably HATU, etc.

[0127] Examples of the base used in the amidation reaction with a condensing agent include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.) and pyridines (pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, etc.), and preferred examples include tertiary amines such as N,N-diisopropylethylamine and 4-methylmorpholine.

[0128] Examples of solvents used in the amidation reaction with a condensing agent include ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), halogen-based solvents (dichloromethane, dichloroethane, chloroform, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), and acetonitrile, and preferred examples include dichloromethane and N,N-dimethylformamide.

[0129] The optimum reaction temperature when carrying out the amidation reaction with a condensing agent is, for example, in the range of 0°C to a temperature near the boiling point of the solvent, preferably in the range of 20°C to 60°C. The optimum reaction time when carrying out the amidation reaction with a condensing agent is, for example, in the range of 1 minute to 24 hours, preferably in the range of 30 minutes to 12 hours. The obtained compound (A-6) may be isolated by a general technique and, if necessary, purified by crystallization or chromatography.

[0130] General manufacturing method B In the formula, L ３ represents a leaving group, R Ａ is C １ -C ６ represents alkyl, and R Ｂ１ represents a pinacolato group, a neopentanediolate group, a catecholate group, or a bicyclo[3.3.1]nonan-9-yl group; X ａ１ , X ａ３ , X ｂ１ , X ｂ２ , X ｂ３ , Y and Z are as defined in the above [1]. ３ Examples of the alkyl group include a halogen atom, an acetyloxy group, a trifluoroacetyloxy group, a methanesulfonyloxy group, a paratoluenesulfonyloxy group, a trifluoromethanesulfonyl group, and a nonafluorobutanesulfonyl group.

[0131] Step 1: Compound (B-2) can be produced by boronation of compound (B-1) with various diborane reagents in the presence of an iridium catalyst and a ligand. The boronation reaction can be carried out with reference to, for example, Angew. Chem. Int. Ed., 2021, 60, 2796-2821. Preferred examples of the iridium catalyst and ligand used in the boronation reaction include bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) and 4,4'-di-tert-butyl-2,2'-bipyridine.

[0132] Examples of the solvent used in the boronation reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.) and hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), and preferably tetrahydrofuran or hexane.

[0133] The optimum reaction temperature for the boronation reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, and preferably in the range of 10°C to 120°C. The reaction time is typically in the range of 30 minutes to 48 hours, and preferably in the range of 1 hour to 24 hours. The resulting compound (B-2) may be isolated by a common technique and, if necessary, purified by crystallization or chromatography.

[0134] Step 2 Compound (B-3) can be produced by subjecting compound (B-2) to an oxidation reaction using an oxidizing agent such as hydrogen peroxide.

[0135] Examples of the solvent used in the oxidation reaction include ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.) and alcohol solvents (methanol, ethanol, isopropanol, butanol, etc.), and preferably methanol.

[0136] The optimum reaction temperature for the oxidation reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, and preferably in the range of 10°C to 60°C. The reaction time is typically in the range of 30 minutes to 24 hours, and preferably in the range of 1 hour to 12 hours. The resulting compound (B-3) may be isolated by a general technique and, if necessary, purified by crystallization or chromatography.

[0137] Step 3: Compound (B-5) is prepared by reacting compound (B-3) with a leaving group L ３ The etherification reaction can be carried out with reference to the method of Williamson (Liebigs Ann. Chem. 1851, 77, 37-49).

[0138] Examples of the base used in the etherification reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), inorganic bases (sodium carbonate, potassium carbonate, cesium carbonate), etc., and preferably inorganic bases such as potassium carbonate.

[0139] Examples of the solvent used in the etherification reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), ester solvents (ethyl acetate, isopropyl acetate, etc.), and acetonitrile, and preferred examples include amide solvents such as 1-methylpyrrolidin-2-one.

[0140] The optimum reaction temperature for the etherification reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, preferably in the range of 10°C to 60°C. The optimum reaction time for the etherification reaction is typically in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The resulting compound (B-5) may be isolated by a conventional technique and, if necessary, purified by crystallization or chromatography.

[0141] General manufacturing method C In the formula, P.G. ２ represents a protecting group for a carboxyl group, Z １ represents a group selected from the group consisting of aryl, heteroaryl, and alkylene, which may have any substituent; X ａ１ , X ａ３ , R ａ２ , X ｂ１ , X ｂ２ , X ｂ３ and Y are as defined in the above [1]. The protecting group for the carboxyl group is C １ - ６ Examples of protecting groups include alkyl esters (methyl ester, ethyl ester, propyl ester, butyl ester, etc.), benzyl esters, aryl esters, etc. Protecting groups and methods of protection and deprotection can be selected in addition to the protecting groups exemplified above. For example, see TW Greene and PGM Wuts, Protective Groups in Organic Synthesis (5th ed., John Wiley & Sons 2014).

[0142] Step 1 Compound (C-2) can be produced by subjecting compound (C-1) to a deprotection reaction. ２When is an alkyl ester such as a methyl ester, it is preferable to perform the deprotection using a base. Examples of the base used in the deprotection reaction include inorganic bases (sodium hydroxide, potassium hydroxide, barium hydroxide, potassium trimethylsiloxide, etc.) and metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), and preferably inorganic bases such as potassium hydroxide. Examples of the solvent used in the deprotection reaction include ether solvents (tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), alcohol solvents (methanol, ethanol, isopropanol, butanol, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), and water. Preferred examples include tetrahydrofuran, methanol, water, etc., or a mixture of these in any ratio.

[0143] The optimal reaction temperature for carrying out the deprotection reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, preferably in the range of 20°C to 120°C. The optimal reaction time for carrying out the deprotection reaction is typically in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 6 hours. The resulting compound (C-2) may be isolated by a general technique and, if necessary, purified by crystallization or chromatography.

[0144] General manufacturing method D In the formula, L ４ represents a leaving group, and Y １ represents a group selected from the group consisting of aryl, heteroaryl, and alkylene, which may have a substituent; X ａ１ , X ａ３ , R ａ２ , X ｂ１ , X ｂ２ , X ｂ３ and Z are as defined in the above [1]. ４is exemplified by a halogen atom, a trifluoromethanesulfonyl group, a nonafluorobutanesulfonyl group, and the like.

[0145] Step 1: Compound (D-2) is prepared by removing a leaving group L ４ The compound (D-1) having the following formula (I) can be produced by coupling reaction with various nucleophiles in the presence of a palladium catalyst, a ligand, and a base. ４ Examples of compound (D-1) having the formula (I) include compounds having a halogen atom as a leaving group and compounds having a leaving group derived from sulfonic acid, which can be prepared by 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" (by R.C. Larock) or "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition" (by M.B. Smith, J. March), and can be used in the coupling reaction. Examples of nucleophiles used in the coupling reaction include amine compounds, alcohol compounds, and compounds having a group derived from a boron atom, which can form a C-N bond, a C-O bond, or a C-C bond, respectively, to produce the desired product. These coupling reactions can be carried out with reference to the method of Buchwald et al. (Org. Synth., 2002, 78, 23), the method of Suzuki et al. (Chem. Rev. 1995, 95, 2457-2483), and the method of Buchwald et al. (J. Am. Chem. Soc. 2001, 123, 12202-12206).

[0146] The palladium catalyst and ligand used in the coupling reaction are a combination of a palladium catalyst available from a commercial supplier, such as allylpalladium(II) chloride (dimer), palladium acetate, or Pd2(dba)3, and a ligand available from a commercial supplier, such as rac-BINAP, dppf, SPhos, or Xantphos, or a palladium-ligand complex such as SPhos Pd G3 or rac-BINAP Pd G4 is preferably used. Examples of the base used in the coupling reaction include tertiary amines (triethylamine, 4-methylmorpholine, 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-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), and preferably inorganic bases such as cesium carbonate.

[0147] Examples of the solvent used in the coupling reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), and acetonitrile, and preferred examples include methyltetrahydrofuran and 1-methylpyrrolidin-2-one.

[0148] The optimum reaction temperature for the coupling reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, preferably in the range of 10°C to 120°C. The optimum reaction time for the coupling reaction is typically in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The resulting compound (D-2) may be isolated by a conventional technique and, if necessary, purified by crystallization or chromatography.

[0149] In addition, the leaving group L of the compound (D-1) ４is a fluorine atom, compound (D-2) can be produced by subjecting compound (D-1) to an SNAr reaction with various nucleophiles in the presence of a base. Examples of the base used in the SNAr reaction include tertiary amines (triethylamine, 4-methylmorpholine, 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-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), and preferred examples include DBU, sodium hydride, potassium carbonate, and potassium tert-butoxide.

[0150] Examples of solvents used in the SNAr reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), hydrocarbon solvents (benzene, toluene, etc.), and amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), and preferred examples include hydrocarbon solvents such as toluene, and amide solvents such as 1-methylpyrrolidin-2-one.

[0151] The optimum reaction temperature for the SNAr reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, preferably in the range of 20°C to 120°C. The optimum 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 resulting compound (D-2) may be isolated by a conventional technique and, if necessary, purified by crystallization or chromatography.

[0152] General manufacturing method E In the formula, L ５ and L ６ each independently represents a leaving group; X ａ１ , X ａ３ , R ａ２ , X ｂ１ , X ｂ２ , Xｂ３ , Y and Z are as defined in the above [1]. ５ and L ６ Examples of the alkyl group include a halogen atom, a trifluoromethanesulfonyl group, a nonafluorobutanesulfonyl group, an acetyloxy group, a trifluoroacetyloxy group, a methanesulfonyloxy group, a paratoluenesulfonyloxy group, a group derived from a boron atom (4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 9-BBN, etc.), and a group derived from zinc.

[0153] Step 1: Compound (E-3) is prepared by removing a leaving group L ５ and a compound (E-1) having a leaving group L ６ In the presence of a palladium catalyst, a ligand, and a base, a coupling reaction can be carried out with a compound (E-2) having the following formula: ５ When is a halogen atom, L ５ Alternatively, the coupling reaction can be carried out after converting the aryl group to another leaving group, such as a group derived from a boron atom or a group derived from zinc. Compounds having these leaving groups can be prepared by 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 (by R.C. Larock) or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (by M.B. Smith and J. March), and can be used in the coupling reaction. The coupling reaction can be carried out by referring 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).

[0154] The palladium catalyst used in the coupling reaction can be one available from a commercial supplier. Palladium and a ligand complex, such as 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, bis(triphenylphosphine)palladium(II) dichloride, dichlorobis(tricyclohexylphosphine)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, or [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, or Org. Examples of catalysts include those by Buchwald et al., such as SPhos Pd G3, XPhos Pd G3, CPhos Pd G3, or XantPhos Pd G3, as described in J. Am. Chem. Soc., 2014, 136, 14027-14030. Palladium can also be used in combination with a ligand. Palladium can be obtained from commercial suppliers, such as palladium acetate, allylpalladium(II) chloride (dimer), or Pd2(dba)3. Ligands can be obtained from commercial suppliers, such as dppf, SPhos, or Xantphos, and can be used in appropriate combinations.

[0155] Examples of the base used in the coupling reaction include tertiary amines (triethylamine, 4-methylmorpholine, 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-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), and preferably inorganic bases such as cesium carbonate.

[0156] Examples of the solvent used in the coupling reaction include ether solvents (tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), and acetonitrile, and preferred examples include 2-methyltetrahydrofuran and 1-methylpyrrolidin-2-one.

[0157] The optimum reaction temperature for the coupling reaction is typically in the range of 0°C to a temperature near the boiling point of the solvent, preferably in the range of 10°C to 120°C. The reaction time is typically in the range of 30 minutes to 24 hours, preferably in the range of 1 hour to 12 hours. The resulting target compound (E-3) may be isolated by a conventional technique and, if necessary, purified by crystallization or chromatography.

[0158] <Pharmaceutical Composition> The present invention provides a pharmaceutical composition containing the compound represented by formula (1) of the present invention. The pharmaceutical composition of the present invention can be formulated by known methods by incorporating a pharmaceutically acceptable carrier in addition to the compound represented by formula (1), a salt of the compound represented by formula (1), or a solvate thereof. For formulation, commonly used excipients, binders, lubricants, colorants, flavoring agents, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. can be used. The composition is formulated by a conventional method by blending ingredients commonly used as raw materials for pharmaceutical formulations. For formulation, known methods can be used to process the active ingredient used in pharmaceuticals into an optimal shape or form, i.e., dosage form, suited to the intended use and intended purpose. Examples of commonly used dosage forms include liquid pharmaceutical preparations (liquids) such as injections, suspensions, emulsions, and eye drops, and solid pharmaceutical preparations (solid preparations) such as tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, lozenges, and suppositories, but are not limited thereto.

[0159] For example, to prepare a liquid formulation, a pharmacologically acceptable carrier or vehicle, specifically, pharmaceutically acceptable additives commonly used in the field of pharmaceutical formulations, such as sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., are added in appropriate combination to the compound represented by formula (1) of the present invention, or a salt thereof, or a solvate thereof, and then the mixture is mixed to form a unit dose required for generally accepted pharmaceutical practice. Alternatively, a solid formulation prepared for liquid formulation can be dissolved as needed by adding an appropriate solvent, such as sterile water or physiological saline, before administration, and then used for administration.

[0160] Such liquid preparations can also be used parenterally, for example, in the form of a sterile solution or suspension injection in water or other pharmaceutically acceptable liquid. For example, they can be formulated by appropriately combining them with pharmacologically acceptable carriers or vehicles, specifically, sterile water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, binders, etc., and blending them in a unit dosage form required for generally accepted pharmaceutical practice. Specific examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain fatty acid triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, cornstarch, inorganic salts, etc. The amount of active ingredient in these preparations is such that an appropriate dose within the indicated range can be obtained. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice using a vehicle such as distilled water for injection.

[0161] Examples of aqueous solutions for injection include isotonic solutions containing physiological saline or other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and may be used in combination with an appropriate solubilizing agent, such as alcohol, specifically ethanol, polyalcohols such as propylene glycol and polyethylene glycol, or nonionic surfactants such as Polysorbate 80 (registered trademark) and HCO-50.

[0162] Examples of oily liquids include sesame oil and soybean oil, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. They may also contain buffers such as phosphate buffer and sodium acetate buffer, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants. The prepared injection solution is usually filled into suitable ampoules.

[0163] For example, to produce a solid preparation, an excipient and, if necessary, pharmaceutically acceptable additives commonly used in the field of pharmaceutical preparations such as a binder, a disintegrant, a lubricant, a colorant, and a flavoring agent are added in appropriate combination to the compound represented by formula (1) of the present invention, or a salt thereof, or a solvate thereof, and then the mixture is made into tablets, powders, fine granules, granules, coated tablets, capsules, dry syrup, troches, suppositories, etc. by a conventional method.

[0164] Examples of pharmaceutically acceptable additives used in such solid preparations include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as lactose, lactose hydrate, fructose, and sucrose; inorganic powders such as silicic anhydride, aluminum magnesium silicate, and aluminum silicate; and purified water.

[0165] 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 starch, pregelatinized starch, etc.), celluloses (e.g., crystalline cellulose), inorganic salts (e.g., calcium silicate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc.), etc.

[0166] Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymers, and the like.

[0167] Examples of disintegrants include croscarmellose sodium, carmellose sodium, hydroxypropyl cellulose, carmellose, carmellose calcium, methylcellulose, crystalline cellulose, sodium lauryl sulfate, povidone, and polysorbate.

[0168] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate, and hardened oils.

[0169] Coloring agents that are permitted to be added to pharmaceuticals are used, and flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, cinnamon powder, etc.

[0170] Of course, these tablets and granules may be coated with sugar or other suitable coatings as necessary. When producing liquid preparations such as syrups and injection preparations, the compound of the present invention or a pharmacologically acceptable salt thereof is formulated in a conventional manner by adding a pH adjuster, a solubilizer, an isotonicity agent, and, if necessary, a solubilizer, a stabilizer, etc.

[0171] The administration is preferably parenteral, but the administration method is not limited to parenteral administration. Specific examples of parenteral administration include injections, intranasal administrations, pulmonary administrations, transdermal administrations, etc. Examples of injections include intravenous injections, intramuscular injections, intraperitoneal injections, subcutaneous injections, etc., which can be used for systemic or local administration.

[0172] Furthermore, the administration method can be selected appropriately depending on the patient's age and symptoms. The dosage of a pharmaceutical composition containing the compound represented by formula (1) of the present invention, or a salt thereof, or a solvate thereof, produced by the method of the present invention, can be selected, for example, from the range of 0.0001 mg to 1000 mg per kg of body weight per administration. Alternatively, the dosage can be selected, for example, from the range of 0.001 to 100,000 mg / body weight per patient, but 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.

[0173] In some embodiments, the compounds of the present invention can be used to activate Nrf2 or to inhibit Keap1 and activate Nrf2.

[0174] In one aspect, the pharmaceutical composition of the present invention is used to treat diseases in a subject, for example, those described in Nature Reviews DrugDiscovery, 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, pulmonary diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary arterial hypertension, and asthma, kidney diseases such as chronic kidney disease and acute kidney injury, ophthalmological diseases such as uveitis, glaucoma, and age-related macular degeneration, liver diseases such as non-alcoholic steatohepatitis, immune / inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and ulcerative colitis, head and neck cancer (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, and colon cancer ( The present invention can be used to treat or prevent cell proliferative disorders exemplified by solid cancers such as appendicitis, rectal cancer, lung cancer (small cell carcinoma, non-small cell carcinoma, etc.), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis / ureter cancer, malignant melanoma, and skin cancer, as well as cancers of the blood and lymphatics such as leukemia (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, and myelodysplastic syndrome.

[0175] As used herein, the term "subject" includes mammals, preferably humans.

[0176] The present invention is further illustrated by the following examples and reference examples. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. Room temperature (rt) refers to 5 to 35°C. HPLC purification of compounds was performed using an AutoPurification HPLC / MS System (Waters) or Trilution (Gilson). 1H-NMR spectra were measured with or without Me4Si as an internal standard 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). NMR was measured using a 300 MHz Bruker (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double doublet, dt = double triplet, td = triple doublet, m = multiplet). NMR data are shown in ppm (parts per million, δ). Mass spectral data were obtained using a Shimadzu Corporation ultra-high performance liquid chromatograph (Nexera UC or Nexera) equipped with a single quadrupole mass spectrometer (LCMS-2020) or a Waters Corporation Acquity ultra-high performance liquid chromatograph (UPLC or UPLC I-Class) equipped with a single quadrupole mass spectrometer (SQD or SQD2). When two retention times are given, they represent the retention times of the respective rotamers. Microwave irradiation was performed using Initiator™ (manufactured by Biotage).

[0177] Analysis condition A: Apparatus: Nexera / 2020; Column: Ascentis Express C18 2.1 mm I.D. x 50 mmL, 2.7 μm; Column temperature: 35°C; Mobile 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; Detection wavelength (PDA total): 210-400 nm. Analysis condition B: Apparatus: Nexera UC / 2020; Column: XSelect CSH C18 2.1 mm I.D. x 50 mmL, 2.5 μm; Column temperature: 35°C; Mobile phase and gradient: A) 0.1% FA, CH3CN; B) 0.1% FA, H2O; A / B = Condition C: 5 / 95 → 100 / 0 (1.75 min) → 100 / 0 (1.25 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210-400 nm Instrument: Nexera 2020 Column: Meteoric Core C18 2.1 mm I.D. 50 mmL, 2.7 μm Column temperature: 35 °C Mobile 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 Detection wavelength (PDA total): 210-400 nm Instrument: Acquity SQD / SQD2 Column: Ascentis Express C18 2.1 mm I.D. 50mmL, 2.7μm Column temperature: 35℃ Mobile 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 Detection wavelength (PDA total): 210-400 nm Analysis condition E Instrument: Acquity SQD / SQD2 Column used: Ascentis Express C18 2.1mm I.D. x 50mmL, 2.7μm Column temperature: 35℃ Mobile phase and gradient: A) 0.Analysis condition F: 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 Detection wavelength (PDA total): 210-400 nm Analysis condition F: Instrument: Acquity SQD / SQD2 Column: Ascentis Express C18 2.1 mm I.D. x 50 mmL, 5 μm Column temperature: 35 °C 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 Detection wavelength (PDA total): 210-400 nm Analysis condition G: Instrument: Nexera / 2020 Column: Ascentis Express C18 2.1mmI.D. x 50mmL, 2.7µm Column temperature: 35°C Mobile 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 Detection wavelength (PDA total): 210-400nm Analysis condition H Instrument: Nexera / 2020 Column used: Meteoric Core C18 2.1mmI.D. x 50mmL, 2.7µm Column temperature: 35°C Mobile 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 Detection wavelength (PDA total): 210-400 nm Analysis conditions I Instrument: Nexera / 2020 Column used: Ascentis Express C18 2.1 mm I.D. x 50 mm L, 2.7 μm Column temperature: 35 °C Mobile 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 Detection wavelength (PDA total): 210-400 nm Analysis condition J Instrument: Nexera / 2020 Column: Meteoric Core C18 2.1 mm I.D. x 50 mmL, 2.7 μm Column temperature: 35 °C Mobile 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 Detection wavelength (PDA total): 210-400 nm Analysis condition K Instrument: Acquity SQD Column: Ascentis Express C18 2.1 mm I.D. x 50 mmL, 2.7 μm Column temperature: 35 °C Mobile 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 Detection wavelength (PDA total): 210-400 nm Analysis condition L Instrument: Nexera / 2020 Column: Ascentis Express C18 2.1 mm I.D. x 50 mmL, 2.7 μm Column temperature: 35 °C Mobile 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 Detection wavelength (PDA total): 210-400 nm Analysis condition M Instrument: Nexera / 2020 Column: Ascentis Express C18 2.1mmI.D. x 50mmL, 5µm Column temperature: 35°C Mobile 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 Detection wavelength (PDA total): 210-400nm Analysis condition N Instrument: Nexera / 2020 Column: Speed ​​Core C18 2.1mmI.D. x 50mmL, 2.7 μm Column temperature: 35 °C Mobile 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 Detection wavelength (PDA total): 210-400 nm Analysis conditions: Instrument: Acquity SQD Column: Ascentis Express C18 2.1 mm I.D. x 50 mmL, 2.7 μm Column temperature: 35 °C Mobile 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 Detection wavelength (PDA total): 210-400 nm Analysis condition P: 210-400 nm total. Instrument: Nexera / 2020. Column: Ascentis Express C18 2.1 mm I.D. x 50 mmL, 2.7 μm. Column temperature: 35°C. Mobile 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. Detection wavelength (PDA total): 210-400 nm. Analysis condition Q: Instrument: Nexera / 2020. Column: Kinetex 1.7 μm C18 2.1 mm I.D. x 50 mmL, 1.7 μm. Column temperature: 35°C. Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O. 0.05% TFA, H2O, A / B = 5 / 95 → 0 / 100 (1.5 min) → 0 / 100 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 210-400 nm Analysis condition R Apparatus: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 3.0 mm.D x 50 mm.L, 2.2 μm Column temperature: 40 °C Mobile 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.Flow rate: 2 mL / min. Detection wavelength (PDA total): 190-400 nm. Analysis condition S. Apparatus: Shimadzu LCMS-2020. Column: Shim-pack XR-ODS 2.1 mm.D x 50 mm.L, 2.6 μm. Column temperature: 40 °C. Mobile 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. Detection wavelength (PDA total): 190-400 nm. Analysis condition T. Apparatus: Shimadzu LCMS-2020. Column: Halo C18 2.1 mm.D x 30 mm.L, 2.0 μm. Column temperature: 40 °C. Mobile 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 Detection wavelength (PDA total): 190-400 nm Analysis condition U Apparatus: Shimadzu LCMS-2020 Column: InertCore C18 2.1 mm.D x 50 mm.L, 2.6 μm Column temperature: 40 °C Mobile phase and gradient: A) 0.05% TFA, CH3CN, B) 0.05% TFA, H2O, A / B = 5 / 95 → 100 / 0 (0.5 min) → 100 / 0 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 190-400 nm Analysis condition V: Instrument: Shimadzu LCMS-2020 Column: Shim-pack XR-ODS 3.0 mm D x 50 mm L, 2.2 μm Column temperature: 40 °C Mobile 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 Detection wavelength (PDA total): 190-400 nm Analysis condition W: Instrument: Shimadzu LCMS-2020 Column: XSelect HSS T3 3.0 mm D x 50 mm L, 2.5 μm Column temperature: 40 °C Mobile 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 Detection wavelength (PDA total): 190-400 nm Analysis condition X Instrument: Shimadzu LCMS-2020 Column: Shim-pack XR-ODS 3.0 mm.D x 50 mm.L, 2.2 μm Column temperature: 40 °C Mobile 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 Detection wavelength (PDA total): 190-400 nm Analysis condition Y Instrument: Shimadzu LCMS-2020 Column: CORTECS C18 2.1 mm D x 50 mm L, 2.7 μm Column temperature: 40 °C Mobile 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 Detection wavelength (PDA total): 190-400 nm Analysis condition Z Instrument: Shimadzu LCMS-2020 Column: Kinetex EVO C18 2.1 mm D x 50 mm L, 2.6 μm Column temperature: 40 °C Mobile phase and gradient: A) CH3CN, B) 6.5 mM NH4HCO3, H2O, A / B = 10 / 90 → 95 / 5 (1.1 min) → 95 / 5 (0.5 min) Flow rate: 1 mL / min Detection wavelength (PDA total): 190-400 nm Analysis condition AA Instrument: Shimadzu LCMS-2020 Column used: Shim-pack XR-ODS 3.0 mm.D x 50 mm.L, 2.2 μm Column temperature: 40 °C Mobile 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.Flow rate: 2 mL / min. Detection wavelength (PDA total): 190-400 nm. Analysis condition AB. Apparatus: Shimadzu LCMS-2020. Column: Waters T3 4.6 mmD x 100 mmL, 3.0 μm. Column temperature: 40 °C. Mobile 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. Detection wavelength (PDA total): 190-400 nm. Analysis condition AC. Apparatus: Shimadzu LCMS-2020. Column: Kinetex XB-C18 3.0 mmD x 30 mmL, 1.7 μm. Column temperature: 40 °C. Mobile 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, Detection wavelength (PDA total): 190-400 nm, Analysis condition AD. Apparatus: Shimadzu LCMS-2020. Column: halo-C18 3.0 mmD x 30 mmL, 2.0 μm. Column temperature: 40 °C. Mobile 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, Detection wavelength (PDA total): 190-400 nm, Analysis condition AE. Apparatus: Shimadzu LCMS-2020 Column: Halo 90A C18 3.0mmD x 30mmL, 2.0µm Column temperature: 40°C Mobile 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 Detection wavelength (PDA total): 190-400nm Analysis condition AF Apparatus: Nexera / 2020 Column: Ascentis Express C18 2.1mmI.D. x 50mmL, 5µm Column temperature: 35°C Mobile phase and gradient: A) 0.Analysis condition AG: 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 Detection wavelength (PDA total): 210-400 nm Instrument: Acquity SQD / SQD2 Column: Ascentis Express C18 2.1 mm I.D. x 50 mmL, 2.7 μm Column temperature: 35 °C Mobile 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 Detection wavelength (PDA total): 210-400 nm Instrument: Shimadzu LCMS-2020 Column: Shim-pack XR-ODS 3mm x 5cm, 2.2µm Column temperature: 40°C Mobile 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 Detection wavelength (PDA total): 220 ± 4nm Analysis condition: AI Instrument: Shimadzu LCMS-2020 Column: Shim-pack XR-ODS 2.2µm 3mm x 5cm Column temperature: 40°C Mobile 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 Detection wavelength (PDA total): 254 ± 4 nm

[0178] Compound 1-7: 4-[3-[2,6-dichloro-4-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound A9: tert-butyl N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate A solution of 3-bromo-2-hydroxybenzaldehyde (5.00 g, 24.9 mmol) and tert-butyl 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 mixture. The mixture was stirred at 35°C for 5 hours and then cooled to room temperature. After stirring at room temperature for 15 hours, water was added to the reaction mixture and stirred for 1 hour. Further water was added and the mixture was stirred for 30 minutes. The reaction mixture was filtered, and the resulting solid was washed with acetonitrile / water (1 / 2). The solid was further washed with heptane and dried under reduced pressure to give the title compound (88%, 6.60 g). LCMS: m / z 300 [M-H] － HPLC retention time: 1.16 minutes (analysis condition G)

[0179] Second Step Compound A10 tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate To a solution of tert-butyl N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate (5.00 g, 16.6 mol) in acetonitrile (30.0 mL), 36% aqueous formaldehyde 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 mixture was cooled to 25°C, water was added, and the mixture was stirred for 30 minutes. Further water was added, and the mixture was stirred for 30 minutes. The reaction mixture was filtered, and the resulting solid was washed with acetonitrile / water (1 / 2). The mixture 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 (analysis condition G)

[0180] Third Step: Compound A4 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To 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 a 1 M solution of lithium(bistrimethylsilyl)amide in tetrahydrofuran (50.6 mL, 50.6 mmol) at room temperature over 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. 2 M 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% aqueous ammonium chloride and 15% aqueous sodium chloride. The washed organic layer was concentrated to give the title compound as a crude product. LCMS: m / z 330 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions D)

[0181] Fourth step Compound A5 Methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Potassium carbonate (2.10 g, 15.2 mmol) and iodomethane (1.58 mL, 25.3 mmol) were added to a solution of 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid (4.18 g, 12.7 mmol) in N,N-dimethylformamide (21.0 mL), and the mixture was stirred at room temperature for 30 minutes. 20% aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 20% aqueous ammonium chloride solution and concentrated. Methanol was added to the resulting 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. Further water was added, and the mixture was stirred for 30 minutes. 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 (analysis condition G)

[0182] Fifth step: Compound A6 tert-butyl 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate A solution of methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (1.21 g, 3.50 mmol) in tetrahydrofuran (5.30 mL) was cooled to -10°C. 2M isopropylmagnesium chloride in tetrahydrofuran (1.91 mL, 3.82 mmol) was added and stirred for 1 hour. 2M zinc(II) chloride in 2-methyltetrahydrofuran (0.955 mL, 1.91 mmol) was added to the reaction mixture. To the reaction mixture were added tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate (1.00 g, 3.18 mmol) and SPhos Pd G3 (0.0250 g, 0.0320 mmol), and the mixture was heated to 45°C and stirred for 90 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and aqueous ammonium chloride were added, followed by extraction with ethyl acetate. The organic layer was washed with aqueous N-acetylcysteine ​​and aqueous sodium chloride, and then concentrated to obtain a crude product. Ethanol was added to the resulting crude product, and the mixture was heated to 80°C to dissolve the product, followed by cooling to room temperature. Heptane was added to the resulting solution, and the mixture was cooled to 0°C. The solid obtained after filtration was washed with ethanol / heptane (1 / 2) and dried under reduced pressure to obtain the title compound (73%, 1.16 g). LCMS: m / z 499 [M+H] ＋ HPLC retention time: 1.40 minutes (analysis condition G)

[0183] Sixth step: Compound A7 methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride To a solution of tert-butyl 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate (10.0 g, 20.1 mmol) in acetonitrile (100 mL) was added a 4M solution of hydrochloric acid in ethyl acetate (25.1 mL, 100 mmol), and the mixture was stirred at room temperature for 2 hours. The resulting solid was collected by filtration to give the title compound (76%, 7.16 g) as crystals. LCMS: m / z 399 [M+H] ＋ HPLC retention time: 0.75 minutes (Analysis conditions G)

[0184] Seventh step: Compound A2 4-bromo-2,6-dichlorobenzoyl chloride To a solution of 4-bromo-2,6-dichlorobenzoic acid (45.5 g, 169 mmol) in toluene (241 mL), thionyl chloride (24.5 mL, 337 mmol) and N,N-dimethylformamide (0.261 mL, 3.37 mmol) were added, and the mixture was stirred at 70°C for 7 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting 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 (analysis condition G). １ H-NMR (400 MHz, CDCl ３ ) δ 7.56 (s, 2H)

[0185] Eighth step: Compound A methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate To a solution of methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato dihydrochloride (9.22 g, 19.6 mmol) in toluene (92.0 mL), 4-bromo-2,6-dichlorobenzoyl chloride (7.33 g, 25.4 mmol) and pyridine (11.1 mL, 137 mmol) were added and the mixture was stirred at 70°C for 12 hours. The reaction mixture was extracted with ethyl acetate and 1M hydrochloric acid, and the organic layer was washed with 50% saturated aqueous sodium bicarbonate and 50% saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the filtrate was concentrated, and the resulting 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 (analysis condition G)

[0186] Ninth step: Compound 1-7: 4-[3-[2,6-dichloro-4-(2,2-difluoro-5-azaspiro[2.3]hexan-5-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 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 for 1.5 hours at 110° C. The reaction mixture was cooled to room temperature, and methanol (0.230 mL) and 8 M aqueous potassium hydroxide solution (0.0575 mL, 0.460 mmol) were added. The mixture was stirred at room temperature for 1 hour and then at 50° C. for 1 hour. Aqueous formic acid was added to the reaction mixture, and the mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (83%, 25.7 mg). LCMS: m / z 674 [M+H] ＋ HPLC retention time: 1.61 minutes, 1.64 minutes (Analysis conditions B)

[0187] Compound 1-33 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound CP5 Methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate 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-dioxane (202 mL) was stirred at 80°C for 7.5 hours. (3R)-1,3-dimethylpiperazine (2.48 g, 21.7 mmol) was added, and the reaction mixture was stirred at 100°C for 49 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was washed with 15% aqueous sodium chloride, and the organic layer was concentrated. The resulting residue 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 (Analysis conditions G)

[0188] Second Step Compound 1-33 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (18.6 g, 27.2 mmol) in 1-methylpyrrolidin-2-one (186 mL), 8M aqueous potassium hydroxide solution (11.9 mL, 95.0 mmol) was added and stirred at 60 °C for 2 hours. Aqueous 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 minutes, 1.04 minutes (Analysis conditions B)

[0189] The compounds shown in Table 1-1 were synthesized by the same procedure as in Step 9 of Compound 1-7, using amines and Compound A shown in Table 1-2, which are known in the literature or commercially available. However, in the synthesis of Compounds 1-1, 1-5, 1-34, 1-41, and 1-42, a toluene solution was used instead of a 1,4-dioxane solution, in the synthesis of Compounds 1-6, 1-16, 1-17, 1-43, and 1-45, a 1-methylpyrrolidin-2-one solution was used, and in the synthesis of Compounds 1-19, 1-20, and 1-44, a solution of 1-methylpyrrolidin-2-one: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.

[0190]

[0191]

[0192] Compound 1-4 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound a1 Benzyl (2R,3R)-3-methoxy-2-methylazetidine-1-carboxylate A solution of benzyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (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. Aqueous formic acid was added to the reaction mixture, and the reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (92%, 261 mg). LCMS: m / z 236 [M+H] ＋ HPLC retention time: 0.71 minutes (Analysis conditions D)

[0193] Second Step Compound 1-4 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of benzyl (2R,3R)-3-methoxy-2-methylazetidine-1-carboxylate (260 mg, 1.11 mmol) in methanol (4.42 mL) was added 10% palladium / carbon (353 mg, 0.332 mmol). The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and a solution of hydrochloric acid in methanol was added to the filtrate. The reaction mixture was concentrated to obtain (2R,3R)-3-methoxy-2-methylazetidine hydrochloride as a crude product. Using the obtained crude product and Compound A, the title compound was obtained by the same procedure as in the ninth step of Compound 1-7. LCMS: m / z 656 [M+H] ＋ HPLC retention time: 1.57 minutes, 1.60 minutes (Analysis conditions B)

[0194] Compound 1-9: 4-[3-[2,6-dichloro-4-(3-methoxy-2,2-dimethylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound b1: 1-benzhydryl-3-methoxy-2,2-dimethylazetidine A solution of 1-benzhydryl-2,2-dimethylazetidin-3-ol (50.0 mg, 0.187 mmol) and iodomethane (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. Aqueous 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 (94%, 49.7 mg). LCMS: m / z 282 [M+H] ＋ HPLC retention time: 0.54 minutes (Analysis conditions D)

[0195] Second Step Compound 1-9: 4-[3-[2,6-dichloro-4-(3-methoxy-2,2-dimethylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of 1-benzhydryl-3-methoxy-2,2-dimethylazetidine (49.0 mg, 0.174 mmol) in methanol (0.871 mL) was added 20% palladium hydroxide on carbon (122 mg, 0.174 mmol). The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite, and a solution of hydrochloric acid in methanol was added to the filtrate. The reaction mixture was concentrated to obtain 3-methoxy-2,2-dimethylazetidine hydrochloride as a crude product. Using the obtained crude product and Compound A, the title compound was obtained by the same procedure as in the ninth step of Compound 1-7. LCMS: m / z 670 [M+H] ＋ HPLC retention time: 1.61 minutes, 1.65 minutes (Analysis conditions B)

[0196] Compound 1-84 4-[3-[2,6-dichloro-4-[(2R,3S)-2-methyl-3-morpholin-4-ylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound c1 Benzyl (2R,3S)-2-methyl-3-morpholin-4-ylazetidine-1-carboxylate A solution of benzyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (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. Morpholine (0.142 mL, 1.63 mmol) was added, and the mixture was stirred at room temperature overnight. Morpholine (0.142 mL, 1.63 mmol) was added, and the mixture was stirred at room temperature overnight, followed by stirring at 40°C for 4 hours. Methanol was added to the reaction mixture, which was then concentrated. The residue was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (57%, 27.0 mg). LCMS: m / z 291 [M+H] ＋ HPLC retention time: 0.84 minutes (Analysis conditions F)

[0197] Second Step Compound 1-84 4-[3-[2,6-dichloro-4-[(2R,3S)-2-methyl-3-morpholin-4-ylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of benzyl (2R,3S)-2-methyl-3-morpholin-4-ylazetidine-1-carboxylate (25.0 mg, 0.0860 mmol) in methanol (0.344 mL) was added 10% palladium / carbon (27.5 mg, 0.0260 mmol). The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and a solution of hydrochloric acid in methanol was added to the filtrate. The reaction mixture was concentrated to obtain 4-[(2R,3S)-2-methylazetidin-3-yl]morpholine hydrochloride as a crude product. Using the obtained crude product and Compound A, the title compound was obtained by the same procedure as in the ninth step of Compound 1-7. LCMS: m / z 711 [M+H] ＋ HPLC retention time: 1.14 minutes (Analysis conditions B)

[0198] Compound 1-85: 4-[3-[2,6-dichloro-4-[(2R,3R)-2-methyl-3-morpholin-4-ylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound c2: Benzyl (2R,3R)-2-methyl-3-morpholin-4-ylazetidine-1-carboxylate A solution of benzyl (2R)-2-methyl-3-oxoazetidine-1-carboxylate (60.0 mg, 0.274 mmol) and morpholine (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 mixture was washed with saturated aqueous sodium bicarbonate. 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 (Analysis conditions F)

[0199] Second Step Compound 1-85: 4-[3-[2,6-dichloro-4-[(2R,3R)-2-methyl-3-morpholin-4-ylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of benzyl (2R,3R)-2-methyl-3-morpholin-4-ylazetidine-1-carboxylate (32.0 mg, 0.110 mmol) in methanol (0.411 mL) was added 10% palladium / carbon (35.2 mg, 0.0330 mmol). The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and a solution of hydrochloric acid in methanol was added to the filtrate. The reaction mixture was concentrated to obtain 4-[(2R,3R)-2-methylazetidin-3-yl]morpholine hydrochloride as a crude product. Using the obtained crude product and Compound A, the title compound was obtained by the same procedure as in the ninth step of Compound 1-7. LCMS: m / z 711 [M+H] ＋ HPLC retention time: 1.16 minutes (Analysis conditions B)

[0200] Compound 1-22 4-[3-[2,6-dichloro-4-[(7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid A solution of tert-butyl (7S)-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (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-Methylpyrrolidin-2-one (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 give tert-butyl (7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate as a crude product. Trifluoroacetic acid (0.501 mL, 6.54 mmol) was added to a solution of the crude product in dichloromethane (1.50 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give (7S)-7-methoxy-5-oxa-2-azaspiro[3.4]octane trifluoroacetate as a crude product. The title compound was obtained using the crude product and Compound A in the same manner as in Step 9 of Compound 1-7. However, toluene was used as the solvent instead of 1,4-dioxane. LCMS: m / z 698 [M+H] ＋ HPLC retention time: 1.63 minutes, 1.64 minutes (Analysis conditions B)

[0201] Compound 1-23 4-[3-[2,6-dichloro-4-[(7R)-7-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained using tert-butyl (7R)-7-hydroxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate in the same manner as in the preparation of compound 1-22. LCMS: m / z 698 [M+H]＋ HPLC retention time: 1.62 minutes, 1.63 minutes (Analysis conditions B)

[0202] Compound 1-31 4-[3-[2,6-dichloro-4-[(8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound e1 tert-butyl (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate Compound e2 tert-butyl (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate To a solution of tert-butyl 8-methoxy-5-oxa-2-azaspiro[3.4]oct-7-ene-2-carboxylate (33.8 mg, 0.140 mmol) in methanol (2.8 mL) was added 10% palladium on carbon (6.76 mg, 0.0640 mmol). The mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl 8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate as a racemic mixture. The resulting racemic mixture was purified by SFC (CHIRALPAKING, supercritical carbon dioxide / ethanol / tert-butyl methyl ether) to give tert-butyl (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (31%, 10.7 mg) and tert-butyl (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (25%, 8.40 mg).

[0203] Compound e1 tert-butyl (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate LCMS: m / z 244 [M+H] ＋SFC retention time: 4.72 minutes (analysis conditions: CHIRALPAK IG 4.6 mm ID x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether=1 / 1]=90 / 10 (10 minutes), 40°C, 210 nm)

[0204] Compound e2 tert-butyl (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate LCMS: m / z 244 [M+H] ＋ SFC retention time: 5.37 minutes (analysis conditions: CHIRALPAK IG 4.6 mm ID x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether=1 / 1]=90 / 10 (10 minutes), 40°C, 210 nm)

[0205] Second Step Compound 1-31 4-[3-[2,6-dichloro-4-[(8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Trifluoroacetic acid (0.250 mL, 3.26 mmol) was added to a solution of tert-butyl (8S)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (10.7 mg, 0.0440 mmol) in dichloromethane (0.750 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the title compound was obtained using the resulting crude product and Compound A in the same manner as in the ninth step of Compound 1-7. However, toluene was used as the solvent instead of 1,4-dioxane. LCMS: m / z 698 [M+H] ＋ HPLC retention time: 1.67 minutes, 1.68 minutes (Analysis conditions B)

[0206] Compound 1-30 4-[3-[2,6-dichloro-4-[(8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained by the same procedure as in the preparation of Compound 1-31 using Compound 1-31 and tert-butyl (8R)-8-methoxy-5-oxa-2-azaspiro[3.4]octane-2-carboxylate obtained in the first step. LCMS: m / z 698 [M+H] ＋ HPLC retention time: 1.67 minutes, 1.68 minutes (Analysis conditions B)

[0207] Compound 1-24 4-[3-[2,6-dichloro-4-[(1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound f1 O-tert-butyl 6-methoxy-2-azaspiro[3.3]heptane-2-carbothioate To a solution of carbon disulfide (0.0280 mL, 0.458 mmol) in tetrahydrofuran (1.00 mL), 2 M sodium tert-butoxide in tetrahydrofuran (0.489 mL, 0.978 mmol) was added 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 mixture 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. The mixture was stirred at 0°C for 1 hour. 1 M aqueous potassium hydroxide solution was added to the reaction mixture, which was extracted with diethyl ether and passed through a phase separator. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (85%, 63.3 mg). LCMS: m / z 188 [M-tBu+H] ＋HPLC retention time: 0.93 minutes (Analysis conditions D)

[0208] Second step: Compound f2O-tert-butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate Compound f3O-tert-butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate A solution of o-tert-butyl 6-methoxy-2-azaspiro[3.3]heptane-2-carbothioate (63.3 mg, 0.260 mmol) in tetrahydrofuran (1.30 mL) was cooled to -78 °C. Tetramethylethylenediamine (0.118 mL, 0.780 mmol) and 1.05 M sec-butyllithium cyclohexane hexane solution (0.495 mL, 0.520 mmol) were added, and the mixture was stirred at -78 °C for 35 minutes. Iodomethane (0.0650 mL, 1.04 mmol) was added, and the mixture was stirred at -78 °C for 10 minutes, followed by stirring at room temperature for 40 minutes. Water was added to the reaction mixture, which was then extracted with diethyl ether and passed through a phase separator. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give O-tert-butyl 6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (61%, 40.7 mg) as a diastereomeric mixture. The diastereomeric mixture (40.7 mg, 0.158 mmol) was purified by HPLC (CHIRALPAK IE, hexane / 2-propanol) to give O-tert-butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (47%, 19.0 mg) and O-tert-butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (34%, 14.0 mg) as a racemic mixture.

[0209] Compound f2O-tert-butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate LCMS: m / z 202 [M-tBu+H] ＋SFC retention time: 4.16 minutes, 5.18 minutes (analysis conditions: CHIRALPAK IC 4.6 mm ID x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether=1 / 1]=90 / 10 (10 minutes), 40°C, 254 nm)

[0210] Compound f3O-tert-butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate LCMS: m / z 202 [M-tBu+H] ＋ SFC retention time: 4.79 minutes, 5.88 minutes (analysis conditions: CHIRALPAK IC 4.6 mm ID x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether=1 / 1]=90 / 10 (10 minutes), 40°C, 254 nm)

[0211] Third step: Compound f4O-tert-butyl (1S,4s,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate Compound f5O-tert-butyl (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate Compound f6O-tert-butyl (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate Compound f7O-tert-butyl (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate The racemic mixture of O-tert-butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (19.0 mg, 0.0740 mmol) was purified by HPLC (CHIRALPAKIC, hexane / 2-propanol) to give O-tert-butyl (1S,4s,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (41%, 7.70 mg) and O-tert-butyl (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (39%, 7.40 mg).

[0212] Compound f4O-tert-butyl (1S,4s,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate LCMS: m / z 202 [M-tBu+H] + SFC retention time: 4.09 min (Analysis conditions: CHIRALPAK IC 4.6 mm I.D. x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether = 1 / 1] = 90 / 10 (10 minutes), 40°C, 254 nm)

[0213] Compound f5O-tert-butyl (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate LCMS: m / z 202 [M-tBu+H] ＋ SFC retention time: 5.09 minutes (analysis conditions: CHIRALPAK IC 4.6 mm ID x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether=1 / 1]=90 / 10 (10 minutes), 40°C, 254 nm)

[0214] The racemic mixture of O-tert-butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (14.0 mg, 0.0540 mmol) was purified by HPLC (CHIRALPAKIC, hexane / 2-propanol) to give O-tert-butyl (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (36%, 5.10 mg) and O-tert-butyl (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (40%, 5.60 mg).

[0215] Compound f6O-tert-butyl (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate LCMS: m / z 202 [M-tBu+H] + SFC retention time: 4.73 minutes (Analysis conditions: CHIRALPAK IC 4.6 mm I.D. x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether = 1 / 1] = 90 / 10 (10 minutes), 40°C, 254 nm)

[0216] Compound f7O-tert-butyl (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate LCMS: m / z 202 [M-tBu+H] ＋ SFC retention time: 5.81 minutes (analysis conditions: CHIRALPAK IC 4.6 mm ID x 250 mm, 5 μm, supercritical carbon dioxide / [ethanol / tert-butyl methyl ether=1 / 1]=90 / 10 (10 minutes), 40°C, 254 nm)

[0217] Fourth Step Compound 1-24 4-[3-[2,6-dichloro-4-[(1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Trifluoroacetic acid (0.00335 mL, 0.0440 mmol) was added to a solution of o-tert-butyl (1R,4r,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate (5.60 mg, 0.0220 mmol) in dichloromethane (0.218 mL), and the mixture was stirred at room temperature overnight. Trifluoroacetic acid (0.0335 mL, 0.0440 mmol) was added, and the mixture was stirred at room temperature for an additional hour. The reaction mixture was concentrated, and the resulting crude product and Compound A were used to obtain the title compound by the same procedure as in the ninth step of Compound 1-7. LCMS: m / z 696 [M+H] ＋ HPLC retention time: 1.75 minutes, 1.78 minutes (Analysis conditions B)

[0218] Compound 1-25 4-[3-[2,6-dichloro-4-[(1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained using O-tert-butyl (1S,4r,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate in the same manner as in the fourth step of Compound 1-24. LCMS: m / z 696 [M+H] ＋ HPLC retention time: 1.75 minutes, 1.78 minutes (Analysis conditions B)

[0219] Compound 1-26 4-[3-[2,6-dichloro-4-[(1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained using O-tert-butyl (1R,4s,6S)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate in the same manner as in the fourth step of Compound 1-24. LCMS: m / z 696 [M+H] ＋HPLC retention time: 1.75 minutes, 1.78 minutes (Analysis conditions B)

[0220] Compound 1-27 4-[3-[2,6-dichloro-4-[(1S,4s,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained using O-tert-butyl (1S,4s,6R)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate in the same manner as in the fourth step of Compound 1-24. LCMS: m / z 696 [M+H] ＋ HPLC retention time: 1.74 minutes, 1.78 minutes (Analysis conditions B)

[0221] Compound 1-86: 4-[3-[2,6-dichloro-4-[rel-(6R,7R)-6-methoxy-7-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound g1: tert-butyl 6-(dimethylhydrazinylidene)-2-azaspiro[3.3]heptane-2-carboxylate A solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (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 evaporating the tetrahydrofuran, 1M aqueous sodium hydroxide solution was added. The reaction mixture was extracted with ethyl acetate and passed through a phase separator. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate, followed by ethyl acetate / methanol) to obtain the title compound (93%, 111 mg). LCMS: m / z 254 [M+H] ＋ HPLC retention time: 0.83 minutes (Analysis conditions F)

[0222] Second step: Compound g2rac-tert-butyl (5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate Compound g3rac-tert-butyl (5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate A solution of tert-butyl 6-(dimethylhydrazinylidene)-2-azaspiro[3.3]heptane-2-carboxylate (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 in tetrahydrofuran, ethylbenzene, and heptane (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 then saturated aqueous oxalic acid (1.80 mL) and ethyl acetate (1.80 mL) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and passed through a phase separator. After concentrating the organic layer, tert-butyl 5-methyl-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate was obtained as a crude product. A solution of the obtained crude product in dichloromethane (3.00 mL) and methanol (3.00 mL) was cooled to 0 °C, and sodium borohydride (26.5 mg, 0.700 mmol) was added. The reaction mixture was stirred at 0 °C for 35 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane and passed through a phase separator. After concentrating the organic layer, tert-butyl 6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate (84%, 67.0 mg) was obtained as a diastereomeric mixture. The diastereomeric mixture (59.0 mg, 0.260 mmol) was purified by HPLC (CHIRALPAK IE, acetonitrile / water) to give rac-tert-butyl (5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate (53%, 31.3 mg) and rac-tert-butyl (5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate (28%, 16.5 mg).

[0223] Compound g2rac-tert-butyl (5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate LCMS: m / z 228 [M+H] ＋ １ H-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).

[0224] Compound g3rac-tert-butyl (5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate LCMS: m / z 228 [M+H] ＋ １ H-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).

[0225] Third Step Compound 1-86: 4-[3-[2,6-dichloro-4-[rac-(6R,7R)-6-methoxy-7-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using rac-tert-butyl (5R,6R)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate and Compound A, the title compound was obtained in the same manner as in the preparation of Compound 1-22. LCMS: m / z 696 [M+H] ＋ HPLC retention time: 1.74 minutes, 1.78 minutes (Analysis conditions B)

[0226] Compound 1-87 4-[3-[2,6-dichloro-4-[rac-(6R,7S)-6-methoxy-7-methyl-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using rac-tert-butyl (5R,6S)-6-hydroxy-5-methyl-2-azaspiro[3.3]heptane-2-carboxylate and Compound A, the title compound was obtained in the same manner as in the preparation of Compound 1-22. LCMS: m / z 696 [M+H] ＋ HPLC retention time: 1.78 minutes, 1.81 minutes (Analysis conditions B)

[0227] Compound 1-47 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound CP1 Methyl 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A suspension of compound A (35.5 mg, 0.0550 mmol), 2-azaspiro[3.3]heptane-6-carbonitrile (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-dioxane (0.550 mL) was stirred at 100°C for 30 minutes. Aqueous 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 (78%, 29.6 mg). LCMS: m / z 691 [M+H] ＋ HPLC retention time: 0.96 minutes (Analysis conditions D)

[0228] Second Step Compound 1-47 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid A solution of methyl 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (29.6 mg, 0.0430 mmol) and trimethylstannane (77.0 mg, 0.428 mmol) in chlorobenzene (0.940 mL) was stirred at 135°C for 14 hours. Aqueous formic acid was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (98%, 4.50 mg). LCMS: m / z 677 [M+H] ＋ HPLC retention time: 1.62 minutes (Analysis conditions B)

[0229] Compound 1-15 4-[3-[2,6-dichloro-4-(3-cyano-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound CP2 Methyl 4-[3-[2,6-dichloro-4-(3-cyano-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was synthesized using 3-methylazetidine-3-carbonitrile hydrochloride and Compound A in the same manner as in the first step of Compound 1-47. However, 1-methylpyrrolidin-2-one was used as the solvent instead of 1,4-dioxane. LCMS: m / z 665 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions D)

[0230] Second Step Compound 1-15 4-[3-[2,6-dichloro-4-(3-cyano-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was synthesized using methyl 4-[3-[2,6-dichloro-4-(3-cyano-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate in the same manner as in the second step of compound 1-47. LCMS: m / z 651 [M+H] ＋ HPLC retention time: 1.50 minutes (Analysis conditions B)

[0231] In the following syntheses, the intermediates shown in Tables 1-3 were used.

[0232]

[0233] Compound B Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate Step 1 Compound B1 4-bromo-5-fluoro-2-morpholin-4-ylbenzoic acid Morpholine (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, followed by extraction and washing 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 (Analysis conditions N)

[0234] Second step Compound B2 methyl 4-bromo-5-fluoro-2-morpholin-4-ylbenzoate To a solution of 4-bromo-5-fluoro-2-morpholin-4-ylbenzoic acid (400 mg, 1.32 mmol) in dichloromethane (5.00 mL) and methanol (1.00 mL) was added 2M trimethylsilyldiazomethane-hexane solution (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 reaction mixture was concentrated. The reaction mixture was then purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (81%, 341 mg). LCMS: m / z 318 [M+H] ＋ HPLC retention time: 1.10 minutes (Analysis conditions N)

[0235] Third Step: Compound B3 tert-butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate A solution of methyl 4-bromo-5-fluoro-2-morpholin-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(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.344 g, 0.422 mmol) in 1,4-dioxane (16.9 mL) was stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature, and tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate (2.65 g, 8.43 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.344 g, 0.422 mmol), potassium carbonate (3.50 g, 25.3 mmol), and water (4.22 mL) were added, followed by stirring 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 Celite. The organic layer was washed with brine, dried, and concentrated. The resulting 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 (analysis condition G)

[0236] Fourth step: Compound B4 methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride To a solution of tert-butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate (100 mg, 0.212 mmol) in dichloromethane (1.058 mL) was added 4M hydrochloric acid in 1,4-dioxane (0.794 mL, 3.17 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound as a crude product. LCMS: m / z 373 [M+H] ＋ HPLC retention time: 0.49 minutes (Analysis conditions D)

[0237] Fifth step: Compound B methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate A solution of methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-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 (analysis condition G)

[0238] Compound C4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid Tetrahydrofuran (0.0641 mL) and methanol (0.0641 mL) were added to methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate (16.0 mg, 0.0260 mmol), and 5M aqueous sodium hydroxide solution (0.0513 mL, 0.256 mmol) was added, followed by stirring at 60°C for 15 minutes. 1M hydrochloric acid was added to the reaction mixture, which was then 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 minutes, 1.16 minutes (analysis condition G)

[0239] Compound D methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Step 1 Compound D2 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (615 mg, 4.11 mmol) in 1-methylpyrrolidin-2-one (3.43 mL), potassium tert-butoxide (584 mg, 5.21 mmol) was added and stirred at room temperature for 5 hours. 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 obtain the title compound (94%, 400 mg). LCMS: m / z 312 [M+H] ＋ HPLC retention time: 0.64 minutes (Analysis conditions F)

[0240] Second step Compound D3 Methyl 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Using 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, the title compound was obtained by the same procedure as in the second step of Compound B. LCMS: m / z 326 [M+H] ＋ HPLC retention time: 0.82 minutes (Analysis conditions D)

[0241] Third Step: Compound D4 tert-butyl 8-[4-methoxycarbonyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate Using methyl 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate, the title compound was obtained by the same procedure as in the third step of Compound B. LCMS: m / z 481 [M+H] ＋ HPLC retention time: 0.98 minutes (Analysis conditions D)

[0242] Fourth step: Compound D5 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride The title compound was obtained by the same procedure as in the fourth step of Compound B using tert-butyl 8-[4-methoxycarbonyl-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate. LCMS: m / z 381 [M+H] ＋ HPLC retention time: 0.52 minutes (Analysis conditions D)

[0243] Fifth step: Compound D methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato dihydrochloride, the title compound was obtained by the same procedure as in the fifth step of Compound B. LCMS: m / z 631 [M+H] ＋ HPLC retention time: 1.00 minutes (Analysis conditions D)

[0244] Compound E Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate Step 1 Compound E1 4-bromo-2-morpholin-4-ylbenzoic acid Morpholine (5.76 mL, 66.1 mmol) was added to a solution of 4-bromo-2-fluorobenzoic acid (672 mg, 3.07 mmol) in 1-methylpyrrolidin-2-one (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 (Analysis conditions G)

[0245] Second step Compound E2 methyl 4-bromo-2-morpholin-4-ylbenzoate Using 4-bromo-2-morpholin-4-ylbenzoic acid, the title compound was obtained by the same procedure as in the second step of Compound B. LCMS: m / z 300 [M+H] ＋ HPLC retention time: 1.10 minutes (analysis condition G)

[0246] Third Step: Compound E3 tert-butyl 8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate Using methyl 4-bromo-2-morpholin-4-ylbenzoate, the title compound was obtained by the same procedure as in the third step of Compound B. LCMS: m / z 455 [M+H] ＋ HPLC retention time: 1.31 minutes (analysis condition G)

[0247] Fourth step: Compound E4 methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate dihydrochloride Using tert-butyl 8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate, the title compound was obtained by the same procedure as in the fourth step of Compound B. LCMS: m / z 355 [M+H] ＋ HPLC retention time: 0.67 minutes (Analysis conditions G)

[0248] Fifth step: Compound E methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate Using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate dihydrochloride, the title compound was obtained by the same procedure as in the fifth step of Compound B. LCMS: m / z 605 [M+H] ＋ HPLC retention time: 1.35 minutes (analysis condition G)

[0249] Compound F4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid Using methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate, the title compound was obtained in the same manner as in the preparation of Compound C. LCMS: m / z 591 [M+H] ＋ HPLC retention time: 1.13 minutes, 1.15 minutes (Analysis conditions G)

[0250] Compound G Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzothiazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate Step 1 Compound G2 2-Ethylhexyl 3-(2-bromo-6-cyanophenyl)sulfanylpropanoate Potassium carbonate (4.15 g, 30.0 mmol) was added to a solution of 3-bromo-2-fluorobenzonitrile (2.00 g, 10.0 mmol) and 2-ethylhexyl 3-sulfanylpropanoate (2.49 mL, 11.0 mmol) in tetrahydrofuran (40.0 mL), 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 minutes (analysis condition G)

[0251] Second Step Compound G4 2-Ethylhexyl 3-[2-bromo-6-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]sulfanylpropanoate To a solution of 2-ethylhexyl 3-(2-bromo-6-cyanophenyl)sulfanylpropanoate (1.99 g, 5.00 mmol) and cobalt(II) chloride hexahydrate (2.38 g, 10.0 mmol) in methanol (25.0 mL), sodium borohydride (567 mg, 15.0 mmol) was added portionwise 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 an additional 1 hour. The reaction mixture was cooled to 0°C, 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, passed through a phase separator, and then concentrated. The resulting residue was added with methanol and formic acid, and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to yield the title compound (95%, 965 mg). LCMS: m / z 524 [M+Na] ＋ HPLC retention time: 1.73 minutes (analysis condition G)

[0252] Third Step: Compound G5 tert-butyl N-[(3-bromo-2-sulfanylphenyl)methyl]carbamate A solution of 2-ethylhexyl 3-[2-bromo-6-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]sulfanylpropanoate (950 mg, 1.89 mmol) in tetrahydrofuran (12.6 mL) was cooled to -78°C, and 1.7 M potassium tert-pentoxide toluene solution (2.22 mL, 3.78 mmol) was added dropwise, followed by stirring at -78°C for 30 minutes. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, passed through a phase separator, and concentrated to give the title compound as a crude product. LCMS: m / z 262 [M-tBu+H] ＋ HPLC retention time: 1.27 minutes (analysis condition G)

[0253] Fourth Step: Compound G6 tert-butyl 8-bromo-2,4-dihydro-1,3-benzothiazine-3-carboxylate A solution of tert-butyl N-[(3-bromo-2-sulfanylphenyl)methyl]carbamate (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 poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, passed through a phase separator, and concentrated. 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 (analysis condition G)

[0254] Fifth step: Compound G7 tert-butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzothiazine-3-carboxylate Using tert-butyl 8-bromo-2,4-dihydro-1,3-benzothiazine-3-carboxylate and methyl 4-bromo-5-fluoro-2-morpholin-4-ylbenzoate, the title compound was obtained by the same procedure as in the third step of Compound B. LCMS: m / z 489 [M+H] ＋ HPLC retention time: 1.34 minutes (analysis condition G)

[0255] Sixth Step: Compound G8 Methyl 4-(3,4-dihydro-2H-1,3-benzothiazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride The title compound was synthesized using tert-butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzothiazine-3-carboxylate in the same manner as in the fourth step of Compound B. LCMS: m / z 389 [M+H] ＋ HPLC retention time: 0.69 minutes (Analysis conditions G)

[0256] Seventh step Compound G methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzothiazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was obtained using methyl 4-(3,4-dihydro-2H-1,3-benzothiazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride in the same manner as in the fifth step of Compound B, except that triethylamine was used instead of N,N-diisopropylethylamine. LCMS: m / z 639 [M+H] ＋ HPLC retention time: 1.37 minutes, 1.39 minutes (Analysis conditions G)

[0257] Compound H Methyl 4-[3-(4-bromo-2-chlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride and 4-bromo-2-chlorobenzoyl chloride, the title compound was obtained by the same procedure as in the fifth step of Compound B. LCMS: m / z 615 [M+H] ＋ HPLC retention time: 0.97 minutes (Analysis conditions N)

[0258] Compound I Methyl 4-[3-(4-bromo-2-chlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride and 4-bromo-2-chlorobenzoyl chloride. LCMS: m / z 589 [M+H] ＋ HPLC retention time: 1.32 minutes (Analysis conditions N)

[0259] Compound J: methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate Step 1: Compound J2: methyl 4-bromo-2-chloro-5-methylbenzoate To a solution of methyl 4-bromo-3-methylbenzoate (500 mg, 2.18 mmol) in dichloromethane (5.46 mL), N-chlorosuccinimide (350 mg, 2.62 mmol), palladium(II) acetate (24.5 mg, 0.109 mmol), sodium peroxodisulfate (1.04 g, 4.37 mmol), and trifluoromethanesulfonic acid (0.579 mL, 6.55 mmol) were added, and the mixture was stirred at 60° C. for 7 hours. Purification by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) gave the title compound (62%, 430 mg). LCMS: m / z 263 [M+H] ＋ HPLC retention time: 0.94 minutes (Analysis conditions D)

[0260] Second step: Compound J3 4-bromo-2-chloro-5-methylbenzoic acid 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-dioxane (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 and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated to give the title compound as a crude product. LCMS: m / z 247 [M-H] － HPLC retention time: 0.72 minutes (Analysis conditions D)

[0261] Third step: Compound J4 4-bromo-2-chloro-5-methylbenzoyl chloride A solution of 4-bromo-2-chloro-5-methylbenzoic acid (250 mg, 1.00 mmol) and oxalyl 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 mixture was concentrated to give the title compound as a crude product.

[0262] Fourth step: Compound J: methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride and 4-bromo-2-chloro-5-methylbenzoyl chloride. LCMS: m / z 629 [M+H] ＋ HPLC retention time: 1.02 minutes (Analysis conditions D)

[0263] Compound K methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate Step 1 Compound K2 methyl 4-bromo-2-chloro-5-methoxybenzoate Using methyl 4-bromo-3-methoxybenzoate, the title compound was obtained by the same procedure as in the first step of compound J. LCMS: m / z 279 [M+H] ＋ HPLC retention time: 1.20 minutes (analysis condition G)

[0264] Second step: Compound K3 4-bromo-2-chloro-5-methoxybenzoic acid Using methyl 4-bromo-2-chloro-5-methoxybenzoate, the title compound was obtained in the same manner as in the second step of Compound J. LCMS: m / z 263 [M−H] － HPLC retention time: 0.69 minutes (Analysis conditions D)

[0265] Third step: Compound K4 4-bromo-2-chloro-5-methoxybenzoyl chloride Using 4-bromo-2-chloro-5-methoxybenzoic acid, the title compound was obtained as a crude product in the same manner as in the third step of Compound J.

[0266] Fourth step: Compound K methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was synthesized using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride and 4-bromo-2-chloro-5-methoxybenzoyl chloride in the same manner as in the fifth step of Compound B. LCMS: m / z 619 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions D)

[0267] Compound L methyl 4-[2-(4-bromo-2,6-dichlorobenzoyl)-4-oxo-1,3-dihydrophthalazin-5-yl]-2-morpholin-4-ylbenzoate Step 1 Compound L4 methyl 2-bromo-6-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoate 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 hydrazodicarboxylate (20.5 g, 88.0 mmol) and cesium carbonate (14.4 g, 44.2 mmol) were added, followed by stirring at room temperature for 15 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then 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 (analysis condition G)

[0268] Second step: Compound L5 tert-butyl 5-bromo-4-oxo-1,3-dihydrophthalazine-2-carboxylate To a solution of methyl 2-bromo-6-[[(2-methylpropan-2-yl)oxycarbonyl-[(2-methylpropan-2-yl)oxycarbonylamino]amino]methyl]benzoate (5.61 g, 12.2 mmol) in tetrahydrofuran (150 mL) was added 1M lithium bis(trimethylsilyl)amide solution (15.9 mL, 15.9 mmol), and the mixture was stirred at 60°C for 12 hours. Aqueous formic acid 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 (Analysis conditions G)

[0269] Third Step: Compound L6 tert-butyl 5-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-4-oxo-1,3-dihydrophthalazine-2-carboxylate The title compound was synthesized using tert-butyl 5-bromo-4-oxo-1,3-dihydrophthalazine-2-carboxylate and methyl 4-bromo-2-morpholin-4-ylbenzoate in the same manner as in the third step of Compound B. LCMS: m / z 468 [M+H] ＋ HPLC retention time: 1.07 minutes (analysis condition G)

[0270] Fourth step: Compound L methyl 4-[2-(4-bromo-2,6-dichlorobenzoyl)-4-oxo-1,3-dihydrophthalazin-5-yl]-2-morpholin-4-ylbenzoate To tert-butyl 5-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-4-oxo-1,3-dihydrophthalazine-2-carboxylate (50 mg, 0.107 mmol), a 4M solution of hydrochloric acid in 1,4-dioxane (0.535 mL, 2.14 mmol) was added, 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-dichlorobenzoyl 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 (analysis condition G)

[0271] Compound M methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-5-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate Step 1 Compound M2 tert-butyl N-[(2-fluoro-6-hydroxyphenyl)methyl]carbamate To a solution of 2-bromo-3-fluorophenol (500 mg, 2.62 mmol) in 1,4-dioxane (10.0 mL) and water (2.00 mL), cataCXium® A Pd G3 (28.6 mg, 0.0390 mmol), potassium carbonate (1.09 mg, 7.85 mmol), and potassium [[(tert-butoxycarbonyl)amino]methyl]trifluoroborate (1.24 g, 5.24 mmol) were added and the mixture was stirred at 130° C. for 20 minutes under microwave irradiation. 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 (analysis condition G)

[0272] Second step: Compound M3 tert-butyl N-[(3-bromo-6-fluoro-2-hydroxyphenyl)methyl]carbamate A solution of tert-butyl N-[(2-fluoro-6-hydroxyphenyl)methyl]carbamate (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 minutes. 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 (analysis condition G)

[0273] Third Step: Compound M4 tert-butyl 8-bromo-5-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate To a solution of tert-butyl N-[(3-bromo-6-fluoro-2-hydroxyphenyl)methyl]carbamate (600 mg, 1.87 mmol) in dichloroethane (30.0 mL), p-toluenesulfonic acid (35.6 mg, 0.187 mmol) and 90% paraformaldehyde (625 mg, 18.7 mmol) were added, and the mixture was stirred at 90°C overnight. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (64%, 399 mg). LCMS: m / z 332 [M+H] ＋ HPLC retention time: 1.34 minutes (analysis condition G)

[0274] Fourth Step: Compound Z6 (2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)boronic acid A solution of methyl 4-bromo-5-fluoro-2-morpholin-4-ylbenzoate (96.0 mg, 0.302 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (11.0 mg, 0.0150 mmol), potassium acetate (44.4 mg, 0.453 mmol), and bis(pinacolato)diboron (77.0 mg, 0.302 mol) in 1,4-dioxane (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 (Analysis conditions G)

[0275] Fifth step: Compound M5 tert-butyl 5-fluoro-8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate To a solution of tert-butyl 8-bromo-5-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate (200 mg, 0.602 mmol) in 1,4-dioxane (2.40 mL) - water (0.600 mL), (2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)boronic acid (205 mg, 0.723 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (22.0 mg, 0.0300 mmol), and potassium carbonate (250 mg, 1.81 mmol) were added and stirred at 90°C for 3 hours. 2-Fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)boronic acid (205 mg, 0.723 mmol) was added to the reaction mixture and stirred at 90°C overnight. To the reaction mixture were added 2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)boronic acid (205 mg, 0.723 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (22.0 mg, 0.0300 mmol), and the mixture was stirred at 90°C for 3 hours. Aqueous 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 obtain the title compound (69%, 205 mg). LCMS: m / z 491 [M+H] ＋ HPLC retention time: 1.36 minutes (analysis condition G)

[0276] Sixth Step: Compound M6 Methyl 5-fluoro-4-(5-fluoro-3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate dihydrochloride The title compound was obtained using tert-butyl 5-fluoro-8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate and the same procedure as in the fourth step of Compound B. LCMS: m / z 362 [M-CH + H] HPLC retention time: 0.69 minutes (analysis condition N). １ H-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).

[0277] Seventh step: Compound M methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-5-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using methyl 5-fluoro-4-(5-fluoro-3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate dihydrochloride and 4-bromo-2,6-dichlorobenzoyl chloride. LCMS: m / z 641 [M+H] ＋ HPLC retention time: 1.40 minutes (Analysis conditions N)

[0278] Compound N-methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate Step 1 Compound N-tert-butyl N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate To a solution of 3-bromo-4-fluoro-2-hydroxybenzonitrile (970 mg, 4.49 mmol) in tetrahydrofuran (20.0 mL) was added 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, and the mixture was concentrated. 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 aqueous sodium bicarbonate 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 aqueous ammonium chloride, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (79%, 1.13 g). LCMS: m / z 318 [MH] － HPLC retention time: 1.18 minutes (Analysis conditions N)

[0279] Second step: Compound N4 tert-butyl 8-bromo-7-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate To a solution of tert-butyl N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate (600 mg, 1.87 mmol) in toluene (5.00 mL), p-toluenesulfonic acid monohydrate (1.78 mg, 0.00937 mmol) and paraformaldehyde (281 mg, 9.37 mmol) were added and the mixture was stirred at 100°C for 3 hours. The reaction mixture was further 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 minutes (analysis condition G)

[0280] Third step: Compound N7 methyl 2-morpholin-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate A solution of methyl 4-bromo-2-morpholin-4-ylbenzoate (1.60 g, 5.33 mmol), bis(pinacolato)diboron (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-dioxane (10.0 mL) was stirred at 85°C for 2 hours. A 1 / 1 ethyl acetate / hexane solution was added to the reaction mixture, which was then filtered and concentrated. The resulting 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 (analysis condition G)

[0281] Fourth step: Compound N5 tert-butyl 7-fluoro-8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate A solution of methyl 2-morpholin-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (85.0 mg, 0.246 mmol), tert-butyl 8-bromo-7-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate (68.0 mg, 0.205 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (15.0 mg, 0.0200 mmol), and 2 M aqueous sodium carbonate solution (0.307 mL, 0.614 mmol) in 1,4-dioxane (1.00 mL) was stirred at 90° C. for 1.5 hours. The reaction mixture was mixed with the compound obtained separately in the same manner as above, and an aqueous formic acid solution was added. The mixture was purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (71.0 mg). LCMS: m / z 473 [M+H] ＋ HPLC retention time: 1.30 minutes (analysis condition G)

[0282] Fifth step: Compound N-methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate To tert-butyl 7-fluoro-8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate (344 mg, 0.728 mmol), a 4M solution of hydrochloric acid in 1,4-dioxane (3.64 mL, 14.6 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and 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) were added to the resulting residue 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 (analysis condition O)

[0283] Compound O: Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Step 1: Compound O1: 2,6-dichloro-4-fluorobenzoyl chloride Using 2,6-dichloro-4-fluorobenzoic acid, the title compound was obtained as a crude product by the same procedure as in the third step of Compound J.

[0284] Second step Compound O methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride and 2,6-dichloro-4-fluorobenzoyl chloride, the title compound was obtained by the same procedure as in the fifth step of Compound B. LCMS: m / z 589 [M+H] ＋ HPLC retention time: 0.96 minutes (Analysis conditions D)

[0285] Compound P4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (100 mg, 0.170 mmol) in 1-methylpyrrolidin-2-one (1.70 mL) was added 2M aqueous lithium hydroxide solution (0.424 mL, 0.848 mmol) and stirred at room temperature for 14 hours. 1-Methylpyrrolidin-2-one (1.70 mL) and 2M aqueous lithium hydroxide solution (0.424 mL, 0.848 mmol) were added to the reaction mixture and stirred at room temperature for 1.5 hours. Aqueous 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 (63%, 61.9 mg). LCMS: m / z 575 [M+H] ＋ HPLC retention time: 0.77 minutes (Analysis conditions D)

[0286] Compound Q Ethyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate Step 1 Compound Q1 Ethyl 4-bromo-2-morpholin-4-ylbenzoate Potassium carbonate (2.17 g, 15.7 mmol) and iodoethane (0.632 mL, 7.86 mmol) were added to a solution of 4-bromo-2-morpholin-4-ylbenzoic acid (1.50 g, 5.24 mmol) in N,N-dimethylformamide (26.2 mL), and the mixture was stirred at 25°C for 2.5 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Purification by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) gave the title compound (99%, 1.63 g). LCMS: m / z 314 [M+H] ＋ HPLC retention time: 0.86 minutes (analysis condition O)

[0287] Second step Compound Q4 tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate A solution of tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate (3.40 g, 10.8 mmol), bis(pinacolato)diboron (5.50 g, 21.6 mmol), potassium acetate (4.25 g, 43.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.792 g, 1.08 mmol) in 1,4-dioxane (108 mL) was stirred at 110°C for 18 hours. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (32%, 1.26 g). LCMS: m / z 362 [M+H] ＋ HPLC retention time: 1.36 minutes (analysis condition G)

[0288] Third Step: Compound Q2 tert-butyl 8-(4-ethoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate To a solution of ethyl 4-bromo-2-morpholin-4-ylbenzoate (1.30 g, 3.76 mmol) and tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate (1.36 g, 4.14 mmol) in 1,4-dioxane (11.4 mL) / water (1.14 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.275 g, 0.376 mmol) and potassium carbonate (1.56 g, 11.3 mmol), and the mixture was stirred at 90° C. for 2 hours. The reaction mixture was concentrated and extracted with ethyl acetate, and the organic layer was washed with water. After concentration, the resulting residue was purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (81%, 1.43 g). LCMS: m / z 469 [M+H] ＋ HPLC retention time: 1.38 minutes (analysis condition G)

[0289] Fourth step: Compound Q3 Ethyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate hydrochloride Using tert-butyl 8-(4-ethoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate, the title compound was obtained by the same procedure as in the fourth step of Compound B. LCMS: m / z 369 [M+H] ＋ HPLC retention time: 0.74 minutes (analysis condition G)

[0290] Fifth step: Compound Q ethyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using ethyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate hydrochloride and 2,6-dichloro-4-fluorobenzoyl chloride. LCMS: m / z 559 [M+H] ＋HPLC retention time: 1.33 minutes (analysis condition G)

[0291] Compound R methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate dihydrochloride and 2,6-dichloro-4-fluorobenzoyl chloride. LCMS: m / z 545 [M+H] ＋ HPLC retention time: 1.26 minutes (analysis condition G)

[0292] Compound S Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride and 2,6-dichloro-4-fluorobenzoyl chloride. LCMS: m / z 563 [M+H] ＋ HPLC retention time: 0.91 minutes (Analysis conditions D)

[0293] Compound T Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-methyl-6-morpholin-4-ylbenzoate Step 1 Compound T1 4-Bromo-2-methyl-6-morpholin-4-ylbenzoic acid The title compound was obtained by the same procedure as in the first step of Compound B using 4-bromo-2-fluoro-6-methylbenzoic acid. LCMS: m / z 300 [M+H] ＋ HPLC retention time: 0.89 minutes (Analysis conditions N)

[0294] Second step Compound T2 methyl 4-bromo-2-methyl-6-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the second step of Compound B using 4-bromo-2-methyl-6-morpholin-4-ylbenzoic acid. LCMS: m / z 314 [M+H] ＋ HPLC retention time: 0.91 minutes (Analysis conditions D)

[0295] Third Step: Compound T3 tert-butyl 8-(4-methoxycarbonyl-3-methyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate The title compound was obtained by the same procedure as in the third step of Compound Q using methyl 4-bromo-2-methyl-6-morpholin-4-ylbenzoate and tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate. LCMS: m / z 469 [M+H] ＋ HPLC retention time: 1.06 minutes (Analysis conditions D)

[0296] Fourth step: Compound T4 methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-methyl-6-morpholin-4-ylbenzoate dihydrochloride The title compound was obtained by the same procedure as in the fourth step of Compound B using tert-butyl 8-(4-methoxycarbonyl-3-methyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate. LCMS: m / z 369 [M+H] ＋ HPLC retention time: 0.79 minutes (Analysis conditions N)

[0297] Fifth step: Compound T methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-methyl-6-morpholin-4-ylbenzoate 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 oxalyl chloride (0.0109 mL, 0.125 mmol) in dichloromethane (0.566 mL) and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture was added methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-methyl-6-morpholin-4-ylbenzoate dihydrochloride (50.0 mg, 0.113 mmol). The mixture was cooled to 0°C, and N,N-diisopropylethylamine (0.0990 mL, 0.566 mmol) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to afford the title compound (71%, 44.7 mg). LCMS: m / z 559 [M+H] ＋ HPLC retention time: 1.02 minutes (Analysis conditions D)

[0298] Compound U: Methyl 4-[3-(2-chloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate Step 1: Compound U2: 2-chloro-4-fluorobenzoyl chloride The title compound was obtained as a crude product by the same procedure as in the third step of Compound J using 2-chloro-4-fluorobenzoic acid.

[0299] Second step Compound U methyl 4-[3-(2-chloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using 2-chloro-4-fluorobenzoyl chloride and methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride. LCMS: m / z 529 [M+H] ＋ HPLC retention time: 1.23 minutes (analysis condition G)

[0300] Compound V4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid Step 1 Compound V2 Methyl 2-chloro-4-fluoro-5-methoxybenzoate The title compound was obtained by the same procedure as in the first step of compound J using methyl 4-fluoro-3-methoxybenzoate. LCMS: m / z 219 [M+H] ＋ HPLC retention time: 1.08 minutes (Analysis conditions G)

[0301] Second Step Compound V3 2-chloro-4-fluoro-5-methoxybenzoic acid 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-dioxane (2.61 mL)-water (1.31 mL) was stirred at room temperature for 2 hours. Hydrochloric acid was added, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After passing through a phase separator, the organic layer was concentrated to give the title compound as a crude product. LCMS: m / z 205 [M+H] ＋ HPLC retention time: 0.59 minutes (Analysis conditions D)

[0302] Third step: Compound V4 2-chloro-4-fluoro-5-methoxybenzoyl chloride Using 2-chloro-4-fluoro-5-methoxybenzoic acid, the crude product of the title compound was obtained by the same procedure as in the third step of Compound J.

[0303] Fourth step Compound V5 methyl 4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate dihydrochloride and 2-chloro-4-fluoro-5-methoxybenzoyl chloride. LCMS: m / z 558 [M+H] ＋ HPLC retention time: 0.88 minutes (Analysis conditions D)

[0304] Fifth Step: Compound V: 4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid The title compound was obtained using methyl 4-[3-(2-chloro-4-fluoro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate in the same manner as in the preparation of Compound P. LCMS: m / z 545 [M+H] ＋ HPLC retention time: 0.72 minutes (Analysis conditions D)

[0305] Compound W: Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzoate Step 1: Compound X7: 2-(aminomethyl)-6-bromophenol hydrochloride To a solution of tert-butyl N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate (500 mg, 1.66 mmol) in 1,4-dioxane (4.14 mL), a 4M 1,4-dioxane solution (4.14 mL, 16.6 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give the title compound as a crude product. LCMS: m / z 202 [M+H] ＋ HPLC retention time: 0.28 minutes (Analysis conditions D)

[0306] Second Step Compound W1: N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-fluorobenzamide 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. A solution of 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) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated to obtain the title compound as a crude product. LCMS: m / z 392 [M+H] ＋ HPLC retention time: 0.80 minutes (Analysis conditions Z)

[0307] Third Step: Compound W2 (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-(2,6-dichloro-4-fluorophenyl)methanone To a solution of N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-fluorobenzamide (13.3 g, 33.8 mmol) in toluene (33.0 mL) / 1,4-dioxane (33.0 mL), p-toluenesulfonic acid (6.43 g, 33.8 mmol) and paraformaldehyde (19.6 g, 677 mmol) were added, and the mixture was stirred at 90°C for 5 hours. Ethyl acetate and saturated aqueous sodium carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. This mixture was mixed with a compound obtained separately in the same manner as above, and ethanol was added. Trituration gave the title compound (8.52 g). LCMS: m / z 404 [M+H] ＋ HPLC retention time: 1.46 minutes (Analysis conditions S)

[0308] Fourth step: Compound W9: Methyl 5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate To a solution of methyl 4-bromo-5-fluoro-2-hydroxybenzoate (16.1 g, 64.7 mmol) in 1,4-dioxane (220 mL), bis(pinacolato)diboron (32.8 g, 129 mmol), potassium acetate (19.0 g, 194 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2.64 g, 3.23 mmol) were added, and the mixture was stirred at 100°C for 16 hours. The obtained crude product was used in the subsequent reaction. LCMS: m / z 297 [M+H] ＋ HPLC retention time: 0.96 minutes (Analysis conditions D)

[0309] Fifth step: Compound W3 methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoate To a solution of methyl 5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (15.4 g, 51.8 mmol) and (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-(2,6-dichloro-4-fluorophenyl)methanone (21.0 g, 51.8 mmol) in 1,4-dioxane (210 mL) / water (21.0 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.90 g, 2.59 mmol) and potassium carbonate (14.3 g, 104 mmol), and the mixture was 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 (Analysis conditions D)

[0310] Sixth step: Compound W4 methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate To a solution of methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoate (45.4 mg, 0.0920 mmol) in N,N-dimethylformamide (0.919 mL), N,N-diisopropylethylamine (0.0320 mL, 0.184 mmol) and N-phenylbis(trifluoromethanesulfonimide) (49.2 mg, 0.138 mmol) were added and 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 (Analysis conditions D)

[0311] Seventh step: Compound W5 methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate To a solution of methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate (17.9 g, 28.6 mmol) in 1,4-dioxane (178 mL), bis(pinacolato)diboron (14.5 g, 57.1 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.05 g, 1.43 mmol), and potassium acetate (8.41 g, 85.7 mmol) were added, and the mixture was stirred at 100°C for 16 hours. LCMS: m / z 604 [M+H] ＋ HPLC retention time: 0.89 minutes (Analysis conditions T)

[0312] Eighth step Compound W6 methyl 2-bromo-4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluorobenzoate A solution of methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoato (200 mg, 0.331 mmol) and copper(II) bromide (222 mg, 0.993 mmol) in N,N-dimethylformamide (3.00 mL) and water (1.00 mL) was stirred at 80°C for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then concentrated. The resulting 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 (Analysis conditions AA)

[0313] Ninth step: Compound W methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzoate A solution of methyl 2-bromo-4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-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-Methylpyrrolidin-2-one and aqueous formic acid were added to the reaction mixture, and the mixture was purified by HPLC (acetonitrile / water, 0.5% trifluoroacetic acid) to give the title compound (26%, 110 mg). LCMS: m / z 589 [M+H] ＋ HPLC retention time: 0.96 minutes (Analysis conditions D)

[0314] Compound X methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate Step 1 Compound X2 methyl 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoate To 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-dioxaborolan-2-yl)pyrazole (460 mg, 2.21 mmol) in 1,4-dioxane (8.37 mL)-water (0.837 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (135 mg, 0.184 mmol) and potassium carbonate (764 mg, 5.53 mmol), and the mixture was stirred at 100°C for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.5% formic acid) to give the title compound (581 mg) quantitatively. LCMS: m / z 285 [M+H] ＋ HPLC retention time: 0.74 minutes (Analysis conditions D)

[0315] Second step: Compound X3: 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoic acid To a solution of methyl 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoate (582 mg, 2.04 mmol) in dimethyl sulfoxide (3.06 mL) and water (1.02 mL) was added 5M aqueous sodium hydroxide (2.04 mL, 10.2 mmol), and the mixture was stirred at 60°C for 3 hours. Aqueous formic acid 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 (86%, 477 mg). LCMS: m / z 271 [M+H] ＋ HPLC retention time: 0.56 minutes (Analysis conditions K)

[0316] Third Step: Compound X4: N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-(1-methylpyrazol-4-yl)benzamide To 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) were added 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), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered and then 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 (Analysis conditions D)

[0317] Fourth Step: Compound X5 (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone The title compound was obtained by the same procedure as in the third step of compound W using N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-(1-methylpyrazol-4-yl)benzamide. LCMS: m / z 466 [M+H] ＋ HPLC retention time: 0.85 minutes (Analysis conditions D)

[0318] Fifth step: Compound X6: methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoate The title compound was obtained by the same procedure as in the third step of Compound B using (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone and methyl 4-bromo-5-fluoro-2-hydroxybenzoate. LCMS: m / z 556 [M+H] ＋ HPLC retention time: 0.93 minutes (Analysis conditions D)

[0319] Sixth Step: Compound X methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate To a solution of methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoate (66.6 mg, 0.120 mmol) in N,N-dimethylformamide (1.20 mL), N,N-diisopropylethylamine (0.0417 mL, 0.239 mmol) and N-phenylbis(trifluoromethanesulfonimide) (64.1 mg, 0.180 mmol) were added and stirred at room temperature overnight. The reaction mixture was poured into 1M hydrochloric acid and extracted with ethyl acetate. The resulting 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 (Analysis conditions D)

[0320] Compound Y: Methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate Step 1: Compound Y1: (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]phenyl]methanone To a solution of (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-(2,6-dichloro-4-fluorophenyl)methanone (500 mg, 1.23 mmol) in 1-methylpyrrolidin-2-one (2.15 mL), (3R)-1,3-dimethylpiperazine (705 mg, 6.17 mmol) and N,N-diisopropylethylamine (0.00215 mL, 12.3 mmol) were added, and the mixture was stirred at 200°C for 1.5 hours under microwave irradiation, followed by stirring at 220°C for 1.5 hours. Aqueous formic acid 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 (Analysis conditions D)

[0321] Second step Compound Y2 methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoat Using (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]phenyl]methanone and methyl 4-bromo-5-fluoro-2-hydroxybenzoate, the title compound was obtained by the same procedure as in the third step of Compound B. LCMS: m / z 588 [M+H] ＋ HPLC retention time: 0.71 minutes (Analysis conditions T)

[0322] Third Step Compound Y: methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy)benzoate The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-hydroxybenzoate in the same manner as in the sixth step of Compound W, except that triethylamine was used in place of N,N-diisopropylethylamine. LCMS: m / z 720 [M+H] ＋ HPLC retention time: 0.68 minutes (Analysis conditions D)

[0323] Compound Z: methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate Step 1: Compound Z: tert-butyl N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate 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 1 M borane-tetrahydrofuran complex (1.63 mL, 1.63 mmol) was added, followed by stirring at 60°C for 2.5 hours. The reaction mixture was cooled to 0°C, and 5 M hydrochloric acid (0.358 mL, 1.79 mmol) was added, followed by stirring at 60°C for 2 hours. The reaction mixture was cooled to 0°C, and 6 M aqueous sodium hydroxide solution (0.298 mL, 1.79 mmol) and di-tert-butyl dicarbonate (0.266 mL, 0.976 mmol) were added, followed by stirring at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium hydrogen chloride 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 (analysis condition O)

[0324] Second step: Compound Z3 tert-butyl 8-bromo-7-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate Using tert-butyl N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate, the title compound was obtained in the same manner as in the third step of Compound W. LCMS: m / z 332 [M+H] ＋ HPLC retention time: 0.95 minutes (analysis condition O)

[0325] Third Step: Compound Z4 tert-butyl 7-fluoro-8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate To a solution of tert-butyl 8-bromo-7-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate (400 mg, 1.20 mmol) and (2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)boronic acid (639 mg, 1.81 mmol) in 1,4-dioxane (5.02 mL) and water (1.00 mL) was added potassium phosphate (1.28 g, 6.02 mmol) and XPhos Pd G3 (51.0 mg, 0.0600 mmol), and the mixture was stirred at 50°C for 4.5 hours. Extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium hydrogen chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (92%, 544 mg). LCMS: m / z 491 [M+H] ＋ HPLC retention time: 0.96 minutes (analysis condition O)

[0326] Fourth step: Compound Z5 methyl 5-fluoro-4-(7-fluoro-3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoate hydrochloride Using tert-butyl 7-fluoro-8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate, the title compound was obtained by the same procedure as in the fourth step of Compound B. LCMS: m / z 391 [M+H] ＋ HPLC retention time: 0.49 minutes (analysis condition O)

[0327] Fifth step: Compound Z methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate The title compound was obtained using methyl 5-fluoro-4-(7-fluoro-3,4-dihydro-2H-1,3-benzoxazin-8-yl)-2-morpholin-4-ylbenzoato hydrochloride and 4-bromo-2,6-dichlorobenzoyl chloride in the same manner as in the fifth step of Compound B, except that diisopropylamine was used instead of N,N-diisopropylethylamine. LCMS: m / z 641 [M+H] ＋ HPLC retention time: 0.99 minutes (analysis condition O)

[0328] Compound 1-61 4-[3-[2,6-dichloro-4-(5-oxa-2-azaspiro[3.4]octan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using Compound D and 5-oxa-2-azaspiro[3.4]octane 2,2,2-trifluoroacetate, the title compound was obtained in the same manner as in the ninth step of Compound 1-7. LCMS: m / z 650 [M+H] ＋ HPLC retention time: 1.65 minutes, 1.68 minutes (Analysis conditions B)

[0329] Compound 1-71 4-[3-[2-chloro-4-(3-methoxyazetidin-1-yl)-5-methylbenzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound CP8 Methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato dihydrochloride and 4-bromo-2-chloro-5-methylbenzoyl chloride. LCMS: m / z 629 [M+H] ＋ HPLC retention time: 1.02 minutes (Analysis conditions D)

[0330] Second Step Compound 1-71 4-[3-[2-chloro-4-(3-methoxyazetidin-1-yl)-5-methylbenzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained by the same procedure as in the ninth step of Compound 1-7 using methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate and 3-methoxyazetidine hydrochloride. LCMS: m / z 622 [M+H] ＋ HPLC retention time: 1.48 minutes (Analysis conditions B)

[0331] Compound 1-74 4-[3-[2-chloro-5-methoxy-4-(3-methoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound CP9 Methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained by the same procedure as in the fifth step of Compound B using methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato dihydrochloride and 4-bromo-2-chloro-5-methoxybenzoyl chloride. LCMS: m / z 645 [M+H] ＋ HPLC retention time: 0.97 minutes (Analysis conditions D)

[0332] Second Step Compound 1-74 4-[3-[2-chloro-5-methoxy-4-(3-methoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained by the same procedure as in the ninth step of Compound 1-7 using methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate and 3-methoxyazetidine hydrochloride. LCMS: m / z 638 [M+H] ＋ HPLC retention time: 1.47 minutes (Analysis conditions B)

[0333] Compound 1-55: 4-[3-[2,6-dichloro-4-[4-(oxetan-3-yl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid A solution of Compound B (12.0 mg, 0.0190 mmol), 1-(oxetan-3-yl)piperazine (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 aqueous sodium hydroxide 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 minutes, 0.80 minutes (Analysis conditions A)

[0334] Compound 1-54: 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid A solution of Compound B (1.72 g, 2.76 mmol), 1-(2-methoxyethyl)piperazine (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-dioxane (5.00 mL), and 5M aqueous sodium hydroxide solution (2.76 mL, 13.8 mmol) were added, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was concentrated to remove 1,4-dioxane, and formic acid was added. The reaction mixture was purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (67%, 1.24 g). LCMS: m / z 673 [M+H] ＋HPLC retention time: 0.77 minutes, 0.82 minutes (Analysis conditions A)

[0335] Compound 1-88 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound CP6 methyl 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A solution of compound H (3.46 g, 5.62 mmol), 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-dioxane (34.6 mL) was heated at 100°C for 2 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was washed with 15% aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated, and the resulting 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 (Analysis conditions AF)

[0336] Second Step Compound 1-88 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (3.17 g, 4.79 mmol) in tetrahydrofuran (7.61 mL) were added ethanol (7.61 mL) and 8M aqueous potassium hydroxide solution (2.99 mL, 23.9 mmol), and the mixture was heated at 60°C for 35 minutes. The reaction mixture was cooled to 0°C, and 0.5M hydrochloric acid was added. The resulting solid was collected by filtration 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 (Analysis conditions B)

[0337] Compound 1-83: 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound CP7: 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of compound D (24.0 g, 38.0 mmol) in 1,3-dimethyl-2-imidazolidinone (120 mL) was added 8 M aqueous potassium hydroxide solution (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 2 M hydrochloric acid and water were added, followed by stirring at room temperature for 30 minutes. The resulting solid was collected by filtration and washed with water to obtain the title compound (90%, 21.0 g). LCMS: m / z 617 [M+H] ＋ HPLC retention time: 1.17, 1.21 minutes (analysis condition G)

[0338] Second Step Compound 1-83 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid (21.0 g, 34.0 mmol), 6-methoxy-2-azaspiro[3.3]heptane hydrochloride (8.34 g, 50.9 mmol), allylpalladium(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) in tetrahydrofuran (679 mL) was added sodium tert-butoxide (13.1 g, 136 mmol). Aqueous hexane (20 mmol) was added and stirred at 30°C for 3 hours. To the reaction mixture, 0.5M aqueous potassium hydrogen sulfate solution, ethyl acetate, N-acetylcysteine, and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution. It 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 resulting solid was collected by filtration and washed with acetonitrile / water (1 / 2) to obtain the title compound (70%, 15.8 g). LCMS: m / z 664 [M+H] ＋ HPLC retention time: 1.67, 1.70 minutes (Analysis conditions B)

[0339] The compounds shown in Table 1-4 were obtained using the corresponding intermediates and commercially available amine reagents shown in Table 1-5 in the same manner as in the preparation of Compound 1-55, except that a 1,4-dioxane solution was used instead of a toluene solution in the synthesis of Compound 1-59.

[0340]

[0341]

[0342] Compound 1-73 4-[3-[2-chloro-5-methoxy-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid A solution of Compound K (60.0 mg, 0.0970 mmol), 2-oxa-6-azaspiro[3.3]heptane 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(0)-chloroform adduct (10.0 mg, 0.00968 mmol) in 1-methylpyrrolidin-2-one (0.960 mL) was stirred for 2 hours at 100°C. After cooling to room temperature, 8M aqueous potassium hydroxide solution (0.121 mL, 0.970 mmol) was added, and the mixture was stirred at 60°C for 30 minutes. Aqueous formic acid was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (55%, 33.2 mg). LCMS: m / z 624 [M+H] ＋ HPLC retention time: 1.34 minutes (Analysis conditions B)

[0343] The compounds shown in Table 1-6 were obtained using the corresponding intermediates and the amine reagents shown in Table 1-7 in the same manner as in the preparation of Compound 1-73. However, for Compounds 1-57, 1-67, and 1-76, palladium(II) acetate was used instead of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct. Furthermore, for 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 1-methylpyrrolidin-2-one solvent.

[0344]

[0345]

[0346] Compound 1-64: 4-[3-[2,6-dichloro-4-(4-methylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid A solution of compound F (10.0 mg, 0.0170 mmol), 1-methylpiperazine (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 mixture was cooled to room temperature, and 1-methylpiperazine (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, followed by heating 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 minutes, 0.80 minutes (Analysis conditions A)

[0347] Compound 1-51: 4-[3-[2,6-dichloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid 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-methylpyrrolidin-2-one (1.00 mL) was stirred at 100° C. for 15 hours. Aqueous formic acid 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 minutes, 1.35 minutes (Analysis conditions B)

[0348] Compound 1-52 4-[3-[2,6-dichloro-4-(2-oxopyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid Step 1 Compound CP3 Methyl 4-[3-[2,6-dichloro-4-(2-oxopyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate A solution of compound B (60.0 mg, 0.0960 mmol), pyrrolidin-2-one (16.4 mg, 0.192 mmol), potassium carbonate (39.8 mg, 0.288 mmol), copper(I) iodide (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-methylpyrrolidin-2-one (0.960 mL) was stirred at 100° C. for 4.5 hours. The reaction mixture was cooled to room temperature, and pyrrolidin-2-one (8.18 mg, 0.0960 mmol), potassium carbonate (39.8 mg, 0.288 mmol), copper(I) iodide (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, followed by stirring at 100°C for 4.5 hours. Aqueous formic acid was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (44%, 26.5 mg). LCMS: m / z 628 [M+H] ＋ HPLC retention time: 0.99 minutes (Analysis conditions D)

[0349] Second Step Compound 1-52 4-[3-[2,6-dichloro-4-(2-oxopyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid A solution of methyl 4-[3-[2,6-dichloro-4-(2-oxopyrrolidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate (26.3 mg, 0.0420 mmmmol) and trimethylstannane (30.3 mg, 0.167 mmmmol) in chlorobenzene (0.140 mL) was stirred at 200°C for 0.75 hours under microwave irradiation. Aqueous formic acid was added to the reaction mixture, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (97%, 24.9 mg). LCMS: m / z 614 [M+H] ＋ HPLC retention time: 1.35 minutes, 1.36 minutes (Analysis conditions B)

[0350] Compound 1-50 4-[3-[2,6-dichloro-4-(2-oxoazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid A solution of compound C (40.0 mg, 0.0660 mmol), azetidin-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-dioxane (0.800 mL) was stirred at 100° C. for 2 hours. Aqueous formic acid 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 minutes, 1.36 minutes (Analysis conditions D)

[0351] Compound 2-6: 4-[3-[2-chloro-5-methoxy-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid A solution of compound K (52.0 mg, 0.0840 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (22.7 mg, 0.109 mmol), potassium carbonate (34.8 mg, 0.252 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (6.14 mg, 0.00839 mmol) in 1,4-dioxane (0.400 mL) and water (0.0400 mL) was stirred for 2 hours at 100° C. The reaction mixture was filtered and concentrated, and then 5 M aqueous sodium hydroxide solution (0.0503 mL, 0.252 mmol) and 1,4-dioxane (0.500 mL) were added to the resulting residue, followed by stirring at 60° C. for 1 hour. Aqueous formic acid and dimethyl sulfoxide were added to the reaction mixture, and the mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (69%, 35.0 mg). LCMS: m / z 607 [M+H] ＋ HPLC retention time: 0.98 minutes (Analysis conditions A)

[0352] The compounds shown in Table 2-1 were synthesized using various boronic acids or boronic acid esters known in the literature or commercially available, or the boronic acids or boronic acid esters shown in Table 2-2, following the same procedures as in the synthesis of Compound 2-6. However, in the synthesis of Compound 2-4, tetrakis(triphenylphosphine)palladium was used instead of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and in the synthesis of Compound 2-5, toluene was used instead of 1,4-dioxane / water.

[0353]

[0354]

[0355] Compound 3-24-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound BRO4[3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid A solution of compound A (1.00 g, 1.54 mmol), bis(pinacolato)diboron (0.781 g, 3.08 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.126 g, 0.154 mmol), and potassium acetate (0.453 g, 4.61 mmol) in 1,4-dioxane (5.13 mL) was stirred at 100°C for 2 hours. Ethyl acetate was added to the reaction solution, and the mixture was filtered through Celite. Water was added to the filtrate, which was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. To a solution of the residue in ethanol (14.0 mL) was added a solution of periodic acid (0.526 g, 2.06 mmol) in water (1.40 mL). The reaction solution was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (89%, 0.845 g). LCMS: m / z 615 [M+H] ＋ HPLC retention time: 0.82 minutes, 0.85 minutes (Analysis conditions D)

[0356] Second step Compound 3-2a methyl 4-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A solution of [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid (48.1 mg, 0.0780 mmol), 3-bromo-5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine (13.0 mg, 0.0600 mmol), APhos Pd G3 (3.82 mg, 0.00602 mmol), and potassium carbonate (33.3 mg, 0.241 mmol) in 1,4-dioxane (0.540 mL) and water (0.00540 mL) was stirred at 60° C. for 1 hour. Aqueous 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 (92%, 38.9 mg). LCMS: m / z 706 [M+H] ＋ HPLC retention time: 0.70 minutes (Analysis conditions D)

[0357] Third Step Compound 3-24-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-(5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (38.9 mg, 0.0550 mmol) in 1-methylpyrrolidin-2-one (0.550 mL) was added 8M aqueous potassium hydroxide solution (0.0688 mL, 0.551 mmol). The reaction mixture was stirred at 60°C for 1 hour. Aqueous 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 minutes, 1.18 minutes (Analysis conditions B)

[0358] Compound 3-6: 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound h6: 7-bromo-2-methylpyrazolo[4,3-c]pyridine To a solution of 7-bromo-1H-pyrazolo[4,3-c]pyridine (80.0 mg, 0.404 mmol) in N,N-dimethylformamide (2.02 mL), 1 M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (0.606 mL, 0.606 mmol) and iodomethane (0.0760 mL, 1.21 mmol) were added and the mixture was stirred at room temperature for 15 minutes. Aqueous formic acid 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 the title compound (12%, 10.4 mg). １ H-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).

[0359] Second step Compound 3-6a methyl 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained by the same procedure as in the second step of Compound 3-2 using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and 7-bromo-2-methylpyrazolo[4,3-c]pyridine. LCMS: m / z 702 [M+H] ＋HPLC retention time: 0.69 minutes, 0.72 minutes (Analysis conditions D)

[0360] Third Step Compound 3-6: 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using methyl 4-[3-[2,6-dichloro-4-(2-methylpyrazolo[4,3-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate, the title compound was obtained by the same procedure as in the third step of compound 3-2. LCMS: m / z 688 [M+H] ＋ HPLC retention time: 1.15 minutes, 1.19 minutes (Analysis conditions B)

[0361] Compound 3-10: 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound h10: 7-bromo-2-methyltriazolo[4,5-c]pyridine To a solution of 7-bromo-3H-triazolo[4,5-c]pyridine (199 mg, 1.00 mmol) in N,N-dimethylformamide (5.00 mL), 1 M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (1.50 mL, 1.50 mmol) and iodomethane (0.188 mL, 3.00 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Aqueous 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 (33%, 69.2 mg). LCMS: m / z 213 [M+H] ＋ HPLC retention time: 0.50 minutes (Analysis conditions D)

[0362] Second step Compound 3-10a methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained by the same procedure as in the second step of Compound 3-2 using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and 7-bromo-2-methyltriazolo[4,5-c]pyridine. LCMS: m / z 703 [M+H] ＋ HPLC retention time: 0.91 minutes, 0.94 minutes (Analysis conditions D)

[0363] 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate, the title compound was obtained by the same procedure as in the third step of compound 3-2. LCMS: m / z 689 [M+H] ＋ HPLC retention time: 1.43 minutes, 1.45 minutes (Analysis conditions B)

[0364] Compound 3-17 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound 3-17a Methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Compound 3-19a Methyl 4-[3-[2,6-dichloro-4-(3-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate To a solution of 7-bromo-3H-triazolo[4,5-b]pyridine (100 mg, 0.502 mmol) in tetrahydrofuran (2.51 mL), 1 M sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.754 mL, 0.754 mmol) and iodomethane (0.0940 mL, 1.51 mmol) were added and the mixture was stirred at room temperature for 18 hours. 1 M sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.754 mL, 0.754 mmol) was added and the mixture was stirred at room temperature for 1 hour. 1 M sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.754 mL, 0.754 mmol) and iodomethane (0.094 mL, 1.51 mmol) were added and the mixture was stirred at room temperature for 1 hour. Aqueous formic acid was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (methanol / water, 0.01M ammonium acetate) to give a mixture of 7-bromo-2-methyltriazolo[4,5-b]pyridine and 7-bromo-3-methyltriazolo[4,5-b]pyridine (25%, 27.0 mg). Using the resulting mixture and [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]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, for purification, reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) followed by SFC (ACQUITY UPC2 Torus 1-AA, supercritical carbon dioxide / methanol) was used. Compound 3-17a LCMS: m / z 703 [M+H] ＋ SFC retention time: 3.18 minutes (Analysis conditions: ACQUITY UPC2 Torus 1-AA 4.6 mm ID x 50 mm, 5 μm, supercritical carbon dioxide / methanol = 70 / 30 (10 minutes), 40°C, 270 nm) Compound 3-19a LCMS: m / z 703 [M+H] ＋SFC retention time: 2.44 minutes (analysis conditions: ACQUITY UPC2 Torus 1-AA 4.6 mm ID x 50 mm, 5 μm, supercritical carbon dioxide / methanol = 70 / 30 (10 minutes), 40°C, 270 nm)

[0365] 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate, the title compound was obtained by the same procedure as in the third step of compound 3-2. LCMS: m / z 689 [M+H] ＋ HPLC retention time: 1.52 minutes, 1.56 minutes (Analysis conditions B)

[0366] Compound 3-19: 4-[3-[2,6-dichloro-4-(3-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using methyl 4-[3-[2,6-dichloro-4-(3-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate, the title compound was obtained by the same procedure as in the third step of compound 3-2. LCMS: m / z 689 [M+H] ＋ HPLC retention time: 1.57 minutes, 1.58 minutes (Analysis conditions B)

[0367] 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound h26 7-Bromo-4-methoxy-2-methyltriazolo[4,5-c]pyridine Compound h27 7-bromo-4-methoxy-3-methyltriazolo[4,5-c]pyridine To a solution of 7-bromo-4-methoxy-3H-triazolo[4,5-c]pyridine (40.0 mg, 0.175 mmol) in tetrahydrofuran (0.900 mL), 2.4 M lithium bis(trimethylsilyl)amide tetrahydrofuran solution (0.109 mL, 0.262 mmol) and iodomethane (0.0660 mL, 1.05 mmol) were added, and the mixture was stirred at room temperature for 68 hours. Aqueous formic acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound h26 (5.0%, 2.10 mg) and the title compound h27 (42%, 17.8 mg). Compound h26 LCMS: m / z 243 [M+H] ＋ HPLC retention time: 0.66 minutes (Analysis conditions D) Compound h27 LCMS: m / z 243 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions D)

[0368] Second step Compound 3-26a Methyl 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained by the same procedure as in the second step of Compound 3-2 using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and 7-bromo-4-methoxy-2-methyltriazolo[4,5-c]pyridine. LCMS: m / z 733 [M+H] ＋ HPLC retention time: 1.07 minutes, 1.10 minutes (Analysis conditions K)

[0369] 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using methyl 4-[3-[2,6-dichloro-4-(4-methoxy-2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate, the title compound was obtained by the same procedure as in the third step of compound 3-2. LCMS: m / z 719 [M+H] ＋ HPLC retention time: 1.70 minutes, 1.71 minutes (Analysis conditions B)

[0370] 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound 3-27a Methyl 4-[3-[2,6-dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid, compound 3-26, and 7-bromo-4-methoxy-3-methyltriazolo[4,5-c]pyridine obtained in the first step, the title compound was obtained by the same procedure as in the second step of compound 3-2. LCMS: m / z 733 [M+H] ＋ HPLC retention time: 1.08 minutes (Analysis conditions K)

[0371] 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using methyl 4-[3-[2,6-dichloro-4-(4-methoxy-3-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate, the title compound was obtained by the same procedure as in the third step of compound 3-2. LCMS: m / z 719 [M+H] ＋ HPLC retention time: 1.69 minutes (Analysis conditions B)

[0372] The compounds shown in Table 3-1 were synthesized in the same manner as in the second step of Compound 3-2 using [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and an aryl bromide shown in Table 3-1. However, in the synthesis of Compounds 3-14a, 3-15a, and 3-18a, tetrakis(triphenylphosphine)palladium(0) was used instead of APhos Pd G3, and sodium carbonate was used instead of potassium carbonate.

[0373]

[0374] Second Step: The compounds shown in Table 3-2 were synthesized using the esters obtained in the first step and shown in Table 3-1, in the same manner as in the second step of compound 3-2.

[0375]

[0376] Compound 3-1: 4-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid Step 1: Compound BRO1: [3,5-dichloro-4-[8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid To a solution of compound B (300 mg, 0.481 mmol), bis(pinacolato)diboron (244 mg, 0.961 mmol), and potassium acetate (141 mg, 1.44 mmol) in 1,4-dioxane (2.40 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (35.2 mg, 0.0480 mmol). The reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was concentrated, and the residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (100%, 284 mg). LCMS: m / z 589 [M+H] ＋ HPLC retention time: 0.76 minutes, 0.79 minutes (Analysis conditions D)

[0377] Second step Compound 3-1a methyl 4-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate A solution of [3,5-dichloro-4-[8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid (30.0 mg, 0.0510 mmol), 2-(4-bromopyrazol-1-yl)-2-methylpropan-1-ol (16.7 mg, 0.0760 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (3.73 mg, 0.00509 mmol) and potassium carbonate (21.1 mg, 0.153 mmol) in 1,4-dioxane (0.191 mL) and water (0.0636 mL) was stirred at 100°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 (66%, 22.9 mg). LCMS: m / z 683 [M+H] ＋ HPLC retention time: 0.85 minutes, 0.86 minutes (Analysis conditions D)

[0378] Third Step: Compound 3-14-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate in the same manner as in the third step of Compound 3-2. LCMS: m / z 669 [M+H] ＋ HPLC retention time: 1.01 minutes, 1.04 minutes (Analysis conditions A)

[0379] Compound 3-28: 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid Step 1: Compound BRO2: [3,5-dichloro-4-[8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid To a solution of compound E (175 mg, 0.289 mmol), bis(pinacolato)diboron (147 mg, 0.579 mmol), and potassium acetate (85.0 mg, 0.868 mmol) in 1,4-dioxane (3.00 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (21.2 mg, 0.0290 mmol). The reaction mixture was stirred at 90°C for 1 hour. Aqueous formic acid was added to the reaction mixture, and the reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (77%, 127 mg). LCMS: m / z 571 [M+H] ＋ HPLC retention time: 1.11 minutes (analysis condition G)

[0380] Second step Compound 3-28a Methyl 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate The title compound was obtained using [3,5-dichloro-4-[8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and 4-bromo-1-(2-methoxyethyl)pyrazole in the same manner as in Compound 3-1, Step 2. LCMS: m / z 651 [M+H] ＋ HPLC retention time: 1.22 minutes, 1.24 minutes (Analysis conditions G)

[0381] Third Step Compound 3-28: 4-[3-[2,6-dichloro-4-[1-(2-methoxyethyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid 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-benzoxazin-8-yl]-2-morpholin-4-ylbenzoate in the same manner as in the third step of Compound 3-2. LCMS: m / z 637 [M+H] ＋ HPLC retention time: 1.01 minutes, 1.04 minutes (Analysis conditions A)

[0382] Compound 4-24-[3-[2,6-dichloro-4-(3-ethoxy-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 1-Methylpyrrolidin-2-one (0.600 mL) was added to 3-ethoxy-3-methylazetidine 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 aqueous potassium hydroxide solution (0.0742 mL, 0.594 mmol) was added, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was neutralized with aqueous formic acid, and 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 minutes, 1.66 minutes (Analysis conditions B)

[0383] The compounds shown in Table 4-1 were synthesized using the amines shown in Table 4-2, which are known in the literature or commercially available, in the same manner as in the production method of Compound 4-2. However, potassium tert-butoxide was used instead of potassium carbonate in the synthesis of Compounds 4-18, 4-7, and 4-17, and triethylamine was used in the synthesis of Compounds 4-20, 4-22, 4-23, 4-24, 4-25, 4-27, 4-28, and 4-29.

[0384]

[0385]

[0386] Compound 4-12 4-[3-[2,6-dichloro-4-(4-cyclopropylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Compound O (25.0 mg, 0.0420 mmol) and 1-cyclopropylpiperazine (16.1 mg, 0.127 mmol) were stirred in 1-methylpyrrolidin-2-one (0.106 mL) at 130°C for 6 hours. After cooling the reaction mixture, 8M aqueous potassium hydroxide solution (0.0265 mL, 0.212 mmol) was added and the mixture was stirred at 60°C for 30 minutes. The reaction mixture was neutralized with aqueous formic acid, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (73%, 21.1 mg). LCMS: m / z 681 [M+H] ＋ HPLC retention time: 1.03, 1.06 minutes (Analysis conditions B)

[0387] The compounds shown in Table 4-3 were synthesized using the amines shown in Table 4-4, which are known in the literature or commercially available, in the same manner as in the preparation of Compound 4-12.

[0388]

[0389]

[0390] Compound 4-13 4-[3-[4-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2,6-dichlorobenzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Potassium tert-butoxide (42 mg, 0.375 mmol) was added to (9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (37.4 mg, 0.174 mmol) in 1-methylpyrrolidin-2-one (0.0870 mL), 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 minutes, 1.06 minutes (Analysis conditions B)

[0391] Compound 4-14 4-[3-[4-[(9aR)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2,6-dichlorobenzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was synthesized using compound P and (9aR)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride in the same manner as in the preparation of compound 4-13. LCMS: m / z 697 [M+H] ＋ HPLC retention time: 1.03 minutes, 1.06 minutes (Analysis conditions B)

[0392] Compound 4-15 4-[3-[2,6-dichloro-4-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid N,N-Diisopropylethylamine (35.9 mg, 0.278 mmol), Compound P (20.0 mg, 0.0350 mmol), and 2-methyl-1-piperazin-1-ylpropan-2-ol dihydrochloride (24.1 mg, 0.104 mmol) were added to 1-methylpyrrolidin-2-one (0.174 mL) and 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 (Analysis conditions B)

[0393] Compound 4-19: 4-[3-(2,6-dichloro-4-morpholin-4-ylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Compound P (20.0 mg, 0.0340 mmol) and morpholine (15.2 mg, 0.174 mmol) were stirred in 1-methylpyrrolidin-2-one (0.0870 mL) 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 (Analysis conditions B)

[0394] The compounds shown in Table 4-5 were synthesized using the amines shown in Table 4-6, which are known in the literature or commercially available, in the same manner as in the preparation of Compound 4-19.

[0395]

[0396]

[0397] Compound 4-42 4-[3-[2,6-dichloro-4-[[(2S)-1,4-dioxan-2-yl]methoxy]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 1-Methylpyrrolidin-2-one (0.254 mL) was added to [(2R)-1,4-dioxan-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. The reaction mixture was neutralized with aqueous formic acid, and the reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to obtain the title compound (69%, 23.8 mg). LCMS: m / z 673 [M+H] ＋ HPLC retention time: 1.43 minutes (Analysis conditions B)

[0398] The compounds shown in Table 4-7 were synthesized using the alcohols shown in Table 4-8, which were either known in the literature or commercially available, in the same procedure as in the preparation of compound 4-42. However, sodium tert-butoxide was used instead of potassium tert-butoxide in the synthesis of compounds 4-43, 4-44, and 4-45, and sodium hydride was used in the synthesis of compound 4-46. An ethyl ester intermediate was used in compound 4-43, and a methyl ester intermediate was used in compounds 4-44, 4-45, 4-46, and 4-47, but the hydrolysis reaction of the ester also proceeded simultaneously. Furthermore, for compounds 4-48, 4-49, 4-50, 4-51, 4-52, and 4-53, the hydrolysis reaction was carried out by adding 8 M aqueous potassium hydroxide solution after the aromatic nucleophilic substitution reaction and stirring at 60°C for 30 minutes.

[0399]

[0400]

[0401] Compound 4-40 4-[3-(2,6-dichloro-4-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Compound 4-41 4-[3-[2,6-dichloro-4-(oxan-4-ylmethoxy)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Using compound O and oxan-4-ylmethanol, 4-[3-(2,6-dichloro-4-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid and 4-[3-[2,6-dichloro-4-(oxan-4-ylmethoxy)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid were obtained in the same manner as in the preparation of compound 42. Compound 4-40 LCMS: m / z 587 [M+H] ＋ HPLC retention time: 1.47, 1.49 minutes (Analysis conditions B) Compound 4-41 LCMS: m / z 671 [M+H] ＋ HPLC retention time: 1.54, 1.55 minutes (Analysis conditions B)

[0402] Compound 5-7: 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Synthesis Method A: First Step Compound AZ1: Methyl 4-[3-[2,6-dichloro-4-(3-hydroxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A suspension of compound A (2.00 g, 3.08 mmol), azetidin-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-methylpyrrolidin-2-one (28.0 mL) and water (2.80 mL) was stirred at 100° C. for 4 hours. Aqueous 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 (83%, 1.64 g). LCMS: m / z 642 [M+H] ＋ HPLC retention time: 0.85 minutes (Analysis conditions D)

[0403] Second step: Compound AZ2 methyl 4-[3-[2,6-dichloro-4-(3-oxoazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Methyl 4-[3-[2,6-dichloro-4-(3-hydroxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (1.64 g, 2.55 mmol) and Dess-Martin periodinane (1.08 g, 2.55 mmol) in dichloromethane (25.5 mL) was 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 an additional 2 hours. Dichloromethane and aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, passed through a phase separator, and then concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (81%, 1.33 g). LCMS: m / z 640 [M+H] ＋ HPLC retention time: 0.91 minutes (Analysis conditions D)

[0404] Third Step Compound 5-7: 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-(3-oxoazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (25.0 mg, 0.0390 mmol) and 2-methyl-1,3-propanediol (0.00693 ml, 0.0780 mmol) in acetonitrile (0.195 ml) was added trimethylsilyl trifluoromethanesulfonate (0.00377 ml, 0.0200 mmol), and the mixture was stirred at room temperature for 1 hour and then at 70°C for 4 hours. Tetrahydrofuran (0.0980 ml) and methanol (0.0980 ml) were added to the reaction mixture, followed by 8M aqueous potassium hydroxide solution (0.0980 ml, 0.780 mmol), and the mixture was stirred at 60° C. for 30 minutes. Aqueous 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 (75%, 20.3 mg). LCMS: m / z 698 [M+H] ＋ HPLC retention time: 1.60, 1.63 minutes (Analysis conditions B)

[0405] Compound 5-7: 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid. Synthesis Method B, Step 1: Compound ACP2, benzyl 7-methyl-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate To a solution of benzyl 3-oxoazetidine-1-carboxylate (15.0 g, 73.1 mmol) in acetonitrile (300 mL), 2-methyl-1,3-propanediol (13.0 mL, 146 mmol) and trimethylsilyl trifluoromethanesulfonate (6.60 mL, 36.5 mmol) were added, and the mixture was stirred at 70°C for 4.5 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate and 15% aqueous sodium chloride. The organic layer was then dried over magnesium sulfate and concentrated. The resulting 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 (analysis condition G)

[0406] Second step: Compound ACP3 7-methyl-5,9-dioxa-2-azaspiro[3.5]nonane To a solution of benzyl 7-methyl-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (13.5 g, 48.7 mmol) in 1,4-dioxane (135 mL), 20% palladium hydroxide on activated carbon (wet) (1.20 g, 1.70 mmol) was added and the mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through Celite and washed with 1,4-dioxane to obtain the title compound as a crude product in 1,4-dioxane solution.

[0407] Third step Compound AC7 Methyl 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A mixture of Compound A (15.6 g, 24.0 mmol), a 3.05 wt% solution of 7-methyl-5,9-dioxa-2-azaspiro[3.5]nonane-1,4-dioxane (146 g, 31.2 mmol), cesium carbonate (23.5 g, 72.0 mmol), and a 1,4-dioxane solution (109 mL) of rac-BINAP Pd G4 (724 mg, 0.720 mmol) was stirred at 60°C for 16 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. A 5% aqueous solution of N-acetylcysteine ​​was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes and extracted. The organic layer was washed with a 15% aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (20.3 g) as a mixture with ethyl acetate. LCMS: m / z 712 [M+H] ＋ HPLC retention time: 3.22 minutes (Analysis conditions AF)

[0408] Fourth Step Compound 5-7: 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (17.1 g, 24.0 mmol) in tetrahydrofuran (42.7 mL) and methanol (42.7 mL) was added 8M aqueous potassium hydroxide solution (9.00 mL, 72.0 mmol) and stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and 8M aqueous potassium hydroxide solution (0.900 mL, 7.20 mmol) was added, followed by stirring at 50°C for 1.5 hours. The reaction mixture was cooled to room temperature, and 1M hydrochloric acid was added, followed by stirring at room temperature for 1 hour. The resulting solid was collected by filtration, washed with ethanol / water, then with ethanol and hexane / ethyl acetate, and further washed with ethanol to give the title compound (90%, 15.0 g). LCMS: m / z 698 [M+H] ＋ HPLC retention time: 1.60, 1.63 minutes (Analysis conditions B)

[0409] Compound 5-9 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound ACP4 Benzyl 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate To a solution of benzyl 3-oxoazetidine-1-carboxylate (15.0 g, 73.1 mmol) in acetonitrile (300 mL), 2,2-dimethyl-1,3-propanediol (14.5 ml, 146 mmol) and trimethylsilyl trifluoromethanesulfonate (6.60 ml, 36.5 mmol) were added, and the mixture was stirred at 70°C for 7 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate and 15% aqueous sodium chloride. The organic layer was then dried over magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (84%, 17.9 g). LCMS: m / z 292 [M+H] ＋ HPLC retention time: 1.15 minutes (analysis condition G)

[0410] Second step: Compound ACP5 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane To a solution of benzyl 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane-2-carboxylate (3.63 g, 12.5 mmol) in 1,4-dioxane (36.3 mL), 20% palladium hydroxide on activated carbon (wet) (306 mg, 0.436 mmol) was added, and the mixture was stirred under a hydrogen atmosphere for 14 hours. The reaction solution was filtered through Celite, washed with 1,4-dioxane, and concentrated to obtain the title compound as a crude product in 1,4-dioxane.

[0411] Third step Compound AC9 Methyl 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A mixture of Compound A (4.40 g, 6.77 mmol), a 6.58 wt% solution of 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane-1,4-dioxane (21.0 g, 8.80 mmol), cesium carbonate (6.61 g, 20.3 mmol), and a 1,4-dioxane solution (30.8 mL) of rac-BINAP Pd G4 (204 mg, 0.203 mmol) was stirred at 60°C for 4.5 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was washed with 15% aqueous sodium chloride solution and then extracted. The organic layer was dried over sodium sulfate and concentrated. Ethyl acetate and hexane were added to the resulting residue, and the mixture was triturated to quantitatively obtain the title compound (4.96 g). LCMS: m / z 726 [M+H] ＋ HPLC retention time: 1.48 minutes (analysis condition G)

[0412] Fourth Step Compound 5-9: 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (12.8 g, 17.6 mmol) in tetrahydrofuran (32.0 mL) and methanol (32.0 mL) was added 8 M aqueous potassium hydroxide solution (6.61 mL, 52.8 mmol), and the mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid was added. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 3% aqueous N-acetylcysteine ​​and 15% aqueous sodium chloride, dried over sodium sulfate, and concentrated. Ethanol was added to the residue, and the mixture was heated to 60°C. Water was added and the mixture was cooled to room temperature. Water was further added, and the resulting solid was collected by filtration and washed with ethanol / water (1 / 6) to obtain the title compound (88%, 11.0 g). LCMS: m / z 712 [M+H] ＋ HPLC retention time: 1.68, 1.72 minutes (Analysis conditions B)

[0413] Compound 5-16 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound ACP6 Benzyl 3,3-dimethoxyazetidine-1-carboxylate Methanol (89 ml, 2.19 mol) and trimethylsilyl trifluoromethanesulfonate (6.60 ml, 36.5 mmol) were added to benzyl 3-oxoazetidine-1-carboxylate (15.0 g, 73.1 mmol), and the mixture was stirred at 70°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate and 15% aqueous sodium chloride. The organic layer was then dried over magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (90%, 16.5 g). LCMS: m / z 252 [M+H] ＋ HPLC retention time: 1.00 minutes (Analysis conditions G)

[0414] Second step: Compound ACP7 3,3-dimethoxyazetidine To a solution of benzyl 3,3-dimethoxyazetidine-1-carboxylate (14.5 g, 57.7 mmol) in 1,4-dioxane (145 mL), 20% palladium hydroxide on activated carbon (wet) (1.42 g, 2.02 mmol) was added, and the mixture was stirred under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered through Celite and washed with 1,4-dioxane to obtain the title compound as a crude product in 1,4-dioxane solution.

[0415] Third step Compound AC16 methyl 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A mixture of compound D (15.6 g, 24.7 mmol), a 3.15 wt% 3,3-dimethoxyazetidine-1,4-dioxane solution (119 g, 32.1 mmol), cesium carbonate (24.1 g, 74.0 mmol), and a 1,4-dioxane solution (46.8 mL) of rac-BINAP Pd G4 (745 mg, 0.740 mmol) was stirred at 60°C for 16.5 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. 2-Methyltetrahydrofuran and a 5% aqueous solution of N-acetylcysteine ​​were added to the filtrate, and the mixture was stirred at room temperature for 30 minutes. After filtration, the organic layer was washed with a 15% aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (95%, 15.6 g). LCMS: m / z 668 [M+H] ＋ HPLC retention time: 1.37 minutes (analysis condition G)

[0416] Fourth Step Compound 5-16 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (15.6 g, 23.3 mmol) in tetrahydrofuran (39.0 mL) and methanol (39.0 mL) was added 8M aqueous potassium hydroxide solution (8.75 mL, 70.0 mmol), and the mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and 1M hydrochloric acid was added. The resulting solid was collected by filtration and washed with ethanol / water (1 / 4) to give the title compound (90%, 13.7 g). LCMS: m / z 654 [M+H] ＋ HPLC retention time: 1.63, 1.65 minutes (Analysis conditions B)

[0417] Using diols shown in Table 5-2, which are known in the literature or commercially available, the compounds shown in Table 5-1 were synthesized in the same manner as in the third step of Synthesis Method A for Compound 5-7.

[0418]

[0419]

[0420] Compound 5-1 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound AC1 Methyl 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A solution of methyl 4-[3-[2,6-dichloro-4-(3-oxoazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (1.65 g, 2.58 mmol), p-toluenesulfonic acid monohydrate (147 mg, 0.774 mmol), and methanol (5.22 ml, 129 mmol) in trimethyl orthoformate (7.00 ml) was heated at 100°C for 5 hours. The reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (67%, 1.18 g). LCMS: m / z 686 [M+H] ＋ HPLC retention time: 0.98 minutes (Analysis conditions D)

[0421] Second step: Compound 5-14-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (1.18 g, 1.72 mmol) in tetrahydrofuran (5.60 ml) and methanol (2.80 ml) was added 8M aqueous sodium hydroxide (2.15 ml, 17.2 mmol) and stirred at 60 °C for 1 hour. After adding aqueous formic acid to the reaction mixture, the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) and mixed with a compound obtained separately in the same manner as above. Ethyl acetate and water were added, and the organic layer was extracted and filtered. Concentration afforded the title compound (1.36 g). LCMS: m / z 672 [M+H] ＋ HPLC retention time: 1.55, 1.58 minutes (Analysis conditions B)

[0422] Compound 5-4 4-[3-[2,6-dichloro-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound AC4 Methyl 4-[3-[2,6-dichloro-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A solution of methyl 4-[3-[2,6-dichloro-4-(3-oxoazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (35.0 mg, 0.0550 mmol), ethylene glycol (0.00606 ml, 0.109 mmol), and p-toluenesulfonic acid monohydrate (1.04 mg, 0.00546 mmol) in toluene (0.273 ml) was stirred at 110° C. for 4 hours. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (5%, 1.9 mg). LCMS: m / z 684 [M+H] ＋ HPLC retention time: 0.97 minutes (Analysis conditions D)

[0423] Second Step Compound 5-4: 4-[3-[2,6-dichloro-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (1.90 mg, 0.00278 mmol) in tetrahydrofuran (0.00925 ml) and methanol (0.0185 ml), 8M aqueous sodium hydroxide solution (0.00867 ml, 0.00690 mmol) was added and heated at 60°C for 1 hour. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (32%, 0.60 mg). LCMS: m / z 670 [M+H] ＋ HPLC retention time: 1.50, 1.51 minutes (Analysis conditions B)

[0424] Compound 5-14 4-[3-[2,6-dichloro-4-[3-[(3S)-3-methylmorpholin-4-yl]azetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Sodium triacetoxyborohydride (12.7 mg, 0.0600 mmol) was added to a dichloromethane solution (0.300 ml) of methyl 4-[3-[2,6-dichloro-4-(3-oxoazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (19.2 mg, 0.0300 mmol), S-3-methylmorpholine (0.00606 ml, 0.0600 mmol), and acetic acid (0.00172 ml, 0.0300 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and methanol (0.150 ml) and tetrahydrofuran (0.150 ml) were added. 5M aqueous sodium hydroxide solution (0.120 mL, 0.600 mmol) was added, followed by stirring at 60°C for 1 hour. This was mixed with a compound obtained separately in the same manner as above, and purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (10.4 mg). LCMS: m / z 711 [M+H] ＋ HPLC retention time: 1.09 minutes (Analysis conditions B)

[0425] The compounds shown in Table 5-3 were synthesized in the same manner as in the preparation of Compound 5-14 using amines shown in Table 5-4, which are known in the literature or commercially available, and methyl 4-[3-[2,6-dichloro-4-(3-oxoazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato.

[0426]

[0427]

[0428] Compound 5-10 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azadispiro[3.1.56.14]dodecan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound AZ3 Methyl 4-[3-[2,6-dichloro-4-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained using Compound A and 2-azaspiro[3.3]heptan-6-ol in the same manner as in the first step of Compound 5-7 Synthesis Method A. LCMS: m / z 682 [M+H] ＋ HPLC retention time: 0.88, 0.89 minutes (Analysis conditions D)

[0429] Second step Compound AZ4 methyl 4-[3-[2,6-dichloro-4-(6-oxo-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate in the same manner as in the second step of Compound 5-7 Synthesis Method A. LCMS: m / z 680 [M+H] ＋ HPLC retention time: 0.92 minutes (Analysis conditions D)

[0430] Third Step Compound 5-10 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azadispiro[3.1.56.14]dodecan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-(6-oxo-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate and 1,3-propanediol in the same manner as in the third step of Synthesis Method A for Compound 5-7. LCMS: m / z 724 [M+H] ＋ HPLC retention time: 1.56, 1.57 minutes (Analysis conditions B)

[0431] Compound 5-11 4-[3-[2,6-dichloro-4-(6,6-dimethoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound AC14 Methyl 4-[3-[2,6-dichloro-4-(6,6-dimethoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained by the same procedure as in the first step of compound 5-1 using methyl 4-[3-[2,6-dichloro-4-(6-oxo-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate. LCMS: m / z 726 [M+H] ＋ HPLC retention time: 1.03 minutes (Analysis conditions D)

[0432] Second Step Compound 5-11 4-[3-[2,6-dichloro-4-(6,6-dimethoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained by the same procedure as in the second step of compound 5-1 using methyl 4-[3-[2,6-dichloro-4-(6,6-dimethoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate. LCMS: m / z 712 [M+H] ＋ HPLC retention time: 1.61, 1.64 minutes (Analysis conditions B)

[0433] Compound 5-12 4-[3-[2,6-dichloro-4-[(2R)-3,3-dimethoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound AZ5 Methyl 4-[3-[2,6-dichloro-4-[(2R)-3-hydroxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained by the same procedure as in the first step of Synthesis Method A for Compound 5-7 using Compound A and (2R,3R)-2-methylazetidin-3-ol hydrochloride. LCMS: m / z 656 [M+H] ＋ HPLC retention time: 0.87 minutes (Analysis conditions D)

[0434] Step 2 Compound AZ6 methyl 4-[3-[2,6-dichloro-4-[(2R)-2-methyl-3-oxoazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-[(2R)-3-hydroxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate in the same manner as in the second step of Compound 5-7 Synthesis Method A. LCMS: m / z 654 [M+H] ＋ HPLC retention time: 0.94 minutes (Analysis conditions D)

[0435] Third step Compound AC15 methyl 4-[3-[2,6-dichloro-4-[(2R)-3,3-dimethoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained using methyl 4-[3-[2,6-dichloro-4-[(2R)-2-methyl-3-oxoazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate in the same manner as in the first step of compound 5-1. LCMS: m / z 700 [M+H] ＋ HPLC retention time: 1.03 minutes (Analysis conditions D)

[0436] Fourth Step Compound 5-12 4-[3-[2,6-dichloro-4-[(2R)-3,3-dimethoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid The title compound was obtained by the same procedure as in the second step of compound 5-1 using methyl 4-[3-[2,6-dichloro-4-[(2R)-3,3-dimethoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate. LCMS: m / z 686 [M+H] ＋ HPLC retention time: 1.61, 1.64 minutes (Analysis conditions B)

[0437] Compound 6-1 4-[3-[2,6-dichloro-4-[3-methoxy-3-(methoxymethyl)azetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound AL1 Methyl 4-[3-[2,6-dichloro-4-[3-hydroxy-3-(hydroxymethyl)azetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A suspension of compound A (30.0 mg, 0.460 mmol), 3-(hydroxymethyl)azetidin-3-ol oxalate (27.3 mg, 0.0920 mmol), rac-BINAP Pd G4 (2.32 mg, 0.00231 mmol), and cesium carbonate (75.0 mg, 0.231 mmol) in 1,4-dioxane (0.231 mL) was stirred at 110° C. for 1 hour. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (31%, 9.60 mg). LCMS: m / z 672 [M+H] ＋ HPLC retention time: 0.78 minutes, 0.80 minutes (Analysis conditions D)

[0438] Second step: Compound 6-14-[3-[2,6-dichloro-4-[3-methoxy-3-(methoxymethyl)azetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-[3-hydroxy-3-(hydroxymethyl)azetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (9.60 mg, 0.0140 mmol) and iodomethane (0.00268 mL, 0.0430 mmol) in tetrahydrofuran, sodium hydride (2.28 mg, 0.0570 mmol) was added at 0°C and stirred at room temperature for 5 hours. Then, 8 M aqueous potassium hydroxide solution (0.0178 mL, 0.143 mmol) and methanol (0.143 mL) were added at room temperature, and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid) to give the title compound (58.2%, 5.70 mg). LCMS: m / z 686 [M+H] ＋ HPLC retention time: 1.51 minutes (Analysis conditions B)

[0439] Compound AL2 Methyl 4-[3-[2,6-dichloro-4-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was synthesized using Compound A and 3-(trifluoromethyl)azetidin-3-ol hydrochloride in the same manner as in the first step of Compound 6-1. LCMS: m / z 710 [M+H] ＋ HPLC retention time: 0.95 minutes (Analysis conditions D)

[0440] Compound AL3 Methyl 4-[3-[2,6-dichloro-4-[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was synthesized using Compound A and (3-fluoroazetidin-3-yl)methanol hydrochloride in the same manner as in the first step of Compound 6-1. LCMS: m / z 674 [M+H] ＋ HPLC retention time: 0.87, 0.88 minutes (Analysis conditions D)

[0441] Compound AL4 methyl 4-[3-[2,6-dichloro-4-[rac-(1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate To a solution of compound A (25.0 mg, 0.0420 mmol) in 1-methylpyrrolidin-2-one (0.210 mL), rac-(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ol (10.8 mg, 0.0850 mmol) and N,N-diisopropylethylamine (0.0222 mL, 0.127 mmol) were added, and the mixture was stirred at 130°C for 5 hours under microwave irradiation. Aqueous 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 (49%, 14.5 mg). LCMS: m / z 696 [M+H] ＋ HPLC retention time: 0.92 minutes (Analysis conditions D)

[0442] Compound AL5 methyl 4-[3-[2,6-dichloro-4-[rac-(1R,5S,6S)-6-hydroxy-3-azabicyclo[3.2.0]heptan-3-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate To a solution of tert-butyl rac-(1R,5S,6S)-6-hydroxy-3-azabicyclo[3.2.0]heptane-3-carboxylate (26.2 mg, 0.123 mmol) in dichloromethane (0.262 mL) was added trifluoroacetic acid (0.262 mL, 3.41 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give rac-(1R,5S,6S)-3-azabicyclo[3.2.0]heptan-6-ol 2,2,2-trifluoroacetate as a crude product. A solution of the obtained crude product, Compound A (40.0 mg, 0.062 mmol), rac-BINAP Pd G4 (6.19 mg, 0.00615 mmol), and cesium carbonate (100 mg, 0.308 mmol) in 1,4-dioxane (0.300 mL) was stirred at 100°C for 1 hour and then at 120°C for 2 hours. The reaction mixture was purified by HPLC (acetonitrile / water, 0.1% formic acid), and fractions containing the title compound were collected and concentrated. Dichloromethane (0.300 mL), methanol (0.300 mL), and sodium borohydride (4.65 mg, 0.123 mmol) were added to the ...

Claims

1. Formula (1): 【Chemistry 1】 [In the formula, X ａ１ is CR ａ１ or N, X ａ３ is CR ａ３ or N, R ａ１ , R ａ２ and R ａ３ are each independently hydrogen, halogen, or C １ -C ６ alkoxy; X ｂ１ , X ｂ２ and X ｂ３ are each independently CH ２ , O, NH, S and C═O; Y is C ６ -C １０ aryl or 5- to 10-membered heteroaryl, ６ -C １０ Aryl and 5- to 10-membered heteroaryl are R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ and optionally substituted with one or more groups selected from the group consisting of The R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, Hydroxy C ２ -C ６ Alkoxy, 4-10 membered heterocyclyloxy, C １ -C ６ Alkoxy, C １ -C ６ Alkylamino C １ -C ６ Alkoxy, 5-10 membered heteroaryloxy, C １ -C ６ alkylthio, a 4- to 10-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl which may have a substituent, and C １ -C ６ Alkyl (C １ -C ６ Alkoxy C １ -C ６ is selected from the group consisting of aryl, arylalkyl, arylamino, Z is C ６ -C １０ Aryl, 5-10 membered heteroaryl or C １ -C ６ alkyl, ６ -C １０ Aryl, 5- to 10-membered heteroaryl and C １ -C ６ Alkyl is R ｚ３ and R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ and optionally substituted with one or more groups selected from the group consisting of R ｚ３ The following substituent group A: 【Chemistry 2】 A group selected from (In the formula, The wavy line is the C ６ -C １０ Aryl, 5-10 membered heteroaryl or C １ -C ６ represents the point of attachment to the alkyl, R ５ is hydroxy, C １ -C ６ Alkoxy, mono or di C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino, n is 1 or 2; R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl (5-10 membered heteroaryl C １ -C ６ (alkyl)amino, optionally substituted C １ -C ６ is selected from the group consisting of alkyl(4- to 10-membered heterocyclyl)amino and optionally substituted 4- to 8-membered cyclic amino. or a salt thereof, or a solvate thereof.

2. X ｂ１ CH ２ And X ｂ２ CH ２ , O, NH or C═O, and X ｂ３ CH ２ , O, NH, S or C=O, or a salt thereof, or a solvate thereof, according to claim 1 .

3. X ｂ１ and X ｂ２ CH ２ And X ｂ３ is O or X ｂ１ and X ｂ３ CH ２ And X ｂ２ is O or X ｂ１ and X ｂ２ CH ２ And X ｂ３ is S or X ｂ１ CH ２ And X ｂ２ is NH, and X ｂ３ is C=O or X ｂ１ and X ｂ２ CH ２ And X ｂ３ is NH or X ｂ１ CH ２ And X ｂ２ is C=O, and X ｂ３ is NH or X ｂ１ and X ｂ３ CH ２ And X ｂ２ is NH or X ｂ１ , X ｂ２ and X ｂ３ CH ２ The compound according to claim 1 , or a salt thereof, or a solvate thereof.

4. X ａ１ is CR ａ１ And X ａ３ is CR ａ３ or N, or a salt thereof, or a solvate thereof, according to claim 1 .

5. Z is phenyl, pyridyl or C ２ -C ５ alkyl, and the phenyl, pyridyl and C ２ -C ５ Alkyl is R ｚ３ and R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ and optionally substituted with one or more groups selected from the group consisting of R ｚ３ The following substituent group B: 【Chemistry 3】 A group selected from (In the formula, The wavy line indicates the phenyl, pyridyl or C ２ -C ５ represents the point of attachment to the alkyl, R ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino, R ｚ１ , R ｚ２ , R ｚ４ and R ｚ５ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkyl (5-10 membered heteroaryl C １ -C ６ (alkyl)amino, optionally substituted C １ -C ６ is selected from the group consisting of alkyl(4- to 10-membered heterocyclyl)amino and optionally substituted 4- to 8-membered cyclic amino. That is, 2. The compound according to claim 1, or a salt thereof, or a solvate thereof.

6. R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, or C １ -C ６ is selected from the group consisting of alkyl, R ｚ４ C which may have a substituent １ -C ６ Alkyl (5-10 membered heteroaryl C １ -C ２ (alkyl)amino, optionally substituted C １ -C ６ alkyl(4- to 10-membered heterocyclyl)amino or optionally substituted 4- to 8-membered cyclic amino.

2. The compound according to claim 1, or a salt thereof, or a solvate thereof.

7. Y is phenyl or 6- to 10-membered heteroaryl, and the phenyl and 6- to 10-membered heteroaryl are R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ and optionally substituted with one or more groups selected from the group consisting of The R ｙ１ , R ｙ２ , R ｙ３ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl, C １ -C ３ Alkoxy, 5-6 membered heterocyclyl C １ -C ４ Alkoxy, Hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl group optionally having a substituent, and C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ (alkyl)amino; 2. The compound according to claim 1, or a salt thereof, or a solvate thereof.

8. Y is phenyl or 6- to 10-membered heteroaryl, and the phenyl and 6- to 10-membered heteroaryl are R ｙ３ is substituted with a group other than hydrogen, and R ｙ１ , R ｙ２ , R ｙ４ and R ｙ５ and optionally substituted with one or more groups selected from the group consisting of The R ｙ１ , R ｙ２ , R ｙ４ and R ｙ５ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy; The R ｙ３ 5-6 membered heterocyclyl C １ -C ４ Alkoxy, Hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl group optionally having a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ alkyl)amino; 2. The compound according to claim 1, or a salt thereof, or a solvate thereof.

9. Z is the following formula (2): 【Chemistry 4】 [In the formula, The wavy line represents the attachment point of Z. R ｚ３ The following substituent group B: 【Chemistry 5】 A group selected from (In the formula, The wavy lines represent the attachment points. R ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino. X ｚ is CR ｚ５ or N, R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, or C １ -C ６ is selected from the group consisting of alkyl, R ｚ４ C which may have a substituent １ -C ６ Alkyl (5-10 membered heteroaryl C １ -C ２ (alkyl)amino, optionally substituted C １ -C ６ alkyl(4- to 10-membered heterocyclyl)amino or an optionally substituted 4- to 8-membered cyclic amino. is a group represented by 2. The compound according to claim 1, or a salt thereof, or a solvate thereof.

10. Y is the following formula (3): 【Chemistry 6】 [In the formula, The wavy line represents the attachment point of Y. X ｙ１ is CR ｙ３ or N, X ｙ２ is CR ｙ４ or N, X ｙ３ is CR ｙ５ or N, R ｙ１ and R ｙ５ are each independently hydrogen, halogen, cyano, or C １ -C ３ is selected from the group consisting of alkyl, R ｙ２ and R ｙ４ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy; R ｙ３ 5-6 membered heterocyclyl C １ -C ４ Alkoxy, Hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl group optionally having a substituent, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ alkyl)amino, X ｙ１ is CR ｙ３ If R ｙ２ and R ｙ３ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring, X ｙ１ is CR ｙ３ And X ｙ２ is CR ｙ４ If R ｙ３ and R ｙ４ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring, X ｙ２ is CR ｙ４ And X ｙ３ is CR ｙ５ If R ｙ４ and R ｙ５ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring. is a group represented by 2. The compound according to claim 1, or a salt thereof, or a solvate thereof.

11. Formula (4): 【Chemistry 7】 [In the formula, X ａ３ is CR ａ３ or N, R ａ１ , R ａ２、 and R ａ３ are each independently hydrogen, halogen, or C １ -C ６ alkoxy; X ｂ１ and X ｂ２ CH ２ And X ｂ３ is O or X ｂ１ and X ｂ３ CH ２ And X ｂ２ is O or X ｂ１ and X ｂ２ CH ２ And X ｂ３ is S or X ｂ１ CH ２ And X ｂ２ is NH, and X ｂ３ is C=O or X ｂ１ and X ｂ２ CH ２ And X ｂ３ is NH or X ｂ１ CH ２ And X ｂ２ is C=O, and X ｂ３ is NH or X ｂ１ and X ｂ３ CH ２ And X ｂ２ is NH or X ｂ１ , X ｂ２ and X ｂ３ CH ２ and X ｙ１ is CR ｙ３ or N, X ｙ２ is CR ｙ４ or N, X ｙ３ is CR ｙ５ or N, R ｙ１ and R ｙ５ are each independently hydrogen, halogen, cyano, or C １ -C ３ is selected from the group consisting of alkyl, R ｙ２ and R ｙ４ are each independently hydrogen, halogen, cyano, C １ -C ３ Alkyl, C ２ -C ４ Alkenyl, C ３ -C ６ Cycloalkyl and C １ -C ３ alkoxy; R ｙ３ 5-6 membered heterocyclyl C １ -C ４ Alkoxy, Hydroxy C ３ -C ６ Alkoxy, 5-6 membered heterocyclyloxy, C １ -C ３ Alkoxy, C １ -C ４ Alkylamino C １ -C ３ Alkoxy, 5-6 membered heteroaryloxy, C １ -C ４ alkylthio, a 5- to 6-membered saturated heterocyclic ring having a bond to a carbon atom on the ring and optionally having a substituent, a 4- to 10-membered saturated heterocyclic ring having a bond to a nitrogen atom on the ring and optionally having a substituent, a 5- to 10-membered heteroaryl group having an optionally substituted group, or C １ -C ３ Alkyl (C １ -C ３ Alkoxy C １ -C ２ is selected from the group consisting of aryl, arylalkyl, arylamino, X ｙ１ is CR ｙ３ If R ｙ２ and R ｙ３ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring, X ｙ１ is CR ｙ３ And X ｙ２ is CR ｙ４ If R ｙ３ and R ｙ４ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring, X ｙ２ is CR ｙ４ And X ｙ３ is CR ｙ５ If R ｙ４ and R ｙ５ may be taken together with the carbon atom to which it is attached to form a 5- or 6-membered heteroaryl ring, R ｚ３ The following substituent group B: 【Chemistry 8】 (In the formula, The wavy line indicates the R ｚ３ and R ｚ３ represents the point of attachment to the ring to which it is attached, R ５ is hydroxy, C １ -C ６ Alkoxy, Mono C １ -C ６ Alkylamino or C １ -C ６ alkylsulfonylamino. X ｚ is CR ｚ５ or N, R ｚ１ , R ｚ２ and R ｚ５ are each independently hydrogen, halogen, or C １ -C ６ is selected from the group consisting of alkyl, R ｚ４ C which may have a substituent １ -C ６ Alkyl (5-10 membered heteroaryl C １ -C ２ (alkyl)amino, optionally substituted C １ -C ６ alkyl(4- to 10-membered heterocyclyl)amino or an optionally substituted 4- to 8-membered cyclic amino. is a group represented by 2. The compound according to claim 1, or a salt thereof, or a solvate thereof.

12. X ｂ１ and X ｂ２ CH ２ And X ｂ３ The compound according to claim 1 , or a salt thereof, or a solvate thereof, wherein

13. R ５ is hydroxy or C １ -C ６ The compound according to claim 1, which is alkylsulfonylamino, or a salt thereof, or a solvate thereof.

14. X ｚ is CR ｚ５ and R ｚ１ , R ｚ２ and R ｚ５ The compound according to claim 1, or a salt thereof, or a solvate thereof, wherein each of is independently selected from the group consisting of hydrogen, fluorine, chlorine, methyl and ethyl.

15. R ｚ４ is hydrogen, halogen, C １ -C ６ Alkyl and C １ -C ６ or a 4- to 6-membered cyclic amino group which may have one or more substituents selected from the group consisting of alkoxy; １ -C ２ Alkylene and C containing one oxygen atom １ -C ２ The compound according to claim 1, which is a 4- to 6-membered cyclic amino having a bridging group selected from the group consisting of alkylene, or a salt thereof, or a solvate thereof.

16. R ｚ４ is hydrogen, halogen and C １ -C ６ C, which may have a substituent selected from the group consisting of alkyl １ -C ３ Alkyl (5-6 membered heteroaryl C １ -C ２ alkyl)amino or hydrogen, halogen and C １ -C ６ C, which may have a substituent selected from the group consisting of alkyl １ -C ３ The compound according to claim 1, which is alkyl(4- to 6-membered heterocyclyl)amino, or a salt thereof, or a solvate thereof.

17. R ｙ１ is chlorine, and X ｙ１ is CR ｙ３ And X ｙ２ is CR ｙ４ And X ｙ３ is CR ｙ５ and R ｙ３ is a 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, or a 5- to 10-membered heteroaryl having an optionally having a substituent, and R ｙ２ , R ｙ４ and R ｙ５ The compound according to claim 1 , or a salt thereof, or a solvate thereof, wherein is hydrogen.

18. R ａ１ is hydrogen or fluorine, R ａ２ is hydrogen or methoxy, and R ａ３ The compound according to claim 1 , or a salt thereof, or a solvate thereof, wherein is hydrogen or fluorine.

19. R ｚ４ is 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, morpholin-4-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, (2S,3S)-3-methoxy-2-methylazetidin-1-yl, 1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl, 4,4-difluoropiperidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, methyl(1,2-oxazol-3-ylmethyl)amino, methyl(oxetan-3-yl)amino, methyl-[(3R)-oxolan-3-yl]amino or methyl-(3-methyloxetan-3-yl)amino, or a salt thereof, or a solvate thereof according to claim 1.

20. R ｙ３ is 1-methylpyrazol-4-yl, 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl, 4-methylpiperazin-1-yl, (2R)-2,4-dimethylpiperazin-1-yl, 6-methoxy-2-azaspiro[3.3]heptan-2-yl, 4-(2-methoxyethyl)piperazin-1-yl, 3-methoxyazetidin-1-yl, 4-(oxetan-3-yl)piperazin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, (2R,5R)-2,4,5-trimethylpiperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl or morpholin-4-yl, or a salt thereof or a solvate thereof according to claim 1.

21. A compound selected from the following compounds, or a salt thereof, or a solvate thereof: 4-[3-[2,6-dichloro-4-[(2R,3R)-3-methoxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[6-(difluoromethoxy)-2-azaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxypyridin-3-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(4-ethylpiperazin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7-methyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azadispiro[3.1.56.14]dodecan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(3,3-dimethoxyazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-[6-(2,2-difluoroethyl)-2,6-diazaspiro[3.3]heptan-2-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-ylbenzoic acid, 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, and 4-[3-[5-chloro-7-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)-2,3-dimethylbenzimidazole-4-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

22. 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

23. 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

24. A salt of 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

25. A solvate of 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

26. 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

27. 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

28. A salt of 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

29. A solvate of 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

30. 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

31. 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

32. A salt of 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

33. A solvate of 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

34. 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

35. 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

36. A salt of 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

37. A solvate of 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

38. 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid or a salt thereof, or a solvate thereof.

39. 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

40. A salt of 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

41. A solvate of 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.

42. A pharmaceutical composition comprising the compound according to any one of claims 1 to 41, or a salt thereof, or a solvate thereof.

43. A pharmaceutical composition comprising as an active ingredient the compound or a salt thereof, or a solvate of either of claims 1 to 41.

44. 43. The pharmaceutical composition according to claim 42 for the prevention and / or treatment of a neurodegenerative disease, a pulmonary disease or a renal disease.

45. Use of the compound according to any one of claims 1 to 41, or a salt thereof, or a solvate thereof, for the manufacture of a pharmaceutical composition for the prevention and / or treatment of a neurodegenerative disease, a pulmonary disease, or a renal disease.

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