Classifications

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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/08—Bridged systems
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
  • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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  • C07D237/30—Phthalazines
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  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to a nitrogen-containing heterocyclic compound having an Nrf2 activating action, a salt thereof, or a solvate thereof, and uses thereof. It also relates to medicaments and pharmaceutical compositions containing them as active ingredients.
• Nrf2 is a regulatory factor for a group of 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 by the proteasome pathway, but under stress conditions, it releases from Keap1 to avoid degradation and translocates into the nucleus. After that, Nrf2 forms a heterodimer with small Maf group factors and binds to antioxidant response elements (AREs) to induce transcription of downstream molecules.
• AREs antioxidant response elements
• Nrf2 activation exhibits a wide range of pharmacological effects such as anti-inflammatory, anti-fibrotic, and anti-apoptotic effects, and is thought to act protectively against various diseases.
• neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis, and pulmonary diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, Chronic Obstructive Pulmonary Disease, Pulmonary Arterial Hypertension, Asthma, Chronic Kidney Disease and Acute Renal Injury in Kidney Disease, Uveitis in Ophthalmic Disease, Glaucoma, Age-Related Macular Degeneration, Nonalcoholic Steatohepatitis in Liver Disease, Immunity - Inflammatory diseases include multiple sclerosis, rheumatoid arthritis, ulcerative colitis and the like (Non-Patent Documents 3 to 7).
• Bardoxolone methyl (CDDO-Me, Patent Document 1) is for various chronic kidney diseases, and RTA-408 (omaveloxolone, Patent Document 2) is Friedreich. Clinical trials are being conducted for ataxia and the like. Dimethyl fumarate (Patent Document 3) is used as a therapeutic agent for multiple sclerosis. However, these compounds are compounds that covalently bind to Keap1. Concerns about the risk of heart failure due to interaction of the covalent binding site of bardoxolone methyl with non-target proteins have been reported (Non-Patent Document 8).
• Non-Patent Documents 1 to 3 the compounds described in Patent Document 4 have been reported as Nrf2 activators. However, clinical development has not yet been achieved, and the development of non-covalent Nrf2 activators expected to reduce interactions with non-target proteins is desired (Non-Patent Documents 1 to 3). .
• 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 has reduced interaction with non-target proteins due to covalent bonding.
• Another object of the present invention is to provide prophylactic or therapeutic agents for various diseases, such as neurodegenerative diseases, pulmonary diseases and renal diseases, containing them as active ingredients.
• the present inventors have made intensive studies in order to solve such problems, and found that a compound having a basic skeleton represented by formula (I), which has a chemical structure significantly different from that of known Nrf2 activators, or its pharmacology
• the inventors have found that a pharmaceutically acceptable salt or a solvate thereof has an excellent Nrf2 activating action, and have completed the present invention.
• X a1 is CR a1 or N
• X a3 is CR a3 or N
• R a1 , R a2 and R a3 are each independently selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkoxy
• X b1 , X b2 and X b3 are each independently selected from the group consisting of CH 2 , O, NH, S and C ⁇ O
• Y is C 6 -C 10 aryl or 5-10 membered heteroaryl, said C 6 -C 10 aryl and 5-10 membered heteroaryl consisting of R y1 , R y2 , R y3 , R y4 and R y5 optionally substituted with one or more groups selected from the group Said R y1 , R y2 , R y3 , R y4 and R y5 are each
• R z1 , R z2 and R z5 are each independently selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkyl; R z4 is optionally substituted C 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, The compound according to any one of [1] to [5], a salt thereof, or a solvate thereof.
• Y is phenyl or 6- to 10-membered heteroaryl, wherein said phenyl and 6- to 10-membered heteroaryl are one or more groups selected from the group consisting of R y1 , R y2 , R y3 , R y4 and R y5 may be replaced with 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 4 alkylamino C 1 -C 3 alkoxy, 5- 6-membered heteroaryloxy, C 1 -C 4 alkylthio, 5- to 6-membere
• Y is phenyl or 6- to 10-membered heteroaryl, wherein said phenyl and 6- to 10-membered heteroaryl are groups consisting of R y1 , R y2 , R y4 and R y5 wherein R y3 is substituted with a group other than hydrogen; optionally substituted with one or more groups selected from 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 - is selected from the group consisting of C3 alkoxy, R y3 is 5- to 6-membered heterocyclyl C 1 -C 4 alkoxy, hydroxy C 3 -C 6 alkoxy, 5- to 6-membered heterocyclyloxy, C 1 -C 3 alkoxy, C 1 -C 4 alkylamino C 1 -C 3- al
• Z is the following formula (2): [In the formula, The dashed line represents the point of attachment of Z, R z3 is the following Substituent Group B: A group selected from (wherein The wavy line represents the point of attachment, 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 selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkyl;
• R z4 is optionally substituted C 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.
• ] is a group represented by The compound according to any one of [1] to [8], a salt thereof, or a solvate thereof.
• Y is the following formula (3): [In the formula, The wavy line represents the point of attachment 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 selected from the group consisting of hydrogen, halogen, cyano and C 1 -C 3 alkyl; R y2 and R y4 are each independently 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 selected, R y3 is 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
• X a3 is CR a3 or N; R a1 , R a2 and R a3 are each independently selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkoxy; X b1 and X b2 are CH2 and X b3 is O, or X b1 and X b3 are CH2 and X b2 is O, or X b1 and X b2 are CH2 and X b3 is S, or X b1 is CH2 , X b2 is NH and X b3 is C ⁇ O, or X b1 and X b2 are CH2 and X b3 is NH, or X b1 is CH2 , X b2 is C ⁇ O, X b3 is
• X z is CR z5 or N;
• R z1 , R z2 and R z5 are each independently selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkyl;
• R z4 is optionally substituted C 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.
• ] is a group represented by [1] The compound according to any one of [1] to [10], a salt thereof, or a solvate thereof.
• R z4 is a 4- to 6-membered cyclic amino optionally having one or more substituents selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; any one of [ 1 ] to [14], which is a 4- to 6-membered cyclic amino having a bridging group selected from the group consisting of C 1 -C 2 alkylene and C 1 -C 2 alkylene containing one oxygen atom in The compound or its salt or those solvates as described in .
• C 1 -C 3 alkyl(5- to 6-membered heteroarylC 1 -C 2 alkyl)amino optionally having substituent(s) selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkyl in which R z4 is [ 1 ] - [ 14], a compound or a salt thereof, or a solvate thereof.
• R y1 is chlorine
• X y1 is CR y3
• X y2 is CR y4
• X y3 is CR y5
• R y3 has a bond to a nitrogen atom on the ring and has a substituent; [ 1 ] to [ 16], a compound or a salt thereof, or a solvate thereof.
• 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 any one of [1] to [18
• 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-methoxyazetidine- 1-yl, 4-(oxetan-3-yl)piperazin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, (2R,5R)-2,4,5-trimethyl
• the compound or salt thereof according to any one of [1] to [19], which is piperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl or morpholin-4-yl, or solvates thereof.
• a compound or a salt or solvate thereof selected from the following compounds: compound 1-4, compound 1-18, compound 1-21, compound 1-33, compound 1-54, compound 1-83, compound 1-88, compound 2-2, compound 4-8, compound 4-37, compound 5-1, compound 5-2, compound 5-7, compound 5-9, compound 5-10, compound 5-16, compound 7-2, compound 13-16, compound 13-21, compound 14-1, Compound 19-9, and Compound 19-15.
• a pharmaceutical composition comprising the compound of any one of [1] to [22], a salt thereof, or a solvate thereof.
• the pharmaceutical composition of [23] for prevention and/or treatment of neurodegenerative disease, pulmonary disease, or renal disease.
• [25] Preventing neurodegenerative disease, lung disease, or renal disease and/or comprising administering an effective amount of the compound according to any one of [1] to [22] or a salt thereof or a solvate thereof to a subject Method of treatment.
• the compound according to the present invention or a pharmacologically acceptable salt thereof or a solvate thereof has an Nrf2 activating action and is a prophylactic or therapeutic agent for various diseases such as neurodegenerative diseases, pulmonary diseases and renal diseases. is provided.
• Halogen in the present specification is exemplified by F, Cl, Br or I.
• alkyl refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and refers to heteroatoms (atoms other than carbon and hydrogen atoms) in the skeleton. ) or a subset of hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms without containing unsaturated carbon-carbon bonds. Alkyl includes not only straight chain but also branched chain.
• the alkyl is preferably alkyl having 1 to 20 carbon atoms (C 1 -C 20 , hereinafter “C p -C q ” means having p to q carbon atoms), more preferably C 1 -C 10 alkyl, more preferably C 1 -C 6 alkyl.
• alkenyl refers to monovalent radicals having at least one double bond (two adjacent sp 2 carbon atoms). Depending on the configuration of the double bond and substituents (if any), the geometry of the double bond can be
• E E
• Z cis or trans configuration.
• Alkenyl includes not only straight-chain but also branched ones. Alkenyl preferably includes C 2 -C 10 alkenyl, more preferably C 2 -C 6 alkenyl.
• alkynyl refers to monovalent radicals having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight chain but also branched ones. Alkynyl preferably includes C 2 -C 10 alkynyl, more preferably C 2 -C 6 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, 3-methyl-(5-phenyl)-4-pentynyl and the like.
• cycloalkyl means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclocyclic and spirocyclic rings. Cycloalkyl preferably includes C 3 -C 8 cycloalkyl. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl and the like.
• cycloalkylalkyl means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with “cycloalkyl” defined above.
• Cycloalkylalkyl is preferably C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, more preferably C 3 -C 6 cycloalkyl C 1 -C 2 alkyl.
• Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
• aminoalkyl means a group in which one or more hydrogens of "alkyl” as defined above are replaced with “amino” as defined below.
• aminoalkyl amino C 1 -C 6 alkyl is preferred.
• Specific examples of aminoalkyl include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, 4-aminobutyl and the like.
• protected aminoalkyl means a group in which the amino group included in the above-defined “aminoalkyl” is protected with any protecting group.
• amino-protecting groups include Fmoc, Boc, Cbz, Alloc, Teoc, trifluoroacetyl, pentafluoropropionyl, phthaloyl, tosyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4-di nitrobenzenesulfonyl and the like.
• hydroxyalkyl means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with hydroxyl groups. Hydroxyalkyl preferably includes hydroxyC 1 -C 6 alkyl. Specific examples of hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 5-hydroxypentyl and the like.
• haloalkyl means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with halogen.
• Haloalkyl is preferably haloC 1 -C 6 alkyl, more preferably C 1 -C 6 fluoroalkyl.
• Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5 - difluoropentyl and the like.
• Carboxyalkyl means a group in which one or more hydrogens of "alkyl” as defined above are replaced with carboxy.
• Carboxyalkyl preferably includes carboxyC 1 -C 6 alkyl. Specific examples of carboxyalkyl include carboxymethyl and the like.
• aryl means a monovalent aromatic hydrocarbon ring and an aromatic hydrocarbon ring group.
• Aryl preferably includes C 6 -C 10 aryl. Specific examples include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl) and the like.
• heterocyclyl means a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms.
• a heterocyclyl may have double and or triple bonds in the ring, a carbon atom in the ring may be oxidized to form a carbonyl, and may be single or fused rings.
• a condensed ring a condensed ring may be formed with an aromatic ring such as a benzene ring, a pyridine ring, or a pyrimidine ring.
• a condensed ring may be formed with a saturated alicyclic ring such as a cyclopentane ring or cyclohexane ring, 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 4-10 (4- to 10-membered heterocyclyl), more preferably 4-7 (4- to 7-membered heterocyclyl).
• heterocyclyl examples 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, benzo oxazoly
• heteroaryl means an aromatic cyclic monovalent group and an aromatic heterocyclic group containing 1 to 5 heteroatoms in addition to carbon atoms.
• the ring may be monocyclic, condensed with another ring, or partially saturated.
• the number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5- to 10-membered heteroaryl), more preferably 5 to 7 (5- to 7-membered heteroaryl).
• heteroaryl examples 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,
• aralkyl (arylalkyl) means a group in which at least one hydrogen atom of "alkyl” defined above is replaced with “aryl” defined above.
• Aralkyl is preferably C 7 -C 14 aralkyl, more preferably C 7 -C 10 aralkyl. Specific examples of aralkyl include benzyl, phenethyl, 3-phenylpropyl and the like.
• heteroarylalkyl means a group in which at least one hydrogen atom of "alkyl” defined above is replaced with “heteroaryl” defined above.
• the heteroarylalkyl is preferably a 5- to 10-membered heteroaryl C 1 -C 6 alkyl, more preferably a 5- to 10-membered heteroaryl C 1 -C 2 alkyl.
• heteroarylalkyl examples 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, 2- (5-benzofuranyl)ethyl and the like.
• heterocyclylalkyl means a group in which one or more hydrogen atoms of "alkyl” as defined above are replaced with “heterocyclyl” as defined above.
• the heterocyclylalkyl is preferably 4- to 7-membered heterocyclyl C 1 -C 6 alkyl, more preferably 4- to 7-membered heterocyclyl C 1 -C 2 alkyl.
• Specific examples of heterocyclylalkyl include 2-(tetrahydro-2H-pyran-4-yl)ethyl, 2-(azetidin-3-yl)ethyl, 4-(oxolan-2-ylmethyl)piperazin-1-yl etc.
• a “saturated heterocyclic group” as used herein means a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms.
• a saturated heterocyclic group may have double and/or triple bonds in the ring and a carbon atom in the ring may be optionally oxidized to form a carbonyl.
• the saturated heterocyclic group may be monocyclic, and other rings such as aromatic rings such as benzene ring, pyridine ring and pyrimidine ring, saturated alicyclic rings such as cyclopentane ring and cyclohexane ring, tetrahydropyran ring and dioxane ring.
• the saturated heterocyclic group preferably includes a 4- to 10-membered saturated heterocyclic group.
• saturated heterocyclic groups include azetidinyl, oxoazetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 4-oxopyrrolidinyl, piperidinyl, 4-oxopiperidinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, oxazolidonyl, dioxolanyl, di
• alkoxy means an oxy group to which the above-defined “alkyl” is attached.
• Alkoxy preferably includes C 1 -C 6 alkoxy. Specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, 3-methylbutoxy and the like.
• haloalkoxy means a group in which one or more hydrogen atoms in "alkoxy” defined above are replaced with halogen.
• Haloalkoxy is preferably C 1 -C 6 haloalkoxy, more preferably C 1 -C 6 fluoroalkoxy.
• Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and the like.
• cycloalkoxy means an oxy group to which the above-defined “cycloalkyl” is attached. Cycloalkoxy preferably includes C 3 -C 8 cycloalkoxy. Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, cyclopentyloxy and the like.
• Alkoxyalkyl as used herein means a group in which one or more hydrogen atoms of "alkyl” as defined above are replaced with “alkoxy” as defined above.
• Alkoxyalkyl is preferably C 1 -C 6 alkoxyC 1 -C 6 alkyl, more preferably C 1 -C 6 alkoxyC 1 -C 2 alkyl.
• alkoxyalkyl examples include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and the like.
• cycloalkoxyalkyl means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with “cycloalkoxy” defined above.
• Cycloalkoxyalkyl is preferably C 3 -C 8 cycloalkoxy C 1 -C 6 alkyl, more preferably C 3 -C 6 cycloalkoxy C 1 -C 2 alkyl.
• Specific examples of cycloalkoxyalkyl include cyclopropoxymethyl, cyclobutoxymethyl and the like.
• aryloxy means an oxy group to which the above-defined "aryl” is attached.
• Aryloxy preferably includes C 6 -C 10 aryloxy.
• Specific examples of aryloxy include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
• heterocyclyloxy means an oxy group to which the above-defined “heterocyclyl” is attached.
• the number of atoms constituting the ring of heterocyclyloxy is preferably 4-10 (4- to 10-membered heterocyclyloxy), more preferably 4-7 (4- to 7-membered heterocyclyloxy).
• heterocyclyloxy examples include azetidinyloxy, oxiranyloxy, oxetanyloxy, azetidinyloxy, dihydrofuryloxy, tetrahydrofuryloxy, dihydropyranyloxy, tetrahydropyranyloxy, tetrahydropyridyloxy , tetrahydropyrimidyloxy, morpholinyloxy, thiomorpholinyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, pyrazolidinyloxy, imidazolinyloxy, imidazolidinyloxy, oxa zolidinyloxy, isoxazolidinyloxy, thiazolidinyloxy, isothiazolidinyloxy, 1,2-thiazinanoxy, thiadiazolidinyloxy, oxazolidonoxy, benzodioxanyloxy, benzoxazo
• heteroaryloxy means an oxy group to which "heteroaryl” defined above is bonded.
• the number of atoms constituting the ring of heteroaryloxy is preferably 5 to 10 (5- to 10-membered heteroaryloxy), more preferably 5 to 7 (5- to 7-membered heteroaryloxy).
• heteroaryloxy examples include furyloxy, thienyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, thiazolyloxy, isothiazolyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thiadiazolyl oxy, triazolyloxy, tetrazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinyloxy, pyrazinyloxy, triazinyloxy, benzofuranyloxy, benzothienyloxy, benzothiadiazolyloxy, benzothiazolyloxy , benzoxazolyloxy, benzoxadiazolyloxy, benzimidazolyloxy, indolyloxy, isoindolyloxy, indazolyloxy, quinolyloxy, isoquinolyloxy, cinnolinyloxy, quinazoliny
• aralkoxy means an oxy group to which the above-defined “aralkyl” is attached.
• aralkoxy C 7 -C 14 aralkoxy is preferred, and C 7 -C 10 aralkoxy is more preferred.
• Specific examples of aralkoxy include benzyloxy, phenethyloxy, 3-phenylpropoxy and the like.
• heteroarylalkoxy means an oxy group to which the above-defined “heteroarylalkyl” is attached.
• heteroarylalkoxy 5- to 10-membered heteroaryl C 1 -C 6 alkoxy is preferred, and 5- to 10-membered heteroaryl C 1 -C 2 alkoxy is more preferred.
• Specific examples of heteroarylalkoxy include 3-thienylmethoxy and 3-pyridylmethoxy.
• Aralkoxyalkyl as used herein means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with “aralkoxy” defined above.
• Aralkoxyalkyl is preferably C 7 -C 14 aralkoxyC 1 -C 6 alkyl, more preferably C 7 -C 14 aralkoxyC 1 -C 2 alkyl.
• Specific examples of aralkoxyalkyl include benzyloxymethyl, 1-(benzyloxy)ethyl and the like.
• heteroarylalkoxyalkyl means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with “heteroarylalkoxy” defined above.
• heteroarylalkoxyalkyl 5- to 10-membered heteroaryl C 1 -C 6 alkoxyC 1 -C 6 alkyl is preferred, and 5- to 10-membered heteroaryl C 1 -C 2 alkoxyC 1 -C 2 alkyl is more preferred.
• Specific examples of heteroarylalkoxyalkyl include 3-pyridylmethoxymethyl and the like.
• heterocyclylalkoxy means an oxy group in which "alkyl” is bonded to "heterocyclyl” as defined above.
• the number of atoms constituting the heterocyclyl ring is preferably 4-10 (4- to 10-membered heterocyclyl), more preferably 4-7 (4- to 7-membered heterocyclyl), and alkyl is C 1 -C 6 alkyl. is preferred, more preferably C 1 -C 4 alkyl.
• Preferred heterocyclylalkoxy are 4-10 membered heterocyclyl C 1 -C 6 alkoxy, more preferably 4-7 membered heterocyclyl C 1 -C 2 alkoxy.
• heterocyclylalkoxy examples include oxolan-2-ylmethoxy, oxolan-3-ylmethoxy, oxan-4-ylmethoxy, 1,4-dioxan-2-ylmethoxy, (1-methylpiperidin-4-yl)methoxy, 3 -morpholin-4-ylpropoxy and the like.
• hydroxyalkoxy means a group in which "hydroxy” is bonded to "alkoxy" as defined above. Hydroxyalkoxy is preferably hydroxy C 2 -C 6 alkoxy, more preferably hydroxy C 3 -C 6 alkoxy. Hydroxyalkoxy specifically includes 3-hydroxy-3-methylbutoxy, 4-hydroxybutoxy and the like.
• alkoxyalkoxy means a group in which "alkoxy” is bonded to "alkoxy" as defined above.
• Alkoxyalkoxy is preferably C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, more preferably C 1 -C 3 alkoxy, C 1 -C 2 alkoxy.
• Alkoxyalkoxy specifically includes 2-methoxyethoxy and the like.
• alkylaminoalkoxy means a group in which "alkylamino” is bonded to "alkoxy" as defined above.
• Alkylaminoalkoxy is preferably bis(C 1 -C 6 alkyl)amino C 1 -C 6 alkoxy, more preferably bis(C 1 -C 4 alkyl)amino C 1 -C 3 alkoxy.
• Alkylaminoalkoxy specifically includes 2-(dimethylamino)ethoxy and the like.
• Aryloxyalkyl as used herein means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with “aryloxy” defined above.
• aryloxyalkyl C 6 -C 10 aryloxy C 1 -C 6 alkyl is preferred, and C 6 -C 10 aryloxy C 1 -C 2 alkyl is more preferred.
• Specific examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.
• amino means narrowly -NH2 and broadly -NRR', where R and R' are independently hydrogen, alkyl, alkenyl, alkynyl, cyclo is selected from alkyl, heterocyclyl, aryl, or heteroaryl, or R and R' together with the nitrogen atom to which they are attached form a ring.
• Preferred amino groups include -NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, 4- to 8-membered cyclic amino and the like.
• monoalkylamino means a group of "amino” as defined above, wherein R is hydrogen and R' is “alkyl” as defined above.
• Monoalkylamino preferably includes mono C 1 -C 6 alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino and t-butylamino.
• dialkylamino means a group of “amino” as defined above in which R and R' are independently “alkyl” as defined above. Dialkylamino preferably includes di-C 1 -C 6 alkylamino. Specific examples of dialkylamino include dimethylamino and diethylamino.
• Cyclic amino as used herein means 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". Cyclic amino preferably includes 4- to 8-membered cyclic amino. Specific examples of 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.
• aminocarbonyl means a carbonyl group to which "amino" as defined above is attached.
• Aminocarbonyl preferably includes —CONH 2 , mono-C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, 4- to 8-membered cyclic aminocarbonyl.
• aminocarbonyl examples include —CONH 2 , dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholylcarbonyl, nylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl and the like. be done.
• aminocarbonylalkyl as used herein means a group in which one or more hydrogen atoms of "alkyl” as defined above are replaced with “aminocarbonyl” as defined above.
• the aminocarbonylalkyl is preferably aminocarbonyl C 1 -C 6 alkyl, more preferably aminocarbonyl C 1 -C 4 alkyl.
• aminocarbonylalkyl examples include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonyl methyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl) ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, 4-(dimethylaminocarbonyl)butyl and the like.
• alkylsulfonyl means a sulfonyl group to which "alkyl” as defined above is attached.
• Alkylsulfonyl preferably includes C 1 -C 6 alkylsulfonyl. Specific examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl and the like.
• alkylsulfonylamino means a group in which sulfonyl is attached to "amino" as defined above. Preferred are C 1 -C 6 alkylsulfonyl-NH-, (C 1 -C 6 alkylsulfonyl-) 2 N-, and the like. Specific examples of aminoalkylsulfonyl include methylsulfonylamino, ethylsulfonylamino, bis(methylsulfonyl)amino, bis(ethylsulfonyl)amino and the like.
• alkylsulfonylalkyl means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with “alkylsulfonyl” defined above.
• the alkylsulfonylalkyl is preferably C 1 -C 6 alkylsulfonyl C 1 -C 6 alkyl, more preferably C 1 -C 6 alkylsulfonyl C 1 -C 2 alkyl.
• Specific examples of alkylsulfonylalkyl include methylsulfonylmethyl, 2-(methylsulfonyl)ethyl and the like.
• alkylthio means a thio group to which the above-defined “alkyl” is attached, preferably C 1 -C 6 alkylthio.
• alkylthio include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, i-butylthio, s-butylthio and t-butylthio.
• acyl alkanoyl
• acyl means a group in which a carbonyl group is bonded to hydrogen or the above “alkyl”.
• Acyl preferably includes C 1 -C 6 acyl, more preferably C 2 -C 4 acyl.
• Specific examples of acyl include formyl, acetyl, propionyl, butanoyl and the like.
• haloacyl haloalkanoyl
• haloacyl means a group in which the above “haloalkyl” is bonded to a carbonyl group.
• Haloacyl preferably includes C 2 -C 6 haloacyl, more preferably C 2 -C 4 haloacyl.
• Specific examples of haloacyl include trifluoroacetyl, trichloroacetyl, pentafluoropropionyl, 2,3,3,3-tetrafluoro-2-(trifluoromethyl)propionyl, 3,3,3-trifluoro-2- Examples include (trifluoromethyl)propionyl.
• alkylene means a divalent group derived from the above “alkyl” by further removing one hydrogen atom, preferably C 1 -C 8 alkylene, C 4 -C 8 Alkylene is more preferred.
• alkylene include -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 -, -(CH 2 ) 4- , -CH ( CH3 ) CH2CH2- , -C ( CH3 ) 2CH2- , -CH2CH ( CH3 ) CH2- , -CH2C ( CH3 ) 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 -, -
• arylene means a divalent group derived from the above “aryl” by further removing one hydrogen atom.
• Arylene may be monocyclic or condensed. Although the number of atoms constituting the arylene ring is not particularly limited, it 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.
• Aromatic hydrocarbon ring as used herein means a hydrocarbon ring composed of a single ring or a condensed ring exhibiting aromaticity.
• the aromatic hydrocarbon ring preferably includes a 6- to 10-membered aromatic hydrocarbon ring.
• Specific examples of aromatic hydrocarbon rings include benzene rings and naphthalene rings.
• Heteroaromatic ring as used herein means a cyclic compound composed of a single ring or a condensed ring exhibiting aromaticity and containing one or more heteroatoms.
• the aromatic heterocycle preferably includes a 5- to 10-membered aromatic heterocycle.
• Specific examples of aromatic heterocyclic rings include furan ring, thiophene ring, pyrrole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, and triazole.
• Alicyclic ring as used herein means a non-aromatic hydrocarbon ring.
• the alicyclic ring may have an unsaturated bond in the ring, or may be a polycyclic ring having two or more rings. Also, a carbon atom constituting a ring may be oxidized to form a carbonyl.
• the alicyclic ring preferably includes a 3- to 8-membered alicyclic ring.
• alicyclic ring examples include cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring, bicyclo[2.2.1]heptane ring and the like.
• saturated heterocycle herein is meant a non-aromatic heterocycle containing from 1 to 5 heteroatoms in addition to carbon atoms and no double and/or triple bonds in the ring. do.
• the saturated heterocyclic ring may be monocyclic, or may form a condensed ring with another ring such as an aromatic ring such as a benzene ring.
• the saturated heterocyclic ring preferably includes a 4- to 10-membered saturated heterocyclic ring.
• saturated heterocycles include, for example, azetidine ring, oxoazetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pyrrolidine ring, 2-oxopyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxopiperidine ring, piperazine ring, pyrazolidine ring, imidazolidine ring, oxazolidine ring, isoxazolidine ring, thiazolidine ring, isothiazolidine ring, thiadiazolidine ring, oxazolidone ring, dioxolane ring, dioxane ring, thietane ring, octa hydroindole ring, indoline ring, azepane ring, dioxepane ring,
• heterocyclic ring as used herein means a non-aromatic heterocyclic ring containing preferably 1 to 5, more preferably 1 to 3 heteroatoms in the ring-constituting atoms. Heterocycles may have double and/or triple bonds in the ring, carbon atoms in the ring may be oxidized to form carbonyls, and may be monocyclic, fused, or spirocyclic.
• the number of atoms constituting the heterocyclic ring is preferably 3 to 12 (3- to 12-membered heterocyclic ring), more preferably 4 to 10 (4- to 10-membered heterocyclic ring).
• heterocyclic rings include azetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pyrrolidine ring, 4-oxopyrrolidine ring, piperidine ring, 4-oxopiperidine ring, and piperazine.
• carboxyl group-protecting group includes an alkyl ester-type protecting group, a benzyl ester-type protecting group, a substituted alkyl ester-type protecting group, and the like.
• 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. .
• hydroxy-protecting group includes an alkyl ether-type protecting group, an aralkyl ether-type protecting group, a silyl ether-type protecting group, a carbonate-type protecting group, and the like.
• Halogen-derived substituents in the present specification include fluoro (-F), chloro (-Cl), bromo (-Br), iodine (-I), and the like.
• azide -N3 , also referred to as "azido group”
• cyano -CN
• primary amino -NH2
• secondary amino -NH- R
• tertiary amino -NR(R')
• aminocarbonylamino -NR-CO-NR'R''
• thiol -SH
• thio thio
• thio thio
• thio thio
• thio thio
• thio thio
• thio thio
• thio thio
• thio thio
• thio thio
• thio thio
• SR thio
• sulfo -SO3H
• pentafluorosulfanyl -SF5
• the "boron atom-derived substituent" used herein includes boryl (-BR(R')), dioxyboryl (-B(OR)(OR')), trifluoroborate salt ( -BF3- ), and the like. exemplified. Specifically, these two substituents R and R' are substituents each independently selected from among alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc.
• boron atom or a "substituent derived from a boron atom” in which these two substituents R and R' form a ring together with the atoms to which R and R' are respectively attached That is, a cyclic boryl group is exemplified.
• Preferred "boron atom-derived substituents" are exemplified by cyclic boryl groups. More specific examples of cyclic boryl groups include pinacolatoboryl groups, neopentanediolateboryl groups, catecholatoboryl groups, and 9-borabicyclo[3.3.1]nonan-9-yl groups.
• the "zinc-derived group” used herein is exemplified by an alkyl zinc group (-Zn-( C1 - C6 alkyl)) or a zinc halide group (-Zn-X).
• Preferred "zinc-derived groups” are exemplified by -ZnMe, -ZnEt, -ZnPr, -ZnCl, -ZnBr and -ZnI.
• the preparation of compounds with these "zinc-derived groups” is described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th edition, John Wiley & Sons, Inc. 2019) and R. C. Laroch, Comprehensive Organic Transformations (3rd edition). Ed., JohnWiley & Sons, Inc. 2018).
• optionally substituted means that a certain group may be substituted with any substituent. Furthermore, each of these may be provided with a substituent, and these substituents are not limited. One or two or more may be freely selected independently from among the groups.
• One or more as used herein means one or two or more numbers. When “one or more” is used in the context of substituents on a group, the term means from one to the maximum number of substituents allowed by the group.
• the term "about” when used in combination with a numerical value means a value range of +10% and -10% of that numerical value.
• A, B, and/or C includes any combination in which “and” and “or” are appropriately combined.
• A, B, and/or C includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.
• One embodiment of the present invention is a compound represented by general formula (1) (hereinafter also referred to as “compound (1)”) or a salt or solvate thereof.
• X a1 is CR a1 or N.
• X a1 is preferably CR a1 .
• X a3 is CR a3 or N.
• X a3 is preferably CR a3
• R a1 is hydrogen, halogen or C 1 -C 6 alkoxy.
• R a1 is preferably hydrogen or fluorine.
• R a2 is hydrogen, halogen or C 1 -C 6 alkoxy.
• R a2 is preferably hydrogen or methoxy.
• R a3 is hydrogen, halogen or C 1 -C 6 alkoxy.
• R a3 is preferably hydrogen or fluorine.
• Xb1 is preferably CH2 .
• X b2 is CH 2 , O, NH, S or C ⁇ O.
• X b2 is preferably CH 2 , O, NH or C ⁇ O, more preferably CH 2 .
• X b3 is CH 2 , O, NH, S or C ⁇ O.
• X b3 is preferably CH 2 , O, NH, S or C ⁇ O, more preferably O.
• X b1 is CH 2
• X b2 is CH 2 , O, NH or C ⁇ O
• X b1 and X b2 are CH2 and X b3 is O
• X b1 and X b3 are CH2 and Xb2 is O
• X b3 is NH
• X b1 is CH2
• X b2 is C ⁇ O
• X b3 is NH
• or X b1 and X b3 are CH2
• X b2 is NH
• Z is C 6 -C 10 aryl, 5-10 membered heteroaryl or C 1 -C 6 alkyl, and said C 6 -C 10 aryl, 5-10 membered heteroaryl and C 1 -C
• the 6- alkyl is substituted with R z3 and optionally substituted with one or more groups selected from the group consisting of R z1 , R z2 , R z4 and R z5 .
• Z is preferably substituted with R z3 and optionally substituted with one or more groups selected from the group consisting of R z1 , R z2 , R z4 and R z5 , phenyl, pyridyl or C 2 - It is C5 alkyl.
• Z is preferably of formula (2): [Where the wavy line represents the point of attachment of Z and X z is CR z5 or N. ] is a group represented. In formula (2), preferably X z is CR z5 .
• R z1 , R z2 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 alkyl(4- to 10-membered heterocyclyl)amino and optionally substituted 4- to 8-membered is selected from the group consisting of cyclic amino;
• R z1 , R z2 and R z5 are preferably each independently selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkyl, more preferably each independently hydrogen, fluorine, chlorine, methyl and ethyl.
• R z4 is hydrogen, halogen, C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkyl (5- to 10-membered heteroaryl C 1 -C 6 alkyl) It is amino, optionally substituted C 1 -C 6 alkyl(4- to 10-membered heterocyclyl)amino or optionally substituted 4- to 8-membered cyclic amino.
• R z4 is preferably optionally substituted C 1 -C 6 alkyl(5- to 10-membered heteroarylC 1 -C 2 alkyl)amino, optionally substituted C 1 -C 6- alkyl(4-10-membered heterocyclyl)amino or 4-8-membered cyclic amino optionally having a substituent, more preferably hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy 4- to 6-membered cyclic amino optionally having one or more substituents selected from the group consisting of; the group consisting of C 1 -C 2 alkylene and C 1 -C 2 alkylene containing one oxygen atom on the ring 4- to 6-membered cyclic amino having a bridging group selected from; C 1 -C 3 alkyl optionally having a substituent selected from the group consisting of hydrogen, halogen and C 1 -C 6 alkyl (5- 6-membered heteroaryl C 1 -C 2
• Rz3 is a carboxyl group or its biological equivalent.
• a biological equivalent is a chemical compound described by Matsuoka et al. Functional groups having different structures but capable of exhibiting similar biological effects are exemplified. Equivalents of carboxyl groups are exemplified by functional groups with acidic protons. Rz3 can also include compounds that can be converted to a carboxyl group or a bioisostere thereof after administration to a subject, such as prodrugs thereof.
• R z3 is specifically the following Substituent Group A: wherein the wavy line represents the point of attachment, 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 z3 is preferably the following Substituent Group B: wherein the wavy line represents the point of attachment and R 5 is hydroxy, C 1 -C 6 alkoxy, mono C 1 -C 6 alkylamino or C 1 -C 6 alkylsulfonylamino. be.
• R 5 is preferably hydroxy or C 1 -C 6 alkylsulfonylamino.
• Y is C 6 -C 10 aryl or 5-10 membered heteroaryl, and the C 6 -C 10 aryl and 5-10 membered heteroaryl are R y1 , R y2 , R y3 , R It may be substituted with one or more groups selected from the group consisting of y4 and Ry5 .
• Y is preferably phenyl or 6- to 10-membered heteroaryl optionally substituted with one or more groups selected from the group consisting of R y1 , R y2 , R y3 , R y4 and R y5 ; More preferably, phenyl or 6- to 10-membered heteroaryl substituted with R y3 and optionally substituted with one or more groups selected from the group consisting of R y1 , R y2 , R y4 and R y5 is.
• Y preferably has formula (3): [Where the dashed line represents the point of attachment of Y, X y1 is CR y3 or N, X y2 is CR y4 or N, and X y3 is CR y5 or N. ] is a group represented by In formula (3), X y1 is preferably CR y3 , X y2 is CR y4 , and X y3 is CR y5 .
• 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, 4-10 membered heterocyclyl C 1 -C 6 alkoxy, hydroxy C 2 -C 6 alkoxy, 4-10 membered heterocyclyloxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino C 1 - C6 alkoxy, 5- to 10-membered heteroaryloxy, C1 - C6 alkylthio, 4- to 10-membered saturated heterocyclic group having a bond on a ring carbon atom 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
• R y1 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, hydroxyC 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 alkylaminoC 1 -C 3 alkoxy, 5- to 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, 4- to 10-membered saturated heterocyclic group having a bond to the nitrogen atom and optionally having substituents, 5- to 10-membered aromatic heterocyclic group optional
• R y2 is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, 4-10 membered heterocyclyl C 1 -C 6 alkoxy, hydroxy C 2 -C 6 alkoxy, 4-10 membered heterocyclyloxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino C 1 - C6 alkoxy, 5- to 10-membered heteroaryloxy, C1 - C6 alkylthio, 4- to 10-membered saturated heterocyclic group having a bond on a ring carbon atom 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
• R 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, hydroxyC 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 alkylaminoC 1 -C 3 alkoxy, 5- to 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, 4- to 10-membered saturated heterocyclic group having a bond to the nitrogen atom and optionally having substituents, 5- to 10-membered aromatic heterocyclic group optional
• 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, 4-10 membered heterocyclyl C 1 -C 6 alkoxy, hydroxy C 2 -C 6 alkoxy, 4-10 membered heterocyclyloxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino C 1 - C6 alkoxy, 5- to 10-membered heteroaryloxy, C1 - C6 alkylthio, 4- to 10-membered saturated heterocyclic group having a bond on a ring carbon atom and optionally having a substituent , 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 heteroary
• R 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, hydroxyC 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 alkylaminoC 1 -C 3- alkoxy, 5- to 6-membered heteroaryloxy, C 1 -C 4 alkylthio, 5- to 6-membered saturated heterocyclic group having a bond to a carbon atom on the ring and optionally having a substituent, on the ring optionally substituted 4-10 membered saturated heterocyclic group, optionally substituted 5-10 membered heteroaryl or C 1 -C 3 alkyl (
• 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, 4-10 membered heterocyclyl C 1 -C 6 alkoxy, hydroxy C 2 -C 6 alkoxy, 4-10 membered heterocyclyloxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino C 1 -C 6 alkoxy, 5- to 10-membered heteroaryloxy, C 1 -C 6 alkylthio, having a bond on a carbon atom on the ring and optionally having a substituent 4- to 10-membered saturated heterocyclic group, 4- to 10-membered saturated heterocyclic group having a bond to a nitrogen atom on the ring and optionally having a substituent, 5 to
• Another embodiment of the present invention is a compound represented by general formula (4) (hereinafter also referred to as "compound (4)"), a salt, or a solvate thereof.
• X 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 X 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 , Same as R z3 , R z4 and X z .
• the compounds described herein can be salts or solvates thereof.
• Salts of compounds include, for example, hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; carboxylates such as acetates, citrates, malate, tartrates, succinates, salicylates; or alkali metal salts such as sodium salts and potassium salts; alkaline earth salts such as magnesium salts and calcium salts.
• Metal salts; ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts, and the like are included.
• solvate refers to a compound formed with a solvent to form a single molecular cluster, and if it is a solvate formed with a solvent that is acceptable for ingestion accompanying administration of a drug, It is not particularly limited. Examples include hydrates, alcoholates (ethanolates, methanolates, 1-propanolates, 2-propanolates, etc.), solvates with a single solvent such as dimethylsulfoxide, as well as , solvates formed with a plurality of solvents for one molecule of the compound, and solvates formed with a plurality of types of solvents for one molecule of the compound.
• the solvent is water, it is called a hydrate.
• the solvate of the compound of the present invention is preferably a hydrate, and such a hydrate is specifically a 1-10 hydrate, preferably a 1-5 hydrate, more preferably a 1-3 hydrates.
• the compound according to the present invention When the compound according to the present invention is obtained as a free form, the compound can be converted into a salt that the compound may form or a hydrate or solvate thereof according to a conventional method. Examples thereof include hydrates and ethanolates of the compound represented by formula (1) or salts thereof.
• a hydrate or solvate may be produced in crystalline or amorphous form, and, if crystalline, may be polymorphic.
• a solvent such as ethanol and/or water is added to the compound represented by formula (1), followed by stirring, cooling, concentration, and/or drying. Hydrates or solvates can be obtained by conventional methods.
• the compound according to the present invention when obtained as a salt, hydrate, or solvate of the compound, the compound can be converted to its free form according to a conventional method.
• the compounds described herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• Isotope abundance ratio in nature by replacing any atom in a compound with another isotopic atom with the same atomic number (proton number) but different mass number (sum of protons and neutrons)
• compounds substituted with isotopes in abundance ratios different from that is, compounds labeled with isotope atoms.
• Examples of isotopic elements included in the compounds herein include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms, respectively, 2 H, 3 H , 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 35 S, 18 F, 36 Cl and the like.
• Isotopically-labeled compounds are useful as therapeutic or prophylactic agents, research reagents (eg, assay reagents), and diagnostic agents (eg, in vivo imaging agents).
• Compounds herein containing all proportions of radioactive or non-radioactive isotopes are included within the scope of this invention.
• a compound labeled with an isotope atom can be produced by using a reagent or solvent containing the corresponding isotope atom in a manner similar to that for producing an unlabeled compound.
• the compounds described herein, salts thereof, or solvates thereof include all stereoisomers (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), isomers thereof, and isomers thereof. racemates, and other mixtures.
• the compounds of this invention may possess one or more points of asymmetry, and the invention includes racemic mixtures, diastereomeric mixtures and enantiomers of such compounds.
• the target product of the process can be obtained by, for example, protecting and deprotecting a functional group.
• protecting groups see, for example, T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis (5th edition, John Wiley & Sons 2014). Protection of functional groups and part of deprotection are also described in the following schemes.
• the compounds of the present invention can be synthesized, for example, by the production methods shown below.
• Amino protecting groups (PG 1 ) include formyl, C 1 -C 6 alkylcarbonyl (acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), carbamoyl, C 1 —C6 alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl group, sec-butoxycarbonyl group, t-butoxycarbonyl group, etc.), substituted silyl group (trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc.), aralkyloxycarbonyl group (benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, etc.), allyl group, aralkyl group (benzy
• Leaving groups (L 1 and L 2 ) in general production method A are halogen atoms, trifluoromethanesulfonyl groups, nonafluorobutanesulfonyl groups, acetyloxy, trifluoroacetyloxy groups, methanesulfonyloxy groups, and p-toluenesulfonyloxy groups. , groups derived from boron atoms (4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 9-BBN, etc.), groups derived from zinc, and the like.
• Compound (A-3) is prepared by reacting compound (A-1) having leaving group L1 and compound (A- 2 ) having leaving group L2 in the presence of a palladium catalyst, a ligand and a base. , can be produced by performing a coupling reaction.
• the compound having a leaving group L 1 and the compound having L 2 include a compound having a halogen atom as a leaving group, a compound having a leaving group derived from sulfonic acid, a compound having a leaving group derived from a boron atom, zinc Compounds with derived groups are exemplified and are prepared by methods well known to those skilled in the art, such as Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition, by RC Larock, or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (by M. B. Smith, J. March), etc., and can be used in the coupling reaction.
• the coupling reaction can be performed 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). can.
• Palladium catalysts used in the coupling reaction can be used from commercial suppliers. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride complexed with palladium and ligands 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,
• Bases used in the coupling reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), carbonates, or inorganic bases such as 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.), preferably inorganic compounds such as cesium carbonate. Bases are exemplified.
• Solvents 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.), or acetonitrile, preferably 2-methyltetrahydrofuran or 1-methylpyrrolidin-2- On is exemplified.
• ether solvents tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane,
• the optimum reaction temperature for the coupling reaction is usually in the range of 0°C to around the boiling point of the solvent, preferably in the range of 10°C to 120°C.
• the reaction time is usually in the range of 30 minutes to 24 hours, preferably 1 hour to 12 hours.
• the resulting target compound (A-3) may be isolated by common techniques and, if necessary, purified by crystallization or chromatography.
• Compound (A-4) can be produced by deprotecting the protecting group of compound (A-3).
• the protecting group PG 1 is a C 1 -C 6 alkoxycarbonyl group such as t-butoxycarbonyl
• the deprotection reaction is preferably carried out using an acid.
• Acids used in the deprotection reaction include inorganic acids (hydrogen chloride, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), sulfonic acids (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), carboxylic acids, 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.), preferably hydrogen chloride, methanesulfonic acid, trifluoroacetic acid, and the like.
• Solvents 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.
• ester solvents ethyl acetate, isopropyl acetate, etc.
• 1,4-dioxane and ethyl acetate preferably 1,4-dioxane and ethyl acetate.
• the optimum reaction temperature for the deprotection reaction is usually in the range of 0°C to around the boiling point of the solvent, preferably in the range of 10°C to 100°C.
• the optimum reaction time for the deprotection reaction is usually in the range of 30 minutes to 12 hours, preferably in the range of 1 hour to 6 hours.
• the resulting compound (A-4) may be isolated by common techniques and, if necessary, purified by crystallization or chromatography. Compound (A-4) may be obtained as a salt with the acid used in the reaction, and such a salt can also be subjected to the next step.
• Step 3 Compound (A-6) can be produced by converting compound (A-5) into an acid chloride and then subjecting compound (A-4) to an amidation reaction in the presence of a base.
• reagents for converting compound (A-5) to acid chloride include thionyl chloride, oxalyl chloride, Ghosez reagent and the like.
• Bases used in the amidation reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.) and diamines (N,N,N',N'-tetramethylethylenediamine, etc.).
• guanidine guanidine, tetramethylguanidine, etc.
• pyridine pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, etc.
• N,N-diisopropylethylamine and 4 - Tertiary amines such as methylmorpholine are exemplified.
• Solvents 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 solvents diichloromethane, dichloroethane, chloroform, etc.
• amide solvents N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.
• ester solvents ethyl acetate, acetic acid isopropyl, etc.
• acetonitrile and water, preferably dichloromethane and acetonitrile.
• the optimum reaction temperature for carrying out the amidation reaction is exemplified 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 exemplified in the range of 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
• Compound (A-6) can be obtained by, for example, amidating compound (A-4) and compound (A-5) in the presence of a base using a condensing agent, in addition to the method via an acid chloride. It can be manufactured by doing.
• Condensing agents used in the amidation reaction are benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP® )), PyAOP, BroP, PyCloP, PyBroP (registered trademark), BOP condensing agents such as DEPBT, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpho Lithium chloride n-hydrate (DMT-MM), 2-(1H-benzotriazol-1-yl)-1,1,3,3-te
• Bases used in the amidation reaction with a condensing agent include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), pyridine (pyridine, 2,6-lutidine, 2,4, 6-collidine, 4-dimethylaminopyridine, etc.), preferably tertiary amines such as N,N-diisopropylethylamine and 4-methylmorpholine.
• tertiary amines triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.
• pyridine pyridine, 2,6-lutidine, 2,4, 6-collidine, 4-dimethylaminopyridine, etc.
• tertiary amines such as N,N-diisopropylethylamine and 4-methylmorpholine.
• 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 solvents diichloromethane, dichloroethane, chloroform, etc.
• amide solvents N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.
• ester solvents ethyl acetate, isopropyl acetate, etc.
• acetonitrile preferably dichloromethane and N,N-dimethylformamide.
• the optimum reaction temperature for performing the amidation reaction with the condensing agent is exemplified 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 amidation reaction with the condensing agent is exemplified in the range of 1 minute to 24 hours, preferably 30 minutes to 12 hours.
• the resulting compound (A-6) may be isolated by common techniques and, if necessary, purified by crystallization or chromatography.
• L 3 represents a leaving group
• R A represents C 1 -C 6 alkyl
• R B1 represents a pinacolate group, a neopentanediolate group, a catecholate group, or a bicyclo[3.3.1]nonane- represents a 9-yl group
• X a1 , X a3 , X b1 , X b2 , X b3 , Y and Z are as defined in [1] above.
• Leaving group L3 in general production method B is exemplified by a halogen atom, an acetyloxy group, a trifluoroacetyloxy group, a methanesulfonyloxy group, a paratoluenesulfonyloxy group, a trifluoromethanesulfonyl group, a nonafluorobutanesulfonyl group, and the like.
• Compound (B-2) can be produced by subjecting compound (B-1) to a boronation reaction using various diborane reagents in the presence of an iridium catalyst and a ligand.
• the boronation reaction can be performed, for example, with reference to Angew. Chem. Int. Ed., 2021, 60, 2796-2821.
• Iridium catalysts and ligands used in the boronation reaction are bis(1,5-cyclooctadiene)di- ⁇ -methoxydiiridium (I) and 4,4′-di-tert-butyl-2,2′.
• - Bipyridine and the like are preferably exemplified.
• Solvents 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.), preferably tetrahydrofuran or hexane.
• 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, tol
• the optimum reaction temperature for the boronation reaction is usually exemplified 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 usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
• the resulting compound (B-2) may be isolated by common techniques and, if necessary, purified by crystallization or chromatography.
• Compound (B-3) can be produced by subjecting compound (B-2) to an oxidation reaction using an oxidizing agent exemplified by hydrogen peroxide.
• Solvents 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.), alcohol solvents Solvents (methanol, ethanol, isopropanol, butanol, etc.) are exemplified, preferably methanol.
• the optimum reaction temperature for the oxidation reaction is usually in the range of 0°C to around the boiling point of the solvent, preferably in the range of 10°C to 60°C.
• the reaction time is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.
• the resulting compound (B-3) may be isolated by common techniques and, if necessary, purified by crystallization or chromatography.
• Step 3 Compound (B-5) can be produced by subjecting compound (B-3) and compound (B-4) having leaving group L3 to an etherification reaction in the presence of a base.
• the etherification reaction can be carried out with reference to Williamson's method (Liebigs Ann. Chem. 1851, 77, 37-49).
• 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), and the like.
• An inorganic base such as potassium carbonate is preferred.
• Solvents 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.
• acetonitrile preferably Amide solvents such as 1-methylpyrrolidin-2-one are exemplified.
• the optimum reaction temperature for the etherification reaction is usually in the range of 0°C to around 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 usually 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 common techniques and, if necessary, purified by crystallization or chromatography.
• PG 2 represents a carboxyl group-protecting group
• Z 1 represents a group selected from the group consisting of optionally substituted aryl, heteroaryl and alkylene
• X a1 , X a3 , R a2 , X b1 , X b2 , X b3 and Y have the same definitions as in [1] above.
• Carboxyl-protecting groups are exemplified by C 1-6 alkyl esters (methyl ester, ethyl ester, propyl ester, butyl ester, etc. ) , benzyl ester, aryl ester and the like.
• the selection of protecting groups and methods of protection and deprotection can be selected. & Sons 2014).
• Compound (C-2) can be produced by subjecting compound (C-1) to a deprotection reaction.
• the protecting group PG2 is an alkyl ester such as a methyl ester
• it is preferably deprotected using a base.
• Bases used in the deprotection reaction include inorganic bases (sodium hydroxide, potassium hydroxide, barium hydroxide, potassium trimethylsiloxide, etc.), or metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), preferably inorganic bases such as potassium hydroxide.
• Solvents 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.), alcohols, solvent (methanol, ethanol, isopropanol, butanol, etc.), amide solvent (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), water, preferably tetrahydrofuran , methanol, water, etc., or a mixture thereof at an arbitrary ratio.
• ether solvents tetrahydrofuran, methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl
• the optimum reaction temperature for the deprotection reaction is usually in the range of 0°C to around the boiling point of the solvent, preferably in the range of 20°C to 120°C.
• the optimum reaction time for the deprotection reaction is usually 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 common techniques and, if necessary, purified by crystallization or chromatography.
• L 4 represents a leaving group
• Y 1 represents a group selected from the group consisting of optionally substituted aryl, heteroaryl and alkylene
• X a1 , X a3 , R a2 , X b1 , X b2 , X b3 and Z have the same definitions as in [1] above.
• the leaving group L4 in the general production method D is exemplified by a halogen atom, a trifluoromethanesulfonyl group, a nonafluorobutanesulfonyl group, and the like.
• Compound (D-2) is produced by subjecting compound (D-1) having leaving group L4 to a coupling reaction with various nucleophiles in the presence of a palladium catalyst, a ligand and a base. be able to.
• the compound (D-1) having a leaving group L4 is exemplified by a compound having a halogen atom as a leaving group and a compound having a leaving group derived from sulfonic acid.
• the nucleophilic agent used in the coupling reaction is exemplified by amine compounds, alcohol compounds, and compounds having a group derived from a boron atom. Objects can be manufactured. These coupling reactions were carried out according to the method of Buchwald et al. (Org. Synth., 2002, 78, 23), the method of Suzuki et al. Am. Chem. Soc. 2001, 123, 12202-12206)).
• Palladium catalysts and ligands used in the coupling reaction are palladium catalysts available from commercial suppliers exemplified by allylpalladium(II) chloride (dimer), palladium acetate, or Pd2 (dba) 3 , used in combination with ligands available from commercial suppliers exemplified by rac-BINAP, dppf, SPhos, or Xantphos; Complexes are preferably used.
• Bases used in the coupling reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), carbonates, or inorganic bases such as 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.), preferably inorganic compounds such as cesium carbonate. Bases are exemplified.
• Solvents 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.), acetonitrile, preferably methyltetrahydrofuran and 1-methylpyrrolidin-2-one. be done.
• ether solvents tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.
• the optimum reaction temperature for the coupling reaction is usually in the range of 0°C to around 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 usually 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 common techniques and, if necessary, purified by crystallization or chromatography.
• Bases 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, carbonate cesium, etc.), metal alkoxides (sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium tert-butoxide, potassium tert-pentoxide, etc.), preferably DBU, sodium hydride, potassium carbonate, or potassium tert - Butoxide and the like are exemplified.
• 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.), Examples include hydrocarbon solvents (benzene, toluene, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one, etc.), preferably hydrocarbons such as toluene. and amide solvents such as 1-methylpyrrolidin-2-one.
• ether solvents tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxye
• the optimum reaction temperature for the SNAr reaction is usually in the range of 0°C to around 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 usually 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 common techniques and, if necessary, purified by crystallization or chromatography.
• L 5 and L 6 each independently represent a leaving group, X a1 , X a3 , R a2 , X b1 , X b2 , X b3 , Y and Z have the same definitions as in [1] above. be.
• Leaving groups L5 and L6 in general production method E are halogen atom, trifluoromethanesulfonyl group, nonafluorobutanesulfonyl group, acetyloxy group, trifluoroacetyloxy group, methanesulfonyloxy group, paratoluenesulfonyloxy group, boron Atom-derived groups (4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 9-BBN, etc.), zinc-derived groups, and the like are exemplified.
• Compound (E-3) is prepared by reacting compound (E-1) having leaving group L 5 and compound (E-2) having leaving group L 6 in the presence of a palladium catalyst, a ligand and a base. , can be produced by performing a coupling reaction.
• the leaving group L5 of the compound (E-1) is a halogen atom
• the coupling reaction can also be carried out after converting L5 into another leaving group such as a boron atom-derived group or a zinc-derived group. .
• Palladium catalysts used in the coupling reaction can be used from commercial suppliers. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride complexed with palladium and ligands 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,
• Bases used in the coupling reaction include tertiary amines (triethylamine, 4-methylmorpholine, N,N-diisopropylethylamine, DBU, DABCO, etc.), carbonates, or inorganic bases such as 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.), preferably inorganic compounds such as cesium carbonate. Bases are exemplified.
• Solvents 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.), or acetonitrile, preferably 2-methyltetrahydrofuran or 1-methylpyrrolidin-2- On is exemplified.
• ether solvents tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane,
• the optimum reaction temperature for the coupling reaction is usually in the range of 0°C to around the boiling point of the solvent, preferably in the range of 10°C to 120°C.
• the reaction time is usually in the range of 30 minutes to 24 hours, preferably 1 hour to 12 hours.
• the resulting target compound (E-3) may be isolated by common techniques and, if necessary, purified by crystallization or chromatography.
• the present invention provides pharmaceutical compositions containing the compounds represented by formula (1) of the present invention.
• the pharmaceutical composition of the present invention comprises a compound represented by formula (1) of the present invention, a salt of the compound represented by formula (1), or a solvate thereof and a pharmaceutically acceptable carrier. It can be introduced and formulated by known methods. Excipients, binders, lubricants, coloring agents, flavoring agents and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antiseptics, and An oxidizing agent or the like can be used, and ingredients generally used as raw materials for pharmaceutical formulations are blended and formulated by a conventional method.
• active ingredients used in pharmaceuticals can be processed into the optimum shape or properties, ie dosage form, according to the method of use and purpose of use by known methods.
• Commonly used dosage forms include liquid pharmaceutical preparations (solutions) such as injections, suspensions, emulsions, and eye drops, tablets, powders, fine granules, granules, coated tablets, capsules, and dry syrups. , lozenges, and solid pharmaceutical preparations (solid preparations) such as suppositories, but are not limited to these.
• the compound represented by the formula (1) of the present invention, or a salt thereof, or a solvate thereof is added with a pharmacologically acceptable carrier or medium, specifically, sterilized.
• pharmacologically acceptable agents commonly used in the field of pharmaceutical formulations, such as water, saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, binders, etc. It is formulated by adding an appropriate combination of excipients, and then blending in a unit dosage form generally required for pharmaceutical practice.
• a solid formulation prepared for a liquid formulation can be administered after adding an appropriate solvent such as sterilized water or physiological saline to dissolve it when necessary before administration.
• Such liquid preparations can also be used parenterally, for example, in the form of injections of sterile solutions or suspensions in water or other pharmaceutically acceptable liquids.
• 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 admixed in a unit dosage form required for generally accepted pharmaceutical practice.
• compositions for injection can be formulated according to normal pharmaceutical practice using a vehicle such as distilled water for injection.
• Aqueous solutions for injection include isotonic solutions containing physiological saline and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, and suitable solubilizers such as alcohol, Specifically, ethanol, polyalcohols such as propylene glycol, polyethylene glycol, and nonionic surfactants such as polysorbate 80 (registered trademark) and HCO-50 may be used in combination.
• Sesame oil and soybean oil are examples of oily liquids, and benzyl benzoate and benzyl alcohol may be used together as solubilizers. It may also be blended with buffers such as phosphate buffers, sodium acetate buffers, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants.
• buffers such as phosphate buffers, sodium acetate buffers, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants.
• a prepared injection solution is usually filled into a suitable ampoule.
• the compound represented by the formula (1) of the present invention a salt thereof, or a solvate thereof is added with an excipient, and if necessary, a binder, a disintegrant,
• an appropriate combination of pharmaceutically acceptable additives that are commonly used in the field of pharmaceutical formulations such as lubricants, coloring agents, and flavoring agents
• tablets, powders, fine granules, granules, and coatings are prepared by conventional methods. Tablets, capsules, dry syrups, lozenges, suppositories, etc.
• compositions include, for example, animal and vegetable oils such as soybean oil, beef tallow, synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; octyldodecyl myristate, myristic ester oils such as isopropyl acid; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resin; silicone oil; Surfactants such as polyoxyethylene polyoxypropylene block copolymers; Water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methylcellulose; Lower alcohols such as ethanol and isopropanol; Glycerin, propylene polyhydric alcohols such as glycol, dipropylene glycol and sorbitol; sugars such as lactose, lactose hydrate, fructose and sucrose; inorganic powders such as an animal and vegetable oils such as soybean oil
• excipients examples 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.), cellulose (eg, crystalline cellulose), inorganic salts (eg, calcium silicate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc.), and the like.
• 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.
• cellulose eg, crystalline cellulose
• inorganic salts eg, calcium silicate, an
• binders include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene block polymer, and the like.
• disintegrants examples include croscarmellose sodium, carmellose sodium, hydroxypropylcellulose, carmellose, carmellose calcium, methylcellulose, crystalline cellulose, sodium lauryl sulfate, povidone, polysorbate, and the like.
• lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate, and hydrogenated oils.
• coloring agents those that are permitted to be added to pharmaceuticals are used, and as flavoring agents, cocoa powder, mint brain, aromatic powder, mint oil, borneol, cinnamon powder, etc. are used.
• these tablets and granules can be coated with sugar or other appropriate coatings as necessary.
• the compound of the present invention or a pharmacologically acceptable salt thereof may be added with a pH adjuster, a solubilizer, a tonicity agent, etc., if necessary. Add solubilizers, stabilizers, etc. as necessary, and formulate in a conventional manner.
• parenteral administration is not limited to parenteral administration.
• parenteral administration include injection dosage forms, nasal dosage forms, pulmonary dosage forms, transdermal dosage forms, and the like.
• injection dosage forms include systemic or local administration by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, and the like.
• the administration method can be appropriately selected according to the patient's age and symptoms.
• the dosage of the pharmaceutical composition containing the compound represented by the formula (1) of the present invention, or a salt thereof, or a solvate thereof produced by the method of the present invention is, for example, 1 kg of body weight per dose. It is possible to choose between 0.0001 mg and 1000 mg per dose. Alternatively, for example, the dose can be selected in the range of 0.001 to 100000 mg/body per patient, but is not necessarily limited to these figures.
• the dosage and administration method vary depending on the patient's body weight, age, symptoms, etc., but can be appropriately selected by those skilled in the art.
• the compounds of the invention can be used to activate Nrf2, or to inhibit Keap1 and activate Nrf2.
• the pharmaceutical composition of the present invention is used to treat diseases in a subject, such as those described in Nature Reviews DrugDiscovery, 2019, 18, p295-317, more specifically Alzheimer's disease, Parkinson's disease, Huntington's disease in a subject, Neurodegenerative diseases such as 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, asthma, chronic kidney disease, kidney diseases such as acute kidney injury, ophthalmic diseases such as uveitis, glaucoma, age-related macular degeneration, liver diseases such as non-alcoholic steatohepatitis, multiple sclerosis, rheumatoid arthritis, ulcerative colitis, etc.
• Neurodegenerative diseases such as Friedreich's ataxia and amyotrophic lateral sclerosis
• pulmonary diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic
• Immune/inflammatory diseases head and neck cancer (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, stomach cancer, colon cancer (cecum cancer, colon cancer, rectal cancer, etc.), lung cancer (small cell cancer, non-small cell cancer, 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 cancer, bladder cancer, renal pelvic/ureteral cancer, malignant melanoma, solid tumors such as skin cancer, leukemia (acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, myelodysplastic syndrome, etc. It
• the term "subject” includes mammals, preferably humans.
• NMR data are given in ppm (parts per million, ⁇ ).
• the mass spectral data was obtained from a single quadrupole mass spectrometer (LCMS-2020) with an ultra-performance liquid chromatography (Nexera UC or Nexera) manufactured by Shimadzu Corporation or Acquity ultra-performance liquid chromatography (UPLC or UPLC I-Class manufactured by Waters). ) using a single quadrupole mass spectrometer (SQD or SQD2). Two entries for retention time indicate the retention time for each rotamer.
• Microwave irradiation was performed using InitiatorTM (manufactured by Biotage).
• Second step compound A10 tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate
• a 36% formaldehyde aqueous solution (5.06 mL, 66.2 mmol) and formic acid (5.08 mL, 132 mmol) were added and stirred at 56° C. for 7 hours.
• the reaction solution was cooled to 25°C, water was added, and the mixture was stirred for 30 minutes. Additional water was added and stirred for 30 minutes.
• the reaction solution was filtered and the obtained solid was washed with acetonitrile/water (1/2). Drying under reduced pressure gave the title compound (81%, 4.20 g).
• Third step compound A4 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 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 1 M lithium (bistrimethylsilyl)amide in tetrahydrofuran solution (50.6 mL, 50.6 mmol) at room temperature over 12 minutes.
• a 2M isopropylmagnesium chloride-tetrahydrofuran solution (1.91 mL, 3.82 mmol) was added and stirred for 1 hour.
• a 2M zinc (II) chloride-2-methyltetrahydrofuran solution (0.955 mL, 1.91 mmol) was added to the reaction solution.
• 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, 0.0250 g, 0.0250 g, 0.18 mmol) were added to the reaction mixture.
• 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)benzoato Methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl ) 4-bromo-2,6-dichlorobenzoyl chloride (7.33 g, 25.4 mmol) and pyridine in a toluene (92.0 mL) solution of benzoate dihydrochloride (9.22 g, 19.6 mmol).
• 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 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 (18.6 g, 27.2 mmol) of 1-methylpyrrolidin-2-one 8M aqueous potassium hydroxide solution (11.9 mL, 95.0 mmol) was added to
• 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-benzoxazine -8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 10% palladium on carbon (353 mg, 0 .332 mmol) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and a hydrochloric acid-methanol solution was added to the filtrate.
• 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 1-benzhydryl-3-methoxy-2,2-dimethylazetidine (49.0 mg, 0.174 mmol) in 20% palladium hydroxide on carbon (122 mg, 0.174 mmol) in methanol (0.871 mL) ) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere.
• Trifluoromethanesulfonic anhydride (0.0401 mL, 0.244 mmol) was added and stirred at -78°C for 1 hour. Add morpholine (0.142 mL, 1.63 mmol) and stir overnight at room temperature. Morpholine (0.142 mL, 1.63 mmol) was added and stirred overnight at room temperature and then at 40° C. for 4 hours. Methanol was added to the reaction mixture, the mixture was concentrated, and 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 condition F)
• 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
• benzyl (2R,3S)-2-methyl-3-morpholin-4-ylazetidine-1-carboxylate (25.0 mg, 0.0860 mmol) in methanol (0.344 mL) was added with 10% palladium on carbon ( 27.5 mg, 0.0260 mmol) was added.
• 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 10% palladium on carbon ( 35.2 mg, 0.0330 mmol) was added. The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through celite, and a hydrochloric acid-methanol solution was added to the filtrate.
• the resulting racemic mixture was purified by SFC (CHIRALPAKIG, supercritical carbon dioxide/ethanol/tert-butyl methyl ether) and 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) was obtained.
• SFC CHIRALPAKIG, supercritical carbon dioxide/ethanol/tert-butyl methyl ether
• 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
• 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)
• Trifluoroacetic acid (0.250 mL, 3.26 mmol
• Second step compound f2 O-tert-butyl (4s,6s)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate compound f3 O-tert-butyl (4r,6r)-6-methoxy-1-methyl-2-azaspiro[3.3]heptane-2-carbothioate
• 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 1.05M sec-butyllithium cyclohexane hexane solution (0.495 mL, 0.520 mmol) were added and stirred at -78°C for 35 minutes.
• Iodomethane (0.0650 mL, 1.04 mmol) was added and stirred at ⁇ 78° C. for 10 minutes and then at room temperature for 40 minutes. Water was added to the reaction solution, extracted with diethyl ether, and passed through a phase separator.
• the diastereomeric mixture (40.7 mg, 0.158 mmol) was purified by HPLC (CHIRALPAK IE, hexane/2-propanol) and 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-Carbothioato (34%, 14.0 mg) was obtained as a racemic mixture.
• HPLC CHIRALPAK IE, hexane/2-propanol
• O-tert-butyl (4s,6s)-6-methoxy-1-methyl-2 - azaspiro[3.3]heptane-2-carbothioate (47%, 19.0 mg)
• 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 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 (0.0220 mmol).
• tert-butyl 6-(dimethylhydrazinylidene)-2-azaspiro[3.3]heptane-2-carboxylate 89.5 mg, 0.353 mmol
• tetrahydrofuran (3.60 mL) was heated to -78°C.
• the reaction was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and passed through a phase separator. After concentration of 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 resulting 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 was stirred at 0° C. for 35 minutes.
• a saturated sodium bicarbonate aqueous solution was added to the reaction solution, extracted with dichloromethane, and passed through a phase separator.
• 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) and 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) was obtained.
• 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-benzoxazine-8 -yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid methyl 4-[3-[2,6-dichloro-4-(6-cyano-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (29.6 mg, 0.0430 mmol), trimethylstannanol ( 77.0 mg, 0.428 mmol) in chlorobenzene (0.940 mL) was
• 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 Methyl 4-[3-[2,6-dichloro-4-(3-cyano-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl] Using -5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate, the title compound is synthesized in the same manner as in step 2 of compound 1-47. bottom.
• Second step compound B2 Methyl 4-bromo-5-fluoro-2-morpholin-4-ylbenzoate 4-bromo-5-fluoro-2-morpholin-4-ylbenzoic acid (400 mg, 1.32 mmol) in dichloromethane (5.00 mL)-methanol (1.00 mL), 2M trimethylsilyldiazomethane-hexane solution (1.32 mL, 2.63 mmol) was added and stirred at room temperature for 30 minutes. Acetic acid was added to the reaction solution, the reaction solution was concentrated, and then the reaction mixture was 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 condition N)
• Second step compound D3 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 Step 2 of compound B using 4-bromo-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid.
• LCMS m/z 326 [M+H] + HPLC retention time: 0.82 minutes (analysis condition D)
• Second step compound E2 Methyl 4-bromo-2-morpholin-4-ylbenzoate
• the title compound was obtained by the same procedure as in Step 2 of compound B using 4-bromo-2-morpholin-4-ylbenzoic acid.
• LCMS m/z 300 [M+H] + HPLC retention time: 1.10 minutes (analysis condition G)
• Second step compound G4 2-ethylhexyl 3-[2-bromo-6-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]phenyl]sulfanylpropanoate 2-ethylhexyl 3-(2-bromo-6-cyanophenyl)sulfanylpropanoate (1.99 g, 5.00 mmol), cobalt (II) chloride hexahydrate (2.38 g, 10.0 mmol) ) in methanol (25.0 mL) was added portionwise sodium borohydride (567 mg, 15.0 mmol) and stirred at room temperature for 2 hours.
• Second step compound J3 4-bromo-2-chloro-5-methylbenzoic acid Lithium hydroxide (117 mg, 4.88 mmol) was added and stirred at room temperature for 1 hour. 5M Hydrochloric acid (1.63 mL, 8.13 mmol) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated to give the title compound as a crude product.
• LCMS m/z 247 [MH] - HPLC retention time: 0.72 minutes (analysis condition D)
• 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. bottom.
• N,N-dimethylformamide (0.000776 mL, 0.0100 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound as a crude product.
• Second step compound K3 4-bromo-2-chloro-5-methoxybenzoic acid
• the title compound was obtained by the same method as compound J, step 2 using methyl 4-bromo-2-chloro-5-methoxybenzoate.
• LCMS m/z 263 [MH] - HPLC retention time: 0.69 minutes (analysis condition D)
• Third step compound K4 4-bromo-2-chloro-5-methoxybenzoyl chloride
• the title compound was obtained as a crude product by the same procedure as in Step 3 of Compound J using 4-bromo-2-chloro-5-methoxybenzoic acid.
• Second step compound L5 tert-butyl 5-bromo-4-oxo-1,3-dihydrophthalazine-2-carboxylate
• 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 with 1M lithium bis(trimethylsilyl)amide solution (15.9 mL, 15.9 mmol) and stirred at 60° C. for 12 hours. An aqueous formic acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
• Second step compound M3 tert-butyl N-[(3-bromo-6-fluoro-2-hydroxyphenyl)methyl]carbamate tert-butyl N-[(2-fluoro-6-hydroxyphenyl)methyl]carbamate (560 mg, 2.32 mmol), N,N-diisopropylethylamine (0.992 mL, 6.96 mmol) in dichloromethane (40 .0 mL) solution 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 was stirred at 0° C. for 30 minutes.
• the reaction was stirred at 60° C. for 15 hours. Methanol was added to the reaction solution and the mixture was concentrated. Tetrahydrofuran (10.0 mL) and 2M hydrochloric acid (5.61 mL, 11.2 mmol) were added and heated at 60° C. for 3 hours. The reaction solution was cooled to 0° C., saturated aqueous sodium hydrogen carbonate solution was added, di-tert-butyl dicarbonate (1.96 g, 8.98 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and concentrated.
• Second step compound N4 tert-butyl 8-bromo-7-fluoro-2,4-dihydro-1,3-benzoxazine-3-carboxylate
• tert-butyl N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate 600 mg, 1.87 mmol
• toluene 5.00 mL
• paraformaldehyde 281 mg, 9.37 mmol
• 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)benzoato Methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl ) Using benzoato dihydrochloride and 2,6-dichloro-4-fluorobenzoyl chloride, the title compound was obtained by the same procedure as in Step 5 of Compound B.
• LCMS m/z 589 [M+H] + HPLC retention time: 0.96 minutes (analysis condition D)
• 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 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).
• 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 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.
• the title compound was obtained by the same operation as in the fifth step of compound B.
• LCMS m/z 529 [M+H] + HPLC retention time: 1.23 minutes (analysis condition G)
• Second step compound V3 2-chloro-4-fluoro-5-methoxybenzoic acid 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) - A solution of water (1.31 mL) was stirred at room temperature for 2 hours. After adding hydrochloric acid, the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and 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 condition D)
• 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 and stirred at room temperature for 1 hour.
• 2-(aminomethyl)-6-bromophenol hydrochloride (5.90 g, 24.7 mmol) and N,N-diisopropylethylamine (6.39 g, 49.5 mmol).
• N-dimethylformamide (70.0 mL) solution was added dropwise, and the mixture was stirred at room temperature for 1 hour.
• Third step compound W2 (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-(2,6-dichloro-4-fluorophenyl)methanone N-[(3-bromo-2-hydroxyphenyl)methyl]-2,6-dichloro-4-fluorobenzamide (13.3 g, 33.8 mmol) in toluene (33.0 mL)/1,4- p-Toluenesulfonic acid (6.43 g, 33.8 mmol) and paraformaldehyde (19.6 g, 677 mmol) were added to a dioxane (33.0 mL) solution and stirred at 90° C. for 5 hours.
• 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)benzoato Methyl 4-[3-(2,6-dichloro-4-fluorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(trifluoromethylsulfonyloxy) To a solution of benzato (17.9 g, 28.6 mmol) in 1,4-dioxane (178 mL) was added bis(pinacolato)diboron (14.5 g, 57.1 mmol), 1,1′-bis(diphenylphosphine).
• Second step compound X3 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoic acid
• a solution of methyl 2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoate (582 mg, 2.04 mmol) in dimethylsulfoxide (3.06 mL)-water (1.02 mL) was added with 5M water.
• An aqueous sodium oxide solution (2.04 mL, 10.2 mmol) was added, and the mixture was stirred at 60°C for 3 hours.
• the title compound was obtained by the same procedure as in Step 3 of compound B using methanone and methyl 4-bromo-5-fluoro-2-hydroxybenzoate.
• Compound W was obtained using tert-butyl N-[(3-bromo-4-fluoro-2-hydroxyphenyl)methyl]carbamate, and the title compound was obtained in the same manner as in the third step.
• 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 methyl 4-[3-(4-bromo-2-chloro-5-methylbenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa- Using 8-azabicyclo[3.2.1]octan-8-yl)benzoate and 3-methoxyazetidine hydrochloride, the title compound was obtained by the same procedure as in step 9 of compound 1-7.
• LCMS m/z 622 [M+H] + HPLC retention time: 1.48 minutes (analysis condition B)
• 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 methyl 4-[3-(4-bromo-2-chloro-5-methoxybenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa- Using 8-azabicyclo[3.2.1]octan-8-yl)benzoate and 3-methoxyazetidine hydrochloride, the title compound was obtained by the same procedure as in step 9 of compound 1-7.
• 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 Methyl 4-[3-[2-chloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8- yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (3.17 g, 4.79 mmol) in tetrahydrofuran (7.61 mL) Ethanol (7.61 mL) and 8M aqueous potassium hydrox
• 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-benzoxazine-8 -yl]-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 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-
• 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-yl benzoic acid 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 mmmol) and trimethylstananol (30.3 mg, 0.167 mmmol) in chlorobenzene (0.140 mL) was heated to 200 mL under microwave.
• 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
• 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 at 100° C.
• boronic acids or boronate esters known in the literature or commercially available, or boronic acids or boronate esters shown in Table 2-2 are used in the same manner as in the method for producing compound 2-6, as shown in Table 2-1.
• a compound was synthesized. 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.
• 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)benzoato [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 1,4 - A solution of dioxan
• Third step compound 3-2 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)benzoic acid 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 (38.9 mg, 0.0550 mmol) in 1-methylpyrrolidin-2-one (0.5
• 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-benzoxazine-8- yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2, Using 4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and 7-bromo-2-methylpyrazolo[4,3-c]pyridine in the same manner as in the second step of compound 3-2 Work-up gave the title compound.
• 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-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2, the second step of compound 3-2 using 4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and 7-bromo-2-methyltriazolo[4,5-c]pyridine; The title compound was obtained by the same operation.
• 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-benzoxazine-8 -yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-c]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate by the same procedure as in the third step of compound 3-2 , to give the title compound.
• 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-benzoxazine-8 -yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid methyl 4-[3-[2,6-dichloro-4-(2-methyltriazolo[4,5-b]pyridin-7-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate by the same procedure as in the third step of compound 3-2 , to give the title compound.
• 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 [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 to give compound 3-2.
• the title compound was obtained by the same operation as in the second step.
• 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 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 third step of compound 3-2 and The title compound was obtained by the same operation.
• Step 1 The compound shown in Table 3-1 was treated with [3,5-dichloro-4-[8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1 ]Octane-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and aryl bromides listed in Table 3-1 to give compound 3- Synthesized by the same operation as in the second step of 2. However, in synthesizing Compound Nos. 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.
• Second step The compounds shown in Table 3-2 were synthesized using the esters shown in Table 3-1 obtained in the first step and the same procedure as in the second step of compound 3-2.
• 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 [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)
• 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 [3,5-dichloro-4-[8-(4-methoxycarbonyl-3-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carbonyl]phenyl]boronic acid and Using 4-bromo-1-(2-methoxyethyl)pyrazole, the title compound was obtained in the same manner as in Compound 3-1, Step 2.
• 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 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 (25.0 mg, 0.0390 mmol) and 2-methyl-1,3-propanediol (0.00693 ml , 0.0780 mmol) in aceton
• Trimethylsilyl sulfonate (6.60 mL, 36.5 mmol) was added and stirred at 70° C. for 4.5 hours. The reaction was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate and washed with a 5% aqueous sodium hydrogencarbonate solution and a 15% aqueous sodium chloride solution, then the organic layer was dried over magnesium sulfate and concentrated. The obtained 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)
• Second step compound ACP3 7-methyl-5,9-dioxa-2-azaspiro[3.5]nonane A 20% Palladium hydroxide-activated carbon (hydrous) (1.20 g, 1.70 mmol) was added and stirred under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite and washed with 1,4-dioxane to obtain the title compound as a crude product in 1,4-dioxane solution.
• Second step compound ACP5 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane 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-activated carbon (hydrous) (306 mg, 0.436 mmol) was added to the solution, 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 solution.
• 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 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 (12.8 g, 17.6 mmol) in tetrahydrofuran (32.0
• Second step compound ACP7 3,3-dimethoxyazetidine 20% palladium hydroxide-activated carbon (hydrous) (1. 42 g, 2.02 mmol) was added and stirred under a hydrogen atmosphere for 7 hours. The reaction solution was filtered through celite and washed with 1,4-dioxane to obtain the title compound as a crude product in 1,4-dioxane solution.
• 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 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 (15.6 g, 23.3 mmol) in tetrahydrofuran (39.0 mL) and methanol (39.0 mL) 8M aqueous potassium hydroxide solution (8.75 mL, 70.0 mmol) was added
• Second step 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 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) solution was added with 8M aqueous sodium hydroxide
• 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-benzoxazine -8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid methyl 4-[3-[2,6-dichloro-4-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)benzoyl]-2,4-dihydro-1,3-benzo Oxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (1.90 mg, 0.00278 mmol) in tetrahydrofuran (0 .00925 ml) and methanol (0.0185
• 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-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate methyl 4-[3-[2,6-dichloro-4-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate in the same manner as in step 2 of Synthetic Method A for compound 5-7 to give the title compound.
• Third step compound 5-10 4-[3-[2,6-dichloro-4-(7,11-dioxa-2-azadispiro[3.1.56.14]dodecane-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 methyl 4-[3-[2,6-dichloro-4-(6-oxo-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate and 1,3-propanediol, Synthetic Method for Compound 5-7 The title compound was obtained by the same operation as in the third step of A
• 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-benzoxazine -8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid methyl 4-[3-[2,6-dichloro-4-(6,6-dimethoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzo Oxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate in the same manner as in step 2 of compound 5-1 gave the title compound.
• Second step compound AZ6 4-[3-[2,6-dichloro-4-[(2R)-2-methyl-3-oxoazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8- yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate methyl 4-[3-[2,6-dichloro-4-[(2R)-3-hydroxy-2-methylazetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate in the same manner as in step 2 of Synthetic Method A for compound 5-7 to obtain the title compound.
• LCMS m/z 654 [M+H] + HPLC retention time: 0.
• Second step 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 Methyl 4-[3-[2,6-dichloro-4-[3-hydroxy-3-(hydroxymethyl)azetidin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8- yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (9.60 mg, 0.0140 mmol), iodomethane (0.00268 mL, 0.0430 mmol) in tetrahydrofuran) was
• the reaction mixture was concentrated under reduced pressure to obtain rac-(1R,5S,6S)-3-azabicyclo[3.2.0]heptan-6-ol 2,2,2-trifluoroacetate as a crude product.
• the resulting crude product and compound A (40.0 mg, 0.062 mmol), rac-BINAP Pd G4 (6.19 mg, 0.00615 mmol), cesium carbonate (100 mg, 0.308 mmol)
• a solution of 1,4-dioxane (0.300 mL) was stirred at 100° C. for 1 hour and then at 120° C. for 2 hours.
• the reaction solution was purified by HPLC (acetonitrile/water, 0.1% formic acid), and fractions containing the title compound were collected and concentrated.
• Second step compound AM1 methyl 4-[3-[2,6-dichloro-4-(2,6-diazaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8- yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato 2,2,2-trifluoroacetate tert-butyl 6-[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]-2,6-diazaspiro[3.3]heptane-2-carboxylate (230 mg, 0.300 mmol) in dichloromethane Trifluoroace
• Third step compound 7-2 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 methyl 4-[3-[2,6-dichloro-4-(2,6-diazaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8- yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato 2,2,2-trifluoroacetate (20.0 mg, 0.0260 mmol) in acetonitrile (0.128 m
• Second step compound 7-7 4-[3-[2,6-dichloro-4-[6-(2-cyano-2-methylpropyl)-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 methyl 4-[3-[2,6-dichloro-4-[6-(2-cyano-2-methylpropyl)-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)benzoate (29.8 mg, 0.0400 mmol) in 1,4-dioxane (0
• Second step compound AM11 Methyl 4-[3-[2,6-dichloro-4-(2,7-diazaspiro[3.4]octan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8- yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato 2,2,2-trifluoroacetate tert-butyl 2-[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]-2,7-diazaspiro[3.4]octane-7-carboxylate to compound 7-2.
• the title compound was synthesized by the same
• Second step compound 8-4 4-[3-[2,6-dichloro-4-[meso-4-(2-methoxyethyl)-3,5-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-[meso-3,5-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 was used to synthesize the title compound in the same manner as in step 3 of compound 8-1. .
• Second step compound AM15 4-[3-[4-(azetidin-3-yloxy)-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 2,2,2-trifluoroacetate 4-[3-[2,6-dichloro-4-[1-[(2-methylpropan-2-yl)oxycarbonyl]azetidin-3-yl]oxybenzoyl]-2,4-dihydro-1,3 -benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, second step of compound 7-2
• the title compound was synthesized by the same procedure as described above.
• Third step compound 8-8 4-[3-[2,6-dichloro-4-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]oxybenzoyl]-2,4-dihydro-1,3-benzoxazine -8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 4-[3-[4-(azetidin-3-yloxy)-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 Using 2,2,2-trifluoroacetate, the title compound was obtained in the same manner as in Step 3 of Compound 7-2.
• Second step compound 9-4 4-[3-[2,6-dichloro-4-(2-cyclopropyl-2,6-diazaspiro[3.3]heptan-6-yl)benzoyl]-2,4-dihydro-1,3-benzo Oxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid methyl 4-[3-[2,6-dichloro-4-(2-cyclopropyl-2,6-diazaspiro[3.3]heptan-6-yl)benzoyl]-2,4-dihydro-1,3- Benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (19.6 mg, 0.0280 mmol), 5M water A solution of aqueous sodium oxide (0.0554 mL, 0.277 mmol
• Second step compound AM28 Methyl 4-[3-[2,6-dichloro-4-(2,6-diazaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8- yl]-5-fluoro-2-morpholin-4-ylbenzoate 2,2,2-trifluoroacetate tert-butyl 6-[3,5-dichloro-4-[8-(2-fluoro-4-methoxycarbonyl-5-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine- Using 3-carbonyl]phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate, the title compound was synthesized in the same manner as in step 2 of compound 7-2.
• LCMS m/z 641 [M+H] + HPLC retention time: 0.59 minutes, 0.61 minutes (analysis condition D)
• Third step compound 10-11 4-[3-[2,6-dichloro-4-[2-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptan-6-yl]benzoyl]-2,4-dihydro- 1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid Methyl 4-[3-[2,6-dichloro-4-(2,6-diazaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8- Synthesized by using yl]-5-fluoro-2-morpholin-4-ylbenzoato 2,2,2-trifluoroacetate and following the same procedure as in compound 9-12. However, oxetan-3-one was used instead of paraformaldehyde. LCMS: m/z 683 [M+H] + HPLC retention time: 0.98 minutes
• Second step compound 10-3 4-[3-[2,6-dichloro-4-[(3R)-3,4-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-[(3R)-3-methylpiperazin-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 (8.00 mg, 0.0120 mmol), paraformaldehyde (3.66 mg, 0.0120 mmol).
• Trifluoromethanesulfonic anhydride (0.0163 mL, 0.0930 mmol) was added and stirred at -78°C for 30 minutes.
• 3-(Difluoromethoxy)azetidine hydrochloride (19.9 mg, 0.125 mmol) and N,N-diisopropylethylamine (0.0434 mL, 0.249 mmol) were added and stirred overnight at room temperature. Methanol was added to the reaction solution and concentrated.
• Second step compound 11-5 4-[3-[2,6-dichloro-4-[3-(3-methoxyazetidin-1-yl)-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
• Methyl 4-[3-[2,6-dichloro-4-(3-hydroxy-3-methylazetidin-1-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]
• the title compound was obtained by the same procedure as for compound 11-4 using -5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate.
• Trifluoromethanesulfonic anhydride (0.0137 mL, 0.0640 mmol) was added and stirred at -78°C for 1.5 hours. Cyclopropanol (0.0102 mL, 0.160 mmol) and 1 M potassium tert-butoxide solution (0.160 mL, 0.160 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was purified by HPLC (acetonitrile/water, 0.1% formic acid) to give the title compound (38%, 22.7 mg). LCMS: m/z 722 [M+H] + HPLC retention time: 1.08 minutes (analysis condition D)
• Second step compound 11-10 4-[3-[2,6-dichloro-4-(6-cyclopropyloxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine -8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid methyl 4-[3-[2,6-dichloro-4-(6-cyclopropyloxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzo Oxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (22.7 mg, 0.0310 mmol) in methanol (0 .157 mL) and 1,4-dioxane (0.472 mL)
• Second step compound 12-2 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2 -(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzoic acid Methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro- 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)benzoate (14.2 mg, 0.0220 mmol) in tetrahydrofuran (0.109 mL)-methanol (0.109 mL) ) solution was added with 5M aqueous sodium hydroxide solution (0.0436 mL, 0.218 m
• Amine synthesis compound z1 benzyl (2S,3S)-3-hydroxy-2-methylazetidine-1-carboxylate A solution of benzyl (2S)-2-methyl-3-oxoazetidine-1-carboxylate (100 mg, 0.456 mmol) in tetrahydrofuran (2.28 mL) was cooled to -78°C. A 1M lithium tri(sec-butyl)borohydride tetrahydrofuran solution (0.547 mL, 0.547 mmol) was added dropwise, and the mixture was stirred at -78°C for 1 hour.
• Second step compound ME19 Methyl 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro- 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato 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 (14.0 mg, 0.0280 mmol) in dichloromethane (0.281 mL) was cooled to 0° C.
• Second step compound INT2 Di-tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrophthalazine-2,3-dicarboxylate
• Di-tert-butyl 5-iodo-1,4-dihydrophthalazine-2,3-dicarboxylate (222 mg, 0.482 mmol), bis(pinacolato)diboron (223 mg, 1.99 mmol), potassium acetate (142 mg, 1.45 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (19.8 mg, 0.0240 mmol) in 1,4-dioxane.
• Third step compound LP12b Di-tert-butyl 5-(4-ethoxycarbonyl-3-morpholin-4-ylphenyl)-1,4-dihydrophthalazine-2,3-dicarboxylate
• Di-tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrophthalazine-2,3-dicarboxylate 29.0 mg, 0.0630 mmol
• ethyl 4-bromo-2-morpholin-4-ylbenzoate (21.7 mg, 0.0690 mmol
• sodium carbonate 20.0 mg, 0.189 mmol
• [1 A solution of 1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (4.61 mg, 0.00630 mmol) in 1,4-dioxane (0.300 mL) was stirred at 90° C.
• Second step compound DP13 Methyl 3-fluoro-2-methyl-6-morpholin-4-ylbenzoate To a solution of the crude product of 3-fluoro-2-methyl-6-morpholin-4-ylbenzoic acid in dichloromethane (5.19 mL) and methanol (1.30 mL) was added 2M trimethylsilyldiazomethane hexane solution (0.422 mL, 0.844 mmol) was added. After stirring at room temperature for 1 hour, the solution was cooled to 0° C. and a solution of di-tert-butyl hydrazodicarboxylate (236 mg, 1.01 mmol) in tetrahydrofuran (2.00 mL) was added.
• Second step compound DP8 Ethyl 3,5-difluoro-2-morpholin-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Using ethyl 3,5-difluoro-2-morpholin-4-ylbenzoate, the crude product of the title compound was synthesized in the same manner as in Step 3 of compound 13-3.
• Second step compound LP13b 3-fluoro-4-[3-[(2-methylpropan-2-yl)oxycarbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-yl benzoin acid tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate and 4- Using bromo-3-fluoro-2-morpholin-4-ylbenzoic acid, the title compound was synthesized in the same manner as in Step 4 of Compound 13-3.
• LCMS m/z 459 [M+H] + HPLC retention time: 1.15 minutes (analysis condition G)
• Third step compound 13-5 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-3-fluoro-2 - morpholin-4-yl benzoic acid 3-fluoro-4-[3-[(2-methylpropan-2-yl)oxycarbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4-yl benzoin
• the title compound was synthesized in the same manner as in the fourth step of compound 13-2 using an acid.
• Second step compound CMA4 4-chloro-6-(1-methylpyrazol-4-yl)pyridine-3-carboxylic acid
• Methyl 4-chloro-6-(1-methylpyrazol-4-yl)pyridine-3-carboxylate (384 mg, 1.53 mmol) and 5M aqueous sodium hydroxide solution (3.05 mL, 15.3 mmol)
• a solution of methanol (7.00 mL) and tetrahydrofuran (7.00 mL) was stirred at room temperature for 1 hour. After adding formic acid to the reaction mixture, it was purified by reverse phase column chromatography (acetonitrile/water, 0.1% formic acid) to give the title compound (35%, 127 mg).
• Second step compound 13-8 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-7-fluoro-2,4-dihydro-1,3-benzoxazin-8-yl]-5 -fluoro-2-morpholin-4-ylbenzoic acid 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 synthesized in the same manner as in the 4th and 5th steps of compound 13-2.
• Second step compound 13-11 4-[3-(6-chloro-1-methylindole-5-carbonyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-yl benzoin acid
• Methyl 4-[3-(6-chloro-1-methylindole-5-carbonyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate
• Lithium hydroxide monohydrate (50.0 mg, 1.19 mmol) in water in a solution of (30.0 mg, 0.0530 mmol) in methanol (3.00 mL) and tetrahydrofuran (3.00 mL).
• Second step compound 13-12 4-[3-(5-chloro-1-methylindole-6-carbonyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-yl benzoin acid Methyl 4-[3-(5-chloro-1-methylindole-6-carbonyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate Using , the title compound was synthesized by the same procedure as in the second step of compound 13-11. LCMS: m/z 550 [M+H] + HPLC retention time: 1.42 minutes (analysis condition B)
• Ghosez was added to a solution of 2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoic acid (698 mg, 2.21 mmol) in ethyl acetate (14.0 mL).
• Third step compound 13-16 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8 -yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid methyl 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine- 8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (196 mg, 0.281 mmol) and 8M aqueous potassium hydroxide solution (0 .352 mL, 2.81 mmol) in tetrahydr
• Second step compound MCL2 2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoic acid
• Sodium tert-butoxide (2.78 g, 28.9 mmol) was added to a solution of (2R,5R)-1,2,5-trimethylpiperazine (1.63 g, 12.7 mmol) in tetrahydrofuran (18.4 mL). was added.
• 4-bromo-2-chlorobenzoic acid (2.00 g, 8.49 mmol) and rac-BINAP (0.264 g, 0.425 mmol) in 4-methyltetrahydropyran (6.00 mL). solution was added.
• N,N-diisopropylethylamine (16.0 mL, 92.0 mmol) was added to the reaction solution, and the mixture was stirred at 25° C. for 1 hour.
• water, 15% aqueous sodium chloride solution, 8M aqueous sodium hydroxide solution and 1M hydrochloric acid were added, and the organic layer obtained by extraction was concentrated.
• 1M hydrochloric acid and ethyl acetate were added to the resulting residue for reverse extraction, and 8M aqueous sodium hydroxide solution and 2M hydrochloric acid were added to the resulting aqueous layer, followed by extraction with 4-methyltetrahydropyran.
• Second step compound 14-1 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholine-4 - ylbenzoic acid
• Second step compound EE2 Ethyl 2-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-4-bromo-5-fluorobenzoate
• Ethyl 4-bromo-2,5-difluorobenzoate (30.0 mg, 0.113 mmol) and 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride
• a solution of salt 38.9 mg, 0.260 mmol
• toluene (0.300 mL) was stirred at 110° C. overnight.
• Second step compound BA2 [3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]boronic acid Using (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone, the compound A crude product of the title compound was synthesized in the same manner as in the second step of 13-2.
• LCMS m/z 432 [M+H]+ HPLC retention time: 0.89 minutes, 0.91 minutes (analysis condition G)
• Second step compound ME18 Methyl 4-[2-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-4-oxo-1,3-dihydrophthalazin-5-yl]-2-morpholin-4 - ylbenzoate 8-bromo-3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydrophthalazin-1-one is used to synthesize the quaternary reaction of compound 13-3.
• the title compound was synthesized by the same procedure as in the process.
• Third step compound 14-4 4-[2-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-4-oxo-1,3-dihydrophthalazin-5-yl]-2-morpholine-4- ylbenzoic acid Methyl 4-[2-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-4-oxo-1,3-dihydrophthalazin-5-yl]-2-morpholin-4 The title compound was synthesized in the same manner as in the fifth step of Compound 13-2 using -ylbenzoate. LCMS: m/z 606 [M+H] + HPLC retention time: 0.82 minutes, 0.89 minutes (analysis condition A)
• Second step compound UP6 (8-bromo-2,4-dihydro-1H-quinazolin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone N-[(2-amino-3-bromophenyl)methyl]-2,6-dichloro-4-(1-methylpyrazol-4-yl)benzamide (59.0 mg, 0.130 mmol) paraformaldehyde (39 .0 mg, 1.30 mmol) in toluene (0.300 mL) was stirred at 90° C. for 1 hour.
• Third step compound 14-5 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2,4-dihydro-1H-quinazolin-8-yl]-2-morpholin-4-ylbenzoyl acid (8-bromo-2,4-dihydro-1H-quinazolin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone and 2-morpholin-4-yl -4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid is used to synthesize the title compound in the same manner as in Step 4 of Compound 13-3 bottom.
• LCMS m/z 592 [M+H] + HPLC retention time: 0.96 minutes (analysis condition A)
• triphosgene (26.1 mg, 0.0880 mmol) and triethylamine (0.246 mL, 1.76 mmol) were added at 0°C.
• triphosgene (39.2 mg, 0.132 mmol) and triethylamine (0.123 mL, 0.881 mmol) were added at 0°C.
• saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, passed through a phase separator, and then concentrated.
• Second step compound 14-6 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2-oxo-1,4-dihydroquinazolin-8-yl]-2-morpholin-4-yl benzoic acid 8-bromo-3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-1,4-dihydroquinazolin-2-one and 2-morpholin-4-yl-4-( Using 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, the title compound was synthesized in the same manner as in Step 4 of Compound 13-3.
• LCMS m/z 606 [M+H] + HPLC retention time: 1.03 minutes (analysis condition A)
• Second step compound UD2 (8-bromo-4,4-dideuterio-2H-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone
• tert-butyl 8-bromo-4,4-dideuterio-2H-1,3-benzoxazine-3-carboxylate the title compound was synthesized in the same manner as in Step 4 of Compound 13-2.
• LCMS m/z 468 [M+H] + HPLC retention time: 1.17 minutes (analysis condition G)
• Third step compound 14-7 4-[4,4-dideuterio-3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-2H-1,3-benzoxazin-8-yl]-2-morpholine -4-yl benzoic acid 4-bromo-2-morpholin-4-ylbenzoic acid (30.5 mg, 0.107 mmol), bis(pinacolato)diboron (27.1 mg, 0.107 mmol), potassium acetate (15.7 mg, 0.160 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (3.90 mg, 0.00533 mmol) in 1,4-dioxane (0.300 mL).
• Second step compound UP10 (8-bromo-1,4-dihydro-2,3-benzoxazin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone
• tert-butyl 8-bromo-1,4-dihydro-2,3-benzoxazine-3-carboxylate the title compound was synthesized in the same manner as in Step 4 of compound 13-2.
• LCMS m/z 466 [M+H] + HPLC retention time: 0.89 minutes (analysis condition O)
• Third step compound 14-8 4-[3-[2,6-dichloro-4-(1-methylpyrazol-4-yl)benzoyl]-1,4-dihydro-2,3-benzoxazin-8-yl]-2-morpholine-4 - ylbenzoic acid (8-bromo-1,4-dihydro-2,3-benzoxazin-3-yl)-[2,6-dichloro-4-(1-methylpyrazol-4-yl)phenyl]methanone and 4-bromo- Using 2-morpholin-4-ylbenzoic acid, the title compound was synthesized in the same manner as in the fourth step of Compound 13-3.
• Second step compound 14-9 4-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)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 (8-bromo-2,4-dihydro-1,3-benzoxazin-3-yl)-[2,6-dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]methanone and 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid, the same procedure as in the third step of compound 14-7
• the title compound was synthesized by.
• Second step compound PN1 Methyl 4-[3-[2,6-dichloro-4-(1H-pyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4 - ylbenzoate Methyl 4-[3-[2,6-dichloro-4-[1-(oxan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl ]-2-morpholin-4-ylbenzoate (34.1 mg, 0.0500 mmol) and 4M hydrochloric acid ethyl acetate solution (0.315 mL, 1.26 mmol) in ethanol (0.336 mL) at room temperature.
• Third step compound 15-1 4-[3-[2,6-dichloro-4-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8 -yl]-2-morpholin-4-ylbenzoic acid Methyl 4-[3-[2,6-dichloro-4-(1H-pyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-2-morpholin-4 -ylbenzoate (14.5 mg, 0.0240 mmol), isobutylene oxide (0.00328 mL, 0.0370 mmol) and cesium carbonate (15.9 mg, 0.0490 mmol) in N,N-dimethylformamide (0 .200 mL) solution was stirred at 60° C.
• Second step compound PN2 Methyl 4-[3-[2,6-dichloro-4-(1H-pyrazol-4-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2 - morpholin-4-ylbenzoate Methyl 4-[3-[2,6-dichloro-4-[1-(oxan-2-yl)pyrazol-4-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl ]-5-Fluoro-2-morpholin-4-ylbenzoate was used to synthesize the title compound in the same manner as in Step 2 of compound 15-1.
• LCMS m/z 611 [M+H] + HPLC retention time: 0.78 minutes, 0.81 minutes (analysis condition G)

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