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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • 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
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to novel pyrazole derivatives and their uses.
• Poly(ADP-ribosyl)ation is a biochemical reaction in which ADP-ribose is chain-added to glutamic acid or aspartic acid residues of proteins using nicotinamide adenine dinucleotide as a substrate.
• the poly(ADP-ribose) chain produced is composed of up to nearly 200 ADP-ribose.
• the poly(ADP-ribosyl)transferase (PARP) family is known as an enzyme that catalyzes the poly(ADP-ribosyl)ation reaction.
• Tankyrase is composed of an ankyrin domain that recognizes proteins to undergo poly(ADP-ribosyl)ation, a sterile alpha motif (SAM) domain involved in self-multimerization, and a PARP catalytic domain that controls poly(ADP-ribosyl)ation reactions.
• SAM sterile alpha motif
• Tankyrase binds to various proteins via the ankyrin region in the molecule and converts them into poly(ADP-ribosyl).
• Tankyrase binding proteins include TRF1, NuMA, Plk1, Miki, Axin, TNKS1BP1, IRAP, Mcl-1, 3BP2, and the like.
• Tankyrase regulates the physiological functions of these proteins by converting them into poly(ADP-ribosyl). Therefore, inhibition of tankyrase is considered to be useful for controlling the physiological functions of the protein, such as cell proliferation, cell differentiation, and tissue formation.
• tankyrase inhibitory compounds having tankyrase inhibitory activity examples include compound XAV939 described in Non-Patent Document 1, compounds described in Patent Documents 1 and 2, NVP-TNKS656 described in Non-Patent Document 2, and Non-Patent Document 3. and G007-LK described in Patent Document 3, 2-(piperidin-1-yl)pyrimidin-4(3H)-ones having a spiro structure described in Patent Document 4, and dihydroquinazolinone compounds described in Patent Document 5 , etc. are known.
• ⁇ -catenin is a protein encoded by the CTNNB1 gene in humans, and accumulation of ⁇ -catenin due to loss-of-function mutations of ⁇ -catenin inhibitors such as APC or gain-of-function mutations of ⁇ -catenin is caused by hepatocytes. It is associated with many cancers, including colon cancer, lung cancer, breast cancer, ovarian cancer, and endometrial cancer. Therefore, substances that reduce or inhibit ⁇ -catenin are considered to be effective against these cancers.
• tankyrase inhibitors and ⁇ -catenin lowering/inhibitors are effective against fibrosarcoma, ovarian cancer, glioblastoma, pancreatic cancer, breast cancer, astrocytoma, lung cancer, gastric cancer, hepatocellular carcinoma, and multiple myeloma.
• colon cancer, bladder cancer leukemia, infectious diseases such as herpes simplex virus and Epstein-Barr virus, fibrosis such as pulmonary fibrosis, cherubism, and multiple sclerosis.
• amyotrophic lateral sclerosis, skin/cartilage damage, and metabolic diseases and may be effective in suppressing cancer metastasis.
• the present invention has been made in view of the problems of the prior art, and has excellent tankyrase inhibitory activity, and is useful for the treatment and prevention of proliferative diseases such as cancer, and other pulmonary fibrosis.
• the present invention aims to provide a novel compound that is also useful for the treatment of fibrosis such as liver cirrhosis, its uses, and intermediate compounds useful for the production of the novel compound.
• the gist of the present invention is as follows.
• the compound represented by the above formula (I) has the following formula (Ia): (In the formula, R 1 , R 2 , R 3 and R 4 are the same or different, hydrogen atom, halogen atom, hydroxyl group, carboxyl group, substituted or unsubstituted amino group, substituted or unsubstituted C 1-6 - Alkyl group, substituted or unsubstituted C 1-6 -alkoxy group, substituted or unsubstituted C 1-6 -alkylthio group, substituted or unsubstituted C 1-6 -alkoxy-carbonyl group, substituted or unsubstituted aromatic represents a group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted acyl group, and Ar 1 , Ar 2 , L 1 and L 2 have the same meanings as in formula (I) above.)
• Ar 1 , Ar 2 , L 1 and L 2 have the same meaning
• a tankyrase inhibitor containing the compound according to any one of (1) to (3) above, a salt thereof, or a solvate thereof.
• a ⁇ -catenin-lowering agent containing the compound according to any one of (1) to (3) above, a salt thereof, or a solvate thereof.
• trisubstituted pyrazole derivatives having excellent tankyrase inhibitory activity can be provided.
• the 5- or 6-membered ring represented by Ring is, for example, a carbon ring such as a benzene ring, a cyclohexane ring, a cyclohexadiene ring, a cyclohexene ring, a cyclopentadiene ring, a cyclopentene ring, a cyclopentane ring; Furan ring, thiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, furazane ring
• heterocycles such as
• the 5- or 6-membered ring is a halogen atom, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted C 1-6 -alkyl group, a substituted or unsubstituted C 1-6 -alkoxy group, Substituted or unsubstituted C 1-6 -alkylthio group, substituted or unsubstituted C 1-6 -alkoxy-carbonyl group, substituted or unsubstituted aromatic group, substituted or unsubstituted aralkyl group, substituted or unsubstituted It may be substituted with one or more substituents selected from acyl groups and the like.
• examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• C 1-6 -alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, and cyclopropyl group. group, cyclobutyl group, cyclopentyl group, and cyclohexyl group.
• Examples of the C 1-6 -alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, and hexyl group.
• Examples include oxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, and cyclohexyloxy group.
• Examples of the C 1-6 -alkylthio group include methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, hexylthio group group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, and cyclohexylthio group.
• Examples of the C 1-6 -alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbonyl group. , pentyloxycarbonyl group, isopentyloxycarbonyl group, hexyloxycarbonyl group, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxycarbonyl group, and cyclohexyloxycarbonyl group.
• aromatic groups include aromatic hydrocarbon groups such as phenyl, tolyl, and naphthyl; furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, Triazolyl group (1,2,3-triazolyl group, 1,2,4-triazolyl group), pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, quinolyl group, isoquinolyl group, indolyl group, pyridothienopyrimidine ring group, etc. aromatic heterocyclic groups.
• Examples of the aralkyl group include benzyl group, phenethyl group, and naphthylmethyl group.
• Substituents on the aromatic group and aralkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, C 1-6 -alkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group , C 1-6 -alkoxy groups such as pentyloxy group, isopentyloxy group, hexyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; methoxycarbon
• acyl group examples include C 1-6 -aliphatic acyl groups such as formyl group, acetyl group, propionyl group (propanoyl group), butyryl group (butanoyl group), valeryl group (pentanoyl group), and hexanoyl group; benzoyl group, Examples include aromatic acyl groups (aroyl groups) such as toluoyl groups.
• the C 1-6 -alkyl group, C 1-6 -alkoxy group, C 1-6 -alkylthio group, C 1-6 -alkoxy-carbonyl group and acyl group are aromatic groups, acyl groups, hydroxyl groups, and carboxyl groups. , a halogen atom, a C 1-6 -alkoxy group (eg, a methoxy group, an ethoxy group, a propoxy group), and the like.
• the C 1-6 -alkyl group substituted with a halogen atom includes, for example, a trifluoromethyl group.
• substituted or unsubstituted amino groups include the following formula: NRR' (wherein R and R' are the same or different, a hydrogen atom, a carboxyl group, a substituted or unsubstituted C 1-6 -alkyl group, a substituted or unsubstituted C 1-6 -alkoxy group, substituted or unsubstituted C 1-6 -alkoxy-carbonyl group, substituted or unsubstituted aromatic group, substituted or unsubstituted aralkyl group, or substituted or unsubstituted represents an acyl group, and R and R' may form a substituted or unsubstituted heterocycle together with the nitrogen atom to which they are bonded.
• the substituted amino group include amino groups mono- or di-substituted with the C 1-6 -alkyl group, such as methylamino and dimethylamino groups.
• the chain members forming the linking group represented by L 1 or L 2 in the formulas (I), (Ia), (II) and (III) are selected from carbon atoms, nitrogen atoms, oxygen atoms and sulfur atoms. preferably contains carbon atoms.
• the linking group may have a side chain consisting of, for example, the substituted or unsubstituted C 1-6 -alkyl group, and may include a cyclic structure such as a spiro ring, cycloalkane ring, benzene ring, or heterocycle. good.
• the number of chain members is the minimum number of chain members. For example, a 1,2-phenylene group has two chain members, a 1,3-phenylene group has three chain members, and a 1,4-phenylene group has four chain members.
• linking group having two or more chain members examples include those shown below.
• L 1 is preferably a direct bond
• Ar 1 is preferably an aromatic group substituted with a carboxyl group, more preferably substituted with a carboxyl group. It is a phenyl group.
• Ar 2 is preferably a substituted or unsubstituted phenyl group, or an oxadiazolyl group substituted with a substituted or unsubstituted phenyl group.
• the compound represented by the formula (II) or (III) is a novel intermediate compound useful for producing the compound represented by the formula (I) or (Ia).
• the protecting group for the nitrogen atom constituting the pyrazole ring is not particularly limited as long as it is a protecting group useful as a protecting group for the NH group of the pyrazole ring, but for example, tetrahydropyranyl. (THP), trityl group (Tr), 2-methoxypropan-2-yl group, 1-methoxycyclohexyl group, and the like.
• the salt of the compound represented by formula (I), (Ia), (II) or (III) is preferably a pharmaceutically acceptable salt, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, Inorganic acids such as hydriodic acid, nitric acid, pyrosulfuric acid, metaphosphoric acid, or citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, sulfonic acids (for example, methanesulfonic acid, p-toluenesulfonic acid, Examples include salts with organic acids such as naphthalene sulfonic acid.
• a pharmaceutically acceptable salt such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, Inorganic acids such as hydriodic acid, nitric acid, pyrosulfuric acid, metaphosphoric acid, or citric acid, benzoic acid, acetic acid, propionic acid
• Examples of the solvate of the compound represented by formula (I), (Ia), (II) or (III) or a salt thereof include hydrates.
• the compound represented by the formula (I), (Ia), (II) or (III) or a salt thereof or a solvate thereof may have one or more asymmetric carbon atoms, depending on the type of substituent, etc.
• optically active forms based on one or more asymmetric carbon atoms, enantiomers, arbitrary mixtures thereof, racemates, etc. are all included within the scope of the present invention.
• groups having an unsaturated double bond may exist in a cis- or trans-form.
• the compound represented by the formula (I), (Ia), (II) or (III) or a salt thereof or a solvate thereof may include possible isomers (rotamers, rotamers, atropisomer, tautomer, etc.), which may exist as a single isomer or as a mixture thereof.
• the compound may have one or two of these isomers or isotopes. It may be a mixture of the above or a racemate.
• the compound (I) of the present invention obtained as described above can be converted into the desired salt by a method known per se or a method analogous thereto.
• the trisubstituted pyrazole derivatives of the present invention have excellent tankyrase inhibitory and/or ⁇ -catenin-lowering effects. Therefore, various solid tumors and hematological tumors (e.g., fibrosarcoma, ovarian cancer, glioblastoma, pancreatic cancer) are associated with tankyrase and/or ⁇ -catenin, or the intracellular molecular reactions involving these.
• various solid tumors and hematological tumors e.g., fibrosarcoma, ovarian cancer, glioblastoma, pancreatic cancer
• breast cancer, astrocytoma lung cancer, stomach cancer, liver cancer, colon cancer, bladder cancer, leukemia, etc.
• infectious diseases such as herpes simplex virus and Epstein-Barr virus Fibrosis such as pulmonary fibrosis and liver cirrhosis
• Neurodegenerative diseases such as cherubism, multiple sclerosis, and amyotrophic lateral sclerosis
• Various forms of inflammatory diseases such as skin and cartilage damage
• Metabolic diseases such as obesity
• it can be administered alone or in combination with at least one of conventionally known treatment methods including conventional surgery, radiation therapy, and anticancer drug treatment.
• the tankyrase inhibitor and ⁇ -catenin lowering agent of the present invention may further contain other therapeutic agents other than the trisubstituted pyrazole derivative of the present invention, Other therapeutic agents may also be used in combination at the same time or at different times.
• the other therapeutic agents include, for example, other anticancer agents (anti-cell proliferation, anti-malignant tumor, DNA damaging agents, and combinations thereof; more specifically, alkylating agents (temozolomide, melphalan, etc.) , antimetabolites (gemcitabine, cytarabine (Ara-C), fluorouracil (5-FU), pemetrexed, mercaptopurine, methotrexate, etc.), plant alkaloids (irinotecan (SN-38), etoposide (VP-16), etc.), Cancer antibiotics (actinomycin D, daunorubicin, doxorubicin, bleomycin, mitoxantrone, etc.), platinum drugs (oxaliplatin, carboplatin, cisplatin, etc.); microtubule inhibitors (paclitaxel, vinblastine, vincristine, vindesine, vinorelbine, docetaxel) , cabazitaxel, eribulin, etc.
• the pharmaceutical composition of the present invention can be administered by either oral or parenteral administration routes, such as inhalation administration, nasal administration, eye drops administration, subcutaneous administration, intravenous administration, intramuscular administration, rectal administration, and transdermal administration. It can be administered to humans or non-human animals. Therefore, the pharmaceutical composition of the present invention can be formulated into an appropriate dosage form depending on the route of administration.
• oral or parenteral administration routes such as inhalation administration, nasal administration, eye drops administration, subcutaneous administration, intravenous administration, intramuscular administration, rectal administration, and transdermal administration. It can be administered to humans or non-human animals. Therefore, the pharmaceutical composition of the present invention can be formulated into an appropriate dosage form depending on the route of administration.
• Examples of the dosage form of the pharmaceutical composition of the present invention include tablets, pills, capsules, granules, powders, fine granules, troches, elixirs, suspensions, emulsions, and syrups.
• Oral preparations such as inhalants, nasal solutions, and eye drops; Injections such as intravenous and intramuscular injections; Parenteral preparations such as suppositories, lotions, sprays, ointments, creams, and patches. Examples include agents.
• the pharmaceutical composition of the present invention may contain excipients, fillers, wetting agents, surfactants, disintegrants, binders, lubricants, and dispersants commonly used in the pharmaceutical field, depending on the dosage form. may further contain additives such as buffering agents, preservatives, solubilizing agents, preservatives, flavoring agents, soothing agents, stabilizers, lubricants, and coloring agents. It can be manufactured by the method.
• the additives include lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, olive oil, propylene glycol, polyethylene glycol. , syrup, vaseline, glycerin, ethanol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, etc.
• the content of the trisubstituted pyrazole derivative of the present invention (where the trisubstituted pyrazole derivative is a compound represented by formula (I), a salt thereof, a solvate thereof, a tautomer thereof) , and in the case of a mixture of stereoisomers, their total content) cannot be generalized because it is adjusted appropriately depending on the dosage form, but usually the total content of the cell growth inhibitor is Based on the mass, the amount is 0.01 to 70% by mass, preferably 0.05 to 50% by mass in terms of free form.
• the dosage of the trisubstituted pyrazole derivative of the present invention (the trisubstituted pyrazole derivative may be a compound represented by the above formula (I), a salt thereof, a solvate thereof, a tautomer thereof, a stereoisomer thereof, etc.) (in the case of a mixture of two or more drugs, the total amount thereof) should be adjusted as appropriate for each individual case, taking into consideration the usage, age, weight, sex of the patient, differences in disease, severity of symptoms, etc. Therefore, although it cannot be generalized, the amount is usually 0.1 to 2000 mg, preferably 1 to 1000 mg, in terms of free form, per day for adults, and this is administered once a day or in divided doses.
• Tr trityl group [Cp * RhCl 2 ] 2 ; (pentamethylcyclopentadienyl) rhodium(III) dichloride dimer Pd(PPh 3 ) 4 ; tetrakis(triphenylphosphine) palladium(0) DMF; dimethylformamide NIS; N-iodosuccinimide; PdCl 2 (dppf)CH 2 Cl 2 ; [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct THF; tetrahydrofuran Pd 2 (dba) 3 ; tris(dibenzylideneacetone)dipalladium(0) Xantphos; 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene DMSO; dimethyl
• naming software such as ACD/Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.
• Example 2 4-iodo-1-trityl-3-vinyl-1H-pyrazole A 1.6 M butyllithium/hexane solution (15.00 ml, 24.00 mmol) was added dropwise to a THF solution (40 ml) of methyltriphenylphosphonium bromide (9.261 g, 25.92 mmol) at -78°C, and the temperature was naturally raised to 0°C. The mixture was stirred for 1 hour. The reaction solution was added dropwise to a THF solution (80 ml) of the compound obtained in Example 1 (7.411 g, 15.96 mmol) at 0°C, and after cooling, the mixture was stirred at room temperature for 1 hour.
• Example 3 3-(4-iodo-1-trityl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• the compound obtained in Example 2 (1.528g, 3.305mmol), N-(pivaloyloxy)benzamide (899.6mg, 4.066mmol), cesium acetate (3.30g, 17.19mmol) in chloroform (5.5ml)-methanol (11ml)
• the mixture was suspended in a mixed solution, [Cp * RhCl 2 ] 2 (126.7 mg, 0.2049 mmol) was added, and the mixture was stirred at room temperature overnight.
• Example 4 3-(4-phenyl-1-trityl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• phenylboronic acid 131.09mg, 1.075mmol
• Pd(PPh 3 ) 4 22.44 mg, 19.42 ⁇ mol
• Saturated brine was added to the reaction solution, and the mixture was extracted with chloroform. After drying over magnesium sulfate, a crude product was obtained by concentrating under reduced pressure.
• MS (ESI) m/z: 532 [M+H] +
• Example 5 3-(4-phenyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• Acetic acid (5 ml) and water (1 ml) were added to the crude product obtained in Example 4, and the mixture was stirred at 50 to 60°C for 6 hours.
• a saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product.
• Example 6 3-(5-iodo-4-phenyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one NIS (153.6 mg, 0.6827 mmol) was added to a mixed solution of the compound obtained in Example 5 (162.0 mg, 0.5599 mmol) in acetonitrile (5 ml)-DMF (2.5 ml) and heated at 40°C for 56 hours. NIS (82.89mg, 0.3684mmol) was added, and the mixture was further heated at 40°C for 41 hours. Water, ethyl acetate, and chloroform were added to the reaction solution, and the mixture was concentrated under reduced pressure, and the resulting precipitate was filtered.
• NIS 82.89mg, 0.3684mmol
• Example 7 (E)-3-(4-phenyl-5-styryl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• the compound obtained in Example 6 (49.70mg, 0.1197mmol), (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (46.02mg, 0.2000mmol), PdCl 2 (dppf)CH 2 Cl 2 (23.70 mg, 29.02 ⁇ mol) was added to a suspension of 2M potassium carbonate aqueous solution (200 ⁇ l) and 1,4-dioxane-water (5:1) mixed solution (1 ml), and nitrogen was added.
• Example 8 3-(5-phenethyl-4-phenyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• the compound obtained in Example 7 (38.1 mg, 97.33 ⁇ mol) and 50% water-containing 5% palladium on carbon (15 mg) were suspended in a mixed solvent of THF (6 ml) and methanol (2 ml), and the mixture was stirred at room temperature under a hydrogen atmosphere. The mixture was stirred vigorously in the evening.
• Example 10 (E)-3- ⁇ 4-phenyl-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)vinyl]-1H-pyrazol-3-yl ⁇ -3,4 -dihydroisoquinolin-1(2H)-one
• Example 11 3- ⁇ 4-phenyl-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-1H-pyrazol-3-yl ⁇ -3,4-dihydroisoquinoline- 1(2H)-on
• Example 12 (E)-3- ⁇ 4-(4-methoxyphenyl)-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)vinyl]-1H-pyrazol-3-yl ⁇ -3,4-dihydroisoquinolin-1(2H)-one
• the title compound was synthesized in the same manner as Examples 4 to 6 and 10 by replacing the boronic acid in Example 4 with (4-methoxyphenyl)boronic acid.
• Example 13 3- ⁇ 4-(4-methoxyphenyl)-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]-1H-pyrazol-3-yl ⁇ -3, 4-dihydroisoquinolin-1(2H)-one
• Example 14 3-[4-(4-methoxyphenyl)-5- ⁇ [(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]thio ⁇ -1H-pyrazol-3-yl]-3 ,4-dihydroisoquinolin-1(2H)-one 3-[5-iodo-4-(4-methoxyphenyl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinolin-1(2H)-one (418.26 mg) obtained in the process of Example 12 , 0.9394mmol), S-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]ethanethioate (261.2mg, 1.115mmol), Pd 2 (dba) 3 (190.2mg, 0.2077 mmol) and Xantphos (216.8 mg, 0.3747 mmol) were suspended in 1,4-dioxane (9.5 ml) and heated at 85°
• Example 15 3-(4-(4-methoxyphenyl)-5- ⁇ [(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]sulfonyl ⁇ -1H-pyrazol-3-yl)-3 ,4-dihydroisoquinolin-1(2H)-one
• the compound obtained in Example 14 (61.30 mmg, 0.1203 mmol) was dissolved in a mixed solvent of sulfolane (1 ml) and chloroform (1 ml), m-CPBA (75%, 85.6 mg, 0.3720 mmol) was added, and the mixture was left at room temperature for 5 hours.
• Example 16 3-[4-phenyl-5-( ⁇ [5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl ⁇ thio)-1H-pyrazol-3-yl]-3 ,4-dihydroisoquinolin-1(2H)-one
• the compound obtained in Example 6 and the thioester used in Example 14 were converted into S- ⁇ [5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl ⁇ ethanethioate.
• the title compound was synthesized in the same manner as in Example 14 except for the following substitutions.
• Example 17 3-[4-(4-methoxyphenyl)-5-( ⁇ [5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl ⁇ thio)-1H-pyrazole-3 -yl]-3,4-dihydroisoquinolin-1(2H)-one
• the same procedure as in Example 14 was carried out by replacing the thioester used in Example 14 with S- ⁇ [5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl ⁇ ethanethioate.
• the title compound was synthesized by the method. MS (ESI) m/z: 524 [M+H] +
• Example 18 N-(2- ⁇ [4-(4-methoxyphenyl)-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazol-5-yl]thio ⁇ ethyl )benzamide
• the title compound was synthesized in the same manner as in Example 14 except that the thioester used in Example 14 was replaced with S-(2-benzamidoethyl)ethanethioate.
• Example 20 1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazole 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (26.97 mmol), potassium vinyltrifluoroborate (7.230 g, 53.98 mmol), 2M potassium carbonate aqueous solution (54.0 ml) and 1, Pd(PPh 3 ) 4 (621.0 mg, 0.5374 mmol) was added to a suspension of 4-dioxane-water (5:1) mixed solution (250 ml), and the mixture was heated to 95°C using a microwave synthesizer under a nitrogen atmosphere. The mixture was allowed to react for 2 hours.
• Example 21 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazole A 1.6 M butyllithium/hexane solution (18 ml) was added dropwise to a THF (40 ml) solution of the compound obtained in Example 20 (4.647 g, 26.07 mmol) at -78°C. The mixture was stirred for 30 minutes at -78°C, and a solution of iodine (3.696 g, 14.52 mmol) in THF (40 ml) was added dropwise at -78°C. The mixture was allowed to naturally warm up to room temperature over 2 hours, and then for an additional 2.5 hours. Stirred.
• Example 22 (E)-2-phenyl-5- ⁇ 2-[1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazol-5-yl]vinyl ⁇ -1,3,4-oxa diazole
• Example 23 (E)-3- ⁇ 5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)vinyl]-1-(tetrahydro-2H-pyran-2-yl)-1H- Pyrazol-3-yl ⁇ -3,4-dihydroisoquinolin-1(2H)-one
• Example 24 (E)-3- ⁇ 5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)vinyl]-1H-pyrazol-3-yl ⁇ -3,4-dihydroisoquinoline- 1(2H)-on
• the compound obtained in Example 23 (1.055 g, 2.257 mmol) was dissolved in 1,4-dioxane, hydrochloric acid-methanol (1 ml of concentrated hydrochloric acid/10 ml of methanol) was added, and the mixture was heated to 50°C. After cooling, water was added and the resulting precipitate was collected by filtration to obtain the title compound (814.7 mg, 94%).
• Example 25 (E)-3- ⁇ 4-iodo-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)vinyl]-1H-pyrazol-3-yl ⁇ -3,4 -dihydroisoquinolin-1(2H)-one
• Example 26 (E)-3- ⁇ 4-iodo-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)vinyl]-1-(tetrahydro-2H-pyran-2-yl )-1H-pyrazol-3-yl ⁇ -3,4-dihydroisoquinolin-1(2H)-one
• a methylene chloride solution of the compound obtained in Example 25, 15 equivalents of DHP, and 0.2 equivalents of CSA was stirred for 11 hours. Saturated sodium bicarbonate solution was added, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure.
• Example 28 Methyl(E)-4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazole) -2-yl)vinyl]-1H-pyrazol-4-yl ⁇ benzoate
• a crude product was obtained from the compound obtained in Example 27 in the same manner as in Example 24.
• the title compound (77% (2 steps)) was obtained by purification.
• Example 29 (E)-4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazole- 2-yl)vinyl]-1H-pyrazol-4-yl ⁇ benzoic acid
• Water (4 ml), methanol (4 ml), and 5N sodium hydroxide-methanol solution were added to the compound obtained in Example 28 (76.32 mg, 0.1475 mmol), and the mixture was heated with a dryer for 3 minutes. 1N hydrochloric acid was added and the resulting precipitate was collected by filtration to obtain the title compound (70.84 mg, 95%).
• Example 30 4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl) ethyl]-1H-pyrazol-4-yl ⁇ benzoic acid
• the title compound (34.03 mg, 86%) was obtained in the same manner as in Example 8 using the compound obtained in Example 29 (39.40 mg, 78.25 ⁇ mol) and 10% palladium on carbon as a catalyst.
• Example 31 (E)-6- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazole- 2-yl)vinyl]-1H-pyrazol-4-yl ⁇ -1H-indole-3-carboxylic acid
• the experiment was carried out by replacing the boronic acid used in Example 27 with methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxylate.
• the title compound was obtained by a method similar to Examples 27-29.
• Example 32 (E)-6- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazole- 2-yl)vinyl]-1H-pyrazol-4-yl ⁇ -1H-indole-2-carboxylic acid
• the experiment was carried out by replacing the boronic acid used in Example 27 with ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate.
• the title compound was obtained by a method similar to Examples 27-29.
• Example 33 6- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl) ethyl]-1H-pyrazol-4-yl ⁇ -1H-indole-3-carboxylic acid
• Example 34 6- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl) ethyl]-1H-pyrazol-4-yl ⁇ -1H-indole-2-carboxylic acid
• Example 35 (E)-3- ⁇ 4-[4-(1H-tetrazol-5-yl)phenyl]-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)vinyl] -1H-pyrazol-3-yl ⁇ -3,4-dihydroisoquinolin-1(2H)-one
• the title compound was obtained in the same manner as in Examples 27 and 28, except that the boronic acid used in Example 27 was replaced with (4-(1H-tetrazol-5-yl)phenyl)boronic acid.
• Example 36 (E)-2-Methyl-2-(4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3 ,4-oxadiazol-2-yl)vinyl]-1H-pyrazol-4-yl ⁇ phenyl)propanoic acid Replacing the boronic acid used in Example 27 with methyl 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate, The title compound was obtained in the same manner as in Examples 27-29. MS (ESI) m/z: 546 [M+H] +
• Example 38 (E)-4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazole- 2-yl)vinyl]-1H-pyrazol-4-yl ⁇ benzenesulfonamide
• the title compound was obtained in the same manner as in Examples 27 and 28, except that the boronic acid used in Example 27 was replaced with (4-sulfamoylphenyl)boronic acid.
• Example 39 (E)-5- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazole- 2-yl)vinyl]-1H-pyrazol-4-yl ⁇ picolinic acid
• Example 40 4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl) ethyl]-1H-pyrazol-4-yl ⁇ benzamide
• Example 41 4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl) ethyl]-1H-pyrazol-4-yl ⁇ benzenesulfonamide
• Example 43 5-bromo-3-(1-trityl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• the compound of Example 42 (843.3 mg, 2.507 mmol), 3-bromo-N-[(tert The title compound (902.7 mg, 68%) and its isomer (247.9 mg, 19%) were obtained from -butoxycarbonyl)oxy]benzamide (954.8 mg, 3.020 mmol).
• Example 44 5-Methyl-3-(1-trityl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• a suspension of the compound obtained in Example 43 (443.1 mg, 0.8289 mmol), potassium carbonate (363.8 mg, 2.632 mmol), and trimethylboroxine (116 ⁇ l, 0.8298 mmol) in 1,4-dioxane solution (12 ml) was added.
• Pd(PPh 3 ) 4 (108.1 mg, 93.55 ⁇ mol) was added, and the mixture was reacted at 100° C. for 38.5 hours under a nitrogen atmosphere.
• Example 46 3-(4-iodo-1H-pyrazol-3-yl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
• Example 47 3-[4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
• Example 48 3-[4-(4-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-5-methyl-3,4-dihydroisoquinoline-1(2H) -on
• the title compound was obtained from the compound obtained in Example 47 in a similar manner except that the boronic acid used in Example 4 was replaced with (4-methoxyphenyl)boronic acid.
• Example 49 3-[4-(4-methoxyphenyl)-1H-pyrazol-3-yl]-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
• Example 50 3-[5-iodo-4-(4-methoxyphenyl)-1H-pyrazol-3-yl]-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
• Example 51 (E)-3- ⁇ 4-(4-methoxyphenyl)-5-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)vinyl]-1H-pyrazol-3-yl ⁇ -5-Methyl-3,4-dihydroisoquinolin-1(2H)-one From the compound obtained in Example 50, the title compound was obtained in a similar manner except that the boronic acid ester used in Example 7 was replaced with the compound obtained in Example 9. MS (ESI) m/z: 504 [M+H] +
• Example 53 2-ethynyl-5-(4-fluorophenyl)-1,3,4-oxadiazole The title compound was obtained from 5-(4-fluorophenyl)-1H-tetrazole in the same manner as in Example 52. MS (ESI) m/z: 189 [M+H] +
• Example 54 (E)-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-5-(4-methylphenyl)-1,3,4 -Oxadiazole
• the title compound was obtained from the compound obtained in Example 52 in the same manner as in Example 9.
• Example 55 (E)-2-(4-fluorophenyl)-5-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]-1,3,4 -Oxadiazole
• the title compound was obtained from the compound obtained in Example 53 in the same manner as in Example 9.
• Example 56 (E)-4- ⁇ 3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4- Oxadiazol-2-yl)vinyl]-1H-pyrazol-4-yl ⁇ benzoic acid
• MS (ESI) m/z: 518 [M+H] +
• Example 57 (E)-4-(3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-methylphenyl)-1 ,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained in the same manner as in Example 56 using the compound obtained in Example 54.
• Example 58 (E)-4-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -3-(5-methyl-1-oxo- 1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazol-4-yl)benzoic acid Using the compound obtained in Example 55, the title compound was obtained in the same manner as in Example 56. MS (ESI) m/z: 536 [M+H] +
• Example 59 4- ⁇ 3-(5-Methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(5-phenyl-1,3,4-oxadiazole- 2-yl)ethyl]-1H-pyrazol-4-yl ⁇ benzoic acid
• Example 60 4-(3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-methylphenyl)-1,3,4 -oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 57 in the same manner as in Example 30.
• Example 61 4-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethyl ⁇ -3-(5-methyl-1-oxo-1,2, 3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 58 in the same manner as in Example 30.
• Example 62 3-(1-trityl-1H-pyrazol-3-yl)-5-vinyl-3,4-dihydroisoquinolin-1(2H)-one The title compound was obtained in the same manner as in Example 27 using the compound obtained in Example 43 and potassium vinyltrifluoroborate. MS (ESI) m/z: 482 [M+H] +
• Example 63 5-ethyl-3-(1-trityl-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one The title compound was obtained from the compound obtained in Example 62 in the same manner as in Example 8. MS (ESI) m/z: 484 [M+H] +
• Example 64 3-(4-bromo-1-trityl-1H-pyrazol-3-yl)-5-ethyl-3,4-dihydroisoquinolin-1(2H)-one
• the compound obtained in Example 63 (233.0 mg, 0.4818 mmol) was dissolved in DMF (4.5 ml) and methylene chloride (4.5 ml), NBS (111.8 mg, 0.6281 mmol) was added, and the mixture was stirred at room temperature for 21 hours.
• a saturated aqueous sodium thiosulfate solution was added, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure.
• Example 65 Methyl 4-[3-(5-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1-trityl-1H-pyrazol-4-yl]benzoate The title compound was obtained from the compound obtained in Example 64 in the same manner as in Example 27. MS (ESI) m/z: 618 [M+H] +
• Example 66 Methyl 4-[3-(5-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazol-4-yl]benzoate The title compound was obtained from the compound obtained in Example 65 in the same manner as in Example 5 at a reaction temperature of 95°C. MS (ESI) m/z: 376 [M+H] +
• Example 67 Methyl 4-[3-(5-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-iodo-1H-pyrazol-4-yl]benzoate From the compound obtained in Example 66, the title compound was obtained in the same manner as in Example 6 using DMF as a solvent. MS (ESI) m/z: 502 [M+H] +
• Example 68 Methyl(E)-4-(3-(5-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-methylphenyl)- 1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoate From the compound obtained in Example 67, the title compound was obtained in a similar manner except that the boronic acid ester used in Example 7 was replaced with the compound obtained in Example 54. MS (ESI) m/z: 560 [M+H] +
• Example 69 (E)-4-(3-(5-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-methylphenyl)-1 ,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• THF 2 ml
• methanol 1 ml
• water (1 ml) were added to the compound obtained in Example 68 (48.0 mg, 85.77 ⁇ mol) and lithium hydroxide (16.3 mg, 680.6 ⁇ mol), and the mixture was stirred at 50°C for 3 hours. did.
• Example 70 4-(3-(5-ethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-methylphenyl)-1,3,4 -oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 69 in the same manner as in Example 30.
• Example 72 (E)-4-(3-(5-isopropyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-methylphenyl)-1 ,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained in the same manner as in Examples 62 to 69 using potassium isopropenyl trifluoroborate.
• Example 73 4-(3-(1-oxo-5-propyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-methylphenyl)-1,3,4 -oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• Example 74 4-(3-(5-isopropyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-methylphenyl)-1,3,4 -oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 72 in the same manner as in Example 70.
• Example 76 N-(pivaloyloxy)-3,5-bis(trifluoromethyl)benzamide The title compound was obtained in the same manner as in Example 75. MS (ESI) m/z: 358 [M+H] +
• Example 78 2-Fluoro-5-methyl-N-(pivaloyloxy)benzamide The title compound was obtained in the same manner as in Example 75. MS (ESI) m/z: 254 [M+H] +
• Example 80 (E)-2-(4-fluorophenyl)-5- ⁇ 2-[1-(tetrahydro-2H-pyran-2-yl)-3-vinyl-1H-pyrazol-5-yl]vinyl ⁇ -1, 3,4-oxadiazole
• Example 81 (E)-5,7-difluoro-3-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• Example 82 (E)-3-(4-bromo-5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1-(tetrahydro-2H- Pyran-2-yl)-1H-pyrazol-3-yl)-5,7-difluoro-3,4-dihydroisoquinolin-1(2H)-one
• a mixed solution of the compound obtained in Example 81 396.3 mg, 0.7599 mmol
• NBS (185.0 mg, 1.039 mmol) in DMF (5 ml) and methylene chloride (5 ml) was stirred at room temperature for 20 hours.
• Example 83 Methyl (E)-4-(3-(5,7-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) )-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzoate From the compound obtained in Example 82, the title compound was obtained in the same manner as in Example 27. MS (ESI) m/z: 656 [M+H] +
• Example 84 Methyl(E)-4-(3-(5,7-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) )-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoate
• the compound obtained in Example 83 (0.1596 mmol), acetic acid (4 ml), methanol (2 ml), and water (0.5 ml) were heated at 90°C for 1 hour.
• the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and after stirring, the mixture was collected by filtration to obtain the title compound (80%).
• Example 85 (E)-4-(3-(5,7-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) -1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 84 in the same manner as in Example 69.
• Example 86 4-(3-(5,7-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl)-1,3 ,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid From the compound obtained in Example 85, the title compound was obtained in the same manner as in Example 70. MS (ESI) m/z: 560 [M+H] +
• Example 87 (E)-5,7-difluoro-3-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -4-[4- (trifluoromethoxy)phenyl]-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• the title compound was obtained from the compound obtained in Example 82, [4-(trifluoromethoxy)phenyl]boronic acid, in the same manner as in Examples 83 and 84.
• Example 88 (E)-4-(3-(5,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) -1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 80, 3,5-dimethyl-N-(pivaloyloxy)benzamide, in the same manner as in Examples 81 to 85.
• Example 89 (E)-4-(3-(5,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) -1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)-2-fluorobenzoic acid
• the title compound was obtained in the same manner as in Example 88, except that the boronic acid used in Example 88 was replaced with [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid.
• Example 90 4-(3-(5,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl)-1,3 ,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 88 in the same manner as in Example 86.
• Example 91 4-(3-(5,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl)-1,3 ,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)-2-fluorobenzoic acid
• the title compound was obtained from the compound obtained in Example 89 in the same manner as in Example 86.
• Example 92 (E)-4-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -3-[1-oxo-5,7- Bis(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]-1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compounds obtained in Examples 76 and 80 in the same manner as in Examples 81 to 85.
• Example 93 4-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethyl ⁇ -3-[1-oxo-5,7-bis(trifluoro methyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]-1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 92 in the same manner as in Example 86.
• Example 94 (E)-4-(3-(5,7-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) -1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)-2-fluorobenzoic acid
• the title compound was obtained in the same manner as in Examples 83 to 85 except that the boronic acid in Example 83 was replaced with (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid.
• Example 95 4-(3-(5,7-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl)-1,3 ,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)-2-fluorobenzoic acid
• the title compound was obtained from the compound of Example 94 in the same manner as in Example 86.
• Example 96 (E)-4-(3-(5,8-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) -1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained in the same manner as in Example 88 by replacing the compound obtained in Example 77 with the benzamide of Example 88.
• Example 97 (E)-4-(3-(5,8-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) -1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)-2-fluorobenzoic acid
• the title compound was obtained from the compound obtained in Example 77 in the same manner as in Example 89.
• Example 98 4-(3-(5,8-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl)-1,3 ,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 96 in the same manner as in Example 86.
• Example 99 4-(3-(5,8-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl)-1,3 ,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)-2-fluorobenzoic acid
• the title compound was obtained from the compound obtained in Example 97 in the same manner as in Example 86.
• Example 100 (E)-4-(3-(8-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluoro Phenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 78 in the same manner as in Examples 81 to 85.
• Example 101 (E)-2-Fluoro-4-(3-(8-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5- (4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the compound obtained in Example 78 was subjected to the same reaction as in Example 81, and the title compound was obtained in the same manner as in Examples 82 to 85 using (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid. I got it.
• MS (ESI) m/z: 572 [M+H] +
• Example 102 2-Fluoro-4-(3-(8-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluoro phenyl)-1,3,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 101 in the same manner as in Example 86.
• Example 103 (E)-4-(3-[8-fluoro-1-oxo-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]-5- ⁇ 2-[5- (4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 79 in the same manner as in Examples 81 to 85.
• Example 104 (E)-3-(3-(5,7-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl) -1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained in the same manner as in Examples 81 to 85 except that the boronic acid in Example 83 was replaced with [3-(methoxycarbonyl)phenyl]boronic acid.
• Example 105 4-(3-[8-fluoro-1-oxo-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]-5- ⁇ 2-[5-(4-fluoro phenyl)-1,3,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 103 in the same manner as in Example 86.
• Example 106 3-(3-(5,7-difluoro-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(4-fluorophenyl)-1,3 ,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 104 in the same manner as in Example 86.
• Example 107 3-[5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinolin-1(2H)-one
• the title compound was obtained from the compound obtained in Example 21, N-(pivaloyloxy)benzamide, in the same manner as in Example 3.
• Example 108 3-[5-(5-phenylpent-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinoline- 1(2H)-on
• the compound obtained in Example 107 (433.7 mg), 5-phenyl-1-pentyne (160 ⁇ l), Pd(PPh 3 ) 4 (140.0 mg), copper(I) iodide (59.0 mg), triethylamine (3.5 ml) ) solution in THF (10 ml) was stirred at room temperature for 1 hour, 5-phenyl-1-pentyne (80 ⁇ l) was added, and after another 1.5 hours, 5-phenyl-1-pentyne (160 ⁇ l) was added and stirred for 18 hours.
• Example 109 3-[4-bromo-5-(5-phenylpent-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-3,4 -dihydroisoquinolin-1(2H)-one
• Example 110 Methyl 4-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-(5-phenylpent-1-yn-1-yl)-1-(tetrahydro-2H -pyran-2-yl)-1H-pyrazol-4-yl]benzoate
• the title compound was obtained from the compound obtained in Example 109 in the same manner as in Example 27.
• Example 111 Methyl 4-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-(5-phenylpent-1-yn-1-yl)-1H-pyrazole-4- benzoate
• the title compound was obtained from the compound obtained in Example 110 in the same manner as in Example 84 at a reaction temperature of 70°C.
• Example 112 4-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-(5-phenylpent-1-yn-1-yl)-1H-pyrazol-4-yl ]benzoic acid
• Example 113 4-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-(5-phenylpentyl)-1H-pyrazol-4-yl]benzoic acid
• Example 114 2-Fluoro-4-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-(5-phenylpent-1-yn-1-yl)-1H-pyrazole -4-yl]benzoic acid
• the title compound was obtained in the same manner as in Examples 110 to 112 except that the boronic acid in Example 110 was replaced with (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid.
• Example 115 2-Fluoro-4-[3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-(5-phenylpentyl)-1H-pyrazol-4-yl]benzoic acid
• Example 116 3- ⁇ 1-(Tetrahydro-2H-pyran-2-yl)-5-[(trimethylsilyl)ethynyl]-1H-pyrazol-3-yl ⁇ -3,4-dihydroisoquinolin-1(2H)-one
• Compound obtained in Example 107 (860.0mg, 2.032mmol), trimethylsilylacetylene (425 ⁇ l, 6.094mmol), triethylamine (1.135ml, 15.45mmol), copper(I) iodide (70.1mg, 0.3681mmol), PdCl 2
• a THF solution (10 ml) of (PPh 3 ) 2 (184.3 mg, 0.2626 mmol) was stirred at room temperature for 17.5 hours.
• Example 117 3-[5-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinolin-1(2H)-one
• a suspension of the compound obtained in Example 116 (659.0 mg, 1.674 mmol) and potassium carbonate (474.4 mg, 3.432 mmol) in methanol (16 ml) was stirred at room temperature for 2 minutes while being irradiated with ultrasound.
• Acetic acid (392 ⁇ l) was added, and the mixture was further stirred while being irradiated with ultrasonic waves.
• Example 118 (E)-3- ⁇ 1-(tetrahydro-2H-pyran-2-yl)-5-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Vinyl]-1H-pyrazol-3-yl ⁇ -3,4-dihydroisoquinolin-1(2H)-one
• Example 119 (E)-3-(5- ⁇ 2-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1-(tetrahydro-2H-pyran-2 -yl)-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• the title compound was obtained from the compound obtained in Example 118, 2-bromo-5-(pyridin-2-yl)-1,3,4-oxadiazole, in the same manner as in Example 22.
• Example 120 (E)-3-(4-bromo-5- ⁇ 2-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1-(tetrahydro-2H -pyran-2-yl)-1H-pyrazol-3-yl)-3,4-dihydroisoquinolin-1(2H)-one
• the title compound was obtained from the compound obtained in Example 119 in the same manner as in Example 82.
• Example 121 Methyl(E)-4-(3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(pyridin-2-yl)-1,3 ,4-oxadiazol-2-yl]vinyl ⁇ -1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzoate
• the title compound was obtained from the compound obtained in Example 120 in the same manner as in Example 27.
• Example 122 Methyl(E)-4-(3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(pyridin-2-yl)-1,3 ,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoate
• the title compound was obtained from the compound obtained in Example 121 in the same manner as in Example 84 at a reaction temperature of 70°C.
• Example 123 (E)-4-(3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(pyridin-2-yl)-1,3, 4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• Example 124 (E)-4-(3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(pyridin-3-yl)-1,3, 4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from 2-bromo-5-(pyridin-3-yl)-1,3,4-oxadiazole in the same manner as in Examples 119 to 123.
• Example 125 (E)-4-(3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5- ⁇ 2-[5-(pyridin-4-yl)-1,3, 4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-4-yl)benzoic acid
• the title compound was obtained from 2-bromo-5-(pyridin-4-yl)-1,3,4-oxadiazole in the same manner as in Examples 119 to 123.
• Example 126 (E)-4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(1-phenyl-1H-imidazol-4-yl)vinyl] -1H-pyrazol-4-yl ⁇ benzoic acid
• the title compound was obtained from 4-iodo-1-phenyl-1H-imidazole in the same manner as in Examples 119 to 123.
• Example 127 (E)-4- ⁇ 3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-5-[2-(1-phenyl-1H-imidazol-5-yl)vinyl] -1H-pyrazol-4-yl ⁇ benzoic acid
• the title compound was obtained from 5-iodo-1-phenyl-1H-imidazole in the same manner as in Examples 119 to 123.
• Example 128 3-[5-(3-hydroxyprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinoline- 1(2H)-on Compound obtained in Example 107 (1.624 mmol), 2-propyn-1-ol (104 ⁇ l), PdCl 2 (dppf)CH 2 Cl 2 (71.5 mh), copper(I) iodide (42.3 mg), triethylamine (906 ⁇ l) in THF (16 ml) was stirred at room temperature for 40 minutes and at 60°C for 2 hours, then PdCl 2 (dppf)CH 2 Cl 2 (42.7 mg) and 2-propyn-1-ol (55 ⁇ l) were added.
• Example 129 3-[5-(3-hydroxypropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinolin-1(2H)-one
• Example 130 3-[4-bromo-5-(3-hydroxypropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-3,4-dihydroisoquinoline-1(2H) -on
• the title compound was obtained from the compound obtained in Example 129 in the same manner as in Example 82 using methylene chloride as a solvent.
• Example 131 Methyl 4-[5-(3-hydroxypropyl)-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl]benzoate
• the title compound was obtained from the compound obtained in Example 130 in the same manner as in Example 27.
• Example 132 Methyl 4-[5-(3-iodopropyl)-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl]benzoate Iodine (99.0 mg) was added to a methylene chloride solution of the compound obtained in Example 131 (150.5 mg), imidazole (72.3 mg), and PPh 3 (99.7 mg) at 0°C, and the mixture was stirred at room temperature for 30 minutes.
• Example 133 Methyl 4-(5- ⁇ 3-[benzyl(methyl)amino]propyl ⁇ -3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1-(tetrahydro-2H-pyran) -2-yl)-1H-pyrazol-4-yl)benzoate
• Example 134 Methyl 4-(5- ⁇ 3-[benzyl(methyl)amino]propyl ⁇ -3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazol-4-yl) benzoate
• the title compound was obtained from the compound obtained in Example 133 in the same manner as in Example 111.
• Example 135 4-(5- ⁇ 3-[benzyl(methyl)amino]propyl ⁇ -3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazol-4-yl)benzoin acid 1N NaOH (630 ⁇ l) was added to a THF-methanol mixed solution (1:1, 500 ⁇ l) of the compound (21.3 mg) obtained in Example 134, and the mixture was stirred at 50° C. for 25 minutes. The reaction solution was concentrated under reduced pressure, 1N HCl (630 ⁇ l) was added to the resulting residue, and the mixture was further concentrated under reduced pressure.
• Example 136 4- ⁇ 5-[3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl]-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H -pyrazol-4-yl ⁇ benzoic acid
• the title compound was obtained in the same manner as in Examples 133 to 135 using 1,2,3,4-tetrahydroisoquinoline.
• Example 137 4- ⁇ 5-[3-(isoindolin-2-yl)propyl]-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazol-4-yl ⁇ benzoic acid
• Example 138 2-bromo-5-methyl-N-(pivaloyloxy)benzamide The title compound was obtained in the same manner as in Example 75. MS (ESI) m/z: 314 [M+H] +
• Example 139 8-bromo-3-[5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-5-methyl-3,4-dihydroisoquinoline-1(2H)- on The compound obtained in Example 138 (hereinafter abbreviated as benzamide, 359.0mg), the compound obtained in Example 21 (hereinafter abbreviated as iodo compound, 676.0mg), cesium acetate (3.677g), [Cp * RhCl 2 ] A suspension of 2 (96.5 mg) in methanol (2 ml) was stirred at 60°C. After 20 minutes, benzamide (352.8 mg) and methanol (2 ml) were added.
• Example 140 8-bromo-3-[5-(3-hydroxyprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-5-methyl -3,4-dihydroisoquinolin-1(2H)-one From the compound obtained in Example 139, the title compound was obtained in the same manner as in Example 128 using PdCl 2 (PPh 3 ) 2 . MS (ESI) m/z: 444 [M+H] +
• Example 141 3-[5-(3-hydroxypropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-5-methyl-3,4-dihydroisoquinoline-1(2H) -on
• the title compound was obtained from the compound obtained in Example 140 in the same manner as in Example 129 in the presence of triethylamine.
• Example 142 3-[4-bromo-5-(3-hydroxypropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl]-5-methyl-3,4-dihydroisoquinoline- 1(2H)-on
• Example 143 Methyl 4-[5-(3-hydroxypropyl)-3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1-(tetrahydro-2H-pyran-2 -yl)-1H-pyrazol-4-yl]benzoate
• the title compound was obtained from the compound obtained in Example 142 in the same manner as in Example 131.
• Example 144 Methyl 4-[5-(3-iodopropyl)-3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1-(tetrahydro-2H-pyran-2 -yl)-1H-pyrazol-4-yl]benzoate
• the title compound was obtained from the compound obtained in Example 143 in the same manner as in Example 132.
• Example 145 Methyl 4-(5- ⁇ 3-[benzyl(methyl)amino]propyl ⁇ -3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1-(tetrahydro -2H-pyran-2-yl)-1H-pyrazol-4-yl)benzoate
• the title compound was obtained from the compound obtained in Example 144 in the same manner as in Example 133.
• Example 146 Methyl 4-(5- ⁇ 3-[benzyl(methyl)amino]propyl ⁇ -3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazole- 4-yl)benzoate
• the title compound was obtained from the compound obtained in Example 145 in the same manner as in Example 134.
• Example 147 4-(5- ⁇ 3-[benzyl(methyl)amino]propyl ⁇ -3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazole-4 -yl)benzoic acid
• the title compound was obtained from the compound obtained in Example 146 in the same manner as in Example 135.
• Example 148 4- ⁇ 5-[3-(3,4-dihydroisoquinolin-2(1H)-yl)propyl]-3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3- yl)-1H-pyrazol-4-yl ⁇ benzoic acid
• the title compound was obtained from the compound obtained in Example 144 in the same manner as in Example 136.
• Example 149 4- ⁇ 5-[3-(isoindolin-2-yl)propyl]-3-(5-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)-1H-pyrazole- 4-yl ⁇ benzoic acid
• Example 150 (E)-5,7-difluoro-3-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazole-3 -yl)-3,4-dihydroisoquinolin-1(2H)-one
• the title compound was obtained from the compound obtained in Example 81 in the same manner as in Example 66.
• Example 151 5,7-difluoro-3-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-3-yl)- 3,4-dihydroisoquinolin-1(2H)-one
• Example 152 (E)-3-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-3-yl)-5, 7-Bis(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one
• Example 153 3-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethyl ⁇ -1H-pyrazol-3-yl)-5,7-bis( Trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one
• Example 154 (E)-5,8-difluoro-3-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazole-3 -yl)-3,4-dihydroisoquinolin-1(2H)-one
• Example 155 (E)-8-Fluoro-3-(5- ⁇ 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]vinyl ⁇ -1H-pyrazol-3-yl )-5-Methyl-3,4-dihydroisoquinolin-1(2H)-one
• Example 156 Tankyrase inhibitory activity test The tankyrase inhibitory activity ( The inhibitory activity against tankyrase 1 (TNKS1) and the inhibitory activity against tankyrase 2 (TNKS2)) was evaluated. First, Flag-tagged tankyrase 1 (1,024-1, 327aa, SAM+PARP) and tankyrase 2 (613-1,116aa, ANK5+SAM+PARP) were synthesized using a cell-free protein synthesis system, and then added to Tris buffer (50mM Tris -HCl (pH 8.0), 150mM NaCl, 10% glycerol).
• Tris buffer 50mM Tris -HCl (pH 8.0), 150mM NaCl, 10% glycerol).
• test compound DMSO was used as a control
• assay buffer 50mM Tris-HCl (pH 8.0), 4mM MgCl 2 , 0.2mM DTT
• assay buffer 50mM Tris-HCl (pH 8.0), 4mM MgCl 2 , 0.2mM DTT
• a biotin-labeled NAD solution 225 ⁇ M NAD, 25 ⁇ M 6-Biotin-17-NAD (Trevigen) was added as a donor substrate, mixed, and reacted at 30° C. for 45 minutes. Distilled water was added to blank wells instead of biotin-labeled NAD solution.
• TNKS1 inhibitory activity against tankyrase 1
• TNKS2 inhibitory activity against tankyrase 2
• Example 157 Western blot analysis of proteins Human colon cancer COLO-320DM cells were treated with 0.1 ⁇ M of the example compound or an equal volume of dimethyl sulfoxide as a blank, and cultured for 16 hours. The cells were washed with phosphate buffered saline and added with whole cell extraction buffer (50 mM Tris-HCl pH 8.0, 150 mM NaCl, 1% Nonidet P-40, 0.125 mM dithiothreitol, 2% Protease Inhibitor Cocktail, 1% Phosphatase Inhibitor Cocktail) and allowed to stand on ice for 30 minutes while stirring every 10 minutes. After cold centrifugation for 10 minutes, the supernatant was collected as a standard.
• whole cell extraction buffer 50 mM Tris-HCl pH 8.0, 150 mM NaCl, 1% Nonidet P-40, 0.125 mM dithiothreitol, 2% Protease Inhibitor Cocktail, 1% Phosphata
• the membrane was stained with 2% Ponceau S and 5% acetic acid solution, immersed in Blocking One solution for 1 hour, and then stained with a primary antibody solution (anti-nonphosphorylated (activated) ⁇ - catenin antibody or anti-glyceraldehyde-3-phosphate dehydrogenase antibody) and shaken overnight at 4°C. After washing this membrane three times for 10 minutes with TBST (1 ⁇ TBS, 0.1% Tween20), it was immersed in secondary antibody (ECL anti-mouse/rabbit IgG antibody) diluted in Block Ace/TBST, and incubated for 1 hour at room temperature. I placed it.
• a primary antibody solution anti-nonphosphorylated (activated) ⁇ - catenin antibody or anti-glyceraldehyde-3-phosphate dehydrogenase antibody
• secondary antibody ECL anti-mouse/rabbit IgG antibody
• the membrane was then washed 4 times for 10 min with TBST and ECL
• the target protein band was detected using Western Blotting Detection Reagents.
• the band intensity of each protein was corrected by the band intensity of glyceraldehyde-3-phosphate dehydrogenase.
• the relative protein amount of each evaluation compound is shown in the table below, setting the blank protein amount as 1.

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