CA3015331C - 5-methyl-6-phenyl-4,5-dihydro-2h-pyridazin-3-one derivative - Google Patents

Abstract

The present invention provides an agent for treating malignant tumor, comprising a compound of formula (1): wherein R1 to R4 are hydrogen atom, halogen, or etc., Y is optionally-substituted alkylene group or etc.

Description

5 10 15 20 25 Date Reçue/Date Received 2023-06-16 1 5-METHYL-6-PHENYL-4,5-DIHYDRO-2H-PYRIDAZIN-3-ONE DERIVATIVE [Technical Field] [0001] The present invention may relate to a 5-methyl-6-phenyl-4,5- dihydro-2H-pyridazin-3-one derivative having antitumor activity, in particular, antitumor activity in brain* [Background Art]

[0002] Since nitrogen mustard was clinically used as an antineoplastic drug in the 1940s for the first time in the world, many antitumor drugs have been developed until now. Many of these antitumor drugs, however, can also exhibit cytotoxic action to normal cells, and thereby can show severe side-effects such as gastrointestinal dysfunction, myelosuppression, and hair loss. Therefore, most of theseantitumor drugs are limited to the usage, and often show partial and short-term effects. Along with the recent developments in molecular biology, it has been tried to identify more highly tumor-selective molecular targets to improve the effect and side-effect, and such trials have attained some progress. However, the positive effects are not so expected in tumors which have low express/contribution of molecular targets, and the side-effects are not low as desired. Thus, it has been desired to develop novel drugs. [0003] 5 10 15 20 Date Reçue/Date Received 2023-06-16 Some antitumor drugs having a phenyldihydropyridazinone moiety which the present invention comprises are known, but all those structures are different from that of the present invention (Patent Literature 1 and Patent Literature 2). [Citation List] [Patent Literature] [0004] [PL 1] WO 2009/114993 [PL 2] WO 2014/164704 [Summary] [0004a] Certain exemplary embodiments provide a compound of formula (1): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R1 to R4 are independently hydrogen atom, halogen, OH, CN, Ci-6 alkyl group, halogenated Ci-6 alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, or halogenated Ci-g alkoxy group, provided that one or two of R1 to R4 are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms, and Y is Ci-6 alkylene or 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 3 C2-6 alkenylene group, wherein the alkylene or alkenylene group may be substituted with one or more substituents which is or are Ci-g alkyl group, halogen, or halogenated C1-6 alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkylene or alkenylene group and another substitutable carbon atom in the alkylene or alkenylene group, or two substitutable carbon atoms in the substituent bonding to the alkylene or alkenylene group may be combined together to form a 3- to 6-membered carbon ring. [Technical Problem]

[0005] The main purpose of the present invention is to provide a compound having a potent anticancer effect, low side-effects, which is expected to have good water-solubility. [Solution to Problem] [0006] The present inventors have extensively studied and then have found that a novel compound represented by the following formula (1) has a potent antitumor activity, particularly antitumor activity in brain. Based upon the new findings, the present invention has been completed. The present invention provides 5-methyl-6-phenyl-4,5-dihydro-2H pyridazin-3-one derivative represented by the followingformula (1) or a pharmaceutically acceptable salt thereof (hereinafter, sometimes referred to as "the present 5 10 15 20 Date Reçue/Date Received 2023-06-16 4 compound"). The present invention mainly is mentioned below. [0007] (Term 1) A compound of formula (1): [Chem. 1] r2 or a pharmaceutically acceptable salt thereof wherein R1 to R4 are independently hydrogen atom, halogen, OH, CN, Ci-6 alkyl group, halogenated Ci-6 alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, or halogenated Ci-g alkoxy group provided that one or two of R1 to R4 are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms, and Y is Ci~6 alkylene or C2—6 alkenylene group, wherem the alkylene or alkenylene group may be substituted with one or more substituents selected independently from the group consisting of C1-6 alkyl group, halogen, and halogenated Ci-e alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkylene or alkenylene group and another substitutable carbon atom in the alkylene or 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 5 alkenylene group, or two substitutable carbon atoms in the substituent bonding to the alkylene or alkenylene group may be combined together to form a 3- to 6-membered carbon ring. [0008] (Term 2) The compound of Term 1 or a pharmaceutically acceptable salt thereof, wherein any two of R1 to R4 are hydrogen atoms. [0009] (Term 3) The compound of Term 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 to R4 are independently hydrogen atom, halogen, OH, CN, C1-4 alkyl group, halogenated C1-4 alkyl group, C2-4 alkenyl group, C1-4 alkoxy group, or halogenated C1-4 alkoxy group. [O01O] (Term 4) The compound of Term 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 to R4 are independently hydrogen atom, fluorine atom, chlorine atom, OH, CN, C1-4 alkyl group, vinyl group, or C1-4 alkoxy group. [0011] (Term 5) The compound of any one of Terms 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the alkylene or alkenylene group in Y is substituted with one or more substituents selected independently from the group consisting of C1-4 alkyl group, halogen, and halogenated C1-4 alkyl group, further wherein a substitutable carbon atom in 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 6 the substituent bonding to the alkylene or alkenylene group and another substitutable carbon atom in the alkylene or alkenylene group, or two substitutable carbon atoms in the substituent bonding to the alkylene or alkenylene group may be combined together to form a 3- to 6-membered carbon ring. [0012] (Term 6) The compound of any one of Terms 1 to 4 or a pharmaceutically acceptable salt thereof, wherein a carbon atom of the alkylene or alkenylene group in Y is substituted with one or two substituents selected independently from the group consisting of C1-4 alkyl group and halogenated C1-4 alkyl group, further when the carbon atom is substituted with two substituents, each substitutable carbon atom in the two substituents may be combined together to form a 3- to 6- membered carbon ring. [0013] (Term 7) The compound of any one of Terms 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the alkylene or alkenylene group xn Y has no substxtuent. [0014] (Term 8) The compound of any one of Terms 1 to 7 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1) is represented in the following formula. [Chern. 2] 5 10 15 20 Date Reçue/Date Received 2023-06-16 R2 [0015] (Term 9) The compound of Term 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: Example 1: 6-[3-bromo-5-chloro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 2: 6-[3,5-dichloro-4-(2-hydroxy-2- methyIpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 7: 6-[3-chloro~5-fluoro-4-(3-hydroxy-2,2- dimethyIpropoxy)phenyl]-5-methy1-4,5-dihydro-2H-pyridazin- 3-one, Example 12: 6-[3-bromo-2-fluoro-4-(3- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 19: 6-[3-chloro-2-fluoro-4-(3- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 8 Example 22: 6-[3-chloro-2-fluoro-4-(3-hydroxypropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 24: 6-[3-bromo-2-fluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 26: 6-[3-bromo-5-fluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 31: 6-[3-chloro-4-(2-hydroxy-2-methylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 36: 6-[3-chloro-2-fluoro-4-(2-hydroxy-2- methylpropoxy)-5-methylphenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one, Example 40: 6-{3-chloro-4-[(2R)-2-hydroxypropoxy]-5- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 44: 6-{3-chloro-4-[(1-hydroxycyclopropyl)methoxy]- 5-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 47: 6-{3-chloro-2-fluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one, Example 48: 6-[3-bromo-2-fluoro-4-(2- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 53: 6-[3,5-dichloro-4-(2-hydroxypropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one, 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 9 Example 54: 6-[3-chloro-2-fluoro-4-(2- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 55: 6-[3-chloro-4-(2-hydroxypropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 57: 6-[3-bromo-5-chloro-4-(2- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 59 : 6-[2-fluoro-4-(2-hydroxypropoxy)-3- vinylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 64: 6-[3-chloro-2-fluoro-4-(2- hydroxybutoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 69: 6-[3-bromo-5-fluoro-4-(3-hydroxy-2,2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one, Example 72: 6-[3-chloro-4-(3-hydroxy-2,2-dimethylpropoxy)- 5-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 99: 6-[3-chloro-5-fluoro-4-(4-hydroxy-2,2- dimethylbutoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 100: 6-[3,5-dichloro-4-(4-hydroxy-2,2- dimethylbutoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 109: 6-[3,5-dichloro-4-(2,2-difluoro-3- 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 10 hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 112: 6-[3-bromo~4-(2,2-difluoro-3-hydroxypropoxy)- 2-fluorophenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 113: 6-[3-chloro-4-(2,2-difluoro-3-hydroxypropoxy)- 5-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 118: (5R)-(-)-6-[3-chloro-2-fluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 120: (5R)-(-)-6-[4-(2,2-difluoro-3-hydroxypropoxy)- 2-fluoro-3-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one, Example 124: (5R)-(-)-6-[2,3-difluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 125: (5R)-(-)-6-[3-fluoro-4-(3-hydroxy-2,2- dimethylpropoxy)-5-methylphenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-onef Example 127: (5R)-(-)-6-[3-bromo-5-chloro-4-(3-hydroxy-2,2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one, Example 131: 6-[3-chloro-2,5-difluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3~ one, Example 137: 6-[3-chloro-2-fluoro-4-(3-hydroxy-2,2- 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 11 dimethylpropoxy)-5-methylphenyl]-5-methyl-4,5-dihydro~2Hpyridazin-3-one, Example 140: 6-[3-chloro-2,5-difluoro-4-(3- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, Example 142: 6-[3-chloro-4-(3-hydroxy-2-methylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 148: 6-[3-chloro-2-fluoro-4-(2-hydroxypropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 151: 6-{3-chloro-2-fluoro-4-[(Z)-4-hydroxy-2- butenyloxy]-5-methylphenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one, Example 155: 6-(3-chloro-4-{[(IS*,2R*)-2- (hydroxymethyl)cyclopropyl]methoxy}-5-methylpheny1)-5- methyl-4,5-dihydro-2H-pyridazin-3-one, Example 159: 6-[3-chloro-4-(2,2-difluoro-3-hydroxypropoxy)- 2-fluoro-5-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one, Example 160: 6-[4-(2,2-difluoro-3-hydroxypropoxy)-2-fluoro- 3,5-dimethylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, Example 167: 6-{3-chloro-2-fluoro-4-[(1- hydroxycyclopropyl)methoxy]-5-methylphenyl}-5-methyl-4,5- dihydro-2H-pyridazin-3-one, Example 168: 6-{3-bromo-2-fluoro-4-[(lhydroxycyclopropyl)methoxy]phenyl]-5-methyl-4,5-dihydro-2H 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 12 pyridazin-3-one, Example 170: 6-{3,5-dichloro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one, and Example 184: 6-[2-fluoro-4-(2-hydroxy-2-methylpropoxy)-3- (trifluoromethyl)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one. [0016] (Term 10) A pharmaceutical composition comprising the compound of any one of Terms 1 to 9 or a pharmaceutically acceptable salt thereof. [0017] (Term 11) An agent for treating malignant tumor, comprising the compound of any one of Terms 1 to 9 or a pharmaceutically acceptable salt thereof. [0018] (Term 12) A method for treating or preventing malignant tumor, comprising administering a therapeutically effective amount of the compound of any one of Terms 1 to 9 or a pharmaceutically acceptable salt thereof to a patient in need thereof. [0019] (Term 13) The pharmaceutical composition of Term 10 for use in treating or preventing malignant tumor. [0020] 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 13 (Term 14) Use of the compound of any one of Terms 1 to 9 or a pharmaceutically acceptable salt thereof in the manufacture of an agent for treating malignant tumor. [0021] Preferably, the malignant tumor defined in the above Terms 11 to 14 is particularly bram tumor. [Effect of Invention] [0022] The compound of the present invention can be a useful agent for treating tumor, particularly malignant tumor, in more detail, the compound is useful as a novel agent for treating childhood brain tumor selected from the group consisting of astrocytoma, malignant medulloblastoma, germ cell tumor, craniopharyngioma, and ependymoma; adult brain tumor selected from the group consisting of glioma, meningioma, pituitary adenoma, and nerve sheath tumor; head and neck cancer selected from the group consisting of maxillary sinus cancer, pharyngeal cancer (e.g. nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), laryngeal cancer, oral cancer (e.g. lip cancer, tongue cancer), and salivary gland cancer (e.g. parotid gland cancer); thoracic cancer and tumor selected from the group consisting of small cell lung cancer, non-small-cell lung cancer, thymoma, and mesothelioma; gastrointestinal cancer and tumor selected from the group consisting of esophageal cancer, liver cancer, 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 14 primary liver cancer, gallbladder cancer, bile duct cancer, gastric cancer, colorectal cancer (e.g. rectal cancer, anal cancer), pancreatic cancer, and pancreatic endocrine tumor; urologic cancer and tumor selected from the group consisting of penile cancer, renal pelvic/ureter cancer, renal cell cancer, testicular tumor (also referred to as testicular neoplasm), prostate cancer, bladder cancer, Wilms* tumor, and urothelial carcinoma; gynecologic cancer and tumor selected from the group consisting of vulvar cancer, cervical cancer, uterine body cancer, endometrial cancer, uterine sarcoma, choriocarcinoma, vaginal cancer, breast cancer, ovarian cancer, and ovarian germ cell tumor; adult and childhood soft tissue sarcoma; bone tumor selected from the group consisting of osteosarcoma and Ewing's tumor; endocrine tissue cancer and tumor selected from the group consisting of adrenocortical carcinoma and thyroid cancer; malignant lymphoma and leukemia selected from the group consisting of malignant lymphoma, non-Hodgkin’s lymphoma, Hodgkin's disease, multiple myeloma, plasma cell neoplasm, acute myeloid leukemia, acute lymphoblastic leukemia, adult T-cell leukemia-lymphoma, chronic myeloid leukemia, and chronic lymphocytic leukemia; or skin cancer and tumor selected from the group consisting of chronic myeloproliferative disorder, malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and mycosis fungoides. 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 15 In particular, the compound of the present invention is expected to have a high safety, for example, because the compound has no myelosuppressive action or the like that is a frequently-occurring side-effect in using a conventional anti-malignant tumor agent. In addition, the compound has a good water—solubility, thus it is expected to be used m the treatment via various administration ways. [Description of Embodiments]

[0023] The compound of the present invention may be in the form of hydrate and/or solvate, and hence the present compound also encompasses hydrate and/or solvate thereof.

[0024] The compound of the present invention may have one chiral carbon atom or optionally more chiral carbon atoms. Unless otherwise indicated, the present compound also encompasses all stereoisomers thereof. The compound of formula (1) may have a chiral carbon at 5th position of its 4,5-dihydro-2H-pyridazin-3-one moiety. Unless otherwise indicated here, the compound of formula (1) may encompass all stereoisomers, preferably a stereoisomer having R configuration at 5th position.

[0025] In addition, the compound of formula (1) (deuterium form) in which any one or more :H atoms are replaced by 2H(D) atoms 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 16 is within the scope of the present invention. There may exist a polymorphism in a crystal of the compound of formula (1) or a pharmaceutically acceptable salt thereof, and hence such crystal polymorphism is also within the scope of the present invention.

[0026] Each term used herein is explained below. The term "halogen" herein means fluorine atom, chlorine atom, bromine atom or iodine atom. Preferably, it is fluorine atom or chlorine atom.

[0027] The term "alkyl group” herein means a saturated straight or branched chain hydrocarbon group. For example, the "C1-4 alkyl" or "Ci-g alkyl" means an alkyl having 1 - 4 or 1 - 6 carbon atoms, respectively. The "C1-4 alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. The "C1-6 alkyl” includes pentyl, isopentyl, neopentyl, and hexyl, besides the above C1-4 alkyl. [0028] The term "halogenated alkyl group" means an alkyl group in which one or more replaceable hydrogen atoms are replaced by the same or different and one or more halogen atoms. For example, the term "halogenated C1-6 alkyl group" means an alkyl group having 1-6 carbon atoms, in which one or more replaceable hydrogen atoms are replaced by the same or 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 17 different and one or more halogen atoms, and it includes, for example, trifluoromethyl, pentafluoroethyl, 2- chloroethyl, 2-bromoethyl, heptafluoropropyl, 3-bromopropyl, nonafluorobutyl, tridecafluorohexyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1,2,2- tetraf1uoropropyl, 3,3,3—trifluoropropy1, and 2,2,3,3,3— pentafluoropropyl, and it is preferably trifluoromethyl. [0029] The term "C2-6 alkenyl group" means an unsaturated straight or branched chain C2-6 hydrocarbon group having 1-3 carbon¬ carbon double bonds. Preferably, it is "C2-4 alkenyl group". The "C2-6 alkenyl group" includes, for example, ethenyl (i.e., vinyl group), propenyl, butenyl, pentenyl, and hexenyl. [0030] The term "alkoxy group" means "alkyl-O- group". For example, the "C1-6 alkoxy group" means "Ci-g alkyl-O- group", wherein the part "C1-6 alkyl" is as defined in the above-defined "Ci- 6 alkyl". Preferably, it is "C1-4 alkoxy group". The "C1-6 alkoxy group" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0031] The term "alkylene group" means a saturated straight or branched chain divalent hydrocarbon group. For example, the "Ci-6 alkylene group" means an alkylene group having 1-6 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 18 carbon atoms. The "Ci-g alkylene group” includes, for example, methylene, ethylene, propylene, butylene, 1-methylpropylene, 2-methylpropylene, pentylene, 1-methylbutylene, 2- methylbutylene, hexylene, 2—ethylbutylene, and 1,3— dimethylbutylene•

[0032] The term "alkenylene group" means an unsaturated straight or branched chain divalent hydrocarbon group having 1 or more carbon-carbon double bonds. For example, the "C2-6 alkenylene group" means a C2-6 alkylene group having 1-3 carbon-carbon double bonds. The "C2-S alkenylene group" includes, for example, ethynylene group, propynylene group, butynylene group, pentynylene group, and hexynylene group.

[0033] In the phrase "a substitutable carbon atom in the substituent bonding to the alkylene or alkenylene group and another substitutable carbon atom in the alkylene or alkenylene group, or two substitutable carbon atoms in the substituent bonding to the alkylene or alkenylene group may be combxned together to form a 3- to 6-membered carbon ring" in Y, the term "substitutable carbon atom in the substituent bonding to the alkylene or alkenylene group" means a substitutable carbon atom in the C1-6 alkyl group or the halogenated C1-6 alkyl group which is selected as a substituent of the alkylene or alkenylene group in Y, and the term "3- to 6-membered carbon 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 19 ring" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and a halogenated product thereof.

[0034] The term "pharmaceutically acceptable salt" includes, as an acid addition salt, an inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate, an organic acid salt such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate, and an amino acid salt such as glutamate and aspartate; and as a basic salt, an alkali metal salt such as sodium salt and potassium salt, an alkalineearth metal salt such as calcium salt, and ammonium salt. [0035] General process to prepare the present compound The above 4,5-dihydro-2H-pyridazin-3-one compound of formula (1) or a salt thereof can be prepared m a general manner of organic synthesis, for example, in the manner below, but the present invention should not be limited thereto. Material compounds used herein may be obtained from commercially available products or prepared in a conventional manner as appropriate. [0036] 5 10 15 20 Date Reçue/Date Received 2023-06-16 20 [Chem. 3] Scheme 1 R2a X1~Y1OH (3) Xf :Leaving group Wherein Rla to R4a are independently hydrogen atom, halogen, CN, Ci—g alkyl group, halogenated Ci-g alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, or halogenated Ci-s alkoxy group, provided that one or two of Rla to R4a are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms. X1 denotes a leaving group. Y1 is Ci-e alkylene or C2-6 alkenylene group, wherein the alkylene or alkenylene group may be substituted with one or more substituents selected independently from the group consisting of Ci-g alkyl group, fluorine group, and fluorinated C1-6 alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkylene or alkenylene group and another substitutable carbon atom in the alkylene or alkenylene group, or two substitutable carbon atoms in the substituent bonding to the alkylene or alkenylene group may be combined together to form a 3- to 6-membered carbon ring. [0037] According to the method shown in Scheme 1, Compound (la) can 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 21 be prepared by reacting Compound (2) and Compound (3), in an appropriate solvent or without a solvent, in the presence or absence of a basic compound.

[0038] The leaving group X1 used herein includes halogen group such as fluorxne, chlorine, bromxne, and xodxne; substituted sulfonyloxy group such as Ci-g alkylsulfonyloxy group (e.g. methanesulfonyloxy, ethanesulfonyloxy), C6-i« arylsulfonyloxy group (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy), and C7-16 aralkylsulfonyloxy group (e.g. benzylsulfonyloxy); acyloxy group such as acetoxy and benzoyloxy; oxy group substituted with heterocyclyl or aryl such as succinimide, benzotriazole, quinoline, and 4-nitrophenyl; and heterocyclyl such as imidazole.

[0039] The solvent used herein can be broadly chosen from known solvents unless it negatively affects the reaction. The solvent used herein includes, for example, water; ethers such as dxoxane, tetrahydrofuran (THF), dxethyl ether, diethylene glycol dimethyl ether (diglyme), and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; alcohols such as methanol, ethanol, and 2- propanol; ketones such as acetone and methyl ethyl ketone; 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 22 polar solvents such as N,N-dimethy1formamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphate triamide, and acetonitrile; and a mixture thereof.

[0040] The basic compound used herein can be broadly chosen from known basxc compounds, which includes, for example, an alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; an alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; an acetates such as sodium acetate and potassium acetate; an alkali metals such as sodium and potassium; inorganic salts such as sodium amide, sodium hydride, and potassium hydride; an alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; an organic bases such as triethylamine, diisopropylethylamine, tripropylamine, pyridme, gumolme, 1,5—diazabicyclo[4.3•0]non™5—ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4- diazabicyclo[2.2.2]octane (DABCO). These basic compounds may be used as a single ingredient or in a combination of two or more ingredients.

[0041] If necessary, in the reaction, alkali metal iodide such as 23 potassium iodide and sodium iodide can be used as a reaction accelerator.

[0042] The amount of Compound (3) used herexn xs generally at least 5 about 0.5 mole, preferably about 0.5 to 10 moles per one mole of Compound (2). The amount of the basic compound used herein is generally about 0.5 to 10 moles, preferably about 0.5 to 6 moles per one mole of Compound (2). The above reaction is carried out generally at 0°C to 250°C, preferably 10 at 0°C to 200°C, under ordinary pressure or increased pressure, and the reaction is completed in about 1 to 80 hours. In addition, the reaction can be carried out under microwave irradiation. [0043] 15 [Chern. 4] Scheme 2 Wherein Rlb to R4b are independently hydrogen atom, halogen, Ci-6 alkyl group, halogenated Ci-6 alkyl group, C2-e alkenyl group, Ci-6 alkoxy group, or halogenated Ci-6 alkoxy group, Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 24 provided that one or two of Rlb to R4b are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms. Y2 is Ci alkyl or Cm alkenyl group which has oxo group, wherein the alkyl or alkenyl group may be substituted with one or more substituents selected independently from the group consisting of Ci~6 alkyl group, halogen, and halogenated Ci-6 alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkyl or alkenyl group and another substitutable carbon atom in the alkyl or alkenyl group, or two substitutable carbon atoms in the substituent bonding to the alkyl or alkenyl group may be combined together to form a 3- to 6-membered carbon ring, provided that the carbon atom to which the oxo group binds is not next to the halogen atom or the oxygen atom between the benzene ring and Y2, and the oxo group is not bound to the olefin carbon. R5 is Cn alkyl group. X2 is halogen atom. Y3 is C3-6 alkyl or C4-6 alkenyl group which has hydroxy group, wherein the alkyl or alkenyl group may be substituted with one or more substituents selected independently from the group consisting of Ci-g alkyl group, halogen, and halogenated Cj-6 alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkyl or alkenyl group and another substitutable carbon atom in the alkyl or alkenyl group, or two substitutable carbon atoms in the substituent bonding to the alkyl or alkenyl group may be combined 5 10 15 20 Date Reçue/Date Received 2023-06-16 25 together to form a 3- to 6-membered carbon ring, provided that the carbon atom to which the hydroxy group binds is not next to the halogen atom or the oxygen atom between the benzene ring and Y3, and the hydroxy group is not bound to the olefin carbon, and the hydroxy group is not primary alcohol • 1 is an xnteger of 2 to 5, m xs an xnteger of 3 to 5, and n is an integer of 1 to 4, provided that 1 + n and m + n E 6. 6,

[0044] According to the method shown in Scheme 2, Compound (lb) having hydroxy group in Y3 can be prepared by reacting Compound (4) having oxo group in Y2 with Grignard reagent (R5MgX2) or lithium reagent (R5Li) in an appropriate inert solvent such as diethyl ether and THF.

[0045] The amount of the Grignard reagent (R5MgX2) or lithium reagent (R5Li) of formula (5) used herein is generally at least about 0.5 mole, preferably about 3 to 10 moles per one mole of Compound (4). The above reaction is carried out generally at -78SC to room temperature, preferably at 0°C to room temperature, and the reaction is completed in about 1 to 24 hours. [0046] [Chern. 5] 26 Scheme 3 Wherein R1 to R4 are as defined above. R6 and R7 are independently hydrogen atom, Ci-e alkyl group, or halogenated Ci-6 alkyl group. R6 and R7 may be combined together at each 5 substitutable carbon atom in R6 and R7 to form a 3- to 6- membered carbon ring.

[0047] According to the method shown in Scheme 3, Compound (lc) can be prepared by reacting Compound (6) and Compound (7), in an 10 appropriate solvent, in the presence of a basic compound. [0048] The solvent used herein can be broadly chosen from known solvents unless at negatxvely affects the reactxon. The solvent used herein includes, for example, polar solvents 15 such as DMF, DMSO, and acetonitrile; ketones such as acetone and methyl ethyl ketone; hydrocarbons such as benzene, toluene, xylene, tetralin, and liquid paraffin; alcohols such as methanol, ethanol, 2-propanol, n-butanol, and tert¬ butanol; ethers such as THF, dioxane, dipropyl ether, diethyl Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 27 ether, and diglyme; esters such as methyl acetate, ethyl acetate, isopropyl acetate, and tert-butyl acetate; and a mixture thereof.

[0049] The basic compound used herein can be broadly chosen from known basxc compounds, whxch xncludes, for example the basxc compounds listed in Scheme 1.

[0050] The amount of Compound (7) used herein is generally about 0.5 to 5 moles, preferably about 0.5 to 3 moles per one mole of Compound (6). The amount of the basic compound used herein is generally about 0.1 to 5 moles, preferably about 1 to 2 moles, per one mole of Compound (6).

[0051] The above reaction can be carried out, for example, as follows: Compound (6) is dissolved in a reaction solvent, a basic compound is added to the stirred solution under icecold or at room temperature, the reaction mixture is stirred at room temperature to 80 C for 30 mxnutes to 1 hour, Compound (7) is added thereto, and then the reaction mixture is stirred at generally room temperature to 100°C, preferably at 50 to 80°C, for 30 minutes to 60 hours, preferably 1 to 50 hours. [0052] [Chern. 6] 5 10 15 20 Date Reçue/Date Received 2023-06-16 28 Scheme 4 Wherein Rlc to R4c are independently hydrogen atom, halogen, OH, CN, Ci-6 alkyl group, fluorinated Ci-6 alkyl group, C2-6 alkenyl group, Ci-g alkoxy group, or fluorinated C1-6 alkoxy group, provided that one or two of Rlc to R4c are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms. R8 is C1-6 alkyl group. Y1 is as defined above.

[0053] According to the method shown in Scheme 4, Compound (Id) can be prepared by reacting Compound (8) and hydrazine, in an appropriate solvent, in the presence or absence of an acidic compound.

[0054] The solvent used herein is an inert solvent, which includes, for example, alcohols such as methanol, ethanol and 2- propanol; acetic acid; and water; preferably ethanol. [0055] The hydrazine used herein is generally a hydrate thereof or a mineral acid salt thereof such as hydrochloride and sulfate. 29 The amount of hydrazine used herein is generally about one or more moles, preferably about 1 to 3 moles per one mole of Compound (8). [0056] 5 The reaction temperature is not limited in specific, which includes a temperature from room temperature to reflux temperature of the used solvent, and it is preferable to heat the reaction media to promote the reaction. The reaction time is generally 0.1 to 100 hours. 10 [0057] [Chern. 7] Scheme 5 Wherein R1 to R4 are as defined above. Y4 is Ci-g alkyl or C2-6 alkenyl group which has oxo group, wherein the alkyl or 15 alkenyl group may be substituted with one or more substituents selected independently from the group consisting of Ci-6 alkyl group, halogen, and halogenated Ci-e alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkyl or alkenyl group and 20 another substitutable carbon atom in the alkyl or alkenyl Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 30 group, or two substitutable carbon atoms in the substituent bonding to the alkyl or alkenyl group may be combined together to form a 3- to 6-membered carbon ring, provided that the carbon atom to which the oxo group binds is not next to the halogen atom or the oxygen atom between the benzene ring and Y4, and the oxo group is not bound to the olefin carbon. Y5 represents a substituent in which the oxo group moiety of Y4 is reduced to a hydroxyl group.

[0058] According to the method shown in Scheme 5, Compound (le) having hydroxy group in Y5 can be prepared by reacting Compound (9) having oxo group in Y4 with a hydride reductant in an appropriate solvent.

[0059] The hydride reductant used herein includes, for example, sodium borohydride, zinc borohydride, and these hydride reductants may be used as a single ingredient or in a combination of two or more ingredients. The reduction with a hydride reductant may be generally carried out in a solvent. The solvent used herein includes, for example, water; alcohols such as methanol and 2-propanol; and ethers such as THF, diethyl ether, diisopropyl ether, and diglyme. These solvents may be used as a single solvent or in a combination of two or more solvents. [0060] 5 10 15 20 Date Reçue/Date Received 2023-06-16 31 The reaction temperature is not limited in specific, which is generally at -60 to 150°C, preferably at -30 to 100°C. The reaction time is generally 10 minutes to 15 hours. [0061] [Chern. 8] Wherein R1 to R4 are as defined above. Y6 is C1-5 alkylene or C2-5 alkenylene group, wherein the alkylene or alkenylene group may be substituted with one or more substituents selected independently from the group consisting of C1-6 alkyl group, halogen, and halogenated C1-6 alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkylene or alkenylene group and another substitutable carbon atom in the alkylene or alkenylene group, or two substitutable carbon atoms in the substituent bonding to the alkylene or alkenylene group may be combined together to form a 3- to 6-membered carbon ring. R9 is Ci-e alkyl group.

[0062] According to the method shown in Scheme 6, Compound (If) can 5 10 15 20 Date Reçue/Date Received 2023-06-16 32 be prepared by reacting Compound (10) with a hydride reductant in an appropriate solvent.

[0063] The hydride reductant used herein includes, for example, diisobutylaluminum hydride, sodium borohydride, and lithium borohydride-trimethoxyborane. These reductants may be used as a single ingredient or in a combination of two or more ingredients. The amount of the hydride reductant used herein is generally at least equimolar to Compound (If), preferably in the range of equimolar to 15 times molar.

[0064] The reduction reaction may be carried out in a suitable solvent, for example, water; alcohols such as methanol, ethanol, and 2-propanol; ethers such as THF, diethyl ether, diisopropyl ether, and diglyme; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; or a mixture thereof, at about -60°C to 150°C, preferably -30°C to 100°C, generally for about 10 minutes to 40 hours. [0065] [Chern. 9] 5 10 15 20 Date Reçue/Date Received 2023-06-16 33 Scheme 7 (11) (1g) Wherein Rld to R4d are independently a leaving group, hydrogen atom, halogen, OH, CN, Ci-6 alkyl group, halogenated Ci-6 alkyl group, C2-6 alkenyl group, Ci-g alkoxy group, or halogenated C1-6 alkoxy group, provided that at least one of Rld to R4d is a leaving group, one or two thereof are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms. The leaving group includes chlorine, bromine, iodine, and a substituted sulfonyloxy group. Y is as defined above. Rle to R4e are independently hydrogen atom, halogen, OH, CN, C1-6 alkyl group, halogenated Ci-g alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, or halogenated Ci-e alkoxy group, provided that at least one of Rle to R4e is CN, one or two thereof are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms. The leaving group in Compound (11) is replaced by CN at the same position in Compound (1g).

[0066] According to the method shown in Scheme 7, Compound (1g) can be prepared by reacting Compound (11) and a cyanating agent, 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 34 in an appropriate solvent, in the presence of a palladium compound.

[0067] The solvent used herexn includes, for example, ethers such as THF, ethylene glycol dimethyl ether, tert-butyl methyl ether, and 1,4—dioxane; aliphatic hydrocarbons such as hexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; alcohols such as methanol and ethanol; acid amides such as DMF and N-methyl-2-pyrrolidone (NMP); sulfoxides such as DMSO; and a mixture thereof, preferably DMF.

[0068] The cyanating agent used herein includes, for example, zinc cyanide, and the palladium compound used herein include, for example, tetrakis(triphenylphosphine)palladium. The amount of cyanating agent used herein is generally 1 to 5 moles per one mole of Compound (11), and the amount of palladium compound used herein is generally 0.01 to 0.5 moles per one mole of Compound (11).

[0069] The reaction temperature is generally in the range of 50 to 200°C. The reaction time is generally in the range of 0.5 to 24 hours. In addition, the reaction can be carried out under microwave irradiation. [0070] 5 10 15 Date Reçue/Date Received 2023-06-16 35 [Chem. 10] (1h) Wherein R1£ to R4f are independently hydrogen atom, halogen, OH, hydroxy group protected with a protecting group for hydroxy group (hereinafter, this is abbreviated as "protected hydroxy group"), CN, Ci-6 alkyl group, halogenated Ci-6 alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, or halogenated C1-6 alkoxy group, provided that one or two of Rlf to R4f are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms. P1 is a protecting group for hydroxy group. When one or more of Rlf to R4f are protected hydroxy group, the protecting group can be removed at the same time of the deprotection of P1. R1 to R4, and Y are as defined above.

[0071] The protecting group for hydroxy group used herein is not 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 36 limited unless it negatively affects the reaction. The protecting group includes, for example, a silyl protecting group (e.g. trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl), an acetal protecting group (e.g. tetrahydropyranyl (THP), methoxymethyl (MOM), methylthxomethyl, ethoxyethyl, benzyloxymethyl), and an acyl protecting group (e.g. acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, onitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl or 4-nitrobenzoyl).

[0072] According to the method shown in Scheme 8, Compound (15) can be prepared by reacting Compound (13) and Compound (14), in an appropriate solvent, in the presence of the Mitsunobu reagent and a phosphine. [0073] The Mitsunobu reagent includes, for example, diethyl azodicarboxylate and bis(2-methoxyethyl) azodicarboxylate. The amount of Mitsunobu reagent used herein is 1 to 10 moles, preferably 1 to 5 moles per one mole of Compound (13) shown in Scheme 8. The amount of Compound (14) used herein is 1 to 10 moles, preferably 1 to 5 moles per one mole of Compound (13) shown in Scheme 8. The phosphine reagent used herein includes, for example, triphenylphosphine and 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 37 tributylphosphine. The amount of phosphine reagent used herein is 1 to 10 moles, preferably 1 to 5 moles per one mole of Compound (13) shown in Scheme 8.

[0074] The solvent used herein is not limited unless it negatively affects the reaction. The preferred solvent used herein includes, for example, toluene, benzene, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, NMP, DMSO, and a mixture thereof. [0075] The reaction temperature is generally at -78 to 200°C, preferably at 0 to 50°C. The reaction time is generally 5 minutes to 3 days, preferably 10 minutes to 10 hours. [0076] According to the method shown in Scheme 8, Compound (lh) can be prepared by deprotecting Compound (15).

[0077] When the protecting group for hydroxy group is a silyl-type protecting group, the deprotection can be carried out by hydrolysis under an acidic condition or by using a fluoride ion. For example, in case of tert-butyldimethylsilyl group selected as the silyl protecting group, the deprotection reaction is carried out with a fluoride ion. Suitable fluoride ion sources include, for example, tetrabutylammonium fluoride and hydrogen fluoride-pyridine, preferably tetrabutylammonium fluoride. The amount of the 5 10 15 20 Date Reçue/Date Received 2023-06-16 38 fluorine compound used herein is 1 to 10 moles, preferably 1 to 5 moles per one mole of Compound (15) shown in Scheme 8.

[0078] The solvent used herein is not limited unless it negatively affects the reaction. The solvent used herein includes, for example, THF, acetonitrile, and methylene chloride.

[0079] The deprotection reaction can be carried out at 0°C to a reflux temperature of the used reaction solvent, preferably 0°C to room temperature. The reaction time is generally 5 minutes to 3 days, preferably 10 minutes to 10 hours. [0080] When the protecting group for hydroxy group is an acetal protecting group such as a methoxymethyl group, the deprotection can be generally carried out by using an acid hydrolysis condition. The "acid" used in the acid hydrolysis includes, for example, acetic acid , hydrochloric acid and phosphoric acid, preferably hydrochloric acid. The amount of the acid is in the range of suitably 1 to 1000 moles, preferably 1 to 10 moles per one mole of Compound (15) shown in Scheme 8. [0081] 5 10 15 20 Date Reçue/Date Received 2023-06-16 39 The solvent used herein is not limited unless it negatively affects the reaction. The solvent used herein includes, for example, dichloromethane, methanol, and water.

[0082] The reaction time may vary depending on a material compound used herein, reaction temperature, or other factors, but it is suitably in the range of 0.5 hour to 24 hours.

[0083] When the protecting group for hydroxy group is an acyl-type protecting group, the deprotection can be generally carried out by using a basic hydrolysis condition. The solvent used herein includes, for example, water; alcohols such as methanol, ethanol, 2-propanol, and tert-butanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether, dioxane, THF, monoglyme, and diglyme; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; DMSO; DMF; hexamethylphosphate triamide; and a mixture thereof* The basic compound used herein includes, for example, carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; and metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. These 40 basic compounds may be used as a single ingredient or in a combination of two or more ingredients.

[0084] The hydrolysis reaction can proceed generally at at 0 to 5 200°C, preferably at 0 to 150°C, and the reaction is completed generally in about 10 minutes to 50 hours. [0085] When there are plural protecting groups for hydroxy group in Rlf to R4f and P1, the protecting groups may be the same or 10 different. If the protecting groups are different, the deprotection reaction can be carried out by combining plural deprotection conditions suitable for each protecting group. [0086] [Chem. 11] Scheme 9 Oi) Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 41 Wherein R1^ to are independently hydrogen atom, halogen, protected hydroxy group, CN, Ci-g alkyl group, halogenated Ci-6 alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, or halogenated C1-6 alkoxy group, provided that at least one of R1^ to R4s is protected hydroxy group, one or two thereof are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms. Rlh to R4h are independently hydrogen atom, halogen, OH, CN, Ci-e alkyl group, halogenated C1-6 alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, or halogenated Ci-6 alkoxy group, provided that at least one of R1h to R4h is hydroxy group, one or two thereof are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms. Protected hydroxy group in Compound (17) is deprotected to OH at the same position in Compound (li). Y4 and Y5 are as defined above.

[0087] The reaction of Compound (16) and a hydride reductant can be carried out in a reaction condition similar to the reaction of Scheme 5.

[0088] The deprotection of Compound (17) can be carried out in a reaction condition similar to the reaction of Scheme 8. [0089] [Chern. 12] 42 Scheme 10 Wherein Rla to R4a, and X1 are as defined above. Y7 is C2-6 alkenyl group, wherein the alkenyl group may be substituted with one or more substituents selected independently from 5 the group consisting of Ci-6 alkyl group, halogen, and halogenated Ci-g alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkenyl group and another substitutable carbon atom in the alkenyl group, or two substitutable carbon atoms xn the substxtuent bondxng 10 to the alkenyl group may be combined together to form a 3- to 6-membered carbon ring. Y8 represents a group in which the double bond in the alkenyl group of Y7 is converted to an epoxy group Y9 represents a group in which the epoxy group of Y8 is ring-opened. 15 [0090] Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 43 The reaction of Compound (2) and Compound (18) can be carried out in a reaction condition similar to the reaction of Scheme 1. [0091] According to the method shown in Scheme 10, Compound (20) can be prepared by reacting Compound (19) and an oxidant in an appropriate solvent or without a solvent. The oxidant used herein includes, for example, m-chloroperbenzoic acid, peracetic acid, oxone, and hydrogen peroxide. The solvent used herein can be broadly chosen from known solvents unless it negatively affects the reaction. The solvent used herein includes, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane and heptane; alcohols such as methanol and ethanol; halogenated solvents such as chloroform, dichloromethane, and dichloroethane; nitriles such as acetonitrile and butyronitrile; esters such as ethyl acetate, butyl acetate, and methyl formate; amides such as DMF and N,Ndimethylacetamide; and a mixture thereof.

[0092] The amount of the oxidant used herein is generally about 1 to 5 moles per one mole of Compound (19). The above reaction is carried out generally at 0°C to 100’C, preferably at 0°C to room temperature, and the reaction is generally completed in about 0.5 to 24 hours. 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 44

[0093] According to the method shown in Scheme 10, Compound (lj) can be prepared by ring-opening Compound (20) under the hydrogenation condition, in an appropriate solvent, in the presence of a palladium compound.

[0094] The reductant used herein includes, for example, hydrogen and ammonium formate and these reductants may be used as a single ingredient or in a combination of two ingredients. [0095] The palladium compound used herein include, for example, palladium-carbon (10 % w/w). The amount of palladium compound used herein is generally 0.01 to 0.5 moles per one mole of Compound (20).

[0096] The solvent used herein can be broadly chosen from known solvents unless it negatively affects the reaction. The solvent used herein includes, for example, ethers such as dioxane, THF, diethyl ether, diglyme, and ethylene glycol dimethyl ether; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; alcohols such as methanol, ethanol, and 2- propanol; polar solvents such as DMF, DMSO and acetonitrile; and a mixture thereof. [0097] 45 5 The above reaction is carried out generally at 0°C to 70°C, preferably at 0°C to room temperature, and the reaction is generally completed in about 0.5 to 24 hours. [0098] [Chem. 13] Wherein [0099] to R^, Y, and are as defined above. The reaction of Compound (21) and hydrazine can be carried 10 out in a reaction condition similar to the reaction of Scheme 4. The deprotection of Compound (22) can be carried out in a reaction condition similar to the reaction of Scheme 8. [0100] The present compound of formula (1) can be prepared according 15 to the above synthetic processes, and it can be also prepared Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 46 based on the synthetic processes described in the reference examples and examples herein, considering the prior art known at the time of the filing date.

[0101] If necessary, the starting materials and intermediates shown in the above schemes can be protected with a suitable protecting group before starting the reaction, and then the protecting group can be removed in a known manner after the reaction.

[0102] Each product prepared according to the above schemes can be purified from each reaction mixture as follows, for example, the reaction mixture is cooled, the reaction mixture is treated in an isolation procedure such as filtration, concentration, and extraction to isolate the crude product, and the crude product is purified in a conventional manner of purification such as column chromatography and recrystaliization.

[0103] The starting materials and products shown in each scheme also include a solvate thereof as an additional form, for example, a hydrate and ethanolate.

[0104] The starting materials and products shown in each scheme may be used in a preferred salt form. Each product in each step 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 47 can be used in its next step without isolation. [0105] The present compound (1)f intermediates prepared in the above schemes, and starting materials thereof may include geometric isomer, stereoisomer, tautomer and optical isomer thereof.

[0106] Each isomer can be isolated by a conventional manner. For example, racemic compounds can be divided by a general optical resolution such as crystallization and chromatography to optically pure isomers thereof. In addition, an optically pure compound can be also prepared from an appropriate material.

[0107] The compound of the present invention can be a useful agent for treating tumor, particularly malignant tumor, in more detail, the compound can be a novel agent for treating and/or preventing childhood brain tumor selected from the group consisting of astrocytoma, malignant medulloblastoma, germ cell tumor, craniopharyngioma, and ependymoma; adult brain tumor selected from the group consisting of glioma, meningioma, pituitary adenoma, and nerve sheath tumor; head and neck cancer selected from the group consisting of maxillary sinus cancer, pharyngeal cancer (e.g. nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 48 cancer), laryngeal cancer, oral cancer (e.g. lip cancer, tongue cancer), and salivary gland cancer (e.g. parotid gland cancer); thoracic cancer and tumor selected from the group consisting of small cell lung cancer, non-small-cell lung cancer, thymoma, and mesothelioma; gastrointestinal cancer and tumor selected from the group consisting of esophageal cancer, liver cancer, primary liver cancer, gallbladder cancer, bile duct cancer, gastric cancer, colorectal cancer (e.g. rectal cancer, anal cancer), pancreatic cancer, and pancreatic endocrine tumor; urologic cancer and tumor selected from the group consisting of penile cancer, renal pelvic/ureter cancer, renal cell cancer, testicular tumor (also referred to as testicular neoplasm), prostate cancer, bladder cancer, Wilms’ tumor, and urothelial carcinoma; gynecologic cancer and tumor selected from the group consisting of vulvar cancer, cervical cancer, uterine body cancer, endometrial cancer, uterine sarcoma, choriocarcinoma, vaginal cancer, breast cancer, ovarian cancer, and ovarian germ cell tumor; adult and childhood soft tissue sarcoma; bone tumor selected from the group consisting of osteosarcoma and Ewing’s tumor; endocrine tissue cancer and tumor selected from the group consisting of adrenocortical carcinoma and thyroid cancer; malignant lymphoma and leukemia selected from the group consisting of malignant lymphoma, nonHodgkin's lymphoma, Hodgkin’s disease, multiple myeloma, 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 49 plasma cell neoplasm, acute myeloid leukemia, acute lymphoblastic leukemia, adult T-cell leukemia-lymphoma, chronic myeloid leukemia, and chronic lymphocytic leukemia; or skin cancer and tumor selected from the group consisting of chronic myeloproliferative disorder, malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and mycosis fungoides. The administration route of the present compound may be selected from oral administration, parenteral administration or rectal administration, and the daily dosage may vary depending on the compound structure, the administration route, the condition/age of patients, etc. For example, in case of oral administration, the present compound may be administered to a human being or a mammal in a dosage of generally about 0.01 pg - 10 mg, preferably about 1 pg - 5 mg, per kg of its body weight, in one to several divided doses. For example, in case of parenteral administration such as intravenous injection, the present compound may be administered to a human being or a mammal in a dosage of generally about 0.01 pg - 10 mg, preferably about 1 pg — 5 mg, per kg of its body weight.

[0108] The dosage form in the present invention includes tablet, capsule, granule, powder, syrup, suspension, injection, suppository, eyedrop, ointment, liniment, patch, and inhalant. These dosage forms can be prepared in a 5 10 15 20 Date Reçue/Date Received 2023-06-16 50 conventional manner. If the dosage form is a liquid one, it may be a formulation to prepare a solution or suspension in use by mixing it with water, appropriate water-solution, or other appropriate solvent. The tablet and the granule may be coated in a well-known manner. Furthermore, these dosage forms may comprise another therapeutically-useful ingredient. [0109] In case that the present compound is formulated into a single dosage form, the dosage form may include the present compound in 0.1 - 70 % (w/w) per the whole composition, but the present invention is not limited thereto. Preferably, it is 5 - 40 % (w/w) per the whole composition. [Examples]

[0110] The present invention is explained in more detail in the following by referring to Reference examples, Examples and Test, however, the present invention should not be limited thereto. [0111] (Reference example 1) Production of (4-bromo-2-chloro-6-methylphenoxy)-tertbutyldimethylsilane [Chem. 14] 51 To a mixture of —bromo—2—chloro—6—methylphenol (15*3 g) m DMF (120 mL) were added imidazole (6.1 g) and tertbutylchlorodimethylsilane (10.9 g), and the mixture was 5 stirred at room temperature overnight. The solvent was removed, and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The 10 obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 0 to 99 : 1) to afford the title compound as a colorless oil (20.0 g). ^-NMR (CDC13) 5: 0.24 (6H, s), 1.03 (9H, s), 2.22 (3H, s), 7.14-7.17 (1H, m), 7.30-7.33 (1H, m). 15 [0112] (Reference example 2) Production of methyl 2-(4-bromo-2-chloro-6- fluorophenoxy)acetate [Chem. 15] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 52 To a mixture of 4™bromo—2—ch1oro—6”f1uoropheno1 (2*0 g) and potassium carbonate (1.47 g) in DMF (15 mL) was added methyl bromoacetate (0.924 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 80 ; 20 to 60 : 40) to afford the title compound as a colorless oil (2.53 g). ^-NMR (CDC13) 5: 3.81 (3H, s), 4.73 (2H, s), 7.20 (1H, dd, J = 10.4, 2.3 Hz), 7.33-7.37 (1H, m). [0113] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 2. (Reference example 3) Methyl 2-(4-bromo-2-fluoro-6-methylphenoxy)acetate [Chem. 16] 53 1H-NMR (CDCI3) 5: 2.33 (3H, s), 3.79 (3H, s), 4.69 (2H, d, J = 1.0 Hz), 7.06-7.11 (2H, m). [0114] 5 (Reference example 4) Methyl 2-(4-bromo-3-fluoro-2-methylphenoxy)acetate [Chem. 17] F ifî-NMR (CDCI3) 5: 2.24 (3H, d, J = 2.3 Hz), 3.80 (3H, s), 10 4.65 (2H, s), 6.42 (1H, dd, J = 8.9, 1.2 Hz), 7.28 (1H, t, J = 8.9 Hz). [0115] (Reference example 5) Production of methyl 2-(4-bromo-2-chloro-3- 15 fluorophenoxy)acetate [Chem. 18] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 54 F To a mixture of 2”chloro~3"—'fluorophenol (2 6 g) in acetic acid (30 mL) was added pyridinium bromide perbromide (6.0 g), and the mixture was stirred at room temperature for 4.5 hours. To the reaction mixture was added aqueous sodium thiosulfate, and the mixture was extracted with toluene. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed to afford a yellow oil (3.4 g). This oil was dissolved in DMF (30 mL), and potassium carbonate (4.9 g) and methyl bromoacetate (2.0 mL) were added to the mixture. The mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 0 to 84 : 16) to afford the title compound as a colorless oil (2.3 g). 'H-NMR (CDC13) 5: 3.81 (3H, s), 4.73 (2H, s), 6.56 (1H, dd, J = 9.0, 1.8 Hz), 7.37 (1H, dd, J = 9.0, 7.4 Hz). 5 10 15 20 Date Reçue/Date Received 2023-06-16 55 [0116] (Reference example 6) Production of 1-[(4-bromo-2-chloro-6- fluorophenoxy)methyl]cyclopropan-l-ol [Chem. 19] Under an argon atmosphere, to a mixture of methyl 2-(4-bromo- 2-chloro-6-fluorophenoxy)acetate (Reference example 2, 2.53 g) in THF (30 mL) was added tetraisopropyl orthotitanate (2.49 mL) at 0°C. Ethylmagnesium bromide (3.0 M diethyl ether solution, 7.65 mL) was slowly added thereto at 0°C, and the reaction mixture was stirred at room temperature for one hour. To the reaction mixture was added 1 M hydrochloric acid at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 0 to 80 : 20) and then by amino silica gel column chromatography (methylene chloride : methanol = 100 : 0 to 90 : 10) to afford the title compound as a colorless oil (1.15 g). 56 iH-NMR (CDCI3) 5: 0.60-0.66 (2H, m), 0.89-0.95 (2H, m), 2.95 (1H, s), 4.14 (2H, s), 7.21 (1H, dd, J = 9.8, 2.2 Hz), 7.33- 7.37 (1H, m). [0117] 5 The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 6. (Reference example 7) 1-[(2,3-Difluorophenoxy)methyl]cyclopropan-l-ol 10 [Chem. 20] F !H-NMR (CDCI3) 5: 0.68-0.74 (2H, m), 0.95-1.00 (2H, m), 2.78 (1H, s), 4.08 (2H, s), 6.71-6.84 (2H, m), 6.93-7.02 (1H, m). [0118] 15 (Reference example 8) 1-[(4—Bromo-2,6-dimethylphenoxy)methyl]cyclopropan-l-ol [Chem. 21] Date Reçue/Date Received 2023-06-16 57 1H-NMR (CDCI3) 5: 0.66—0.71 (2H, m), 0.93-0.98 (2H, m), 2.26- 2.28 (6H, m), 2.77 (1H, s), 3.78 (2H, s), 7.13-7.16 (2H, m). [0119] 5 (Reference example 9) 1-[(4-Bromo-2-chloro-6-methylphenoxy)methyl]cyclopropan-1- ol [Chem. 22] 10 nH-NMR (CDCI3) 5: 0.66-0.73 (2H, m), 0.92-0.98 (2H, m), 2.32 (3H, s), 2.90 (1H, s), 3.95 (2H, s), 7.23 (1H, dd, J = 2.4, 0.6 Hz), 7.37 (1H, d, J = 2.4 Hz). [0120] (Reference example 10) 15 1-[(4—Bromo-2-fluoro-6-methylphenoxy)methyl]cyclopropan-1- ol [Chem. 23] Date Reçue/Date Received 2023-06-16 58 iR-NMR (CDCI3) 5: 0.62-0.68 (2H, m) . 5 [0121] (Reference example 11) 1- [ (4-Bromo-3-fluoro-2-methylphenoxy) methyl] cyclopropan-1- ni ni h h mu Hit 1 h miii ni» । iiw । iinr ^i.h.i । m ol [Chem. 24] 10 iH-NMR (CDC13)5: 0.69-0.75 (2H (1H, m) . [0122] 15 (Reference example 12) 1- [ (4-Bromo-2-chloro-3-f luorophenoxy) methyl] cyclopropan-1- ol [Chem. 25] 4.00 (2H, s) , 6.53 (1H (3H, s) , 2.76 (1H, d, J (2H, m), 0.90-0.95 (2H, m) , 2.30 m) , 0.95-1.00 (2H, m) , 2.22 (3H, d, J = 2.3 Hz), 2.59 (1H 1.0 Hz), 4.02 (2H, s) , 7.07-7.13 dd, J =8.9, 1.3 Hz), 7.25-7.32 Date Reçue/Date Received 2023-06-16 59 F ^-NMR (CDCI3) 5: 0.70-0.76 (2H, m), 0.96-1.03 (2H, m), 2.81 (1H, s), 4.07 (2H, s), 6.65 (1H, dd, J= 9.0, 1.8 Hz), 7.38 (1H, dd, J = 9.0, 7.5 Hz). 5 [0123] (Reference example 13) Production of {1-[(4-bromo-2-chloro-6- fluorophenoxy)methyl]cyclopropyloxy)triethylsilane [Chem. 26] 10 To a mixture of 1-[(4-bromo-2-chloro-6- fluorophenoxy)methyl]cyclopropan-l-ol (Reference example 6, 1.15 g) in methylene chloride (15 mL) were added 2,6-lutidine (0.544 mL) and triethylsilyl trifluoromethanesulfonate 15 (0.968 mL) at 0°C. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added water, and then the mixture was extracted with methylene Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 60 chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane . ethyl acetate = 100 : 0 to 85 : 15) to afford the title compound as a colorless oil (1.08 g). 1H-NMR (CDC13) 5: 0.64 (6H, q, J = 7.8 Hz), 0.77-0.84 (2H, m), 0.84-0.91 (2H, m), 0.95 (9H, t, J = 7.8 Hz), 4.05 (2H, s), 7.17 (1H, dd, J = 10.0, 2.4 Hz), 7.30-7.33 (1H, m). [0124] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 13. (Reference example 14) {1-[(2,3- Difluorophenoxy)methy1]cyclopropyloxy}triethy1si1ane [Chem. 27] 'H-NMR (CDCI3) 5: 0.62-0.70 (6H, m), 0.73-0.78 (2H, m), 0.86- 0.99 (11H, m), 4.02 (2H, s), 6.67-6.81 (2H, m), 6.91-7.00 61 (1H, m). [0125] (Reference example 15) {1-[(4-Bromo-2,6- 5 dimethylphenoxy)methyl]cyclopropyloxy}triethylsilane [Chem. 28] ir-NMR (CDC13) 5: 0.64 (6H, q, J = 7.9 Hz), 0.74-0.79 (2H, m), 0.87-0.92 (2H, m), 0.96 (9H, t, J = 7.9 Hz), 2.25 (6H, 10 s), 3.73 (2H, s), 7.12 (2H, s). [0126] (Reference example 16) {1-[(4-Bromo-2-chloro-6~ methylphenoxy)methyl]cyclopropyloxy}triethylsilane 15 [Chem. 29] iH-NMR (CDCI3) 5: 0.60-0.68 (6H, m), 0.77-0.81 (2H, m), 0.86- Date Reçue/Date Received 2023-06-16 62 0.91 (2H, m), 0.92-0.98 (9H, m), 2.32 (3H, s), 3.90 (2H, s), 7.21 (1H, dd, J = 2.4, 0.7 Hz), 7.33 (1H, dd, J = 2.4, 0.5 Hz). [0127] 5 (Reference example 17) {1-[(4-Bromo-2-fluoro-6- methylphenoxy)methyl]cyclopropyloxy)triethylsilane [Chem. 30] 10 iH-NMR (CDC13) 5: 0.62 (6H, q, J = 8.0 Hz), 0.68-0.74 (2H, m), 0.83-0.89 (2H, m), 0.94 (9H, t, J = 8.0 Hz), 2.30 (3H, s), 3.98 (2H, s), 7.04-7.09 (2H, m). [0128] (Reference example 18) 15 (1—[(4—Bromo—3—fluoro—2— methylphenoxy)methyl]cyclopropyloxy}triethylsilane [Chem. 31] Date Reçue/Date Received 2023-06-16 63 1H-NMR (CDC13) 5: 0.59-0.68 (6H, m), 0.73-0.78 (2H, m), 0.85- 0.90 (2H, m), 0.93 (9H, t, J = 7.9 Hz), 2.20 (3H, d, J = 2.3 Hz), 3.96 (2H, s), 6.50 (1H, dd, J = 8.9, 1.3 Hz), 7.24-7.30 5 (1H, m). [0129] (Reference example 19) {l-[(4-Bromo-2-chloro-3- fluorophenoxy)methyl]eyelopropyloxy}triethylsilane 10 [Chem. 32] ’H-NMR (CDCI3) 5: 0.61-0.71 (6H, m), 0.75-0.98 (13H, m), 4.03 (2H, s), 6.63 (1H, dd, J - 9.0, 1.7 Hz), 7.36 (1H, dd, J = 9.0, 7.6 Hz). 15 [0130] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 64 (Reference example 20) Production of 3-chloro-5-fluoro~4-{[1- (triethylsilyloxy)cyclopropyl]methoxy}benzaldehyde [Chem. 33] Under an argon atmosphere, to a mixture of {1-[(4-bromo-2- chloro-6-fluorophenoxy)methyl]cyclopropyloxy}triethylsilane (Reference example 13, 1.08 g) in THF (10 mL) at -78“C was added n-butyl lithium (1.6 M n-hexane solution, 1.73 mL), and under the same condition, the reaction mixture was stirred for 30 minutes. At -78°C, DMF (0.224 mL) was added to the reaction mixture, and the reaction mixture was stirred at -78°C for 30 minutes and then at room temperature for 30 minutes. To the reaction mixture was added aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 0 to 90 : 10) to afford the title compound as a colorless oil (873 mg). iH-NMR (CDC13) 5: 0.63 (6H, q, J = 7.9 Hz), 0.78-0.85 (2H, 5 10 15 20 Date Reçue/Date Received 2023-06-16 65 m), 0.86-0.99 (2H, m), 0.94 (9H, t, J = 7.9 Hz), 4.23 (2H, s), 7.53 (1H, dd, J = 10.7, 2.0 Hz), 7.69-7.72 (1H, m), 9.84 (1H, d, J = 2.0 Hz). [0131] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 20. (Reference example 21) 3,5-Dimethyl-4-{[1- (triethylsilyloxy)cyclopropyl]methoxy[benzaldehyde [Chern. 34] ^-NMR (CDCI3) 5: 0.64 (6H, q, J = 7.9 Hz), 0.76-0.80 (2H, m), 0.86-0.92 (2H, m), 0.96 (9H, t, J = 7.9 Hz), 2.36 (6H, s), 3.83 (2H, s), 7.55 (2H, s), 9.87 (1H, s). [0132] (Reference example 22) 3-Chloro-5-methyl-4-[[1- (triethylsilyloxy)cyclopropyl]methoxy[benzaldehyde [Chern. 35] 66 ^-NMR (CDCI3) 5: 0.59-0.70 (6H, m), 0.76-1.01 (13H, m), 2.43 (3H, s), 4.02 (2H, s), 7.61 (1H, d, J = 1.6 Hz), 7.73 (1H, d, J = 1.6 Hz), 9.86 (1H, s). 5 [0133] (Reference example 23) 2-Fluoro-3-methyl-4-{[1- (triethylsilyloxy)cyclopropyl]methoxy[benzaldehyde [Chem. 36] ’H-NMR (CDCI3) 5: 0.63 (6H, q, J = 7.9 Hz), 0.75-0.80 (2H, m), 0.87-0.98 (11H, m), 2.20 (3H, d, J = 2.1 Hz), 4.08 (2H, s), 6.70 (1H, d, J = 8.8 Hz), 7.70 (1H, t, J = 8.8 Hz), 10.22 (1H, s). 15 [0134] (Reference example 24) Date Reçue/Date Received 2023-06-16 61 3-Fluoro-5-methyl-4-{ [1- (triethylsilyloxy) cyclopropyl]methoxylbenzaldehyde [Chem. 37] 5 ’li-NMR (CDC13) 5: 0.61 (6H, q, J = 7.9 Hz), 0.71-0.76 (2H, m) , 0.85-0.90 (2H, m) , 0.93 (9H, t, J = 7.9 Hz), 2.39 (3H, s) , 4.18 (2H, s), 7.44 (1H, dd, J =11.4, 1.9 Hz), 7.47-7.50 (1H, m) , 9.84 (1H, d, J = 2.0 Hz). [0135] 10 (Reference example 25) — - - - 3-Chloro~2-fluoro-4-{ [1- (triethylsilyloxy)cyclopropyl]methoxylbenzaldehyde [Chem. 38] F 15 'H-NMR (CDCI3) 5: 0.66 (6H, q, J = 7.9 Hz), 0.78-0.84 (2H, m) , 0.89-0.98 (11H, m) , 4.14 (2H, s) , 6.82 (1H, d, J = 9.0 Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 68 Hz), 7.77 (1H, dd, J= 9.0, 7.7 Hz), 10.22 (1H, s). [0136] (Reference example 26) Production of 2,3-difluoro-4-([1- (triethylsilyloxy)cyclopropyl]methoxyjbenzaldehyde [Chem. 39] Under an argon atmosphere, to a mixture of {l-[(2,3- difluorophenoxy)methyl]cyclopropyloxy}triethylsilane (Reference example 14, 1.4 g) and 2,2,6,6- tetramethylpiperidine (0.8 mL) in THF (10 mL) at -78°C was added n-butyl lithium (1.6 M n-hexane solution, 2.9 mL). The mixture was stirred at -78°C for 30 minutes, and then DMF (0.4 mL) was added thereto. The reaction mixture was stirred at -78°C for 30 minutes, and then at room temperature for 30 minutes. To the reaction mixture was added aqueous ammonium chloride at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified 5 10 15 20 Date Reçue/Date Received 2023-06-16 69 by silica gel column chromatography (heptane : ethyl acetate = 94 : 6 to 76 : 24) to afford the title compound as a colorless oil (1.3 g). 1H-NMR (CDC13) 5: 0.60-0.69 (6H, m), 0.74-0.79 (2H, m), 0.86- 0.96 (11H, m), 4.11 (2H, s), 6.79-6.86 (1H, m), 7.57-7.64 (1H f m) f 10.20 (1H, s). [0137] (Reference example 27) Production of 3-bromo-2-fluoro-4-methoxybenzaldehyde [Chem. 40] F A mixture of 2-bromo-3-fluoroanisole (25 g), hexamethylenetetramine (34.2 g), and trifluoroacetic acid (150 mL) was stirred at 90°C for 27 hours. The reaction mixture was allowed to cool to room temperature, and then 1 M hydrochloric acid was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate, and then the organic layer was concentrated to about half of its volume. To the concentrated organic layer was added aqueous sodium hydroxide, and then the organic layer was separated from the mixture and washed with brine. The organic layer 5 10 15 20 Date Reçue/Date Received 2023-06-16 70 was dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 94 : 6 to 73 : 27) to afford the title compound as a white solid (22.3 g). hH-NMR (CDCI3) 5: 4.01 (3H, s), 6.82 (1H, d, J = 8.8 Hz), 7.85 (1H, dd, J = 8.8, 7.7 Hz), 10.22 (1H, d, J = 0.7 Hz). [0138] (Reference example 28) Production of 2-fluoro-4-methoxy~3-methylbenzaldehyde [Chem. 41] To a mixture of 3-bromo-2-fluoro-4-methoxybenzaldehyde (Reference example 27, 6.0 g) in 1,2-dimethoxyethane (90 mL) were added methyl boronate (4.6 g), tripotassium phosphate (16.4 g) and [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride complex with methylene chloride (1.1 g). The reaction mixture was refluxed for 24 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and then ethyl acetate was added thereto. The mixture was 5 10 15 20 Date Reçue/Date Received 2023-06-16 71 filtered through a Celite™ pad, and then aqueous ammonium chloride was added to the filtrate. The organic layer was separated from the mixture, washed with brine, dried over anhydrous sodxum sulfate, and fxltrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 0 to 73 : 27) to afford the title compound as a white solid (3.8 g). ’li-NMR (CDC13) 5: 2.15 (3H, d, J = 2.2 Hz), 3.92 (3H, s), 6.74 (1H, d, J = 8.7 Hz), 7.73 (1H, t, J = 8.7 Hz), 10.22 (1H, s). [0139] (Reference example 29) Production of 3-chloro-2-fluoro-4-hydroxy-5- methylbenzaldehyde [Chem. 42] F To a mixture of 2-fluoro-4-hydroxy-5-methylbenzaldehyde (2.7 g) in acetic acid (5 mL) was added sulfuryl chloride (2.8 mL), and the mixture was stirred at room temperature for 3 hours. Sulfuryl chloride (0.7 mL) was added thereto, and 5 10 15 20 Date Reçue/Date Received 2023-06-16 72 the reaction mixture was stirred at room temperature further for one hour. To the reaction mixture was added ice in water at 0°C, and the obtained precipitates were collected on a filter. The collected precipitates were dissolved m ethyl acetate, the mixture was dried over anhydrous sodium sulfate and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 88 : 12 to 67 : 33) to afford the title compound as a white solid (1.3 g). *H-NMR (DMSO-d6) 5: 2.23 (3E, s), 7.56 (1H, dd, J = 7.9, 0.7 Hz), 10.02 (1H, s), 10.98 (1H, brs). [0140] (Reference example 30) Production of 5-chloro-2-fluoro-4-methoxy-3- methylbenzaldehyde [Chern. 43] Under an argon atmosphere, to a mixture of l-chloro-4-fluoro- 2-methoxy-3-methylbenzene (2.6 g) in methylene chloride (30 mL) were added titanium tetrachloride (8.1 mL) and dichloromethyl methyl ether (2.7 mL) at 0°C. The reaction 5 10 15 20 Date Reçue/Date Received 2023-06-16 73 mixture was stirred at 0"C for 1.5 hours, and then poured into ice in water. The mixture was stirred at room temperature for one hour, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 0 to 90 : 10) to afford the title compound as a white solid (2.6 g). *H-NMR (CDC13) 5: 2.28 (3H, d, J = 2.4 Hz), 3.91 (3H, s), 7.75 (1H, d, J = 7.3 Hz), 10.24 (1H, s). [0141] (Reference example 31) Production of 3-chloro-2,4-dimethoxybenzaldehyde [Chern. 44] A suspension of 3-chloro-2,4-dihydroxybenzaldehyde (3.35 g), methyl iodide (12.1 mL), and potassium carbonate (26.8 g) in acetone (70 mL) was stirred at 40°C overnight. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated. The obtained crude product was purified 74 by silica gel column chromatography (heptane : ethyl acetate = 85 : 15) to afford the title compound as a pale yellow solid (2.57 g). 1H-NMR (CDC13) 5: 3.99 (3H, s), 4.01 (3H, s), 6.84 (1H, d, J 5 = 9.0 Hz), 7.79-7.82 (1H, m), 10.24 (1H, s). [0142] (Reference example 32) Production of 3-bromo-5-chloro-4- (methoxymethyloxy)benzaldehyde 10 [Chem. 45] 0 To a mixture of 3-Bromo-5-chloro-4-hydroxybenzaldehyde (1.00 g) m dichloroethane (20 mL) were added N,N— diisopropylethylamine (2.23 mL) and chloromethyl methyl 15 ether (0.645 mL), and the mixture was refluxed overnight. The reaction mixture was concentrated, water was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 75 solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate =83: 17 to 67 : 33) to afford the title compound as a white solid (920 mg). iH-NMR (CDC13) 5 3.72 (3H, s), 5.29 (2H, s), 7.87 (1H, d, J <2.0 H [0143] .00 (I*>8, f d f il —— 2*0 Hz), 9.87 (1H? s) * The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 32. (Reference example 33) 3-Bromo-5-fluoro-4-(methoxymethyloxy)benzaldehyde [Chern. 46] Br iR-NMR (CDCI3) 5: 3.63 (3H, s), 5.34 (2H, d, J = 1.0 Hz), 7.59 (1H, dd, J —— 10.6, 1.9 Hz), 7 »89 (1 dd, 0" —— 1.9, 1•3 Hz), 9.86 (1H, d, J = 2.1 Hz). [0144] (Reference example 34) 3,5-Dichloro~4-(methoxymethyloxy)benzaldehyde [Chern. 47] 76 Cl iR-NMR (CDC13) 5: 3.70 (3H, s), 5.29 (2H, s), 7.84 (2H, s), 9.87 (1H, s). [0145] 5 (Reference example 35) 4-Benzyloxy-3-chloro-2-(methoxymethyloxy)benzaldehyde [Chem. 48] ifi-NMR (CDCI3) 5: 3.63 (3H, s), 5.24 (2H, s), 5.25 (2H, s), 10 6.90 (1H, d, J = 8.8 Hz), 7.32-7.48 (5H, m), 7.77 (1H, d, J =8.8 Hz), 10.23 (1H, s). [0146] (Reference example 36) 4-Benzyloxy-2-(methoxymethyloxy)-3-methylbenzaldehyde 15 [Chem. 49] Date Reçue/Date Received 2023-06-16 77 ïfi-NMR (CDC13) 5: 2.24 (3H, s), 3.61 (3H, s), 5.08 (2H, s), 5.16 (2H, s), 6.83 (1H, d, J = 8.5 Hz), 7.32-7.46 (5H, m), 7.72 (1H, d, J = 8.8 Hz), 10.19 (1H, s). 5 [0147] (Reference example 37) 3-Chloro-2-fluoro-4-(methoxymethyloxy)-5-methylbenzaldehyde [Chem. 50] 10 ’H-NMR (CDCI3) 5: 2.34-2.36 (3H, m), 3.65 (3H, s), 5.20 (2H, s), 7.62 (1H, dd, J = 7.6, 0.7 Hz), 10.26 (1H, s). [0148] (Reference example 38) Production of 1-[4-(tert-butyldimethylsilyloxy)-3-chloro-5- 15 methylphenyl]propan-l~one Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 78 [Chem. 51] 0 Under an argon atmosphere, to a mixture of (4-bromo-2-chloro- 6-methylphenoxy)-tert-butyldimethylsilane (Reference example 1, 10.0 g) in THF (100 mL) at -78°C was added dropwise n-butyl lithium (2.65 M n-hexane solution, 11.8 mL). The reaction mixture was stirred at the same temperature for 30 minutes, and then N,N-dimethylpropanamide (3.9 mL) was added thereto. The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. To the reaction mixture at -78°C was added aqueous ammonium chloride to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate =100 : 0 to 91 : 9) to afford the title compound as a pale yellow oil (6.3 g). iH-NMR (CDC13) 5: 0.28 (6H, s), 1.04 (9H, s), 1.20 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 2.92 (2H, q, J = 7.3 Hz), 7.67 (1H, d, J = 2.1 Hz), 7.81 (1H, d, J = 2.1 Hz). 5 10 15 20 Date Reçue/Date Received 2023-06-16 79 [0149] (Reference example 39) Production of methyl 4-[4-(tert-butyldimethylsilyloxy)-3- chloro-5-methylphenyl]-3-methyl-4-oxobutanoate [Chem. 52] Under an argon atmosphere, to a mixture of l-[4-(tertbutyldimethylsilyloxy)-3-chloro-5-methylphenyl]propan-1-one (Reference example 38, 6.3 g) in THF (100 mL) at -78°C was added dropwise lithium diisopropylamide (2.0 M, a mixed solution of THF/heptane/ethylbenzene, 15.0 mL). The mixture was stirred at the same temperature for one hour, and then methyl bromoacetate (2.9 mL) was added thereto. The reaction mixture was stirred at -78°C for 15 minutes, and then at room temperature overnight. The reaction mixture was cooled on ice-methanol bath, and then aqueous ammonium chloride was added thereto. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 5 10 15 20 Date Reçue/Date Received 2023-06-16 80 0 to 82 : 18) to afford the title compound as a pale yellow oil (2.7 g). !H-NMR (CDC13) 5: 0.28 (6H, s), 1.04 (9H, s), 1.21 (3H, d, J = 7.1 Hz), 2.30 (3H, s), 2.44 (1H, dd, J = 16.8, 5.7 Hz), 2.94 (1H, dd, J = 16.8, 8.5 Hz), 3.65 (3H, s), 3.80-3.90 (1H, nt), 7.70 (1H, d, d — 2.3 Hz), 7.85 (1H, d, J — 2.3 Hz).

[0150] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 39. (Reference example 40) Methyl 4-(3,5-difluoro-4-methoxyphenyl)-3-methyl-4- oxobutanoate [Chem. 53] F iH-NMR (CDC13) 5: 1.21 (3H, d, J = 7.2 Hz), 2.46 (1H, dd, J = 17.0, 5.3 Hz), 2.96 (1H, dd, J = 17.0, 9.0 Hz), 3.65 (3H, s), 3.73-3.85 (1H, m), 4.11 (3H, t, J = 1.6 Hz), 7.52-7.60 (2H, m). [0151] (Reference example 41) 5 10 15 20 Date Reçue/Date Received 2023-06-16 81 Production of methyl 4-[3-bromo-5-chloro-4- (methoxymethyloxy)phenyl]-3-methyl-4-oxobutanoate [Chern. 54] Cl Under an argon atmosphere, to 3-bromo-5-chloro-4- (methoxymethyloxy)benzaldehyde (Reference example 32, 885 mg) were added lithium chloride (7 mg) and trimethylsilyl cyanide (0.509 mL), and the mixture was stirred at 50°C for 2 hours. THF (30 mL) was added to the mixture to dissolve the mixture, and then the reaction mixture was cooled to - 78°C. To the mixture was slowly added lithium diisopropylamide (2.0 M, a mixed solution of THF/heptane/ethylbenzene, 1.90 mL), and the mixture was stirred at -78°C for 30 minutes. Methyl crotonate (0.369 mL) was added to the reaction mixture, and then the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The residue was purified by silica gel column chromatography (heptane : ethyl 5 10 15 20 Date Reçue/Date Received 2023-06-16 82 acetate =83 : 17 to 67 : 33) to afford the title compound as a pale yellow oil (1.15 g). !H-NMR (CDC13) 5: 1.21 (3H, d, J = 7.1 Hz), 2.46 (1H, dd, J = 17.1, 5.1 Hz), 2.96 (1H, dd, J = 17.1, 9.0 Hz), 3.65 (3H, s), 3.71 (3H, s), 3.74-3.87 (1H, m), 5.26 (2H, s), 7.97 (1H, d, [0152] 2!.0 11îz), (3 * Î1 (>111, d, 2! * ^3 Hz.). The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 41. (Reference example 42) Methyl 4-(3-chloro-5-fluoro-4-methoxyphenyl)-3-methyl-4- oxobutanoate [Chem. 55] iH-NMR (CDC13) 5: 1.21 (3H, d, J = 17.0, 5.2 Hz), 2.97 (1H, dd, J s), 3.75-3.86 (1H, m), 4.08 (3H, dd, J = 11.8, 2.1 Hz), 7.80-7.83 [0153] (Reference example 43) = 7.2 Hz), 2.47 (1H, dd, J = 17.0, 8.9 Hz), 3.65 (3H, d, J = 2.7 Hz), 7.66 (1H, (1H, m). 83 Methyl 4-(3-chloro-2~fluoro-4-methoxyphenyl)-3-methyl-4- oxobutanoate [Chem. 56] 5 ^-NMR (CDC13) 5: 1.22 (3H, dd, J = 7.1, 1.0 Hz), 2.44 (1H, dd, J = 16.8, 5.3 Hz), 2.96 (1H, ddd, J = 16.8, 8.8, 1.8 Hz), 3.65 (3H, s), 3.73-3.83 (1H, m), 3.98 (3H, s), 6.83 (1H, dd, J = 9.0, 1.3 Hz), 7.82 (1H, dd, J = 9.0, 8.1 Hz). [0154] 10 (Reference example 44) Methyl 4-(2,4-dimethoxy-3-methylphenyl)-3-methyl-4- — - - ’ - - ** - •* - - •* oxobutanoate [Chem. 57] 15 1H-NMR (CDCI3) 5: 1.14 (3H, d, J = 7.3 Hz), 2.17 (3H, s), 2.38 (1H, dd, J = 16.6, 5.7 Hz), 2.89 (1H, dd, J = 16.6, 8.3 Hz), 3.67 (3H, s), 3.77 (3H, s), 3.87 (3H, s), 3.88-3.98 (1H, m), 6.68 (1H, d, J = 8.5 Hz), 7.53 (1H, d, J = 8.5 Hz). Date Reçue/Date Received 2023-06-16 84 [0155] (Reference example 45) Methyl 4-(3-chloro-2,4-dimethoxyphenvl)-3-methyl-4- oxobutanoate 5 [Chem. 58] 'H-NMR (CDC13) 5: 1.15 (3H, d, J = 7.1 Hz), 2.40 (1H, dd, J = 16.9, 5.4 Hz), 2.91 (1H, dd, J = 16.9, 8.8 Hz), 3.67 (3H, s), 3.84-3.95 (1H, m), 3.94 (3H, s), 3.95 (3H, s), 6.79 (1H, 10 d, J = 8.8 Hz), 7.61 (1H, d, J = 8.8 Hz). [0156] (Reference example 46) Methyl 4-[3-bromo-5-fluoro-4-(methoxymethyloxy)phenyl]-3- methyl-4-oxobutanoate 15 [Chem. 59] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 85 JH-NMR (CDCI3) 5: 1.22 (3H, d, J = 7.2 Hz), 2.47 (1H, dd, J = 17.0, 5.3 Hz), 2.97 (1H, dd, J = 17.0, 9.0 Hz), 3.63 (3H, s), 3.65 (3H, s), 3.75-3.86 (1H, m), 5.31 (2H, d, J = 0.6 Hz), 7.70 (1H, dd, J = 11.5, 2.1 Hz), 8.00 (1H, t, J = 2.1 Hz). [0157] (Reference * example 47) - * Methyl 4-(3-bromo-2-fluoro-4-methoxyphenyl)-3-methyl-4- oxobutanoate 1H-NMR (CDCI3) 5: 1.22 (3H, dd, J = 7.1, 0.9 Hz), 2.44 (1H, dd, J = 16.7, 5.4 Hz), 2.95 (1H, ddd, J = 16.7, 8.7, 1.8 Hz), 3.65 (3H, s), 3.73-3.83 (1H, m), 3.98 (3H, s), 6.79 (1H, dd, J = 9.0, 1.2 Hz), 7.88 (1H, dd, J= 9.0, 8.2 Hz). [0158] (Reference example 48) Methyl 4-[4-(methoxymethyloxy)-3,5-dimethylphenyl]-3- methyl-4-oxobutanoate [Chem. 61] 86 ^-NMR (CDCI3) 5: 1.21 (3H, d, J = 7.2 Hz), 2.34 (6H, s), 2.44 (1H, dd, J = 16.7, 5.9 Hz), 2.95 (1H, dd, J= 16.7, 8.3 Hz), 3.62 (3H, s), 3.65 (3H, s), 3.85-3.96 (1H, m), 5.01 (2H, 5 s), 7.68 (2H, s). [0159] (Reference example 49) Methyl 4-(3-fluoro-4-methoxy-5-methylphenvl)-3-methyl-4- oxobutanoate 10 [Chem. 62] ’H-NMR (CDCI3) 5: 1.21 (3H, d, J = 7.2 Hz), 2.30 (3H, s), 2.45 (1H, dd, J = 16.9, 5.6 Hz), 2.95 (1H, dd, J = 16.9, 8.5 Hz), 3.65 (3H, s), 3.79-3.90 (1H, m), 4.01 (3H, d, J = 2.9 15 Hz), 7.54-7.62 (2H, m). [0160] (Reference example 50) Date Reçue/Date Received 2023-06-16 87 Methyl 4-(2-fluoro-4-methoxy-3-methylphenyl)-3-methyl-4- oxobutanoate [Chem. 63] 5 ^-NMR (CDC13) 5: 1.21 (3H, dd, J = 7.1, 0.9 Hz), 2.15 (3H, d, J = 2.4 Hz), 2.41 (1H, dd, J = 16.6, 5.8 Hz), 2.94 (1H, ddd, J = 16.6, 8.3, 1.7 Hz), 3.65 (3H, s), 3.76-3.86 (1H, m), 3.90 (3H, s), 6.71 (1H, d, J = 8.8 Hz), 7.74 (1H, t, J = 8.8 Hz). 10 [0161] (Reference example 51) Methyl 4-(5-chloro-2-fluoro-4-methoxy-3-methylphenyl)-3- methyl-4-oxobutanoate [Chem. 64] 0 F 15 *H-NMR (CDC13) 5: 1.21 (3H, dd, J - 7.1, 0.9 Hz), 2.27 (3H, dd, J = 2.7, 0.5 Hz), 2.43 (1H, dd, J = 16.9, 5.4 Hz), 2.95 (1H, ddd, J = 16.9, 8.7, 1.7 Hz), 3.66 (3H, s), 3.71-3.80 Date Reçue/Date Received 2023-06-16 88 (1H, m), 3.88 (3H, s), 7.73 (1H, dd, J= 7.6, 0.6 Hz). [0162] (Reference example 52) Methyl 4-[4-benzyloxy-3-chloro-2-(methoxymethyloxy)phenyl]- 5 3-methyl-4-oxobutanoate [Chem. 65] iH-NMR (CDC13) 5: 1.14 (3H, d, J = 7.1 Hz), 2.39 (1H, dd, J = 16.6, 5.9 Hz), 2.86 (1H, dd, J = 16.6, 8.1 Hz), 3.58 (3H, 10 s), 3.66 (3H, s), 3.84-3.96 (1H, m), 5.12 (1H, d, J = 5.6 Hz), 5.17 (1H, d, J = 5.6 Hz), 5.21 (2H, s), 6.83 (1H, d, J = 8.8 Hz), 7.31-7.49 (5H, m), 7.53 (1H, d, J = 8.8 Hz). [0163] (Reference example 53) 15 Methyl 4-[4-benzyloxy-2-(methoxymethyloxy)-3-methylphenyl]- 3-methyl-4-oxobutanoate [Chem. 66] Date Reçue/Date Received 2023-06-16 89 ^-NMR (CDCI3) 5: 1.14 (3H, d, J = 7.1 Hz), 2.27 (3H, s), 2.37 (1H, dd, J = 16.6, 6.1 Hz), 2.87 (1H, dd, J = 16.6, 7.8 Hz), 3.54 (3H, s), 3.66 (3H, s), 3.83-3.95 (1H, m), 4.96 (1H, 5 d, J = 6.6 Hz), 5.02 (1H, d, J = 6.1 Hz), 5.13 (2H, s), 6.75 (1H, d, J = 8.8 Hz), 7.31-7.55 (6H, m). [0164] (Reference example 54) Methyl 4-[3-chloro-2-fluoro-4-(methoxymethyloxy)-5- 10 methylphenyl]-3-methyl-4-oxobutanoate [Chem. 67] *H-NMR (CDC13) 5: 1.22 (3H, s), 2.44 (1H, dd, J = 16.9, 15 8.8, 1.6 Hz), 3.64 (3H, s), dd, J = 7.1, 0.9 Hz), 2.33 (3H, 5.4 Hz), 2.96 (1H, ddd, J = 16.9, 3.65 (3H, s), 3.71-3.81 (1H, m), Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 90 5.15-5.19 (2H, m), 7.60 (1H, dd, J = 8.0, 0.7 Hz). [0165] (Reference example 55) Production of methy1 4-(3-chloro-5-fluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-3-methyl-4-oxobutanoate [Chern. 68] Under an argon atmosphere, to 3-chloro-5-fluoro-4-{[1- (triethylsilyloxy)cyclopropyl]methoxy}benzaldehyde (Reference example 20, 873 mg) were added trimethylsilyl cyanide (0.391 mL) and lithium chloride (6 mg), and the mixture was stirred at 50°C for 2 hours. The mixture was allowed to cool to room temperature, and THF (10 mL) was added to the mixture. The mixture was stirred at -78°C. At the same temperature, Ixthxum dxxsopropylamxde (2.0 M, a mixed solution of THF/heptane/ethylbenzene, 1.34 mL) was added to the mixture, and the mixture was stirred for 30 minutes. To the mixture was added methyl crotonate (0.284 mL) at -78°C, and the mixture was stirred for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 91 dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The residue was dissolved in THF (10 mL), and tetrabutylammonium fluoride (1.0 M THF solution, 2.92 mL) was added thereto. The reaction mixture was stirred at room temperature for one hour, and water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 90 : 10 to 60 : 40) to afford the title compound as a pale yellow oil (352 mg). ir-NMR (CDC13) 8: 0.63-0.69 (2H, m), 0.92-0.98 (2H, m), 1.22 (3H, d, J = 7.1 Hz), 2.47 (1H, dd, J = 17.1, 5.1 Hz), 2.95 (1H, s), 2.98 (1H, dd, J = 17.1, 9.0 Hz), 3.65 (3H, s), 3.76- 3.86 (1H, m), 4.27 (2H, s), 7.67 (1H, dd, J = 11.4, 2.1 Hz), 7.83-7.85 (1H, m). [0166J The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 55. (Reference example 56) Methyl 4-{2,3-difluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-3-methyl-4-oxobutanoate [Chern. 69] 92 1H-NMR (CDCI3) 5: 0.72—0.78 (2H, m)r 0.98-1.04 (2H, m), 1.22 (3H, d, J = 7.1 Hz), 2.44 (1H, dd, J = 16.8, 5.4 Hz), 2.77 (1H, s), 2.96 (1H, ddd, J = 16.8, 8.8, 1.6 Hz), 3.65 (3H, 5 s), 3.70-3.81 (1H, m), 4.15 (2H, s), 6.78-6.86 (1H, m), 7.61- 7.68 (1H, m). [0167] (Reference example 57) Methyl 4-{4-[(1-hydroxycyclopropyl)methoxy]-3,5- dimethylphenyl}-3-methyl-4-oxobutanoate "* *■ - [Chern. 70] “* ------ - -•* - - - — 10 m-NMR (CDCI3) 5: 0.68-0.73 (2H, m), 0.94-1.00 (2H, m), 1.21 (3H, d, J = 7.1 Hz), 2.35 (6H, s), 2.44 (1H, dd, J = 16.8, 15 5.7 Hz), 2.79 (1H, s), 2.95 (1H, dd, J = 16.8, 8.5 Hz), 3.65 (3H, s), 3.85 (2H, s), 3.86-3.96 (1H, m), 7.68 (2H, s). [0168] Date Reçue/Date Received 2023-06-16 5 10 15 Date Reçue/Date Received 2023-06-16 93 (Reference example 58) Methyl 4-{3-chloro-4-[(1-hydroxycyclopropyl)methoxy]-5- methylphenyl -* *■ }' -3-methyl-4-oxobutanoate [Chem. 71] iH-NMR (CDC13) 5: 0.69-0.74 (2H, m), 0.95-1.00 (2H, m), 1.21 (3H, d, J = 7.2 Hz), 2.40 (3H, s), 2.46 (1H, dd, J = 17.0, 5.4 Hz), 2.92 (1H, s), 2.96 (1H, dd, J = 17.0, 8.9 Hz), 3.65 (3H, s), 3.79-3.90 (1H, m), 4.03 (2H, s), 7.74 (1H, d, J = 2.1 Hz), 7.86 (1H, d, J = 2.1 Hz). [0169] (Reference example 59) Methyl 4-{3-fluoro-4-[(1-hydroxycyclopropyl)methoxy]-5- methylpheny1}-3-methyl-4-oxobutanoate [Chem. 72] iH-NMR (CDC13) 5: 0.65-0.73 (2H, m), 0.92-0.98 (2H, m), 1.21 5 10 15 20 Date Reçue/Date Received 2023-06-16 94 (3H, d, J = 7.2 Hz), 2.38 (3H, s), 2.45 (1H, dd, J = 17.0, 5.5 Hz), 2.73 (1H, s), 2.96 (1H, dd, J = 17.0, 8.7 Hz), 3.65 (3H, s), 3.79-3.91 (1H, m), 4.16-4.18 (2H, m), 7.58 (1H, dd, J = 12.0, 1.8 Hz), 7.61-7.64 (1H, m). [0170] (Reference example 60) Methyl 4-{2-fluoro-4-[(1-hydroxycyclopropyl)methoxy]-3- methylphenyl}-3-methyl~4-oxobutanoate [Chem. 73] iH-NMR (CDC13) 5: 0.71-0.77 (2H, m), 0.96-1.02 (2H, m), 1.21 (3H, d, J = 7.1 Hz), 2.21 (3H, d, J = 2.3 Hz), 2.41 (1H, dd, J = 16.7, 5.7 Hz), 2.59 (1H, s), 2.94 (1H, ddd, J = 16.7, 8.5, 1.7 Hz), 3.65 (3H, s), 3.76-3.87 (1H, m), 4.05-4.13 (2H, m), 6.68 (1H, d, J = 8.8 Hz), 7.72 (1H, t, J = 8.8 Hz). [0171] (Reference example 61) Methyl 4-{3-chloro-2-fluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-3-methyl-4-oxobutanoate [Chem. 74] 95 ^-NMR (CDCI3) 5: 0.74-0.79 (2H, m), 0.99-1.05 (2H, m), 1.22 (3H, dd, J = 7.1, 0.9 Hz), 2.44 (1H, dd, J = 16.8, 5.3 Hz), 2.82 (1H, s), 2.96 (1H, ddd, J = 16.8, 8.8, 1.8 Hz), 3.65 5 (3H, s), 3.72-3.83 (1H, m), 4.15 (2H, s), 6.80 (1H, dd, J= 9.0, 1.3 Hz), 7.80 (1H, dd, J = 9.0, 8.1 Hz). [0172] (Reference example 62) Production of 4-(3,5-dichloro-4-hydroxyphenyl)-3~methyl-4- 10 oxobutanoic acid [Chern. 75] Under an argon atmosphere, to 3,5-dichloro-4- (methoxymethyloxy)benzaldehyde (Reference example 34, 3.28 15 g) were added trimethylsilyl cyanide (2.25 mL) and lithium chloride (30 mg), and the mixture was stirred at 50°C for 2 hours. The mixture was allowed to cool to room temperature, Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 96 and THF (40 mL) was added to the mixture. Lithium diisopropylamide (2.0 M, a mixed solution of THF/heptane/ethylbenzene, 7.67 mL) was added to the mixture at -78°C, and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added methyl crotonate (1.63 mL) at -78°C, and the mixture was stirred for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed and the obtained residue was dissolved in THF (40 mL), and tetrabutylammonium fluoride (1.0 M THF solution, 16.7 mL) was added to the solution. The reaction mixture was stirred at room temperature for one hour. And then, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The residue was purified by silica gel column chromatography (heptane : ethyl acetate = 90 : 10 to 70 : 30), and the desired fractions were concentrated. The residue was added 1 M aqueous sodium hydroxide, and the aqueous solution was washed with methylene chloride. The aqueous layer was acidified with 6 M hydrochloric acid, and then the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the 5 10 15 20 Date Reçue/Date Received 2023-06-16 97 solvent was removed to afford the title compound as a white solid (1.16 g). iH-NMR (CDC13) 5: 1.23 (3H, d, J = 7.3 Hz), 2.51 (1H, dd, J = 17.2, 5.0 Hz), 3.01 (1H, dd, J = 17.2, 8.9 Hz), 3.72-3.85 (1H, m), 7.92 (2H, s). [0173] (Reference example 63) Production of 4-(2-fluoro-4--methoxy-3-methylphenyl)-3~ methyl-4-oxobutanoic acid [Chem. 76] To a mixture of methyl 4-(2-fluoro-4-methoxy-3- methylphenyl)-3-methyl-4-oxobutanoate (Reference example 50, 7.8 g) in ethanol (60 mL) was added 5 M aqueous sodium hydroxide (17.5 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was diluted with water, and the mixture was acidified with 6 M hydrochloric acid at 0°C. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed to afford the title compound as a white solid (7.9 g). 5 10 15 20 Date Reçue/Date Received 2023-06-16 98 iH-NMR (DMSO-d6) 5: 1.08 (3H, d, J = 7.1 Hz), 2.10 (3H, d, J = 1.8 Hz), 2.36 (1H, dd, J = 16.8, 5.2 Hz), 2.69 (1H, dd, J = 16.8, 8.9 Hz), 3.58-3.70 (1H, m), 3.90 (3H, s), 6.97 (1H, d, J = 8.8 Hz), 7.71 (1H, t, J = 8.8 Hz), 12.13 (1H, s).

[0174] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 63. (Reference example 64) 4-(3-Bromo-2-fluoro-4-methoxyphenyl)-3-methyl-4-oxobutanoic acid [Chem. 77] ifi-HMR (DMS0-d6) 5: 1.09 (3H, d, J = 7.1 Hz), 2.39 (1H, dd, J = 17.0, 5.1 Hz), 2.71 (1H, ddd, J = 17.0, 8.9, 1.3 Hz), 3.58-3.69 (1H, m), 3.98 (3H, s), 7.12 (1H, dd, J = 9.0, 1.0 Hz), 7.88 (1H, t, J = 9.0 Hz), 12.17 (1H, brs). [0175] (Reference example 65) 4-(5—Chloro-2-fluoro-4-methoxy-3-methylphenyl)-3-methyl-4- oxobutanoic acid 99 [Chem. 78] ^-NMR. (DMS0-d6) 5: 1.09 (3H, d, J = 7.1 Hz), 2.24 (3H, d, J = 2.6 Hz), 2.41 (1H, dd, J = 17.0, 5.1 Hz), 2.70 (1H, ddd, 5 J = 17.0, 8.9, 1.3 Hz), 3.56-3.67 (1H, m), 3.84 (3H, s), 7.70 (1H, d, J = 7.6 Hz), 12.21 (1H, brs). [0176] (Reference example 66) 4-[4-Benzyloxy-2-(methoxymethyloxy)-3-methylphenyl]-3- 10 methyl-4-oxobutanoic acid [Chern. 79] 'H-NMR (CDC13) 5: 1.16 (3H, d, J = 7.1 Hz), 2.26 (3H, s), 2.45 (1H, dd, J = 16.6, 5.7 Hz), 2.90 (1H, dd, J - 16.6, 7.8 Date Reçue/Date Received 2023-06-16 100 Hz), 3.52 (3H, s), 3.85-3.97 (1H, m), 4.95-5.02 (2H, m), 5.13 (2H, s), 6.76 (1H, d, J = 8.5 Hz), 7.31-7.53 (6H, m). [0177] (Reference example 67) 5 4-[4-Benzyloxy-3-chloro-2-(methoxymethyloxy)phenyl]-3- methyl-4-oxobutanoic acid [Chem. 80] 1H-NMR (CDCI3) 5: 1.16 (3H, d, J = 7.1 Hz), 2.46 (1H, dd, J 10 = 16.7, 5.7 Hz), 2.91 (1H, dd, J = 16.7, 7.9 Hz), 3.56 (3H, s), 3.86-3.95 (1H, m), 5.13 (2H, s), 5.21 (2H, s), 6.84 (1H, d, J = 8.8 Hz), 7.32-7.49 (5H, m), 7.52 (1H, d, J = 8.8 Hz). [0178] (Reference example 68) 15 4-{2,3-Difluoro-4-[(1-hydroxycyclopropyl)methoxy]phenyl]-3- methyl-4-oxobutanoic acid [Chem. 81] Date Reçue/Date Received 2023-06-16 101 1H-NMR (DMSO-d6) 5: 0.63-0.76 (4H, m), 1.10 (3H, d, J = 7.1 Hz), 2.39 (1H, dd, J = 17.0, 5.1 Hz), 2.71 (1H, dd, J = 17.0, 8.5Hz), 3.56-3.69 (1H, m), 4.18 (2H, s), 5.67 (1H, s), 7.14- 5 7.21 (1H, m), 7.60-7.67 (1H, m), 12.17 (1H, brs). [0179] (Reference example 69) 4-{2-Fluoro-4-[(1-hydroxycyclopropyl)methoxy]-3- methylphenyl}-3-methyl-4-oxobutanoic acid 10 [Chem. 82] iR-NMR (DMSO-d6) 5: 0.61-0.76 (4H, m), 1.08 (3H, d, J = 7.1 Hz), 2.15 (3H, d, J = 2.3 Hz), 2.35 (1H, dd, J = 16.9, 5.3 Hz), 2.69 (1H, ddd, J = 16.9, 8.9, 1.2 Hz), 3.59-3.70 (1H, 15 m), 4.09 (2H, s), 5.63 (1H, s), 6.94 (1H, d, J = 8.9 Hz), 7.66 (1H, t, J = 8.9 Hz), 12.12 (1H, s). [0180] Date Reçue/Date Received 2023-06-16 102 (Reference example 70) 4-{3-Chloro-2-fluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl)-3-methyl-4-oxobutanoic acid 5 [Chem. 83] ^-NMR (DMSO-d6) 5: 0.64-0.77 (4H, m), 1.09 (3H, d, J = 7.1 Hz), 2.40 (1H, dd, J = 17.0, 5.1 Hz), 2.70 (1H, ddd, J = 17.0, 8.9, 1.1 Hz), 3.58-3.68 (1H, m), 4.21 (2H, s), 5.64 10 (1H, s), 7.18 (1H, dd, J = 9.1, 1.0 Hz), 7.79 (1H, t, J = 9.1 Hz), 12.18 (1H, brs). [0181] (Reference example 71) Production of 4-(3-chloro-4-hydroxy-5-methylphenyl)-3- 15 methyl-4-oxobutanoic acid [Chem. 84] Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 103 To a mixture of methyl 4-[4-(tert-butyldimethylsilyloxy)-3- chloro-5-methylphenyl]-3-methyl-4-oxobutanoate (Reference example 39, 500 mg) in methanol (10 mL) was added 5 M aqueous sodium hydroxide (0.520 mL). The reaction mixture was stirred at room temperature overnight, and then 5M aqueous sodium hydroxide (0.260 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours, and then at 50°C for 2 hours. The reaction mixture was concentrated. To the obtained residue was added diethyl ether, and then the mixture was extracted with water. The separated aqueous layer was acidified with 6 M hydrochloric acid, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed to afford the title compound as a pale yellow solid (317 mg). 1H-NMR (DMSO-d6) 5: 1.06 (3E, d, J = 7.1 Hz), 2.27 (3H, s), 2.36 (1H, dd, J = 17.1, 4.9 Hz), 2.68 (1H, dd, J = 17.1, 9.5 Hz), 3.75-3.88 (1H, m), 7.74-7.75 (1H, m), 7.80 (1H, d, J = 2.0 Hz), 10.12 (1H, brs), 12.13 (1H, brs). [0182] (Reference example 72) Production of 6-[3-chloro-2~fluoro-4-(methoxymethyloxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 85] 5 10 15 20 Date Reçue/Date Received 2023-06-16 104 To a mixture of methyl 4-[3-chloro-2-fluoro-4- (methoxymethyloxy)-5-methylphenyl]-3-methyl-4-oxobutanoate (Reference example 54, 2.91 g) in ethanol (35 mL) was added 5 M aqueous sodium hydroxide (4.37 mL), and the reaction mixture was stirred at room temperature for 30 minutes. After cooling the reaction mixture at 0°C, the reaction mixture was acidified with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed to afford a yellow oil (2.96 g). The oil was dissolved in ethanol (30 mL), and hydrazine monohydrate (1.3 mL) and acetic acid (1.5 mL) were added to the solution. The mixture was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate was added thereto at 0°C, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 77 : 23 to 47 : 5 10 15 20 Date Reçue/Date Received 2023-06-16 105 53) to afford the title compound as a white solid (1.65 g). iH-NMR (DMSO-d6) 5: 1.05 (3E, d, J = 7.2 Hz), 2.26 (1H, dd, J = 16.7, 3.8 Hz), 2.29 (3H, s), 2.70 (1H, dd, J = 16.7, 6.8 Hz), 3.10-3.20 (1H, m), 3.56 (3H, s), 5.13 (2H, s), 7.45 (1H, dd, J = 8.5, 0.5 Hz), 11.08 (1H, s). [0183] (Reference example 73) Production of 6-(2-fluoro-4--methoxy-3-methylphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 86] A. f To a mixture of 4-(2-fluoro-4-methoxy-3-methylphenyl)-3- methyl-4-oxobutanoic acid (Reference example 63, 4.6 g) in ethanol (60 mL) were added hydrazine monohydrate (1.3 mL) and acetxc acxd (1.6 mL), and then the mxxture was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature, and the obtained precipitates were collected on a filter to afford the title compound as a white solid (2.4 g). iH-NMR (DMSO-d6) 6: 1.03 (3H, d, J = 7.2 Hz), 2.08 (3H, d, J = 2.2 Hz), 2.23 (1H, dd, J = 16.8, 3.7 Hz), 2.66 (1H, dd, J 106 = 16.8, 6.8 Hz), 3.07-3.17 (1H, m), 3.85 (3H, s), 6.88 (1H, d, J = 8.8 Hz), 7.40 (1H, t, J = 8.8 Hz), 10.92 (1H, s). [0184] The following compounds were prepared from each appropriate 5 starting material in a similar manner to Reference example 73. (Reference * example 74) - * 6-(3,5-Difluoro-4-methoxyphenyl)~5~methyl~4,5-dihydro-2Hpyridazin-3-one 10 [Chem. 87] ^-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.8 Hz), 2.68 (1H, dd, J = 16.8, 6.9 Hz), 3.33-3.44 (1H, m), 3.97 (3H, s), 7.47-7.57 (2H, m), 11.05 (1H, s). 15 [0185] (Reference example 75) 6-(3—Chloro-5-fluoro-4-methoxyphenyl)-5-methyl-4,5—dihydro- 2H-pyridazin-3-one [Chem. 88] Date Reçue/Date Received 2023-06-16 107 1H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 Hz), 3.36-3.45 (1H, m), 3.94 (3H, d, J = 1.6 Hz), 7.62-7.71 (2H, m), 11.07 (1H, 5 s). [0186] (Reference example 76) 6-(3-Chloro-2-fluoro-4-methoxyphenyl)-5-methyl-4,5-dihydro- 2H-pyridazin-3-one 10 [Chem. 89] m-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J = 16.8, 3.6 Hz), 2.70 (1H, dd, J = 16.8, 6.8 Hz), 3.09- 3.20 (1H, m), 3.93 (3H, s), 7.09 (1H, d, J = 9.0 Hz), 7.57 15 (1H, t, J = 9.0 Hz), 11.03 (1H, s). [0187] Date Reçue/Date Received 2023-06-16 108 (Reference example 77) 6-(2,4-Dimethoxy-3-methylphenyl)-5-methy1-4,5-dihydro-2Hpyridazin-3-one [Chem. 90] ïR-NMR (CDC13) 5: 1.08 (3H, d, J = 7.3 Hz), 2.16 (3H, s), 2.43 (1H, dd, J = 16.9, 4.5 Hz), 2.75 (1H, dd, J = 16.9, 6.8 Hz), 3.28-3.38 (1H, m), 3.70 (3H, s), 3.85 (3H, s), 6.67 (1H, d, J = 8.5 Hz), 7.15 (1H, d, J = 8.5 Hz), 8.48 (1H, brs). 10 [0188] (Reference example 78) 6-(3-Chloro-2,4-dimethoxyphenyl)-5-methyl-4,5-dihydro~2Hpyridazin-3-one [Chem. 91] 'H-NMR (CDC13) 5: 1.10 (3H, d, J = 7.3 Hz), 2.44 (1H, dd, J = 17.0, 4.5 Hz), 2.75 (1H, dd, J = 17.0, 6.8 Hz), 3.26-3.36 Date Reçue/Date Received 2023-06-16 109 (1H, m), 3.85 (3H, s), 3.94 (3H, s), 6.77 (1H, d, J = 8.5 Hz), 7.24 (1H, d, J = 8.5 Hz), 8.45 (1H, brs). [0189] (Reference example 79) 5 6-[4-(Methoxymethyloxy)-3,5-dimethylphenyl]-5-methyl-4,5- dihydro—2H—pyrxdazxn—3—one [Chem. 92] iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 2.22 (1H, d, J 10 = 16.9 Hz), 2.26 (6H, s), 2.65 (1H, dd, J - 16.9, 6.8 Hz), 3.33-3.41 (1H, m), 3.51 (3H, s), 4.96 (2H, s), 7.46 (2H, s), 10.88 (1H, s). [0190] (Reference example 80) 15 6-(3,5-Dichloro-4-hydroxyphenyl)-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chem. 93] Date Reçue/Date Received 2023-06-16 110 1H-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.3 Hz), 2.21 (1H, d, J = 16.7 Hz), 2.67 (1H, dd, J = 16.7, 7.0 Hz), 3.26-3.46 (1H, m), 7.73 (2H, s), 10.57 (1H, s), 10.97 (1H, s). 5 [0191] (Reference example 81) 6-(3-Fluoro-4-methoxy-5-methylphenyl)-5-methyl-4,5-dihydro- 2H-pyridazin-3-one [Chem. 94] 10 m-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.9 Hz), 2.27 (3H, s), 2.67 (1H, dd, J = 16.9, 6.9 Hz), 3.32-3.42 (1H, m), 3.86 (3H, d, J = 1.7 Hz), 7.42-7.50 (2H, m), 10.96 (1H, s). 15 [0192] Date Reçue/Date Received 2023-06-16 Ill (Reference example 82) 6-(5-Chloro-2-fluoro-4-methoxy-3-methylphenyl)-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chem. 95] iH-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.21-2.29 (1H, m), 2.21 (3H, d, J = 2.3 Hz), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.08-3.19 (1H, m), 3.80 (3H, s), 7.52 (1H, d, J = 7.9 Hz), 11.07 (1H, s). 10 [0193] (Reference example 83) Production of 6-[4-benzyloxy-2-(methoxymethyloxy)-3- * ** **■ * methylphenyl]-5~methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 96] Date Reçue/Date Received 2023-06-16 112 A mixture of 4-[4-benzyloxy-2-(methoxymethyloxy)-3- methylphenyl]-3-methyl-4-oxobutanoic acid (Reference example 66, 3.20 g) and hydrazine monohydrate (0.626 mL) in 5 ethanol (30 mL) was stirred at room temperature for 3 days. The precipitates were collected on a filter to afford the title compound as a white solid (1.56 g). *H-NMR (CDCI3) 5: 1.10 (3H, d, J = 7.3 Hz), 2.28 (3H, s), 2.44 (1H, dd, J = 16.9, 4.6 Hz), 2.82 (1H, dd, J = 17.0, 7.0 10 Hz), 3.31-3.41 (1H, m), 3.53 (3H, s), 4.92 (1H, d, J = 5.6 Hz), 5.03 (1H, d, J = 5.6 Hz), 5.13 (2H, s), 6.78 (1H, d, J = 8.5 Hz), 7.16 (1H, d, J = 8.5 Hz), 7.33-7.49 (5H, m), 8.42 (1H, s). [0194] 15 The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 83. (Reference example 84) Date Reçue/Date Received 2023-06-16 113 6-(3-Bromo-2-fluoro-4-methoxyphenyl)-5-methyl-4,5-dihydro- 2H-pyridazin-3-one [Chem. 97] 5 ’li-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J = 16.9, 3.7 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.09- 3.19 (1H, m), 3.92 (3H, s), 7.05 (1H, dd, J= 8.9, 1.2 Hz), 7.60 (1H, t, J = 8.9 Hz), 11.02 (1H, s). [0195] 10 (Reference example 85) —*- - - - - 6-[4-Benzyloxy-3-chloro-2-(methoxymethyloxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 98] 15 1H-NMR (CDC13) 5: 1.07 (3H, d, J = 7.3 Hz), 2.42 (1H, dd, J Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 114 = 17.0, 4.8 Hz), 2.80 (1H, dd, J = 17.0, 7.0 Hz), 3.30-3.41 (1H, m), 3.53 (3H, s), 5.03 (1H, d, J = 5.6 Hz), 5.15-5.22 (3H, m), 6.82 (1H, d, J = 8.8 Hz), 7.19 (1H, d, J = 8.5 Hz), 7.31-7.49 (5H, m), 8.45 (1H, s). [0196] (Reference example 86) Production of 6-(3-chloro-4-hydroxy-5-methylphenyl)-5- methyl-4,5-dihydro-2H~pyridazin-3-one [Chem. 99] To a mixture of methyl 4-[4-(tert-butyldimethylsilyloxy)-3- chloro-5-methylphenyl]-3-methyl-4-oxobutanoate (Reference example 39, 2.7 g) in ethanol (35 mL) were added hydrazine monohydrate (1.0 mL) and acetic acid (1.2 mL) , and then the mixture was refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate was added thereto at 0°C, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was removed. The obtained crude solid was washed by trituration with diisopropyl ether, and 115 then collected on a filter to afford the title compound as a white solid (1.5 g). !H-NMR (DMS0-d6) Ô: 1.03 (3H, d, J = 7.2 Hz), 2.20 (1H, d, J = 16.8 Hz), 2.24 (3H, s), 2.65 (1H, dd, J = 16.8, 6.9 Hz), 5 3.27-3.40 (1H, m), 7.50 (1H, d, J = 2.2 Hz), 7.58 (1H, d, J <2.z* II .4 (>1H, 1)tUm £!), >1 .8^5 (1>II, ) « [0197] (Reference example 87) Production of 6-(3-bromo-5-chloro-4-hydroxyphenyl)-5- 10 methyl-4,5-dihydro-2H~pyridazin-3-one [Chem. 100] To a mixture of methyl 4-[3-bromo-5-chloro-4- (methoxymethyloxy)phenyl]-3-methyl-4-oxobutanoate 15 (Reference example 41, 1.15 g) in ethanol (15 mL) were added acetic acid (0.518 mL) and hydrazine monohydrate (0.440 mL), and then the mixture was refluxed for 13 hours. The reaction mixture was concentrated, water was added to the residue, and then the mixture was extracted with ethyl acetate. The 20 organic layer was washed with water and brine, dried over Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 116 anhydrous sodium sulfate, and filtrated, and the solvent was removed. The residue was recrystallized from heptane/ethyl acetate to afford the title compound as a pale yellow solid (713 mg). iH-NMR (DMSO~d6) 5: 1.03 (3H, d, J = 7.3 Hz), 2.18-2.24 (1H, m), 2.66 (1«H, dd, il — 16.9, 6•3 Hz), 3.30 3 »45 (1“H, Rt), 7.76 (1H, d, J = 2.2 Hz), 7.87 (1H, d, J = 2.2 Hz), 10.50 (1H, brs), 10.98 (1H, s).

[0198] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 87. (Reference example 88) 6-(3-Bromo-5-fluoro-4-hydroxyphenyl)-5-methyl-4,5-dihydro- 2H-pyridazin-3-one [Chern. 101] iH-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.3 Hz), 2.21 (1H, d, J - 16.7 Hz), 2.67 (1H, dd, J = 16.7, 6.8 Hz), 3.32-3.41 (1H, m), 7.59 (1H, dd, J = 12.2, 2.1 Hz), 7.73 (1H, t, J = 2.1 Hz), 10.85 (1H, brs), 10.95 (1H, s). 5 10 15 20 Date Reçue/Date Received 2023-06-16 117 [0199] (Reference example 89) Production of 6- (3-chloro-2-fluoro-4-hydroxyphenyl) -5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 102] To a mixture of 6- (3-chloro-2-fluoro-4-methoxyphenyl) -5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 76, 1.4 g) in methylene chloride (50 mL) was added aluminum chloride (14.2 g) at 0°C. Under an argon atmosphere, the reaction mixture was stirred at room temperature overnight. After cooling the reaction mixture at 0°C, ice in water and 5 M aqueous sodium hydroxide were added thereto. The separated aqueous layer was acidified with 6 M hydrochloric acid at 0 C, and then the mixture was extracted with ethyl acetate/THF. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained solid was washed by trituration with ethanol, and then collected on a filter to afford the title compound as a pale yellow solid (0.9 g). iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.23 (1H, dd, 5 10 15 20 Date Reçue/Date Received 2023-06-16 118 J - 16.8, 3.4 Hz), 2.67 (1H, dd, J - 16.8, 6.8 Hz), 3.06- 3.18 (1H, m), 6.87 (1H, dd, J - 8.8, 1.3 Hz), 7.41 (1H, t, J = 8.8 Hz), 10.98 (1H, s), 11.04 (1H, s). [0200] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 89. (Reference example 90) 6-(3,5-Difluoro-4-hydroxyphenyl)-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chern. 103] iH-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.2 Hz), 2.21 (1H, d, J = 16.8 Hz), 2.66 (1H, dd, J = 16.8, 6.9 Hz), 3.29-3.41 (1H, m), 7.39-7.50 (2H, m), 10.63 (1H, brs), 10.95 (1H, s). [0201] (Reference example 91) 6-(3-Chloro-5-fluoro~4-hydroxyphenyl)-5-methyl~4,5-dihydro~ 2H-pyridazin-3-one [Chem. 104] 119 0' ^-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.3 Hz), 2.21 (1H, d, J = 16.7 Hz), 2.67 (1H, dd, J = 16.7, 7.0 Hz), 3.30-3.43 (1H, m), 7.51-7.65 (2H, m), 10.83 (1H, brs), 10.96 (1H, s). 5 [0202] (Reference example 92) Production of 6-(2-fluoro-4-hydroxy-3-methylphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 105] Under an argon atmosphere, to a mixture of 6-(2-fluoro-4- methoxy-3-methylphenyl)-5-methyl-4,5-dihydro-2H-pyridazin- 3-one (Reference example 73, 3.6 g) in methylene chloride (80 ml) was added dropwise boron tribromide (1 M methylene 15 chloride solution, 100 mL) at 0°C, and then the mixture was stirred at room temperature for 3 days. To the reaction mixture was added ice in water, and the mixture was stirred Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 120 at room temperature for 30 minutes. The mixture was extracted with a mixture of ethyl acetate/THF, and then the solvent was removed. The residue was dissolved in 1 M aqueous sodium hydroxide, and then washed with methylene chloride. To the separated aqueous layer was acidified with 6 M hydrochloric acid at 0°C, and then the mixture was extracted with ethyl acetate/THF. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained solid was washed by trituration with diisopropyl ether, and then collected on a filter to afford the title compound as a gray solid (2.7 g). ir-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.1 Hz), 2.05 (3H, d, J = 2.2 Hz), 2.21 (1H, dd, J = 16.7, 3.4 Hz), 2.63 (1H, dd, J = 16.7, 6.6 Hz), 3.05-3.16 (1H, m), 6.68 (1H, d, J = 8.4 Hz), 7.24 (1H, t, J = 8.4 Hz), 10.12 (1H, d, J = 2.0 Hz), 10.86 (1H, s). [0203J The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 92. (Reference example 93) 6-(2,4-Dihydroxy-3-methylphenyl)-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chern. 1061 121 1H-NMR (DMS0-d6) 5: 1.09 (3H, d, J = 7.3 Hz), 1.98 (3H, s), 2.21-2.28 (1H, m), 2.73 (1H, dd, J = 16.9, 6.6 Hz), 3.41- 3.51 (1H, m), 6.43 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 8.5 5 Hz), 9.80 (1H, s), 10.97 (1H, s), 12.48 (1H, s). [0204] (Reference example 94) 6-(3-Bromo-2-fluoro-4-hydroxyphenyl)-5-methvl-4,5-dihydro- - -* *- -* ' * -* 2H-pyridazin-3-one 10 [Chem. 107] iR-NMR (DMSO~d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.23 (1H, dd, J = 16.8, 3.5 Hz), 2.67 (1H, dd, J = 16.8, 6.7 Hz), 3.06- 3.17 (1H, m), 6.84 (1H, dd, J = 8.7, 1.3 Hz), 7.44 (1H, t, 15 J = 8.7 Hz), 10.96 (1H, s), 11.07 (1H, d, J = 1.7 Hz). [0205] (Reference example 95) Date Reçue/Date Received 2023-06-16 122 6-(3-Fluoro-4-hydroxy-5-methylphenyl)-5-methyl-4,5-dihydro- 2H-pyridazin-3-one 5 (1H, s). [0206] 2.20 (1H, d, J 16.7, 6.8 Hz) ’li-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz) = 16.7 Hz), 2.21 (3H, s), 2.64 (1H, dd, J 3.29-3.39 (1H, m), 7.34-7.44 (2H, m), 9.79 (1H, s) , 10.85 10 (Reference example 96) — - - - - 6-(5-Chloro-2-fluoro-4-hydroxy-3-methylphenyl)-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chem. 109] 15 *H-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.2 Hz) 2.14 (3H, d, J = 2.4 Hz), 2.22 (1H, dd, J = 16.7, 3.7 Hz), 2.66 (1H, dd, J = 16.7, 6.7 Hz) 3.07-3.17 (1H, m), 7.41 (1H, d, J = 7.9 Hz), Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 123 10.00 (1H, s), 10.96 (1H, s). [0207] (Reference example 97) Production of 6-(3-chloro-2,4-dihydroxyphenyl)-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chern. 110] Under an argon atmosphere, to a mixture of 6-(3-chloro-2,4- dimethoxyphenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 78, 2.55 g) in methylene chloride (100 mL) was added dropwise boron tribromide (1 M methylene chloride solution, 45.1 mL) at 0°C. The mixture was stirred at room temperature for 3 days. The reaction was quenched by adding methanol slowly at 0°C, and then the solvent was removed. The resxdue was dxluted wxth ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and filtrated. And, the solvent was removed. The mixture was dissolved in DMF (15 mL), lithium chloride (1.91 g) was added thereto. The mixture was stirred at 240°C under microwave irradiation for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with 5 10 15 20 Date Reçue/Date Received 2023-06-16 124 ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate =67 : 33 to 33 : 67), and then recrystallized from ethanol to afford the title compound as a white solid (1.21 g)• ifi-NMR (DMSO-d6) 5: 1.10 (3H, d, J = 7.3 Hz), 2.27 (1H, d, J = 16.1 Hz), 2.78 (1H, dd, J = 16.7, 6.7 Hz), 3.41-3.56 (1H, m), 6.57 (1H, d, J = 8.9 Hz), 7.42 (1H, d, J = 8.9 Hz), 10.67 (1H, brs), 11.07 (1H, s), 13.03 (1H, s). [0208] (Reference example 98) Production of 6-[4-hydroxy-2-(methoxymethyloxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3~one [Chern. Ill] A mixture of 6-[4-benzyloxy-2-(methoxymethyloxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 83, 1.55 g) and palladium-carbon (10% w/w, 5 10 15 20 Date Reçue/Date Received 2023-06-16 125 100 mg) in ethanol/THF (1 : 1, 40 mL) was allowed to be under a hydrogen atmosphere. The mixture was stirred at room temperature for 2 hours, and then stirred at 40°C for 2 hours. The mxxture was filtered through a Celxte pad, and the filtrate was concentrated. The residual solid was washed by trituration with diethyl ether, and then collected on a filter to afford the title compound as a white solid (1.13 g)• ’li-NMR (DMSO-d6) 5: 0.90 (3H, d, J = 7.1 Hz), 2.07 (3H, s), 2.21 (1H, dd, J = 16.7, 4.8 Hz), 2.63 (1H, dd, J = 16.6, 6.8 Hz), 3.09-3.20 (1H, m), 3.41 (3H, s), 4.87-4.92 (2H, m), 6.64 (1H, d, J = 8.3 Hz), 6.96 (1H, d, J = 8.3 Hz), 9.73 (1H, s), 10.76 (1H, s). [0209] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 98. (Reference example 99) 6-[3-Chloro-4-hydroxy-2-(methoxymethyloxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chern. 112] 126 1H-NMR (CDC13) 5: 1.08 (3H, d, J = 7.3 Hz), 2.42 (1H, dd, J = 17.0, 4.6 Hz), 2.79 (1H, dd, J = 17.0, 7.0 Hz), 3.27-3.39 (1H, m), 3.54 (3H, s), 5.02 (1H, d, J = 5.6 Hz), 5.14 (1H, 5 d, J = 5.6 Hz), 5.84 (1H, brs), 6.88 (1H, d, J = 8.5 Hz), 7.19 (1H, d, J = 8.5 Hz), 8.47 (1H, s). [0210] (Reference example 100) 6-[3-Bromo-2-fluoro-4-(methoxymethyloxy)phenyl]-5-methyl- 10 4,5-dihydro-2H-pyridazin-3-one [Chem. 113] To a mixture of 6-(3-bromo-2-fluoro-4-hydroxyphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 94, 15 2.37 g) in methylene chloride (30 mL) were added N,Ndiisopropylethylamine (2.06 mL) and chloromethyl methyl Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 127 ether (1.16 mL), and then the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 80 : 20 to 67 : 33) to afford the title compound as a white solid (1.97 g). iH-NMR (DMSO-d6) 5: 1.04 (3E, d, J = 7.3 Hz), 2.25 (1H, dd, J = 16.9, 3.7 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.08- 3.20 (1H, m), 3.42 (3H, s), 5.38 (2H, s), 7.12 (1H, dd, J= 8.8, 1.2 Hz), 7.59 (1H, t, J = 8.8 Hz), 11.05 (1H, brs). [0211] (Reference example 101) Production of 6-[2-fluoro-4-(methoxymethyloxy)-3- vinylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 114] To a mixture of 6-[3-bromo-2-fluoro-4- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2H 5 10 15 20 Date Reçue/Date Received 2023-06-16 128 pyridazin-3-one (Reference example 100, 4.87 g) in 1,2- dimethoxyethane/water (3 : 1, 32 mL) were added potassium vinyltrifluoroborate (3.78 g), potassium carbonate (4.87 g), and [1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with methylene chloride (1.15 g). Then, the mixture was stirred at 150°C under microwave irradiation for one hour. The reaction mixture was poured into water/ethyl acetate, and then the mixture was filtered through a Celite pad. And, the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate =80 : 20 to 67 : 33) to afford the title compound as a pale yellow solid (3.01 g). iH-NMR (CDC13) 5: 1.20 (3H, d, J = 7.1 Hz), 2.43 (1H, dd, J = 16.9, 3.4 Hz), 2.74 (1H, dd, J = 16.9, 6.6 Hz), 3.21-3.33 (1H, m), 3.50 (3H, s), 5.26 (2H, s), 5.54-5.60 (1H, m), 5.98- 6.08 (1H, m), 6.81 (1H, dd, (J — 18.1, 12*0 Hz), 6.95 (1H, dd, J = 8.8, 1.0 Hz), 7.37 (1H, t, J = 8.8 Hz), 8.60 (1H, brs). [0212] (Reference example 102) 5 10 15 20 Date Reçue/Date Received 2023-06-16 129 Production of 6-[3-ethyl-2-fluoro-4- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chem. 115] To a mixture of 6-[2-fluoro-4-(methoxymethyloxy)-3- vinylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 101, 292 mg) in ethanol (10 mL) was added platinum-carbon (1 w/w %, 195 mg). The reaction mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through a Celite pad, and then the filtrate was concentrated to afford the title compound as a white solid (280 mg). 1H-NMR (CDC13) 5: 1.16 (3H, t, J = 7.6 Hz), 1.20 (3H, d, J = 7.3 Hz), 2.42 (1H, dd, J = 16.9, 3.4 Hz), 2.66-2.79 (3H, m), 3.21-3.34 (1H, m), 3.49 (3H, s), 5.24 (2H, s), 6.90 (1H, dd, J = 8.8, 1.0 Hz), 7.33 (1H, t, J = 8.8 Hz), 8.53 (1H, brs). [0213] (Reference example 103) Production of 6-(3-ethyl-2~fluoro~4-hydroxyphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 116] 5 10 15 20 Date Reçue/Date Received 2023-06-16 130 To a mixture of 6-[3-ethyl-2-fluoro-4- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one (Reference example 102, 280 mg) in ethanol (10 mL) was added 6 M hydrochloric acid (0.476 mL), and then the mixture was stirred at 60°C for 7 hours. To the reaction mixture was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 33 : 67 to 17 : 83) to afford the title compound as a white solid (151 mg). iH-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.3 Hz), 1.08 (3H, t, J = 7.3 Hz), 2.20 (1H, dd, J = 16.9, 3.7 Hz), 2.52-2.68 (3H, m), 3.04-3.18 (1H, m), 6.68 (1H, d, J = 8.5 Hz), 7.24 (1H, t, J = 8.8 Hz), 10.09 (1H, brs), 10.87 (1H, brs).

[0214] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 103. 5 10 15 131 Date Reçue/Date Received 2023-06-16 (Reference example 104) 6-(4-Hydroxy-3,5-dimethylphenyl)-5-methy1-4,5-dihydro-2Hpyridazin-3-one [Chem. 117] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.19 (6H, s), 2.19 (1H, d, J = 16.7 Hz), 2.61 (1H, dd, J = 16.7, 6.8 Hz), 3.27-3.38 (1H, m), 7.36 (2H, s), 8.59 (1H, s), 10.75 (1H, s). [0215] (Reference example 105) 6-(2-Fluoro-4-hydroxy-3-vinylphenyl)-5-methyl-4,5-dihydro- 2H-pyridazin-3-one [Chem. 118] 'H-NMR (DMSO-d6) 6: 1.03 (3H, d, J = 7.3 Hz), 2.21 (1H, dd, J - 16.9, 3.7 Hz), 2.64 (1H, dd, J = 16.9, 6.8 Hz), 3.04- 132 3.16 (1H, m), 5.45-5.53 (1H, m), 5.96-6.05 (1H, m), 6.71- 6.81 (2H, m), 7.30 (1H, t, J = 8.8 Hz), 10.56 (1H, d, J = 1.2 Hz), 10.91 (1H, s). [0216] 5 (Reference example 106) 6-(3—Chloro—2—fluoro—4—hydroxy—5—methylpheny1)—5—methyl— 4,5-dihydro-2H-pyridazin-3-one [Chem. 119] 10 *H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.19-2.27 (1H, m), 2.20 (3H, s), 2.67 (1H, dd, J= 16.7, 6.7 Hz), 3.08-3.18 (1H, m), 7.32 (1H, d, J = 8.8 Hz), 10.02 (1H, s), 10.97 (1H, s). [0217] 15 (Reference example 107) Production of 6-[2-(methoxymethyloxy)-3-methyl-4-(2- oxopropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 120] Date Reçue/Date Received 2023-06-16 133 0^ To a mixture of 6-[4-hydroxy-2-(methoxymethyloxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 98, 140 mg) and potassium carbonate (83 5 mg) in DMF (3 mL) was added bromoacetone (0.052 mL) at 0°C, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium 10 sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 60 : 40 to 40 : 60). The obtained solid was washed by trituration with diethyl ether, and then collected on a filter to afford the 15 title compound as a white solid (120 mg). 1H-NMR (CDC13) 5: 1.07 (3H, d, J = 7.3 Hz), 2.28 (3H, s), 2.32 (3H, s), 2.41 (1H, dd, J= 17.0, 4.6 Hz), 2.79 (1H, dd, J =17.0, 7.0Hz), 3.26-3.37 (1H, m), 3.51 (3H, s), 4.56 (2H, s), 4.90 (1H, d, J- 5.6 Hz), 5.00 (1H, d, J = 5.6 Hz), 6.52 Date Reçue/Date Received 2023-06-16 134 (1H, d, J = 8.5 Hz), 7.13 (1H, d, J = 8.5 Hz), 8.42 (1H, s).

[0218] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 5 107. (Reference example 108) 6-[2,3-Difluoro-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3~one [Chern. 121] iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 2.16 (3H, s), 2.25 (1H, dd, J = 16.7, 3.3 Hz), 2.70 (1H, dd, J = 16.7, 6.8 Hz), 3.10-3.23 (1H, m), 5.04 (2H, s), 6.91-7.01 (1H, m), 7.28-7.38 (1H, m), 11.03 (1H, s). 15 [0219] (Reference example 109) 6-[3,5-Dichloro-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chern. 122] Date Reçue/Date Received 2023-06-16 135 1H-NMR (DMS0-d6) ô: 1.04 (3H, d, J = 7.3 Hz), 2.20-2.28 (1H, m), 2.23 (3H, s), 2.70 (1H, dd, J- 16.7, 7.0 Hz), 3.37-3.49 (1H, m), 4.73 (2H, s), 7.84 (2H, s), 11.10 (1H, s). 5 [0220] (Reference example 110) 6-[3-Chloro-2~fluoro-4~(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chem. 123] m-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 2.18 (3H, s), 2.25 (1H, dd, J = 16.6, 3.7 Hz), 2.69 (1H, dd, J = 16.6, 6.8 Hz), 3.10-3.19 (1H, m), 5.06 (2H, s), 6.95 (1H, dd, J = 8.9, 1.5 Hz), 7.49 (1H, t, J = 8.9 Hz), 11.03 (1H, s). 15 [0221] Date Reçue/Date Received 2023-06-16 136 (Reference example 111) 6-[3-Chloro-2-(methoxymethyloxy)-4-(2-oxopropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 124] 0 'H-NMR (CDC13) 5: 1.08 (3H, d, J = 7.3 Hz), 2.37 (3H, s), 2.42 (1H, dd, J = 17.0, 4.9 Hz), 2.80 (1H, dd, J = 17.0, 7.0 Hz), 3.29-3.40 (1H, m), 3.54 (3H, s), 4.60 (2H, s), 5.04 (1H, d, J = 5.6 Hz), 5.18 (1H, d, J = 5.6 Hz), 6.63 (1H, d, J = 10 8.8 Hz), 7.22 (1H, d, J = 8.8 Hz), 8.44 (1H, s). [0222] (Reference example 112) 6-[3-Chloro-5-fluoro-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro~2H-pyridazin-3-one 15 [Chem. 125] Date Reçue/Date Received 2023-06-16 137 1H-NMR (DMS0-d6) ô: 1.04 (3H, d, J = 7.3 Hz), 2.17 (3H 2.24 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 3.35-3.45 (1H, m), 4.95 (2H, d, J = 2.0 Hz), 7.62 (1H, 5 J = 13.2, 2.1 Hz), 7.67-7.71 (1H, m), 11.06 (1H, s). [0223] (Reference example 113) 6-[3-Bromo-5-fluoro-4-(2-oxopropoxy)phenyl]-5-methyl-4 dihydro-2H-pyridazin-3-one 10 [Chem. 126] 1H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.19 (3H 2.23 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 3.34-3.45 (1H, m), 4.92 (2H, d, J = 2.1 Hz), 7.65 (1H, 15 J = 13.4, 2.1 Hz), 7.82 (1H, t, J = 2.1 Hz), 11.06 (1H s), Hz), dd, 5— s), Hz), dd, s). Date Reçue/Date Received 2023-06-16 138 [0224] (Reference example 114) 6-[3-Bromo-2-fluoro-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one 5 [Chem. 127] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.19 (3H, s), 2.25 (1H, dd, J = 16.8, 3.7 Hz), 2.69 (1H, dd, J = 16.8, 6.7 Hz), 3.08-3.19 (1H, m), 5.04 (2H, s), 6.90 (1H, dd, J - 8.9, 10 1.2 Hz), 7.52 (1H, t, J = 8.9 Hz), 11.02 (1H, s). [0225] (Reference example 115) 6-[3,5-Dimethyl-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one 15 [Chem. 128] Date Reçue/Date Received 2023-06-16 139 1H-NMR (DMS0-d6) ô: 1.05 (3H, d, J = 7.3 Hz), 2.17 (3H, s), 2.22 (1H, d, J = 16.8 Hz), 2.24 (6H, s), 2.64 (1H, dd, J = 16.8, 6.8 Hz), 3.31-3.42 (1H, m), 4.52 (2H, s), 7.45 (2H, 5 s), 10.88 (1H, s). [0226] (Reference example 116) 6-[3-Fluoro-5-methyl-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one 10 [Chem. 129] iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 2.14 (3H, s), 2.22 (1H, d, J = 16.7 Hz), 2.31 (3H, s), 2.66 (1H, dd, J = 16.7, 6.8 Hz), 3.32-3.42 (1H, m), 4.84 (2H, d, J = 1.7 Hz), 15 7.40-7.48 (2H, m), 10.95 (1H, s). Date Reçue/Date Received 2023-06-16 140 [0227] (Reference example 117) 6-[3-Chloro-5-methyl-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro~2H-pyridazin-3~one 5 [Chem. 130] iH-NMR (CDC13) 5: 1.24 (3H, d, J = 7.3 Hz), 2.36 (3H, s), 2.38 (3H, s), 2.47 (1H, dd, J= 17.1, 1.2 Hz), 2.69 (1H, dd, J =17.1, 6.8Hz), 3.23-3.33 (1H, m), 4.51 (2H, s), 7.50 (1H, 10 d, J = 2.2 Hz), 7.62 (1H, d, J = 2.2 Hz), 8.73 (1H, brs). [0228] (Reference example 118) 6-[3-Bromo-5-chloro-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro~2H-pyridazin-3-one 15 [Chem. 131] Date Reçue/Date Received 2023-06-16 141 1H-NMR (CDC13) 5: 1.25 (3H, d, J = 7.3 Hz), 2.45 (3H, s), 2.45-2.55 (1H, m), 2.70 (1H, dd, J = 17.1, 6.8 Hz), 3.20- 3.31 (1H, m), 4.54 (2H, s), 7.75 (1H, d, J = 2.2 Hz), 7.87 5 (1H, d, J = 2.2 Hz), 8.58 (1H, brs). [0229] (Reference example 119) 6-[2-Fluoro-3-methyl-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one 10 [Chem. 132] iH-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.2 Hz), 2.14 (3H, d, J - 2.0 Hz), 2.18 (3H, s), 2.23 (1H, dd, J = 16.9, 3.6 Hz), 2.66 (1H, dd, J = 16.9, 6.7 Hz), 3.07-3.17 (1H, m), 4.92 (2H, 15 s), 6.74 (1H, d, J = 8.7 Hz), 7.33 (1H, t, J = 8.7 Hz), 10.93 Date Reçue/Date Received 2023-06-16 142 (1H, s). [0230] (Reference example 120) 6-[2-Fluoro-4-(2-oxopropoxy)-3-vinylphenyl]-5-methyl-4,5- 5 dihydro-2H-pyridazin-3-one [Chem. 133] iH-NMR (CDC13) 5: 1.20 (3H, d, J = 6.8 Hz), 2.31 (3H, s), 2.43 (1H, dd, J = 17.1, 3.7 Hz), 2.74 (1H, dd, J = 17.1, 6.8 10 Hz), 3.21-3.33 (1H, m), 4.63 (2H, s), 5.59-5.66 (1H, m), 6.06-6.13 (1H, m), 6.56 (1H, dd, J= 8.8, 1.0 Hz), 6.85 (1H, dd, J = 18.1, 12.0 Hz), 7.39 (1H, t, J = 8.8 Hz), 8.58 (1H, brs). [0231] 15 (Reference example 121) 6-[3—Ethyl-2-fluoro-4-(2-oxopropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chem. 134] Date Reçue/Date Received 2023-06-16 143 1H-NMR (CDCI3) 5: 1.16-1.24 (6H, m), 2.31 (3H, s), 2.42 (1H, dd, J= 16.9, 3.4 Hz), 2.69-2.83 (3H, m), 3.20-3.33 (1H, m), 4.58 (2H, s), 6.51 (1H, d, J = 8.8 Hz), 7.35 (1H, t, J = 8.8 5 Hz), 8.48 (1H, brs). [0232] (Reference example 122) 6-[2,3-Dlfluoro-4~(2-oxobutoxy)phenyl]-5-methyl~4,5- dihydro-2H-pyridazin-3-one 10 [Chem. 135] m-NMR (DMSO-d6) 5: 0.98 (3H, t, J = 7.3 Hz), 1.05 (3H, d, J = 7.1 Hz), 2.25 (1H, dd, J = 16.7, 3.3 Hz), 2.48-2.58 (2H, m), 2.70 (1H, dd, J = 16.7, 6.8 Hz), 3.09-3.22 (1H, m), 5.05 15 (2H, s), 6.89-7.01 (1H, m), 7.29-7.38 (1H, m), 11.03 (1H, S) . Date Reçue/Date Received 2023-06-16 144 [0233] (Reference example 123) 6-[3-Chloro-5-fluoro-4-(2-oxobutoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one 5 [Chem. 136] iH-NMR (DMSO-d6) 6: 0.98 (3H, t, J = 7.3 Hz), 1.04 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.9 Hz), 2.54 (2H, q, J = 7.3 Hz), 2.69 (1H, dd, J = 16.9, 7.1 Hz), 3.34-3.45 (1H, m), 10 4.96 (2H, d, J = 2.0 Hz), 7.58-7.64 (1H, m), 7.67-7.72 (1H, m), 11.06 (1H, s). [0234] (Reference example 124) 6-[3,5-Dichloro-4-(2-oxobutoxy)phenyl]-5-methyl-4,5- 15 dihydro-2H-pyridazin-3-one [Chem. 137] Date Reçue/Date Received 2023-06-16 145 1H-NMR (DMS0-d6) 5: 1.00 (3H, t, J = 7.3 Hz), 1.04 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.9 Hz), 2.62 (2H, q, J = 7.3 Hz), 2.70 (1H, dd, J = 16.9, 7.1 Hz), 3.38-3.49 (1H, m), 5 4.75 (2H, s), 7.84 (2H, s), 11.10 (1H, s). [0235] (Reference example 125) 6-[3-Chloro-2-fluoro-4-(2-oxobutoxy)phenyl]-5~methyl-4,5- dihydro-2H-pyridazin-3-one 10 [Chem. 138] iH-NMR (DMSO-d6) 5: 0.98 (3H, t, J = 7.2 Hz), 1.04 (3H, d, J - 7.3 Hz), 2.25 (1H, dd, J = 16.7, 3.7 Hz), 2.56 (2H, q, J = 7.2 Hz), 2.69 (1H, dd, J = 16.7, 6.7 Hz), 3.10-3.19 (1H, 15 m), 5.07 (2H, s), 6.94 (1H, dd, J= 8.8, 1.5 Hz), 7.49 (1H, Date Reçue/Date Received 2023-06-16 146 t, J = 8.8 Hz), 11.03 (1H, s). [0236] (Reference example 126) 6-[3-Chloro-5-methy1-4-(2-oxobutoxy)phenyl]-5-methyl-4,5- 5 dihydro-2H-pyridazin-3-one [Chern. 139] 0 ]H-NMR (CDC13) 8: 1.17 (3H, t, J = 7.3 Hz), 1.24 (3H, d, J = 7.3 Hz), 2.36 (3H, s), 2.47 (1H, dd, J = 17.1, 1.0 Hz), 2.65- 10 2.80 (3H, m), 3.23-3.33 (1H, m), 4.53 (2H, s), 7.49 (1H, dd, J- 2.2, 0.7 Hz), 7.62 (1H, d, J = 2.2 Hz), 8.76 (1H, brs). [0237] (Reference * example ...J».... 127)* . 6-[3—Bromo-5-chloro-4-(2-oxobutoxy)phenyl]-5-methyl-4,5- 15 dihydro-2H-pyridazin-3-one [Chem. 140] Date Reçue/Date Received 2023-06-16 147 1H-NMR (CDC13) 5: 1.17 (3H, t, J = 7.3 Hz), 1.25 (3H, d, J = 7.3 Hz), 2.49 (1H, dd, J = 16.9, 1.0 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 2.83 (2H, q, J = 7.3 Hz), 3.20-3.31 (1H, m), 5 4.57 (2H, s), 7.75 (1H, d, J = 2.2 Hz), 7.87 (1H, d, J = 2.2 Hz), 8.77 (1H, brs). [0238] (Reference example 128) 6-[2-Fluoro-4-(2-oxobutoxy)-3-vinylphenyl]-5-methyl-4,5- 10 dihydro-2H-pyridazin-3-one [Chem. 141] lH-NMR (CDC13) 5: 1.13 (3H, t, J = 7.3 Hz), 1.20 (3H, d, J = 7.1 Hz), 2.43 (1H, dd, J = 16.9, 3.4 Hz), 2.63 (2H, q, J = 15 7.3 Hz), 2.73 (1H, dd, J = 16.9, 6.6 Hz), 3.21-3.33 (1H, m), Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 148 4.65 (2H, s), 5.59-5.66 (1H, m), 6.06-6.15 (1H, m), 6.54- 6.59 (1H, m), 6.85 (1H, dd, J = 18.1, 12.0 Hz), 7.39 (1H, t, J = 8.5 Hz), 8.64 (1H, brs). [0239] (Reference example 129) Production of methyl 3-[2—bromo-6-chloro-4—(4-methyl-6-oxo- 4,5-dihydro-lH-pyridazin-3-yl)phenoxy]-2,2- dimethylpropionate [Chem. 142] A suspension of 6-(3-bromo-5-chloro-4-hydroxyphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 87, 500 mg), methyl 2,2-dimethyl-3- (methylsulfonyloxy)propanoate (430 mg), and cesium carbonate (769 mg) in NMP (4 mL) was stirred at 150°C under microwave irradiation for 1.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained 5 10 15 20 Date Reçue/Date Received 2023-06-16 149 crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 50 : 50 to 33 : 67) to afford the title compound as a pale yellow solid (342 mg). iH-NMR (CDC13) 5 1.24 (3H, d, J = 7.6 Hz), 1.41 (6H, s), 2.48 (1H, dd, J = 17.1, 1.0 Hz), 2.69 (1H, dd, J = 17.1, 6.8 Hz), 3.20-3.30 (1H, m), 3.74 (3H, s), 4.08 (2H, s), 7.72 (1H, d, J = 2.2 Hz), 7.84 {1H, d, J = 2.2 Hz), 8.67 (1H, brs).

[0240] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 129. (Reference example 130) Methyl 3-[2-bromo-6-fluoro-4-(4-methyl-6-oxo-4,5-dihydrolH-pyridazin-3-yl)phenoxy]-2,2-dimethylpropionate [Chern. 143] *H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.28 (6H, s), 2.23 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 Hz), 3.35-3.45 (1H, m), 3.63 (3H, s), 4.16 (2H, d, J = 1.5 Hz), 150 7.67 (1H, dd, J = 12.8, 2.1 Hz), 7.80 (1H, t, J = 2.1 Hz), 11.07 (1H, s). [0241] (Reference excample 131) 5 Methyl 3- [2-bromo-3-fluoro-4- (4-methyl-6-oxo-4, 5-dihydro- 1H— pyx?idazx n—3— yl) phenoxy] —2, 2 —dimethyIpxopxonate [Chem. 144] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 1.29 (6H, s) , 10 2.25 (1H, dd, J = 16.8, 3.7 Hz), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.09-3.20 (1H, m) , 3.63 (3H, s) , 4.14 (2H, s) , 7.05 (1H, dd, J - 8.9, 1.1 Hz), 7.58 (1H, t, J = 8.9 Hz), 11.02 (1H, s) . [0242] 15 (Reference example 132) Methyl 3-[2, 6-dimethyl-4- (4-methyl-6-oxo-4,5-dihydro-lHpyridazin-3-yl) phenoxy]-2,2-dimethylpropionate [Chem. 145] Date Reçue/Date Received 2023-06-16 151 1H-NMR (DMS0-d6) ô: 1.05 (3H, d, J = 7.3 Hz), 1.28 (6H, s), 2.17-2.27 (1H, m), 2.22 (6H, s), 2.64 (1H, dd, J = 16.7, 6.8 Hz), 3.30-3.40 (1H, m), 3.67 (3H, s), 3.74 (2H, s), 7.44 (2H, 5 s), 10.87 (1H, s). [0243] (Reference example 133) Methyl 3-[2-chloro-6-methyl-4-(4-methyl-6-oxo-4,5-dihydrolH-pyridazin-3-yl)phenoxy]-2,2-dimethylpropionate 10 [Chem. 146] m-NMR (CDC13) 5: 1.23 (3H, d, J = 7.3 Hz), 1.38 (6H, s), 2.31 (3H, s), 2.46 (1H, dd, J= 16.8, 1.0 Hz), 2.68 (1H, dd, J =16.8, 6.8 Hz), 3.23-3.33 (1H, m), 3.75 (3H, s), 3.95 (2H, 15 s), 7.46 (1H, d, J = 2.2 Hz), 7.59 (1H, d, J = 2.2 Hz), 8.73 (1H, brs). Date Reçue/Date Received 2023-06-16 152 [0244] (Reference example 134) Methyl 3-[2-fluoro-6-methyl-4-(4-methyl-6-oxo-4,5-dihydrolH-pyridazin-3-yl)phenoxy]-2,2-dimethylpropionate 5 [Chem. 147] ir-NMR (CDC13) 5: 1.24 (3H, t, J = 6.8 Hz), 1.34 (6H, s), 2.25 (3H, s), 2.46 (1H, d, J = 17.0 Hz), 2.69 (1H, dd, J = 17.0, 6.8 Hz), 3.23-3.32 (1H, m), 3.72 (3H, s), 4.09-4.14 10 (2H, m), 7.28-7.36 (2H, m), 8.53 (1H, s). [0245] (Reference example 135) Production of 2,2-difluoro-3-[3-fluoro-2-methyl-4-(4- methyl-6-oxo-4,5-dihydro-lH-pyridazin-3-yl)phenoxy]propyl 15 methanesulfonate [Chem. 148] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 153 A suspension of 6-(2-fluoro-4-hydroxy-3-methylphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 92, 500 mg), 2,2-difluoro-3-(methylsulfonyloxy)propyl methanesulfonate (1.70 g), and cesium carbonate (2.07 g) in NMP (4 mL) was stirred at 150°C under microwave irradiation for 1.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 65 : 35 to 45 : 55) to afford the title compound as a pale yellow amorphous (324 mg). 'H-NMR (DMSO-d6) 5: 1.03 (3E, d, J = 7.3 Hz), 2.13 (3H, d, J = 2.2 Hz), 2.24 (1H, dd, J = 16.7, 3.8 Hz), 2.67 (1H, dd, J = 16.7, 6.7 Hz), 3.04-3.19 (1H, m), 3.32 (3H, s), 4.54 (2H, t, J = 12.6 Hz), 4.73 (2H, t, J = 13.4 Hz), 6.98 (1H, d, J = 8.8 Hz), 7.41 (1H, t, J = 8.8 Hz), 10.96 (1H, s).

[0246] The following compounds were prepared from each appropriate 154 starting material in a similar manner to Reference example 135. (Reference example 136) 3-[2,3-Difluoro-4-(4-methyl-6-oxo-4,5-dihydro-lH-pyridazin- 5 3-yl)phenoxyJ -2,2-difluoropropyl methanesulfonate [Chem. 149] ir-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 2.26 (1H, dd, J = 16.9, 3.4 Hz), 2.71 (1H, dd, J = 16.9, 6.7 Hz), 3.13- 10 3.22 (1H, m), 3.32 (3H, s), 4.60-4.76 (4H, m), 7.16-7.26 (1H, m), 7.38-7.47 (1H, m), 11.06 (1H, s). [0247] (Reference * example -J» 137)* 3-[2,6-Dichloro-4-(4-methyl-6-oxo-4,5-dihydro-lH-pyridazin- 15 3-yl)phenoxy]-2,2-difluoropropyl methanesulfonate [Chem. 150] Date Reçue/Date Received 2023-06-16 155 1H-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.25 (1H, d, J = 16.9 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.34 (3H, s), 3.39-3.51 (1H, m), 4.49 (2H, t, J = 13.1 Hz), 4.76 (2H, t, 5 J = 13.6 Hz), 7.81-7.90 (2H, m), 11.12 (1H, s). [0248] (Reference example 138) 3-[2-Chloro-3-fluoro-4-(4-methyl-6-oxo-4,5-dihydro-lHpyridazin-3-yl)phenoxy]-2,2-difluoropropyl methanesulfonate 10 [Chem. 151] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 2.26 (1H, dd, J = 16.9, 3.7 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.07- 3.21 (1H, m), 3.33 (3H, s), 4.58-4.78 (4H, m), 7.17-7.25 (1H, 15 m), 7.55-7.63 (1H, m), 11.06 (1H, s). Date Reçue/Date Received 2023-06-16 156 [0249] (Reference example 139) 3-[2-Chloro-6-fluoro-4-(4-methyl-6-oxo-4,5-dihydro-lHpyridazin-3-yl)phenoxy]-2,2-difluoropropyl methanesulfonate 5 [Chem. 152] iH-NMR (DMSO-d6) 6: 1.04 (3H, d, J = 7.1 Hz), 2.25 (1H, d, J = 17.0 Hz), 2.70 (1H, dd, J = 17.0, 7.0 Hz), 3.32 (3H, s), 3.37-3.49 (1H, m), 4.58 (2H, t, J = 13.1 Hz), 4.73 (2H, t, 10 J = 13.6 Hz), 7.65-7.75 (2H, m), 11.10 (1H, s). [0250] (Reference example 140) 3-[2-Bromo-3-fluoro-4-(4-methyl-6-oxo-4,5-dihydro-lHpyridazin-3-yl)phenoxy]-2,2-difluoropropyl methanesulfonate 15 [Chem. 153] Date Reçue/Date Received 2023-06-16 157 iH-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 2.26 (1H, dd, J = 16.6, 3.8 Hz), 2.70 (1H, dd, J = 16.6, 6.8 Hz), 3.07- 3.20 (1H, m), 3.36 (3H, s), 4.55-4.81 (4H, m), 7.16 (1H, d, J = 8.8 Hz), 7.62 (1H, t, J = 8.8 Hz), 11.06 (1H, s). 5 [0251] (Reference example 141) 2,2-Difluor0-3-[3-(methoxymethyloxy)-2-methyl-4-(4-methyl- 6-OXO-4,5-dihydro-1H-pyridazin-3-yl)phenoxy]propyl methanesulfonate 10 [Chem. 154] iH-NMR (CDCI3) 5: 1.07 (3H, d, J = 7.3 Hz), 2.22 (3H, s), 2.42 (1H, dd, J = 17.1, 4.9 Hz), 2.79 (1H, dd, J = 17.1, 7.0 Hz), 3.10 (3H, s), 3.25-3.37 (1H, m), 3.51 (3H, s), 4.29 (2H, 15 t, J = 11.4 Hz), 4.61 (2H, t, J = 11.8 Hz), 4.89 (1H, d, J = 5.9 Hz), 5.00 (1H, d, J = 5.6 Hz), 6.67 (1H, d, J = 8.5 Hz), 7.16 (1H, d, J = 8.5 Hz), 8.43 (1H, brs). [0252] (Reference example 142) Date Reçue/Date Received 2023-06-16 158 2,2-Difluoro-3-[3-fluoro-4-(4-methyl-6-oxo-4,5-dihydro-lHpyridazin-3-yl)-2-vinylphenoxy]propyl methanesulfonate [Chem. 155] 5 ifl-NMR (CDCI3) 5: 1.20 (3H, d, J = 7.1 Hz), 2.43 (1H, dd, J = 17.1, 3.7 Hz), 2.70-2.80 (1H, m), 3.09 (3H, s), 3.21-3.32 (1H, m), 4.34 (2H, t, J = 11.2 Hz), 4.58 (2H, t, J = 11.7 Hz), 5.59-5.65 (1H, m), 5.95-6.03 (1H, m), 6.69-6.80 (2H, m), 7.43 (1H, t, J = 8.5 Hz), 8.47 (1H, brs). 10 [0253J (Reference example 143) 3-[2—Chloro-6-methyl-4-(4-methyl-6-oxo-4,5-dihydro-lHpyridazin-3-yl)phenoxy]-2,2-difluoropropyl methanesulfonate [Chem. 156] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 159 iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.1 Hz), 2.24 (1H, d, J = 16.9 Hz), 2.34 (3H, s), 2.68 (1H, dd, J = 16.9, 6.8 Hz), 3.30-3.45 (1H, m), 3.31 (3H, s), 4.37 (2H, t, J = 13.2 Hz), 4.75 (2H, t, J = 13.6 Hz), 7.64 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 2.0 Hz), 11.01 (1H, s). [0254] (Reference example 144) Production of 6-{4-[(Z)-4-(tert-butyldimethylsilyloxy)-2- butenyloxy]-3-chloro-2-fluorophenyl]-5-methyl-4,5-dihydro- 2H-pyridazin-3-one [Chem. 157] A mixture of 6-(3-chloro-2-fluoro-4-hydroxyphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 89, 250 nig), (Z)—4—(tert—butyldimethylsilyloxy)—2—buten—1—ol (217 mg), bis(2-methoxyethyl) azodicarboxylate (251 mg), and triphenylphosphine (281 mg) in THF (10 mL) was stirred at room temperature overnight. Bis(2-methoxyethyl) azodicarboxylate (251 mg) and triphenylphosphine (281 mg) were added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 4 hours. The 5 10 15 20 Date Reçue/Date Received 2023-06-16 160 solvent was removed, and the obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 65 : 35 to 45 : 55) to afford the title compound as a white solid (296 mg). iR-NMR (CDC13) 5: 0.09 (6H, s), 0.92 (9H, s), 1.21 (3H, d, J = 7.1 Hz), 2.44 (1H, dd, J = 17.1, 3.2 Hz), 2.74 (1H, dd, J = 17.1, 6.7 Hz), 3.22-3.32 (1H, m), 4.33 (2H, dd, J = 5.3, 1.3 Hz), 4.81 (2H, dd, J = 5.5, 1.1 Hz), 5.65-5.86 (2H, m), 6.78 (1H, dd, J = 8.8, 1.5 Hz), 7.45 (1H, t, J = 8.8 Hz), 8.47 (1H, s).

[0255] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 144. (Reference example 145) 6-{4-[(Z)-4-(tert-Butyldimethylsilyloxy)-2-butenyloxy]-3- chloro~5-methylphenyl)-5~methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 158] Cl 5 10 15 20 Date Reçue/Date Received 2023-06-16 161 iH-NMR (CDC13) 5; 0.06 (6H, s), 0.89 (9H, s), 1.24 (3H, d, J = 7.6 Hz), 2.34 (3H, s), 2.47 (1H, dd, J = 17.1, 1.0 Hz), 2.70 (1H, dd, J = 17.1, 6.8 Hz), 3.24-3.33 (1H, m), 4.25- 4.28 (2H, m), 4.57-4.61 (2H, m), 5.74-5.87 (2H, m), 7.47- 7.49 (1H, m), 7.61 (1H, d, J = 2.2 Hz), 8.60 (1H, brs). [0256] (Reference example 146) 6-{4-[(Z)-4-(tert-Butyldimethylsilyloxy)-2~butenyloxy]-2- fluoro-3-vinylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 159] ifi-HMR (CDCI3) 5: 0.09 (6H, s), 0.91 (9H, s), 1.19 (3H, d, J = 7.3 Hz), 2.42 (1H, dd, J = 16.9 3.4 Hz), 2.73 (1H, dd, J = 16.9, 6.6 Hz), 3.21-3.32 (1H, m), 4.28-4.34 (2H, m), 4.71- 4.77 (2H, m), 5.50-5.58 (1H, m), 5.68-5.83 (2H, m), 6.04- 6.09 (1H, m), 6.71 (1H, d, J = 8.5 Hz), 6.80 (1H, dd, J = 18.1, 12.2 Hz), 7.38 (1H, t, J - 8.5 Hz), 8.52 (1H, brs). [0257] (Reference example 147) 162 6-{4-[(Z)-4-(tert-Butyldimethylsilyloxy)-2-butenyloxy]-2- fluoro-3-methylpheny1}-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 160] 'H-NMR (CDC13) 5: 0.09 (6H, s), 0.91 (9H, s), 1.20 (3H, d, J = 7.1 Hz), 2.15 (3H, d, J = 2.2 Hz), 2.42 (1H, dd, J = 17.0, 3.5 Hz), 2.73 (1H, dd, J = 17.0, 6.7 Hz), 3.20-3.33 (1H, m), 4.28-4.34 (2H, m), 4.67-4.75 (2H, m), 5.66-5.83 (2H, m), 10 6.66 (1H, d, J = 8.8 Hz), 7.34 (1H, t, J = 8.8 Hz), 8.43 (1H, s). [0258] (Reference example 148) 6—{4—[(Z)—4—(tert—Butyldimethylsilyloxy)—2—butenyloxy]—2,3— 15 difluorophenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 161] Date Reçue/Date Received 2023-06-16 163 1H-NMR (CDC13) 5: 0.09 (6H, s), 0.91 (9H, s), 1.22 (3H, d, J = 7.1 Hz), 2.45 (1H, dd, J = 17.0, 3.3 Hz), 2.74 (1H, dd, J = 17.0, 6.7 Hz), 3.21-3.33 (1H, m), 4.32 (2H, dd, J = 5.4, 5 1.5 Hz), 4.80 (2H, dd, J = 5.9, 1.2 Hz), 5.66-5.75 (1H, m), 5.75-5.84 (1H, m), 6.75-6.84 (1H, m), 7.25-7.34 (1H, m), 8.51 (1H, brs). [0259] (Reference example 149) 10 6-{4-[(Z)-4-(tert-Butyldimethylsilyloxy)-2-butenyloxy]-3- chloro-5-fluoropheny1}-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 162] Date Reçue/Date Received 2023-06-16 164 iH-NMR (CDC13) 5: 0.06 (6H, s), 0.89 (9H, s), 1.24 (3H, d, J = 7.6 Hz), 2.49 (1H, dd, J = 17.0, 0.7 Hz), 2.70 (1H, dd, J = 17.0, 7.0 Hz), 3.18-3.31 (1H, m), 4.26 (2H, d, J = 3.9 Hz), 4.78 (2H, d, J = 4.2 Hz), 5.73-5.83 (2H, m), 7.44 (1H, dd, 5 J = 12.0, 2.2 Hz), 7.54 (1H, t, J = 2.2 Hz), 8.54 (1H, s). [0260] (Reference * example 150) - * - 6-{3-Bromo-4-[(Z)-4-(tert-butyldimethylsilyloxy)-2- butenyloxy]-5-fluorophenyl]-5-methyl-4,5-dihydro-2H- 10 pyridazin-3-one [Chem. 163] 1H-NMR (CDCI3) 5: 0.06 (6H, s), 0.89 (9H, s), 1.24 (3H, d, J = 7.3 Hz), 2.48 (1H, dd, J = 17.1, 1.5 Hz), 2.70 (1H, dd, J 15 = 17.1, 6.8 Hz), 3.18-3.31 (1H, m), 4.27 (2H, d, J = 4.6 Hz), 4.78 (2H, d, J = 5.1 Hz), 5.73-5.83 (2H, m), 7.48 (1H, dd, J = 12.1, 2.1 Hz), 7.70 (1H, t, J = 2.1 Hz), 8.61 (1H, brs). [0261] (Reference example 151) Date Reçue/Date Received 2023-06-16 165 6-{ 4— [3— (tert-Butyldimethylsilyloxy) propoxy]-3-chloro-2- hydroxyphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 164] 5 ’li-NMR (CDC13) 5: 0.04 ( 6H, s) , 0.88 (9H, s) , 1.30 (3H, d, J = 7.3 Hz), 2.04 (2H, quintet, J = 6.1 Hz), 2.52 (1H, d, J = 17.1 Hz), 2.74 (1H, dd, J = 17.1, 6.6 Hz), 3.38-3.50 (1H, m) , 3.85 (2H, t, J = 6.1 Hz), 4.19 (2H, t, J = 6.1 Hz), 6.56 (1H, d, J = 8.8 Hz), 7.30 (1H, d, J = 8.8 Hz), 8.47 (1H, 10 brs), 12.38 (1H, s) . [0262] (Reference example 152) 6-{ 4-[3- (tert-Butyldimethylsilyloxy) propoxy] -2-hydroxy-3- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one 15 [Chem. 165] iH-NMR (CDCI3) 5: 0.04 (6H, s) , 0.89 (9H, s) , 1.29 (3H, d, J Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 166 = 7.3 Hz), 2.01 (2H, quintet, J = 6.1 Hz), 2.13 (3H, s), 2.46-2.54 (1H, m), 2.72 (1H, dd, J = 16.8, 6.6 Hz), 3.40- 3.52 (1H, m), 3.83 (2H, t, J = 6.1 Hz), 4.11 (2H, t, J = 6.1 Hz), 6.48 (1H, d, J = 8.8 Hz), 7.23-7.28 (1H, m), 8.37 (1H, brs), 11.89 (1H, s). [0263] (Reference example 153) 6-{4-[3-(tert-Butyldimethylsilyloxy)propoxy]-2~fluoro-3- vinylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 166] 1H-NMR (CDC13) 5: 0.04 (6H, s), 0.88 (9H, s), 1.19 (3H, d, J = 7.1 Hz), 2.03 (2H, quintet, J = 6.1 Hz), 2.42 (1H, dd, J = 16.9, 3.4 Hz), 2.73 (1H, dd, J = 16.9, 6.6 Hz), 3.21-3.33 (1H, m), 3.82 (2H, t, J = 6.1 Hz), 4.15 (2H, t, J = 6.1 Hz), 5.49-5.57 (1H, m), 5.99-6.08 (1H, m), 6.73 (1H, d, J = 8.8 Hz), 6.80 (1H, dd, J = 18.1, 12.2 Hz), 7.38 (1H, t, J = 8.8 Hz), 8.53 (1H, brs). [0264] (Reference example 154) 167 6-{4—[4—(tert-Butyldimethylsilyloxy)butoxy]-3-chloro-5- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 167] 5 iH-NMR (CDC13) 5: 0.06 (6H, s), 0.90 (9H, s), 1.24 (3H, d, J = 7.3 Hz), 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 2.33 (3H, s), 2.43-2.51 (1H, m), 2.68 (1H, dd, J= 16.9, 6.8 Hz), 3.23- 3.34 (1H, m), 3.70 (2H, t, J = 6.4 Hz), 3.96 (2H, t, J = 6.4 Hz), 7.47 (1H, dd, J = 2.2, 0.7 Hz), 7.57-7.61 (1H, m), 8.54 10 (1H, s). [0265] (Reference example 155) 6-{3-Bromo-4-[4-(tert-butyldimethylsilyloxy)butoxy]-5- fluorophenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one 15 [Chem. 168] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 168 iH-NMR (CDC13) 5: 0.06 (6H, s), 0.89 (9H, s), 1.24 (3H, d, J = 7.3 Hz), 1.69-1.79 (2H, m), 1.83-1.93 (2H, m), 2.48 (1H, dd, J = 16.9, 1.0 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.18- 3.32 (1H, m), 3.69 (2H, t, J = 6.2 Hz), 4.19 (2H, td, J = 6.5, 1.3 Hz), 7.48 (1H, dd, J = 12.2, 2.2 Hz), 7.67-7.72 (1H, m), 8.55 (1H, Idits). [0266] (Reference example 156) 6-{4—[4-(tert-Butyldimethylsilyloxy)butoxy]-3,5- dichlorophenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 169] ^-NMR (CDCI3) 5: 0.06 (6H, s), 0.90 (9H, s), 1.25 (3H, d, J = 7.3 Hz), 1.71-1.82 (2H, m), 1.88-1.98 (2H, m), 2.49 (1H, d, J = 16.9 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.19-3.33 (1H, m), 3.71 (2H, t, J = 6.2 Hz), 4.08 (2H, t, J = 6.5 Hz), 7.68 (2H, s), 8.53 (1H, brs). [0267] (Reference example 157) 6-{4—[4-(tert-Butyldimethylsilyloxy)butoxy]-2,3- difluorophenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one 169 [Chem. 170] 1H-NMR (CDC13) 5: 0.06 (6H, s), 0.90 (9H, s), 1.21 (3H, d, J = 7.1 Hz), 1.64-1.76 (2H, m), 1.86-1.96 (2H, m), 2.45 (1H, 5 dd, J = 17.0, 2.9 Hz), 2.74 (1H, dd, J = 17.0, 6.7 Hz), 3.20- 3.34 (1H, m), 3.69 (2H, t, J = 6.1 Hz), 4.12 (2H, t, J = 6.5 Hz), 6.74-6.81 (1H, m), 7.24-7.34 (1H, m), 8.55 (1H, brs). [0268] (Reference example 158) 10 6-{4-[4-(tert-Butyldimethylsilyloxy)butoxy]-2-fluoro-3- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3~one [Chem. 171] *H-NMR (CDC13) 5: 0.06 (6H, s), 0.90 (9H, s), 1.19 (3H, d, J 15 = 7.1 Hz), 1.67-1.76 (2H, m), 1.82-1.94 (2H, m), 2.15 (3H, d, J = 2.2 Hz), 2.42 (1H, dd, J = 16.9, 3.5 Hz), 2.73 (1H, Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 170 dd, J - 16.9, 6.8 Hz), 3.22-3.33 (1H, m) , 3.69 (2H, t, J = 6.2 Hz), 4.03 (2H, t, J = 6.3 Hz), 6.65 (1H, d, J = 8.8 Hz), 7.34 (1H, t, J = 8.8 Hz), 8.48 (1H, s). [0269] (Reference example 159) 6— {4— [4— (te rt—Hutyldxmethylsxlyloxy) butoxy] — 3—chloro—2— fluorophenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 172] iH-NMR (CDC13) 5: 0.06 (6H, s) , 0.90 (9H, s) , 1.21 (3H, d, J = 7.3 Hz), 1.68-1.78 (2H, m) , 1.87-1.99 (2H, m) , 2.44 (1H, dd, J = 17.0, 3.3 Hz) , 2.74 (1H, dd, J = 17.0, 6.7 Hz) , 3.22- 3.34 (1H, m) , 3.70 (2H, t, J = 6.2 Hz), 4.12 (2H, t, J = 6.5 Hz), 6.76 (1H, dd, J = 8.8, 1.2 Hz), 7.45 (1H, t, J = 8.8 Hz), 8.49 (1H, ss ) » [0270] (Reference example 160) 6~ { 4—[4- (tert-Butyldimethylsilyloxy) butoxy]-2-hydroxy-3- methylphenyl}-5-methyl-4,5-dihydro-2H~pyridazin-3-one [Chem. 173] 171 Uî-NMR (CDC13) 5: 0.06 (6H, s), 0.90 (9H, s), 1.28 (3H, d, J = 7.6 Hz), 1.67-1.77 (2H, m), 1.83-1.94 (2H, m), 2.14 (3H, s), 2.49 (1H, d, J = 17.1 Hz), 2.72 (1H, dd, J = 17.1, 6.6 5 Hz), 3.40-3.50 (1H, m), 3.69 (2H, t, J = 6.4 Hz), 4.03 (2H, t, J = 6.4 Hz), 6.46 (1H, d, J = 9.0 Hz), 7.24 (1H, d, J = 9.0 Hz), 8.48 (1H, brs), 11.90 (1H, s). [0271] (Reference example 161) 10 6-{4-[4-(tert-Butyldimethylsilyloxy)butoxy]-3-chloro-2- hydroxyphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 174] iH-NMR (CDC13) 5: 0.06 (6H, s), 0.90 (9H, s), 1.29 (3H, d, J 15 - 7.6 Hz), 1.68-1.78 (2H, m), 1.88-1.98 (2H, m), 2.49-2.55 (1H, m), 2.74 (1H, dd, J= 17.1, 6.6 Hz), 3.38-3.48 (1H, m), 3.70 (2H, t, J = 6.4 Hz), 4.11 (2H, t, J = 6.4 Hz), 6.53 Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 (1H ,d, J - 9.0 Hz), 7.29 (1H, d, J = 9.0 Hz), 8.57 (1H, brs), 12.40 (1H ,s) . [0272] (Reference example 162) 6-{ 4-[4- (tert-Butyldimethylsilyloxy) butoxy]-2-£luoro-3- vinylphenyl}-5-methyl-4, 5-dihydro-2H-pyridazin-3-one [Chem. 175] ifi-NMR (CDC13) 5: 0.06 (6H, s) , 0.90 (9H, s) , 1.19 (3H, d, J = 7.1 Hz), 1.66-1.76 (2H, m) , 1.86-1.97 (2H, m) , 2.42 (1H, dd, J = 16.9, 3.4 Hz) , 2.73 (1H, dd, J = 16.9, 6.6 Hz) , 3.21- 3.32 (1H, m), 3.69 (2H, t, J = 6.4 Hz), 4.07 (2H, t, J = 6.4 Hz), 5.49-5.57 (1H, m) , 6.01-6.09 (1H, m) , 6.70 (1H, d, J = 8.1 Hz), 6.81 (1H, dd, J = 18.1, 12.0 Hz), 7.35-7.40 (1H, in) , 8.51 (1H, brs) • [0273] (Reference example 163) 6~ { 4—[4- (tert-Butyldimethylsilyloxy) butoxy]-3-ethyl-2- fluorophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 176] 173 1H-NMR (CDC13) 5: 0.06 (6H, s), 0.90 (9H, s), 1.14 (3H, t, J = 7.3 Hz), 1.19 (3H, d, J = 7.3 Hz), 1.66-1.76 (2H, m), 1.82- 1.94 (2H, m), 2.41 (1H, dd, J = 17.1, 3.4 Hz), 2.64-2.78 (3H, 5 m), 3.21-3.32 (1H, m), 3.69 (2H, t, J = 6.4 Hz), 4.03 (2H, t, J = 6.4 Hz), 6.66 (1H, d, J = 8.5 Hz), 7.34 (1H, t, J = 8.5 Hz), 8.48 (1H, brs). [0274] (Reference example 164) 10 6—{4—[(E)—4—(tert-Butyldimethylsilyloxy)-2-butenyloxy]-3- chloro-2-fluoropheny1}-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 177] 15 1H-NMR (CDC13) 5: 0.08 (6H, s), 0.92 (9H, s), 1.21 (3H, d, J Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 174 = 7.1 Hz), 2.44 (1H, dd, J = 17.0, 3.3 Hz), 2.74 (1H, dd, J = 17.0, 6.7 Hz), 3.23-3.32 (1H, m), 4.22-4.25 (2H, m), 4.66- 4.69 (2H, m), 5.90-6.03 (2H, m), 6.77 (1H, dd, J = 8.8, 1.5 Hz), 7.45 (1H, t, J = 8.8 Hz), 8.49 (1H, brs). [0275] (Reference example 165) 6-{4—[5-(tert-Butyldimethylsilyloxy)pentoxy]-3-chloro-2- fluorophenyl)-5~methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 178] iH-NMR (CDCls) 5: 0.05 (6H, s), 0.89 (9H, s), 1.20 (3H, d, J = 7.3 Hz), 1.50-1.65 (4H, m), 1.88 (2H, quintet, J = 6.6 Hz), 2.43 (1H, dd, J = 17.1, 3.2 Hz), 2.73 (1H, dd, J = 17.1, 6.8 Hz), 3.22-3.33 (1H, m), 3.65 (2H, t, J = 6.1 Hz), 4.08 (2H, t, J = 6.6 Hz), 6.75 (1H, dd, J = 9.0, 1.5 Hz), 7.42-7.49 (1H, m), 8.49 (1H, brs). [0276] (Reference example 166) Production of 2,2-difluoro-3-[3-fluoro-2-methyl-4-(4- methyl-6-oxo-4,5-dihydro-lH-pyridazin-3-yl)phenoxy]propyl benzoate 5 10 15 20 Date Reçue/Date Received 2023-06-16 175 A mixture of 2,2-difluoro-3-[3-fluoro-2-methyl-4-(4-methyl- 6-oxo—4,5-dihydro-lH-pyridazin-3-yl)phenoxy]propyl methanesulfonate (Reference example 135, 324 mg) and sodium benzoate (229 mg) in DMF (4 mL) was stirred at 180°C under microwave irradiation for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 70 : 30 to 50 : 50) to afford the title compound as a white solid (253 mg). ’H-NMR (DMS0-d6) 5: 1.02 (3H, d, J = 7.1 Hz), 2.12 (3H, d, J = 2.2 Hz), 2.23 (1H, dd, J = 16.7, 3.8 Hz), 2.67 (1H, dd, J = 16.7, 6.8 Hz), 3.03-3.19 (1H, m), 4.63 (2H, t, J = 12.7 Hz), 4.84 (2H, t, J - 13.8 Hz), 7.01 (1H, d, J = 8.8 Hz), 7.40 (1H, t, J = 8.8 Hz), 7.52-7.60 (2H, m), 7.67-7.75 (1H, m), 7.98-8.05 (2H, m), 10.96 (1H, s). 176

[0277] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 166. 5 (Reference example 167) 3—[2,3-Difluoro-4-(4—methy1—6—oxo—4,5—dihydro—1H—pyridazm— 3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 180] 10 *H-NMR (DMSO-d6) 5: 1.04 (3E, d, J = 7.1 Hz), 2.25 (1H, dd, J - 16.9, 3.4 Hz), 2.71 (1H, dd, J = 16.9, 6.8 Hz), 3.08- 3.22 (1H, m), 4.67-4.87 (4H, m), 7.20-7.27 (1H, m), 7.37- 7.46 (1H, m), 7.53-7.60 (2H, m), 7.68-7.74 (1H, m), 7.98- 8.05 (2H, m), 11.06 (1H, s). 15 [0278] (Reference example 168) 3-[2,6-Dichloro-4-(4-methyl-6-oxo-4,5-dihydro-lH-pyridazin- 3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 181] Date Reçue/Date Received 2023-06-16 1H-NMR (DMS0-d6) 5: 1.03 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.9 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.39-3.49 (1H, m), 4.56 (2H, t, J = 12.8 Hz), 4.86 (2H, t, J = 13.6 Hz), 5 7.54-7.61 (2H, m), 7.68-7.76 (1H, m), 7.83-7.88 (2H, m), 7.99-8.06 (2H, m), 11.12 (1H, s). [0279] (Reference example 169) 3-[2-Chloro-3-fluoro-4-(4-methyl-6-oxo-4,5-dihydro-lH- 10 pyridazin-3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 182] *H-NMR (DMSO-d6)5: 1.03 (3H, d, J = 7.3 Hz), 2.25 (1H, dd, J = 16.9, 3.7 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.06-3.21 15 (1H, m), 4.67-4.91 (4H, m), 7.20-7.28 (1H, m), 7.52-7.63 (3H, Date Reçue/Date Received 2023-06-16 178 m), 7.67-7.74 (1H, m), 7.98-8.05 (2H, m), 11.05 (1H, s). [0280] (Reference example 170) 3-[2-Chloro-6-fluorq-4-(4-methyl-6-oxo-4 r 5-dihydro-lH- 5 pyridazin-3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 183] 0' v ir-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J - 16.7, 7.0 Hz), 3.34-3.45 (1H, 10 m), 4.67 (2H, t, J = 12.9 Hz), 4.83 (2H, t, J = 13.7 Hz), 7.52-7.61 (2H, m), 7.64-7.75 (3H, m), 7.98-8.04 (2H, m), 11.09 (1H, s). [0281] (Reference example 171) 15 3-[2—Bromo-3-fluoro-4-(4-methyl-6-oxo~4,5-dihydro-lHpyridazin-3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 184] Date Reçue/Date Received 2023-06-16 179 ^-NMR (DMS0-d6) 5: 1.03 (3H, d, J = 7.3 Hz), 2.25 (1H, dd, J = 16.9, 3.9 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.07- 3.19 (1H, m), 4.75 (2H, t, J = 12.6 Hz), 4.84 (2H, t, J = 5 13.9 Hz), 7.19 (1H, dd, J = 8.8, 1.2 Hz), 7.53-7.64 (3H, m), 7.67-7.74 (1H, m), 7.98-8.04 (2H, m), 11.05 (1H, s). [0282] (Reference example 172) 3-[2-Chloro-6-methyl-4-(4-methyl-6-oxo-4,5-dihydro-lH- 10 pyridazin-3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 185] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J - 16.9 Hz), 2.33 (3H, s), 2.68 (1H, dd, J = 16.9, 6.8 Hz), 15 3.27-3.43 (1H, m), 4.45 (2H, t, J = 12.9 Hz), 4.85 (2H, t, J = 13.6 Hz), 7.55-7.61 (2H, m), 7.62-7.64 (1H, m), 7.67- Date Reçue/Date Received 2023-06-16 180 7.69 (1H, m), 7.70-7.75 (1H, m), 8.00-8.07 (2H, m), 11.01 (1H, s). [0283] (Reference example 173) 5 2,2-Difluor0-3-[3-fluoro-4-(4-methyl-6-oxo-4,5-dihydro-lHpyridazin-3-yl)-2-vinylphenoxy]propyl benzoate [Chem. 186] iH-NMR (CDC13) 5: 1.19 (3H, d, J = 7.1 Hz), 2.43 (1H, dd, J 10 = 17.1, 3.7 Hz), 2.70-2.80 (1H, m), 3.19-3.31 (1H, m), 4.39 (2H, t, J = 11.2 Hz), 4.75 (2H, t, J = 12.5 Hz), 5.55-5.62 (1H, m), 5.97-6.05 (1H, m), 6.70-6.81 (2H, m), 7.37-7.49 (3H, m), 7.56-7.64 (1H, m), 8.00-8.06 (2H, m), 8.51 (1H, brs). [0284] 15 (Reference example 174) Production of (3R)-4-(3-chloro-4-hydroxy-5-methylphenyl)-3- methyl-N-[(IS)-1-(4-nitrophenyl)ethyl]-4-oxobutanamide [Chem. 187] Date Reçue/Date Received 2023-06-16 181 To a mixture of 4-(3-chloro-4-hydroxy-5-methylphenyl)-3- methyl-4-oxobutanoic acid (Reference example 71, 317 mg) in DMF (10 mL) were added (S)-1-(4-nitrophenyl)ethylamine 5 hydrochloride (275 mg), triethylamine (0.189 mL), 1- hydroxybenzotriazole monohydrate (208 mg), and l—(3— dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (260 mg). The reaction mixture was stirred at room temperature for 3 days. To the reaction mixture was added saturated 10 aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude diastereomer was purified by silica gel column chromatography (heptane : 15 ethyl acetate = 67 : 33 to 25 : 75) to afford the title compound as a pale yellow amorphous (206 mg). iR-NMR (CDC13) 5: 1.18 (3H, d, J = 7.1 Hz), 1.44 (3H, d, J = 7.1 Hz), 2.30-2.38 (4H, m), 2.80 (1H, dd, J = 14.9, 9.0 Hz), 3.85-3.97 (1H, m), 5.07 (1H, quintet, J = 7.1 Hz), 5.99 (1H, Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 182 d, J = 6.8 Hz), 6.08 (1H, s), 7.41-7.48 (2H, m), 7.70 (1H, d, J = 1.5 Hz), 7.85 (1H, d, J = 2.2 Hz), 8.15-8.22 (2H, m). [0285] (Reference example 175) Production of 2-{2-chloro-6-methyl-4-[(2R)-2-methyl-3- {[(lS)-l-(4- nitrophenyl)ethyl]carbamoyl[propanoyl]phenoxy[ethyl 4- bromobenzoate [Chem. 188] To a mixture of (3R)-4-(3-chloro-4-hydroxy-5-methylphenyl)- 3-methyl-N-[(IS)-1-(4-nitrophenyl)ethyl]-4-oxobutanamide (Reference example 174, 206 mg) in THF (5.0 mL) were added 2-hydroxyethyl 4-bromobenzoate (162 mg) and triphenylphosphine (174 mg), and the mixture was cooled on ice bath. Bis(2-methoxyethyl) azodicarboxylate (155 mg) was slowly added to the reaction mixture, and then the reaction mixture was stirred at room temperature overnight. The solvent was removed, and the obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 67 : 33 to 33 : 67) to afford the title compound 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 183 as a colorless solid (205 mg). iR-NMR (CDCI3) 5: 1.17 (3H, d, J = 7.3 Hz), 1.45 (3H, d, J = 7.1 Hz), 2.31-2.39 (4H, m), 2.82 (1H, dd, J = 14.9, 9.3 Hz), 3.85-3.96 (1H, m), 4.32-4.38 (2H, m), 4.64-4.70 (2H, m), 5.08 (1H, quintet, J = 7.1 Hz), 5.96 (1H, d, J = 7.1 Hz), 7.41-7.47 (2H, m), 7.57-7.63 (2H, m), 7.71 (1H, d, J = 1.5 Hz), 7.85 (1H, d, J = 2.2 Hz), 7.87-7.93 (2H, m), 8.15-8.21 (2H, m).

[0286] The obtained compound was recrystallized from ethyl acetate/heptane to give a single crystal thereof. According to the X-ray crystal structure analysis of the single crystal, the stereochemistry at the 3rd position of the butanamide moiety thereof was determined as R. <Crystallographic data> Composition formula: CzgHagBrClNzO?, Molecular weight: 631.90, monoclinic Space group P2i(#4), a = 4.7154(5)Â, b=20.026(2)Â, c = 15.3231(18)Â, V=1433.7(3)Â3, Z=2, De = 1.464 g/cm3, R-factor = 0.1308 [0287] (Reference example 176) Production of 3-bromo-2-fluoro~4-hydroxy-5- methylbenzaldehyde [Chern. 1891 184 To a solution of 2-fluoro-4-hydroxy-5-methylbenzaldehyde (3.39 g) in acetic acid (20 mL) was added pyridinium bromide perbromide (8.44 g), and the mixture was stirred at 75°C for 5 one hour. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was added water, and the precipitates were collected on a filter, washed with water, and dried to afford the title compound as a pale brown solid (4.77 g). 10 ]H-NMR (DMSO-d6) 5: 2.25 (3H, s), 7.59 (1H, dd, J = 8.1, 0.7 Hz), 10.02 (1H, s), 10.82 (1H, brs). [0288] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 15 28. (Reference example 177) 2-Fluoro-4-(methoxymethyloxy)-3,5-dimethylbenzaldehyde [Chern. 190] Date Reçue/Date Received 2023-06-16 185 JH-NMR (CDC13) 5: 2.25 (3H, d, J = 2.3 Hz), 2.29 (3H, s), 3.62 (3H, s), 5.03 (2H, s), 7.55 (1H, d, J = 7.9 Hz), 10.27 (1H, s). [0289] 5 The following compound was prepared from the appropriate starting material in a similar manner to Reference example 30. (Reference example 178) 3-Chloro-2,5-difluoro-4-methoxybenzaldehyde 10 [Chem. 191] iH-NMR (CDCI3) 5: 4.16 (3H, d, J = 3.4 Hz), 7.53 (1H, dd, J = 11.4, 6.3 Hz), 10.23 (1H, d, J = 3.2 Hz). [0290] 15 (Reference example 179) Production of 5-chloro-2,4-dihydroxy-3-methylbenzaldehyde [Chem. 192] Date Reçue/Date Received 2023-06-16 186 To a mixture of 2,4-dihydroxy-3-methylbenzaldehyde (6.09 g) in dichloroethane (80 mL) was added N-chlorosuccinimide (6.41 g), and the mixture was stirred at 60°C for 3 hours. 5 The solvent was removed, and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 10 95 : 5 to 74 : 26) to afford the title compound as a white solid (6.76 g). iH-NMR (DMSO-d6) 5: 2.07 (3H, d, J = 0.6 Hz), 7.68-7.70 (1H, m), 9.77 (1H, s), 10.52 (1H, brs), 11.36 (1H, s). [0291] 15 (Reference example 180) Production of 2,4-bis(benzyloxy)-5-chloro-3- methylbenzaldehyde [Chem. 193] Date Reçue/Date Received 2023-06-16 187 To a mixture of 5-chloro-2,4-dihydroxy-3-methylbenzaldehyde (Reference example 179, 6.76 g) in DMF (75 mL) were added potassium carbonate (15.0 g) and benzyl bromide (10.8 mL), 5 and the mixture was stirred at room temperature for one hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtrated, and concentrated. The obtained solid was washed 10 by trituration with diisopropyl ether, and then collected on a filter to afford the title compound as a pale brown solid (11.3 g). 'H-NMR (DMSO-d6) 5: 2.20 (3H, d, J = 0.5 Hz), 5.03 (2H, s), 5.05 (2H, s), 7.35-7.55 (10H, m), 7.66-7.67 (1H, m), 9.99 15 (1H, s).

[0292] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 180. Date Reçue/Date Received 2023-06-16 188 (Reference example 181) 2,4-Bis(benzyloxy)-3-chloro-5-methylbenzaldehyde [Chern. 194] 5 'H-NMR (CDC13) 5: 2.25 (3H, d, J = 0.7 Hz), 5.06 (2H, s), 5.14 (2H, s), 7.35-7.53 (10H, m), 7.58 (1H, d, J = 0.7 Hz), 10.05 (1H, s). [0293] (Reference example 182) 10 Production of 4-benzyloxy-5-chloro-2-hydroxy-3- methylbenzaldehyde [Chem. 195] To a mixture of 2,4-bis(benzyloxy)-5-chloro-3- 15 methylbenzaldehyde (Reference example 180, 11.33 g) in Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 189 toluene (140 mL) / diethyl ether (20 mL) was added magnesium bromide (8.53 g). Under an argon atmosphere, the mixture was stirred at 100°C for one hour. The reaction mixture was allowed to cool to room temperature, 1 M hydrochloric acid was added thereto, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 95 : 5 to 90 : 10 to 75 : 25) to afford the title compound as a white solid (4.26 g). iH-NMR (CDC13) 5: 2.15 (3H, d, J = 0.5 Hz), 5.02 (2H, s), 7.34-7.53 (6H, m), 9.77 (1H, s), 11.37 (1H, s). [0294] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 182. (Reference example 183) 4-Benzyloxy-3-chloro-2~hydroxy-5-methylbenzaldehyde [Chern. 196] 5 10 15 190 Date Reçue/Date Received 2023-06-16 JH-NMR (CDC13) 5: 2.21 (3H, d, J = 0.9 Hz), 5.08 (2H, s), 7.29-7.31 (1H, m), 7.36-7.53 (5H, m), 9.79 (1H, s), 11.57 (1H, s). [0295] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 32. (Reference example 184) 2-Fluoro-4-(methoxymethyloxy)-5-methylbenzaldehyde [Chem. 197] !H-NMR (CDCI3) 5: 2.22 (3H, s), 3.49 (3H, s), 5.26 (2H, s), 6.85 (1H, d, J = 12.5 Hz), 7.65 (1H, dd, J = 8.1, 0.7 Hz), 10.21 (1H, s). [0296] (Reference example 185) 3-Bromo-2-fluoro-4-(methoxymethyloxy)-5-methylbenzaldehyde [Chem. 198] 191 iR-NMR (CDC13) 5: 2.36-2.39 (3H, m), 3.66 (3H, s), 5.18 s), 7.67 (1H, dd, J = 7.7, 0.7 Hz), 10.26 (1H, s). [0297] 5 (Reference example 186) 4-Benzyloxy-3-chloro-2-(methoxymethyloxy)-5- methylbenzaldehyde [Chem. 199] 10 nH-NMR (CDCI3) 5: 2.26 (3H, d, J = 0.7 Hz), 3.63 (3H, 5.03 (2H, s), 5.20 (2H, s), 7.34-7.51 (5H, m), 7.62-7.63 m), 10.27 (1H, s)» [0298] (Reference example 187) 15 4-Benzyloxy-5-chloro-2-(methoxymethyloxy)-3- methylbenzaldehyde [Chem. 200] (2H, s), (1H, Date Reçue/Date Received 2023-06-16 192 1H-NMR (CDC13) 5: 2.19 (3H, d, J = 0.5 Hz), 3.58 (3H, s), 5.03 (2H, s), 5.04 (2H, s), 7.34-7.50 (5H, m), 7.78-7.80 (1H, m), 10.20 (1H, s). 5 [0299] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 41. (Reference example 188) 10 Methyl 4-[2-fluoro-4-(methoxymethyloxy)-5-methylphenyl]-3- methyl-4-oxobutanoate [Chem. 201] iR-NMR (CDCI3) 5: 1.21 (3H, d, J = 7.1 Hz), 2.20 (3H, s), 15 2.41 (1H, dd, J = 16.7, 5.9 Hz), 2.94 (1H, ddd, J = 16.7, 8.4, 1.8 Hz), 3.49 (3H, s), 3.65 (3H, s), 3.73-3.84 (1H, m), Date Reçue/Date Received 2023-06-16 193 5.24 (2H, s), 6.83 (1H, d, J = 13.2 Hz), 7.69 (1H, d, J = 8.5 Hz). [0300] (Reference example 189) 5 Methyl 4-(3-chloro-2,5-di£luoro-4-methoxyphenyl)-3-methyl- 4-oxobutanoate [Chem. 202] iH-NMR (CDC13) 5: 1.22 (3H, dd, J = 7.2, 1.0 Hz), 2.45 (1H, 10 dd, J = 17.0, 5.1 Hz), 2.97 (1H, ddd, J = 17.0, 9.1, 1.9 Hz), 3.65 (3H, s), 3.69-3.80 (1H, m), 4.12 (3H, d, J = 3.1 Hz), 7.57 (1H, dd, J = 12.1, 6.5 Hz). [0301] (Reference * example ...J».... 190)* . 15 Methyl 4-[2~fluoro-4-(methoxymethyloxy)-3,5- dimethylphenyl]-3-methyl-4-oxobutanoate [Chem. 203] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 194 iH-NMR (CDC13) 5; 1.21 (3H, d, J = 7.1 Hz), 2.24 (3H, d, J = 2.7 Hz), 2.27 (3H, s), 2.42 (1H, dd, J = 16.7, 5.7 Hz), 2.94 (1H, ddd, J = 16.7, 8.4, 1.6 Hz), 3.61 (3H, s), 3.65 (3H, s), 3.73-3.86 (1H, m), 5.00 (2H, s), 7.52 (1H, d, J = 8.5 Hz). [0302] (Reference example 191) Methyl 4-[4-benzyloxy-3-chloro-2-(methoxymethyloxy)-5- methylphenyl]-3-methyl-4-oxobutanoate [Chem. 204] iH-NMR (CDCI3) 5: 1.15 (3H, d, J = 7.3 Hz), 2.25 (3H, d, J = 0.6 Hz), 2.40 (1H, dd, J = 16.6, 6.1 Hz), 2.87 (1H, dd, J = 16.6, 7.8 Hz), 3.57 (3H, s), 3.68 (3H, s), 3.82-3.92 (1H, m), 5.00 (2H, s), 5.08 (1H, d, J 5.6 Hz), 5.13 (1H, d, J = 5.6 Hz), 7.32-7.33 (1H, m), 7.35-7.53 (5H, m). [0303] (Reference example 192) Methyl 4-[4-benzyloxy-5-chloro-2-(methoxymethyloxy)-3- methylphenyl]-3-methyl-4-oxobutanoate [Chern. 205] 195 iH-NMR (CDC12) ^5 * 2». 2« ^2 ( —i ïî, ci f H ) , ^2 . H, ci, cl" 0.5 Hz), 2.39 (1H, dd, J = 16.7, 5.9 Hz), 2.87 (1H, dd, J = 16.7, 8.1 Hz), 3.50 (3H, s) , 3.68 (3H, s), 3.76-3.87 (1H, 5 m) , 4.92 (1H, d, J = 6.0 Hz), 4.99 (1H, d, J = 6.0 Hz), 5.00 (2H, s) , 7.34-7.52 (6H, m).

[0304] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 10 63. (Reference example 193) 4- (3-Chloro-2,5-dif luoro-4-methoxyphenyl) -3-methyl-4- oxobutanoic acid [Chem. 206] 15 'H-NMR (DMSO-d6) 6: 1.10 (3H, d, J = 7.1 Hz), 2.43 (1H, dd, J - 17.0, 5.1 Hz), 2.71 (1H, ddd, J = 17.0, 8.8, 1.2 Hz), Date Reçue/Date Received 2023-06-16 196 3.57-3.69 (1H, m), 4.08 (3H, d, J = 2.9 Hz), 7.73 (1H, dd, J = 12.2, 6.7 Hz), 12.25 (1H, s). [0305] (Reference example 194) 5 4-[2-Fluoro-4-(methoxymethyloxy)-3,5-dimethylphenyl]-3- methyl-4-oxobutanoic acid [Chem. 207] iH-NMR (DMSO-d6) 5: 1.08 (3H, d, J = 7.1 Hz), 2.19 (3H, d, J 10 = 2.4 Hz), 2.25 (3H, s), 2.37 (1H, dd, J = 16.9, 5.3 Hz), 2.69 (1H, ddd, J - 16.9, 8.9, 1.3 Hz), 3.52 (3H, s), 3.58- 3.68 (1H, m), 5.04 (2H, s), 7.50 (1H, d, J = 8.5 Hz), 12.16 (1H, brs)* [0306] 15 (Reference example 195) 4-[4—Benzyloxy-3-chloro-2-(methoxymethyloxy)-5- methylphenyl]-3-methyl-4-oxobutanoic acid [Chem. 208] Date Reçue/Date Received 2023-06-16 197 ^-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.25 (3H, s), 2.34 (1H, dd, J = 16.7, 6.0 Hz), 2.64 (1H, dd, J = 16.7, 7.7 Hz), 3.45 (3H, s), 3.67-3.77 (1H, m), 4.98-5.02 (3H, m), 5 5.04 (1H, d, J = 5.9 Hz), 7.34-7.56 (6H, m), 12.16 (1H, brs). [0307] (Reference example 196) 4-[4-Benzyloxy-5-chloro-2-(methoxymethyloxy)-3- methylphenyl]-3-methyl-4-oxobutanoic acid 10 [Chem. 209] iH-NMR (DMSO-d6) 6: 1.05 (3H, d, J = 7.1 Hz), 2.20 (3H, d, J = 0.5 Hz), 2.34 (1H, dd, J = 16.8, 5.9 Hz), 2.64 (1H, dd, J = 16.8, 7.8 Hz), 3.40 (3H, s), 3.64-3.74 (1H, m), 4.90 (1H, 15 d, J = 6.1 Hz), 4.95 (1H, d, J = 6.1 Hz), 4.99 (2H, s), 7.36- 7.53 (5H, m), 7.55-7.56 (1H, m), 12.22 (1H, brs). [0308] Date Reçue/Date Received 2023-06-16 198 The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 73. (Reference example 197) 5 6-(3-Chloro-2,5-difluoro-4-methoxyphenyl)-5-methyl-4,5- dihydro—2H—pyrrdazin—3~one [Chern. 210] iR-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.26 (1H, dd, 10 J = 16.9, 3.7 Hz), 2.71 (1H, dd, J = 16.9, 6.8 Hz), 3.12- 3.22 (1H, m), 4.00 (3H, d, J = 2.1 Hz), 7.57 (1H, dd, J = 12.3, 7.1 Hz), 11.14 (1H, s). [0309] (Reference example 198) 15 6-[2—Fluoro-4-(methoxymethyloxy)-3,5-dimethylphenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 211] Date Reçue/Date Received 2023-06-16 199 1H-NMR (DMS0-d6) ô: 1.04 (3H, d, J = 7.2 Hz), 2.17 (3H, d, J = 2.4 Hz), 2.20-2.27 (1H, m), 2.23 (3H, s), 2.66 (1H, dd, J = 16.7, 6.7 Hz), 3.07-3.18 (1H, m), 3.52 (3H, s), 5.00 (2H, 5 s), 7.26 (1H, d, J = 8.8 Hz), 10.98 (1H, s). [0310] (Reference example 199) 6-[4-Benzyloxy-3-chloro-2-(methoxymethyloxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one 10 [Chem. 212] m-NMR (DMSO-d6) 5: 0.94 (3H, d, J = 7.2 Hz), 2.24 (3H, d, J = 0.7 Hz), 2.26 (IE, dd, J = 16.7, 5.4 Hz), 2.67 (1H, dd, J - 16.7, 7.0 Hz), 3.11-3.23 (1H, m), 3.46 (3H, s), 4.96 (2H, 15 s), 5.01-5.06 (2H, m), 7.18-7.19 (1H, m), 7.34-7.55 (5H, m), 10.96 (1H, s). Date Reçue/Date Received 2023-06-16 200 [0311] (Reference example 200) 6-[4-Benzyloxy-5-chloro-2-(methoxymethyloxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one 5 [Chern. 213] iH-NMR (DMSO-d6) 5: 0.94 (3H, d, J = 7.2 Hz), 2.21 (3H, s), 2.26 (1H, dd, J = 16.8, 5.8 Hz), 2.67 (1H, dd, J = 16.8, 6.9 Hz), 3.10-3.20 (1H, m), 3.42 (3H, s), 4.93 (1H, d, J = 6.0 10 Hz), 4.95 (1H, d, J = 6.0 Hz), 4.96 (2H, s), 7.29-7.31 (1H, m), 7.35-7.54 (5H, m), 10.95 (1H, s). [0312] (Reference example 201) 6—[2-Fluoro-4-(methoxymethyloxy)—5—methylphenyl]—5—methyl— 15 4,5-dihydro~2H-pyridazin-3-one [Chern. 214] Date Reçue/Date Received 2023-06-16 201 1H-NMR (MSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.17 (3H, s), 2.22 (1H, dd, J = 16.7, 3.3 Hz), 2.66 (1H, dd, J = 16.7, 6.8 Hz), 3.10-3.18 (1H, m), 3.39 (3H, s), 5.28 (2H, s), 6.95 (1H, 5 d, J = 13.4 Hz), 7.42 (1H, dd, J = 9.0, 0.7 Hz), 10.95 (1H, s).

[0313] The following compound was prepared from the appropriate starting material in a similar manner to Reference example (Reference example 202) 6-(3-Chloro-2,5-difluoro-4-hydroxyphenyl)-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chern. 215] iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.24 (1H, dd, Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 202 J - 16.8, 3.4 Hz), 2.68 (1H, dd, J - 16.8, 6.8 Hz), 3.10- 3.21 (1H, m), 7.45 (1H, dd, J = 11.7, 7.2 Hz), 11.05 (1H, s), 11.37 (1H, brs). [0314] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 98. (Reference example 203) 6-[3—Chloro-4-hydroxy-2-(methoxymethyloxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 216] ^-NMR (DMSO-d6) 5: 0.92 (3H, d, J = 7.3 Hz), 2.18 (3H, d, J = 0.7 Hz), 2.23 (1H, dd, J = 16.7, 5.1 Hz), 2.64 (1H, dd, J = 16.7, 6.8 Hz), 3.12-3.22 (1H, m), 3.44 (3H, s), 4.96 (1H, d, J = 5.7 Hz), 4.99 (1H, d, J = 5.7 Hz), 7.03-7.05 (1H, m), 9.50 (1H, brs), 10.86 (1H, s). [0315] (Reference example 204) 6-[5—Chloro-4-hydroxy-2-(methoxymethyloxy)-3-methylphenyl]- 5-methyl~4,5-dihydro-2H-pyridazin-3-one 203 [Chem. 217] ci ïR-NMR (DMSO-d6) 5: 0.91 (3H, d, J = 7.3 Hz), 2.16 (3H, s), 2.23 (1H, dd, J = 16.8, 5.4 Hz), 2.64 (1H, dd, J = 16.8, 7.0 5 Hz), 3.10-3.19 (1H, m), 3.41 (3H, s), 4.89 (1H, d, J = 6.0 Hz), 4.91 (1H, d, J = 6.0 Hz), 7.13-7.15 (1H, m), 9.54 (1H, s), 10.85 (1H, s).

[0316] The following compounds were prepared from each appropriate 10 starting material in a similar manner to Reference example 103. (Reference example 205) 6-(2-Fluoro-4-hydroxy-5-methylphenyl)-5-methyl-4,5-dihydro- 2H-pyridazin-3-one 15 [Chern. 218] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 204 iH-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.1 Hz), 2.09 (3H, s), 2.20 (1H, dd, J = 16.7, 3.1 Hz), 2.64 (1H, dd, J = 16.7, 6.7 Hz), 3.08-3.16 (1H, m), 6.59 (1H, d, J = 13.2 Hz), 7.32 (1H, dd, J = 9.3, 0.7 Hz), 10.19 (1H, brs), 10.87 (1H, s). [0317] (Reference example 206) 6-(2—Fluoro-4-hydroxy-3,5-dimethylphenyl)-5-methyl—4,5- dihydro-2H-pyridazin-3-one [Chem. 219] !H-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.2 Hz), 2.10 (3H, d, J = 2.2 Hz), 2.15 (3H, s), 2.20 (1H, dd, J = 16.7, 3.4 Hz), 2.63 (1H, dd, J = 16.7, 6.7 Hz), 3.05-3.16 (1H, m), 7.14 (1H, d, J = 9.0 Hz), 9.03 (1H, s), 10.87 (1H, s).

[0318] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 107. (Reference example 207) 6-[5-Chloro-2~fluoro-3-methyl-4-(2~oxopropoxy)phenyl]-5- 205 methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 220] ’li-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.18 (3H, s), 5 2.21-2.29 (4H, m), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.07- 3.17 (1H, m), 4.72 (2H, s), 7.53 (1H, d, J = 7.8 Hz), 11.07 (1H, s). [0319] (Reference example 208) 10 6-[3-Chloro-2-fluoro-5-methyl-4-(2-oxopropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 221] *H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.19 (3H, s), 15 2.22-2.30 (1H, m), 2.28 (3H, s), 2.70 (1H, dd, J= 16.8, 6.8 Hz), 3.09-3.19 (1H, m), 4.73 (2H, s), 7.44 (1H, d, J = 8.4 Date Reçue/Date Received 2023-06-16 206 Hz), 11.08 (1H, s). [0320] (Reference example 209) 6-[3—Chloro-2,5-difluoro-4-(2-oxopropoxy)phenyl]-5-methyl- 5 4,5-dihydro-2H-pyridazin-3-one [Chem. 222] F 0 1H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.16 (3H, s), 2.26 (1H, dd, J = 16.8, 3.5 Hz), 2.70 (1H, dd, J = 16.8, 6.8 10 Hz), 3.12-3.21 (1H, m), 5.02-5.07 (2H, m), 7.53 (1H, dd, J = 13.0, 7.1 Hz), 11.13 (1H, s). [0321] (Reference example 210) 6-[3-Chloro-2-(methoxymethyloxy)-5-methyl-4-(2- 15 oxopropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 223] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 207 iH-NMR (DMSO-d6) 5: 0.93 (3H, d, J = 7.3 Hz), 2.19 (3H, s), 2.25 (1H, dd, J = 16.8, 5.6 Hz), 2.26 (3H, d, J = 0.7 Hz), 2.66 (1H, dd, J = 16.8, 6.9 Hz), 3.10-3.20 (1H, m), 3.45 (3H, s), 4.66 (2H, s), 5.01 (1H, d, J = 5.9 Hz), 5.02 (1H, d, J = 5.9 Hz), 7.17-7.18 (1H, m), 10.95 (1H, s). [0322] (Reference * example 211) - * - 6-[3-Chloro-2~(methoxymethyloxy)-4-(2-oxobutoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 224] 0^ ^-NMR (CDC13) 5: 1.07 (3H, d, J = 7.3 Hz), 1.14 (3H, t, J = 7.3 Hz), 2.41 (1H, dd, J = 16.9, 4.6 Hz), 2.69-2.85 (3H, m), 3.30-3.40 (1H, m), 3.54 (3H, s), 4.63 (2H, s), 5.04 (1H, d, J = 5.6 Hz), 5.18 (1H, d, J = 5.6 Hz), 6.63 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 8.8 Hz), 8.52 (1H, brs). [0323] (Reference example 212) Production of 6-[3-chloro-4-(2-hydroxy-2-methylpropoxy)-2- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro~2H 5 10 15 20 Date Reçue/Date Received 2023-06-16 208 pyridazin-3-one [Chern. 225] A mixture of 6-[3-chloro-4-hydroxy-2- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one (Reference example 99, 130 mg), l-chloro-2- methyl-2-propanol (0.268 mL), and potassium carbonate (241 mg) in ethanol (2.0 mL)/water (0.2 mL) was stirred at 80“C for 7 hours. The reaction mixture was poured into aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was removed to afford the title compound as a colorless oil (130 mg). 'H-NMR (CDCI3) 5: 1.07 (3H, d, J = 7.3 Hz), 1.39 (6H, s), 2.42 (1H, dd, J = 17.0, 4.8 Hz), 2.80 (1H, dd, J = 17.0, 7.0 Hz), 3.30-3.41 (1H, m), 3.53 (3H, s), 3.87 (2H, s), 5.01- 5.06 (1H, m), 5.14-5.20 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 7.22 (1H, d, J = 8.5 Hz), 8.44 (1H, brs).

[0324] The following compounds were prepared from each appropriate 209 starting material in a similar manner to Reference example 212. (Reference example 213) 6-[3-Chloro-4-(2-hydroxy-2-methylpropoxy)-2- 5 (methoxymethyloxy)-5-methylphenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chern. 226] ir-NMR (DMSO-d6) 5: 0.93 (3H, d, J = 7.3 Hz), 1.28 (6H, s), 10 2.21-2.29 (1H, m), 2.27 (3H, d, J = 0.7 Hz), 2.66 (1H, dd, J =16.8, 6.9 Hz), 3.10-3.20 (1H, m), 3.45 (3H, s), 3.64 (2H, s), 4.64 (1H, s), 5.00 (1H, d, J = 5.8 Hz), 5.02 (1H, d, J = 5.8 Hz), 7.15-7.16 (1H, m), 10.94 (1H, s). [0325] 15 (Reference example 214) 6-[4—(2-Hydroxy-2-methylpropoxy)-2-(methoxymethyloxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 227] Date Reçue/Date Received 2023-06-16 210 ^-NMR (CDCI3) 5: 1.07 (3H, d, J = 7.3 Hz), 1.38 (6H, s), 2.16 (1H, s), 2.24 (3H, s), 2.41 (1H, dd, J = 17.1, 4.6 Hz), 2.79 (1H, dd, J = 17.1, 6.8 Hz), 3.28-3.38 (1H, m), 3.51 (3H, 5 s), 3.82 (2H, s), 4.89 (1H, d, J = 5.6 Hz), 5.00 (1H, d, J = 5.6 Hz), 6.67 (1H, d, J = 8.5 Hz), 7.14 (1H, d, J = 8.5 Hz), 8.46 (1H, brs). [0326] (Reference example 215) 10 6-[5-Chloro-4-(2-hydroxy-2-methylpropoxy)-2- (methoxymethyloxy)-3-methylphenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chern. 228] 15 'H-NMR (DMSO-d6) 6: 0.93 (3H, d, J = 7.3 Hz), 1.28 (6H, s), 2.251 (1H, dd, J = 16.8, 5.8 Hz), 2.255 (3H, d, J = 0.6 Hz), Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 211 2.66 (1H, dd, J = 16.8, 6.9 Hz), 3.09-3.20 (1H, m), 3.42 (3H, s), 3.64 (2H, s), 4.66 (1H, s), 4.92 (1H, d, J = 6.0 Hz), 4.96 (1H, d, J = 6.0 Hz), 7.24-7.25 (1H, m), 10.94 (1H, s). [0327] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 135. (Reference example 216) 3-[6—Chloro-3-fluoro-2-methyl-4-(4-methyl-6-oxo-4,5 dihydro-lH-pyridazin-3-yl)phenoxy]-2,2~difluoropropyl methanesulfonate [Chem. 229] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.22-2.30 (4H, m), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.09-3.18 (1H, m), 3.34 (3H, s), 4.43 (2H, t, J = 13.3 Hz), 4.75 (2H, t, J = 13.5 Hz), 7.57 (1H, d, J = 7.8 Hz), 11.09 (1H, s). [0328] (Reference example 217) 3-[2—Chloro-3-fluoro-6-methyl-4-(4-methyl-6-oxo-4,5 dihydro-lH-pyridazin-3-yl)phenoxy]-2,2~difluoropropyl 212 methanesulfonate [Chem. 230] 1H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.26 (1H, dd, 5 J = 16.8, 3.8 Hz), 2.30 (3H, s), 2.70 (1H, dd, J = 16.8, 6.8 Hz), 3.10-3.20 (1H, m), 3.34 (3H, s), 4.44 (2H, t, J = 13.2 Hz), 4.75 (2H, t, J = 13.5 Hz), 7.48 (1H, d, J = 8.2 Hz), 11.10 (1H, s). [0329] 10 (Reference example 218) 2,2-Difluor0-3-[3-fluoro-2,6-dimethyl-4-(4-methyl~6-oxo- 4,5-dihydro-lH~pyridazin-3-yl)phenoxy]propyl methanesulfonate [Chern. 231] 15 'H-NMR (DMSO-d6) 6: 1.04 (3H, d, J = 7.2 Hz), 2.19 (3H, d, J = 2.3 Hz), 2.24 (1H, dd, J = 16.8, 3.8 Hz), 2.25 (3H, s), Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 2.67 (1H, dd, J- 16.8, 6.8 Hz), 3.06-3.17 (1H, m), 3.31 (3H, s), 4.27 (2H, t, J = 13.2 Hz), 4.74 (2H, t, J = 13.6 Hz), 7.28 (1H, d, J = 8.8 Hz), 11.00 (1H, s). [0330] (Reference example 219) 3-[2-Chloro-3,6-difluoro-4-(4—methyl-6-oxo-4,5-dihydro-lHpyridazin-3-yl)phenoxy]-2,2-difluoropropyl methanesulfonate [Chem. 232] iH-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.27 (1H, dd, J - 16.9, 3.8 Hz), 2.71 (1H, dd, J = 16.9, 6.8 Hz), 3.13- 3.22 (1H, m), 3.31 (3H, s), 4.60-4.78 (4H, m), 7.63 (1H, dd, J = 12.0, 7.0 Hz), 11.17 (1H, s).

[0331] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 144. (Reference example 220) 6-(4-{[(1S*,2R*)~2~(tertButyldimethylsilyloxymethyl)cyclopropyl]methoxy}-3-chloro- 2-fluorophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one 214 [Chem. 233] 1H-NMR (CDC13) 5: 0.04 (3H, s), 0.05 (3H, s), 0.49 (1H, d, J = 5.6 Hz), 0.85-0.95 (10H, m), 1.21 (3H, d, J = 7.1 Hz), 5 1.25-1.37 (1H, m), 1.38-1.49 (1H, m), 2.44 (1H, dd, J= 17.1, 3.2 Hz), 2.74 (1H, dd, J = 17.1, 6.7 Hz), 3.22-3.33 (1H, m), 3.65-3.73 (1H, m), 3.81-3.88 (1H, m), 4.13-4.23 (2H, m), 6.73-6.79 (1H, m), 7.42-7.49 (1H, m), 8.53 (1H, s). [0332] 10 (Reference example 221) 6-(4-{[(1S*,2R*)-2-(tertButyldimethylsilyloxymethyl)cyclopropyl]methoxy)-3-chloro- 5-methylphenyl)-5-methyl~4,5-dihydro-2H-pyridazin-3-one [Chem. 234] 'H-NMR (CDCI3) 5: 0.046 (3H, s), 0.054 (3H, s), 0.38-0.45 (1H, m), 0.87-0.94 (10H, m), 1.22-1.34 (4H, m), 1.39-1.51 Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 215 (1H, m) , 2.36 (3H, s) , 2.43-2.51 (1H, m) , 2.69 (1H, dd, J = 17.1, 6.8 Hz), 3.23-3.34 (1H, m) , 3.71 (2H, d, J = 7.1 Hz), 3.94 (1H, dd, J = 10.4, 7.9 Hz), 4.12 (1H, dd, J = 10.4, 7.4 Hz), 7.48 (1H, d, J = 2.2 Hz), 7.60 (1H, d, J = 2.2 Hz), 8.54 (1H, brs) . [0333] (Reference example 222) 6- (4-{ [ (1S*,2S*)~2~ (tertButyldimethylsilyloxymethyl) cyclopropyl]methoxy}-3-chloro- 2-f luorophenyl) -5-methyl-4, 5-dihydro-2H-pyridazin-3-one [Chem. 235] ifi-HMR (CDCls) 5: 0.06 (6H, s) , 0.58-0.70 (2H, m) , 0.89 (9H, in ) , 1>.0 8 1«. I» '/ ( 1»II, m ) , 1>. 1»8 I*.2> «3 ( 4II, Hi) , >2>. 4. ( 1> II, dd, iJ 17.0, 3.3 Hz), 2.74 (1H, dd, J = 17.0, 6.7 Hz), 3.22-3.33 (1H, m) , 3.52-3.66 (2H, m) , 3.91-4.07 (2H, m) , 6.71-6.79 (1H, m) , 7.44 (1H, t, J = 8.5 Hz), 8.51 (1H, brs). [0334] (Reference example 223) 6-{ 4-[ (Z) -4- (tert-Butyldimethylsilyloxy) -2-butenyloxy]-2- 216 fluoro-3,5-dimethylphenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chem. 236] 5 iH-NMR (CDC13) 5: 0.06 (6H, s), 0.89 (9H, s), 1.20 (3H, d, J = 7.2 Hz), 2.22 (3H, d, J = 2.4 Hz), 2.26 (3H, s), 2.43 (1H, dd, J = 17.0, 3.4 Hz), 2.74 (1H, dd, J = 17.0, 6.7 Hz), 3.22- 3.32 (1H, m), 4.21-4.28 (2H, m), 4.42 (2H, d, J = 5.3 Hz), 5.72-5.86 (2H, m), 7.21 (1H, d, J = 8.8 Hz), 8.47 (1H, brs). 10 [0335J (Reference example 224) g{4—[(z)-4-(tert-Butyldimethylsilyloxy)-2-butenyloxy]-3- chloro-2-fluoro-5-methylphenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one 15 [Chem. 237] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 217 iH-NMR (CDC13) S: 0.06 (6H, s), 0.89 (9H, s) , 1.21 (3H, dd, J = 7.2, 0.6 Hz), 2.27-2.30 (3H, m) , 2.45 (1H, dd, J = 17.0, 3.4 Hz), 2.74 (1H, dd, J = 17.0, 6.7 Hz), 3.22-3.31 (1H, m) , 4.25-4.28 (2H, m) , 4.59-4.63 (2H, m) , 5.74-5.87 (2H, m) , 7.31 (1H, dd, J = 8.3, 0.7 Hz), 8.52 (1H, s) . [0336] (Reference example 225) 6-{ 4-[ (Z) -4- (tert-Butyldimethylsilyloxy) -2~butenyloxy]-3- chloro-2,5-difluorophenyl}-5-methyl-4,5-dihydro~2Hpyridazin-3-one [Chern. 238] ifi-HMR (CDCI3) 5: 0.06 (6H, s) , 0.89 (9H, s) , 1.22 (3H, d, J = 7.2 H ( 1«H, dd, J1 ïî ( îlrH, dd, = 17.0, 6.8 Hz), 3.25-3.34 (1H, m), 4.25-4.29 (2H, m) , 4.82- 4.86 (2H, m) , 5.71-5.84 (2H, m) , 7.34 (1H, dd, J = 11.7, 7.0 Hz) , 8.55 (1H, s) . [0337] (Reference example 226) 6-{ 4-[ (Z) -4- (tert-Butyldimethylsilyloxy) -2-butenyloxy]-2- 218 hydroxy-3-methylphenyl)-5-methyl-4,5-dihydro-2H-pyridazin- 3-one [Chem. 239] 5 ’li-NMR (CDC13) 5: 0.09 (6H, s) , 0.92 (9H, s) , 1.29 (3H, d, J = 7.3 Hz), 2.14 (3H, s) , 2.47-2.53 (1H, m) , 2.73 (1H, dd, J = 16.9, 6.6 Hz), 3.40-3.51 (1H, m) , 4.30-4.35 (2H, m) , 4.67- 4.71 (2H, m) , 5.69-5.80 (2H, m) , 6.46 (1H, d, J = 8.8 Hz), 7.21-7.28 (1H, m) , 8.38 (1H, s) , 11.90 (1H, s). 10 [0338] (Reference example 227) 6-{ 4-[ (Z) -4- (tert-Butyldimethylsilyloxy) -2-butenyloxy]-3- chloro-2-hydroxyphenyl]-5-methyl~4,5-dihydro-2H-pyridazin- 3-one 15 [Chem. 240] iH-NMR (CDC13) 5: 0.12 (6H, s) , 0.95 (9H, s) , 1.33 (3H, d, J Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 219 = 7.6 Hz), 2.52-2.59 (1H, m), 2.78 (1H, dd, J = 17.1, 6.6 Hz), 3.41-3.53 (1H, m), 4.34-4.40 (2H, m), 4.80-4.86 (2H, m), 5.72-5.86 (2H, m), 6.58 (1H, d, J = 9.3 Hz), 7.32 (1H, d, J = 9.3 Hz), 8.40-8.53 (1H, m), 12.41 (1H, d, J = 2.4 Hz). [0339] (Reference example 228) Production of 6-[4-(3-hydroxypropoxy)-2-(methoxymethyloxy)- 3-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 241] To a mixture of 6-[4-hydroxy-2-(methoxymethyloxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 98, 611 mg), 3-(tert butyldimethylsilyloxy)propan-l-ol (627 mg), and triphenylphosphine (864 mg) m THF (12 mL) was added bis(2— methoxyethyl) azodicarboxylate (771 mg) at 0°C, and then the mixture was stirred at room temperature overnight. The solvent was removed, and then the residue was purified by silica gel column chromatography (heptane : ethyl acetate = 85 : 15 to 35 : 65) to afford a pale yellow oil(1.04 g). The oil was dissolved in THF (10 mL), tetrabutylammonium 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 220 fluoride (1.0 M THF solution, 2.76 mL) was added to the mixture at O^C, and then the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated, water was added to the resxdue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 50 : 50 to 0 : 100) to afford the title compound as a colorless amorphous (635 mg). iH-NMR (CDC13) 5: 1.06 (3H, d, J = 7.3 Hz), 1.77-1.85 (1H, m), 2.09 (2H, quintet, J = 6.0 Hz), 2.19 (3H, s), 2.41 (1H, dd, J = 17.1, 4.6 Hz), 2.78 (1H, dd, J = 17.1, 7.0 Hz), 3.28- 3.37 (1H, m), 3.50 (3H, s), 3.87-3.91 (2H, m), 4.15 (2H, t, J = 6.0 Hz), 4.88 (1H, d, J = 5.6 Hz), 4.98 (1H, d, J = 5.6 Hz), 6.70 (1H, d, J = 8.5 Hz), 7.14 (1H, d, J= 8.5 Hz), 8.56 (1H, brs). [0340] The following compounds were prepared from each appropriate starting material in a similar manner to Reference example 228. (Reference example 229) 6-[3—Chloro-4-[(Z)-4-hydroxy-2-butenyloxy]-2- (methoxymethyloxy)phenyl]~5-methyl-4,5-dihydro-2H 221 pyridazin-3-one [Chem. 242] ifi-NMR (CDC13) 5: 1.07 (3H, d, J = 7.3 Hz), 1.63-1.68 (1H, 5 m), 2.42 (1H, dd, J = 17.0, 4.8 Hz), 2.80 (1H, dd, J = 17.0, 7.0Hz), 3.31-3.40 (1H, m), 3.53 (3H, s), 4.29-4.35 (2H, m), 4.72-4.77 (2H, m), 5.02 (1H, d, J = 5.6 Hz), 5.16 (1H, d, J = 5.6 Hz), 5.83-5.96 (2H, m), 6.78 (1H, d, J = 8.5 Hz), 7.22 (1H, d, J= 8.5 Hz), 8.52 (1H, s). 10 [0341] (Reference example 230) 6-[3-Chloro-4-(4-hydroxybutoxy)-2- (methoxymethyloxy)phenyl]-5~methyl-4,5-dihydro-2Hpyridazin-3-one 15 [Chem. 243] iH-NMR (CDCI3) 5: 1.07 (3H, d, J = 7.3 Hz), 1.50-1.54 (1H, Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 222 m), 1.77-1.85 (2H, m), 1.94-2.01 (2H, m) , 2.42 (1H, dd, J = 17.0, 4.8 Hz), 2.80 (1H, dd, J = 17.0, 7.0 Hz), 3.32-3.40 (1H, m) , 3.53 (3H, s), 3.74-3.79 (2H, m) , 4.11 (2H, t, J = 6.1 Hz), 5.01 (1H, d, J = 5.6 Hz), 5.16 (1H, d, J = 5.6 Hz), 6.77 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 8.8 Hz), 8.45 (1H, brs). [0342] (Reference example 231) 6- [3—Chloro-4- (3-hydroxypropoxy) -2- (methoxymethyloxy) -5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 244] ^-NMR (CDC13) 5: 1.08 (3H, d, J = 7.6 Hz), 1.90 (1H, t, J = 5.5 Hz), 2.07-2.13 (2H, m) , 2.30 (3H, d, J = 0.7 Hz), 2.42 (1»II, dd, I»7 « 0, . 9 Ji1z ) , .80 (1»H, dd, (J «1'7. , ^7 H zi ) , 3.30-3.39 (1H, m) , 3.52 (3H, s) , 3.97 (2H, td, J = 5.9, 5.5 Hz), 4.09 (2H, t, J = 5.9 Hz), 4.98 (1H, d, J = 5.4 Hz), 5.12 (1H, d, J = 5.4 Hz), 7.08 (1H, d, J = 0.7 Hz), 8.49 (1H, s) .

[0343] The following compounds were prepared from each appropriate 223 starting material in a similar manner to Reference example 166. (Reference example 232) 3-[6-Chloro-3-fluoro-2-methyl-4-(4-methy1-6-oxo-4,5- 5 dihydro-lH-pyridazin-3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 245] ir-NMR (DMS0-d6) 5: 1.03 (3H, d, J = 7.2 Hz), 2.20-2.30 (1H, 10 m), 2.24 (3H, d, J = 2.4 Hz), 2.69 (1H, dd, J = 16.7, 6.7 Hz), 3.07-3.18 (1H, m), 4.51 (2H, t, J = 13.2 Hz), 4.85 (2H, t, J = 13.6 Hz), 7.52-7.62 (3H, m), 7.70-7.75 (1H, m), 8.00- 8.07 (2H, m), 11.09 (1H, s). [0344] 15 (Reference example 233) 3-[2—Chloro-3-fluoro-6-methyl-4-(4-methyl-6-oxo-4,5- dihydro-lH-pyridazin-3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 246] Date Reçue/Date Received 2023-06-16 224 ^-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 2.26 (1H, dd, J = 16.8, 3.7 Hz), 2.30 (3H, s), 2.70 (1H, dd, J = 16.8, 6.8 Hz), 3.09-3.19 (1H, m), 4.52 (2H, t, J = 13.1 Hz), 4.85 (2H, 5 t, J = 13.6 Hz), 7.47 (1H, d, J = 7.9 Hz), 7.55-7.62 (2H, m), 7.69-7.76 (1H, m), 8.01-8.07 (2H, m), 11.10 (1H, s). [0345] (Reference example 234) 2,2-Difluor0-3-[3-fluoro-2,6~dimethyl-4-(4-methyl~6-oxo- 10 4,5-dihydro-lH-pyridazin-3-yl)phenoxy]propyl benzoate [Chem. 247] m-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.2 Hz), 2.18 (3H, d, J = 2.2 Hz), 2.23 (3H, s), 2.24 (1H, dd, J = 16.7, 3.9 Hz), 15 2.66 (1H, dd, J = 16.7, 6.8 Hz), 3.06-3.16 (1H, m), 4.36 (2H, t, J = 13.2 Hz), 4.84 (2H, t, J = 13.7 Hz), 7.27 (1H, d, J = 8.9 Hz), 7.54-7.62 (2H, m), 7.69-7.75 (1H, m), 8.02-8.08 Date Reçue/Date Received 2023-06-16 225 (2H, m), 11.00 (1H, s). [0346] (Reference example 235) 3-[2—Chloro-3,6-difluoro-4-(4-methyl-6—oxo—4,5-dihvdro-lH- 5 pyridazin-3—yl)phenoxyJ -2,2-difluoropropyl benzoate [Chem. 248] ir-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.27 (1H, dd, J = 16.8, 3.6 Hz), 2.71 (1H, dd, J = 16.8, 6.9 Hz), 3.11- 10 3.21 (1H, m), 4.75 (2H, t, J = 13.0 Hz), 4.83 (2H, t, J = 13.7 Hz), 7.52-7.65 (3H, m), 7.68-7.75 (1H, m), 7.97-8.05 (2H, m), 11.17 (1H, s). [0347] (Reference * example -J. 236)* 15 Production of 3-[2-chloro-3~hydroxy-4-(4-methyl-6—oxo-4,5- dihydro-lH-pyridazin-3-yl)phenoxy]-2,2-difluoropropyl benzoate [Chem. 249] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 22 6 A suspension of 6-[3-chloro-4-hydroxy-2- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one (Reference example 99, 350 mg), 2,2- difluoro-3-(methylsulfonyloxy)propyl methanesulfonate (943 mg), and cesium carbonate (1.53 g) in NMP (2.0 mL) was stirred at 150°C under microwave irradiation for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The residue was purified by silica gel column chromatography (heptane : ethyl acetate = 50 : 50 to 0 : 100) to afford a mixture containing the desired intermediate. A solution of the obtained mixture and sodium benzoate (121 mg) in NMP (2.0 mL) was stirred at 180°C under microwave irradiation for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained 5 10 15 20 Date Reçue/Date Received 2023-06-16 227 crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 67 : 33 to 33 : 67) and then by diol silica gel column chromatography (heptane » ethyl acetate = 75 z 25 to 33 z 67) to afford the title compound as a colorless solid (38 mg). 1H-NMR (CDCI3) 5: 1.28 (3H, d, J = 7.3 Hz), 2.53 (1H, d, J = 16.6 Hz), 2.75 (1H, dd, J = 16.6, 6.6 Hz), 3.38-3.43 (1H, m), 4.42 (2H, t, J = 11.2 Hz), 4.48 (2H, t, J = 12.7 Hz), 6.55 (1H, d, J = 9.3 Hz), 7.31 (1H, d, J = 9.3 Hz), 7.41- 7.48 (2H, m), 7.55-7.63 (1H, m), 8.00-8.06 (2H, m), 9.10 (1H, s), 12.54 (1H, s). [0348] (Reference example 237) Production of 4-benzyloxy-l-bromo-2-fluoro-3- (trifluoromethyl)benzene [Chern. 250] Under an argon atmosphere, to a mixture of 4-benzyloxy-1- bromo-2-fluorobenzene (6.10 g) in THF (20 mL) was added dropwise lithium diisopropylamide (2.0 M, a mixed solution of THF/heptane/ethylbenzene, 13.6 mL) at -78°C. The reaction 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 228 mixture was stirred at the same temperature for 30 minutes, and then iodine (6.61 g) was added thereto. The reaction mixture was stirred at -78°C for 1.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and then brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The residue was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 0 to 95 : 5 to 91 : 9), and then the obtained solid was washed by trituration with heptane to afford a white solid (5.12 g). The white solid (5.12 g) was dissolved in NMP (40 mL), and then methyl difluoro(fluorosulfonyl)acetate (12.8 mL) and copper iodide (4.79 g) were added thereto. Under an argon atmosphere, the mixture was stirred at 100°C for 18 hours. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added thereto, and then the mixture was filtered through a Celite pad. The separated organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 100 : 0 to 83 : 17) to afford the title compound as a white solid (3.93 g). 1H-NMR (CDC13) 5: 5.17 (2H, s), 6.74 (1H, d, J = 8.8 Hz), 5 10 15 20 Date Reçue/Date Received 2023-06-16 229 7.31-7.43 (5H, m), 7.57-7.63 (1H, m). [0349] The following compound was prepared from the appropriate starting material m a similar manner to Reference example 20. (Reference example 238) 4-Benzyloxy-2-fluoro-3-(trifluoromethyl)benzaldehyde [Chem. 251] iR-NMR (CDC13) 5: 5.28 (2H, s), 6.95 (1H, d, J = 8.8 Hz), 7.32-7.45 (5H, m), 8.01 (1H, dd, J =8.8, 7.9 Hz), 10.25 (1H, s). [0350] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 41. (Reference example 239) Methyl 4-[4-benzyloxy-2-fluoro-3-(trifluoromethyl)phenyl]- 3~methyl~4~oxobutanoate [Chem. 252] 230 iR-NMR (CDC13) 5: 1.22 (3H, dd, J = 7.0, 0.9 Hz), 2.44 (1H, ïî «Z ^2* * ( «1»ïï c.1c.ici' .1" C5 * 13 j 8.9, 1.8 Hz) , 3.64 (3H, s), 3.69-3.79 (1H, m) , 5.25 (2H, s) , 6.91 (1H, d, 5 J =9.0 Hz), 7.31-7.44 (5H, m) , 7.96-8.03 (1H, m) .

[0351] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 63. 10 (Reference example 240) 4-[4-Benzyloxy-2-fluoro-3- (trifluoromethyl)phenyl]-3- methyl-4-oxobutanoic acid [Chern. 253] 15 iH-NMR (DMSO-d6) 5: 1.10 (3H, d, J = 7.1 Hz), 2.41 (1H, dd, J = 17.0, 5.3 Hz), 2.71 (1H, ddd, J = 17.0, 9.0, 0.9 Hz), 3.55-3.67 (1H, m), 5.39 (2H, s) , 7.32-7.49 (6H, m), 8.05- 8.13 (1H, m), 12.20 (1H, s) . Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 231

[0352] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 83. (Reference example 241) 6-[4-Benzyloxy-2-fluoro-3-(trifluoromethyl)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 254] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J - 16.7, 4.2 Hz), 2.69 (1H, dd, J = 16.7, 6.7 Hz), 3.05- 3.19 (1H, m), 5.34 (2H, s), 7.28 (1H, d, J= 9.2 Hz), 7.32- 7.50 (5H, m), 7.77-7.87 (1H, m), 11.05 (1H, s). [0353] The following compound was prepared from the appropriate starting material in a similar manner to Reference example 98. (Reference example 242) 6-[2-Fluoro-4-hydroxy-3-(trifluoromethyl)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chern. 255] 232 ^-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.23 (1H, dd, J = 16.8, 3.8 Hz), 2.67 (1H, dd, J = 16.8, 6.8 Hz), 3.04- 3.15 (1H, m), 6.90 (1H, d, J = 8.8 Hz), 7.61-7.68 (1H, m), 5 10.99 (1H, s), 11.40 (1H, brs). [0354] (Example 1) Production of 6-[3-bromo~5-chloro~4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- 10 one [Chern. 256] To the mixture of 6-(3-Bromo-5-chloro-4-hydroxyphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 87, 15 300 mg) was dissolved in ethanol-water (4 : 1, 10 mL) were added l-chloro-2-methyl-2-propanol (0.388 mL) and potassium Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 233 carbonate (522 mg). The reaction mixture was refluxed for 8 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 67 : 33 to 33 : 67). The obtained solid was recrystallized from 2-propanol to afford the title compound as a white powder (107 mg). Melting point : 176.6-178.2°C

[0355] The following compounds were prepared from each appropriate starting material in a similar manner to Example 1. (Example 2) 6-[3,5-Dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5- methyl~4,5-dihydro-2H-pyridazin-3-one [Chem. 257] 'H-NMR (DMSO-d6) 6: 1.05 (3H, d, J = 7.3 Hz), 1.29 (6H, s), 2.24 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J = 16.7, 7.0 Hz), 234 3.37-3.49 (1H, m), 3.75 (2H, s), 4.68 (1H, brs), 7.82 (2H, s), 11.09 (1H, s). [0356] (Sxample 3) 5 6-[3-Chloro-2-fluoro-4-(2-hydroxyethoxy)phenyl]-5-methyl- 4,5—dxhydro—2H—pyrxdazxn—3—one [Chem. 258] ir-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.25 (1H, dd, 10 J = 16.7, 3.5 Hz), 2.69 (1H, dd, J = 16.7, 6.7 Hz), 3.10- 3.20 (1H, m), 3.76 (2H, dt, J - 5.4, 5.0 Hz), 4.17 (2H, t, J= 5.0 Hz), 4.91 (1H, t, J = 5.4 Hz), 7.10 (1H, dd, J = 8.9, 1.5 Hz), 7.53 (1H, t, J = 8.9 Hz), 11.01 (1H, s). [0357] 15 (Example 4) 6-[3—Chloro-4-(2-hydroxyethoxy)-5-methylphenyl]-5-methyl- 4,5~dihydro~2H-pyridazin-3-one [Chem. 259] Date Reçue/Date Received 2023-06-16 235 Melting point: 157.4-157.6°C [0358] (Example 5) 5 Production of 6-[3-chloro~2-fluoro-4-(3-hydroxy-2,2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one [Chern. 260] 10 A suspension of 6-(3-chloro-2-fluoro-4-hydroxyphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 89, 302 mg), 3-bromo-2,2-dimethyl-l-propanol (0.434 mL), and cesium carbonate (767 mg) in NMP (3 mL) was stirred at 130°C under microwave irradiation for one hour. The reaction 15 mixture was poured into water, and the mixture was extracted Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 236 with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by amino silica gel column chromatography (heptane : ethyl acetate = 50 : 50 to 0 : 100 to ethyl acetate : methanol = 90 : 10), and the desired fractions were concentrated. The residue was crystallized from ethyl acetate, and the precipitates were collected on a filter to afford the title compound as a white powder (37 mg). iH-NMR (DMSO-d6) 5: 0.96 (6H, s), 1.04 (3H, d, J = 7.1 Hz), 2.25 (1H, dd, J = 16.9, 3.7 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.11-3.18 (1H, m), 3.31 (2H, d, J = 5.4 Hz), 3.86 (2H, s), 4.65 (1H, t, J = 5.4 Hz), 7.06 (1H, dd, J = 8.8, 1.5 Hz), 7.53 (1H, t, J = 8.8 Hz), 11.01 (1H, s).

[0359] The following compounds were prepared from each appropriate starting material in a similar manner to Example 5. (Example 6) 6-[3,5-Difluoro-4-(3-hydroxy~2,2-dimethylpropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 2611 237 1H-NMR (DMS0-d6) ô: 0.93 (6H, s), 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.7 Hz), 2.68 (1H, dd, J = 16.7, 7.0 Hz), 3.27 (2H, d, J = 5.3 Hz), 3.34-3.42 (1H, m), 3.92 (2H, s), 5 4.62 (1H, t, J = 5.3 Hz), 7.44-7.57 (2H, m), 11.05 (1H, s). [0360] (Example 7) 6-[3-Chloro-5-fluoro-4-(3-hydroxy-2,2- dimethyIpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- — -* *■ - —-*...n. — - < - »* - - -*■ »* 10 3-one [Chern. 262] lH-NMR (DMSO-d6) 5: 0.96 (6H, s), 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.9 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 15 3.29-3.34 (2H, m), 3.36-3.46 (1H, m), 3.92 (2H, d, J = 1.7 Date Reçue/Date Received 2023-06-16 238 Hz), 4.61 (1H, brs), 7.63 (1H, dd, J = 12.8, 2.1 Hz), 7.66- 7.68 (1H, m), 11.06 (1H, s). [0361] (Example 8) 5 6-[2-Fluoro-4-(3-hydroxy-2,2-dimethylpropoxy)-3- methylpheny1]—5—methyl—4,5—dihydro—2H—pyrxdazxn—3—one [Chem. 263] iH-NMR (DMS0-d6) 5: 0.95 (6H, s), 1.03 (3H, d, J = 7.2 Hz), 10 2.11 (3H, d, J = 2.2 Hz), 2.22 (1H, dd, J - 16.7, 3.7 Hz), 2.66 (1H, dd, J = 16.7, 6.7 Hz), 3.07-3.16 (1H, m), 3.29- 3.32 (2H, m), 3.75 (2H, s), 4.63 (1H, t, J = 5.4 Hz), 6.84 (1H, d, J = 8.5 Hz), 7.37 (1H, t, J = 8.5 Hz), 10.91 (1H, s)• 15 [0362] (Example 9) 6-[2,3-Difluoro-4-(3-hydroxy-2,2-dimethylpropoxy)phenyl]-5- methyl-4,5-dihydro~2H-pyridazin-3-one [Chem. 264] Date Reçue/Date Received 2023-06-16 239 1H-NMR (DMS0-d6) 5: 0.94 (6H, s), 1.05 (3H, d, J = 7.3 Hz), 2.25 (1H, dd, J = 16.7, 3.3 Hz), 2.70 (1H, dd, J = 16.7, 7.0 Hz), 3.10-3.22 (1H, m), 3.28 (2H, d, J = 5.4 Hz), 3.85 (2H, 5 s), 4.67 (1H, t, J = 5.4 Hz), 7.03-7.14 (1H, m), 7.30-7.45 (1H, m), 11.02 (1H, s). [0363] (Example 10) 6-[2,3-Difluoro-4-(3-hydroxypropoxy)phenyl]-5-methyl-4,5- 10 dihydro-2H-pyridazin-3-one [Chern. 265] hH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.1 Hz), 1.84-1.95 (2H, m), 2.25 (1H, dd, J = 16.9, 3.3 Hz), 2.70 (1H, dd, J = 16.9, 15 6.8 Hz), 3.09-3.23 (1H, m), 3.49-3.64 (2H, m), 4.20 (2H, t, J = 6.3 Hz), 4.59 (1H, t, J = 5.1 Hz), 7.03-7.15 (1H, m), 7.34-7.44 (1H, m), 11.03 (1H, s). Date Reçue/Date Received 2023-06-16 240 [0364] (Example 11) 6-[3-Bromo-5-fluoro-4- (3-hydroxypropoxy) phenyl]-5-methy1- 4, 5-dxhydro-2H-pyridazin-3-one 'H-NMR (DMSO-d6) 6: 1.04 (3H, d, J = 7.3 Hz), 1.82-1.92 (2H, m) , 2.23 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 Hz), 3.35-3.45 (1H, m) , 3.55-3.64 (2H, m), 4.16-4.24 (2H, 10 m) , 4.54 (1H, t, J = 4.8 Hz), 7.67 (1H, dd, J = 12.7, 2.1 Hz), 7.82 (1H, t, J = 2.1 Hz), 11.07 (1H, s) . [0365] (Exantple 12) 6-[3-Bromo-2-fluoro~4- (3-hydroxypropoxy) phenyl]-5-methyl- 15 4, 5—dxhydro—2H—pyrxdazxn—3—one [Chern. 267] Date Reçue/Date Received 2023-06-16 241 1H-NMR (LMS0-d6) ô: 1.04 (3H, d, J = 7.2 Hz), 1.85-1.95 (2H, m), 2.24 (1H, dd, J - 16.9, 3.7 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.09-3.19 (1H, m), 3.56-3.64 (2H, m), 4.20 (2H, t, 5 J = 6.2 Hz), 4.58 (1H, t, J = 5.2 Hz), 7.04 (1H, dd, J- 8.9, 1.0 Hz), 7.58 (1H, t, J = 8.9 Hz), 11.02 (1H, s). [0366] (Example 13) 6-[3,5-Difluoro-4-(3-hydroxypropoxy)phenyl]-5-methyl-4,5- 10 dihydro-2H-pyridazin-3-one [Chern. 268] iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.77-1.89 (2H, m), 2.24 (1H, d, J = 16.7 Hz), 2.68 (1H, dd, J = 16.7, 7.0 15 Hz), 3.33-3.47 (1H, m), 3.51-3.62 (2H, m), 4.23 (2H, t, J = Date Reçue/Date Received 2023-06-16 242 6.3 Hz), 4.53 (1H, t, J = 5.0 Hz), 7.45-7.61 (2H, m) , 11.06 (1H, s) . [0367] (Sxajn.ple 14) 5 6- [ 4- (3-Hydroxypropoxy) -3,5-dimethylphenyl]-5-methyl-4,5- dihydro—2H—pyrxdazxn—3—one [Chem. 269] ir-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 1.84-1.93 (2H, 10 m), 2.21 (1H, d, J = 16.8 Hz), 2.24 (6H, s), 2.64 (1H, dd, J - 16.8, 6.9 Hz), 3.30-3.40 (1H, m), 3.58-3.66 (2H, m) , 3.82 (2H, t, J = 6.4 Hz) , 4.50 (1H, t, J = 5.1 Hz) , 7.44 (2H, s) , 10.86 (1H, s). [0368] 15 (Example 15) 6- [3-Chloro-5-f luoro-4- (3-hydroxypropoxy) phenyl]-5-methyl- 4, 5~dihydro~2H-pyridazin-3-one [Chem. 270] Date Reçue/Date Received 2023-06-16 243 1H-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.80-1.92 (2H, m), 2.24 (1H, d, J = 16.9 Hz), 2.69 (1H, dd, J = 16.9, 7.0 Hz), 3.35-3.47 (1H, m), 3.52-3.64 (2H, m), 4.14-4.26 (2H, 5 m), 4.53 (1H, t, J = 5.1 Hz), 7.60-7.72 (2H, m), 11.06 (1H, S). [0369] (Example 16) 6-[3,5-Dichloro~4-(3-hydroxypropoxy)phenyl]-5-methyl-4,5- 10 dihydro-2H-pyridazin-3-one [Chern. 271] 1H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.87-1.98 (2H, m), 2.23 (1H, d, J = 17.0 Hz), 2.69 (1H, dd, J = 17.0, 7.0 15 Hz), 3.36-3.49 (1H, m), 3.57-3.66 (2H, m), 4.10 (2H, t, J = 6.5 Hz), 4.53 (1H, t, J = 5.1 Hz), 7.82 (2H, s), 11.08 (1H, Date Reçue/Date Received 2023-06-16 244 s). [0370] (Example 17) 6-[3-Chloro-4-(3-hydroxypropoxy)-5-methylphenyl]-5-methyl- 5 4,5-dihydro-2H-pyridazin-3-one [Chern. 272] Melting point: 129.7-132.6°C [0371] 10 (Example 18) 6-[3-Bromo-5-chloro-4-(3-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chern. 273] 15 Melting point: 153.0-156.6°C Date Reçue/Date Received 2023-06-16 245 [0372] (Example 19) 6-[3-Chloro-2-fluoro-4-(3-hydroxypropoxy)phenyl]-5-methyl- 4,5-dxhydro-2H-pyridazin-3-one 5 [Chem. 274] 'H-NMR (DMSO-d6) 6: 1.04 (3H, d, J = 7.3 Hz), 1.87-1.93 (2H, m), 2.25 (1H, dd, J - 16.7, 3.5 Hz), 2.70 (1H, dd, J = 16.7, 6.7 Hz), 3.10-3.19 (1H, m), 3.56-3.62 (2H, m), 4.21 (2H, t, 10 J = 6.3 Hz), 4.59 (1H, t, J = 5.1 Hz), 7.09 (1H, dd, J = 8.8, 1.5 Hz), 7.55 (1H, t, J = 8.8 Hz), 11.02 (1H, s). [0373] (Example 20) 6-[3-Fluoro-4-(3-hydroxypropoxy)-5-methylphenyl]-5-methyl- 15 4,5—dxhydro—2H—pyrxdazxn—3—one Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 246 iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 1.80-1.90 (2H, m), 2.22 (1H, d, J = 16.8 Hz), 2.27 (3H, s), 2.66 (1H, dd, J = 16.8, 6.9 Hz), 3.31-3.41 (1H, m), 3.55-3.62 (2H, m), 4.06-4.13 (2H, m), 4.52 (1H, t, J = 5.1 Hz), 7.40-7.48 (2H, m), 10.95 (1H, s). [0374] (Example 21) 6-[2-Fluoro-4-(3-hydroxypropoxy)-3-methylphenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chem. 276] !H-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.2 Hz), 1.84-1.93 (2H, m), 2.08 (3H, d, J = 2.2 Hz), 2.22 (1H, dd, J = 16.8, 3.7 Hz), 2.66 (1H, dd, J = 16.8, 6.7 Hz), 3.07-3.17 (1H, m), 3.55-3.63 (2H, m), 4.10 (2H, t, J = 6.2 Hz), 4.56 (1H, t, J = 5.2 Hz), 6.87 (1H, d, J = 8.8 Hz), 7.38 (1H, t, J = 8.8 Hz), 10.92 (1H, s). [0375] (Example 22) 6-[3—Chloro-2-fluoro-4-(3-hydroxypropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one 247 [Chem. 277] 1H-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 1.87-1.96 (2H, m), 2.22-2.29 (1H, m), 2.27 (3H, s), 2.69 (1H, dd, J= 16.8, 5 6.8 Hz), 3.09-3.19 (1H, m), 3.59-3.66 (2H, m), 4.02 (2H, t, J = 6.5 Hz), 4.54 (1H, t, J = 5.1 Hz), 7.43 (1H, d, J = 8.7 Hz), 11.07 (1H, s). [0376] (Example 23) 10 6-[3-Ethyl-2-fluoro-4-(3-hydroxypropoxy)phenyl]-5~methyl- 4,5-dihydro-2H-pyridazin-3-one [Chem. 278] lH-NMR (CDC13) 5: 1.15 (3H, t, J = 7.6 Hz), 1.19 (3H, d, J = 15 7.3 Hz), 1.56-1.62 (1H, m), 2.09 (2H, quintet, J = 6.1 Hz), 2.41 (1H, dd, J = 16.9, 3.4 Hz), 2.63-2.78 (3H, m), 3.21- Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 248 3.33 (1H, m), 3.85-3.93 (2H, m), 4.16 (2H, t, J = 6.1 Hz), 6.70 (1H, d, J = 8.3 Hz), 7.33-7.38 (1H, m), 8.49 (1H, brs). [0377] (Example 24) Production of 6-[3-“bromo-2“-fluoro (2-hydroxy-2- mesthyIpropoxy)ph@ny11 “"“S^nusthyl » 5“dihydro“2H*"oyridcizm*”3 one [Chern. 279] Under an argon atmosphere, to a solution of 6-[3-bromo-2- fluoro-4-(2-oxopropoxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one (Reference example 114, 357 mg) in THF (10 mL) was added dropwise methylmagnesium bromide (3 M diethyl ether solution, 1.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 23 hours. The reaction mixture was cooled at 0°C, aqueous ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 5 10 15 20 Date Reçue/Date Received 2023-06-16 249 33 : 67 to 6 : 94). The obtained solid was washed by trituration with diisopropyl ether, and then collected on a filter to afford the title compound as a white solid (18 mg). ’H-NMR (DMSO-d6) 5: 1.04 (3E, d, J = 7.3 Hz), 1.25 (6H, s), 2.24 (1H, dd, J = 16.8, 3.7 Hz), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.09-3.19 (1H, m), 3.86 (2H, s), 4.70 (1H, s), 7.03 (1H, dd, J = 8.9, 1.2 Hz), 7.57 (1H, t, J = 8.9 Hz), 11.01 (1H, s).

[0378] The following compounds were prepared from each appropriate starting material in a similar manner to Example 24. (Example 25) 6-[3-Chloro-5-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 280] ’H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.25 (6H, s), 2.24 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J = 16.7, 7.0 Hz), 3.35-3.45 (1H, m), 3.87 (2H, d, J = 1.2 Hz), 4.64 (1H, s), 7.64 (1H, dd, J = 12.7, 2.2 Hz), 7.68 (1H, t, J = 2.2 Hz), 250 11.06 (1H, s). [0379] (Example 26) 6-[3-Bromo-5-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5- 5 methyl-4,5-dihydro-2H-pyridazin-3-one [ In ] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.26 (6H, s), 2.23 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 Hz), 10 3.34-3.45 (1H, m), 3.86 (2H, d, J = 1.3 Hz), 4.64 (1H, s), 7.67 (1H, dd, J = 12.9, 2.1 Hz), 7.81 (1H, t, J = 2.1 Hz), 11.06 (1H, s). [0380] (Example 27) 15 Production of 6-[2,3-difluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 282] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 251 A suspension of 6-(2,3-difluoro-4-hydroxyphenyl)-5-methyl- 4,5-dihydro-2H~pyridazin-3-one (480 mg), 2,2- dimethyloxirane (0.231 mL), and potassium carbonate (415 mg) in DMF (3 mL) was stirred at 160°C under microwave irradiation for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 60 : 40 to 33 : 67). The obtained solid was washed by trituration with diisopropyl ether, and then collected on a filter to afford the title compound as a white solid (326 mg). m-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.21 (6H, s), 2.25 (1H, dd, J = 16.9, 3.4 Hz), 2.70 (1H, dd, J = 16.9, 6.7 Hz), 3.11-3.21 (1H, m), 3.87 (2H, s), 4.71 (1H, s), 7.06- 7.13 (1H, m), 7.34-7.41 (1H, m), 11.02 (1H, s). [0381] 252 The following compounds were prepared from each appropriate starting material in a similar manner to Example 27. (Example 28) 6-[2-Hydroxy-4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl]- 5-meLhyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 283] ir-NMR (DMSO-d6) 5: 1.10 (3H, d, J = 7.3 Hz), 1.23 (6H, s), 2.05 (3H, s), 2.23-2.31 (1H, m), 2.76 (1H, dd, J = 16.7, 6.7 10 Hz), 3.47-3.57 (1H, m), 3.74 (2H, s), 4.65 (1H, s), 6.55 (1H, d, J = 9.0 Hz), 7.42 (1H, d, J = 9.0 Hz), 11.03 (1H, s), 12.46 (1H, s). [0382] (Example 29) 15 6-[3—Chloro-2-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 284] Date Reçue/Date Received 2023-06-16 253 1H-NMR (DMS0-d6) ô: 1.04 (3H, d, J = 7.3 Hz), 1.24 (6H, s), 2.25 (1H, dd, J = 16.9, 3.7 Hz), 2.70 (1H, dd, J = 16.9, 6.7 Hz), 3.09-3.20 (1H, m), 3.87 (2H, s), 4.71 (1H, s), 7.06- 5 7.11 (1H, m), 7.53 (1H, t, J = 8.8 Hz), 11.02 (1H, s). [0383] (Example 30) 6-[3,5-Difluoro~4-(2-hydroxy-2-methylpropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one 10 [Chern. 285] ’H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.20 (6H, s), 2.20-2.27 (1H, m), 2.68 (1H, dd, J = 16.7, 7.0 Hz), 3.33- 3.43 (1H, m), 3.89 (2H, s), 4.61 (1H, s), 7.46-7.55 (2H, m), 15 11.05 (1H, s). [0384] Date Reçue/Date Received 2023-06-16 254 (Example 31) 6-[3-Chloro-4-(2-hydroxy-2-methylpropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 286] 'H-NMR (DMS0-d6) 6: 1.05 (3H, d, J = 7.3 Hz), 1.28 (6H, s), 2.19-2.26 (1H, m), 2.33 (3H, s), 2.67 (1H, dd, J =16.9, 6.8 Hz), 3.33-3.43 (1H, m), 3.64 (2H, s), 4.64 (1H, s), 7.58- 7.67 (2H, m), 10.98 (1H, s). 10 [0385] (Example 32) 6-[4-(2-Hydroxy~2-methylpropoxy)-3,5-dimethylphenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 287] Date Reçue/Date Received 2023-06-16 255 iH-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.4 Hz), 1.27 (6H, s), 2.21 (1H, d, J = 16.7 Hz), 2.26 (6H, s), 2.64 (1H, dd, J = 16.7, 6.8 Hz), 3.32-3.40 (1H, m), 3.46-3.52 (2H, m), 4.60 (1H, s), 7.45 (2H, s), 10.87 (1H, s). 5 [0386] (Example 33) 6-[3—Fluoro-4-(2-hydroxy-2-methylpropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro~2H-pyridazin-3-one [Chem. 288] 10 !H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 1.23 (6H, s), 2.22 (1H, d, J = 16.7 Hz), 2.30 (3H, s), 2.66 (1H, dd, J = 16.7, 6.8 Hz), 3.31-3.42 (1H, m), 3.77 (2H, d, J = 1.5 Hz), 4.61 (1H, s), 7.41-7.49 (2H, in), 10.95 (1H, s). 15 [0387] (Example 34) 6-[2—Fluoro-4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl]- 5~methyl~4,5-dihydro~2H-pyridazin-3-one [Chem. 289] Date Reçue/Date Received 2023-06-16 256 1H-NMR (DMS0-d6) ô: 1.03 (3H, d, J = 7.2 Hz), 1.23 (6H 2.13 (3H, d, J = 2.2 Hz), 2.23 (1H, dd, J = 16.7, 3.7 2.66 (1H, dd, J = 16.7, 6.7 Hz), 3.06-3.18 (1H, m), 3.76 5 s), 4.68 (1H, s), 6.84 (1H, d, J = 8.7 Hz), 7.37 (1H, = 8.7 Hz), 10.92 (1H, s). [0388] (Example 35) 6-[5-Chloro-2-fluoro-4-(2-hydroxy-2-methylpropoxy)-3- 10 methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3~one [Chern. 290] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 1.28 (6H 2.21-2.29 (1H, m), 2.24 (3H, d, J = 2.4 Hz), 2.68 (1H, 15 J = 16.8, 6.8 Hz), 3.08-3.19 (1H, m), 3.67 (2H, s), 4.69 s), 7.52 (1H, d, J = 7.9 Hz), 11.06 (1H, s). s), Hz), (2H, t, J s), dd, (1H, Date Reçue/Date Received 2023-06-16 257 [0389] (Example 36) 6-[3-Chloro-2-fluoro-4-(2-hydroxy-2-methylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one 5 [Chem. 291] 'H-NMR (DMSO-d6) 6: 1.05 (3H, d, J = 7.2 Hz), 1.28 (6H, s), 2.25 (1H, dd, J = 16.9, 3.8 Hz), 2.29 (3H, s), 2.69 (1H, dd, J =16.8, 6.8 Hz), 3.09-3.20 (1H, m), 3.68 (2H, s), 4.67 (1H, 10 s), 7.43 (1H, d, J = 8.4 Hz), 11.07 (1H, s). [0390] (Example 37) 6-{3—Chloro-5-fluoro-4-[3,3,3-trifluoro-2-hydroxy-2- (trifluoromethyl)propoxy]phenyl]-5-methyl-4,5-dihydro-2H- 15 pyridazin-3-one [Chem. 292] Date Reçue/Date Received 2023-06-16 258 ^-NMR. (DMS0-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.7 Hz), 2.70 (1H, dd, J = 16.7, 7.0 Hz), 3.36-3.47 (1H, m), 4.48 (2H, s), 7.66-7.74 (2H, m), 8.46 (1H, brs), 11.11 5 (1H, s). [0391] (Example 38) 6-{3-Bromo-5-fluoro-4-[3,3,3-trifluoro-2-hydroxy-2- (trifluoromethyl)propoxy]phenyl}-5-methyl-4,5-dihydro-2H- 10 pyridazin-3-one [Chem. 293] F F 'H-NMR (DMSO-d6) ô: 1.04 (3H, d, J = 7.3 Hz), 2.19-2.30 (1H, m), 2.70 (1H, dd, J = 16.7, 7.0 Hz), 3.35-3.48 (1H, m), 4.47 Date Reçue/Date Received 2023-06-16 259 (2H, s), 7.72 (1H, dd, J= 12.7, 2.2 Hz), 7.82-7.86 (1H, m), 8.44 (1H, s), 11.10 (1H, s). [0392] (Example 39) 5 6-{3-Chloro-4-[(2S)-2-hydroxypropoxy]-5-methylphenyl}-5- methyl-4,5—dxhydro—2H—pyrxdazxn—3—one [Chem. 294] iH-NMR (CDC13) S: 1.24 (3H, d, J = 7.3 Hz), 1.28 (3H, d, J = 10 6.6 Hz), 2.36 (3H, s), 2.47 (1H, dd, J =16.9, 1.2 Hz), 2.61 (1H, d, J = 3.4 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.23- 3.34 (1H, m), 3.77-3.83 (1H, m), 3.91-3.96 (1H, m), 4.20- 4.31 (1H, m), 7.49 (1H, d, J = 2.2 Hz), 7.61 (1H, d, J = 2.2 Hz), 8 « 62 (1H, a)» 15 [0393] (Example 40) 6-{3—Chloro-4-[(2R)-2-hydroxypropoxy]-5-methylphenyl}-5- methyl-4,5-dxhydro~2H-pyridazin-3-one [Chem. 295] Date Reçue/Date Received 2023-06-16 260 ^-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.1 Hz), 1.19 (3H, d, J = 6.4 Hz), 2.20-2.26 (1H, m), 2.33 (3H, s), 2.66 (1H, dd, J = 16.9, 6.8 Hz), 3.32-3.42 (1H, m), 3.67-3.83 (2H, m), 3.92- 5 4.03 (1H, m), 4.86 (1H, brs), 7.60 (1H, d, J = 2.0 Hz), 7.65 (1H, d, J = 2.0 Hz), 10.98 (1H, s). [0394] (Example 41) Production of 6-{3~chloro-5-fluoro-4-[(1- 10 hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chern. 296] To a mixture of methyl 4-{3-chloro-5-fluoro-4-[(1- 15 hydroxycyclopropyl)methoxy]phenyl}-3-methyl-4-oxobutanoate (Reference example 55, 352 mg) in ethanol (10 mL) were added Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 261 hydrazine monohydrate (0.149 mL) and acetic acid (0.175 mL), and then the mixture was refluxed for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organxc layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 25 : 75 to 0 : 100), and the desired fractions were concentrated. The residue was recrystallized from 2- propanol to afford the title compound as a white solid (91 mg). iH-NMR (DMSO-d6) 5: 0.61-0.73 (4H, m), 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J = 16.7, 7.0 Hz), 3.35-3.46 (1H, m), 4.10 (2H, s), 5.54 (1H, s), 7.63 (1H, dd, J = 12.5, 2.2 Hz), 7.66-7.69 (1H, m), 11.06 (1H, s). [0395] The following compounds were prepared from each appropriate starting material in a similar manner to Example 41. (Example 42) 6-{2,3-Difluoro-4-[(1-hydroxycyclopropyl)methoxy]phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 297] 262 1H-NMR (DMS0-d6) ô: 0.61-0.75 (4H, m), 1.05 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J = 16.8, 3.4 Hz), 2.70 (1H, dd, J = 16.8, 6.8 Hz), 3.12-3.22 (1H, m), 4.12 (2H, s), 5.65 (1H, s), 7.05- 5 7.13 (1H, m), 7.33-7.41 (1H, m), 11.02 (1H, s). [0396] (Example 43) 6-{4~[(1-Hydroxycyclopropyl)methoxy]-3,5-dimethylphenyl}-5- methyl-4,5-dihydro-2H-pyridazin-3-one 10 [Chern. 298] m-NMR (DMSO-d6) 5: 0.58-0.72 (4H, m), 1.05 (3H, d, J = 7.3 Hz), 2.21 (1H, d, J = 16.8 Hz), 2.27 (6H, s), 2.64 (1H, dd, J =16.8, 6.9Hz), 3.30-3.39 (1H, m), 3.74 (2H, s), 5.62 (1H, 15 s), 7.44 (2H, s), 10.86 (1H, s). [0397] Date Reçue/Date Received 2023-06-16 263 (Example 44) 6-{3-Chloro-4-[(1-hydroxycyclopropyl)methoxy]-5- methylphenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 299] iR-NMR (DMSO-d6) 5: 0.60-0.74 (4H, m), 1.05 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.7 Hz), 2.36 (3H, s), 2.67 (1H, dd, J =16.7, 7.0 Hz), 3.32-3.43 (1H, m), 3.90 (2H, s), 5.62 (1H, s), 7.59 (1H, d, J = 2.1 Hz), 7.65 (1H, d, J = 2.1 Hz), 10.97 10 (1H, s). [0398] (Example 45) 6-{3-Fluoro-4-[(1-hydroxycyclopropyl)methoxy]-5- methylphenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one 15 [Chern. 300] Date Reçue/Date Received 2023-06-16 264 1H-NMR (DMS0-d6) ô: 0.55-0.70 (4H, m), 1.05 (3H, d, J = 7.2 Hz), 2.22 (1H, d, J = 16.8 Hz), 2.33 (3H, s), 2.66 (1H, dd, J =16.8, 6.8 Hz), 3.32-3.42 (1H, m), 4.00 (2H, s), 5.53 (1H, 5 s), 7.40-7.48 (2H, m), 10.95 (1H, s). [0399] (Example 46) 6-{2-Fluoro-4-[(l-hydroxycyclopropyl)methoxy]-3- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one 10 [Chern. 301] ’H-NMR (DMSO-d6) 5: 0.60-0.75 (4H, m), 1.03 (3H, d, J = 7.2 Hz), 2.13 (3H, d, J = 2.2 Hz), 2.22 (1H, dd, J = 16.8, 3.7 Hz), 2.66 (1H, dd, J = 16.8, 6.7 Hz), 3.07-3.18 (1H, m), 15 4.03 (2H, s), 5.60 (1H, s), 6.86 (1H, d, J = 8.7 Hz), 7.35 (1H, t, J = 8.7 Hz), 10.92 (1H, s). Date Reçue/Date Received 2023-06-16 265 [0400] (Example 47) 6-{3-Chloro-2-fluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro-2H- 5 pyridazin-3-one [Chem. 302] iH-NMR (DMSO-d6) 5: 0.61-0.76 (4H, m), 1.04 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J = 16.7, 3.7 Hz), 2.70 (1H, dd, J = 16.7, 10 6.8 Hz), 3.10-3.19 (1H, m), 4.15 (2H, s), 5.61 (1H, s), 7.10 (1H, dd, J = 9.0, 1.3 Hz), 7.52 (1H, t, J = 9.0 Hz), 11.03 (1H, s). [0401] (Example 48) 15 Production of 6-[3-bromo-2—fluoro-4-(2- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 303] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 266 To a mixture of 6-[3-bromo-2-fluoro-4-(2-oxopropoxy)phenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 114, 321 mg) in methanol (4.5 mL) was added sodium borohydride (68 mg) at 0°C, and then the mixture was stirred at the same temperature for one hour. To the reaction mixture were added water and brine, and then the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained solid was washed by trituration with diisopropyl ether, and then collected on a filter to jC l?' tii(.1« compound as a white solid (270 mg). iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 1.20 (3H, d, J = 6.0 Hz), 2.24 (1H, dd, J = 16.8, 3.7 Hz), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.09-3.19 (1H, m), 3.88-4.08 (3H, m), 4.92 (1H, d, J = 4.6 Hz), 7.04 (1H, dd, J = 8.9, 1.1 Hz), 7.57 (1H, t, J = 8.9 Hz), 11.01 (1H, s). [0402] The following compounds were prepared from each appropriate starting material in a similar manner to Example 48. 267 (Example 49) 6-[2,3-Difluoro-4-(2-hydroxypropoxy)phenyl]-5-methyl~4,5- dihydro-2H-pyridazin-3-one [Chem. 304] 'H-NMR (DMSO-d6) 6: 1.05 (3H, d, J = 7.1 Hz), 1.16 (3H, d, J = 6.1 Hz), 2.25 (1H, dd, J = 16.9, 3.2 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.10-3.22 (1H, m), 3.91-4.05 (3H, m), 4.96 (1H, d, J = 4.6 Hz), 7.05-7.14 (1H, m), 7.33-7.42 (1H, m), 10 11.03 (1H, s). [0403] (Example 50) 6-[3-Bromo-5-fluoro~4-(2-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin~3-one 15 [Chem. 305] Date Reçue/Date Received 2023-06-16 268 1H-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 1.20 (3H, d, J = 6.1 Hz), 2.23 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 Hz), 3.35-3.45 (1H, m), 3.83-4.07 (3H, m), 4.86 (1H, d, 5 J = 4.8 Hz), 7.67 (1H, dd, J = 12.7, 2.1 Hz), 7.81 (1H, t, J = 2.1 Hz), 11.06 (1H, s). [0404] (Example 51) 6-[4-(2-Hydroxypropoxy)-3,5-dimethylphenyl]-5-methyl-4,5- 10 dihydro-2H-pyridazin-3-one [Chern. 306] *H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.4 Hz), 1.19 (3H, d, J = 6.3 Hz), 2.21 (1H, d, J = 16.7 Hz), 2.26 (6H, s), 2.64 (1H, 15 dd, J = 16.7, 6.8 Hz), 3.29-3.40 (1H, m), 3.54-3.66 (2H, m), Date Reçue/Date Received 2023-06-16 269 3.91-4.01 (1H, m), 4.85 (1H, d, J = 4.9 Hz), 7.44 (2H, s), 10.86 (1H, s). [0405] (Sxample 52) 5 6-[3-Chloro-5-fluoro-4-(2-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chem. 307] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.18 (3H, d, J 10 = 5.9 Hz), 2.24 (1H, d, J = 16.9 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.35-3.46 (1H, m), 3.81-4.06 (3H, m), 4.86 (1H, d, J =4.6 Hz), 7.58-7.72 (2H, m), 11.06 (1H, s). [0406] (Kxample 53) 15 6-[3,5-Pichloro-4-(2-hydroxypropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chem. 308] Date Reçue/Date Received 2023-06-16 270 1H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.21 (3H, d, J = 6.1 Hz), 2.24 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J = 16.7, 7.0Hz), 3.37-3.47 (1H, m), 3.74-3.81 (1H, m), 3.89-3.96 (1H, 5 m), 3.97-4.07 (1H, m), 4.89 (1H, d, J = 4.9 Hz), 7.82 (2H, s), 11.09 (1H, s). [0407] (Example 54) 6-[3-Chloro-2-fluoro-4-(2-hydroxypropoxy)phenyl]-5-methyl- 10 4,5-dihydro-2H-pyridazin-3-one [Chern. 309] *H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.18 (3H, d, J = 6.1 Hz), 2.25 (1H, dd, J = 16.9, 3.7 Hz), 2.70 (1H, dd, J 15 = 16.9, 6.8 Hz), 3.10-3.19 (1H, m), 3.91-4.05 (3H, m), 4.93 Date Reçue/Date Received 2023-06-16 271 (1H, d, J = 4.6 Hz), 7.09 (1H, dd, J = 8.8, 1.2 Hz), 7.53 (1H, t, J = 8.8 Hz), 11.02 (1H, s). [0408] (Example 55) 5 6-[3-Chloro-4-(2-hydroxypropoxy)-5-methylphenylJ -5-methyl- 4,5—dxhydro—2H—pyrxdazxn—3—one [Chem. 310] iH-NMR (CDC13) 5: 1.24 (3H, d, J = 7.3 Hz), 1.28 (3H, d, J = 10 6.4Hz), 2.36 (3H, s), 2.47 (1H, dd, J =16.8, 1.0 Hz), 2.61 (1H, d, J = 3.7 Hz), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.23- 3.33 (1H, m), 3.77-3.83 (1H, m), 3.92-3.96 (1H, m), 4.19- 4.31 (1H, m), 7.49 (1H, dd, J = 2.2, 0.5 Hz), 7.61 (1H, d, J = 2.2 Hz), 8.67 (1H, brs). 15 [0409] (Example 56) 6-[3-Fluoro-4-(2-hydroxypropoxy)-5-methylphenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chem. 311] Date Reçue/Date Received 2023-06-16 272 1H-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.16 (3H, d, J = 6.1 Hz), 2.22 (1H, d, J = 16.7 Hz), 2.29 (3H, s), 2.66 (1H, dd, J= 16.7, 6.8 Hz), 3.30-3.42 (1H, m), 3.80-3.97 (3H, m), 5 4.83 (1H, d, J = 4.6 Hz), 7.40-7.50 (2H, m), 10.95 (1H, s). [0410] (Example 57) 6-[3-Bromo-5-chloro-4-(2-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one 10 [Chern. 312] iH-NMR (CDC13) 5: 1.24 (3H, d, J = 7.3 Hz), 1.28 (3H, d, J = 6.4 Hz), 2.49 (1H, dd, J- 17.1, 1.0 Hz), 2.66-2.75 (2H, m), 3.20-3.31 (1H, m), 3.88-3.94 (1H, m), 4.10-4.14 (1H, m), 15 4.21-4.34 (1H, m), 7.74 (1H, d, J = 2.2 Hz), 7.87 (1H, d, J Date Reçue/Date Received 2023-06-16 273 =2.2 Hz), 8.72 (1H, brs). [0411] (Example 58) 6-[2-Fluoro-4-(2-hydroxypropoxy)-3-methylphenyl]-5-methyl- 5 4,5-dihydro-2H-pyridazin-3-one [Ohem 313] ir-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.2 Hz), 1.18 (3H, d, J = 6.2 Hz), 2.11 (3H, d, J = 2.2 Hz), 2.22 (1H, dd, J = 16.8, 10 3.7 Hz), 2.66 (1H, dd, J = 16.8, 6.7 Hz), 3.06-3.18 (1H, m), 3.80-4.03 (3H, m), 4.89 (1H, d, J = 4.8 Hz), 6.86 (1H, d, J = 8.7 Hz), 7.36 (1H, t, J = 8.7 Hz), 10.92 (1H, s). [0412] (Example 59) 15 6-[2—Fluoro-4-(2-hydroxypropoxy)-3-vinylphenyl]-5-methyl- 4,5-dihydro~2H-pyridazin-3-one [Chem. 314] Date Reçue/Date Received 2023-06-16 274 1H-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.18 (3H, d, J = 6.1 Hz), 2.23 (1H, dd, J = 16.9, 3.9 Hz), 2.66 (1H, dd, J = 16.9, 6.8 Hz), 3.06-3.18 (1H, m), 3.86-4.06 (3H, m), 4.93 5 (1H, d, J = 4.6 Hz), 5.51-5.59 (1H, m), 6.02-6.10 (1H, m), 6.81 (1H, dd, J = 18.1, 12.0 Hz), 6.94 (1H, d, J = 8.8 Hz), 7.43 (1H, t, J = 8.8 Hz), 10.96 (1H, brs). [0413] (Example 60) 10 6-[3-Ethyl-2-fluoro-4-(2-hydroxypropoxy)phenyl]-5-methy1- 4,5-dihydro-2H-pyridazin-3-one [Chern. 315] iH-NMR (CDC13) 5: 1.16 (3H, t, J = 7.6 Hz), 1.20 (3H, d, J = 15 7.3 Hz), 1.32 (3H, d, J = 6.4 Hz), 2.13-2.18 (1H, m), 2.42 (1H, dd, J =16.9, 3.4 Hz), 2.66-2.78 (3H, m), 3.21-3.33 (1H, m), 3.84-3.91 (1H, m), 3.98 (1H, dd, J= 9.0, 3.4 Hz), 4.18- Date Reçue/Date Received 2023-06-16 275 4.30 (1H, m), 6.68 (1H, d, J = 8.5 Hz), 7.36 (1H, t, J = 8.5 Hz), 8.49 (1H, brs). [0414] (Example 61) 5 6-[2,3-Difluoro-4-(2-hydroxybutoxy)phenyl]-5-methyl-4,5- [Chem. 316] iH-NMR (DMSO-d6) 5: 0.93 (3H, t, J = 7.4 Hz), 1.05 (3H, d, J 10 = 7.1 Hz), 1.34-1.48 (1H, m), 1.50-1.63 (1H, m), 2.25 (1H, dd, J = 16.9, 3.3 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.09- 3.23 (1H, m), 3.67-3.78 (1H, m), 3.94-4.07 (2H, m), 4.93 (1H, d, J = 5.4 Hz), 7.06-7.14 (1H, m), 7.31-7.43 (1H, m), 11.02 (1H, s). 15 [0415] (Example 62) 6-[3—Chloro-5-fluoro-4-(2-hydroxybutoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chern. 317] Date Reçue/Date Received 2023-06-16 276 ^-NMR (DMS0-d6) 5: 0.92 (3H, t, J = 7.4 Hz), 1.04 (3H, d, J = 7.3 Hz), 1.34-1.50 (1H, m), 1.56-1.71 (1H, m), 2.24 (1H, d, J = 17.0 Hz), 2.69 (1H, dd, J = 17.0, 7.0 Hz), 3.35-3.46 5 (1H, m) , 3.63-3.75 (1H, m), 3.92-4.09 (2H, m), 4.82 (1H, d, J = 5.4 Hz), 7.57-7.72 (2H, m), 11.06 (1H, s). [0416] (Example 63) 6- [3,5-Dichloro-4-(2-hydroxybutoxy)phenyl]-5-methyl-4,5- 10 dihydro-2H-pyridazin-3-one [Chern. 318] iH-NMR (DMSO-d6) 5: 0.95 (3H, t, J = 7.4 Hz), 1.04 (3H, d, J - 7.3 Hz), 1.35-1.52 (1H, m), 1.60-1.76 (1H, m), 2.24 (1H, 15 d, J = 16.9 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.37-3.47 (1H, m), 3.71-3.81 (1H, m), 3.82-3.88 (1H, m), 3.89-3.96 (1H, Date Reçue/Date Received 2023-06-16 277 m), 4.85 (1H, d, J = 5.4 Hz), 7.82 (2H, s) , 11.08 (1H, s) . [0417] (Example 64) 6- [ 3—Chloro-2-f luoro-4- (2-hydroxybutoxy) phenyl]-5-methyl- 5 _4z_52^ih^xO22H2^Yridaziri232One [Chern. 319] OH iH-NMR (DMSO-d6) 5: 0.93 (3H, t, J = 7.4 Hz), 1.04 (3H, d, J = 7.1 Hz), 1.39-1.50 (1H, m) , 1.56-1.67 (1H, m) , 2.25 (1H, 10 dd, J = 16.7, 3.7 Hz) , 2.69 (1H, dd, J- 16.7, 6.7 Hz) , 3.10- 3.18 (1H, m) , 3.71-3.78 (1H, m) , 3.98-4.06 (2H, m) , 4.90 (1H, d, J = 5.4 Hz), 7.10 (1H, dd, J = 8.9, 1.5 Hz), 7.53 (1H, t, J =8.9 Hz), 11.02 (1H, s). [0418] 15 (Example 65) 6-[3-Chloro-4- (2-hydroxybutoxy) -5-methylphenyl]-5-methy1- 4, 5-dihydro-2H-pyridazin-3-one [Chem. 320] Date Reçue/Date Received 2023-06-16 278 ^-NMR. (CDCI3) 5: 1.04 (3H, t, J = 7.6 Hz), 1.24 (3H, d, J = 7.3 Hz), 1.61 (2H, quintet, J = 7.6 Hz), 2.36 (3H, s), 2.47 (1H, dd, J = 16.8, 1.0 Hz), 2.56 (1H, d, J = 3.9 Hz), 2.69 5 (1H, dd, J =16.8, 6.8 Hz), 3.23-3.34 (1H, m), 3.83-3.88 (1H, m), 3.93-4.04 (2H, m), 7.47-7.51 (1H, m), 7.61 (1H, d, J = 2.2 Hz), 8.65 (1H, brs). [0419] (Example 66) 10 6-[3-Bromo-5-chloro-4-(2-hydroxybutoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin~3-one [Chem. 321] 1H-NMR (CDC13) 5: 1.05 (3H, t, J = 7.3 Hz), 1.24 (3H, d, J = Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 279 7.3 Hz), 1.62 (2H, quintet, J = 6.8 Hz), 2.49 (1H, d, J = 16.9 Hz), 2.63-2.75 (2H, m), 3.20-3.31 (1H, m), 3.93-4.06 (2H, m), 4.10-4.18 (1H, m), 7.74 (1H, d, J = 2.2 Hz), 7.86 (1H, d, J = 2.2 Hz), 8.66 (1H, brs). [0420] (Example 67) 6-[2—Fluoro-4-(2-hydroxybutoxy)-3-vinylphenyl]-5-methyl- 4,5-dihydro-2H~pyridazin~3-one [Chem. 322] OH iH-NMR (CDC13) 5: 1.05 (3H, t, J = 7.3 Hz), 1.19 (3H, d, J = 7.3 Hz), 1.59-1.70 (2H, m), 2.15 (1H, d, J = 3.7 Hz), 2.42 (1H, dd, J = 17.1, 3.7 Hz), 2.73 (1H, dd, J = 17.1, 6.8 Hz), 3.21-3.33 (1H, m), 3.90-4.10 (3H, m), 5.53-5.61 (1H, m), 5.97—6.06 (1H, m), 6.69-6.75 (1H, m), 6.78 (1H, dd, J = 18.1, 12.0 Hz), 7.40 (1H, t, J = 8.8 Hz), 8.55 (1H, brs). [0421] (Example 68) Production of 6-[3-bromo-5-chloro-4-(3-hydroxy-2,2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin 5 10 15 20 Date Reçue/Date Received 2023-06-16 280 3-one [Chem. 323] Under an argon atmosphere, to a mixture of methyl 3-[2-bromo- 6-chloro-4-(4-methyl-6-oxo-4,5-dihydro-lH-pyridazin-3- yl)phenoxy]-2,2-dimethylpropionate (Reference example 129, 342 mg) in THF (10 mL) was slowly added diisobutylaluminum hydride (1 M n-hexane solution, 3.17 mL) at 0°C. The mixture was stirred at room temperature for 2 hours, hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 50 : 50 to 25 : 75). The obtained solid was recrystallized from 2-propanol to afford the title compound as a white powder (111 mg). Melting point : 198.0-199.7°C

[0422] The following compounds were prepared from each appropriate 281 starting material in a similar manner to Example 68. (Example 69) 6-[3-Bromo-5-fluoro-4-(3 * -hydroxy-2,* 2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one [Chern. 324] iH-NMR (DMS0-d6) 5: 0.98 (6H, s), 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.9 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 10 3.30-3.34 (2H, m), 3.34-3.45 (1H, m), 3.92 (2H, d, J = 1.8 Hz), 4.61 (1H, t, J = 5.3 Hz), 7.66 (1H, dd, J = 13.1, 2.2 Hz), 7.79-7.83 (1H, m), 11.05 (1H, s). [0423] (Example 70) 15 6-[3—Bromo-2-fluoro-4-(3-hydroxy-2,2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin~ 3-one [Chem. 325] Date Reçue/Date Received 2023-06-16 282 2.24 (1H, dd, J = 16.8, 3.7 Hz), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.09-3.19 (1H, m), 3.33 (2H, d, J = 5.4 Hz), 3.85 (2H, 5 s), 4.65 (1H, t, J = 5.4 Hz), 7.01 (1H, dd, J = 8.9, 1.2 Hz), 7.57 (1H, t, J = 8.9 Hz), 11.01 (1H, s). [0424] (Example 71) 6-[4-(3-Hydroxy~2,2-dimethylpropoxy)-3,5-dimethylphenyl]-5- 10 methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 326] m-NMR (DMSO-d6) 5: 0.99 (6H, s), 1.05 (3H, d, J = 7.2 Hz), 2.21 (1H, d, J = 16.8 Hz), 2.25 (6H, s), 2.64 (1H, dd, J = 15 16.8, 6.8 Hz), 3.30-3.38 (3H, m), 3.47 (2H, s), 4.58 (1H, t, J = 5.1 Hz), 7.44 (2H, s), 10.86 (1H, s). [0425] Date Reçue/Date Received 2023-06-16 283 (Example 72) 6-[3-Chloro-4-(3-hydroxy-2,2-dimethylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 327] 'H-NMR (CDC13) 5: 1.09 (6H, s), 1.24 (3H, d, J = 7.6 Hz), 2.14 (1H, t, J = 6.4 Hz), 2.35 (3H, s), 2.47 (1H, dd, J = 16.8, 1.0 Hz), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.23-3.34 (1H, m), 3.65 (2H, d, J = 6.4 Hz), 3.74 (2H, s), 7.48 (1H, 10 dd, J - 2.2, 0.7 Hz), 7.61 (1H, d, J = 2.2 Hz), 8.63 (1H, brs). [0426] (Example 73) 6-[3—Fluoro-4-(3-hydroxy-2,2-dimethylpropoxy)-5- 15 methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 328] Date Reçue/Date Received 2023-06-16 284 1H-NMR (DMS0-d6) ô: 0.95 (6H, s), 1.05 (3H, d, J = 7.2 Hz), 2.22 (1H, d, J = 16.7 Hz), 2.28 (3H, s), 2.66 (1H, dd, J = 16.7, 7.0 Hz), 3.27-3.42 (3H, m), 3.79 (2H, d, J = 1.7 Hz), 5 4.60 (1H, t, J = 5.3 Hz), 7.39-7.48 (2H, m), 10.94 (1H, s). [0427] (Example 74) Production of 6-[2-hydroxy-4-(2-hydroxypropoxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one 10 [Chern. 329] To a mixture of 6-[2-(methoxymethyloxy)-3-methyl-4-(2- oxopropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 107, 120 mg) in methanol (2 mL) was added 15 sodium borohydride (27 mg) at 0°C, and the mixture was Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 285 stirred at room temperature for one hour. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was dissolved in ethanol (2 mH), and hydrogen chlorxde (2 HI ethanol solutxon, 0 »350 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 2 days. The precipitates were collected on a filter to afford the title compound as a pale yellow solid (83 mg). 'H-NMR (DMSO-d6) 6: 1.10 (3H, d, J = 7.3 Hz), 1.18 (3H, d, J = 6.1 Hz), 2.03 (3H, s), 2.27 (1H, d, J = 16.9 Hz), 2.76 (1H, dd, J = 16.9, 6.6 Hz), 3.47-3.57 (1H, m), 3.76-3.83 (1H, m), 3.86-3.92 (1H, m), 3.92-4.02 (1H, m), 4.86 (1H, brs), 6.57 (1H, d, J = 9.0 Hz), 7.42 (1H, d, J = 9.0 Hz), 11.03 (1H, s), 12.46 (1H, s). [0428] The following compound was prepared from the appropriate starting material in a similar manner to Example 74. (Example 75) 6-[3-Chloro~2-hydroxy-4-(2-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one [Chem. 330] 286 1H-NMR (DMS0-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 1.19 (3H, d, J = 5.9 Hz), 2.26-2.34 (1H, m), 2.80 (1H, dd, J = 16.7, 6.7 Hz), 3.50-3.60 (1H, m), 3.83-3.93 (1H, m), 3.94-4.05 (2H, 5 m), 4.87-4.94 (1H, m), 6.74 (1H, d, J = 9.0 Hz), 7.55 (1H, d, J = 9.0 Hz), 11.13 (1H, s), 13.01 (IE, s). [0429] (Example 76) Production of 6-{3-chloro-2-fluoro-4-[(Z)-4-hydroxy-2- 10 butenyloxy]phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 331] To a mixture of 6-{4-[(Z)-4-(tert-butyldimethylsilyloxy)-2- butenyloxy]-3-chloro-2-fluorophenyl)-5-methyl-4,5-dihydro- 15 2H-pyridazin-3-one (Reference example 144, 296 mg) in THF (5 mL) was added tetrabutylammonium fluoride (1.0 M THF solution, Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 287 0.805 mL), and then the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the obtained crude product was purified by silica gel column chromatography (heptane • ethyl acetate = 10 : 90 to 0 : 100). The obtained solid was washed by trituration with diisopropyl ether, and then collected on a filter to afford the title compound as a white solid (135 mg). ’li-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 2.25 (1H, dd, J = 16.9, 3.4 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.09- 3.21 (1H, m), 4.11 (2H, t, J = 5.0 Hz), 4.78-4.89 (3H, m), 5.59-5.70 (1H, m), 5.73-5.83 (1H, m), 7.09 (1H, dd, J= 9.0, 1.2 Hz), 7.54 (1H, t, J = 9.0 Hz), 11.03 (1H, s). [0430] The following compounds were prepared from each appropriate starting material in a similar manner to Example 76. (Example 77) 6-[3-Chloro-2-hydroxy-4-(3-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin~3-one [Chern. 332] 288 Melting point: 225.0-225.3°C [0431] (Example 78) 6-[2-Hydroxy-4-(3-hydroxypropoxy)-3-methylphenyl]-5-methyl- 5 4,5-dihydro-2H-pyridazin-3-one [Chern. 333] Melting point: 199.1-200.1°C [0432] 10 (Example 79) 6-[3-Chloro-4-(4-hydroxybutoxy)-5-methylphenyl]-5~methyl- 5-dihydro-2H-pyridazin-3-one [Chem. 334] 15 iR-NMR (CDC13) 5: 1.24 (3H, d, J = 7.6 Hz), 1.57 (1H, t, J = 5.4 Hz), 1.78-1.98 (4H, m), 2.34 (3H, s), 2.43-2.51 (1H, m), 2.68 (1H, dd, J =16.9, 6.8 Hz), 3.23-3.34 (1H, m), 3.76 (2H, Date Reçue/Date Received 2023-06-16 289 q, J = 6.1 Hz), 3.98 (2H, t, J = 6.1 Hz), 7.47 (1H, dd, J = 2.2, 0.7 Hz), 7.58-7.62 (1H, m), 8.63 (1H s). [0433] (Example 80) 5 6-[3-Bromo-5-fluoro-4-(4-hydroxybutoxy)phenyl]-5-methyl~ 4,5~dxhydro—2H—pyrxdazxn—3—one [Chem. 335] iH-NMR (CDC13) 5: 1.24 (3H, d, J = 7.3 Hz), 1.42 (1H, t, J = 10 5.5Hz), 1.77-1.87 (2H, m), 1.88-1.97 (2H, m), 2.48 (1H, dd, J - 17.0, 0.9 Hz), 2.70 (1H, dd, J = 17.0, 6.8 Hz), 3.19- 3.32 (1H, m), 3.76 (2H, q, J = 5.5 Hz), 4.21 (2H, td, J = 6.1, 1.2 Hz), 7.48 (1H, dd, J = 12.3, 2.1 Hz), 7.70 (1H, t, J = 2.1 Hz), 8.53 (1H, brs). 15 [0434] (Example 81) 6-[3,5-Dichloro-4-(4-hydroxybutoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chem. 336] Date Reçue/Date Received 2023-06-16 290 1H-NMR (CDCI3) 5: 1.25 (3H, d, J = 7.3 Hz), 1.47 (1H, t, J = 5.5 Hz), 1.79-1.90 (2H, m), 1.92-2.02 (2H, m), 2.49 (1H, dd, J = 17.1, 1.0 Hz), 2.70 (1H, dd, J = 17.1, 6.8 Hz), 3.17- 5 3.33 (1H, m), 3.77 (2H, q, J = 5.5 Hz), 4.10 (2H, t, J = 6.2 Hz), 7.69 (2H, s), 8.58 (1H, brs). [0435] (Example 82) 6-[2,3-Difluoro~4-(4-hydroxybutoxy)phenyl]-5-methyl-4,5- 10 dihydro-2H-pyridazin-3-one [Chern. 337] ’H-NMR (CDCI3) 5: 1.22 (3H, d, J = 7.1 Hz), 1.44 (1H, t, J = 5.4 Hz), 1.72-1.84 (2H, m), 1.90-2.00 (2H, m), 2.45 (1H, dd, 15 J = 17.0, 3.1 Hz), 2.74 (1H, dd, J = 17.0, 6.7 Hz), 3.21- 3.33 (1H, m), 3.75 (2H, q, J = 5.4 Hz), 4.13 (2H, t, J = 6.2 Hz), 6.74-6.84 (1H, m), 7.27-7.35 (1H, m), 8.51 (1H, brs). Date Reçue/Date Received 2023-06-16 291 [0436] (Example 83) 6-[2-Fluoro-4-(4-hydroxybutoxy)-3-methylphenyl]-5-methy1- 4,5-dihydro-2H-pyridazin-3-one 5 [Chem. 338] 'H-NMR (CDC13) 5: 1.20 (3H, d, J = 7.1 Hz), 1.41 (1H, t, J = 5.4 Hz), 1.73-1.84 (2H, m), 1.85-2.00 (2H, m), 2.15 (3H, d, J = 2.4 Hz), 2.42 (1H, dd, J = 17.0, 3.3 Hz), 2.74 (1H, dd, 10 J = 17.0, 6.7 Hz), 3.22-3.33 (1H, m), 3.75 (2H, q, J = 5.4 Hz), 4.05 (2H, t, J = 6.1 Hz), 6.66 (1H, d, J = 8.8 Hz), 7.35 (1H, t, J = 8.8 Hz), 8.46 (1H, brs). [0437] (Example 84) 15 6-[3—Chloro-2-fluoro-4-(4-hydroxybutoxy)phenyl]-5-methyl- 425^dih^dro2^H2pyridazin232one [Chem. 339] Date Reçue/Date Received 2023-06-16 292 (T 1H-NMR (CDCI3) 5: 1.21 (3H, d, J = 7.3 Hz), 1.48 (1H, t, J = 5.5 Hz), 1.76-1.85 (2H, m), 1.93-2.02 (2H, m), 2.44 (1H, dd, J = 17.0, 3.3 Hz), 2.74 (1H, dd, J = 17.0, 6.7 Hz), 3.17- 5 3.34 (1H, m), 3.76 (2H, q, J = 5.5 Hz), 4.14 (2H, t, J = 6.1 Hz), 6.77 (1H, dd, J = 8.9, 1.3 Hz), 7.46 (1H, t, J = 8.9 Hz), 8.53 (1H, brs). [0438] (Example 85) 10 6-[2-Fluoro-4-(3-hydroxypropoxy)-3-vinylphenyl]-5-methy1- 4,5-dihydro-2H-pyridazin-3-one [Chern. 340] iH-NMR (CDC13) 5: 1.19 (3H, d, J = 6.8 Hz), 1.70 (1H, t, J = 15 5.1 Hz), 2.10 (2H, quintet, J - 6.1 Hz), 2.42 (1H, dd, J = 17.1, 3.7 Hz), 2.73 (1H, dd, J = 17.1, 6.8 Hz), 3.21-3.33 (1H, m), 3.86-3.91 (2H, m), 4.20 (2H, t, J = 6.1 Hz), 5.52- Date Reçue/Date Received 2023-06-16 293 5.59 (1H, m), 5.98-6.06 (1H, m), 6.74 (1H, dd, J= 8.8, 0.5 Hz), 6.78 (1H, dd, J = 18.1, 12.0 Hz), 7.39 (1H, t, J = 8.8 Hz), 8.62 (1H, brs). [0439] 5 (Example 86) 6-{3-Chloro-4-[(Z)-4-hydroxy-2-butenyloxy]-5-methylphenyl}- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 341] 10 1H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.7 Hz), 2.31 (3H, s), 2.67 (1H, dd, J = 16.7, 7.0 Hz), 3.33-3.43 (1H, m), 4.00-4.04 (2H, m), 4.53-4.56 (2H, m), 4.77 (1H, t, J = 5.4 Hz), 5.69-5.78 (2H, m), 7.61 (1H, dd, J = 2.2, 0.7 Hz), 7.67 (1H, d, J = 2.2 Hz), 10.99 (1H, s). 15 [0440] (Example 87) 6-[2—Hydroxy-4-(4-hydroxybutoxy)-3-methylphenyl]-5—methyl- 4,5-dihydro-2H-pyridazin-3-one [Chem. 342] Date Reçue/Date Received 2023-06-16 294 10 Melting point: 178.7-179.9°C [0441] (Example 88) 6-[3—Chloro-2-hydroxy-4-(4-hydroxybutoxy)phenyl]-5—methyl- 4,5-dihydro~2H-pyridazin-3-one [Chem. 343] Melting point: 204.5-204.9°C [0442] (Example 89) 6-[2—Fluoro-4-(4-hydroxybutoxy)-3-vinylphenyl]-5-methyl- 4,5~dihydro-2H-pyridazin-3-one [Chem. 344] Date Reçue/Date Received 2023-06-16 295 Me11mg point* 106.4-107 «4 0 [0443] (Example * * 90) ' 5 6-[3—Chloro-2-fluoro-4-[(E)-4-hydroxy-2-butenyloxy]phenyl}- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 345] ^-NMR (DMSO-d6) 5: 1.04 (3E, d, J = 7.1 Hz), 2.25 (1H, dd, 10 J = 16.9, 3.7 Hz), 2.69 (1H, dd, J = 16.9, 6.7 Hz), 3.11- 3.19 (1H, m), 3.98-4.02 (2H, m), 4.73 (2H, dd, J = 5.6, 1.2 Hz), 4.83 (1H, t, J = 5.5 Hz), 5.81-5.89 (1H, m), 5.96-6.04 (1H, m), 7.10 (1H, dd, J = 9.0, 1.2 Hz), 7.54 (1H, dd, J = 9.0, 8.8 Hz), 11.02 (1H, brs). 15 [0444] (Example 91) 6-[3-Chloro-2~fluoro-4-(5~hydroxypentoxy)phenyl]-5-methylDate Reçue/Date Received 2023-06-16 296 4,5-dihydro-2H-pyridazin-3-one [Chem. 346] ifi-NMR (CDC13) 5: 1.20 (3H, dd, J = 7.3, 0.5 Hz), 1.38 (1H, 5 t, J = 5.1 Hz), 1.54-1.72 (4H, m), 1.85-1.96 (2H, m), 2.43 (1H, dd, J = 16.9, 3.2 Hz), 2.73 (1H, dd, J = 16.9, 6.6 Hz), 3.21-3.33 (1H, m), 3.66-3.74 (2H, m), 4.10 (2H, t, J = 6.4 Hz), 6.75 (1H, dd, J = 9.0, 1.5 Hz), 7.42-7.50 (1H, m), 8.66 (1H, brs). 10 [0445] (Example 92) 6-[2-Fluoro-4-[(Z)-4-hydroxy-2-butenyloxy]-3-methylphenyl]- 5-methyl-4,5-dihydro-2H~pyridazin-3-one [Chern. 347] 'H-NMR (DMSO-d6) 6: 1.03 (3H, d, J = 7.3 Hz), 2.09 (3H, d, J = 2.2 Hz), 2.23 (1H, dd, J = 16.7, 3.7 Hz), 2.66 (1H, dd, J Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 297 = 16.7, 6.7 Hz), 3.06-3.18 (1H, m) , 4.10 (2H, t, J = 5.3 Hz), 4.71 (2H, d, J = 5.6 Hz), 4.82 (1H, t, J = 5.3 Hz), 5.59- 5.69 (1H, m) , 5.70-5.80 (1H, m) , 6.88 (1H, d, J = 8.9 Hz), 7.37 (1H, t, J = 8.9 Hz), 10.92 (1H, s). [0446] (Example 93) 6-{ 2,3-Difluoro-4-[ (Z) -4-hydroxy-2-butenyloxy]phenyl}-5- methyl-4, 5-dihydro-2H~pyridazin-3-one [Chem. 348] 1H-NMR (DMSO-d6) 5: 1.05 (3E, d, J = 7.1 Hz), 2.25 (1H, dd, J - 16.9, 3.4 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.09- 3.23 (1H, m) , 4.08-4.13 (2H, m) , 4.80 (2H, d, J = 6.1 Hz), 4.84 (1H, t, J = 5.4 Hz), 5.59-5.70 (1H, m) , 5.72-5.82 (1H, iw) , ^7 * 0 '7. 1> ( 1»II, m ) , '7..34 '7 * 4 ^3 ( 1«II, Hi) , 1»1«. 0.3 ( I.H, £5 ) . [0447] (Example 94) 6-{ 3—Chloro-5-f luoro-4- [ (Z) -4-hydroxy-2-butenyloxy]phenyl }- 5~methyl~4, 5-dihydro~2H-pyridazin-3-one [Chem. 349] 298 ^-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 2.24 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J = 16.7, 7.0 Hz), 3.35-3.46 (1H, m), 3.96-4.03 (2H, m), 4.71-4.83 (3H, m), 5.61-5.81 (2H, m), 5 7.64 (1H, dd, J = 12.3, 2.1 Hz), 7.69 (1H, t, J = 2.1 Hz), 11.07 (1H, s). [0448] (Example 95) 6-{3-Bromo-5-fluoro-4-[(Z)-4-hydroxy-2-butenyloxy]phenyl}- 10 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 350] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J - 16.9 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.34-3.46 (1H, 15 m), 3.96-4.07 (2H, m), 4.68-4.84 (3H, m), 5.60-5.81 (2H, m), 7.67 (1H, dd, J = 12.5, 2.2 Hz), 7.82 (1H, t, J = 2.2 Hz), Date Reçue/Date Received 2023-06-16 299 11.07 (1H, s). [0449] (Example 96) 6—{2—Fluoro—4—[(Z)—4—hydroxy—2—butenyloxy]—3—vinylphenyl}— 5 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 351] 'H-NMR (CDC13) 5: 1.19 (3H, d, J = 7.3 Hz), 1.68 (1H, t, J = 5.6 Hz), 2.42 (1H, dd, J = 17.1, 3.7 Hz), 2.73 (1H, dd, J = 10 17.1, 6.8 Hz), 3.20-3.34 (1H, m), 4.30 (2H, t, J = 5.1 Hz), 4.72 (2H, d, J - 5.1 Hz), 5.51-5.59 (1H, m), 5.79-5.95 (2H, m), 5.99-6.09 (1H, m), 6.72 (1H, d, J = 8.8 Hz), 6.80 (1H, dd, J = 18.1, 12.2 Hz), 7.39 (1H, t, J = 8.8 Hz), 8.62 (1H, brs). 15 [0450] (Example 97) 6-[3-ELhyl-2-fluoro-4-(4-hydroxybutoxy)phenyl]-5-methyl- 4,5~dihydro~2H-pyridazin-3-one [Chern. 352] Date Reçue/Date Received 2023-06-16 300 1H-NMR (CDCI3) 5: 1.14 (3H, t, J = 7.6 Hz), 1.20 (3H, d, J = 7.3 Hz), 1.38 (1H, t, J = 5.4 Hz), 1.73-1.84 (2H, m), 1.87- 1.98 (2H, m), 2.41 (1H, dd, J = 17.1, 3.4 Hz), 2.64-2.78 (3H, 5 m), 3.21-3.34 (1H, m), 3.71-3.79 (2H, m), 4.05 (2H, t, J = 6.4 Hz), 6.67 (1H, d, J = 8.8 Hz), 7.35 (1H, t, J = 8.8 Hz), 8.47 (1H, brs). [0451] (Example 98) 10 Production of 6-[3-chloro-4-(4-hydroxy-2,2-dimethylbutoxy)- 5-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin~3-one [Chern. 353] To a mixture of 6-(3-chloro-4~hydroxy-5-methylphenyl)-5- 15 methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 86, 255 mg), 4-(tert-butyldimethylsilyloxy)-2,2-dimethylbutanDate Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 301 l-ol (258 mg), and triphenylphosphine (291 mg) in THF (10 mL) was added bis(2-methoxyethyl) azodicarboxylate (260 mg) at 0“C, and then the mixture was stirred at room temperature overnight* The solvent was removed, and then the residue was purified by silica gel column chromatography (heptane : ethyl acetate =50 : 50) to afford a pale yellow solid (165 mg). The obtained solid was dissolved in THF (5 mL). To the solution was added tetrabutylammonium fluoride (1.0 M THF solution, 0.424 mL) at 0°C, and then the solution was stirred at 50°C for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 50 : 50 to 0 : 100), and the desired fractions were concentrated. The residue was crystallized from diisopropyl ether /ethyl acetate, and the precipitates were collected on a filter to afford the title compound as a white powder (59 mg). iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.06 (6H, s), 1.60 (2H, t, J = 7.3 Hz), 2.22 (1H, d, J = 16.5 Hz), 2.31 (3H, s), 2.67 (1H, dd, J= 16.5, 7.0 Hz), 3.34-3.42 (1H, m), 3.52-3.59 (2H, m), 3.58 (2H, s), 4.32 (1H, t, J = 5.0 Hz), 7.59-7.61 (1H, m), 7.65-7.67 (1H, m), 10.98 (1H, s). [0452] 302 The following compounds were prepared from each appropriate starting material in a similar manner to Example 98. (Example 99) 6-[3—Chloro-5-fluoro-4-(4-hydroxy-2,2- 5 dimethylbutoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chern. 354] ifi-NMR (DMSO-d6) 5: 1.03 (6H, s), 1.04 (3H, d, J = 7.6 Hz), 10 1.57 (2H, t, J = 7.3 Hz), 2.23 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J - 16.7, 7.0 Hz), 3.35-3.46 (1H, m), 3.52 (2H, t, J- 7.3 Hz), 3.83 (2H, d, J = 1.5 Hz), 4.32 (1H, brs), 7.64 (1H, dd, J = 12.6, 2.1 Hz), 7.68 (1H, t, J = 2.1 Hz), 11.06 (1H, s). 15 [0453] (Example 100) 6-[3,5-Dichloro-4-(4-hydroxy-2,2-dimethylbutoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 355] Date Reçue/Date Received 2023-06-16 303 1H-NMR (DMSO-d6) ô: 1.04 (3H, d, J = 7.1 Hz), 1.07 (6H, s), 1.60 (2H, t, J = 7.3 Hz), 2.23 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J= 16.7, 7.0 Hz), 3.36-3.47 (1H, m), 3.55 (2H, t, 5 J = 7.3 Hz), 3.71 (2H, s), 4.19-4.45 (1H, m), 7.82 (2H, s), 11.08 (1H, s). [0454] (Example 101) 6-[3-Fluoro-4-(4-hydroxy-2,2-dimethylbutoxy)-5- 10 methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3~one [Chern. 356] *H-NMR (DMSO-d6) 5: 1.02 (6H, s), 1.05 (3H, d, J = 7.3 Hz), 1.57 (2H, t, J = 7.3 Hz), 2.22 (1H, d, J = 16.6 Hz), 2.28 15 (3H, s), 2.66 (1H, dd, J = 16.6, 6.8 Hz), 3.27-3.42 (1H, m), Date Reçue/Date Received 2023-06-16 304 3.48-3.57 (2H, m) , 3.72 (2H, d, J = 1.5 Hz), 4.32 (1H, t, J = 5.0 Hz), 7.40-7.48 (2H, m) , 10.95 (1H, s). [0455] (Example 102) 5 6-[2,3-Difluoro-4- (4-hydroxy-2, 2-dimethylbutoxy) phenyl]-5- methyl- 4,5— dxhydxo— 2 H—pyxzxdazxn- 3—one [Chem. 357] iH-NMR (DMS0-d6) 5: 1.00 (6H, s) , 1.05 (3H, d, J = 7.3 Hz), 10 1.55 (2H, t, J = 7.3 Hz), 2.25 (1H, dd, J - 16.9, 3.4 Hz), 2.70 (1H, dd, J- 16.9, 6.8 Hz), 3.09-3.22 (1H, m) , 3.51 (2H, t, J = 7.3 Hz), 3.82 (2H, s) , 4.34 (1H, brs), 7.02-7.12 (1H, m) , 7.38 (1H, td, J = 8.7, 2.2 Hz), 11.02 (1H, s) . [0456] 15 (Example 103) 6-[3-Chloro~2-fluoro-4- (4-hydroxy-2, 2- dimethylbutoxy) phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 358] Date Reçue/Date Received 2023-06-16 305 1H-NMR (DMSO-d6) ô: 1.03 (6H, s), 1.04 (3H, d, J = 7.3 Hz), 1.57 (2H, t, J = 7.4 Hz), 2.25 (1H, dd, J = 16.9, 3.7 Hz), 2.69 (1H, dd, J = 16.9, 6.7 Hz), 3.07-3.22 (1H, m), 3.51 (2H, 5 t, J = 7.4 Hz), 3.83 (2H, s), 4.34 (1H, brs), 7.05 (1H, dd, J = 9.0, 1.2 Hz), 7.53 (1H, t, J = 9.0 Hz), 11.01 (1H, s). [0457] (Example 104) Production of 2-fluoro-6-(2-hydroxypropoxy)-3-(4-methyl-6- 10 oxo-4,5-dihydro-lH-pyridazin-3-yl)benzonitrile [Chern. 359] mixture 6-[3-bromo-2-fluoro-4-(2- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- 15 one (Example 48, 180 mg), zinc cyanide (105 mg), and tetrakis(triphenylphosphine)palladium (29 mg) in DMF (2.5 Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 306 mL) was stirred at 150°C under microwave irradiation for 30 minutes. To the reaction mixture were added ethyl acetate and water, and then the mixture was filtered through a Celite pad. The organic layer was separated, washed with brine, dried with anhydrous sodium sulfate, filtrated, and then concentrated. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 40 : 60 to 0 : 100), and the desired fractions were concentrated. The residue was crystallized from diisopropyl ether. The precipitates were collected on a filter to afford the title compound as a white solid (93 mg). iH-NMR (DMSO-d6) 6: 1.05 (3H, d, J = 7.3 Hz), 1.18 (3H, d, J = 6.2 Hz), 2.26 (1H, dd, J = 16.9, 3.4 Hz), 2.71 (1H, dd, J = 16.9, 6.8 Hz), 3.11-3.22 (1H, m), 3.95-4.14 (3H, m), 4.99 (1H, d, J = 4.8 Hz), 7.21 (1H, d, J = 9.0 Hz), 7.90 (1H, t, J = 9.0 Hz), 11.09 (1H, s). [0458] The following compound was prepared from the appropriate starting material in a similar manner to Example 104. (Example 105) 2-Fluoro-6-(2-hydroxy-2-methylpropoxy)-3-(4-methyl-6-oxo- 4,5-dihydro-lH-pyridazin-3-yl)benzonitrile [Chem. 360] 307 ^-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.1 Hz), 1.23 (6H, s), 2.26 (1H, dd, J = 16.9, 3.4 Hz), 2.71 (1H, dd, J = 16.9, 6.8 Hz), 3.12-3.22 (1H, m), 3.97 (2H, s), 4.77 (1H, s), 7.21 (1H, 5 d, J = 9.0 Hz), 7.90 (1H, t, J = 9.0 Hz), 11.09 (1H, s). [0459] (Example 106) Production of 2-fluoro-6-(3-hydroxypropoxy)-3-(4-methyl-6- oxo-4,5-dihydro~lH-pyridazin-3-yl)benzonitrile 10 [Chem. 361] A mixture of 6-[3-bromo-2-fluoro-4-(3- hydroxypropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one (Example 12, 150 mg), zinc cyanide (108 mg), and 15 tetrakis(triphenylphosphine)palladium (24 mg) in DMF (1.5 mL) was stirred at 100°C overnight. The reaction mixture was allowed to cool to room temperature, and then Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 308 tetrakis(triphenylphosphine)palladium (97 mg) was added thereto. The reaction mixture was stirred at 100°C further for one day. The reaction mixture was allowed to cool to room temperature, water and ethyl acetate were added to the reaction mixture, and then the mixture was filtered through a Celite pad. The organic layer of the filtrate was separated, washed with water and brine, dried with anhydrous sodium sulfate, filtrated, and then concentrated to afford a solid (191 mg). The solid was dissolved in DMF (2.0 mL), imidazole (34 mg) and tert-butyldimethylchlorosilane (69 mg) were added to the mixture, and the mixture was stirred at room temperature overnight. Imidazole (34 mg) and tertbutyldimethylchlorosilane (69 mg) were further added thereto, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 85 : 15 to 15 : 85) to afford a white solid (45 mg). To a solution of the obtained white solid (45 mg) in THF (1.0 mL) under ice-cold was added tetrabutylammonium fluoride (1.0 M THF solution, 0.16 mL). The mixture was stirred at room temperature for one hour. To the reaction mixture were added water and brine, 5 10 15 20 Date Reçue/Date Received 2023-06-16 309 and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 10 : 90 to 0 : 100 to ethyl acetate : methanol = 90 : 10). The obtained solid was washed by trituration with diisopropyl ether, and then collected on a filter to afford the title compound as a white solid (26 mg). iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.0 Hz), 1.86-1.96 (2H, m), 2.26 (1H, d, J = 16.9 Hz), 2.70 (1H, dd, J = 16.9, 6.5 Hz), 3.12-3.22 (1H, m), 3.53-3.64 (2H, m), 4.25-4.33 (2H, m), 4.58-4.66 (1H, m), 7.20 (1H, d, J = 8.9 Hz), 7.92 (1H, t, J = 8.9 Hz), 11.09 (1H, s). [0460] (Example 107) Production of 6-[4-(2,2-difluoro-3-hydroxypropoxy)-2- fluoro-3-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- ong [Chem. 362] 5 10 15 20 Date Reçue/Date Received 2023-06-16 310 To a mixture of 2,2-difluoro-3-[3-fluoro-2-methyl-4-(4- methyl-6-oxo-4,5-dihydro-lH-pyridazin-3-yl)phenoxy]propyl benzoate (Reference example 166, 253 mg) in methanol (2 mL) was added 5 M aqueous sodium hydroxide (0.349 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude solid was recrystallized from heptane/ethyl acetate to üijClî' jck1 DiCi tii1.1« ci compound as a white solid (117 mg). iR-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.1 Hz), 2.11 (3H, d, J = 2.2 Hz), 2.23 (1H, dd, J = 16.7, 3.8 Hz), 2.67 (1H, dd, J = 16.7, 6.7 Hz), 3.06-3.20 (1H, m), 3.71-3.87 (2H, m), 4.39 (2H, t, J = 12.6 Hz), 5.65-5.73 (1H, m), 6.97 (1H, d, J = 8.8 Hz), 7.40 (1H, t, J = 8.8 Hz), 10.95 (1H, s). [0461] The following compounds were prepared from each appropriate starting material in a similar manner to Example 107. 311 (Example 108) 6-[4-(2,2-Difluoro-3-hydroxypropoxy)-2,3-difluorophenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 363] ^-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J - 16.8, 3.4 Hz), 2.71 (1H, dd, J = 16.8, 6.8 Hz), 3.12- 3.23 (1H, m), 3.76 (2H, td, J= 13.7, 6.3 Hz), 4.51 (2H, t, J = 12.8 Hz), 5.71 (1H, t, J = 6.3 Hz), 7.15-7.24 (1H, m), 10 7.38-7.46 (1H, m), 11.06 (1H, s). [0462] (Example 109) 6-[3,5-Dichloro-4-(2,2-difluoro-3-hydroxypropoxy)phenyl]-5- methy1-4,5—dxhydro—2H—pyrxdazxn—3—one 15 [Chem. 364] Date Reçue/Date Received 2023-06-16 312 (r 1H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.9 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.37-3.49 (1H, m), 3.82 (2H, td, J = 13.9, 6.1 Hz), 4.38 (2H, t, J = 13.2 5 Hz), 5.65 (1H, t, J = 6.1 Hz), 7.85 (2H, s), 11.11 (1H, s). [0463] (Example 110) 6-[3-Chloro-4-(2,2-difluoro-3-hydroxypropoxy)-2- fluorophenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one 10 [Chern. 365] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 2.25 (1H, dd, J = 16.9, 3.8 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.09- 3.22 (1H, m), 3.80 (2H, td, J= 13.7, 6.2 Hz), 4.51 (2H, t, 15 J = 12.6 Hz), 5.70 (1H, t, J = 6.2 Hz), 7.19 (1H, dd, J = Date Reçue/Date Received 2023-06-16 313 9.0, 1.5 Hz), 7.53-7.61 (1H, m), 11.04 (1H, s). [0464] (Example 111) 6-[3-Chloro-4-(2,2-difluoro-3-hydroxypropoxy)-5- [Chem. 366] o ir-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 2.24 (1H, d, J = 16.9 Hz), 2.69 (1H, dd, J - 16.9, 7.1 Hz), 3.36-3.47 (1H, 10 m), 3.80 (2H, td, J = 13.8, 6.1 Hz), 4.47 (2H, t, J = 13.1 Hz), 5.65 (1H, t, J = 6.1 Hz), 7.63-7.74 (2H, m), 11.09 (1H, s). [0465] (Example 112) 15 6-[3—Bromo-4-(2,2-difluoro-3-hydroxypropoxy)-2- fluorophenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 367] Date Reçue/Date Received 2023-06-16 314 1H-NMR (DMS0-d6) ô: 1.04 (3H, d, J = 7.1 Hz), 2.25 (1H, dd, J = 16.9, 3.7 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.08- 3.21 (1H, m), 3.82 (2H, td, J= 13.8, 6.2 Hz), 4.50 (2H, t, 5 J = 12.3 Hz), 5.70 (1H, t, J = 6.2 Hz), 7.15 (1H, dd, J = 8.8, 1.2 Hz), 7.60 (1H, t, J = 8.8 Hz), 11.04 (1H, s). [0466] (Example 113) 6-[3-Chloro-4-(2,2-difluoro-3-hydroxypropoxy)-5- 10 methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 368] iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz) 2.23 (1H, d, J - 16.7 Hz), 2.33 (3H, s), 2.68 (1H, dd, J = 16.7, 7.0 Hz), 15 3.33-3.45 (1H, m), 3.81 (2H, td, J= 13.9, 6.0 Hz), 4.27 (2H, t, J = 13.4 Hz), 5.65 (1H, t, J = 6.0 Hz), 7.62 (1H, d, J = Date Reçue/Date Received 2023-06-16 315 2.2 Hz), 7.68 (1H, d, J = 2.2 Hz), 11.00 (1H, s). [0467] (Example 114) 6-[4—(2,2-Difluoro-3-hydroxypropoxy)-2-fluoro-3- 5 vinylphenyl]-5-meLhyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 369] iH-NMR (CDC13) 8: 1.19 (3H, d, J = 7.1 Hz), 2.13 (1H, t, J = 7.1 Hz), 2.42 (1H, dd, J = 17.1, 3.7 Hz), 2.73 (1H, dd, J = 10 17.1, 6.8 Hz), 3.20-3.31 (1H, m), 4.00 (2H, td, J = 12.5, 7.1 Hz), 4.34 (2H, t, J = 11.5 Hz), 5.56-5.63 (1H, m), 5.98- 6.06 (1H, m), 6.70-6.83 (2H, m), 7.41 (1H, t, J = 8.5 Hz), 8.57 (1H, brs). [0468] 15 (Example 115) Production of 6-[4-(2,2-difluoro-3-hydroxypropoxy)-2- hydroxy-3-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one [Chem. 370] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 316 A mixture of 2,2-difluoro-3-[3-(methoxymethyloxy)-2-methyl- 4-(4-methyl-6-oxo-4,5-dihydro-lH-pyridazin-3- yl)phenoxy]propyl methanesulfonate (Reference example 141, 80 mg) and sodium benzoate (51 mg) in DMF (2 mL) was stirred at 180°C under microwave irradiation for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate =50 : 50) to afford a colorless oil. The oil was dissolved in ethanol (2 mL), 5 M aqueous sodium hydroxide (0.046 mL) was added thereto, and the mixture was stirred at room temperature for one hour. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was dissolved in ethanol (2 mL), hydrogen chloride (2 M ethanol solution, 5 10 15 20 Date Reçue/Date Received 2023-06-16 317 0.058 mL) was added thereto, and the mixture was stirred at room temperature overnight. The precipitates were collected on a filter to afford the title compound as a white solid (20 mg). iH-NMR (DMSO~d6) 6: 1.10 (3H, d, J = 7.3 Hz), 2.04 (3H, s), 2.27 (1H, d, J = 16.6 Hz), 2.77 (1H, dd, J = 16.7, 6.7 Hz), 3.47-3.61 (1H, m), 3.73-3.86 (2H, m), 4.35 (2H, t, J = 12.7 Hz), 5.66 (1H, t, J = 6.2 Hz), 6.66 (1H, d, J = 9.0 Hz), 7.46 (1H, d, J = 9.0 Hz), 11.06 (1H, s), 12.54 (1H, s). [0469] (Example 116) Production of (5R)-(~)-6-[3-chloro-4~(2-hydroxyethoxy)-5- methylphenyl]-5~methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 371] To a mixture of 2-{2-chloro-6-methyl-4-[(2R)-2-methyl-3- {[(IS)—1—(4— nitrophenyl)ethyl]carbamoyl}propanoyl]phenoxy}ethyl 4- bromobenzoate (Reference example 175, 300 mg) in 2-propanol (5.0 mL) were added acetic acid (0.272 mL) and hydrazine 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 318 monohydrate (0.115 mL), and then the mixture was stirred at 60°C overnight. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate* The organxc layer was washed wxth water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The residue was purified by silica gel column chromatography (heptane : ethyl acetate = 80 : 20 to 50 : 50). The obtained solid was washed by trituration with ethyl acetate/heptane, and then collected on a filter to afford a colorless solid (168 mg). The solid was dissolved in ethanol (5.0 mL), and 5 M aqueous sodium hydroxide (0.140 mL) was added to the mixture. The mixture was stirred at room temperature for 15 minutes, water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 25 : 75 to 0 : 100). The obtained solid was recrystallized from ethyl acetate/heptane to afford the title compound as a colorless solid (50 mg, >99% ee). The optical purity was determined by high performance liquid chromatography (HPLC) analysis. Optical rotation : [o£]d24 -322.4° (c = 0.21, MeOH) 1H-NMR (CDC13) 5: 1.24 (3H, d, J = 7.3 Hz), 2.28 (1H, t, J = 5 10 15 20 Date reçue/Oate received 2024-02-13 319 6.4 Hz), 2.37 (3H, s), 2.44-2.52 (1H, m), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.23-3.34 (1H, m), 3.94-4.01 (2H, m), 4.03- 4.13 (2H, m), 7.49-7.50 (1H, m), 7.62 (1H, d, J = 2.0 Hz), 8.59 (1H, brs). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK™ IA column (0.46 cmcp x 25 cm) Eluent: hexane/ethanol =60/40 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 7.22 min (>99% ee). [0001] Each absolute configuration of Examples 117 - 127 shown below was extrapolated by comparison with Example 116. (Example 117) (5R)-(-)-6-[3,5-Difluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chem. 1] 6-[3,5-Difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Example 30, 267 mg) 5 10 15 20 25 Date reçue/Oate received 2024-02-13 320 was optically-resolved by chiral column chromatography according to the following preparative condition, and then recrystallized from heptane/ethanol to afford the title compound as a white solid (33 mg, 99% ee). <Preparative condition> Column: Daicel CHIRALFLASH™ IA (3.0 cmcp x 10 cm) Eluent: hexane/ethanol = 60/40 Flow rate: 12 ml/min Detection: UV (254 nm). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK AS-RH (0.46 cimp x 15 cm) Eluent: acetonitrile/water = 50/50 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 4.6 min [a]D24 -306.4° (c = 0.25, MeOH) ir-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.20 (6H, s), 2.23 (1H, d, J = 16.7 Hz), 2.68 (1H, dd, J = 16.7, 7.0 Hz), 3.34-3.44 (1H, m), 3.89 (2H, s), 4.62 (1H, s), 7.43-7.60 (2H, m), 11.05 (1H, s). [0002] (Example 118) Production of (5R)-(-)-6-[3-chloro-2-fluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one 5 10 15 20 Date Reçue/Date Received 2023-06-16 321 [Chem. 373] 6-[3-Chloro-2-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one (Example 29, 200 mg) was optically-resolved by chiral column chromatography according to the following preparative condition, and then recrystallized from 2-propanol to afford the title compound as a white solid (46 mg, 95% ee). <Preparative condition> Column: Daicel CHIRALFLASH IA (3.0 cmq> x 10 cm) Eluent: hexane/ethanol = 70/30 Flow rate: 12 ml/min Detection: UV (254 nm). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 cmcp x 25 cm) Eluent: hexane/ethanol = 30/70 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 5.2 min Optical rotation : [a]D24 -123.0° (c - 0.28, MeOH) 5 10 15 20 Date Reçue/Date Received 2023-06-16 322 iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 1.24 (6H, s), 2.25 (1H, dd, J = 16.8, 3.5 Hz), 2.70 (1H, dd, J = 16.8, 6.8 Hz), 3.09-3.20 (1H, m) , 3.87 (2H, s) , 4.69 (1H, s) , 7.08 (1H, dd, J = 9.0, 1.3 Hz), 7.49-7.58 (1H, m) , 11.01 (1H, s) .

[0472] The following compound was prepared front th© appropriate starting material in a similar manner to Example 118. (Example 119) Production of (5R) - (-) -6-{3-chloro-5-fluoro-4-[ (1- hydroxycyclopropyl) methoxy]phenyl]-5-methyl-4,5-dihydro-2H- !■ i i i ffil W M II II 1* ** Ali II Mi II i II i II mi ii' 11 i III pyridazin-3-one [Chern. 374] Optical purity: >99% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 emo x 25 cm) Eluent: hexane/ethanol = 40/60 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 6.0 min 5 10 15 20 Date Reçue/Date Received 2023-06-16 323 Optical rotation : [«Id24 -274.6° (c = 0.31, MeOH) iH-NMR (DMSO-d6) 5: 0.61-0.73 (4H, m), 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.7 Hz), 2.69 (1H, dd, J = 16.7, 6.7 Hz), 3.34-3.47 (1H, m), 4.10 (2H, s), 5.54 (1H, s), 7.58- 7.72 (2H, m), 11.06 (1H, s). [0473] (Example 120) Production of (5R)-(-)-6-[4-(2,2-difluoro-3- hydroxypropoxy)-2-fluoro-3-methylphenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chern. 375] 6-[4-(2,2-Difluoro-3-hydroxypropoxy)-2-fluoro-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Example 107, 130 mg) was optically-resolved by chiral column chromatography according to the following preparative condition, and then recrystallized from ethyl acetate/heptane to afford the title compound as a white solid (33 mg, 99% ee). <Preparative condition> 5 10 15 20 Date Reçue/Date Received 2023-06-16 324 Column: Daicel CHIRALFLASH IA (3.0 cmcp x 10 cm) Eluent: hexane/ethanol = 75/25 Flow rate: 12 ml/min Detection: UV (254 nm). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 cmcp x 25 cm) Eluent: hexane/ethanol = 50/50 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 5.7 min Optical rotation : [oc]D27 -101.5° (c = 0.29, MeOH) iH-NMR (DMSO-d6) 6: 1.03 (3H, d, J = 7.1 Hz), 2.11 (3H, d, J = 2.2 Hz), 2.23 (1H, dd, J = 16.7, 3.8 Hz), 2.67 (1H, dd, J = 16.7, 6.7 Hz), 3.05-3.18 (1H, m) , 3.79 (2H, td, J= 13.7, 6.0 Hz) , 4.39 (2H, t, J = 12. 6 Hz) , 5.68 (1H, t, J = 6.0 Hz) , 6.97 (1H, d, J = 8.8 Hz), 7.40 (1H, t, J = 8.8 Hz), 10.95 (1H, s) . [0474J The following compounds were prepared from each appropriate starting material in a similar manner to Example 120. (Example 121) (5R) — (- ) -6- [3,5-Dif luoro-4- (3-hydroxypropoxy) phenyl]-5- methyl-4, 5-dihydro~2H-pyridazin-3-one [Chern. 376] 5 10 15 20 Date Reçue/Date Received 2023-06-16 325 Optical purity: 95% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.4 6 cmcp x 25 cm) Eluent: hexane/ethanol = 60/40 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 6.9 min [a]D24 -293.5° (c = 0.30, MeOH) 1H-NMR (DMSO-d6) 5: 1.05 (3E, d, J = 7.3 Hz), 1.76-1.90 (2H, m), 2.24 (1H, d, J = 16.7 Hz), 2.68 (1H, dd, J = 16.7, 7.0 Hz), 3.36-3.46 (1H, m), 3.52-3.60 (2H, m), 4.23 (2H, t, J = 6.3 Hz), 4.53 (1H, t, J = 5.1 Hz), 7.44-7.59 (2H, m), 11.05 (1H, s). [0475] (Example 122) (5R) — (- ) -6- [3-Chloro-2-f luoro-4- (3-hydroxy-2, 2- dimethylpropoxy)phenyl]-5~methyl-4,5-dihydro-2H-pyridazin- 3-one [Chern. 3771 5 10 15 20 Date Reçue/Date Received 2023-06-16 Optical purity: 96% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 emo x 25 cm) Eluent: hexane/ethanol = 60/40 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 7.2 min [a]D24 -114.2° (c = 0.28, MeOH) iH-NMR (DMSO-d6) 5: 0.96 (6H, s), 1.04 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J = 16.8, 3.6 Hz), 2.70 (1H, dd, J - 16.8, 6.7 Hz), 3.09-3.20 (1H, m), 3.29-3.34 (2H, m), 3.86 (2H, s), 4.66 (1H, t, J = 5.4 Hz), 7.06 (1H, d, J = 9.3 Hz), 7.49- 7.58 (1H, m), 11.01 (1H, s). [0476] (Example 123) (5R)-(-)-6-[2,3-Difluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chern. 378] 327 Optical purity: 99% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.4 6 cmcp x 25 cm) 5 Eluent: hexane/ethanol = 60/40 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 8.0 min [a]D24 -138.7° (c = 0.44, MeOH) 10 1H-NMR (DMSO-d6) 5: 0.61-0.76 (4H, m), 1.05 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J = 16.8, 3.4 Hz), 2.70 (1H, dd, J = 16.8, 6.8 Hz), 3.11-3.22 (1H, m), 4.12 (2H, s), 5.66 (1H, s), 7.05- 7.14 (1H, m), 7.33-7.41 (1H, m), 11.03 (1H, s). [0477] 15 (Example 124) Production of (5R)-(-)-6-[2,3-difluoro-4-(2-hydroxy-2- methyIpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one [Chern. 379] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 328 6-[2,3-Difluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Example 27, 117 mg) was optically-resolved by chiral column chromatography according to the following preparative condition, and then recrystallized from ethanol/heptane to afford the title compound as a white solid (30 mg, 99% ee). <Preparative condition> Column: Daicel CHIRALFLASH IA (3.0 cmcp x 10 cm) Eluent: hexane/ethanol = 80/20 Flow rate: 12 ml/min Detection: UV (254 nm). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK AS—RH (0.46 cmcp x 15 cm) Eluent: acetonitrile/water = 40/60 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 5.9 min Optical rotation : [o£]d24 -137.6° (c = 0.38, MeOH) iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.21 (6H, s), 5 10 15 20 Date Reçue/Date Received 2023-06-16 329 2.25 (1H, dd, J = 16.7, 3.3 Hz), 2.70 (1H, dd, J - 16.7, 6.7 Hz), 3.10-3.23 (1H, m), 3.87 (2H, s), 4.71 (1H, s), 7.05- 7.14 (1H, m), 7.34-7.41 (1H, m), 11.02 (1H, s).

[0478] The following compounds were prepared from each appropriate starting material in a similar manner to Example 124. (Example 125) (5R)-(-)-6-[3-Fluoro-4~(3-hydroxy-2,2-dimethylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 380] Optical purity: >99% ee <HPLC conditions of optical purity analysis> Column: Darcel CHTRALPAK (0.46 cmcp x 25 cm) Eluent: hexane/ethanol = 50/50 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 5.6 min [a]D24 -249.7° (c = 0.23, MeOH) iH-NMR (DMSO-d6) 5: 0.95 (6H, s), 1.05 (3H, d, J = 7.3 Hz), 5 10 15 20 Date Reçue/Date Received 2023-06-16 2.22 (1H, d, J = 16.9 Hz), 2.28 (3H, s), 2.66 (1H, dd, J = 16.9, 6.8 Hz), 3.27-3.42 (1H, m), 3.28-3.33 (2H, m), 3.79 (2H, d, J = 1.7 Hz), 4.60 (1H, t, J = 5.3 Hz), 7.38-7.49 (2H, m), 10.95 (1H, s). [0479] (Example 126) (5R)—(-)-6-[3-Chloro-2-fluoro-4-(2-hydroxyethoxy)phenyl]-5- methyl-4,5-dihydro-2H~pyridazin-3-one [Chem. 381] Optical purity: 98% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 emo x 25 cm) Eluent: hexane/ethanol = 60/40 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 8.4 min [a]d24 -137.2° (c = 0.22, MeOH) *H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J = 16.8, 3.7 Hz), 2.69 (1H, dd, J = 16.8, 6.7 Hz), 3.09- 3.20 (1H, m), 3.73-3.79 (2H, m), 4.17 (2H, t, J = 4.9 Hz), 5 10 15 20 Date Reçue/Date Received 2023-06-16 331 4.91 (1H, t, J = 5.3 Hz), 7.10 (1H, dd, J = 9.0, 1.3 Hz), 7.53 (1H, t, J = 9.0 Hz), 11.01 (1H, s). [0480] (Example 127) (5R)-(-)-6-[3-Bromo-5-chloro-4-(3-hydroxy-2,2- 3-one [Chern. 382] Optical purity: 97% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 emo x 25 cm) Eluent: hexane/ethanol = 60/40 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 5.5 min [a]d24 -231.9° (c = 0.18, MeOH) lH-NMR (DMSO-d6) 5: 1.03 (6H, s), 1.04 (3H, d, J = 6.8 Hz), 2.23 (1H, d, J = 16.9 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.34 (2H, d, J = 5.3 Hz), 3.37-3.47 (1H, m), 3.77 (2H, s), 5 10 15 20 Date Reçue/Date Received 2023-06-16 332 4.58 (1H, t, J = 5.3 Hz), 7.85 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 2.2 Hz), 11.08 (1H, s). [0481] (Example 128) Production of 6-[3-chloro-2-hydroxy-4- (2-hydroxy-2- iti©thylprouoxy) ph©ny11 “"“S —rfiothyl » 5“dihydro“2H*"oyridcizm-3 one [Chem. 383] To a mixture of 6- [3-chloro-4- (2-hydroxy-2-methylpropoxy)- 2- (methoxymethy1oxy ) pheny1]-5-methy1-4,5-dihydro-2Hpyridazin-3-one (Reference example 212, 130 mg) in ethanol (2.0 mL) was added hydrogen chloride (2 M ethanol solution, 0.351 mL) , and the mixture was stirred at room temperature overnxght. The reactxon mxxture was concentrated, and the residue was washed by trituration with diethyl ether to afford the title compound as a white solid (100 mg). ’li-NMR (DMSO-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 1.24 (6H, s), 2.25-2.34 (1H, m) , 2.81 (1H, dd, J = 17.0, 6.7 Hz), 3.48- 3.60 (1H, m) , 3.83 (2H, s) , 4.67 (1H, brs), 6.73 (1H, d, J = 9.3 Hz), 7.56 (1H, d, J = 9.3 Hz), 11.13 (1H, s) , 13.01 333 (1H, s). [0482] The following compounds were prepared from each appropriate starting material in a similar manner to Example 128. 5 (Example 129) 6-[3-Chloro-2-hydroxy-4-(2-hydroxy-2-methylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 384] 10 iH-NMR (DMSO-d6) 5: 1.12 (3H, d, J = 7.3 Hz), 1.28 (6H, s), 2.24-2.34 (1H, m), 2.26 (3H, s), 2.80 (1H, dd, J - 16.9, 6.6 Hz), 3.51-3.61 (1H, m), 3.64 (2H, s), 4.63 (1H, s), 7.46 (1H, s), 11.17 (1H, s), 12.78 (1H, s). [0483] 15 (Example 130) 6-[5—Chloro-2-hydroxy-4-(2-hydroxy-2-methylpropoxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 385] Date Reçue/Date Received 2023-06-16 334 1H-NMR (MS0-d6) 5: 1.10 (3H, d, J = 7.3 Hz), 1.28 (6H, s), 2.15 (3H, s), 2.27 (1H, dd, J= 16.8, 0.9 Hz), 2.78 (1H, dd, J = 16.8, 6.7 Hz), 3.50-3.66 (3H, m), 4.66 (1H, s), 7.55 (1H, 5 s), 11.18 (1H, s), 12.60 (1H, s). [0484] The following compounds were prepared from each appropriate starting material in a similar manner to Example 1. (Example 131) 10 6-[3-Chloro-2,5-difluoro-4-(2-hydroxy-2- methyIpropoxy)phenyl]-5-methyl-4,5-dihydro-2H~pyridazin-3- one [Chem. 386] 15 *H-NMR (DMSO-d6) 5: 1.06 (3H, d, J = 7.2 Hz), 1.24 (6H, s), 2.26 (1H, dd, J = 16.8, 3.5 Hz), 2.70 (1H, dd, J = 16.8, 6.8 Hz), 3.12-3.23 (1H, m), 3.91-3.97 (2H, m), 4.66 (1H, s), Date Reçue/Date Received 2023-06-16 335 7.55 (1H, dd, J = 12.3, 7.1 Hz), 11.13 (1H, s). [0485] (Example 132) 6-[2-Fluoro-4-(2-hydroxy-2-methylpropoxy)-3,5- 5 dimethylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 387] 1H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.3 Hz), 1.27 (6H, s), 2.17 (3H, d, J = 2.3 Hz), 2.22 (3H, s), 2.23 (1H, dd, J = 10 16.8, 3.8 Hz), 2.66 (1H, dd, J = 16.8, 6.7 Hz), 3.07-3.17 (1H, m), 3.51 (2H, s), 4.65 (1H, s), 7.24 (1H, d, J = 8.9 Hz), 10.96 (1H, s). [0486] (Example 133) 15 6-[2-Fluoro~4-(2-hydroxy~2-methylpropoxy)-3-vinylphenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 388] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 336 iH-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.6 Hz), 1.23 (6H, s), 2.23 (1H, dd, J = 16.9, 4.2 Hz), 2.66 (1H, dd, J = 16.9, 6.8 Hz), 3.06-3.18 (1H, m) , 3.82 (2H, s), 4.71 (1H, s), 5.53- 5.60 (1H, m) , 6.03-6.11 (1H, m) , 6.83 (1H, dd, J = 18.1, 12.0 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.43 (1H, t, J = 8.8 Hz), 1» 0. 9 (1II, st ) » [0487] (Example 134) 6- [ 3—Ethyl-2-fluoro-4- (2-hydroxy-2-methylpropoxy) phenyl]-5- methyl-4,5-dihydro-2H~pyridazin-3-one [Chem. 389] nH-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.3 Hz), 1.11 (3H, t, J = 7.3 Hz), 1.24 (6H, s) , 2.22 (1H, dd, J = 16.9, 3.9 Hz), 2.61—2.71 (3H, m) , 3.06-3.18 (1H, m) , 3.76 (2H, s) , 4.68 (1H, s) , 6.84 (1H, d, J = 9.0 Hz), 7.37 (1H, t, J = 9.0 Hz), 10.92 (1H, s) . [0488] (Example 135) 6- [2—Fluoro-4- (2-hydroxyethoxy)-3-vinylphenyl]-5-methyl- 4, 5-dihydro-2H-pyridazin-3-one 337 [Chem. 390] hH-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.1 Hz), 2.23 (1H, dd, J = 16.9, 3.9 Hz), 2.66 (1H, dd, J = 16.9, 6.8 Hz), 3.06- 5 3.18 (1H, m), 3.72-3.80 (2H, m), 4.10 (2H, t, J = 4.6 Hz), 4.91 (1H, t, J = 5.6 Hz), 5.54 (1H, dt, J = 12.2, 2.0 Hz), 6.06 (1H, dt, J = 18.1, 2.0 Hz), 6.80 (1H, dd, J = 18.1, 12.2 Hz), 6.95 (1H, d, J = 8.8 Hz), 7.43 (1H, t, J = 8.8 Hz), 10.95 (1H, s). 10 [0489] The following compounds were prepared from each appropriate starting material in a similar manner to Example 5. (Example 136) 6-[5-Chloro~2-fluoro-4-(3-hydroxy-2,2-dimethylpropoxy)-3- 15 methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 391] iH-NMR (DMSO-d6) 5: 1.00 (6H, s), 1.04 (3H, d, J = 7.2 Hz), Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 338 2.20-2.29 (4H, m), 2.68 (1H, dd, J - 16.8, 6.8 Hz), 3.09- 3.19 (1H, m), 3.34 (2H, d, J = 5.2 Hz), 3.66 (2H, s), 4.64 (1H, t, J = 5.2 Hz), 7.51 (1H, d, J = 8.1 Hz), 11.06 (1H, s). [0490] (Example 137) 6-[3—Chloro-2-fluoro-4-(3-hydroxy-2,2-dimethylpropoxy)-5- methylphenyl]~5~methyl~4,5-dihydro-2H-pyridazin-3-one [Chem. 392] iH-NMR (DMSO-d6) 5: 1.00 (6H, s), 1.04 (3H, d, J = 7.2 Hz), 2.21—2.30 (4H, m), 2.69 (1H, dd, J = 16.7, 6.7 Hz), 3.09- 3.19 (1H, m), 3.34 (2H, d, J = 5.2 Hz), 3.68 (2H, s), 4.62 (1H, t, J — 5.2 Hz), 7.42 (1H, d, J — 8.5 Hz), 11.07 (1H, s). [0491] (Example 138) 6-[2-Fluoro-4-(3-hydroxy-2,2-dimethylpropoxy)-3,5- dimethylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 3931 339 1H-NMR (MS0-d6) 5: 0.99 (6H, s), 1.03 (3H, d, J = 7.2 Hz), 2.16 (3H, d, J = 2.1 Hz), 2.18-2.27 (1H, m), 2.21 (3H, s), 2.66 (1H, dd, J = 16.9, 6.6 Hz), 3.06-3.16 (1H, m), 3.35 (2H, 5 d, J = 5.1 Hz), 3.50 (2H, s), 4.62 (1H, t, J = 5.1 Hz), 7.23 (1H, d, J = 9.0 Hz), 10.96 (1H, s). [0492] (Example 139) 6-[3-Chloro-2,5~difluoro-4-(3-hydroxy-2,2- 10 dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- — *■ - —-*...n. — - < - »* - - -*■ »* 3-one [Chern. 394] iH-NMR (DMSO-d6) 5: 0.96 (6H, s), 1.05 (3H, d, J = 7.2 Hz), 15 2.26 (1H, dd, J = 16.9, 3.5 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.12-3.21 (1H, m), 3.29-3.33 (2H, m), 3.98-4.00 (2H, m), 4.63 (1H, t, J = 5.3 Hz), 7.55 (1H, dd, J = 12.5, 7.1 Date Reçue/Date Received 2023-06-16 340 Hz), 11.13 (1H, s). [0493] (Example 140) 6-[3—Chloro-2,5-difluoro-4-(3-hydroxypropoxy)phenyl]-5- 5 methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 395] iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.82-1.92 (2H, m), 2.26 (1H, dd, J = 16.9, 3.6 Hz), 2.70 (1H, dd, J = 16.9, 10 6.8Hz), 3.12-3.22 (1H, m), 3.55-3.63 (2H, m), 4.24-4.32 (2H, m), 4.55 (1H, t, J = 5.1 Hz), 7.56 (1H, dd, J = 12.1, 7.1 Hz), 11.14 (1H, s). [0494] (Example 141) 15 6-[2—Fluoro-4-(3-hydroxypropoxy)-3,5-dimethylphenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 396] Date Reçue/Date Received 2023-06-16 341 ^-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 1.84-1.94 (2H, m), 2.15 (3H, d, J = 2.3 Hz), 2.19-2.27 (1H, m), 2.21 (3H, s), 2.66 (1H, dd, J = 16.7, 6.7 Hz), 3.06-3.17 (1H, m), 3.58- 5 3.66 (2H, m), 3.85 (2H, t, J = 6.3 Hz), 4.53 (1H, t, J = 5.1 Hz), 7.24 (1H, d, J = 8.9 Hz), 10.96 (1H, s). [0495] (Example 142) Production of 6-[3-chloro-4-(3-hydroxy-2-methylpropoxy)-5- 10 methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 397] A suspension of 6-(3-chloro-4-hydroxy-5-methylphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 86, 15 251 mg), 3-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (364 mg), and cesium carbonate (647 mg) in NMP (3.0 mL) was stirred at 150°C under microwave irradiation for 30 minutes. Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 342 To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtrated, and the solvent was removed. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 50 : 50 to 0 : 100 to ethyl acetate : methanol = 90 : 10), and the desired fractions were concentrated. The residue was crystallized from diisopropyl ether/2-propanol to afford the title compound as a white powder (224 mg). 'H-NMR (DMSO-d6) 6: 1.03 (3H, d, J = 6.6 Hz), 1.05 (3H, d, J = 6.3 Hz), 2.01-2.07 (1H, m), 2.22 (1H, d, J = 16.7 Hz), 2.31 (3H, s), 2.67 (1H, dd, J = 16.7, 7.0 Hz), 3.35-3.54 (3H, m), 3.72-3.77 (1H, m), 3.85-3.91 (1H, m), 4.56 (1H, t, J = 5.1 Hz), 7.60 (1H, d, J = 2.2 Hz), 7.66 (1H, d, J = 2.2 Hz), 10.99 (1H, s). [0496] The following compound was prepared from the appropriate starting material in a similar manner to Example 142. (Example 143) 6-[3-Chloro-4-(3-hydroxybutoxy)-5-methylphenyl]-5-methy1- 4,5-dihydro-2H-pyridazin-3-one [Chem. 398] 343 HT" ^-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.3 Hz), 1.13 (3H, d, J = 6.1 Hz), 1.74-1.88 (2H, m), 2.23 (1H, d, J = 16.7 Hz), 2.31 (3H, s), 2.67 (1H, dd, J = 16.7, 7.0 Hz), 3.33-3.42 (1H, 5 m), 3.82-4.03 (3H, m), 4.53 (1H, d, J = 4.9 Hz), 7.60 (1H, d, J = 2.2 Hz), 7.66 (1H, d, J = 2.2 Hz), 10.99 (1H, s). [0497] The following compounds were prepared from each appropriate starting material in a similar manner to Example 98. 10 (Example 144) 6-{3-Chloro-4-[1-(hydroxymethyl)cyclopropylmethoxy]-5- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 399] 15 *H-NMR (DMSO-d6) 5: 0.52-0.55 (4H, m), 1.05 (3H, d, J = 7.3 Hz), 2.22 (1H, d, J = 16.9 Hz), 2.32 (3H, s), 2.67 (1H, dd, J = 16.9, 6.8 Hz), 3.32-3.42 (1H, m), 3.53 (2H, d, J = 5.6 Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 344 Hz), 3.80 (2H, s), 4.57 (1H, t, J = 5.6 Hz), 7.59 (1H, d, J = 2.2 Hz), 7.64 (1H, d, J = 2.2 Hz), 10.97 (1H, s). [0498] (Example 145) 6-{2,3-Difluoro-4-[1- (hydroxymethyl)cyclopropylmethoxy]phenyl}-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chem. 400] iH-NMR (DMS0-d6) 5: 0.52-0.54 (4H, m), 1.05 (3H, d, J = 7.1 Hz), 2.24 (1H, dd, J = 16.9, 3.4 Hz), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.12-3.20 (1H, m), 3.39 (2H, d, J = 5.6 Hz), 4.03 (2H, s), 4.67 (1H, t, J = 5.6 Hz), 7.04-7.10 (1H, m), 7.37 (1H, td, J = 8.8, 2.2 Hz), 11.02 (1H, s). [0499] (Example 146) Production of 6-[3-chloro-2-hydroxy-4-(4-hydroxy-2,2- dimethylbutoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazîn-3- one [Chem. 401] 5 10 15 20 Date Reçue/Date Received 2023-06-16 A mixture of 6-[3-chloro-4-hydroxy-2- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one (Reference example 99, 250 mg), 4-(tert¬ butyldimethylsilyloxy)-2,2-dimethylbutan-l-ol (214 mg), triphenylphosphine (285 mg), and bis(2-methoxyethyl) azodicarboxylate (255 mg) in THF (10 mL) was stirred at room temperature overnight. The solvent was removed, and the residue was purified by silica gel column chromatography (heptane : ethyl acetate = 67 : 33 to 33 : 67) to afford a mixture containing the desired intermediate. To a mixture of the above intermediate in ethanol (2.0 mL) was added hydrogen chloride (2 M ethanol solution, 1.0 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtrated, and the filtrate was concentrated, and the obtained solid was washed by trituration with ethyl acetate/heptane to afford the title compound as a colorless solid (28 mg). iH-NMR (DMSO-d6) 5: 1.02 (6H, s), 1.10 (3H, d, J = 7.6 Hz), 1.57 (2H, t, J = 7.6 Hz), 2.29 (1H, d, J = 16.9 Hz), 2.80 (1H, dd, J= 16.9, 6.8 Hz), 3.47-3.60 (3H, m), 3.79 (2H, s), 4.32 (1H, t, J- 4.9 Hz), 6.70 (1H, d, J = 9.0 Hz), 7.55 (1H, 346 d, J = 9.0 Hz), 11.12 (1H, s), 13.00 (1H, s). [0500] The following compounds were prepared from each appropriate starting material m a similar manner to Example 48. 5 (Example 147) 6-[5—Chloro-2-fluoro-4-(2-hydroxypropoxy)-3-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 402] 10 iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 1.19 (3H, d, J = 6.2 Hz), 2.20-2.29 (4H, m), 2.68 (1H, dd, J - 16.8, 6.8 Hz), 3.08-3.19 (1H, m), 3.74-3.84 (2H, m), 3.94-4.04 (1H, m), 4.90-4.95 (1H, m), 7.51 (1H, d, J = 7.9 Hz), 11.06 (1H, s). 15 [0501] (Example 148) 6-[3-Chloro~2-fluoro-4-(2-hydroxypropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 403] Date Reçue/Date Received 2023-06-16 347 ^-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 1.19 (3H, d, J = 6.3 Hz), 2.25 (1H, dd, J = 16.8, 3.7 Hz), 2.29 (3H, s), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.09-3.20 (1H, m), 3.73- 5 3.86 (2H, m), 3.93-4.05 (1H, m), 4.90 (1H, d, J = 4.9 Hz), 7.43 (1H, d, J = 8.3 Hz), 11.07 (1H, s). [0502] (Example 149) 6-[3-Chloro-2,5~difluoro-4-(2-hydroxypropoxy)phenyl]-5- 10 methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 404] ’H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 1.18 (3H, d, J = 6.2 Hz), 2.26 (1H, dd, J = 16.9, 3.5 Hz), 2.70 (1H, dd, J 15 - 16.9, 6.8 Hz), 3.11-3.23 (1H, m), 3.89-4.12 (3H, m), 4.88 (1H, d, J = 4.8 Hz), 7.55 (1H, dd, J = 12.3, 7.1 Hz), 11.14 (1H, s). Date Reçue/Date Received 2023-06-16 348

[0503] The following compounds were prepared from each appropriate starting material in a similar manner to Example 76. (Example 150) 5 6-{2-Fluoro-4-[(Z)-4-hydroxy-2-butenyloxy]-3,5- dimethylphenyl}~~5—methyl~~4,5~~dihydro~~2H~pyridazin~~3—one [Chern. 405] iH-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.16 (3H, d, J 10 = 2.3 Hz), 2.20-2.28 (1H, m), 2.22 (3H, s), 2.66 (1H, dd, J = 16.7, 6.7 Hz), 3.06-3.16 (1H, m), 3.97-4.07 (2H, m), 4.39- 4.46 (2H, m), 4.77 (1H, t, J = 5.3 Hz), 5.68-5.79 (2H, m), 7.25 (1H, d, J = 8.9 Hz), 10.97 (1H, s). [0504] 15 (Example 151) 6-{3-Chloro-2-fluoro-4-[(Z)-4-hydroxy-2-buLenyloxy]-5- methylphenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 406] Date Reçue/Date Received 2023-06-16 349 ^-NMR (DMS0-d6) 5: 1.05 (3H, d, J = 7.1 Hz), 2.22-2.32 (1H, m), 2.27 (3H, s), 2.70 (1H, dd, J= 16.8, 6.8 Hz), 3.10-3.19 (1H, m), 3.97-4.07 (2H, m), 4.56-4.63 (2H, m), 4.78 (1H, t, 5 J = 5.4 Hz), 5.69-5.81 (2H, m), 7.44 (1H, d, J = 8.7 Hz), 11.08 (1H, s). [0505] (Example 152) 6-{3-Chloro-2,5-difluoro-4-[(Z)-4-hydroxy-2- 10 butenyloxy]phenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 407] m-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.26 (1H, dd, J = 16.8, 3.6 Hz), 2.71 (1H, dd, J = 16.8, 6.8 Hz), 3.12- 15 3.23 (1H, m), 3.97-4.05 (2H, m), 4.76-4.86 (3H, m), 5.63- 5.82 (2H, m), 7.56 (1H, dd, J = 12.0, 7.1 Hz), 11.14 (1H, s). Date Reçue/Date Received 2023-06-16 350 [0506] (Example 153) 6-{2-Hydroxy-4-[(Z)-4-hydroxy-2-butenyloxy]-3- methylphenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one 5 [Chem. 408] iR-NMR (DMSO-d6) 5: 1.10 (3H, d, J = 7.3 Hz), 2.01 (3H, s), 2.27 (1H, d, J = 16.7 Hz), 2.76 (1H, dd, J = 16.7, 6.7 Hz), 3.47-3.58 (1H, m), 4.05-4.14 (2H, m), 4.65-4.71 (2H, m), 10 4.81 (1H, t, J = 5.3 Hz), 5.60-5.77 (2H, m), 6.60 (1H, d, J = 8.8 Hz), 7.43 (1H, d, J = 8.8 Hz), 11.04 (1H, s), 12.48 (1H, s). [0507] (Example 154) 15 6-(3—Chloro-2-fluoro-4-{[(IS*,2R*)-2- (hydroxymethyl)cyclopropyl]methoxylphenyl)-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chem. 409] Date Reçue/Date Received 2023-06-16 351 iR-NMR (DMS0-d6) ô: 0.36-0.43 (1H, m), 0.77-0.85 (1H, m), 1.04 (3H, d, J = 7.3 Hz), 1.14-1.26 (1H, m), 1.29-1.40 (1H, m), 2.25 (1H, dd, J = 16.7, 3.5 Hz), 2.69 (1H, dd, J = 16.7, 5 6.8 Hz), 3.09-3.21 (1H, m), 3.46-3.55 (2H, m), 4.20 (2H, d, J =7.6 Hz), 4.39-4.47 (1H, m), 7.04-7.10 (1H, m), 7.53 (1H, t, J = 8.8 Hz), 11.02 (1H, s). [0508] (Example 155) 10 6-(3-Chloro-4-{[(lS*,2R*)-2- (hydroxymethyl)cyclopropyl]methoxy}-5-methylpheny1)-5- methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 410] 15 iH-NMR (DMSO-d6) 5: 0.28-0.35 (1H, m), 0.74-0.83 (1H, m), 1.05 (3H, d, J = 7.3 Hz), 1.11-1.23 (1H, m), 1.28-1.40 (1H, m), 2.19-2.27 (1H, m), 2.33 (3H, s), 2.67 (1H, dd, J= 16.9, 6.8 Hz), 3.33-3.51 (3H, m), 3.82-3.92 (1H, m), 4.00-4.09 (1H, Date Reçue/Date Received 2023-06-16 352 m), 4.41 (1H, t, J = 5.3 Hz), 7.58-7.62 (1H, m), 7.64-7.68 (1H, m), 10.98 (1H, s). [0509] (Example 156) 5 6-(3-Chloro-2-fluoro-4-{[(IS*,2S*)-2- (hydroxymethyl)cyclopropyl]methoxy[phenyl)-5-methyl-4,5- dihydro-2H-pyridazin-3-one [Chem. 411] 10 ]H-NMR (DMSO-d6) 5: 0.49-0.58 (2H, m), 0.99-1.20 (5H, m), 2.25 (1H, dd, J = 16.9, 3.5 Hz), 2.69 (1H, dd, J = 16.9, 6.8 Hz), 3.07-3.20 (1H, m), 3.25-3.41 (2H, m), 3.88-3.98 (1H, m), 4.11-4.20 (1H, m), 4.51 (1H, t, J = 5.6 Hz), 7.02-7.11 (1H, m), 7.53 (1H, t, J = 8.8 Hz), 11.02 (1H, s). 15 [0510] (Example 157) 6-{3-Chloro-2-hydroxy-4-[(Z)-4-hydroxy-2- butenyloxy]phenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 412] Date Reçue/Date Received 2023-06-16 353 ^-NMR (DMS0-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 2.26-2.32 (1H, m), 2.80 (1H, dd, J = 16.9, 6.6 Hz), 3.49-3.61 (1H, m), 4.08- 4.16 (2H, m), 4.75-4.86 (3H, m), 5.59-5.69 (1H, m), 5.70- 5 5.80 (1H, m), 6.75 (1H, d, J = 9.0 Hz), 7.57 (1H, d, J = 9.0 Hz), 11.13 (1H, s), 13.02 (1H, s).

[0511] The following compounds were prepared from each appropriate starting material in a similar manner to Example 107. 10 (Example 158) 6-[5-Chloro-4-(2,2-difluoro-3-hydroxypropoxy)-2-fluoro-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 413] 15 *H-NMR (DMSO-d6) 5: 1.04 (3H, d, J = 7.2 Hz), 2.21-2.31 (4H, m), 2.69 (1H, dd, J = 16.7, 6.7 Hz), 3.08-3.18 (1H, m), 3.80 (2H, td, J = 13.8, 6.1 Hz), 4.32 (2H, t, J = 13.5 Hz), 5.68 Date Reçue/Date Received 2023-06-16 354 (1H, t, J - 6.1 Hz), 7.55 (1H, d, J = 7.9 Hz), 11.08 (1H, s). [0512] (Example 159) 5 6-[3-Chloro-4-(2,2-difluoro-3-hydroxypropoxy)-2-fluoro-5- [Chem. 414] iH-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.26 (1H, dd, 10 J = 16.9, 3.8 Hz), 2.29 (3H, s), 2.70 (1H, dd, J = 16.9, 6.8 Hz), 3.10-3.20 (1H, m), 3.81 (2H, td, J - 13.9, 6.1 Hz), 4.32 (2H, t, J = 13.4 Hz), 5.67 (1H, t, J = 6.1 Hz), 7.46 (1H, d, J = 8.5 Hz), 11.09 (1H, s). [0513] 15 (Example 160) 6~[4—(2,2-Difluoro-3-hydroxypropoxy)-2-fluoro-3,5- dimethylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 415] Date Reçue/Date Received 2023-06-16 355 ^-NMR (DMS0-d6) 5: 1.04 (3H, d, J = 7.1 Hz), 2.18 (3H, d, J = 2.3 Hz), 2.237 (1H, dd, J = 16.8, 3.7 Hz), 2.238 (3H, s), 2.66 (1H, dd, J = 16.8, 6.8 Hz), 3.06-3.17 (1H, m), 3.80 (2H, 5 td, J = 13.8, 6.1 Hz), 4.14 (2H, t, J = 13.3 Hz), 5.68 (1H, t, J = 6.1 Hz), 7.27 (1H, d, J = 8.8 Hz), 11.00 (1H, s). [0514] (Example 161) 6-[3-Chloro-4-(2,2-difluoro-3-hydroxypropoxy)-2,5- 10 difluorophenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 416] ’H-NMR (DMSO-d6) 5: 1.05 (3H, d, J = 7.2 Hz), 2.27 (1H, dd, J = 16.9, 3.6 Hz), 2.71 (1H, dd, J = 16.9, 6.8 Hz), 3.12- 15 3.23 (1H, m), 3.79 (2H, td, J= 13.8, 6.2 Hz), 4.55 (2H, t, J = 13.1 Hz), 5.68 (1H, t, J = 6.2 Hz), 7.61 (1H, dd, J = 12.2, 7.1 Hz), 11.16 (1H, s). Date Reçue/Date Received 2023-06-16 356 [0515] (Example 162) 6-[3-Chloro-4-(2,2-difluoro-3-hydroxypropoxy)-2- hydroxyphenyl]-5-methyl-4,5-dihydro~2H-pyridazin-3—one 5 [Chem. 417] iR-NMR (DMSO-d6) 5: 1.10 (3H, d, J = 7.3 Hz), 2.29 (1H, d, J = 16.8 Hz), 2.80 (1H, dd, J = 16.8, 6.8 Hz), 3.50-3.62 (1H, m), 3.80 (2H, td, J = 13.9, 6.4 Hz), 4.46 (2H, t, J = 12.5 10 Hz), 5.68 (1H, t, J = 6.4 Hz), 6.83 (1H, d, J = 9.3 Hz), 7.60 (1H, d, J = 9.3 Hz), 11.16 (1H, s), 13.08 (1H, s). [0516] The following compounds were prepared from each appropriate starting material in a similar manner to Example 74. 15 (Example 163) 6-[3-Chloro-2-hydroxy-4-(2-hydroxybutoxy)phenyl]-5-methyl- 4,5~dihydro~2H-pyridazin-3-one [Chem. 418] Date Reçue/Date Received 2023-06-16 357 ^-NMR (DMS0-d6) 5: 0.93 (3H, t, J = 7.3 Hz), 1.11 (3H, d, J = 7.3 Hz), 1.37-1.51 (1H, m), 1.56-1.70 (1H, m), 2.29 (1H, d, J = 16.9 Hz), 2.79 (1H, dd, J = 16.9, 6.8 Hz), 3.49-3.60 5 (1H, m) , 3.68-3.79 (1H, m), 3.90-4.05 (2H, m), 4.85-4.90 (1H, m), 6.75 (1H, d, J = 9.3 Hz), 7.55 (1H, d, J = 9.3 Hz), 11.13 (1H, s), 13.00-13.03 (1H, m). [0517] (Example 164) 10 6-[3-Chloro-2-hydroxy-4-(2-hydroxypropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 419] iH-NMR (DMSO-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 1.19 (3H, d, J 15 - 6.2 Hz), 2.25 (3H, s), 2.30 (1H, dd, J = 16.8, 1.1 Hz), 2.79 (1H, dd, J = 16.8, 6.7 Hz), 3.51-3.61 (1H, m) , 3.68- 3.81 (2H, m), 3.93-4.03 (1H, m), 4.84-4.90 (1H, m), 7.46 (1H, Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 358 s), 11.17 (1H, s), 12.78 (1H, s). [0518] (Example 165) Production of 6-{3-bromo-5-chloro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro~2Hpyridazin-3-one [Chern. 420] To a mixture of 6-(3-bromo-5-chioro-4-hydroxyphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 87, 318 mg) and [1-(tetrahydro-2H-pyran-2- yloxy)cyclopropyl]methanol (207 mg) in THF (5.0 mL) were added triphenylphosphine (315 mg) and bis(2-methoxyethyl) azodicarboxylate (281 mg) at 0°C. The reaction mixture was stirred at room temperature for one hour, and then the solvent was removed. The residue was diluted with ethyl acetate, washed with 1 M aqueous sodium hydroxide and then brine, dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by silica gel column chromatography (heptane : ethyl acetate = 71 : 29 to 50 : 50 to 32 : 68) to afford a colorless amorphous. The amorphous 5 10 15 20 Date Reçue/Date Received 2023-06-16 359 was dissolved in ethanol (5.0 mL), pyridinium ptoluenesulfonate (23 mg) was added to the mixture, and the mixture was stirred at 60°C for 30 minutes. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M aqueous sodium hydroxide and then brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The obtained solid was washed by trituration with diisopropyl ether to afford the title compound as a white solid (282 mg). ^-NMR (DMSO-d6) 5: 0.67-0.78 (4H, m), 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 Hz), 3.36-3.46 (1H, m), 3.97-4.03 (2H, m), 5.63 (1H, s), 7.85 (1H, d, J = 2.2 Hz), 7.95 (1H, d, J = 2.2 Hz), 11.08 (1H, s). [0519] The following compounds were prepared from each appropriate starting material in a similar manner to Example 165. (Example 166) 6-{2-Hydroxy-4-[(l-hydroxycyclopropyl)methoxy]-3- methylphenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 421] 360 1H-NMR (DMSO-d6) 5: 0.60-0.73 (4H, m), 1.10 (3H, d, J = 7.3 Hz), 2.05 (3H, s), 2.26 (1H, d, J = 16.7 Hz), 2.76 (1H, dd, J = 16.7, 6.7 Hz), 3.47-3.58 (1H, m), 3.96-4.05 (2H, m), 5 5.55 (1H, s), 6.57 (1H, d, J = 9.0 Hz), 7.41 (1H, d, J = 9.0 Hz), 11.02 (1H, s), 12.45 (1H, s). [0520] (Example 167) 6-{3-Chloro-2-fluoro-4-[(1-hydroxycyclopropyl)methoxy]-5- 10 methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 422] m-NMR (DMSO-d6) 5: 0.61-0.74 (4H, m), 1.05 (3H, d, J = 7.2 Hz), 2.25 (1H, dd, J =16.9, 3.7 Hz), 2.32 (3H, s), 2.69 (1H, 15 dd, J = 16.9, 6.8 Hz), 3.09-3.19 (1H, m), 3.95 (2H, s), 5.63 (1H, s), 7.39-7.45 (1H, m), 11.06 (1H, s). [0521] Date Reçue/Date Received 2023-06-16 361 (Example 168) 6-{3-Bromo-2-fluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl)-5-methyl-4,5-dihydro-2Hpyridazin-3-one 5 [Chern. 423] ^-NMR (DMSO-d6) 5: 0.64-0.76 (4H, m), 1.04 (3H, d, J = 7.2 Hz), 2.24 (1H, dd, J = 16.8, 3.7 Hz), 2.69 (1H, dd, J = 16.8, 6.8 Hz), 3.08-3.19 (1H, m), 4.15 (2H, s), 5.59 (1H, s), 7.06 10 (1H, dd, J = 9.0, 1.0 Hz), 7.56 (1H, t, J = 9.0 Hz), 11.01 (1H, s). [0522] (Example 169) 6-{3-Bromo-5-fluoro-4-[(1- 15 hydroxycyclopropyl)methoxy]phenyl)-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chern. 424] Date Reçue/Date Received 2023-06-16 362 (F 1H-NMR (MS0-d6) 5: 0.65-0.72 (4H, m), 1.04 (3H, d, J = 7.3 Hz), 2.23 (1H, d, J = 16.8 Hz), 2.69 (1H, dd, J = 16.8, 6.9 Hz), 3.35-3.45 (1H, m), 4.09 (2H, s), 5.55 (1H, s), 7.66 (1H, 5 dd, J = 12.5, 2.1 Hz), 7.81 (1H, t, J = 2.1 Hz), 11.06 (1H, s). [0523] (Example 170) 6-{3,5-Dichloro~4-[(1-hydroxycyclopropyl)methoxy]phenyl)-5- 10 methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 425] m-NMR (DMSO-d6) 5: 0.66-0.75 (4H, m), 1.04 (3H, d, J = 7.2 Hz), 2.24 (1H, d, J = 16.9 Hz), 2.69 (1H, dd, J = 16.9, 7.0 15 Hz), 3.36-3.47 (1H, m), 4.01 (2H, s), 5.61 (1H, s), 7.81 (2H, s), 11.08 (1H, s). [0524] Date Reçue/Date Received 2023-06-16 363 (Example 171) 6-{2-Fluoro-4-[(1-hydroxycyclopropyl)methoxy]-3,5- dimethylphenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 426] iH-NMR (DMSO-d6) 5: 0.59-0.71 (4H, m), 1.04 (3H, d, J = 7.2 Hz), 2.19 (3H, d, J = 2.4 Hz), 2.23 (1H, dd, J = 16.8, 3.8 Hz), 2.24 (3H, s), 2.65 (1H, dd, J = 16.8, 6.7 Hz), 3.06- 3.17 (1H, m), 3.77 (2H, s), 5.65 (1H, s), 7.23 (1H, d, J = 10 8.9 Hz), 10.96 (1H, s). [0525] (Example 172) 6-{3—Chloro-2,5-difluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro-2H- 15 pyridazin-3-one [Chem. 427] Date Reçue/Date Received 2023-06-16 5 10 15 20 Date Reçue/Date Received 2023-06-16 364 iH-NMR (DMSO-d6) 5: 0.62-0.72 (4H, m), 1.05 (3H, d, J = 7.2 Hz), 2.26 (1H, dd, J = 16.8, 3.6 Hz), 2.70 (1H, dd, J = 16.8, 6.8 Hz), 3.12-3.21 (1H, m), 4.17 (2H, s), 5.54 (1H, s), 7.54 (1H, dd, J = 12.1, 7.1 Hz), 11.13 (1H, s). [0526] (Sxample 173) Production of 6-[3-chloro-2-hydroxy-4-(3-hydroxypropoxy)-5- methylphenyl]~5~methyl~4,5-dihydro-2H-pyridazin-3-one [Chem. 428] To a mixture of 6-[3-chloro-4-hydroxy-2-(methoxymethyloxy)- 5-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 203, 313 mg) and 3-(tetrahydro-2H-pyran- 2-yloxy)propan-l-ol (208 mg) in THF (5.0 mL) were added triphenylphosphine (341 mg) and bis(2-methoxyethyl) azodicarboxylate (304 mg) at 0°C, and then the mixture was stirred at room temperature for one hour. The solvent was removed, and the residue was diluted with ethyl acetate. The solution was washed with 1 M aqueous sodium hydroxide and then brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The obtained crude product 5 10 15 20 Date Reçue/Date Received 2023-06-16 365 was purified by silica gel column chromatography (heptane : ethyl acetate = 61 : 39 to 40 : 60 to 33 : 67) to afford a colorless amorphous. The amorphous was dissolved in ethanol (5.0 mL), and hydrogen chloride (2 M ethanol solution, 1.0 mL) was added to the mixture. The mixture was stirred at room temperature for one hour. To the reaction mixture was added water, and the precipitates were collected on a filter, and dried to afford the title compound as a white solid (256 mg). iH-NMR (DMSO-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 1.85-1.96 (2H, m), 2.23 (3H, s), 2.30 (1H, d, J = 16.8 Hz), 2.79 (1H, dd, J - 16.8, 6.7 Hz), 3.50-3.67 (3H, m), 3.98 (2H, t, J = 6.5 Hz), 4.51 (1H, t, J = 5.1 Hz), 7.46 (1H, s), 11.17 (1H, s), 12.77 (1H, s). [0527] The following compounds were prepared from each appropriate starting material in a similar manner to Example 173. (Example 174) 6-{3—Chloro-2-hydroxy—4-[(1- hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chern. 429] 366 1H-NMR (MS0-d6) 5: 0.62-0.74 (4H, m), 1.11 (3H, d, J = 7.3 Hz), 2.29 (1H, d, J = 16.8 Hz), 2.80 (1H, dd, J = 16.8, 6.8 Hz), 3.50-3.60 (1H, m), 4.07-4.15 (2H, m), 5.57 (1H, s), 5 6.76 (1H, d, J = 9.2 Hz), 7.55 (1H, d, J = 9.2 Hz), 11.12 (1H, s), 13.01 (1H, s). [0528] (Example 175) 6-{3-Chloro-2-hydroxy-4-[(1-hydroxycyclopropyl)methoxy]-5- 10 methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 430] m-NMR (DMSO-d6) 5: 0.62-0.74 (4H, m), 1.12 (3H, d, J = 7.3 Hz), 2.29 (3H, s), 2.30 (1H, dd, J= 16.9, 1.3 Hz), 2.79 (1H, 15 dd, J = 16.9, 6.7 Hz), 3.51-3.62 (1H, m), 3.87-3.94 (2H, m), 5.61 (1H, s), 7.46 (1H, s), 11.16 (1H, s), 12.76 (1H, s). [0529] Date Reçue/Date Received 2023-06-16 367 (Example 176) 6-{5-Chloro-2-hydroxy-4-[(l-hydroxycyclopropyl)methoxy]-3- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 431] iH-NMR (DMS0-d6) 5: 0.61-0.73 (4H, m), 1.10 (3H, d, J = 7.3 Hz), 2.19 (3H, s), 2.27 (1H, dd, J= 16.9, 1.2 Hz), 2.77 (1H, dd, J = 16.9, 6.7 Hz), 3.50-3.60 (1H, m), 3.88 (2H, s), 5.64 (1H, s), 7.53 (1H, s), 11.17 (1H, s), 12.58 (1H, s). 10 [0530] (Example 177) Production of 6-[4-(1,l-difluoro-2-hydroxyethoxy)-2-fluoro- 5-methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 432] 15 To a mixture of 6-(2-fluoro-4-hydroxy-5-methylphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example Date Reçue/Date Received 2023-06-16 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 368 205, 472 mg) and ethyl bromodifluoroacetate (0.385 mL) in DMF (10 mL) was added potassium carbonate (415 mg) at 0°C. The mixture was gradually warmed to room temperature, and stirred overnight » To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The residue was purified by silica gel column chromatography (heptane : ethyl acetate = 68 : 32 to 47 : 53 to 40 : 60) to afford a colorless amorphous. The amorphous was dissolved in THF (6.0 mL), and lithium borohydride (44 mg) was added to the mixture at 0°C. The reaction mixture was stirred at room temperature for one hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The obtained crude product was purified by silica gel column chromatography (heptane : ethyl acetate = 53 : 47 to 32 : 68 to 29 : 71), and the desired fractions were concentrated. The residue was washed by trituration with diisopropyl ether to afford the title compound as a white solid (44 mg). iH-NMR (DMSO-d6) 5: 1.06 (3H, d, J = 7.2 Hz), 2.21-2.29 (1H, m), 2.22 (3H, s), 2.69 (1H, dd, J= 16.8, 6.8 Hz), 3.11-3.21 (1H, m), 3.85-3.96 (2H, m), 5.94 (1H, t, J = 6.7 Hz), 7.14 (1H, d, J - 11.7 Hz), 7.54 (1H, d, J = 8.5 Hz), 11.06 (1H, 5 10 15 20 Date Reçue/Date Received 2023-06-16 369 s). [0531] Each absolute configuration of Examples 178 - 183 shown below was extrapolated by comparison with Example 116. (Example 178) Production of (5R)-(-)-6-[2-hydroxy-4-(3-hydroxypropoxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 433] 6-[4-(3-Hydroxypropoxy)-2-(methoxymethyloxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one (Reference example 228, 695 mg) was optically-resolved by chiral column chromatography according to the following preparative condition to afford chiral 6-[4-(3- hydroxypropoxy)-2-(methoxymethyloxy)-3-methylphenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one as a colorless amorphous (322 mg, 99% ee). <Preparative condition> Column: Daicel CHIRALFLASH IA (3.0 cmtp x 10 cm) Eluent: hexane/ethanol = 80/20 Flow rate: 15 ml/min 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 370 Detection: UV (254 nm). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 cmcp x 25 cm) Eluent: hexane/ethanol — 40/60 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 4.7 min 1H-NMR (CDC13) 5: 1.06 (3H, d, J = 7.3 Hz), 1.77-1.85 (1H, m), 2.09 (2H, quintet, J = 6.0 Hz), 2.19 (3H, s), 2.41 (1H, dd, J = 17.1, 4.6 Hz), 2.78 (1H, dd, J = 17.1, 7.0 Hz), 3.28- 3.37 (1H, m), 3.50 (3H, s), 3.87-3.91 (2H, m), 4.15 (2H, t, J = 6.0 Hz), 4.88 (1H, d, J = 5.6 Hz), 4.98 (1H, d, J = 5.6 Hz), 6.70 (1H, d, J = 8.5 Hz), 7.14 (1H, d, J= 8.5 Hz), 8.56 (1H, brs). [0532] To a mixture of the above-obtained chiral 6-[4-(3- hydroxypropoxy)-2-(methoxymethyloxy)-3-methylphenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one (291 mg) in ethanol (1.5 mL) was added hydrogen chloride (2 M ethanol solution, 0.865 mL), and then the mixture was stirred at room temperature for one hour. The precipitated solid was collected on a filter, and then recrystallized from 2- propanol to afford the title compound as a white solid (182 mg, >99% ee). <HPLC conditions of optical purity analysis> 5 10 15 20 Date Reçue/Date Received 2023-06-16 371 Column: Daicel CHIRALPAK AS-RH (0.46 cmtp x 15 cm) Eluent: acetonitrile/water = 40/60 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 5.2 min Optical rotation : [a]D3- -332.1° (c = 0.26, MeOH) ^H-NMR (DMSO-d6) 6: 1.10 (3H, d, J = 7.3 Hz), 1.84-1.92 (2H, m), 2.01 (3H, s), 2.27 (1H, dd, J= 16.9, 1.3 Hz), 2.76 (1H, dd, J = 16.9, 6.6 Hz), 3.48-3.61 (3H, m), 4.08 (2H, t, J = 6.2 Hz), 4.55 (1H, t, J = 5.1 Hz), 6.59 (1H, d, J = 9.0 Hz), 7.43 (1H, d, J = 9.0 Hz), 11.03 (1H, s), 12.46 (1H, s). [0533] The following compounds were prepared from each appropriate starting material in a similar manner to Example 178. (Example 179) (5R)-(-)-6-[2-hydroxy-4-(2-hydroxy-2-methylpropoxy)-3- methylphenyl]-5~methyl-4,5-dihydro-2H-pyridazin-3-one [Chern. 434] Chiral 6-[4-(2-hydroxy-2-methylpropoxy)-2- (methoxymethyloxy)-3-methylphenyl]-5-methyl-4,5-dihydro-2H 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 372 pyridazin-3-one Optical purity: 98% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 emo x 25 cm) Eluent: hexane/ethanol = 50/50 Flow rate: 1.0 ml/mm Detection: UV (254 nm). Retention time: 5.6 min ’li-NMR (CDC13) 5: 1.07 (3H, d, J = 7.3 Hz), 1.38 (6H, s), 2.16 (1H, s), 2.24 (3H, s), 2.41 (1H, dd, J = 17.1, 4.6 Hz), 2.79 (1H, dd, J = 17.1, 6.8 Hz), 3.28-3.38 (1H, m), 3.51 (3H, s), 3.82 (2H, s), 4.89 (1H, d, J = 5.6 Hz), 5.00 (1H, d, J = 5.6 Hz), 6.67 (1H, d, J = 8.5 Hz), 7.14 (1H, d, J = 8.5 Hz), 8.46 (1H, brs). [0534] (5R)-(-)-6-[2-hydroxy-4-(2-hydroxy-2-methylpropoxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one Optical purity: 98% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK AS-RH (0.46 cm(p x 15 cm) Eluent: acetonitrile/water = 35/75 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 7.5 min Optical rotation : [a]D31 -312.2° (c = 0.24, MeOH) 5 10 15 20 373 Date Reçue/Date Received 2023-06-16 iH-NMR (DMSO-d6) 5: 1.10 (3H, d, J = 7.3 Hz), 1.23 (6H, s), 2.05 (3H, s), 2.23-2.31 (1H, m), 2.76 (1H, dd, J = 16.7, 6.7 Hz), 3.47-3.57 (1H, m), 3.74 (2H, s), 4.65 (1H, s), 6.55 (1H, d, J = 9.0 Hz), 7.42 (1H, d, J = 9.0 Hz), 11.03 (1H, s), 12.46 (1H, s). [0535] (Example 180) (5R)-(-)-6-[3~chloro-2~hydroxy-4-(4-hydroxybutoxy)phenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 435] Chiral 6-[3-chloro-4-(4-hydroxybutoxy)-2- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one Optical purity: >99% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 cmcp x 25 cm) Eluent: hexane/ethanol = 15/85 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 4.6 min iH-NMR (CDC13) 5: 1.07 (3H, d, J = 7.3 Hz), 1.50-1.54 (1H, 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 374 m), 1.77-1.85 (2H, m), 1.94-2.01 (2H, m), 2.42 (1H, dd, J = 17.0, 4.8 Hz), 2.80 (1H, dd, J = 17.0, 7.0 Hz), 3.32-3.40 (1H, m), 3.53 (3H, s), 3.74-3.79 (2H, m), 4.11 (2H, t, J = 6.1 Hz), 5.01 (1H, d, J = 5.6 Hz), 5.16 (1H, d, J = 5.6 Hz), 6.77 (1H, d, J = 8.8 Hz), 7.21 (1H, d, J = 8.8 Hz), 8.45 (1H, brs). [0536] (5R)-(-)-6-[3-chloro-2-hydroxy-4-(4-hydroxybutoxy)phenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one Optical purity: >99% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK AS-RH (0.46 cmcp x 15 cm) Eluent: acetonitrile/water = 40/60 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 4.7 min Optical rotation: [ck]d31 -305.4° (c = 0.24, MeOH) iR-NMR (DMSO-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 1.53-1.64 (2H, m), 1.73-1.84 (2H, m), 2.25-2.34 (1H, m), 2.79 (1H, dd, J = 16.9, 6.8 Hz), 3.42-3.50 (2H, m), 3.50-3.60 (1H, m), 4.12 (2H, t, J = 6.4 Hz), 4.46 (1H, t, J = 5.1 Hz), 6.73 (1H, d, J = 9.0 Hz), 7.56 (1H, d, J = 9.0 Hz), 11.13 (1H, brs), 13.01 (1H, brs). [0537] (Example 181) 5 10 15 20 Date Reçue/Date Received 2023-06-16 375 (5R)-(-)-6-[3-chloro-2-hydroxy-4-(3-hydroxypropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one [Chem. 436] Chiral 6-[3-chloro-4-(3-hydroxypropoxy)-2- (methoxymethyloxy)-5-methylphenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one Optical purity: >99% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 emo x 25 cm) Eluent: hexane/ethanol = 25/75 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 3.9 min 1H-NMR (CDCI3) 5: 1.08 (3H, d, J = 7.6 Hz), 1.90 (1H, t, J = 5.5 Hz), 2.07-2.13 (2H, m), 2.30 (3H, d, J = 0.7 Hz), 2.42 (1H, dd, J = 17.0, 4.9 Hz), 2.80 (1H, dd, J = 17.0, 7.0 Hz), 3.30-3.39 (1H, m), 3.52 (3H, s), 3.97 (2H, td, J = 5.9, 5.5 Hz), 4.09 (2H, t, J = 5.9 Hz), 4.98 (1H, d, J = 5.4 Hz), 5.12 (1H, d, J = 5.4 Hz), 7.08 (1H, d, J = 0.7 Hz), 8.49 (1H, S). 5 10 15 20 Date Reçue/Date Received 2023-06-16 376 [0538] (5R)-(-)-6-[3-chloro-2-hydroxy-4-(3-hydroxypropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one Optical purity: 96% ee <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK AS-RH (0.46 cmcp x 15 cm) Eluent: acetonitrile/water = 40/60 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 4.7 min Optical rotation: [«Id31 -286.0° (c = 0.23, MeOH) iH-NMR (DMSO-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 1.85-1.96 (2H, m), 2.23 (3H, s), 2.30 (1H, d, J = 16.8 Hz), 2.79 (1H, dd, J = 16.8, 6.7 Hz), 3.50-3.67 (3H, m), 3.98 (2H, t, J = 6.5 Hz), 4.51 (1H, t, J = 5.1 Hz), 7.46 (1H, s), 11.17 (1H, s), 12.77 (1H, s). [0539] (Example 182) Production of (5R)-(-)-6-[3-chloro-2-hydroxy-4-(2—hydroxy- 2-methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one [Chern. 437] 5 10 15 20 Date Reçue/Date Received 2023-06-16 377 6—[3-Chloro-4—(2—hydroxy—2—methyIpropoxy)—2— (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one (Reference example 212, 525 mg) was optically-resolved by chiral column chromatography according to the following preparative condition to afford chiral 6- [4-(3—hydroxypropoxy)-2-(methoxymethyloxy)-3-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one as a colorless amorphous (220 mg, 99% ee). <Preparative condition> Column: Daicel CHIRALFLASH TA (3.0 cmtp x 10 cm) Eluent: hexane/ethanol = 75/25 Flow rate: 15 ml/min Detection: UV (254 nm). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 cmcp x 25 cm) Eluent: hexane/ethanol = 40/60 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 5.2 min ir-NMR (CDC13) 5: 1.07 (3H, d, J = 7.3 Hz), 1.39 (6H, s), 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 378 2.42 (1H, dd, J = 17.0, 4.8 Hz), 2.80 (1H, dd, J - 17.0, 7.0 Hz), 3.30-3.41 (1H, m), 3.53 (3H, s), 3.87 (2H, s), 5.01- 5.06 (1H, m), 5.14-5.20 (1H, m), 6.76 (1H, d, J = 8.5 Hz), 7.22 (1H, d, J = 8.5 Hz), 8.44 (1H, brs).

[0540] To a mixture of the above-obtained chiral 6-[4-(3- hydroxypropoxy)-2-(methoxymethyloxy)-3-methylphenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one (164 mg) in ethanol (1.0 mL) was added hydrogen chloride (2 M ethanol solution, 0.442 mL), and then the mixture was stirred at room temperature for one hour. The precipitates were collected on a filter, and then recrystallized from 2-propanol to afford the title compound as a white solid (57 mg, 99% ee). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK AS-RH (0.46 amp x 15 cm) Eluent: acetonitrile/water = 35/65 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 6.5 mxn Optical rotation : [of]n30 -291.0° (c = 0.26, MeOH) m-NMR (DMSO-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 1.24 (6H, s), 2.25-2.34 (1H, m), 2.81 (1H, dd, J = 17.0, 6.7 Hz), 3.48- 3.60 (1H, m), 3.83 (2H, s), 4.67 (1H, brs), 6.73 (1H, d, J = 9.3 Hz), 7.56 (1H, d, J = 9.3 Hz), 11.13 (1H, s), 13.01 (1H, s). 5 10 15 20 Date Reçue/Date Received 2023-06-16 379 [0541] (Example 183) Production of hydroxy-2-butenyloxy]phenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one [Chem. 438] Chiral 6-[3—Chloro-4-[(Z)-4-hydroxy-2-butenyloxy]-2- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one (Reference example 229, 497 mg) was optically-resolved by chiral column chromatography according to the following preparative condition to afford chiral 6- [3-chloro-4-[(Z)-4-hydroxy-2-butenyloxy]-2- (methoxymethyloxy)phenyl]-5-methyl-4,5-dihydro-2Hpyridazin-3-one as a colorless amorphous (232 mg, >99% ee). <Preparative condition> Column: Daicel CHIRALFLASH IA (3.0 cmcp x 10 cm) Eluent: hexane/ethanol = 70/30 Flow rate: 15 ml/min Detection: UV (254 nm). <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK IA (0.46 emo x 25 cm) 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 380 Eluent: hexane/ethanol = 20/80 Flow rate: 1.0 ml/min Detection: UV (254 nm). Retention time: 4 » 6 mm iH-NMR (CDC13) 5: 1.07 (3H, d, J = 7.3 Hz), 1.63-1.68 (1H, mt) , ( 1>1 , cld, t) 1> 1. 0, ^1. £1 11 ) , 2*80 (1H, dd, J 17.0, 7.0 Hz), 3.31-3.40 (1H, m), 3.53 (3H, s) , 4.29-4.35 (2H, m), 4.72-4.77 (2H, m) , 5.02 (1H, d, J = 5.6 Hz), 5.16 (1H, d, J = 5.6 Hz) , 5.83-5.96 (2H, m) , 6.78 (1H, d, J = 8.5 Hz) , 7.22 (1H, d, J= 8.5 Hz), 8.52 (1H, s) .

[0542] To a mixture of the above-obtained chiral 6- [3-chloro-4- [ (Z) -4-hydroxy-2-butenyloxy]-2- (methoxymethyloxy) phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one (204 mg) in ethanol (1.0 mL) was added hydrogen chloride (2 M ethanol solution, 0.442 mL) , and then the mixture was stirred at room temperature for one hour. The precipitates were collected on a filter, and then recrystallized from hexane/2-propanol to afford the title compound as a white solid (54 mg, 93% ee) . <HPLC conditions of optical purity analysis> Column: Daicel CHIRALPAK AS-RH (0.46 cmcp x 15 cm) Eluent: acetonitrile/water = 35/65 Flow rate: 1.0 ml/min Detection: UV (254 nm). 5 10 15 20 Date Reçue/Date Received 2023-06-16 381 Retention time: 6.5 min Optical rotation : [a]D31 -274.0°(c = 0.23, MeOH) iH-NMR (DMSO-d6) 5: 1.11 (3H, d, J = 7.3 Hz), 2.26-2.32 (1H, m), 2.80 (1H, dd, J = 16.9, 6.6 Hz), 3.49-3.61 (1H, m), 4.08- 4.16 (2H, m), 4.75-4.86 (3H, m), 5.59-5.69 (1H, m), 5.70- 5.80 (1H, m), 6.75 (1H, d, J — 9.0 Hz), 7.57 (1H, d, J 9.0 Hz), 11.13 (1H, s), 13.02 (1H, s). [0543] (Example 184) Production of 6-[2-fluoro-4-(2-hydroxy-2-methylpropoxy)-3- (trifluoromethyl)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one [Chern. 439] To a mixture of 6-[2-fluoro-4-hydroxy-3- (trifluoromethyl)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one (Reference example 242, 290 mg) in DMF (5.0 mL) were added potassium carbonate (207 mg) and 3-chloro-2-methyl-1- propene (0.117 mL), and then the mixture was stirred at 80°C for one hour. 3-Chloro-2-methyl-l-propene (0.029 mL) was added to the reaction mixture, and then the reaction mixture 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 382 was stirred at 80°C further for 30 minutes. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M aqueous sodium hydroxide and then brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The obtained solid was washed by trituration with diisopropyl ether to afford a white solid (276 mg). The white solid (242 mg) was dissolved in methylene chloride (3.5 mL), mchloroperbenzoic acid (280 mg) was added to the solution at 0°C. The reaction mixture was stirred at room temperature for 3 hours. Aqueous sodium thiosulfate was added to the reaction mixture at 0®C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and then brine, dried over anhydrous sodium sulfate, filtrated, and then concentrated. The residue was purified by silica gel column chromatography (heptane : ethyl acetate = 47 : 53 to 26 : 74 to 12 : 88), and the obtained solid was washed by trituration with diisopropyl ether to afford a white solid (163 mg). A mixture of the white solid (140 mg), ammonium formate (74 mg), and palladium-carbon (10 % w/w, 14 mg) in ethanol (7.0 mL) was allowed to be under a hydrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered through a Celite pad, and the filtrate 5 10 15 20 25 Date Reçue/Date Received 2023-06-16 383 was concentrated. The residual solid was washed by trituration with diisopropyl ether, and then collected on a filter to afford the title compound as a white solid (108 mg). iR-NMR (DMSO-d6) 5: 1.03 (3H, d, J = 7.2 Hz), 1.21 (6H, s), 2.25 (1H, dd, J = 16.8, 4.2 Hz), 2.69 (1H, dd, J = 16.8, 6.7 Hz), 3.06-3.17 (1H, m), 3.88 (2H, s), 4.72 (1H, s), 7.17 (1H, d, J = 9.0 Hz), 7.76-7.83 (1H, m), 11.05 (1H, s). [0544] (Test) The growth inhibitory activity against human childhood brain tumor cell lines (PFSK-1) was measured with WST-8 reagent [2—(2-methoxy-4—nxtrophenyl)—3—(4—nitropheny1)—5—(2,4— disulfophenyl)-2H—tétrazolium monosodium salt, Cell Counting Kit-8™], according to the method described in Tominaga, H. et al., Anal. Commun., 1999, 36, 47-50. Briefly, PFSK-1 was seeded in 96-well microplate at 100 pL/well with Roswell Park Memorial Institute (RPMI) 1640 medium containing 10 % fetal bovine serum (FBS), and the cells were incubated in the presence of 5 % carbon dioxide (CO2) at 37°C for 24 hours. 50 uL of each test compound diluted with the medium was added to each well, and then the cells were incubated further for 3 days. After the incubation, 15 pL of Cell Counting Kit- 8™ was added to each well, and the cells were incubated for one and half hours. Then, optical density (OD) values at 384 measurement wavelength 450 nm and reference wavelength 630 nm were measured and the difference thereof was calculated. From the calculated difference, the OD value difference (at measurement wavelength 450 nm and reference wavelength 630 5 nm) of the control well which includes no cell was subtracted to afford cell-growth activity in each well. The cell growth inhibitory activity of each test compound was calculated by comparing the cell-growth activity with each test compound to the cell-growth activity without any 10 test compound (control), and each IC50 (nM) which is the concentration inhibiting 50 % of the cell growth was calculated. The results are shown in the table below. Date Reçue/Date Received 2023-06-16 385 Example :c5û (nM) Example IC50 Î Example (nM) | IC50 (nM) Example IC50 (nM) 1.1 2 1.0 6 3.8 7 1.0 8 7.9 9 4.2 10 3.7 11 3.0 12 1.9 14 8.0 15 4.0 16 3.6 17 2. 9 18 4.0 19 1.3 20 4.2 21 4.0 22 1.9 23 8.0 24 1.7 25 2 •6 26 2.0 28 6.3 31 1.1 32 4.0 33 5.1 34 5. 2 35 6.3 36 1.0 .37 8.8 38 5. 2 39 2.8 40 1.6 43 4.3 44 1.0 45 7.2 4 6 3.9 47 2.4 48 0.9 49 2.8 50 2.9 51 5.5 52 3.8 53 1.9 54 0.5 55 1. 9 56 7.6 57 <1.0 58 2.8 59 2.2 60 4.7 61 4.7 62 8.9 63 5.C 64 2 .1 65 4.3 66 4.1 67 3.6 69 1.2 70 5.3 71 3.9 72 0.9 7 4 4 »1 75 3.2 76 2.7 77 5.3 78 6. 6 79 5.6 80 5.1 81 4.7 82 6.0 93 6.6 84 3.3 85 4.0 86 4.6 87 9.8 88 9.5 89 4.9 90 3.9 91 6.0 92 4.9 93 3.1 34 3.0 95 3.0 96 3.9 97 8.6 98 3.6 99 <1.0 100 1.6 101 7.5 102 3.4 1,03 2.6 104 105 9.0 106 6.4 108 4.1 109 1.6 110 7.8 111 3.0 112 2.3 113 1*1 114 3.3 115 5.9 116 4.3 117 3.0 118 <1.0 119 2.9 120 2.4 121 3.8 122 4.1 123 3. 3 124 2.3 125 1.5 126 2.9 127 <1.0 129 3.6 130 7.0 131 1.0 132 3.0 133 3.4 134 7.1 135 6.8 136 5.2 137 <1.0 138 3.9 139 2.7 140 2.0 141 4. 6 142 1.0 143 6.9 14 4 4 .2 145 7.1 146 6.8 147 7.6 148 <1.0 149 3.6 150 5.7 151 1.3 152 3.4 153 5.3 154 2.9 155 2.2 156 2.9 158 4.3 159 <1.0 160 1.9 161 2.7 162 6.4 163 5.2 164 4.9 165 2.6 166 4.7 167 1.3 168 2.3 169 4.0 170 2.5 171 6.3 172 5.2 174 4.2 175 4.1 176 9.2 177 4.0 178 4. 6 179 3.3 j 180 6.5 181 3.9 182 2.9 183 4.5 184 2.2 Date Reçue/Date Received 2023-06-16

Claims (12)

1. 5 10 15 20 Date reçue/Date received 2024-02-13 386 CLAIMS or a pharmaceutically acceptable stereoisomer thereof, salt thereof, or a wherein R1 to R4 are independently hydrogen atom, halogen, OH, CN, Ci—6 alkyl group, halogenated Ci-6 alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, or halogenated C1-6 alkoxy group, provided that one or two of R1 to R4 are hydrogen atoms, but it is not that all of three or four thereof are hydrogen atoms, and Y is C1-6 alkylene or C2-6 alkenylene group, wherein the alkylene or alkenylene group may be substituted with one or more substituents which is or are C1-6 alkyl group, halogen, or halogenated C1-6 alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkylene or alkenylene group and another substitutable carbon atom in the alkylene or alkenylene group, or two substitutable carbon atoms in the substituent bonding to the alkylene or alkenylene group may be combined together to 5 10 15 20 25 Date reçue/Date received 2024-02-13 387 form a 3- to 6-membered carbon ring.
2. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein any two of R1 to R4 are hydrogen atoms.
3. 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R1 to R4 are independently hydrogen atom, halogen, OH, CN, Ci-4 alkyl group, halogenated Ci-4 alkyl group, C2-4 alkenyl group, C1-4 alkoxy group, or halogenated C1-4 alkoxy group.
4. 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R1 to R4 are independently hydrogen atom, fluorine atom, chlorine atom, OH, CN, C1-4 alkyl group, vinyl group, or C1-4 alkoxy group.
5. 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the alkylene or alkenylene group in Y is substituted with one or more substituents which is or are C1-4 alkyl group, halogen, or halogenated C1-4 alkyl group, further wherein a substitutable carbon atom in the substituent bonding to the alkylene or alkenylene group and another substitutable carbon atom in the alkylene or alkenylene group, or two substitutable carbon 5 10 15 20 Date reçue/Date received 2024-02-13 388 atoms in the substituent bonding to the alkylene or alkenylene group may be combined together to form a 3- to 6- membered carbon ring.
6. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein a carbon atom of the alkylene or alkenylene group in Y is substituted with one or two substituents which is or are Ci-4 alkyl group or halogenated Ci-4 alkyl group, further when the carbon atom is substituted with two substituents, each substitutable carbon atom in the two substituents may be combined together to form a 3- to 6-membered carbon ring.
7. 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the alkylene or alkenylene group in Y has no substituent.
8. 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound of formula (1) is represented in the following formula: 5 10 15 20 Date reçue/Date received 2024-02-13 389 R2
9. 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which is: 6-[3-bromo-5-chloro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5- methy1-4,5-dihydro-2H-pyridazin-3-one, 6-[3,5-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-5-fluoro-4-(3-hydroxy-2,2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one, 6-[3-bromo-2-fluoro-4-(3-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-2-fluoro-4-(3-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-2-fluoro-4-(3-hydroxypropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-bromo-2-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5- methy1-4,5-dihydro-2H-pyridazin-3-one, 6-[3-bromo-5-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl]-5- 5 10 15 20 25 Date reçue/Date received 2024-02-13 390 methy1-4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-4-(2-hydroxy-2-methylpropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-2-fluoro-4-(2-hydroxy-2-methylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-{3-chloro-4-[(2R)-2-hydroxypropoxy]-5-methylphenyl}-5- methyl-4,5-dihydro-2H-pyridazin-3-one, 6-{3-chloro-4-[(l-hydroxycyclopropyl)methoxy]-5- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-{2-fluoro-4-[(l-hydroxycyclopropyl)methoxy]-3- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-{3-chloro-2-fluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one, 6-[3-bromo-2-fluoro-4-(2-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one, 6-[3,5-dichloro-4-(2-hydroxypropoxy)phenyl]-5-methyl-4,5- dihydro-2H-pyridazin-3-one, 6-[3-chloro-2-fluoro-4-(2-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-4-(2-hydroxypropoxy)-5-methylphenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one, 6-[3-bromo-5-chloro-4-(2-hydroxypropoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one, 6-[2-fluoro-4-(2-hydroxypropoxy)-3-vinylphenyl]-5-methyl 5 10 15 20 25 Date reçue/Date received 2024-02-13 391 4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-2-fluoro-4-(2-hydroxybutoxy)phenyl]-5-methyl- 4,5-dihydro-2H-pyridazin-3-one, 6-[3-bromo-5-fluoro-4-(3-hydroxy-2,2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one, 6-[3-chloro-4-(3-hydroxy-2,2-dimethylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-5-fluoro-4-(4-hydroxy-2,2- dimethylbutoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, 6-[3,5-dichloro-4-(4-hydroxy-2,2-dimethylbutoxy)phenyl]-5- methy1-4,5-dihydro-2H-pyridazin-3-one, 2-fluoro-6-(2-hydroxypropoxy)-3-(4-methyl-6-oxo-4,5- dihydro-IH-pyridazin-3-yl)benzonitrile, 6-[3,5-dichloro-4-(2,2-difluoro-3-hydroxypropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-bromo-4-(2,2-difluoro-3-hydroxypropoxy)-2- fluorophenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-4-(2,2-difluoro-3-hydroxypropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, (5R)-(-)-6-[3-chloro-2-fluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, (5R)-(-)-6-[4-(2,2-difluoro-3-hydroxypropoxy)-2-fluoro-3- 5 10 15 20 25 Date reçue/Date received 2024-02-13 392 methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, (5R)-(-)-6-[2,3-difluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, (5R)-(-)-6-[3-fluoro-4-(3-hydroxy-2,2-dimethylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, (5R)-(-)-6-[3-bromo-5-chloro-4-(3-hydroxy-2,2- dimethylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one, 6-[3-chloro-2,5-difluoro-4-(2-hydroxy-2- methylpropoxy)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3- one, 6-[3-chloro-2-fluoro-4-(3-hydroxy-2,2-dimethylpropoxy)-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-2,5-difluoro-4-(3-hydroxypropoxy)phenyl]-5- methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-4-(3-hydroxy-2-methylpropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[3-chloro-2-fluoro-4-(2-hydroxypropoxy)-5-methylphenyl]- 5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-{3-chloro-2-fluoro-4-[(Z)-4-hydroxy-2-butenyloxy]-5- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-(3-chloro-4-{[(lS*,2R*)-2- (hydroxymethyl)cyclopropyl]methoxy}-5-methylphenyl)-5- methyl-4,5-dihydro-2H-pyridazin-3-one, 5 10 15 20 Date reçue/Date received 2024-02-13 393 6-[3-chloro-4-(2,2-difluoro-3-hydroxypropoxy)-2-fluoro-5- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-[4-(2,2-difluoro-3-hydroxypropoxy)-2-fluoro-3,5- dimethylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-{3-chloro-2-fluoro-4-[(1-hydroxycyclopropyl)methoxy]-5- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 6-{3-bromo-2-fluoro-4-[(1- hydroxycyclopropyl)methoxy]phenyl}-5-methyl-4,5-dihydro-2Hpyridazin-3-one, 6-{3,5-dichloro-4-[(1-hydroxycyclopropyl)methoxy]phenyl}-5- methy1-4,5-dihydro-2H-pyridazin-3-one, 6-{3-chloro-2-hydroxy-4-[(1-hydroxycyclopropyl)methoxy]-5- methylphenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one, (5R)-(-)-6-[2-hydroxy-4-(2-hydroxy-2-methylpropoxy)-3- methylphenyl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, or 6-[2-fluoro-4-(2-hydroxy-2-methylpropoxy)-3- (trifluoromethyl)phenyl]-5-methyl-4,5-dihydro-2H-pyridazin- 3-one.
10. 10. An agent for treating a malignant tumor, comprising the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable excipient, carrier or diluent. 394
11. 11. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof to treat a malignant tumor.
12. 12. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof for the manufacture of a medicament for treating a malignant tumor. Date reçue/Date received 2024-02-13