Fused polycyclic substituted 5-carboxylic acid thienopyrimidinedione compounds and uses thereof

Abstract

The present invention discloses a series of fused polycyclic substituted 5-carboxylic acid thienopyrimidinedione compounds and their uses, specifically, those of formula (II): The compound represented by TIFF2024507408000065.tif5475 and pharma- ceutically acceptable salts thereof are disclosed.

Description

[Technical Field]

[0001] This application claims priority to CN202110204744.5 filed on February 23, 2021, CN202110523923.5 filed on May 13, 2021, and CN202210125821.2 filed on February 10, 2022.

[0002] This application relates to a series of fused polycyclic ring-substituted 5-carboxythienopyrimidinedione compounds and uses thereof, and in particular to compounds of formula (II) and pharmaceutically acceptable salts thereof: [Background technology]

[0003] Endometriosis is the presence of endometrial tissue outside the uterus. While not fatal, endometriosis can cause symptoms such as chronic pelvic pain and dysmenorrhea. While not incurable, these conditions can cause significant hardship in patients' lives, including pain and infertility. It is extremely difficult to cure and prone to recurrence. Clinical treatment for this disease also has drawbacks, including long treatment times, numerous side effects, and inconvenient administration. According to the World Bank's 2017 population census, approximately 190 million women worldwide suffer from endometriosis.

[0004] The pathogenesis of endometriosis is poorly understood, and current clinical treatment options focus on controlling estrogen levels, inflammation, or both. For example, first-line treatments utilize nonsteroidal anti-inflammatory drugs or oral contraceptives, while second-line treatments include oral aromatase inhibitors, danazol, or injectable gonadotropin-releasing hormone (GnRH) agonists. However, oral contraceptives have a non-response rate of nearly one-third to one-quarter of patients, while progesterone has the side effect of increasing obesity and is contraindicated, particularly for patients seeking pregnancy. Aromatase inhibitors have side effects such as cardiac toxicity and dyslipidemia, while gonadotropin-releasing hormones have perimenopausal side effects. Polypeptide GnRH receptor agonist or antagonist compounds face many challenges, including oral absorption, dosage, drug stability, duration of action, and metabolic stability.

[0005] Small molecule compounds can be administered orally, offering clear advantages: convenient and rapid administration. GnRH receptor antagonists competitively bind to the GnRH receptor and directly inhibit the hypothalamic-pituitary-ovarian axis by blocking GnRH receptor binding, thereby inhibiting the secretion of follicle-stimulating hormone and luteinizing hormone and reducing estrogen levels. Elagolix, the first small molecule GnRH receptor antagonist to be marketed, is currently at the forefront of development. In December 2020, the FDA approved the second small molecule oral antagonist, Relugolix, for the treatment of advanced prostate cancer. It has also been approved in Japan for the treatment of uterine fibroids and is currently undergoing phase 3 clinical trials for the treatment of endometriosis. A third antagonist, Linzagolix, is already in phase 3 clinical trials for the treatment of endometriosis and uterine fibroids. [ka] Although many meaningful clinical trials have been conducted in these areas, continued research is still needed to develop more effective small molecule GnRH receptor antagonists. Summary of the Invention

[0006] The present disclosure provides novel GnRH receptor antagonists having a fused polycyclic structure, which have significant inhibitory activity against the GnRH receptor.

[0007] The present disclosure provides a compound of formula (II): [ka] [In the formula, L1 and L2 each independently represent -(CH2) n -Selected from; L3 and L4 are each independently selected from -CH2-, -CH=CH-, -O-, and -S-; R1 and R2 are each independently H, OH, F, Cl, or C 1-3 Alkyl and C 1-3 alkoxy, wherein C 1-3 Alkyl and C 1-3 Alkoxy is optionally, independently, one, two, or three R a may be replaced by; Alternatively, R1 and R2 together with the carbon atom to which they are commonly bonded form C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 3-6 The cycloalkyl or 4-6 membered heterocycloalkyl optionally contains one, two, or three R b may be replaced by; R3, R4, R5, R6, R7, R8 and R9 are each independently H, F, Cl, Br, I, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 cycloalkyl, wherein C1-3 Alkyl, C 1-3 Alkoxy and C 3-6 Cycloalkyl may each independently optionally be one, two, or three R c may be replaced by; n is selected from 0, 1 and 2; R a , R b and R c are each independently selected from H, F, Cl, Br, I, NH2 and OH. or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments disclosed herein, R and R are each independently selected from H, OH, F, and CH, where CH is optionally substituted with one, two, or three F, and all other variables are as defined herein.

[0009] In some embodiments disclosed herein, R1 and R2 above are each independently selected from H, and all other variables are as defined herein.

[0010] In some embodiments disclosed herein, R1 and R2 above are together with the atom to which they are commonly attached form cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, or azetidinyl, wherein cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, or azetidinyl optionally has one, two, or three R b and other variables are as defined herein.

[0011] In some embodiments disclosed herein, R and R, together with the atom to which they are commonly bonded, form cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, and azetidinyl, wherein cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, and azetidinyl are optionally substituted with one, two, or three F, and all other variables are as defined herein.

[0012] In some embodiments disclosed herein, R and R, taken together with the atom to which they are commonly bonded, represent: [ka] where the other variables are as defined herein.

[0013] In some embodiments disclosed herein, R3, R4, R5, and R6 are each independently selected from H, F, Cl, OH, NH2, CN, CH3, CF3, OCH3, and OCF3, and all other variables are as defined herein.

[0014] In some embodiments disclosed herein, R3, R4, R5, and R6 above are each independently selected from H and F, and all other variables are as defined herein.

[0015] In some embodiments disclosed herein, the structural moiety: [ka] teeth, [ka] and the other variables are as defined herein.

[0016] In some embodiments disclosed herein, R7, R8, and R9 are each independently selected from H, F, Cl, OH, NH2, CN, CH3, CF3, OCH3, and OCF3, and all other variables are as defined herein.

[0017] In some embodiments disclosed herein, R7, R8, and R9 above are each independently selected from H and F, and all other variables are as defined herein.

[0018] In some embodiments disclosed herein, the structural moiety: [ka] teeth, [ka] and other variables are as defined herein.

[0019] In some embodiments disclosed herein, the structural moiety: [ka] teeth, [ka] and other variables are as defined herein.

[0020] In some embodiments disclosed herein, L3 and L4 above are each independently selected from O, and all other variables are as defined herein.

[0021] In some embodiments disclosed herein, n is selected from 1 and 2, and all other variables are as defined herein.

[0022] In some embodiments disclosed herein, the structural moiety: [ka] teeth, [ka] and the other variables are as defined herein.

[0023] In some embodiments disclosed herein, the structural moiety: [ka] teeth, [ka] and the other variables are as defined herein.

[0024] In some embodiments disclosed herein, the structural moiety: [ka] teeth, [ka] and the other variables are as defined herein.

[0025] In some embodiments disclosed herein, the structural moiety: [ka] teeth, [ka] and the other variables are as defined herein.

[0026] In some embodiments disclosed herein, the compound is as described above, or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] wherein L1, L2, R1, R2, R3, R4, R5 and R6 are each as defined herein. or a pharmaceutically acceptable salt thereof.

[0027] The present disclosure also provides a compound of formula (I): [ka] [In the formula, L1 and L2 each independently represent -(CH2) n -Selected from; L3 and L4 are each independently selected from -CH2-, -CH=CH-, -O-, and -S-; R1 and R2 are each independently H, OH, F, Cl, or C 1-3 Alkyl and C 1-3 alkoxy, wherein C 1-3 Alkyl and C 1-3 The alkoxy optionally contains one, two, or three R a may be replaced by; Alternatively, R1 and R2 together with the atom to which they are commonly bonded form C 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 3-6 The cycloalkyl or 4-6 membered heterocycloalkyl optionally contains one, two, or three R b may be replaced by; R3, R4, R5 and R6 are each independently selected from H, F, Cl, Br and I; n is selected from 0, 1 and 2; R a and R b are each independently selected from H, F, Cl, Br, and I; The "4-6 membered heterocycloalkyl" contains 1, 2 or 3 heteroatoms selected from N, NH, O and S. or a pharmaceutically acceptable salt thereof.

[0028] The present disclosure also includes embodiments resulting from any combination of the above variables.

[0029] The present disclosure relates to a compound shown below or a pharmaceutically acceptable salt thereof: [ka] to provide.

[0030] The present disclosure also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament related to a GnRH receptor antagonist.

[0031] In some embodiments of the present disclosure, the above-mentioned GnRH receptor antagonist-related medicament is a medicament for preventing and / or treating diseases related to endometriosis and / or uterine fibroids.

[0032] Technical Effects The compounds of the present disclosure have significant inhibitory effects on human gonadotropin-releasing hormone receptors and can significantly inhibit the increase in endometriotic lesion volume in mice with excellent efficacy; PK results show that the compounds of the present disclosure have high plasma exposure, low clearance, long half-life, and high oral bioavailability, exhibiting excellent pharmacokinetic properties and making them good molecules for development into oral administration.

[0033] Definitions and Terminology Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings: A particular term or phrase should not be considered unclear or ambiguous in the absence of a specific definition, but should be understood in its conventional sense. When a trade name is mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0034] The term "pharmaceutically acceptable" is used herein to mean compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0035] The term "pharmaceutically acceptable salt" refers to a salt of a compound disclosed herein prepared by reacting a compound having certain substituents disclosed herein with a relatively non-toxic acid or base. When a compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amine salts, magnesium salts, or similar salts. When a compound disclosed herein contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts (wherein inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphoric acid, etc.); and organic acid salts (wherein organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc.); and salts of amino acids (e.g., arginine, etc.), and salts of organic acids (e.g., glucuronic acid, etc.). Certain compounds disclosed herein contain both basic and acidic functional groups and can be converted into any base or acid addition salt.

[0036] The pharmaceutically acceptable salts disclosed herein can be prepared from a parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base form of the compound with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof.

[0037] The compounds disclosed herein may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic and other mixtures, e.g., mixtures enriched in enantiomers or diastereoisomers, and all of these are encompassed within the scope disclosed herein. Substituents such as alkyl may have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are encompassed within the scope disclosed herein.

[0038] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another.

[0039] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" arise from the lack of free rotation of double or single bonds between carbon atoms forming the ring.

[0040] Unless otherwise specified, the term "diastereomer" means a stereoisomer containing two or more chiral centers in the molecule and having a non-mirror-image relationship between the molecules.

[0041] Unless otherwise specified, "(+)" refers to the dextro isomer, "(-)" refers to the levo isomer, and "(±)" refers to the racemate.

[0042] Solid wedge connections unless otherwise noted: [ka] and dotted wedge bonds: [ka] indicates the absolute configuration of the stereocenter; a straight solid bond: [ka] and a straight dotted bond: [ka] indicates the relative configuration of stereocenters; wavy line: [ka] is a solid wedge connection: [ka] or a dotted wedge bond: [ka] or a wavy line: [ka] is a straight solid line connection: [ka] and a straight dotted bond: [ka] Shows.

[0043] Unless otherwise specified, when a compound contains double bond structures such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond is bonded to two different substituents (in double bonds involving nitrogen atoms, a pair of lone electrons on the nitrogen atom is considered to be one of the substituents to which it is bonded), the atoms on the double bond in the compound are represented by wavy lines: [ka] When a group is bonded to the substituent with , the compound represents a (Z) isomer, an (E) isomer, or a mixture of the two isomers of the compound. For example, a compound having the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2), or as a mixture of the two isomers of formula (A-1) and formula (A-2); a compound having the following formula (B) means that the compound exists as a single isomer of formula (B-1) or formula (B-2), or as a mixture of the two isomers of formula (B-1) and formula (B-2). A compound having the following formula (C) means that the compound exists as a single isomer of formula (C-1) or formula (C-2), or as a mixture of the two isomers of formula (C-1) and formula (C-2). [ka]

[0044] Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional groups that are in dynamic equilibrium at room temperature and can rapidly convert into one another. When tautomers are possible (as in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via recombination of some bonding electrons. A specific example of keto-enol isomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0045] Unless otherwise specified, the terms "enriched in one isomer," "enriched in an isomer," "enriched in one enantiomer," or "enantiomer-enriched" mean less than 100% isomer or enantiomer content, and 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more of the isomer or enantiomer.

[0046] Unless otherwise specified, the terms "isomeric excess" or "enantiomeric excess" refer to the relative percentage difference between two isomers or two enantiomers. For example, if one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomeric or enantiomeric excess (ee value) is 80%.

[0047] The compounds disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) or C-14( 14

[0013] Deuterated drugs can be labeled with radioactive isotopes such as CI (C). As another example, hydrogen can be replaced with deuterium to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon. Deuterated drugs offer advantages over non-deuterated drugs, including reduced toxic side effects, improved drug stability, enhanced efficacy, and a longer biological half-life of the drug. All variations in the isotopic composition of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure.

[0048] The term "optionally" or "optionally" means that the subsequent event or condition may, but need not, occur, and includes cases where the event or condition may or may not occur.

[0049] The term "substituted" means that one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. No position on an aromatic ring can be substituted by oxo. The term "optionally substituted," unless otherwise specified, means that an atom is substituted by a substituent, and the type and number of substituents can be any, as long as it is chemically achievable.

[0050] When any variable (e.g., R) occurs more than one time in a constituent or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0 to 2 R, that group may optionally be substituted with up to 2 R, and the definition of R at each occurrence is independent. Furthermore, combinations of the above substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0051] When the number of bonding groups is 0, such as -(CRR)0-, this means that the bonding group is a single bond.

[0052] When one of the variables is a single bond, it means that the two groups connected by the single bond are directly joined. For example, if L in ALZ represents a single bond, then the structure of ALZ is actually AZ.

[0053] Unless otherwise specified, if a group has one or more bondable sites, any one or more sites of that group can be bonded to other groups via chemical bonds. The bonding position of the chemical bond is variable, and if there are H atom(s) at the bondable site(s), when the bondable site(s) with H atom(s) are bonded to a chemical bond, the number of H atoms at this site decreases correspondingly as the number of bonded chemical bonds increases, and the group becomes a group of corresponding valence. The chemical bond between said site and other groups is represented by a straight solid bond: [ka] , dotted line bond of a straight line: [ka] , or a wavy line: [ka] For example, the straight solid bond in -OCH3 indicates that the group is attached to another group through the oxygen atom in the group; [ka] A straight dotted bond in indicates that the group is attached to another group through both ends of the nitrogen atom in the group; [ka] The wavy lines in indicate that the group is attached to another group through the 1- and 2-carbon atoms in the phenyl group; [ka] Any available binding site on the piperidinyl group has at least four binding modes: [ka] indicates that the group can be attached to another group through one chemical bond containing an N-; [ka] for, [ka] However, when one chemical bond is bonded, one hydrogen atom is removed from this site, and this group becomes the corresponding monovalent piperidinyl group; [ka] indicates that the carbon atom at position 3 of the cyclohexyl group is bonded to another group via a double bond.

[0054] Unless otherwise specified, the term "C 1-3 The terms "alkyl," either alone or in combination with other terms, refer to a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. 1-3 Alkyl has C 1-2 Alkyl, C 2-3 alkyl, etc. It may also be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methenyl). 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0055] Unless otherwise specified, the term "C 1-3 "Alkoxy," each alone or in combination with other terms, refers to an alkyl group containing 1 to 3 carbon atoms and attached to the remainder of the molecule by an oxygen atom. 1-3 Alkoxy groups include C 1-2 Alkoxy group, C 2-3 C includes alkoxy groups, C3 alkoxy groups and C2 alkoxy groups. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy).

[0056] Unless otherwise specified, "C 3-6"Cycloalkyl" refers to a saturated monocyclic hydrocarbon group of 3 to 6 carbon atoms. 3-6 Cycloalkyl includes C 3-5 Cycloalkyl, C 4-5 Cycloalkyl and C 5-6 cycloalkyl, etc.; may be monovalent, divalent or polyvalent. C 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0057] Unless otherwise specified, the term "4-6 membered heterocycloalkyl," each alone or in combination with other terms, refers to a saturated monocyclic group of 4 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and (O) p and p is 1 or 2). Furthermore, with respect to "4- to 6-membered heterocycloalkyl," a heteroatom may be present at the position where the heterocycloalkyl group is attached to the remainder of the molecule. 4- to 6-membered heterocycloalkyl includes 5- to 6-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, and 6-membered heterocycloalkyl, etc. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0058] Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 and includes any range of n to n+m, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 Similarly, an n-membered ring to an n+m-membered ring indicates that the number of atoms on the ring is n to n+m, for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range of n to n+m, for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0059] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the embodiments listed below, embodiments formed by combining the embodiments listed below with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Alternative embodiments include, but are not limited to, the embodiments disclosed herein.

[0060] The structure of the compounds disclosed herein can be confirmed by conventional methods well known to those skilled in the art.When the present disclosure relates to the absolute configuration of a compound, this absolute configuration can be confirmed by conventional techniques in the art, such as single crystal X-ray diffraction (SXRD).In single crystal X-ray diffraction (SXRD), the diffraction intensity data of the grown single crystal is collected using a Bruker D8 venture diffractometer with CuKα radiation as a light source, in the scanning mode of φ / scan; after collecting relevant data, the crystal structure is further analyzed by direct method (Shelxs97) to confirm the absolute configuration.

[0061] The following abbreviations are used in this disclosure: DMSO refers to dimethyl sulfoxide; MeOH refers to methanol; ACN refers to acetonitrile; DEA refers to diethylamine; CO2 refers to carbon dioxide; psi refers to pounds per square inch; Ac refers to acetyl, Ph refers to phenyl; DMAC refers to N,N-dimethylacetamide; Solutol refers to polyethylene glycol-15 hydroxystearate; and PEG refers to polyethylene glycol.

[0062] The solvents used in this disclosure are commercially available. Compound names are based on common naming principles in the art or by ChemDraw® software, where commercially available compounds are named by their vendor directory name.

[0063] Detailed Description of the Invention Hereinafter, the present disclosure will be described in detail by examples. However, these examples are not intended to have any adverse limitations on the present disclosure. The present disclosure is described in detail in this specification, and embodiments are also disclosed in this specification. It will be clear to those skilled in the art that various changes and modifications can be made to the embodiments disclosed herein without departing from the spirit and scope disclosed herein.

[0064] Reference example 1: Intermediate BB-1 [ka]

[0065] Process 1

[0066] To a solution of compound B-1 (dimethyl maleate, 50 g, 346.92 mmol) and methyl thioglycolate (37.01 g, 348.68 mmol) in tetrahydrofuran (300 mL), piperidine (886.18 mg, 10.41 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. After the completion of the reaction was determined by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1), 300 mL of water was added. The mixture was extracted twice with ethyl acetate, each time with 200 mL of ethyl acetate. The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain compound B-2.

[0067] 1 H NMR (400 MHz, CDCl3) δ = 3.89 - 3.81 (m, 1H), 3.76 (s, 3H), 3.75 (d, 3H), 3.69 (s, 3H), 3.55 - 3.32 (m, 2H), 3.00 (m, 1H), 2.73 (m, 1H).

[0068] Process 2

[0069] Sodium (2.78 g, 120.92 mmol) was added to methanol (10 mL) below 20°C. The mixture was stirred below 64°C until the solid dissolved, resulting in a solution of sodium in methanol. The solution was cooled to 20°C and then added to a solution of B-2 (10 g, 39.96 mmol) in tetrahydrofuran (20 mL). The reaction solution was stirred at 66°C under nitrogen for 3 h. Isopropyl ether (100 mL) and acetic acid (1 mL) were added. The mixture was cooled to 20°C and then filtered. The filter cake was added to a mixture of phosphoric acid (10 mL) and water (20 mL), and the mixture was extracted twice with ethyl acetate, each time with 20 mL of ethyl acetate. The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give compound B-3.

[0070] Process 3

[0071] A mixture of compound B-3 (7.4 g, 33.91 mmol), pyridine (4.03 g, 50.89 mmol), and hydroxylamine hydrochloride (2.47 g, 35.57 mmol) was stirred at 50 °C for 2 h. 2 mL of phosphoric acid and 20 mL of water were added to the reaction solution, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, washed with 20 mL of saturated sodium bicarbonate, washed once with 20 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give compound B-4.

[0072] Process 4

[0073] To compound B-4 (5.2 g, 22.29 mmol) in acetic acid (5 mL) was added 4 moles of hydrochloric acid / ethyl acetate (52.00 mL) per liter, and the reaction solution was stirred for 12 hours at 25° C. The reaction solution was filtered, and the filter cake was concentrated to dryness under reduced pressure to obtain compound B-5 hydrochloride.

[0074] MS-ESI calculated value is [M+H-MeOH] + The result was 184.0 and findings were 184.1.

[0075] Process 5

[0076] To compound B-5 (2 g, 7.95 mmol, hydrochloride) in tetrahydrofuran (20 mL) and water (10 mL) was added potassium carbonate (1.65 g, 11.92 mmol). Phenyl chloroformate (2.49 g, 15.89 mmol) was added dropwise at 5-10 °C. The reaction solution was stirred at 5-10 °C for 1 h. 50 mL of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, each time with 50 mL of water. The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, and ethyl acetate (5 mL) and petroleum ether (50 mL) were added. The mixture was slurried at 30 °C for 30 minutes and filtered. The filter cake was dried under reduced pressure to obtain compound BB-1.

[0077] MS-ESI calculated values ​​are [M+H] + The result was 336.1, and the findings were 336.1.

[0078] Reference example 2: Intermediate BB-2 [ka]

[0079] Process 1

[0080] To a solution of compound B-6 (3-bromopropanol, 5 g, 35.97 mmol) and 4-dimethylaminopyridine (439.49 mg, 3.6 mmol) in dichloromethane (25 mL) was added a solution of acetic anhydride (4.04 g, 39.57 mmol) in dichloromethane (5 mL) dropwise. The mixture was warmed to 25 °C and stirred at 25 °C for 4 h. The reaction solution was washed with 1 mol / L hydrochloric acid (10 mL × 2). The aqueous phase was collected and extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with saturated aqueous sodium bicarbonate (10 mL × 2) and saturated brine (10 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give intermediate compound BB-2.

[0081] 1 H NMR (400 MHz, CDCl3) δ= 4.18 - 4.25 (m, 2 H), 3.44 - 3.51 (m, 2 H), 2.15 - 2.23 (m, 2 H), 2.07 (s, 3 H).

[0082] Example 1 [ka]

[0083] Process 1

[0084] Lithium diisopropylamide (166.53 mL, concentration: 2 mol / L) was added dropwise to a solution of compound 1a (3,4-difluoroanisole, 40 g, 277.5 mmol) in tetrahydrofuran (400 mL) at -70 °C. The reaction mixture was stirred at -70 °C for 0.5 h. A solution of N,N-dimethylformamide (25.62 mL, 333.06 mmol) in tetrahydrofuran (24 mL) was added dropwise to the reaction mixture at -70 °C to -60 °C, and the reaction mixture was stirred at -70 °C for 1 h. Acetic acid (25 mL) and water (100 mL) were added to the reaction mixture at -65 °C, and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed sequentially with water (100 mL x 3) and saturated brine (100 mL x 3). The organic phases were collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 1b.

[0085] Process 2

[0086] To a solution of compound 1b (10 g, 58.10 mmol) in dichloromethane (100 mL) was added boron tribromide (29.11 g, 116.19 mmol) dropwise at -20 °C. The mixture was slowly warmed to 25 °C and stirred at 25 °C for 12 h. Methanol (200 mL) and water (100 mL) were added dropwise to the reaction mixture. The mixture was heated to 40 °C and stirred at 40 °C for 2 h. The phases were separated. The aqueous phase was extracted with dichloromethane (300 mL x 2), and the combined organic phases were extracted with aqueous sodium hydroxide (1 mol / L, 400 mL x 3). The extract was acidified to pH 2-3 with concentrated hydrochloric acid and extracted with ethyl acetate (300 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 1c.

[0087] 1 H NMR (400 MHz, CDCl3) δ = 11.13 (s, 1H), 10.29 (s, 1H), 7.37 (q, J = 9.3 Hz, 1H), 6.77 - 6.68 (m, 1H).

[0088] Process 3

[0089] To a solution of compound 1c (1.5 g, 9.49 mmol) in N,N-dimethylformamide (20 mL) was added sodium iodide (284.42 mg, 1.90 mmol) and potassium carbonate (1.97 g, 14.23 mmol). The mixture was stirred at 25 °C for 0.5 h. Compound BB-2 (2.06 g, 11.39 mmol) was then added, and the mixture was heated to 60 °C and stirred at 60 °C for 12 h. The reaction mixture was poured into 30 mL of water, and the mixture was extracted with ethyl acetate (50 mL × 5). The combined organic phases were washed with water (20 mL × 5) and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give compound 1d.

[0090] 1H NMR (400 MHz, CDCl3) δ = 10.45 - 10.38 (m, 1H), 7.37 - 7.28 (m, 1H), 6.74 - 6.65 (m, 1H), 4.28 (t, J = 6.2 Hz, 2H), 4.16 - 4.13 (m, 2H), 2.22 - 2.16 (m, 2H), 2.06 (s, 3H).

[0091] Process 4

[0092] At 0°C, a solution of compound 1d (3.25 g, 12.59 mmol) in tetrahydrofuran (30 mL) was added with a solution of sodium borohydride (490 mg, 12.95 mmol) in water (3 mL), and the reaction mixture was stirred at 0°C for 0.5 h. At 0°C, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with water (10 mL x 2) and saturated brine (10 mL x 1). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give compound 1e.

[0093] Process 5

[0094] To a solution of compound 1e (2.65 g, 10.18 mmol) and 5-fluoro-2-hydroxybenzaldehyde (1.57 g, 11.2 mmol) in tetrahydrofuran (20 mL) was added tri-n-butylphosphine (3.71 g, 18.33 mmol), and the mixture was stirred for 0.1 h. Next, at 0 °C, a solution of azodicarbonyldipiperidine (4.62 g, 18.33 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was warmed to 25 °C and stirred at 25 °C for 12 h. The reaction mixture was poured into 10 mL of water, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (10 mL × 3) and brine (10 mL × 3). The organic phases were collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1 / 0 to 20 / 1) to obtain Compound 1f.

[0095] 1 H NMR (400 MHz, CDCl3) δ = 10.31 (d, J = 3.2 Hz, 1H), 7.49 (dd, J = 3.2, 8.4 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.23 - 7.18 (m, 1H), 7.18 - 7.11 (m, 1H), 6.72 - 6.57 (m, 1H), 5.25 (d, J = 2.8 Hz, 2H), 4.19 (t, J = 6.2 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 2.09 - 2.06 (m, 2H), 2.04 (s, 3H).

[0096] Process 6

[0097] To a solution of compound 1f (1.04 g, 2.72 mmol) in dichloromethane (10 mL) at 0 °C, m-chloroperoxybenzoic acid (1.66 g, 85% purity, 8.16 mmol) was added, and the mixture was warmed to 25 °C and stirred at 25 °C for 12 h. 2 mL of saturated aqueous sodium sulfite solution was added to the reaction solution, followed by 10 mL of water. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (10 mL × 2), saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by preparative chromatography (petroleum ether:ethyl acetate = 3:1) to give compound 1g.

[0098] 1 H NMR (400 MHz, CDCl3) δ = 8.19 (s, 1H), 7.18 - 7.08 (m, 2H), 7.00 - 6.93 (m, 1H), 6.89 (dd, J = 3.2, 8.4 Hz, 1H), 6.63 - 6.57 (m, 1H), 5.14 - 5.09 (m, 2H), 4.23 (t, J = 6.2 Hz, 2H), 4.04 (t, J = 6.2 Hz, 2H), 2.14 - 2.09 (m, 2H), 2.06 (s, 3H).

[0099] Process 7

[0100] To a solution of compound 1g (1 g, 2.51 mmol) in methanol (10 mL), an aqueous solution of potassium hydroxide (1 mL, 20% purity, 489.03 μmol) was added, and the mixture was stirred at 25 °C for 6 h. The reaction solution was poured into 10 mL of water, and then the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with water (10 mL × 2) and saturated brine (10 mL × 2). The organic phases were collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5 / 1-3 / 1) to obtain compound 1h.

[0101] 1 H NMR (400 MHz, CDCl3) δ = 7.15 (q, J = 9.2 Hz, 1H), 7.00 (dd, J = 5.2, 8.8 Hz, 1H), 6.91 (s, 1H), 6.69 - 6.62 (m, 2H), 6.53 (dt, J = 3.0, 8.6 Hz, 1H), 5.17 (d, J = 2.0 Hz, 2H), 4.22 (t, J = 5.8 Hz, 2H), 3.88 (q, J = 5.0 Hz, 2H), 2.49 (br s, 1H), 2.15 - 2.05 (m, 2H).

[0102] Process 8

[0103] To a solution of compound 1h (421 mg, 1.28 mmol) in tetrahydrofuran (400 mL) at 0 °C, sodium hydride (135.04 mg, 60% purity, 3.38 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. To the reaction mixture was added a solution of p-toluenesulfonyl chloride (244.50 mg, 1.28 mmol) in tetrahydrofuran (5 mL) dropwise at 0 °C, and the mixture was stirred at 25 °C for 12 h. To the reaction solution was added 10 ml of water, and the mixture was extracted with ethyl acetate (30 ml × 3). The combined organic phases were washed with water (10 ml × 2), saturated brine (10 ml × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 1i.

[0104] Process 9

[0105] To a solution of compound 1i (53 mg, 170.82 μmol) in acetic acid (1 mL) at 80° C., nitric acid (1.46 mL, 60% purity, 19.51 mmol) was added dropwise, and the mixture was stirred at 80° C. for 2 h. The reaction solution was poured into 40 mL of ice water, and the mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (30 mL×5). The combined organic phases were washed with water (30 mL×3), saturated brine (20 mL×1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 1j.

[0106] 1 H NMR (400 MHz, CDCl3) δ = 7.92 (d, J = 7.6 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.76 - 6.73 (d, J = 12.0 Hz, 1H), 6.57 - 6.12 (m, 1H), 5.20 (d, J = 1.2 Hz, 2H), 4.48 - 4.42 (m, 2H), 4.37 - 4.31 (m, 2H), 2.17 - 2.14 (m, 2H).

[0107] Step 10

[0108] To a solution of compound 1j (46 mg, 129.48 μmol) in ethyl acetate (10 mL) was added wet palladium on carbon (10 mg, 10% purity). The atmosphere was replaced with hydrogen three times. The mixture was stirred under a hydrogen atmosphere (15 psi) at 24° C. for 12 h. The reaction solution was filtered through diatomaceous earth and filtered. The filtrate was concentrated to give compound 1k.

[0109] 1 H NMR (400 MHz, CDCl3) δ = 7.17 - 7.07 (m, 2H), 6.82 - 6.78 (m, 1H), 6.76 (d, J = 11.6 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H), 6.63 - 6.56 (m, LC-MS: m / z = 326.1 [M+H] + .

[0110] Step 11

[0111] To a solution of compound 1k (41 mg, 78.41 μmol) in tetrahydrofuran (3 mL) was added compound BB-1 (26.29 mg, 78.41 μmol) and triethylamine (7.93 mg, 78.41 μmol). The mixture was stirred at 70°C for 10 h. The reaction solution was poured into 10 mL of water, and the mixture was extracted with ethyl acetate (30 mL x 5). The combined organic phases were washed with water (10 mL x 3), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative chromatography (petroleum ether:ethyl acetate = 2 / 1) to give compound 1l.

[0112] 1H NMR (400 MHz, CDCl3) δ = 8.86 (s, 1H), 7.97 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.16 - 7.06 (m, 1H), 6.84 (d, J = 11.6 Hz, 1H), 6.78 (m, 1H), 6.57 (br s, 1H), 5.16 (d, J = 1.6 Hz, 2H), 4.36 (t, J = 5.2 Hz, 2H), 4.22 (t, J = 5.2 Hz, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 2.11 (m, 2H); LC-MS: m / z = 567.1 [M+H] + .

[0113] Step 12

[0114] To a solution of compound 1l (22 mg, 28.57 μmol, 73.57% purity) in tetrahydrofuran (2 mL) and methanol (1 mL) was added a solution of lithium hydroxide monohydrate (5.99 mg, 142.85 μmol) in water (1 mL), and the mixture was stirred at 26 °C for 2 h. The reaction solution was adjusted to a pH of about 6 by adding 1 mol / L dilute hydrochloric acid, and then extracted with ethyl acetate (5 mL × 5). The organic phases were combined and washed with water (5 mL × 3). The organic phases were collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by preparative chromatography (dichloromethane:methanol = 10 / 1) to obtain compound 1.

[0115] 1H NMR (400 MHz, DMSO-d6) δ = 12.05 - 11.76 (br s, 1H), 7.44 - 7.32 (m, 1H), 7.29 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 12.0 Hz, 1H), 7.08 - 7.00 (m, 1H), 5.75 (s, 1H), 5.14 - 5.09 (m, 1H), 5.09 - 5.04 (m, 1H), 4.48 (br t, J = 4.8 Hz, 2H), 4.30 (br t, J = 4.6 Hz, 2H), 2.01 - 1.91 (m, 2H); LC-MS: m / z = 521.1 [M+H] + .

[0116] Example 2 [ka]

[0117] Process 1

[0118] To a solution of compound 2a (1,1-cyclopropyldimethanol, 10 g, 97.91 mmol) in dichloromethane (20 mL) at 0-5 °C, a solution of the hydrobromide in acetic acid (72.00 g, 293.65 mmol, 33% purity) was added dropwise, and the mixture was stirred at 10-20 °C for 2 h. 100 mL of water was added, and the mixture was extracted twice with dichloromethane, each time with 20 mL. The combined organic phases were washed twice with saturated sodium bicarbonate, each time with 50 mL. The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give compound 2b.

[0119] Process 2

[0120] To a solution of compound 2,3-difluoro-6-hydroxybenzaldehyde (5 g, 31.63 mmol) in N,N-dimethylformamide (50 mL) were added potassium carbonate (6.57 g, 47.55 mmol), sodium iodide (948.08 mg, 6.33 mmol), and compound 2b (9.82 g, 47.44 mmol). The mixture was stirred at 60 °C for 12 h. 100 mL of water was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate. The combined organic phases were washed twice with 50 mL of water, then with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica gel, 100-200 mesh, petroleum ether:ethyl acetate = 1:0 to 10:1) to give compound 2c.

[0121] Process 3

[0122] To a solution of compound 2c (4.5 g, 15.83 mmol) in tetrahydrofuran (40 mL) was added a solution of sodium borohydride (0.83 g, 21.94 mmol) in water (5 mL) at 0-5 °C. The reaction solution was stirred at 25 °C for 1 h. 50 mL of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, each time with 20 mL of water. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give compound 2d.

[0123] Process 4

[0124] To a solution of 2d (4.4 g, 15.37 mmol) in dichloromethane (40 mL) at 0-5 °C, pyridine (3.65 g, 46.11 mmol) and sulfoxide chloride (3.66 g, 30.74 mmol) were added. The reaction was stirred under nitrogen at 25 °C for 12 h. 50 mL of water was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate. The combined organic phases were washed with 20 mL of saturated sodium bicarbonate, then once with 30 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give compound 2e.

[0125] Process 5

[0126] To a solution of 5-fluoro-2-hydroxybenzaldehyde (1.84 g, 13.13 mmol) and 2e (4.0 g, 13.13 mmol) in acetonitrile (40 mL), potassium carbonate (2.72 g, 19.69 mmol) and sodium iodide (196.77 mg, 1.31 mmol) were added, and the reaction mixture was stirred at 60 °C under nitrogen for 12 h. The reaction mixture was filtered, and the filtrate was added to 50 mL of water. The mixture was extracted twice with ethyl acetate, each time with 50 mL of water. The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 1:0 to 20:1) to obtain 2f.

[0127] Process 6

[0128] Compound 2f (2.2 g, 5.39 mmol) in dichloromethane (25 mL) was added with m-chloroperoxybenzoic acid (1.20 g, 5.93 mmol, 85% purity) at 0-5°C, and the reaction solution was stirred at 30°C for 36 h. The reaction solution was filtered, and the filtrate was added to 20 mL of saturated aqueous sodium bicarbonate solution. The mixture was extracted twice with 20 mL of dichloromethane. The combined organic phases were extracted twice with 20 mL of saturated sodium bicarbonate, then washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain compound 2g.

[0129] Process 7

[0130] To compound 2g (2.2 g, 5.18 mmol) in methanol (10 mL) and water (2 mL) was added potassium carbonate (2.15 g, 15.55 mmol). The reaction solution was stirred at 40 °C for 2 h. 30 mL of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, each time with 20 mL of water. The combined organic phases were washed with 30 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain compound 2h.

[0131] Process 8

[0132] To a solution of compound 2h (1.63 g, 4.60 mmol) in tetrahydrofuran (30 mL) at 0 °C, sodium hydride (552.04 mg, 13.80 mmol, 60% purity) and p-toluenesulfonyl chloride (877.06 mg, 4.60 mmol) were added, and the reaction was stirred under nitrogen at 35 °C for 60 h. To the reaction solution, 2 mL of saturated aqueous ammonium chloride and 10 mL of water were added, and the mixture was extracted twice with ethyl acetate, each time with 10 mL of water. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 1:0 to 10:1) to give compound 2i.

[0133] 1 H NMR (400 MHz, CDCl3) δ = 7.19 - 7.06 (m, 2H), 6.75 - 6.67 (m, 3H), 5.17 (d, J = 1.6 Hz, 2H), 4.13 (s, 2H), 3.98 (s, 2H), 0.72 (s, 4H).

[0134] Process 9

[0135] To a solution of compound 2i (360 mg, 1.07 mmol) in acetic acid (3 mL) at 60 °C, nitric acid (518.84 mg, 5.35 mmol, 65% purity) was added dropwise, and the reaction was stirred at 60 °C for 2 h. 10 mL of water was added to the reaction solution. The solid was precipitated and filtered. The filter cake was dried under reduced pressure and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 10:1-5:1) to give compound 2j.

[0136] Step 10

[0137] To a solution of compound 2j (200 mg, 524.52 μmol) in ethanol (4 mL) and water (0.8 mL) at 79 °C, ammonium chloride (140.29 mg, 2.62 mmol) and reduced iron powder (146.46 mg, 2.62 mmol) were added, and the reaction mixture was stirred at 79 °C for 3 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, each time with 10 mL of water. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 1:0 to 5:1) to give compound 2k.

[0138] LC-MS: m / z = 352.1 [M+H] +

[0139] Step 11

[0140] To a solution of compound BB-1 (143.17 mg, 426.96 μmol) and compound 2k (150 mg, 426.96 μmol) in tetrahydrofuran (5 mL), triethylamine (43.2 mg, 426.96 μmol) was added, and the reaction mixture was stirred at 35 °C for 60 h. The reaction mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain compound 2l.

[0141] LC-MS: m / z = 593.2 [M+H] +

[0142] Step 12

[0143] To compound 2l (100 mg, 168.77 μmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added a solution of lithium hydroxide monohydrate (35.41 mg, 843.83 μmol) in water (2 mL), and the reaction was stirred at 20 °C for 2 h. The reaction solution was adjusted to pH 4-5 with 1 mole of hydrochloric acid per liter. The solid was precipitated and filtered. The filter cake was concentrated to dryness under reduced pressure. Ethyl acetate (5 mL) and petroleum ether (25 mL) were added. The mixture was slurried at 20 °C for 30 minutes and then filtered. The filter cake was dried under reduced pressure to give compound 2.

[0144] 1 H NMR (400 MHz, DMSO-d6) δ = 11.72 (br s, 1H), 7.38 (q, J = 9.6 Hz, 1H), 7.25 (br d, J = 8.0 Hz, 1H), 7.16 - 7.03 (m, 2H), 6.99 (br s, 1H), 5.10 (br s, 2H), 4.28 (s, 2H), 4.10 - 4.03 (m, 2H), 0.68 - 0.60 (m, 4H); LC-MS: m / z = 547.1 [M+H] + .

[0145] Example 3 [ka]

[0146] Process 1

[0147] To a solution of compound 3a (4-bromo-1-butanol, 10 g, 65.35 mmol) in dichloromethane (100 mL) at 0-5 °C, triethylamine (9.92 g, 98.03 mmol) and acetic anhydride (7.34 g, 71.89 mmol) were added, and the mixture was stirred under nitrogen at 25 °C for 12 h. 100 mL of water was added to the reaction solution, and the mixture was extracted twice with dichloromethane, each time with 100 mL of water. The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 3b.

[0148] Process 2

[0149] To a solution of compound 2,3-difluoro-6-hydroxymethylbenzaldehyde (4 g, 25.30 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (5.26 g, 38.04 mmol), sodium iodide (758.45 mg, 5.06 mmol), and compound 3b (6.42 g, 32.89 mmol). The mixture was stirred at 60 °C for 12 h. 100 mL of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, each time with 50 mL. The combined organic phases were washed twice with water, each with 50 mL, and then with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 3c.

[0150] Process 3

[0151] To a solution of compound 3c (5 g, 18.37 mmol) in tetrahydrofuran (30 mL) was added a solution of sodium borohydride (800 mg, 21.15 mmol) in water (3 mL) at 0-5 °C. The reaction solution was stirred at 25 °C for 1 h. 50 mL of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate, each time with 20 mL of water. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 3d.

[0152] Process 4

[0153] To 5-fluoro-2-hydroxybenzaldehyde (2.66 g, 18.96 mmol) and 3d (5.2 g, 18.96 mmol) in tetrahydrofuran (50 mL) at 0-5 °C, tri-n-butylphosphine (5.75 g, 28.44 mmol) and azodicarbonyldipiperidine (7.18 g, 28.44 mmol) were added. The reaction was stirred under nitrogen at 25 °C for 12 h. The reaction solution was filtered, and the filtrate was added to 50 mL of water. The mixture was extracted twice with ethyl acetate, each time with 50 mL of water. The combined organic phases were washed once with 50 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 1:0 to 20:1) to give 3e.

[0154] Process 5

[0155] To a solution of compound 3e (2.6 g, 6.56 mmol) in dichloromethane (30 mL), m-chloroperoxybenzoic acid (1.33 g, 6.56 mmol, 85% purity) was added, and the reaction solution was stirred at 25 °C for 12 h. The reaction solution was filtered, and the filtrate was added to 30 mL of sodium bicarbonate. The mixture was extracted twice with dichloromethane, each time with 10 mL of water. The combined organic phases were washed twice with saturated sodium bicarbonate, each with 30 mL of water, and then with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 1:0-10:1) to give compound 3f.

[0156] Process 6

[0157] To compound 3f (1.5 g, 3.90 mmol) in methanol (2 mL) and water (2 mL) was added potassium carbonate (1.08 g, 7.81 mmol). The reaction solution was stirred at 25° C. for 12 hours. 30 mL of water was added to the reaction solution, and the mixture was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, washed with 30 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 3g.

[0158] 1 H NMR (400 MHz, CDCl3) δ = 7.14 (q, J = 9.2 Hz, 1H), 7.02-7.0 (m, 1H), 6.66 - 6.45 (m, 2H), 6.63-6.53 (m, 1H), 5.11 (d, J = 1.8 Hz, 2H), 4.07 (t, J = 6.0 Hz, 2H), 3.70 (t, J = 6.0 Hz, 2H), 1.97 - 1.89 (m, 2H), 1.76 - 1.70 (m, 2H).

[0159] Process 7

[0160] To a solution of compound 3g (800 mg, 2.34 mmol) in tetrahydrofuran (20 mL) at 0 °C, sodium hydride (233.71 mg, 5.84 mmol, 60% purity) and p-toluenesulfonyl chloride (445.56 mg, 2.34 μmol) were added, and the reaction was stirred under nitrogen at 25 °C for 60 h. To the reaction solution, 2 mL of saturated aqueous ammonium chloride and 10 mL of water were added, and the mixture was extracted twice with ethyl acetate, each time with 10 mL of water. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 1:0 to 10:1) to give compound 3h.

[0161] 1H NMR (400 MHz, CDCl3) δ = 7.17 - 7.10 (m, 2H), 6.70-6.62 (m, 3H), 5.04 (d, J = 2.0 Hz, 2H), 4.16 - 4.13 (m, 4H), 2.10 - 2.04 (m, 4H).

[0162] Process 8

[0163] To a solution of compound 3h (100 mg, 308.36 μmol) in acetic acid (1 mL) at 0-5°C, nitric acid (149.46 mg, 1.54 mmol, 65% purity) was added, and the reaction was stirred at 60°C for 1 h. 10 mL of water was added to the reaction solution. The solid was precipitated and filtered. The filter cake was dried under reduced pressure, and then ethyl acetate (1 mL) and petroleum ether (10 mL) were added. The mixture was slurried at 25°C for 30 min and filtered. The filter cake was dried under reduced pressure to give compound 3i.

[0164] Process 9

[0165] To a solution of compound 3i (100 mg, 270.79 μmol) in ethyl acetate (10 mL) was added wet palladium on carbon (10 mg, 10% purity, 50% water), and the reaction was stirred under 15 psi hydrogen at 25° C. for 7 h. The reaction solution was filtered, and the filtrate was concentrated to give compound 3j.

[0166] LC-MS: m / z = 340.1 [M+H] + .

[0167] Step 10

[0168] To a solution of compound BB-1 (69.18 mg, 206.30 μmol) and compound 3j (70 mg, 206.30 μmol) in tetrahydrofuran (5 mL), triethylamine (41.75 mg, 412.60 μmol) was added, and the reaction was stirred at 35° C. for 36 h. The reaction solution was concentrated to dryness under reduced pressure, and ethyl acetate (2 mL) and petroleum ether (20 mL) were added. The mixture was slurried at 25° C. for 30 min and filtered. The filter cake was dried under reduced pressure to give compound 3k.

[0169] LC-MS: m / z = 581.3 [M+H] + .

[0170] Step 11

[0171] To a solution of compound 3k (150 mg, 258.39 μmol) in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), lithium hydroxide monohydrate (65.06 mg, 1.55 mmol) was added, and the reaction was stirred at 25 °C for 2 h. The reaction solution was adjusted to pH 4-5 with 1 mol of hydrochloric acid per liter and stirred at 25 °C for 10 min. The solid was precipitated and filtered. The filter cake was concentrated to dryness under reduced pressure, and ethyl acetate (5 mL) and petroleum ether (20 mL) were added. The mixture was slurried at 25 °C for 30 min, filtered, dried under reduced pressure, and then purified by preparative high-performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile %: 47%-67%) to give compound 3.

[0172] 1H NMR (400 MHz, DMSO-d6) δ = 12.03 (br s, 1H), 7.44 (q, J = 9.6 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.17 (d, J = 11.2 Hz, 1H), 6.95 - 6.88 (m, 1H), 4.99 (s, 2H), 4.17 - 4.14 (m, 4H), 1.96 (br s, 4H); LC-MS: m / z = 535.1 [M+H] + .

[0173] Example 4 [ka]

[0174] Process 1

[0175] Compound 4a (3-bromopropanol, 12 g, 86.34 mmol) was dissolved in 60 mL of dichloromethane, and triethylamine (13.10 g, 129.50 μmol) was added. The reaction solution was stirred at 25°C for 20 minutes and then cooled to 0°C. Next, acetic anhydride (10.58 g, 103.60 mmol) was dissolved in 10 mL of dichloromethane, and the solution was added dropwise to the reaction solution. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was poured into 50 mL of water, and the pH was adjusted to 3-5 with 1N dilute hydrochloric acid. The organic phase was washed three times with 30 mL of water each time. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain compound 4b.

[0176] 1 H NMR (400 MHz, CDCl3) δ = 4.21 (t, J = 6.4 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H), 2.25 - 2.13 (m, 2H), 2.07 (s, 3H).

[0177] Process 2

[0178] Compound 3,5-difluoro-2-hydroxybenzaldehyde (7.5 g, 47.44 mmol) and compound 4b (11.16 g, 61.67 mmol) were dissolved in 100 mL of N,N-dimethylformamide, and then potassium carbonate (13.11 g, 94.88 mmol) was added. The mixture was then heated to 75 °C and stirred at 75 °C for 12 hours. The reaction solution was cooled to 25 °C and poured into 200 mL of water. The mixture was extracted with ethyl acetate three times, each time with 100 mL of ethyl acetate. The combined organic phases were washed four times with 100 mL of water. The organic phase was concentrated, and the crude product was purified using a silica gel column (silica gel, 100-200 mesh, petroleum ether:ethyl acetate = 1 / 0-20 / 1) to obtain compound 4c.

[0179] Process 3

[0180] Compound 4c (12 g, 46.47 mmol) was dissolved in 100 mL of tetrahydrofuran and 10 mL of water, and the solution was cooled to 0 °C. Sodium borohydride (2.11 g, 55.77 mmol) was added in batches, and the mixture was then stirred at 25 °C for 3 h. The reaction was quenched with 1 mol / L dilute hydrochloric acid to a pH of about 6, and then extracted twice with 50 mL of ethyl acetate each time. The organic phases were combined, washed once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 4d.

[0181] Process 4

[0182] Compound 4d (8 g, 30.74 mmol), 5-fluorosalicylaldehyde (5.6 g, 39.96 mmol), and tri-n-butylphosphine (12.44 g, 61.48 mmol) were dissolved in 50 mL of tetrahydrofuran, and the solution was cooled to 0 °C. Next, azodicarbonyldipiperidine (15.51 g, 61.48 mmol) was added in batches, and the mixture was stirred at 25 °C under nitrogen for 12 h. The reaction solution was poured into 50 mL of water, and the mixture was extracted twice with ethyl acetate, each time with 50 mL of water. The organic phases were combined and concentrated. The crude product was purified using a silica gel column (silica gel, 100-200 mesh, petroleum ether:ethyl acetate = 1 / 0-20 / 1) to give compound 4e.

[0183] Process 5

[0184] Compound 4e (6.5 g, 17.00 mmol) was dissolved in 55 mL of dichloromethane, and m-chloroperoxybenzoic acid (4.83 g, 23.80 mmol, purity: 85%) was added. The mixture was then heated to 35 °C and stirred at 35 °C for 12 h. The reaction solution was cooled to 25 °C and filtered. The filtrate was washed twice with 25 mL of water, then twice with 20 mL of saturated sodium bicarbonate, and twice with 30 mL of saturated sodium sulfite solution. The organic phase was concentrated, and the crude product was purified using a silica gel column (silica gel, 100-200 mesh, petroleum ether:ethyl acetate = 1 / 0-20 / 1) to obtain compound 4f.

[0185] Process 6

[0186] Compound 4f (5 g, 12.55 mmol) was dissolved in 50 mL of methanol and 10 mL of water, and potassium carbonate (5.2 g, 37.66 mmol) was added. The mixture was then stirred at 25 °C for 12 h. The mixture was filtered, and the filtrate was concentrated. The crude product was diluted with 20 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 4g.

[0187] Process 7

[0188] Compound 4g (1.63 g, 4.97 mmol) was dissolved in 20 mL of tetrahydrofuran, and the solution was cooled to 0 °C. Sodium hydride (595.77 mg, 60% purity, 14.90 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. p-Toluenesulfonyl chloride (946.61 mg, 4.97 mmol) was then added, and the mixture was heated to 50 °C and stirred at 50 °C for 24 h. The reaction solution was cooled to 25 °C and then quenched by adding 20 mL of saturated ammonium chloride solution. The mixture was extracted once with 20 mL of ethyl acetate and concentrated. The crude product was purified using a silica gel column (silica gel, 100-200 mesh, petroleum ether:ethyl acetate = 1 / 0-20 / 1) to give compound 4h.

[0189] Process 8

[0190] Compound 4h (130 mg, 418.99 μmol) was dissolved in 2 mL of acetic acid, and nitric acid (81.24 mg, 837.99 μmol, purity: 65%) was added. The mixture was then heated to 65°C and stirred at 65°C for 1 hour. The reaction solution was cooled to 25°C and poured into 5 mL of water. The mixture was extracted twice with ethyl acetate, each time with 5 mL of ethyl acetate. The combined organic phases were washed twice with 5 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 4i.

[0191] Process 9

[0192] Compound 4i (110 mg, 309.63 μmol) was dissolved in 3 mL of ethyl acetate, and palladium on carbon (50 mg, purity: 10%) was added under nitrogen. The atmosphere was replaced with hydrogen three times, and the mixture was stirred under a hydrogen atmosphere (15 psi) at 25 °C for 12 h. The reaction solution was filtered, and the filtrate was concentrated to give compound 4j, which was used directly in the next step.

[0193] LC-MS: m / z = 326.1 [M+H] + .

[0194] Step 10

[0195] Compound 4j (100 mg, 307.43 μmol) and compound BB-1 (103.09 mg, 307.43 μmol) were dissolved in 5 mL of tetrahydrofuran solution, and triethylamine (31.11 mg, 307.43 μmol) was added. The mixture was then heated to 70 °C and stirred at 70 °C for 12 h. The reaction solution was concentrated, and the crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 4k.

[0196] LC-MS: m / z = 567.1 [M+H] + .

[0197] Step 11

[0198] Compound 4k (80 mg, 141.22 μmol) was dissolved in 3 mL of tetrahydrofuran and 0.5 mL of methanol. Lithium hydroxide monohydrate (35.56 mg, 847.30 μmol) was dissolved in 0.5 mL of water, and the solution was added dropwise to the reaction solution. The mixture was then stirred at 25 °C for 2 h. The mixture was adjusted to pH 2-3 with 1 mol / L dilute hydrochloric acid and then diluted with 3 mL of water. The mixture was extracted three times with 3 mL of ethyl acetate. The organic phases were combined, washed once with 5 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 4.

[0199] 1 H NMR (400 MHz, DMSO-d6) δ = 14.45 (br s, 1H), 12.03 (s, 1H), 7.47 - 7.35 (m, 3H), 7.26 (br d, J = 10.4 Hz, 1H), 7.18 (br d, J = 8.4 Hz, 1H), 5.09 (s, 2H), 4.37 (br s, 2H), 4.21 (br s, 2H), 2.09 (br s, 2H); LC-MS: m / z = 521.1 [M+H] + .

[0200] Biological Assay Data Assay Example 1. Assay of the activity of compounds of the present disclosure on the human gonadotropin-releasing hormone receptor

[0201] Assay Objective: To detect the inhibitory activity of the assay compounds on gonadotropin-releasing hormone receptors at the cellular level using FLIPR detection technology.

[0202] Key materials and sources in the assay Fluo-4 Direct TM Kit--Invitrogen-F10471 384-well polylysine-coated cell plate -- Greiner-781946 384-well Compound Plate--Greiner-781280 ECHO (Sonic Pipetting System) for Compound Preparation - Labcyte FLIPR (Fluorescence Imaging Plate Reader) - Molecular Devices

[0203] Assay procedure GnRH / HEK293 (human embryonic kidney 293) cultured cells in the logarithmic growth phase were washed with DPBS (Dulbecco's phosphate-buffered saline) buffer and an appropriate amount of 0.05% EDTA (ethylenediaminetetraacetic acid)-trypsin was added. The cells were placed in a 37°C carbon dioxide incubator for 1-2 minutes and then removed from the incubator. The digestion was terminated by adding medium to the cells. The cells were dispersed by repeated pipetting and collected by centrifugation. The cells were seeded into 384-well poly-lysine-coated cell plates at a density of 20,000 cells / well in 20 μL and incubated overnight in a 5% CO2, 37°C incubator.

[0204] The next day, 20 μL of 2× Fluo-4 Direct TMBuffer was added to each well, and the plate was incubated in a 5% CO2, 37°C incubator for 50 minutes. The cells were then allowed to stand at room temperature for 10 minutes. 0.2 mM leuprolide acetate was serially diluted 4-fold in ECHO to a concentration of 10, and 900 nL of the diluted solution was transferred to the compound plate. 30 μL of FLIPR buffered saline was added to the compound plate, which was then centrifuged at 1000 rpm for 1 minute. The FLIPR instrument software was run, and 10 μL of assay buffer salt solution was added according to the program. The fluorescent signal was read. Next, 10 μL of a reference compound as an agonist was added, and the fluorescent signal was read. ECHO 80 Calculate 6×EC 80 Agonists were prepared at concentrations of 1000 mg / mL.

[0205] 2 mM assay compound and appropriate concentrations of reference compound were serially diluted 4-fold to 10-fold in ECHO, and 900 nL of the diluted solution was transferred to the compound plate. 30 μL of FLIPR buffered saline was added to the compound plate, and the plate was centrifuged at 1000 rpm for 1 minute. The FLIPR instrument software was started, and 10 μL of assay compound and reference compound were added to the cell plate according to the program. The fluorescent signal was read. Next, 10 μL of agonist at 6×EC80 concentration was added to the cell plate, and the fluorescent signal was read.

[0206] IC of compounds that inhibit calcium flux at the gonadotropin-releasing hormone receptor 50 , i.e., in cells stably expressing the GnRH receptor, Ca 2+ The drug concentration at which the flow was inhibited by half was calculated. 50 was calculated by GraphPad Prism 5.0 software.

[0207] Assay Results

[0208] The inhibitory activity of the compounds of the present disclosure against the human gonadotropin-releasing hormone receptor was determined by the assay described above, and the determined IC 50 are shown in Table 1:

[0209] Table 1. IC of compounds of the present disclosure that inhibit the activity of human gonadotropin-releasing hormone receptor 50 [Table 1]

[0210] Conclusion: The compounds of the present disclosure have significant inhibitory activity against the human gonadotropin-releasing hormone receptor.

[0211] Assay Example 2. In vivo efficacy evaluation

[0212] Assay Purpose: To evaluate the efficacy of compounds of the present disclosure in a mouse model of endometriosis.

[0213] Assay scheme:

[0214] Main reagents and consumables C57BL6 / J female mouse, calipers (ARZ-1331), 8-0 suture, stereomicroscope.

[0215] 2.2 Assay steps Detection of animal estrous cycle in 8-week-old C57BL6 / J female mice: Since the entire duration of the estrous cycle is approximately 4 days, mice that were in a specific estrous cycle on the day of measurement were selected based on the actual smear results by vaginal smear observation.

[0216] Modeling: The uterine horns of donor mice undergoing estrous cycling were excised and opened longitudinally. The excised biopsies were cut into 2 x 2 mm pieces. Recipient mice were anesthetized with isoflurane gas, and a 1 cm incision was made along the midline to expose the abdominal cavity. Endometriotic mice: Four donor uterine fragments were sutured to the peritoneal wall of mice undergoing estrous cycling; sham-operated mice: Abdominal fat fragments of similar size were sutured. The transplanted tissue, abdominal muscle, and skin were sutured with 8-0 black silk suture. Sham group: The abdominal cavity of each mouse in the sham-operated group was opened and fat fragments were transplanted; the other procedures were the same.

[0217] After 4 weeks of modeling, a second laparotomy was performed, and the ectopic lesion volume (V1) was measured using a caliper and calculated to determine the success of modeling. Twelve mice with relatively uniform V1 were selected and divided into two groups of six mice each: vehicle (vehicle control group) and drug group.

[0218] Sham group (sham operation group, 6 animals): normal feeding; Vehicle group (vehicle control group, 6 animals): vehicle was intragastrically administered once daily for 8 consecutive weeks. The vehicle was 10% DMAC + 10% solutol + 80% saline; Compound group (6 animals): 100 mpk was intragastrically administered every day at 10:00 AM for 8 consecutive weeks, and the vehicle was 10% DMAC + 10% solutol + 80% saline.

[0219] After 8 weeks of administration, samples were obtained from the mice. The volume of the ectopic lesion (V2) was measured using a vernier caliper and calculated. The inhibition rate was calculated using the formula: ectopic lesion volume V = π / 6 × length × width × height (where length indicates the length of the ectopic lesion, width indicates the width of the ectopic lesion, and height indicates the height of the ectopic lesion).

number

[0220] Assay Results: The assay results are shown in Table 2.

[0221] Table 2. Inhibitory results of compounds of the present disclosure in endometriosis model mice [Table 2]

[0222] Assay Conclusion: The compounds of the present disclosure can significantly inhibit the increase in the volume of endometriotic lesions in mice and have excellent efficacy in vivo.

[0223] Assay Example 3: Pharmacokinetic Evaluation Assay Purpose: To study the in vivo pharmacokinetic properties of compounds of the present disclosure in mice.

[0224] Assay scheme:

[0225] Each assay compound was mixed with DMAC and vortexed for 2 minutes. The assay compound solutions in DMAC were mixed and vortexed for 2 minutes to prepare a clear 10 mg / mL solution. 0.0600 mL of the 10 mg / mL solution was added to 0.300 mL of Solutol, and the mixture was vortexed for 2 minutes. 2.400 mL of saline was then added, and the mixture was vortexed for 2 minutes to obtain a 0.2 mg / mL solution, which was used for administration to the PO group. 0.500 mL of the PO administration solution was vortexed for 2 minutes, followed by the addition of 0.0500 mL of DMAC. This mixture was vortexed for 2 minutes, followed by the addition of 0.0500 mL of Solutol. The mixture was vortexed for 2 minutes, and finally, 0.400 mL of saline was added. This mixture was vortexed for 2 minutes to obtain a clear 0.1 mg / mL solution, which was then filtered through a microporous membrane to obtain the solution for administration to the IV group.

[0226] Four male CD-1 mice were divided into two groups. Animals in Group 1 received a single intravenous dose of 0.5 mg / kg, in which the vehicle was 10% DMAC / 10% Solutol / 80% normal saline, in a dose volume of 5 mL / kg. Animals in Group 2 received 2 mg / kg of the test compound orally by oral gavage, in which the oral vehicle was 10% DMAC / 10% Solutol / 80% normal saline, in a dose volume of 10 mL / kg. Whole blood samples were collected at 0.033 hours (intravenous injection only), 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, and 12 hours after dosing. The whole blood was centrifuged at 3200 x g for 10 minutes at 2-8°C to obtain plasma. Plasma concentrations of the compounds were measured by LC / MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

[0227] Assay Results

[0228] The results of the assay are shown in Table 3. The parameters have the following meaning: IV: intravenous injection; PO: oral administration; C0: initial plasma drug concentration; C max : Maximum drug concentration in the systemic circulation; T max :C max Time required to reach T 1 / 2 : Half-life; V dss : apparent volume of distribution; Cl: clearance rate; AUC 0-last : Area under the drug-time curve.

[0229] Table 3. Plasma pharmacokinetic (PK) measurement results of Compound 1 [Table 3]

[0230] Conclusion: The compounds of the present disclosure exhibit excellent pharmacokinetic properties with high plasma exposure, low clearance rate, long half-life, and high oral bioavailability. Furthermore, the present invention includes the following aspects. [Aspect 1] Formula (II):

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Claims

1. Formula (II): 【Chemistry 1】 [In the formula, L 1 and L 2 are each independently -(CH 2 ) n - and; L 3 and L 4 are each independently selected from -O- and -S-; R 1 and R 2 are each independently H, F, Cl and C 1-3 alkyl, wherein C 1-3 The alkyl may optionally be one, two, or three R a may be replaced by; Alternatively, R 1 and R 2 together with the atom to which they are commonly bonded 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 3-6 The cycloalkyl or 4-6 membered heterocycloalkyl optionally contains one, two, or three R b may be replaced by; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently H, F, Cl, Br, I, CN and C 1-3 alkyl, wherein C 1-3 The alkyl may each independently optionally be one, two, or three R c may be replaced by; n is selected from 1 and 2; R a , R b and R c are each independently selected from H, F, Cl, Br and I. or a pharmaceutically acceptable salt thereof.

2. R 1 and R 2 are each independently H, F and CH 3 wherein CH 3 is optionally substituted by one, two or three F; or, R 1 and R 2 are each independently selected from H; or, R 1 and R 2 together with the atom to which they are commonly attached form cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl, wherein cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or azetidinyl is optionally substituted by one, two or three F; or, R 1 and R 2 together with the atoms to which they are commonly bonded 【Chemistry 2】 10. The compound of claim 1, wherein the compound forms:

3. R 3 , R 4 , R 5 and R 6 are each independently selected from H and F; or, Structural part: 【Transformation 3】 but, 【Chemistry 4】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

4. R 7 , R 8 and R 9 are each independently selected from H and F; or, Structural part: 【Transformation 5】 but, 【Transformation 6】 2. The compound of claim 1, wherein:

5. L 3 and L 4 is each independently O, or a pharmaceutically acceptable salt thereof.

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

7. Structural part: 【Transformation 7】 but, 【Transformation 8】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

8. The compound is 【Chemistry 9】 where L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 or a pharmaceutically acceptable salt thereof, wherein each of

9. The compound is 【Chemistry 10】 wherein: L 1 and L 2 are each independently -(CH 2 ) n -Selected from; L 3 and L 4 are each independently selected from -O- and -S-; R 1 and R 2 are each independently H, F, Cl and C 1-3 alkyl, wherein C 1-3 The alkyl may optionally be one, two, or three R a may be replaced by; Alternatively, R 1 and R 2 together with the atom to which they are commonly bonded 3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein C 3-6 The cycloalkyl or 4-6 membered heterocycloalkyl optionally contains one, two, or three R b may be replaced by; R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, and I; n is selected from 1 and 2; R a and R b are each independently selected from H, F, Cl, Br, and I; The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the "4-6 membered heterocycloalkyl" contains 1, 2 or 3 heteroatoms selected from N, NH, O and S.

10. A compound shown below or a pharmaceutically acceptable salt thereof: 【Chemistry 11】

11. 11. A pharmaceutical composition for treating a disease, comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein the disease is a disease associated with a GnRH receptor antagonist, or the disease is a disease associated with endometriosis and / or uterine fibroids.

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