Fused heterocycle-substituted thienopyrimidinedione derivative and use thereof

Abstract

The present invention provides a fused heterocycle-substituted thienopyrimidinedione derivative and a pharmaceutical composition comprising same. The compound or pharmaceutical composition can be used for preventing, treating, or alleviating diseases mediated by GnRH receptor antagonists in patients, such as endometriosis, hysteromyoma, benign prostatic hyperplasia, uterine fibroid, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, short stature, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, and pituitary tumor.

Description

Fused heterocyclic substituted thiophene-pyrimidine dione derivatives and their applications

[0001] This application claims the following priority:

[0002] CN202510354214.7, application date March 24, 2025. Technical Field

[0003] This invention belongs to the pharmaceutical field, specifically relating to fused heterocyclic substituted thiophene-pyrimidine dione derivatives and their applications. Background Technology

[0004] Gonadotropin-releasing hormone (GnRH) is a decapeptide hormone primarily secreted by the hypothalamus. It is transported to the pituitary gland via the hypothalamic-pituitary portal circulation system, where it binds to GnRH receptor cells in the anterior pituitary gland, stimulating the synthesis and release of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Gonadotropins act on the gonads, regulating the normal development of the ovary and corpus luteum, playing a crucial role in the hypothalamic-pituitary-gonadal axis. Drugs regulating GnRH mainly include agonists and antagonists.

[0005] Peptide GnRH receptor antagonists, including cetrorexate and ganiritaxel, block the binding of GnRH to its receptor by rapidly and competitively binding to the GnRH receptor, thus inhibiting the formation of the dimer complex and signal transduction, and consequently suppressing the release of LH and FSH. However, peptide compounds have issues related to oral absorption, dosage form, dose-volume relationship, drug stability, duration of action, and metabolic stability. Small molecule GnRH receptor antagonists offer advantages such as convenient and rapid oral administration and fewer side effects. Studies have shown that small molecule antagonists have significant therapeutic effects on hormone-dependent diseases such as endometriosis, uterine fibroids, precocious puberty, and prostate cancer.

[0006] In July 2018, the FDA approved the first small-molecule GnRH antagonist, Elagolix, developed by AbbVie, for the treatment of moderate to severe pain caused by endometriosis. In December 2020, the FDA approved the first indication for the second small-molecule oral antagonist, Relugolix, for the treatment of advanced prostate cancer, and its indication for the treatment of uterine fibroids has been approved in Japan. The third antagonist, Linzagolix, was approved in the EU and the UK in June 2022 for the treatment of moderate to severe symptoms of uterine fibroids in women of reproductive age. Shanghai Baozheng Pharmaceutical has acquired the development rights for Linzagolix in Greater China, and its Phase III clinical trial in premenopausal women in China with endometriosis-related pain has completed the enrollment of the first patient.

[0007] Currently, researchers have conducted studies in an effort to find effective small-molecule GnRH receptor antagonists. For example, patent applications such as PCT / CN2022 / 128588, CN202210471493.1, PCT / CN2022 / 077112, PCT / CN2022 / 077035, CN202111037295.6, CN202180030371.2, CN202080103762.8, and CN202010942953.5 disclose numerous small-molecule GnRH receptor antagonists. Although these compounds are comparable to marketed small-molecule antagonists in terms of activity, they still have certain shortcomings. For example, the preferred compound reported in PCT / CN2022 / 077112 has a cell activity IC50 value of [missing information]. 50 Its concentration is 3.1 nanomolar, while its half-life in plasma is only 5.56 hours, which is significantly less than that of the marketed small molecule antagonist Linzagolix. Therefore, it is necessary to continue researching and developing more comprehensive and effective small molecule GnRH receptor antagonists. Summary of the Invention

[0008] The purpose of this invention is to provide a novel class of compounds with excellent GnRH receptor inhibitory activity and pharmacokinetic properties.

[0009] Specifically, the present invention provides a compound, which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I).

[0010] in:

[0011] L1, L2, L3, L4, and L5 are independently selected from -O-, -S-, and -(CR6R7), respectively. n -, -C(=O)- and -NR8-, and at least one of L1, L2, L3, L4 and L5 is -NR8-;

[0012] T1 and T2 are independently O, S, NH, N-NO2 or N-CN, respectively;

[0013] A1 is either CR9 or N;

[0014] Y and Z are independently selected from -O-, -S-, and -CR, respectively. 10 R 11 -;

[0015] R1 is B(OH)2, C(=O)OW1, C(=O)NW2W3 or S(=O)2W4, where W1, W2, and W3

[0016] W4 and W4 are independently selected from H, D, and C, respectively. 1-6 Alkyl, C 3-8 cycloalkyl and C 6-10 Aryl;

[0017] R2, R3, and R9 are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, NO2, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH and NO2;

[0018] Each R4 is independently H, D, F, Cl, Br, I, CN, OH, COOH, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 alkylthio group or 3-7 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The alkylthio group and the 3-7 membered heterocyclic group may optionally be independently replaced by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, CN, oxo (=O), OH, COOH, NO2 and NH2; or two adjacent R4 groups may optionally form a 3-6 membered cycloalkyl or a 3-7 membered heterocyclic group with the carbon atom attached to them, wherein the 3-6 membered cycloalkyl or 3-7 membered heterocyclic group may optionally be independently replaced by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2 and OH;

[0019] R5 represents H, D, F, Cl, Br, I, OH, NH2, CN, NO2, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be independently and optionally replaced by one, two or three substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH, NO2;

[0020] Each R6, R7, R10 and R 11 Each element is independently selected from H, D, F, Cl, Br, I, OH, and C. 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, oxo (=O), CN, NH2 and OH; or R6 and R7, R 10 With R 11 Each cycloalkyl group or heterocyclic group may be optionally formed with the carbon atom it is connected to in a 3-6 membered cycloalkyl group or a 3-7 membered heterocyclic group, wherein the cycloalkyl group or heterocyclic group may be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2 and OH;

[0021] R8 is H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthioyl or 3-6 membered cycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 The alkylthio group and the 3-6 membered cycloalkyl group may be optionally and independently replaced by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, CN, OH, COOH, NO2 and the 3-6 membered cycloalkyl group;

[0022] m can be 1, 2, 3, or 4;

[0023] n is 1, 2, or 3.

[0024] In some implementation schemes,

[0025] In some implementations, when L1 is -O- or -S-, L2, L3 and L4 are independently -CR6R7- or -C(=O)-, and L5 is -NR8-;

[0026] In some implementations, or when L1 is -NR8-, L2, L3 and L4 are independently -CR6R7- or -C(=O)-, and L5 is -O- or -S-;

[0027] In some implementations, when L1 is -CR6R7-, L2 is -NR8-, L3 and L4 are independently -CR6R7- or -C(=O)-, and L5 is -O- or -S-.

[0028] In some implementations, when L1 is -O- or -S-, L2 and L3 are independently -CR6R7-, L4 is -NR8-, and L5 is -CR6R7- or -C(=O)-.

[0029] In some implementations, when L1, L2, L3, and L4 are all -CR6R7-, L5 is -NR8-.

[0030] In some implementations, Z is -CR when Y is -O- or -S-. 10 R 11 -;

[0031] In some implementations, when Y is -CR 10 R 11 When -, Z is -O- or -S-.

[0032] In some implementations, R1 is B(OH)2, C(=O)OW1, C(=O)NW2W3;

[0033] Among them, W1, W2, and W3 are independently selected from H, D, and C, respectively. 1-6 alkyl;

[0034] Alternatively, W1, W2, and W3 can be independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, respectively.

[0035] Alternatively, W1, W2, and W3 can be independently selected from H and D, respectively.

[0036] In some implementations, R2, R3, and R9 are independently selected from H, D, F, Cl, Br, I, and C, respectively. 1-6 Alkyl and C 1-6 Alkoxy; the C 1-6 Alkyl and C 1-6 The alkoxy group can be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I;

[0037] In some embodiments, R2, R3, and R9 are independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2;

[0038] In some implementations, R2, R3, and R9 are independently selected from H, D, F, Cl, Br, and I, respectively.

[0039] In some implementations, each R4 is independently H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl or C 1-6 Alkoxy; the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, CN;

[0040] In some embodiments, each R4 is independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2;

[0041] In some embodiments, two adjacent R4 atoms optionally form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclopropoxy groups with the carbon atom they are attached to. The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy and It can be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH.

[0042] In some embodiments, R5 is selected from H, D, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2.

[0043] In some implementation schemes, each of R6, R7, and R 10 and R 11 Selected independently from H, D, F, Cl, Br, I, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I; or R6 and R7, R 10 With R 11Each of the carbon atoms optionally bonded to it forms a 3-6 membered cycloalkyl group or a 3-7 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group and the 3-7 membered heterocyclic group may be independently and optionally replaced by one, two or three substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH;

[0044] In some implementation schemes, each of R6, R7, and R 10 and R 11 Each of the following is independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2; or R6 and R7, R 10 With R 11 The carbon atoms that are optionally bonded to each other can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, or cyclopentoxy, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, and cyclopentoxy groups can be independently and optionally replaced by one, two, or three substituents selected from H, D, F, Cl, Br, I, CN, NH2, and OH.

[0045] In some implementations, R8 is H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl, C 1-6 alkoxy, cyclopropyl, or cyclobutyl; the C 1-6 Alkyl, C 1-6 The alkoxy, cyclopropyl, and cyclobutyl groups may be optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from H, D, F, Cl, Br, I, CN, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0046] In some embodiments, it is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

[0047] The present invention also relates to the use of the aforementioned compounds or pharmaceutical compositions thereof in the preparation of medicaments for the prevention, treatment or relief of GnRH receptor antagonist-mediated diseases in patients.

[0048] Some implementations include GnRH receptor antagonists mediated diseases such as endometriosis, uterine fibroids, benign prostatic hyperplasia, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, short stature, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, and pituitary tumors. Endometriosis and uterine fibroids are preferred.

[0049] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I).

[0050] The compounds of this invention have a significant inhibitory effect on gonadotropin-releasing hormone (GnRH) receptors, high plasma exposure, long half-life, high oral bioavailability, and excellent pharmacokinetic properties.

[0051] Definitions and general terms

[0052] This invention will list in detail the relevant literature for the specific details provided, and the embodiments are accompanied by diagrams of structural and chemical formulas. This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances. Many documents and similar substances distinguish or conflict with this application, including but not limited to the definitions of terms, usages of terms, described techniques, or the scope controlled as described in this application.

[0053] Unless otherwise stated, the following definitions will apply in this invention. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, and the Chemical Handbook, 75th Ed, 1994. Furthermore, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007; therefore, all content incorporates these references.

[0054] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0055] Compounds described herein may optionally be substituted with one or more substituents, such as those of the general formula in this invention, or specific examples, subclasses, and a class of compounds included in this invention, as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether or not preceding the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents described may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxyl, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclic, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, etc.

[0056] The term "alkyl" as used in this invention includes a monovalent hydrocarbon group with 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, consisting of a saturated straight-chain or branched chain, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t... -Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl -1-Butyl (-CH2CH(CH3)CH2CH3), n-Hexyl (-CH2CH2CH2CH2CH2CH3), 2-Hexyl (-CH(CH3)CH2CH2CH2CH3), 3-Hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C) H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, and n-octyl, etc. The term "alkyl" and its prefix "alkane" are used here, both encompassing straight-chain and branched saturated carbon chains.

[0057] The term "alkoxy" as used in this invention refers to an alkyl group, as defined herein, that is attached to other parts of a compound molecule via an oxygen atom. In some embodiments, the alkoxy group is C10. 1-4 Alkoxy groups; examples of which include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups. Furthermore, the alkoxy group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0058] The term "cycloalkyl" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic carbocyclic system containing 3-12 carbon atoms, which is a saturated ring or a ring containing one or more unsaturated bonds, but never an aromatic ring. In one embodiment, the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, it contains 3-8 carbon atoms; and in yet another embodiment, it contains 3-6 carbon atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. The cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0059] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring is aromatic, and each ring comprises a ring of 3-7 atoms with one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, anthraceneyl, indanyl, indenyl, etc. The aryl group may be independently and optionally replaced by one or more substituents described in this invention.

[0060] A ring system formed by a substituent connected to a ring by a bond means that the substituent can be substituted at any substituted position on the ring. For example, formula (a) means that the substituent R can be monosubstituted or polysubstituted at any possible substituted position on the pyridine ring.

[0061] Unless otherwise explicitly stated, the descriptive phrases “each and each is independently”, “each and each is independently”, and “each and each is independently” used throughout this document are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0062] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, geometric isomers, or conformational isomers, is within the scope of this invention.

[0063] Unless otherwise indicated, the structural formulas and compounds described in this invention include all isomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers), nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, compounds of this invention that are individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs are also within the scope of this invention.

[0064] The structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other atoms are all within the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as those doped with radioactive isotopes, are also within the scope of the present invention. 3 H and 14 Those of type C can be used for drug and / or substrate tissue distribution determination. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred because they are easy to prepare and detectable. Furthermore, heavier isotopes (e.g., deuterium, i.e., 2 H) substitution can provide certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some cases. The isotopically labeled compounds and their prodrugs used in the methods of this invention can generally be prepared by using readily available isotopically labeled reagents instead of non-isotopically labeled reagents according to compound preparation procedures disclosed in the art.

[0065] "Metabolic product" refers to the product obtained in vivo by the metabolism of a specific compound described in this invention or its pharmaceutically acceptable salt, analogue, or derivative, which exhibits similar activity to the compound of formula (I) in vivo or in vitro. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such a product can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, or enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0066] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name compounds whose plane polarization is rotated. (-) or l indicates the compound is levorotatory, while (+) or d indicates it is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures differ. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0067] The terms "tautomer" or "tautomerism form" refer to isomers of different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerization between keto-enol and imine-enamine forms. Valence tautomers include interconversions involving the recombination of bonding electrons.

[0068] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to: inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and N+ (C 1-4 Salts of alkyl groups (4). This invention also envisions quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0069] In this invention, "hydrate" refers to an associative compound formed when the solvent molecules are water.

[0070] The term "solvent" in this invention refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0071] The term "nitrogen oxide" in this invention refers to an N-oxide formed by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), for example, by reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).

[0072] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0073] Unless otherwise stated herein or the context clearly indicates otherwise, the terms “an,” “a,” “the,” and similar terms used herein, as well as in the context of the invention (especially in the context of the claims), may be interpreted as including both the singular and the plural.

[0074] The term “GnRH receptor antagonist” as used in this article refers to substances that can inhibit gonadotropin-releasing hormone (GnRH) receptors. Detailed Implementation

[0075] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0076] Example 1: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 1)

[0077] Step 1: (3-(3,4-difluoro-2-formylphenoxy)propyl)tert-butyl carbamate

[0078] 2,3-Difluoro-6-hydroxybenzaldehyde (2.00 g, 12.65 mmol) and tert-butyl 2,3-difluoro-6-hydroxybenzaldehyde (3-bromopropyl)carbamate (4.52 g, 18.98 mmol) were dissolved in acetonitrile (50 mL), and potassium carbonate (5.24 g, 37.95 mmol) was added. The mixture was heated at 50 °C overnight. After cooling to room temperature, the acetonitrile was removed by concentration, and the product was purified by column chromatography to obtain 3.60 g of the product.

[0079] Step 2: Synthesis of tert-butyl (3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)propyl)carbamate

[0080] (3-(3,4-difluoro-2-formylphenoxy)propyl)carbamate tert-butyl ester (3.6 g, 11.42 mmol) was dissolved in ethanol (50 mL), and sodium borohydride (0.435 g, 11.50 mmol) was added. The mixture was reacted at room temperature for 1 hour. After concentration, the product was purified by column chromatography to give 3.33 g of the product.

[0081] Step 3: Synthesis of tert-butyl (3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)propyl)carbamate

[0082] 2,4-Difluoro-5-nitrophenol (1.84 g, 10.49 mmol) and (3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)propyl)carbamate tert-butyl ester (3.33 g, 10.49 mmol) were dissolved in tetrahydrofuran (50 mL), triphenylphosphine (3.30 g, 12.59 mmol) was added, and diisopropyl azodicarbonate (2.50 mL, 12.59 mmol) was added dropwise. The mixture was reacted overnight at room temperature, and the product was concentrated and separated by column chromatography to obtain 4.48 g of the product.

[0083] Step 4: Synthesis of 1,2,11-trifluoro-12-nitro-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxazonyl undecene

[0084] 3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)propyl)tert-butyl carbamate (3.30 g, 6.96 mmol) was dissolved in trifluoroacetic acid (30 mL) and reacted at room temperature for 1 hour. After the starting material was completely converted, the crude product was concentrated and used directly in the next step of the reaction without purification.

[0085] Cesium fluoride (10.57 g, 69.56 mmol) was dispersed in N,N-dimethylmethaneamide (40 mL) and heated to 50 °C. The crude product was dissolved in N,N-dimethylmethaneamide (40 mL) and added dropwise to the reaction system. The reaction was continued to be heated for 3 hours. After cooling, the reaction solution was poured into water (250 mL), filtered, and dried to obtain 3.15 g of product, which was used directly in the next reaction without purification.

[0086] Step 5: Synthesis of tert-butyl 1,2,11-trifluoro-12-nitro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-carboxylic acid

[0087] 1,2,11-Trifluoro-12-nitro-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxazonium undecylene (300 mg, 0.85 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.35 mL, 2.54 mmol), 4-dimethylaminopyridine (34 mg, 0.28 mmol), and di-tert-butyl dicarbonate (0.39 mL, 1.70 mmol) were added. The mixture was reacted overnight at room temperature. After concentration, the product was purified by column chromatography to give 228 mg of the product.

[0088] Step 6: Synthesis of tert-butyl 12-amino-1,2,11-trifluoro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-carboxylic acid

[0089] 1,2,11-trifluoro-12-nitro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-carboxylic acid tert-butyl ester (228 mg, 0.50 mmol) was dissolved in ethyl acetate (5 mL), 10% palladium / carbon (29 μL, 0.28 mmol) was added, nitrogen gas was introduced, and the reaction was carried out at room temperature overnight. After filtration, the product was concentrated to obtain 211 mg.

[0090] LC-MS(ESI):[M+H] + =425.3;

[0091] Step 7: Synthesis of tert-butyl 1,2,11-trifluoro-12-(5-(methoxycarbonyl)-4-oxo-2-thio-1,2-dihydrothiophene[3,4-d]pyrimidin-3(4H)-yl)-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-carboxylic acid

[0092] 12-Amino-1,2,11-trifluoro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-carboxylic acid tert-butyl ester (80 mg, 0.19 mmol) and 4-((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylic acid dimethyl ester (79 mg, 0.22 mmol) were dissolved in tetrahydrofuran (2 mL), and triethylamine (105 μL, 0.75 mmol) was added. The mixture was reacted overnight at 60 °C. After cooling, the mixture was concentrated and purified by column chromatography to give 81 mg of the product.

[0093] Step 8: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0094] 1,2,11-trifluoro-12-(5-(methoxycarbonyl)-4-oxo-2-thio-1,2-dihydrothieno[3,4-d]pyrimidin-3(4H)-yl)-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-carboxylic acid tert-butyl ester (81 mg, 0.12 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (0.5 mL), and a solution of lithium hydroxide monohydrate (26 mg, 0.62 mmol) in water (0.5 mL) was added. The reaction was carried out at room temperature for 1 hour. After the starting material was completely converted, the solution was adjusted to acidity with dilute hydrochloric acid, extracted with ethyl acetate (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product.

[0095] Add 1 mL of trifluoroacetic acid to the crude product and react at room temperature for 1 hour. After concentrating to remove the trifluoroacetic acid, purify the product by high performance liquid chromatography to obtain 27 mg of product.

[0096] LC-MS(ESI):[M+H] + =536.3;

[0097] 1H NMR (400MHz, DMSO-d6) δ13.79(s,2H),7.52–7.46(m,1H),7.37(dd,J=19.3,9.6Hz,1H),7.05(d,J=7.3Hz,1H),6.85–6 .76(m,2H),5.15(d,J=10.7Hz,2H),5.00(d,J=11.6Hz,1H),4.42-4.28(m,2H),3.56–3.40(m,2H),1.87-1.77(s,2H).

[0098] Example 2: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 2)

[0099] Step 1: Synthesis of 1,2,11-trifluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-12-amine

[0100] 12-Amino-1,2,11-trifluoro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-carboxylic acid tert-butyl ester (211 mg, 0.50 mmol) was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride (132 mg, 3.48 mmol) was added. The mixture was heated at 60 °C overnight. After complete conversion of the starting material, ethyl acetate was added under ice-water bath to quench the reaction, and the product was concentrated and then purified by column chromatography to obtain 17 mg of product.

[0101] LC-MS(ESI):[M+H] + =339.2;

[0102] Step 2: Synthesis of methyl 4-oxo-2-thio-3-(1,2,11-trifluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0103] 1,2,11-Trifluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-12-amine (17 mg, 0.05 mmol) and dimethyl 4-((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylic acid (26 mg, 0.07 mmol) were dissolved in tetrahydrofuran (1 mL), and triethylamine (28 μL, 0.20 mmol) was added. The mixture was reacted at 70 °C for 3 hours. After the raw materials were completely converted, the crude product (28 mg) was directly concentrated.

[0104] LC-MS(ESI):[M+H] + =564.3;

[0105] Step 3: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0106] Methyl 4-oxo-2-thio-3-(1,2,11-trifluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (28 mg, 0.05 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and a solution of lithium hydroxide monohydrate (21 mg, 0.50 mmol) in water (0.5 mL) was added. After complete conversion of the raw material, the solution was adjusted to acidity with dilute hydrochloric acid. The solution was extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high performance liquid chromatography to obtain 8 mg of the product.

[0107] LC-MS(ESI):[M+H] + =550.0;

[0108] 1 H NMR (400MHz, DMSO-d6) δ13.69(s,2H),7.51(s,1H),7.46(dd,J=19.4,9.7Hz,1H),7.33(d,J=7.3Hz,1H),7.21–7.10(m,1H) ,6.87–6.78(m,1H),5.08(dd,J=18.3,10.3Hz,2H),4.26–4.16(m,2H),3.27–3.13(m,2H),2.71(s,3H),1.94–1.85(m,2H).

[0109] Example 3: Synthesis of 3-(1,2-difluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 3)

[0110] Step 1: Synthesis of 1,2-difluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-12-amine

[0111] 211 mg (0.50 mmol) of 12-amino-1,2,11-trifluoro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (2 mL), and lithium aluminum hydride (132 mg, 3.48 mmol) was added. The mixture was heated at 60 °C overnight. After complete conversion of the starting material, ethyl acetate was added under ice-water bath to quench the reaction, and the product was concentrated and then purified by column chromatography to obtain 24 mg of product.

[0112] LC-MS(ESI):[M+H] + =321.2;

[0113] Step 2: Synthesis of methyl 3-(1,2-difluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0114] 1,2-Difluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-12-amine (24 mg, 0.075 mmol) and dimethyl 4-((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylic acid (39 mg, 0.11 mmol) were dissolved in tetrahydrofuran (1 mL), and triethylamine (41.7 μL, 0.30 mmol) was added. The reaction was carried out at 70 °C. The starting material was completely converted, and the product was concentrated to obtain 40 mg of product.

[0115] LC-MS(ESI):[M+H] + =546.3;

[0116] Step 3: Synthesis of 3-(1,2-difluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0117] Methyl 3-(1,2-difluoro-9-methyl-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (40 mg, 0.07 mmol) was dissolved in tetrahydrofuran (0.5 mL), methanol (0.5 mL), and a solution of lithium hydroxide monohydrate (31 mg, 0.74 mmol) in water (0.5 mL) was added. The reaction proceeded almost completely. The solution was adjusted to acidity with dilute hydrochloric acid. The solution was extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high-performance liquid chromatography to obtain 10 mg of the product.

[0118] LC-MS(ESI):[M+H] + =532.1;

[0119] 1 H NMR(400MHz,DMSO-d6)δ13.57(s,2H),7.52(s,1H),7.31–7.23(m,3H),7.23–7.16(m,1H),6.82(d, J=12.2Hz,1H),4.99(s,2H),4.25–4.09(m,2H),3.28–3.13(m,2H),2.71(s,3H),1.97–1.81(m,2H).

[0120] Example 4: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-9-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 4)

[0121] Step 1: Synthesis of 2,2,2-trifluoro-1-(1,2,11-trifluoro-12-nitro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-9(6H)-yl)ethane-1-one

[0122] 1,2,11-Trifluoro-12-nitro-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxazonium undecene (400 mg, 1.13 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (471 μL, 3.39 mmol), 4-dimethylaminopyridine (69 mg, 0.56 mmol), and trifluoroacetic anhydride (188 μL, 1.35 mmol) were added. The reaction was carried out overnight at room temperature. After complete conversion of the starting material, the reaction was quenched with saturated sodium bicarbonate solution in an ice-water bath, extracted with dichloromethane (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 317 mg of product.

[0123] Step 2: Synthesis of 1-(12-amino-1,2,11-trifluoro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-yl)-2,2,2-trifluoroethane-1-one

[0124] 2,2,2-Trifluoro-1-(1,2,11-trifluoro-12-nitro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-9(6H)-yl)ethane-1-one (317 mg, 0.70 mmol) was dissolved in ethyl acetate (4 mL), and 10% palladium / carbon (37 mg, 0.35 mmol) was added. The reaction was carried out overnight at room temperature under a hydrogen atmosphere. The product was concentrated by filtration through a membrane to obtain 290 mg of product.

[0125] LC-MS(ESI):[M+H] + =421.1;

[0126] Step 3: Synthesis of 1,2,11-trifluoro-9-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-12-amine

[0127] 1-(12-amino-1,2,11-trifluoro-7,8-dihydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-9(6H)-yl)-2,2,2-trifluoroethane-1-one (180 mg, 0.43 mmol) was dissolved in tetrahydrofuran (0.5 mL), and a tetrahydrofuran solution of borane (2.14 mL, 2.14 mmol) was added. The reaction was carried out at 50 °C for 2 hours. Half of the starting material remained, and lithium aluminum hydride (0.174 mL, 0.56 mmol) was added. The reaction was carried out at 50 °C for 2 hours. The starting material was completely converted, and the reaction was quenched with ethyl acetate. Column chromatography purification yielded 173 mg of the product.

[0128] LC-MS(ESI):[M+H] + =407.2;

[0129] Step 4: Synthesis of methyl 4-oxo-2-thio-3-(1,2,11-trifluoro-9-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0130] Dimethyl 4-((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylate (224 mg, 0.64 mmol) and 1,2,11-trifluoro-9-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecene-12-amine (173 mg, 0.43 mmol) were dissolved in tetrahydrofuran (3 mL), and triethylamine (236 μL, 1.70 mmol) was added. The mixture was heated at 60 °C for 3 hours. After cooling, the mixture was concentrated and purified by column chromatography to give 202 mg of the product.

[0131] Step 5: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-9-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0132] Methyl 4-oxo-2-thio-3-(1,2,11-trifluoro-9-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-15H-dibenzo[b,i][1,8]dioxa[4]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (202 mg, 0.32 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL), and a solution of lithium hydroxide monohydrate (67 mg, 1.60 mmol) in water (1 mL) was added. The reaction was carried out at room temperature for 1 hour. After the starting material was completely converted, the pH was adjusted to acidic by adding dilute hydrochloric acid, extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative column chromatography to obtain 67 mg of the product.

[0133] LC-MS(ESI):[M+H] + =618.3;

[0134] 1H NMR (400MHz, DMSO-d6) δ13.46(s,2H),7.51(s,1H),7.43(dd,J=19.3,9.5Hz,1H),7.37–7.29(m,2H),7.07(dd,J =9.1,2.3Hz,1H),5.08(s,2H),4.29–4.21(m,2H),4.11(q,J=9.5Hz,2H),3.44–3.37(m,2H),1.89–1.79(m,2H).

[0135] Example 5: Synthesis of 2,4-dioxo-3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 5)

[0136] Step 1: Synthesis of tert-butyl (3,4-difluorophenyl)carbamate

[0137] 3,4-Difluoroaniline (7.7 mL, 77.45 mmol) was dissolved in tetrahydrofuran (100 mL). Di-tert-butyl dicarbonate (21.5 mL, 100.69 mmol), 4-dimethylaminopyridine (0.95 g, 7.75 mmol), and triethylamine (23.47 g, 232.36 mmol) were added to the reaction solution. The reaction solution was stirred at 25 °C for 2 hours. The reaction solution was diluted with water (300 mL) and then extracted with ethyl acetate (300 mL × 2). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 7.5 g of the product.

[0138] Step 2: Synthesis of tert-butyl (3,4-difluoro-2-formylphenyl)carbamate

[0139] Under nitrogen protection at -78°C, tert-butylcarbamate (6.5 g, 28.36 mmol) was reacted with n-butyllithium (5.45 g, 85.07 mmol) in a tetrahydrofuran (100 mL) solution. The reaction mixture was stirred at -78°C for 1 hour, followed by the addition of N,N-dimethylformamide (6.6 mL, 85.07 mmol). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution and then extracted with ethyl acetate (500 mL × 2). The organic phase was washed with a sodium chloride aqueous solution (500 mL). The organic phase was dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 2.5 g of the final product.

[0140] 1H NMR (400MHz, CHLOROFORM-d) δ = 10.42 (br s, 1H), 10.38 (s, 1H), 8.25 (ddd, J = 2.1, 3.5, 9.6Hz, 1H), 7.47-7.32 (m, 1H), 1.55 (s, 8H).

[0141] Step 3: Synthesis of tert-butyl (3,4-difluoro-2-(hydroxymethyl)phenyl)carbamate

[0142] Sodium borohydride (147 mg, 38.88 mmol) was added to an ethanol (30 mL) solution of (2.5 g, 9.72 mmol) of tert-butyl carbamate. The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate (200 mL × 2), washed once with an aqueous solution of sodium chloride, dried, filtered, and evaporated to dryness to obtain 2.3 g of product.

[0143] Step 4: Synthesis of 6-((tert-Butoxycarbonyl)amino)-2,3-difluorobenzylbenzoate

[0144] Triethylamine (3.7 mL, 26.62 mmol) and benzoyl chloride (1.37 g, 9.76 mmol) were added sequentially to dichloromethane (30 mL) containing tert-butyl (3,4-difluoro-2-(hydroxymethyl)phenyl)carbamate (2.3 g, 8.87 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was evaporated to dryness to obtain the crude product, which was then separated by silica gel column chromatography to obtain 2.5 g of the product.

[0145] Step 5: Synthesis of 6-amino-2,3-difluorobenzylbenzoate

[0146] The raw material 6-((tert-butoxycarbonyl)amino)-2,3-difluorobenzyl benzoate (250 mg, 0.69 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at 20 °C for 1 hour. The reaction solution was evaporated to dryness to obtain the crude product, which was then separated by high performance liquid chromatography to obtain 70 mg of the product.

[0147] LC-MS(ESI):[M+H] + =264.0;

[0148] Step 6: Synthesis of 6-(3-(((tert-butyldimethylsilyl)oxy)propamido)-2,3-difluorobenzylbenzoate

[0149] 3-((dimethyl(2-methylpropyl-2-yl)silyl)oxy)propionic acid (3 g, 14.68 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.64 g, 9.57 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred for 0.5 hours. Then, 6-amino-2,3-difluorobenzyl benzoate (2.1 g, 7.98 mmol) and ethyl diisopropylamine (2 g, 15.47 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (300 mL), washed once with water (100 mL), then washed with 5% calcium chloride aqueous solution (100 mL × 2), and finally washed with saturated brine (100 mL). The organic phase was then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 3.1g of the product.

[0150] LC-MS(ESI):[M+H] + =450.1;

[0151] Step 7: Synthesis of 6-(3-(((tert-butyldimethylsilyl)oxy)-N-methylpropionamido)-2,3-difluorobenzylbenzoate

[0152] 6-(3-(((tert-butyldimethylsilyl)oxy)propamido)-2,3-difluorobenzylbenzoate (2 g, 4.45 mmol) was dissolved in tetrahydrofuran (20 mL), and cesium carbonate (2.90 g, 8.90 mmol) and methyl iodoforme (0.3 mL, 5.34 mmol) were added. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into ice water (20 mL), and extracted with ethyl acetate (40 mL × 3). The extract was dried over saturated brine, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 1.2 g of the product.

[0153] LC-MS(ESI):[M+H] + =464.2;

[0154] Step 8: Synthesis of 6-((3-(((tert-butyldimethylsilyl)oxy)propyl)(methyl)amino)-2,3-difluorobenzylbenzoate

[0155] 6-(3-(((tert-butyldimethylsilyl)oxy)-N-methylpropionamido)-2,3-difluorobenzylbenzoate (560 mg, 1.21 mmol) was dissolved in tetrahydrofuran (10 mL), and borane dimethyl sulfide (0.4 mL, 3.62 mmol) was added at 0 °C. The reaction mixture was stirred at 40 °C for 1 hour. The reaction mixture was poured into an ice-cold sodium carbonate solution (20 mL), and extracted with ethyl acetate (40 mL × 3). The extract was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 380 mg of the product.

[0156] LC-MS(ESI):[M+H] + =450.2;

[0157] Step 9: Synthesis of (6-((3-(((tert-butyldimethylsilyl)oxy)propyl)(methyl)amino)-2,3-difluorophenyl)methanol

[0158] 6-((3-(((tert-butyldimethylsilyl)oxy)propyl)(methyl)amino)-2,3-difluorobenzylbenzoate (380 mg, 0.85 mmol) was dissolved in ethanol (5 mL), and sodium hydroxide (47 mg, 1.17 mmol) and water (1 mL) were added at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into 20 mL of ice water, and extracted with ethyl acetate (40 mL × 3). The extract was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 260 mg of the product.

[0159] LC-MS(ESI):[M+H] + =346.1;

[0160] Step 10: Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-(((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluoro-N-methylaniline

[0161] (6-((3-(((tert-butyldimethylsilyl)oxy)propyl)(methyl)amino)-2,3-difluorophenyl)methanol (200 mg, 0.58 mmol), 2,4-difluoro-5-nitrophenol (111 mg, 0.64 mmol), and triphenylphosphine (228 mg, 0.87 mmol) were dissolved in tetrahydrofuran (1 mL). Diisopropyl azodicarbonate (0.2 mL, 0.87 mmol) was added to the reaction solution, and the reaction solution was stirred at 20 °C for 1 hour. The reaction solution was evaporated to dryness to obtain the crude product, which was then separated by silica gel column chromatography to obtain 220 mg of the product.

[0162] LC-MS(ESI):[M+H] +=503.2;

[0163] Step 11: Synthesis of 1,2,11-trifluoro-5-methyl-12-nitro-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecene

[0164] N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-(((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluoro-N-methylaniline (200 mg, 0.40 mmol) and cesium fluoride (604 mg, 3.98 mmol) were dissolved in N,N-dimethylformamide (100 mL), and the reaction mixture was stirred at 60 °C for 3 hours. The reaction mixture was diluted with water (200 mL) and then extracted with ethyl acetate (200 mL × 3). The organic phase was washed twice with saturated brine. The organic phases were combined, dried, filtered, and evaporated to dryness to obtain 130 mg of crude product, which was directly used in the next step.

[0165] LC-MS(ESI):[M+H] + =369.1;

[0166] Step 12: Synthesis of 1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecene-12-amine

[0167] 1,2,11-trifluoro-5-methyl-12-nitro-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecene (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (1 mL). Tetrahydroxydiboron (512 mg, 1.63 mmol) and 4,4'-bispyridine (5 mg, 0.03 mmol) were added to the reaction solution, and the reaction solution was stirred at 20 °C for 10 minutes. The reaction solution was diluted with water (50 mL), and then extracted with ethyl acetate (50 mL × 3). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 100 mg of product.

[0168] LC-MS(ESI):[M+H] + =339.1;

[0169] Step 13: Synthesis of dimethyl 4-(3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0170] Dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylate (40 mg, 0.12 mmol), 1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecene-12-amine (40 mg, 0.12 mmol), and triethylamine (43 mg, 0.35 mmol) were dissolved in tetrahydrofuran (1 mL), and the reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was then separated by silica gel column chromatography to obtain 45 mg of the product.

[0171] LC-MS(ESI):[M+H] + =580.2;

[0172] Step 14: Synthesis of 2,4-dioxo-3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0173] Dimethyl 4-(3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid (40 mg, 0.07 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide (8 mg, 0.35 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 °C for 30 minutes. The reaction solution was adjusted to a weakly acidic state with dilute hydrochloric acid (1 M) aqueous solution, and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 20 mg of the product.

[0174] LC-MS(ESI):[M+H] + =534.0;

[0175] 1 H NMR (400MHz, DMSO-d6) δ = 12.16 (s, 1H), 7.53-7.33 (m, 3H), 7.25-7.06 (m, 2H), 5.23- 5.04(m,2H),4.27-4.05(m,2H),3.21-3.10(m,2H),2.55(s,3H),1.87-1.69(m,2H).

[0176] Example 6: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 6)

[0177] Step 1: Synthesis of methyl 4-oxo-2-thio-3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0178] 1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecene-12-amine (40 mg, 0.12 mmol), dimethyl 4-((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylic acid (42 mg, 0.12 mmol), and triethylamine (60 mg, 0.59 mmol) were dissolved in tetrahydrofuran (1 mL), and the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was then separated by silica gel column chromatography to obtain 45 mg of the product.

[0179] LC-MS(ESI):[M+H] + =564.1;

[0180] Step 2: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0181] Methyl 4-oxo-2-thio-3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (40 mg, 0.07 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide (8 mg, 0.35 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 °C for 30 minutes. The reaction solution was adjusted to weak acidity with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 10 mg of the product.

[0182] LC-MS(ESI):[M+H] + =550.0;

[0183] 1 H NMR (400MHz, DMSO-d6) δ = 13.49 (s, 1H), 7.53 (s, 1H), 7.47-7.37 (m, 1H), 7.29 (d, J = 7.6Hz, 1H), 7.23-7.16 (m,1H),7.14(d,J=10.9Hz,1H),5.14(s,2H),4.24-4.11(m,2H),3.22-3.04(m,2H),2.55(s,3H),1.79(br d,J=4.6Hz,2H).

[0184] Example 7: Synthesis of 2-thio-3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)-2,3-dihydrothieno[3,4-d]pyrimidin-4(1H)-one (Compound 7)

[0185] Step 1: Synthesis of methyl 4-((phenoxycarbonylthioyl)amino)thiophene-3-carboxylic acid

[0186] Methyl 4-aminothiophene-3-carboxylate (2 g, 12.72 mmol) was dissolved in a mixed solution of water (20 mL) and tetrahydrofuran (40 mL). Sodium bicarbonate (6.41 g, 76.34 mmol) was added to the reaction solution, followed by thiochlorocarboxylate (2.6 mL, 19.09 mmol). The reaction solution was stirred at 25 °C for 2 hours. The reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed twice with a saturated calcium chloride aqueous solution. The organic phase was dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 2 g of product.

[0187] LC-MS(ESI):[M+H] + =293.9;

[0188] Step 2: Synthesis of 2-thio-3-(1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecen-12-yl)-2,3-dihydrothiopheno[3,4-d]pyrimidin-4(1H)-one

[0189] Methyl 4-((phenoxycarbonylthioyl)amino)thiophene-3-carboxylic acid (40 mg, 0.12 mmol), 1,2,11-trifluoro-5-methyl-5,7,8,15-tetrahydro-6H-dibenzo[b,f][1,4]dioxa[8]azacycloundecene-12-amine (38 mg, 0.11 mmol), and triethylamine (36 mg, 0.35 mmol) were dissolved in tetrahydrofuran (3 mL), and the reaction solution was stirred at 70 °C for 2 hours. The reaction solution was evaporated to dryness to obtain the crude product, which was then separated by high performance liquid chromatography to obtain 45 mg of the product.

[0190] LC-MS(ESI):[M+H] + =506.1;

[0191] 1 H NMR (400MHz, DMSO-d6) δ = 13.10 (s, 1H), 8.58 (d, J = 3.3Hz, 1H), 7.52-7.38 (m ,1H),7.32-7.25(m,1H),7.24-7.15(m,2H),7.11(d,J=11.0Hz,1H),5.12(br s,2H),4.25-4.04(m,2H),3.71(s,3H),3.30-3.10(m,2H),1.91-1.65(m,2H).

[0192] Example 8: Synthesis of 2,4-dioxo-3-(3,12,13-trifluoro-8-methyl-9-oxo-7,8,9,14-tetrahydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 8)

[0193] Step 1: Synthesis of 3,4-difluoro-2-carboxybenzoic acid

[0194] At -40°C, lithium diisopropylamino (160 mL, 320.00 mmol) was dissolved in tetrahydrofuran (100 mL), purged three times with nitrogen. Then, 3,4-difluorobenzoic acid (20 g, 126.50 mmol) was dissolved in tetrahydrofuran (100 mL), and this solution was slowly added dropwise to the above system. After the addition was complete, the mixture was stirred for 1 hour. Then, anhydrous N,N-dimethylformamide (25 g, 342.04 mmol) was added to the reaction solution. After the addition was complete, the reaction solution was slowly heated to room temperature and stirred for another hour. The reaction solution was quenched in a system of dilute hydrochloric acid (1 M, 500 mL) and ethyl acetate (500 mL), and then allowed to stand for separation. The aqueous phase was extracted once with ethyl acetate (300 mL). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 20 g of the product.

[0195] Step 2: Synthesis of 3,4-difluoro-2-(hydroxymethyl)benzoic acid

[0196] 3,4-Difluoro-2-carboxybenzoic acid (1 g, 5.37 mmol) was dissolved in methanol (10 mL), and sodium borohydride (0.25 g, 6.61 mmol) was slowly added under ice-water bath conditions, with stirring continued for 1 hour. The reaction solution was quenched with dilute hydrochloric acid, extracted with dichloromethane (100 mL × 2), the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 1.0 g of crude product. This crude product was used directly in the next reaction.

[0197] Step 3: Synthesis of 4,5-difluoroisobenzofuran-1(3H)-one

[0198] 3,4-Difluoro-2-(hydroxymethyl)benzoic acid (800 mg, 4.25 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL, 67.31 mmol) was added. The mixture was then stirred at room temperature for 12 hours. The reaction solution was directly evaporated to dryness, ethyl acetate (100 mL) was added, and the mixture was washed with water (50 mL) and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 617 mg of the final product.

[0199] Step 4: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-difluoro-2-(hydroxymethyl)-N-methylbenzamide

[0200] Aluminum trichloride (1.2 g, 9.00 mmol) was dissolved in dichloromethane (30 mL). 2,2,3,3-Tetramethyl-7-aza-4-oxa-3-silazoctane (3.0 g, 15.84 mmol) was added under ice-water bath conditions, and the mixture was then heated to room temperature and stirred for 0.5 hours. The reaction solution was then cooled to 0 °C, and 4,5-difluoroisobenzofuran-1(3H)-one (610 mg, 3.59 mmol) was added. Stirring continued for 1 hour until the reactants were completely reacted and a product was formed. The reaction solution was quenched in water and then extracted with dichloromethane (100 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by normal-phase chromatography to obtain 414 mg of the product.

[0201] LC-MS(ESI):[M+H] + =360.1;

[0202] Step 5: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluoro-N-methylbenzamide

[0203] N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-difluoro-2-(hydroxymethyl)-N-methylbenzamide (300 mg, 0.83 mmol), 2,4-difluoro-5-nitrophenol (200 mg, 1.14 mmol), and triphenylphosphine (300 mg, 1.14 mmol) were dissolved in tetrahydrofuran (15 mL) under nitrogen protection. Then, diisopropyl azodicarbonate (240 mg, 1.19 mmol) was slowly added to the reaction system. The mixture was stirred at room temperature for 12 hours. After the reactants had reacted completely, a product was formed. The reaction solution was quenched with water (100 mL), and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 415 mg of the product.

[0204] LC-MS(ESI):[M+H] + =403.1;

[0205] Step 6: Synthesis of 3,12,13-trifluoro-8-methyl-2-nitro-7,8-dihydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecene-9(14H)-one

[0206] N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluoro-N-methylbenzamide (200 mg, 0.39 mmol) and cesium fluoride (600 mg, 3.95 mmol) were dissolved in N,N-dimethylformamide (200 mL), and then heated to 70 °C and stirred for 12 hours. The reaction solution was quenched in water (200 mL), and then extracted with ethyl acetate (200 mL × 2). The organic phases were combined and washed with 5% calcium chloride aqueous solution (100 mL × 2), followed by washing once with saturated brine. The organic phases were then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 128 mg of the product.

[0207] LC-MS(ESI):[M+H] + =383.1;

[0208] Step 7: Synthesis of 2-amino-3,12,13-trifluoro-8-methyl-7,8-dihydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecene-9(14H)-one

[0209] 3,12,13-trifluoro-8-methyl-2-nitro-7,8-dihydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecene-9(14H)-one (88 mg, 0.23 mmol) and 4,4'-bipyridine (10 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide (1 mL), and then tetrahydroxydiboron (80 mg, 0.89 mmol) was added. The reaction solution was added to ethyl acetate (200 mL), washed with water (100 mL × 2) and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 75 mg of the product.

[0210] LC-MS(ESI):[M+H] + =353.1;

[0211] Step 8: Synthesis of dimethyl 4-(3-(3,12,13-trifluoro-8-methyl-9-oxo-7,8,9,14-tetrahydro-6H-dibenzo[b,i]1,4]dioxa[7]azacycloundecen-2-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0212] Dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylate (110 mg, 0.33 mmol), 2-amino-3,12,13-trifluoro-8-methyl-7,8-dihydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecene-9(14H)-one (95 mg, 0.27 mmol), and diisopropylethylamine (100 mg, 0.77 mmol) were dissolved in tetrahydrofuran (6 mL), and the mixture was heated to 70 °C and stirred for 12 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 155 mg of crude product, which was used directly in the next step.

[0213] LC-MS(ESI):[M+H] + =594.1;

[0214] Step 9: Synthesis of 2,4-dioxo-3-(3,12,13-trifluoro-8-methyl-9-oxo-7,8,9,14-tetrahydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0215] 4-(3-(3,12,13-trifluoro-8-methyl-9-oxo-7,8,9,14-tetrahydro-6H-dibenzo[b,i]1,4]dioxa[7]azacycloundecen-2-yl)ureo)thiophene-2,3-dicarboxylic acid dimethyl ester (145 mg, 0.24 mmol) was dissolved in methanol (6 mL), and lithium hydroxide solution (1 mL, 2.00 mmol) was added. The mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to approximately 4 with dilute hydrochloric acid (1 M), and then extracted with dichloromethane (100 mL × 2). After combining the organic phases, the mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 35 mg of the final product.

[0216] LC-MS(ESI):[M+H] + =548.1;

[0217] 1H NMR (400MHz, DMSO-d6) δ = 14.53 (s, 1H), 12.07-12.02 (m, 1H), 7.51-7.42 (m, 1H), 7.39 (m, 1H), 7.27 (m, 1H), 7.20-7.12 (m, 2H),5.43(m,1H),4.82-4.72(m,1H),4.37-4.25(m,1H),4.12-4.02(m,1H),3.88-3.76(m,1H),3.42(m,1H),3.05(m,3H).

[0218] Example 9: Synthesis of 2,4-dioxo-3-(3,12,13-trifluoro-8-methyl-7,8,9,14-tetrahydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 9)

[0219] Step 1: Synthesis of 3,12,13-trifluoro-8-methyl-7,8,9,14-tetrahydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecene-2-amine

[0220] 2-Amino-3,12,13-trifluoro-8-methyl-7,8-dihydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecene-9(14H)-one (40 mg, 0.11 mmol) was dissolved in tetrahydrofuran (1 mL). Borane dimethyl sulfide (33.4 mg, 0.44 mmol) was added to the reaction solution, and the reaction solution was stirred at 40 °C for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and then extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed once with saturated sodium chloride aqueous solution, and then dried, filtered, and evaporated to dryness to obtain 38 mg of product, which was directly used in the next step.

[0221] LC-MS(ESI):[M+H] + =339.1;

[0222] Step 2: Synthesis of dimethyl 4-(3-(3,12,13-trifluoro-8-methyl-7,8,9,14-tetrahydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecen-2-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0223] 3,12,13-trifluoro-8-methyl-7,8,9,14-tetrahydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecene-2-amine (30 mg, 0.09 mmol), dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylate (30 mg, 0.09 mmol), and triethylamine (27 mg, 0.27 mmol) were dissolved in tetrahydrofuran (3 mL), and the reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was then separated by silica gel column chromatography to obtain 35 mg of the product.

[0224] LC-MS(ESI):[M+H] + =580.2;

[0225] Step 3: Synthesis of 2,4-dioxo-3-(3,12,13-trifluoro-8-methyl-7,8,9,14-tetrahydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0226] Dimethyl 4-(3-(3,12,13-trifluoro-8-methyl-7,8,9,14-tetrahydro-6H-dibenzo[b,i][1,4]dioxa[7]azacycloundecen-2-yl)ureo)thiophene-2,3-dicarboxylic acid (30 mg, 0.05 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide (6.2 mg, 0.26 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 °C for 30 minutes. Dilute hydrochloric acid (1 M) was added to the reaction solution to adjust the pH to 7, and then the solution was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 5 mg of the product.

[0227] LC-MS(ESI):[M+H] + =534.1;

[0228] 1 H NMR (400MHz, DMSO-d6)δ=12.01(s,1H),7.45-7.37(m,1H),7.33-7.20(m,4H),5.33-5.12(m,2H),4.30-4.15(m,2H),3.84-3.71(m,2H),2.71(br d,J=3.0Hz,2H),2.24(s,3H).

[0229] Biological test data

[0230] Experimental Example 1: Determination of the activity of the compounds of the present invention on gonadotropin-releasing hormone (GnRH) receptors

[0231] The objective of this experiment was to utilize a stable cell line of CHO (Chinese hamster ovary cells) expressing the GnRH receptor, stimulated with different concentrations of test compounds, and then determine the inhibitory effect of the compounds on the GnRH receptor using the HTRF-IP1 (homogeneous time-resolved fluorescence-inositol monophosphate) kit.

[0232] Main reagents, equipment and brands:

[0233] F-12 culture medium – Hyclone

[0234] Fetal Bovine Serum (FBS) – AusGeneX

[0235] Hygromycin B – Solarbio

[0236] DMSO (Dimethyl Sulfoxide) – Sigma

[0237] GnRH-I——GLPBIO

[0238] 0.25% Trypsin-EDTA (trypsin-ethylenediaminetetraacetic acid) solution – Gibco

[0239] IP-One-Gq kit – Cisbio

[0240] Main experimental instruments, brands and models:

[0241] Biosafety Cabinet – ESCO – AC2-6S1-TC

[0242] Carbon dioxide cell incubator – ESCO – CLM-240B-8-TC

[0243] Inverted Microscope – Olympus – CKX53

[0244] HTS High-Throughput Drug Screening Multifunctional Microplate Reader – BMG – PHERAstar FSX

[0245] Low-speed centrifuge – YIDA – TD25M

[0246] Microplate low-speed centrifuge – Xiangzhi – TD5B

[0247] Experimental plan:

[0248] (1) Cell preparation

[0249] This study used a CHO cell line stably expressing the human GnRH receptor (GnRHR). The human GnRHR-CHO cell line was cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at 37°C and 5% carbon dioxide. During cell passage, the old medium was removed, and the cells were washed once with PBS (phosphate-buffered saline), followed by the addition of an appropriate amount of 0.25% Trypsin-EDTA solution and incubation at 37°C. When the intercellular spaces widened, preheated complete medium (37°C) was added, and the cells were gently dissociated from the culture dish by pipetting and transferred to sterile centrifuge tubes. Cells were collected by centrifugation at 1000 rpm for 5 minutes. To maintain cell viability, the cell density was controlled at approximately 80%.

[0250] (2) Determination of the activity of the test compound against the GnRH receptor

[0251] Prepare 1×Stimulation Buffer according to the IP-One-Gq kit instructions. Serially dilute the test compound and positive control compound to 10 concentrations using DMSO, then dilute the compound 100-fold with 1×Stimulation Buffer.

[0252] Human GnRHR-CHO cells in logarithmic growth phase were washed with PBS buffer, and an appropriate amount of 0.25% Trypsin-EDTA was added. The cells were then incubated at 37°C in a CO2 incubator for 1-2 minutes to digest. Cells were removed and culture medium was added to terminate the digestion. The cell suspension was centrifuged at 1000 rpm for 5 minutes to remove the culture medium. Cells were thoroughly dispersed with 1×Stimulation Buffer. After counting and dilution, 9.1 μL (10,000 cells) was seeded per well in a 384-well plate.

[0253] Add 1.4 μL of the serially diluted test compound and positive control compound solutions to the corresponding wells. Add 1.4 μL of DMSO to the negative control wells (the final volume fraction of DMSO in all wells is 0.1%). Centrifuge at 1000 rpm for 1 min and incubate at 37°C for 10 min. Prepare GnRH-I solution using 1×Stimulation Buffer, add 3.5 μL (final concentration 20 nM) to each well, centrifuge, and incubate at 37°C for 60 min to induce IP1 production. Dilute d2-IP1 and Anti-IP1-Cryptate 20-fold using Lysis & Detection Buffer from the kit. After cell incubation, add 3 μL of d2-IP1 and 3 μL of Anti-IP1-Cryptate to each well sequentially. Centrifuge at 1000 rpm for 1 min and incubate at room temperature in the dark for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader under excitation at 330 nm. The inhibitory activity (IC50) of the compound against the gonadotropin-releasing hormone receptor was calculated using a GraphPad Prism 8 nonlinear fitting formula. 50 The value is the drug concentration at which the production of IP1 in cells that stably express the human GnRH receptor is inhibited by half.

[0254] Experimental Results: The inhibitory activity of some compounds of this invention on human gonadotropin-releasing hormone (GnRH) receptors was determined by the above experimental method, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 1.

[0255] Table 1 shows the inhibitory IC50 values ​​of the compounds on human gonadotropin-releasing hormone receptor activity. 50

[0256] Experimental conclusion: The compound of this invention has a significant inhibitory effect on gonadotropin-releasing hormone (GnRH) receptors.

[0257] Experimental Example 2: Rat Pharmacokinetic Test of the Compounds of the Present Invention

[0258] Experimental Objective: Using male SD rats as subjects, this study aimed to determine the plasma drug concentration at different time points after oral administration of the compound of this invention in rats using LC / MS / MS. The goal was to investigate the pharmacokinetic behavior of the compound in rats and evaluate its pharmacokinetic characteristics.

[0259] 1) Experimental reagents

[0260] The compound of this invention, Linzagolix.

[0261] 2) Laboratory animals

[0262] Adult male SD rats

[0263] 3) Experimental methods

[0264] Six male rats weighing 180–260 g were randomly divided into two groups: one group received a single oral dose of 2 mg / kg, and the other group received a single intravenous dose of 0.5 mg / kg via tail vein. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. After pretreatment, plasma samples were analyzed by LC / MS / MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples, obtaining drug concentration-time curves. Pharmacokinetic parameters were calculated using the non-compartmental membrane type in WinNonlin software.

[0265] Experimental conclusion: The compound of this invention exhibits lower clearance rate in plasma, significantly prolonged half-life, and significantly increased exposure, demonstrating superior pharmacokinetic properties.

[0266] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

Claims

1. A compound, which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I); in: L1, L2, L3, L4, and L5 are independently selected from -O-, -S-, and -(CR6R7), respectively. n -, -C(=O)- and -NR8-, and at least one of L1, L2, L3, L4 and L5 is -NR8-; T1 and T2 are independently O, S, NH, N-NO2 or N-CN, respectively; A1 is either CR9 or N; Y and Z are independently selected from -O-, -S-, and -CR, respectively. 10 R 11 -; R1 is B(OH)₂, C(=O)OW₁, C(=O)NW₂W₃ or S(=O)₂W₄, wherein W₁, W₂, W₃ and W₄ are independently selected from H, D, C, and D, respectively. 1-6 Alkyl, C 3-8 cycloalkyl and C 6-10 Aryl; R2, R3, and R9 are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, NO2, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH and NO2; Each R4 is independently H, D, F, Cl, Br, I, CN, OH, COOH, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 alkylthio group or 3-7 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The alkylthio group and the 3-7 membered heterocyclic group may optionally be independently replaced by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, CN, oxo (=O), OH, COOH, NO2 and NH2; or two adjacent R4 groups may optionally form a 3-6 membered cycloalkyl or a 3-7 membered heterocyclic group with the carbon atom attached to them, wherein the 3-6 membered cycloalkyl or 3-7 membered heterocyclic group may optionally be independently replaced by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2 and OH; R5 represents H, D, F, Cl, Br, I, OH, NH2, CN, NO2, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be independently and optionally replaced by one, two or three substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH, NO2; Each R6, R7, R 10 and R 11 Each element is independently selected from H, D, F, Cl, Br, I, OH, and C. 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, oxo (=O), CN, NH2 and OH; or R6 and R7, R 10 With R 11 Each cycloalkyl group or heterocyclic group may be optionally formed with the carbon atom it is connected to in a 3-6 membered cycloalkyl group or a 3-7 membered heterocyclic group, wherein the cycloalkyl group or heterocyclic group may be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2 and OH; R8 is H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthioyl or 3-6 membered cycloalkyl; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 The alkylthio group and the 3-6 membered cycloalkyl group may be optionally and independently replaced by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, CN, OH, COOH, NO2 and the 3-6 membered cycloalkyl group; m can be 1, 2, 3, or 4; n is 1, 2, or 3.

2. The compound according to claim 1, characterized in that, When L1 is -O- or -S-, L2, L3 and L4 are independently -CR6R7- or -C(=O)-, and L5 is -NR8-. Alternatively, when L1 is -NR8-, L2, L3, and L4 are independently -CR6R7- or -C(=O)-, and L5 is -O- or -S-. Alternatively, when L1 is -CR6R7-, L2 is -NR8-, L3 and L4 are independently -CR6R7- or -C(=O)-, and L5 is -O- or -S-. Alternatively, when L1 is -O- or -S-, L2 and L3 are independently -CR6R7-, L4 is -NR8-, and L5 is -CR6R7- or -C(=O)-. Alternatively, when L1, L2, L3, and L4 are all -CR6R7-, L5 is -NR8-.

3. The compound according to claim 1, characterized in that, When Y is -O- or -S-, Z is -CR. 10 R 11 -; Or when Y is -CR 10 R 11 When -, Z is -O- or -S-.

4. The compound according to claim 1, characterized in that: R1 is B(OH)2, C(=O)OW1, C(=O)NW2W3; Among them, W1, W2, and W3 are independently selected from H, D, and C, respectively. 1-6 alkyl; Alternatively, W1, W2, and W3 can be independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, respectively. Alternatively, W1, W2, and W3 can be independently selected from H and D, respectively.

5. The compound according to claim 1, characterized in that: R2, R3, and R9 are independently selected from H, D, F, Cl, Br, I, and C, respectively. 1-6 Alkyl and C 1-6 Alkoxy; the C 1-6 Alkyl and C 1-6 The alkoxy group can be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I; Alternatively, R2, R3, and R9 can be independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2; Alternatively, R2, R3, and R9 can be independently selected from H, D, F, Cl, Br, and I, respectively.

6. The compound according to claim 1, characterized in that: Each R4 group is independently H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl or C 1-6 Alkoxy; the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, CN; Alternatively, each R4 may be independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2; Alternatively, two adjacent R4 atoms may optionally form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclopropoxy groups with the carbon atom they are attached to. The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy and It can be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH.

7. The compound according to claim 1, characterized in that: R5 is selected from H, D, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2.

8. The compound according to claim 1, characterized in that: Each R6, R7, R 10 and R 11 Selected independently from H, D, F, Cl, Br, I, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I; or R6 and R7, R 10 With R 11 Each of the carbon atoms optionally bonded to it forms a 3-6 membered cycloalkyl group or a 3-7 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group and the 3-7 membered heterocyclic group may be independently and optionally replaced by one, two or three substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH; Or each of R6, R7, R 10 and R 11 Each of the following is independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2; or R6 and R7, R 10 With R 11 The carbon atoms that are optionally bonded to each other can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, or cyclopentoxy, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, and cyclopentoxy groups can be independently and optionally replaced by one, two, or three substituents selected from H, D, F, Cl, Br, I, CN, NH2, and OH.

9. [Amended according to Rule 26, 15.04.2026] The compound according to claim 1, characterized in that: R8 is H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl, C 1-6 alkoxy, cyclopropyl, or cyclobutyl; the C 1-6 Alkyl, C 1-6 The alkoxy, cyclopropyl, and cyclobutyl groups may be optionally and independently substituted by 1, 2, 3, 4, or 5 substituents selected from H, D, F, Cl, Br, I, CN, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

10. The compound according to any one of claims 1-9, wherein it is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

11. A pharmaceutical composition comprising the compound of any one of claims 1-10; the pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

12. Use of the compound of any one of claims 1-10 or the pharmaceutical composition of claim 11 in the preparation of a medicament for the prevention, treatment or relief of a patient’s GnRH receptor antagonist-mediated disease.

13. The use according to claim 12, wherein, The diseases mediated by the GnRH receptor antagonists include endometriosis, uterine fibroids, benign prostatic hyperplasia, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, short stature, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer, and pituitary tumors.

Images