Fused heterocycle-substituted pyrimidinedione derivatives and uses thereof

Abstract

The present application provides a class of fused heterocycle-substituted pyrimidine dione derivatives and pharmaceutical compositions thereof, which can be used for preventing, treating or alleviating GnRH receptor antagonist-mediated diseases in patients, such as endometriosis, uterine fibroids, benign prostatic hypertrophy, adenomyosis, 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

[0001] This application claims the following priority:

[0002] CN202510355961.2, application date March 24, 2025. Technical Field

[0003] This invention belongs to the pharmaceutical field, specifically relating to fused heterocyclic substituted 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]

[0008] 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. Therefore, it is essential to continue researching and developing more comprehensive and effective small-molecule GnRH receptor antagonists. Summary of the Invention

[0009] The purpose of this invention is to provide a novel class of compounds with excellent GnRH receptor inhibitory activity and pharmacokinetic properties.

[0010] 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).

[0011] (I);

[0012] in:

[0013] L1, L2, L3, and L4 are independently selected from the following: -O-, -S-, and -(CR5R6), respectively. n -;

[0014] T1 and T2 are independently O, S, NH, N-NO2 or N-CN, respectively;

[0015] A1 is either CR4 or N;

[0016] Y and Z are independently selected from bond, -O-, -S-, -S(=O)-, -SO2-, -CR7R8- and -C(=O)-, respectively;

[0017] X1, X2, and X3 are independently selected from bonds, O, S, N, and CR, respectively. 10 ,and Not for ;

[0018] R1 is , C(=O)OW1, C(=O)NW2W3 or S(=O)2W4, where W1, W2, W3 and W4 are independently selected from H, D, C respectively. 1-6 Alkyl, C 3-8 cycloalkyl and C 6-10 Aryl;

[0019] R2, R3, and R4 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;

[0020] Each of R5, R6, R7, and R8 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 R5 and R6, R7 and R8 may be optionally substituted with the carbon atom they are connected to to form C 3-6 cycloalkyl or 3-7 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl and 3-7 membered heterocyclic groups 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] Each R9 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 1-6The alkylthio group and the 3-7 membered heterocyclic group may optionally be independently substituted 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 R9s may optionally form a 4-7 membered cycloalkane with the carbon atom attached to them, said 4-7 membered cycloalkane may optionally be independently substituted by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0022] Each R 10 Independently, H, D, F, Cl, Br, I, OH, NH2, 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 independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br and I;

[0023] m can be 1, 2, 3, or 4;

[0024] n is 1, 2, or 3.

[0025] In some implementations, R1 is , , C(=O)OW1, C(=O)NW2W3;

[0026] In some implementation schemes, W1, W2, and W3 are independently selected from H, D, and C, respectively. 1-6 alkyl.

[0027] In some embodiments, W1, W2, and W3 are independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, respectively.

[0028] In some implementations, W1, W2, and W3 are independently selected from H and D, respectively.

[0029] In some implementations, R2 and R3 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 and I;

[0030] In some embodiments, R2 and R3 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.

[0031] In some implementations, R2 and R3 are independently selected from H, D, F, Cl, Br, and I, respectively.

[0032] In some embodiments, R4 is selected from H, D, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3 and -CH2CF2CHF2.

[0033] In some implementations, each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, 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, and I; or R5 and R6, R7 and R8 may be optionally substituted with the carbon atom they are connected to to form a C12 group. 3-6 cycloalkyl or 3-7 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl and 3-7 membered heterocyclic groups may be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH;

[0034] In some embodiments, each of R5, R6, R7, and R8 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 R5 and R6, R7 and R8 may optionally form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy or cyclopentoxy with the carbon atom they are connected to, respectively, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy and cyclopentoxy may be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH.

[0035] In some implementations, each R9 is independently H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl, C 1-6 alkoxy or 3-7 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 The alkoxy group and the 3-7 membered heterocyclic group may optionally be independently substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I and CN; or two adjacent R9s may optionally form a 4-7 membered cycloalkane with the carbon atom attached to them, said 4-7 membered cycloalkane may optionally be independently substituted by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Substituents of haloalkoxy groups;

[0036] In some embodiments, each R9 is independently 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, or -OCH2CF2CHF2; or two adjacent R9s may optionally form a 4-7 membered cycloalkane with the carbon atom to which they are attached. The 4-7 membered cycloalkanes may be independently and optionally substituted by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2, OH, 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.

[0037] In some implementation schemes, each R 10 Independently, it can be 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 or -OCH2CF2CHF2.

[0038] In some implementation schemes, for , , , , , , , , , , or .

[0039] In some embodiments, the compound of the present invention 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:

[0040] , ,

[0041] , ,

[0042] , ,

[0043] , ,

[0044] , ,

[0045] , ,

[0046] , ,

[0047] , ,

[0048] , , ,

[0049] , , ,

[0050] , , , , or

[0051] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, mediator or combination thereof thereof.

[0052] 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.

[0053] 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.

[0054] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I).

[0055] The compounds of this invention have a significant inhibitory effect on gonadotropin-releasing hormone (GnRH) receptors.

[0056] Definitions and general terms

[0057] 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.

[0058] 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.

[0059] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0060] Compounds described herein may optionally be substituted with one or more substituents, such as the general formula compounds of this invention, or the specific examples, subclasses, and classes 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 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), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclic, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, etc.

[0061] 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, saturated straight-chain or branched, 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)CH2CH3), 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.

[0062] The term “heteroatom” refers to one or more O, S, N, P, and Si, including C, N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form where the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NR (like NR in N-substituted pyrrolidinyl); or the -CH2- in the heterocycle is oxidized to form the -C(=O)- form.

[0063] The term "alkoxy" or "alkyloxy" 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.

[0064] The terms "cycloalkyl," "cycloalkane," or "carbocyclic" refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic carbocyclic system containing 3 to 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 to 10 carbon atoms; in another embodiment, it contains 3 to 8 carbon atoms; and in yet another embodiment, it contains 3 to 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.

[0065] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein, referring to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring comprising 3-12 ring atoms, excluding aromatic rings, wherein at least one ring atom is a heteroatom. In one embodiment, the "heterocyclic group" or "heterocycle" comprises 3-10 ring atoms; in another embodiment, the "heterocyclic group" or "heterocycle" comprises 3-8 ring atoms; in yet another embodiment, the "heterocyclic group" or "heterocycle" comprises 5-8 ring atoms; in yet another embodiment, the "heterocyclic group" or "heterocycle" comprises 3-6 ring atoms; in yet another embodiment, the "heterocyclic group" or "heterocycle" comprises 5-6 ring atoms; and in yet another embodiment, the "heterocyclic group" or "heterocycle" comprises 4-6 ring atoms. Unless otherwise stated, the heterocyclic group may be carbon-based or nitrogen-based, and the heteroatom has the meaning as described herein. Examples of heterocyclic groups include, but are not limited to: ethylene oxide, azirrobutyl, oxoheterobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H -pyranyl, 4H-pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, dithiaranyl, thiaranyl, homopiperazine, homopiperidinyl, oxeheptane, thioheptane, oxazolidinyl, diazadinyl, thioazolidinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl and 1,2,3,6-tetrahydropyridinyl. Examples of heterocyclic groups in which the -CH2- group is substituted by -C(=O)- include, but are not limited to: 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridinyl, pyrimidinide, and 5,6-dihydropyridin-2(1H)-keto. Examples of oxidation of the sulfur atom in the heterocyclic group include, but are not limited to, sulfolane and 1,1-dioxothiomorpholino groups. The heterocyclic group may optionally be substituted with one or more substituents described in this invention.

[0066] 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.

[0067] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system containing 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring system is an aromatic ring, and at least one ring system contains one or more heteroatoms, wherein each ring comprises a ring consisting of 5-7 atoms, and has one or more attachment sites connected to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." The heteroaryl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the 5-10 atom-containing heteroaryl group comprises 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom may be further oxidized.

[0068] Examples of heteroaryl groups include, but are not limited to: furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl, etc. Azolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl), triazolyl, thiophene (e.g., 2-thiophene, 3-thiophene), pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5 -Thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes, but is by no means limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxonelyl, indolinyl, isoquinolinyl (e.g., 1-isoquinolinyl) Quinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, , , , , , , , , , , , , , ... , , , wait

[0069] 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.

[0070] (a)

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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 C14 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.

[0075] "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 activity similar to that of 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.

[0076] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: SP 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.

[0077] 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.

[0078] As used in this invention, "pharmaceutically acceptable salts" 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: SM Berge 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.

[0079] In this invention, "hydrate" refers to an associative compound formed when the solvent molecules are water.

[0080] 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.

[0081] 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 LWDeady's 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).

[0082] As used in this invention, the term "prodrug" 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; in 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 ACS Symposium 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.

[0083] 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.

[0084] The term “GnRH receptor antagonist” as used in this article refers to substances that can inhibit gonadotropin-releasing hormone (GnRH) receptors. Detailed Implementation

[0085] 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.

[0087] Example 1: 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid (Compound 1)

[0088]

[0089]

[0090] Step 1: Synthesis of dimethyl 2-aminothiophene-3,4-dicarboxylic acid ester

[0091] Methyl 2-oxopropionate (2.3 mL, 25.17 mmol), methyl cyanoacetate (3010 mg, 30.38 mmol), and sulfur (1 g, 29.46 mmol) were added to N,N'-dimethylformamide (30 mL). The mixture was stirred at 20°C for 45 minutes. Triethylamine (6 mL, 43.17 mmol) was then slowly added dropwise to the reaction system. The reaction mixture was heated to 75°C and stirred for 16 hours. The reaction solution was poured into a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was then purified by normal-phase column chromatography to obtain 2400 mg of the product.

[0092] Step 2: Synthesis of dimethyl 2-(((phenoxycarbonylthioyl)amino)thiophene-3,4-dicarboxylic acid ester

[0093] Dimethyl 2-aminothiophene-3,4-dicarboxylic acid (800 mg, 3.82 mmol) and potassium carbonate (1000 mg, 7.24 mmol) were dissolved in tetrahydrofuran (20 mL) and water (10 mL). Phenyl chloroformate (1.0 mL, 7.65 mmol) was added at 0 °C, and the reaction was carried out with stirring for 2 hours. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was obtained by rotary evaporation. The crude product was then purified by normal-phase column chromatography to give 600 mg of the final product.

[0094] LC-MS(ESI): [M+H] + = 352.0;

[0095] Step 3: Synthesis of 2-(benzyloxy)-5-fluorobenzaldehyde

[0096] 5-Fluoro-2-hydroxybenzyl-1-carboxaldehyde (27 g, 192.71 mmol) and benzyl bromide (27.7 mL, 231.25 mmol) were dissolved in N,N'-dimethylformamide (300 mL), and potassium carbonate (53.26 g, 385.41 mmol) was added in a single batch. After the addition was complete, the reaction mixture was heated to 50 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was diluted with water (200 mL), extracted with ethyl acetate (200 mL × 2), the organic phases were combined, washed twice with saturated calcium chloride aqueous solution, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 41 g of white solid product.

[0097] Step 4: Synthesis of methyl 2-(benzyloxy)-5-fluorophenylcarbamate

[0098] 2-(benzyloxy)-5-fluorobenzaldehyde (40 g, 173.73 mmol) was dissolved in dichloromethane (200 mL), and m-chloroperoxybenzoic acid (45 g, 260.60 mmol) was added in a single batch at room temperature. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solution was quenched with saturated sodium sulfite solution, extracted with ethyl acetate (500 mL × 2), and the organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography to give 39 g of a colorless oily liquid product.

[0099] Step 5: Synthesis of 2-(benzyloxy)-5-fluorophenol

[0100] Methyl 2-(benzyloxy)-5-fluorophenylcarbamate (39 g, 158.38 mmol) was dissolved in ethanol (200 mL) and water (40 mL). Sodium hydroxide (31.68 g, 791.91 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was adjusted to acidity with hydrochloric acid aqueous solution (4 M), extracted with ethyl acetate (300 mL × 2), the organic phases were combined, washed with saturated brine, dried, concentrated, and evaporated to dryness to give 32 g of a yellow oily product.

[0101] 1 H NMR (400 MHz, DMSO-d6) δ = 9.55 (s, 1H), 7.45 (s, 2H), 7.37 (s,2H), 7.34 - 7.25 (m, 1H), 6.98 - 6.89 (m, 1H), 6.68 - 6.59 (m, 1H), 6.55 -6.44 (m, 1H), 5.06 (s, 2H).

[0102] Step 6: Synthesis of 3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropionic acid

[0103] 2-(benzyloxy)-5-fluorophenol (20 g, 91.65 mmol) was dissolved in N,N'-dimethylformamide (200 mL), and cesium carbonate (59.72 g, 183.29 mmol) was added in a single batch. The mixture was stirred at 50 °C for 0.5 h, followed by the addition of ethyl 3-bromo-2,2-difluoropropionate (25.85 g, 119.14 mmol). The reaction mixture was then reacted at 55 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with water, and the pH was adjusted to 6 with dilute hydrochloric acid solution (1 M). The mixture was then extracted with ethyl acetate (300 mL × 2). The organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 5 g of a yellow solid.

[0104] LC-MS(ESI): [MH] - = 325.2.

[0105] Step 7: Synthesis of 3-(2-(benzyloxy)-5-fluorophenyl]oxy)-2,2-difluoropropane-1-ol

[0106] 3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropionic acid (3 g, 9.19 mmol) was dissolved in tetrahydrofuran (30 mL), and a solution of lithium aluminum hydride (520 mg, 9.19 mmol) in tetrahydrofuran (5.5 mL) was added dropwise. After the addition was complete, the reaction was carried out at 25 °C for 0.5 hours. After the reaction was complete, the reaction solution was diluted with tetrahydrofuran (500 mL), and the reaction was quenched by slowly adding water (0.5 mL). Then, a 15% sodium hydroxide aqueous solution (1 mL) was added and stirred for 0.5 hours, followed by the addition of anhydrous sodium sulfate and stirring for 1 hour. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The product was purified by silica gel column chromatography to obtain 2.5 g of a pale yellow solid.

[0107] LC-MS(ESI): [MH] - = 311.2.

[0108] Step 8: Synthesis of 3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropyltrifluoromethanesulfonate

[0109] 3-(2-(benzyloxy)-5-fluorophenyl]oxy)-2,2-difluoropropane-1-ol (2.5 g, 8.01 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of pyridine (1.9 mL, 24.02 mmol), and the mixture was cooled to 0 °C. Trifluoromethanesulfonic anhydride (2.4 mL, 14.41 mmol) was then slowly added dropwise, and the reaction was carried out at 0 °C for 0.5 hours. After the reaction was complete, the reaction solution was quenched with dilute hydrochloric acid aqueous solution (50 mL), followed by the addition of dichloromethane (100 mL). The mixture was separated, the organic phase was washed with brine, dried over sodium sulfate, and evaporated to dryness to obtain 3.50 g of a yellow oily product. The crude product was used directly in the next reaction without purification.

[0110] Step 9: Synthesis of 6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorobenzaldehyde

[0111] 2,3-Difluoro-6-hydroxybenzyl-1-carboxaldehyde (1.25 g, 7.88 mmol) was dissolved in N,N'-dimethylformamide (30 mL), followed by the addition of potassium carbonate (2.18 g, 15.75 mmol). After stirring at 45 °C for 0.5 hours, a solution of 3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropyltrifluoromethanesulfonate (3.5 g, 7.88 mmol) in N,N'-dimethylformamide (10 mL) was added, and the reaction was stirred at room temperature for 1 hour. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. After separation, the aqueous phase was extracted with ethyl acetate (60 mL). The combined organic phases were washed with brine, dried, and then evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 3.00 g of a colorless oily product.

[0112] LC-MS(ESI): [M+H] + = 453.1.

[0113] Step 10: Synthesis of (6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methanol

[0114] 6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorobenzaldehyde (3 g, 6.63 mmol) was dissolved in ethanol (30 mL), and sodium borohydride (500 mg, 13.26 mmol) was slowly added. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 hours. The reaction solution was quenched by slowly adding dilute hydrochloric acid aqueous solution (1 M), and then extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine, dried, and concentrated to give 2.90 g of a colorless oily product.

[0115] LC-MS (ESI): [M+Na] + = 477.1.

[0116] Step 11: Synthesis of 2-(3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-2,2-difluoropropoxy)-4-fluorophenol

[0117] The starting material (6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methanol (2.90 g, 6.38 mmol)) was dissolved in isopropanol (30 mL), and 10% palladium / carbon (679 mg) was added under a nitrogen atmosphere. The reaction solution was purged three times with hydrogen, and then heated to 50 °C for 1 hour under a hydrogen atmosphere. The reaction solution was filtered, and the filter cake was washed with methanol (50 mL). The combined organic phases were evaporated to dryness to give 2.30 g of a yellow oily product.

[0118] LC-MS(ESI): [MH] - = 363.1.

[0119] Step 12: Synthesis of 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0120] 2-(3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-2,2-difluoropropoxy)-4-fluorophenol (2.5 g, 6.86 mmol) was dissolved in toluene (250 mL), and (tributyl-λ5-oxophosphine) acetonitrile (3.31 g, 13.73 mmol) was added dropwise at room temperature. After the addition was complete, the reaction mixture was heated to 80°C and reacted for 16 hours. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by Prep-TLC to give 850 mg of a white solid.

[0121] Step 13: Synthesis of 1,2,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0122] 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (850 mg, 2.45 mmol) was dissolved in acetic acid (16 mL), and concentrated nitric acid (16 mL) was slowly added at 80 °C. After the addition was complete, the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was added to ice water, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with brine (50 mL), filtered, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 180 mg of white solid product.

[0123] Step 14: Synthesis of 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine

[0124] 1,2,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (180 mg, 0.46 mmol) was dissolved in N,N'-dimethylformamide (3 mL), and 4,4'-bispyridine (7.2 mg, 0.05 mmol) and diboronic acid (165 mg, 1.84 mmol) were added in one batch. The reaction mixture was stirred at 25 °C for 5 minutes. Water (40 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (60 mL × 2 times). The combined organic phases were washed once with saturated brine (50 mL) and once with saturated calcium chloride aqueous solution (50 mL), then dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to obtain 160 mg of a yellow oily product.

[0125] LC-MS(ESI): [M+H] + =362.1.

[0126] Step 15: Synthesis of dimethyl 2-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-3,4-dicarboxylic acid ester)

[0127] Dimethyl 2-(((phenoxycarbonylthioyl)amino)thiophene-3,4-dicarboxylic acid (100 mg, 0.30 mmol) and 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (108.38 mg, 0.30 mmol) were dissolved in tetrahydrofuran (2 mL), and then triethylamine (0.1 mL, 0.89 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (100 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain 80 mg of the product.

[0128] LC-MS(ESI): [M+H] + = 603.0;

[0129] Step 16: Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid

[0130] Dimethyl 2-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-yl)ureo)thiophene-3,4-dicarboxylic acid (60 mg, 0.10 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL), followed by the addition of lithium hydroxide (42 mg, 1.00 mmol). The reaction was carried out at 20 °C with stirring for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with 1N dilute hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 49.45 mg of the product.

[0131] LC-MS(ESI): [M+H] + = 557.0;

[0132] 1H NMR (400 MHz, DMSO-d6) δ = 13.96 (s, 1H), 13.29 - 12.81 (s, 1H), 7.94 (s, 1H), 7.56 - 7.50 (m, 1H), 7.50 - 7.46 (m, 1H), 7.44 (d, J = 11.2 Hz,1H), 7.29 - 7.23 (m, 1H), 5.25 - 5.03 (m, 2H), 4.76 - 4.67 (m, 2H), 4.67 -4.56 (m, 2H).

[0133] Example 2: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid (Compound 2)

[0134]

[0135] Step 1: Synthesis of dimethyl 2-(((phenoxycarbonylthioyl)amino)thiophene-3,4-dicarboxylic acid ester

[0136] Dimethyl 2-aminothiophene-3,4-dicarboxylic acid (500 mg, 4.65 mmol) and potassium carbonate (650 mg, 9.41 mmol) were dissolved in tetrahydrofuran (20 mL) and water (10 mL). Then, 0.6 mL of thiochloroformate-O-phenyl ester (9.30 mmol) was added at 0 °C, and the reaction was stirred at this temperature for 2 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 600 mg of the product.

[0137] Step 2: Synthesis of dimethyl 2-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)thioureoyl)thiophene-3,4-dicarboxylic acid ester

[0138] Dimethyl 4-(((phenoxycarbonylthioyl)amino)thiophene-2,3-dicarboxylic acid (60 mg, 0.18 mmol) and 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (100 mg, 0.28 mmol) (as per step 12 of Exercise 1) were dissolved in tetrahydrofuran (2 mL), and then triethylamine (0.1 mL, 0.85 mmol) was added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine, dried, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 90 mg of the product.

[0139] LC-MS(ESI): [M+H] + = 619.0;

[0140] Step 3: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid

[0141] Dimethyl 2-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b, f][1,4,8]triazolylcycloundecene-12-yl)thioureoyl)thiophene-3,4-dicarboxylic acid (60 mg, 0.10 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL), followed by the addition of lithium hydroxide (50 mg, 1.13 mmol). The reaction was carried out at 20 °C with stirring for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with 1 mol of dilute hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried, and evaporated to dryness to obtain the crude product. The crude product was then purified by high performance liquid chromatography to obtain 60.82 mg of the product.

[0142] LC-MS(ESI): [M+H] + = 573.0;

[0143] 1H NMR (400 MHz, DMSO-d6) δ = 8.13 (s, 1H), 7.97 (s, 1H), 7.48 (d, J =10.4 Hz, 1H), 7.31 (d, J = 4.2 Hz, 1H), 7.29 (s, 1H), 7.27 - 7.20 (m, 1H), 5.19 - 5.13 (m, 1H), 5.10 - 5.03 (m, 1H), 4.68 (t, J = 12 Hz, 2H), 4.60 (t, J= 12 Hz, 2H).

[0144] Example 3: Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecane-12-yl)-1,2,3,4-tetrahydropyrido[3,4-d]pyrimidine-5-carboxylic acid (Compound 3)

[0145]

[0146] Step 1: Synthesis of methyl 3-bromo-5-((3,4-dimethylbenzyl)amino)isonicotinic acid

[0147] Methyl 3-bromo-5-fluoroisonicotinic acid (2 g, 8.55 mmol) and (2,4-dimethoxyphenyl)methylamine hydrochloride (1.8 g, 8.97 mmol) were dissolved in dimethyl sulfoxide (20 mL), and potassium carbonate (2.3 g, 17.09 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was poured into ice water (80 mL), extracted with ethyl acetate (200 mL × 3), and the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 3 g of product.

[0148] LC-MS(ESI):[M+H] + =381.0;

[0149] Step 2: Synthesis of dimethyl 5-((3,4-dimethylbenzyl)amino)pyridine-3,4-dicarboxylic acid

[0150] Methyl 3-bromo-5-((3,4-dimethylbenzyl)amino)isonicotinic acid (2.5 g, 6.56 mmol) was dissolved in N,N-dimethylformamide (16 mL) and methanol (4 mL). Dichlorobis(triphenylphosphine)palladium (1 g, 1.31 mmol) and triethylamine (2.7 mL, 19.67 mmol) were added. The reaction mixture was purged with nitrogen three times, and the reaction system was stirred at 80 °C under a carbon dioxide atmosphere for 16 hours. The reaction mixture was poured into ice water (40 mL), extracted with ethyl acetate (50 mL × 3), dried over saturated brine, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 1.3 g of the final product.

[0151] LC-MS(ESI):[M+H] + =361.1;

[0152] Step 3: Synthesis of dimethyl 5-aminopyridine-3,4-dicarboxylic acid ester

[0153] Dimethyl 5-((3,4-dimethylbenzyl)amino)pyridine-3,4-dicarboxylic acid (1.3 g, 3.61 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL, 40.39 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was first evaporated directly to dryness, then saturated sodium bicarbonate solution (50 mL) was added, followed by extraction with dichloromethane (80 mL × 3). The mixture was dried over saturated brine, and the organic phase was evaporated to dryness to give 620 mg of product.

[0154] Step 4: Synthesis of dimethyl 5-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecane-12-yl)ureo)pyridine-3,4-dicarboxylic acid ester

[0155] Dimethyl 5-aminopyridine-3,4-dicarboxylic acid (200 mg, 0.95 mmol) was dissolved in dichloromethane (10 mL). Triphosgene (93 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.90 mmol) were added at 0 °C, followed by 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecane-12-amine (275 mg, 0.76 mmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into ice water (20 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 350 mg of the product.

[0156] LC-MS(ESI):[M+H] + =598.3;

[0157] Step 5: Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecane-12-yl)-1,2,3,4-tetrahydropyrido[3,4-d]pyrimidine-5-carboxylic acid

[0158] Dimethyl 5-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecane-12-yl)ureo)pyridine-3,4-dicarboxylic acid ester (175 mg, 0.29 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide (37 mg, 0.88 mmol) was added at 0 °C, and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into water (10 mL), and an appropriate amount of hydrochloric acid aqueous solution (1 M) was added dropwise to adjust the pH to weakly acidic. Ethyl acetate (30 mL × 3) was added for extraction, and the organic phase was dried by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 54 mg of the product.

[0159] LC-MS(ESI):[M+H] + = 552.2;

[0160] 1 H NMR(400 MHz, DMSO-d6) δ = 12.14(s, 1H), 8.68(s, 1H), 8.40(s, 1H),7.56 - 7.46(m, 2H), 7.44(m, 1H), 7.33 - 7.13(m, 1H), 5.11(s, 2H), 4.74 - 4.58(m, 4H).

[0161] Example 4 Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecane-12-yl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (Compound 4)

[0162]

[0163] Step 1: Synthesis of methyl 2-(((2,4-dimethoxyphenyl)methyl)amino)-4-iodopyridine-3-carboxylic acid

[0164] Methyl 2-fluoro-4-iodopyridine-3-carboxylic acid (2.9 mL, 19.93 mmol) and (2,4-dimethoxyphenyl)methylamine (4.0 mL, 26.91 mmol) were dissolved in dimethyl sulfoxide (30 mL), and potassium carbonate (5.5 g, 39.80 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, ethyl acetate (300 mL) was added, and the mixture was washed with water (150 mL × 3), followed by a final wash with saturated brine (100 mL). 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 8.0 g of the final product.

[0165] LC-MS(ESI):[M+H] + =429.0;

[0166] Step 2: Synthesis of methyl 2-(((2,4-dimethoxyphenyl)methyl)amino)-3-(methoxycarbonyl)pyridine-4-carboxylic acid

[0167] Methyl 2-{[(2,4-dimethoxyphenyl)methyl]amino}-3-(methoxycarbonyl)pyridine-4-carboxylic acid ester (7.5 g, 17.51 ​​mmol) and triethylamine (5 mL, 35.97 mmol) were dissolved in N,N-dimethylamide (80 mL) and methanol (40 mL). The mixture was purged with carbon monoxide three times, and the reaction solution was heated and stirred for 12 hours under a carbon monoxide (50 Psi) atmosphere. After the reaction was completed, the mixture was cooled to room temperature, washed once with water (100 mL), washed twice with 5% calcium chloride aqueous solution (150 mL × 2), and then washed with saturated brine (100 mL). Finally, the mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 8 g of crude product.

[0168] LC-MS(ESI):[M+H] + =361.1;

[0169] Step 3: Synthesis of methyl 2-amino-3-(methoxycarbonyl)pyridine-4-carboxylic acid

[0170] Methyl 2-(((2,4-dimethoxyphenyl)methyl)amino)-3-(methoxycarbonyl)pyridine-4-carboxylic acid (5 g, 20.81 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (10 mL, 134.63 mmol) was added, and the mixture was stirred for 1 hour. After the reaction was complete, the reaction solution was directly evaporated to dryness to obtain the crude product. The crude product was dissolved in ethyl acetate (300 mL), washed with saturated sodium bicarbonate solution (150 mL × 2), washed with water (150 mL), and washed with saturated brine (150 mL). Finally, it was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 4.5 g of crude product. The crude product was dissolved in 20 mL of ethyl acetate, and then added dropwise to petroleum ether (300 mL). A large amount of yellow solid precipitated. After stirring for 1 hour, the mixture was filtered, and the filter cake was then dried using an oil pump to obtain 2.8 g of product.

[0171] 1 H NMR(400 MHz, CHLOROFORM-d) δ(ppm) = 8.27(m, 1H), 7.76 - 7.69(m,1H), 7.40(m, 1H), 7.28(s, 1H), 6.67(d, 1H), 6.29(s, 2H), 3.90(m, 6H).

[0172] Step 4: Synthesis of methyl dimethyl 2-((phenoxycarbonyl)amino)pyridine-3,4-dicarboxylic acid ester

[0173] Methyl 2-amino-3-(methoxycarbonyl)pyridine-4-carboxylic acid ester (210 mg, 1.00 mmol) and benzoyl chloride (0.15 mL, 1.19 mmol) were dissolved in dichloromethane (5 mL). Then, pyridine (0.15 mL, 1.86 mmol) was slowly added under ice-water bath conditions. The reaction mixture was stirred under ice bath conditions for 1 hour. Ethyl acetate (200 mL) was added to the reaction mixture, followed by washing with water (100 mL × 2) and saturated brine (100 mL). Finally, the organic phase was 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 (HPLC) to obtain 80 mg of the final product.

[0174] 1 H NMR (400 MHz, CHLOROFORM-d) δ(ppm) = 9.50(s, 1H), 8.69(d, 1H), 7.46- 7.37(m, 2H), 7.29 - 7.26(m, 3H), 4.03 - 3.91(m, 6H).

[0175] Step 5: Synthesis of dimethyl-2-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecane-12-yl)ureo)pyridine-3,4-dicarboxylic acid

[0176] The starting materials, dimethyl 2-((phenoxycarbonyl)amino)pyridine-3,4-dicarboxylic acid methyl ester (82 mg, 0.25 mmol), 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolium cycloundecane-12-amine (90 mg, 0.25 mmol), and diethylpropylamine (0.1 mL, 0.72 mmol), were dissolved in tetrahydrofuran (3 mL) and stirred overnight at 60 °C. After the reaction was complete, ethyl acetate (200 mL) was added, followed by washing with water (100 mL × 2), and then once with saturated brine (100 mL). Finally, the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 115 mg of crude product.

[0177] LC-MS(ESI):[M+H] + =598.1;

[0178] Step 6: Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecane-12-yl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid

[0179] The starting materials, dimethyl-2-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecane-12-yl)ureo)pyridine-3,4-dicarboxylic acid (115 mg, 0.19 mmol) and lithium hydroxide (500 mg, 11.92 mmol), were dissolved in a system of tetrahydrofuran (6 mL), methanol (3 mL), and water (3 mL). After stirring at room temperature for 12 hours, the reaction solution was directly filtered and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 18.71 mg of the final product.

[0180] LC-MS(ESI):[M+H] + = 552.2;

[0181] 1H NMR(400 MHz, DMSO-d6) δ(ppm) = 12.37(s, 1H), 8.71(d,1H), 7.66 -7.54(m, 1H), 7.53 - 7.48(m, 2H), 7.43(d,1H), 7.31 - 7.21(m, 2H), 5.12(s, 2H),4.76 - 4.57(m, 4H).

[0182] Example 5 Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecyl-12-yl)-1,2,3,4-tetrahydroquinazoline-5-carboxylic acid (Compound 5)

[0183]

[0184] Step 1: Synthesis of 3-(phenoxycarbonyl)aminodimethyl phthalate

[0185] Dimethyl 3-aminophthalate (0.6 mL, 3.82 mmol) and potassium carbonate (1.00 mg, 7.24 mmol) were dissolved in tetrahydrofuran (20 mL) and water (10 mL). Phenyl chloroformate (1.0 mL, 7.65 mmol) was added at 0 °C, and the reaction was stirred for 2 hours at this temperature. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the crude product was obtained by rotary evaporation. The crude product was then purified by silica gel column chromatography to give 602 mg of the product.

[0186] LC-MS (ESI): [M+Na] + =352.0;

[0187] Step 2: Synthesis of methyl 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecyl-12-yl)-1,2,3,4-tetrahydroquinazoline-5-carboxylic acid

[0188] 3-(phenoxycarbonyl)aminodimethyl phthalate (100 mg, 0.30 mmol) and 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolium cyclohexane-12-amine (110 mg, 0.30 mmol) were dissolved in tetrahydrofuran (2 mL), and then triethylamine (0.1 mL, 0.91 mmol) was added. The reaction was heated to 60 °C and reacted for 16 hours. After cooling, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (40 mL × 3), the organic phase was washed with saturated brine, dried, and evaporated to dryness. The crude product was purified by normal-phase column chromatography to give 73 mg of the product.

[0189] LC-MS(ESI): [M+H] + =565.0;

[0190] Step 3: Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecyl-12-yl)-1,2,3,4-tetrahydroquinazoline-5-carboxylic acid

[0191] Methyl 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecyl-12-yl)-1,2,3,4-tetrahydroquinazoline-5-carboxylic acid (40 mg, 0.07 mmol) was dissolved in methanol (1 mL) and water (0.3 mL), and lithium hydroxide monohydrate (40 mg, 0.95 mmol) was added. The reaction was carried out at 20 °C with stirring for 16 hours. After adjusting the pH of the reaction solution to below 5 with dilute hydrochloric acid (1 M) aqueous solution, the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (20 mL), dried, and evaporated to dryness to obtain the crude product. The crude product was then prepared by high performance liquid chromatography (HPLC) to obtain 22 mg of the product.

[0192] LC-MS(ESI): [M+H] + =551.0;

[0193] 1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 11.81 (s, 1H), 7.73 (t, J= 7.8 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.43 (d, J = 10.9 Hz, 1H), 7.33 – 7.23(m, 2H), 7.13 (d, J = 7.4 Hz, 1H), 5.11 (s, 2H), 4.69 (t, J = 11.5 Hz, 2H), 4.62 (t, J = 11.6 Hz, 2H).

[0194] Biological test data

[0195] Experimental Example 1: Determination of the activity of the compounds of the present invention against human gonadotropin-releasing hormone (GnRH) receptors.

[0196] The objective of this experiment was to utilize a stable cell line of CHO (Chinese hamster ovary cells) expressing the human 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.

[0197] Main reagents, equipment and brands:

[0198] F-12 culture medium – Hyclone

[0199] Fetal Bovine Serum (FBS) — AusGeneX

[0200] Hygromycin B – Solarbio

[0201] DMSO (Dimethyl Sulfoxide) – Sigma

[0202] GnRH-I——GLPBIO

[0203] 0.25% Trypsin-EDTA (trypsin-ethylenediaminetetraacetic acid) solution – Gibco

[0204] IP-One-Gq kit – Cisbio

[0205] Main experimental instruments, brands and models:

[0206] Biosafety Cabinet – ESCO – AC2-6S1-TC

[0207] Carbon dioxide cell incubator – ESCO – CLM-240B-8-TC

[0208] Inverted Microscope – Olympus – CKX53

[0209] HTS High-Throughput Drug Screening Multifunctional Microplate Reader – BMG – PHERAstar FSX

[0210] Low-speed centrifuge – YIDA – TD25M

[0211] Microplate low-speed centrifuge – Xiangzhi – TD5B

[0212] Experimental plan:

[0213] (1) Cell preparation

[0214] 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%.

[0215] (2) Determination of the activity of the test compound against the GnRH receptor

[0216] 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.

[0217] 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 min to remove the culture medium. Cells were thoroughly dispersed in 1×Stimulation Buffer. After counting and dilution, 9.1 μL (10,000 cells) was seeded per well in 384-well plates.

[0218] 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, and 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.

[0219] 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.

[0220] Table 1 shows the inhibitory IC50 values ​​of the compounds on the activity of human gonadotropin-releasing hormone receptors. 50

[0221]

[0222] Experimental conclusion: The compound of this invention has a significant inhibitory effect on gonadotropin-releasing hormone (GnRH) receptors.

[0223] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are 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); (I)； in: L1, L2, L3, and L4 are independently selected from the following: -O-, -S-, and -(CR5R6), respectively. n -; T1 and T2 are independently O, S, NH, N-NO2 or N-CN, respectively; A1 is either CR4 or N; Y and Z are independently selected from bond, -O-, -S-, -S(=O)-, -SO2-, -CR7R8- and -C(=O)-, respectively; X1, X2, and X3 are independently selected from bonds, O, S, N, and CR, respectively. 10 ,and Not for ; R1 is , C(=O)OW1, C(=O)NW2W3 or S(=O)2W4, where W1, W2, W3 and W4 are independently selected from H, D, C respectively. 1-6 Alkyl, C 3-8 cycloalkyl and C 6-10 Aryl; R2, R3, and R4 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 of R5, R6, R7, and R8 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 R5 and R6, R7 and R8 may be optionally substituted with the carbon atom they are connected to to form C 3-6 cycloalkyl or 3-7 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl and 3-7 membered heterocyclic groups 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; Each R9 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 substituted 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 R9s may optionally form a 4-7 membered cycloalkane with the carbon atom attached to them, said 4-7 membered cycloalkane may optionally be independently substituted by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Substituents of haloalkoxy groups; Each R 10 Independently, H, D, F, Cl, Br, I, OH, NH2, 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 independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br and I; m can be 1, 2, 3, or 4; n is 1, 2, or 3.

2. The compound according to claim 1, characterized in that: R1 is , , 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.

3. The compound according to claim 1, characterized in that: R2 and R3 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 and I; Alternatively, R2 and R3 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.

4. The compound according to claim 1, characterized in that: R4 is selected from H, D, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3 and -CH2CF2CHF2.

5. The compound according to claim 1, characterized in that: Each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, 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, and I; or R5 and R6, R7 and R8 may be optionally substituted with the carbon atom they are connected to to form a C12 group. 3-6 cycloalkyl or 3-7 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl and 3-7 membered heterocyclic groups may be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH; Alternatively, each of R5, R6, R7, and R8 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, -OC H2CF3 and -OCH2CF2CHF2; or R5 and R6, R7 and R8 may optionally form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy or cyclopentoxy with the carbon atom they are connected to, respectively, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy and cyclopentoxy may be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH.

6. The compound according to claim 1, characterized in that: Each R9 is independently H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl, C 1-6 alkoxy or 3-7 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 The alkoxy group and the 3-7 membered heterocyclic group may optionally be independently substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I and CN; or two adjacent R9s may optionally form a 4-7 membered cycloalkane with the carbon atom attached to them, said 4-7 membered cycloalkane may optionally be independently substituted by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Substituents of haloalkoxy groups; Alternatively, each R9 may independently be 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, or -OCH2CF2CHF2; or two adjacent R9s may optionally form a 4-7 membered cycloalkane with the carbon atom to which they are attached. The 7-membered cycloalkanes may be independently and optionally substituted by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2, OH, 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.

7. The compound according to claim 1, characterized in that: Each R 10 Independently, it can be 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 or -OCH2CF2CHF2.

8. The compound according to claim 1, characterized in that: for , , , , , , , , , , or .

9. The compound according to any one of claims 1-8, 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: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , or .

10. A pharmaceutical composition comprising the compound of any one of claims 1-9; the pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

11. Use of the compound of any one of claims 1-9 or the pharmaceutical composition of claim 10 in the preparation of a medicament for the prevention, treatment or relief of a patient’s GnRH receptor antagonist-mediated disease.

12. The use according to claim 11, 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