Fused heterocycle-substituted thienopyrimidinedione derivatives and uses thereof

Abstract

The present application provides a class of fused heterocycle-substituted thienopyrimidine diketone 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] CN202510355222.3, 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 inhibiting 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 found that small molecule antagonists have significant therapeutic effects on hormone-dependent diseases such as endometriosis, 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. 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. Despite the significant amount of meaningful research already conducted in this field, further research and development of more effective small-molecule GnRH receptor antagonists is still needed. 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 or S;

[0015] Y and Z are independently selected from bond, -O-, -S-, -CR7R8- and -C(=O)-, respectively;

[0016] 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;

[0017] 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 1-6Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl group may be independently and optionally substituted by one, two or three substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH and NO2;

[0018] Each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, OH, and C, respectively. 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 one, two, or three 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 a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl group may be independently and optionally substituted by one, two, or three substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2, and OH;

[0019] Ring A is selected from C 7-10 Bicyclic aryl, 5-6 membered monocyclic heteroaryl, 7-12 membered bicyclic heteroaryl;

[0020] Each R9 is independently H, D, F, Cl, Br, I, CN, oxo (=O), 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 or 3-7 membered heterocyclic group may be optionally and independently replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, oxo (=O), OH, COOH, NO2 and NH2;

[0021] m is 1, 2, 3, 4 or 5;

[0022] n is 1, 2, or 3.

[0023] In some embodiments, ring A is selected from any of the following groups:

[0024] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0025] In some embodiments, R1 is COOW1, wherein W1 is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl;

[0026] R2, R3, and R4 are independently selected from H, D, F, Cl, Br, I, 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;

[0027] Each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, OH, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be independently and optionally substituted by one, two, or three 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 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups may be optionally substituted by one, two, or three substituents selected from H, D, F, Cl, Br, I, NH2, OH, and oxo (=O);

[0028] Each R9 is independently selected from H, D, F, Cl, Br, I, 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.

[0029] In some implementations, R1 is COOH;

[0030] R2 and R4 are independently H or D;

[0031] R3 is selected from F, Cl, Br, and I;

[0032] Each of R5, R6, R7 and R8 is independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl and isopropyl; or R5 and R6, R7 and R8 are optionally formed with the carbon atom they are connected to to form a cyclopropyl group.

[0033] In some embodiments, the structure of the compound of formula I is shown in formulas I-1 to I-9:

[0034] (I-1) (I-2)

[0035] (I-3) (I-4)

[0036] (I-5) (I-6)

[0037] (I-7) (I-8)

[0038] (I-9).

[0039] Among them, T1, T2, L2, L3, R2, R3, R4, R5, R6, R7, R8, R 9、 Ring A is as defined in this invention.

[0040] 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:

[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, high plasma exposure, long half-life, high oral bioavailability, and excellent pharmacokinetic properties.

[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.

[0086] Example 1 Synthesis of 3-(11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-b]pyridin-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid (Compound 1)

[0087]

[0088] Step 1: Synthesis of dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid ester

[0089] 4-Amino-3-(methoxycarbonyl)thiophene-2-carboxylic acid methyl ester hydrochloride (2.00 g, 9.29 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL), potassium carbonate (2.57 g, 18.58 mmol) was added, and then phenyl chloroformate (1.8 mL, 13.93 mmol) was slowly added dropwise. The reaction was carried out at 25 °C for 3 hours. After the reaction was complete, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL × 2), dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 1.5 g of white solid product.

[0090] LC-MS(ESI): [M+H] + = 336.1;

[0091] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 9.06 (s, 1H), 7.87 (s, 1H), 7.47 -7.40 (m, 2H), 7.32 - 7.28 (m, 1H), 7.26 - 7.20 (m, 2H), 3.99 (s, 3H), 3.95(s, 3H).

[0092] Step 2: Synthesis of methyl 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridinecarboxylate

[0093] Cesium carbonate (15.96 g, 48.97 mmol) and (3-bromopropoxy)(tert-butyl)dimethylsilane (9.1 mL, 39.18 mmol) were added to a solution of methyl 3-hydroxypyridine-2-carboxylic acid (5 g, 32.65 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was reacted at 28 °C for 3 hours. After the reaction was complete, the solution was diluted with water (200 mL), extracted with ethyl acetate (200 mL x 2), washed with brine (100 mL x 2), and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 5.2 g of a colorless oily product.

[0094] LC-MS(ESI): [M+H] + = 326.1;

[0095] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.23 ​​(dd, J = 2.3, 3.4 Hz, 1H), 7.46 - 7.28 (m, 2H), 4.21 - 4.10 (m, 2H), 3.93 (s, 3H), 3.80 (t, J = 5.9 Hz,2H), 2.02 - 1.95 (m, 2H), 0.84 (s, 9H).

[0096] Step 3: Synthesis of (3-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-2-yl)methanol

[0097] Under nitrogen protection, sodium borohydride (0.46 g, 12.28 mmol) was slowly added to a methanol (30 mL) solution of methyl 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridinecarboxylate (2 g, 6.14 mmol) at 0 °C. The reaction solution was reacted at 28 °C for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (100 mL x 2), washed with brine (100 mL x 2), dried, and concentrated to obtain 1.5 g of colorless oily product, which was directly used in the next reaction.

[0098] LC-MS(ESI): [M+H] + = 298.1.

[0099] Step 4: Synthesis of 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-((2,4-difluoro-5-nitrophenoxy)methyl)pyridine

[0100] To a solution of compound (3-((tert-butyldimethylsilyl)oxy)propoxy)pyridin-2-yl)methanol (2 g, 6.72 mmol) in toluene (50 mL), (tributyl-λ5-phosphine)acetonitrile (4.87 g, 20.17 mmol) was added, and the reaction was carried out at 90 °C for 16 hours. The reaction solution was concentrated and evaporated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 550 mg of a yellow oily product.

[0101] LC-MS(ESI): [M+H] + = 455.2.

[0102] Step 5: Synthesis of 3-[(2-{[(2,4-difluoro-5-nitrophenyl)oxy]methyl}pyridin-3-yl)oxy]-prop-1-ol]

[0103] A solution of 1,4-dioxane hydrochloric acid (2M, 1 mL) was added dropwise to a solution of 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-((2,4-difluoro-5-nitrophenoxy)methyl)pyridine (100 mg, 0.22 mmol) in dioxane (3 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reactants were concentrated to give 75 mg of a yellow oily product, which was used directly in the next step of the reaction.

[0104] LC-MS(ESI): [M+H] + = 341.1.

[0105] Step 6: Synthesis of 11-fluoro-12-nitro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolecycloundeceno[6,7-b]pyridine

[0106] The starting material 3-[(2-{[(2,4-difluoro-5-nitrophenyl)oxy]methyl}pyridin-3-yl)oxy]-prop-1-ol (140 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (30 mL), and dried cesium fluoride (0.1 mL, 2.06 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 3 hours under a nitrogen atmosphere. Saturated brine (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated calcium chloride aqueous solution (50 mL), dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 40 mg of a yellow solid product.

[0107] LC-MS(ESI): [M+H] + = 321.3;

[0108] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.23 ​​(d, J = 4.5 Hz, 1H), 7.84 (d,J = 7.6 Hz, 1H), 7.37 - 7.27 (m, 1H), 7.23 - 7.20 (m, 1H), 6.70 (d, J = 12.0Hz, 1H), 5.17 (s, 2H), 4.53 - 4.33 (m, 2H), 4.31 - 4.12 (m, 2H), 2.19 - 2.00 (m, 2H).

[0109] Step 7: Synthesis of 11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolecycloundeceno[6,7-b]pyridine-12-amine

[0110] The starting material 11-fluoro-12-nitro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolecycloundeceno[6,7-b]pyridine (40 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 4-(pyridin-4-yl)pyridine (1.02 mg, 0.01 mmol) and (dihydroxyboryl)boranediol (47 mg, 0.52 mmol) were added. The reaction mixture was stirred at 25 °C for 5 minutes. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated calcium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 38 mg of yellow oil.

[0111] LC-MS(ESI): [M+H] + = 291.1.

[0112] Step 8: Synthesis of dimethyl 4-(3-(11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-b]pyridin-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0113] The starting materials 11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolecycloundeceno[6,7-b]pyridine-12-amine (38 mg, 0.13 mmol) and dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (43.90 mg, 0.13 mmol) were dissolved in tetrahydrofuran (1 mL), and then triethylamine (0.1 mL, 0.39 mmol) was added. The reaction mixture was stirred at 70 °C for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 40 mg of white solid product.

[0114] LC-MS(ESI): [M+H] + = 532.1.

[0115] Step 9: Synthesis of 3-(11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-b]pyridin-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid

[0116] Dimethyl 4-(3-(11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-b]pyridin-12-yl)ureo)thiophene-2,3-dicarboxylic acid (40 mg, 0.08 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide (15.79 mg, 0.38 mmol) was added in a single batch. The reaction mixture was stirred at 25 °C for 1 hour. The pH of the reaction mixture was adjusted to 3-4 with dilute hydrochloric acid (2 M). A white solid precipitated in the aqueous phase. The mixture was then filtered directly, and the filter cake was washed once with water (20 mL). The filtrate was lyophilized to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 15 mg of the product.

[0117] LC-MS(ESI): [M+H] + = 486.1;

[0118] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.93 - 2.03 (m, 2 H), 4.34 (br t, J=4.71 Hz, 2 H), 4.43 (br s, 2 H), 5.05 (s, 2 H), 7.25 (d, J=11.37 Hz, 1 H),7.31 - 7.36 (m, 2 H), 7.36 - 7.40 (m, 1 H), 7.59 - 7.64 (m, 1 H), 8.13 - 8.14(m, 1 H), 8.14 - 8.17 (m, 1 H), 11.83 - 12.12 (m, 1 H).

[0119] Example 2 Synthesis of 3-(13-fluoro-9,10-dihydroxy-8H,17H-benzo[2,3][1,4,8]triazolylcycloundeceno[7,6-h]quinoline-14-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid (Compound 2)

[0120]

[0121] Step 1: Synthesis of 8-bromo-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)quinoline

[0122] Potassium carbonate (462 mg, 3.35 mmol) and (3-bromopropoxy)(tert-butyl)dimethylsilane (0.6 mL, 2.68 mmol) were added to a solution of 8-bromoquinoline-7-ol (500 mg, 2.23 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the solution was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was evaporated to dryness and purified by silica gel column chromatography to obtain 670 mg of a colorless, transparent oil.

[0123] LC-MS(ESI): [M+H] + = 396.0;

[0124] Step 2: Synthesis of 7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-8-methylquinoline

[0125] Compounds 8-bromo-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)quinoline (0.1 mL, 0.76 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol), and cesium carbonate (329 mg, 1.01 mmol) were dissolved in dioxane (5 mL). The reaction mixture was reacted at 90 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was diluted with water and then extracted with ethyl acetate (20 mL x 2). The organic phase was washed twice with saturated calcium chloride aqueous solution. The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain 150 mg of a white product.

[0126] LC-MS(ESI): [M+H] + = 332.2;

[0127] Step 3: Synthesis of 8-(bromomethyl)-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)quinoline

[0128] 7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-8-methylquinoline (500 mg, 1.51 mmol), N-bromosuccinimide (295 mg, 1.66 mmol), and azobisisobutyronitrile (13 mg, 0.08 mmol) were dissolved in carbon tetrachloride (20 mL), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL), then extracted with dichloromethane (100 mL × 2), the organic phase was washed with water (100 mL), dried, and concentrated to obtain 420 mg of crude product, which was directly used in the next step.

[0129] LC-MS(ESI): [M+H] + = 412.1;

[0130] Step 4: Synthesis of 7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-8-((2,4-difluoro-5-nitrophenoxy)methyl)quinoline

[0131] Sodium carbonate (305 mg, 2.88 mmol) was added to a solution of 8-(bromomethyl)-7-(3-((tert-butyldimethylsilyl)oxy)propoxy)quinoline (500 mg, 1.44 mmol) and 2,4-difluoro-5-nitrophenol (377.86 mg, 2.16 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with saturated ammonium chloride aqueous solution and then extracted with ethyl acetate (100 mL × 2). The organic phase was washed twice with saturated calcium chloride aqueous solution. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 550 mg of white product.

[0132] LC-MS(ESI): [M+H] + = 505.2;

[0133] Step 5: Synthesis of 3-((8-((2,4-difluoro-5-nitrophenoxy)methyl)quinoline-7-yl)oxy)propane-1-ol

[0134] Hydrochloric acid / 1,4-dioxane (1447 mg, 7.93 mmol) was added to a dioxane (5 mL) solution of compound 7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-8-((2,4-difluoro-5-nitrophenoxy)methyl)quinoline (400 mg, 0.79 mmol), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to obtain a pale yellow solid, which was then slurried with petroleum ether / ethyl acetate = 5 / 1 (10 mL) for 10 minutes, and then filtered to obtain 300 mg of white solid.

[0135] LC-MS(ESI): [M+H] + = 391.1;

[0136] Step 6: Synthesis of 13-fluoro-14-nitro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[7,6-h]quinoline

[0137] Cesium fluoride (700 mg, 4.61 mmol) was added to a solution of compound 3-((8-((2,4-difluoro-5-nitrophenoxy)methyl)quinolin-7-yl)oxy)propane-1-ol (300 mg, 0.77 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at 75 °C for 3 hours. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed twice with saturated calcium chloride aqueous solution, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 112 mg of a pale yellow solid.

[0138] LC-MS(ESI): [M+H] + = 371.1;

[0139] 1 H NMR (400 MHz, DMSO-d6) δ = 8.97 (dd, J = 1.6, 3.9 Hz, 1H), 8.44 -8.22 (m, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.64 (d, J= 9.1 Hz, 1H), 7.43 (dd, J = 4.2, 8.2 Hz, 1H), 7.28 (d, J = 13.4 Hz, 1H), 5.72 (s, 2H), 4.69 - 4.58 (m, 2H), 4.48 (t, J = 4.6 Hz, 2H), 2.06 - 1.99 (m,2H).

[0140] Step 7: Synthesis of 13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[7,6-h]quinoline-14-amine

[0141] 13-fluoro-14-nitro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[7,6-h]quinoline (100 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (2 mL). Diboronic acid (97 mg, 1.08 mmol) and 4,4'-bispyridine (0.01 mL, 0.01 mmol) were added to the solution. The reaction mixture was stirred at 25 °C for 10 minutes. The reactants were diluted with water (20 mL) and then extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated calcium chloride, dried, and concentrated to obtain 90 mg of the product, which was directly used in the next step.

[0142] LC-MS(ESI): [M+H] + = 341.2;

[0143] Step 8: Synthesis of dimethyl 4-(3-(13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolylcycloundeceno[7,6-h]quinoline-14-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0144] Triethylamine (47.57 mg, 0.47 mmol) was added to a tetrahydrofuran solution of compound 13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolcycloundeceno[7,6-h]quinoline-14-amine (80 mg, 0.24 mmol) and dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (94.58 mg, 0.28 mmol) (synthetic method as described in step 1 of Example 1). The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), washed with water (50 mL), dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain 55 mg of a clear oily product.

[0145] LC-MS(ESI): [M+H] + = 582.2;

[0146] Step 9: Synthesis of 3-(13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolylcycloundeceno[7,6-h]quinolin-14-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid

[0147] Dimethyl 4-(3-(13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[7,6-h]quinoline-14-yl)ureo)thiophene-2,3-dicarboxylic acid (50 mg, 0.09 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL), methanol (0.50 mL), and water (0.5 mL), and then lithium hydroxide (10.0 mg, 0.43 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with hydrochloric acid (2 M, 5 mL), diluted with water (10 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with water (10 mL), dried, and concentrated to obtain the crude product. The crude product was dissolved in acetonitrile / water and lyophilized to obtain 32 mg of product.

[0148] LC-MS(ESI): [M+H] + =536.1;

[0149] 1 H NMR (400 MHz, DMSO-d6) δ = 12.16 - 11.74 (m, 1H), 8.92 (d, J = 3.4Hz, 1H), 8.33 (br d, J = 8.2 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.68 (d, J =9.0 Hz, 1H), 7.54 - 7.41 (m, 1H), 7.38 - 7.30 (m, 2H), 7.20 (d, J = 11.2 Hz,1H), 5.71 - 5.62 (m, 2H), 4.60 (br s, 2H), 4.42 - 4.28 (m, 2H), 2.08 (br d, J= 3.9 Hz, 2H).

[0150] Example 3 Synthesis of 12-(5-carboxy-2,4-dioxo-1,2-dihydrothieno[3,4-d]pyrimidin-3(4H)-yl)-11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-b]pyridine 1-oxide (Compound 3)

[0151]

[0152] Step 1: Synthesis of 1-oxide of 12-(5-carboxy-2,4-dioxo-1,2-dihydrothieno[3,4-d]pyrimidin-3(4H)-yl)-11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-b]pyridine

[0153] 3-(11-fluoro-7,8-dihydro-6H,15H-benzo[2,3][1,4,8]triazolium cycloundec[6,7-b]pyridin-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (5 mg, 0.01 mmol) (synthetic method as described in Example 1) was dissolved in dichloromethane (1 mL), and m-chloroperoxybenzoic acid (4 mg, 0.02 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain a crude product, which was then separated by high performance liquid chromatography to obtain 2.11 mg of the product.

[0154] LC-MS(ESI): [M+H] + =502.1;

[0155] 1 H NMR (400 MHz, DMSO-d6) δ = 11.78 (s, 1H), 7.97 (s, 1H), 7.40 - 7.35(m, 1H), 7.32 (s, 1H), 7.25 - 7.20 (m, 1H), 7.18 - 7.12 (m, 2H), 5.18 - 5.03 (m, 2H), 4.56 (br s, 2H), 4.38 - 4.26 (m, 2H), 2.00 (br d, J = 4.3 Hz, 2H).

[0156] Example 4: Synthesis of 3-(13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-c]imidazo[1,2-a]pyridin-14-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 4)

[0157]

[0158] Step 1: Synthesis of tert-butyl 3-(2-methyl-1H-imidazol-1-yl)propionate

[0159] 2-Methylimidazole (19.0 mL, 243.58 mmol) and 2-methylpropyl-2-ylpropyl-2-enoate (37.1 mL, 255.75 mmol) were added to a sealed flask, and the mixture was heated to 80 °C and stirred for 1 hour. The reaction solution was then concentrated and evaporated to dryness to obtain 51 g of product.

[0160] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 6.88 (d, 1H), 6.83 (d, J = 1.2 Hz,1H), 4.10 (t, 2H), 2.62 (t, 2H), 2.38 (s, 3H), 1.41 (s, 9H).

[0161] Step 2: Synthesis of tert-butyl 3-(2-(2-(benzyloxy)-2-oxoethyl)-1H-imidazol-1-yl)propionate

[0162] 45 g (214.00 mmol) of tert-butyl 3-(2-methyl-1H-imidazol-1-yl)propionate and 89.2 mL (642.00 mmol) of triethylamine were dissolved in acetonitrile (450 mL). The system was cooled to 0 °C, and then benzyl chloromethaneate (36.5 mL, 256.80 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the reaction solution was brought to room temperature and reacted for 1 hour. Water (500 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed once with brine (1 L), dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 25.0 g of the product.

[0163] LC-MS(ESI): [M+H] + = 345.1.

[0164] Step 3: Synthesis of 3-(2-(2-(benzyloxy)-2-oxoethyl)-1H-imidazol-1-yl)propionic acid

[0165] 23 g (66.78 mmol) of tert-butyl 3-(2-(2-(benzyloxy)-2-oxoethyl)-1H-imidazol-1-yl)propionate was dissolved in 100 mL of dichloromethane. Trifluoroacetic acid (100 mL, 1346.26 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated to dryness, and dioxane hydrochloride solution (2 M, 100 mL) was added and stirred for 30 minutes. The reaction mixture was then evaporated to dryness again, and after adding 500 mL of pure water, it was lyophilized to obtain 21 g of the product.

[0166] LC-MS(ESI): [M+H]+ = 289.2.

[0167] Step 4: Synthesis of 7-hydroxy-5,6-dihydroimidazo[1,2-a]pyridine-8-carboxylic acid benzyl ester

[0168] 21 g (72.84 mmol) of 3-(2-(2-(benzyloxy)-2-oxoethyl)-1H-imidazol-1-yl)propionic acid was dissolved in acetonitrile (200 mL), followed by the addition of triethylamine (60.7 mL, 437.04 mmol). Then, carbonyl diimidazole (35.43 g, 218.52 mmol) was added in portions to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature for 32 hours. Upon completion of the reaction, 100 mL of water was added to the reaction mixture, and the aqueous phase was purified by high-performance liquid chromatography to obtain 7 g of the product.

[0169] 1 H NMR (400 MHz, CHLOROFORM-d) δ =11.80 - 11.61 (s, 1H), 7.51 - 7.44(m, 2H), 7.38 (s, 2H), 7.33 - 7.27 (m, 1H), 7.17 - 7.14 (m, 1H), 7.00 - 6.97 (m, 1H), 5.22 (s, 2H), 4.14 - 4.00 (m, 2H), 2.49 (t, 2H).

[0170] Step 5: Synthesis of 7-hydroxyimidazo[1,2-a]pyridine-8-carboxylic acid benzyl ester

[0171] 7-Hydroxy-5,6-dihydroimidazo[1,2-a]pyridine-8-carboxylic acid benzyl ester (5 g, 18.50 mmol) was dissolved in dioxane (50 mL), and 2,3,5,6-tetrachlorobenzene-1,4-dione (6.82 g, 27.75 mmol) was added. The mixture was heated to 60 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was directly concentrated. The concentrated solid was added to ethanol (50 mL), stirred for 1 hour, and then filtered. The filtrate was directly purified by reverse-phase column chromatography, and the fraction was evaporated to dryness to obtain 2.20 g of product.

[0172] LC-MS(ESI): [M+H] + =269.1.

[0173] Step 6: Synthesis of 7-(3-(((tert-butyldimethylsilyl)oxy)propoxy)imidazo[1,2-a]pyridine-8-carboxylic acid benzyl ester

[0174] 7-Hydroxyimidazo[1,2-a]pyridine-8-carboxylic acid benzyl ester (2.20 g, 8.20 mmol) was dissolved in N,N-dimethylformamide (22 mL), followed by the addition of cesium carbonate (8.02 g, 24.60 mmol). The mixture was heated to 80 °C and stirred for 0.5 h. Subsequently, 7-bromo-2,2,3,3-tetramethyl-4-oxa-3-silylheptane (3.8 mL, 16.40 mmol) was added dropwise to the reaction mixture, and the mixture was heated to 80 °C and stirred for 1 h. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL × 3), 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 2.1 g of the product.

[0175] LC-MS(ESI): [M+H] + =441.2.

[0176] Step 7: Synthesis of (7-(3-(((tert-butyldimethylsilyl)oxy)propoxy)imidazo[1,2-a]pyridin-8-yl)methanol

[0177] 1.50 g (3.40 mmol) of 7-(3-(((tert-butyldimethylsilyl)oxy)propoxy)imidazo[1,2-a]pyridine-8-carboxylic acid benzyl ester was dissolved in ethanol (15 mL). Calcium chloride (0.76 g, 6.81 mmol) and sodium borohydride (0.64 g, 17.02 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with 1M hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed once with brine (10 mL), filtered, dried, and then evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 500 mg of the product.

[0178] LC-MS(ESI): [M+H] + =337.2.

[0179] Step 8: Synthesis of 7-(3-(((tert-butyldimethylsilyl)oxy)propoxy)-8-((2,4-difluoro-5-nitrophenoxy)methyl)imidazo[1,2-a]pyridine

[0180] (7-(3-(((tert-butyldimethylsilyl)oxy)propoxy)imidazo[1,2-a]pyridin-8-yl)methanol (125.92 mg, 0.72 mmol) was dissolved in tetrahydrofuran (3 mL), and triphenylphosphine (257.22 mg, 0.98 mmol) and 2,4-difluoro-5-nitrophenol (125.92 mg, 0.72 mmol) were added. After stirring for 10 minutes, diisopropyl azodicarbonate (0.2 mL, 0.98 mmol) was added. The reaction mixture was then reacted at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL), 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 25 mg of the product.

[0181] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 8.50 - 8.41 (m, 1H), 8.18 - 8.09(m, 1H), 7.80 - 7.69 (m, 1H), 7.53 - 7.46 (m, 1H), 7.37 - 7.28 (m, 1H), 7.05- 6.98 (m, 1H), 5.54 (s, 2H), 4.35 - 4.26 (m, 2H), 3.85 - 3.77 (m, 2H), 2.08- 1.95 (m, 2H), 0.87 (s, 9H), 0.02 (s, 6H).

[0182] Step 9: Synthesis of 13-fluoro-14-nitro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolecycloundeceno[6,7-c]imidazo[1,2-a]pyridine

[0183] 7-(3-(((tert-butyldimethylsilyl)oxy)propoxy)-8-((2,4-difluoro-5-nitrophenoxy)methyl)imidazo[1,2-a]pyridine (25 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (20 mL), and cesium fluoride (76.94 mg, 0.51 mmol) was added to the mixture. The reaction solution was heated to 70 °C and reacted for 1 hour. After the reaction was complete, saturated brine (50 mL) was added to the reaction solution, and then the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with saturated calcium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 18 mg of crude product.

[0184] Step 10: Synthesis of 13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolecycloundeceno[6,7-c]imidazo[1,2-a]pyridine-14-amine

[0185] 13-fluoro-14-nitro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-c]imidazo[1,2-a]pyridine (18 mg, 0.05 mmol) and 4,4'-bispyridine (1 mg, 0.01 mmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the addition of tetrahydroxydiboron (17.96 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 5 minutes. After the reaction was complete, saturated brine (10 mL) was added, followed by extraction with dichloromethane (20 mL × 3). The combined organic phases were washed once with saturated calcium chloride aqueous solution (50 mL). After separation, the organic phases were dried over anhydrous sodium sulfate and evaporated to dryness to obtain 16 mg of crude product.

[0186] LC-MS(ESI): [M+H] + =330.1.

[0187] Step 11: Synthesis of dimethyl 4-(3-(13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-c]imidazo[1,2-a]pyridin-14-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0188] 13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-c]imidazo[1,2-a]pyridine-14-amine (17 mg, 0.05 mmol) and methyl 3-(methoxycarbonyl)-4-{[(phenoxy)carbonyl]amino}thiophene-2-carboxylic acid (synthesized according to step 1 of Example 1) (17.31 mg, 0.05 mmol) were dissolved in tetrahydrofuran (0.5 mL), and triethylamine (0.1 mL, 0.52 mmol) was added. The reaction mixture was heated to 70 °C and reacted for 1 hour. After the reaction was complete, water (10 mL) and ethyl acetate (20 mL × 2) were added directly. The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 2 mg of the product.

[0189] LC-MS(ESI): [M+H] + =571.1.

[0190] Step 12: Synthesis of 3-(13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolecycloundeceno[6,7-c]imidazo[1,2-a]pyridin-14-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid

[0191] Dimethyl 4-(3-(13-fluoro-9,10-dihydro-8H,17H-benzo[2,3][1,4,8]triazolium cycloundeceno[6,7-c]imidazo[1,2-a]pyridin-14-yl)ureo)thiophene-2,3-dicarboxylic acid (2 mg, 0.01 mmol) was dissolved in tetrahydrofuran (0.5 mL), methanol (0.2 mL), and water (0.2 mL). Lithium hydroxide monohydrate (1.03 mg, 0.02 mmol) was then added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the pH of the reaction mixture was adjusted to acidic by adding 1 M dilute hydrochloric acid, followed by extraction with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL), 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 0.41 mg of the product.

[0192] LC-MS(ESI): [M+H] + =525.1.

[0193] 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.43 - 11.02 (s, 1H), 8.33 - 8.24 (m,1H), 7.85 - 7.79 (m, 1H), 7.45 (s, 1H), 7.20 - 7.09 (m, 2H), 7.08 - 7.03 (m,1H), 6.61 - 6.54 (m, 1H), 5.27 - 5.19 (m, 2H), 4.55 - 4.46 (m, 2H), 4.32 -4.25 (m, 2H), 2.04 - 2.00 (m, 2H).

[0194] Example 5 Synthesis of 2,4-dioxo-3-(2,2,12-trifluoro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecen-13-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 5)

[0195]

[0196] Step 1: Synthesis of 2,2-difluorobenzo[d][1,3]dioxanetanol

[0197] 5-Bromo-2,2-difluorobenzo[d][1,3]diazole (3 g, 17.33 mmol) was dissolved in water (30 mL) and 1,4-dioxane (30 mL) and cooled. Tris(dibenzylacetone)dipalladium(0) (0.58 g, 0.63 mmol), 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (0.61 g, 1.27 mmol), and potassium hydroxide (1.42 g, 25.32 mmol) were added to the solution under a nitrogen atmosphere, and the mixture was stirred at 80 °C for 5 hours. After the reaction was complete, the reaction mixture was poured into water (300 mL), extracted with ethyl acetate (50 mL × 5), and the combined organic phases were washed with water (200 mL × 3) and washed once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 2.20 g of the product.

[0198] Step 2: Synthesis of tert-butyl(3-((2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)oxy)propoxy)dimethylsilane

[0199] 2,2-Difluorobenzo[d][1,3]dioxane (1.06 g, 5.66 mmol), (3-bromopropoxy)(tert-butyl)dimethylsilane (2.2 g, 12.64 mmol), potassium carbonate (3.49 g, 25.27 mmol), and sodium iodide (379 mg, 2.53 mmol) were added to a 50 mL single-necked flask, followed by the addition of N,N-dimethylformamide (20 mL). The mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 2 hours. The reaction mixture was then poured into water (400 mL) and extracted with ethyl acetate (500 mL × 5). The combined organic phases were washed with water (200 mL × 3) and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 2.22 g of the product.

[0200] Step 3: Synthesis of 5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)-2,2-difluorobenzo[d][1,3]dioxane-4-carboxaldehyde

[0201] 2.1 g (6.06 mmol) of tert-butyl(3-((2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)oxy)propoxy)dimethylsilane was dissolved in anhydrous tetrahydrofuran (25 mL), and 2,5-dimethyl-2,5-diazahexane (1.8 mL, 12.12 mmol) was added. Then, n-butyllithium (1.3 mL, 9.09 mmol) was slowly added below -60 °C. After half an hour, N,N-dimethylformamide (0.6 mL, 7.88 mmol) was added, and the mixture was stirred for 40 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was then poured into water (300 mL), extracted with ethyl acetate (50 mL × 5), and the combined organic phases were washed with water (200 mL × 3) and once with saturated brine (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1.21 g of the product.

[0202] Step 4: Synthesis of (5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)-2,2-difluorobenzo[d][1,3]dihydroxy-4-yl)methanol

[0203] A solution of sodium borohydride (118 mg, 2.65 mmol) in 10 mL of tetrahydrofuran (900 mg, 2.65 mmol) was added to a solution of 5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)-2,2-difluorobenzo[d][1,3]dioxane-4-carboxaldehyde (10 mL), and the mixture was reacted at 0 °C for 10 min. After the reaction was complete, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 600 mg of crude product. The product was used directly in the next reaction without purification.

[0204] Step 5: Synthesis of tert-butyl(3-((4-((2,4-difluoro-5-nitrophenoxy)methyl)-2,2-difluorobenzo[d][1,3]dioxane-5-yl)oxy)propoxy)dimethylsilane

[0205] To a solution of (300 mg, 0.87 mmol) 5-(3-((tert-butyldiphenylsilyl)oxy)propoxy)-2,2-difluorobenzo[d][1,3]dihydroxy-4-yl)methanol (300 mg, 0.87 mmol), 2,4-difluoro-5-nitrophenol (153 mg, 0.87 mmol), in tetrahydrofuran (3 mL), diisopropyl azodicarbonate (240 mg, 1.195 mmol) and triphenylphosphine (314 mg, 1.195 mmol) were added, and the mixture was reacted at 25 °C for 3 hours. The reaction mixture was then poured into water (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 200 mg of the product.

[0206] Step 6: Synthesis of 3-((4-((2,4-difluoro-5-nitrophenoxy)methyl)-2,2-difluorobenzo[d][1,3]dioxanepentanol)oxy)prop-1-ol

[0207] 160 mg (0.29 mmol) of tert-butyl(3-((4-((2,4-difluoro-5-nitrophenoxy)methyl)-2,2-difluorobenzo[d][1,3]dioxacyclopentanol-5-yl)oxy)propoxy)dimethylsilane was dissolved in methanol (1 mL). A solution of 1,4-dioxane in hydrochloric acid (4 M, 2 mL) was added under ice bath conditions, and the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain 102 mg of crude product, which was used directly in the next reaction without purification.

[0208] Step 7: Synthesis of 2,2,12-trifluoro-13-nitro-8,9-dihydro-7H,16H-[1,3]dioxane[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolecycloundecene

[0209] Cesium fluoride (360 mg, 1.30 mmol) was added to a solution of 3-((4-((2,4-difluoro-5-nitrophenoxy)methyl)-2,2-difluorobenzo[d][1,3]dioxane)oxy)prop-1-ol (200 mg, 0.52 mmol) in N,N-dimethylformamide (10 mL), and the mixture was incubated overnight at 80 °C. The reaction mixture was then poured into water (10 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed once with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 70 mg of the product.

[0210] Step 8: Synthesis of 2,2,12-trifluoro-8,9-dihydro-7H,16H-[1,3]dioxane[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene-13-amine

[0211] 2,2,12-trifluoro-13-nitro-8,9-dihydro-7H,16H-[1,3]dioxane[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene (70 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 4,4'-bispyridine (2.6 mg, 0.03 mmol) and bisboronic acid (23.81 mg, 0.64 mmol) were added at once. The reaction mixture was stirred at 25 °C for 5 minutes. After the reaction was complete, water (20 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 2 times). The organic phases were combined and washed once each with saturated saline (50 mL) and saturated calcium chloride aqueous solution (50 mL). The mixture was then dried with anhydrous sodium sulfate, filtered, and then evaporated to dryness to obtain 68.5 mg of product. The product was used directly in the next reaction without purification.

[0212] LC-MS(ESI): [M+H] + =370.3;

[0213] Step 9: Synthesis of dimethyl 4-(3-(2,2,12-trifluoro-8,9-dihydro-7H,16H-[1,3]dioxane[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene-13-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0214] 2,2,12-trifluoro-8,9-dihydro-7H,16H-[1,3]dioxane[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolium-13-undecene-13-amine (62 mg, 0.2 mmol) was dissolved in tetrahydrofuran (1 mL), and then 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid dimethyl ester (78.3 mg, 0.25 mmol) and triethylamine (0.1 mL, 0.39 mmol) were added. The reaction mixture was stirred at 70 °C for 4 hours. After the reaction was complete, water (10 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed once with saturated brine (50 mL). The mixture was then dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 20 mg of the product.

[0215] LC-MS(ESI): [M+H]+ =611.5;

[0216] Step 10: Synthesis of 2,4-dioxo-3-(2,2,12-trifluoro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecen-13-yl)-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid

[0217] Dimethyl 4-(3-(2,2,12-trifluoro-8,9-dihydro-7H,16H-[1,3]dioxane[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene-13-yl)ureo)thiophene-2,3-dicarboxylic acid (20 mg, 0.1 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (5.7 mg, 0.25 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (50 mL), filtered, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 10 mg of product.

[0218] LC-MS(ESI): [M+H] + = 565.1;

[0219] 1 H NMR(500 MHz, DMSO-d6) δ ppm 14.64 (s, 1H), 11.92(s, 1H), 7.33(d, J= 8.9 Hz, 2H), 7.25(d, J = 7.7 Hz, 1H), 7.16(d, J = 11.3 Hz, 1H), 7.00(d, J =8.8 Hz, 1H), 4.46(s, 2H), 4.30(s, 2H), 2.00(d, J = 20.2 Hz, 2H).

[0220] Example 6 Synthesis of 3-(2,3-dichloro-10-fluoro-6,7-dihydro-5H,14H-benzo[b]thieno[2,3-f][1,4,8]triazolylcycloundecen-11-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 6)

[0221]

[0222] Step 1: Synthesis of methyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate

[0223] Methyl 3-hydroxythiophene-2-carboxylate (7 g, 44.26 mmol) was dissolved in acetic acid (35 mL), and N-chlorosuccinimide (15.36 g, 115.07 mmol) was slowly added. The reaction was carried out at 85 °C for 5 hours. After the reaction was complete, water (150 mL) and ethyl acetate (60 mL) were added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3) after separation. The organic phases were combined, washed with brine (20 mL), dried, and then evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 3.06 g of the product.

[0224] Step 2: Synthesis of methyl 3-(3-((tert-butyldiphenylsilyl)oxy)propoxy)-4,5-dichlorothiophene-2-carboxylate

[0225] Methyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (1.5 g, 6.61 mmol) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (1.83 g, 13.21 mmol), sodium iodide (0.20 g, 1.32 mmol), and 7-bromo-2,2,3,3-tetramethyl-4-oxa-3-silylheptane (2.3 mL, 9.91 mmol) were added. The mixture was heated to 80 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 2.21 g of the product.

[0226] Step 3: Synthesis of (3-((tert-butyldiphenylsilyl)oxy)propoxy)-4,5-dichlorothiophen-2-yl)methanol

[0227] Methyl 3-(3-((tert-butyldiphenylsilyl)oxy)propoxy)-4,5-dichlorothiophene-2-carboxylate (2.00 g, 2.50 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (720 mg, 3.30 mmol) was slowly added in an ice bath, and the mixture was slowly heated to room temperature and reacted for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 1.850 g of the product.

[0228] Step 4: Synthesis of tert-butyl(3-(4,5-dichloro-2-(2,4-difluoro-5-nitrophenoxy)methyl)thiophen-3-yl)oxy)propoxy)dimethylsilane

[0229] (3-((tert-butyldiphenylsilyl)oxy)propoxy)-4,5-dichlorothiophene-2-yl)methanol (1.24 g, 7.11 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and triphenylphosphine (2.54 g, 9.69 mmol) and 2,4-difluoro-5-nitrophenol (962 mg, 3.99 mmol) were added to the reaction solution. Diisopropyl azodicarbonate (1.9 mL, 9.69 mmol) was added under ice bath conditions, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 950 mg of the product.

[0230] Step 5: Synthesis of 2,3-dichloro-10-fluoro-11-nitro-6,7-dihydro-5H,14H-benzo[b]thiopheno[2,3-f][1,4,8]triazolecycloundecene

[0231] Cesium fluoride (760 mg, 2.30 mmol) was added to a solution of tert-butyl(3-(4,5-dichloro-2-(2,4-difluoro-5-nitrophenoxy)methyl)thiophen-3-yl)oxy)propoxy)dimethylsilane (600 mg, 0.52 mmol) in N,N-dimethylformamide (200 mL), and the mixture was incubated overnight at 80 °C. After the reaction was complete, the mixture was poured into water (60 mL), extracted with ethyl acetate (25 mL × 3), and the combined organic phases were washed with saturated brine (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give 230 mg of the product.

[0232] Step 6: Synthesis of 2,3-dichloro-10-fluoro-6,7-dihydro-5H,14H-benzo[b]thiopheno[2,3-f][1,4,8]triazolylcycloundecene-11-amine

[0233] 2,3-Dichloro-10-fluoro-11-nitro-6,7-dihydro-5H,14H-benzo[b]thieno[2,3-f][1,4,8]triazolylcycloundecene (120 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 4,4'-bispyridine (1.6 mg, 0.01 mmol) and bisboronic acid (47 mg, 0.52 mmol) were added in a single batch. The reaction mixture was stirred at 25 °C for 5 minutes. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 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 47 mg of product. The product was used directly in the next reaction without purification.

[0234] LC-MS(ESI): [M+H] + =365.1;

[0235] Step 7: Synthesis of dimethyl 4-(3-(2,3-dichloro-10-fluoro-6,7-dihydro-5H,14H-benzo[b]thiopheno[2,3-f][1,4,8]triazolylcycloundecen-11-yl)thioureo)thiophene-2,3-dicarboxylic acid ester

[0236] 2,2,12-trifluoro-8,9-dihydro-7H,16H-[1,3]dioxane[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolium-13-undecene-13-amine (40 mg, 0.2 mmol) was dissolved in tetrahydrofuran (1 mL), and then 4-((phenylthiocarbonyl)amino)thiophene-2,3-dicarboxylic acid dimethyl ester (78.3 mg, 0.25 mmol) and triethylamine (0.1 mL, 0.39 mmol) were added. The reaction mixture was stirred at 70 °C for 4 hours. After the reaction was complete, water (10 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed once with saturated brine (50 mL). The mixture was then dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain 20 mg of the product.

[0237] LC-MS(ESI): [M+H] + =622.1;

[0238] Step 8: Synthesis of 3-(2,3-dichloro-10-fluoro-6,7-dihydro-5H,14H-benzo[b]thieno[2,3-f][1,4,8]triazolylcycloundecen-11-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0239] Dimethyl 4-(3-(2,3-dichloro-10-fluoro-6,7-dihydro-5H,14H-benzo[b]thieno[2,3-f][1,4,8]triazolylcycloundecen-11-yl)thioureo)thiophene-2,3-dicarboxylic acid (20 mg, 0.1 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (5.7 mg, 0.25 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 °C for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (50 mL), filtered, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 10 mg of the product.

[0240] LC-MS(ESI): [M+H] + = 576.1;

[0241] 1 H NMR(500 MHz, DMSO-d6) δ ppm 13.51(s, 1H), 7.52(s, 1H), 7.20(dd, J= 17.8, 9.2 Hz, 2H), 5.28(d, J = 123.5 Hz, 2H), 4.47(s, 2H), 4.23(s, 2H),2.10(s, 2H).

[0242] Example 7 Synthesis of 3-(2,3-dichloro-6,6,10-trifluoro-6,7-dihydro-5H,14H-benzo[b]thieno[2,3-f][1,4,8]triazolylcycloundecen-11-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 7)

[0243]

[0244] Step 1: Synthesis of methyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate

[0245] Methyl 3-hydroxythiophene-2-carboxylate (7 g, 44.26 mmol) was dissolved in acetic acid (35 mL), and N-chlorosuccinimide (15.36 g, 115.07 mmol) was slowly added. The reaction mixture was reacted at 85 °C for 5 hours. Water (50 mL) and ethyl acetate (60 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 3.12 g of the final product.

[0246] Step 2: Synthesis of methyl 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)-4,5-dichlorothiophene-2-carboxylate

[0247] Methyl 4,5-dichloro-3-hydroxythiophene-2-carboxylate (1.8 g, 6.61 mmol) was dissolved in N,N-dimethylformamide (15 mL). Potassium carbonate (2.31 g, 13.21 mmol), sodium iodide (0.25 g, 1.32 mmol), and 6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silanoheptane-7-yltrifluoromethanesulfonate (2.3 mL, 9.91 mmol) were added to the solution. The mixture was heated to 80 °C for 12 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 2.32 g of the product.

[0248] Step 3: Synthesis of (3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)-4,5-dichlorothiophen-2-yl)methanol

[0249] Methyl 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)-4,5-dichlorothiophene-2-carboxylate (2.21 g, 2.50 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (683 mg, 3.30 mmol) was slowly added in an ice bath, and the mixture was slowly heated to room temperature and reacted for 1 hour. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 1.73 g of the product.

[0250] Step 4: Synthesis of tert-butyl(3-(4,5-dichloro-2-(2,4-difluoro-5-nitrophenoxy)methyl)thiophen-3-yl)oxy)-2,2-difluoropropoxy)dimethylsilane

[0251] (3-((tert-butyldiphenylsilyl)oxy)propoxy)-4,5-dichlorothiophene-2-yl)methanol (0.80 g, 7.11 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and triphenylphosphine (2.03 g, 9.69 mmol) and 2,4-difluoro-5-nitrophenol (662 mg, 3.99 mmol) were added to the reaction solution under ice bath conditions. Diisopropyl azodicarbonate (1.4 mL, 9.69 mmol) was then added, and the reaction was carried out overnight at room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give 630 mg of the product.

[0252] Step 5: Synthesis of 2,3-dichloro-6,6,10-trifluoro-11-nitro-6,7-dihydro-5H,14H-benzo[b]thiopheno[2,3-f][1,4,8]triazolecycloundecene

[0253] Cesium fluoride (672 mg, 2.30 mmol) was added to a solution of tert-butyl(3-(4,5-dichloro-2-(2,4-difluoro-5-nitrophenoxy)methyl)thiophen-3-yl)oxy)-2,2-difluoropropoxy)dimethylsilane (600 mg, 0.52 mmol) in N,N-dimethylformamide (200 mL), and the mixture was incubated overnight at 80 °C. The reaction mixture was then poured into water (30 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed once with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give 223 mg of the product.

[0254] Step 6: Synthesis of 2,3-dichloro-6,6,10-trifluoro-6,7-dihydro-5H,14H-benzothiopheno[2,3-f][1,4,8]triazolylcycloundecene-11-amine

[0255] 2,3-Dichloro-10-fluoro-11-nitro-6,7-dihydro-5H,14H-benzo[b]thieno[2,3-f][1,4,8]triazolylcycloundecene (220 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 4,4'-bispyridine (2 mg, 0.01 mmol) and bisboronic acid (77 mg, 0.52 mmol) were added in a single batch. The reaction mixture was stirred at 25 °C for 5 minutes. Water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2 times). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give 85 mg of the product. The product was used directly in the next reaction without purification.

[0256] LC-MS(ESI): [M+H] + =401.1;

[0257] Step 7: Synthesis of dimethyl 4-(3-(2,3-dichloro-6,6,10-trifluoro-6,7-dihydro-5H,14H-benzo[b]thiopheno[2,3-f][1,4,8]triazolylcycloundecene-11-yl)thioureo)thiophene-2,3-dicarboxylic acid ester

[0258] 2,3-Dichloro-6,6,10-trifluoro-6,7-dihydro-5H,14H-benzothieno[2,3-f][1,4,8]triazolium cycloundecene-11-amine (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (1 mL), and dimethyl 4-((phenylthiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (156 mg, 0.25 mmol) and triethylamine (0.1 mL, 0.39 mmol) were added. The reaction mixture was stirred at 70 °C for 4 hours. After cooling, water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed once with saturated brine (50 mL), 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 30 mg of the product.

[0259] LC-MS(ESI): [M+H] + =658.1;

[0260] Step 8: Synthesis of 3-(2,3-dichloro-6,6,10-trifluoro-6,7-dihydro-5H,14H-benzo[b]thieno[2,3-f][1,4,8]triazolylcycloundecen-11-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0261] Dimethyl 4-(3-(2,3-dichloro-6,6,10-trifluoro-6,7-dihydro-5H,14H-benzo[b]thieno[2,3-f][1,4,8]triazolylcycloundecen-11-yl)thioureo)thiophene-2,3-dicarboxylic acid (20 mg, 0.1 mmol)) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (6 mg, 0.25 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 °C for 1 hour. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (50 mL), filtered, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 8 mg of the product.

[0262] LC-MS(ESI): [M+H] + = 612.1;

[0263] 1 H NMR(500 MHz, DMSO-d6) δ ppm 13.75(s, 1H), 7.50(s, 1H), 7.39(d, J =10.5 Hz, 1H), 7.30(d, J = 7.3 Hz, 1H), 5.18(s, 2H), 4.73 – 4.47(m, 4H).

[0264] Example 8 Synthesis of 2,4-dioxo-3-(3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolcycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 8)

[0265]

[0266] Step 1: Ethyl 3-hydroxybenzothiophene-2-carboxylate

[0267] Methyl 2-(mercaptomethyl)benzoate (1.00 g, 5.94 mmol) and ethyl bromoacetate (0.7 mL, 5.94 mmol) were added to 15 mL of dry tetrahydrofuran at 0 °C. Potassium tert-butoxide (4.02 g, 35.67 mmol) was slowly added, and the mixture was heated to room temperature for 15 minutes. Water (50 mL) and ethyl acetate (60 mL) were added to the reaction mixture. After separation, the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried, and then evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 1321 mg of the product.

[0268] Step 2: Synthesis of ethyl 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)benzothiophene-2-carboxylate

[0269] Ethyl 3-hydroxybenzothiophene-2-carboxylate (1.1 g, 6.61 mmol) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (0.69 g, 13.21 mmol), sodium iodide (0.25 g, 1.32 mmol), and 6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silanoheptane-7-yltrifluoromethanesulfonate (2.3 mL, 9.91 mmol) were added. The mixture was heated to 80 °C for 12 hours under a nitrogen atmosphere. Water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 1.52 g of the product.

[0270] Step 3: Synthesis of (3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)benzothiophene-2-yl)methanol

[0271] Ethyl 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)benzothiophene-2-carboxylate (1.41 g, 2.50 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (732 mg, 3.30 mmol) was slowly added in an ice bath, and the mixture was slowly heated to room temperature and reacted for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 610 mg of the product.

[0272] Step 4: Synthesis of tert-butyl(3-((2-(2,4-difluoro-5-nitrophenoxy)methyl)benzothiophene-3-yl)oxy)-2,2-difluoropropoxy)dimethylsilane

[0273] (3-((tert-butyldiphenylsilyl)oxy)propoxy)-4,5-dichlorothiophene-2-yl)methanol (0.80 g, 7.11 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and triphenylphosphine (2.03 g, 9.69 mmol) and 2,4-difluoro-5-nitrophenol (601 mg, 3.99 mmol) were added to the reaction solution under ice bath conditions. Diisopropyl azodicarbonate (1.4 mL, 9.69 mmol) was added, and the reaction was carried out overnight at room temperature. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give 300 mg of product.

[0274] Step 5: Synthesis of 3,7,7-trifluoro-2-nitro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolecycloundecene

[0275] Cesium fluoride (472 mg, 2.30 mmol) was added to a solution of tert-butyl(3-((2-(2,4-difluoro-5-nitrophenoxy)methyl)benzothiophene-3-yl)oxy)-2,2-difluoropropoxy)dimethylsilane (300 mg, 0.52 mmol) in N,N-dimethylformamide (20 mL), and the mixture was incubated overnight at 80 °C. The reaction mixture was then poured into water (100 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give 130 mg of the product.

[0276] Step 6: Synthesis of 3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecene-2-amine

[0277] 3,7,7-trifluoro-2-nitro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecene (130 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 4,4'-bispyridine (4 mg, 0.01 mmol) and bisboronic acid (37 mg, 0.13 mmol) were added in a single batch. The reaction mixture was stirred at 25 °C for 5 minutes. Water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). 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 evaporated to dryness to obtain 85 mg of product. The product was used directly in the next reaction without purification.

[0278] LC-MS(ESI): [M+H] + =382.1;

[0279] Step 7: Synthesis of dimethyl 4-(3-(3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecen-2-yl)ureo)thiophene-2,3-dicarboxylate

[0280] 3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecene-2-amine (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (1 mL), followed by the addition of dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (156 mg, 0.25 mmol) and triethylamine (0.1 mL, 0.39 mmol). The reaction mixture was stirred at 70 °C for 4 hours. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed once with saturated brine (50 mL), 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 (petroleum ether: ethyl acetate = 6:1) to give 35 mg of the product.

[0281] LC-MS(ESI): [M+H] + =623.1;

[0282] Step 8: Synthesis of 2,4-dioxo-3-(3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolcycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0283] Dimethyl 4-(3-(3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecen-2-yl)ureo)thiophene-2,3-dicarboxylic acid (35 mg, 0.1 mmol)) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (5.7 mg, 0.25 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (50 mL), filtered, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 12 mg of the product.

[0284] LC-MS(ESI): [M+H] + =577.1;

[0285] 1 H NMR(500 MHz, DMSO-d6) δ ppm 14.43(s, 1H), 11.98(s, 1H), 7.95(s,2H), 7.72 – 7.25(m, 4H), 6.71(s, 1H), 5.37(s, 2H), 4.77(s, 4H).

[0286] Example 9 Synthesis of 4-oxo-2-thio-3-(7,7,11-trifluoro-1,7,8,15-tetrahydro-2H,6Hbenzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 9)

[0287]

[0288] Step 1: Synthesis of bicyclo[4.2.0]oct-1,3,5-trien-3-ol

[0289] 4-Bromo-1,2-dihydrocyclobutane[1,2-a]benzene (25 g, 136.57 mmol) was dissolved in 1,4-dioxane (60 mL) and water (240 mL). Tris(dibenzylacetone)dipalladium (2.50 g, 2.73 mmol), [bis(2-methylpropyl-2-yl)]{2,3,4,5-tetramethyl-6-[2,4,6-tris(propyl-2-ylphenyl)phenyl]phenyl}phosphine (2.63 g, 5.46 mmol) and potassium hydroxide (15.33 g, 273.15 mmol) were added under nitrogen atmosphere and the mixture was stirred overnight at 80 °C under nitrogen protection. Water (1000 mL) and ethyl acetate (600 mL) were added to the reaction solution. After separation, the aqueous phase was extracted with ethyl acetate (300 mL × 2). The organic phases were combined, washed with brine, dried, and then evaporated to dryness to obtain the crude product. The product was purified by silica gel column chromatography to obtain 14.2 g.

[0290] Step 2: Synthesis of 4-bromobicyclo[4.2.0]oct-1,3,5-trien-3-ol

[0291] Bicyclo[4.2.0]octyl-1,3,5-trien-3-ol (14 g, 116.52 mmol) was dissolved in N,N-dimethylformamide (280 mL), and N-succinimide bromide (20.74 g, 116.52 mmol) was added in portions at -5 °C, and the reaction was carried out at this temperature for 12 hours. Water (800 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (500 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 11.2 g of the product.

[0292] Step 3: Synthesis of 4-bromo-3-hydroxybicyclo[4.2.0]octa-1,3,5-triene-2-carboxaldehyde

[0293] 4-Bromobicyclo[4.2.0]oct-1,3,5-trien-3-ol (11 g, 55.26 mmol) was dissolved in acetonitrile (50 mL), and magnesium chloride (12.44 g, 130.62 mmol) and triethylamine (45.5 mL, 326.55 mmol) were added. The mixture was heated at 40 °C for 1 hour under nitrogen protection. Then, paraformaldehyde (3.95 g, 131.60 mmol) was added to the system, and the mixture was reacted at 80 °C overnight under nitrogen protection. Water (500 mL) was added to the reaction mixture, and the solution was adjusted to acidity with hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (500 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 7.80 g of the product.

[0294] Step 4: Synthesis of 4-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)bicyclo[4.2.0]octa-1,3,5-triene-2-carboxaldehyde

[0295] 4-Bromo-3-hydroxybicyclo[4.2.0]octa-1,3,5-trien-2-carboxaldehyde (2.4 g, 6.61 mmol) was dissolved in N,N-dimethylformamide (25 mL), and potassium carbonate (3.23 g, 13.21 mmol), sodium iodide (1.25 g, 1.32 mmol), and 6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silanoheptane-7-yltrifluoromethanesulfonate (5.12 g, 9.91 mmol) were added. The mixture was heated to 80 °C for 12 hours under a nitrogen atmosphere. After cooling, water (250 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 2.83 g of the product.

[0296] Step 5: Synthesis of (4-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)methanol

[0297] 4-Bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)bicyclo[4.2.0]octa-1,3,5-trien-2-carboxaldehyde (2.41 g, 2.50 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and sodium borohydride (932 mg, 3.30 mmol) was slowly added in an ice bath. The mixture was slowly heated to room temperature and reacted for 1 hour. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 1.89 g of the product.

[0298] Step 6: Synthesis of (3-((4-bromo-2-(2,4-difluoro-5-nitrophenoxy)methyl)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)oxy)-2,2-difluoropropoxy)(tert-butyl)dimethylsilane

[0299] (4-Bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)methanol (1.80 g, 7.11 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and triphenylphosphine (1.40 g, 9.69 mmol) and 2,4-difluoro-5-nitrophenol (601 mg, 3.99 mmol) were added to the reaction solution. Diisopropyl azodicarbonate (1.4 mL, 9.69 mmol) was added under ice bath conditions, and the reaction was carried out overnight at room temperature. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 1.12 g of the product.

[0300] Step 7: Synthesis of 4-bromo-7,7,11-trifluoro-12-nitro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene

[0301] Cesium fluoride (3.21 mg, 1.30 mmol) was added to a solution of (3-((4-bromo-2-(2,4-difluoro-5-nitrophenoxy)methyl)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)oxy)-2,2-difluoropropoxy)(tert-butyl)dimethylsilane (1.12 g, 0.25 mmol) in N,N-dimethylformamide (100 mL), and the mixture was incubated overnight at 80 °C. The reaction mixture was then poured into water (300 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give 420 mg of the product.

[0302] Step 8: Synthesis of 4-bromo-7,7,11-trifluoro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene-12-amine

[0303] 3,7,7-trifluoro-2-nitro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecene (830 mg, 0.13 mmol) was dissolved in ethyl acetate (10 mL), and palladium on carbon (200 mg) was added in a single batch. The mixture was stirred overnight under a hydrogen atmosphere. The reaction solution was filtered and evaporated to dryness to give 800 mg of the product, which was used directly in the next step of the reaction without purification.

[0304] LC-MS(ESI): [M+H] + =431.1;

[0305] Step 9: Synthesis of 7,7,11-trifluoro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene-12-amine

[0306] 4-Bromo-7,7,11-trifluoro-1,7,8,15-tetrahydro-2H,6Hbenzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene-12-amine (800 mg, 3.61 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and butyllithium (565 mg, 18.04 mmol) was added at -78 °C. The reaction was carried out at -78 °C for 1 h under nitrogen protection. Water (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed once with saturated brine (50 mL), then dried over anhydrous sodium sulfate. The solution was filtered and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to give 535 mg of the product.

[0307] LC-MS(ESI): [M+H] + =352.1;

[0308] Step 10: Synthesis of dimethyl 4-(3-(7,7,11-trifluoro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolylcycloundecene-12-yl)thioureo)thiophene-2,3-dicarboxylic acid ester

[0309] 7,7,11-trifluoro-1,7,8,15-tetrahydro-2H,6Hbenzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene-12-amine (200 mg, 0.2 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of dimethyl 4-((phenylthiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (2.04 g, 0.25 mmol) and triethylamine (0.1 mL, 0.39 mmol). The reaction mixture was stirred at 70 °C for 4 hours. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed once with saturated brine (50 mL), 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 (petroleum ether: ethyl acetate = 1:1) to give 200 mg of the product.

[0310] LC-MS(ESI): [M+H] +=609.1;

[0311] Step 11: Synthesis of 4-oxo-2-thio-3-(7,7,11-trifluoro-1,7,8,15-tetrahydro-2H,6Hbenzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0312] Dimethyl 4-(3-(7,7,11-trifluoro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolylcycloundecen-12-yl)thioureo)thiophene-2,3-dicarboxylic acid (200 mg, 0.3 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide monohydrate (82 mg, 1.2 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (50 mL), filtered, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 60 mg of the product.

[0313] LC-MS(ESI): [M+H] + =563.1;

[0314] 1 H NMR(500 MHz, DMSO-d6) δ ppm 14.18(s, 1H), 13.51(s, 1H), 7.54(s,1H), 7.45(d, J = 7.5 Hz, 1H), 7.27(d, J = 10.6 Hz, 1H), 7.13(d, J = 7.9 Hz, 1H), 7.06(d, J = 7.9 Hz, 1H), 5.07(t, J = 7.1 Hz, 2H), 4.58 – 4.48(m, 4H), 3.13(dd, J = 10.4, 3.9 Hz, 2H), 3.04(d, J = 3.6 Hz, 2H).

[0315] Example 10 Synthesis of 4-oxo-2-thio-3-(3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolcycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 10)

[0316]

[0317] Step 1: Synthesis of ethyl 3-hydroxybenzothiophene-2-carboxylate

[0318] A solution of methyl 2-(mercaptomethyl)benzoate (1.00 g, 5.94 mmol) and ethyl bromoacetate (0.7 mL, 5.94 mmol) was added to 15 mL of dry tetrahydrofuran at 0 °C. Potassium tert-butoxide (4.00 g, 35.67 mmol) was gradually added. The reaction mixture was stirred, heated to room temperature, and reacted for 15 minutes. Water (50 mL) and ethyl acetate (60 mL) were added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (30 mL × 3). 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 1.32 g of the product.

[0319] Step 2: Synthesis of ethyl 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)benzothiophene-2-carboxylate

[0320] Ethyl 3-hydroxybenzothiophene-2-carboxylate (1.1 g, 6.61 mmol) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (0.69 g, 13.21 mmol), sodium iodide (0.25 g, 1.32 mmol), and 6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silanoheptane-7-yltrifluoromethanesulfonate (2.3 mL, 9.91 mmol) were added. The mixture was heated to 80 °C for 12 hours under a nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 1.51 g of the product.

[0321] Step 3: Synthesis of (3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)benzothiophene-2-yl)methanol

[0322] Ethyl 3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)benzothiophene-2-carboxylate (1.41 g, 2.50 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (732 mg, 3.30 mmol) was slowly added in an ice bath, and the mixture was slowly heated to room temperature and reacted for 1 hour. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 810 mg of the product.

[0323] Step 4: Synthesis of tert-butyl(3-((2-(2,4-difluoro-5-nitrophenoxy)methyl)benzothiophene-3-yl)oxy)-2,2-difluoropropoxy)dimethylsilane

[0324] (3-((tert-butyldiphenylsilyl)oxy)propoxy)-4,5-dichlorothiophene-2-yl)methanol (0.80 g, 7.11 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and triphenylphosphine (2.03 g, 9.69 mmol) and 2,4-difluoro-5-nitrophenol (601 mg, 3.99 mmol) were added to the reaction solution under ice bath conditions. The reaction was allowed to proceed overnight at room temperature. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 300 mg of the product.

[0325] Step 5: Synthesis of 3,7,7-trifluoro-2-nitro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolecycloundecene

[0326] Cesium fluoride (472 mg, 1.30 mmol) was added to a solution of tert-butyl(3-((2-(2,4-difluoro-5-nitrophenoxy)methyl)benzothiophene-3-yl)oxy)-2,2-difluoropropoxy)dimethylsilane (300 mg, 0.52 mmol) in N,N-dimethylformamide (200 mL), and the reaction was carried out overnight at 80 °C. After the reaction was complete, the reaction mixture was poured into water (300 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to give 130 mg of the product.

[0327] Step 6: Synthesis of 3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecene-2-amine

[0328] 3,7,7-trifluoro-2-nitro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecene (130 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 4,4'-bispyridine (4 mg, 0.04 mmol) and bisboronic acid (37 mg, 0.52 mmol) were added in one step. The reaction mixture was stirred at 25 °C for 5 minutes. Water (60 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to obtain 85 mg of the product, which was used directly in the next reaction without purification.

[0329] LC-MS(ESI): [M+H] + =382.1;

[0330] Step 7: Synthesis of dimethyl 4-(3-(3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecen-2-yl)thioureo)thiophene-2,3-dicarboxylate

[0331] 3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecene-2-amine (160 mg, 0.2 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of dimethyl 4-((phenylthiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (313 mg, 0.25 mmol) and triethylamine (0.1 mL, 0.39 mmol). The reaction mixture was stirred at 70 °C for 4 hours. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. Purification by silica gel column chromatography yielded 200 mg of the product.

[0332] LC-MS (ESI): [M+Na] + =607.1;

[0333] Step 8: Synthesis of 4-oxo-2-thio-3-(3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolcycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0334] Dimethyl 4-(3-(3,7,7-trifluoro-7,8-dihydro-6H,15H-benzo[b]benzo[4,5]thieno[2,3-f][1,4,8]triazolylcycloundecen-2-yl)thioureo)thiophene-2,3-dicarboxylic acid (35 mg, 0.1 mmol)) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (5.7 mg, 0.25 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 3 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (50 mL), filtered, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 10 mg of the product.

[0335] LC-MS(ESI): [M+H] + =593.1;

[0336] 1 H NMR(500 MHz, DMSO-d6) δ ppm 13.61(s, 1H), 8.01 – 7.91(m, 2H), 7.54– 7.43(m,3H), 7.36(dd, J = 9.0, 6.2 Hz, 2H), 5.38(d, J = 5.3 Hz, 2H), 4.88 –4.57(m, 4H).

[0337] Example 11 Synthesis of 3-(12-fluoro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecen-13-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 11)

[0338]

[0339] Step 1: Synthesis of benzo[d][1,3]dioxanol-5-ol

[0340] 5-Bromobenzo[d][1,3]dioxane (3 g, 17.33 mmol) was dissolved in water (30 mL) and 1,4-dioxane (30 mL) and cooled. Tris(dibenzylacetone)dipalladium(0) (0.58 g, 0.63 mmol), 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (0.61 g, 1.27 mmol), and potassium hydroxide (1.42 g, 25.32 mmol) were added under a nitrogen atmosphere and stirred at 80 °C for 5 hours. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (50 mL × 5), and the combined organic phases were washed with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Purification by silica gel column chromatography yielded 2.20 g of the product.

[0341] Step 2: Synthesis of 3-(benzo[d][1,3]dioxo-5-yloxy)propoxy)(tert-butyl)dimethylsilane

[0342] Benzo[d][1,3]dioxanol-5-ol (2.06 g, 5.66 mmol), (3-bromopropoxy)(tert-butyl)dimethylsilane (4.2 g, 12.64 mmol), potassium carbonate (6.49 g, 25.27 mmol), and sodium iodide (0.1 mL, 2.53 mmol) were added to a 50 mL single-necked flask, followed by the addition of N,N-dimethylformamide (40 mL). The mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 2 hours. The reaction mixture was then poured into 400 mL of water and extracted with ethyl acetate (500 mL × 5). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to give 1.50 g of the product.

[0343] Step 3: Synthesis of 5-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzo[d][1,3]dioxo-4-carboxaldehyde

[0344] 1.42 g (6.06 mmol) of tert-butyl(3-((2,2-difluorobenzo[d][1,3]dihydroxy-5-yl)oxy)propoxy)dimethylsilane was dissolved in anhydrous tetrahydrofuran (25 mL), followed by the addition of 1.8 mL (12.12 mmol) of 2,5-dimethyl-2,5-diazahexane, and then slowly added to n-butyllithium (1.3 mL, 9.09 mmol) below -60°C. After half an hour, 0.6 mL (7.88 mmol) of N,N-dimethylformamide was added, and the mixture was stirred for 40 minutes. Upon completion of the reaction, 2 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The reaction system was then poured into water (300 mL), extracted with ethyl acetate (50 mL × 5), the combined organic phases were washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 750 mg of the product.

[0345] Step 4: Synthesis of (5-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzo[d][1,3]dioxanol-4-yl)methanol

[0346] A solution of sodium borohydride (118 mg, 2.65 mmol) in water (1 mL) was added to a tetrahydrofuran (10 mL) solution of 5-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzo[d][1,3]dioxo-4-carboxaldehyde (600 mg, 2.05 mmol), and the mixture was reacted at 0°C for 10 minutes. After the reaction was complete, the mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain 520 mg of crude product, which was used directly in the next reaction without purification.

[0347] Step 5: Synthesis of tert-butyl(3-((4-(2,4-difluoro-5-nitrophenoxy)methyl)benzo[d][1,3]dioxanol-5-yl)oxy)propoxy)dimethylsilane

[0348] To a solution of (300 mg, 0.87 mmol) methanol (300 mg, 240 mg, 1.195 mmol) and 2,4-difluoro-5-nitrophenol (153 mg, 0.87 mmol) in tetrahydrofuran (3 mL), diisopropyl azodicarbonate (240 mg, 1.195 mmol) and triphenylphosphine (314 mg, 1.195 mmol) were added, and the mixture was reacted at 25 °C for 3 h. The reaction mixture was then poured into water (60 mL), extracted with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography to give 200 mg of the product.

[0349] Step 6: Synthesis of 3-((4-(2,4-difluoro-5-nitrophenoxy)methyl)benzo[d][1,3]dioxanol-5-yl)oxy)prop-1-ol

[0350] The compound tert-butyl(3-((4-((2,4-difluoro-5-nitrophenoxy)methyl)-2,2-difluorobenzo[d][1,3]dioxane-5-yl)oxy)propoxy)dimethylsilane (160 mg, 0.29 mmol) was dissolved in methanol (1 mL), and hydrochloric acid / dioxane (4 M, 2 mL) was added under ice bath conditions. The reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to obtain 80 mg of crude product, which was used directly in the next step of the reaction without purification.

[0351] Step 7: Synthesis of 12-fluoro-13-nitro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolecycloundecene

[0352] Cesium fluoride (160 mg, 1.30 mmol) was added to a solution of 3-((4-((2,4-difluoro-5-nitrophenoxy)methyl)-2,2-difluorobenzo[d][1,3]dioxane)oxy)prop-1-ol (80 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL), and the mixture was reacted overnight at 80 °C. After the reaction was complete, the mixture was poured into water (30 mL), extracted with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography to give 20 mg of the product.

[0353] Step 8: Synthesis of 12-fluoro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene-13-amine

[0354] 12-Fluoro-13-nitro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene (20 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 4,4'-bispyridine (2 mg, 0.03 mmol) and bisboronic acid (14 mg, 0.64 mmol) were added in one step. The reaction mixture was stirred at 25 °C for 5 minutes. Water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2 times). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give 21.5 mg of the product, which was used directly in the next reaction without purification.

[0355] LC-MS(ESI): [M+H] + =334.3;

[0356] Step 9: Synthesis of dimethyl 4-(3-(12-fluoro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene-13-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0357] 12-Fluoro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene-13-amine (20 mg, 0.1 mmol) was dissolved in tetrahydrofuran (1 mL), followed by the addition of dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (18 mg, 0.11 mmol) and triethylamine (0.1 mL, 0.39 mmol). The reaction mixture was stirred at 70 °C for 4 hours. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL), 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 10 mg of the product.

[0358] LC-MS(ESI): [M+1] + =575.5;

[0359] Step 10: Synthesis of 3-(12-fluoro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecen-13-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid

[0360] Dimethyl 4-(3-(12-fluoro-8,9-dihydro-7H,16H-[1,3]dioxo[4',5':5,6]benzo[1,2-f]benzo[b][1,4,8]triazolylcycloundecene-13-yl)ureo)thiophene-2,3-dicarboxylic acid (15 mg, 0.1 mmol)) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (6 mg, 0.25 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 7 with hydrochloric acid (1 M). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (20 mL), filtered, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 2 mg of product.

[0361] LC-MS(ESI): [M+H] + = 529.1;

[0362] 1 H NMR(500 MHz, DMSO-d6) δ ppm 11.46(s, 1H), 9.37(s, 1H), 7.17(d, J =7.8 Hz, 1H), 7.10(d, J = 11.4 Hz, 1H), 7.03(d, J = 10.5 Hz, 1H), 6.97(d, J =7.1 Hz, 1H), 6.81(d, J = 8.5 Hz, 1H), 5.98(d, J = 11.7 Hz, 2H), 5.03(s, 2H), 4.32(s, 2H), 4.27(s, 2H), 1.99(s, 2H).

[0363] Example 12 Synthesis of 3-(11-fluoro-1,7,8,15-tetrahydro-2H,6Hbenzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 12)

[0364]

[0365] Step 1: Synthesis of 4-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)bicyclo[4.2.0]octa-1,3,5-trien-2-carboxaldehyde

[0366] Potassium carbonate (890 mg, 6.44 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)prop-1-ol (1.5 mL, 6.43 mmol), 4-bromo-3-hydroxybicyclo[4.2.0]octa-1,3,5-trien-2-carboxaldehyde (730 mg, 3.22 mmol) in N,N-dimethylformamide (10 mL), and the mixture was heated at 80 °C overnight. After cooling, the mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give 1.19 g of the product.

[0367] Step 2: Synthesis of (4-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)methanol

[0368] 4-Bromo-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)bicyclo[4.2.0]octa-1,3,5-trien-2-carboxaldehyde (1.19 g, 2.98 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). Sodium borohydride (0.23 g, 5.96 mmol) was added under ice-water bath, and the reaction was carried out at room temperature for 1 hour. TLC monitoring showed that the starting material disappeared. After concentration, the solution was diluted with dichloromethane and separated by silica gel column chromatography to obtain 980 mg of the product.

[0369] Step 3: Synthesis of (3-((4-bromo-2-(2,4-difluoro-5-nitrophenoxy)methyl)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)oxy)propoxy)(tert-butyl)dimethylsilane

[0370] 2,4-Difluoro-5-nitrophenol (513 mg, 2.93 mmol) and (4-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)methanol (980 mg, 2.44 mmol) were dissolved in tetrahydrofuran (10 mL), followed by the addition of triphenylphosphine (961 mg, 3.66 mmol) and diisopropyl azodicarbonate (725.5 μL, 3.66 mmol). The mixture was reacted overnight at room temperature. TLC monitoring showed the formation of new spots. After dilution with ethyl acetate (100 mL), the mixture was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to yield 911 mg of the product.

[0371] 1 H NMR (500 MHz, CDCl3) δ 7.80 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 10.6Hz, 2H), 7.07 (t, J = 10.0 Hz, 1H), 5.21 (s, 2H), 4.06 (t, J = 6.4 Hz, 2H), 3.85 (t, J = 6.1 Hz, 2H), 3.13 (d, J = 1.4 Hz, 4H), 2.04 (p, J = 6.2 Hz, 2H), 0.86 (s, 9H).

[0372] Step 4: Synthesis of 4-bromo-11-fluoro-12-nitro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene

[0373] (3-((4-bromo-2-(2,4-difluoro-5-nitrophenoxy)methyl)bicyclo[4.2.0]octa-1,3,5-trien-3-yl)oxy)propoxy)(tert-butyl)dimethylsilane (911 mg, 1.63 mmol) was dissolved in N,N-dimethylformamide (90 mL), and cesium fluoride (2478 mg, 16.31 mmol) was added. The reaction was carried out overnight at 80 °C under nitrogen protection. TLC monitoring showed complete conversion of the starting material. After cooling, the product was diluted with ethyl acetate (800 mL), washed successively with water (200 mL × 3), saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 345 mg of the product.

[0374] 1 H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 4.8Hz, 2H), 6.97 (d, J = 11.3 Hz, 1H), 5.02 (s, 2H), 4.42 (t, J = 5.1 Hz, 2H), 4.26 (t, J = 5.1 Hz, 2H), 3.18 (d, J = 6.0 Hz, 4H), 2.23 – 2.14 (m, 2H).

[0375] Step 5: Synthesis of 4-bromo-11-fluoro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene-12-amine

[0376] 4-Bromo-11-fluoro-12-nitro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene (341 mg, 0.80 mmol) was dissolved in tetrahydrofuran (10 mL) and ethyl acetate (10 mL), and 5% palladium / carbon (75 mg, 0.70 mmol) was added. The mixture was hydrogenated overnight at room temperature. The solution was filtered through diatomaceous earth to obtain 286 mg of crude product, which was used directly in the next reaction without purification.

[0377] LC-MS(ESI): [M+H] + =394.1;

[0378] Step 6: 11-Fluoro-1,7,8,15-Tetrahydro-2H,6HBenz[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene-12-amine

[0379] 4-Bromo-11-fluoro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene-12-amine (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1 mL), and NBuLi (252 μL, 0.63 mmol) was added at -78 °C. After reacting for 30 minutes, the reaction was quenched with saturated ammonium chloride solution. After extraction with ethyl acetate (10 mL × 3), the product was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 20 mg of the product.

[0380] LC-MS(ESI): [M+H] + =316.3;

[0381] Step 7: 4-(3-(11-fluoro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolylcycloundecene-12-yl)thioureo)thiophene-2,3-dicarboxylic acid dimethyl ester

[0382] 11-Fluoro-1,7,8,15-tetrahydro-2H,6Hbenzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolecycloundecene-12-amine (20 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1.5 mL), and 4-((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylic acid dimethyl ester (25 mg, 0.07 mmol) and triethylamine (26.4 μL, 0.19 mmol) were added. The mixture was heated at 70 °C for 3 hours. After cooling, the mixture was concentrated and separated by column chromatography to obtain 20 mg of the product.

[0383] LC-MS(ESI): [M+H] + =573.3;

[0384] Step 8: Synthesis of 3-(11-fluoro-1,7,8,15-tetrahydro-2H,6Hbenzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0385] Dimethyl 4-(3-(11-fluoro-1,7,8,15-tetrahydro-2H,6H-benzo[b]cyclobutane[5,6]benzo[1,2-f][1,4,8]triazolylcycloundecen-12-yl)thioureo)thiophene-2,3-dicarboxylate (20 mg, 0.03 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL), and lithium hydroxide monohydrate (15 mg, 0.36 mmol) in water (0.5 mL) was added. The reaction was carried out at room temperature for 1 hour. LC-MS monitoring showed complete conversion of the starting material. The solution was adjusted to acidity with hydrochloric acid, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, purified by reverse-phase preparative column chromatography, and lyophilized to give 4.0 mg of the product.

[0386] LC-MS(ESI): [M+H] + =527.3;

[0387] 1 H NMR (500 MHz, DMSO-d6) δ 7.50 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 11.2 Hz, 1H), 6.95 (q, J = 7.9 Hz, 2H), 5.04 (s, 2H), 4.38 –4.33 (m, 2H), 4.26 – 4.21 (m, 2H), 3.12 – 3.07 (m, 2H), 3.02 – 2.98 (m, 2H), 2.01 – 1.92 (m, 2H).

[0388] Biological test data

[0389] Experimental Example 1: Determination of the activity of the compounds of the present invention against gonadotropin-releasing hormone (GnRH) receptors

[0390] 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.

[0391] Main reagents, equipment and brands:

[0392] F-12 culture medium – Hyclone

[0393] Fetal Bovine Serum (FBS) — AusGeneX

[0394] Hygromycin B – Solarbio

[0395] DMSO (Dimethyl Sulfoxide) – Sigma

[0396] GnRH-I——GLPBIO

[0397] 0.25% Trypsin-EDTA (trypsin-ethylenediaminetetraacetic acid) solution – Gibco

[0398] IP-One-Gq kit – Cisbio

[0399] Main experimental instruments, brands and models:

[0400] Biosafety Cabinet – ESCO – AC2-6S1-TC

[0401] Carbon dioxide cell incubator – ESCO – CLM-240B-8-TC

[0402] Inverted Microscope – Olympus – CKX53

[0403] HTS High-Throughput Drug Screening Multifunctional Microplate Reader – BMG – PHERAstar FSX

[0404] Low-speed centrifuge – YIDA – TD25M

[0405] Microplate low-speed centrifuge – Xiangzhi – TD5B

[0406] Experimental plan:

[0407] (1) Cell preparation

[0408] 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%.

[0409] (2) Determination of the activity of the test compound against the GnRH receptor

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] Table 1 shows the inhibitory IC50 values ​​of the compounds on human gonadotropin-releasing hormone receptor activity. 50

[0415]

[0416] Results: The compounds of this invention have a significant inhibitory effect on gonadotropin-releasing hormone (GnRH) receptors.

[0417] 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); (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 or S; Y and Z are independently selected from bond, -O-, -S-, -CR7R8- and -C(=O)-, respectively; 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 one, two or three 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, respectively. 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 one, two, or three 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 a 3-6 membered cycloalkyl or a 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl group may be independently and optionally substituted by one, two, or three substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2, and OH; Ring A is selected from C 7-10 Bicyclic aryl, 5-6 membered monocyclic heteroaryl, 7-12 membered bicyclic heteroaryl; Each R9 is independently H, D, F, Cl, Br, I, CN, oxo (=O), 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 or 3-7 membered heterocyclic group may be optionally and independently replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, oxo (=O), OH, COOH, NO2 and NH2; m is 1, 2, 3, 4 or 5; n is 1, 2, or 3.

2. The compound according to claim 1, characterized in that: Ring A is selected from any of the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. The compound according to claim 1, characterized in that: R1 is COOW1, where W1 is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl; R2, R3, and R4 are independently selected from H, D, F, Cl, Br, I, 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; Each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, OH, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group may be independently and optionally substituted by one, two, or three 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 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups may be optionally substituted by one, two, or three substituents selected from H, D, F, Cl, Br, I, NH2, OH, and oxo (=O); Each R9 is independently selected from H, D, F, Cl, Br, I, 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.

4. The compound according to claim 1, characterized in that: R1 is COOH; R2 and R4 are independently H or D; R3 is selected from F, Cl, Br, and I; Each of R5, R6, R7 and R8 is independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl and isopropyl; or R5 and R6, R7 and R8 are optionally formed with the carbon atom they are connected to to form a cyclopropyl group.

5. The compound according to claim 1, characterized in that: The structures of compounds of formula I are shown in formulas I-1 to I-9: (I-1)、 (I-2) (I-3)、 (I-4) (I-5)、 (I-6) (I-7)、 (I-8) （I-9）。 6. 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 .

7. A pharmaceutical composition comprising the compound of any one of claims 1-6; the pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

8. Use of the compound of any one of claims 1-6 or the pharmaceutical composition of claim 7 in the preparation of a medicament for the prevention, treatment or relief of a patient’s GnRH receptor antagonist-mediated disease.

9. The use according to claim 8, 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.

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