Fused heterocycle-substituted thienopyrimidinedione derivative and use thereof

Abstract

Provided are a fused heterocycle-substituted thienopyrimidinedione derivative and a pharmaceutical composition thereof. The compound or the pharmaceutical composition can be used for preventing, treating or alleviating diseases mediated by a GnRH receptor antagonist in a patient, such as endometriosis, uterine myoma, 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.

Description

Fused heterocyclic substituted thiophene-pyrimidine dione derivatives and their applications

[0001] This application claims the following priority:

[0002] CN202510355737.3, 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 suppressing the release of LH and FSH. However, peptide compounds have issues related to oral absorption, dosage form, dose-volume relationship, drug stability, duration of action, and metabolic stability. Small molecule GnRH receptor antagonists offer advantages such as convenient and rapid oral administration and fewer side effects. Studies have shown that small molecule antagonists have significant therapeutic effects on hormone-dependent diseases such as endometriosis, uterine fibroids, precocious puberty, and prostate cancer.

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

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

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

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

[0010] in:

[0011] L1, L2, L3, and L4 are independently selected from the following: -O-, -S-, and -(CR5R6), respectively. n -;

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

[0013] A1 is either CR4 or N;

[0014] Y and Z are independently selected from bond, -O-, -S-, -S(=O)-, -SO2-, -CR7R8- and -C(=O)-, respectively;

[0015] R1 is C(=O)OW1, C(=O)NW2W3 or S(=O)2W4, where W1, W2, W3 and W4 are independently selected from H, D, and C respectively. 1-6 Alkyl, C 3-8cycloalkyl and C 6-10 Aryl;

[0016] R2, R3, and R4 are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, NO2, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH and NO2;

[0017] 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 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, oxo (=O), CN, NH2 and OH; or R5 and R6, R7 and R8 may be optionally substituted with the carbon atom they are connected to to form a 3-6 membered cycloalkyl group or a 3-7 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group and the 3-7 membered heterocyclic group may be independently and optionally substituted by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2 and OH;

[0018] Each R9 is independently H, D, F, Cl, Br, I, CN, OH, COOH, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 alkylthio group or 3-7 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The alkylthio group and the 3-7 membered heterocyclic group can be optionally and independently replaced by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, CN, oxo (=O), OH, COOH, NO2 and NH2;

[0019] R 10 For H, D, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6The alkoxy group can be independently and optionally replaced by one, two or three substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH, NO2;

[0020] m can be 1, 2, 3, or 4;

[0021] n is 1, 2, or 3;

[0022] Wherein, formula (I) is not one of the following compounds:

[0023] In some embodiments, it is a compound as shown in formula (I-1) or formula (I-2), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound shown in formula (I-1) or formula (I-2):

[0024] In some implementations, R1 is C(=O)OW1、C(=O)NW2W3.

[0025] In some implementation schemes, W1, W2, and W3 are independently selected from H, D, and C, respectively. 1-6 alkyl.

[0026] In some embodiments, W1, W2, and W3 are independently selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, respectively.

[0027] In some implementations, W1, W2, and W3 are independently selected from H and D, respectively.

[0028] In some implementations, R2, R3, and R4 are independently selected from H, D, F, Cl, Br, I, and C, respectively. 1-6 Alkyl and C 1-6 Alkoxy; the C 1-6 Alkyl and C 1-6 The alkoxy group can be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br and I.

[0029] In some embodiments, R2, R3, and R4 are independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2.

[0030] In some implementations, R2, R3, and R4 are independently selected from H, D, F, Cl, Br, and I, respectively.

[0031] In some implementations, each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, and C. 1-6 Alkyl and C 1- 6-alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br and I; or R5 and R6, R7 and R8 may be optionally substituted with the carbon atom they are connected to to form a 3-6 membered cycloalkyl group or a 3-7 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group and the 3-7 membered heterocyclic group may be independently and optionally substituted by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH.

[0032] In some embodiments, each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, and -OCF2CHF. 2. -OCH2CF3 and -OCH2CF2CHF2; or R5 and R6, R7 and R8 may optionally form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy or cyclopentoxy with the carbon atom they are connected to, respectively, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy and cyclopentoxy may be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH.

[0033] In some implementations, each R9 is independently H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl, C 1-6 alkoxy or 3-7 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 The alkoxy group and the 3-7 membered heterocyclic group may be optionally and independently replaced by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I and CN.

[0034] In some embodiments, each R9 is independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2.

[0035] In some implementation schemes, R 10 Selected from H, D, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3 and -CH2CF2CHF2.

[0036] 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:

[0037] 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.

[0038] 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.

[0039] 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.

[0040] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I).

[0041] 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.

[0042] Definitions and general terms

[0043] 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.

[0044] 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.

[0045] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0046] 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 or not preceding the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents described may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxyl, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclic, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, etc.

[0047] The term "alkyl" as used in this invention includes a monovalent hydrocarbon group with 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, consisting of a saturated straight-chain or branched chain, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t... -Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl -1-Butyl (-CH2CH(CH3)CH2CH3), n-Hexyl (-CH2CH2CH2CH2CH2CH3), 2-Hexyl (-CH(CH3)CH2CH2CH2CH3), 3-Hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C) H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, and n-octyl, etc. The term "alkyl" and its prefix "alkane" are used here, both encompassing straight-chain and branched saturated carbon chains.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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, oxacyclobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxaneyl, dithiaalkyl, thiaalkyl, homopiperazineyl, homopiperidinyl, oxacycloheptyl, thioheptanyl, oxacyclohept ... basalt, diazoxide Basic, sulfur-nitrogen The heterocyclic groups include, but are not limited to, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl and 1,2,3,6-tetrahydropyridinyl. Examples of heterocyclic groups where the -CH2- group is substituted with -C(=O)- include, but are not limited to: 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, pyrimidinedionyl, and 5,6-dihydropyridin-2(1H)-keto. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic groups may optionally be substituted with one or more of the substituents described in this invention.

[0052] 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.

[0053] 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.

[0054] 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-benzodioxonyl, 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

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] The structural formulas of the compounds described in this invention include enriched isotopes of one or more different atoms. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other atoms are all within the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as those doped with radioactive isotopes, are also included. 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., 2H) 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.

[0060] "Metabolic product" refers to the product obtained in vivo by the metabolism of a specific compound described in this invention or its pharmaceutically acceptable salt, analogue, or derivative, which exhibits similar activity to the compound of formula (I) in vivo or in vitro. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such a product can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, or enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0061] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name compounds whose plane polarization is rotated. (-) or l indicates the compound is levorotatory, while (+) or d indicates it is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures differ. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0062] 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.

[0063] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to: inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and N+ (C 1-4 Salts of alkyl groups (4). This invention also envisions quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0064] In this invention, "hydrate" refers to an associative compound formed when the solvent molecules are water.

[0065] 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.

[0066] The term "nitrogen oxide" in this invention refers to an N-oxide formed by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), for example, by reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).

[0067] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0068] 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.

[0069] The term “GnRH receptor antagonist” as used in this article refers to substances that can inhibit gonadotropin-releasing hormone (GnRH) receptors. Detailed Implementation

[0070] 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.

[0071] Example 1 Synthesis of 2,4-dioxo-3-(3,12,13-trifluoro-6,6-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 1)

[0072] Step 1: Synthesis of 3-hydroxy-3-methylbutyl methanesulfonate

[0073] 3-Methylbutane-1,3-diol (10 g, 96.02 mmol), triethylamine (14.57 g, 144.02 mmol), and ethyl acetate (100 mL) were added to a 250 mL single-necked flask. After mixing, the mixture was cooled in an ice bath, and methanesulfonyl chloride (13.20 g, 115.22 mmol) was added. The mixture was then transferred to room temperature, and a large amount of white solid precipitated. TLC analysis showed that the reactants had reacted completely. The reaction was stopped, and the mixture was filtered. The filter cake was washed with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated ammonium chloride aqueous solution (30 mL × 2) and brine (30 mL × 2). The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 15.6 g of a light brown liquid. The product was used directly in the next reaction without further purification.

[0074] Step 2: Synthesis of 2,3-difluoro-6-hydroxybenzaldehyde

[0075] Anhydrous aluminum trichloride (7.75 g, 58.10 mmol) was added to a solution of 2,3-difluoro-6-methoxybenzaldehyde (5 g, 29.05 mmol) in 50 mL of dichloromethane under stirring in an ice bath. The mixture was stirred at room temperature for 0.5 hours. TLC showed no starting material remaining. The reaction mixture was poured into a stirred ice-water bath, and the pH was adjusted to <6 with dilute hydrochloric acid. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to remove at least the solvent residue. The product, red crystals, was allowed to evaporate naturally in an open container to obtain 4.32 g of the product.

[0076] 1 H NMR (500MHz, DMSO-d6) δ11.00(s,1H),10.25(s,1H),7.60(t,J=10.5,9.2Hz,1H),6.80(d,J=9.3,3.6,1.9Hz,1H).

[0077] Step 3: Synthesis of 3,4-difluoro-2-(hydroxymethyl)phenol

[0078] 2,3-Difluoro-6-hydroxybenzaldehyde (3.3 g, 17.83 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium borohydride (1.01 g, 26.74 mmol) was added with stirring in an ice bath, followed by dropwise addition of water (0.5 mL). The reaction was carried out at room temperature for 30 minutes. TLC showed no remaining starting material, and the reaction was stopped. The solution was diluted with a small amount of ice water, and the pH was adjusted to <6 with dilute hydrochloric acid (2 M). Extraction was performed with ethyl acetate (50 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.00 g of the target compound as a pale yellow solid.

[0079] 1 H NMR (500MHz, DMSO-d6) δ9.78 (s, 1H), 7.21–7.05 (m, 1H), 6.63–6.57 (m, 1H), 4.49 (d, J = 2.1Hz, 2H), 3.62–3.58 (m, 1H).

[0080] Step 4: Synthesis of 4-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-2-methylbut-2-ol

[0081] In a 50 mL single-necked flask, 3,4-difluoro-2-(hydroxymethyl)phenol (300 mg, 1.87 mmol), 3-hydroxy-3-methylbutyl methanesulfonate (683 mg, 3.75 mmol), sodium iodide (56 mg, 0.37 mmol), and cesium carbonate (1.22 g, 3.75 mmol) were added, followed by N,N-dimethylformamide (5 mL). The mixture was heated to 120 °C under nitrogen protection and stirred for 30 minutes. TLC showed no reactants remaining, and the reaction was stopped and allowed to return to room temperature. The mixture was diluted with a small amount of ice water, and the pH was adjusted to <6 with dilute hydrochloric acid (2 M). Extraction was performed with ethyl acetate (30 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 460 mg of the target compound as a pale yellow oil.

[0082] 1 H NMR(500MHz,DMSO-d6)δ7.28(q,J=9.7Hz,1H),6.82(d,J=9.3Hz,1H),4.92(d,J=5.6Hz,1H),4.4 9(dd,J=5.4,2.1Hz,2H),4.38(s,1H),4.10(t,J=6.9Hz,2H),1.86(t,J=6.9Hz,2H),1.17(s,6H).

[0083] Step 5: Synthesis of 2,3-difluoro-6-(3-hydroxy-3-methylbutoxy)benzyl methanesulfonate

[0084] 4-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-2-methylbut-2-ol (433 mg, 1.76 mmol), ethyl acetate (5 mL), and triethylamine (267 mg, 2.64 mmol) were added to a 50 mL single-necked flask. Methanesulfonyl chloride (302 mg, 2.64 mmol) was added under ice-water bath conditions, and the mixture was transferred to room temperature and reacted for 3 hours. After filtration, the organic phase was washed successively with water (20 mL × 2), saturated ammonium chloride aqueous solution (30 mL), and brine (30 mL). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated to obtain 627 mg of a milky white liquid containing the target compound. The product was used directly in the next reaction without purification.

[0085] 1 H NMR (500MHz, DMSO-d6) δ7.42 (q, J=9.7Hz, 1H), 6.92 (ddd, J=9.4, 3.7, 1.9Hz, 1H), 4.72 (d, J=1. 6Hz, 2H), 4.38 (s, 1H), 4.16 (t, J = 6.9Hz, 2H), 2.32 (s, 3H), 1.87 (t, J = 6.9Hz, 2H), 1.18 (s, 6H).

[0086] Step 6: Synthesis of 4-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)-2-methylbut-2-ol

[0087] Add 2,3-difluoro-6-(3-hydroxy-3-methylbutoxy)benzyl methanesulfonate (627 mg, 1.93 mmol), 2,4-difluoro-5-nitrophenol (355 mg, 2.03 mmol), sodium iodide (348 mg, 2.32 mmol), cesium carbonate (1.26 g, 3.87 mmol), and N,N-dimethylformamide (10 mL) to a 50 mL single-necked flask. Heat to 80 °C and stir for 1 hour. TLC showed no reactants remaining. Dilute with a small amount of water, adjust pH to <6 by adding dilute hydrochloric acid (2 M) dropwise under ice-water bath, extract with ethyl acetate (50 mL × 2), wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain 496 mg of the target compound as a pale yellow viscous liquid.

[0088] 1 H NMR (500MHz, DMSO-d6) δ8.12(t,J=7.8Hz,1H),7.78(t,J=11.0Hz,1H),7.47(q,J=258.8,9.7Hz,1H),6 .95(s,1H),5.29–5.26(m,2H),4.33(s,1H),4.13(t,J=6.9Hz,2H),1.79(t,J=6.9Hz,2H),1.10(s,6H).

[0089] Step 7: Synthesis of 1,2,11-trifluoro-8,8-dimethyl-12-nitro-7,8-dihydro-6H,15H-bisbenzo[b,f][1,4,8]triazolecycloundecene

[0090] 4-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)-2-methylbutane-2-ol (800 mg, 1.98 mmol) was dissolved in N,N-dimethylformamide (80 mL). Cesium carbonate (1300 mg, 3.99 mmol) was added to the system at room temperature, and the mixture was heated to 60 °C and stirred for 12 hours. After the reaction was complete, the reaction solution was poured into water (500 mL), extracted with ethyl acetate (200 mL × 2), washed with saturated ammonium chloride aqueous solution, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 40 mg of a yellow solid.

[0091] 1H NMR(400MHz, METHANOL-d4)δ7.94(d,J=7.6Hz,1H),7.31-7.22(m,1H),7.20(d,J=12.4Hz,1H),6. 98-6.92(m,1H),5.08(d,J=1.6Hz,2H),4.39(t,J=5.6Hz,2H),2.12(t,J=5.6Hz,2H),1.45(s,6H).

[0092] Step 8: Synthesis of 1,2,11-trifluoro-8,8-dimethyl-7,8-dihydro-6H,15H-bisbenzo[b,f][1,4,8]triazolylcycloundecene-12-amine

[0093] 1,2,11-trifluoro-8,8-dimethyl-12-nitro-7,8-dihydro-6H,15H-bisbenzo[b,f][1,4,8]triazolylcycloundecene (40 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of bisboronic acid (60 mg, 0.67 mmol) and 4,4'-bispyridine (0.01 mL, 0.01 mmol). The reaction was carried out at 25 °C with stirring for 30 minutes. After the reaction was complete, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 40 mg of a yellow oily product.

[0094] LC-MS(ESI):[M+H] + =354.1;

[0095] Step 9: Synthesis of dimethyl 4-(3-(3,12,13-trifluoro-6,6-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-2-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0096] 1,2,11-trifluoro-8,8-dimethyl-7,8-dihydro-6H,15H-bisbenzo[b,f][1,4,8]triazolcycloundecene-12-amine (40 mg, 0.10 mmol) and dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (45 mg, 0.13 mmol) were dissolved in tetrahydrofuran (2 mL), and then triethylamine (0.1 mL, 0.72 mmol) was added. The reaction was heated to 70 °C and stirred for 4 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL), and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography to give 50 mg of a yellow solid.

[0097] LC-MS(ESI):[M+H] + =595.2;

[0098] Step 10: Synthesis of 2,4-dioxo-3-(3,12,13-trifluoro-6,6-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0099] Dimethyl 4-(3-(3,12,13-trifluoro-6,6-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-2-yl)ureo)thiophene-2,3-dicarboxylic acid (50 mg, 0.08 mmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (0.5 mL). Lithium hydroxide (5.0 mg, 0.21 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 6-7 with hydrochloric acid (1 M), and then extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 30 mg of the product.

[0100] LC-MS(ESI):[M+H] + =549.2;

[0101] 1 H NMR (400MHz, DMSO-d6) δ12.62-11.39(m,1H),7.57-7.48(m,2H),7.33(s,1H),7.27(d,J=11.2Hz,1H),7. 13(dd,J=2.4,9.2Hz,1H),5.06-4.94(m,2H),4.40(t,J=5.6Hz,2H),2.11(t,J=5.6Hz,2H),1.36(s,6H).

[0102] Example 2 Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (Compound 2)

[0103] Step 1: Synthesis of 2-(benzyloxy)-5-fluorobenzaldehyde

[0104] 5-Fluoro-2-hydroxybenzyl-1-carboxaldehyde (27 g, 192.71 mmol) and benzyl bromide (27.7 mL, 231.25 mmol) were dissolved in N,N-dimethylformamide (300 mL) and potassium carbonate (53.26 g, 385.41 mmol) was added in one batch. After the addition was complete, the reaction mixture was heated to 50 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed twice with saturated calcium chloride aqueous solution, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 41 g of white solid product.

[0105] Step 2: Synthesis of methyl 2-(benzyloxy)-5-fluorophenylcarbamate

[0106] 2-(benzyloxy)-5-fluorobenzaldehyde (40 g, 173.73 mmol) was dissolved in dichloromethane (200 mL), and m-chloroperoxybenzoic acid (45 g, 260.60 mmol) was added in a single batch at room temperature. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solution was quenched with saturated sodium sulfite solution, extracted with ethyl acetate (500 mL × 2), and the organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography to give 39 g of a colorless oily liquid product.

[0107] Step 3: Synthesis of 2-(benzyloxy)-5-fluorophenol

[0108] Methyl 2-(benzyloxy)-5-fluorophenylcarbamate (39 g, 158.38 mmol) was dissolved in ethanol (200 mL) and water (40 mL). Sodium hydroxide (31.68 g, 791.91 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was adjusted to acidity with hydrochloric acid (4 M), extracted with ethyl acetate (300 mL × 2), the organic phases were combined, washed with saturated brine, dried, and concentrated to dryness to give 32 g of a yellow oily product.

[0109] 1 H NMR(400MHz,DMSO-d6)δ9.55(s,1H),7.45(s,2H),7.37(s,2H),7.34-7.25(m ,1H),6.98-6.89(m,1H),6.68-6.59(m,1H),6.55-6.44(m,1H),5.06(s,2H).

[0110] Step 4: Synthesis of 3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropionic acid

[0111] 2-(benzyloxy)-5-fluorophenol (20 g, 91.65 mmol) was dissolved in N,N-dimethylformamide (200 mL), and cesium carbonate (59.72 g, 183.29 mmol) was added in one batch. The mixture was stirred at 50 °C for 0.5 h, and then ethyl 3-bromo-2,2-difluoropropionate (25.85 g, 119.14 mmol) was added. The reaction mixture was reacted at 55 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with water, and the pH was adjusted to 6 with dilute hydrochloric acid (1 M). The mixture was then extracted with ethyl acetate (300 mL × 2). The organic phases were combined and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 5 g of a yellow solid.

[0112] LC-MS(ESI):[MH] - =325.2;

[0113] Step 5: Synthesis of 3-(2-(benzyloxy)-5-fluorophenyl]oxy)-2,2-difluoropropane-1-ol

[0114] 3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropionic acid (3 g, 9.19 mmol) was dissolved in tetrahydrofuran (30 mL), and a solution of lithium aluminum hydride (520 mg, 9.19 mmol) in tetrahydrofuran (5.5 mL) was added dropwise. After the addition was complete, the reaction was carried out at 25 °C for 0.5 hours. After the reaction was complete, the reaction solution was diluted with tetrahydrofuran (500 mL), and the reaction was quenched by slowly adding water (0.5 mL). Then, 15% sodium hydroxide aqueous solution (1 mL) was added and stirred for 0.5 hours, followed by the addition of anhydrous sodium sulfate and stirring for 1 hour. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The product was purified by silica gel column chromatography to obtain 2.5 g of a pale yellow solid.

[0115] LC-MS(ESI):[MH] - =311.2;

[0116] Step 6: Synthesis of 3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropyltrifluoromethanesulfonate

[0117] 3-(2-(benzyloxy)-5-fluorophenyl]oxy)-2,2-difluoropropane-1-ol (2.5 g, 8.01 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of pyridine (1.9 mL, 24.02 mmol), and the mixture was cooled to 0 °C. Trifluoromethanesulfonic anhydride (2.4 mL, 14.41 mmol) was then slowly added dropwise, and the reaction was carried out at 0 °C for 0.5 hours. After the reaction was complete, the reaction solution was quenched with dilute hydrochloric acid (50 mL), followed by the addition of dichloromethane (100 mL). The mixture was separated, the organic phase was washed with brine, dried over sodium sulfate, and evaporated to dryness to obtain 3.50 g of a yellow oily product. The crude product was used directly in the next reaction without purification.

[0118] Step 7: Synthesis of 6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorobenzaldehyde

[0119] 2,3-Difluoro-6-hydroxybenzyl-1-carboxaldehyde (1.25 g, 7.88 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of potassium carbonate (2.18 g, 15.75 mmol). The mixture was stirred at 45 °C for 0.5 hours, then a solution of 3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropyltrifluoromethanesulfonate (3.5 g, 7.88 mmol) in N,N'-dimethylformamide (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. After separation, the aqueous phase was extracted with ethyl acetate (60 mL). The combined organic phases were washed with brine, dried, and then evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 3.00 g of a colorless oily product.

[0120] LC-MS(ESI):[M+H] + =453.1;

[0121] Step 8: Synthesis of (6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methanol

[0122] 6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorobenzaldehyde (3 g, 6.63 mmol) was dissolved in ethanol (30 mL), and sodium borohydride (500 mg, 13.26 mmol) was slowly added. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 hours. The reaction solution was quenched by slow addition of dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine, dried, and concentrated to give 2.90 g of a colorless oily product.

[0123] LC-MS (ESI): [M+Na] + =477.1;

[0124] Step 9: Synthesis of 2-(3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-2,2-difluoropropoxy)-4-fluorophenol

[0125] (6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methanol (2.90 g, 6.38 mmol) was dissolved in isopropanol (30 mL), and 10% palladium / carbon (679 mg) was added under a nitrogen atmosphere. The reaction mixture was purged with hydrogen three times, and then heated to 50 °C for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered, and the filter cake was washed with methanol (50 mL). The combined organic phases were evaporated to dryness to give 2.30 g of a yellow oily product.

[0126] LC-MS(ESI):[MH] - =363.1;

[0127] Step 10: Synthesis of 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0128] 2-(3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-2,2-difluoropropoxy)-4-fluorophenol (2.5 g, 6.86 mmol) was dissolved in toluene (250 mL), and (tributyl-λ5-oxophosphine) acetonitrile (3.31 g, 13.73 mmol) was added dropwise at room temperature. After the addition was complete, the reaction solution was heated to 80 °C and reacted for 16 hours. Water (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL × 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by Prep-TLC to give 850 mg of a white solid.

[0129] Step 11: Synthesis of 1,2,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0130] 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene (850 mg, 2.45 mmol) was dissolved in acetic acid (16 mL), and concentrated nitric acid (16 mL) was slowly added at 80 °C. After the addition was complete, the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was added to ice water, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with brine (50 mL), filtered, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 180 mg of a white solid product.

[0131] Step 12: Synthesis of 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine

[0132] 1,2,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (180 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 4,4'-bispyridine (7 mg, 0.05 mmol) and diboronic acid (165 mg, 1.84 mmol) were added in one step. The reaction mixture was stirred at 25 °C for 5 minutes. Water (40 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (60 mL × 2 times). The combined organic phases were washed once with saturated brine (50 mL) and once with saturated calcium chloride aqueous solution (50 mL), then dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to obtain 160 mg of a yellow oily product.

[0133] LC-MS(ESI):[M+H] + =362.1.

[0134] Step 13: Synthesis of dimethyl 4-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester)

[0135] 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (1 mL), followed by the addition of dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (51 mg, 0.15 mmol) and triethylamine (0.1 mL, 0.42 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 to give 58 mg of a yellow solid.

[0136] LC-MS(ESI):[M+H] + =603.1.

[0137] Step 14: Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0138] Dimethyl 4-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid (50 mg, 0.08 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (17 mg, 0.41 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), and the organic phase was washed once with brine (50 mL). The mixture was 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 15 mg of the product.

[0139] LC-MS(ESI):[M+H] + =557.1;

[0140] 1 H NMR(400MHz,DMSO-d6)δ14.18-14.68(m,1H),12.06–11.92(m,1H),7.54–7.45(m,2H),7.4 2(d,J=11.0Hz,1H),7.33(s,1H),7.28–7.21(m,1H),5.16–5.10(m,2H),4.74–4.59(m,4H).

[0141] Example 3 Synthesis of 4-oxo-2-thiooxy-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (Compound 3)

[0142] Step 1: Synthesis of 2,3-difluoro-6-methoxybenzaldehyde

[0143] At -70°C, lithium diisopropylamino (73.4 mL, 555.09 mmol) was added dropwise to a tetrahydrofuran (400 mL) solution of compound 1,2-difluoro-4-methoxybenzene (32.5 mL, 277.55 mmol), and the reaction mixture was stirred at -70°C for 0.5 hours. From -70°C to -60°C, a tetrahydrofuran (24 mL) solution of N,N-dimethylformamide (21.5 mL, 277.55 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at -70°C for 1 hour. Acetic acid (25 mL) and water (100 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed successively with water (100 mL × 3) and saturated brine (100 mL × 3). The collected organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 30 g of a yellow liquid product.

[0144] 1 H NMR (500MHz, DMSO-d6) δ10.27(s,1H),7.73(dd,J=19.5,9.4Hz,1H),7.09–7.01(m,1H),3.91(s,3H).

[0145] Step 2: Synthesis of 2,3-difluoro-6-hydroxybenzaldehyde

[0146] Anhydrous aluminum chloride (9.30 g, 116.20 mmol) was added to a solution of 2,3-difluoro-6-methoxybenzaldehyde (25 g, 145.25 mmol) in dichloromethane (900 mL) under an ice-water bath. After the addition was complete, the mixture was stirred at room temperature for 0.5 hours. The pH was then adjusted to below 5, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under a vacuum of 400 °C at 30 °C to remove at least a small amount of solvent residue. The residue was allowed to evaporate naturally in an open container to obtain 20.0 g of a yellow solid product. The crude product was used directly in the next reaction without purification.

[0147] 1 H NMR (500MHz, DMSO-d6) δ11.00(s,1H),10.25(s,1H),7.60(t,J=10.5,9.2Hz,1H),6.80(d,J=9.3,3.6,1.9Hz,1H).

[0148] Step 3: Synthesis of propyl 3-(3,4-difluoro-2-formylphenoxy)acetate

[0149] Sodium iodide (1.90 g, 12.65 mmol) and potassium carbonate (1.34 g, 8.92 mmol) were added to a solution of 2,3-difluoro-6-hydroxybenzaldehyde (10.00 g, 63.25 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred at 25 °C for 0.5 h, and then 3-bromopropyl acetate (17.18 g, 94.88 mmol) was added. The mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL × 5), and the combined organic phases were washed with water (50 mL × 5) and once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 9.8 g of a colorless liquid product.

[0150] Step 4: Synthesis of propyl 3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)acetate

[0151] At 0°C, a solution of sodium borohydride (880 mg, 23.24 mmol) in water (20 mL) was added to a tetrahydrofuran (100 mL) solution of propyl 3-(3,4-difluoro-2-formylphenoxy)acetate (4.00 g, 15.49 mmol). The mixture was then heated to 25°C and stirred for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.00 g of a yellow liquid product. The crude product was used directly in the next reaction without purification.

[0152] Step 5: Synthesis of propyl 3-(2-(chloromethyl)-3,4-difluorophenoxy)acetate

[0153] At 0°C, 1.80 g (6.92 mmol) of propyl 3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)acetate was added to 2 mL of dichloromethane, followed by stirring at 25°C under nitrogen protection for 12 hours. All solvent was removed to obtain 1.70 g of a yellow liquid crude product, which was used directly in the next reaction without purification.

[0154] Step 6: Synthesis of 3-(2-(chloromethyl)-3,4-difluorophenoxy)prop-1-ol

[0155] At 0°C, concentrated hydrochloric acid (1.06 g, 10.77 mmol) was added to 15 mL of methanol containing 1.50 g (5.38 mmol) of compound 3-(2-(chloromethyl)-3,4-difluorophenoxy)acetic acid, followed by heating to 25°C and stirring for 12 hours. The solvent was removed to obtain 1.10 g of a yellow liquid product. The crude product was used directly in the next reaction without purification.

[0156] Step 7: Synthesis of 3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)prop-1-ol

[0157] 3-(2-(chloromethyl)-3,4-difluorophenoxy)prop-1-ol (700 mg, 2.96 mmol) was dissolved in acetonitrile (10 mL), and 2,4-difluoro-5-nitrophenol (544 mg, 3.10 mmol), potassium carbonate (818 mg, 5.92 mmol), and sodium iodide (44 mg, 0.30 mmol) were added. The reaction mixture was stirred at 60 °C for 1 hour. Water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (10 mL × 2) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 400 mg of a yellow liquid product.

[0158] Step 8: Synthesis of 1,2,11-trifluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0159] Cesium fluoride (194 mg, 2.56 mmol) was added to a solution of 3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)prop-1-ol (200 mg, 0.52 mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred at 80 °C for 2 hours under nitrogen protection. Afterward, the mixture was allowed to return to room temperature, and water (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with water (10 mL × 2) and then with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 60 mg of a yellow liquid.

[0160] Step 9: Synthesis of 1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine

[0161] To a 2 mL solution of ethyl acetate (50 mg, 0.14 mmol) of 1,2,11-trifluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene, 10% palladium / carbon (8 mg) was added. The reaction mixture was stirred at 25 °C under hydrogen protection for 12 hours. The mixture was then filtered and concentrated under reduced pressure to give 40 mg of a yellow oily liquid product. The crude product was used directly in the next reaction without purification.

[0162] LC-MS(ESI):[M+H] + =326.1;

[0163] Step 10: Synthesis of dimethyl 4-(3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12yl)thioureo)thiophene-2,3-dicarboxylic acid ester

[0164] At 0°C, thiocarbonyl diimidazole (16 mg, 0.09 mmol) was added to a solution of 1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (30 mg, 0.09 mmol) in dichloromethane (1 mL), and the reaction was continued at this temperature for 2 hours. After complete conversion of the starting material, triethylamine (52 μL, 0.37 mmol) and methyl 4-amino-3-(methoxycarbonyl)thiophene-2-carboxylic acid hydrochloride (23 mg, 0.09 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. The product was then diluted with ethyl acetate (20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 20 mg of a yellow oily crude product. This product was used directly in the next reaction without purification.

[0165] Step 11: Synthesis of 4-oxo-2-thiooxy-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0166] Crude 4-(3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12yl)thioureo)thiophene-2,3-dicarboxylic acid dimethyl ester (20 mg, 0.034 mmol) was dissolved in tetrahydrofuran (1 mL), and methanol (0.5 mL), water (0.5 mL), and lithium hydroxide monohydrate (19 mg, 0.45 mmol) were added. The mixture was reacted at room temperature for 1 hour. After the starting material disappeared, dilute hydrochloric acid was added to adjust the pH to 2-3, and the mixture was extracted with ethyl acetate (10 mL × 3). After drying and concentration, the product was purified by reverse-phase column chromatography to obtain 8 mg of product.

[0167] LC-MS(ESI):[MH] - =535.2;

[0168] 1H NMR (500MHz, DMSO-d6) δ14.16(s,1H),13.45(s,1H),7.52(s,1H),7.37(q,J=9.4Hz,1H),7.17(d,J=7.6Hz,1H),7.11( d,J=11.3Hz,1H),7.04(d,J=7.5Hz,1H),5.16–5.07(m,2H),4.54–4.44(m,2H),4.36–4.26(m,2H),1.98–1.93(m,2H).

[0169] Example 4 Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thiooxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 4)

[0170] Step 1: Synthesis of dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid ester

[0171] 4-Amino-3-(methoxycarbonyl)thiophene-2-carboxylic acid methyl ester hydrochloride (1.00 g, 3.97 mmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL). Then, potassium carbonate (1.04 g, 7.53 mmol) and phenyl thiochloroformate (1.00 g, 5.79 mmol) were slowly added. The reaction mixture was stirred at 20 °C for 1 hour. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture 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, concentrated, and purified by column chromatography to give 1.10 g of a yellow oily product.

[0172] LC-MS(ESI):[M+H] + =352.1;

[0173] 1 H NMR (400MHz, CDCl3) δ10.57(s,1H),8.89(s,1H),7.43(t,J=7.6Hz,2H),7.30(t,J=7.3Hz,1H),7.12(d,J=7.7Hz,2H),3.97(s,3H),3.93(s,3H).

[0174] Step 2: Synthesis of methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thiooxy-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0175] To a tetrahydrofuran (2 mL) solution of 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (100 mg, 0.28 mmol) (synthetic method as described in step 12 of Example 2), dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (97 mg, 0.28 mmol) and triethylamine (0.1 mL, 0.83 mmol) were added. The reaction mixture was stirred at 70 °C for 2 h. 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, concentrated, and purified by column chromatography to give 98 mg of a yellow solid product.

[0176] LC-MS(ESI):[M+H] + =587.1;

[0177] 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),7.48(dd,J=19.1,9.5Hz,1H),7.42(s,1H),7.38(d,J=7.6Hz,1H),7.34(d,J=10.9H z,1H),7.24(d,J=8.8Hz,1H),5.12(dd,J=24.1,11.1Hz,2H),4.69(t,J=11.8Hz,2H),4.61(t,J=11.4Hz,2H),3.83(s,3H).

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

[0179] To a solution of methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thiooxy-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (98 mg, 0.17 mmol) in tetrahydrofuran (1 mL), water (0.5 mL), methanol (0.5 mL), and lithium hydroxide monohydrate (32 mg, 0.76 mmol) were added. The reaction mixture was allowed to react at room temperature for 1 hour, and the starting material was monitored for complete conversion. After the reaction was complete, the pH was adjusted to 2-3 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse-phase column chromatography to give 31 mg of the product.

[0180] LC-MS(ESI):[MH] - =571.1;

[0181] 1 H NMR(400MHz,DMSO-d6)δ13.42(s,2H),7.52(s,1H),7.50–7.44(m,1H),7.41–7.33(m,2H), 7.26–7.21(m,1H),5.15(q,J=10.8Hz,2H),4.70(t,J=11.7Hz,2H),4.63(t,J=11.2Hz,2H).

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

[0183] Step 1: Synthesis of 7-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silylheptane)

[0184] 6-((6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silylheptane-7-yl)oxy)-2,3-difluorobenzyl-1-carboxaldehyde (8 g, 16.31 mmol) and ethylene glycol (1.2 mL, 21.20 mmol) were dissolved in toluene (80 mL), and p-toluenesulfonic acid (0.31 g, 1.63 mmol) was added. The reaction mixture was stirred at 110 °C for 16 hours. A saturated sodium bicarbonate aqueous solution (100 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 brine (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 8.1 g of the product.

[0185] 1 H NMR(400MHz, CDCl3)δ7.64(s,4H),7.46-7.36(m,6H),7.16-7.08(m,1H),6.70-6.63(m, 1H),6.30-6.26(m,1H),4.34(s,2H),4.19-4.14(m,2H),4.01-3.91(m,4H),1.05(s,9H).

[0186] Step 2: Synthesis of 3-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-2,2-difluoropropane-1-ol

[0187] 7-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-6,6-difluoro-2,2-dimethyl-3,3-diphenyl-4-oxa-3-silanheptan (8.1 g, 15.15 mmol) was dissolved in tetrahydrofuran (30 mL), and a 1M tetrabutylammonium fluoride solution (30.3 mL, 30.30 mmol) in tetrahydrofuran was added. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 3.9 g of the product.

[0188] 1 H NMR (400MHz, CDCl3) δ7.20-7.08(m,1H),6.69-6.61(m,1H),6.30(s,1H),4.29(t,J=11.6Hz,2H),4.23-4.17(m,2H),4.07-4.02(m,2H),3.96(br t,J=12.5Hz,2H),2.63-2.49(m,1H).

[0189] Step 3: Synthesis of 3-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-2,2-difluoropropionic acid

[0190] 3-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-2,2-difluoropropane-1-ol (3.9 g, 13.17 mmol) was dissolved in acetonitrile (40 mL) and water (10 mL). Potassium bromide (15.67 g, 131.66 mmol) and 2,2,6,6-tetramethylpiperidine oxide (0.62 g, 3.95 mmol) were added. After the addition was complete, the reaction solution was cooled to 0 °C and stirred for 0.5 hours. Then, sodium hypochlorite (15.7 mL, 39.50 mmol) and saturated sodium bicarbonate (30 mL) buffer were slowly added to the reaction solution, and the mixture was heated to room temperature for 1 hour. The reaction solution was quenched with methanol, and the pH was adjusted to weakly acidic with 1 M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 1.5 g of product.

[0191] LC-MS(ESI):[MH] + =311.3;

[0192] Step 4: Synthesis of methyl 3-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-2,2-difluoropropionate

[0193] 3-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-2,2-difluoropropionic acid (1.45 g, 4.67 mmol) was dissolved in dichloromethane (10 mL) and methanol (10 mL), and trimethylsilyldiazomethane (3.7 mL, 9.35 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was directly concentrated and evaporated to dryness to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 1.2 g of product.

[0194] LC-MS(ESI):[MH] + =325.3;

[0195] Step 5: Synthesis of 4-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-3,3-difluoro-2-methylbutane-2-ol

[0196] Methyl 3-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-2,2-difluoropropionate (1.05 g, 3.24 mmol) was dissolved in tetrahydrofuran (15 mL). A 3.0 M methyl magnesium chloride tetrahydrofuran solution (3.2 mL, 9.72 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. An aqueous solution of ammonium chloride (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 1.0 g of the product.

[0197] Step 6: Synthesis of 6-((2,2-difluoro-3-hydroxy-3-methylbutyl)oxy)-2,3-difluorobenzene-1-carboxaldehyde

[0198] 4-((2-(1,3-dioxacyclopentan-2-yl)-3,4-difluorophenyl)oxy)-3,3-difluoro-2-methylbutane-2-ol (1.00 g, 3.08 mmol) was dissolved in acetone (10 mL), and then p-toluenesulfonic acid monohydrate (0.9 mL, 6.17 mmol) was added. The mixture was heated to 50 °C and reacted for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 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 separated by silica gel column chromatography to obtain 830 mg of the product.

[0199] 1 H NMR (400MHz, CDCl3) δ10.42 (s, 1H), 7.47-7.37 (m, 1H), 6.79-6.72 (m, 1H), 4.49-4.41 (m, 2H), 1.43 (d, J = 0.9Hz, 6H).

[0200] Step 7: Synthesis of 4-((3,4-difluoro-2-(hydroxymethyl)phenyl)oxy)-3,3-difluoro-2-methylbutane-2-ol

[0201] 6-((2,2-difluoro-3-hydroxy-3-methylbutyl)oxy)-2,3-difluorobenzyl-1-carboxaldehyde (830 mg, 2.96 mmol) was dissolved in ethanol (10 mL), and sodium borohydride (224 mg, 5.92 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Ammonium chloride aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 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 separated by silica gel column chromatography to obtain 620 mg of the product.

[0202] LC-MS (ESI): [M+Na] + =305.1;

[0203] Step 8: Synthesis of 4-((2-(((2,4-difluoro-5-nitrophenyl)oxy)methyl)-3,4-difluorophenyl)oxy)-3,3-difluoro-2-methylbutane-2-ol

[0204] 4-((3,4-difluoro-2-(hydroxymethyl)phenyl)oxy}-3,3-difluoro-2-methylbutane-2-ol (580 mg, 2.06 mmol), 2,4-difluoro-5-nitrophenol (360 mg, 2.06 mmol), and triphenylphosphine (808 mg, 3.08 mmol) were dissolved in tetrahydrofuran (10 mL), and diisopropyl azodicarbonate (0.6 mL, 3.08 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was then directly added to water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed once with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 810 mg of the product.

[0205] 1 H NMR (400MHz, CDCl3) δ7.91(s,1H),7.25-7.14(m,1H),7.10-7.00(m,1H),6.74-6.65(m,1H),5.30(s,2H),4.44(s,2H),2.12(s,1H),1.37(s,6H).

[0206] Step 9: Synthesis of 1,2,7,7,11-pentafluoro-8,8-dimethyl-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene

[0207] 4-((2-(((2,4-difluoro-5-nitrophenyl)oxy)methyl)-3,4-difluorophenyl)oxy)-3,3-difluoro-2-methylbutane-2-ol (700 mg, 1.59 mmol) was dissolved in N,N-dimethylformamide (700 mL), and cesium carbonate (5.19 g, 15.93 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with saturated sodium chloride aqueous solution (500 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated calcium chloride aqueous solution (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 200 mg of the product.

[0208] Step 10: Synthesis of 1,2,7,7,11-pentafluoro-8,8-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine

[0209] 1,2,7,7,11-pentafluoro-8,8-dimethyl-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (200 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (5 mL), and tetrahydroxydiboron (171 mg, 1.91 mmol) and 4,4'-bipyridine (7 mg, 0.05 mmol) were added. The reaction mixture was stirred at 20 °C for 5 minutes, diluted 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 give 180 mg of product.

[0210] LC-MS (ESI): [M+Na] + =390.1;

[0211] Step 11: Synthesis of methyl 3-(methoxycarbonyl)-4-((((7,12,12,18,19-pentafluoro-11,11-dimethyl-3,10,14-trioxotricyclo[13.4.0.04,9]nonadecan-1(19),4(9),5,7,15(16),17-hexene-6-yl)amino)carbonyl)amino)thiophene-2-carboxylic acid

[0212] Triethylamine (0.1 mL, 0.69 mmol) was added to a tetrahydrofuran (2 mL) solution of methyl 3-(methoxycarbonyl)-4-(((phenoxy)carbonyl)amino)thiophene-2-carboxylic acid (77 mg, 0.23 mmol) and 1,2,7,7,11-pentafluoro-8,8-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (90 mg, 0.23 mmol). The reaction mixture was stirred at 70 °C for 2 hours. The mixture was diluted with water (20 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 separated by silica gel column chromatography to obtain 85 mg of the product.

[0213] LC-MS (ESI): [M+Na] + =631.1;

[0214] Step 12: Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-8,8-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0215] Methyl 3-(methoxycarbonyl)-4-((((7,12,12,18,19-pentafluoro-11,11-dimethyl-3,10,14-trioxotricyclo[13.4.0.04,9]nonadecan-1(19),4(9),5,7,15(16),17-hexene-6-yl)amino)carbonyl)amino)thiophene-2-carboxylic acid (85 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL), and then lithium hydroxide monohydrate (28 mg, 0.67 mmol) was added. The reaction solution was stirred at 20 °C for 1 hour. The pH of the reaction solution was adjusted to 7 with 1 M hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with brine (50 mL), filtered, dried, and then evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 35 mg of the product.

[0216] LC-MS(ESI):[M+H] + =585.1;

[0217] 1 H NMR(400MHz,DMSO-d6)δ14.32(s,1H),12.02(s,1H),7.63-7.59(m,1H),7.58-7.49(m,1H) ,7.42-7.29(m,2H),7.28-7.21(m,1H),5.02-4.92(m,2H),4.76-4.64(m,2H),1.45(s,6H).

[0218] Example 6: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-8,8-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 6)

[0219] Step 1: Synthesis of methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-8,8-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0220] To a tetrahydrofuran (2 mL) solution of 1,2,7,7,11-pentafluoro-8,8-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (90 mg, 0.23 mmol), triethylamine (0.1 mL, 0.69 mmol) and dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (89 mg, 0.25 mmol) were added (synthetic method as described in step 1 of Example 4). The reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL × 3). 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 separated by silica gel column chromatography to obtain 120 mg of the product.

[0221] LC-MS (ESI): [M+Na] + =615.1;

[0222] Step 2: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-8,8-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0223] Methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-8,8-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (110 mg, 0.18 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (38 mg, 0.89 mmol) was added to the mixture. The reaction solution was stirred at 20 °C for 1 hour. The pH of the reaction solution 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 with brine (50 mL), filtered, dried, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 38 mg of the product.

[0224] LC-MS(ESI):[M+H] + =601.1;

[0225] 1H NMR (400MHz, DMSO-d6) δ14.25-13.83(m,1H),13.63-13.29(m,1H),7.58-7.48(m,3H),7.35-7.30(m,1H),7.28-7.22(m,1H),4.96(br s,2H),4.77-4.62(m,2H),1.45(br d,J=5.8Hz,6H).

[0226] Example 7 Synthesis of 2,4-dioxo-3-(1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 7)

[0227] Step 1: Synthesis of 2-(2,2-difluoro-3-hydroxypropyl)-3,6-difluorobenzaldehyde

[0228] Sodium hydride (1.12 g, 28.11 mmol) was added to a solution of 2,2-difluoropropane-1,3-diol (3.15 g, 28.11 mmol) in N,N-dimethylformamide (30 mL) at 0 °C. The reaction mixture was reacted at 0 °C for 0.5 h. Then, 2,3,6-trifluorobenzaldehyde (3 g, 18.74 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (200 mL), and then extracted with ethyl acetate (100 mL × 2). The organic phase was washed once with a saturated aqueous solution of ammonium chloride (100 mL). The organic phases were combined, dried, and evaporated to dryness to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 1.3 g of the product.

[0229] 1 H NMR (400MHz, CDCl3) δ10.37 (s, 1H), 7.52-7.34 (m, 1H), 6.96 (dt, J = 3.3, 9.4Hz, 1H), 4.50 (t, J = 11.7Hz, 2H), 4.06 (br t, J = 12.5Hz, 2H).

[0230] Step 2: Synthesis of 3-(3,6-difluoro-2-(hydroxymethyl)phenoxy)-2,2-difluoropropane-1-ol

[0231] Sodium borohydride (0.3 mL, 7.93 mmol) was slowly added to an ethanol (20 mL) solution of compound 2-(2,2-difluoro-3-hydroxypropyl)-3,6-difluorobenzaldehyde (1 g, 3.97 mmol). The reaction mixture was stirred at 15 °C for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL), and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried, and evaporated to dryness to give 700 mg of the product.

[0232] 1 H NMR (400MHz, CDCl3) δ7.10 (s, 1H), 6.75 (dt, J = 3.7, 8.8Hz, 1H), 4.72 (s, 2H), 4.41 (t, J = 11.8Hz, 2H), 3.96 (t, J = 12.4Hz, 2H).

[0233] Step 3: Synthesis of 3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,6-difluorophenoxy)-2,2-difluoropropane-1-ol

[0234] To a solution of 3-(3,6-difluoro-2-(hydroxymethyl)phenoxy)-2,2-difluoropropane-1-ol (400 mg, 1.57 mmol) in toluene (3 mL), 2,4-difluoro-5-nitrophenol (331 mg, 1.89 mmol) and cyanomethylenetri-n-butylphosphine (1.63 g, 4.72 mmol) were added, and the reaction mixture was stirred at 90 °C for 1 hour. After the reaction mixture was evaporated to dryness, it was separated by silica gel column chromatography to obtain 450 mg of the product.

[0235] 1 H NMR (400MHz, CDCl3) δ7.91-7.79(m,1H),7.17-7.06(m,1H),7.02-6.95(m,1H), 6.82(dt,J=3.6,8.8Hz,1H),5.17(s,2H),4.41(dt,J=0.8,12.2Hz,2H),3.88(br t,J=12.6Hz,2H),2.00(s,1H).

[0236] Step 4: Synthesis of 1,4,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0237] Cesium fluoride (886 mg, 5.84 mmol) was added to a solution of 3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,6-difluorophenoxy)-2,2-difluoropropane-1-ol (400 mg, 0.97 mmol) in N,N-dimethylformamide (400 mL). The reaction mixture was stirred at 70 °C for 1 hour. The reaction mixture was diluted with water (500 mL) and then extracted with ethyl acetate (500 mL × 2). The organic phase was washed with saturated calcium chloride aqueous solution (500 mL × 2). The organic phases were combined, dried, and evaporated to dryness to give 320 mg of the product.

[0238] Step 5: Synthesis of 1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine

[0239] To a solution of 1,4,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (350 mg, 0.89 mmol) in N,N'-dimethylformamide (3 mL), bis(boronic acid) (400 mg, 4.47 mmol) and 4,4'-bipyridine (14 mg, 0.09 mmol) were added, and the reaction mixture was stirred at 15 °C for 10 min. The reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated calcium chloride aqueous solution (50 mL × 2), and the organic phases were combined, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 300 mg of the product.

[0240] LC-MS(ESI):[M+H] + =362.1;

[0241] Step 6: Synthesis of dimethyl 4-(3-(1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)urea)thiophene-2,3-dicarboxylic acid ester

[0242] To a solution of compound 1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (120 mg, 0.33 mmol) in tetrahydrofuran (2 mL), dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid ester (134 mg, 0.40 mmol) and triethylamine (100 mg, 0.99 mmol) were added, and the reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 80 mg of the product.

[0243] LC-MS(ESI):[M+H]+ =603.1;

[0244] Step 7: Synthesis of 2,4-dioxo-3-(1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0245] Lithium hydroxide monohydrate (16 mg, 0.38 mmol) was added to a 2 mL mixture of tetrahydrofuran, methanol, and water containing 80 mg (0.13 mmol) of dimethyl 4-(3-(1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)urea)thiophene-2,3-dicarboxylic acid. The reaction mixture was stirred at 15 °C for 30 min. The reaction mixture was quenched with dilute hydrochloric acid (1 M) to adjust the pH to weakly acidic, and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 40 mg of the product.

[0246] LC-MS(ESI):[M+H] + =557.2;

[0247] 1 H NMR (400MHz, DMSO-d6) δ14.40 (s, 1H), 12.03 (s, 1H), 7.63 (d, J = 7.5Hz, 1H), 7.54-7.42 (m, 2H),7.37(s,1H),7.16(dt,J=3.7,9.0Hz,1H),5.17(s,2H),4.60(td,J=11.5,16.1Hz,4H).

[0248] Example 8: Synthesis of 4-oxy-3-(1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 8)

[0249] Step 1: Synthesis of methyl 4-oxy-3-(1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester

[0250] To a tetrahydrofuran (3 mL) solution of compound 1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (150 mg, 0.42 mmol), dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (175 mg, 0.50 mmol) (synthetic method as described in step 1 of Example 4) and triethylamine (84 mg, 0.83 mmol) were added. The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 120 mg of the product.

[0251] LC-MS(ESI):[M+H] + =587.2.

[0252] Step 2: Synthesis of 2,4-dioxo-3-(1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0253] A solution of methyl 4-oxy-3-(1,4,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester (100 mg, 0.17 mmol) in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added to a solution of lithium hydroxide monohydrate (63 mg, 1.5 mmol) in water (0.5 mL). The reaction mixture was stirred at 15 °C for 30 minutes. The reaction mixture was quenched with dilute hydrochloric acid (1 M), the pH was adjusted to weakly acidic, and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 40 mg of the product.

[0254] LC-MS(ESI):[M+H] + =573.0;

[0255] 1 H NMR (400MHz, DMSO-d6) δ7.57-7.51(m,2H),7.51-7.44(m,1H),7.43-7.39(m,1H),7.15(dt,J=3.9,9.0Hz,1H),5.24-5.10(m,2H),4.71-4.51(m,4H).

[0256] Example 9: 3-(1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 9)

[0257] Step 1: Synthesis of 2,3,5,6-tetrafluorobenzoate

[0258] 2,3,5,6-Tetrafluorobenzoic acid (4.0 g, 20.61 mmol) was dissolved in methanol (40 mL), and thionyl chloride (1.6 mL, 21.64 mmol) was slowly added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was evaporated to dryness to obtain the crude product, which was then separated by silica gel column chromatography to obtain 3.2 g of the product.

[0259] Step 2: Synthesis of methyl 2-(2,2-difluoro-3-hydroxypropoxy)-3,5,6-trifluorobenzoate

[0260] 1,1-Difluoroethane-1,2-diol (1.2 g, 10.71 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (428 mg, 10.71 mmol) was added at 0 °C and stirred for 30 minutes. Then, 2,3,5,6-tetrafluorobenzoate (1485 mg, 7.14 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at 0 °C for another 30 minutes. The reaction mixture was poured into a saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed twice with a saturated calcium chloride aqueous solution. The organic phases were dried and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 718 mg of the product.

[0261] LC-MS(ESI):[M+H] + =301.1;

[0262] 1 H NMR (400MHz, CDCl3) δ7.16 (m, 1H), 4.42 (t, J = 11.6Hz, 2H), 4.00 (s, 3H), 3.99-3.90 (m, 2H), 2.77 (s, 1H).

[0263] Step 3: Synthesis of 2,2-difluoro-3-(3,4,6-trifluoro-2-(hydroxymethyl)phenoxy)prop-1-ol

[0264] Methyl 2-(2,2-difluoro-3-hydroxypropoxy)-3,5,6-trifluorobenzoate (800 mg, 2.67 mmol) was dissolved in tetrahydrofuran (8 mL). Lithium aluminum hydride (200 mg, 2.67 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at 20 °C for 3 hours. Water (0.5 mL), 15% sodium hydroxide aqueous solution (0.5 mL), and then water (1.5 mL) were slowly added to the reaction mixture. After stirring for another 30 minutes, the mixture was filtered directly, and the combined organic phases were evaporated to dryness to obtain 716 mg of the product.

[0265] Step 4: Synthesis of 3-(2-(((2,4-difluoro-5-nitrophenoxy)methyl)-3,4,6-trifluorophenoxy)-2,2-difluoropropane-1-ol

[0266] 2,2-Difluoro-3-(3,4,6-trifluoro-2-(hydroxymethyl)phenoxy)prop-1-ol (700 mg, 2.57 mmol) and 2,4-difluoro-5-nitrophenol (450 mg, 2.57 mmol) were dissolved in toluene (7 mL), and (tributyl-λ5-oxophosphine)acetonitrile (1241 mg, 5.14 mmol) was added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 700 mg of the product.

[0267] 1 H NMR (400MHz, CDCl3) δ7.92-7.85(m,1H),7.17-7.04(m,2H),5.27(s,2H),4.43(t,J=12.0Hz,2H),4.01-3.87(m,2H),1.99(s,1H).

[0268] Step 5: Synthesis of 1,2,4,7,11-hexafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0269] 3-(2-(((2,4-difluoro-5-nitrophenoxy)methyl)-3,4,6-trifluorophenoxy)-2,2-difluoropropane-1-ol (640 mg, 1.49 mmol) was dissolved in N,N-dimethylformamide (600 mL), and cesium fluoride (2.3 g, 14.91 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (500 mL × 3), the organic phases were combined, washed with saturated calcium chloride aqueous solution (500 mL), and evaporated to dryness to give 360 ​​mg of product.

[0270] Step 6: Synthesis of 1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine

[0271] 1,2,4,7,11-hexafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (350 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (5 mL), and bis(boronic acid) (383 mg, 4.28 mmol) and 4,4'-bispyridine (13 mg, 0.09 mmol) were slowly added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 295 mg of the product.

[0272] LC-MS(ESI):[M+H] + =380.1;

[0273] Step 7: Synthesis of dimethyl 4-(3-(1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0274] 1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (85 mg, 0.22 mmol) and 3-methyl(methoxycarbonyl)-4-(((phenoxy)carbonyl)amino)thiophene-2-carboxylic acid ester (86 mg, 0.26 mmol) were dissolved in tetrahydrofuran (2 mL), and triethylamine (0.1 mL, 0.67 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 90 mg of the product.

[0275] LC-MS (ESI): [M+Na] + =643.0;

[0276] Step 8: Synthesis of 3-(1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0277] Dimethyl 4-(3-(1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid (80 mg, 0.13 mmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (0.5 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was slowly added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (10 mL), and the pH was adjusted to weakly acidic by adding an appropriate amount of hydrochloric acid (1 M). Ethyl acetate (30 mL × 3) was added for extraction, and the organic phase was dried by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 46 mg of the product.

[0278] LC-MS(ESI):[M+H] + =575.1;

[0279] 1 H NMR(400MHz,DMSO-d6)δ14.35(s,1H),12.89(s,1H),7.83 -7.65(m,1H),7.62(d,J=7.6Hz,1H),7.45(d,J=10.4Hz,1H),7.31(s,1H),5.21(s,2H),4.63-4.53(m,4H).

[0280] Example 10 Synthesis of 3-(1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 10)

[0281] Step 1: Synthesis of methyl 3-(1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0282] 1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (200 mg, 0.53 mmol) and dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (223 mg, 0.64 mmol) (synthetic method as described in step 1 of Example 4) were dissolved in tetrahydrofuran (5 mL), and triethylamine (0.2 mL, 1.59 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 155 mg of the product.

[0283] LC-MS(ESI):[M+H] + =605.0;

[0284] Step 2: Synthesis of 3-(1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0285] Methyl 3-(1,2,4,7,11-hexafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (150 mg, 0.25 mmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (0.5 mL). Lithium hydroxide monohydrate (30 mg, 0.71 mmol) was slowly added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (10 mL), and the pH was adjusted to weakly acidic by adding an appropriate amount of hydrochloric acid (1 M). Ethyl acetate (30 mL × 3) was added for extraction. The organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 99 mg of the product.

[0286] LC-MS(ESI):[M+H] + =591.0;

[0287] 1 H NMR (400MHz, DMSO-d6) δ14.10 (s, 1H), 13.45 (s, 1H), 7.82-7.75 (m, 1H), 7.54 (d, J = 7. 6Hz,1H),7.52(s,1H),7.40(d,J=10.4Hz,1H),5.26-5.14(m,2H),4.65-4.52(m,4H).

[0288] Example 11 2,4-Dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl-15,15-d2)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 11)

[0289] Step 1: Synthesis of methyl 6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorobenzoate

[0290] Methyl 2,3-difluoro-6-hydroxybenzoate (349 mg, 1.86 mmol) and potassium carbonate (699 mg, 5.06 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 3-((2-(benzyloxy)-5-fluorophenyl)oxy)-2,2-difluoropropyltrifluoromethanesulfonate (750 mg, 1.69 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 12 hours. The reaction solution was poured into water (20 mL), and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated brine, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 720 mg of the product.

[0291] LC-MS (ESI): [M+Na] + =505.1;

[0292] Step 2: Synthesis of (6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methane-d2-ol

[0293] Methyl 6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorobenzoate (700 mg, 1.45 mmol) was dissolved in tetrahydrofuran (10 mL), and deuterated lithium aluminum hydride (304 mg, 7.26 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. Water (0.5 mL), 15% sodium hydroxide solution (0.5 mL), and water (1.5 mL) were slowly added to the reaction mixture at 0 °C, and the mixture was stirred for 15 minutes. A suitable amount of sodium sulfate was then added, and stirring continued for another 15 minutes. The mixture was filtered, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 660 mg of the final product.

[0294] LC-MS (ESI): [M+Na] + =479.1;

[0295] Step 3: Synthesis of 2-(3-(3,4-difluoro-2-(hydroxymethyl-d2)phenoxy)-2,2-difluoropropoxy)-4-fluorophenol

[0296] (6-(3-(2-(benzyloxy)-5-fluorophenoxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methane-d2-ol (640 mg, 0.01 mmol) was dissolved in isopropanol (50 mL), and then palladium / carbon (149 mg) was slowly added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction solution was filtered, and the organic phase was evaporated to dryness to give 510 mg of the product.

[0297] LC-MS(ESI):[MH] - =365.1;

[0298] Step 4: Synthesis of 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene-15,15-d2

[0299] 2-(3-(3,4-difluoro-2-(hydroxymethyl-d2)phenoxy)-2,2-difluoropropoxy)-4-fluorophenol (570 mg, 1.56 mmol) was dissolved in toluene (500 mL), and (tributyl-λ5-oxophosphine)acetonitrile (1.1 g, 4.67 mmol) was added. The reaction mixture was stirred at 80 °C for 1 hour. The reaction solution was directly evaporated to dryness, water (20 mL) was added, and then extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 260 mg of the product.

[0300] 1 H NMR (400MHz, CDCl3) δ7.24-7.12(m,2H),6.95-6.80(m,3H),4.46(t,J=11.2Hz,2H),4.42-4.33(m,2H).

[0301] Step 5: Synthesis of 1,2,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene-15,15-d2

[0302] 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-15,15-d2 (230 mg, 0.66 mmol) was dissolved in glacial acetic acid (1 mL, 17.45 mmol), and concentrated nitric acid (1 mL) was added at 60 °C. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 65 mg of the product.

[0303] Step 6: Synthesis of 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-15,15-d2-12-amine

[0304] 1,2,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-15,15-d2 (60 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (1 mL), and bis(boronic acid) (68 mg, 0.76 mmol) and 4,4'-bispyridine (5 mg, 0.02 mmol) were added. The reaction mixture was reacted at 20 °C for 1 hour. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 66 mg of the product.

[0305] LC-MS(ESI):[M+H] + =364.0;

[0306] Step 7: Synthesis of dimethyl 4-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl-15,15-d2)ureo)thiophene-2,3-dicarboxylic acid ester

[0307] 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-15,15-d2-12-amine (65 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), and then triethylamine (0.1 mL, 0.54 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 30 mg of the product.

[0308] LC-MS(ESI):[M+H] + =605.1;

[0309] Step 8: Synthesis of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl-15,15-d2)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0310] Dimethyl 4-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl-15,15-d2)ureo)thiophene-2,3-dicarboxylic acid (25 mg, 0.04 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL). Lithium hydroxide monohydrate (8.0 mg, 0.2 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (10 mL), and the pH was adjusted to weakly acidic by adding an appropriate amount of hydrochloric acid (1 M). Ethyl acetate (30 mL × 3) was added for extraction. The organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 14 mg of the product.

[0311] LC-MS(ESI):[M+H] + =559.0;

[0312] 1 H NMR (400MHz, DMSO-d6) δ14.35(s,1H),11.95(s,1H),7.52-7.37(m,3H),7.37-7.29(m,1H),7.28-7.21(m,1H),4.74-4.58(m,4H).

[0313] Example 12: Synthesis of (R)-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 12a) and (S)-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 12b).

[0314] Step 1: Synthesis of 1-(6-(3-(((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)ethane-1-ol

[0315] 6-(3-(((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)-2,3-difluorobenzaldehyde (3.5 g, 7.13 mmol) was dissolved in tetrahydrofuran (30 mL), and 2.5 M methyl magnesium bromide tetrahydrofuran solution (7.1 mL, 21.40 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into ice water (20 mL), and extracted with ethyl acetate (40 mL × 3). The extract was dried over saturated brine, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 3.0 g of the final product.

[0316] LC-MS (ESI): [M+Na] + =529.1;

[0317] Step 2: Synthesis of tert-butyl(3-(2-(1-(2,4-difluoro-5-nitrophenoxy)ethyl)-3,4-difluorophenoxy)-2,2-difluoropropoxy)diphenylsilane

[0318] 1-(6-(3-(((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)ethane-1-ol (1.0 g, 1.97 mmol), 2,4-difluoro-5-nitrophenol (414 mg, 2.37 mmol), and triphenylphosphine (776 mg, 2.96 mmol) were dissolved in tetrahydrofuran (10 mL), and diisopropyl azodicarbonate (0.6 mL, 2.96 mmol) was added dropwise at 0 °C. The reaction mixture was reacted at 20 °C for 1 hour. The reaction mixture was poured into ice water (20 mL), extracted with ethyl acetate (40 mL × 3), dried over saturated brine, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 800 mg of the product.

[0319] LC-MS (ESI): [M+Na] + =686.2;

[0320] Step 3: Synthesis of 1,2,7,7,11-pentafluoro-15-methyl-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0321] 750 mg (1.13 mmol) of tert-butyl(3-(2-(1-(2,4-difluoro-5-nitrophenoxy)ethyl)-3,4-difluorophenoxy)-2,2-difluoropropoxy)diphenylsilane was dissolved in 500 mL of N,N-dimethylformamide, and 200 mg (11.30 mmol) of cesium fluoride was added. The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was then poured into 500 mL of ice water, and extracted with ethyl acetate (500 mL × 3). The extract was dried over saturated brine and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 210 mg of the product.

[0322] Step 4: Synthesis of (R)-1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine and (S)-1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine

[0323] 1,2,7,7,11-pentafluoro-15-methyl-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (210 mg, 0.52 mmol) was dissolved in N,N'-dimethylformamide (5 mL), and bis(boronic acid) (139 mg, 1.55 mmol) and 4,4'-bispyridine (5.0 mg, 0.05 mmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated calcium chloride aqueous solution, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the racemic mixture, and then further purified by SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm), Condition: CO2-EtOH (0.1% NH4OH). 3· Two chiral target products were obtained by separation using H2O.

[0324] LC-MS(ESI):[M+H] + =376.1;

[0325] Step 5: Synthesis of (R)-4-(3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid dimethyl ester and (S)-4-(3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid dimethyl ester)

[0326] (R)-1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine or (S)-1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (40 mg, 0.11 mmol) and methyl 3-(methoxycarbonyl)-4-(((phenoxy)carbonyl)amino)thiophene-2-carboxylate (43 mg, 0.13 mmol) were dissolved in tetrahydrofuran (1 mL), and then triethylamine (0.1 mL, 0.32 mmol) was added. The reaction solution was reacted at 60 °C for 3 hours. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 51 mg of the product.

[0327] LC-MS(ESI):[M+H] + =617.0;

[0328] Step 6: Synthesis of (R)-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid and (S)-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0329] Dimethyl (R)-4-(3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester or (S)-4-(3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester (50 mg, 0.08 mmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (0.5 mL). Lithium hydroxide monohydrate (10 mg, 0.24 mmol) was slowly added, and the reaction solution was stirred at 20 °C for 1 hour. The reaction solution was poured into water (10 mL), and an appropriate amount of hydrochloric acid (1 M) was added to adjust the pH to weakly acidic. Ethyl acetate (30 mL × 3) was added for extraction, and the organic phase was dried by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain the corresponding target product.

[0330] LC-MS(ESI):[M+H] + =571.2;

[0331] 1 H NMR(400MHz,DMSO-d6)δ14.47(s,1H),11.96(s,1H),7.43-7.34(m,2H),7.30 -7.20(m,1H),7.27-7.15(m,2H),5.99-5.85(m,1H),4.82-4.75(m,1H),4.68-4.56(m,2H),4.55–4.48(m,1H),1.60(d,J=6.4Hz,3H).

[0332] Example 13 Synthesis of (Z)-2-(cyanimino)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 13a) and (E)-2-(cyanimino)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 13b).

[0333] Step 1: Synthesis of methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0334] 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (450 mg, 1.25 mmol) and dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (500 mg, 1.42 mmol) (synthetic method as described in step 1 of Example 4) were dissolved in tetrahydrofuran (6 mL), and then triethylamine (378 mg, 3.74 mmol) was added. The reaction mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was filtered and evaporated to dryness to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain 730 mg of the product.

[0335] LC-MS(ESI):[M+H] + =587.1;

[0336] Step 2: Synthesis of methyl 2-(methylthio)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0337] Methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester (330 mg, 0.56 mmol) and iodomethane (240 mg, 1.69 mmol) were dissolved in N,N-dimethylformamide (4 mL), followed by the addition of potassium carbonate (233 mg, 1.69 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed once with saturated calcium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 330 mg of the product.

[0338] LC-MS(ESI):[M+H] + =601.1;

[0339] Step 3: Synthesis of 2-(methylthio)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0340] Methyl 2-(methylthio)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester (320 mg, 0.53 mmol), lithium bromide (463 mg, 5.33 mmol), and triethylamine (539 mg, 5.33 mmol) were dissolved in acetonitrile (3 mL) and water (3 mL). The reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to 2-3 with 1 M hydrochloric acid. It was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed once with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 310 mg of product.

[0341] LC-MS(ESI):[M+H] + =587.1;

[0342] Step 4: Synthesis of 2-(methanesulfonyl)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0343] 2-(methylthio)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid (100 mg, 0.18 mmol) and m-chloroperoxybenzoic acid (104 mg, 0.52 mmol) were dissolved in dichloromethane (4 mL), and the reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with saturated sodium sulfite solution (50 mL), diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed once 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 silica gel column chromatography to give 70 mg of the product.

[0344] LC-MS(ESI):[M+H] + =619.0;

[0345] 1H NMR (400MHz, DMSO-d6) δ14.09(s,1H),8.58(s,1H),7.55(d,J=7.6Hz,1H),7.53-7.47(m,1H),7.44 (d,J=10.8Hz,1H),7.25(dd,J=2.4,9.6Hz,1H),5.15-5.04(m,2H),4.76-4.65(m,4H),3.51(s,3H).

[0346] Step 5: Synthesis of (Z)-2-(cyanimino)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid and (E)-2-(cyanimino)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0347] 2-(methanesulfonyl)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]oxacycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid (50 mg, 0.08 mmol), azobenzonitrile (34 mg, 0.40 mmol), and ethyl diisopropylamine (32 mg, 0.24 mmol) were dissolved in 1,4-dioxane (2 mL). The reaction mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, the pH of the reaction mixture was adjusted to 2-3 with 1 M hydrochloric acid. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL × 2). The organic phases were washed once with a saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a crude product. The crude product was separated by high performance liquid chromatography to obtain 10 mg of product.

[0348] LC-MS(ESI):[M+H] + =581.1;

[0349] 1 H NMR(400MHz,DMSO-d6)δ14.57-14.32(m,1H),12.02(s,1H),7.64(s,1H),7.5 2-7.37(m,3H),7.25(d,J=10.0Hz,1H),5.20-5.09(m,2H),4.76-4.58(m,4H).

[0350] Example 14 2-Imine-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 14)

[0351] Step 1: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0352] The starting material 2-(methanesulfonyl)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid (120 mg, 0.19 mmol) (synthetic method as described in Example 13) was dissolved in tetrahydrofuran (2 mL) and ammonia (2 mL). The reaction mixture was stirred at 20 °C for 1 hour. The pH of the reaction mixture was adjusted to 2-3 with 1M hydrochloric acid. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed once 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 separated by high performance liquid chromatography to obtain 20 mg of the final product.

[0353] LC-MS(ESI):[M+H] + =556.0;

[0354] 1H NMR(400MHz,DMSO-d6)δ14.36-13.92(m,1H),9.35(s,1H),9.23(s,1H),8.08-8.00(m,2H),7.51(s ,1H),7.34(s,1H),7.30-7.22(m,1H),5.08(s,2H),4.60(t,J=11.6Hz,2H),4.48(t,J=11.6Hz,2H).

[0355] Example 15 Synthesis of (R)-4-oxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 15a) and (S)-4-oxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 15b).

[0356] Step 1: Synthesis of (R)-4-oxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid methyl ester and (S)-4-oxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid methyl ester

[0357] (R)-1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine or (S)-1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (40 mg, 0.11 mmol) and dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (41 mg, 0.12 mmol) were dissolved in tetrahydrofuran (1 mL), and then triethylamine (0.1 mL, 0.32 mmol) was added. The reaction solution was reacted at 60 °C for 3 hours. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was then subjected to silica gel column chromatography to obtain the target product.

[0358] LC-MS (ESI): [M+Na] + =601.0;

[0359] Step 2: Synthesis of (R)-4-oxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid and (S)-4-oxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0360] Methyl (R)-4-oxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylate or (S)-4-oxo-3-(1,2,7,7,11-pentafluoro-15-methyl-7,8-dihydro-6H, Methyl 15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (40 mg, 0.07 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (0.5 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was slowly added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (10 mL), and the pH was adjusted to weakly acidic by adding an appropriate amount of hydrochloric acid (1 M). Ethyl acetate (30 mL × 3) was added for extraction, and the organic phase was dried by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain the corresponding target product.

[0361] LC-MS(ESI):[M+H] + =587.1;

[0362] 1 H NMR(400MHz,DMSO-d6)δ14.18(s,1H),13.16(s,1H),7.51(s,1H),7.37(m,1H),7.26-7.18(m,2H),7.18-7.1 0(m,1H),5.93(m,1H),4.91-4.74(m,1H),4.67-4.59(m,1H),4.58-4.41(m,2H),1.60(dd,J=2.8,6.4Hz,3H).

[0363] Example 16 Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-15,15-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 16)

[0364] Step 1: Synthesis of methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-15,15-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0365] 1,2,7,7,11-pentafluoro-15,15-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (25 mg, 0.06 mmol) and dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (27 mg, 0.08 mmol) were dissolved in tetrahydrofuran (1 mL), and then triethylamine (69 mg, 0.68 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, the mixture was filtered and evaporated to dryness to obtain the crude product. The crude product was purified by preparative thin-layer chromatography to obtain 20 mg of the final product.

[0366] LC-MS(ESI):[M+H] + =615.1;

[0367] Step 2: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-15,15-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0368] The starting materials 4-oxo-3-(1,2,7,7,11-pentafluoro-15,15-dimethyl-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid methyl ester (15 mg, 0.02 mmol) and lithium hydroxide monohydrate (6 mg, 0.14 mmol) were dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). The reaction mixture was stirred at 20 °C for 1 hour. The pH of the reaction solution was adjusted to 2-3 with hydrochloric acid (1M). The reaction solution was diluted with water (50mL) and extracted with ethyl acetate (50mL×2). The organic phases were combined and washed once with saturated sodium chloride aqueous solution (50mL). The mixture was 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 3mg of product.

[0369] LC-MS(ESI):[M+H] + =601.0;

[0370] 1 H NMR(400MHz,DMSO-d6)δ7.46-7.34(m,1H),7.32-7.16(m,2H),7.05-6.96(m,1H),6.67(br dd,J=2.8,8.7Hz,1H),4.93-4.67(m,2H),4.36-3.93(m,2H),1.97(br d,J=6.0Hz,3H),1.89(s,3H).

[0371] Example 17 Synthesis of 4-oxo-3-(3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcycloundecene[2,3-b]pyridin-2-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 17)

[0372] Step 1: Synthesis of 6-(2,2-difluoro-3-hydroxypropoxy)-2,3-difluorobenzaldehyde

[0373] 6-(3-(((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)-2,3-difluorobenzaldehyde (1.6 g, 3.30 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.9 mL, 6.60 mmol) was added. The reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1.1 g of the product.

[0374] LC-MS(ESI):[M+H] + =253.0;

[0375] Step 2: Synthesis of 3-(3,4-difluoro-2-formylphenoxy)-2,2-difluoropropyltrifluoromethanesulfonate

[0376] 6-(2,2-difluoro-3-hydroxypropoxy)-2,3-difluorobenzaldehyde (850 mg, 3.37 mmol) and pyridine (0.4 mL, 5.06 mmol) were dissolved in dichloromethane (15 mL). Trifluoromethanesulfonic anhydride (0.8 mL, 5.06 mmol) was added at 0 °C, and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into ice water (30 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1.1 g of the product.

[0377] Step 3: Synthesis of 3,6-difluoropyridine-2-amine

[0378] 2,3,6-Trifluoropyridine (10 g, 75.15 mmol) was dissolved in ammonia (50 mL, 1298.15 mmol), and the reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 7.0 g of the product.

[0379] 1 H NMR (400MHz, CDCl3) δ7.34-7.28(m,1H),6.19(m,1H),5.31-4.22(m,2H).

[0380] Step 4: Synthesis of 5-bromo-3,6-difluoropyridine-2-amine

[0381] 3,6-Difluoropyridine-2-amine (4.4 g, 33.82 mmol) was dissolved in acetonitrile (200 mL), and N-bromosuccinimide (6.0 g, 33.82 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into ice water (300 mL), extracted with ethyl acetate (500 mL × 3), and the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 5.0 g of the product.

[0382] 1 H NMR (400MHz, DMSO-d6) δ7.87 (dd, J=7.2, 9.2Hz, 1H), 6.86 (s, 2H).

[0383] Step 5: Synthesis of 5-bromo-3,6-difluoro-N,N'-bis(4-methoxybenzyl)pyridine-2-amine

[0384] 5-Bromo-3,6-difluoropyridine-2-amine (3.5 g, 16.60 mmol) was dissolved in dimethylacetamide (20 mL). Sodium hydride (2 g, 49.81 mmol) was added at 0 °C and stirred for 0.5 hours. Then, 1-(chloromethyl)-4-methoxybenzene (4.5 mL, 33.21 mmol) was added, and the reaction mixture was stirred at 20 °C for 1.5 hours. The reaction mixture was then poured into ice water (30 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 5.2 g of the final product.

[0385] LC-MS(ESI):[M+H] + =449.0;

[0386] Step 6: Synthesis of (6-(bis(4-methoxybenzyl)amino)-2,5-difluoropyridin-3-yl)boronic acid

[0387] 5-Bromo-3,6-difluoro-N,N'-bis(4-methoxybenzyl)pyridine-2-amine (3.8 g, 8.46 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (4.4 g, 16.92 mmol), bis[5-(diphenylphosphino)cyclopentan-1,3-dienyl]-2-iron(II)palladium chloride (0.62 g, 0.85 mmol) and potassium acetate (1.66 g, 16.92 mmol) were dissolved in dioxane (60 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was first evaporated to dryness, then poured into water (30 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 2.6 g of the product.

[0388] LC-MS(ESI):[M+H] + =497.2;

[0389] Step 7: Synthesis of 6-(bis(4-methoxybenzyl)amino)-2,5-difluoropyridine-3-ol

[0390] (6-(bis(4-methoxybenzyl)amino)-2,5-difluoropyridin-3-yl)boronic acid (2.6 g, 5.24 mmol) was dissolved in tetrahydrofuran (10 mL), and hydrogen peroxide (10 mL, 332.26 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into a saturated sodium sulfite solution (25 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed twice with a saturated calcium chloride aqueous solution. The organic phases were dried and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1.5 g of the product.

[0391] LC-MS(ESI):[M+H] + =387.1;

[0392] Step 8: Synthesis of 6-(3-((6-(bis(4-methoxybenzyl)amino)-2,5-difluoropyridin-3-yl)oxy)-2,2-difluoropropoxy)-2,3-difluorobenzaldehyde

[0393] 6-(bis(4-methoxybenzyl)amino)-2,5-difluoropyridin-3-ol (1.0 g, 2.59 mmol) was dissolved in dimethylformamide (10 mL), and potassium carbonate (1.1 g, 7.76 mmol) and 3-(3,4-difluoro-2-formylphenoxy)-2,2-difluoropropyltrifluoromethanesulfonate (1.2 g, 3.11 mmol) were added. The reaction mixture was stirred at 60 °C for 6 hours. The reaction mixture was poured into ice water (30 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 480 mg of the product.

[0394] LC-MS(ESI):[M+H] + =621.1;

[0395] Step 9: Synthesis of (6-(3-((6-(bis(4-methoxybenzyl)amino)-2,5-difluoropyridin-3-yl)oxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methanol

[0396] 6-(3-((6-(bis(4-methoxybenzyl)amino)-2,5-difluoropyridin-3-yl)oxy)-2,2-difluoropropoxy)-2,3-difluorobenzaldehyde (460 mg, 0.74 mmol) was dissolved in ethanol (5 mL), and sodium borohydride (80 mg, 1.11 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into ice water (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 340 mg of the product.

[0397] LC-MS(ESI):[M+H] + =623.1;

[0398] Step 10: Synthesis of 3,7,7,12,13-pentafluoro-N,N'-bis(4-methoxybenzyl)-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcycloundecene[2,3-b]pyridine-2-amine

[0399] (6-(3-((6-(bis(4-methoxybenzyl)amino)-2,5-difluoropyridin-3-yl)oxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methanol (320 mg, 0.51 mmol) was dissolved in dimethylformamide (60 mL), and sodium hydride (41 mg, 1.03 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (500 mL × 3), the organic phases were combined, washed with saturated calcium chloride, and evaporated to dryness to give 180 mg of product.

[0400] LC-MS(ESI):[M+H] + =603.0;

[0401] Step 11: Synthesis of 3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolecycloundecaamino[2,3-b]pyridine-2-amine

[0402] 3,7,7,12,13-pentafluoro-N,N'-bis(4-methoxybenzyl)-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcycloundecene[2,3-b]pyridine-2-amine (150 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL, 13.46 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 20 °C for 5 hours. The reaction mixture was poured into ice water (30 mL), and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. Then, it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 52 mg of the product.

[0403] LC-MS(ESI):[M+H] + =363.0;

[0404] Step 12: Synthesis of methyl 4-oxo-3-(3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcycloundecene[2,3-b]pyridin-2-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0405] 3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolecycloundecaamino[2,3-b]pyridine-2-amine (25 mg, 0.22 mmol) and dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (25 mg, 0.26 mmol) were dissolved in tetrahydrofuran (2 mL), and triethylamine (0.1 mL, 0.67 mmol) was added. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 21 mg of the product.

[0406] LC-MS(ESI):[M+H] + =588.0;

[0407] Step 13: Synthesis of 4-oxo-3-(3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcycloundecene[2,3-b]pyridin-2-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0408] Methyl 4-oxo-3-(3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcycloundecene[2,3-b]pyridin-2-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (20 mg, 0.02 mmol) was dissolved in tetrahydrofuran (0.5 mL), methanol (0.5 mL), and water (0.3 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was slowly added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (10 mL), and the pH was adjusted to weakly acidic by adding an appropriate amount of hydrochloric acid (1 M). Ethyl acetate (30 mL × 3) was added for extraction, and the organic phase was dried by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 2 mg of the product.

[0409] LC-MS(ESI):[M+H] + =574.1;

[0410] 1H NMR (400MHz, DMSO-d6) δ13.71(s,2H),8.07(d,J=9.2Hz,1H),7.50(s,1H),7.46(d,J=9 .6Hz,1H),7.21-7.11(m,1H),5.42-5.30(m,2H),4.86-4.67(m,2H),4.65-4.47(m,2H).

[0411] Example 18 Synthesis of 2,4-dioxo-3-(3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcycloundecene[2,3-b]pyridin-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 18)

[0412] Step 1: Synthesis of dimethyl 4-(3-(3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazoliumcycloundecaamino[2,3-b]pyridin-2-yl)ureo)thiophene-2,3-dicarboxylic acid ester)

[0413] 3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolecycloundecaamino[2,3-b]pyridine-2-amine (25 mg, 0.07 mmol) and dimethyl 4-((phenoxythiocarbonyl)amino)thiophene-2,3-dicarboxylic acid (25 mg, 0.08 mmol) were dissolved in tetrahydrofuran (1 mL), and triethylamine (0.03 mL, 0.21 mmol) was added. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 11 mg of the product.

[0414] LC-MS(ESI):[M+H] + =604.0;

[0415] Step 2: Synthesis of 2,4-dioxo-3-(3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcycloundecene[2,3-b]pyridin-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0416] Dimethyl 4-(3-(3,7,7,12,13-pentafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolium cycloundecaamino[2,3-b]pyridin-2-yl)ureo)thiophene-2,3-dicarboxylate (10 mg, 0.02 mmol) was dissolved in tetrahydrofuran (0.5 mL), methanol (0.5 mL), and water (0.3 mL). Lithium hydroxide monohydrate (10 mg, 0.24 mmol) was slowly added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (10 mL), and the pH was adjusted to weakly acidic by adding an appropriate amount of hydrochloric acid (1 M). Ethyl acetate (30 mL × 3) was added for extraction, and the organic phase was dried by rotary evaporation to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 1 mg of the product.

[0417] LC-MS(ESI):[M+H] + =558.1;

[0418] 1 H NMR (400MHz, DMSO-d6) δ14.16 (s, 1H), 12.17-11.72 (m, 1H), 8.11 (d, J = 9.2Hz, 1H), 7.5 2-7.44(m,1H),7.27-7.15(m,2H),5.39-5.33(m,2H),4.73(m,2H),4.62-4.52(m,2H).

[0419] Example 19 Synthesis of 2,4-dioxo-3-(1',2',7',7',11'-pentafluoro-6',7'-dihydro-15'H-spiro[cyclopropane-1,8'-dibenzo[b,f][1,4,8]triazolylcycloundecene]-12'-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 19)

[0420] Step 1: Synthesis of methyl 1-(benzyloxy)cyclopropane-1-carboxylic acid

[0421] 1-Hydroxycyclopropane-1-carboxylic acid methyl ester (10 g, 86.12 mmol) was dissolved in N,N-dimethylformamide (100 mL), and the solution was cooled to 0–5 °C. Sodium hydrogen hydrate (4.48 g, 111.95 mmol) was added in portions at 0 °C. After the addition was complete, the mixture was stirred for 0.5 h. Then, benzyl bromide (12.4 mL, 103.34 mmol) was added dropwise to the reaction mixture, and the mixture was heated to room temperature and stirred for 6 h. After the reaction was complete, the reaction was quenched with saturated sodium chloride solution (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed once with saturated calcium chloride aqueous solution (200 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 give 9.1 g of the product.

[0422] 1 H NMR (400MHz, CDCl3) δ7.39-7.28(m,5H),4.67(s,2H),3.78(s,3H),1.40-1.35(m,2H),1.28-1.25(m,2H).

[0423] Step 2: Synthesis of 1-(benzyloxy)cyclopropane-1-carboxylic acid

[0424] 1-(benzyloxy)cyclopropane-1-carboxylic acid methyl ester (4.00 g, 19.39 mmol) was dissolved in ethanol (20 mL) and water (5 mL), and then sodium hydroxide (3.88 g, 96.97 mmol) solid was added. The reaction mixture was stirred at 20 °C for 1 hour. The pH of the reaction mixture was adjusted to acidic by adding 1 molar hydrochloric acid, followed by extraction with ethyl acetate (100 mL × 2). The combined organic phases were washed once with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give 3.7 g of product.

[0425] Step 3: Synthesis of 1-(benzyloxy)cyclopropane-1-carbonyl chloride

[0426] Add 1-(benzyloxy)cyclopropane-1-carboxylic acid (3700 mg, 19.25 mmol), sulfoxide (27.9 mL, 385.00 mmol), and one drop of N,N-dimethylformamide to a round-bottom flask. After the addition of the reactants, stir the reaction mixture at 70 °C for one hour. The reaction mixture was then directly evaporated to dryness to obtain 4 g of the product.

[0427] Step 4: Synthesis of 1-(1-(benzyloxy)cyclopropyl)-2-chloroethane-1-one

[0428] 1-(benzyloxy)cyclopropane-1-carbonyl chloride (4 g, 18.99 mmol) was dissolved in tetrahydrofuran (20 mL) and acetonitrile (20 mL), and the reaction solution was cooled to 0 °C in an ice bath. Trimethylsilyldiazomethane solution (19.0 mL, 37.98 mmol) was slowly added to the reaction solution. After the addition was complete, the reaction solution was stirred at 0 °C for 1 hour. Then, concentrated hydrochloric acid (3.2 mL, 37.98 mmol) was added, and the reaction solution was stirred at 0 °C for another hour. Ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL) were added directly to the reaction solution. After separation, the aqueous phase was extracted once with ethyl acetate (50 mL). The combined organic phases were washed once with saturated brine (100 mL), then dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 2.4 g of product.

[0429] 1H NMR (400MHz, CDCl3) δ7.38-7.33(m,5H),4.59(s,2H),4.55(s,2H),1.50-1.44(m,2H),1.42-1.38(m,2H).

[0430] Step 5: Synthesis of 1-(1-(benzyloxy)cyclopropyl)-2-iodoethane-1-one

[0431] 1-(1-(benzyloxy)cyclopropyl)-2-chloroethane-1-one (2.40 g, 10.68 mmol) and sodium iodide (1.92 g, 12.82 mmol) were dissolved in acetone (24 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered directly, and the filter cake was washed with 50 mL of acetone. The filtrate was directly evaporated to dryness to give 3.3 g of product.

[0432] 1 H NMR (400MHz, CDCl3) δ7.42-7.28(m,5H),4.64(s,2H),4.08(s,2H),1.51-1.45(m,2H),1.44-1.38(m,2H).

[0433] Step 6: Synthesis of 1-(1-(benzyloxy)cyclopropyl)-2-(3,4-difluoro-2-(hydroxymethyl)phenoxy)ethane-1-one

[0434] 1-(1-(benzyloxy)cyclopropyl)-2-iodoethane-1-one (3.00 g, 9.49 mmol), 3,4-difluoro-2-hydroxymethylphenol (1.01 g, 6.33 mmol), N,N-dimethylformamide (20 mL), and potassium carbonate (2.62 g, 18.98 mmol) were added sequentially to a reaction flask, and the reaction mixture was stirred at 50 °C for 1 hour. Ethyl acetate (50 mL) and aqueous solution (50 mL) were added to the reaction mixture. After separation, the aqueous phase was extracted once with ethyl acetate (50 mL). The combined organic phases were washed once with saturated brine (50 mL), then dried over anhydrous sodium sulfate, 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.

[0435] LC-MS (ESI): [M+Na] + =371.3;

[0436] Step 7: Synthesis of 6-(2-(1-(benzyloxy)cyclopropyl)-2-oxoethoxy)-2,3-difluorobenzylbenzoate

[0437] 1-(1-(benzyloxy)cyclopropyl)-2-(3,4-difluoro-2-(hydroxymethyl)phenoxy)ethane-1-one (2.00 g, 5.74 mmol) and triethylamine (2.4 mL, 17.22 mmol) were dissolved in dichloromethane (20 mL). After cooling the reaction mixture to 0 °C in an ice bath, a solution of benzoyl chloride (0.9 mL, 7.46 mmol) in dichloromethane (5 mL) was slowly added dropwise to the reaction system. The reaction mixture was heated to 20 °C and stirred for 1 hour. The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then filtered. The filtrate was evaporated to dryness, and the crude product was purified by silica gel column chromatography to obtain 2.1 g of the product.

[0438] LC-MS (ESI): [M+Na] + =475.3;

[0439] Step 8: Synthesis of 6-(2-(1-(benzyloxy)cyclopropyl)-2,2-difluoroethoxy)-2,3-difluorobenzylbenzoate

[0440] 6-(2-(1-(benzyloxy)cyclopropyl)-2-oxoethoxy)-2,3-difluorobenzylbenzoate (2.1 g, 4.64 mmol) and diethylaminosulfur trifluoride (12.3 mL, 92.83 mmol) were added sequentially to a reaction flask. The reaction mixture was stirred at 40 °C for 10 hours. The reaction mixture was quenched dropwise on ice. The aqueous phase was adjusted to neutral pH with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The crude product obtained by rotary evaporation was purified by silica gel column chromatography to give 1.0 g of the product.

[0441] LC-MS (ESI): [M+Na] + =497.2;

[0442] Step 9: Synthesis of (6-(2-(1-(benzyloxy)cyclopropyl)-2,2-difluoroethoxy)-2,3-difluorophenyl)methanol

[0443] 6-(2-(1-(benzyloxy)cyclopropyl)-2,2-difluoroethoxy)-2,3-difluorobenzylbenzoate (950 mg, 2.00 mmol) was dissolved in ethanol (10 mL) and water (2 mL). Sodium hydroxide (400 mg, 10.01 mmol) was then added to the reaction solution in portions, and the mixture was stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give 700 mg of the product.

[0444] LC-MS (ESI): [M+Na]+ =393.1;

[0445] Step 10: Synthesis of 1-(2-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-1,1-difluoroethyl)cyclopropane-1-ol

[0446] (6-(2-(1-(benzyloxy)cyclopropyl)-2,2-difluoroethoxy)-2,3-difluorophenyl)methanol (700 mg, 1.89 mmol), palladium on carbon (100 mg, 0.95 mmol), and methanol (7 mL) were added sequentially to a reaction flask under a nitrogen atmosphere. The reaction mixture was purged with hydrogen three times. After purging, the reaction solution was heated to 60 °C and stirred under a hydrogen atmosphere for 3 hours. The reaction solution was directly filtered, and the filter cake was washed with (50 mL) methanol. The filtrates were combined and evaporated to dryness to obtain 510 mg of product.

[0447] LC-MS (ESI): [M-OH] + =263.1;

[0448] Step 11: Synthesis of 1-(2-(2-(((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)-1,1-difluoroethyl)cyclopropane-1-ol

[0449] 1-(2-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-1,1-difluoroethyl)cyclopropane-1-ol (530 mg, 1.89 mmol), 2,4-difluoro-5-nitrophenol (364 mg, 2.08 mmol), and triphenylphosphine (843 mg, 3.22 mmol) were dissolved in tetrahydrofuran (5 mL) and cooled to 0 °C in an ice bath. Diisopropyl azodicarbonate (0.6 mL, 2.84 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the reaction solution was heated to room temperature and stirred for 0.5 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered. The crude product obtained by rotary evaporation was purified by reverse-phase column chromatography to give 750 mg of the product.

[0450] Step 12: Synthesis of 1',2',7',7',11'-pentafluoro-12'-nitro-6',7'-dihydro-15'H-spiro[cyclopropane-1,8'-dibenzo[b,f][1,4,8]triazolecycloundecene].

[0451] 1-(2-(2-((((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)-1,1-difluoroethyl)cyclopropane-1-ol (0.70 g, 1.60 mmol) and cesium carbonate (2.61 g, 8.00 mmol) were dissolved in N,N-dimethylformamide (350 mL). The reaction mixture was purged with nitrogen three times and heated to 80 °C under a nitrogen atmosphere with stirring for 1 hour. The reaction mixture was then extracted directly with saturated brine (300 mL) and ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated calcium chloride aqueous solution (200 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give 660 mg of product.

[0452] Step 13: Synthesis of 1',2',7',7',11'-pentafluoro-6',7'-dihydro-15'H-spiro[cyclopropane-1,8'-dibenzo[b,f][1,4,8]triazolylcycloundecene]-12'-amine

[0453] 1',2',7',7',11'-pentafluoro-12'-nitro-6',7'-dihydro-15'H-spiro[cyclopropane-1,8'-dibenzo[b,f][1,4,8]triazolylcycloundecene] (660 mg, 1.58 mmol) and 4,4'-bipyridine (25 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (6 mL). Tetrahydroxydiboron (567 mg, 6.33 mmol) was then added in portions to the reaction mixture, which was stirred at room temperature for 5 minutes. Water (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed once with saturated brine (50 mL) and once with saturated calcium chloride solution (50 mL), then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 310 mg of the product.

[0454] LC-MS(ESI):[M+H] + =388.1;

[0455] Step 14: Synthesis of dimethyl 4-(3-(1',2',7',7',11'-pentafluoro-6',7'-dihydro-15'H-spiro[cyclopropane-1,8'-dibenzo[b,f][1,4,8]triazolylcycloundecene]-12'-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0456] 1',2',7',7',11'-pentafluoro-6',7'-dihydro-15'H-spiro[cyclopropane-1,8'-dibenzo[b,f][1,4,8]triazolylcycloundecene]-12'-amine (60 mg, 0.15 mmol) and methyl 3-(methoxycarbonyl)-4-{[(phenoxy)carbonyl]amino}thiophene-2-carboxylate (57 mg, 0.17 mmol) were dissolved in tetrahydrofuran (1 mL), and triethylamine (0.1 mL, 0.46 mmol) was added. The reaction mixture was stirred at 70 °C for 2 hours. Water (10 mL) was added directly to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The crude product obtained by rotary evaporation was purified by silica gel column chromatography to give 76 mg of the product.

[0457] LC-MS(ESI):[M+H] + =629.2;

[0458] Step 15: Synthesis of 2,4-dioxo-3-(1',2',7',7',11'-pentafluoro-6',7'-dihydro-15'H-spiro[cyclopropane-1,8'-dibenzo[b,f][1,4,8]triazolylcycloundecene]-12'-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0459] Dimethyl 4-(3-(1',2',7',7',11'-pentafluoro-6',7'-dihydro-15'H-spiro[cyclopropane-1,8'-dibenzo[b,f][1,4,8]triazolylcycloundecene]-12'-yl)ureo)thiophene-2,3-dicarboxylic acid (76 mg, 0.12 mmol) was dissolved in tetrahydrofuran (1 mL), water (0.5 mL), and methanol (0.5 mL), and lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly added to 1M hydrochloric acid (20 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, and filtered. The crude product obtained by rotary evaporation of the filtrate was prepared by high performance liquid chromatography to yield 35 mg of the product.

[0460] LC-MS(ESI):[M+H] + =583.2;

[0461] 1H NMR(400MHz,DMSO-d6)δ14.85-14.08(m,1H),12.09-11.73(m,1H),7.54-7.43(m,2H),7 .38-7.31(m,1H),7.30-7.16(m,2H),5.21-5.09(m,2H),4.74(s,2H),1.28-1.16(m,4H).

[0462] Example 20 Synthesis of 7-chloro-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (Compound 20)

[0463] Step 1: Synthesis of dimethyl 4-amino-5-chlorothiophene-2,3-dicarboxylic acid ester

[0464] N-chlorosuccinimide (2 mg, 5.58 mmol) was added to a solution of 4-amino-3-(methoxy)thiophene-2-dicarboxylic acid dimethyl ester (1000 mg, 4.65 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography to obtain 200 mg of the product.

[0465] Step 2: Synthesis of dimethyl 5-chloro-4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid ester

[0466] Pyridine (0.050 mL, 0.60 mmol) and methyl phenylcarbonylchloroformate (0.015 mL, 0.12 mmol) were added to a tetrahydrofuran (2 mL) solution of 4-amino-5-chlorothiophene-2,3-dicarboxylic acid dimethyl ester (30 mg, 0.12 mmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography to obtain 20 mg of the product.

[0467] 1 H NMR (400MHz, CDCl3) δ7.42-7.38(m,2H),7.27-7.23(m,1H),7.21-7.16(m,2H),3.94(s,3H),3.92-3.87(m,3H).

[0468] Step 3: Synthesis of methyl 7-chloro-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0469] Dimethyl 5-chloro-4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (70 mg, 0.19 mmol), 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (68 mg, 0.19 mmol), and triethylamine (27 mg, 0.27 mmol) were dissolved in 3 mL of water. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was then separated by column chromatography to obtain 15 mg of the product.

[0470] LC-MS(ESI):[M+H] + =605.1;

[0471] Step 4: Synthesis of 7-chloro-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0472] Methyl 7-chloro-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (10 mg, 0.02 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (3 mg, 0.08 mmol) was added to the mixture, and the reaction solution was stirred at 20 °C for 30 minutes. The pH of the reaction solution was adjusted to <7 by adding 1 M dilute hydrochloric acid, then diluted with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 5 mg of the product.

[0473] LC-MS(ESI):[M+H] + =591.0;

[0474] 1H NMR (400MHz, DMSO-d6) δ7.55-7.38(m,3H),7.25(br dd,J=1.9,8.9Hz,1H),5.20-5.08(m,2H),4.77-4.57(m,4H).

[0475] Example 21 Synthesis of 7-fluoro-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (Compound 21)

[0476] Step 1: Synthesis of dimethyl 4-((tert-butylcarbonyl)amino)thiophene-2,3-dicarboxylic acid ester

[0477] Dimethyl 4-aminothiophene-2,3-dicarboxylic acid (2 g, 9.29 mmol) was dissolved in dichloromethane (60 mL), followed by the addition of di-tert-butyl dicarboxylic acid ester (2.4 mL, 11.15 mmol), 4-dimethylaminopyridine (0.5 g, 4.09 mmol), and triethylamine (2.6 mL, 18.59 mmol). The reaction mixture was stirred at 20 °C for 16 hours. The reaction solution was evaporated to dryness to obtain the crude product, which was then separated by column chromatography to obtain 1 g of the product.

[0478] Step 2: Synthesis of dimethyl 4-((tert-butylcarbonyl)amino)-5-fluorothiophene-2,3-dicarboxylic acid ester

[0479] Dimethyl 4-((tert-butylcarbonyl)amino)thiophene-2,3-dicarboxylic acid (315 mg, 1.0 mmol) was dissolved in acetonitrile (2 mL), and 1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octanetetrafluoroborate (453 mg, 1.28 mmol) was slowly added. The reaction mixture was stirred at 20 °C for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed twice with water (80 mL), followed by washing once with saturated sodium chloride (100 mL) aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography to obtain 150 mg of the product.

[0480] 1 H NMR (400MHz, CDCl3) δ6.37(s,1H),4.15(s,3H),3.91(s,3H),1.50(s,9H).

[0481] Step 3: Synthesis of dimethyl 4-amino-5-fluorothiophene-2,3-dicarboxylic acid ester

[0482] 150 mg (0.45 mmol) of dimethyl 4-((tert-butylcarbonyl)amino)-5-fluorothiophene-2,3-dicarboxylic acid was dissolved in 2 mL of trifluoroacetic acid, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was then evaporated to dryness to give 100 mg of the product.

[0483] LC-MS(ESI):[M+H] + =201.9;

[0484] Step 4: Synthesis of dimethyl 5-fluoro-4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid ester

[0485] Pyridine (118.7 mg, 1.50 mmol) and methyl phenylcarbonylchloroformate (47 mg, 0.30 mmol) were added to a tetrahydrofuran (4 mL) solution of 4-amino-5-fluorothiophene-2,3-dicarboxylic acid dimethyl ester (70 mg, 0.3 mmol). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 40 mg of the product.

[0486] Step 5: Synthesis of dimethyl 5-fluoro-4-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]trioxaneundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0487] Dimethyl 5-fluoro-4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (35 mg, 0.10 mmol), 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (36 mg, 0.10 mmol), and triethylamine (8 mg, 0.07 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was then separated by silica gel column chromatography to obtain 15 mg of the product.

[0488] LC-MS(ESI):[M+H] + =621.1;

[0489] Step 6: Synthesis of 7-fluoro-2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0490] Dimethyl 5-fluoro-4-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]trioxane-undecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid (10 mg, 0.02 mmol) was dissolved in a mixed solution of tetrahydrofuran (0.4 mL), methanol (0.2 mL), and water (0.2 mL). Lithium hydroxide monohydrate (3 mg, 0.07 mmol) was then added to the reaction solution, and the mixture was stirred at 20 °C for 30 minutes. The pH was adjusted to <7 with 1 M dilute hydrochloric acid, followed by extraction with ethyl acetate (50 mL × 2). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high-performance liquid chromatography (HPLC) to yield 6 mg of the final product.

[0491] LC-MS(ESI):[M+H] + =575.1;

[0492] 1 H NMR (400MHz, DMSO-d6) δ7.59-7.45(m,1H),7.44-7.34(m,2H),7.31-7.22(m,1H),5.18-5.01(m,2H),4.77-4.51(m,4H).

[0493] Example 22 Synthesis of 3-(11-chloro-1,2,7,7-tetrafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (Compound 22)

[0494] Step 1: Synthesis of 4-chloro-2-fluoro-5-nitrophenol

[0495] Aluminum trichloride (259 mg, 1.95 mmol) was added to a solution of 1-chloro-5-fluoro-4-methoxy-2-nitrobenzene (200 mg, 0.97 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at 45 °C for 2 hours. The reaction mixture was quenched with dilute hydrochloric acid (1 M), diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, filtered, dried, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 150 mg of the product.

[0496] Step 2: Synthesis of tert-butyl(3-(2-((4-chloro-2-fluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)-2,2-difluoropropoxy)diphenylsilane

[0497] 4-Chloro-2-fluoro-5-nitrophenol (110 mg, 0.57 mmol), (6-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropoxy)-2,3-difluorophenyl)methanol (283 mg, 0.57 mmol), and triphenylphosphine (226 mg, 0.86 mmol) were dissolved in tetrahydrofuran (5 mL). Then, diisopropyl azodicarbonate (0.2 mL, 0.86 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 300 mg of the final product.

[0498] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=7.8Hz,1H),7.62-7.55(m,4H),7.50-7.42(m,2H),7.40-7.33(m,4H),7.26-7.16(m,2H),6.79-6.67( m,1H),5.34-5.20(m,1H),5.09(d,J=1.2Hz,2H),4.38(t,J=11.6Hz,2H),3.91(t,J=12.0Hz,2H),1.45(d,J=6.2Hz,6H),1.05(s,9H).

[0499] Step 3: Synthesis of 1,2,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolecycloundecene

[0500] Cesium fluoride (228 mg, 1.50 mmol) was added to tert-butyl(3-(2-(((4-chloro-2-fluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)-2,2-difluoropropoxy)diphenylsilane (200 mg, 0.30 mmol) in N,N-dimethylformamide (150 mL). The reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (100 mL × 2), and washed with saturated sodium chloride aqueous solution (100 mL × 2). The combined organic phases were dried, filtered, and evaporated to dryness to obtain 100 mg of crude product.

[0501] Step 4: Synthesis of 1,2,7,7,11-pentachloro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine

[0502] To a solution of 1,2,7,7,11-pentafluoro-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (100 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL), tetrahydroxydiboron (22 mg, 0.25 mmol) and 4,4-bipyridine (0.031 mL, 0.25 mmol) were added, and the reaction mixture was stirred at 20 °C for 10 minutes. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL × 2). The organic phase was washed twice with a saturated calcium chloride aqueous solution. The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 80 mg of the product.

[0503] LC-MS(ESI):[M+H] + =378.1;

[0504] Step 5: Synthesis of dimethyl 4-(3-(11-chloro-1,2,7,7-tetrafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester)

[0505] 1,2,7,7,11-pentachloro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (40 mg, 0.11 mmol), dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (36 mg, 0.11 mmol), and triethylamine (32 mg, 0.32 mmol) were dissolved in tetrahydrofuran (5 mL), and the reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was evaporated to dryness to obtain a crude product, which was then separated by silica gel column chromatography to obtain 25 mg of the product.

[0506] Step 6: Synthesis of 3-(11-chloro-1,2,7,7-tetrafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0507] Dimethyl 4-(3-(11-chloro-1,2,7,7-tetrafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid (20 mg, 0.03 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (7 mg, 0.17 mmol) was added to the reaction solution, and the reaction solution was stirred at 15 °C for 30 minutes. Dilute hydrochloric acid (2 M) was added to the reaction solution to adjust the pH to <7, and then water (20 mL) was added for dilution. The solution was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 10 mg of the product.

[0508] LC-MS(ESI):[M+H] + =573.1;

[0509] 1 H NMR (400MHz, DMSO-d6) δ14.45(s,1H),11.97(s,1H),7.57(d,J=7.8Hz,2H),7.55- 7.45(m,1H),7.38-7.23(m,2H),5.30-5.10(m,2H),4.66(td,J=11.3,19.3Hz,4H).

[0510] Example 23 Synthesis of 3-(11-chloro-1,2,7,7-tetrafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (Compound 23)

[0511] Step 1: Synthesis of methyl 3-(11-chloro-1,2,7,7-tetrafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0512] 1,2,7,7,11-pentachloro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (50 mg, 0.13 mmol), dimethyl 4-((phenoxycarbonylthioyl)amino)thiophene-2,3-dicarboxylic acid (47 mg, 0.13 mmol), and triethylamine (15 mg, 0.13 mmol) were dissolved in tetrahydrofuran (3 mL). The mixture was stirred at 80 °C for 3 hours. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, filtered, dried, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 15 mg of the product.

[0513] LC-MS(ESI):[M+H] + =603.2;

[0514] Step 2: Synthesis of 3-(11-chloro-1,2,7,7-tetrafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0515] Methyl 3-(11-chloro-1,2,7,7-tetrafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-4-oxo-2-thio-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (15 mg, 0.02 mmol) was dissolved in a mixed solvent of tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (3 mg, 0.07 mmol) was added to the mixture, and the reaction solution was stirred at 20 °C for 0.5 hours. The pH of the reaction solution was adjusted to <7 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 10 mg of the product.

[0516] LC-MS(ESI):[M+H] + =589.2;

[0517] 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),7.57-7.43(m,2H),7.42-7.34(m,1H),7.30-6.97(m,2H),5.28-5.08(m,2H),4.74-4.50(m,4H).

[0518] Example 24 2,4-dioxo-3-(1 3 ,1 46 5 -trifluoro-2,5,7-trioxa-1,6(1,2)-dibenzo-3(1,3)-cyclobutane-cyclooctane-6 4 Synthesis of (-yl)-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid (Compound 24)

[0519] Step 1: Synthesis of methyl 3-(3,4-difluorophenoxy)cyclobutane-1-carboxylate

[0520] Methyl 3-hydroxycyclobutane-1-carboxylate (5 g, 38.42 mmol), 3,4-difluorophenol (5 g, 38.42 mmol), triphenylphosphine (15.12 g, 57.63 mmol), and diisopropyl azodicarbonate (11.65 g, 57.63 mmol) were dissolved in tetrahydrofuran (50 mL). The reaction mixture was stirred at 50 °C for 12 hours. After cooling to room temperature, water (300 mL) was added, and the mixture was extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed once with saturated sodium chloride aqueous solution (300 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 give 6.16 g of the product.

[0521] 1H NMR (400MHz, CDCl3) δ7.04 (q, J=9.2Hz, 1H), 6.61 (ddd, J=2.8, 6.4, 12.0Hz, 1H), 6.54-6.43 (m, 1H), 4.82 (q,J=6.4Hz,1H),3.74(s,3H),3.25-3.12(m,1H),2.73(ddd,J=4.0,7.2,13.6Hz,2H),2.51-2.37(m,2H).

[0522] Step 2: Synthesis of (3-(3,4-difluorophenoxy)cyclobutyl)methanol

[0523] Methyl 3-(3,4-difluorophenoxy)cyclobutane-1-carboxylate (3 g, 12.39 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C, and then lithium aluminum hydride (14.9 mL, 37.16 mmol) was added dropwise. After the addition was complete, the temperature was slowly raised to room temperature, and the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was then cooled to 0°C, and water (20 mL) was slowly added dropwise to quench the reaction. Anhydrous sodium sulfate was added for drying, and the product was then filtered and evaporated to dryness to obtain 2.59 g of product.

[0524] 1H NMR(400MHz, CDCl3)δ7.09-6.97(m,1H),6.60(ddd,J=2.8,6.8,12.0Hz,1H),6.52-6.44(m, 1H),4.67(quin,J=6.4Hz,1H),3.72(d,J=6.4Hz,2H),2.64-2.49(m,1H),2.41-2.24(m,4H).

[0525] Step 3: Synthesis of tert-butyl((3-(3,4-difluorophenoxy)cyclobutyl)methoxy)dimethylsilane

[0526] (3-(3,4-difluorophenoxy)cyclobutyl)methanol (2.59 g, 12.09 mmol) and tert-butyldimethylchlorosilane (5.47 g, 36.27 mmol) were dissolved in N,N-dimethylformamide (30 mL), followed by the addition of imidazole (2.47 g, 36.27 mmol). The reaction mixture was stirred at 20 °C for 12 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed once with saturated calcium chloride aqueous solution (200 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 3.8 g of the final product.

[0527] 1 H NMR(400MHz, CDCl3)δ7.03(q,J=9.2Hz,1H),6.59(ddd,J=2.8,6.4,12.0Hz,1H),6.51-6.44(m,1H),4.66(q,J=6.4H z,1H),3.65(d,J=5.2Hz,2H),2.50(qt,J=4.8,9.6Hz,1H),2.39-2.19(m,4H),0.96-0.92(m,9H),0.12-0.08(m,6H).

[0528] Step 4: Synthesis of 6-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)-2,3-difluorobenzaldehyde

[0529] 3.8 g (11.57 mmol) of tert-butyl((3-(3,4-difluorophenoxy)cyclobutyl)methoxy)dimethylsilane was dissolved in tetrahydrofuran (40 mL), purged with nitrogen three times, cooled to -78 °C, and lithium diisopropylamine (11.6 mL, 23.14 mmol) was added. The reaction was allowed to proceed for 30 minutes, followed by the addition of N,N-dimethylformamide (2.7 mL, 34.71 mmol). The mixture was then heated to 20 °C and stirred at 20 °C for 1 hour. The reaction mixture was quenched dropwise in a saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed once with a saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 4 g of product.

[0530] LC-MS(ESI):[M+H] + =357.2;

[0531] Step 5: Synthesis of (6-(3-((((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)-2,3-difluorophenyl)methanol

[0532] 6-(3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)-2,3-difluorobenzaldehyde (4 g, 11.22 mmol) was dissolved in methanol (40 mL), cooled to 0°C, and then sodium borohydride (0.85 g, 22.44 mmol) was added. The mixture was then heated to 20°C and stirred at 20°C for 1 hour. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed once with saturated sodium chloride aqueous solution (200 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 2.86 g of the final product.

[0533] 1H NMR (400MHz, CDCl3) δ7.00 (q, J=9.2Hz, 1H), 6.39-6.31 (m, 1H), 4.78 (br s,2H),4.77-4.71(m,1H),3.70-3.62(m,2H),2.51(td,J=4.4,9.6Hz,2H),2.42-2.21(m,4H),0.94(s,9H),0.11-0.08(m,6H).

[0534] Step 6: Synthesis of tert-butyl((3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)cyclobutyl)methoxy)dimethylsilane

[0535] (6-(3-((((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)-2,3-difluorophenyl)methanol (2.86 g, 7.98 mmol), 2,4-difluoro-5-nitrophenol (1.68 g, 9.58 mmol), triphenylphosphine (3.14 g, 11.97 mmol), and diisopropyl azodicarbonate (2.42 g, 11.97 mmol) were dissolved in tetrahydrofuran (30 mL). The reaction mixture was stirred at 20 °C for 1 hour. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed once with saturated sodium chloride aqueous solution (200 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 2.3 g of the final product.

[0536] 1H NMR(400MHz, CDCl3) δ7.98(dd,J=7.2,8.0Hz,1H),7.17-7.00(m,2H),6.44-6.36(m,1H),5.30(d,J=1.2Hz,2H),4.75(q,J=6.4Hz,1 H),3.66(d,J=5.2Hz,2H),2.52(tt,J=4.8,9.6Hz,1H),2.41-2.32(m,2H),2.31-2.21(m,2H),0.96-0.92(m,9H),0.11-0.08(m,6H).

[0537] Step 7: 1 3 ,1 4 6 5 -trifluoro-6 4 Synthesis of -nitro-2,5,7-trioxa-1,6(1,2)-dibenzo-3(1,3)-cyclobutane and cyclooctane

[0538] tert-butyl((3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)cyclobutyl)methoxy)dimethylsilane (600 mg, 1.16 mmol) and cesium fluoride (1768 mg, 11.64 mmol) were dissolved in N,N-dimethylformamide (600 mL), and the reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, and water (500 mL) was added. The mixture was extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed once with a saturated calcium chloride aqueous solution (500 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 400 mg of the product.

[0539] LC-MS(ESI):[M+H] + =382.1;

[0540] Step 8: 1 3 ,1 4 65 -trifluoro-2,5,7-trioxa-1,6(1,2)-diphenyl-3(1,3)-cyclobutane-cyclooctane-6 4 Synthesis of -amines

[0541] 1 3 ,1 4 6 5 -trifluoro-6 4 Nitro-2,5,7-trioxa-1,6(1,2)-dibenzo-3(1,3)-cyclobutanecyclooctane (350 mg, 0.92 mmol) and tetrahydroxydiboron (329 mg, 3.67 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 4,4-bipyridine (14 mg, 0.09 mmol). The reaction mixture was stirred at 20 °C for 0.5 hours. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed once with saturated calcium chloride aqueous solution (500 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by platelet analysis to obtain 10 mg of the final product.

[0542] LC-MS(ESI):[M+H] + =352.1;

[0543] Step 9: 4-(3-(1) 3 ,1 4 6 5 -trifluoro-2,5,7-trioxa-1,6(1,2)-dibenzo-3(1,3)-cyclobutane-cyclooctane-6 4 Synthesis of dimethyl 2,3-dicarboxylic acid ester (Urethio)thiophene

[0544] 1 3 ,1 4 6 5 -trifluoro-2,5,7-trioxa-1,6(1,2)-diphenyl-3(1,3)-cyclobutane-cyclooctane-6 4 Amine (10 mg, 0.03 mmol) and dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (11 mg, 0.03 mmol) were dissolved in tetrahydrofuran (1 mL), and then triethylamine (9 mg, 0.09 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 15 mg of the final product.

[0545] LC-MS(ESI):[M+H] + =593.1;

[0546] Step 10: 2,4-dioxo-3-(1 3 ,14 6 5 -trifluoro-2,5,7-trioxa-1,6(1,2)-dibenzo-3(1,3)-cyclobutane-cyclooctane-6 4 Synthesis of 1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0547] 4-(3-(1) 3 ,1 4 6 5 -trifluoro-2,5,7-trioxa-1,6(1,2)-dibenzo-3(1,3)-cyclobutane-cyclooctane-6 4 Dimethyl 2,3-dicarboxylic acid ester (10 mg, 0.02 mmol) and lithium hydroxide monohydrate (4 mg, 0.1 mmol) were dissolved in a mixed solution of tetrahydrofuran (0.5 mL), methanol (0.25 mL), and water (0.25 mL). The reaction solution was stirred at 20 °C for 30 minutes. The pH of the reaction solution was adjusted to 2-3 with hydrochloric acid (1 M). After dilution with water (50 mL), the reaction solution was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed once 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 5 mg of product.

[0548] LC-MS(ESI):[M+H] + =547.1;

[0549] 1H NMR (400MHz, DMSO-d6) δ11.95 (br s, 1H), 7.72 (d, J = 7.6Hz, 1H), 7.49-7.36 (m, 2H), 7.29 (br s,1H),6.85(ddd,J=1.6,4.2,9.0Hz,1H),6.45-6.31(m,1H),5.14-4.74(m,2H),4.46(s,2H),2.40-2.28(m,3H),2.17-2.00(m,2H).

[0550] Example 25 Synthesis of 2,4-dioxo-3-(1,2,9,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-undecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 25)

[0551] Step 1: Synthesis of 6-(allyloxy)-2,3-difluorobenzaldehyde

[0552] 2,3-Difluoro-6-hydroxybenzaldehyde (20 g, 75.90 mmol) and sodium carbonate (24.13 g, 227.70 mmol) were dissolved in acetonitrile (100 mL), followed by the addition of allyl bromide (9.9 mL, 113.85 mmol). The mixture was heated to 60 °C and stirred for 2 hours. The reaction solution was extracted with water (100 mL) and ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness, and the crude product was purified by silica gel column chromatography to give 6.5 g of the product.

[0553] Step 2: Synthesis of (6-(allyloxy)-2,3-difluorophenyl)methanol

[0554] 6-(allyloxy)-2,3-difluorobenzaldehyde (6.5 g, 32.80 mmol) was dissolved in ethanol (60 mL), and sodium borohydride (1.24 g, 32.80 mmol) was added. The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was extracted with water (100 mL) and ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and filtered. The crude product obtained by rotary evaporation was purified by silica gel column chromatography to give 6.1 g of the product.

[0555] LC-MS (ESI): [M-OH] + =183.1;

[0556] Step 3: Synthesis of 1-(allyloxy)-2-(chloromethyl)-3,4-difluorobenzene

[0557] Dissolve 6.1 g (30.47 mmol) of (6-(allyloxy)-2,3-difluorophenyl)methanol in 60 mL of toluene, and slowly add 4.4 mL of thionyl chloride.

[0558] The reaction mixture (60.95 mmol) was stirred at 25 °C for 1 hour. Water (100 mL) was added to the reaction solution, followed by the addition of a saturated sodium bicarbonate aqueous solution to adjust the pH to neutral. The aqueous phase was extracted with ethyl acetate (100 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness to give 6.2 g of product.

[0559] Step 4: Synthesis of 2-((6-(allyloxy)-2,3-difluorobenzyl)oxy)-4-bromo-5-fluorobenzaldehyde

[0560] 1-(allyloxy)-2-(chloromethyl)-3,4-difluorobenzene (6.8 g, 31.10 mmol) and 4-bromo-5-fluoro-2-hydroxybenzene-1-carboxaldehyde (6.13 g, 27.99 mmol) were dissolved in N,N-dimethylformamide (40 mL), and potassium carbonate (12.90 g, 93.31 mmol) was added. The mixture was heated to 60 °C and reacted for 1 hour. The reaction solution was directly extracted with water (100 mL) and ethyl acetate (100 mL × 2). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then filtered. The crude product obtained by rotary evaporation was purified by silica gel column chromatography to give 10.2 g of the product.

[0561] Step 5: Synthesis of 1-(2-((6-(allyloxy)-2,3-difluorobenzyl)oxy)-4-bromo-5-fluorophenyl)prop-2-en-1-ol

[0562] 10.2 g (25.42 mmol) of 2-((6-(allyloxy)-2,3-difluorobenzyl)oxy)-4-bromo-5-fluorobenzaldehyde was dissolved in 50 mL of tetrahydrofuran. After cooling the reaction solution to 0 °C, a tetrahydrofuran solution of 50.8 mL (50.85 mmol) of vinyl magnesium bromide was slowly added dropwise, and the mixture was heated to room temperature for 1 hour. The reaction solution was then extracted with 100 mL of ammonium chloride aqueous solution and ethyl acetate (100 mL × 2). The combined organic phases were washed once with 200 mL of saturated saline solution and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 9 g of the final product.

[0563] Step 6: Synthesis of 12-bromo-1,2,11-trifluoro-6,9-dihydro-15H-dibenzo[b,f][1,5]dioxane-undecene-9-ol

[0564] 1-(2-((6-(allyloxy)-2,3-difluorobenzyl)oxy)-4-bromo-5-fluorophenyl)prop-2-en-1-ol (3.3 g, 7.71 mmol) and a catalytically stoichiometric amount of Zhan's catalyst were dissolved in dichloromethane and stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was filtered through a silica gel column, and the mother liquor was evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 960 mg of the product.

[0565] Step 7: Synthesis of 12-bromo-1,2,11-trifluoro-15H-dibenzo[b,f][1,5]dioxane-undecene-9(6H)-one

[0566] 12-Bromo-1,2,11-trifluoro-6,9-dihydro-15H-dibenzo[b,f][1,5]dioxane-undecen-9-ol (960 mg, 2.39 mmol) and 2-iodobenzoic acid (3.0 g, 10.71 mmol) were added to acetonitrile (10 mL). The reaction mixture was heated at 60 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate (100 mL) was added, and the mixture was filtered. The mother liquor was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography to obtain 710 mg.

[0567] Step 8: Synthesis of 12-bromo-1,2,9,9,11-pentafluoro-6,9-dihydro-15H-dibenzo[b,f][1,5]dioxane-undecene

[0568] 12-Bromo-1,2,11-trifluoro-15H-dibenzo[b,f][1,5]dioxane-undecene-9(6H)-one (710 mg, 1.78 mmol) was dissolved in diethylaminosulfuric acid (8 mL), purged with nitrogen three times, and then heated and stirred at 45 °C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, and then extracted with ethyl acetate (100 mL × 2) and water (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 200 mg of the product.

[0569] 1 H NMR (400MHz, CDCl3) δ7.44-7.39(m,1H),7.35(m,1H),7.30-7.27(m,1H),7.23-7.14(m,1H),6.94(m,1H),6.09-5.98(m,1H),4.89-4.85(m,2H).

[0570] Step 9: Synthesis of 12-bromo-1,2,9,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-undecene

[0571] 12-Bromo-1,2,9,9,11-pentafluoro-6,9-dihydro-15H-dibenzo[b,f][1,5]dioxane-undecene (150 mg, 0.36 mmol) and palladium / carbon (200 mg, 10%) were dissolved in ethyl acetate (10 mL), purged with nitrogen three times, then with hydrogen three times, and stirred for 4 hours. The reaction solution was filtered and evaporated to dryness to give 130 mg of the product.

[0572] 1H NMR (400MHz, CDCl3) δ7.30-7.23(m,1H),7.07-6.95(m,2H),6.67-6.58(m,1H),5.26-5. 21(m,2H),2.89-2.53(m,2H),2.20-2.01(m,1H),1.47-1.43(m,2H),1.35-1.24(m,1H).

[0573] Step 10: Synthesis of N-(1,2,9,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-12-yl)-1,1-diphenyltoluidine

[0574] 12-Bromo-1,2,9,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-130 mg (0.32 mmol), diphenyltoluidine (100 mg, 0.55 mmol), tris(dibenzylindeneacetone)dipalladium(0) (30 mg, 0.03 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (40 mg, 0.07 mmol), and cesium carbonate (300 mg, 0.92 mmol) were dissolved in dioxane (5 mL) and stirred at 80 °C for 3 hours. After the reaction was completed and cooled to room temperature, the mixture was diluted with ethyl acetate (200 mL), washed once with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 55 mg of the product.

[0575] LC-MS(ESI):[M+H] + =524.2;

[0576] Step 11: Synthesis of 1,2,9,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-undecene-12-amine

[0577] N-(1,2,9,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-undecen-12-yl)-1,1-diphenyltoluidine (32 mg, 0.06 mmol) and palladium hydroxide (50 mg, 0.36 mmol) were dissolved in ethyl acetate (3 mL) and isopropanol (1 mL). The mixture was purged with nitrogen three times, then with hydrogen three times, and stirred for 1 hour. After the reaction was complete, the mixture was directly filtered and concentrated to obtain 35 mg of crude product.

[0578] LC-MS(ESI):[M+H] + =360.0;

[0579] Step 12: Synthesis of dimethyl 4-(3-(1,2,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-undecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0580] 1,2,9,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-undecene-12-amine (35 mg, 0.03 mmol) was dissolved in tetrahydrofuran (3 mL), followed by the addition of triethylamine (50 mg, 0.49 mmol) and methyl 3-(methoxycarbonyl)-4-{[(phenoxy)carbonyl]amino}thiophene-2-carboxylate (25 mg, 0.07 mmol). The mixture was then stirred at 60 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was directly purified by high-performance liquid chromatography to obtain 5 mg of the product.

[0581] LC-MS(ESI):[M+H] + =601.0;

[0582] Step 13: Synthesis of 2,4-dioxo-3-(1,2,9,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-undecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0583] Dimethyl 4-(3-(1,2,9,11-pentafluoro-6,7,8,9-tetrahydro-15H-dibenzo[b,f][1,5]dioxane-undecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid (5 mg, 0.01 mmol) and lithium hydroxide aqueous solution (0.5 mL, 1.00 mmol, 2 M) were dissolved in tetrahydrofuran (1 mL) and methanol (0.5 mL). The reaction solution was stirred at room temperature for 0.5 hours, and the pH of the reaction solution was adjusted to approximately 4 with dilute hydrochloric acid (1 M). The solution was then filtered, and the filtrate was directly purified by high performance liquid chromatography to obtain 2 mg of the product.

[0584] LC-MS(ESI):[M+H] + =550.0;

[0585] 1 H NMR (400MHz, DMSO-d6) δ7.57-7.40(m,3H),7.13-7.01(m,2H),5.33-5.25(m,2H),4.24-4.23(m,2H),2.60(m,2H),1.58-1.46(m,2H).

[0586] Example 26 Synthesis of 2,4-dioxo-3-(14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-diphenyl-7(1,3)-cyclobutane-cyclonaphthyl-15-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 26)

[0587] Step 1: Synthesis of methyl 3-((3,4-difluorophenoxy)methyl)cyclobutane-1-carboxylic acid

[0588] Methyl 3-(hydroxymethyl)cyclobutane-1-carboxylate (3.5 mL, 27.75 mmol), 3,4-difluorophenol (3.2 mL, 30.52 mmol), and triphenylphosphine (7.3 g, 27.75 mmol) were dissolved in tetrahydrofuran (40 mL). Diisopropyl azodicarbonate (5.8 mL, 29.13 mmol) was slowly added at room temperature, and the reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was poured into ice water (40 mL), extracted with ethyl acetate (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was extracted with silica gel column chromatography to obtain 5.0 g of the final product.

[0589] LC-MS(ESI):[M+H] + =257.1;

[0590] Step 2: Synthesis of (3-(((3,4-difluorophenoxy)methyl)cyclobutyl)methanol

[0591] Methyl 3-((3,4-difluorophenoxy)methyl)cyclobutane-1-carboxylic acid (4 g, 15.61 mmol) was dissolved in tetrahydrofuran (40 mL), and lithium aluminum hydride (9.4 mL, 23.41 mmol) was added at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. Water (1 mL), 15% sodium hydroxide solution (1 mL), and then water (3 mL) were slowly added to the reaction mixture. After stirring for another 0.5 hours, the mixture was filtered directly, and the combined organic phases were evaporated to dryness to obtain 3.4 g of the product.

[0592] LC-MS (ESI): [M-OH] + =211.1;

[0593] Step 3: Synthesis of tert-butyl((3-((3,4-difluorophenoxy)methyl)cyclobutyl)methoxy)dimethylsilane

[0594] (3-(((3,4-difluorophenoxy)methyl)cyclobutyl)methanol (3.4 g, 14.90 mmol) was dissolved in dichloromethane (40 mL). Imidazole (3.0 g, 44.69 mmol) and tert-butyldimethylchlorosilane (3.4 g, 22.34 mmol) were added at 0 °C, and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into ice water (40 mL), and dichloromethane (60 mL × 3) was added for extraction. The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 4.2 g of the product.

[0595] Step 4: Synthesis of 6-((3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)methoxy)-2,3-difluorobenzaldehyde

[0596] tert-butyl((3-((3,4-difluorophenoxy)methyl)cyclobutyl)methoxy)dimethylsilane (3 g, 8.76 mmol) was dissolved in tetrahydrofuran (30 mL). Diisopropylaminolithium (8.8 mL, 17.52 mmol) was added at -78 °C and stirred for 0.5 h. Then, N,N-dimethylformamide (2.0 mL, 26.28 mmol) was added, and the reaction mixture was allowed to return to room temperature and stirred for another 1.5 h. The reaction mixture was poured into 80 mL of ice-cold ammonium chloride aqueous solution, and extracted with ethyl acetate (120 mL × 3). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 3.1 g of the final product.

[0597] LC-MS(ESI):[M+H] + =371.2;

[0598] Step 5: Synthesis of (6-(((3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)methoxy)-2,3-difluorophenyl)methanol

[0599] 6-((3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)methoxy)-2,3-difluorobenzaldehyde (3 g, 8.10 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (306 mg, 8.10 mmol) was added at 0 °C. The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into ice water (60 mL), and the pH was adjusted to weakly acidic by adding 1 M HCl. Ethyl acetate (100 mL × 3) was added for extraction, and the product was dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 2.4 g of the product.

[0600] LC-MS (ESI): [M-OH] + =355.1;

[0601] Step 6: Synthesis of tert-butyl((3-((2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)methyl)cyclobutyl)methoxy)dimethylsilane

[0602] (6-(((3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)methoxy)-2,3-difluorophenyl)methanol (2.3 g, 6.17 mmol), triphenylphosphine (1.8 g, 6.79 mmol), and 2,4-difluoro-5-nitrophenol (1.2 g, 6.79 mmol) were dissolved in tetrahydrofuran (20 mL). Diisopropyl azodicarbonate (1.3 mL, 6.79 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into 50 mL of ice water, extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1.8 g of the product.

[0603] LC-MS(ESI):[M+H] + =530.1;

[0604] Step 7: Synthesis of 14,45,46-trifluoro-15-nitro-2,5,9-trioxa-1,4(1,2)-diphenyl-7(1,3)-cyclobutane-acyclic naphthane

[0605] 0.8 g (1.51 mmol) of tert-butyl((3-((2-((2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)methyl)cyclobutyl)methoxy)dimethylsilane was dissolved in 800 mL of N,N-dimethylformamide. Cesium fluoride (688 mg, 4.53 mmol) was added under a nitrogen atmosphere, and the reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was then poured into ice water (400 mL), extracted with ethyl acetate (400 mL × 3), washed twice with saturated calcium chloride aqueous solution, and dried over anhydrous sodium sulfate and evaporated to dryness to obtain 590 mg of the product.

[0606] Step 8: Synthesis of 14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-diphenyl-7(1,3)-cyclobutane-15-amine

[0607] 14,45,46-trifluoro-15-nitro-2,5,9-trioxa-1,4(1,2)-diphenyl-7(1,3)-cyclobutane-acyclic naphthane (0.5 g, 1.26 mmol) and (dihydroxyboryl)boranediol (567 mg, 6.32 mmol) were dissolved in N,N-dimethylformamide (10 mL). 4,4'-bipyridine (20 mg, 0.13 mmol) was slowly added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into ice water (60 mL), and extracted with ethyl acetate (120 mL × 3). The mixture was washed twice with saturated calcium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 200 mg of the product.

[0608] LC-MS(ESI):[M+H] + =366.1;

[0609] Step 9: Synthesis of dimethyl 4-(3-(14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-dibenzo-7(1,3)-cyclobutanecyclonaphthyl-15-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0610] 14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-diphenyl-7(1,3)-cyclobutane-15-naphthane-15-amine (100 mg, 0.27 mmol) and dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid (101 mg, 0.30 mmol) were dissolved in tetrahydrofuran (2 mL), and triethylamine (0.1 mL, 0.82 mmol) was added. The reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (40 mL × 3), and the organic phases were combined and washed once with saturated brine. The organic phases were dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 165 mg of the product.

[0611] LC-MS(ESI):[M+H] + =607.2;

[0612] Step 10: Synthesis of 2,4-dioxo-3-(14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-diphenyl-7(1,3)-cyclobutane-cyclonaphthyl-15-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0613] Dimethyl 4-(3-(14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-dibenzo-7(1,3)-cyclobutanecyclonaphthyl-15-yl)ureo)thiophene-2,3-dicarboxylic acid (160 mg, 0.26 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (10 mL), and the pH was adjusted to weakly acidic by adding an appropriate amount of 1M hydrochloric acid. Ethyl acetate (30 mL × 3) was added for extraction. The organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 75 mg of the product.

[0614] LC-MS(ESI):[M+H] + =561.2;

[0615] 1 H NMR (400MHz, DMSO-d6) δ14.55(s,1H),11.98(s,1H),7.49-7.40(m,1H),7.40-7.33(m,2H),7.18-7.13(d,J=1 1.2Hz,1H),6.86-6.79(m,1H),5.06(s,2H),3.97(s,2H),3.92(s,2H),2.78-2.67(m,4H),2.14-2.03(m,2H).

[0616] Example 27 Synthesis of 4-oxo-2-thio-3-(14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-dibenzo-7(1,3)-cyclobutane-acyclic naphthyl-15-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 27)

[0617] Step 1: Synthesis of methyl 4-oxo-2-thio-3-(14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-dibenzo-7(1,3)-cyclobutanecyclonaphthyl-15-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0618] 14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-diphenyl-7(1,3)-cyclobutane-15-naphthyl-15-amine (90 mg, 0.25 mmol) and dimethyl 4-((phenoxycarbonylthioyl)amino)thiophene-2,3-dicarboxylic acid (95 mg, 0.27 mmol) were dissolved in tetrahydrofuran (2 mL), and triethylamine (0.1 mL, 0.74 mmol) was added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (40 mL × 3), and the organic phases were combined and washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 155 mg of the product.

[0619] LC-MS(ESI):[M+H] + =591.1;

[0620] Step 2: Synthesis of 4-oxo-2-thio-3-(14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-dibenzo-7(1,3)-cyclobutane-acyclic naphthyl-15-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0621] Methyl 4-oxo-2-thio-3-(14,45,46-trifluoro-2,5,9-trioxa-1,4(1,2)-dibenzo-7(1,3)-cyclobutanecyclonaphthyl-15-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (150 mg, 0.25 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (0.5 mL), and water (0.5 mL). Lithium hydroxide monohydrate (53 mg, 1.26 mmol) was added, and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into 10 mL of water, and the pH was adjusted to weakly acidic by adding an appropriate amount of 1M hydrochloric acid. Ethyl acetate (20 mL × 3) was added for extraction. The organic phase was dried and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 72 mg of the product.

[0622] LC-MS(ESI):[M+H] + =577.2;

[0623] 1H NMR (400MHz, DMSO-d6) δ14.20(s,1H),13.48(s,1H),7.52(s,1H),7.49-7.40(m,1H),7.33-7.26(d,J=8.0Hz,1H),7.15-7.08( d,J=11.6Hz,1H),6.86-6.79(m,1H),5.13-4.99(m,2H),3.96(s,2H),3.95-3.88(m,2H),2.81-2.66(m,4H),2.14-2.04(m,2H).

[0624] Example 28 Synthesis of 3-(3-chloro-7,7,12,13-tetrafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolium cycloundeceno[2,3-b]pyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 28)

[0625] Step 1: Synthesis of 5-bromo-6-fluoropyridine-2-amine

[0626] 6-Fluoropyridine-2-amine (24 g, 214.08 mmol) was dissolved in acetonitrile (120 mL), and N-bromosuccinimide (38.10 g, 214.08 mmol) was added at 0 °C. The reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was poured into 200 mL of ice water, and extracted with ethyl acetate (400 mL × 3). The organic phase was washed with saturated brine, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 36 g of the product.

[0627] Step 2: Synthesis of 5-bromo-3-chloro-6-fluoropyridine-2-amine

[0628] 5-Bromo-6-fluoropyridine-2-amine (35 g, 183.25 mmol) was dissolved in acetonitrile (500 mL), and N-chlorosuccinimide (24.47 g, 183.25 mmol) was added at 0 °C. The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was poured into ice water (300 mL), and extracted with ethyl acetate (500 mL × 3). The organic phase was washed with saturated brine, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 24 g of the product.

[0629] Step 3: Synthesis of dimethyl 4-(3-(5-bromo-3-chloro-6-fluoropyridin-2-yl)ureido)thiophene-2,3-dicarboxylic acid ester

[0630] 5-Bromo-3-chloro-6-fluoropyridine-2-amine (2000 mg, 8.87 mmol) was dissolved in tetrahydrofuran (30 mL). Bistrimethylsilylaminolithium (10.6 mL, 10.65 mmol) was added at 0 °C and stirred for 0.5 hours. Then, methyl 3-(methoxycarbonyl)-4-(((phenyloxy)carbonyl)amino)thiophene-2-carboxylate (2975 mg, 8.87 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was then poured into 100 mL of ammonium chloride aqueous solution, and extracted with ethyl acetate (200 mL × 3). The extract was then dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 800 mg of the final product.

[0631] LC-MS(ESI):[M+H] + =465.9;

[0632] Step 4: Synthesis of dimethyl 4-(3-(3-chloro-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-2-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0633] Dimethyl 4-(3-(5-bromo-3-chloro-6-fluoropyridin-2-yl)ureido)thiophene-2,3-dicarboxylic acid (300 mg, 0.64 mmol), 2-(5,5-dimethyl-1,3,2-dioxaborhexacyclohex-2-yl)-5,5-dimethyl-1,3,2-dioxaborhexacyclohexane (218 mg, 0.96 mmol), bis[5-(diphenylphosphino)cyclopentan-1,3-dienyl]-λ2-iron(II)dichloromethane palladium chloride (105 mg, 0.13 mmol), and potassium acetate (126 mg, 1.29 mmol) were dissolved in dioxane (1 mL). The mixture was purged with nitrogen three times, and the reaction solution was stirred at 100 °C for 1 hour. The reaction solution was directly filtered and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 130 mg of the product.

[0634] LC-MS(ESI):[M+H] + =432.0;

[0635] Step 5: Synthesis of dimethyl 4-(3-(3-chloro-6-fluoro-5-hydroxypyridin-2-yl)ureido)thiophene-2,3-dicarboxylic acid ester

[0636] Hydrogen peroxide (981 mg, 9.04 mmol) was added to a tetrahydrofuran (1 mL) solution of 4-(3-(3-chloro-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridin-2-yl)ureo)thiophene-2,3-dicarboxylic acid dimethyl ester (130 mg, 0.30 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched with a saturated aqueous sodium sulfite solution and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain 80 mg of the product, which was used directly in the next step.

[0637] LC-MS(ESI):[M+H] + =403.9;

[0638] Step 6: Synthesis of dimethyl 4-(3-(3-chloro-5-(3-(3,4-difluoro-2-carboxyphenoxy)-2,2-difluoropropoxy)-6-fluoropyridin-2-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0639] Dimethyl 4-(3-(3-chloro-6-fluoro-5-hydroxypyridin-2-yl)ureido)thiophene-2,3-dicarboxylic acid (80 mg, 0.20 mmol), trifluoromethanesulfonic acid-3-[(3,4-difluoro-2-formylphenyl)oxy]-2,2-difluoropropyl ester (76 mg, 0.20 mmol), and potassium carbonate (68 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (100 mL × 3). The organic phase was washed once with saturated sodium chloride aqueous solution. The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 60 mg of the product.

[0640] Step 7: Synthesis of dimethyl 4-(3-(3-chloro-5-(3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-2,2-difluoropropoxy)-6-fluoropyridin-2-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0641] Sodium borohydride (7 mg, 0.19 mmol) was added to an ethanol (1 mL) solution of 4-(3-(3-chloro-5-(3-(3,4-difluoro-2-carboxyphenoxy)-2,2-difluoropropoxy)-6-fluoropyridin-2-yl)ureo)thiophene-2,3-dicarboxylic acid dimethyl ester (60 mg, 0.09 mmol). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution, then extracted with ethyl acetate (50 mL × 2), washed once with saturated brine, and the organic phase was dried, filtered, and evaporated to dryness to obtain 60 mg of crude product, which was directly used in the next step.

[0642] LC-MS(ESI):[M+H] + =640.1;

[0643] Step 8: Synthesis of 3-(3-chloro-7,7,12,13-tetrafluoro-7,8-dihydro-6H,14H-benzo[9,10][1,4,8]triazolylcyclodecyl[2,3-b]pyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0644] Dimethyl 4-(3-(3-chloro-5-(3-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-2,2-difluoropropoxy)-6-fluoropyridin-2-yl)ureo)thiophene-2,3-dicarboxylic acid (50 mg, 0.08 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (9 mg, 0.23 mmol) was added to the reaction solution, and the reaction solution was stirred at 50 °C for 30 minutes. The pH of the reaction solution was adjusted to 7 by adding dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 15 mg of the product.

[0645] LC-MS(ESI):[M+H] + =574.1;

[0646] 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.58-7.41(m,1H),7.27-7.11(m,2H),5.44-5.34(m,2H),4.79-4.64(m,2H),4.55(br t,J=11.2Hz,2H).

[0647] Example 29 Synthesis of 2,4-dioxo-3-(3,7,7,12,13-pentafluoro-5,6,7,8-tetrahydro-14H-benzo[2,3][1,5]dioxane-undecene[6,7-b]pyridin-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 29)

[0648] Step 1: Synthesis of dimethyl 4-(3-(5-bromo-3,6-difluoropyridin-2-yl)ureido)thiophene-2,3-dicarboxylic acid ester

[0649] 5-Bromo-3,6-difluoropyridine-2-amine (3 g, 14.35 mmol) and methyl 3-(methoxycarbonyl)-4-(((phenyloxy)carbonyl)amino)thiophene-2-carboxylate (5.7 g, 17.00 mmol) were dissolved in tetrahydrofuran (30 mL), cooled to 0 °C, and bis(trimethylsilylamino)lithium (32 mL, 32.00 mmol) was added. The mixture was then stirred in an ice bath for 2 hours. The reaction solution was quenched with ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (100 mL × 3), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1.7 g of the final product.

[0650] LC-MS(ESI):[MH] + =417.9;

[0651] Step 2: Synthesis of dimethyl 4-(3-(3,6-difluoro-5-vinylpyridin-2-yl)ureido)thiophene-2,3-dicarboxylic acid ester

[0652] Dimethyl 4-(3-(5-bromo-3,6-difluoropyridin-2-yl)ureido)thiophene-2,3-dicarboxylic acid (1.6 g, 3.83 mmol), potassium vinyltrifluoroborate (30 mg, 0.22 mmol), potassium phosphate (2.8 g, 13.19 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (200 mg, 0.27 mmol) were dissolved in dioxane (20 mL) and water (2 mL). After purging with nitrogen three times, the mixture was stirred at 80 °C for 2 hours. The reaction solution was evaporated to dryness, ethyl acetate (500 mL) was added, and the mixture was washed with water (200 mL × 2), followed by washing with saturated brine. The solution was then 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 825 mg of the final product.

[0653] LC-MS(ESI):[M+H] + =366.0;

[0654] Step 3: Synthesis of methyl 3-(5-(3,3-difluoro-4-hydroxybutyl)-3,6-difluoro-1,2-dihydropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid

[0655] Dimethyl 4-(3-(3,6-difluoro-5-vinylpyridin-2-yl)ureido)thiophene-2,3-dicarboxylic acid (600 mg, 1.64 mmol), 2-bromo-2,2-difluoroethane-1-ol (900 mg, 5.59 mmol), tricyclo[3.3.1.13,7]decane-1-thiol (20 mg, 0.12 mmol), 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (10 mg, 0.01 mmol), and diethylamine (360 mg, 3.56 mmol) were dissolved in acetonitrile (2 mL) and water (1 mL). The mixture was then stirred under blue light for 2 hours. The reaction mixture was quenched with 100 mL of water, then extracted with ethyl acetate (300 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 304 mg of the final product.

[0656] LC-MS(ESI):[M+H] + =450.0;

[0657] Step 4: Synthesis of methyl 3-(5-(3,3-difluoro-4-hydroxybutyl)-3,6-difluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheneno[3,4-d]pyrimidine-5-carboxylic acid

[0658] Methyl 3-(5-(3,3-difluoro-4-hydroxybutyl)-3,6-difluoro-1,2-dihydropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (300 mg, 0.67 mmol) was dissolved in dichloromethane (10 mL), and then manganese dioxide (1.0 g, 11.50 mmol) was added and the mixture was stirred for 36 hours. The reaction mixture was diluted with dichloromethane (100 mL), filtered, and the filter cake was washed once with dichloromethane (50 mL). The organic phases were combined and evaporated to dryness to obtain 210 mg of crude product, which was used directly in the next reaction step.

[0659] LC-MS(ESI):[M+H] + =448.0;

[0660] Step 5: Synthesis of methyl 3-(5-(3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)butyl)-3,6-difluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheneno[3,4-d]pyrimidine-5-carboxylic acid

[0661] Methyl 3-(5-(3,3-difluoro-4-hydroxybutyl)-3,6-difluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester (190 mg, 0.42 mmol) and pyridine (100 mg, 1.26 mmol) were dissolved in dichloromethane (5 mL). Trifluoromethanesulfonic anhydride (200 mg, 0.71 mmol) was added dropwise under an ice-water bath, and the mixture was stirred for 1 hour. The reaction mixture was quenched in water (50 mL) and then extracted with dichloromethane (100 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 220 mg of crude product, which was used directly in the next step.

[0662] LC-MS(ESI):[M+H] + =580.0;

[0663] Step 6: Synthesis of methyl 3-(5-(4-(3,4-difluoro-2-carboxyphenoxy)-3,3-difluorobutyl)-3,6-difluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheneno[3,4-d]pyrimidine-5-carboxylic acid

[0664] Methyl 3-(5-(3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)butyl)-3,6-difluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester (200 mg, 0.35 mmol), 2,3-difluoro-6-hydroxybenzyl-1-carboxaldehyde (150 mg, 0.95 mmol), and potassium carbonate (200 mg, 1.45 mmol) were dissolved in N,N-dimethylformamide (5 mL), and then heated and stirred at 50 °C for 2 hours. The reaction mixture was quenched with water (100 mL), and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 110 mg of the product.

[0665] LC-MS(ESI):[M+H] + =588.1;

[0666] Step 7: Synthesis of methyl 3-(5-(4-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-3,3-difluorobutyl)-3,6-difluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheneno[3,4-d]pyrimidine-5-carboxylic acid

[0667] Methyl 3-(5-(4-(3,4-difluoro-2-carboxyphenoxy)-3,3-difluorobutyl)-3,6-difluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (110 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL). Sodium borohydride (10 mg, 0.26 mmol) was added under ice-water bath, and the mixture was stirred for 0.5 hours until the reactants reacted and the product was formed. The reaction solution was quenched in water (50 mL), and the pH was adjusted to approximately 6 with dilute hydrochloric acid. The solution was then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 100 mg of the product, which was used directly in the next step.

[0668] LCMS(ESI):[M+H] + =572.1;

[0669] Step 8: Synthesis of 2,4-dioxo-3-(3,7,7,12,13-pentafluoro-5,6,7,8-tetrahydro-14H-benzo[2,3][1,5]dioxane-undecene[6,7-b]pyridin-2-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0670] Methyl 3-(5-(4-(3,4-difluoro-2-(hydroxymethyl)phenoxy)-3,3-difluorobutyl)-3,6-difluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (65 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (65 mL). Sodium hydride (50 mg, 1.25 mmol) was added under ice-water bath, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was quenched in ice-cold saturated ammonium chloride aqueous solution (50 mL), and the pH was adjusted to approximately 6 with dilute hydrochloric acid (1 M). Ethyl acetate (100 mL × 3) was added for extraction. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 4.99 mg of the final product.

[0671] LC-MS(ESI):[M+H] + =608.9;

[0672] 1 H NMR (400MHz, DMSO-d6) δ7.48(m,1H),7.40-7.31(m,2H),7.27-7.22(m,1H),7.17(s,1H),5.19-5.07(m,2H),4.73-4.59(m,4H),3.07(m,2H).

[0673] Example 30 Synthesis of 2,4-dioxo-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxamide (Compound 30)

[0674] Step 1: Synthesis of dimethyl 4-(3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0675] 1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (1.50 g, 4.61 mmol) and dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylate (1.62 g, 4.84 mmol) were dissolved in tetrahydrofuran (15 mL), and triethylamine (0.6 mL, 4.61 mmol) was added. The mixture was then heated to 70 °C and reacted for 12 hours. After cooling, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The combined organic phases were washed with water (10 mL × 2) and saturated brine (10 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1.50 g of the product.

[0676] LC-MS(ESI):[MH] - =565.0;

[0677] Step 2: Synthesis of 2,4-dioxo-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0678] Compound 4-(3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid dimethyl ester (1.50 g, 2.65 mmol) was dissolved in tetrahydrofuran (15 mL) and methanol (5 mL). Lithium hydroxide monohydrate (798 mg, 19 mmol) was dissolved in water (5 mL) and added dropwise to the reaction solution. The mixture was then stirred at 25 °C for 2 hours. The pH was adjusted to 2-3 with dilute hydrochloric acid (1 M), diluted with water (30 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. After drying over anhydrous sodium sulfate, the mixture was filtered and purified by column chromatography to give 1.10 g of the product.

[0679] LC-MS(ESI):[M+H] + =521.0;

[0680] Step 3: Synthesis of 2,4-dioxo-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxamide

[0681] 2,4-Dioxo-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (20 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), and 4-dimethylaminopyridine (5 mg, 0.04 mmol), diisopropylethylamine (70 μL, 0.40 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (22 mg, 0.06 mmol) and ammonium chloride (11 mg, 0.21 mmol) were added. The mixture was reacted overnight at 50 °C. After cooling to room temperature, ethyl acetate (20 mL) was added for dilution, followed by washing with water (5 mL × 3) and saturated saline (5 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high performance liquid chromatography to obtain 4 mg of product.

[0682] LC-MS(ESI):[M+H] + =520.2;

[0683] 1 H NMR (500MHz, DMSO-d6) δ11.72(s,1H),9.67(s,1H),8.05(s,1H),7.38(q,J=9.6Hz,1H),7.25(d,J=7.7Hz,1H),7.21(s,1H),7.14(d, J=11.3Hz,1H),7.05(d,J=9.2Hz,1H),5.08(q,J=11.3Hz,2H),4.47(t,J=4.5Hz,2H),4.30(t,J=4.4Hz,2H),1.94(d,J=35.3Hz,2H).

[0684] Example 31: Synthesis of N-(methanesulfonyl)-2,4-dioxy-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]trioxane-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxamide (Compound 31)

[0685] Step 1: Synthesis of N-(methanesulfonyl)-2,4-dioxy-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]trioxane-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxamide

[0686] 2,4-Dioxo-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (50 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of methanesulfonamide (48 mg, 0.50 mmol), 4-dimethylaminopyridine (37 mg, 0.30 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol). The mixture was reacted overnight at room temperature. The product was diluted with ethyl acetate (30 mL), washed with water (5 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high-performance liquid chromatography (HPLC) to obtain 9.5 mg of the product.

[0687] LC-MS(ESI):[M+H] + =598.1;

[0688] 1 H NMR (500MHz, DMSO-d6) δ13.55(s,1H),11.98(s,1H),7.47(s,1H),7.42–7.34(m,1H),7.26(d,J=7.7Hz,1H),7.17(d,J=11. 3Hz,1H),7.05(d,J=8.3Hz,1H),5.11–5.03(m,2H),4.51–4.43(m,2H),4.34–4.25(m,2H),3.39(s,3H),2.02–1.94(m,2H).

[0689] Example 32 Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-6H,8H,15Hspiro[dibenzo[b,f][1,4,8]triazolylcycloundecene-7,3'-oxetane]-12yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 32)

[0690] Step 1: Synthesis of ((3-(bromomethyl)oxetane-3-yl)methoxy)(tert-butyl)dimethylsilane

[0691] (3-(bromomethyl)oxetane-3-yl)methanol (2.5 mL, 22.10 mmol) was dissolved in dichloromethane (30 mL), and imidazole (3.01 g, 44.19 mmol) and tert-butyldimethylchlorosilane (4.00 g, 26.51 mmol) were added. The mixture was reacted overnight at room temperature. After filtration to remove the dichloromethane, the product was dissolved in a solvent (petroleum ether: ethyl acetate = 10:1), filtered through silica gel, and concentrated to give 7.31 g of crude product. The crude product was used directly in the next reaction without further purification.

[0692] Step 2: Synthesis of 6-((3-(((tert-butyldimethylsilyl)oxy)methyl)oxetane-3-yl)methoxy)-2,3-difluorobenzaldehyde

[0693] ((3-(bromomethyl)oxetane-3-yl)methoxy)(tert-butyl)dimethylsilane and 2,3-difluoro-6-hydroxybenzaldehyde (1.07 g, 6.77 mmol) were dissolved in N,N'-dimethylformamide (6 mL), and potassium carbonate (1.87 g, 13.55 mmol) and sodium iodide (1.02 g, 6.77 mmol) were added. The mixture was heated at 80 °C overnight. After cooling, the mixture was diluted with ethyl acetate (60 mL), washed successively with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give 1.92 g of the product.

[0694] Step 3: Synthesis of (6-(3-(((tert-butyldimethylsilyl)oxy)methyl)oxetane-3-yl)methoxy)-2,3-difluorophenyl)methanol

[0695] 6-((3-(((tert-butyldimethylsilyl)oxy)methyl)oxetane-3-yl)methoxy)-2,3-difluorobenzaldehyde (920 mg, 2.47 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and sodium borohydride (93 mg, 2.47 mmol) was added at 0 °C. The mixture was reacted at room temperature for 2 hours. Extraction was performed with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.70 g of crude product, which was used directly in the next reaction without purification.

[0696] Step 4: Synthesis of tert-butyl((3-((2-(2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)methyl ester)oxetane-3-yl)methoxy)dimethylsilane

[0697] 6-(3-(((tert-butyldimethylsilyl)oxy)methyl)oxetane-3-yl)methoxy)-2,3-difluorophenyl)methanol (700 mg, 1.87 mmol), 2,4-difluoro-5-nitrophenol (327 mg, 1.87 mmol), and triphenylphosphine (981 mg, 3.74 mmol) were dissolved in tetrahydrofuran (4 mL). Diisopropyl azodicarbonate (0.60 mL, 2.80 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 1 hour. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 367 mg of the product.

[0698] 1 H NMR (500MHz, CDCl3) δ7.87(t,J=7.6Hz,1H),7.19(q,J=9.3Hz,1H),7.05(t,J=10.1Hz,1H),6.71(d,J=8.6 Hz,1H),5.24(s,2H),4.53(d,J=6.2Hz,2H),4.45(d,J=6.2Hz,2H),4.20(s,2H),3.88(s,2H),0.86(s,9H).

[0699] Step 5: 1,2,11-trifluoro-12-nitro-6H,8H,15Hspiro[dibenzo[b,f][1,4,8]triazolylcycloundecene-7,3'-oxetane]

[0700] tert-Butyl((3-((2-(2,4-difluoro-5-nitrophenoxy)methyl)-3,4-difluorophenoxy)methyl ester)oxetane-3-yl)methoxy)dimethylsilane (367 mg, 0.69 mmol) was dissolved in N,N-dimethylformamide (60 mL), and cesium fluoride (1.05 g, 6.91 mmol) was added. The mixture was heated at 80 °C for 4 hours. After cooling, ethyl acetate (200 mL) was added, and the mixture was washed successively with water (100 mL × 5) and saturated brine (100 mL). The mixture was dried over sodium sulfate, filtered, concentrated, and separated by column chromatography to give 106 mg of the product.

[0701] 1 H NMR(500MHz,DMSO-d6)δ7.87(d,J=7.7Hz,1H),7.48–7.37(m,2H),7.17(d,J=7.5Hz,1H ),5.17(s,2H),4.68(s,2H),4.62(s,2H),4.49(d,J=6.4Hz,2H),4.41(d,J=6.4Hz,2H).

[0702] Step 6: Synthesis of 1,2,11-trifluoro-6H,8H,15H-spiro[dibenzo[b,f][1,4,8]triazolylcycloundecene-7,3'-oxetane]-12amine

[0703] 1,2,11-trifluoro-12-nitro-6H,8H,15Hspiro[dibenzo[b,f][1,4,8]triazolylcycloundecene-7,3'-oxetane] (106 mg, 0.27 mmol) was dissolved in ethyl acetate (2 mL), and 5% palladium / carbon (20 mg) was added. The mixture was hydrogenated overnight at room temperature and pressure. The palladium / carbon was removed by filtration through a membrane filter, and the concentrate yielded 95 mg of crude product, which was used directly in the next reaction without further purification.

[0704] LC-MS(ESI):[M+H] + =568.3;

[0705] Step 7: Synthesis of methyl 4-oxo-2-thio-3-(1,2,11-trifluoro-6H,8H,15H-spiro[dibenzo[b,f][1,4,8]triazolylcycloundecene-7,3'-oxetane]-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0706] 1,2,11-trifluoro-6H,8H,15Hspiro[dibenzo[b,f][1,4,8]triazolylcycloundecene-7,3'-oxetane]-12amine (95 mg, 0.26 mmol) was dissolved in tetrahydrofuran (2 mL), and 4-((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylic acid dimethyl ester (109 mg, 0.31 mmol) and triethylamine (0.11 mL, 0.81 mmol) were added. The mixture was heated at 70 °C for 2 hours. After cooling, the mixture was concentrated and separated by column chromatography to give 126 mg of the product.

[0707] LC-MS(ESI):[M+H] + =593.3;

[0708] Step 8: Synthesis of 4-oxo-2-thio-3-(1,2,11-trifluoro-6H,8H,15H-spiro[dibenzo[b,f][1,4,8]triazolylcycloundecene-7,3'-oxetane]-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0709] Methyl 4-oxo-2-thio-3-(1,2,11-trifluoro-6H,8H,15H-spiro[dibenzo[b,f][1,4,8]triazolylcycloundecene-7,3'-oxetane]-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (126 mg, 0.21 mmol) was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL), and a solution of lithium hydroxide monohydrate (45 mg, 1.07 mmol) in water (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The pH was adjusted to 2-3 with hydrochloric acid (1 M), and the product was extracted with ethyl acetate (30 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high performance liquid chromatography to obtain 69 mg of the product.

[0710] LC-MS(ESI):[M+H] + =579.3;

[0711] 1 H NMR (500MHz, DMSO-d6) δ14.11(s,1H),13.45(s,1H),7.52(s,1H),7.46–7.38(m,1H),7.29(d,J=7.6H z,1H),7.25(d,J=10.9Hz,1H),7.22–7.17(m,1H),5.09(s,2H),4.68–4.61(m,2H),4.56–4.44(m,6H).

[0712] Example 33 Synthesis of 3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione (Compound 33)

[0713] Step 1: Synthesis of methyl 4-((phenoxycarbonyl)amino)thiophene-3-carboxylate

[0714] Methyl thiophene-3-carboxylate (4.05 g, 20.91 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL), followed by the addition of potassium carbonate (5.79 g, 41.90 mmol). Phenyl chloroformate (2.9 mL, 23.01 mmol) was added dropwise under an ice-water bath, and the reaction was carried out at room temperature for 3 hours. After dilution with water (30 mL), the mixture was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 6.45 g of the product.

[0715] LC-MS(ESI):[M+H] + =278.1;

[0716] Step 2: Synthesis of methyl 4-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-yl)ureo)thiophene-3-carboxylate

[0717] 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (302 mg, 0.84 mmol) and methyl 4-((phenoxycarbonyl)amino)thiophene-3-carboxylate (154 mg, 0.56 mmol) were dissolved in tetrahydrofuran (5 mL), and triethylamine (349 μL, 2.51 mmol) was added. The mixture was reacted overnight at 60 °C. After cooling and concentration, the product was purified by column chromatography to give 277 mg of the product.

[0718] LC-MS(ESI):[MH] - =543.1;

[0719] Step 3: Synthesis of 3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione

[0720] Methyl 4-(3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-3-carboxylate (277 mg, 0.51 mmol) was dissolved in tetrahydrofuran (2 mL), and a methanol solution of sodium methoxide (29 mg, 0.53 mmol) in 1 mL was added dropwise. The reaction was carried out at room temperature for 1 hour. The solution was adjusted to acidity with dilute hydrochloric acid (1 M), and then ethyl acetate and petroleum ether (1:1) were added. After filtration and drying, 135 mg of the product was obtained.

[0721] LC-MS(ESI):[M+H] + =513.1;

[0722] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),8.50(d,J=3.2Hz,1H),7.50(dd,J=19.4,9.4Hz,2H),7.46(d,J=7.7Hz,1H),7.38( d,J=10.9Hz,1H),7.29–7.22(m,1H),6.95(d,J=3.2Hz,1H),5.12(s,2H),4.69(t,J=11.4Hz,2H),4.62(t,J=11.6Hz,2H).

[0723] Example 34 Synthesis of 2,2-dioxide of 4-oxo-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-3,4-dihydro-1H-thieno[3,4-c][1,2,6]thiadiazine-5-carboxylic acid (Compound 34)

[0724] Step 1: Synthesis of (2,3,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-yl)aminosulfonyl fluoride

[0725] 1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (100 mg, 0.31 mmol) was dissolved in dichloromethane (4 mL), and 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazolium-3-onium trifluoromethanesulfonate (49 mg, 0.15 mmol) was added under ice-water bath. The reaction was carried out overnight at room temperature. The solution was diluted with dichloromethane (30 mL), washed with 0.1 M hydrochloric acid, dried over saturated brine and anhydrous sodium sulfate, filtered, and concentrated to obtain 120 mg of crude product, which was used directly in the next reaction without purification.

[0726] LC-MS(ESI):[MH] - =406.1;

[0727] Step 2: Synthesis of dimethyl 4-((N-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-yl)amino)thiophene-2,3-dicarboxylic acid ester

[0728] (2,3,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)aminosulfonyl fluoride (120 mg, 0.29 mmol) was dissolved in dichloromethane (2 mL), and calcium bis(trifluoromethylsulfonyl)imide (333 mg, 1.03 mmol), triethylenediamine (154 mg, 1.37 mmol), and dimethyl 4-aminothiophene-2,3-dicarboxylate (148 mg, 0.69 mmol) were added. The mixture was reacted at room temperature for 3 hours. After concentration, the product was purified by column chromatography to give 140 mg of the product.

[0729] Step 3: Synthesis of 2,2-dioxide of 4-oxo-3-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-3,4-dihydro-1H-thiopheno[3,4-c][1,2,6]thiadiazine-5-carboxylic acid

[0730] Dimethyl 4-((N-(1,2,11-trifluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-yl)amino)thiophene-2,3-dicarboxylate (300 mg, 0.50 mmol) was dissolved in anhydrous dimethyl sulfoxide (5 mL), and potassium tert-butoxide (111 mg, 0.99 mmol) was added. The mixture was reacted at 120 °C for 1 hour. After cooling, hydrochloric acid (1 M) was added to adjust the pH to acidic, and ethyl acetate (30 mL × 3) was added for extraction. The extract was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative high-performance liquid chromatography to obtain 63 mg of the product.

[0731] LC-MS(ESI):[MH] - =555.2;

[0732] 1 H NMR(500MHz,DMSO-d6)δ7.38(q,J=9.6Hz,1H),7.19–7.12(m,3H),7.03(d,J=9.2Hz,1H),5.14(d, J=11.3Hz,1H),5.06(d,J=11.2Hz,1H),4.50–4.43(m,2H),4.34–4.27(m,2H),2.00–1.94(m,2H).

[0733] Example 35 Synthesis of 2-hydroxy-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 35)

[0734] Step 1: Synthesis of 2-hydroxy-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0735] 1.0 g (1.75 mmol) of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid was dissolved in acetic acid (10 mL), and hydrogen peroxide (594 μL, 5.24 mmol) was added dropwise under an ice-water bath. The reaction was carried out overnight at room temperature. After dilution with ethyl acetate (50 mL), the solution was filtered and dried to give 750 mg of the product.

[0736] LC-MS(ESI):[M+H] + =559.2;

[0737] 1 H NMR (400MHz, DMSO) δ11.13(s,1H),10.30(s,1H),8.34(d,J=1.4Hz,1H),8.13(s,1H),8.03(d,J=7.9Hz,1H),7.59–7.4 6(m,1H),7.41–7.34(m,1H),7.31(dd,J=9.2,2.1Hz,1H),5.11(s,2H),4.67(t,J=11.6Hz,2H),4.57(t,J=11.7Hz,2H).

[0738] Example 36 Synthesis of 4-oxo-2-(oxo-1,4-sulfonamide)-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 36)

[0739] Step 1: Synthesis of 4-oxo-2-(oxo-1,4-sulfonamide)-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid APH231553-208

[0740] 4-O-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (6 g, 10.48 mmol) was dissolved in tetrahydrofuran (50 mL). m-chloroperoxybenzoic acid (2.13 g, 10.48 mmol) was added at 0 °C, and the reaction was carried out for 30 minutes at this temperature. Petroleum ether (100 mL) was added to precipitate the product. After filtration, the filter cake was dissolved by sonication in ethyl acetate (50 mL). Petroleum ether (50 mL) was added again to precipitate the product. The product was filtered and dried to obtain 5.4 g of the product.

[0741] LC-MS(ESI):[M+H] + =589.1;

[0742] 1H NMR (400MHz, DMSO-d6) δ14.48(s,1H),9.84(s,1H),8.28(s,1H),7.55(d,J=7.6Hz,1H),7.51–7. 41(m,2H),7.25–7.16(m,1H),5.26(d,J=11.4Hz,1H),5.19(d,J=11.3Hz,1H),4.79–4.62(m,4H).

[0743] Example 37 Synthesis of 1-methyl-2,4-dioxy-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 37)

[0744] Step 1: Synthesis of methyl 1-methyl-2,4-dioxy-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester

[0745] To a solution of 2,4-dioxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (50 mg, 0.09 mmol) in N,N-dimethylformamide (1 mL), iodomethane (64 mg, 0.45 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was diluted with saturated ammonium chloride aqueous solution (50 mL), and then extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated ammonium chloride aqueous solution (50 mL × 2). The organic phases were combined, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 50 mg of the product.

[0746] LC-MS(ESI):[M+H] + =585.3;

[0747] 1 H NMR (400MHz, DMSO-d6) δ7.61-7.54(m,1H),7.54-7.37(m,3H),7.26(td,J=1.9,7.2Hz,1H),5.11(s,2H),4.76-4.55(m,4H),3.85(s,3H).

[0748] Step 2: Synthesis of 1-methyl-2,4-dioxy-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0749] To a solution of methyl 1-methyl-2,4-dioxy-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester (40 mg, 0.07 mmol) in tetrahydrofuran (0.4 mL) and methanol (0.2 mL), lithium bromide (29 mg, 0.34 mmol) in water (0.2 mL) and triethylamine (35 mg, 0.35 mmol) were added. The reaction mixture was stirred at 15 °C for 3 hours. The reaction solution was quenched with dilute hydrochloric acid (1 M), the pH was adjusted to weakly acidic, and then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography to obtain 28 mg of the product.

[0750] LC-MS(ESI):[M+H] + =571.1;

[0751] 1 H NMR (400MHz, DMSO-d6) δ14.52(s,1H),7.70(br s,1H),7.57-7.37(m,3H),7.32-7.19(m,1H),5.14(s,2H),4.78-4.53(m,4H),3.50(s,3H).

[0752] Example 38 2-(Methylsulfonyl)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 38)

[0753] Step 1: Synthesis of methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0754] 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (450 mg, 1.25 mmol) and 4-(((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylic acid ethylenedimethyl-4-((phenoxycarbonylthio)amino)thiophene-2,3-dicarboxylic acid dimethyl ester (500 mg, 1.42 mmol) were dissolved in tetrahydrofuran (6 mL), and then triethylamine (378 mg, 3.74 mmol) was added. The reaction mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was filtered and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 730 mg of the product.

[0755] LC-MS(ESI):[M+H] + =587.1;

[0756] Step 2: Synthesis of methyl 2-(methylthio)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0757] Methyl 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-thio-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester (330 mg, 0.56 mmol) and iodomethane (240 mg, 1.69 mmol) were dissolved in N,N-dimethylformamide (4 mL), followed by the addition of potassium carbonate (233 mg, 1.69 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed once with saturated calcium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 330 mg of the product.

[0758] LC-MS(ESI):[M+H] + =601.1;

[0759] Step 3: Synthesis of 2-(methylthio)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0760] Methyl 2-(methylthio)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid ester (320 mg, 0.53 mmol), lithium bromide (463 mg, 5.33 mmol), and triethylamine (539 mg, 5.33 mmol) were dissolved in acetonitrile (3 mL) and water (3 mL). The reaction mixture was stirred at 50 °C for 12 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to 2-3 with 1 M hydrochloric acid. It was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed once with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 310 mg of product.

[0761] LC-MS(ESI):[M+H] + =587.1;

[0762] Step 4: Synthesis of 2-(methanesulfonyl)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0763] 2-(methylthio)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid (50 mg, 0.09 mmol) and m-chloroperoxybenzoic acid (52 mg, 0.26 mmol) were dissolved in dichloromethane (2 mL), and the reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched with saturated sodium sulfite solution (50 mL), diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed once 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 separated by high performance liquid chromatography to obtain 4 mg of product.

[0764] LC-MS(ESI):[M+H] + =619.0;

[0765] 1H NMR (400MHz, DMSO-d6) δ14.09(s,1H),8.58(s,1H),7.55(d,J=7.6Hz,1H),7.53-7.47(m,1H),7.44 (d,J=10.8Hz,1H),7.25(dd,J=2.4,9.6Hz,1H),5.15-5.04(m,2H),4.76-4.65(m,4H),3.51(s,3H).

[0766] Example 39 Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 39)

[0767] Step 1: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0768] 2-(methanesulfonyl)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid (50 mg, 0.08 mmol) was dissolved in methanol (1 mL), and sodium borohydride (7 mg, 0.16 mmol) was added. The reaction mixture was stirred at 20 °C for 1 hour. The pH of the reaction mixture was adjusted to 2-3 with 1 M hydrochloric acid. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed once 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 separated by high performance liquid chromatography to obtain 10 mg of the product.

[0769] LC-MS(ESI):[M+H] + =541.1;

[0770] 1 H NMR (400MHz, DMSO-d6) δ15.02-14.65(m,1H),8.46(s,1H),8.29(s,1H),7.69(d,J= 7.6Hz,1H),7.59-7.46(m,2H),7.29-7.22(m,1H),5.16(s,2H),4.76-4.61(m,4H).

[0771] Example 40 Synthesis of 2-amino-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 40)

[0772] Step 1: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0773] 120 mg (0.19 mmol) of 2-(methanesulfonyl)-4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-3,4-dihydrothieno[3,4-d]pyrimidine-5-carboxylic acid was dissolved in tetrahydrofuran (2 mL) and ammonia (2 mL). The reaction mixture was stirred at 20 °C for 1 hour. The pH of the reaction mixture was adjusted to 2-3 with 1 M hydrochloric acid. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed once 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 separated by high performance liquid chromatography to obtain 2 mg of the product.

[0774] LC-MS(ESI):[M+H] + =556.0;

[0775] 1 H NMR (400MHz, DMSO-d6) δ15.10-14.33(m,1H),7.68-7.43(m,4H),7.33-7.20(m,1H),6.86-6.60(m,2H),5.27-5.04(m,2H),4.79-4.47(m,4H).

[0776] Example 41 Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (Compound 41)

[0777] Step 1: Synthesis of 4-((tert-Butoxycarbonyl)amino)-2-(methoxycarbonyl)thiophene-3-carboxylic acid

[0778] A methanol (50 mL) solution of 4-((tert-Butoxycarbonyl)amino)thiophene-2,3-dicarboxylic acid dimethyl ester (4 g, 12.68 mmol) was added to a water solution of lithium hydroxide monohydrate (533 mg, 12.68 mmol). The reaction mixture was stirred at 20 °C for 2 hours. The pH of the reaction mixture was adjusted to <7 with dilute hydrochloric acid (1 M), and then extracted with ethyl acetate (200 mL × 2). The combined organic phases were dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by high performance liquid chromatography to obtain 400 mg of the product.

[0779] LC-MS(ESI):[MH] + =300.2;

[0780] 1 H NMR (400MHz, DMSO-d6) δ8.94(br s,1H),7.69(s,1H),3.81(s,3H).

[0781] Step 2: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-3-((1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)carbonyl)thiophene-2-carboxylic acid

[0782] 4-((tert-Butoxycarbonyl)amino)-2-(methoxycarbonyl)thiophene-3-carboxylic acid (400 mg, 1.33 mmol), 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine (480 mg, 1.33 mmol), and N,N-diisopropylethylamine (1.8 mL, 10.62 mmol) were dissolved in dichloromethane (5 mL). 1-Butylphosphine anhydride (5295 mg, 7.97 mmol) was added to the reaction mixture, and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (200 mL × 2). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was separated by silica gel column chromatography to obtain 420 mg of the product.

[0783] LC-MS(ESI):[M+H] + =645.2;

[0784] Step 3: Synthesis of methyl 4-amino-3-((1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)carbamoyl)thiophene-2-carboxylic acid

[0785] A solution of methyl 4-((tert-butoxycarbonyl)amino)-3-((1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)carbonyl)thiophene-2-carboxylic acid (400 mg, 0.62 mmol) in dichloromethane (5 mL) was added to a solution of trifluoroacetic acid (0.5 mL, 6.21 mmol). The reaction mixture was stirred at 20 °C for 30 minutes. The pH of the reaction mixture was adjusted to <7 with a saturated sodium bicarbonate aqueous solution, and then extracted with dichloromethane (200 mL × 2). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain 280 mg of the product.

[0786] LC-MS(ESI):[M+H] + =545.0;

[0787] Step 4: Synthesis of methyl 4-oxy-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0788] Methyl 4-amino-3-((1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)carbamoyl)thiophene-2-carboxylic acid (20 mg, 0.04 mmol), 2,2,2-trifluoroacetaldehyde (7 mg, 0.07 mmol), magnesium sulfate (4 mg, 0.04 mmol), and p-toluenesulfonic acid (6 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 130 °C for 16 hours. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated calcium chloride aqueous solution (20 mL × 3). The organic phases were combined, dried, filtered, and evaporated to dryness to obtain 20 mg of the product.

[0789] LC-MS(ESI):[M+H] + =625.0;

[0790] Step 5: Synthesis of 4-oxo-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolylcycloundecen-12-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid

[0791] Methyl 4-oxy-3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-diphenyl[b,f][1,4,8]triazolcycloundecen-12-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydrothiophene[3,4-d]pyrimidine-5-carboxylic acid (20 mg, 0.03 mmol) was dissolved in tetrahydrofuran (1 mL). Lithium bromide (8 mg, 0.10 mmol) and triethylamine (10 mg, 0.10 mmol) were added to the mixture, and the reaction was stirred at 20 °C for 1 hour. The product (7 mg) was obtained directly by high-performance liquid chromatography.

[0792] LC-MS(ESI):[M+H] + =611.1;

[0793] 1 H NMR (400MHz, DMSO-d6) δ7.57-7.33(m,4H),7.30-7.19(m,1H),6.59-6.46(m,1H),5.84-5.69(m,1H),5.23-5.06(m,2H),4.75-4.55(m,4H).

[0794] Example 42 Synthesis of 3-(2,11-difluoro-1-(2-methoxyethoxy)-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 42)

[0795] Step 1: Synthesis of 3-fluoro-2-hydroxy-6-methoxybenzene-1-carboxaldehyde

[0796] 2-Fluoro-5-methoxyphenol (5 g, 35.18 mmol) was dissolved in tetrahydrofuran (200 mL), and triethylamine (24.4 mL, 175.90 mmol), magnesium chloride (5.72 g, 28.14 mmol), and paraformaldehyde (210 mg, 2.33 mmol) were added. The reaction mixture was heated to 80 °C and reacted for 1 hour. 1 M hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with brine (50 mL), dried over sodium sulfate-free solution, filtered, and the filtrate was then evaporated to dryness to obtain 5 g of product.

[0797] Step 2: Synthesis of 3-fluoro-6-methoxy-2-(2-methoxyethoxy)benzaldehyde

[0798] 3-Fluoro-2-hydroxy-6-methoxybenzaldehyde (4 g, 23.51 mmol) and 1-bromo-2-methoxyethane (3.4 mL, 35.97 mmol) were dissolved in N,N”-dimethylformamide (100 mL), followed by the addition of potassium carbonate (9 g, 65.12 mmol). The reaction mixture was heated to 60 °C and stirred for 12 hours. The reaction mixture was then poured into an aqueous solution (500 mL) and extracted with ethyl acetate (500 mL). The organic phase was washed with a saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1.7 g of the final product.

[0799] LC-MS(ESI):[M+H] + =229.1;

[0800] Step 3: Synthesis of 3-fluoro-6-hydroxy-2-(2-methoxyethoxy)benzaldehyde

[0801] Aluminum trichloride (1.0 mL, 18.00 mmol) was dissolved in dichloromethane (100 mL). 3-fluoro-6-methoxy-2-(2-methoxyethoxy)benzaldehyde (1650 mg, 7.23 mmol) was added at -10 °C, and the reaction was gradually restored to 20 °C with stirring for 16 hours. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (200 mL), washed with saturated brine, dried, and evaporated to dryness to give 1.1 g of the product.

[0802] LC-MS(ESI):[M+H] + =215.1;

[0803] Step 4: Synthesis of 6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-3-fluoro-2-(2-methoxyethoxy)benzaldehyde

[0804] 3-Fluoro-6-hydroxy-2-(2-methoxyethoxy)benzaldehyde (1 g, 4.67 mmol) and 7-bromo-2,2,3,3-tetramethyl-4-oxa-3-silylheptane (1.8 mL, 7.90 mmol) were dissolved in acetonitrile (20 mL), and then potassium carbonate (2 g, 14.47 mmol) was added. The reaction mixture was heated to 70 °C and stirred for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 800 mg of the product.

[0805] LC-MS(ESI):[M+H] + =387.2;

[0806] Step 5: Synthesis of (6-(3-(((tert-butyldimethylsilyl)oxy)propoxy)-3-fluoro-2-(2-methoxyethoxy)phenyl)methanol

[0807] 6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-3-fluoro-2-(2-methoxyethoxy)benzaldehyde (800 mg, 2.07 mmol) was dissolved in methanol (10 mL), and sodium borohydride (150 mg, 3.97 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 400 mg of the product.

[0808] LC-MS (ESI): [M-OH] + =371.2;

[0809] Step 6: Synthesis of tert-butyl(3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-4-fluoro-3-(2-methoxyethoxy)phenoxy)propoxy)dimethylsilane

[0810] (6-(3-(((tert-butyldimethylsilyl)oxy)propoxy)-3-fluoro-2-(2-methoxyethoxy)phenyl)methanol (400 mg, 1.03 mmol), 2,4-difluoro-5-nitrophenol (200 mg, 1.14 mmol), and triphenylphosphine (400 mg, 1.53 mmol) were dissolved in tetrahydrofuran (10 mL), and the reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was then added to water (100 mL), and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 300 mg of the product.

[0811] Step 7: Synthesis of 2,11-difluoro-1-(2-methoxyethoxy)-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolyl undecene

[0812] 300 mg (0.55 mmol) of tert-butyl(3-(2-((2,4-difluoro-5-nitrophenoxy)methyl)-4-fluoro-3-(2-methoxyethoxy)phenoxy)propoxy)dimethylsilane was dissolved in 5 mL of N,N”-dimethylformamide, and then cesium fluoride (200 mg, 1.32 mmol) was added. The reaction mixture was heated to 60 °C and stirred for 3 hours. The reaction mixture was then added to 100 mL of water and extracted with 200 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 100 mg of the product.

[0813] Step 8: Synthesis of 2,11-difluoro-1-(2-methoxyethoxy)-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolcycloundecene-12-amine

[0814] 2,11-Difluoro-1-(2-methoxyethoxy)-12-nitro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene (100 mg, 0.24 mmol) was dissolved in N,N'-dimethylformamide (5 mL), followed by the addition of 4,4'-bipyridine (8 mg, 0.05 mmol) and (dihydroxyboryl)boranediol (130 mg, 1.45 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The reaction solution was then added to water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried, and evaporated to dryness to obtain 70 mg of the product.

[0815] LC-MS(ESI):[M+H] + =382.1;

[0816] Step 9: Synthesis of dimethyl 4-(3-(2,11-difluoro-1-(2-methoxyethoxy)-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-yl)ureo)thiophene-2,3-dicarboxylic acid ester

[0817] 2,11-Difluoro-1-(2-methoxyethoxy)-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecene-12-amine (70 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL), followed by the addition of methyl 3-(methoxycarbonyl)-4-{[(phenoxy)carbonyl]amino}thiophene-2-carboxylic acid ester (80 mg, 0.24 mmol) and triethylamine (0.1 mL, 0.37 mmol). The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was then added to water (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 90 mg of the final product.

[0818] LC-MS (ESI): [M+Na] + =645.0;

[0819] Step 10: Synthesis of 3-(2,11-difluoro-1-(2-methoxyethoxy)-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)-2,4-dioxo-1,2,3,4-tetrahydrothiopheno[3,4-d]pyrimidine-5-carboxylic acid

[0820] Dimethyl 4-(3-(2,11-difluoro-1-(2-methoxyethoxy)-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]triazolylcycloundecen-12-yl)ureo)thiophene-2,3-dicarboxylic acid (90 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL). Lithium hydroxide monohydrate (10 mg, 0.24 mmol) was then added, and the reaction was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (100 mL × 2), and the organic phase was discarded. The pH of the aqueous phase was adjusted to 6-7 with hydrochloric acid (1 M), and then extracted again with ethyl acetate (100 mL). The product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 29.35 mg of a white solid.

[0821] LC-MS(ESI):[M+H] + =577.1;

[0822] 1 H NMR (400MHz, DMSO-d6) δ14.51(s,1H),12.00(s,1H),7.35(s,1H),7.32(d,J=7.6Hz,1H),7.28-7.19(m,2H),6.91(dd,J=3.6,9.2Hz,1H) ,5.11-4.97(m,2H),4.35(t,J=4.4Hz,2H),4.31(t,J=4.4Hz,2H),4.24-4.12(m,2H),3.70-3.57(m,2H),3.29(s,3H),2.01-1.95(m,2H).

[0823] Example 43 Synthesis of 3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]trioxaneundecen-12-yl)-2-thiooxy-2,3-dihydrothieno[3,4-d]pyrimidine-4(1H)-one (Compound 43)

[0824] Step 1: Synthesis of methyl 4-((phenoxycarbonylthio)amino)thiophene-3-carboxylic acid

[0825] The starting material, methyl 4-aminothiophene-3-carboxylic acid hydrochloride (10 g, 51.64 mmol), was dissolved in water (40 mL) and tetrahydrofuran (80 mL), stirred until homogeneous, and cooled to 0–10 °C. Sodium bicarbonate (9.11 g, 108.44 mmol) was then slowly added to the reaction system, followed by the slow dropwise addition of phenyl thiochloroformate (9.81 g, 56.80 mmol). The reaction was maintained at 0–10 °C for 15 minutes. The reaction solution was diluted with water (20 mL), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (30 mL × 3) and evaporated to dryness to obtain the crude product (17.65 g). The crude product was used directly in the next reaction without purification.

[0826] LC-MS(ESI):[M+H] + =294.1;

[0827] Step 2: Synthesis of 3-(1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]trioxaneundecen-12-yl)-2-thiooxy-2,3-dihydrothieno[3,4-d]pyrimidine-4(1H)-one

[0828] Methyl 4-((phenoxycarbonylthio)amino)thiophene-3-carboxylic acid (15.15 g, 51.64 mmol) and 1,2,7,7,11-pentafluoro-7,8-dihydro-6H,15H-dibenzo[b,f][1,4,8]trioxane-undecene-12-amine (13.82 g, 38.25 mmol) were dissolved in tetrahydrofuran (138 mL), and then triethylamine (5.81 g, 57.38 mmol) was added. The reaction mixture was heated to 70 °C and reacted for 36 hours. The reaction mixture was cooled to room temperature and evaporated to dryness to obtain the crude product. The crude product was purified by slurry mixing in a tetrahydrofuran / ethyl acetate system (30 mL / 150 mL) to obtain 14.74 g of the product.

[0829] LC-MS(ESI):[M+H] + =529.0;

[0830] 1H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.58(d,J=3.3Hz,1H),7.52–7.43(m,1H),7.38(d,J=7.6Hz,1H),7.32(d,J=10.9Hz,1H),7 .24(ddd,J=9.3,3.8,1.8Hz,1H),7.17(d,J=3.2Hz,1H),5.19–5.08(m,2H),4.70(t,J=11.4Hz,2H),4.62(td,J=11.3,2.7Hz,2H).

[0831] Biological test data

[0832] Experimental Example 1: Determination of the activity of the compounds of the present invention on gonadotropin-releasing hormone (GnRH) receptors

[0833] 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.

[0834] Main reagents, equipment and brands:

[0835] F-12 culture medium – Hyclone

[0836] Fetal Bovine Serum (FBS) – AusGeneX

[0837] Hygromycin B – Solarbio

[0838] DMSO (Dimethyl Sulfoxide) – Sigma

[0839] GnRH-I——GLPBIO

[0840] 0.25% Trypsin-EDTA (trypsin-ethylenediaminetetraacetic acid) solution – Gibco

[0841] IP-One-Gq kit – Cisbio

[0842] Main experimental instruments, brands and models:

[0843] Biosafety Cabinet – ESCO – AC2-6S1-TC

[0844] Carbon dioxide cell incubator – ESCO – CLM-240B-8-TC

[0845] Inverted Microscope – Olympus – CKX53

[0846] HTS High-Throughput Drug Screening Multifunctional Microplate Reader – BMG – PHERAstar FSX

[0847] Low-speed centrifuge – YIDA – TD25M

[0848] Microplate low-speed centrifuge – Xiangzhi – TD5B

[0849] Experimental plan:

[0850] (1) Cell preparation

[0851] 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%.

[0852] (2) Determination of the activity of the test compound against the GnRH receptor

[0853] 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.

[0854] Human GnRHR-CHO cells in logarithmic growth phase were washed with PBS buffer, and an appropriate amount of 0.25% Trypsin-EDTA was added. The cells were then incubated at 37°C in a CO2 incubator for 1-2 minutes to digest. Cells were removed and culture medium was added to terminate the digestion. The cell suspension was centrifuged at 1000 rpm for 5 minutes to remove the culture medium. Cells were thoroughly dispersed with 1×Stimulation Buffer. After counting and dilution, 9.1 μL (10,000 cells) was seeded per well in a 384-well plate.

[0855] Add 1.4 μL of the serially diluted test compound and positive control compound solutions to the corresponding wells. Add 1.4 μL of DMSO to the negative control wells (the final volume fraction of DMSO in all wells is 0.1%). Centrifuge at 1000 rpm for 1 min and incubate at 37°C for 10 min. Prepare GnRH-I solution using 1×Stimulation Buffer, add 3.5 μL (final concentration 20 nM) to each well, centrifuge, and incubate at 37°C for 60 min to induce IP1 production. Dilute d2-IP1 and Anti-IP1-Cryptate 20-fold using Lysis & Detection Buffer from the kit. After cell incubation, add 3 μL of d2-IP1 and 3 μL of Anti-IP1-Cryptate to each well sequentially. Centrifuge at 1000 rpm for 1 min and incubate at room temperature in the dark for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader under excitation at 330 nm. The inhibitory activity (IC50) of the compound against the gonadotropin-releasing hormone receptor was calculated using a GraphPad Prism 8 nonlinear fitting formula. 50 The value is the drug concentration at which the production of IP1 in cells that stably express the human GnRH receptor is inhibited by half.

[0856] The structure of compound C is See Example 1 of WO2022 / 179476A1.

[0857] Linzagolix is ​​a gonadotropin-releasing hormone (GnRH) receptor antagonist developed by KISSEIPHARMACEUTICAL CO.,LTD in Japan. Its structural formula is:

[0858] 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.

[0859] Table 1 shows the inhibitory IC50 values ​​of the compounds on human gonadotropin-releasing hormone receptor activity. 50

[0860] Experimental conclusion: The compound of this invention has a significant inhibitory effect on gonadotropin-releasing hormone (GnRH) receptors.

[0861] Experimental Example 2: Rat Pharmacokinetic Test of the Compounds of the Present Invention

[0862] Experimental Objective: Using male SD rats as test subjects, this study aimed to determine the plasma drug concentration at different time points after oral administration of the compound of this invention in rats using LC / MS / MS. The goal was to investigate the pharmacokinetic behavior of the compound in rats and evaluate its pharmacokinetic characteristics.

[0863] 1) Experimental reagents

[0864] The compounds of this invention, compound C, Linzagolix.

[0865] 2) Laboratory animals

[0866] Adult male SD rats

[0867] 3) Experimental methods

[0868] Six male rats weighing 180–260 g were randomly divided into two groups: one group received a single oral dose of 2 mg / kg, and the other group received a single intravenous dose of 0.5 mg / kg via tail vein. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Plasma samples were pretreated and then analyzed by LC / MS / MS in MRM mode. A suitable standard curve was established to quantify the target compound in the plasma samples, obtaining drug concentration-time curves. Pharmacokinetic parameters were calculated using the non-compartmental membrane type of WinNonlin software. The experimental results are shown in Table 2.

[0869] Table 2 Pharmacokinetic parameters

[0870] '--' indicates that no test was conducted or no data was obtained.

[0871] Experimental conclusion: The compound of this invention exhibits lower clearance rate in plasma, significantly prolonged half-life, and significantly increased exposure, demonstrating superior pharmacokinetic properties.

[0872] Experimental Example 3: Determination of the activity of the compounds of the present invention against mouse-derived gonadotropin-releasing hormone (GnRH) receptors.

[0873] 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.

[0874] Main reagents, equipment and brands:

[0875] F-12 culture medium – Hyclone

[0876] Fetal Bovine Serum (FBS) – AusGeneX

[0877] Hygromycin B – Solarbio

[0878] DMSO (Dimethyl Sulfoxide) – Sigma

[0879] GnRH-I——GLPBIO

[0880] 0.25% Trypsin-EDTA (trypsin-ethylenediaminetetraacetic acid) solution – Gibco

[0881] IP-One-Gq kit – Cisbio

[0882] Main experimental instruments, brands and models:

[0883] Biosafety Cabinet – ESCO – AC2-6S1-TC

[0884] Carbon dioxide cell incubator – ESCO – CLM-240B-8-TC

[0885] Inverted Microscope – Olympus – CKX53

[0886] HTS High-Throughput Drug Screening Multifunctional Microplate Reader – BMG – PHERAstar FSX

[0887] Low-speed centrifuge – YIDA – TD25M

[0888] Microplate low-speed centrifuge – Xiangzhi – TD5B

[0889] Experimental plan:

[0890] (1) Cell preparation

[0891] This study used a CHO cell line stably expressing the mouse-derived GnRH receptor (GnRHR). The mouse-derived 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 (37°C) complete medium 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%.

[0892] (2) Determination of the activity of the test compound against the GnRH receptor

[0893] 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.

[0894] Logarithmic growth phase mouse GnRHR-CHO cells were washed with PBS buffer, and 0.25% Trypsin-EDTA was added. The cells were then incubated at 37°C in a CO2 incubator for 1-2 minutes to digest. Cells were removed and culture medium was added to terminate the digestion. The cell suspension was centrifuged at 1000 rpm for 5 minutes to remove the culture medium. 1×Stimulation Buffer was added to thoroughly disperse the cells. After counting and dilution, 9.1 μL (10,000 cells) was seeded per well in 384-well plates.

[0895] Add 1.4 μL of the serially diluted test compound and positive control compound solutions to the corresponding wells. Add 1.4 μL of DMSO to the negative control wells (the final volume fraction of DMSO in all wells is 0.1%). Centrifuge at 1000 rpm for 1 min and incubate at 37°C for 10 min. Prepare GnRH-I solution using 1×Stimulation Buffer, add 3.5 μL (final concentration 8 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 the Lysis & Detection Buffer provided in 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 stably expressing the mouse-derived GnRH receptor is inhibited by half.

[0896] The structure of compound C is See Example 1 of WO2022 / 179476A1.

[0897] Linzagolix is ​​a gonadotropin-releasing hormone (GnRH) receptor antagonist developed by KISSEIPHARMACEUTICAL CO.,LTD in Japan. Its structural formula is:

[0898] Experimental Results: The inhibitory activity of some compounds of this invention on mouse 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.

[0899] Table 1 shows the inhibitory IC50 values ​​of the compounds on mouse gonadotropin-releasing hormone receptor activity. 50

[0900] Experimental conclusion: The compound of this invention has a significant inhibitory effect on mouse gonadotropin-releasing hormone (GnRH) receptors.

[0901] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

Claims

1. A compound, which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I); in: L1, L2, L3, and L4 are independently selected from the following: -O-, -S-, and -(CR5R6), respectively. n -; T1 and T2 are independently O, S, NH, N-NO2 or N-CN, respectively; A1 is either CR4 or N; Y and Z are independently selected from bond, -O-, -S-, -S(=O)-, -SO2-, -CR7R8- and -C(=O)-, respectively; R1 is C(=O)OW1, C(=O)NW2W3 or S(=O)2W4, where W1, W2, W3 and W4 are independently selected from H, D, and C respectively. 1-6 Alkyl, C 3-8 cycloalkyl and C 6-10 Aryl; R2, R3, and R4 are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, NO2, and C, respectively. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH and NO2; Each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, OH, and C, 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 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, oxo (=O), CN, NH2 and OH; or R5 and R6, R7 and R8 may be optionally substituted with the carbon atom they are connected to to form a 3-6 membered cycloalkyl group or a 3-7 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group and the 3-7 membered heterocyclic group may be independently and optionally substituted by 1, 2 or 3 substituents selected from H, D, oxo (=O), F, Cl, Br, I, CN, NH2 and OH; Each R9 is independently H, D, F, Cl, Br, I, CN, OH, COOH, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 alkylthio group or 3-7 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 The alkylthio group and the 3-7 membered heterocyclic group can be optionally and independently replaced by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I, CN, oxo (=O), OH, COOH, NO2 and NH2; R 10 For H, D, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be independently and optionally replaced by one, two or three substituents selected from H, D, F, Cl, Br, I, oxo (=O), NH2, CN, OH, NO2; m can be 1, 2, 3, or 4; n is 1, 2, or 3; Wherein, formula (I) is not one of the following compounds:

2. The compound according to claim 1, characterized in that, It is a compound as shown in formula (I-1) or formula (I-2), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound shown in formula (I-1) or formula (I-2).

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

4. The compound according to claim 1 or 2, characterized in that: R2, R3, and R4 are independently selected from H, D, F, Cl, Br, I, and C, respectively. 1-6 Alkyl and C 1-6 Alkoxy; the C 1-6 Alkyl and C 1-6 The alkoxy group can be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br and I; Alternatively, R2, R3, and R4 can be independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2; Alternatively, R2, R3, and R4 can be independently selected from H, D, F, Cl, Br, and I, respectively.

5. The compound according to claim 1 or 2, characterized in that: Each of R5, R6, R7, and R8 is independently selected from H, D, F, Cl, Br, I, and C, respectively. 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group may be independently and optionally substituted by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br and I; or R5 and R6, R7 and R8 may be optionally substituted with the carbon atom they are connected to to form a 3-6 membered cycloalkyl group or a 3-7 membered heterocyclic group, wherein the 3-6 membered cycloalkyl group and the 3-7 membered heterocyclic group may be independently and optionally substituted by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH; Alternatively, each of R5, R6, R7, and R8 may be independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -O CH2CF3 and -OCH2CF2CHF2; or R5 and R6, R7 and R8 may optionally form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy or cyclopentoxy with the carbon atom they are connected to, respectively, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy and cyclopentoxy may be independently and optionally replaced by 1, 2 or 3 substituents selected from H, D, F, Cl, Br, I, CN, NH2 and OH.

6. The compound according to claim 1 or 2, characterized in that: Each R9 is independently H, D, F, Cl, Br, I, CN, NO2, C 1-6 Alkyl, C 1-6 alkoxy or 3-7 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 The alkoxy group and the 3-7 membered heterocyclic group may be optionally and independently replaced by 1, 2, 3, 4 or 5 substituents selected from H, D, F, Cl, Br, I and CN; Alternatively, each R9 may be independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, and -OCH2CF2CHF2.

7. The compound according to claim 1 or 2, characterized in that: R 10 Selected from H, D, F, Cl, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3 and -CH2CF2CHF2.

8. A compound having one of the following structures, or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

9. A pharmaceutical composition comprising the compound of any one of claims 1-8; the pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

10. Use of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 in the preparation of a medicament for the prevention, treatment or relief of a patient’s GnRH receptor antagonist-mediated disease.

11. The use according to claim 10, 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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