Gonadotropin-releasing hormone antagonists, methods of making and using the same

Abstract

The present application relates to a kind of gonadotropin releasing hormone antagonists, it has the antagonistic activity to gonadotropin releasing hormone, and can be used to prevent or treat sex hormone-dependent diseases, such as benign prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea and the like, or its prodrug, or its pharmaceutically acceptable salt, or its hydrate or solvate, and the pharmaceutical composition containing it.

Description

[0001] This application is a divisional application of the invention patent application filed on October 31, 2022, with application number 202280071722.9 and invention title "Gonadotropin-releasing hormone antagonist and its preparation method and application". Technical Field

[0002] This invention belongs to the field of pharmaceutical technology and relates to compounds and pharmaceutical compositions for the prevention or treatment of hormone-dependent diseases, as well as methods of use and applications thereof. In particular, this invention describes substituted pyrimidine dione compounds that can function as gonadotropin-releasing hormone receptor antagonists and their uses. Background Technology

[0003] The secretion of anterior pituitary hormones is controlled by feedback mechanisms, including peripheral hormones secreted from the target organs of the respective hormones and secretory-regulating hormones from the hypothalamus (the superior central organ of the anterior pituitary) (these hormones are collectively referred to as "hypothalamic hormones"). Currently, nine hormones have been identified as hypothalamic hormones, including, for example, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH). These hypothalamic hormones are believed to exert their effects through receptors thought to be located in the anterior pituitary; efforts have been made to identify receptors specific to these hormones—specific gene expression. Therefore, antagonists or agonists that specifically and selectively act on these receptors should control the effects of hypothalamic hormones and the secretion of anterior pituitary hormones. Thus, such antagonists or agonists are expected to prevent or treat anterior pituitary hormone-dependent diseases.

[0004] GnRH receptor superagonists, which inhibit GnRH receptor function, have been used to treat hormone-dependent diseases such as prostate cancer, breast cancer, and endometriosis. GnRH receptor superagonists bind to GnRH receptors and exert an initial, transient gonadotropin secretion-stimulating effect, the so-called "flare-up phenomenon," before inhibiting function by causing gonadotropin depletion and GnRH receptor downregulation. Therefore, because GnRH receptor superagonists initially promote gonadotropin secretion, they have the drawback of temporarily exacerbating the disease. In contrast, GnRH receptor antagonists (hereinafter referred to as "GnRH antagonists") inhibit binding to GnRH receptors, thus promising a rapid inhibitory effect without gonadotropin secretion.

[0005] Currently known compounds with GnRH antagonistic activity are mostly peptides, such as GnRH-derived linear peptides (US5,140,009 and US5,171,835), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol.36, pp.3265-3273 (1993)), decapeptide compounds modified at positions 5 or 6 (WO9846634A1), and decapeptide compounds modified at position 8 (EP0277829B1), etc.

[0006] Peptide compounds present many unresolved issues related to oral absorption, dosage form, dose-volume relationship, drug stability, duration of action, and metabolic stability. Given the limitations of peptide GnRH receptor antagonists, some non-peptide GnRH receptor antagonists have been proposed and entered the development, clinical trial, and market launch stages. For example, Elagolix (also known as NBI-56418 or ABT-620), a small-molecule GnRH receptor antagonist developed by Abbott Laboratories and Neurocrine Biosciences Inc., is currently in Phase III clinical trials, primarily for the treatment of endometriosis (Phase III) and uterine fibroids (Phase II).

[0007] Relugolix, also known as TAK-385, is a small-molecule oral GnRH receptor antagonist developed by Takada Pharmaceutical Co., Ltd. of Japan. It is used to treat endometriosis, uterine fibroids, and prostate cancer.

[0008] Despite a great deal of meaningful research already being conducted in this field, further research is needed to develop more effective small molecule GnRH receptor antagonists. Summary of the Invention

[0009] This invention provides compounds of formula (I), pharmaceutically acceptable salts or stereoisomers thereof,

[0010]

[0011] in:

[0012] X1 is independently selected from: O or S;

[0013] X2 and X3 are each independently selected from: CR4 or N;

[0014] X4 is independently selected from: CR 3c Or N;

[0015] X5 is independently selected from: CR6 or N;

[0016] R1 is independently selected from: H, D, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0017] R2 is independently selected from: H, D, C1-C6 alkyl, and R 2a -O-substituted C1-C6 alkyl groups;

[0018] R 2a Independently selected from: C1-C6 haloalkyl groups;

[0019] R 3a R 3b R 3c R 3d R 3e Each is independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl;

[0020] R4 is independently selected from: H, D, halogen, -CN, -NO2, -NH2, -OH, -SH, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C6 cycloalkyl;

[0021] R5 is independently selected from: H, D, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, C1-C6 haloalkoxy;

[0022] R6 is independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0023] In some embodiments of the present invention, R1 is independently preferred from: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl.

[0024] In some embodiments of the invention, R2 is independently preferred from: H, D, and R. 2a-O-substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl; R 2a Independently preferred from: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl.

[0025] In some embodiments of the invention, R2 is further preferably independently derived from: R 2a -O-substituted: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl. R 2a Further preferred independently from: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl.

[0026] In some embodiments of the present invention, R2 is more preferably selected independently from: trifluoromethyl-O-methyl, trifluoromethyl-O-ethyl, trifluoromethyl-O-n-propyl, trifluoromethyl-On-butyl, trifluoromethyl-On-pentyl, trifluoromethyl-On-hexyl, trichloromethyl-O-methyl, trichloromethyl-O-ethyl, trichloromethyl-O-n-propyl, trichloromethyl-On-butyl, trichloromethyl-On-pentyl, and trichloromethyl-On-hexyl.

[0027] In some embodiments of the present invention, R 3a R 3b R 3c R 3d R 3e Each of the following is independently preferred from: H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0028] In some embodiments of the present invention, R4 is independently selected from: H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy. tert-Butoxy, n-pentoxy, S-pentoxy, hexoxy, 2-ethylbutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, S-pentylthio, hexylthio, 2-ethylbutylthio, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, n-pentylamino, S-pentylamino, hexylamino, 2-ethylbutylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0029] In some embodiments of the present invention, R5 is independently selected from: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 2,2-dichloroethyl, 3,3,3-trichloroethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2-dichloroethyl, 2,2,3 ... Fluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, 2-ethylbutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy.

[0030] In some embodiments of the present invention, R6 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, 2-ethylbutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy.

[0031] In some embodiments of the present invention, compounds of formula (II), pharmaceutically acceptable salts or stereoisomers thereof are provided.

[0032]

[0033] in:

[0034] X1 is independently selected from: O or S;

[0035] X2 and X3 are each independently selected from: CR4 or N;

[0036] X5 is independently selected from: CH or N;

[0037] R1 is independently selected from: H, D, C1-C6 alkyl;

[0038] R2 is independently selected from: H, D, C1-C6 alkyl, and C1-C6 alkyl substituted with R2a-O-;

[0039] R 2a Independently selected from: C1-C6 haloalkyl groups;

[0040] R 3a R 3e Each is independently selected from: H, D, halogens, and C1-C6 haloalkyl groups;

[0041] R4 is independently selected from: H, D, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino;

[0042] R5 is independently selected from: H, D, C1-C6 alkyl, C1-C6 alkoxy.

[0043] In some embodiments of the present invention, compounds of formula (II), pharmaceutically acceptable salts or stereoisomers thereof are provided.

[0044] in:

[0045] X1 is independently selected from: O or S;

[0046] X2 and X3 are both selected from: N;

[0047] X5 is independently selected from: CH or N;

[0048] R1 is independently selected from: H, D, C1-C6 alkyl; the C1-C6 alkyl is preferably selected from: methyl, ethyl;

[0049] R2 is independently selected from: H, D, C1-C6 alkyl, and R 2a -O-substituted C1-C6 alkyl groups; the C1-C6 alkyl groups are preferably selected from: methyl, ethyl, n-propyl, and n-butyl.

[0050] R 2a The halogen is independently selected from: C1-C6 haloalkyl groups; the halogen is preferably selected from: fluorine and chlorine; the C1-C6 haloalkyl groups are preferably selected from: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl.

[0051] R 3a R 3e Each is independently selected from: H, D, halogen, C1-C6 haloalkyl; the halogen is preferably selected from: fluorine, chlorine; the C1-C6 haloalkyl is preferably selected from: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl;

[0052] R4 is independently selected from: C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, and C1-C6 alkylamino; the C1-C6 alkoxy is preferably selected from: methoxy, ethoxy, n-propoxy, and n-butoxy; the C1-C6 haloalkoxy is preferably selected from: fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, and trichloromethoxy; the C1-C6 alkylthio is preferably selected from: methylthio, ethylthio, n-propylthio, and n-butylthio; the C1-C6 alkylamino is preferably selected from: methylamino, ethylamino, n-propylamino, and n-butylamino.

[0053] R5 is independently selected from: H, D, C1-C6 alkyl, C1-C6 alkoxy; the C1-C6 alkyl is preferably selected from: methyl, ethyl, n-propyl, n-butyl; the C1-C6 alkoxy is preferably selected from: methoxy, ethoxy, n-propoxy, n-butoxy.

[0054] In some embodiments of the present invention, compounds of formula (II), pharmaceutically acceptable salts or stereoisomers thereof are provided.

[0055] in:

[0056] X1 is independently selected from: O or S;

[0057] X2 and X3 are both selected from: N;

[0058] X5 is independently selected from: CH or N;

[0059] R1 is independently selected from: H, D, C1-C6 alkyl;

[0060] R2 is R 2a -O-substituted C1-C6 alkyl; preferably R2 is independently selected from methyl, ethyl, propyl, R 2a It is trifluoromethyl;

[0061] R 3a R 3e Each is independently selected from: H, D, halogen, C1-C6 haloalkyl; the halogen is preferably selected from: fluorine, chlorine; the C1-C6 haloalkyl is preferably selected from: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl;

[0062] R4 is independently selected from: C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, and C1-C6 alkylamino; the C1-C6 alkoxy is preferably selected from: methoxy, ethoxy, n-propoxy, and n-butoxy; the C1-C6 haloalkoxy is preferably selected from: fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, and trichloromethoxy; the C1-C6 alkylthio is preferably selected from: methylthio, ethylthio, n-propylthio, and n-butylthio; the C1-C6 alkylamino is preferably selected from: methylamino, ethylamino, n-propylamino, and n-butylamino.

[0063] R5 is independently selected from: H, D, C1-C6 alkyl, C1-C6 alkoxy; the C1-C6 alkyl is preferably selected from: methyl, ethyl, n-propyl, n-butyl; the C1-C6 alkoxy is preferably selected from: methoxy, ethoxy, n-propoxy, n-butoxy.

[0064] In some embodiments of the present invention, compounds of formula (II), pharmaceutically acceptable salts or stereoisomers thereof are provided.

[0065] in:

[0066] X1 is independently selected from: O or S;

[0067] X2 and X3 are both selected from: CR4;

[0068] X5 is independently selected from: CH or N;

[0069] R1 is independently selected from: H, D, C1-C6 alkyl; the C1-C6 alkyl is preferably selected from: methyl, ethyl;

[0070] R2 is independently selected from: H, D, C1-C6 alkyl, and R 2a -O-substituted C1-C6 alkyl groups; the C1-C6 alkyl groups are preferably selected from: methyl, ethyl, n-propyl, and n-butyl.

[0071] R 2a The halogen is independently selected from: C1-C6 haloalkyl groups; the halogen is preferably selected from: fluorine and chlorine; the C1-C6 haloalkyl groups are preferably selected from: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl.

[0072] R 3a R 3e Each is independently selected from: H, D, halogen, C1-C6 haloalkyl; the halogen is preferably selected from: fluorine, chlorine; the C1-C6 haloalkyl is preferably selected from: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl;

[0073] R4 is independently selected from: H, D, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy; the C1-C6 alkoxy is preferably selected from: methoxy, ethoxy, n-propoxy, n-butoxy; the C1-C6 haloalkoxy is preferably selected from: fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy; the C1-C6 alkylthio is preferably selected from: methylthio, ethylthio, n-propylthio, n-butylthio; the C1-C6 alkylamino is preferably selected from: methylamino, ethylamino, n-propylamino, n-butylamino.

[0074] R5 is independently selected from: H, D, C1-C6 alkyl, C1-C6 alkoxy; the C1-C6 alkyl is preferably selected from: methyl, ethyl, n-propyl, n-butyl; the C1-C6 alkoxy is preferably selected from: methoxy, ethoxy, n-propoxy, n-butoxy.

[0075] In some embodiments of the present invention, compounds of formula (II), pharmaceutically acceptable salts or stereoisomers thereof are provided.

[0076] in:

[0077] X1 is independently selected from: O or S;

[0078] X2 and X3 are both selected from: CR4;

[0079] X5 is independently selected from: CH or N;

[0080] R1 is independently selected from: H, D, C1-C6 alkyl; the C1-C6 alkyl is preferably selected from: methyl, ethyl;

[0081] R2 is independently selected from: H, D, C1-C6 alkyl, and R 2a -O-substituted C1-C6 alkyl groups; the C1-C6 alkyl groups are preferably selected from: methyl, ethyl, n-propyl, and n-butyl.

[0082] R 2a The halogen is independently selected from: C1-C6 haloalkyl groups; the halogen is preferably selected from: fluorine and chlorine; the C1-C6 haloalkyl groups are preferably selected from: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl.

[0083] R 3a R 3e Each is independently selected from: H, D, halogen, C1-C6 haloalkyl; the halogen is preferably selected from: fluorine, chlorine; the C1-C6 haloalkyl is preferably selected from: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl;

[0084] R4 is a C1-C6 haloalkoxy group, preferably fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, or trichloromethoxy.

[0085] R5 is independently selected from: H, D, C1-C6 alkyl, C1-C6 alkoxy; the C1-C6 alkyl is preferably selected from: methyl, ethyl, n-propyl, n-butyl; the C1-C6 alkoxy is preferably selected from: methoxy, ethoxy, n-propoxy, n-butoxy.

[0086] In some embodiments of the present invention, compounds of formula (III), pharmaceutically acceptable salts or stereoisomers thereof are provided.

[0087]

[0088] in,

[0089] X5 and X6 are independently selected from CR6 or N, and X5 and X6 are not simultaneously CR6 or N;

[0090] R1 is independently selected from: H, D, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0091] R2 is independently selected from: H, D, C1-C6 alkyl, and R 2a -O-substituted C1-C6 alkyl groups;

[0092] R 2a Independently selected from: C1-C6 haloalkyl groups;

[0093] R3a R 3e Each is independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl;

[0094] R4 is independently selected from: H, D, halogen, -CN, -NO2, -NH2, -OH, -SH, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C6 cycloalkyl;

[0095] R5 is independently selected from: H, D, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and C1-C6 haloalkoxy.

[0096] In some embodiments of the present invention, the following compounds, pharmaceutically acceptable salts or stereoisomers thereof are provided:

[0097]

[0098]

[0099]

[0100]

[0101] .

[0102] This invention also provides a pharmaceutical composition comprising any of the above-described compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, or various sustained-release formulations. The pharmaceutical composition can be administered orally or parenterally (e.g., intravenously, subcutaneously, or topically). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type, generally with a daily dose of approximately 1-200 mg.

[0103] This invention also provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of hormone-dependent diseases. The hormone-dependent diseases include hormone-dependent cancers, bone metastases of hormone-dependent cancers, benign prostatic hyperplasia, prostate cancer, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, and benign or malignant tumors or hot flashes that are hormone-independent and sensitive to LH-RH (luteinizing hormone-releasing hormone). The hormone-dependent cancers mentioned above are selected from prostate cancer, uterine cancer, breast cancer, and pituitary cancer.

[0104] In some embodiments of the present invention, the above-mentioned compounds, their pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions are used in the preparation of reproductive regulators, contraceptives, ovulation inducers; or in the preparation of medicaments for the prevention of postoperative recurrence of hormone-dependent cancers.

[0105] The compound provided by this invention has one or more of the following technical advantages:

[0106] 1. It exhibits a significant binding ability to human GnRHR;

[0107] 2. It has a significant inhibitory effect on human GnRHR;

[0108] 3. It exhibits lower inhibitory activity against human hERG potassium channels and less cardiotoxicity;

[0109] 4. Can improve permeability in Caco-2 cells;

[0110] 5. It can increase the in vivo exposure and absolute bioavailability of drugs, and has excellent pharmacokinetic properties;

[0111] 6. Higher drug concentrations are found in the target organ, the pituitary gland.

[0112] Definitions and Explanations

[0113] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0114] The term "pharmaceutically acceptable" as used in this invention refers to compounds, compositions, and / or dosage forms that, within the limits of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0115] The term "pharmaceutically acceptable salt" as used in this invention refers to salts of the compounds of this invention, prepared by reacting compounds with specific substituents discovered in this invention with relatively non-toxic acids or bases. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of this invention contain basic functional groups and can thus be converted into any acid addition salt.

[0116] Some compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0117] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0118] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0119] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient, including but not limited to: adhesives, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0120] This invention is intended to include all isotopes of atoms present in the compounds of this invention. Isotopes include atoms with the same number of atoms but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14 C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of an additional unlabeled reagent.

[0121] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1-C6 indicates 1 to 6 carbons, C 1-10 Selected from C1, C2, C3, C4, C5, and C6; examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl), etc.

[0122] Unless otherwise specified, the term “halogen” or “halogen” itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0123] The term “haloalkyl” is intended to include both monohaloalkyl and polyhaloalkyl straight-chain or branched alkyl groups. For example, the term “C1-C6 haloalkyl” is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, etc. Unless otherwise specified, examples of C1-C6 haloalkyl groups include, but are not limited to: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, and pentachloroethyl.

[0124] Unless otherwise specified, "alkoxy" represents the aforementioned alkyl group (including cycloalkyl or haloalkyl) having a specific number of carbon atoms connected by an oxygen bridge. Typical alkoxy groups include C0... 1-6Alkoxy groups, such as: C1, C2, C3, C4, C5, C6 alkoxy groups; C3, C4, C5, C6 cycloalkoxy groups; and C1, C2, C3, C4, C5, C6 haloalkoxy groups. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, and 2-ethylbutoxy. Examples of cycloalkoxy groups include, but are not limited to: cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Examples of haloalkoxy groups include, but are not limited to: fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0125] Unless otherwise specified, the term "alkathio" means an alkyl group attached to the remainder of the molecule by a sulfur atom, wherein the alkyl group has the meaning as described in this invention. In some embodiments, the alkathio group contains 1-6 carbon atoms; in other embodiments, the alkathio group contains 1-4 carbon atoms; and in still other embodiments, the alkathio group contains 1-3 carbon atoms. The alkathio group may optionally be substituted by one or more substituents described in this invention. Examples of alkathio groups include, but are not limited to, methylthio (MeS, -SCH3), ethylthio (EtS, -SCH2CH3), n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, S-pentylthio, hexylthio, 2-ethylbutylthio, etc.

[0126] Unless otherwise specified, the terms "alkylamino" or "alkylamino" indicate that the amino group is independently replaced by one or two alkyl groups, including "N-alkylamino" and "N,N-dialkylamino," wherein the alkyl group has the meaning as described in this invention. In some embodiments, suitable alkylamino groups may be monoalkylamino or dialkylamino, each alkyl group containing 1-6 carbon atoms. Such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N-dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, n-pentanamino, S-pentanamino, hexanamino, 2-ethylbutylamino, etc.

[0127] Unless otherwise specified, cycloalkyl groups include any stable cyclic or polycyclic hydrocarbon group in which all carbon atoms are saturated, and which may be monosubstituted or polysubstituted, and may be monovalent, divalent, or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0128] Compounds are named manually or using ChemDraw® software; commercially available compounds are named using supplier catalog names. Attached Figure Description

[0129] Figure 1 Mean drug-time curve after intravenous (1 mg / kg) administration in SD rats

[0130] Figure 2 Mean drug-time curve after oral administration (12 mg / kg) to SD rats Detailed Implementation

[0131] The present invention will be further illustrated below with reference to specific embodiments and test examples, but this does not limit the scope of the invention in any way.

[0132] Example 1: Synthesis of Compound 1

[0133]

[0134] Synthesis route:

[0135]

[0136] Step 1: Synthesis of compound 1-1:

[0137] Ethyl chloroformate (56.2 mL, 588 mmol) was added to 2.36 L of toluene containing compound SM1 (90.0 g, 294 mmol), and the reaction was carried out at 110 °C for 3 h. Ethyl chloroformate (56.2 mL, 588 mmol) was added again, and the reaction was carried out at 110 °C for 3 h. More ethyl chloroformate (56.2 mL, 588 mmol) was added, and the reaction was carried out at 110 °C for another 6 h. After cooling to 25 °C, the mixture was concentrated under vacuum. 600 mL of methyl tert-butyl ether was added to the residue, the mixture was filtered, the filter cake was collected, washed with 100 mL of methyl tert-butyl ether, and dried to give compound 1-1 (107.57 g, 96.8%) as a yellow powder. MS m / z (ESI): 379 [M+H] + ; 1 HNMR (400 MHz CDCl3), δ 1.36 (t, J=7.20 Hz, 3H), 1.42 (t, J = 7.20 Hz, 3H), 2.42 (s, 3 H), 4.31 (q, J = 7.20 Hz, 2 H), 4.40 (q, J = 7.20 Hz, 2H), 7.53 -7.59 (m, 2 H), 8.24 - 8.29 (m, 2 H), 10.66 (s, 1 H).

[0138] Step 2: Synthesis of compounds 1-2:

[0139] K₂CO₃ (43.22 g, 312.71 mmol, 1.1 eq) and KI (51.91 g, 312.71 mmol, 1.1 eq) were added to a solution of compound 1-1 (107.57 g, 284.28 mmol, 1 eq) in DMF (3400 mL). Then, a solution of 2,6-difluorobenzyl chloride (55.46 g, 341.14 mmol, 1.2 eq) in DMF (190 mL) was added to the mixture. The mixture was stirred at 25°C for 17 hours. The resulting precipitate was filtered off, and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (700 mL) and water (700 mL), and extracted with ethyl acetate (300 mL x 2). The extract was washed with 500 mL of water and 500 mL of brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was mixed with MTBE (540 mL) and stirred at 25 °C for 30 min. The precipitate was filtered to give compounds 1-2 (127 g, 251.73 mmol, yield 88.55%) as a pale yellow solid. MS m / z (ESI): 505 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ1.20 (s, 2H), 1.33 (t, J = 6.80 Hz, 4H), 2.40(s, 3H), 4.18 - 4.34 (m, 4H), 4.98 (s, 2H), 6.86 (t, J = 8.00 Hz, 2H), 7.22 -7.31 (m, 1H), 7.52 (d, J = 8.80 Hz, 2H), 8.25 - 8.30 (m, 2H).

[0140] Step 3: Synthesis of compounds 1-3:

[0141] Compounds 1-2 (50 g, 99.11 mmol, 1 eq), NBS (22.05 g, 123.88 mmol, 1.25 eq), and AIBN (1.63 g, 9.91 mmol, 0.1 eq) were stirred in ethyl acetate (600 mL) at 80 °C for 2 h. Then, NBS (3.53 g, 19.82 mmol, 0.20 eq) and AIBN (162.74 mg, 991.08 μmol, 0.01 eq) were added to the system, and the mixture was heated at 80 °C for another 2 h. After cooling to room temperature, the reaction mixture was diluted (200 mL), and water (300 mL) and the extraction layer (200 mL * 2) were prepared. The extract was washed with 300 mL of water and 500 mL of brine, dried over Na₂SO₄, and concentrated under reduced pressure. Crude compounds 1-3 were obtained (61.55 g of crude product) for the next step. MS m / z (ESI): 585, 583 [M+H] + .

[0142] Step 4: Synthesis of compounds 1-4:

[0143] A solution of compounds 1-3 (40.0 g, 68.5 mmol) in ethyl acetate (400 mL) was mixed with DIPEA (17.7 g, 137 mmol, 23.9 mL) and N-(2-methoxyethyl)methylamine (9.17 g, 103 mmol, 11.0 mL) and stirred at 25 °C for 16 h. LC-MS showed that the starting material was completely consumed. The mixture was washed with water (200 mL × 2) and brine (150 mL). The aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined, dried over Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by silica gel (CH₂Cl₂: MeOH = 10:1) column chromatography to give compounds 1-4 (60.0 g, 95.3%) as a yellow oil. MS m / z (ESI): 592 [M+H] + ; 1H NMR (400 MHz CDCl3), δ8.24 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.29 - 7.25 (m, 1H), 6.86 (t, J = 8.0 Hz, 2H), 5.01(s, 2H), 4.23 - 4.20 (m, 4H), 3.63 (s, 2H), 3.37 - 3.36 (m, 2H), 3.28 (s,3H), 2.46 (s, 2H), 2.08 (s, 3H), 1.35 - 1.19 (m, 6H).

[0144] Step 5: Synthesis of compounds 1-5:

[0145] Compounds 1-4 (60.0 g, 101 mmol) were placed in EtOH (900 mL) solution, and Pd / C (12.0 g, 20.28 mmol, 10% purity, 0.2 eq) was added under N2 protection, followed by vacuum degassing and H2 replacement three times. The mixture was stirred at 25°C under an H2 atmosphere (25 psi) for 16 hours. TLC (CH2Cl2: MeOH = 10:1, Rf = 0.2) showed that the starting material was completely consumed. The mixture was filtered, and the filter cake was washed with EtOH (500 mL) and THF (500 mL). The organic layer was removed by vacuum. The residue was dissolved in tetrahydrofuran (150 mL), and the solvent was removed by vacuum. This process was repeated three times. Compounds 1-5 (56.0 g, 90.5 mmol, yield 89.2%, purity 90.8%) were obtained as palm oil. MS m / z (ESI): 562 [M+H] + ; 1 H NMR(400 MHz CDCl3), δ7.25 - 7.21 (m, 1H), 7.17 (d, J = 6.8 Hz, 2H), 6.83 (t, J =8.0 Hz, 2H), 6.66 (d, J = 8.0 Hz, 2H), 4.99 (s, 2H), 4.23 - 4.18 (m, 4H), 3.59 (s, 2H), 3.34 - 3.31 (m, 2H), 3.26 (s, 3H), 2.39 (s, 2H), 2.05 (s, 3H), 1.32 - 1.18 (m, 6H).

[0146] Step 6: Synthesis of compounds 1-6:

[0147] DIPEA (25.7 g, 199 mmol, 34.7 mL) and CDI (32.3 g, 199 mmol) were added to a dichloromethane (600 mL) solution of compounds 1-5 (56.0 g, 99.7 mmol), and the mixture was stirred at 25 °C for 16 h. After the reaction was complete, DIPEA (64.4 g, 498 mmol, 86.8 mL) was added, followed by the addition of methoxyamine (41.6 g, 498 mmol, HCl) in portions at 0 °C, and the mixture was stirred at 0–25 °C for 4 h. LC-MS showed that the starting material was completely consumed. The mixture was diluted with CH2Cl2 (1.00 L), washed with water (500 mL) and brine (500 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. Compounds 1-6 were purified by silica gel column chromatography (64.0 g, 92.7 mmol, yield 93.0%, purity 92.0%) as butter. MS m / z (ESI): 635 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ7.64 (br.s, 1H), 7.51 (d, J = 8.4 Hz,2H), 7.37 (d, J = 8.4 Hz, 2H), 7.25 - 7.21 (m, 1H), 6.85 (t, J = 8.4 Hz, 2H),5.00 (s, 2H), 4.23 - 4.19 (m, 4H), 3.82 (s, 3H), 3.63 - 3.59 (m, 2H), 3.37 -3.36 (m, 2H), 3.27 (s, 3H), 2.43 (s, 2H), 2.07 (s, 3H), 1.33 - 1.19 (m, 6H).

[0148] Step 7: Synthesis of compounds 1-7:

[0149] NaOH (2 M, 315.11 mL, 5 eq) was added to an ethanol (700 mL) solution of compounds 1-6 (80.0 g, 126 mmol), and the mixture was stirred at 60 °C for 16 h. LC-MS showed that the starting material was completely consumed. The mixture was then removed from the solvent with aq. HCl under reduced pressure and the pH was adjusted to 6-7. The aqueous layer was extracted with ethyl acetate (1.00 L × 10), and the combined organic layers were dried over Na₂SO₄ and removed from the solvent under reduced pressure to give compounds 1-7 (67.0 g, 96.9 mmol, 76.9% yield, 87.8% purity) as a yellow solid. MS m / z (ESI): 607 [M+H] + ;1 H NMR (400 MHz DMSO-d6), δ9.68 (br.s, 1H),9.15 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.41 - 7.37 (m, 1H), 7.16 (d, J = 8.4Hz, 2H), 7.04 (t, J = 8.0 Hz, 2H), 4.89 (s, 2H), 3.97 - 3.93 (m, 2H), 3.62(s, 3H), 3.49 - 3.46 (m, 2H), 3.18 (s, 3H), 2.83 (s, 2H), 2.38 (s, 3H), 1.07(t, J = 7.2 Hz, 3H).

[0150] Step 8: Synthesis of compounds 1-8:

[0151] A solution of compounds 1-7 (60.0 g, 98.9 mmol) and 3-amino-6-methoxypyridazine (25.0 g, 199 mmol) were dissolved in DMF (1800 mL), and DIPEA (127 g, 989 mmol, 172 mL) and 1-propylphosphoric anhydride (189 g, 296 mmol, 176 mL, 50% purity) were added. The mixture was stirred for 3 hours at 25°C. LC-MS showed that the starting material was completely consumed. The mixture was poured into cold water (4.00 L), and the aqueous layer was extracted with ethyl acetate (2.00 L x 3). The combined organic layers were washed with water (1.00 L), brine (1.00 L), dried over Na2SO4, and the solvent was removed. The resulting brown oil of compounds 1-8 (64.0 g, 56.4 mmol, 57.0% yield, 62.9% purity) was obtained by reducing the pressure. MS m / z (ESI): 714 [M+H] + .

[0152] Step 9: Synthesis of compounds 1-9:

[0153] A methanol solution (900 mL) of compounds 1-8 (64.0 g, 56.4 mmol, 62.9% purity) was added fractionally to CH3ONa (30.5 g, 564 mmol), and the mixture was stirred at 25 °C for 16 hours. LC-MS showed that the starting material was completely consumed. The mixture was poured into cold aq. NH4Cl solution (1.50 L), extracted with ethyl acetate (1.50 L × 2), washed with water (1.00 L) and brine (500 mL), dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography yielded compounds 1-9 (24.0 g, 32.3 mmol, yield 57.3%, purity 90.0%) as a yellow solid. MS m / z (ESI): 668 [M+H] + .

[0154] Step 10: Synthesis of compounds 1-10:

[0155] A solution of 1-chloroethyl chloroformate (1.58 g, 11.0 mmol) in tetrahydrofuran (200 mL) was added to a solution of compounds 1-9 (4.80 g, 7.19 mmol), and the mixture was stirred at -70 to 25 °C for 3 hours. LC-MS showed that the starting material was completely consumed. The mixture was poured into 1.00 L of water, extracted with 1.00 L × 2 ethyl acetate solutions, washed with 500 mL of brine, dried over Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by pulping with 500 mL of methyl tert-butyl ether and filtered to give compounds 1-10 (22.0 g, 30.7 mmol, yield 85.6%, purity 86.0%) as a yellow solid. MS m / z (ESI): 615 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ7.70 (br.s, 1H), 7.62 (d, J =8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 9.2 Hz, 1H), 7.40 - 7.25(m, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 5.35 (s, 2H), 4.80 (s, 2H), 4.20 (s, 3H), 3.83 (s, 3H).

[0156] Step 11: Synthesis of compounds 1-11:

[0157] DIPEA (41.6 g, 322 mmol, 56.1 mL) was added to a DMF (500 mL) solution of compounds 1-10 (22.0 g, 35.8 mmol) and 2-(trifluoromethoxy)ethylamine (23.7 g, 143 mmol, HCl), and the mixture was stirred at 25 °C for 24 hours. After the reaction was complete, the mixture was poured into 1.50 L of water, extracted with 1.00 L × 3 of ethyl acetate, washed with 500 mL × 2 of water, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography yielded compound 1-11 (15.5 g, 19.0 mmol, yield 53.2%, purity 87.0%) as a yellow solid. MS m / z (ESI): 708 [M+H] + ; 1 H NMR (400 MHzCDCl3), δ7.68 (br.s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 9.2 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.16 (d, J = 9.2 Hz, 1H), 6.93(d, J = 8.0 Hz, 2H), 5.36 (s, 2H), 4.20 (s, 3H), 4.03 - 4.01 (m, 2H), 3.91(s, 2H), 3.82 (s, 3H), 3.90 - 3.89 (m, 2H).

[0158] Step 12: Synthesis of Compound 1:

[0159] Compounds 1-11 (5.00 g, 6.36 mmol, 90.0% purity) and paraformaldehyde (1.15 g, 12.7 mmol) were dissolved in methanol (150 mL), and acetic acid (38.2 mg, 636 μmol, 36.4 μL) and NaBH3CN (1.60 g, 25.4 mmol) were added. The mixture was then stirred at 25°C for 16 hours. LC-MS showed that the starting materials were completely consumed. The mixture was poured into aq. NH4Cl solution (1500 mL), extracted with ethyl acetate (1.00 L × 2), and washed with water (500 mL) and brine (500 mL). Compound 1 (4.98 g, 6.57 mmol, 34.4% yield, 95.2% purity) was purified by silica gel (100% EtAOc) and SFC (column: DAICL CHIRALCEL OD (250 mm * 30 mm, 10 μm), mobile phase: [0.1% NH3H2O ​​ETOH], B%: 45%-45%) column chromatography as a white solid. MS m / z (ESI): 722 [M+H] + ; 1 H NMR (400 MHz DMSO-d6), δ9.60(br.s, 1H), 9.07 (br.s, 1H), 7.74 - 7.70 (m, 3H), 7.57 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 5.37 - 5.22 (m, 2H), 4.09 (s, 3H), 4.03 - 4.00 (m, 2H), 3.80 - 3.68 (m, 2H), 3.63 (s, 3H), 2.65 (s,2H), 2.09 (s, 3H). 19 F NMR: (400 MHz DMSO-d6), δ-58.744 ppm, -112.961 ppm.

[0160] Example 2 Synthesis of Compound 2

[0161]

[0162] Synthesis route:

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] Synthesis of compound 2-1:

[0169] Under a nitrogen atmosphere, bis-pinacol boronic acid ester (75.1 g, 296 mmol, 1.20 eq) and Pd(dppf)Cl2 (7.21 g, 9.85 mmol, 0.04 eq) were added to a solution of SM2 (50.0 g, 246 mmol, 1.00 eq) and AcOK (120.87 g, 1.23 mol, 5.00 eq) dioxane (600 mL). The mixture was stirred at 100°C for 1.5 h. LCMS showed that SM2 was consumed, and a main peak was detected. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 75 / 25) and (petroleum ether / ethyl acetate = 5 / 1, 420 mL) at 25°C for 2 h. Compound 2-1 was given as a white solid (20 g, 77.5 mmol, 72.0% yield, 96.9% purity). MS m / z (ESI): 169 [M+H] + ; 1 H NMR (400 MHz CDCl3), δppm 8.94 (s, 1 H), 8.38 - 8.40 (m,1 H), 8.21 (d, J = 8.00 Hz, 1 H), 1.37 (s, 12 H).

[0170] Step 1: Synthesis of compound 2-2:

[0171] Ethyl chloroformate (58.9 g, 542 mmol, 51.7 mL, 5.03 eq) was added to a 200 mL solution of SM3 (20.0 g, 108 mmol, 1.00 eq) in toluene. The mixture was stirred at 110°C for 16 h. LC-MS showed that SM3 was consumed, and a main peak was detected. The mixture was concentrated under reduced pressure to obtain a residue, which was used directly in the next step without purification. Compound 2-2 was given as a gray solid (27.6 g, 97.7 mmol, yield 90.5%, purity 91.1%). MS m / z (ESI): 258 [M+H] + .

[0172] Step 2: Synthesis of compounds 2-3:

[0173] Compound 2-2 (27.1 g, 105.32 mmol, 1 eq) was added to CHCl3 (220 mL) solution with NBS (20.6 g, 115.9 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h, and LC-MS showed that compound 2-2 was consumed and the main peak was detected. This mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 94 / 6). Compound 2-3 (36.2 g, 93.0 mmol, yield 71.1%, purity 86.293%) was given as a white solid. MS m / z (ESI): 336, 338 [M+H] + ; 1 H NMR (400 MHz DMSO-d6), δ ppm 4.20 - 4.29 (m, 4H), 2.22 (s, 3H), 1.24 - 1.33 (m, 6H).

[0174] Step 3: Synthesis of compounds 2-4:

[0175] Compound 2-1 (33.92 g, 135.63 mmol, 2.4 eq), K₂CO₃ (15.62 g, 113.03 mmol, 2 eq), and Pd(dppf)Cl₂ (4.14 g, 5.65 mmol, 0.1 eq) were added to a solution of compound 2-3 (19 g, 56.51 mmol, 1 eq), dioxane (180 mL), and H₂O (18 mL). The mixture was stirred at 80°C for 18 h. LC-MS showed that compound 2-3 was consumed, and many new peaks were formed. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / dichloromethane = 30 / 70, Rf = 0.26). Compound 2-4 (9.48 g, 22.80 mmol, yield 19.22%, purity 91.226%) was obtained as a yellow solid. MS m / z (ESI): 380 [M+H] + .

[0176] Step 4: Synthesis of compounds 2-5:

[0177] Compounds 2-4 (6.00 g, 15.8 mmol, 1.00 eq), KI (2.89 g, 17.4 mmol, 1.10 eq), and K₂CO₃ (2.40 g, 17.4 mmol, 1.10 eq) were added to DMF (50 mL) solution, followed by the addition of 2,6-difluorobenzyl chloride (3.09 g, 19.0 mmol, 1.20 eq). The mixture was stirred at 25°C for 6 hours. LC-MS showed that compound 2-4 was consumed and a main peak formed. The mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL × 3), washed with brine (200 mL × 1), dried over anhydrous Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 80 / 20) to give compounds 2-5 (7.26 g, 14.3 mmol, yield 90.6%, purity 99.8%) as a yellow oil. MS m / z (ESI): 506 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 8.60 (d, J = 1.75 Hz, 1 H), 8.30 (d, J = 8.38 Hz, 1 H), 7.99 - 8.01 (m, 1 H), 7.24 - 7.30 (m, 1 H), 6.82 -6.88 (m, 2 H), 4.97 (s, 2 H), 4.08 - 4.27 (m, 4 H), 2.40 (s, 3 H), 1.30 (m, 3H), 1.18 - 1.25 (m, 3 H).

[0178] Step 5: Synthesis of compounds 2-6:

[0179] NBS (3.07 g, 17.2 mmol, 1.20 eq) and AIBN (235.84 mg, 1.44 mmol, 0.1 eq) were added to a 50 mL solution of compound 2-5 in ethyl acetate, and the mixture was stirred at 80°C for 16 hours. NBS (3.07 g, 17.2 mmol, 1.20 eq) and AIBN (236 mg, 1.44 mmol, 0.10 eq) were added, and the mixture was stirred at 80°C for 4 hours. NBS (3.07 g, 17.2 mmol, 1.20 eq) and AIBN (236 mg, 1.44 mmol, 0.10 eq) were added, and the mixture was stirred at 80°C for 16 hours. LCMS showed that compound 2-5 was consumed and a main peak formed. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL × 2). The aqueous layer was extracted with ethyl acetate (50 mL), and the organic layer was dried with Na₂SO₄ and the solvent was removed under reduced pressure. The residue was used directly in the next step without purification. Compounds 2-6 (13 g, crude) were given as a brown oil. MS m / z (ESI): 584, 586 [M+H] + .

[0180] Step 6: Synthesis of compounds 2-7:

[0181] DIEA (7.19 g, 55.6 mmol, 9.69 mL, 2.50 eq) was added to a DMF (100 mL) solution of compounds 2-6 (13.0 g, 22.3 mmol, 1.00 eq), followed by fractional addition of Me₂NH₃HCl (2.39 g, 29.4 mmol, 1.32 eq). The mixture was stirred at 25 °C for 5 hours. LCMS showed that compounds 2-6 were consumed and a main peak formed. The mixture was poured into water (100 mL), extracted with ethyl acetate (150 mL × 3), washed with brine (100 mL × 2), dried over Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40). Compounds 2-7 (4.10 g, 6.30 mmol, yield 28.3%, purity 84.3%) were obtained as butter. MS m / z (ESI): 549 [M+H] + ; 1H NMR (400 MHz CDCl3), δ ppm 8 .76 (d, J = 1.38 Hz, 1 H), 8.24 - 8.30 (m, 2 H), 7.22 - 7.28 (m, 1 H), 6.81 - 6.86 (m, 2 H), 5.00 (s, 2 H), 4.18 - 4.26 (m, 4H), 3.53 (s, 2H), 2.10 (s, 6H), 1.18 - 1.32 (m, 7H).

[0182] Step 7: Synthesis of compounds 2-8:

[0183] Compound 2-7 (3.10 g, 5.65 mmol, 1.00 eq) was reacted with EtOH (30 mL) under N2 protection with Pd / C (0.6 g, 1.13 mmol, 10% purity, 0.20 eq). The mixture was degassed and H2-displaced three times under vacuum. The mixture was stirred at 25°C for 34 h under H2 atmosphere (20 psi). LC-MS showed that compound 2-7 was consumed and a main peak formed. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with 10 mL of ethanol. The solvent in the filtrate was removed under reduced pressure. THF (30 mL) was added to the residue and distilled to remove it; this process was repeated three times. The residue was purified by silica gel (dichloromethane / methanol = 92 / 8) column chromatography. Compound 2-8 (1.80 g, 2.83 mmol, 48.8% yield, 81.4% purity) was given as a yellow oil. MS m / z (ESI): 519 [M+H] + ; 1 H NMR (400 MHzCDCl3), δ ppm 8.04 (d, J = 2.13 Hz, 1 H), 7.47 (dd, J = 8.44, 2.31 Hz, 1 H), 7.20 - 7.27 (m, 1 H), 6.80 - 6.86 (m, 2 H), 6.52 (d, J = 8.51 Hz, 1 H), 4.98 (s, 2 H), 4.70 (s, 2 H), 4.16 - 4.26 (m, 4 H), 3.54 - 3.70 (m, 2 H), 2.12 (s, 6 H), 1.16 - 1.32 (m, 6 H).

[0184] Step 8: Synthesis of compounds 2-9:

[0185] C₂H₅NCO (822 mg, 11.6 mmol, 916 μL, 10.0 eq) was added to a THF (2 mL) solution of compound 2-8 (1.20 g, 1.16 mmol, 1.00 eq), and the mixture was stirred at 50 °C for 12 h. LC-MS showed that compound 2-8 was consumed and a main peak formed. The reaction mixture was removed under reduced pressure to obtain a residue. The residue was purified by silica gel (dichloromethane / methanol = 10 / 1) column chromatography. Compound 2-9 (1.01 g, crude) was given as a yellow oil. MS m / z (ESI): 590 [M+H] + ; 1 H NMR (400MHz CDCl3), δ ppm 9.17 (s, 1 H), 8.80 (s, 1 H), 8.19 (d, J = 2.00 Hz, 1 H), 7.66 (dd, J = 8.50, 2.25 Hz, 1 H), 7.22 - 7.29 (m, 2 H), 6.93 (d, J = 8.38Hz, 1 H), 6.82 - 6.86 (m, 2 H), 5.00 (s, 2 H), 4.18 - 4.29 (m, 4 H), 3.39 -3.46 (m, 2 H), 3.15 - 3.34 (m, 2 H), 2.17 (s, 6 H), 1.32 (t, J = 7.13 Hz, 3H), 1.23 - 1.27 (m, 3 H), 1.15 - 1.19 (m, 3 H).

[0186] Step 9: Synthesis of compounds 2-10:

[0187] Compound 2-9 (1.01 g, 1.72 mmol, 1.00 eq) in EtOH (10 mL) was added to a NaOH solution (2 M, 4.29 mL, 5.00 eq), and stirred at 60 °C for 2 hours. LC-MS showed that compound 2-9 was consumed and a main peak formed. The pH of the reaction solution was adjusted to 5–7 with HCl (1 mol / L, approximately 8 mL) at 0 °C. The solvent was removed from the mixture by vacuum distillation and lyophilization to obtain the residue. The residue was purified by silica gel (dichloromethane / methanol = 87 / 13) column chromatography. Compound 2-10 (798 mg, 1.20 mmol, yield 70.1%, purity 84.7%) was given as a yellow solid. MS m / z (ESI): 562 [M+H] + ; 1H NMR(400 MHz CDCl3), δ ppm 9.43 (s, 1 H), 7.97 - 8.04 (m, 2 H), 7.51 - 7.60 (m, 2H), 7.36 - 7.43 (m, 1 H), 7.04 (t, J = 8.00 Hz, 2 H), 4.89 (s, 2 H), 4.01 -4.05 (m, 2 H), 3.11 - 3.21 (m, 3 H), 2.94 - 3.01 (m, 1 H), 2.44 (s, 6 H), 1.06 - 1.10 (m, 3 H), 0.94 - 1.04 (m, 3 H).

[0188] Step 10: Synthesis of compound 2-11:

[0189] Compounds 2-10 (220 mg, 356 μmol 1.00 eq) and 3-amino-6-methoxypyridazine (80.2 mg, 641 μmol 1.80 eq) were dissolved in DMF (6 mL), and DIEA (460 mg, 3.56 mmol, 620 μL, 10.00 eq) and T3P (680 mg, 1.07 mmol, 635 μL, 50% purity, 3.00 eq) were added and mixed and stirred at 25°C for 17 hours. Compound 12a (89.1 mg, 712 μmol, 2.00 eq), DIEA (460 mg, 3.56 mmol, 620 μL, 10.00 eq), and T3P (680 mg, 1.07 mmol, 635 μL, 50% purity, 3.00 eq) were added and stirred at 25 °C for 1 hour. Compound 12a (89.1 mg, 712 μmol, 2.00 eq), DIEA (460 mg, 3.56 mmol, 620 μL, 10 eq), and T3P (680 mg, 1.07 mmol, 635 μL, 50% purity, 3.00 eq) were added again, and the mixture was stirred at 25 °C for another 1 hour. LCMS showed that compounds 2-10 were consumed, and the main peak formed. The mixture was poured into water (12 mL) and extracted with ethyl acetate (3 x 10.0 mL). The organic phase was washed with brine (3 x 30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. Compound 2-11 (270 mg, crude) was given as a yellow oil. MS m / z (ESI): 669 [M+H] + .

[0190] Step 11: Synthesis of Compound 2:

[0191] MeONa (218 mg, 4.04 mmol, 10.00 eq) was added to a MeOH solution of compound 2-11 (270 mg, 404 μmol, 1.00 eq) (5 mL) at 0°C, and the mixture was stirred at 25°C for 14 hours. LCMS showed that compound 2-11 was consumed, forming numerous peaks. The reaction solution was purified with aq. NH4Cl solution (13 mL). The mixture was then extracted with ethyl acetate (3 × 10.0 mL) and methane chloride (3 × 10.0 mL). The organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel (dichloromethane / methanol = 10 / 1) column chromatography and Welchx Ultimate C18 150 × 25 mm × 5 μm column chromatography; mobile phase: [water (NH4HCO3)-ACN]; B %: 10%–85%, 12 min. Compound 2 (25.0 mg, 40.06 μmol, yield 9.92%, purity 99.8%) was given as a white solid. MS m / z (ESI): 562 [M+H] + ; 1 H NMR (400 MHz CD30D), δ ppm 8.31 (d, J = 2.13 Hz, 1H), 7.82 (dd, J =8.63, 2.38 Hz, 1 H), 7.64 (d, J = 9.13 Hz, 1 H), 7.32 - 7.49(m, 2 H), 7.19 (d, J = 8.63 Hz, 1 H), 6.93 - 7.07 (m, 2 H), 5.26 - 5.49 (m, 2H), 4.14 (s, 3 H), 3.29 - 3.36 (m, 4 H), 2.07 (s, 6 H), 1.19 (t, J =7.25 Hz,3H). 19 F NMR: (400 MHz CDCl3) δ -114.827 ppm.

[0192] Example 3 Synthesis of Compound 3

[0193] Synthesis of Fragment 1:

[0194]

[0195] Synthesis route:

[0196]

[0197] Steps 1-3: Compounds 1-1, 1-2, and 1-3 were synthesized using the same method as in Example 1.

[0198] Step 4: Combining fragments 1-4:

[0199] Compounds 1-3 (56.5 g, 96.85 mmol, 1 eq), dimethylamine (23.69 g, 290.54 mmol, 26.62 mL, 3 eq, HCl), and DMF (245 mL) were added to a 500 mL single-necked round-bottom flask and incubated at 25°C. Then, triethylamine (39.20 g, 387.39 mmol, 53.92 mL, 4 eq) was added, and the reaction was stirred for 2 hours. The reaction was stopped, water (500 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The liquid was separated, and the organic phase was collected. The organic phase was washed with water (300 mL), dried over anhydrous Na₂SO₄, and concentrated and purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give fragment 1-4 (38.97 g, 71.03 mmol, yield 73.34%) as a pale yellow solid. MS m / z (ESI): 548 [M+H] + ; 1 H NMR (400 MHzCDCl3), δ ppm 1.11 - 1.36 (m, 6H), 2.08 (s, 6H), 3.53 (s, 2H), 4.23 (m, 4H), 5.03 (s, 2H), 6.82 - 6.90 (t, J = 7.60 Hz, 2H), 7.23 - 7.31 (m, 1H), 7.67 (d,J = 8.80 Hz, 2H), 8.25 (d,J = 8.80 Hz, 2H).

[0200] Step 5: Combining fragments 1-5:

[0201] Fragment 1–4 solution (30 g, 54.8 mmol) and 4 mol / L hydrochloric acid / dioxane (27.5 mL, 110 mmol) were hydrogenated in EtOH (822 mL) with over 10% Pd / C (50% wet, 9.73 g) at 25°C for 1 h under 15 psi H₂ pressure. The mixture was filtered through diatomaceous earth, and the filtrate was neutralized with saturated NaHCO₃ solution (200 mL). The mixed filtrate was concentrated under vacuum, diluted with ethyl acetate (300 mL) and water (300 mL), and extracted with ethyl acetate (100 mL x 2). The extract was washed with brine, dried (Na₂SO₄), and concentrated under vacuum to give fragments 1–5 (28.79 g, 55.62 mmol, crude) as a pale yellow oil. MS m / z (ESI): 518 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.17 (s, 3H), 1.31 (t, J = 7.20Hz, 3H), 2.02 (s, 6H), 3.50 (s, 2H), 3.80 (br s, 2H), 4.15 - 4.25 (m, 4H), 5.00 (s, 2 H), 6.66 (d, J = 8.38 Hz, 2 H), 6.78 - 6.87 (m, 2H), 7.16 (d, J =8.40 Hz, 2H) 7.20 - 7.26 (m, 1H).

[0202] Step 6: Combining fragments 1-6:

[0203] N,N-diisopropylethylamine (14.52 g, 112.36 mmol, 19.57 mL, 2.02 eq) and CDI (18.04 g, 111.25 mmol, 2 eq) were added to a CH2Cl2 (720 mL) solution of fragments 1-5 (28.79 g, 55.62 mmol, 1 eq). The mixture was stirred at 25°C for 12 h and then cooled to 0°C. N-(2-methoxyethyl)methylamine (46.36 g, 555.12 mmol, 9.98 eq, HCl) and DIPEA (74.05 g, 572.92 mmol, 99.79 mL, 10.3 eq) were added to the mixture, and the mixture was stirred at 25°C for 12 h. The reaction was washed with a saturated NaHCO3 aqueous solution (200 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (200 mL * 2). The combined organic phases were washed with brine (400 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 30:1 ~ 5:1) to give fragments 1-6 (24.21 g, 40.99 mmol, yield 69.34%) as a pale yellow oil. MS m / z (ESI): 591 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.16 (s,3H), 1.31 - 1.37 (m, 3H), 2.00 (s, 6 H), 3.50 (s, 1 H), 3.79 (s, 3 H), 4.19(m, 4H), 4.99 (s, 2H), 6.83 (t, J = 7.60 Hz, 2 H), 7.19 - 7.26 (m, 1H), 7.32 (d, J = 8.40 Hz, 2H), 7.51 (d, J = 8.80 Hz, 2H), 7.71 - 7.92 (m, 2 H).

[0204] Step 7: Synthesis of Fragment 1:

[0205] 2 mol / L NaOH (102 mL, 204.95 mmol) was added to a 500 mL EtOH solution of fragments 1-6 (24.21 g, 40.99 mmol). After stirring at 60 °C for 6 h, 1 mol / L HCl (205 mL, 205 mmol) was added at 0 °C, and the solution was concentrated under vacuum. The residue was dissolved in 200 mL of ethanol and 200 mL of toluene and concentrated. The residue was diluted with 200 mL of dry ethanol and filtered, and the filtrate was concentrated under reduced pressure. Methyl tert-butyl ether (100 mL) was added to the residue, the precipitate was collected by filtration, washed with 50 mL of methyl tert-butyl ether, and dried to give fragment 1 (17.59 g, 31.3 mmol, 76.3%) as a pale yellow solid. MS m / z (ESI): 563 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.05 - 1.10(m, 3H), 2.44 (s, 6H), 3.62 (s, 3H), 3.90 - 4.17 (m, 4H), 4.90 (s, 2 H), 7.04(t, J = 8.00 Hz, 2H), 7.16 (d, J = 8.00 Hz, 2H), 7.34 - 7.44 (m, 2H), 7.64 -7.73 (d, J = 8.00 Hz, 2H), 9.22 (br s, 1H), 9.71 (br s, 1H).

[0206] Synthesis of compound 3:

[0207]

[0208] Synthesis route:

[0209]

[0210] Synthesis of compound 3-1:

[0211] To a solution of sodium difluorochloroacetate (17.4 g, 114.5 mmol) in DMF (25.0 mL) and water (6.00 mL), K₂CO₃ (8.80 g, 63.6 mmol) was added, followed by dropwise addition of a solution of SM₄ (5.00 g, 31.8 mmol) in DMF (25.0 mL). The system was stirred at 110°C for 12 hours. LC-MS showed that SM₄ was completely consumed. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (200 mL * 3). The bound organic layer was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1) to give compound 3-1 (0.30 g, 1.45 mmol, yield 4.55%) as a yellow oil. 1 H NMR (400 MHz CDCl3), δ ppm 7.96 - 7.92 (m, 1H), 7.58 - 7.56 (t, J = 7.2 Hz 1H), 7.32- 4.29 (m, 1H), 3.53 (t, J = 144 Hz, 1H).

[0212] Synthesis of compound 3-2:

[0213] Pd / C (0.03 g, 10% purity) was added to a MeOH (5.00 mL) solution of compound 3-1 (0.30 g, 1.45 mmol), and hydrogen gas was bubbled through the solution. The mixture was stirred at 25 °C for 16 hours. LC-MS showed that compound 3-1 was completely consumed. The mixture was filtered and concentrated under reduced pressure to give crude compound 3-2 (172 mg, 971 μmol, yield 67.0%) as a yellow solid. MS m / z (ESI): 178 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 6.89 - 6.86 (m, 1H), 6.66- 6.53 (m, 1H), 6.71 - 6.34 (t, J = 147.6 Hz, 1H).

[0214] Step 1: Synthesis of compound 3-3:

[0215] Compounds 3-2 (170 mg, 959 μmol) and fragment 1 (300 mg, 533.25 μmol) were added to ACN (5.00 mL) along with T3P (1.02 g, 1.60 mmol, 951.43 μL, 50% purity) and Et3N (134 mg, 1.33 mmol, 185 μL), and stirred at 40 °C for 2 hours. LC-MS showed that fragment 1 was completely consumed. The pH was adjusted to 5-6 with sodium carbonate solution at 0 °C, then diluted with 20.0 mL of water and extracted with ethyl acetate (30 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 20 / 1 ~ 10 / 1) to give compound 3-3 (130 mg, 145 μmol, yield 27.3%, purity 81.0%) as a yellow oil. MS m / z (ESI): 722 [M+H] + .

[0216] Step 2: Synthesis of Compound 3:

[0217] Sodium methoxide (97.3 mg, 1.80 mmol) was added to a methanol (2.00 mL) solution of compound 3-3 (130 mg, 180 μmol), and the mixture was stirred at 25°C for 2 hours. LC-MS showed that compound 3-3 was completely consumed. The reaction mixture was subjected to layer extraction in 10.0 mL of ammonium chloride aqueous solution and 20.0 mL of ethyl acetate solution. The organic phase was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, dichloromethane:MeOH = 1 / 30-1 / 10). Compound 3 (71.0 mg, 99.8 μmol, yield 55.4%) was given as a yellow solid. MS m / z (ESI): 676 [M+H] + ; 1 H NMR(400 MHz CD3OD), δ ppm 7.71 - 7.69 (d, J = 8.80 Hz, 2H), 7.46 - 7.33 (m,6H), 7.04 - 7.02 (t, J = 8.40 Hz, 2H), 7.06 - 6.73 (t, J = 131.6 Hz, 1H),5.55 - 5.51 (d, J = 16.0 Hz, 1H), 5.41 - 5.37 (d, J = 16.0 Hz, 1H), 4.61(s,1H), 4.26 - 4.17 (m, 2H), 3.74 (s, 3H), 2.17 (s, 6H).

[0218] Example 4 Synthesis of Fragment 2

[0219]

[0220] Synthesis route:

[0221]

[0222]

[0223]

[0224] Step 1: Synthesis of fragment 2-2:

[0225] To a solution of compound 1-1 (5 g, 13.21 mmol, 1 eq) in DMF (150 mL), K₂CO₃ (2.01 g, 14.53 mmol, 1.1 eq) and KI (2.41 g, 14.53 mmol, 1.1 eq) were added. Then, a solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (55.46 g, 341.14 mmol, 1.2 eq) in DMF (190 mL) was added to the mixture. The mixture was stirred at 25°C for 17 hours. The resulting precipitate was filtered off, and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (700 mL) and water (700 mL), and extracted with ethyl acetate (300 mL x 2). The extract was washed with 500 mL of water and 500 mL of brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10⁻¹⁻² / 1). TLC (petroleum ether:dichloromethane = 2:1, plate 2, Rf = 0.67) yielded fragment 2⁻² (7.23 g, 10.30 mmol, yield 77.95%, purity 79%) as a yellow oil. MS m / z (ESI): 555 [M+H] + .

[0226] Step 2: Combining fragments 2-3:

[0227] Fragment 2-2 (7.21 g, 13.00 mmol, 1 eq), AIBN (213.51 mg, 1.30 mmol, 0.1 eq), and NBS (2.89 g, 16.25 mmol, 1.25 eq) were reacted in ethyl acetate (100 mL) at 80 °C for 2 h. Then, NBS (1.39 g, 7.80 mmol, 0.6 eq) and AIBN (106.76 mg, 650.12 μmol, 0.05 eq) were added, and the reaction was continued at 80 °C for another 2 h. Finally, NBS (1.39 g, 7.80 mmol, 0.6 eq) and AIBN (106.76 mg, 650.12 μmol, 0.05 eq) were added, and the reaction was continued at 80 °C for another 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and water (300 mL), and extracted with ethyl acetate (200 mL x 2). The extract was washed with 300 mL of water and 500 mL of brine, dried (Na₂SO₄), and concentrated under reduced pressure. Crude fragments 2-3 (7.22 g, crude product) were obtained and used directly in the next step. MS m / z (ESI): 633 [M+H] + .

[0228] Step 3: Combining fragments 2-4:

[0229] Fragments 2-3 (7.20 g, 11.37 mmol, 1 eq), dimethylamine (3.84 g, 34.11 mmol, 4.32 mL, 40% purity, 3 eq), and DMF (300 mL) were added to a 500 mL single-necked round-bottom flask and incubated at 25°C. Triethylamine (4.60 g, 45.48 mmol, 6.33 mL, 4 eq) was then added, and the reaction was stirred for another 2 hours. The reaction was stopped, water (700 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The liquid was separated, and the organic phase was collected. The organic phase was washed with water (300 mL), dried over anhydrous Na₂SO₄, and concentrated and purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain fragments 2-4 (5.12 g, 7.37 mmol, 64.81% yield, 86% purity) as a pale yellow solid. MS m / z (ESI): 598 [M+H] + .

[0230] Step 4: Combining fragments 2-5:

[0231] Fragments 2-4 (5.12 g) and 4 mol / L hydrochloric acid / 1,4-dioxane (12.5 mL, 110 mmol) were reacted in EtOH (200 mL) with 10% Pd / C (50% wet, 5.0 g) at 15 psi H2 pressure for 6 h at 25°C. The reaction mixture was filtered through diatomaceous earth, and the filtrate was neutralized with saturated NaHCO3 aqueous solution (200 mL). The filtrate was concentrated under vacuum, diluted with ethyl acetate (300 mL) and water (300 mL), and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with brine, dried (Na2SO4), and concentrated under vacuum to give fragment 2-5 (28.79 g, 55.62 mmol, 102% yield) as a pale yellow oil. MS m / z (ESI): 568 [M+H] + .

[0232] Step 5: Synthesis of fragments 2-6:

[0233] N,N-diisopropylethylamine (14.52 g, 112.36 mmol, 19.57 mL, 2.02 eq) and CDI (4.78 g, 29.46 mmol, 4 eq) were added to a CH2Cl2 (100 mL) solution of fragments 2-5 (4.18 g, 7.36 mmol, 1 eq). The mixture was stirred at 25°C for 12 h and then cooled to 0°C. Methoxyamine hydrochloride (6.14 g, 73.50 mmol, 5.58 mL, 9.98 eq) and DIPEA (9.80 g, 75.85 mmol, 13.21 mL, 10.3 eq) were added to the mixture, and the mixture was stirred at 25°C for 12 h. The reaction solution was washed with a saturated NaHCO3 aqueous solution (200 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (200 mL * 2). The bound organic phase was washed with brine (400 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 30:1 ~ 5:1) to give fragments 2-6 (4.22 g, 6.59 mmol, yield 89.45%) as a pale yellow oil. MS m / z (ESI): 641 [M+H] + .

[0234] Step 6: Synthesis of Fragment 2:

[0235] 2 mol / L NaOH (102 mL, 204.95 mmol) was added to a solution of fragments 2-6 (4.22 g, 6.59 mmol, 1 eq) in EtOH (500 mL). After stirring at 40 °C for 12 h, 1 mol / L HCl (205 mL, 205 mmol) was added at 0 °C, and the mixture was concentrated under vacuum. The residue was dissolved in 200 mL of ethanol and 200 mL of toluene and concentrated. The residue was diluted with dry ethanol (200 mL) and filtered, and the filtrate was concentrated under reduced pressure. Methyl tert-butyl ether (100 mL) was added to the residue, and the precipitate was collected by filtration, washed with methyl tert-butyl ether (50 mL), and dried to give fragment 2 (2.0 g, 2.87 mmol, yield 43.62%, purity 88%) as a pale yellow solid. MS m / z (ESI): 613 [M+H] + .

[0236] Example 5: Synthesis of Compound 3A

[0237]

[0238] Synthesis route:

[0239]

[0240] Step 1: Synthesis of compound 3A-1:

[0241] Fragment 2 (700 mg, 1.14 mmol, 1 eq), 3-difluoromethoxy-2-fluoroaniline (364.31 mg, 2.06 mmol, 1.8 eq), and T3P (1.82 g, 2.86 mmol, 1.70 mL, 50% purity, 2.5 eq) and Et3N (346.88 mg, 3.43 mmol, 477.14 μL, 3 eq) were added to ACN (50 mL) solution and stirred at 40°C for 2 hours. The pH was then adjusted to 5-6 with sodium carbonate solution at 0°C, diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL * 3), and concentrated to give compound 3A-1 (300 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 772 [M+H] + .

[0242] Step 2: Synthesis of compound 3A:

[0243] Sodium methoxide (209 mg, 3.88 mmol) was added to a methanol (5.00 mL) solution of compound 3A-1 (300 mg, 388 μmol), and the mixture was stirred at 25°C for 2 hours. LC-MS showed that compound 3A-1 was completely consumed. The reaction mixture was subjected to layer extraction in 10.0 mL of ammonium chloride aqueous solution and 20.0 mL of ethyl acetate solution. The organic phase was concentrated under reduced pressure to obtain the residue. The residue was analyzed by reversed-phase high-performance liquid chromatography (column: Xestim C18 150*40 mm*10 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B %: 50% - 80%, 10 min). The crude product was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) (column: Welch Xtimate C18 150*30mm*5um, mobile phase: [water(TFA)-ACN], B%: 15%-55%, 10min) to obtain compound 3A (191mg, 257.95 μmol, 28.44% yield, 98% purity) as a yellow solid. MS m / z (ESI): 726 [M+H] + ; 1 H NMR (400 MHz CD3OD), δ ppm 7.66 - 7.76 (m, 3 H) 7.57 - 7.65 (m, 1H) 7.43 - 7.52 (m, 2 H) 7.09 - 7.13 (m, 1 H) 6.89 - 6.95 (m, 1 H ) 6.69 -6.76 (m, 1 H) 5.74 (d, J = 16.00 Hz, 1 H) 5.54 (d, J = 16.00 Hz, 1 H) 4.39 -4.54 (m, 2 H) 3.75 (s, 3 H) 2.70 - 2.80 (m, 6 H) .

[0244] Example 6 Synthesis of Compound 4

[0245]

[0246] Synthesis route:

[0247]

[0248] Step 1: Synthesis of compound 4-2:

[0249] Thionyl chloride (15.5 g, 115 mmol, 11.5 mL) was added to a suspension of SM5 (21.0 g, 88.5 mmol) in anhydrous toluene (100 mL), and the mixture was stirred at 85 °C for 12 h, followed by stirring at 100 °C for 4 h. LCMS and TLC (Petroleum ether: EtOAc = 5:1, Rf = 0.31) showed that the starting material was almost completely consumed. The mixture was cooled to 25 °C and quenched with ice water (50.0 mL). The organic layers were separated, and the aqueous layer was extracted with toluene (100 mL). The combined organic layers were dried over anhydrous Na2SO4 and desolventized under reduced pressure to give compound 4-2 (23.0 g, 69.4 mmol, 78.4% yield, 82% purity) as a yellow viscous oil, which was used directly for the next step without further purification. 1 H NMR (400 MHz CDCl3), δppm 8.35(d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 5.56 (s, 1H), 4.34 - 4.28 (m,2H), 1.26 (t, J = 7.2 Hz, 3H).

[0250] Step 2: Synthesis of compound 4-3:

[0251] Solution 1: NaH (3.39 g, 84.6 mmol, 60% purity) was added to a THF (120 mL) solution of tert-butyl cyanoacetate (11.9 g, 84.6 mmol, 12.1 mL) and stirred for 30 min at 0–25 °C. Fresh Solution 1 was added dropwise to a THF (120 mL) solution of compound 4-2 (23.0 g, 84.6 mmol) and continued for 30 min. The mixture was stirred at 25 °C for 16 h and then at 70 °C for 24 h. LC-MS showed that the starting material was completely consumed. The mixture was removed from the solvent under reduced pressure. The mixture was purified by silica gel column chromatography. Compound 4-3 (18.5 g, 42.7 mmol, yield 50.5%, purity 87.0%) was given as an orange solid. MS m / z (ESI): 377 [M+H] + ; 1H NMR (400 MHz CDCl3), δ8.20 (d, J = 9.2 Hz, 2H), 7.63 (d, J = 9.2 Hz, 2H), 5.76 (br.s, 2H), 4.43 -4.38 (m, 2H), 1.53 (s, 9H), 1.39 (t, J = 7.2 Hz, 3H).

[0252] Step 3: Synthesis of compound 4-4:

[0253] ClCO2Et (1.85 g, 17.0 mmol, 1.62 mL) was added to a THF (100 mL) solution of compound 4-3 (5.00 g, 13.3 mmol) and Et3N (4.03 g, 39.8 mmol, 5.55 mL), and the mixture was stirred at 25 °C for 16 h. Another ClCO2Et (1.69 g, 15.5 mmol, 1.48 mL) was added, and the mixture was stirred at 25 °C for 4 h. The solvent was removed under reduced pressure, and the residue was dissolved in 50 mL of methanol. K2CO3 (2.75 g, 19.9 mmol) was added, and the mixture was stirred at 50 °C for 16 h. LCMS showed that the starting material was completely consumed. The mixture was diluted with water (200 mL), extracted with ethyl acetate (150 mL × 3), and the organic layer was washed with water (150 mL) and brine (100 mL). The mixture was dried over Na₂SO₄ and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 4-4 (4.20 g, 8.71 mmol, yield 65.5%, purity 93.0%) as a yellow solid. MS m / z (ESI): 449 [M+H] + ; 1 H NMR (400 MHz CDCl3), δppm 9.02 (br.s, 1H), 8.24 (d, J = 9.2Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 4.44 - 4.38 (m, 2H), 4.33 - 4.30 (m, 2H), 1.55 (s, 9H), 1.41 - 1.35 (m, 6H).

[0254] Step 4: Synthesis of compounds 4-5:

[0255] K₂CO₃ (1.53 g, 11.04 mmol) and KI (1.83 g, 11.0 mmol) were added to a DMF (50.0 mL) solution of compound 4-4 (4.50 g, 10.0 mmol), followed by 2,6-difluorobenzyl chloride (1.96 g, 12.0 mmol). The mixture was stirred at 25 °C for 3 hours. LC-MS showed that the starting material was completely consumed. The mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL × 3), and the organic layer was washed with water (50 mL × 2). The residue was dried with Na₂SO₄ and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1, Rf = 0.46) to give compound 4-5 (4.90 g, 8.14 mmol, yield 81.1%, purity 95.5%) as a yellow oil. MS m / z (ESI): 575 [M+H] + ; 1 H NMR (400MHz CDCl3), δppm 8.23 ​​(d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.27 -7.24 (m, 1H), 6.87 (t, J = 8.0 Hz, 2H), 5.00 (s, 2H), 4.42 - 4.37 (m, 2H), 4.25 - 4.20 (m, 2H), 1.49 (s, 9H), 1.36 (t, J = 7.2 Hz, 3H), 1.25 - 1.23 (m, 3H).

[0256] Step 5: Synthesis of compounds 4-6:

[0257] TFA (9.24 g, 81.0 mmol, 6.00 mL) was added to a CH2Cl2 (25.0 mL) solution of compounds 4-5 (4.90 g, 8.53 mmol), and the mixture was stirred at 25 °C for 3 hours. LCMS showed that the starting material was completely consumed. The mixture was removed from the solvent under reduced pressure. The residue was dissolved in 50 mL of CH2Cl2, and the solvent was removed. This step was repeated three times to give compounds 4-6 (5.20 g, 8.22 mmol, 96.4% yield, TFA) as a brown oil, which was used directly in the next step without purification. MS m / z (ESI): 519 [M+H] + ; 1H NMR (400 MHz CDCl3), δppm 8.28 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.31 - 7.25 (m, 1H), 6.87 (t, J = 8.0 Hz, 2H), 5.02 (s,2H), 4.41 - 4.35 (m, 2H), 4.26 - 4.23 (m, 2H), 1.26 (t, J = 7.2 Hz, 6H).

[0258] Step 6: Synthesis of compounds 4-7:

[0259] A solution of compounds 4-6 (4.00 g, 7.72 mmol) and 3-amino-6-methoxypyridazine (2.00 g, 15.9 mmol) in tetrahydrofuran (80.0 mL) was added to N-methylimidazolium (2.53 g, 30.8 mmol, 2.46 mL) and N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate (4.33 g, 15.4 mmol), and the mixture was stirred at 25°C for 16 hours. LC-MS showed complete consumption of the starting material. The solution in the mixture was removed under reduced pressure. The residue was purified by silica gel (petroleum ether:ethyl acetate = 2:1 ~ 0:1) column chromatography to give compounds 4-7 (2.90 g, 4.27 mmol, yield 55.3%, purity 92.0%) as a yellow oil. MS m / z (ESI): 626 [M+H] + ; 1 H NMR (400 MHz CDCl3), δppm 10.76 (br.s, 1H), 8.49 (d, J = 9.6 Hz, 1H), 8.28 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.25 - 7.23 (m, 1H), 7.09 (d, J = 9.2 Hz, 1H), 6.84 (t, J = 8.0 Hz, 2H), 5.04 (s, 2H), 4.35 - 4.29 (m, 4H), 4.13 (s, 3H), 1.31 - 1.18 (m, 6H).

[0260] Step 7: Synthesis of compounds 4-8:

[0261] LiBH4 (435 mg, 19.9 mmol) was added to a solution of compounds 4-7 (2.50 g, 4.00 mmol) in THF (20 mL) and EtOH (20 mL), and the mixture was stirred at 0 °C for 1 h, followed by stirring at 0–25 °C for 3 h. LCMS showed that the starting material was completely consumed. The mixture was poured into an aq. NH4Cl solution (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to give compounds 4-8 (2.30 g, 3.19 mmol, 79.9% yield, 81.0% purity) as a yellow solid, which was used directly for the next step without purification. MS m / z (ESI): 584 [M+H] + .

[0262] Step 8: Synthesis of compounds 4-9:

[0263] At 0 °C, SOCl2 (905 mg, 7.61 mmol, 552 μL) was added to a CH2Cl2 (50.0 mL) solution of compounds 4-8 (2.22 g, 3.80 mmol), and the mixture was stirred at 0–25 °C for 3 hours. LC-MS showed that the starting material was completely consumed. The solvent was removed from the mixture under reduced pressure to give compounds 4-9 (2.30 g, crude) as a yellow solid, which was used directly for the next step without purification. MS m / z (ESI): 602 [M+H] + .

[0264] Step 9: Synthesis of compounds 4-10:

[0265] Et3N (3.87 g, 38.2 mmol, 5.32 mL) and dimethylamine hydrochloride (1.56 g, 19.1 mmol) were added to a CH2Cl2 (50.0 mL) solution of compounds 4-9 (2.30 g, 3.82 mmol), and the mixture was stirred at 25 °C for 16 h. LC-MS showed that the starting material was completely consumed. The mixture was diluted with CH2Cl2 (100 mL), washed with water (50.0 mL × 2), and the aqueous layer was extracted with CH2Cl2 (50.0 mL). The bound organic layer was washed with brine (50.0 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. Compound 4-10 (1.40 g, 2.13 mmol, yield 55.8%, purity 93.0%) was purified by silica gel column chromatography as a yellow solid. MS m / z (ESI): 611 [M+H] + .

[0266] Step 10: Synthesis of compound 4-11:

[0267] CH3ONa (186 mg, 3.44 mmol) was added to an anhydrous methanol (20 mL) solution of compound 4-10 (210 mg, 344 μmol), and the mixture was stirred at 25 °C for 16 h. LC-MS showed complete consumption of the starting material and the expected product was observed. Four batches of the mixture were combined, poured into aq. NH4Cl solution (150 mL), extracted with ethyl acetate (150 mL × 3), washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography gave compound 4-11 (530 mg, 884 μmol, 64.3% yield, 94.2% purity) as a yellow solid. MS m / z (ESI): 565 [M+H] + ; 1 H NMR (400 MHz CDCl3), δppm 8.35 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 9.2Hz, 2H), 7.42 - 7.35 (m, 2H), 7.17 (d, J = 9.2 Hz, 1H), 6.99 - 6.95 (m, 2H), 5.45 (s, 2H), 4.19 (s, 3H), 4.00 - 3.73 (m, 2H), 2.48 (s, 6H).

[0268] Step 11: Synthesis of compound 4-12:

[0269] Under N2 protection, Pd / C (50.0 mg, 86.0 μol, 10% purity) was added to a solution of compound 4-11 (105 mg, 172 μol) in EtOH (5.00 mL) and THF (5.00 mL), followed by vacuum degassing and H2 purging three times. The mixture was stirred at 25°C for 16 hours under H2 (15 PSI) atmosphere. LCMS showed that the starting material was completely consumed. The mixture was filtered through a diatomaceous earth liner, and the filter cake was washed with 30 mL of ethanol (EtOH). The filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2: MeOH = 10:1, Rf = 0.31) to give compound 4-12 (67.0 mg, 100 μol, yield 58.3%, purity 87.0%) as palm oil. MS m / z (ESI): 535 [M+H + .

[0270] Step 12: Synthesis of Compound 4:

[0271] Compound 4-12 (50.0 mg, 93.5 μmol) was added to CH2Cl2 (5 mL) along with DIPEA (105 mg, 812 μmol, 141 μL) and CDI (60.6 mg, 374 μmol), and stirred at 25 °C for 16 hours. Then, DIPEA (120 mg, 935 μmol, 163 μL) and CDI (60.0 mg, 370 μmol) were added, and the mixture was stirred at 25 °C for 2 hours. Finally, CDI (151 mg, 935 μmol) was added, and the mixture was stirred at 25 °C for 2 hours. Methoxyamine hydrochloride (78.1 mg, 935 μmol) was added, and the mixture was stirred at 25 °C for 2 hours. LC-MS showed that the starting material was completely consumed. The mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL × 2), and brine (20 mL). The organic layer was dried over Na₂SO₄, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography gave compound 4 (35.0 mg, 52.4 μmol, yield 56.0%, purity 91.0%) as a grayish-white solid. MS m / z (ESI): 608 [M+H] + ; 1 H NMR (400 MHz CD3OD), δppm 7.73 - 7.63 (m, 5H), 7.40- 7.36 (m, 2H), 7.05 - 7.01 (m, 3H), 5.46 (s, 2H), 4.16 (s, 3H), 3.75 - 3.73(m, 5H), 2.29 (s, 6H).

[0272] Example 7 Synthesis of Compound 5

[0273]

[0274] Synthesis route:

[0275]

[0276] Step 1: Synthesis of compound 5-1:

[0277] Fragment 2 (700 mg, 1.14 mmol, 1 eq), 3-amino-6-methoxypyridazine (714.91 mg, 5.71 mmol, 5 eq) was dissolved in DMF (10 mL), and T3P (5.82 g, 9.14 mmol, 5.44 mL, 50% purity, 8 eq) and DIEA (2.22 g, 17.14 mmol, 2.99 mL, 15 eq) were added. The mixture was stirred at 25°C for 2 hours. The pH was adjusted to 5-6 with sodium carbonate solution at 0°C, diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure to give compound 5-1 (650 mg, crude) as a yellow oil. MS m / z (ESI): 720 [M+H] + .

[0278] Step 2: Synthesis of Compound 5:

[0279] Compound 5-1 (650 mg, 903.15 μmol, 1 eq) was dissolved in MeOH (20 mL), and NaOMe (487.91 mg, 9.03 mmol, 10 eq) was added. The mixture was stirred at 25 °C for 2 hours. The pH was adjusted to 5-6 with sodium carbonate solution at 0 °C, and then diluted with 100.0 mL of water. The mixture was extracted with ethyl acetate (100 mL * 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was pre-purified by high performance liquid chromatography (column: xestimate C18 150*40mm*10 μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 40%-70%, 10 min). Compound 5 (137 mg, 199.31 μmol, 22.07% yield, 98% purity) was obtained as a yellow solid. MS m / z (ESI): 674 [M+H] + ; 1 H NMR (400 MHz CD3OD), δppm7.55 - 7.72 (m, 5 H) 7.34 - 7.48 (m, 4 H) 4.17 (s, 3 H) 3.74 (s, 1 H) 3.64 -3.87 (m, 1 H) 3.60 - 4.00 (m, 1 H) 2.08 - 2.24 (m, 6 H).

[0280] Example 8 Synthesis of Compound 6

[0281]

[0282] Synthesis route:

[0283]

[0284] Step 1: Synthesis of compound 6-1:

[0285] DMAP (94.3 mg, 771 μmol) and di-tert-butyl dicarbonate (12.6 g, 57.8 mmol, 13.3 mL) were added to a solution of SM6 (5.00 g, 38.6 mmol) in dioxane (100 mL), and the mixture was stirred at 80 °C for 2 hours. LC-MS showed that starting material b1 was completely consumed. The reaction mixture was extracted with ethyl acetate to provide mono- and di-protected amines. The mono- and di-protected amines were dissolved in methanol (100 mL), and potassium carbonate (1.26 g, 9.10 mmol) was added. The mixture was stirred at 25 °C until no di-protected amine was observed on LC-MS. The reaction mixture was poured into water (100.0 mL) and filtered to give compound 6-1 (4.60 g, 18.2 mmol, yield 52.0%, purity 91%) as a yellow solid. MS m / z (ESI): 230 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 8.28 - 8.25 (d, J = 9.2 Hz, 1 H), 7.99 (br s, 1 H), 7.47 - 7.45 (d, J = 9.6 Hz, 1H), 1.54 (s, 9H).

[0286] Step 2: Synthesis of compound 6-2:

[0287] Compound 6-1 (4.60 g, 20.0 mmol) was added to a THF solution (300 mL), and NaH (961 mg, 24.0 mmol, 60.0% purity) was added at 0 °C. The mixture was stirred at 0 °C for 20 min, followed by the addition of MeI (3.70 g, 26.0 mmol, 1.62 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 40 min. LC-MS showed that compound 6-1 was completely consumed. The reaction mixture was quenched with 100 mL of water at 0 °C, extracted with ethyl acetate (150 mL * 3), and the bound organic layer was dried over [Na₂SO₄]. The residue was concentrated by filtration under reduced pressure, yielding a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 20 / 1) to give compound 6-2 (3.00 g, 12.3 mmol, yield 61.4%) as a white solid. MS m / z (ESI): 244 [M+H] + ;1 H NMR (400 MHz CDCl3), δ ppm 8.13 - 8.11 (d, J = 9.2 Hz, 1H), 7.39 - 7.37 (d, J = 9.2 Hz, 1H), 3.55 (s, 3H), 1.55 (s, 9H).

[0288] Step 3: Synthesis of compound 6-3:

[0289] Under nitrogen protection, 1.53 g (2.46 mmol) of BINAP, 8.02 g (24.6 mmol) of Cs₂CO₃, and 1.13 g (1.23 mmol) of Pd₂(dba)₃ were added to a solution of compound 6-2 (3.00 g, 12.3 mmol) and benzophenone imine (2.68 g, 14.77 mmol, 2.48 mL) in toluene (30.0 mL). The mixture was stirred at 110 °C for 16 h under nitrogen protection. LC-MS showed that the starting material was completely consumed. The solvent was removed under reduced pressure to give compound 6-3 (5.00 g, crude product) as a yellow oil. MS m / z (ESI): 389 [M+H] + .

[0290] Step 4: Synthesis of compound 6-4:

[0291] Compound 6-3 (5.00 g, 4.38 mmol, 34.0% purity) was dissolved in THF (100 mL), and HCl (1 M, 10.0 mL) was added. The mixture was stirred at 25 °C for 30 min. LC-MS showed that compound 6-3 was completely consumed. Sodium carbonate solution (5.00 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10.0 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1~4 / 1) to give compound 6-4 (800 mg, 3.57 mmol, 81.5% yield) as a yellow solid. MS m / z (ESI): 244 [M+H] + ; 1 HNMR (400 MHz CDCl3), δ ppm 7.33 - 7.31 (d, J = 9.2 Hz, 1H), 6.76 - 6.74 (d, J= 2.4 Hz, 1H), 6.26 (s, 2H), 3.19 (s, 2H), 1.39 (s, 7H).

[0292] Step 5: Synthesis of compound 6-5:

[0293] Compound 6-4 (500 mg, 2.23 mmol) was dissolved in 4 M HCl / 1,4-dioxane (2.23 mmol, 1 mL) solution and stirred at 25 °C for 2 hours. LC-MS showed that compound 6-4 was completely consumed. Concentration under reduced pressure gave compound 6-5 (276 mg, 2.22 mmol, 99.7% yield) as a white solid. MS m / z (ESI): 125 [M+H] + .

[0294] Step 6: Synthesis of compound 6-6:

[0295] T3P (2.04 g, 3.20 mmol, 1.90 mL, 50.0% purity) and Et3N (1.08 g, 10.6 mmol, 1.48 mL) were added to a solution of fragment 1 (600 mg, 1.07 mmol) and compound 6-5 (264 mg, 2.13 mmol) in ACN (10.0 mL), and the mixture was stirred at 40 °C for 2 hours. LC-MS showed that fragment 1 was completely consumed. The solution was adjusted to pH 5–6 with sodium carbonate solution at 0 °C, diluted with 20.0 mL of water, and extracted with ethyl acetate (30.0 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6-6 as a yellow solid. MS m / z (ESI): 769 [M+H] + .

[0296] Step 7: Synthesis of Compound 6:

[0297] Sodium methoxide (484 mg, 8.97 mmol) was added to a methanol (5.00 mL) solution of compound 6-6 (600 mg, 897 μmol), and the mixture was stirred at 25°C for 2 hours. LC-MS showed that compound 6-6 was completely consumed. The reaction mixture was subjected to layer extraction in 10.0 mL of aqueous ammonium chloride solution and 20.0 mL of ethyl acetate solution. The organic phase was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 20 / 1~10 / 1) to give compound 6 (200 mg, 321 μmol, yield 35.8%) as a white solid. MS m / z (ESI): 623 [M+H] + ; 1H NMR (400 MHzCD3OD), δ ppm 7.75 - 7.73 (d, J = 8.4 Hz, 2H), 7.46 - 7.41 (m, 3H), 7.36 -7.38 (d, J = 9.2 Hz, 1H), 7.08 - 7.02(m, 3H), 5.47 - 5.45 (d, J = 10.4 Hz, 2H), 4.49 - 4.45 (br d, J = 14.8 Hz, 2H), 3.75 (s, 3H), 3.02 (s, 3H), 2.75 (s, 6H).

[0298] Example 9 Synthesis of Compound 7

[0299]

[0300] Synthesis route:

[0301]

[0302]

[0303]

[0304] Step 1: Synthesis of compound 7-1:

[0305] At 0°C, PPh3 (19.2 g, 73.5 mmol) was added to SM7 (10.0 g, 61.3 mmol), 2,2-difluoroethanol (5.03 g, 61.3 mmol), and tetrahydrofuran (100 mL), and the mixture was stirred at 25°C for 20 hours. LC-MS showed that SM7 was completely consumed. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to give compound 7-1 (4.00 g, 17.6 mmol, 28.7%) as a white solid. MS m / z (ESI): 228 [M+H] + ; 1 H NMR (400 MHz CDCl3), δppm 7.89 - 7.86 (m, 1H), 7.80 - 7.78 (m, 2H), 6.38 - 6.09 (m, 1H), 4.42 - 4.35 (m, 2H).

[0306] Step 2: Synthesis of compound 7-2:

[0307] Compound 7-1 (4.00 g, 17.6 mmol) was reacted with NH₂NH₂·H₂O (2.01 g, 39.3 mmol, 1.95 mL, 98.0% purity) in CH₂Cl₂ (100 mL). LC-MS showed that compound 7-1 was completely consumed. The reaction mixture was filtered, the filtrate was washed with 10.0 mL of water, and the bound organic layer was adjusted to pH 1 with HCl / 1,4-dioxane 4M (5.00 mL). Filtration gave compound 7-2 (2.00 g, 14.9 mmol, 85.0% yield) as a white solid. MS m / z (ESI): 134 [M+H] + ; 1 H NMR (400 MHz DMSO-d6), δppm 11.3 (s, 2H), 6.51- 6.22 (m, 1H), 4.36 -4.28 (t, J = 29.6 Hz, 1H).

[0308] Step 3: Synthesis of compound 7-3:

[0309] NaOH (3.29 g, 82.1 mmol) was added to H₂O (40.0 mL) to generate 2N NaOH. This solution was added to an EtOH solution (243 mL) of fragments 1-4 (9.00 g, 16.4 mmol). The mixture was stirred at 60°C for 6 hours. LC-MS showed that fragments 1-4 were completely consumed. 1 N HCl (81.0 mL) was added at 0°C, and the mixture was concentrated under vacuum. The residue was dissolved in diethyl ether (100 mL) and toluene (100 mL), and all solutions were concentrated under vacuum. The residue was diluted with dry ethanol (100 mL) and filtered. The filtrate was concentrated under vacuum, and methyl tert-butyl ether (100 mL) was added to the residue and concentrated under vacuum to give compound 7-3 (8.00 g, 13.8 mmol, yield 84.3%) as a yellow solid. MS m / z (ESI): 520 [M+H] + .

[0310] Step 4: Synthesis of compound 7-4:

[0311] Compound 7-3 (7.00 g, 13.4 mmol), 3-amino-6-methoxypyridazine (3.37 g, 26.9 mmol), and T3P (25.7 g, 40.4 mmol, 24.0 mL, 50.0% purity) and Et3N (3.41 g, 33.6 mmol, 4.69 mL) were added to ACN (100 mL), and the mixture was stirred at 40 °C for 2 hours. LC-MS showed that compound 7-3 was completely consumed. The pH was adjusted to 5–6 with sodium carbonate solution at 0 °C, then diluted with 100 mL of water, and extracted with ethyl acetate (150 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 7-4 (7.70 g, crude) as a yellow solid. MS m / z (ESI): 627 [M+H] + .

[0312] Step 5: Synthesis of compound 7-5:

[0313] Sodium methoxide (6.21 g, 114.9 mmol) was added to a methanol solution (200 mL) of compound 7-4 (7.20 g, 11.4 mmol), and the reaction mixture was stirred at 25 °C for 2 hours. LC-MS showed that compound 7-4 was completely consumed. The reaction mixture was separated into layers between an aqueous solution of ammonium chloride (10.0 mL) and ethyl acetate (200 mL). The organic phase was concentrated under reduced pressure to give compound 7-5 (4.30 g, crude) as a yellow solid. MS m / z (ESI): 581 [M+H] + ; 1 H NMR (400 MHzDMSO-d6), δppm 8.34 - 8.32 ( d, J = 8.40 Hz, 2H), 8.00 - 07.97 ( d, J = 8.80Hz, 2H), 7.76 - 7.74 ( d, J = 9.20 Hz, 2H), 7.51 - 7.44 (m, 1H), 7.17 - 7.13 (t, J = 16.4 Hz, 2H), 5.43 - 5.21 (m, 2H), 4.09 (s, 3H), 3.73 - 3.66 (d, J =27.2 Hz, 2H), 2.08 (s, 6H).

[0314] Step 6: Synthesis of compounds 7-6:

[0315] Compound 7-5 (4.70 g, 8.10 mmol) was dissolved in EtOH (500 mL), and Pd / C (800 mg, 1.62 mmol) was added. The mixture was stirred at 25 °C for 1 hour. LC-MS showed that compound 7-5 was completely consumed. The reaction mixture was concentrated by filtration under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, dichloromethane:MeOH = 10 / 1) to give compound 7-6 (2.90 g, 5.27 mmol, yield 65.0%) as a white solid. MS m / z (ESI): 551 [M+H] + ; 1 H NMR (400MHz CD3OD), δ7.66 - 7.63 (m, 1H), 7.41 - 7.36 (m, 2H), 7.17 - 7.15 (m, 2H), 7.03 - 6.99 (m, 2H), 6.75 - 6.73 (m, 2H), 5.38 (s, 2H), 4.16 (s, 3H), 3.91 -3.83 (m, 2H), 2.04 (s, 6H).

[0316] Step 7: Synthesis of Compound 7:

[0317] DIPEA (94.8 mg, 733 μmol, 127 μL) and CDI (117 mg, 726 μmol) were added to a solution of compound 7-6 (200 mg, 363 μmol) in dichloromethane (5.00 mL). The mixture was stirred at 25°C for 14 hours and then cooled to 0°C. DIPEA (478 mg, 3.71 mmol, 645 μL) and compound 7-2 (485 mg, 3.63 mmol) were added to the mixture, and the mixture was stirred at 25°C for 2 hours. LC-MS showed that compound 7-6 was completely consumed. A sodium carbonate solution (5.00 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10.0 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane:MeOH = 10 / 1) to obtain the crude product, which was then purified by pre-TLC (SiO2, dichloromethane:MeOH = 10 / 1) to obtain compound 7 (10.0 mg, 14.8 μmol, yield 4.09%) as a yellow solid. MS m / z (ESI): 674 [M+H] + ; 1H NMR (400 MHz CD3OD), δppm 7.67 -7.63 (m, 3H), 7.43 - 7.37 (m, 3H), 7.03 - 6.99 (t, J = 16.4 Hz, 2H), 6.29 -6.02 (m, 1H), 3.46 - 3.35 (m, 1H), 5.39 (s, 2H), 4.16 (s, 3H), 4.14 - 4.07 (m, 2H), 2.00 (s, 6H).

[0318] Example 10 Synthesis of Compound 2A

[0319]

[0320] Synthesis route:

[0321]

[0322] Step 1: Synthesis of compound 2A:

[0323] Et3N (110 mg, 1.09 mmol, 152 μL, 6.00 eq) was added to a DMF (5 mL) solution of compound 7-6 (0.10 g, 182 μL, 1.00 eq), and the mixture was stirred at 0 °C for 30 min. Then, ethyl isocyanate (103 mg, 1.99 mmol, 403 μL, 28.0 eq) was added at 0 °C. The mixture was stirred at 50 °C for 17 h under a nitrogen atmosphere. Et3N (55.1 mg, 545 μL, 75.8 μL, 3.00 eq) and ethyl isocyanate (258 mg, 3.63 mmol, 288 μL, 20.00 eq) were added, and the mixture was stirred at 50 °C for 5 h. Et3N (55.1 mg, 545 μol, 75.8 μL, 3.00 eq) and isocyanoethane (387 mg, 5.45 mmol, 431 μL, 30.0 eq) were added, and the mixture was stirred at 50 °C for 5 hours. LC-MS showed that compounds 7-6 were completely consumed. The mixture was poured into water (20 mL), extracted with ethyl acetate (15 mL × 3), washed with brine (10 mL × 2), dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel (dichloromethane / methanol = 94 / 6) column chromatography. Compound 2A (52.3 mg, 81.6 μol, yield 44.9%, purity 97.0%) was given as a white solid. MS m / z (ESI): 622 [M+H] + ; 1H NMR (400 MHz CD3OD), δppm 8.32 (s, 1 H), 7.67 (d, J = 9.13Hz, 1 H), 7.40 (d, J = 8.50 Hz, 2 H), 7.27 - 7.32 (m, 1 H), 7.24 (d, J = 9.13Hz, 1 H), 6.95 (d, J = 8.38 Hz, 2 H), 6.83 - 6.91 (m, 2 H), 6.02 (br t, J =5.32 Hz, 1 H), 5.08 - 5.36 (m, 2 H), 4.19 - 4.19 (m, 1 H), 4.19 (s, 2 H),3.88 - 4.09 (m, 1 H), 3.30 (s, 2 H), 2.19 (s, 6 H), 1.16 (t, J = 7.19 Hz, 3H). 19 F NMR: (400 MHz CDCl3) δ -114.827 ppm.

[0324] Example 11 Synthesis of Fragment 3

[0325]

[0326] Synthesis route:

[0327]

[0328] Step 1: Synthesis of fragment 3-1:

[0329] SM8 (10.0 g, 86.9 mmol) was added to a solution of LDA (2 M, 43.5 mL) in 10.0 mL of THF at -70°C (10.0 mL) (100 mL). The mixture was stirred at -70°C for 30 hours, and then a solution of methyl formate (10.4 g, 174 mmol, 10.5 mL, 2 eq) was added. The mixture was stirred at -70°C for 1 hour, and then at 20°C for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.43) indicated that the reaction was complete. After cooling to 25°C, the mixture was poured into aq. NaHCO3 (100 mL), extracted with ethyl acetate (50.0 mL × 3), and concentrated under reduced pressure to give fragment 3-1 (8.00 g, 55.9 mmol, 64.3%) as a yellow solid. 1 H NMR (400 MHz CDCl3), δ ppm 8.55 (s, 2 H), 10.41 (s, 1 H).

[0330] Step 2: Synthesis of fragment 3-2:

[0331] To a MeOH solution of fragment 3-1 (8.00 g, 55.9 mmol, 1 eq) in 100 mL, a NaBH4 solution of MeOH (3.17 g, 83.9 mmol, 1.5 eq) in 10 mL was added at 0°C. The mixture was stirred at 20°C for 2 hours. LC-MS showed the reaction was complete. The reaction was quenched with water (50 mL), concentrated under reduced pressure, and methanol was removed. The residue was extracted with ethyl acetate (100 mL × 3), the combined organic phases were washed with brine (30.0 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The mixture was slurried with petroleum ether:ethyl acetate = 10:1 (100 mL) at 25°C for 1 hour to give fragment 3-2 (6.21 g, 42.8 mmol, yield 77.6%) as a yellow solid. MS m / z (ESI): 146 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 2.64 (br.s, 1 H), 4.84 (s, 2 H), 8.35 (s, 2 H).

[0332] Step 3: Synthesis of fragment 3-3:

[0333] Under N2 conditions, compound fragment 3-2 (6.21 g, 42.8 mmol, 1 eq) was dissolved in CH2Cl2 (125 mL). DIPEA (8.30 g, 64.2 mmol, 11.2 mL, 1.5 eq) and MsCl (6.00 g, 52.4 mmol, 4.05 mL, 1.22 eq) were added, respectively. The mixture was heated to 25°C and stirred at 25°C for 16 hours. LC-MS showed the reaction was complete. 50 mL of toluene was added twice, and the mixture was reconcentrated. The residue was subjected to column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 ~ 3 / 1) to give fragment 3-3 (2.46 g, 15.0 mmol, 35.1%) as a pale yellow liquid. MS m / z (ESI): 164 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 4.62 (s, 2 H), 8.38 (s, 2 H).

[0334] Step 4: Synthesis of fragments 3-4:

[0335] To a DMF (160 mL) solution of compound 1-1 (5.00 g, 13.2 mmol, 1 eq), KI (2.48 g, 14.9 mmol, 1.13 eq) and K₂CO₃ (2.06 g, 14.9 mmol, 1.13 eq) were added. Then, a DMF (12 mL) solution of fragment 3-3 (2.45 g, 14.9 mmol, 1.13 eq) was added to the mixture. LC-MS showed the reaction was complete. The resulting precipitate was filtered off, and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (70 mL) and water (70 mL), extracted with ethyl acetate (70 mL × 2), washed with water (70 mL) and brine (70 mL), dried over Na₂SO₄, and concentrated under vacuum. Methyl tert-butyl ether (35 mL) was added to the residue, and the precipitate was collected by filtration. Washing with methyl tert-butyl ether (10.0 mL) yielded fragments 3-4 (6.35 g, 12.5 mmol, yield 95.1%) as a pale yellow solid. MS m / z (ESI): 506 [M+H] + ; 1 H NMR(400 MHz CDCl3), δ ppm 1.19 - 1.37 (m, 6 H), 2.41 (s, 3 H), 4.13 - 4.33 (m, 4H), 5.00 (s, 2 H), 7.54 (d, J = 8.80 Hz, 2 H), 8.28 (d, J = 8.80 Hz, 2 H), 8.34 (s, 2 H).

[0336] Step 5: Synthesis of fragments 3-5:

[0337] Fragments 3-4 (6.35 g, 12.56 mmol, 1 eq), NBS (2.79 g, 15.70 mmol, 1.25 eq), and AIBN (206.28 mg, 1.26 mmol, 0.1 eq) were dissolved in ethyl acetate (75 mL) and reacted at 80 °C for 2 h. NBS (447 mg, 2.51 mmol, 0.2 eq) and AIBN (20.6 mg, 125.6 μmol, 0.01 eq) were added to the mixture, and the mixture was heated at 80 °C for 6 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL), extracted with ethyl acetate (30 mL * 2), washed with water (40 mL) and brine (40 mL), dried (Na₂SO₄), and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 ~ 8 / 1) to obtain fragments 3-5 (4.63 g, 7.92 mmol, 63.07%) as a pale yellow solid. MS m / z (ESI): 584, 586 [M+H] + .

[0338] Step 6: Synthesis of fragments 3-6:

[0339] At 25 °C, fragments 3-5 (4.63 g, 7.92 mmol, 1 eq), dimethylamine (1.94 g, 23.8 mmol, 2.18 mL, 3 eq, HCl), and DMF (20.1 mL) were added to a 100 mL single-necked round-bottom flask. Then, triethylamine (3.21 g, 31.7 mmol, 4.41 mL, 4 eq) was added, and the mixture was stirred for 2 hours. LC-MS showed the reaction was complete. The reaction was stopped, water (60 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The liquid was separated, the organic phase was collected, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 ~ 1 / 4) to give fragment 3-6 (3.05 g, 5.56 mmol, yield 70.2%) as a pale yellow solid. MS m / z (ESI): 549 [M+H] + ; 1H NMR (400 MHz CDCl3), δppm 1.10 - 1.25 (m, 3 H), 1.31 (t, J = 7.20 Hz, 3 H), 2.08 (s, 6 H), 3.55 (s,2 H), 4.14 - 4.30 (m, 4 H), 5.05 (s, 2 H), 7.66 (d, J = 7.66 Hz, 2 H), 8.27 (d, J = 8.80 Hz, 2 H), 8.33 (s, 2 H).

[0340] Step 7: Synthesis of fragments 3-7:

[0341] Fragments 3-6 (3.05 g, 5.56 mmol, 1 eq) and HCl / 1,4-dioxane (4 M, 2.78 mL, 2 eq) were added to EtOH (84.0 mL) along with Pd / C (0.99 g, 5.56 mmol, 10% purity, 1.00 eq), and hydrogenated at 25 °C and 15 psi for 1 h. LC-MS showed the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was diluted with saturated NaHCO3 aqueous solution (25 mL). The filtrate was concentrated under reduced pressure, and extracted with ethyl acetate (50 mL) and water (50 mL) (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give fragments 3-7 (2.74 g, 5.28 mmol, more readily, yield 95.0%) as a pale yellow oil, unpurified, and used directly in the next step. MS m / z (ESI): 519 [M+H] + ; 1 H NMR (400 MHz CDCl3), δ ppm 1.11 - 1.24 (m, 3 H), 1.31 (t, J =7.20 Hz, 1 H), 1.28 - 1.34 (m, 3 H), 2.02 - 2.06 (m, 6 H), 3.43 - 3.60 (m, 2H), 3.75 - 3.87 (m, 2 H), 4.15 - 4.31 (m, 4 H), 4.98 - 5.08 (m, 2 H), 6.66 -6.72 (m, 2 H), 7.13 - 7.20 (m, 2 H), 8.27 - 8.33 (m, 2 H).

[0342] Step 8: Combining fragments 3-8:

[0343] N,N-diisopropylethylamine (2.80 g, 21.6 mmol, 3.77 mL, 4.1 eq) and CDI (3.43 g, 21.1 mmol, 4 eq) were added to a CH2Cl2 (70 mL) solution of fragments 3-7 (2.74 g, 5.28 mmol, 1 eq). The mixture was stirred at 25°C for 13 hours. The mixture was cooled to 0°C. Methoxyamine hydrochloride (4.42 g, 52.8 mmol, 10 eq, HCl) and N,N-diisopropylethylamine (6.82 g, 52.8 mmol, 9.20 mL, 10 eq) were added to the mixture, and the mixture was stirred at 25°C for 8 hours. LC-MS showed that the reaction was complete. The reaction was washed with saturated NaHCO3 aqueous solution (80 mL). The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (50 mL × 2). The combined organic phases were washed with brine (100 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, dichloromethane:methanol = 30 / 1 ~ 8 / 1) to give fragment 3-8 (2.82 g, 4.77 mmol, yield 71.57%) as a pale yellow oil. MS m / z (ESI): 578 [M+H] + ; 1 H NMR (400 MHzDMSO-d6), δ ppm 1.00 - 1.22 (m, 6 H), 1.93 (s, 6 H), 3.42 (s, 2 H), 3.63 (s,3 H), 4.07 (q, J = 7.20 Hz, 4 H), 4.97 (s, 2 H), 7.32 (d, J = 7.20 Hz, 2 H), 7.69 (d, J = 8.40 Hz, 2 H), 8.51 (s, 2 H), 9.06 (s, 1 H), 9.62 (s, 1 H).

[0344] Step 9: Synthesis of Fragment 3:

[0345] Sodium hydroxide (953 mg, 23.8 mmol, 5 eq) was added to water (12 mL) to form a 2 M sodium hydroxide solution. The 2 M NaOH solution was added to a solution of EtOH (72 mL) containing fragment 3-8 (2.82 g, 4.77 mmol, 1 eq). The mixture was stirred at 60°C for 2 hours. LC-MS showed the reaction was complete. 1 mol / L HCl (24 mL) was added at 0°C, and the mixture was concentrated under vacuum. The residue was dissolved in 50 mL × 3 of ethanol and 50 mL × 3 of toluene, and concentrated under vacuum. The residue was diluted with dry ethanol and filtered; the filtrate was concentrated under vacuum. The residue was purified by high-performance liquid chromatography (HPLC) under neutral conditions (column: Xate C18 150*40mm*10um, mobile phase: [water(NH4HCO3)-ACN], B%: 10%-50%, 10 min), yielding fragment 3 (1.33 g, 2.36 mmol, yield 49.5%) as a pale yellow solid. MS m / z (ESI): 564 [M+H] + ; 1 H NMR(400 MHz DMSO-d6), δ ppm 1.08 (t, J = 6.82 Hz, 3 H), 2.45 (s, 6 H), 3.63 (s,3 H), 3.95 (s, 2 H), 4.03 (q, J=6.82 Hz, 2 H), 4.95 (s, 2 H), 7.22 (d, J =8.40 Hz, 2 H), 7.72 (d, J = 8.80 Hz, 2 H), 8.49 (s, 2 H), 9.2 (s, 1 H), 9.64 (s, 1 H).

[0346] Example 12 Synthesis of Compound 8

[0347]

[0348] Synthesis route:

[0349]

[0350] Step 1: Synthesis of compound 8-1:

[0351] Fragment 3 (500 mg, 887.20 μmol, 1 eq) and 3-difluoromethoxy-2-fluoroaniline (282.86 mg, 1.60 mmol, 1.8 eq) were dissolved in ACN (10 mL). T3P (1.69 g, 2.66 mmol, 1.58 mL, 50% purity, 3 eq) and Et3N (224.44 mg, 2.22 mmol, 308.72 μL, 2.5 eq) were added, and the mixture was stirred at 40°C for 12 hours. Then, T3P (1.69 g, 2.66 mmol, 1.58 mL, 50% purity, 3 eq) and Et3N (224.44 mg, 2.22 mmol, 308.72 μL, 2.5 eq) were added, and the mixture was stirred at 40°C for 6 hours. The pH was adjusted to 5-6 at 0°C with saturated sodium carbonate solution, then diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure to give compound 8-1 (600 mg, crude) as a yellow oil. MS m / z (ESI): 723 [M+H] + .

[0352] Step 2: Synthesis of Compound 8:

[0353] Compound 8-1 (600 mg, 830.24 μmol, 1 eq) was dissolved in MeOH (10 mL), and NaOMe (448.53 mg, 8.30 mmol, 10 eq) was added. The mixture was stirred at 25°C for 2 hours. At 0°C, the pH was adjusted to 5-6 with saturated sodium carbonate solution, diluted with 100.0 mL of water, extracted with ethyl acetate (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by column chromatography (SiO2, DCM: methanol = 100 / 1 ~ 10 / 1), and further purified by pre-TLC (SiO2, DCM: MeOH = 10:1). Compound 8 (114 mg, 141.88 μmol, 17.09% yield, 96% purity) was given as a yellow solid. MS m / z (ESI): 677 [M+H] + ; 1H NMR (400 MHz CD3OD), δ ppm8.43 (s, 2 H) 7.67 (d, J = 8.00 Hz, 2 H) 7.40 - 7.48 (m, 3 H) 7.25 - 7.39 (m,2 H) 7.06 - 7.11 (m, 1 H) 6.90 (s, 1 H) 6.72 (s, 1 H) 5.32 - 5.61 (m, 2 H)4.60 (br s, 1 H) 3.92 - 4.05 (m, 1 H) 3.55 - 3.80 (m, 4 H) 2.06 - 2.22 (m, 6H).

[0354] Example 13 Synthesis of Compound 8A

[0355]

[0356] Synthesis route:

[0357]

[0358] Step 1: Synthesis of compound 8A-1:

[0359] In a solution of fragment 3 (500 mg, 887.20 μmol, 1 eq), 3-amino-6-methoxypyridazine (555.07 mg, 4.44 mmol, 5 eq), T3P (4.52 g, 7.10 mmol, 4.22 mL, 50% purity, 8 eq), and DIEA (1.72 g, 13.31 mmol, 2.32 mL, 15 eq) from DMF (10 mL) were added. The mixture was stirred at 25°C for 12 hours. At 0°C, the pH was adjusted to 5–6 with saturated sodium carbonate solution, diluted with 100.0 mL of water, extracted with ethyl acetate (30 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 8A-1 (470 mg, crude) was given as a yellow oil. MS m / z (ESI): 671 [M+H] + .

[0360] Step 2: Synthesis of compound 8A:

[0361] NaOMe (378.58 mg, 7.01 mmol, 10 eq) was added to a MeOH (10 mL) solution of compound 8A-1 (470 mg, 700.78 μmol, 1 eq). The mixture was stirred at 25°C for 16 hours. LC-MS showed that the starting material was completely consumed, with 47% of the desired MS detected. The mixture was poured into saturated aq. NH4Cl (50 mL) and extracted with CH2Cl2 (50 mL × 2). The bound organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The mixture was purified by pre-HPLC (column: YMC Triart 30*150mm*7um; mobile phase: [water (ammonia v / v)-ACN]; B%: 0%-60%, 40 min) to obtain compound 8A (70 mg, 104.56 μmol, yield 14.92%, purity 93.3%) as a white solid. MS m / z (ESI): 625 [M+H] + ; 1 H NMR (400 MHz CD3OD), δ ppm 8.41 (s, 2 H) 7.62 - 7.70 (m, 3H) 7.42 - 7.49 (m, 2 H) 7.37 (d, J = 8.0 Hz, 1 H) 5.45 (br s, 2 H) 4.59 (brs, 2 H) 4.16 (s, 3 H) 3.74 (s, 3 H) 2.08 (s, 6 H).

[0362] Experimental Example 1. Screening for In Vitro Antagonistic Activity

[0363] Cells: HEK293 cells stably expressing human GnRHR (Shanghai WuXi AppTec Co., Ltd.)

[0364] Equipment: 384 well plate, Greiner; Vi-cell XR Cell Viability Analyzer, Beckman Coulter; Incubator, Thermo.

[0365] Methods: Stable human GnRHR HEK293 cells were seeded at a density of 20,000 / well in 384-well plates. The next day, Fluo-4 Direct™ No-wash Loading Buffer (Invitrogen) was added to each well, and the plates were incubated at 37°C for 50 min, followed by incubation at room temperature for 10 min. Test compounds were prepared using DMSO, with 10 μL added to each well at concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 976.6 pM, 244.1 pM, 61.0 pM, 15.3 pM, and 3.8 pM. Fluorescence values ​​were measured using a FLIPR Tetra high-throughput real-time fluorescence detection and analysis system. Then, 10 μL of Leuprolideacetate was added, and fluorescence values ​​were measured again. The IC50 values ​​of the compounds were determined. 50 IC 90 The results were obtained using Prism and are shown in Table 1.

[0366] Table 1. In vitro antagonistic activity of the compounds of this invention against human GnRHR

[0367]

[0368] Conclusion: Several compounds of this invention have significant inhibitory effects on human GnRHR.

[0369] Experimental Example 2. In vitro Binding Screening

[0370] Cells: Chem-1 cells stably expressing human GnRHR (Eurofins Panlabs Discovery Services)

[0371] Reagents: [ 125 I] [D-Trp6]-LH-RH, PerkinElmer; [D-Trp6]-LH-RH, Abcam.

[0372] Equipment: MicroBeta2 LumiJET system, PerkinElmer.

[0373] Methods: Chem-1 cell membranes stably expressing human GnRHR were resuspended in HEPES at pH 7.4. 6 μg of human GnRHR cell membrane was added to each well along with 0.05 nM [ 125The [D-Trp6]-LH-RH test compound was incubated at 25°C for 60 min. The compound was dissolved in DMSO at concentrations of 500 nM, 62.5 nM, 7.81 nM, 0.97 nM, 0.12 nM, 15 pM, and 1.9 pM. Nonspecific binding assays were performed using 1 μM [D-Trp6]-LH-RH. Cell membranes were collected by filtration, washed, and then subjected to liquid scintillation assays. The compound binding IC50... 50 IC 90 The results were obtained using Prism and are shown in Table 2.

[0374] Table 2. In vitro binding activity of the compounds of this invention against human GnRHR

[0375]

[0376] Conclusion: The compounds of this invention have a significant binding ability to human GnRHR.

[0377] Experimental Example 3. hERG Test

[0378] Cells: CHO cells stably expressing human hERG potassium channels (Shanghai WuXi AppTec Co., Ltd.)

[0379] Reagents: Physiological Solution (PH=7.4): NaCl 140mM, KCl 4mM, CaCl2 2mM, MgCl2 1mM, Glucose 5mM, HEPES 10mM, Osmolarity ~298mOsm; External Solution (PH=7.4): NaCl 80mM, KCl 4mM, CaCl2 2mM, MgCl2 1mM, Glucose 5mM, NMDG 60mM, HEPES10mM, Osmolarity ~289 mOsm; Internal Solution (PH=7.4): NaCl 10mM, KCl 10mM, KF110mM, HEPES 10mM, EGTA: 10 nM, Osmolarity ~280 mOsm.

[0380] Equipment: QPatch high-throughput fully automated patch clamp system, Sophion.

[0381] Methods: CHO cells stably expressing human hERG potassium channels were digested using TrypLE and resuspended in physiological solutions for later use. Single-cell high-impedance sealing and whole-cell pattern formation were automated using Qpatch. The cell clamping voltage was set at -80 mV, followed by an 80 ms decrease to -50 mV, and then a 4800 ms increase to +20 mV to open the hERG channels. The voltage was then reduced to -50 mV for 5000 ms for data collection and analysis, before finally returning to the clamping voltage (-80 mV, 1000 ms). This process was repeated every 20000 ms. First, 40 μL of solvent control (External Solution + DMSO) was added, and baseline data was collected after 300 ms. Then, 40 μL of different concentrations of the test compound were added, and the test was performed for at least 300 ms. The compounds were dissolved in DMSO, and tested at concentrations of 0.30 μM, 1.00 μM, 3.00 μM, 10.00 μM, and 30.00 μM. hERG assay IC 50 The data was analyzed using DataControl, Excel 2013, and Prism, and the results are shown in Table 3.

[0382] Table 3. Inhibitory effects of the compounds of this invention on human hERG potassium ion channels.

[0383]

[0384] Conclusion: Compounds 1, 2, 2A, 4, 5, 6, 7, and 8A exhibit inhibitory activity against human hERG potassium channels equal to or less than that of Relugolix, suggesting that the compounds of this invention possess lower cardiotoxicity.

[0385] Experimental Example 4. Evaluation of Hepatic Microsomal Metabolic Stability

[0386] Liver microsomes: rat liver microsomes, human liver microsomes

[0387] Reagents: NADPH, Roche Diagnostics Gmbh; ACN, Merck Chemical; Tolbutamide, Sigma.

[0388] Instruments: Pure water system, Millipore; Electronic balance, Mettel TOLEDO; High-speed benchtop centrifuge, Thermo; Water bath constant temperature shaker, Shanghai Yiheng Technology Co., Ltd.; Vortex shaker, Thermo; LC-MS / MS, AB SCIEX.

[0389] Methods: The metabolic stability of the analytes was evaluated using SD rat and human liver microsomes. The analytes were incubated with liver microsomes of different species at 37°C with NADPH. The reaction was terminated at specified time points by adding cold acetonitrile solution containing Tolbutamide internal standard. Samples were pretreated and then semi-quantitatively analyzed by LC-MS / MS. The retention times of the analytes and Tolbutamide internal standard, chromatographic acquisition, and chromatographic integration were performed using Analyst software (AB Sciex, Framingham, Massachusetts, USA). The in vitro elimination rate constant Ke was obtained by converting the ratio of the sample peak area to the internal standard peak area into a residual percentage. The in vitro clearance rate and half-life of the analytes were calculated, and the results are shown in Table 4.

[0390] Table 4. Results of the metabolic stability of the compounds of the present invention in the liver microsomes of rats and humans.

[0391]

[0392] Conclusion: Compounds 4 and 5 showed low clearance rates in the liver microsomes of SD rats, while the remaining compounds showed moderate clearance rates. In the liver microsomes of humans, compound 3 showed moderate clearance rates, while the remaining compounds showed low clearance rates.

[0393] Experimental Example 5. Evaluation of the permeability of the analyte and the substrate of the transporter

[0394] Cells: Caco-2 cells

[0395] Instruments: Pure water system, ELGA LabWate; Biosafety cabinet, NUAIRE; Constant temperature CO2 incubator, Thermo; Microplate reader, PerkinElmer; LC-MS / MS, AB SCIEX.

[0396] Methods: The bidirectional permeability of analytes was determined and efflux was assessed using a Caco-2 monolayer cell model. Caco-2 cells were seeded in 96-well cell culture plates and cultured for 28 days before being used for the transport assay. Analytes were administered bidirectionally. After 120 minutes of incubation, samples from the apical (A), basal (B), and lysed cells were collected. The concentration of analytes in the samples was quantitatively determined using liquid chromatography-tandem mass spectrometry (LC / MS / MS). The apparent permeability coefficients (Papp) in the apical-to-basal (AB) and basal-to-apical (BA) directions, as well as the efflux rate, were calculated based on the analyte concentrations. The results are shown in Table 5.

[0397] Table 5. Permeability results of the compounds of this invention in Caco-2 cells.

[0398]

[0399] Conclusion: Compared with Relugolix, most of the compounds of this invention showed improved permeability in Caco-2 cell experiments, with compound 2 showing a nearly 6-fold improvement in efflux rate.

[0400] Experimental Example 6. Pharmacokinetics and Tissue Distribution Study in SD Rats

[0401] Rats: Male SD rats, 200-250g

[0402] Instruments: Pure water system, Millipore; Electronic balance, Mettel TOLEDO; High-speed benchtop centrifuge, Thermo; Water bath constant temperature shaker, Shanghai Yiheng Technology Co., Ltd.; Vortex shaker, Thermo; LC-MS / MS, AB SCIEX.

[0403] Methods: All compounds were prepared using DMSO and 20% solvent. In the pharmacokinetic studies, the intravenous (iv) dose was 1 mg / kg, and the gavage (ig) dose was 12 mg / kg, with 3 rats in each group. Blood samples were collected from the orbital sinus at set time points before (0 h) and after administration. In the tissue distribution study, the rats were administered 12 mg / kg via gavage. Following administration, the rats were anesthetized and dissected at set time points to collect cardiac blood. The pituitary gland was then perfused from the heart, with 3 rats at each time point. Plasma was placed in heparinized EP tubes and centrifuged at 13500 rpm for 10 min to separate the plasma. The pituitary gland was homogenized with water at a specific ratio. After pretreatment, the plasma and pituitary homogenates were analyzed by LC-MS / MS to determine the concentrations of the analytes in plasma and pituitary gland. The plasma drug concentration data were processed using WinNonlin™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software with a non-compartmental model. The following pharmacokinetic parameters were calculated using the logarithmic linear trapezoidal method: elimination phase half-life (T0). 1 / 2 The mean time of drug residence in the body from 0 to the end time point (MRT) 0-last The area under the time-plasma concentration curve from 0 to the end of the time period (AUC) 0-last ), initial concentration (C0) or maximum concentration C max Absolute bioavailability F. Results are shown in […]. Figures 1-2 and Tables 6-1, 6-2, and 6-3:

[0404] Table 6-1 Pharmacokinetic parameters of SD rats after intravenous administration

[0405]

[0406] Table 6-2 Pharmacokinetic parameters of SD rats after gavage administration

[0407]

[0408] Table 6-3 Distribution of pituitary tissue in SD rats after gavage administration (12 mg / kg)

[0409]

[0410] in conclusion:

[0411] (1) In the gavage administration group, the C of compound 1 max These were 30.7 times and 3.02 times that of Relugolix, compounds 1-9, respectively; the AUC of compound 1 exposure was... last These figures are 36.4 times and 8.80 times higher than those of Relugolix and compounds 1-9, respectively. The absolute bioavailability of compound 1 is 7.79 times and 4.10 times higher than that of Relugolix and compounds 1-9, respectively. The in vivo pharmacokinetic properties of compound 1 are significantly superior to those of Relugolix and compounds 1-9.

[0412] (2) In the gavage administration group, the C of compound 2 max AUC last The absolute bioavailability of compound 2 was 3.63 times, 2.45 times, and 3.47 times that of Relugolix, respectively; and 1.12 times, 0.96 times, and 3.14 times that of compound 2A, respectively. The concentrations of compound 2 in the pituitary gland at 1 h, 4 h, and 12 h were 2.38 times, 1.48 times, and 2.46 times that of Relugolix, respectively; and 8.04 times, 6.60 times, and 3.77 times that of compound 2A, respectively.

[0413] (3) In the gavage administration group, the C of compound 3 max AUC last The absolute bioavailability was 3.83 times, 4.08 times, and 3.19 times that of Relugolix, respectively.

Claims

1. The compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, ， in: X1 is independently selected from: O or S; X2 and X3 are each independently selected from: CR4 or N; X4 is independently selected from: CR 3c Or N; X5 is N; R1 is independently selected from: H, D, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; R2 is independently selected from: H, D, C1-C6 alkyl, and R 2a -O-substituted C1-C6 alkyl groups; R 2a Independently selected from: C1-C6 haloalkyl groups; R 3a R 3b R 3c R 3d R 3e Each is independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; R4 is independently selected from: H, D, halogen, -CN, -NO2, -NH2, -OH, -SH, -COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C3-C6 cycloalkyl; R5 is independently selected from: H, D, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and C1-C6 haloalkoxy.

2. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, wherein, R1 is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl.

3. The compound according to any one of claims 1 or 2, its pharmaceutically acceptable salt or stereoisomer, wherein, R2 is selected from C1-C6 alkyl groups or R 2a -O-substituted C1-C6 alkyl; wherein R2 is independently selected from methyl, ethyl, propyl, R 2a Independently selected from: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl.

4. The compound according to any one of claims 1-3, its pharmaceutically acceptable salt or stereoisomer, wherein, R 3a R 3b R 3c R 3d R 3e Each is independently selected from: H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

5. The compound according to any one of claims 1-4, its pharmaceutically acceptable salt or stereoisomer, wherein, R4 is independently selected from: H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1, 1-dimethylbutyl, 2, 2-dimethylbutyl, 3, 3-dimethylbutyl, 2-ethylbutyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3,3,3-trichloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy. tert-Butoxy, n-pentoxy, S-pentoxy, hexoxy, 2-ethylbutoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, S-pentylthio, hexylthio, 2-ethylbutylthio, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, tert-butylamino, n-pentylamino, S-pentylamino, hexylamino, 2-ethylbutylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

6. The compound according to any one of claims 1-5, its pharmaceutically acceptable salt or stereoisomer, wherein, R5 is independently selected from: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 1, 1-dimethylbutyl, 2, 2-dimethylbutyl, 3, 3-dimethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 3,3,3-trifluoroethyl, 3 3,3-Trichloroethyl, pentafluoroethyl, pentachloroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexoxy, 2-ethylbutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 3,3,3-trifluoroethoxy, 3,3,3-trichloroethoxy, pentafluoroethoxy, pentachloroethoxy.

7. The compound shown in formula (II), its pharmaceutically acceptable salt or stereoisomer, ， in: X1 is independently selected from: O or S; X2 and X3 are each independently selected from: CR4 or N; X5 is independently selected from: CH or N; R1 is independently selected from: H, D, C1-C6 alkyl; R2 is independently selected from: R 2a -O-substituted: methyl, ethyl, n-propyl, n-butyl; R 2a Independently selected from: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl; R 3a R 3e Each is independently selected from: H, D, fluorine, chlorine, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl; R4 is independently selected from: H, D, fluorine, chlorine, methoxy, ethoxy, n-propoxy, n-butoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, methylthio, ethylthio, n-propylthio, n-butylthio, methylamino, ethylamino, n-propylamino, n-butylamino. R5 is independently selected from: H, D, methyl, ethyl, n-propyl, n-butyl, methoxy, ethoxy, n-propoxy, n-butoxy.

8. A pharmaceutically acceptable salt or stereoisomer of a compound selected from: ， ， ， 。 9. A pharmaceutical composition comprising the compound of any one of claims 1-8, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

10. Use of the compound of any one of claims 1-8, its pharmaceutically acceptable salt or stereoisomer, or the pharmaceutical composition of claim 9 in the preparation of a medicament for treating hormone-dependent diseases.

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