Sulfonamide-substituted heteroaryl pyrimidinedione compounds and uses thereof

Abstract

The invention belongs to the field of pharmaceutical technology, and relates to sulfonamide-substituted heteroaryl pyrimidine dione compounds and uses thereof, as well as pharmaceutical compositions containing such compounds, which can be used as gonadotropin-releasing hormone receptor antagonists. It also relates to methods for preparing such compounds and pharmaceutical compositions, and their uses in preventing or treating sex hormone-dependent diseases, including but not limited to prostate cancer, endometriosis, uterine fibroids, precocious puberty and the like.

Description

Technical Field

[0001] 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 their methods of use and applications. In particular, this invention describes sulfonamide-substituted heteroarylpyrimidine dione compounds that can act as gonadotropin-releasing hormone receptor antagonists and their uses. Background Technology

[0002] The secretion of anterior pituitary hormones is controlled by feedback from peripheral hormones secreted from the target organs of the corresponding hormones, as well as from secretory-regulating hormones from the hypothalamus (the upper central organ of the anterior pituitary) (hereinafter, in this specification, 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, sometimes called LH-RH (luteinizing hormone-releasing hormone)). These hypothalamic hormones are thought to exert their effects through receptors believed to be located in the anterior pituitary; and efforts have been made to identify receptors specific to these hormones—including those expressed in humans. 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.

[0003] Currently known compounds with GnRH antagonistic activity are mostly peptide compounds, such as GnRH-derived linear peptides (US 5,140,009 and US 5,171,835), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol.36, pp.3265-3273(1993)), decapeptide compounds modified at positions 5 or 6 (WO9846634 A1), and decapeptide compounds modified at position 8 (EP 0277829B1), etc.

[0004] Peptide compounds present numerous unresolved issues related to oral absorption, dosage form, dose-volume relationship, drug stability, duration of action, and metabolic stability. Therefore, there is a strong need for oral GnRH antagonists, particularly those based on non-peptide compounds, that demonstrate excellent therapeutic efficacy for hormone-dependent diseases such as prostate cancer, endometriosis, and precocious puberty. These antagonists exhibit not only transient pituitary-gonadotropic effects (rapid action) but also superior oral absorption. Summary of the Invention

[0005] The following is a summary description of some aspects of the invention and is not intended to limit it. These aspects and other parts are described in more detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of any discrepancy between the disclosure in this specification and the cited references, the disclosure in this specification shall prevail.

[0006] This invention relates to a novel class of sulfonamide-substituted heteroarylpyrimidine dione compounds that exhibit unexpectedly excellent GnRH antagonistic activity and can be used as gonadotropin-releasing hormone receptor antagonists for the prevention or treatment of sex hormone-dependent diseases, including but not limited to prostate cancer, endometriosis, uterine fibroids, and precocious puberty.

[0007] The compounds of this invention are stable, have good safety, and possess pharmacodynamic and pharmacokinetic advantages, such as a good brain-plasma ratio, good bioavailability, or good metabolic stability, thus showing good prospects for clinical application.

[0008] The present invention also provides methods for preparing such compounds and pharmaceutical compositions containing such compounds.

[0009] On one hand, the present invention relates to a compound, which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

[0010]

[0011] Among them, R 1 R 2a R 2b R 2c R 2d R 3 R 4 R 5a R 5b R 5c R 5d R 5e Z and R have the meanings as described in this invention.

[0012] In some implementations, Z is NH, O, or S.

[0013] In some implementations, R is Where X, Y, V, R 6 and R 7 It has the meaning as described in this invention.

[0014] In some implementations, X is CH or N.

[0015] In some implementations, Y is CH or N.

[0016] In some implementations, V is CH or N.

[0017] In some implementation schemes, R 6 It can be H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl.

[0018] In some implementation schemes, R 7 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms.

[0019] In some implementation schemes, R 1 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms.

[0020] In some implementation schemes, each R 2a R 2b R 2c and R 2d Independently, it is H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1-C6 alkyl), -C(=O)-(C1-C6 alkoxy), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino or hydroxylated C1-C6 alkyl.

[0021] In some implementation schemes, R 3 and R 4 Each of the following can be independently H, D, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl, heteroaryl groups consisting of 5-10 atoms, C3-6 cycloalkyl C 1-6 Alkylene, (heterocyclic group consisting of 3-8 atoms) C 1-6 Alkylene, C 6-10 Aryl C 1-6 Alkylene or (5-10 atoms of heteroaryl) C 1-6 Alkylene.

[0022] In some implementation schemes, R 5a R 5b R 5c R 5d and R 5e Each of these can be independently represented as H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1-C6 alkyl), -C(=O)-(C1-C6 alkoxy), -NHS(=O)2C1-C6 alkyl, -N(C 1-6 Alkyl)S(=O)2C1-C6 alkyl, -S(=O)2C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 alkylamino, hydroxyl-substituted C1-C6 alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-8 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-10 atoms.

[0023] In some implementation schemes, R 6 It can be H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C1-C4 haloalkyl.

[0024] In other implementations, R 6 It can be H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, -CHF2 or -CF3.

[0025] In some implementation schemes, R 7 It is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0026] In other implementations, R 7It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

[0027] In some implementation schemes, R 1 C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyl-substituted C1-C4 alkyl, cyano-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C 6-10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0028] In other implementations, R 1 The following are the compounds: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, isopropoxy, -OCF3, hydroxymethyl, 2-hydroxyethyl, -CH2CN, -CH2 CH2CN, -CH2CH2CH2CN, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indole, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetraazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0029] In some implementation schemes, each R 2a R 2b R 2c and R 2dIndependently, it is H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1-C4 alkyl), -C(=O)-(C1-C4 alkoxy), C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylamino or hydroxylated C1-C4 alkyl.

[0030] In other implementations, each R 2a R 2b R 2c and R 2d Independently, it is H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-CH3, -C(=O)-OCH3, methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF2, -CF3, methoxy, -OCF3, methylamino, dimethylamino, or hydroxymethyl.

[0031] In some implementation schemes, R 3 and R 4 Each of the following can be independently H, D, -OH, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C 6-10 aryl, heteroaryl composed of 5-6 atoms, C 3-6 cycloalkyl C 1-4 Alkylene, (heterocyclic group consisting of 3-6 atoms) C 1-4 Alkylene, C 6-10 Aryl C 1-4 Alkylene or (5-6 atoms of heteroaryl) C 1-4 Alkylene.

[0032] In other implementations, R 3 and R 4Each of the following is independently represented by H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylpropyl, 1-methylpropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, -CHF2, -CF3, methoxy, ethoxy, isopropoxy, -OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, indole, naphthyl, pyrrolidinyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, C 3-6 Cycloalkylmethylene, C 3-6 Cycloalkyl ethylene, C 3-6 Cycloalkylpropylidene, (heterocyclic group composed of 3-6 atoms)methylene, (heterocyclic group composed of 3-6 atoms)ethylidene, phenylmethylene, phenylethylidene, phenylpropylidene, pyridylmethylene, pyrimidinylmethylene, pyrrolylmethylene, pyrazolylmethylene, triazolylmethylene or tetrazolylmethylene.

[0033] In some implementation schemes, R 5a R 5b R 5c R 5d and R 5e Each of the following is independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-(C1-C4 alkyl), -C(=O)-(C1-C4 alkoxy), -S(=O)2C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylamino or hydroxylated C1-C4 alkyl.

[0034] In other implementations, R 5a R 5b R 5c R 5d and R 5e Each of the following can be independently H, D, F, Cl, Br, I, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-CH3, -C(=O)-OCH3, -S(=O)2CH3, methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, -CHF2, -CF3, methoxy, -OCF3, methylamino, dimethylamino, or hydroxymethyl.

[0035] In some embodiments, the compound of the present invention is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0036]

[0037] Among them, R 1 R 3 R 4 R 6 R 7 X and Y have the meanings as described in this invention.

[0038] In some embodiments, the compound of the present invention is a compound of formula (III) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0039]

[0040] Among them, R 1 R 3 R 4 R 6 R 7 V has the meaning as described in this invention.

[0041] In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof:

[0042]

[0043]

[0044] On the other hand, the present invention relates to a pharmaceutical composition comprising the compounds disclosed herein.

[0045] In some embodiments, the pharmaceutical composition of the present invention further comprises pharmaceutically acceptable excipients, carriers, adjuvants, or any combination thereof.

[0046] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions disclosed herein in the preparation of a medicament for the prevention or treatment of hormone-dependent diseases.

[0047] In some embodiments, the sex hormone-dependent diseases described in this invention are sex hormone-dependent cancers, bone metastases of sex hormone-dependent cancers, benign prostatic hyperplasia, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polyatrial ovary syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, benign or malignant tumors or hot flashes that are not hormone-dependent and sensitive to LH-RH (luteinizing hormone-releasing hormone).

[0048] On the one hand, the present invention relates to the use of the compounds or pharmaceutical compositions disclosed herein in the preparation of a medicament, which may be used as a reproduction regulator, a contraceptive, an ovulation inducer, or for the prevention of postoperative recurrence of hormone-dependent cancers.

[0049] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions disclosed in the present invention in the preparation of a medicament for antagonizing gonadotropin-releasing hormone (GnRH).

[0050] On the other hand, the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I), formula (II) or formula (III).

[0051] Biological test results show that the compound of the present invention has strong antagonistic activity against gonadotropin-releasing hormone (GnRH), therefore the compound provided by the present invention can be used as a better GnRH antagonist.

[0052] Any embodiment of any aspect of the present invention may be combined with other embodiments, provided that they do not contradict each other. Furthermore, any technical feature in any embodiment of any aspect of the present invention may be applied to the same technical feature in other embodiments, provided that they do not contradict each other.

[0053] Detailed Description of the Invention

[0054] Definitions and general terms

[0055] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0056] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0057] Unless otherwise stated, the following definitions as used in this invention shall apply. For the purposes of this invention, chemical elements are consistent with the periodic table (CAS edition) and the *Handbook of Chemistry and Physics*, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 1999, and *March's Advanced Organic Chemistry* by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0058] Unless otherwise stated or there is an obvious conflict in the context, the articles “a,” “an,” and “described” as used in this invention are intended to include “at least one” or “one or more.” Therefore, these articles as used in this invention refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or employed in the embodiments described.

[0059] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0060] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and hindered isomers, etc.

[0061] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0062] "Pharmaceutical acceptable" means compounds, ingredients, compositions, and / or dosage forms that, within the bounds of reasonable medical judgment, are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0063] The term "optionally substituted by" can be used interchangeably with the term "unsubstituted or substituted by," meaning that the structure is unsubstituted or substituted by one or more substituents as described in this invention. Substituents as described in this invention include, but are not limited to, D, F, Cl, Br, I, N3, -CN, -NO2, -NH2, -OH, -SH, -COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C =O)-alkyl, -C(=O)-alkoxy, -NHS(=O)2-alkyl, -N(alkyl)S(=O)2-alkyl, -S(=O)2-alkyl, alkyl, alkoxy, alkylthio, alkylamino, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, cyano-substituted alkyl, amino-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkyl-alkylene, heterocyclic-alkylene, aryl-alkylene, heteroaryl-alkylene, etc.

[0064] In various parts of this specification, the substituents of the disclosed compounds are disclosed according to the type or range of groups. In particular, the invention includes every independent sub-combination of the members of these types and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0065] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0066] The terms “halogen” and “halogenated” are used interchangeably in this invention and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0067] As used in this invention, the term "alkyl" or "alkyl group" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1-20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 1-6 carbon atoms; in other embodiments, the alkyl group contains 1-4 carbon atoms; and in still some embodiments, the alkyl group contains 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2(2-methylpropyl)), sec-butyl (s-Bu, -CH(CH3)CH2CH3(1-methylpropyl)), tert-butyl (t-Bu, -C(CH3)3), and so on.

[0068] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon. Unless otherwise specified, the alkylene group contains 1-10 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, it contains 1-4 carbon atoms; and in still other embodiments, it contains 1-2 carbon atoms. Examples of such groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), and so on. The alkylene group may optionally be substituted with one or more substituents described in this invention.

[0069] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2The double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "trans", or the orientation of "E" and "Z". In one embodiment, the alkenyl group comprises 2-8 carbon atoms; in another embodiment, the alkenyl group comprises 2-6 carbon atoms; in yet another embodiment, the alkenyl group comprises 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propenyl, -CH=CH-CH3), etc.

[0070] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; and in yet another embodiment, the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH3), and so on.

[0071] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; and in still other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-propoxy, n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (isopropoxy, i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and so on.

[0072] The term "alkathio" indicates that an alkyl group is attached to the remainder of the molecule by a sulfur atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkathio group contains 1-12 carbon atoms. 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), etc.

[0073] 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. Suitable alkylamino groups can be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N-dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc. The alkylamino group may optionally be replaced by one or more substituents described in this invention.

[0074] The term "hydroxy-substituted alkyl" means that an alkyl group is replaced by one or more hydroxyl groups (-OH), wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the hydroxy-substituted alkyl group contains 1-12 carbon atoms. In some embodiments, the hydroxy-substituted alkyl group contains 1-6 carbon atoms, for example, hydroxy-substituted C1-C6 alkyl; in other embodiments, the hydroxy-substituted alkyl group contains 1-4 carbon atoms, for example, hydroxy-substituted C1-C4 alkyl; and in still other embodiments, the hydroxy-substituted alkyl group contains 1-3 carbon atoms, for example, hydroxy-substituted C1-C3 alkyl. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxypropyl, etc.

[0075] The term "cyano-substituted alkyl" means that an alkyl group is replaced by one or more cyano groups (-CN), wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the cyano-substituted alkyl group contains 1-12 carbon atoms. In some embodiments, the cyano-substituted alkyl group contains 1-6 carbon atoms, for example, cyano-substituted C1-C6 alkyl; in other embodiments, the cyano-substituted alkyl group contains 1-4 carbon atoms, for example, cyano-substituted C1-C4 alkyl; and in still other embodiments, the cyano-substituted alkyl group contains 1-3 carbon atoms, for example, cyano-substituted C1-C3 alkyl. Such examples include, but are not limited to, cyanomethyl (-CH2CN), cyanoethyl (e.g., 2-cyanoethyl, -CH2CH2CN), 2-cyano-1-propyl (-CH2CH(CN)CH3), 3-cyano-1-propyl (-CH2CH2CH2CN), 2,3-dicyanopropyl (-CH2CH(CN)CH2CN), etc.

[0076] The term "amino-substituted alkyl" means that an alkyl group is replaced by one or more amino groups (-NH2), wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the amino-substituted alkyl group contains 1-12 carbon atoms. In some embodiments, the amino-substituted alkyl group contains 1-6 carbon atoms, for example, amino-substituted C1-C6 alkyl; in other embodiments, the amino-substituted alkyl group contains 1-4 carbon atoms, for example, amino-substituted C1-C4 alkyl; and in still other embodiments, the amino-substituted alkyl group contains 1-3 carbon atoms, for example, amino-substituted C1-C3 alkyl. Such examples include, but are not limited to, aminomethyl (-CH2NH2), aminoethyl (e.g., 2-aminoethyl, -CH2CH2NH2), 2-amino-1-propyl (-CH2CH(NH2)CH3), 3-amino-1-propyl (-CH2CH2CH2NH2), 2,3-diaminopropyl (-CH2CH(NH2)CH2NH2), and so on.

[0077] The terms "haloalkyl" or "haloalkoxy" indicate that an alkyl or alkoxy group is substituted by one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described in this invention. Examples of such groups include, but are not limited to, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CHF2, -CH2CF3, -CH2CF2CHF2, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CHF2, -OCH2CF3, -OCH2CF2CHF2, etc. In some embodiments, C1-C6 haloalkyl comprises fluorinated C1-C6 alkyl groups; in other embodiments, C1-C4 haloalkyl comprises fluorinated C1-C4 alkyl groups; and in still other embodiments, C1-C2 haloalkyl comprises fluorinated C1-C2 alkyl groups.

[0078] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 ring carbon atoms. In some embodiments, the cycloalkyl group comprises 3 to 10 ring carbon atoms, such as C1. 3-10 cycloalkyl; in other embodiments, the cycloalkyl group comprises 3-8 cyclic carbon atoms, such as C 3-8 Cycloalkyl; in some further embodiments, the cycloalkyl group comprises 3-6 cyclic carbon atoms, such as C16... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Wherein, as described in this invention, C 3-8 Cycloalkyl groups include C 3-6 cycloalkyl; the C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups may optionally be substituted by one or more substituents described in this invention.

[0079] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms; wherein the heterocyclic group is non-aromatic and does not contain any aromatic ring. Unless otherwise stated, the heterocyclic group can be carbonyl or nitrogenyl, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. The term "heterocyclic group" may be used interchangeably with the term "heterocycle." As described in this invention, the heterocyclic group may consist of 3-8 atoms or 3-6 atoms, wherein the atoms are optionally selected from C, N, O, or S and at least one atom is N, O, or S; wherein the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms; the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms. Specifically, the heterocyclic group consisting of 3-6 atoms includes, but is not limited to, ethylene oxide, aziridine, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl. The heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0080] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring is aromatic and has one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups may include phenyl, indenyl, 2,3-dihydro-1H-indenyl, naphthyl, and anthraceneyl. The aryl group may optionally be substituted with one or more substituents described in this invention. Unless otherwise stated, the group "C"... 6-10 "Aryl" indicates an aryl group containing 6-10 cyclic carbon atoms.

[0081] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system containing 5-12, 5-10, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains 1, 2, 3, or 4 heterocyclic atoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl group has one or more attachment sites attached to the remainder of the molecule. When a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-. Unless otherwise stated, the heteroaryl group may be attached to the remainder of the molecule (e.g., the main structure in the general formula) through any reasonable site (which may be C or N). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group may optionally be replaced by one or more substituents described in this invention. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms, indicating that the heteroaryl group contains 1-9 cyclic carbon atoms and 1, 2, 3 or 4 cyclic heteroatoms selected from O, S and N; in other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms, indicating that the heteroaryl group contains 1-5 cyclic carbon atoms and 1, 2, 3 or 4 cyclic heteroatoms selected from O, S and N; examples of heteroaryl groups consisting of 5-6 atoms include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, etc.

[0082] The term "composed of jk atoms" indicates that the cyclic group is composed of jk ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, and P; j and k are each independently any non-zero natural number, and k > j; "jk" includes j, k, and any natural number between them. For example, "composed of 3-8 atoms", "composed of 3-6 atoms", "composed of 5-10 atoms", or "composed of 5-6 atoms" indicates that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, and P.

[0083] The terms "cycloalkylalkylene", "heterocyclic alkylene", "aryl alkylene", and "heteroaryl alkylene" refer to the fact that each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is independently linked to the remainder of the molecule via an alkylene group, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl, and alkylene groups all have the meanings described in this invention. Examples of aryl alkylene groups include, but are not limited to, phenylmethylene, phenylethylene, and phenylpropylene. Each of the cycloalkylalkylene, heterocyclic alkylene, aryl alkylene, and heteroaryl alkylene groups may optionally be independently substituted by one or more substituents described in this invention.

[0084] As used in this invention, the term "prodrug" refers to the conversion of a compound into a compound represented by formula (I), (II), or (III) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group.

[0085] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0086] The term "pharmaceutically acceptable salt" as used in this invention refers to both organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts obtained by other methods described in the literature, such as ion exchange. This invention also contemplates the formation of quaternary ammonium salts from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates, and aromatic sulfonates.

[0087] In this invention, "solvent" refers to an association formed by one or more solvent molecules and a compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0088] When the solvent is water, the term "hydrate" may be used. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; and in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound.

[0089] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0090] The term “prevention” or “avoidance” refers to the reduction of the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but has not yet experienced or exhibited symptoms of the disease).

[0091] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0092] Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of this invention are included within the scope of this invention.

[0093] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0094] The nitrogen oxides of the compounds of this invention are also included within the scope of this invention. The nitrogen oxides of the compounds of this invention can be prepared by oxidizing the corresponding nitrogen-containing basic substances in the presence of an acid, such as acetic acid, using a common oxidizing agent (e.g., hydrogen peroxide) at elevated temperature, or by reacting with a peracid in a suitable solvent, such as with peracetic acid in dichloromethane, ethyl acetate, or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0095] The compounds shown in formula (I), (II), or (III) may be present in the form of salts. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with other components comprising the formulation and / or the mammals treated therein. In other embodiments, the salt is not necessarily a pharmaceutically acceptable salt and may be an intermediate used for the preparation and / or purification of the compounds shown in formula (I), (II), or (III) and / or for the isolation of enantiomers of the compounds shown in formula (I), (II), or (III).

[0096] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 I.

[0097] On the other hand, the present invention relates to intermediates for preparing compounds of formula (I), formula (II) or formula (III).

[0098] Pharmaceutical compositions, formulations and administration of the compounds of the present invention

[0099] This invention provides a pharmaceutical composition comprising a compound of formula (I), formula (II), or formula (III) or a stereoisomer thereof, a racemic or non-racemic mixture of the isomers, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, or excipient, and optionally, other therapeutic and / or preventative components.

[0100] Suitable carriers, excipients, and formulations are well known to those skilled in the art and described in detail, for example, Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004), Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al., Remington: The Science and Practice of Pharmacy (2000), Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005), Pharmaceutical Press, Chicago.

[0101] It should also be recognized that, when used for therapeutic purposes, certain compounds of the present invention may be present in free form, or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or any other adducts or derivatives that, when administered to a patient in need, directly or indirectly provide the compounds of the present invention or their metabolites or residues.

[0102] Suitable pharmaceutically acceptable excipients vary depending on the specific dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their specific function in the composition. Suitable pharmaceutically acceptable excipients include the following types: diluents, fillers, binders, disintegrants, lubricants, flow aids, granulators, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will recognize that some pharmaceutically acceptable excipients can provide more than one function and offer alternative functions, depending on the amount of that excipient present in the formulation and the other excipients present in the formulation.

[0103] The pharmaceutical compositions disclosed in this invention are prepared using techniques and methods known to those skilled in the art. Descriptions of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0104] Therefore, on the other hand, the present invention relates to a process for preparing pharmaceutical compositions comprising the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, adjuvants, solvents, or combinations thereof, wherein the process includes mixing various components. Pharmaceutical compositions comprising the compounds disclosed herein can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

[0105] The compounds disclosed in this invention are generally formulated into dosage forms suitable for administration to patients via desired routes. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, sac tablets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and sachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0106] In some embodiments, the compounds disclosed in this invention can be formulated into oral dosage forms. In other embodiments, the compounds disclosed in this invention can be formulated into inhaled dosage forms. In still other embodiments, the compounds disclosed in this invention can be formulated into nasal dosage forms. In yet another embodiment, the compounds disclosed in this invention can be formulated into transdermal dosage forms. In still some embodiments, the compounds disclosed in this invention can be formulated into topical dosage forms.

[0107] The pharmaceutical compositions provided by this invention can be provided as compressed tablets, prepared tablets, chewable tablets, instant tablets, recompressed tablets, enteric-coated tablets, sugar-coated tablets, or film-coated tablets.

[0108] The pharmaceutical composition provided by this invention can be provided in soft capsules or hard capsules, and can be prepared from gelatin, methylcellulose, starch or calcium alginate.

[0109] The pharmaceutical compositions provided by this invention can be administered parenterally via injection, infusion, or implantation for local or systemic drug delivery. Parenterial delivery methods used in this invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0110] The pharmaceutical compositions provided by this invention can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for preparation as solutions or suspensions in liquids prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, ibid.).

[0111] On the other hand, the pharmaceutical compositions disclosed in this invention can be formulated into any dosage form suitable for inhalation administration to patients, such as dry powder, aerosol, suspension or solution composition.

[0112] Pharmaceutical compositions suitable for transdermal delivery can be formulated as discontinuous patches intended to maintain close contact with the patient's epidermis for an extended period of time. For example, the active ingredient can be delivered from the patch via iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318(1986).

[0113] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

[0114] Uses of the compounds and pharmaceutical compositions of the present invention

[0115] The compounds and pharmaceutical compositions provided by this invention exhibit excellent GnRH antagonistic activity and low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, and carcinogenicity). Furthermore, the compounds or pharmaceutical compositions are excellent in terms of oral absorption, duration of action, stability, and pharmacokinetics. In addition, the compounds or pharmaceutical compositions are rarely affected by plasma components. Therefore, the compounds or pharmaceutical compositions of this invention can be safely used in mammals (e.g., humans, monkeys, cattle, horses, dogs, cats, rabbits, rats, and mice) to control plasma sex hormone concentrations by utilizing GnRH receptor antagonism to inhibit gonadotropin secretion, thereby preventing and / or treating diseases dependent on male or female hormones and diseases caused by excess of these hormones.

[0116] Specifically, the compounds or pharmaceutical compositions of the present invention are suitable for the prevention and / or treatment of hormone-dependent cancers (e.g., prostate cancer, uterine cancer, breast cancer, pituitary adenoma, etc.), bone metastases of hormone-dependent cancers, benign prostatic hyperplasia, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease (Alzheimer's disease, Alzheimer's type, and mixed types of senile dementia), etc. The compounds of the present invention are also suitable for regulating male and female reproduction (e.g., pregnancy regulators and menstrual cycle regulators, etc.). The compounds or pharmaceutical compositions of the present invention can also be used as male or female contraceptives or as female ovulation inducers. Based on the rebound effect after discontinuation, the compounds or pharmaceutical compositions of the present invention can be used to treat infertility. Furthermore, the compounds or pharmaceutical compositions of the present invention can be used as agents for the prevention and / or treatment of hormone-independent and LH-RH-sensitive benign or malignant tumors. Furthermore, the compounds or pharmaceutical compositions of the present invention can be used as agents for the prevention and / or treatment of irritable bowel syndrome and for the prevention of postoperative recurrence of hormone-dependent cancers (agents for the prevention of postoperative recurrence of prostate cancer; agents for the prevention of postoperative recurrence of breast or ovarian cancer before or after menopause; particularly agents for the prevention of postoperative recurrence of breast or ovarian cancer before menopause).

[0117] Furthermore, the compounds or pharmaceutical compositions of the present invention are suitable for regulating estrus in livestock, improving meat quality, and promoting animal growth. The compounds of the present invention are also suitable as fish spawning promoters.

[0118] The compounds or pharmaceutical compositions of the present invention can also be used to inhibit the transient increase in plasma testosterone concentration (flare phenomenon), a transient increase in plasma testosterone concentration observed upon administration of GnRH superagonists such as leuprorelin acetate. The compounds of the present invention can be used in combination with superagonists such as leuprorelin acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin, and lecirelin. Leuprorelin acetate is particularly preferred.

[0119] The compounds or pharmaceutical compositions of the present invention may also be used, particularly advantageously, in combination with at least one selected from the group consisting of steroidal or non-steroidal anti-androgen or anti-estrogen agents, chemotherapeutic agents, GnRH antagonistic peptides, α-reductase inhibitors, α-receptor inhibitors, aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, adrenal androgen production inhibitors, kinase inhibitors, hormone therapy drugs, and drugs that inhibit cell growth factors or their receptors.

[0120] The aforementioned "chemotherapy agents" include ifosfamide, adriamycin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT, methotrexate, mitomycin C, and mitoxantrone. The aforementioned "GnRH antagonist peptides" include non-oral GnRH antagonist peptides, such as cetrorelix, ganirelix, and abarelix.

[0121] The compounds and pharmaceutical compositions of the present invention, in addition to their therapeutic benefits for humans, can also be used in veterinary treatment of mammals, including pets, introduced breeds of animals, and farm animals. Other examples of animals include horses, dogs, and cats. Herein, the compounds of the present invention include their pharmaceutically acceptable derivatives.

[0122] In some embodiments, the compounds disclosed in this invention, or pharmaceutical compositions comprising the compounds disclosed in this invention, may be administered once, or, according to a dosing regimen, administered several times at different time intervals within a specified time period. The compounds disclosed in this invention may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of this invention may be administered separately to other therapeutic agents via the same or different routes of administration, or administered with them in the same pharmaceutical composition.

[0123] General synthesis steps

[0124] Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0125] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I), (II), or (III). The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0126] Those skilled in the art will recognize that the chemical reactions described herein can be suitably used to prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-illustrative compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described herein, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of the present invention.

[0127] The examples described below, unless otherwise stated, all temperatures are in degrees Celsius. Reagents were purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0128] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after prior drying with anhydrous sodium sulfate.

[0129] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0130] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0131] 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. 1¹H NMR spectra were performed using CDCl3, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks occur, the following abbreviations are used: s (single), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), ddd (doublet of doublets), ddt (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), td (triple doublet), tt (triple triplet), qd (quartet of doublets). The coupling constant J is expressed in Hertz (Hz).

[0132] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 × 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL / min; mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, detection by UV.

[0133] Pure compounds were detected using UV at 210 nm / 254 nm using an Agilent 1260 pre-HPLC or a Calesep pump 250 pre-HPLC (column model: NOVASEP 50 / 80 mm DAC).

[0134] The following abbreviations are used throughout this invention:

[0135] DMF N,N-dimethylformamide mmol millimole

[0136] CDC13 Deuterated chloroform nM, nmol / L (nanomoles per liter)

[0137] DMSO (dimethyl sulfoxide, M, mol / L)

[0138] DMSO-d6 deuterated dimethyl sulfoxide mg

[0139] AIBN (azobisisobutyronitrile) g g

[0140] NBS N-bromosuccinimide kg

[0141] EA (ethyl acetate) mL, ml

[0142] DCM dichloromethane μL, μl microliter

[0143] Saline, physiological saline, Pd / C, palladium / carbon

[0144] PEG400 (min) Polyethylene Glycol 400

[0145] h Hours EDTA-K2 Dipotassium Ethylenediaminetetraacetate

[0146] Pyridine rt, RT room temperature

[0147] The following synthetic methods describe the steps for preparing the compounds disclosed in this invention, unless otherwise stated, wherein R 1 R 6 R 7 X, Y, and V have the definitions described in this invention.

[0148] Intermediate preparation scheme 1

[0149] Mode( 11 The intermediate compound shown in formula () can be prepared by the following process: 1 The compound shown is similar to the compound of formula ( 2 The reaction of ethyl cyanoacetate as shown in the figure yields the product of formula ( 3 The compound shown in formula (); then the compound shown in formula () 3 The compound shown in the figure undergoes cyclization under the action of sulfur powder to obtain the compound of formula ( 4 The compound shown in formula () 4 The compound shown in the figure reacts with ethyl chloroformate to give the product of formula ( 5 The compound shown in formula () 5 The compound shown in the formula () and the compound of formula () 6 The compound shown reacts to obtain the compound of formula ( 7 The compound shown in the formula ( 7 The compound shown in the figure was brominated to obtain the compound of formula ( 8 The compound shown in formula () 8 The compound shown is similar to the compound of formula ( 9 The reaction of the compound shown in the figure yields the compound of formula ( 10 The compound shown in formula ()10 The compound shown in the figure was obtained by ester hydrolysis to obtain the compound of formula ( 11 The intermediate compound shown in the figure.

[0150]

[0151] Synthesis Scheme 1

[0152] Mode( 17 The compound shown in formula () can be prepared by the following process: 11 The compound shown is similar to the compound of formula ( 12 The reaction of the compound shown in the figure yields the compound of formula ( 13 The compound shown in the formula ( 13 The compound shown in the figure has been cyclized to obtain formula ( 14 The compound shown in the formula ( 14 The nitro reduction of the compound shown in the figure yields the compound of formula ( 15 The compound shown in the formula ( 15 The compound shown is similar to the compound of formula ( 16 The compound shown reacts to give ( 17 The target product is shown in the figure.

[0153]

[0154] Synthesis Scheme 2

[0155] Mode( 17’ The compound shown in formula () can be prepared by the following process: 11 The compound shown is similar to the compound of formula ( 12’ The reaction of the compound shown in the figure yields the compound of formula ( 13’ The compound shown in the formula ( 13’ The compound shown in the figure has been cyclized to obtain formula ( 14’ The compound shown in the formula ( 14’ The nitro reduction of the compound shown in the figure yields the compound of formula ( 15’ The compound shown in the formula ( 15’ The compound shown is similar to the compound of formula ( 16 The compound shown reacts to give ( 17’ The target product is shown in the figure.

[0156]

[0157] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention. Example

[0158] Example 1 Synthesis of N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-(3-methoxyureo)phenyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)-N-methylmethanesulfonamide

[0159]

[0160] Step 1: Synthesis of ethyl (E / Z)-2-cyano-3-methyl-4-(4-nitrophenyl)butyl-2-enoate

[0161]

[0162] p-Nitrophenylacetone (5.3 g, 29.6 mmol) and ethyl cyanoacetone (9.64 mL, 88.8 mmol) were added to a 250 mL single-necked round-bottom flask, followed by n-heptanoic acid (4.37 mL, 29.6 mmol), benzylamine (3.6 mL, 32 mmol), and toluene (50 mL). The flask was connected to a water separator, and the reaction was carried out at 130 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, evaporated to dryness under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 18 / 1) to give the title compound as a pale yellow oil (7.24 g, 89.2%).

[0163] MS(ESI,neg.ion)m / z:273.3[MH] - ;

[0164] Step 2) Synthesis of ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ester

[0165]

[0166] Ethyl (E / Z)-2-cyano-3-methyl-4-(4-nitrophenyl)butyl-2-enoate (7.2 g, 26.2 mmol), sulfur powder (1.68 g, 52.4 mmol), and ethanol (80 mL) were added to a 250 mL single-necked round-bottom flask. Diethylamine (6.8 mL, 65 mmol) was added, and the mixture was stirred for 15 minutes. The mixture was then transferred to 65 °C and the reaction was continued for 3 hours. The reaction was stopped, cooled to room temperature, and evaporated under reduced pressure. The mixture was purified by column chromatography (petroleum ether / dichloromethane (v / v) = 5 / 1) to give the title compound as a brownish-red solid (5.23 g, 65.1%).

[0167] MS(ESI,pos.ion)m / z:307.1[M+H] + ;

[0168] 1H NMR (600MHz, CDCl3) δ (ppm) 8.22 (d, J = 8.9Hz, 2H), 7.48 (d, J = 8.9Hz, 2H), 6.27 (s, 2H), 4.33 (q, J = 7.1Hz, 2H), 2.40 (s, 3H), 1.38 (t, J = 7.1Hz, 3H).

[0169] Step 3) Synthesis of ethyl 2-((ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ester become

[0170]

[0171] Ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ester (12 g, 39.2 mmol), pyridine (11 mL, 140 mmol), and dichloromethane (100 mL) were added to a 250 mL single-necked round-bottom flask at 25 °C. Ethyl chloroformate (6.7 mL, 70 mmol) was added, and the mixture was stirred for 2 hours. The reaction was stopped, water (50 mL) was added, the mixture was separated, the organic phase was collected, anhydrous sodium sulfate (1.5 g) was added, and the mixture was dried. The filtrate was evaporated to dryness under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 12 / 1) to give the title compound as a pale yellow solid (10.2 g, 68.8%).

[0172] MS(ESI,pos.ion)m / z:379.1[M+H] + .

[0173] Step 4) Ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thia Synthesis of phen-3-carboxylic acid esters

[0174]

[0175] Ethyl 2-((ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ester (21.4 g, 56.6 mmol), potassium iodide (18.8 g, 113 mmol), potassium carbonate (15.8 g, 113 mmol), and DMF (120 mL) were added to a 500 mL single-necked round-bottom flask at 25 °C. Then, 2,6-difluorobenzyl chloride (18.4 g, 113 mmol) was added, and the reaction was continued for 12 hours. The reaction was stopped, quenched with water (150 mL), and then extracted with dichloromethane (100 mL). The extract was dried over anhydrous sodium sulfate (2 g). The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1) to give the title compound as a pale yellow solid (24.2 g, 84.8%).

[0176] MS(ESI,pos.ion)m / z:505.1[M+H] + .

[0177] Step 5) Ethyl 4-(bromomethyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-5-(4-nitrobenzene) Synthesis of thiophene-3-carboxylic acid ester

[0178]

[0179] Ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ester (12 g, 23.8 mmol), azobisisobutyronitrile (0.81 g, 4.8 mmol), N-bromosuccinimide (5.62 g, 30.9 mmol), and chlorobenzene (60 mL) were added to a 250 mL single-necked round-bottom flask and reacted in an oil bath at 80 °C for 10 hours under nitrogen protection. The reaction was stopped, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate (1 g). The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to give the title compound as a yellow solid (12.8 g, 92.5%).

[0180] Step 6) Ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5- Synthesis of (4-nitrophenyl)thiophene-3-carboxylic acid ester

[0181]

[0182] Ethyl 4-(bromomethyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-5-(4-nitrophenyl)thiophene-3-carboxylic acid ester (23 g, 39.4 mmol), dimethylamine hydrochloride (9.74 g, 118 mmol), and DMF (100 mL) were added to a 500 mL single-necked round-bottom flask at 25 °C. Then, triethylamine (22.1 mL, 158 mmol) was added, and the reaction was stirred for 2 hours. The reaction was stopped, water (250 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was collected, evaporated to dryness under reduced pressure, and the resulting solid was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a pale yellow solid (20.22 g, 93.7%).

[0183] MS(ESI,pos.ion)m / z:548.2[M+H] + ;

[0184] 1H NMR(400MHz, CDCl3)δ(ppm)8.23(d,J=8.8Hz,2H),7.65(d,J=8.8Hz,2H),7.29–7.23(m,1H),6.84(dd,J=13.7,5.8Hz,2 H),5.01(s,2H),4.22(dd,J=14.2,7.1Hz,4H),3.51(s,2H),2.05(s,6H),1.29(t,J=7.1Hz,3H),1.26(t,J=7.1Hz,3H).

[0185] Step 7) 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitro) Synthesis of 3-(thiophene-3-carboxylic acid)

[0186]

[0187] Ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid ester (4.0 g, 7.3 mmol), ethanol (38 mL), and water (10 mL) were added to a 250 mL single-necked round-bottom flask. Potassium hydroxide (0.723 g, 12.9 mmol) was added, and the mixture was reacted in an oil bath at 65 °C for 5 hours. The reaction was stopped, cooled to room temperature, and quenched with concentrated sulfuric acid (0.548 g, 5.48 mmol, 98%). The solvent was evaporated under reduced pressure, and the mixture was purified by column chromatography (dichloromethane / methanol (v / v) = 40 / 1) to give the title compound as a pale yellow solid (3.05 g, 80.4%).

[0188] MS(ESI,pos.ion)m / z:520.0[M+H] + .

[0189] Step 8) Ethyl 2,6-difluorobenzyl (4-((dimethylamino)methyl)-3-((5-( N -Methylmethanesulfonylamino) Synthesis of pyridin-2-yl)carbamoyl)-5-(4-nitrophenyl)thiophen-2-yl)carbamate

[0190]

[0191] 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (1.2 g, 2.3 mmol), N-(6-amino-3-pyridyl)-N-methyl-methanesulfonamide (0.56 g, 2.77 mmol), N,N-diisopropylethylamine (0.77 mL, 4.6 mmol), and DMF (20 mL) were added to a 100 mL single-necked round-bottom flask, followed by the addition of 1-propyl Phosphoric anhydride ethyl acetate solution (4.1 mL, 7.0 mmol, 50%) was stirred in an oil bath at 60 °C for 1.5 h. The reaction was stopped, cooled to room temperature, quenched with water (50 mL), and then sodium bicarbonate solid was added to adjust the pH to 8-9. Dichloromethane was added for extraction (50 mL), the mixture was separated, the organic phase was collected, evaporated under reduced pressure, and the obtained solid was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as an orange solid (1.48 g, 91%).

[0192] MS(ESI,pos.ion)m / z:703.2[M+H] + .

[0193] Step 9) N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4- Synthesis of dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)-N-methylmethanesulfonamide

[0194]

[0195] Ethyl 2,6-difluorobenzyl (4-((dimethylamino)methyl)-3-((5-(N-methylmethanesulfonylamino)pyridin-2-yl)carbamoyl)-5-(4-nitrophenyl)thiophen-2-yl)carbamate (1.48 g, 2.1 mmol) and tetrahydrofuran (25 mL) were added to a 100 mL single-necked round-bottom flask, followed by the addition of cesium carbonate (1.4 g, 4.3 mmol). The reaction was continued with stirring in an oil bath at 70 °C for 1 hour. The reaction was then stopped, cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1) to give the title compound as a yellow solid (1.22 g, 87%). MS (ESI, pos.ion) m / z: 657.1 [M+H] + ;

[0196] 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.63 (d, J = 2.5Hz, 1H), 8.32 (d, J = 8.8Hz, 2H), 8.08 (dd, J = 8.5, 2.7Hz, 1H), 7.99 (d, J = 8.8Hz, 2H), 7 .53(d,J=8.5Hz,1H),7.51–7.42(m,1H),7.14(t,J=8.2Hz,2H),5.36(s,2H),3.68(s,2H),3.35(s,3H),3.10(s,3H),2.09(s,6H).

[0197] Step 10) N-(6-(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-2, Synthesis of 4-dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)-N-methylmethanesulfonamide

[0198]

[0199] N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)-N-methylmethanesulfonamide (1.2 g, 1.8 mmol), tetrahydrofuran (8 mL), ethanol (8 mL), and water (4 mL) were added to a 100 mL single-necked round-bottom flask, and then iron powder (0. 51 g (9.13 mmol) and ammonium chloride (0.2 g, 3.74 mmol) were reacted in an oil bath at 70 °C for 14 hours. After stopping the reaction and cooling to room temperature, the mixture was filtered, and the filtrate was evaporated under reduced pressure to remove most of the solvent. Dichloromethane (40 mL) and water (20 mL) were added, and the mixture was separated. The organic phase was collected, evaporated under reduced pressure, and purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a pale yellow solid (0.9 g, 85%).

[0200] MS(ESI,pos.ion)m / z:627.2[M+H] + .

[0201] Step 11) N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-(3-methoxyurea) (2,3-d)pyrimidin-3(4H)-yl)pyridin-3-yl)-N-methylmethanesulfonate Synthesis of amides

[0202]

[0203] N-(6-(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-3-yl)-N-methylmethanesulfonamide (0.95 g, 1.52 mmol), phenyl N-methoxycarbamate (1.01 g, 6.07 mmol), and DMF (20 mL) were added to 100 mL of water. In a single-necked round-bottom flask, triethylamine (0.85 mL, 6.1 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) were added, and the mixture was reacted in an oil bath at 60 °C for 14 hours. The reaction was stopped, and after cooling to room temperature, water (50 mL) was added, and a solid precipitated. The solid was filtered, collected, and purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a white solid (609 mg, 57%).

[0204] MS(ESI,pos.ion)m / z:700.1[M+H] + ;

[0205] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.63 (s, 1H), 9.08 (s, 1H), 8.63 (d, J = 2.5Hz, 1H), 8.07 (dd, J = 8.5, 2.7Hz, 1H), 7.71 (d, J = 8.6Hz, 2H), 7.52 (dd ,J=8.6,2.5Hz,3H),7.45(dd,J=15.0,8.0Hz,1H),7.13(t,J=8.2Hz,2H),5.34(s,2H),3.63(s,5H),3.35(s,3H),3.10(s,3H),2.05(s,6H).

[0206] Example 2: Synthesis of N-(5-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-(3-methoxyureo)phenyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide

[0207]

[0208] Step 1) Ethyl 2,6-difluorobenzyl (4-((dimethylamino)methyl)-3-((6-(N-methylmethanesulfonylamino)) Synthesis of pyridin-3-yl)carbamoyl)-5-(4-nitrophenyl)thiophen-2-yl)carbamate

[0209]

[0210] The title compound in this step was prepared according to the method described in step 8 of Example 1, namely, by reacting 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (3.6 g, 6.93 mmol), N-(5-amino-2-pyridyl)-N-methyl-methanesulfonamide (1.67 g, 8.3 mmol), N,N-diisopropylethylamine (4.02 mL, 23.0 mmol), and ethyl acetate solution of 1-propylphosphonic anhydride (8.25 mL, 13.9 mmol, 50%) in DMF (35 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give the title compound as a pale yellow solid (3.05 g, 62.6%).

[0211] MS(ESI,pos.ion)m / z:703.2[M+H] + .

[0212] Step 2) N-(5-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4- Synthesis of dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide

[0213]

[0214] The title compound in this step was prepared according to the method described in step 9 of Example 1, namely, by reacting ethyl 2,6-difluorobenzyl (4-((dimethylamino)methyl)-3-((6-(N-methylmethanesulfonylamino)pyridin-3-yl)carbamoyl)-5-(4-nitrophenyl)thiophen-2-yl)carbamate (3.0 g, 4.27 mmol) and cesium carbonate (2.78 g, 8.5 mmol) in tetrahydrofuran (30 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound as a pale yellow solid (2.6 g, 92.8%).

[0215] MS(ESI,pos.ion)m / z:657.1[M+H] + ;

[0216] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.35 (d, J = 2.0Hz, 1H), 8.29 (d, J = 8.7Hz, 2H), 7.84 (d, J = 8.6Hz, 2H), 7.68 (d, J = 7.8Hz, 1H), 7.60 ( d,J=8.7Hz,1H),7.39–7.30(m,1H),6.96(t,J=8.2Hz,2H),5.39(s,2H),3.76(s,2H),3.44(s,3H),3.06(s,3H),2.21(s,6H).

[0217] Step 3) N -(5-(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-2,4- Synthesis of dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide

[0218]

[0219] The title compound in this step was prepared according to the method described in step 10 of Example 1, namely, N-(5-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide (2.5 g, 3.81 mmol), iron powder (1.25 g, 22.3 mmol), and ammonium chloride (0.407 g, 7.7 mmol) were reacted in tetrahydrofuran (25 mL), ethanol (25 mL), and water (12.5 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound as a yellow solid (2.25 g, 94.3%).

[0220] MS(ESI,pos.ion)m / z:627.0[M+H] + ;

[0221] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.51 (s, 1H), 8.03 (d, J = 4.8Hz, 1H), 7.49 (d, J = 8.6Hz, 1H), 7.36–7.27 (m, 1H), 7.11 (d, J = 7.9 Hz,2H),6.90(t,J=8.1Hz,2H),6.72(d,J=8.1Hz,2H),5.31(s,2H),3.44(s,2H),3.39(s,3H),3.06(s,3H),2.55(s,6H).

[0222] Step 4) N-(5-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-(3-methoxyurea)) phenyl)-2,4-dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide Synthesis

[0223]

[0224] The title compound in this step was prepared according to the method described in step 11 of Example 1, namely, N-(5-(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide (2.0 g, 3.19 mmol), phenyl N-methoxycarbamate (1.6 g, 9.57 mmol), triethylamine (1.33 mL, 9.57 mmol), and 4-dimethylaminopyridine (39.4 mg, 0.319 mmol) were reacted in DMF (20 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a white solid (1.41 g, 63.1%).

[0225] MS(ESI,pos.ion)m / z:700.2[M+H] + ;

[0226] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.35 (d, J = 2.2Hz, 1H), 7.67 (dd, J = 7.7, 3.4Hz, 2H), 7.57 (dd, J = 8.4, 6.2Hz, 3H), 7.51 (s, 1H), 7.47 (d, J = 8.5Hz,2H),7.36–7.27(m,1H),6.93(t,J=8.1Hz,2H),5.36(s,2H),3.80(s,3H),3.68(s,2H),3.42(s,3H),3.04(s,3H),2.12(s,6H).

[0227] Example 3: Synthesis of N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-(3-methoxyureo)phenyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridazin-3-yl)-N-methylmethanesulfonamide

[0228]

[0229] Step 1) Ethyl 2,6-difluorobenzyl (4-((dimethylamino)methyl)-3-((6-(N-methylmethanesulfonylamino)) Synthesis of pyridazine-3-yl)carbamoyl)-5-(4-nitrophenyl)thiophene-2-yl)carbamate

[0230]

[0231] The title compound in this step was prepared according to the method described in step 8 of Example 1, namely, by reacting 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (0.99 g, 1.91 mmol), N-(6-aminopyridazin-3-yl)-N-methyl-methanesulfonamide (350 mg, 1.73 mmol), N,N-diisopropylethylamine (1.43 mL, 5.19 mmol), and ethyl acetate solution of 1-propylphosphonic anhydride (1.5 mL, 2.5 mmol, 50%) in DMF (30 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give the title compound as a pale yellow solid (0.5 g, 41%).

[0232] MS(ESI,pos.ion)m / z:704.2[M+H] + .

[0233] Step 2) N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4- Synthesis of dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridazine-3-yl)-N-methylmethanesulfonamide

[0234]

[0235] The title compound in this step was prepared according to the method described in step 9 of Example 1, namely, by reacting ethyl 2,6-difluorobenzyl (4-((dimethylamino)methyl)-3-((6-(N-methylmethanesulfonylamino)pyridazin-3-yl)carbamoyl)-5-(4-nitrophenyl)thiophen-2-yl)carbamate (1.0 g, 1.4 mmol) and cesium carbonate (1.4 g, 4.3 mmol) in tetrahydrofuran (50 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 30 / 1), and the title compound was obtained as a pale yellow solid (0.57 g, 61.3%).

[0236] MS(ESI,pos.ion)m / z:658.1[M+H] + ;

[0237] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.86 (d, J = 9.3 Hz, 1H), 7.68 (s, 1H), 7.56–7.40 (m, 1H), 7.16 (dd, J = 8.0 ,6.3Hz,4H),6.68(d,J=8.4Hz,2H),5.64(s,2H),4.27(s,2H),3.17(s,3H),3.06(s,3H),2.51(s,6H).

[0238] Step 3) N-(6-(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-2,4- Synthesis of dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridazine-3-yl)-N-methylmethanesulfonamide

[0239]

[0240] The title compound in this step was prepared according to the method described in step 10 of Example 1, namely, N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridazin-3-yl)-N-methylmethanesulfonamide (0.57 g, 0.87 mmol), iron powder (242 mg, 4.3 mmol), and ammonium chloride (92 mg, 1.7 mmol) were reacted in tetrahydrofuran (5 mL), ethanol (5 mL), and water (2.5 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound as a pale yellow solid (0.45 g, 82.7%).

[0241] MS(ESI,pos.ion)m / z:628.2[M+H] + ;

[0242] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.99 (d, J = 7.3Hz, 2H), 7.33 (dd, J = 14.7, 8.2Hz, 1H), 7.22 (d, J = 8.1Hz, 2H), 6.9 3(t,J=8.1Hz,2H),6.74(d,J=8.4Hz,2H),5.31(s,2H),3.99(s,2H),3.61(s,3H),3.07(s,3H),2.41(s,6H).

[0243] Step 4) N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-(3-methoxyureo)) phenyl)-2,4-dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridazine-3-yl)-N-methylmethanesulfonamide Synthesis

[0244]

[0245] The title compound in this step was prepared according to the method described in step 11 of Example 1, namely, N-(6-(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridazin-3-yl)-N-methylmethanesulfonamide (0.45 g, 0.72 mmol), phenyl N-methoxycarbamate (0.6 g, 3.6 mmol), and triethylamine (0.4 mL, 2.85 mmol) were reacted in DMF (10 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a white solid (0.28 g, 55.7%).

[0246] MS(ESI,pos.ion)m / z:701.2[M+H] + ;

[0247] 1 H NMR (400MHz, CDCl3) δ (ppm) 8.01 (d, J = 9.2Hz, 1H), 7.74 (s, 1H), 7.64 (d, J = 18.6Hz, 1H), 7.60 (s, 1H), 7.50 (d, J = 8.4 Hz,2H),7.39–7.29(m,1H),6.94(t,J=8.0Hz,2H),5.33(s,2H),3.79(s,2H),3.62(s,3H),3.06(s,3H),2.14(s,6H).

[0248] Example 4: Synthesis of N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-(3-methoxyureo)phenyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide

[0249]

[0250] Step 1) Ethyl 2,6-difluorobenzyl (4-((dimethylamino)methyl)-3-((6-(N-methylmethanesulfonylamino)) Synthesis of pyridin-2-yl)carbamoyl)-5-(4-nitrophenyl)thiophen-2-yl)carbamate

[0251]

[0252] The title compound in this step was prepared according to the method described in step 8 of Example 1, namely, by reacting 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid (2.5 g, 4.8 mmol), N-(5-amino-2-pyridyl)-N-methylmethanesulfonamide (0.87 g, 4.32 mmol), N,N-diisopropylethylamine (1.9 mL, 10.9 mmol), and ethyl acetate solution of 1-propylphosphonic anhydride (5.6 mL, 9.43 mmol, 50%) in DMF (10 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to give the title compound as a pale yellow solid (2.49 g, 82.2%).

[0253] MS(ESI,pos.ion)m / z:703.2[M+H] + .

[0254] Step 2) N -(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4- Synthesis of dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide

[0255]

[0256] The title compound in this step was prepared according to the method described in step 9 of Example 1, namely, by reacting ethyl 2,6-difluorobenzyl (4-((dimethylamino)methyl)-3-((6-(N-methylmethanesulfonylamino)pyridin-2-yl)carbamoyl)-5-(4-nitrophenyl)thiophen-2-yl)carbamate (2.5 g, 3.6 mmol) and cesium carbonate (2.3 g, 7.1 mmol) in tetrahydrofuran (30 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 30 / 1), and the title compound was obtained as a pale yellow solid (2 g, 86%).

[0257] MS(ESI,pos.ion)m / z:657.2[M+H] + .

[0258] Step 3) N-(6-(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-2,4- Synthesis of dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide

[0259]

[0260] The title compound in this step was prepared according to the method described in step 10 of Example 1, namely, N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-nitrophenyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide (2.0 g, 3.05 mmol), iron powder (0.85 g, 15.2 mmol), and ammonium chloride (0.33 g, 6.17 mmol) were reacted in tetrahydrofuran (20 mL), ethanol (20 mL), and water (10 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 30 / 1) to obtain the title compound as a yellow solid (1.2 g, 63%).

[0261] MS(ESI,pos.ion)m / z:627.2[M+H] + ;

[0262] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.91 (t, J = 7.6Hz, 1H), 7.65 (s, 1H), 7.51 (d, J = 8.0Hz, 1H), 7.31 (t, J = 8.4Hz, 1H), 7.16 (d, J = 8 .0Hz,2H),6.92(t,J=8.0Hz,2H),6.73(d,J=8.4Hz,2H),5.45(s,2H),3.96(s,2H),3.38(s,3H),2.98(s,3H),2.55(s,6H).

[0263] Step 4) N-(6-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-6-(4-(3-methoxyureo)) phenyl)-2,4-dioxo-1,2-dihydrothiopheno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide Synthesis

[0264]

[0265] The title compound in this step was prepared according to the method described in step 11 of Example 1, namely, by reacting N-(6-(6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)pyridin-2-yl)-N-methylmethanesulfonamide (1.2 g, 1.9 mmol), phenyl N-methoxycarbamate (1.3 g, 7.8 mmol), triethylamine (0.8 mL, 5.76 mmol), and 4-dimethylaminopyridine (12 mg, 0.098 mmol) in DMF (10 mL). The crude product was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give the title compound as a pale yellow solid (0.26 g, 19%).

[0266] MS(ESI,pos.ion)m / z:700.2[M+H] + ;

[0267] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.88 (t, J = 8.0Hz, 1H), 7.66 (s, 1H), 7.56 (dd, J = 8.4, 2.0Hz, 3H), 7.46 (d, J = 8.4Hz, 2H), 7.37 (d, J = 11.6Hz, 1H), 7. 34–7.29(m,1H),7.24(d,J=7.6Hz,1H),6.93(t,J=8.0Hz,2H),5.35(s, 2H),3.81(s,3H),3.70(s,2H),3.38(s,3H),2.95(s,3H),2.13(s,6H).

[0268] Biological experiments

[0269] Example A: Antagonistic effect of the compounds of the present invention on humanized GnRH receptors

[0270] Experimental Objective

[0271] The antagonistic effect of the compound of this invention on humanized GnRH receptors transfected in RBL-1 cells (rat basophilic leukemia cells) was evaluated by using a fluorescence method to detect cytoplasmic calcium flow.

[0272] Experimental Procedure

[0273] Cells were suspended in HBSS buffer (Invitrogen, Inc.), and 20 mM HEPES buffer (Invitrogen, Inc.) was added. Then, the mixture was incubated at 1.186 × 10⁻⁶ cells / mL. 4Cells were added to the microplate at an average density per well. A fluorescent probe (Fluo8 Direct, AAT Bioquest) was mixed with HBSS buffer (containing 20 mM HEPES buffer, pH 7.4) and added to each well. Cells were incubated at 30°C for 60 min. The plate was then tested using a microplate reader (FlipR Tetra, Molecular Device). The test compound or HBSS buffer (blank control) was added, and after 5 min, 8 nM LH-RH was added. The change in fluorescence intensity, proportional to the intracytoplasmic calcium ion concentration, was measured. The inhibition rate of the compound was calculated using the fluorescence intensity of the blank control group (without the compound) as 100% (inhibition rate 0%). The inhibition rate at different concentrations of the compound was measured, and its IC50 was calculated. 50 Values. The experimental results are shown in Table A below.

[0274] Table A shows the antagonistic effect of the compounds of this invention on humanized GnRH receptors.

[0275] Example No. <![CDATA[IC 50 (nM)]]> Example 1 2.887 Example 2 1.435 Example 3 5.584 Example 4 0.9104

[0276] Experimental results show that the compound of this invention has a good antagonistic effect on humanized GnRH receptors.

[0277] Example B: Pharmacokinetic evaluation of the compounds of the present invention after intravenous or gavage administration to rats and dogs

[0278] The pharmacokinetic studies of the compounds of this invention in rats and / or dogs were evaluated in this invention. Animal information is detailed in Table B.

[0279] Table B: Information on test animals for this invention

[0280]

[0281] Test methods

[0282] The compounds of this invention were administered to test animals in the form of a solution of 10% DMSO + 10% Kolliphor HS15 + 78% Saline + 2% (2% HCl) or a solution of 78% Saline + 2% (2% HCl) + 20% PEG400. Animals were fasted for 12 hours prior to administration but had free access to water. For the intravenous administration group, the dose was 1 mg / kg (rat) or 0.5 mg / kg (dog). Blood samples (approximately 0.2 mL) were collected intravenously at the following time points after administration: 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h (dog) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 h (rat). EDTA-K2 was pre-added to the blood collection vessels as an anticoagulant. For the gavage administration group, the dosage was 5 mg / kg (rat) or 2.5 mg / kg (dog). Following administration, venous blood samples (approximately 0.2 mL) were collected at the following time points: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h (dog) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 h (rat). EDTA-K2 was pre-added to the blood collection vessels as an anticoagulant. Blood samples were centrifuged at 12,000 rpm for 2 minutes, and plasma was collected and stored at -20°C or -70°C.

[0283] The collected plasma samples were processed (frozen plasma was thawed at room temperature, vortexed for 15 seconds to mix, 10-20 μL of plasma was taken, 120-150 μL of acetonitrile solution containing internal standard was added, vortexed for 5 minutes to mix, centrifuged at 4,000 rpm for 5 minutes, 100 μL of supernatant was taken, and 120-150 μL of methanol / water (v / v = 1 / 1) was added to mix) and the concentration of compounds in the plasma was analyzed by LC / MS / MS.

[0284] The analytical results show that the compounds of this invention have good pharmacokinetic properties in rats and / or dogs. This indicates that the compounds of this invention have good drug-like properties and promising clinical application prospects.

[0285] In the description of this specification, the references to terms such as "an embodiment," "an implementation," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment, implementation, or example, which are included in at least one embodiment, implementation, or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment, implementation, or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments, implementations, or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments, implementations, or examples described in this specification, as well as the features of different embodiments, implementations, or examples.

[0286] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:

2. A pharmaceutical composition comprising the compound of claim 1; and The pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

3. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a drug, wherein: The drug is used for preventing or treating sex hormone-dependent diseases; Among them, the sex hormone-dependent disease is sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, prostate hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, polycystic ovary syndrome, acne, alopecia, infertility or irritable bowel syndrome.

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