Deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound and pharmaceutical composition containing the compound

Abstract

Provided are a deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound represented by formula (I) and a pharmaceutical composition containing the compound, or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The compound can be used to treat and / or prevent gonadotropin-releasing hormone (GnRH)-dependent related diseases, such as uterine fibroids, endometriosis, uterine fibroids, amenorrhea, premenstrual syndrome, etc.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and specifically relates to a novel deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound and a pharmaceutical composition containing the compound. Background Art

[0002] Gonadotropin-releasing hormone (GnRH) is a type of hormone secreted by the hypothalamus that stimulates or inhibits the secretion of pituitary gonadotropins and plays an important role in the regulation of vertebrate reproduction.

[0003] Tetrahydrothieno[3,4-d]pyrimidinedione compounds and derivatives are a class of gonadotropin-releasing hormone inhibitors. Patent WO2007042392 discloses a series of tetrahydrothieno[3,4-d]pyrimidinedione derivatives, among which the compound Linzagolix is ​​a selective GnRH inhibitor, with a chemical name of 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid, and has the use of treating uterine fibroids, endometriosis and adenomyosis. Currently, the compound is in Phase II clinical research for the treatment of endometriosis and adenomyosis and Phase III clinical research for uterine fibroids.

[0004] Although gonadotropin-releasing hormone is one of the important targets for the development of drugs for gynecological diseases, except for a few recently launched gonadotropin-releasing hormone inhibitors such as triptorelin and alarelin and Relugolix and Elagolix, the research progress of GnRH inhibitors is still relatively slow.

[0005] Therefore, there is still a need in the art to develop compounds with good inhibitory activity on gonadotropin-releasing hormone or better pharmacodynamics / pharmacokinetic properties. Summary of the invention

[0006] The object of the present invention is to provide a novel compound having gonadotropin-releasing hormone inhibitory activity and better pharmacodynamics / pharmacokinetic properties and use thereof.

[0007] In the first aspect of the present invention, there is provided a deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound represented by formula (I), or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:

[0008]

[0009]

[0010] Where:

[0011] R 1 , R 2 and R 9 are each independently a halogen;

[0012] R 3 , R 4 , R 8 , R 10 , R 11 and R 13 each independently is hydrogen or deuterium;

[0013] R 5 , R 6 , R 7 and R 12 Each is independently selected from: hydrogen, deuterium, C1-C6 alkyl or deuterated C1-C6 alkyl;

[0014] The additional condition is: R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 or R 13 At least one (e.g., 1, 2, 3, 4, 5, or 6) is a deuterated alkyl group or deuterium.

[0015] In another preferred embodiment, the compound of formula (I) contains at least 1 deuterium atom, more preferably 2 or more (such as 3, 4, 5 or 6) deuterium atoms.

[0016] In another preferred embodiment, R 1 , R 2 and R 9 is selected from fluorine, chlorine or bromine.

[0017] In another preferred embodiment, R 1 , R 2 and R 9 For fluorine.

[0018] In another preferred embodiment, R 3 and R 4 For hydrogen.

[0019] In another preferred embodiment, R 4 For deuterium.

[0020] In another preferred embodiment, R 8 and R 10 For hydrogen.

[0021] In another preferred embodiment, R 8 and R 10 For deuterium.

[0022] In another preferred embodiment, R 10 For deuterium.

[0023] In another preferred embodiment, R 11 Selected from: deuterium or hydrogen.

[0024] In another preferred embodiment, R 13 Selected from: deuterium or hydrogen.

[0025] In another preferred embodiment, R 5 , R 12 Selected from: CH3, CH2D, CHD2, CD3, CH2CH3, CD2CH3, CH2CD3 or CD2CD3.

[0026] In another preferred embodiment, R 5 , R 12 Selected from: CD3 or CH3.

[0027] In another preferred embodiment, R 5 It is CD3.

[0028] In another preferred embodiment, R 5 and R 12 It is CD3.

[0029] In another preferred embodiment, R 12 It is CD3.

[0030] In another preferred embodiment, R 12 For CH3, R 5 It is CD3.

[0031] In another preferred embodiment, R 12 CD3, R 5 For CH3.

[0032] In another preferred embodiment, R 6 , R 7 Selected from: deuterium or hydrogen.

[0033] In another preferred embodiment, R 6 and R 7 At the same time, it is deuterium.

[0034] In another preferred embodiment, R 6 and R 7 At the same time, it is hydrogen.

[0035] In another preferred embodiment, R 6 For deuterium.

[0036] In another preferred embodiment, the compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof:

[0037]

[0038]

[0039] In another preferred embodiment, the compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof:

[0040] 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy-d2)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0041]

[0042] 3-(5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d2)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0043]

[0044] 3-(5-((2,3-difluoro-6-(methoxy-d3)benzyl)oxy)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0045]

[0046] 3-(5-((2,3-difluoro-6-(methoxy-d3)benzyl)oxy)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0047]

[0048] 3-(5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d2)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0049]

[0050] 3-(5-(((2,3-difluoro-6-methoxyphenyl)methoxy-d2)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0051]

[0052] 3-(5-((2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0053]

[0054] 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy-d)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0055]

[0056] 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy-d)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0057]

[0058] 3-(5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid;

[0059]

[0060] 3-(5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid

[0061]

[0062] In another preferred embodiment, the compound is It has the following characteristics: MS calculated value: 513; MS measured value: 514 (M+H) + .

[0063] In another preferred embodiment, the compound is It has the following characteristics: MS calculated value: 513; MS measured value: 514 (M+H) + .

[0064] In another preferred embodiment, the compound is It has the following characteristics: MS calculated value: 511; MS measured value: 512 (M+H) + .

[0065] In another preferred embodiment, the compound is It has the following characteristics: MS calculated value: 514; MS measured value: 515 (M+H) + .

[0066] In another preferred embodiment, the compound is It has the following characteristics: MS calculated value: 516; MS measured value: 517 (M+H) + .

[0067] In another preferred embodiment, the compound is It has the following characteristics: MS calculated value: 510; MS measured value: 511 (M+H) + .

[0068] In another preferred embodiment, the compound is It has the following characteristics: MS calculated value: 511; MS measured value: 512 (M+H) + .

[0069] In another preferred embodiment, the deuterium isotope content of deuterium at the deuterium substitution position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, and more preferably greater than 99%.

[0070] In another preferred embodiment, the compound does not include non-deuterated compounds.

[0071] In another preferred embodiment, the non-deuterated compound is 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid.

[0072] In the second aspect of the present invention, a method for preparing a pharmaceutical composition is provided, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, to form a pharmaceutical composition.

[0073] In the third aspect of the present invention, a pharmaceutical composition is provided, which contains a pharmaceutically acceptable carrier and the compound described in the first aspect of the present invention, or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof.

[0074] In another preferred embodiment, the pharmaceutical composition is an injection, capsule, tablet, pill, powder or granule.

[0075] In another preferred embodiment, the pharmaceutical composition further contains another therapeutic drug, and the other therapeutic drug is a drug for cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferative disease, viral disease, metabolic disease, or organ transplantation.

[0076] More preferably, the additional therapeutic drugs include (but are not limited to): elagolix, Relugolix, Triptorelin, Alarelin, 5-fluorouracil, FOLFOX, Avastin TM (avastin, bevacizumab), bexarotene, bortezomib, calcitriol, canertinib, capecitabine, gemcitabine, carboplatin, celecoxib, cetuximab, cisplatin, dasatinib, digoxin, enzastaurin, erlotinib, etoposide, everolimus, fluoroquinolone fulvestrant, gefitinib, genistein, imatinib, irinotecan, lapatinib, lenalidomide, letrozole, leucovorin, matuzumab, oxaliplatin, paclitaxel, doxetaxel, panitumumab, pegfilgrastin, peglated alfa-interferon, pemetrexed, E. Satraplatin, sirolimus, sunitinib, sulindac, taxotere, temodar, temozomolomide, Torisel, temsirolimus, tipifarnib, trastuzumab, valproic acid acid), vinflunine, volociximab, vorinostat, sorafenib, crizotinib, icotinib, lapatinib, tofacitinib, PD-0332991 (palbociclib), ambrisentan, doxorubicin, methotrexate, prednisone, rituximab, CD40 and / or CD154 specific antibodies, fusion proteins, NF-kB inhibitors, non-steroidal anti-inflammatory drugs, coagulation factor FXa inhibitors (such as rivaroxaban, etc.), anti-TNF antibodies, antibiotics such as calicheamicin, actinomycin, doxorubicin, tumor immunotherapy drugs such as anti-PD-1 antibodies, anti-PD-L1 antibodies, etc.

[0077] In another preferred embodiment, the pharmaceutical composition further contains other therapeutic drugs, and the other therapeutic drugs are anti-pain drugs, anti-anxiety drugs, anti-depressant drugs, progesterone and the like.

[0078] In the fourth aspect of the present invention, there is provided the use of the compound described in the first aspect of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate of the pharmaceutical composition described in the third aspect of the present invention, which are used to prepare a pharmaceutical composition for inhibiting gonadotropin-releasing hormone.

[0079] In another preferred embodiment, the pharmaceutical composition is used to prepare drugs for treating and preventing the following diseases: pain, prostate hypertrophy, uterine fibroids, endometriosis, uterine fibroids, amenorrhea, premenstrual syndrome, sleep disorders, acne, hair loss, irritable bowel syndrome, lupus erythematosus and other diseases.

[0080] In the fifth aspect of the present invention, a method for inhibiting gonadotropin-releasing hormone or a method for treating a disease (such as cancer, cell proliferative disease, inflammation, infection, pain, immune disease) is provided, which comprises the steps of administering the compound described in the first aspect of the present invention, or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or administering the pharmaceutical composition described in the third aspect of the present invention to a subject in need of treatment.

[0081] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 This is the blood concentration-time curve of the test drug in Example 8.

[0083] Figure 2 This is the blood concentration-time curve of the test drug in Example 9.

[0084] Figure 3 This is the blood concentration-time curve of the test drug in Example 10.

[0085] Figure 4 This is the blood concentration-time curve of the test drug in Example 11. DETAILED DESCRIPTION

[0086] The inventors have unexpectedly found through research that the deuterated tetrahydrothieno[3,4-d]pyrimidinedione compounds and pharmaceutically acceptable salts thereof of the present invention have significantly better pharmacokinetic and / or pharmacodynamic properties than the undeuterated compounds, and are therefore more suitable as compounds for inhibiting gonadotropin-releasing hormone, and are further more suitable for preparing drugs for treating cancer and gonadotropin-releasing hormone-related diseases. The present invention was completed on this basis.

[0087] definition

[0088] As used herein, "halogen" refers to F, Cl, Br, and I.

[0089] As used herein, "C1-C6 alkyl" refers to a straight or branched alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or the like. "Deuterated C1-C6 alkyl" refers to a group in which one or more hydrogen atoms in the alkyl group are replaced by a deuterium atom.

[0090] As used herein, "superior pharmacokinetic and / or pharmacodynamic properties" refers to a longer drug half-life (t 1 / 2), or higher drug exposure (AUC), or higher maximum drug concentration (Cmax), or lower drug clearance

[0091] As used herein, "deuterated" refers to one or more hydrogens in a compound or group being replaced by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted. The term "one or more deuterated" and "one or more deuterated" can be used interchangeably.

[0092] As used herein, "non-deuterated compound" refers to a compound containing deuterium atoms in a proportion not greater than the natural deuterium isotope content (0.015%).

[0093] In another preferred embodiment, the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%, and more preferably greater than 99.5%.

[0094] In another preferred embodiment, the compound of formula (I) contains at least one deuterium atom.

[0095] Preferably, in the compound of formula (I), N is 14 N and / or O are 16 O.

[0096] In another preferred embodiment, in the compound, 14 The isotopic content of N at the position of the nitrogen atom is ≥95%, more preferably ≥99%.

[0097] In another preferred embodiment, in the compound, 16 The isotopic content of O at the position of the oxygen atom is ≥95%, more preferably ≥99%.

[0098] Preferably, in the compound of formula (I), F is 19 F and / or S is 32 S.

[0099] In another preferred embodiment, in the compound, 19 The isotopic content of F at the position of the nitrogen atom is ≥95%, more preferably ≥99%.

[0100] In another preferred embodiment, in the compound, 32 The isotopic content of S at the position of oxygen atoms is ≥95%.

[0101] Active ingredients

[0102] As used herein, the term "compound of the present invention" refers to a compound of formula (I). The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula (I).

[0103] The compound of formula (I) of the present invention has the following structure:

[0104]

[0105] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 The definition of is as above.

[0106] Preferably, R 1 , R 2 and R 9 For fluorine;

[0107] R 5 , R 12 Each independently selected from: CH3, CH2D, CHD2, CD3, CH2CH3, CD2CH3, CH2CD3 or CD2CD3, preferably CH3 or CD3;

[0108] R 6 , R 7 is deuterium or hydrogen, preferably R 6 and R 7 At the same time, it is deuterium.

[0109] The term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by the compound of the present invention and an acid. Acids suitable for forming salts include but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0110] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0111] In addition, the compounds of the present invention also include prodrugs of deuterated tetrahydrothieno[3,4-d]pyrimidinedione compounds shown in formula (I). The term "prodrug" includes a compound that can be biologically active or inactive, and when taken by an appropriate method, it undergoes metabolism or chemical reactions in the human body and is converted into a class of compounds of formula (I), or a salt or solution composed of a compound of formula (I). The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compound.

[0112] Preparation method

[0113] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any restriction to the present invention. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combination can be easily carried out by those skilled in the art to which the present invention belongs.

[0114] The non-deuterated tetrahydrothieno[3,4-d]pyrimidinedione compounds used in the present invention are known. The corresponding deuterated tetrahydrothieno[3,4-d]pyrimidinedione compounds can be prepared by using the corresponding deuterated starting compounds as raw materials and synthesized by the same route. For example, the compound of formula (I) of the present invention can be prepared according to the preparation method described in WO2007042392, except that deuterated raw materials are used instead of non-deuterated raw materials in the reaction.

[0115] Usually, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 200°C, preferably 0°C to 100°C). The reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.

[0116] The following general preparation route can be used to synthesize the compounds of formula (I) of the present invention.

[0117]

[0118] Synthetic route 1

[0119] Wherein: X is selected from F, Cl, Br, I; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 The definition of is the same as before.

[0120] As shown in the first synthetic route, compound II is reacted with an alkylating agent (such as CD3X, CH3X) under alkaline conditions (such as potassium carbonate) to produce compound III; compound III is reduced with a metal hydride reducing agent (such as sodium borohydride or sodium borodeuteride) to obtain compound IV; formula IV is further halogenated (such as HCl) to form compound V; formula V reacts with a substituted phenol compound VI to obtain compound VII; compound VII is subjected to a selective nitration reaction to obtain formula VIII; the aromatic nitro group in formula VIII is subjected to catalytic hydrogenation conditions such as palladium, platinum, and Raney nickel to obtain aromatic amine IX; compound IX is acylated with compound X under alkaline conditions (such as triethylamine) to form urea to obtain formula XI; the intermediate XI is hydrolyzed with lithium hydroxide and acetic acid itself to form a lactam ring to obtain the compound of the present invention, formula I. The above reaction is preferably carried out in an inert solvent such as ethyl acetate, dichloromethane, methyl tert-butyl ether, n-heptane, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetic acid, etc., at a temperature of 0 to 200°C.

[0121] The starting materials can be purchased from commercial sources or synthesized according to literature reports.

[0122] The preparation method of compound VI is shown in the following synthetic route 2:

[0123]

[0124] Synthetic route 2

[0125] In an inert solvent (such as dichloromethane), the compound of formula XII and m-chloroperbenzoic acid are subjected to a Bayer-Villiger oxidative rearrangement reaction and then further hydrolyzed to obtain compound VI; wherein R 8 , R 9 , R 10 , R 12 The definition of is the same as before.

[0126] The preparation method of compound X is shown in the following synthesis route 3:

[0127]

[0128] Synthesis route 3

[0129] The compound of formula XIII is acylated to form an active amide ester of formula X; wherein R 11 The definition of is the same as before.

[0130] Pharmaceutical compositions and methods of administration

[0131] Since the compounds of the present invention have excellent inhibitory activity on gonadotropin-releasing hormone, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases mediated by gonadotropin-releasing hormone. According to the prior art, the compounds of the present invention can be used to treat the following diseases: cancer, cell proliferative diseases, inflammation, infection, immune diseases, pain, etc.

[0132] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0133] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0134] The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0135] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0136] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0137] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

[0138] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0139] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0140] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0141] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0142] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0143] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0144] The compounds of the present invention have a series of advantages compared to the non-deuterated compounds known in the prior art. The main advantages of the present invention include:

[0145] (1) The compounds of the present invention have excellent inhibitory activity against gonadotropin-releasing hormone.

[0146] (2) The compounds of the present invention have better pharmacokinetic parameter characteristics, can change the drug dosage and form a long-acting preparation, and improve applicability.

[0147] (3) Replacing hydrogen atoms in a compound with deuterium can increase the drug concentration in the animal body due to its deuterium isotope effect, thereby improving the efficacy of the drug.

[0148] (4) Substituting deuterium for hydrogen atoms in a compound may improve the safety of the compound due to the inhibition of certain metabolites.

[0149] (5) The compounds of the present invention, especially compounds 1 and 21, exhibit unexpectedly superior pharmacokinetic properties compared to the control compound Linzagolix.

[0150] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise indicated, parts and percentages are by weight and weight percentage.

[0151] Example 1 Preparation of 3-(5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d2)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 1)

[0152]

[0153] 1. Preparation of methyl 2,3-difluoro-6-(methoxy-d3)benzoate (Compound 3)

[0154] At room temperature, compound 2,3-difluoro-6-hydroxybenzoic acid (5.0 g) and N,N-dimethylformamide (30 ml) were added to the reaction bottle, stirred to dissolve, and the reaction solution became clear; potassium carbonate (12.2 g) was added, stirred for 30 min, deuterated iodomethane (10.0 g) was slowly added dropwise, and the temperature was raised to 40°C after the addition was completed, stirred for 15-20 h, and detected by thin layer chromatography; after the reaction was completed, water (60 ml) and ethyl acetate (60 ml) were added, stirred for 30 min, extracted twice, the organic phases were combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain an oily substance, petroleum ether (12 ml) was added to the oily substance, dissolved, cooled to 0°C, a solid was gradually precipitated, stirred for 3 h, filtered, and dried to obtain 4.8 g of the title compound. 1 H NMR (400MHz, DMSO-d6) δ: 7.70-7.75 (m, 1H), 7.31-7.36 (m, 1H); ESI-MS m / z 209[M+H] + .

[0155] 2. Preparation of (2,3-difluoro-6-(methoxy-d3)phenyl)methane-d2-ol (Compound 4)

[0156] At room temperature, compound 3 (4.2 g) and tetrahydrofuran (20 ml) were added to the reaction bottle, cooled to -10 to -5 °C, sodium borodeuteride (2.54 g) was added, and iodine (5.1 g) and tetrahydrofuran (10 ml) were prepared into a solution under stirring; the temperature was controlled at about -10 °C and the above reaction solution was added dropwise and stirred for 2 h, then the temperature was raised to 40 °C and the reaction was carried out for 48 h. After the reaction was completed, the reaction solution was poured into ice water, toluene was added for extraction, washed with water, and desolventized to obtain 3.8 g of the title compound. ESI-MS m / z162[M+H-H2O]+.

[0157] 3. Preparation of 2-(chloromethyl-d2)-3,4-difluoro-1-(methoxy-d3)benzene (Compound 5)

[0158] Compound 4 (3.8 g), toluene (30 ml) and concentrated hydrochloric acid (30 ml) were added to the reaction flask, and the temperature was raised to 40°C for 24 h. After the reaction was completed, the temperature was lowered, stirring was stopped, the mixture was allowed to stand, and the liquids were separated. Toluene was added to the aqueous layer for extraction, and the mixture was washed with water and desolventized to obtain 3.6 g of the title compound.

[0159] 4. Preparation of 1,2-difluoro-3-((4-fluoro-2-(methoxy-d3)phenoxy)methyl-d2)-4-(methoxy-d3)benzene (Compound 7)

[0160] Compound 5 (3.6 g), 4-fluoro-2-(methoxy-d3)phenol (3.0 g), tetrahydrofuran (30 ml) were added to the reaction bottle, and 25% NaOH aqueous solution (3.5 g) was added, and the temperature was raised to 60°C and reacted for 20 h. Thin layer chromatography was used for detection. After the reaction was completed, the temperature was lowered, water was added, and the mixture was stirred for 30 min, allowed to stand, and separated. Toluene was added to the aqueous layer for extraction, and the mixture was washed with water and desolventized to obtain 6 g of a crude product. The target compound (5.0 g) was obtained by crystallization and purification with isopropanol / water. 1 H NMR (400MHz, DMSO-d6) δ: 7.46-7.41(m, 1H), 7.22-7.17(m, 1H), 7.01-6.97(m, 1H), 6.93-6.89(m, 1H), 6.69-6.64(m, 1H).ESI-MS m / z305[MH] - .

[0161] 5. Preparation of 1,2-difluoro-3-((4-fluoro-2-(methoxy-d3)-5-nitrophenoxy)methyl-d2)-4-(methoxy-d3)benzene (Compound 8)

[0162] Compound 7 (3.0 g), acetic acid (24 ml) and nitric acid (1.4 g) were added to the reaction bottle, and the temperature was raised to 60°C for 8 h. After the reaction was completed, the temperature was lowered to room temperature, water was added, stirred for 2 h, filtered, and dried to obtain the target compound (2.8 g). 1 H NMR (400MHz, DMSO-d6) δ: 7.78-7.76 (d, J=7.6Hz, 1H), 7.54-7.49 (m, 1H), 7.31-7.24 (m, 2H).ESI-MS m / z350[MH] - .

[0163] 6. Preparation of 5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d2)-2-fluoro-4-(methoxy-d3)aniline (Compound 9)

[0164] Compound 8 (2.0 g) and ethyl acetate were added to the reaction bottle, and the mixture was replaced with hydrogen twice. A 10% palladium-carbon catalyst (0.2 g) was added, and the mixture was replaced with hydrogen again. Hydrogen was introduced and stirred at room temperature for 20 h. The reaction was completed after thin layer chromatography. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was removed under reduced pressure to obtain a crude product. The solid was purified by crystallization with methanol and water to obtain 1.5 g of the target compound. 1 H NMR (400MHz, DMSO-d6) δ: 7.43-7.38 (m, 1H), 7.23-7.18 (m, 1H), 6.77 (d, J=12.4Hz, 1H), 6.51 (d, J=8.8Hz, 1H), 4.64 (s, 2H). ESI-MS m / z322[M+H] + , 320[MH] - .

[0165] 7. Preparation of dimethyl 4-(3-(5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d2)-2-fluoro-4-(methoxy-d3)phenyl)ureidothiophene-2,3-dicarboxylate (Compound 11)

[0166] Compound 9 (1.5 g), dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylate (compound 10, 1.6 g), and tetrahydrofuran (15 ml) were added to the reaction bottle, stirred, and triethylamine (0.2 g) was added. The temperature was raised to 30°C, and stirred for 24 h. Thin layer chromatography was performed. When the reaction was completed, the reaction solution was decompressed to remove the solvent to obtain a crude product. Ethyl acetate and methanol were added to slurry to obtain 2.0 g of the title compound. 1H NMR (400MHz, DMSO-d6) δ: 8.95 (s, 1H), 8.83 (s, 1H), 7.94 (s, 1H), 7.73 (d, J = 8.0Hz, 1H), 7.47-7.42 (m, 1H), 7.23-7.18 (m, 1H), 7.01 (d, J = 12.8Hz, 1H) 1H), 3.89(s, 3H), 3.83(s, 3H). ESI-MS m / z 563[M+H] + .

[0167] 8. Preparation of 3-(5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d2)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 1)

[0168] Add compound 11 (2.0 g), tetrahydrofuran (6 ml), methanol (6 ml) and water (6 ml) to the reaction bottle and stir until the solid does not dissolve; prepare a 7.3% aqueous solution of lithium hydroxide monohydrate and add it to the reaction bottle at room temperature, stir for 3 hours, heat to 30°C, stir for 24 hours, the solid in the reaction solution disappears, the solution becomes clear, and the reaction is complete after thin layer chromatography. Add acetic acid to the reaction solution, stir at 30°C for 3-5 hours, and the reaction is complete after thin layer chromatography. Add water, cool to 0-10°C, stir for 2-3 hours, and filter to obtain 1.7 g of the target compound. 1 H NMR (400MHz, DMSO-d6) δ: 14.57 (s, 1H), 12.0 (s, 1H), 7.53-7.48 (m, 1H), 7.39 (s, 1H), 7.27-7.12 (m, 3H). ESI-MS m / z 517[M+H] + .

[0169] Among them, compound 6 is prepared from compound 12 via two-step reaction.

[0170]

[0171] (i) Preparation of 1-(4-fluoro-2-(methoxy-d3)phenyl)ethan-1-one (Compound 14)

[0172] Add 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one (20 g), N,N-dimethylformamide (60 ml), and anhydrous potassium carbonate to the reaction bottle, stir, add deuterated methyl p-toluenesulfonate (compound 13, 32 g) dropwise, stir, gradually precipitate a solid, raise the temperature to 30°C, stir for about 20 h, and check with thin layer chromatography to complete the reaction; pour the reaction solution into water, precipitate a solid, stir for 3 h, filter, rinse the filter cake with water, drain, and air-dry the filter cake to obtain 21.5 g of the title compound.1 H NMR (400MHz, DMSO-d6) δ: 7.71-7.67 (m, 1H), 7.10-7.07 (m, 1H), 6.88-6.83 (m, 1H), 2.51 (s, 3H). ESI-MS m / z 172[M+H] + .

[0173] (ii) Preparation of 4-fluoro-2-(methoxy-d3)phenol (Compound 6)

[0174] 1-(4-fluoro-2-(methoxy-d3)phenyl)ethan-1-one (20 g) and dichloromethane (120 ml) were added to the reaction bottle, stirred, m-chloroperbenzoic acid (44 g) was added, the temperature was raised to reflux for 24 h, and a solid was precipitated; after the reaction was completed, the temperature was lowered to room temperature, filtered, and the solvent was removed under reduced pressure to obtain a crude product; ethanol (60 ml), water (60 ml), and sodium hydroxide (14.4 g) were added to the crude product and stirred for 24 h. Concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 7, and dichloromethane was added for extraction. The organic layer was washed with water and saturated brine, sodium sulfate was added to the organic layer, dried, filtered, and the solvent was removed under reduced pressure to obtain a mixture, ethyl acetate and petroleum ether were added, stirred and slurried, filtered, and the filtrate was decompressed to remove the solvent to obtain a black oily substance. The oily substance was purified by column chromatography (ethyl acetate: petroleum ether = 10:1) to obtain 12.3 g of the title compound. 1 H NMR (400MHz, DMSO-d6) δ: 8.87 (m, 1H), 6.84-6.81 (m, 1H), 6.77-6.74 (m, 1H), 659-6.54 (m, 1H).

[0175] In addition, compound 10 can be prepared by acylation reaction of compound 15 with phenyl chloroformate (compound 16):

[0176] Preparation of dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylate (Compound 10)

[0177]

[0178] Add potassium carbonate (1.1 g) and water (12 ml) to the reaction bottle, stir to dissolve, cool to 5-10°C, add tetrahydrofuran (12 ml), slowly add 4-aminothiophene-2,3-dicarboxylic acid dimethyl ester hydrochloride (compound 15, 2.0 g), stir, add phenyl chloroformate (compound 16, 1.3 g), stir for 20 hours, and detect by thin layer chromatography; after the reaction is completed, stand, separate the liquids, add methyl tert-butyl ether to the aqueous layer for extraction, wash the organic layer with saturated brine, and remove the solvent under reduced pressure to obtain a light yellow liquid. Add methyl tert-butyl ether and heptane to the residue for crystallization to obtain 1.9 g of the title compound. 1H NMR (400MHz, DMSO-d6) δ: 10.23 (m, 1H), 7.80 (s, 1H), 7.45-7.41 (m, 2H), 7.28-7.25 (m, 1H), 7.21-7.19 (m, 2H), 3.82 (s, 6H); ESI-MSm / z 336[M+H] + .ESI-MS.m / z336[M+H] + .

[0179] Example 2 Preparation of 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy-d2)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 17)

[0180]

[0181] The method described in Example 1 is used, except that in the step from formula (II) to formula (III) according to synthetic route 1, deuterated iodomethane (CD3I) is replaced by iodomethane, thereby obtaining the target compound 17. 1 H NMR (400MHz, DMSO-d6) δ: 14.55 (s, 1H), 12.02 (s, 1H), 7.51-7.44 (m, 1H), 7.40 (s, 1 H), 7.26 (d, J=7.2Hz, 1H), 7.13 (d, J=11.6Hz, 1H), 6.93-6.90 (m, 1H), 3.81 (s, 3H). ESI-MS m / z 514[M+H] + .

[0182] Example 3 Preparation of 3-(5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d2)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 18)

[0183]

[0184] The method described in Example 1 is used, except that in the step from formula (V) to formula (VII) according to synthetic route 1, 4-fluoro-2-methoxyphenol is used to replace 4-fluoro-2-(methoxy-d3)phenol to obtain the target compound 18. 1H NMR (400MHz, DMSO-d6) δ: 14.57 (s, 1H), 11.99 (s, 1H), 7.53-7.48 (m, 1H), 7.38 (s, 1H), 7.26-7.18 (m, 2H), 7.14 (d, J=11.6Hz, 1H), 3.84 (s, 3H); ESI-MS m / z 514(M+H) + .

[0185] Example 4 Preparation of 3-(5-((2,3-difluoro-6-(methoxy-d3)benzyl)oxy)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 19)

[0186]

[0187] The method described in Example 1 is carried out, except that in the step from formula (III) to formula (IV) according to synthesis route 1, NaBH4 is used instead of NaBD4, and in the step from formula (V) to formula (VII), 4-fluoro-2-methoxyphenol is used to replace 4-fluoro-2-(methoxy-d3)phenol, thereby obtaining the target compound 19. 1 H NMR (400MHz, DMSO-d6) δ: 14.57 (s, 1H), 12.00 (s, 1H), 7.53-7.48 (m, 1H), 7.39 (s, 1H), 7. 26 (d, J=7.2Hz, 1H), 7.23-7.19 (m, 1H), 7.14 (d, J=11.6Hz, 1H), 4.90 (s, 2H), 3.84 (s, 3H). ESI-MS m / z 512(M+H) + .

[0188] Example 5 Preparation of 3-(5-((2,3-difluoro-6-(methoxy-d3)benzyl)oxy)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 20)

[0189]

[0190] The method described in Example 1 is used, except that in the step from formula (III) to formula (IV) according to synthesis route 1, NaBH4 is used instead of NaBD4 to obtain the target compound 20. 1H NMR (400MHz, DMSO-d6) δ: 14.57 (s, 1H), 12.00 (s, 1H), 7.53-7.48 (m, 1H), 7.39 (s, 1 H), 7.25 (d, J=7.2Hz, 1H), 7.23-7.19 (m, 1H), 7.13 (d, J=11.6Hz, 1H), 4.90 (s, 2H). ESI-MS m / z 515(M+H) + .

[0191] Example 6 Preparation of 3-(5-(((2,3-difluoro-6-methoxyphenyl)methoxy-d2)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 21)

[0192]

[0193] 1. Preparation of (2,3-difluoro-6-methoxyphenyl)methane-d2-ol (Compound 24)

[0194] At room temperature, compound 23 (2.0 g) and tetrahydrofuran (15 ml) were added to the reaction bottle, the temperature was lowered to -10 to -5 °C, sodium borodeuteride (1.3 g) was added, and iodine (2.7 g) and tetrahydrofuran (6 ml) were prepared into a solution under stirring; the temperature was controlled at about -10 °C and the above reaction solution was added dropwise, stirred for 2 h, and then the temperature was raised to 40 °C and the reaction was carried out for 48 h. After the reaction was completed, the reaction solution was poured into ice water, toluene was added for extraction, washed with water, and desolventized to obtain 1.4 g of the title compound. ESI-MS m / z 159 [M+H-H2O] + .

[0195] 2. Preparation of 2-(chloromethyl-d2)-3,4-difluoro-1-methoxybenzene (Compound 25)

[0196] Compound 24 (1.4 g), toluene (15 ml) and concentrated hydrochloric acid (15 ml) were added to the reaction flask, and the temperature was raised to 40°C and the reaction was carried out for 24 hours. After the reaction was completed, the temperature was lowered, stirring was stopped, the mixture was allowed to stand, and the liquids were separated. Toluene was added to the aqueous layer for extraction, and the mixture was washed with water and desolventized to obtain 1.2 g of the title compound.

[0197] 3. Preparation of 1,2-difluoro-3-((4-fluoro-2-methoxyphenoxy)methyl-d2)-4-methoxybenzene (Compound 27)

[0198] Compound 25 (1.2 g), 4-fluoro-2-methoxyphenol (compound 26, 0.9 g), tetrahydrofuran (12 ml) were added to the reaction bottle, and 25% NaOH aqueous solution (1.4 g) was added, and the temperature was raised to 60°C and reacted for 20 h. Thin layer chromatography plate detection was performed. After the reaction was completed, the temperature was lowered, water was added, and the mixture was stirred for 30 min, allowed to stand, and separated. Toluene was added to the aqueous layer for extraction, and the mixture was washed with water and desolventized to obtain 2 g of a crude product. The solid was purified by crystallization from isopropanol / water to obtain 1.0 g of the title compound. 1 H NMR (400MHz, DMSO-d6) δ: 7.50-7.42(m, 1H), 7.05-7.01(m, 1H), 6.92-6.88(m, 2H), 6.70-6.65(m, 1H), 3.80(s, 3H), 3.74(s, 3H); ESI-MS m / z 299[MH] - .

[0199] 4. Preparation of 1,2-difluoro-3-((4-fluoro-2-methoxy-5-nitrophenoxy)methyl-d2)-4-methoxybenzene (Compound 28)

[0200] Compound 27 (1.0 g), acetic acid (8 ml) and nitric acid (0.5 g) were added to the reaction bottle, and the temperature was raised to 60°C for 8 h. After the reaction, the temperature was lowered to room temperature, water was added, stirred for 2 h, filtered and dried to obtain 0.8 g of the title compound. 1 H NMR (400MHz, DMSO-d6) δ: 7.85 (d, J=7.6Hz, 1H), 7.53-7.46 (m, 1H), 7.26 (d, J=13.2Hz, 1H), 6.95-6.91 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H); ESI-MS m / z 344[MH] - .

[0201] 5. Preparation of 5-((2,3-difluoro-6-(methoxy-d3)phenyl)methoxy-d2)-2-fluoro-4-(methoxy-d3)aniline (Compound 29)

[0202] Compound 28 (0.8 g) and ethyl acetate were added to the reaction bottle, and the mixture was replaced with hydrogen twice. A 10% palladium-carbon catalyst (0.1 g) was added, and the mixture was replaced with hydrogen again. Hydrogen was introduced and stirred at room temperature for 20 h. The reaction was completed after detection on a thin layer chromatography plate. The reaction solution was filtered through diatomaceous earth and washed with ethyl acetate. The solvent was removed under reduced pressure to obtain a crude product. The solid was purified by crystallization with methanol and water to obtain 0.5 g of the title compound. 1H NMR (400MHz, DMSO-d6) δ: 7.48-7.41 (m, 1H), 6.91-6.88 (m, 1H), 6.76 (d, J=12. 4Hz, 1H), 6.54 (d, J=8.8Hz, 1H), 4.64 (s, 2H), 3.81 (s, 3H), 3.61 (s, 3H); ESI-MS m / z316[M+H] + .

[0203] 6. Preparation of dimethyl 4-(3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy-d2)-2-fluoro-4-methoxyphenyl)ureidothiophene-2,3-dicarboxylate (Compound 30)

[0204] Compound 29 (0.5 g), dimethyl 4-((phenoxycarbonyl)amino)thiophene-2,3-dicarboxylate (compound 10, 0.6 g), and tetrahydrofuran (5 ml) were added to the reaction bottle, stirred, and triethylamine (0.1 g) was added. The temperature was raised to 30°C, and stirred for 24 h. The reaction was detected by thin layer chromatography. After the reaction was completed, the reaction solution was decompressed to remove the solvent to obtain a crude product. Ethyl acetate and methanol were added to slurry to obtain 0.5 g of the title compound. 1 H NMR (400MHz, DMSO-d6) δ: 8.95 (s, 1H), 8.82 (s, 1H), 7.94 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.49-7.42 (m, 1H ), 7.00 (d, J=12.8Hz, 1H), 6.91-6.89 (m, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.71 (s, 3H); ESI-MS m / z 557[M+H] + .

[0205] 7. Preparation of 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy-d2)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 21)

[0206] Add compound 30 (0.5 g), tetrahydrofuran (1.5 ml), methanol (1.5 ml) and water (1.5 ml) to the reaction bottle and stir until the solid does not dissolve; prepare a 7.3% aqueous solution of lithium hydroxide monohydrate and add it to the reaction bottle at room temperature, stir for 3 hours, heat to 30°C, stir for 24 hours, the solid in the reaction solution disappears, the solution becomes clear, and the reaction is completed by thin layer chromatography. Add acetic acid to the reaction solution, stir at 30°C for 3-5 hours, and detect by thin layer chromatography. Add water, cool to 0-10°C, stir for 2-3 hours, and filter to obtain 0.46 g of the target compound. 1H NMR (400MHz, DMSO-d6) δ: 14.56 (s, 1H), 12.03 (s, 1H), 7.52-7.45 (m, 1H), 7.40 (s, 1H), 7.27 (d, J=7.6Hz, 1H), 7.14 (d, J=11.6Hz, 1H), 6.92-6.90 (m, 1H), 3.81 (s, 6H); ESI-MS m / z 511[M+H] + .

[0207] Example 7 Preparation of 3-(5-((2,3-difluoro-6-methoxybenzyl)oxy)-2-fluoro-4-(methoxy-d3)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (Compound 22)

[0208]

[0209] The target compound 22 was prepared by the method described in Example 1, except that in steps (II) to (III), CH3I was used instead of CD3I, and in steps (III) to (IV), NaBH4 was used instead of NaBD4. 1 H NMR (400MHz, DMSO-d6) δ: 14.55 (s, 1H), 12.02 (s, 1H), 7.52-7.45 (m, 1H), 7.40 (s, 1H), 7. 26 (d, J=7.2Hz, 1H), 7.13 (d, J=11.2Hz, 1H), 6.93-6.90 (m, 1H), 4.96 (s, 2H), 3.81 (s, 3H). ESI-MSm / z 512(M+H) + .

[0210] Example 8: Pharmacokinetic Evaluation in Rats

[0211] 8.1 Pharmacokinetic Test Evaluation

[0212] Male SD rats, weighing about 180g, were fasted overnight and divided into 3 groups, 4 rats in each group, and administered by gavage. The first group was gavaged with 3mg / kg of a control compound Linzagolix and 3mg / kg of an equal mixture of compound 1, the second group was gavaged with 3mg / kg of a control compound Linzagolix and 3mg / kg of an equal mixture of compound 21, and the third group was gavaged with 3mg / kg of a control compound Linzagolix and 3mg / kg of an equal mixture of compound 22. The solvent for each group was 0.5% CMC: 0.1% Tween80 aqueous solution. Blood was collected from each group at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24h after administration, and the concentration of each component in plasma was determined by LC / MS / MS.

[0213] 8.2 Test Results

[0214] The blood concentration-time curves of each drug combination are as follows Figure 1 The pharmacokinetic parameters are shown in Table 1:

[0215] Table 1 Summary of pharmacokinetic parameters of Example 8 (n=4, mean)

[0216]

[0217] As shown in Table 1, when an equal amount of the compound of the present invention and the control compound Linzagolix were administered by gavage to the same rats, the compound of the present invention showed better pharmacokinetic properties in rats compared with the control compound. Among them, the plasma exposure AUC and maximum blood drug concentration (Cmax) of compound 1, compound 21 and compound 22 were improved to a certain extent, among which the improvement of compound 1 and compound 21 was the most significant (AUC increased by 22.2% and 53.7% respectively; Cmax increased by 65.98% and 60.8% respectively).

[0218] Example 9: Pharmacokinetic Evaluation in Rats

[0219] 9.1 Pharmacokinetic Test Evaluation

[0220] Male SD rats, weighing about 180g, were fasted overnight and divided into 3 groups, each with 4 rats, and administered separately in parallel. The first group was given 3mg / kg of the control compound Linzagolix by gavage, the second group was given 3mg / kg of compound 21 by gavage, and the third group was given 3mg / kg of compound 20 by gavage. The solvent for each group was 0.5% CMC: 0.1% Tween80 aqueous solution. Blood was collected from each group at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24h after administration, and the concentration of each component in plasma was determined by LC / MS / MS.

[0221] 9.2 Test Results

[0222] The blood concentration-time curves of each drug combination are as follows Figure 2 The pharmacokinetic parameters are shown in Table 2:

[0223] Table 2 Summary of pharmacokinetic parameters of Example 9: (n=4, mean)

[0224]

[0225] As shown in Table 2, at the same dosage, the maximum blood drug concentrations (Cmax) of Compound 21 and Compound 20 were significantly increased by 38.6% and 41.3%, respectively, compared with the control compound Linzagolix. In addition, the plasma exposure AUC of Compound 21 was also significantly increased (28.1%), while the plasma exposure AUC of Compound 20 was comparable to that of the control compound.

[0226] The results of Example 8 and Example 9 show that compared with the control compound Linzagolix, the compounds of the present invention have better pharmacokinetic properties, especially the compounds 1 and 21 of the present invention have more excellent AUC and Cmax, and thus have better bioavailability and efficacy.

[0227] Example 10: Pharmacokinetic Evaluation in Beagle Dogs

[0228] 1. Pharmacokinetic test evaluation

[0229] Four male beagle dogs, weighing 7-10 kg, were fasted overnight and administered by gavage. Each dog was simultaneously gavaged with a mixture of 5 mg / kg of the control compound Linzagolix and 5 mg / kg of compound 21 in equal amounts. The solvent was a 0.5% CMC: 0.1% Tween80 aqueous solution. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 h after administration, and the concentrations of each component in plasma were determined by LC / MS / MS.

[0230] 2. Test results

[0231] The blood concentration-time curve of the drug is Figure 3 The pharmacokinetic parameters are shown in Table 3:

[0232] Table 3 Summary of pharmacokinetic parameters of Example 10: (n=4, mean)

[0233]

[0234] As shown in Table 3, when an equal amount of the compound 21 of the present invention and the control compound Linzagolix were administered by gavage simultaneously in beagle dogs, the compound of the present invention exhibited better pharmacokinetic properties in beagle dogs compared with the control compound. Compared with the control compound Linzagolix, the plasma exposure AUC and maximum blood drug concentration (Cmax) of the compound 21 of the present invention were greatly improved, and its AUC and Cmax increased by 191.1% and 208.3%, respectively.

[0235] Example 11: Pharmacokinetic Evaluation in Beagle Dogs

[0236] 1. Pharmacokinetic test evaluation

[0237] Four male beagle dogs weighing 7-10 kg were fasted overnight and gavage was performed using a crossover design (2*2 crossover), with a one-week interval between two rounds of administration. Each group was gavaged with 5 mg / kg of the control compound Linzagolix or 5 mg / kg of compound 21. The solvent was a 0.5% CMC: 0.1% Tween80 aqueous solution. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 h after administration, and the concentrations of each component in plasma were determined by LC / MS / MS.

[0238] 2. Test results

[0239] The blood concentration-time curve of the drug is Figure 4 The pharmacokinetic parameters are shown in Table 4:

[0240] Table 4 Summary of pharmacokinetic parameters of Example 11: (n=4, mean)

[0241]

[0242] As shown in Table 4, under the same dosage, the compound 21 of the present invention exhibited better pharmacokinetic properties in beagle dogs than the control compound Linzagolix through 2*2 cross-administration. Compared with the control compound Linzagolix, the plasma exposure AUC and maximum blood drug concentration (Cmax) of the compound of the present invention were greatly improved, with AUC and Cmax increasing by 115.0% and 107.3%, respectively.

[0243] The results of Examples 10 and 11 show that compared with the control compound Linzagolix, the compounds of the present invention have better pharmacokinetic properties, especially the compound 21 of the present invention has more excellent AUC and Cmax, and thus has better bioavailability and efficacy.

[0244] Example 12 Pharmaceutical Composition

[0245] In this example, any one of the compounds of formula I prepared in Examples 1-7 (especially compound 1 or 21) was used to prepare a pharmaceutical composition according to the following formula.

[0246]

[0247]

[0248] According to the conventional method, the above substances are mixed evenly and then put into ordinary gelatin capsules to obtain 1000 capsules.

[0249] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference separately. In addition, it should be understood that after reading the above content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A deuterated tetrahydrothieno[3,4-d]pyrimidinedione compound represented by formula (I) or a pharmaceutically acceptable salt thereof: It is characterized in that The compound is selected from the group consisting of: 。 2. A pharmaceutical composition, characterized in that Comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition further comprises another therapeutic drug, wherein the other therapeutic drug is a drug for treating cancer, cell proliferative disease, cardiovascular disease, inflammation, infection, immune disease, viral disease, analgesia or metabolic disease.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2, characterized in that: Used for preparing a pharmaceutical composition for inhibiting gonadotropin-releasing hormone (GnRH).

Images