Deuterated pyrimidine derivatives and pharmaceutical compositions containing the same

Abstract

The present invention relates to a deuterated pyrimidine derivative represented by formula I or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof. The present invention also relates to a pharmaceutical composition containing a pharmaceutically acceptable carrier and a deuterated pyrimidine derivative or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof. The compound represented by general formula I of the present invention is a BTK inhibitor, which is a preventive and / or therapeutic agent for BTK-related diseases and has a good therapeutic effect on allergic disorders, autoimmune diseases, inflammatory diseases, thromboembolic diseases or cancer.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a deuterated pyrimidine derivative, a pharmaceutical composition containing the compound and application thereof. Background Art

[0002] B cell signal transduction via the B cell receptor (BCR) can produce a wide range of biological output signals, and abnormal BCR-mediated signal transduction can cause dysregulated B cell activation and / or the formation of pathogenic autoantibodies that lead to a variety of autoimmune diseases and / or inflammatory diseases. Mutations in BTK in humans lead to X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). This disease is associated with impaired B cell maturation, reduced immunoglobulin production, impaired immune responses that are independent of T cells, and significant reductions in sustained calcium signals during BCR stimulation. Evidence that BTK plays a role in allergic diseases and / or autoimmune diseases and / or inflammatory diseases has been determined in BTK-deficient mouse models.

[0003] Due to the role of BTK in B cell activation, BTK inhibitors can be used as inhibitors of B cell-mediated pathogenic activities (such as the production of autoantibodies). BTK is also expressed in osteoclasts, mast cells and monocytes and has been shown to be important for the function of these cells.

[0004] Therefore, inhibition of BTK activity can be used to treat allergic diseases and / or autoimmune diseases and / or inflammatory diseases, such as rheumatoid arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis and asthma (Di Paolo et al. (2011) Nature Chem. Biol. 7(1):41-50; Liu et al. (2011) Jour. of Pharm. and Exper. Ther. 338(1):154-163).

[0005] Furthermore, aberrant activation of BTK plays an important role in the pathogenesis of B-cell lymphomas, which means that inhibition of BTK is useful in the treatment of hematological malignancies (Davis et al., Nature 463:88-92, 2010). Since BTK plays a central role as a mediator in multiple signal transduction pathways, inhibiting BTK activity can be anti-inflammatory and / or anti-cancer, and can be used for cancer and the treatment of B-cell lymphoma, leukemia and other hematological malignancies (Mohamed et al., Immunol. Rev. 228:58-73, 2009; Pan, Drug News perspect 21:357-362, 2008; Rokosz et al., Expert Opin. Ther. Targets 12:883-903, 2008; Uckun et al., Anti-cancer Agents Med. Chem. 7:624-632, 2007; Lou et al., J. Med. Chem. 55(10):4539-4550, 2012).

[0006] Moreover, considering the role of BTK in osteoclast function, inhibition of BTK activity can be used to treat bone diseases, such as osteoporosis. Therefore, compounds with BTK inhibitory activity are useful for the treatment of diseases associated with B cells and / or mast cells, such as allergic diseases, autoimmune diseases and, inflammatory diseases, thromboembolic diseases, cancer, etc. (Uckun et al. (2007) Anticancer Agents in Medicinal Chemistry. 7 (6): 624-632).

[0007] Evobrutinib is a BTK inhibitor developed by Merck KGaA in Germany. Data from a Phase II trial published at the 73rd Annual Meeting of the American Academy of Neurology (AAN) in 2021 showed that in patients with multiple sclerosis (MS), treatment with the highly selective oral BTK inhibitor evobrutinib significantly reduced blood neurofilament light chain (NfL) levels, a key biomarker of neural damage and inflammation that can monitor disease activity and treatment response. These data provide key insights into the role that evobrutinib may play in regulating the clinical course of MS and further suggest that BTK inhibition by evobrutinib can reduce tissue damage associated with MS.

[0008] The metabolism of Evobutinib in vivo and in vitro is complex. Li Z et al. studied the metabolites of Evobutinib in rat and human hepatocytes, identified 23 metabolites, and speculated on their metabolic pathways (Li Z, et al. Drug Test Anal. 2019; 11: 129–139). Holger Scheible1 et al. studied the metabolism of Evobutinib in healthy volunteers, identified 40 phase I metabolites and 18 phase II metabolites, and speculated on their metabolic pathways (Scheible H, et al. Clin Transl Sci. 2021; 14: 2420–2430). The specific metabolic pathway of Evobutinib is not very clear, and the elimination half-life of Evobutinib in humans is short, at 1.33 hours (Scheible H, et al. Clin Transl Sci. 2021; 14: 2420–2430). Furthermore, the effects of the absorption, distribution, metabolism and / or excretion of Evobutinib on its efficacy and / or toxicity are still not fully understood, and there is the possibility of improvement.

[0009] The poor absorption, distribution, metabolism and / or excretion (ADME) performance of some current drugs has hampered their wider use or limited their application in specific indications. For example, due to the short elimination half-life of drugs in the body and rapid clearance, the commonly used solution is to administer drugs frequently or in high doses to obtain sufficiently high plasma levels of drugs. However, this introduces a large number of potential treatment problems, such as patient compliance with medication intervals, and higher doses, which will make side effects more severe and increase treatment costs. Rapidly metabolized drugs may also expose patients to undesirable toxic or reactive metabolites.

[0010] Another ADME limitation affecting drugs is the formation of toxic or biologically reactive metabolites. Therefore, some patients receiving drugs may experience toxicity, or the safe dose of such drugs may be limited so that patients receive treatment that is not the best amount (suboptimal). In some cases, changing the dosing interval or formulation method can help reduce clinical adverse reactions, but the frequent formation of such undesirable metabolites is inherent in the metabolism of the compound.

[0011] A potential attractive strategy for improving drug metabolism performance is deuterium modification (modification). In this method, people attempt to slow down the metabolism of the drug, or by replacing one or more hydrogen atoms with deuterium atoms to reduce the formation of undesirable metabolites. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared with hydrogen, deuterium forms a stronger chemical bond with carbon. In selected cases, the bond strength of the increase given by deuterium can positively affect the ADME performance of the drug, with the potential for improving drug effect, safety, and / or tolerability. Meanwhile, because the size and shape of deuterium are substantially equivalent to hydrogen, compared with the original chemical entity that only comprises hydrogen, it is expected that replacing hydrogen with deuterium will not affect the biochemical efficacy and selectivity of the drug.

[0012] However, due to the complex metabolic process of biological systems, the pharmacokinetic properties of drugs in vivo are affected by many factors and also show corresponding complexity. Compared with the corresponding non-deuterated drugs, the changes in the pharmacokinetic properties of deuterated drugs show great contingency and unpredictability. For some compounds, deuteration slows down their metabolic clearance and half-life in the body; for other compounds, deuteration does not cause metabolic changes; for other other compounds, deuteration speeds up metabolic clearance and shortens half-life (Blake, MI et al, J Pharm Sci, 1975, 64: 367-91; Foster, AB, Adv Drug Res 1985, 14: 1-40 ("Foster"); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Dev , 2006, 9: 101-09 ("Fisher")).

[0013] Therefore, deuterium substitution at certain sites of a compound not only fails to increase the half-life, but may shorten it (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, P405-406), deteriorating its pharmacokinetic properties; on the other hand, hydrogen at certain positions on the drug molecule is not easily deuterated due to steric hindrance and other reasons. Even when deuterium atoms are incorporated into known metabolic sites, the effect of deuterium modification (deuterium modification) on drug metabolism is not predictable. Only by actually preparing and testing deuterated drugs can it be determined whether and how the rate of metabolism will be different from the corresponding chemical entity of non-deuterated. Many drugs have multiple sites that may be metabolized. The position (site) where deuterium substitution is required and the degree of deuteration required to find the effect on metabolism, if any, will be different for each drug (Fukuto et al. J. Med. Chem. 1991, 34, 2871-76).

[0014] In addition, deuteration can lead to metabolic switching. The concept of metabolic switching indicates that when a drug is encapsulated by a phase I metabolizing enzyme, it can briefly bind and rebind with the phase I metabolizing enzyme in various conformations before a chemical reaction (such as an oxidation reaction). Therefore, metabolic switching can potentially lead to different proportions of known metabolites and new metabolites. This new metabolic property can cause more or less toxicity. And lead to faster or slower drug clearance, thereby reducing or increasing the drug's in vivo exposure. Such changes caused by metabolic switching are unpredictable, and so far no sufficient a priori prediction has been made for any drug.

[0015] As mentioned above, the effect of deuterium modification on drug metabolism is unpredictable. Evobutinib and its metabolites in vivo have the defect of hepatotoxicity risk, and clinical trials of Evobutinib have also shown hepatotoxicity, causing great clinical concerns. Hepatotoxicity is not only related to the chemical structure, but also closely related to the clinical dosage.

[0016] Therefore, in view of the shortcomings of existing technologies, we design new compounds to increase the exposure of new compounds in the body, reduce the dosage and / or frequency of administration, and reduce liver toxicity; and / or reduce the liver toxicity of its prototype or metabolites through structural modification, or reduce the generation of its toxic metabolites, so as to achieve the purpose of reducing toxicity and increasing efficacy. Summary of the invention

[0017] The purpose of the present invention is to provide a new type of compound having BTK inhibitory activity and better pharmacodynamic properties and its use.

[0018] In the first aspect of the present invention, there is provided a deuterated pyrimidine derivative represented by formula I or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof.

[0019]

[0020] Where: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 or R 20 are each independently selected from hydrogen (H) or deuterium (D), provided that R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 or R 20 At least one of them is deuterium.

[0021] In a preferred embodiment, the compound is a preferred compound selected from the following group or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof:

[0022]

[0023] In another preferred embodiment, the compound is a preferred compound selected from the following group or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof:

[0024]

[0025] 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 a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof to form a pharmaceutical composition.

[0026] In the third aspect of the present invention, a pharmaceutical composition is provided, which contains a pharmaceutically acceptable carrier or excipient and the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate.

[0027] In another preferred embodiment, the pharmaceutical composition is a capsule, tablet, injection, pill, powder or granule.

[0028] In the fourth aspect of the present invention, provided is the use of the compound described in the first aspect of the present invention or its pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate, which is used to prepare a pharmaceutical composition for inhibiting BTK.

[0029] In another preferred embodiment, the pharmaceutical composition is used to prevent and / or treat diseases related to BTK.

[0030] In another preferred embodiment, the pharmaceutical composition is used to prevent and / or treat allergic diseases, autoimmune diseases, inflammatory diseases, thromboembolic diseases or cancer.

[0031] In another preferred embodiment, the pharmaceutical composition is used to treat autoimmune diseases, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), chronic spontaneous urticaria, neuromyelitis optica or rheumatoid arthritis (RA).

[0032] In another preferred embodiment, the pharmaceutical composition is used to treat cancers including (but not limited to): lymphoma, leukemia, non-small cell lung cancer, uterine cancer, colorectal cancer, brain cancer, head cancer, neck cancer, bladder cancer, prostate cancer, breast cancer, kidney cancer, liver cancer, gastric cancer, or pancreatic cancer.

[0033] In the fifth aspect of the present invention, a treatment method is provided, which comprises the steps of administering the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, or administering the pharmaceutical composition described in the third aspect of the present invention to a subject in need of treatment, thereby inhibiting BTK.

[0034] As used herein, "deuterated" refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium. Deuterated can be monosubstituted, disubstituted, polysubstituted or fully substituted.

[0035] 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%), more preferably greater than 50%, more preferably greater than 85%, more preferably greater than 95%, more preferably greater than 99%, more preferably greater than 99.5%. In another preferred embodiment, the compound of formula I contains at least 1 or 3 deuterium atoms, more preferably 5 or 8 deuterium atoms.

[0036] As used herein, the term "compound of the present invention" refers to a compound represented by Formula I. The term also includes a crystalline form of the compound of Formula I, a salt thereof, a hydrate thereof, or a solvate thereof.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug, and pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a 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, phosphoric acid, formic acid, acetic 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, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.

[0038] The positive and progressive effects of the present invention are:

[0039] (1) The compounds of the present invention have good selective BTK inhibitory effects and can be effectively used for treating diseases associated with BTK.

[0040] (2) The compound of the present invention has good selectivity in inhibiting B cell activation and is effectively used as a B cell activation inhibitor.

[0041] (3) The deuterated pyrimidine derivatives of the present invention have low hepatotoxicity, good pharmacokinetic properties, reduced dosage and / or reduced toxic and side effects, and better drugability. DETAILED DESCRIPTION

[0042] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0043] 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 limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs.

[0044] The preparation methods of the non-deuterated pyrimidine derivatives and their physiologically compatible salts used in the present invention are known. The corresponding deuterated pyrimidine derivatives can be synthesized using the corresponding deuterated starting compounds as raw materials and in the same way.

[0045] Example 1: Synthesis of Compound H106

[0046] Synthetic route

[0047]

[0048] Step 1: Synthesis of compound H003

[0049]

[0050] 5,6-Dichloropyrimidin-4-amine (compound H001) (1.51mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (compound H002) (3.02mmol) and N,N-diisopropylethylamine (6.04mmol) were suspended in NMP (2.50ml) and subjected to microwaves at 150°C for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was purified by Biotage column chromatography, eluting with 50-100% EtOAc / hexane, and the fractions containing the product were combined and concentrated under reduced pressure to obtain compound H003 as a yellow viscous oil.

[0051] Step 2: Synthesis of compound H005

[0052]

[0053] Compound H003 (1.70mmol), compound H004 (2.55mmol), palladium acetate (0.08mmol), 2-dicyclohexylphosphine-2', 6'-dimethoxybiphenyl (0.17mmol), potassium carbonate (5.07mmol) were suspended in dioxane (8.00ml) and water (0.80ml) and subjected to microwave at 140°C for 20 minutes. The reaction mixture was cooled to room temperature, Na2S04 was added, filtered through a silica gel column and concentrated under reduced pressure. The crude mixture was purified by Biotage column chromatography, eluting with 80-100% EtOAc / hexane and 0-100% MeOH / EtOA. The fractions containing the product were combined and concentrated under reduced pressure. The residue was lyophilized to obtain compound H005 as a yellow solid.

[0054] Step 3: Synthesis of compound H006

[0055]

[0056] Compound H005 (1.08 mmol) was dissolved in methanol (4.00 ml), and a solution of hydrogen chloride (2.0 M) in diethyl ether (5.40 ml) was added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and lyophilized to obtain compound H006 as a yellow solid.

[0057] Step 4: Synthesis of compound H106

[0058]

[0059] Compound H006 (0.20 mmol) and sodium bicarbonate (23.49 mg; 0.30 mmol) were suspended in THF (3.00 ml) and water (0.30 ml), cooled to 0°C, and compound H007 (0.23 mmol) was added. After the ice bath was allowed to melt, the reaction mixture was stirred overnight at room temperature. The crude mixture was purified by Biotage column chromatography, eluting with 0-50% MeOH / EtOAc. The product fractions were combined and concentrated under reduced pressure. The residue was lyophilized to obtain compound H106 as a white solid. The H NMR spectrum of compound H106 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(3H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0060] Example 2: Synthesis of Compound H106

[0061] For the synthesis of compound H106, step 4 in "Example 1: Synthesis of compound H106" was replaced with the following step 5. The remaining steps were carried out in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H106 as a white solid.

[0062] Step 5: Synthesis of compound H106

[0063]

[0064] Compound H006 (0.09 mmol) and N, N-diethylethylamine (0.02 ml, 0.18 mmol) were suspended in 1-methylpyrrolidin-2-one (0.35 ml) and dichloromethane (2.00 mL), cooled to 0°C, and H007 (0.28 mmol) was added. After the ice bath was allowed to melt, the reaction mixture was stirred overnight at room temperature. The crude mixture was purified by Biotage column chromatography, eluting with 0-40% MeOH / EtOAc. The product fractions were combined and concentrated under reduced pressure. The residue was lyophilized to obtain compound H106 as a white solid. The H NMR spectrum of compound H106 is:1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(3H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0065] Example 3: Synthesis of Compound H106

[0066] For the synthesis of compound H106, step 4 in "Example 1: Synthesis of compound H106" was replaced with the following step 6. The remaining steps were carried out in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H106 as a white solid.

[0067] Step 6: Synthesis of compound H106

[0068]

[0069] Compound H008 (0.01 ml; 0.12 mmol), bis(2-oxo-3-oxazolidinyl)phosphinoyl chloride (42.04 mg; 0.17 mmol) and N,N-diisopropylethylamine (0.07 ml; 0.41 mmol) were suspended in dioxane (3.00 ml), stirred at room temperature for 1 hour, and then compound H006 (40.00 mg; 0.08 mmol) was added. The reaction mixture was stirred overnight at room temperature. The crude mixture was purified by Biotage column chromatography, eluting with 50-100% EtOAc / hexane and 0-40% MeOH / EtOAc. The product fractions were combined and concentrated under reduced pressure. The residue was then purified by preparative HPLC with a mobile phase of 35-45% CH3CN in 0.1% TFA aqueous solution. The product fractions were combined and lyophilized to obtain compound H106 as a white solid. The hydrogen nuclear magnetic resonance spectrum of compound H106 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(3H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0070] Example 4: Synthesis of Compound H106

[0071] For the synthesis of compound H106, step 1 in "Example 1: Synthesis of compound H106" was replaced with the following step 7. The remaining steps were carried out in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H106 as a white solid.

[0072]

[0073] Step 7: Compound H001 (100 mg, 0.61 mmol), compound H002 (117.24 mg, 0.91 mmol) and DBU (0.18 mL 1.22 mmol) were dissolved in DMF (2 ml), and the reaction mixture was stirred at 90°C overnight and cooled to room temperature. The crude mixture was purified by column chromatography, eluting with 0-100% MeOH / EtOAc. The product fractions were combined and concentrated under reduced pressure. The residue was lyophilized to obtain compound H003 as a white solid.

[0074] Example 5: Synthesis of Compound H101

[0075] For the synthesis of compound H101, the compound H007 in step 4 of "Example 1: Synthesis of compound H106" was replaced with compound H009. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H101. The H NMR spectrum of compound H101 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(3H),6.8(2H),6.7(1H),6.0(1H),5. 6(1H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0076]

[0077] Example 6: Synthesis of Compound H102

[0078] For the synthesis of compound H102, the compound H004 in step 2 of "Example 5: Synthesis of compound H101" was replaced with compound H010. The remaining steps were the same as those in "Example 5: Synthesis of compound H101" to obtain compound H102. The H NMR spectrum of compound H102 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(5H),6.8(2H),6.7(1H),6.0(1H),5. 6(1H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0079]

[0080] Example 7: Synthesis of Compound H103

[0081] For the synthesis of compound H103, the compound H004 in step 2 of "Example 5: Synthesis of compound H101" was replaced with compound H011. The remaining steps were the same as those in "Example 5: Synthesis of compound H101" to obtain compound H103. The H NMR spectrum of compound H103 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(5H),6.8(2H),6.7(1H),6.0(1H),5. 6(1H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0082]

[0083] Example 8: Synthesis of Compound H104

[0084] For the synthesis of compound H104, the compound H004 in step 2 of "Example 5: Synthesis of compound H101" was replaced with compound H012. The remaining steps were the same as those in "Example 5: Synthesis of compound H101" to obtain compound H104. The H NMR spectrum of compound H104 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(7H),6.8(2H),6.7(1H),6.0(1H),5. 6(1H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0085]

[0086] Example 9: Synthesis of Compound H105

[0087] For the synthesis of compound H105, the compound H004 in step 2 of "Example 1: Synthesis of compound H106" was replaced with compound H013. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H105. The H NMR spectrum of compound H105 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(8H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0088]

[0089] Example 10: Synthesis of Compound H107

[0090] For the synthesis of compound H107, the compound H004 in step 2 of "Example 1: Synthesis of compound H106" was replaced with compound H010. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H107. The H NMR spectrum of compound H107 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(5H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0091]

[0092] Example 11: Synthesis of Compound H108

[0093] For the synthesis of compound H108, the compound H004 in step 2 of "Example 1: Synthesis of compound H106" was replaced with compound H011. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H108. The H NMR spectrum of compound H108 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(5H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0094]

[0095] Example 12: Synthesis of Compound H109

[0096] For the synthesis of compound H109, ​​the compound H004 in step 2 of "Example 1: Synthesis of compound H106" was replaced with compound H012. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H109. The H NMR spectrum of compound H109 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(7H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0097]

[0098] Example 13: Synthesis of Compound H110

[0099] For the synthesis of compound H110, the compound H004 in step 2 of "Example 5: Synthesis of compound H101" was replaced with compound H014. The remaining steps were the same as those in "Example 5: Synthesis of compound H101" to obtain compound H110. The H NMR spectrum of compound H110 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(4H),6.8(2H),6.7(1H),6.0(1H),5. 6(1H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0100]

[0101] Example 14: Synthesis of Compound H111

[0102] For the synthesis of compound H111, the compound H004 in step 2 of "Example 5: Synthesis of compound H101" was replaced with compound H015. The remaining steps were performed in the same manner as in "Example 5: Synthesis of compound H101" to obtain compound H111. The H NMR spectrum of compound H111 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(6H),6.8(2H),6.7(1H),6.0(1H),5. 6(1H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0103]

[0104] Example 15: Synthesis of Compound H112

[0105] For the synthesis of compound H112, the compound H004 in step 2 of "Example 5: Synthesis of compound H101" was replaced with compound H016. The remaining steps were the same as those in "Example 5: Synthesis of compound H101" to obtain compound H112. The H NMR spectrum of compound H112 is: 1H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(6H),6.8(2H),6.7(1H),6.0(1H),5. 6(1H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0106]

[0107] Example 16: Synthesis of Compound H113

[0108] For the synthesis of compound H113, the compound H004 in step 2 of "Example 1: Synthesis of compound H106" was replaced with compound H014. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H113. The H NMR spectrum of compound H113 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(4H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0109]

[0110] Example 17: Synthesis of Compound H114

[0111] For the synthesis of compound H114, the compound H004 in step 2 of "Example 1: Synthesis of compound H106" was replaced with compound H015. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H114. The H NMR spectrum of compound H114 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(6H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0112]

[0113] Example 18: Synthesis of Compound H115

[0114] For the synthesis of compound H115, the compound H004 in step 2 of "Example 1: Synthesis of compound H106" was replaced with compound H016. The remaining steps were performed in the same manner as in "Example 1: Synthesis of compound H106" to obtain compound H115. The H NMR spectrum of compound H115 is: 1 H-NMR(DMSO-d6)δ8.3(1H),7.4(2H),7.3-7.0(6H),6.8(2H),4.3(1H),4.0(1H),3.1(2H),3.0(1H),2.6(1H),1.8(1H),1.6(2H),0.9(2H).

[0115]

[0116] Example 19: Synthesis of Compound H004

[0117]

[0118] Step 8: Synthesis of Compound H022

[0119] Take phenol-d5 (compound H020) (9.4g), dissolve it in anhydrous tetrahydrofuran (100ml), stir, slowly add sodium hydride (9.6g) in batches, then add 1-bromo-4-iodobenzene (compound H021) (31.1g) in batches, react at room temperature for 15 hours, filter the reactant, spin dry the filtrate, add dichloromethane to dissolve. Pass through a column, elute with petroleum ether: ethyl acetate (1:5), and obtain compound H022 (11.6g)

[0120] Step 9: Synthesis of compound H004

[0121] Compound H022 (4.5 g) was dissolved in dry THF (100 ml), and reacted at -78 °C for 30 min under N2 protection. n-Butyl lithium (1.7 g) was slowly added dropwise, and the temperature was kept at -78 °C for 3 h after the addition was completed. Triisopropyl borate (3.8 g) was then slowly added dropwise, and the temperature was kept at -78 °C for 2 h after the addition was completed. The temperature was slowly raised to room temperature and the reaction was carried out for about 15 hr. After the reaction was completed as monitored by TLC, the reaction solution was slowly quenched with water, extracted and concentrated to obtain compound H004 (2.9 g).

[0122] Example 20: Synthesis of Compound H011

[0123] The synthesis of compound H011 was carried out according to "Example 19: Synthesis of compound H004", except that in step 8, compound H020 was replaced by compound H023. The remaining steps were carried out in the same manner as "Example 19: Synthesis of compound H004" to obtain compound H011.

[0124]

[0125] Example 21: Synthesis of Compound H010

[0126] The synthesis of compound H010 was carried out according to "Example 19: Synthesis of compound H004", except that in step 8, compound H020 was replaced by compound H024, and the remaining steps were carried out in the same manner as "Example 19: Synthesis of compound H004" to obtain compound H010.

[0127]

[0128] Example 22: Synthesis of Compound H012

[0129] The synthesis of compound H012 was carried out according to "Example 19: Synthesis of compound H004", except that in step 8, compound H020 was replaced by compound H025. The remaining steps were carried out in the same manner as "Example 19: Synthesis of compound H004" to obtain compound H012.

[0130]

[0131] Example 23: Synthesis of Compound H014

[0132] The synthesis of compound H014 was carried out according to "Example 19: Synthesis of compound H004", except that in step 8, compound H020 was replaced by compound H026. The remaining steps were carried out in the same manner as "Example 19: Synthesis of compound H004" to obtain compound H014.

[0133]

[0134] Example 24: Synthesis of Compound H015

[0135] The synthesis of compound H015 was carried out according to "Example 19: Synthesis of compound H004", except that in step 8, compound H020 was replaced by compound H027. The remaining steps were carried out in the same manner as "Example 19: Synthesis of compound H004" to obtain compound H015.

[0136]

[0137] Example 25: Synthesis of Compound H016

[0138] The synthesis of compound H016 was carried out according to "Example 19: Synthesis of compound H004", except that in step 8, compound H020 was replaced by compound H028. The remaining steps were carried out in the same manner as "Example 19: Synthesis of compound H004" to obtain compound H016.

[0139]

[0140] Example 26: Pharmacokinetic Evaluation in Rats

[0141] 42 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210 g, were divided into 7 groups (Evobutinib group, compound H101 group, H104 group, H106 group, H108 group, H109 group and H114 group), 6 rats in each group. Evobutinib, compound H101, H104, H106, H108, H109 or H114 were given by single oral gavage at a dose of 15 mg / kg according to the grouping, and their pharmacokinetic differences were compared.

[0142] Rats were fed with standard feed and fasted 12 hours before administration. The administration solution was prepared with 0.5% sodium carboxymethylcellulose (CMC-Na). Blood was collected from the orbital venous plexus at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after administration.

[0143] After the blood sample is collected, it is placed in a centrifuge tube coated with sodium heparin solution. Immediately and gently invert the tube at least 5 times to ensure sufficient mixing and then place it on ice. The blood sample is centrifuged at 5000 rpm for 5 minutes at 4°C to separate the plasma from the red blood cells. Use a pipette to aspirate 100 μL of plasma into a clean plastic centrifuge tube, mark the sample number and blood collection time point. The plasma is stored in a -80°C refrigerator before LC-MS / MS analysis.

[0144] The experimental results show that compared with Evobutinib, the elimination half-life of compound H101 is T 1 / 2 and / or area under the curve AUC and / or maximum plasma concentration C max The elimination half-life of compound H104 was increased by more than 40% compared with that of Evobutinib. 1 / 2 and / or area under the curve AUC and / or maximum plasma concentration C max The elimination half-life of compound H106 was increased by more than 50% compared with that of Evobutinib. 1 / 2 and / or area under the curve AUC and / or maximum plasma concentration C max The elimination half-life of compound H108 was increased by more than 50% compared with that of evobactinib. 1 / 2 and / or area under the curve AUC and / or maximum plasma concentration C max The elimination half-life of compound H109 was increased by more than 50% compared with that of Evobutinib. 1 / 2 and / or area under the curve AUC and / or maximum plasma concentration C maxThe elimination half-life of compound H114 was increased by more than 50% compared with that of Evobutinib. 1 / 2 and / or area under the curve AUC and / or maximum plasma concentration C max An increase of more than 40%.

[0145] From the present results, it can be seen that compound H101, compound H104, compound H106, compound H108, compound H109 and compound H114 of the present invention have better pharmacokinetic properties in animals, indicating better pharmacodynamics and therapeutic effects.

[0146] Example 27: Determination of BTK inhibitory activity

[0147] Using ADP-Glo TM The kit measures the effect of the compound of the present invention on the activity of BTK. The experimental method is as follows: ADP is the product of the kinase reaction, and the kinase activity can usually be detected by detecting the amount of ADP generated. ADP-Glo ​​developed by Promega TM The kit measures the in vitro activity of BTK by detecting the level of ADP produced in the kinase reaction. In the kinase detection experiment, the kinase consumes ATP to phosphorylate the substrate and produces ADP. Then the ADP-Glo ​​reagent is added to terminate the kinase reaction and completely consume the remaining ATP. The kinase detection reagent is then added to convert the generated ADP into new ATP. The luciferase in the detection reagent can catalyze luciferin with the participation of ATP and O2 to produce a light signal, thereby converting the chemical signal into a light signal, and the intensity of the light signal is positively correlated with the amount of ADP produced in the kinase reaction, so that the activity of the kinase BTK can be quantitatively detected.

[0148] All detection experiments were carried out at a constant temperature of 23°C, using Corning 3674 white 384-well detection plates, kinase BTK (Invitrogen), kinase substrates peptide (4:l Glu, Tyr) (Signal Chem) and ATP (Sigma), and light signals were read using an EnVision microplate reader (Perkin Elmer). The detection buffer included 40mM Tris-HCl (pH 7.5), 10mM MgCl2 (Sigma), 2mM MnCl2 (Sigma), 0.05mM DTT (Sigma) and 0.01% BSA (Sigma); the kinase BTK was prepared into a kinase reaction solution with a concentration of 1.3ng / μL using the detection buffer; the substrate reaction solution included 0.25mg / mL peptide substrate and 60μM ATP.

[0149] The compound of the present invention was diluted with DMSO to a 0.5 mM solution, and then three-fold gradient dilution was performed with DMSO to a minimum concentration of 0.025 μM. 50 nL of compound solution of a series of concentrations and 2.5 μL of kinase reaction solution were first added to a 384-well plate using Echo555, mixed evenly, and incubated at room temperature in the dark for 30 minutes; then 2.5 μL of substrate reaction solution was added, and the total reaction volume was 5.05 μL. The reaction mixture was reacted at room temperature in the dark for 60 minutes; then 5 μL of ADP-Glo ​​was added TM The reagent terminated the reaction, mixed evenly and placed at room temperature for 40 minutes; finally, 10 μL of kinase detection reagent was added, placed at room temperature away from light for 30 minutes, and then the value was read on Envision.

[0150] The inhibition percentage was calculated according to the following formula:

[0151] Inhibition % = [1-(RLU compound-RLUmin) / (RLUmax-RLUmin)]×100

[0152] Where RLU compound is the reading at a given concentration of the compound of the present invention, RLUmin is the reading without the addition of kinase BTK, and RLUmax is the reading without the addition of the compound of the present invention. The IC value of the compound was calculated by using the XLfit program in Excel 50 value.

[0153] Table 1: IC values ​​of compounds of the present invention 50 value

[0154] Compound <![CDATA[IC 50 (nM)]]> Compound <![CDATA[IC 50 (nM)]]> H101 11.8 H104 19.2 H103 24.6 H106 18.7 H108 22.5 H109 17.6 H110 27.4 H111 19.4 Evobrutinib 28.2

[0155] It can be seen from the present results that the compounds of the present invention have a good inhibitory effect on BTK, especially compounds H101, H104, H106, H109 and H111 are significantly higher than evobrutinib.

[0156] Example 28: Comparative study of liver toxicity in mice

[0157] (1) Experimental animals

[0158] Thirty-two adult male ICR mice with a body weight of (25±2 g) were selected, and all mice were allowed to freely access water and feed, and maintained under a day-night cycle at a temperature of 25±2° C. and a relative humidity of 50±10%.

[0159] (2) Animal grouping and drug administration

[0160] 32 male ICR mice were divided into four groups, 8 mice in each group, namely normal control group, model group, model + example compound group and model + evobactinib group. The model + example compound group was intragastrically administered with the example compound once a day at a dose (50 mg / kg); the model + evobactinib group was intragastrically administered with evobactinib once a day at a dose (50 mg / kg), respectively, for 8-16 weeks, and the normal control group and the model group were intragastrically administered with an equal volume of purified water. Food was cut off after the last administration, and 1 hour later, the mice in the model group, model + example compound group and model + evobactinib group were intraperitoneally injected with 250 mg / kg of APAP saline solution, respectively. After 24 hours of modeling, blood was collected from the eyeballs of mice in each group in turn, and the serum was separated by centrifugation at 3000r / min for 10 minutes, and stored at 4°C for later use; the liver and spleen were quickly dissected. After washing with 4°C saline, the liver was dried with filter paper and weighed. Part of the liver was fixed in 10% formaldehyde solution for slicing, and the remaining liver was stored in a -80°C low-temperature refrigerator.

[0161] (3) Determination of biochemical indicators in the liver:

[0162] Weigh part of the liver, add 9 times the volume of ice saline, use a tissue homogenizer to make 10% liver tissue homogenate, centrifuge and take the supernatant. Spot the plate according to the kit method, measure the OD value at 450nm, and calculate the MDA content and GSH activity in the liver according to the formula.

[0163] (4) Data processing

[0164] The experimental data were expressed as mean ± standard deviation (±s) and analyzed using SPSS22.0 statistical software. One-way analysis of variance was used to compare the differences between the groups. P < 0.05 was considered a significant difference.

[0165] (5) Effects of the compounds in the present examples on lipid peroxidation in liver tissue of mice with APAP liver injury

[0166] Compared with the normal control group, the MDA content in the liver tissue homogenate of the mice in the model group increased significantly, and the GSH level decreased significantly (P<0.05), resulting in the accumulation of lipid peroxidation products in the mice and the reduction of the antioxidant metabolism level; compared with the model group, there was no significant change in the MDA content and GSH level of the model + example compound group (P>0.05); compared with the model group, the MDA content of the model + evobactinib group increased significantly (P<0.05), and the GSH level decreased significantly (P<0.05), indicating that the example compound of the present application (50 mg / kg) had no significant effect on the lipid peroxidation caused by APAP, while evobactinib (50 mg / kg) had an effect on the lipid peroxidation caused by APAP, suggesting that the mouse liver toxicity of the example compound of the present application is significantly lower than that of evobactinib.

[0167] The results are shown in Table 2.

[0168] Table 2. Effects on lipid peroxidation in liver tissue of mice with APAP liver injury

[0169] Grouping MDA (nmol / mg) GSH (μmol / L) Normal control group A- B- Model Group A+ B+ Model + Example Compound Group A+ B+ Model+Evobutinib group A++ B++

[0170] Marking (grade): A+ is 2.5-3.5; A- is 1-2.3; A++ is 3.8-5; B+ is 29-40; B- is 42-60; B++ is 15-26.

[0171] Conclusion: The compound of the present invention (50 mg / kg) has no significant effect on lipid peroxidation induced by APAP, while Evobutinib (50 mg / kg) has an effect on lipid peroxidation induced by APAP, indicating that the compound of the present invention is significantly less toxic to the mouse liver than Evobutinib.

[0172] Finally, it is necessary to explain that the specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions made to the present invention are also within the scope of the present invention. Therefore, the equalization changes and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention.

Claims

1. A deuterated pyrimidine compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is any of the following compounds:

2. A pharmaceutical composition, characterized in that It comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a BTK inhibitor.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease associated with BTK, wherein the disease associated with BTK is an allergic disorder, an autoimmune disease, an inflammatory disease, a thromboembolic disease or a cancer, and the cancer is selected from lymphoma, leukemia, non-small cell lung cancer, uterine cancer, colorectal cancer, brain cancer, head cancer, neck cancer, bladder cancer, prostate cancer, breast cancer, kidney cancer, liver cancer, gastric cancer or pancreatic cancer.

5. The use according to claim 4, characterized in that: The autoimmune disease is selected from multiple sclerosis, systemic lupus erythematosus, chronic spontaneous urticaria, neuromyelitis optica or rheumatoid arthritis.

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