CN118063429A - Pyridinylamides as BTK inhibitors - Google Patents
Pyridinylamides as BTK inhibitors Download PDFInfo
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- CN118063429A CN118063429A CN202311563071.8A CN202311563071A CN118063429A CN 118063429 A CN118063429 A CN 118063429A CN 202311563071 A CN202311563071 A CN 202311563071A CN 118063429 A CN118063429 A CN 118063429A
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Abstract
The present invention relates to picolinamides as inhibitors of Bruton's Tyrosine Kinase (BTK). Specifically disclosed are deuterated compounds of 2- (4-phenoxyphenyl) -6- [1- (prop-2-enoyl) piperidin-4-yl ] pyridine-3-carboxamide and/or its tautomers, pharmaceutical compositions of its crystalline forms, its salts, its hydrates or solvates, and their use as prophylactic and/or therapeutic agents for BTK-related diseases.
Description
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to a pyridine amide compound serving as a BTK inhibitor.
Background
B cell signaling via the B Cell Receptor (BCR) can produce a wide range of biological output signals, and aberrant BCR-mediated signaling can lead to deregulated B cell activation and/or formation of pathogenic autoantibodies that lead to a variety of autoimmune and/or inflammatory diseases. Mutations in BTK in humans result in X-linked agarobroteinemia (XLA) (Conley et al, annu. Rev. Immunol.27:199-227, 2009). This disease is associated with impaired B cell maturation, reduced immunoglobulin production, impaired T cell-independent immune responses, and a significant decrease in sustained calcium signaling upon BCR stimulation.
Inhibition of BTK activity may be used to treat allergic and/or autoimmune and/or inflammatory diseases, for example: rheumatoid arthritis, polyangiitis, idiopathic Thrombocytopenia Purple (ITP), myasthenia gravis, allergic rhinitis and asthma (Di Paolo et al (2011) Nature chem. Biol.7 (1): 41-50; liu et al (2011) journal. Ofpharm. And expert. Ther.338 (1): 154-163).
Furthermore, abnormal 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). Because BTK plays a central role as a mediator in multiple signal transduction pathways, inhibition of BTK activity can be Anti-inflammatory and/or Anti-cancer for cancer and treatment of B-cell lymphomas, leukemias and other hematological malignancies (Mohamed et al, immunol. Rev.228:58-73, 2009;Pan,DrugNews perspect 21:357-362,2008; rokosz et al, expert Opin. Ther. Targets12:883-903, 2008; uckun et al, anti-CANCERAGENTS Med. Chem.7:624-632,2007; lou et al, J.Med. Chem.55 (10): 4539-4550, 2012).
2- (4-Phenoxyphenyl) -6- [1- (prop-2-enoyl) piperidin-4-yl ] pyridine-3-carboxamide (obutytinib, orelabrutinib, ICP-022) is an inhibitor of Bruton's Tyrosine Kinase (BTK) for the treatment of lymphomas, leukemias and autoimmune diseases. Its elimination half-life in rats is 8.25 hours (Ya-nan Liu et al (2022), frontiers in pharmacology.10.3389/fphar.2022.991281), whereas the effect of the obutytinib drug metabolism and kinetics on the efficacy and/or toxicity is still not well understood, with the possibility of improvement.
Currently, some drugs have poor drug metabolism and kinetic properties, such as: absorption, distribution, metabolism and/or excretion prevent their wider use or limit their use in specific indications. For example, due to the relatively rapid clearance of the drug in the body, a solution is often employed to administer drugs frequently or at high doses to achieve sufficiently high drug plasma levels. However, this introduces a number of potential treatment problems, such as patient compliance with the dosing interval, and higher dosing, side effects are more severe and increase the cost of treatment.
Attempts have been made to improve the drug's metabolism and kinetic properties by modifying (modifying) the drug with deuterium, or by substituting one or more hydrogen atoms with deuterium atoms to reduce the formation of undesired metabolites, etc. Deuterium is a safe, stable, nonradioactive isotope of hydrogen. Deuterium forms a stronger chemical bond with carbon than hydrogen. In selected cases, the increased bond strength imparted by deuterium may improve the pharmacokinetic and kinetic properties of the drug with the potential to improve efficacy, safety, and/or tolerability. Meanwhile, since the size and shape of deuterium is substantially equivalent to hydrogen, substitution of deuterium for hydrogen is expected to not affect the biochemical potency and selectivity of the drug compared to the original chemical entity containing only hydrogen.
However, due to the complex metabolic processes of biological systems, the pharmacokinetic properties of drugs in organisms are affected by various factors, and also show corresponding complexity. Changes in the pharmacokinetic properties of deuterated drugs exhibit great contingency and unpredictability compared to the corresponding non-deuterated drugs. For some compounds, deuteration slows their metabolic clearance in vivo and half-life increases; for other compounds, deuteration does not cause metabolic changes; for other compounds, deuteration accelerates metabolic clearance and half-life shortens (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 De ve l,2006,9:101-09("Fisher")).
Deuteration of certain sites of the compound may not only increase half-life, but may instead shorten it (Scott l. Harbeson, roger d. Tune. Deuterimin Drug Discovery andDevelopme nt, P405-406), deteriorating its pharmacokinetic properties; on the other hand, hydrogen at certain positions on the drug molecule is also not easily deuterated due to steric hindrance and the like.
Even when deuterium atoms are incorporated into known metabolic sites, the effect of deuterium modification (deuterium modification) on the metabolism of the drug is not predictable. Only by actually preparing and testing deuterated drugs can it be determined whether and how the rate of metabolism will differ from the corresponding chemical entity that is not deuterated. Many drugs have multiple sites of possible metabolism. The location (site) where deuterium substitution is required and the degree of deuteration necessary to effect metabolism, if any, is found to be different for each drug (Fukuto et al.J.Med. Chem.1991,34,2871-76).
As previously mentioned, the effect of deuterium modification (deuterium modification) on the metabolism of the drug is unpredictable. The defect that the obutinib and the in-vivo metabolites thereof have the risk of hepatotoxicity is overcome, and clinical experiments of the obutinib also show hepatotoxicity, which causes great clinical worry. Liver toxicity is not only related to chemical structure but also to the clinical dosage.
Therefore, aiming at the defects of the prior art, new compounds are designed, the exposure of the new compounds in vivo is improved, the dosage and/or the frequency of the drugs are reduced, and the hepatotoxicity is reduced; and/or through structural modification, reduce the hepatotoxicity of its original form or metabolite, or reduce the generation of its toxic metabolite, thus achieve the goal of attenuation and synergy.
Disclosure of Invention
The invention aims to provide novel pyridine amide compounds with BTK inhibition activity and application thereof.
In a first aspect of the invention, there is provided a picolinamide compound of formula I, a tautomer thereof, a crystal form thereof, a salt thereof, a hydrate thereof, or a solvate thereof
Wherein:
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18 Or R 19 are each independently selected from hydrogen (H) or deuterium (D), provided that at least one of R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18 or R 19 is deuterium.
In a preferred embodiment, the compound is the compound of claim 1, which is the following compound P001, compound P002, compound P003, compound P004 and compound P005.
In another preferred example, the compound is the compound of claim 1, which is compound P006, compound P007, compound P008, compound P009, compound P010, compound P011, compound P012, compound P013, compound P014, and compound P015.
In a second aspect of the present invention, there is provided a method of preparing a pharmaceutical composition comprising the steps of: a pharmaceutically acceptable carrier is admixed with a compound according to the first aspect of the invention, a tautomer thereof, a crystalline form thereof, a salt thereof, a hydrate thereof, or a solvate thereof, thereby forming a pharmaceutical composition.
In a third aspect of the present invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to the first aspect of the present invention, a tautomer thereof, a crystalline form thereof, a salt thereof, a hydrate thereof or a solvate thereof.
In a fourth aspect of the invention there is provided the use of a compound as described in the first aspect of the invention, a tautomer thereof, a crystal form thereof, a salt thereof, a hydrate thereof, or a solvate thereof, for the preparation of a pharmaceutical composition for inhibiting BTK.
In another preferred embodiment, the pharmaceutical composition is used for preventing and/or treating diseases associated with BTK.
In another preferred embodiment, the pharmaceutical composition is for preventing and/or treating a BTK-related disease, such as an allergic disorder, an autoimmune disease, an inflammatory disease, a thromboembolic disease or cancer.
In a further preferred embodiment of the present invention, the pharmaceutical composition is used for treating rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, teratogenic arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, reiter's syndrome, polychondritis, acute synovitis, spondylitis, glomerulonephritis with nephrotic syndrome, glomerulonephritis without nephrotic syndrome, autoimmune blood system disorder, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, neutropenia, autoimmune gastritis, autoimmune inflammatory bowel disease, ulcerative colitis, crohn's disease, host versus graft disease, allograft rejection, chronic thyroiditis, graves ' disease, scleroderma, type I diabetes, type II diabetes, acute active hepatitis, chronic active hepatitis pancreatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, itching, skin sunburn, vasculitis, behcet's disease, chronic renal insufficiency, stevens-Johnson syndrome, inflammatory pain, idiopathic steatorrhea, cachexia, sarcoidosis, guillain-Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, interstitial pulmonary fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis, sandy lung, chronic inflammatory lung disease, chronic obstructive pulmonary disease, proliferative diseases, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle Cell Lymphoma (MCL), B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia with mature B cells, B cell lymphomas caused by chronic active B cell receptor signaling, and bone diseases associated with multiple myeloma.
In another preferred embodiment, the pharmaceutical composition is used for the treatment of chronic lymphocytic lymphoma, non-hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia.
As used herein, "deuterated" refers to a compound or group in which one or more hydrogens are replaced with deuterium. Deuteration may be mono-, di-, poly-or full-substituted.
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.
As used herein, the term "compounds of the invention" refers to compounds of formula I. The term also includes tautomers of the compounds of formula I, crystalline forms thereof, salts thereof, hydrates thereof or solvates thereof.
As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as 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, and the like; acidic amino acids such as aspartic acid and glutamic acid.
The compounds of the invention or pharmaceutically acceptable derivatives thereof may also be administered simultaneously, prior to, or subsequent to the administration of one or more other therapeutic agents. Such combination therapies include the administration of a single pharmaceutical dosage formulation comprising a compound of the invention and one or more other active agents, as well as the administration of a separate pharmaceutical dosage formulation of the compound of the invention with each active agent itself. For example, a compound of the invention may be administered to a patient with another active agent in a single orally administered composition (e.g., a tablet or capsule), or each agent may be administered in a separate orally administered formulation. Where separate administration formulations are used, the compounds of the invention and one or more additional active agents may be administered at substantially the same time (i.e., simultaneously) or at separate staggered times (i.e., sequentially); combination therapy should be understood to include all such regimens.
The pharmaceutical combination of the present invention may be administered in an amount that is adjusted according to the disease state, the route of administration, the age or weight of the patient. For oral administration to adults, it is usually 0.2-35 mg/kg/day, preferably 0.8-20 mg/kg/day. The appropriate dosage for the present invention is set in consideration of the age, weight, condition, administration route, etc. of the patient, and is usually in the range of 0.1 to 35 mg/kg/day, preferably 0.5 to 15 mg/kg/day for oral administration.
The invention has the positive progress effects that:
(1) The compound has good selective BTK inhibition effect and can be effectively used for diseases related to BTK.
(2) The compound has good selective inhibition of B cell activation, and is effectively used as a B cell activation inhibitor.
(3) The deuterated pyridine amide compound and the pharmaceutically acceptable salt thereof have the advantages of low hepatotoxicity, good pharmacokinetic property, reduced dosage and/or reduced toxic and side effects, and better patentability. Compared with the obutinib, the composition has obviously more excellent pharmacokinetics and/or pharmacodynamics performance and/or safety performance, and is more suitable for preparing and treating diseases related to BTK.
Detailed description of the preferred embodiments
The following more particularly describes the preparation method of the compound of the formula I, but these specific methods do not limit the present invention. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains.
Methods for preparing non-deuterated pyridinamide-type compounds and physiologically compatible salts thereof for use in the present invention are known. Corresponding deuterated pyridine amide compounds can be synthesized by using corresponding deuterated starting compounds as raw materials and using the same route.
Taking compound P001 as an example, a preferred preparation scheme is as follows:
The specific synthetic method is illustrated in example 1.
The invention will be further illustrated with reference to specific examples. These examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
Example 1: synthesis of Compound P001
Synthetic route
Step1: synthesis of Compound P102
To a mixed solution of concentrated sulfuric acid (10 ml) and water (2 ml), 2, 6-dichloronicotinonitrile (compound P101) (10 mmol) was added, heated to 90℃and stirred for l hours. After cooling to room temperature, the reaction mixture was placed in an ice-water bath and the pH was adjusted to 8 with ammonia. Filtering, washing the filter cake with water, and drying to obtain the compound P102.
Step 2: synthesis of Compound P104
To a mixed solution of 1, 4-dioxane (60 ml) and water (12 ml), compound P102 (3.0 mmol), 4-phenoxyphenylboronic acid-d 5 (Compound P103) (3.0 mmol), tris (dibenzylideneacetone) dipalladium (0.55 mmol) and cesium carbonate (6.0 mmol) were added, and the mixture was heated to 120℃and stirred under reflux for 16 hours. Concentrating under reduced pressure, purifying the residue with silica gel column, eluting with dichloromethane/methanol (150/1), and removing solvent to obtain compound P104.
Step 3: synthesis of Compound P106
To a mixed solution of ethylene glycol dimethyl ether (l 0 ml) and water (2 ml), compound P104 (0.50 mmol), 1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) boric acid (compound P105) (0.75 mmol), tetrakis (triphenylphosphine) palladium (0.lmmol) and potassium carbonate (l.5 mmol) were added, heated to 90℃and stirred for 5 hours. Cooling to room temperature, concentrating under reduced pressure, purifying the residue with silica gel column, eluting with dichloromethane/methanol (700/1), and removing solvent to obtain compound P106.
Step 4: synthesis of Compound P107
To ethyl acetate (10 ml), compound P106 (0.45 mmol) and palladium on carbon (10 mg) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere with oxygen being removed for 16 hours. Concentrating under reduced pressure, purifying the residue with silica gel column, eluting with dichloromethane/methanol (70/1), and removing solvent to obtain compound P107.
Step 5: synthesis of Compound P108
To dichloromethane (5 ml) were added compound P107 and trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for l hours. Concentrated under reduced pressure, the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, concentrated under reduced pressure, the residue was purified by a silica gel column with dichloromethane/methanol (70/1 to 5/1) as eluent, the desired product fractions were combined, and the solvent was removed to give compound P108.
Step 6: synthesis of Compound P001
To dichloromethane (6 ml) were added compound P108 (0.40 mmol), allyl chloride-d 3 (compound P109) (0.56 mmol) and triethylamine (0.85 mmol), and the mixture was stirred at 0℃for l hours. The reaction was quenched with water (10 ml), diluted with ethyl acetate (30 ml), and washed with water (20 ml. Times.2) and then with saturated brine (20 ml. Times.2). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, concentrated under reduced pressure, and the residue was purified by a silica gel column. The eluent is dichloromethane/methanol (20/1), and the solvent is removed to obtain a compound P001. The nuclear magnetic resonance hydrogen spectrum of the compound P001 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(3H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 2: synthesis of Compound P002
Synthesis of Compound P002, "example 1: synthesis of Compound P001 "Compound P103 of step 2 is changed to Compound P202. The remaining steps are the same as in "example 1: synthesis of Compound P001 "the procedure was followed to give Compound P002. The nuclear magnetic resonance hydrogen spectrum of the compound P002 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(5H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 3: synthesis of Compound P003
Synthesis of Compound P003, "example 1: synthesis of Compound P001 "Compound P103 of step 2 is changed to Compound P203. The remaining steps are the same as in "example 1: synthesis of Compound P001 "the procedure was followed to give Compound P003. The nuclear magnetic resonance hydrogen spectrum of the compound P003 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(3H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 4: synthesis of Compound P004
Synthesis of compound P004, "example 1: synthesis of Compound P001 "Compound P103 of step 2 is changed to Compound P204. The remaining steps are the same as in "example 1: synthesis of Compound P001 "the procedure was followed to give Compound P004. The nuclear magnetic resonance hydrogen spectrum of the compound P004 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(5H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 5: synthesis of Compound P005
Synthesis of Compound P005, "example 1: synthesis of Compound P001 "Compound P103 of step 2 is changed to Compound P205. The remaining steps are the same as in "example 1: synthesis of Compound P001 "the procedure was followed to give Compound P005. The nuclear magnetic resonance hydrogen spectrum of the compound P005 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(6H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 6: synthesis of Compound P006
Synthesis of Compound P006, "example 1: synthesis of Compound P001 "Compound P109 of step 6 is changed to Compound P206. The remaining steps are the same as in "example 1: synthesis of Compound P001 "the procedure was followed to give Compound P006. The nuclear magnetic resonance hydrogen spectrum of the compound P006 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(3H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 7: synthesis of Compound P007
Synthesis of Compound P007, "example 6: synthesis of Compound P006 "Compound P103 of step 2 is changed to Compound P202. The rest of the procedure is the same as in example 6: synthesis of Compound P006 "procedure, compound P007 was obtained. The nuclear magnetic resonance hydrogen spectrum of the compound P007 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(5H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 8: synthesis of Compound P008
Synthesis of Compound P008, "example 6: synthesis of Compound P006 "Compound P103 of step 2 is changed to Compound P203. The rest of the procedure is the same as in example 6: synthesis of Compound P006 "procedure, compound P008 was obtained. The nuclear magnetic resonance hydrogen spectrum of the compound P008 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(3H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 9: synthesis of Compound P009
Synthesis of Compound P009, "example 6: synthesis of Compound P006 "Compound P103 of step 2 is changed to Compound P204. The rest of the procedure is the same as in example 6: synthesis of Compound P006 "procedure, compound P009 was obtained. The nuclear magnetic resonance hydrogen spectrum of the compound P009 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(5H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 10: synthesis of Compound P010
Synthesis of Compound P010, "example 1: synthesis of Compound P001 "Compound P103 of step 2 is changed to Compound P207. The remaining steps are the same as in "example 1: synthesis of Compound P001 "the procedure was followed to give Compound P010. The nuclear magnetic resonance hydrogen spectrum of the compound P010 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(4H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 11: synthesis of Compound P011
Synthesis of Compound P011, "example 1: synthesis of Compound P001 "Compound P103 of step 2 is changed to Compound P208. The remaining steps are the same as in "example 1: synthesis of Compound P001 "the procedure was followed to give Compound P011. The nuclear magnetic resonance hydrogen spectrum of the compound P011 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(4H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 12: synthesis of Compound P012
Synthesis of Compound P012, "example 1: synthesis of Compound P001 "Compound P103 of step 2 is changed to Compound P209. The remaining steps are the same as in "example 1: synthesis of Compound P001 "the procedure was followed to give Compound P012. The nuclear magnetic resonance hydrogen spectrum of the compound P012 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(6H),5.8(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 13: synthesis of Compound P013
Synthesis of Compound P013, "example 6: synthesis of Compound P006 "Compound P103 of step 2 is changed to Compound P207. The rest of the procedure is the same as in example 6: synthesis of Compound P006 "procedure, compound P013 was obtained. The nuclear magnetic resonance hydrogen spectrum of the compound P013 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(4H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 14: synthesis of Compound P014
Synthesis of Compound P014, "example 6: synthesis of Compound P006 "Compound P103 of step 2 is changed to Compound P208. The rest of the procedure is the same as in example 6: synthesis of Compound P006 "procedure, compound P014 was obtained. The nuclear magnetic resonance hydrogen spectrum of the compound P014 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.5-7.3(2H),7.2-6.9(4H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 15: synthesis of Compound P015
Synthesis of Compound P015, "example 6: synthesis of Compound P006 "Compound P103 of step 2 is changed to Compound P209. The rest of the procedure is the same as in example 6: synthesis of Compound P006 "procedure, compound P015 was obtained. The nuclear magnetic resonance hydrogen spectrum of the compound P015 is ：1H-NMR(CDCl3)δ8.0(1H),7.8-7.6(2H),7.2-6.9(6H),6.6(1H),6.3(1H),5.8(1H),5.7(1H),5.5(1H),4.8(1H),4.1(1H),3.2(1H),3.1(1H),2.8(1H),2.0-1.9(2H),1.8-1.6(2H).
Example 16: synthesis of Compound P103
Step 7 Synthesis of Compound P403
Compound P401 (11.8 g) was taken and dissolved in anhydrous tetrahydrofuran (120 ml), sodium hydride (12.1 g) was slowly added in portions with stirring, 1-bromo-4-iodobenzene (compound P402) (39.1 g) was added in portions and reacted at room temperature for 15hr, the reaction was filtered, the filtrate was dried by spinning, and methylene chloride was added for dissolution. Passing through silica gel column, and using petroleum ether: ethyl acetate (1:5) to afford compound P403 (12.7 g)
Step 8 Synthesis of Compound P103
Compound P403 (5.2 g) was dissolved in dry THF (100 ml), reacted at-78 ℃ for 30min under the protection of N2, N-butyllithium (1.9 g) was slowly added dropwise, and after the addition was completed, the reaction was carried out at-78 ℃ for 3h, triisopropyl borate (4.3 g) was slowly added dropwise, and after the addition was completed, the reaction was carried out at-78 ℃ for 2h, the reaction was slowly warmed to room temperature, and after the reaction was completed, TLC was used to monitor the reaction, the reaction solution was slowly quenched with water, extracted and concentrated to obtain compound P103 (3.0 g).
Example 17: synthesis of Compound P203
Synthesis of Compound P203 as "example 16: synthesis of compound P103 "was performed, except that in step 7, compound P401 was changed to compound P402, and the rest of the procedure was as in" example 16: synthesis of Compound P103 "procedure, compound P203 was obtained.
Example 18: synthesis of Compound P204
Synthesis of Compound P204 as "example 16: synthesis of compound P103 "was performed, except that in step 7, compound P401 was changed to compound P403, and the rest of the procedure was as in" example 16: synthesis of Compound P103 "procedure, compound P204 was obtained.
Example 19: synthesis of Compound P202
Synthesis of Compound P202 as "example 16: synthesis of compound P103 "was performed, except that in step 7, compound P401 was changed to compound P404, and the rest of the procedure was as in" example 16: synthesis of Compound P103 "procedure, compound P202 was obtained.
Example 20: synthesis of Compound P207
Synthesis of Compound P207 as "example 16: synthesis of compound P103 "was performed, except that in step 7, compound P401 was changed to compound P405, and the rest of the procedure was as in" example 16: synthesis of Compound P103 "procedure, compound P207 was obtained.
Example 21: synthesis of Compound P208
Synthesis of Compound P208 as "example 16: synthesis of compound P103 "was performed, except that in step 7, compound P401 was changed to compound P406, and the rest of the procedure was as in" example 16: synthesis of Compound P103 "procedure yielded Compound P208.
Example 22: synthesis of Compound P209
Synthesis of Compound P209 as "example 16: synthesis of compound P103 "was performed, except that in step 7, compound P401 was changed to compound P407, and the rest of the procedure was as in" example 16: synthesis of Compound P103 "procedure yielded Compound P209.
Example 23: rat pharmacokinetics
30 Male Sprague-Dawley rats, 6-9 weeks old, weighing about 220g, were divided into 5 groups (obutytinib group, compound P001 group, compound P002 group, compound P005 group and compound P009 group), 6 each. The pharmacokinetic differences were compared by single gavage administration of 10mg/kg doses of obutinib, compound P001, compound P002, compound P005 and compound P009, respectively, according to the group.
Rats began fasted 12 hours prior to dosing. The dosing solution was formulated with 0.5% sodium carboxymethyl cellulose (CMC-Na). Orbital vein Cong Caixie, blood collection time points were 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, and 24 hours post-administration. After separation of the plasma from the blood sample, the plasma was stored in a-80℃freezer for further use. The LC-MS/MS analysis method is established to measure the plasma sample.
From the test results, it was found that the elimination half-lives T 1/2 and/or the area under the curve AUC and/or the maximum blood concentration C max of the compounds P001, P002, P005 and P009 were increased by 50% or more as compared to the obutinib.
From the results, the compound P001, the compound P002, the compound P005 and/or the compound P009 of the present invention have better pharmacokinetic properties in rats compared to obutytinib, suggesting better pharmacodynamics and therapeutic effects.
Example 24: rat pharmacokinetics
24 Male Sprague-Dawley rats, 6-9 weeks old, weighing about 220g, were divided into 4 groups (obutytinib group, compound P006 group, compound P007 group, compound P012 group) of 6. The pharmacokinetic differences were compared by single gavage administration of 10mg/kg doses of obutinib, compound P006, compound P007 and compound P012, respectively, in groups.
Rats began fasted 12 hours prior to dosing. The dosing solution was formulated with 0.5% sodium carboxymethyl cellulose (CMC-Na). Orbital vein Cong Caixie, blood collection time points were 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, and 24 hours post-administration. After separation of the plasma from the blood sample, the plasma was stored in a-80℃freezer for further use. The LC-MS/MS analysis method is established to measure the plasma sample.
From the test results, it was found that the elimination half-lives T 1/2 and/or the area under the curve AUC and/or the maximum blood concentration C max of the compound P006, the compound P007 and the compound P012 were increased by 40% or more as compared to the obutinib.
From the results, compound P006, compound P007 and/or compound P012 of the present invention have better pharmacokinetic properties in rats compared to obutytinib, suggesting better pharmacodynamics and therapeutic effects.
Example 25: determination of inhibitory Activity of BTK
The effect of the compounds of the invention on the activity of BTK was determined using the ADP-Glo TM kit. The experimental method is as follows:
ADP is a product of a kinase reaction, and kinase activity can be detected by detecting the amount of ADP produced. The ADP-Glo TM kit developed by Promega corporation is to measure the in vitro activity of BTK by detecting the ADP level produced in the kinase reaction. In kinase assay experiments, kinase consumes ATP to phosphorylate substrates while producing ADP. The kinase reaction was then stopped by adding ADP-Glo reagent and the remaining ATP was completely consumed. And then adding a kinase detection reagent to convert the generated ADP into new ATP, wherein luciferase in the detection reagent can catalyze luciferin under the participation of ATP and O 2 to generate an optical signal, so that a chemical signal is converted into an optical signal, and the intensity of the optical signal is positively correlated with the amount of ADP generated in a kinase reaction, thereby quantitatively detecting the activity of kinase BTK.
All assays were performed at 23℃and constant room temperature using Corning 3674 white 384-well assay plates, kinase BTK (Invitrogen), kinase substrate polypeptide (4:l Glu, tyr) (SIGNAL CHEM) and ATP (Sigma), and optical signals were read using a microplate reader EnVision (Perkin Elmer). The detection buffer included 40mM Tris-HCl (pH 7.5), 10mM MgCl 2(Sigma)、2mM MnCl2 (Sigma), 0.05mM DTT (Sigma), and 0.01% BSA (Sigma); preparing kinase BTK into kinase reaction solution with concentration of 1.3 ng/. Mu.L by using detection buffer; the substrate reaction solution included 0.25mg/mL of polypeptide substrate and 60 μMATP.
The compound of the invention is diluted into 0.5mM solution by DMSO, then three-fold gradient dilution is carried out by DMSO to the minimum concentration of 0.025 mu M, 50nL series concentration of compound solution and 2.5 mu L kinase reaction solution are firstly added into 384-well plates by Echo555, and after the mixture is uniformly mixed, the mixture is incubated for 30 minutes at room temperature and in a dark place; subsequently, 2.5. Mu.L of a substrate reaction solution was added thereto, the total reaction volume was 5.05. Mu.L, and the reaction mixture was allowed to react at room temperature for 60 minutes in the absence of light; then adding 5 mu LADP-Glo TM reagent to terminate the reaction, mixing uniformly and then standing at room temperature for 40 minutes; finally, 10. Mu.L of kinase assay reagent was added, left at room temperature for 30 minutes in the dark, and the values were read on Envision.
Percent inhibition was calculated as follows:
Inhibition% = [1- (RLU Compounds of formula (I) -RLUmin)/(RLUmax-RLUmin) ] ×100
Where RLU Compounds of formula (I) is the reading at a given concentration of a compound of the invention, RLU min is the reading without addition of kinase BTK, and RLU max is the reading without addition of a compound of the invention. IC 50 values for compounds were calculated by using XLfit program in Excel.
Table 1: IC 50 value of the inventive Compounds
| Compounds of formula (I) | IC50(nM) | Compounds of formula (I) | IC50(nM) |
| P001 | 1.4 | P002 | 2.7 |
| P006 | 2.4 | P007 | 1.9 |
| P008 | 2.6 | P012 | 3.1 |
| P015 | 3.4 | Orelabrutinib | 3.9 |
From the results, the compounds of the present invention have a remarkable inhibitory effect on BTK.
Example 26: comparison study of mouse liver toxicity
(1) Experimental animal
Adult male ICR mice were selected for 32, body weight (25±2 g), all allowed free water intake and maintenance of feed, and were cycled alternately day and night at a temperature of 25±2 ℃,50±10% relative humidity.
(2) Grouping and administration of animals
The 32 male ICR mice were divided into four groups of 8, each of the normal control group, model group, model+example compound group and model+ Orelabrutinib group. Model + example compound group example compound was administered once daily by intragastric administration at doses (50 mg/kg); the model + Orelabrutinib group was dosed (50 mg/kg) once daily for Orelabrutinib weeks, and the normal control group and model group were each dosed with an equal volume of purified water. Starting run out of grain after the last administration, injecting 250mg/kg of acetaminophen (APAP) physiological saline solution into mice of the model group, the model+example compound group and the model+ Orelabrutinib group respectively at one time after 1h, performing eyeball blood collection on each group of mice in sequence after 24h of molding, centrifuging at 3000r/min for 10min to separate serum, and preserving at 4 ℃ for later use; liver and spleen were dissected rapidly. Washing with 4deg.C physiological saline, drying with filter paper, weighing, fixing part of liver in 10% formaldehyde solution, slicing, and preserving the rest liver in-80deg.C refrigerator.
(3) Determination of biochemical indicators in liver:
Weighing part of liver, adding 9 times of ice physiological saline, homogenizing with a tissue homogenizer to obtain 10% liver tissue homogenate, and centrifuging to obtain supernatant. The plates were spotted according to the kit method, OD values were measured at 450nm, and MDA content and GSH activity in the liver were calculated according to the formula.
(4) Data processing
Experimental data are expressed as mean ± standard deviation (±s), analyzed using SPSS22.0 statistical software, and differences compared between groups using one-way analysis of variance. P <0.05 bit was significantly different.
(5) Effects of the Compounds of the examples of the application on lipid peroxidation of liver tissue of APAP liver injury mice
Compared with the normal control group, the MDA content in the liver tissue homogenate of the mice in the model group is obviously increased, the GSH level is obviously reduced (P is less than 0.05), so that lipid peroxidation products in the mice are accumulated, and the antioxidant metabolism level is reduced; no significant change (P > 0.05) in MDA content and GSH level was observed for the model + example compound group compared to the model group; the significantly increased MDA content (P < 0.05) and significantly decreased GSH levels (P < 0.05) in the model + Orelabrutinib group compared to the model group, indicated that the compound of the present application (50 mg/kg) had no significant effect on APAP-induced lipid peroxidation, while Orelabrutinib (50 mg/kg) had an effect on APAP-induced lipid peroxidation, suggesting that the compound of the present application has a mouse hepatotoxicity of less than Orelabrutinib. The results are shown in Table 2.
TABLE 2 lipid peroxidation effects on APAP liver injury mice liver tissue
| Grouping | MDA(nmol/mg) | GSH(μmol/L) |
| Normal control group | A- | B- |
| Model group | A+ | B+ |
| Model + example compound group | A+ | B+ |
| Model + Orelabrutinib group | A++ | B++ |
Labeling (grade): a+ is 2.4-3.5; a-is 1.5-2.2; a++ is 3.8-5.2; b+ is 28-39; b-is 42-52; b++ is 16-27.
Conclusion: the compound of the present application (50 mg/kg) had no significant effect on lipid peroxidation caused by APAP, whereas Orelabrutinib (50 mg/kg) had an effect on lipid peroxidation caused by APAP, suggesting that the compound of the present application has a mouse hepatotoxicity of less than Orelabrutinib.
Finally, it should be noted that the above describes in detail specific embodiments of the invention, but is only exemplary and the invention is not limited to the above described specific embodiments. Any equivalent modifications and substitutions for the present invention will occur to those skilled in the art, and are also within the scope of the present invention. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present invention without departing from the spirit and scope thereof.
Claims (8)
1. The invention provides a pyridine amide compound of formula I, its tautomer, its crystal form, its salt, its hydrate or solvate
Wherein:
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18 Or R 19 are each independently selected from hydrogen or deuterium, provided that at least one of R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18 or R 19 is deuterium.
2. A compound according to claim 1, a tautomer thereof, a crystalline form thereof, a salt thereof, a hydrate thereof or a solvate thereof, characterized in that the compound is selected from the following structures:
3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-2, a tautomer thereof, a crystalline form thereof, a salt thereof, a hydrate thereof, or a solvate thereof.
4. Use of a picolinamide compound according to any one of claims 1-2, a tautomer thereof, a crystalline form thereof, a salt thereof, a hydrate thereof or a solvate thereof for the preparation of a BTK inhibitor.
5. Use of the pharmaceutical composition of claim 3 for the preparation of a medicament for the treatment and/or prevention of BTK-related diseases.
6. The pharmaceutical composition of claim 5, wherein the BTK-related disease is an allergic disorder, an autoimmune disease, an inflammatory disease, a thromboembolic disease, or cancer.
7. Use of a compound according to any one of claims 1-2, a tautomer thereof, a crystal form thereof, a salt thereof, a hydrate thereof, or a solvate thereof, for the manufacture of a medicament for the treatment of a BTK-mediated disorder, wherein the BTK-mediated disorder is selected from the group consisting of: rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, teratogenic arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, reiter's syndrome, polychondritis, acute synovitis, spondylitis, glomerulonephritis with nephrotic syndrome, glomerulonephritis without nephrotic syndrome, autoimmune blood system disorders, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, neutropenia, autoimmune gastritis, autoimmune inflammatory bowel disease, ulcerative colitis, crohn's disease, host versus graft disease, allograft rejection, chronic thyroiditis, graves ' disease, scleroderma, type I diabetes, type II diabetes, active hepatitis, chronic active hepatitis, pancreatitis, primary biliary cirrhosis myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, itching, sunburn, vasculitis, behcet's disease, chronic renal insufficiency, stevens-Johnson syndrome, inflammatory pain, idiopathic steatorrhea, cachexia, sarcoidosis, guillain-Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, interstitial pulmonary fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis, sandy lung, chronic inflammatory lung disease, chronic obstructive pulmonary disease, proliferative diseases, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic leukemia, acute lymphoblastic leukemia with mature B cells, B-cell lymphomas caused by chronic active B-cell receptor signaling and bone diseases associated with multiple myeloma.
8. The use according to claim 7, wherein the BTK-mediated disorder is a B-cell proliferative disorder selected from the group consisting of chronic lymphocytic lymphoma, non-hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia.
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