阅读说明：本技术 一种FXIa凝血因子抑制剂及其药物组合物、制备方法和医药用途 (FXIa coagulation factor inhibitor, and pharmaceutical composition, preparation method and medical application thereof ) 是由 余尚海 冯焱 李世强 王小林 胡治隆 丁雅雯 戴飞红 贺潜 王朝东 于 2019-04-02 设计创作，主要内容包括：本发明涉及一种式I所示化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药,以及包含其的药物组合物,其制备方法,及其医药用途,所述化合物均具有很好的抗凝血活性,所述式I结构如下：<Image he="357" wi="700" file="DDA0002015828440000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>。(The invention relates to a compound shown in formula I, or a tautomer, an optical isomer, a nitrogen oxide, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a pharmaceutical composition containing the compound, a preparation method and medical application thereof, wherein the compound has good anticoagulant activity, and the structure of the formula I is as follows: 。)

1. A compound of formula I or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt, or prodrug thereof:

wherein R is₁、R₅Are identical or different and are selected, independently of one another, from the group consisting of-C (═ O) R₇；

Each R₂、R₃、R₆Identical or different, independently of one another, from the group consisting of H, halogen, hydroxyl, cyano, nitro, the following radicals unsubstituted or optionally substituted by one, two or more substituents: c_1-12Aliphatic hydrocarbyl, -O-C_1-12Aliphatic hydrocarbon radicals, unsubstituted or optionally substituted by one or two C_1-12Aliphatic hydrocarbyl-substituted amino;

R₄is selected from-L-R₈；

L is selected from C which is unsubstituted or optionally substituted by one, two or more substituents_1-12An aliphatic hydrocarbon group;

R₈selected from the following groups, unsubstituted or optionally substituted with one, two or more substituents: c_6-20Aryl, 5-to 20-membered heteroaryl, C_3-20Cycloalkyl or 3-20 membered heterocyclyl;

R₇selected from H, OH, the following groups being unsubstituted or optionally substituted with one, two or more substituents: c_1-12Aliphatic hydrocarbyl, -O-C_1-12An aliphatic hydrocarbon group;

n, t are identical or different and are independently selected from 0, 1,2, 3,4, 5; m is selected from 0, 1,2 and 3;

each of said substituents being identical or different and being independently selected from halogen, hydroxy, cyano, nitro, unsubstituted or optionally substituted by one or two C_1-12Aliphatic hydrocarbyl substituted amino.

In some embodiments, the aliphatic hydrocarbon group is selected from C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, preferably selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, e.g. selected from C_1-4An alkyl group;

in some embodiments, said C_6-20Aryl is selected from C_6-14Aryl, preferably phenyl.

In some embodiments, said C_3-20Cycloalkyl is selected from C_3-8Cycloalkyl, preferably cyclopropyl.

In some embodiments, the R is₁Is selected from- (C ═ O) CH₃。

In some embodiments, the R is₅Selected from-COOH.

2. The compound of formula I according to claim 1, wherein the structure of formula I has a structure represented by formula Ia or formula Ib below:

in the formula Ia and the formula Ib, R₁、R₂、R₃、R₄、R₅、R₆M, n, t are as defined in formula I.

3. The compound of formula I according to claim 1 or 2, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein the structure of formula I has the following structure of formula II, formula III, formula IV, formula V, formula VI:

in the formulas II, III, IV, V and VI, R₁、R₂、R₃、R₄、R₅、R₆M, n, t are as defined in formula I.

4. A compound of formula I according to any one of claims 1 to 3, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof, is selected from the following compounds:

5. a process for the preparation of a compound of formula I according to any one of claims 1 to 4, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof, comprising one or more of the following steps:

step a:

step b:

step c:

step d:

in the steps a, b, c and d, R₁、R₂、R₃、R₄、R₅、R₆M, n, t are as defined in formula I; x₁，X₂The same or different, are independently selected from halogens.

6. The process of claim 5, wherein the process for the preparation of the compound of formula I further comprises the step e of resolving the stereoisomer:

7. the method according to claim 5 or 6, wherein when R is₅When selected from-COOH, the preparation of said compound of formula I further comprises the following step f:

in step f, G is selected from a protecting group.

8. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 4, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof.

Preferably, the pharmaceutical composition further comprises a therapeutically effective amount of the compound of formula I or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

9. Use of a compound of formula I according to any one of claims 1 to 4 or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the prophylaxis and/or treatment of FXIa-mediated diseases.

10. Use of a compound of formula I according to any one of claims 1 to 4 or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the prophylaxis and/or treatment of cardiovascular and cerebrovascular diseases, wherein the cardiovascular disease is preferably a thromboembolic disease, more preferably a myocardial infarction, angina pectoris, reocclusion and restenosis following angioplasty or aortic coronary bypass, disseminated intravascular coagulation, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an FXIa blood coagulation factor inhibitor, a pharmaceutical composition, a preparation method and medical application thereof.

Background

Blood coagulation is the result of the coordinated activation of various plasma proteins, cofactors and platelets. This cascade reaction is divided into an intrinsic (contact activation) pathway, an extrinsic (tissue factor activation) pathway and a common (production of prothrombin and thrombin) pathway. The most important physiological process in the blood coagulation process is the activation of tissue factors. Tissue factor forms a complex with factor VIIa, catalytically activates factor ten (FX), and activated FXa in turn cleaves prothrombin to produce activated thrombin (FIIa). The activated thrombin (FIIa) is used as a central catalytic enzyme in the blood coagulation process, catalyzes the cleavage of fibrinogen into fibrin and plays a role in blood coagulation. The exogenous way has less enzyme and fast acting. The intrinsic pathway is a coagulation pathway inherent to the body, and activates factor twelve (FXIIa), factor eleven (FXIa), factor nine (FIXa), and factor eight (FVIIIa) through a cascade reaction, which in turn activates factor ten (FXa) and downstream central thrombin (FIIa). Thrombin in turn activates factor eleven (FXIa), producing an amplification effect that accelerates blood coagulation. The endogenous pathway involves more enzymes and is derived from blood, and generally has slow effect. Therefore, FXa plays a very critical role throughout the coagulation process. As a downstream co-regulator of extrinsic and intrinsic coagulation pathways, antagonists thereof are widely used for the prevention and treatment of various thrombi.

In the current cardiovascular drug market, a plurality of FXa antagonists are on the market. Although it has a certain curative effect, the probability of side effects is relatively high, and the most prominent is the bleeding risk. To solve the bleeding problem, factor eleven (FXIa) in the intrinsic pathway has become a hot spot for research in various companies and institutions.

The potential of FXIa as a safer anticoagulant target is reflected in patients with hemophilia C. Patients with FXIa-deficient hemophilia C do not have an active bleeding event, which is evident in comparison to the easy bleeding of hemophilia a eight-factor deficient and hemophilia B nine-factor deficient patients. Although limited sample number (115 patients) studies indicate that FXIa factor deficiency does not protect patients from acute myocardial ischemia, such patients were found to have lower incidence of stroke and deep vein thrombosis.

Knockout mice experiments found that selective knockout of the common pathway factors (factors X, V and II) and exogenous factors (tissue factor and factor VII) in mice resulted in prenatal or perinatal lethality. Factor VIII and factor IX knockout mice, while viable, often suffer from severe bleeding, similar to hemophilia a and B in humans where lack of factor VIII and IX poses a risk of severe bleeding. While mice with selective factor XI knock-out reproduce normally. Also, factor XI deletion protects mice against ferric chloride-induced arterial thrombosis. Also, the absence of factor XI did not affect bleeding and hemostatic function in mice. Thus, this experiment shows that inhibition of factor XI not only prevents thrombosis, but is also safely tolerated.

A number of antibodies, small molecules and antisense nucleotides against FXIa have also demonstrated in animals or clinically that inhibition of FXIa is effective in preventing thrombosis. But the risk of bleeding is greatly reduced compared to existing antithrombotic drugs, such as enoxaparin. The results show that the FXIa is closely related to human thrombotic diseases, the FXIa inhibition has a remarkable anticoagulation effect, but has no obvious bleeding tendency, and the bleeding risk in the clinical anticoagulation process can be greatly reduced.

Therefore, the development of the compound with good anticoagulation effect and small side effect has important research significance.

Disclosure of Invention

The invention provides a compound shown as a formula I or a tautomer, an optical isomer, a nitrogen oxide, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

wherein R is₁、R₅Are identical or different and are selected, independently of one another, from the group consisting of-C (═ O) R₇；

Each R₂、R₃、R₆Identical or different, independently of one another, from the group consisting of H, halogen, hydroxyl, cyano, nitro, the following radicals unsubstituted or optionally substituted by one, two or more substituents: c_1-12Aliphatic hydrocarbyl, -O-C_1-12Aliphatic hydrocarbon radicals, unsubstituted or optionally substituted by one or two C_1-12Aliphatic hydrocarbyl-substituted amino;

R₄is selected from-L-R₈；

L is selected from C which is unsubstituted or optionally substituted by one, two or more substituents_1-12An aliphatic hydrocarbon group;

R₈selected from the following groups, unsubstituted or optionally substituted with one, two or more substituents: c_6-20Aryl, 5-to 20-membered heteroaryl, C_3-20Cycloalkyl or 3-20 membered heterocyclyl;

R₇selected from H, OH, the following groups being unsubstituted or optionally substituted with one, two or more substituents: c_1-12Aliphatic hydrocarbyl, -O-C_1-12An aliphatic hydrocarbon group;

n, t are identical or different and are independently selected from 0, 1,2, 3,4, 5; m is selected from 0, 1,2 and 3;

each of said substituents being identical or different and being independently selected from halogen, hydroxy, cyano, nitro, unsubstituted or optionally substituted by one or two C_1-12Aliphatic hydrocarbyl substituted amino.

In some embodiments, the aliphatic hydrocarbon group is selected from C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, preferably selected from C_1-6Alkyl radical, C₂-6 alkenyl, C_2-6Alkynyl, e.g. selected from C_1-4An alkyl group;

in some embodiments, said C_6-20Aryl is selected from C_6-14Aryl, preferably phenyl.

In some embodiments, said C_3-20Cycloalkyl is selected from C_3-8Cycloalkyl, preferably cyclopropyl.

In some embodiments, the R is₁Is selected from- (C ═ O) CH₃。

In some embodiments, the R is₅Selected from-COOH.

In some embodiments, the structure of formula I has a structure represented by formula Ia or formula Ib:

in the formula Ia and the formula Ib, R₁、R₂、R₃、R₄、R₅、R₆M, n, t are as defined in formula I.

In some embodiments, the structure of formula I has the structure of formula II, formula III, formula IV, formula V, formula VI as follows:

in the formulas II, III, IV, V and VI, R₁、R₂、R₃、R₄、R₅、R₆M, n, t are as defined in formula I.

Preferably, the compound represented by formula I or a tautomer, an optical isomer, a nitrogen oxide, a solvate, a pharmaceutically acceptable salt or a prodrug thereof is selected from the following compounds:

as an example, the compound of formula I, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt, or prodrug thereof, is selected from the following compounds:

the invention also provides a process for the preparation of a compound of formula I, comprising one or more of the following steps:

step a:

step b:

step c:

step d:

in some embodiments, the process for preparing the compound of formula I further comprises the following step e, to resolve stereoisomers:

in some embodiments, when R₅When selected from-COOH, the preparation of said compound of formula I further comprises the following step f:

in the above steps a, b, c, d, e and f, R₁、R₂、R₃、R₄、R₅、R₆M, n, t are as defined in formula I; x₁，X₂The same or different, are independently selected from halogen; g is selected from carboxyl protecting groups.

According to an embodiment of the present invention, in the step (a), M-1 is reacted with tert-butyl methyl malonate to obtain M-2, and the molar ratio of M-1 to tert-butyl methyl malonate may be 1:0.5 to 1.5, preferably 1:0.9 to 1.1, and may be 1: 1; the steps may specifically be: dissolving M-1 in a solvent 1, adding a catalyst 1 at a temperature of-5 ℃, and then adding methyl malonic acid tert-butyl ester; wherein, the methyl malonic acid tert-butyl ester can be dissolved in a solvent 1 to form a solution, and then the solution is added for reaction; the solvent 1 may be selected from N, N-Dimethylformamide (DMF), THF, and the catalyst may be selected from NaH; in the step (a), M-3 is prepared from M-2 and trifluoroacetic acid, and the feeding ratio of M-2 to trifluoroacetic acid is as follows: 1 mmol: 3-8 mL, preferably 1 mmol: 4-6 mL, for example 1 mmol: 5mL, in the reaction, solvent 2, which can be selected from dichloromethane and THF, is used.

According to an embodiment of the invention, in said step (b), M-3 and R₄Reacting L to obtain M-4, wherein L is halogen selected from F, Cl, Br and I, and specifically, adding LHMDS into M-3 and then adding R₄L, said M-3, LHMDS, R₄The molar ratio of L is 1: 1-1.5, for example 1:1.1:1.2, and a solvent 3, which may be selected from THF, is used in the reaction; in the step (b), M-4 reacts in the presence of LIOH and a solvent 4 to obtain M-5, wherein the molar ratio of M-4 to LiOH is 1: 1.2-1.8, for example, 1: 1.5, the solvent 4 can be selected from a mixed solvent of alcohol and water, preferably a mixed solvent of methanol and water, wherein the volume ratio of the alcohol to the water is 4-6: 1, for example 5: 1; in the step (b), M-5 and M-6 react to obtain M-7, and the reaction is carried out in the presence of HATU, DIEA and a solvent 5, wherein the solvent 5 can be selected from DMF and THF.

According to an embodiment of the present invention, in said step (c), M-7 is reacted with M-8 to give M-9, specifically, comprising the step of(c1) Dissolving M-7, pinacol ester diboron and potassium acetate in a solvent 6, and adding Pd (dppf) Cl₂Obtaining a reaction mixed solution, wherein the reaction temperature can be 70-110 ℃, for example 90 ℃, and the solvent 6 can be 1, 4-dioxane; step (c2) the product obtained in step c1 is reacted with M-8, to which an alkaline reagent and Pd (dppf) Cl may be added₂The alkaline agent may be selected from potassium carbonate, sodium carbonate.

According to an embodiment of the present invention, in the step (d), M-9 is reacted in the presence of M-CPBA, solvent 7 to obtain the product of formula I, wherein the molar ratio of M-9 to M-CPBA is 1: 1.5-3, for example 1:2, and the solvent 7 may be selected from one or more of dichloromethane, DMF, THF.

According to an embodiment of the invention, in said step (e), formula I is resolved by chiral resolution to give formula Ia and formula Ib.

According to an embodiment of the present invention, in the step (f), M-10 in trifluoroacetic acid and in the presence of solvent 8 provides a compound of formula I wherein R5 is selected from-COOH, and the molar volume ratio of M-10 to trifluoroacetic acid is 0.12 to 0.2: 1, for example 0.16, said solvent 8 may be chosen from dichloromethane; the G group is introduced by esterification of the carboxyl group, for example G is t-butyl.

The present invention further provides a pharmaceutical composition comprising a compound of formula I as described herein, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt, or prodrug thereof.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a therapeutically effective amount of a compound of formula I of the present invention, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

The carrier in the pharmaceutical composition is "acceptable" in that it is compatible with (and preferably capable of stabilizing) the active ingredient of the composition and is not deleterious to the subject being treated. One or more solubilizing agents may be used as pharmaceutical excipients for the delivery of the active compound.

The invention further provides application of the compound of the formula I or a tautomer, an optical isomer, a nitrogen oxide, a solvate, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition in preparing a medicament for preventing and/or treating FXIa mediated diseases.

The invention further provides the use of the compound of formula I or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof or the pharmaceutical composition for the preparation of a medicament for the prophylaxis and/or treatment of cardiovascular and cerebrovascular diseases, wherein the cardiovascular diseases are preferably thromboembolic diseases, more preferably reocclusion and restenosis after myocardial infarction, angina pectoris, angioplasty or aortic coronary artery bypass, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

The present invention also provides a method for preventing and/or treating FXIa mediated diseases comprising administering to a patient a therapeutically effective dose of the compound of formula I or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof or the pharmaceutical composition.

The present invention also provides a method for the therapeutic prevention and/or treatment of cardiovascular and cerebrovascular diseases selected from the group consisting of myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortic coronary bypass, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis, comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition.

The invention also provides a preparation for inhibiting FXIa, which comprises the compound of formula I or a tautomer, an optical isomer, a nitrogen oxide, a solvate, a pharmaceutically acceptable salt or a prodrug thereof or the pharmaceutical composition.

In some embodiments, the pharmaceutical compositions of the present invention may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

In some embodiments, the pharmaceutical compositions of the present invention provide oral formulations in soft gelatin capsules of the active ingredient in admixture with an inert solid diluent or with a water soluble carrier or oil vehicle; aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents; oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants; dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

In some embodiments, the pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

In some embodiments, the pharmaceutical compositions of the present invention may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

In some embodiments, the pharmaceutical compositions of the present invention may be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

In some embodiments, the compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols. Interpretation of terms

Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

"more" means more than three. If appropriate, for example, 3,4 or 5 can be represented.

The term "aliphatic hydrocarbon group" includes saturated or unsaturated, straight-chain or branched-chain hydrocarbon groups, the type of the aliphatic hydrocarbon group may be selected from alkyl, alkenyl, alkynyl and the like, the number of carbon atoms of the aliphatic hydrocarbon group is preferably 1 to 12, and a further preferred range is 1 to 6, and specifically, the following groups may be included but not limited: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylethenyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl and 1-hexynyl; the "aliphatic hydrocarbon group" moiety contained in the other groups is as explained above.

The term "C_3-20Cycloalkyl "is understood to mean a saturated or unsaturated, monovalent, monocyclic or bicyclic hydrocarbon ring having from 3 to 20 carbon atoms, preferably" C_3-10Cycloalkyl groups ". The term "C_3-10Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5,6, 7, 8, 9 or 10 carbon atoms. Said C is_3-10Cycloalkyl groups may be monocyclic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin rings.

The term "3-20 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclyl group may be bicyclic, for example but not limited to a 5,5 membered ring, such as a hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring. The nitrogen atom containing ring may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 4, 5-dihydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic radical is non-aromatic.

The term "C_6-20Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring of monovalent or partially aromatic character having 6 to 20 carbon atoms, preferably" C_6-14Aryl ". The term "C_6-14Aryl "is to be understood as preferably meaning a mono-, bi-or tricyclic hydrocarbon ring having a monovalent or partially aromatic character with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C_6-14Aryl group "), in particular a ring having 6 carbon atoms (" C₆Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C₉Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C₁₀Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C₁₃Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C)₁₄Aryl), such as anthracenyl.

The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene includes pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, pyridinylene-3-yl, pyridin-4-yl, and pyridinylene-4-yl; thienyl or thienylene includes thien-2-yl, thien-3-yl and thien-3-yl.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Unless otherwise indicated, the groups defined in this specification are equally applicable to other art containing the groupThe phrase. For example, the definition of the term "aliphatic hydrocarbon radical" applies equally to "-O-C_1-12Aliphatic hydrocarbon radical "," optionally substituted by one or two C_1-12Aliphatic hydrocarbyl-substituted amino "and the like.

The compounds of formula I of the present invention further include structures falling within their scope, such as, for example, structures of formula II, formula III, formula IV, formula V, formula VI, and further lower structures.

The compounds of the present invention comprise compounds or tautomers, optical isomers, nitrogen oxides, solvates, pharmaceutically acceptable salts or prodrugs thereof.

Pharmaceutically acceptable salts of the compounds of the invention, which may be prepared by any suitable method available in the literature, may be selected from acid addition salts including, but not limited to, hydrochloride, hydrofluoride, hydrobromide, hydroiodide, sulfate, pyrosulfate, phosphate, nitrate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetate, pyruvate, laurate, benzoate, acetate, glyoxylate, trifluoroacetate, pivalate, propionate, butyrate, hexanoate, heptanoate, undecanoate, stearate, ascorbate, camphorate, camphorsulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, acetate, tosylate, mesylate, malate, maleate, and salts thereof, Salicylates, succinates, gluconates, quinites, pamoates, glycolates, tartrates, lactates, 2- (4-hydroxybenzoyl) benzoates, cyclopentanepropionates, digluconates, 3-hydroxy-2-naphthoates, nicotinates, pamoates, pectinates, 3-phenylpropionates, picrates, pivalates, itaconates, triflates, laurylsulfates, p-toluenesulfonates, napadisylates, malonates, adipates, alginates, mandelates, glucoheptonates, glycerophosphates, sulfosalicylates, hemisulfates or thiocyanates, aspartates, and the like; base addition salts such as alkali metal salts, alkaline earth metal salts, ammonium salts and the like, specifically include but are not limited to: sodium salt, lithium salt, potassium salt, ammonium salt (includingAnd NH₃And salts with organic amines), aluminum salts, magnesium salts, calcium salts, barium salts, ferric salts, ferrous salts, manganese salts, manganous salts, zinc salts, NH₄Salts, methylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, propylamine salt, tripropylamine salt, isopropylamine salt, tert-butylamine salt, N' -dibenzylethylenediamine salt, dicyclohexylamine salt, 1, 6-hexamethylenediamine salt, benzylamine salt, ethanolamine salt, N-dimethylethanolamine salt, N-diethylethanolamine salt, triethanolamine salt, tromethamine salt, lysine salt, arginine salt, histidine salt, glucamine salt, N-methylglucamine salt, dimethylglucamine salt, ethylglucamine salt, meglumine salt, betaine salt, caffeine salt, chloroprocaine salt, procaine salt, lidocaine salt, pyridine salt, picoline salt, piperidine salt, morpholine base salt, piperazine salt, purine salt, cacao salt, choline salt and the like.

The term "solvate" is those forms of the compounds of the present invention which form complexes in the solid or liquid state by coordination with solvent molecules. Hydrates are a particular form of solvates in which the coordination is with water. In the present invention, the preferred solvate is a hydrate.

The term "prodrug", or "prodrug" refers to a compound that is converted in vivo to a compound of the general formula or a particular compound. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrugs of the present invention may be esters, and in the present invention esters may be used as prodrugs of esters of benzene, aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention comprises a hydroxy/carboxy group, i.e., it may be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent.

Depending on the position and nature of the various substituents, the compounds of the present invention may also contain one or more asymmetric centers. Asymmetric carbon atoms may exist in either the (R) or (S) configuration, with only one asymmetric center yielding a racemic mixture and multiple asymmetric centers yielding a diastereomeric mixture. In some cases, asymmetry may also exist due to hindered rotation about a particular bond, for example, the central bond connects two substituted aromatic rings of a particular compound. Also, the substituents may exist in cis or trans isomeric forms.

The compounds of the invention also include all possible stereoisomers of each, either as a single stereoisomer or as any mixture of said stereoisomers (e.g. the R-or S-isomers, or the E-or Z-isomers) in any proportion. Separation of individual stereoisomers (e.g. individual enantiomers or individual diastereomers) of the compounds of the invention may be achieved by any suitable prior art method (e.g. chromatography, particularly, for example, chiral chromatography).

In addition, the compounds may also exist in tautomeric forms. The compounds of the invention include all possible tautomers of the compounds of formula (I) which are in the form of a single tautomer or any mixture of said tautomers in any ratio. All such isomers and mixtures thereof are included in the present invention.

In the present invention, reference to compounds also includes isotopically-labeled compounds, which are identical to those shown in formula I, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of H, C, N, O, S, F and Cl, such as²H、³H、¹³C、¹¹C、¹⁴C、1⁵N、¹⁸O、¹⁷O、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of the present invention, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, by incorporation of a radioactive isotope (such as³H and¹⁴C) the compounds of (a) are useful in drug and/or substrate tissue distribution assays. Tritium (i.e. tritium³H) And carbon 14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detectability. Again, with heavier isotopes such as deuterium (i.e. deuterium)²H) Alternative may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances. The compounds of the invention as claimed may be particularly limited to replacement with deuterium or tritium. Furthermore, the absence of hydrogen in the substituents indicating the term deuterium or tritium alone is not meant to exclude deuterium or tritium, but may equally well comprise deuterium or tritium.

The term "nitroxide" includes nitroxide structures derived from nitrogen-containing sites of compounds of the formula other than the N-oxidation of the pyridine ring.

The term "treating" refers to the application or administration of a compound to a subject for the purpose of curing, alleviating, relieving, altering, remedying, ameliorating, or affecting a disease, disorder, or predisposition. An "effective amount" refers to the amount of a compound required to impart a desired effect to a subject. As recognized by one skilled in the art, the effective amount will vary depending on the route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments (e.g., the use of other active agents).

The term "FXIa" means factor XIa, FXIa coagulation factor or undecafe.

The invention has the beneficial effects that:

the invention provides a FIXa inhibitor with novel structure, which has good anticoagulant activity, and the IC of the FIXa inhibitor is proved to be influenced by the in vitro enzyme activity experiment₅₀Substantially all in the 50.00nM range, the IC of more preferred compounds of the invention₅₀Within 10.00 nM.

Detailed Description

The preparation method of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention. The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.

Reagent names corresponding to English abbreviations