WO2019144811A1 - Tetrahydroisoquinoline derivative and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a tetrahydroisoquinoline derivative as shown in formula (I) and a preparation method therefor and the use thereof, and in particular to a tetrahydroisoquinoline derivative, a pharmaceutically acceptable salt, an ester, a polymorph or a solvate, a stereoisomer, a tautomer or a mixture, or a stable isotope derivative, a metabolite or a prodrug thereof. The present invention also relates to a method for preparing the compound, an intermediate, a pharmaceutical composition comprising the compound and the use of same in the treatment or prevention of thromboembolic conditions. (I)

Description

Tetrahydroisoquinoline derivative, preparation method and use thereof Technical field

The present invention relates to a tetrahydroisoquinoline derivative, a process for the preparation of the compound, and the use of the compound in the treatment or prevention of a thromboembolic disorder.

Background technique

Thromboembolic diseases such as stroke, myocardial infarction, and deep vein thrombosis are important causes of disability and death. Normal coagulation is a tightly regulated equilibrium process that requires maintaining the state of the fluid under normal physiological conditions and has a mechanism to rapidly form a tampon at the site of injury to prevent blood loss from jeopardizing life. The coagulation process can be divided into three interdependent pathways: extrinsic, intrinsic, and common pathways. Among them, coagulation factor XIa is located near the source of the intrinsic coagulation pathway, and the initiation of the intrinsic coagulation pathway and the formation of coagulation factor XIa (by activation of thrombin or coagulation factor XIIa) are important for maintaining blood clot integrity. However, factor XIa is not essential for normal hemostasis. Studies have shown that increased levels of factor XI are associated with venous thrombosis and myocardial infarction in men and increase the risk of cerebrovascular and coronary artery disease. It is thus concluded that inhibition of XIa can effectively inhibit thrombus formation without causing significant bleeding.

Various inhibitors of factor XIa are disclosed in WO2013/055984 and the like. However, the existing factor XIa inhibitors still have shortcomings in terms of metabolic stability and safety in vivo. Therefore, there is an urgent need to develop a novel coagulation factor XIa inhibitor which has a stronger selective inhibition effect on XIa, improved properties such as drug metabolism stability, and less toxic side effects.

Summary of the invention

Summary of invention

It is an object of the present invention to provide a compound which is a more potent and safe inhibitor of factor XIa, a pharmaceutically acceptable salt, ester, polymorph or solvate of said compound, A construct, tautomer or mixture thereof, or a stable isotope derivative, metabolite or prodrug of said compound, which can be used to treat or prevent a thromboembolic disorder. In more detail, the present invention provides a tetrahydroisoquinoline derivative which has good selectivity and has no inhibitory effect on coagulation factors Xa and VIIa while maintaining and enhancing high affinity for coagulation factor XIa, thereby It has a remarkable effect of improving blood solubility, improving metabolic stability in the body, and improving anti-hemagglutination.

In particular, one aspect of the invention relates to the following compounds:

a compound represented by the following formula (I), a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer, a tautomer or a mixture thereof, Or a stable isotope derivative, metabolite or prodrug of the compound,

among them:

Represents a single or double bond;

R ₁ is each independently selected from H, halogen, and 5-6 membered heteroaryl at each occurrence, and a plurality of R ₁ may be the same or different from each other;

R _{2 is} selected from the group consisting of H and O;

R ₃ is each independently selected from H and a hydroxyl group at each occurrence, a plurality of R ₃ may be the same or different from each other, and at least one R _{3 is} not H;

R _{4 is} selected from the group consisting of H and C _1-6 alkyl;

Y is selected from

W is selected from CR ₅ , CR _5a R _5b and C(=O);

Q is selected from N, C and CR ₆ ;

R ₅ , R _5a , R _5b and R ₆ are each independently selected from H and C _1-6 alkyl;

n is selected from any integer between 4-12, inclusive;

m and r are each independently an integer of 1, 2, 3, 4 or 5.

Another aspect of the invention provides a method of preparing the compound, comprising:

(1) Preparation method of intermediate E:

Wherein X is a boric acid or borate group, preferably -B(OH) ₂ or

R ₁ , Y, W, Q, m and r are as defined above;

Route 1:

Step 1: Compound A and Compound B are reacted to form Compound C;

Step 2: Compound C and Compound D are reacted to form Compound E;

Route 2:

Step 3: Compound A and Compound D are reacted to form Compound F;

Step 4: Compound F and Compound B are reacted to form Compound E;

(2) Preparation method of the compound of formula I:

Wherein R ₁ , R ₂ , R ₃ , R ₄ , Y, W, Q, n, m and r are as defined above;

Route 1:

Step 5: Compound E is deprotected under acidic conditions to form compound G;

Step 6: Compound G is formed into a compound of formula I by a condensation reaction with a carboxylic acid, an amine hydrolysis reaction of an ester, a substitution reaction of a halide or a reductive amination reaction of an aldehyde;

Route 2:

Step 7: Compound E selectively removes the protecting group under acidic conditions to form compound J;

Step 8: Compound J is formed by a condensation reaction with a carboxylic acid, an amine hydrolysis reaction of an ester, a substitution reaction of a halide or a reductive amination reaction of an aldehyde to form a compound K;

Step 9: Compound K is deprotected under acidic conditions to form a compound of formula I.

Another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer of the compound, A tautomer or a mixture thereof, or a stable isotope derivative, metabolite or prodrug of said compound, preferably, said pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

Another aspect of the invention provides a pharmaceutical formulation comprising a compound of the invention, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer of the compound, The tautomer or a mixture thereof, or a stable isotope derivative, metabolite or prodrug of the compound as an active ingredient, may be a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.

Another aspect of the invention provides a compound of the invention, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer, tautomer or mixture thereof Or a stable isotope derivative, metabolite or prodrug of the compound or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, in the manufacture of a medicament for the treatment of a disease associated with inhibition of factor XIa Applications. The disease associated with inhibition of factor XIa may be a thromboembolic disorder including, but not limited to, an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, and a thromboembolic disorder of the heart chamber.

Effect of the invention

By introducing a polyhydroxyalkyl group or a polyhydroxyacyl group, the compound of the present invention significantly increases the water solubility of the compound, thereby improving the solubility of the compound in blood and reducing the volume distribution of the drug in the human body. Therefore, the compound of the present invention has not only high affinity for coagulation factor XIa, but also extremely high selectivity to coagulation factors Xa and VIIa, and has good metabolic stability in vivo, improved pharmacokinetic properties, and anticoagulant efficacy.

Detailed description of the invention

definition

Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the invention.

The terms "comprising," "comprising," "having," "containing," Or method steps.

The term "halo" or "halogen" group is defined to include F, Cl, Br or I.

The term "C _1-6 alkyl" refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as C _1-4 alkyl, C _1-2 alkyl, C ₁ alkyl, C ₂ alkane. A group, a C ₃ alkyl group, a C ₄ alkyl group, a C ₅ alkyl group or a C ₆ alkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "5-6 membered heteroaryl" refers to a monocyclic aromatic group containing 5 to 6 ring members, and at least 1 to 4 (eg 1, 2, 3 or 4) of the ring members. It is a hetero atom selected from N, O and S, for example, a 5-membered heteroaryl group, a 6-membered heteroaryl group, a 5-membered nitrogen-containing heteroaryl group or the like. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3 , 4-oxadiazolyl, pyridyl, 2-pyridinone, 4-pyridinone, pyrimidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3- Triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 1H-tetrazolyl, and the like.

The term "stereoisomer" denotes an isomer formed by at least one asymmetric center. In a compound having one or more (eg, one, two, three or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.

Solid lines can be used in this article

Solid wedge

Virtual wedge

The chemical bonds of the compounds of the invention are depicted. A solid line is used to delineate a bond design that is bonded to an asymmetric carbon atom, including all possible stereoisomers at that carbon atom (eg, specific enantiomers, racemic mixtures, etc.). The use of a solid or virtual wedge to characterize the bond to an asymmetric carbon atom indicates the presence of the stereoisomers shown. When present in a racemic mixture, solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise indicated, the compounds of the invention may be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist. The compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).

The invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

It will also be understood that the compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, isotopically labeled compounds or prodrugs, which are administered to a patient in need thereof The compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

The term "substituted" means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by a selected group, provided that the specified atom is not exceeded in the current situation. Normal valence and the substitution forms a stable compound. The number of alternative groups selected is permissible when such combinations form stable compounds.

If a substituent is described as "optionally substituted with", the substituent may be unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted by one or more of the list of substituents, one or more hydrogens on the carbon may be replaced individually and/or together by an optional substituent that is independently selected. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen may each be replaced by an independently selected optional substituent.

If a substituent is described as being "independently selected from," each substituent may be the same or different than another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.

Unless otherwise indicated, a point of attachment of a substituent, as used herein, may come from any suitable position of the substituent.

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., hydrazine (D, ² H), hydrazine (T, ³ H)); isotopes of carbon (e.g., ¹¹ C, ¹³ C) And ¹⁴ C); isotope of chlorine (eg ³⁶ Cl); isotope of fluorine (eg ¹⁸ F); isotope of iodine (eg ¹²³ I and ¹²⁵ I); isotopes of nitrogen (eg ¹³ N and ¹⁵ N); isotopes of oxygen (eg ¹⁵ O, ¹⁷ O and ¹⁸ O); phosphorus isotopes (eg ³² P); and sulfur isotopes (eg ³⁵ S). Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays). The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D ₂ O, acetone-d ₆ or DMSO-d ₆ .

In addition to this, groups not defined here follow the usual definitions.

The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof. Examples include salts formed from alkali metals, alkaline earth metals, ammonium, alkylammonium, and the like, and salts formed with inorganic or organic acids. These salts may be, for example, formate or the like. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound). The compounds of the invention may also be esters per se.

The compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.

The invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association). Prodrugs of the invention may, for example, be known by those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. These references are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

Compound

It is an object of the present invention to provide a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound of the formula (I), wherein the stereoisomer, interconversion of the compound An isomer or a mixture thereof, or a stable isotope derivative, metabolite or prodrug of the compound,

among them:

Represents a single or double bond;

R ₁ is each independently selected from H, halogen, and 5-6 membered heteroaryl at each occurrence, and a plurality of R ₁ may be the same or different from each other;

R _{2 is} selected from the group consisting of H and O;

R ₃ is each independently selected from H and a hydroxyl group at each occurrence, a plurality of R ₃ may be the same or different from each other, and at least one R _{3 is} not H;

R _{4 is} selected from the group consisting of H and C _1-6 alkyl;

Y is selected from

W is selected from CR ₅ , CR _5a R _5b and C(=O);

Q is selected from N, C and CR ₆ ;

R ₅ , R _5a , R _5b and R ₆ are each independently selected from H and C _1-6 alkyl;

n is selected from any integer between 4-12, inclusive;

m and r are each independently an integer of 1, 2, 3, 4 or 5.

In a preferred embodiment, R ₁ is each independently selected from the group consisting of H, fluorine, chlorine, bromine, and a 5-membered heteroaryl group, and the plurality of R _{1 's} may be the same or different from each other. In a more preferred embodiment, each occurrence of R ₁ is independently selected from the group consisting of H, fluorine, chlorine, and a 5-membered heteroaryl group having 1 to 4 nitrogen atoms, for example,

In a preferred embodiment, when

When a single bond is indicated, R ₂ is H;

When the double bond is indicated, R ₂ is O.

In a preferred embodiment, R ₃ is a hydroxyl group.

In a preferred embodiment, R ₄ is H.

In a preferred embodiment, Y is selected from

In a preferred embodiment, W is selected from the group consisting of CH, CH ₂ and C(=O), and Q is selected from the group consisting of C, CH and N. In a more preferred embodiment,

Selected from

In a preferred embodiment, n is any integer between 4-10, inclusive. In a more preferred embodiment, n is an integer of 4, 5 or 6.

In a preferred embodiment, m is an integer of 2, 3, 4 or 5. In a more preferred embodiment, m is 2 or 3.

In a preferred embodiment, r is an integer of 1, 2 or 3. In a more preferred embodiment, r is one.

In a preferred embodiment, the compounds of the invention have the structure of formula (II):

Each of the groups is as defined above.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Each of the groups is as defined above.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Wherein R _{1 is} selected from the group consisting of H, fluorine, chlorine, and

Preferably, R _{1 is} selected from H and

More preferably, R ₁ is H.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Among them, when

When a single bond is indicated, R ₂ is H;

When a double bond is represented, R ₂ is O; preferably,

Indicates a single bond and R ₂ is H.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Wherein R ₃ is each independently selected from H and a hydroxyl group at each occurrence, a plurality of R ₃ may be the same or different from each other, and at least one R _{3 is} not H; preferably, R ₃ is a hydroxyl group.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Wherein n is an arbitrary integer between 4 and 10, inclusive; preferably, n is an integer of 4, 5 or 6; more preferably, n is 5.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Wherein R _{4 is} selected from the group consisting of H and C _1-6 alkyl; preferably, R ₄ is H.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Wherein W is selected from the group consisting of CR ₅ , CR _5a R _5b and C(=O), and R ₅ , R _5a and R _5b are each independently selected from H and C _1-6 alkyl; preferably, W is selected from CH and C (=O); more preferably, W is selected from CH.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Wherein Q is selected from N, C and CR ₆ ; preferably, Q is selected from C and N; more preferably, Q is C.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

among them,"

Selected from

Preferably,

for

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Where Y is selected from

Preferably, Y is

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Wherein r is an integer of 1, 2 or 3; preferably, r is 1.

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

among them,

for

Preferably

In a preferred embodiment, the compounds of the invention have the structure of formula (III):

Wherein R _{1 is} selected from the group consisting of H, fluorine, chlorine, and

Preferably, R _{1 is} selected from H and

More preferably, R ₁ is H;

when

When a single bond is indicated, R ₂ is H;

When a double bond is represented, R ₂ is O; preferably,

Represents a single bond, R ₂ is H;

R ₃ is each independently selected from H and a hydroxyl group at each occurrence, a plurality of R ₃ may be the same or different from each other, and at least one R _{3 is} not H; preferably, R ₃ is a hydroxyl group;

n is any integer between 4-10, inclusive; preferably, n is an integer of 4, 5 or 6; more preferably, n is 5;

R _{4 is} selected from H and C _1-6 alkyl; preferably, R ₄ is H;

W is selected from CR ₅ , CR _5a R _5b and C(=O), and R ₅ , R _5a and R _5b are each independently selected from H and C _1-6 alkyl; preferably, W is selected from CH and C (= O); more preferably, W is selected from CH;

Q is selected from N, C and CR ₆ ; preferably, Q is selected from C and N; more preferably, Q is C;

Y is selected from

Preferably, Y is

r is an integer of 1, 2 or 3; preferably, r is 1.

The present invention encompasses compounds obtained by any combination of the various embodiments.

In a preferred embodiment, the invention provides a compound, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer, tautomer or mixture thereof Or a stable isotope derivative, metabolite or prodrug of said compound, wherein said compound is selected from the group consisting of:

In a preferred embodiment, the invention provides a compound, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer, tautomer or mixture thereof Or a stable isotope derivative, metabolite or prodrug of said compound, wherein said compound is selected from the group consisting of:

Preparation

Another object of the present invention is to provide a process for producing a compound of the above formula (I), which can be produced by a process comprising the following reaction steps as described in the reaction scheme of the following method.

(1) Preparation method of intermediate E:

Wherein X is a boric acid or borate group, preferably -B(OH) ₂ or

R ₁ , Y, W, Q, m and r ^- are as defined above.

Route 1:

Step 1: Compound A and Compound B are reacted to form Compound C;

Step 2: Compound C and Compound D are reacted to form Compound E.

Route 2:

Step 3: Compound A and Compound D are reacted to form Compound F;

Step 4: Compound F and Compound B are reacted to form Compound E.

Wherein the condensation reaction is carried out in the presence of a condensing agent and an organic base, and the condensing agent used may be HATU, HBTU, HCTU, HOBt/EDCI, DMC, DCC, DIC, EDCI, BOP, PyBOP and PyAOP, etc. Preferred are HATU, HOBt/EDCI, EDCI; the organic base used may be TEA, DMAP, DIEA, pyridine, etc., preferably DIEA, TEA, pyridine: the condensation reaction may be carried out in an organic solvent, and suitable organic solvents include DMF, a halogenated hydrocarbon (for example, chloroform, dichloromethane, dichloroethane), an ether (for example, 1,4-dioxane, tetrahydrofuran, dimethyl ether, diethyl ether, methyl tert-butyl ether); the reaction temperature may be 0 to 100 ° C, preferably 0 ° C and room temperature; the reaction time is in the range of 1 to 24 hours, preferably 1 to 3 hours.

The coupling reaction is carried out in the presence of a metal catalyst which is a palladium metal catalyst such as tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino)dilenate. Iron] palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, Preference is given to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; the base is an inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, potassium hydrogencarbonate And sodium hydrogencarbonate, preferably cesium carbonate; the coupling reaction may be carried out in a suitable organic solvent or a mixed solvent of an organic solvent and water, which may be selected from 1,4-dioxane, N, N- Dimethylformamide or a mixed solvent of the above organic solvent and water, for example, a mixed solvent of 1,4-dioxane and water; the coupling reaction is carried out in a suitable protective atmosphere (for example, a nitrogen atmosphere); The temperature may be from 0 to 150 ° C, preferably from 100 to 130 ° C; the reaction time is in the range of from 2 to 48 hours, preferably from 8 to 12 hours.

(2) Preparation method of formula I:

Wherein R ₁ , R ₂ , R ₃ , R ₄ , Y, W, Q, n, m and r ^- are as defined above.

Route 1:

Step 5: Compound E is deprotected under acidic conditions to form compound G;

Step 6: Compound G is a compound of formula I by a condensation reaction with a carboxylic acid, an amine hydrolysis reaction of an ester, a substitution reaction of a halide or a reductive amination reaction of an aldehyde.

Route 2:

Step 7: Compound E selectively removes the protecting group under acidic conditions to form compound J;

Step 8: Compound J is formed by a condensation reaction with a carboxylic acid, an amine hydrolysis reaction of an ester, a substitution reaction of a halide or a reductive amination reaction of an aldehyde to form a compound K;

Step 9: Compound K is deprotected under acidic conditions to form a compound of formula I.

The deprotection reaction is carried out in the presence of a deprotecting agent at low temperature, room temperature or under heating. The deprotecting reagent to be used may be trifluoroacetic acid, hydrochloric acid, sulfuric acid or the like, preferably hydrochloric acid and trifluoroacetic acid; suitable organic solvents include halogenated hydrocarbons (for example, chloroform, dichloromethane, dichloroethane), ethers (for example, 1). , 4-dioxane, tetrahydrofuran, dimethyl ether, diethyl ether, methyl tert-butyl ether), DMF, etc., preferably dichloromethane, tetrahydrofuran, 1,4-dioxane; reaction temperature can be 0-100 °C, preferably 0-50 ° C; the reaction time is in the range of 0.5-24 hours, preferably 0.5-3 hours. For a more detailed procedure, see Greene's Protective Groups in Organic Synthesis (4th Edition) and the like.

The condensation reaction of the carboxylic acid is carried out in the presence of a condensing agent and an organic base, and the condensing agent used may be HATU, HBTU, HCTU, HOBt/EDCI, DMC, DCC, DIC, EDCI, BOP, PyBOP, PyAOP, etc. Preferably, HATU, HOBt/EDCI, EDCI; the organic base used may be TEA, DMAP, DIEA and pyridine, etc., preferably DIEA, TEA, pyridine: the condensation reaction may be carried out in an organic solvent, and the suitable organic solvent includes DMF , halogenated hydrocarbons (such as chloroform, dichloromethane, dichloroethane), ethers (such as 1,4-dioxane, tetrahydrofuran, dimethyl ether, diethyl ether, methyl tert-butyl ether); reaction temperature can be It is 0 to 100 ° C, preferably 0 ° C and room temperature; the reaction time is in the range of 1 to 24 hours, preferably 1 to 3 hours.

The aminolysis reaction of the ester can be carried out in an organic solvent or an organic solvent containing a catalytic amount of a base or a Lewis acid. Suitable bases are sodium alkoxide, sodium, sodium hydride, lithium aluminum hydride, etc., preferably sodium alkoxide; The catalytic amount of the Lewis acid is BBr ₃ , BF ₃ .EtO ₂ or the like, preferably BBr ₃ ; suitable organic solvents include MeOH, xylene, etc.; the reaction temperature may be 60 to 200 ° C, preferably 80 ° C and 120 ° C; reaction time In the range of 1-96 hours, preferably 8-24 hours.

The substitution reaction of the halide is carried out in the presence of a base, and the base used may be an inorganic base K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , KOtBu or the like, preferably K ₂ CO ₃ ; It may be an organic base DBU, DIEA, TEA, pyridine or the like, preferably DBU; the substitution reaction may be carried out in an organic solvent, and suitable organic solvents include DMF, halogenated hydrocarbons (for example, chloroform, dichloromethane, dichloroethane). , ethers (such as 1,4-dioxane, tetrahydrofuran, dimethyl ether, diethyl ether, methyl tert-butyl ether); the reaction temperature can be 0 to 100 ° C, preferably room temperature and 80 ° C; reaction time in 1- Within the range of 96 hours, preferably 3-8 hours.

The reductive amination reaction of the aldehyde is carried out in the presence of a reducing reagent and a catalytic acid, and the reducing reagent used may be NaBH ₄ , Na(CN)BH ₃ , NaBH(OAc) ₃ , Raney Ni or the like, preferably Na ( CN) BH ₃ ; The catalytic amount of acid used may be hydrochloric acid, HOAc, CF ₃ COOH or the like, preferably hydrochloric acid; the reductive amination reaction may be carried out in an organic solvent and water, and suitable organic solvents include MeOH, MeOH and halogen. a mixed solvent of a hydrocarbon (for example, chloroform, dichloromethane, dichloroethane), etc., preferably MeOH; the reaction temperature may be 0 to 100 ° C, preferably 60 ° C and 80 ° C; the reaction time is in the range of 1 to 24 hours, It is preferably 3-8 hours.

Additionally, the compounds of the invention may also be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described above. The reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials employed and suitable for effecting the conversion. Those skilled in the art of organic synthesis should be aware that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require the following determination: modify the order of the synthetic steps or route another specific method route relative to one method to obtain the desired compound of the invention.

It will also be appreciated that another major consideration in designing any synthetic route in the art is the correct selection of protecting groups for protecting the reactive functional groups present in the compounds described herein. An authoritative statement describing many alternatives to trained stakeholders is Greene et al. (Protective Groups in Organic Synthesis, 4th edition, Wiley-Interscience (2006)).

Unless otherwise stated, the substituents of the compounds in the above routes are as defined in the present invention. Those skilled in the art will appreciate that one or more of the above routes may be omitted depending on the desired product structure. Those skilled in the art can also appropriately adjust the order of the reaction steps as needed.

Pharmaceutical composition and pharmaceutical preparation

Another object of the present invention is to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt, ester, polymorph or solvate thereof, Stereoisomers, tautomers or mixtures thereof of the compounds, or stable isotopic derivatives, metabolites or prodrugs of the compounds, and one or more pharmaceutically acceptable carriers.

As used herein, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that can be administered with a therapeutic agent, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Or the tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the invention may act systemically and/or locally. For this purpose, they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration. Nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the invention may be administered in a suitable dosage form. The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups, and the like.

The amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg and the like.

According to one embodiment of the invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents for preventing or treating a disease associated with inhibition of Factor XIa.

Another object of the present invention is to provide a process for the preparation of a pharmaceutical composition of the present invention which comprises administering a compound of the present invention, a pharmaceutically acceptable salt, ester, polymorph or solvate thereof. A stereoisomer, tautomer or mixture thereof of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, in combination with one or more pharmaceutically acceptable carriers.

Another object of the present invention is to provide a pharmaceutical preparation comprising a compound of the present invention, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer of the compound, A tautomer or a mixture thereof, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition of the invention.

Treatment and use

Another object of the present invention is to provide a compound of the present invention, a pharmaceutically acceptable salt, ester, polymorph or solvate thereof, a stereoisomer, tautomer of the compound or a mixture, or a stable isotope derivative, metabolite or prodrug of the compound or a pharmaceutical composition of the invention or a pharmaceutical preparation of the invention, in the preparation of a medicament for preventing or treating a disease associated with inhibition of factor XIa use.

Another object of the present invention is to provide a compound of the present invention, a pharmaceutically acceptable salt, ester, polymorph or solvate thereof, a stereoisomer, tautomer of the compound or A mixture, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, for use in preventing or treating a disease associated with inhibition of factor XIa.

Another object of the present invention is to provide a method for preventing or treating a disease associated with inhibition of Factor XIa, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention, said compound being pharmaceutically acceptable Salts, esters, polymorphs or solvates, stereoisomers, tautomers or mixtures thereof, or stable isotopic derivatives, metabolites or prodrugs of said compounds, or the invention Pharmaceutical composition, or a formulation of the invention.

According to one embodiment of the invention, a disease associated with inhibition of factor XIa that can be prevented or treated using a compound of the invention includes, but is not limited to, a thromboembolic disorder, preferably including arterial cardiovascular thromboembolism Sexual disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders of the heart chamber.

More preferably, the thromboembolic disorder comprises unstable angina pectoris, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, Atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and due to a) resulting from prosthetic valves or other implants, (b) indwelling catheter, (c) stent, (d) extracorporeal circulation, (e) hemodialysis, or (f) exposure of blood to artificial surfaces that are prone to thrombosis Thrombosis.

The term "effective amount" refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.

The dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.

The amount of the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing such A condition or condition or one or more symptoms of such condition or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).

Detailed ways

Preparation example

In order to make the objects and technical solutions of the present invention clearer, the present invention will be further described below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. Further, specific experimental methods not mentioned in the following examples were carried out in accordance with a conventional experimental method.

The structure of the compound described in the following examples was determined by nuclear magnetic resonance ( ¹ H NMR) or mass spectrometry (MS).

^{The 1} H NMR shift (δ) is given in parts per million (ppm). ¹ H NMR was measured by JEOL Eclipse 400 NMR, and the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), hexamethylene dimethyl sulfoxide (DMSO-d ₆ ), internal standard Tetramethylsilane (TMS), chemical shifts are given in units of 10 ^-6 (ppm).

The abbreviations in the nuclear magnetic resonance (NMR) data used in the examples are shown below:

s: single peak, d: doublet, t: triplet, q: quartet, dd: doublet, qd: quadruple, ddd: doublet, ddt: doublet, dddd : double doublet doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz.

MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B;

A high performance liquid phase was prepared using Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mml column).

Thin-layer chromatography silica gel plate (TLC) was prepared by thin-layer chromatography using an aluminum plate (20×20 cm) manufactured by Merck. The specification used for the purification was GF 254 (0.4-0.5 nm) from Yantai.

The reaction was monitored by thin layer chromatography (TLC) or LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound The polarity is adjusted differently or adjusted by adding triethylamine or the like.

The microwave reaction was carried out using a Biotage Initiator + (400 W, RT ~ 300 ° C) microwave reactor.

Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as a carrier. The system of the eluent includes: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.

There is no particular description in the examples, and the reaction temperature is room temperature (20 ° C to 30 ° C).

The reagents used in the present invention were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebe Chemical.

In the conventional synthesis methods, examples, and intermediate synthesis examples, the meanings of the respective abbreviations are as follows.

DMA: N,N-dimethylacetamide; DMSO: dimethyl sulfoxide; NMP: N-methylpyrrolidone; DIBAL-H: diisobutylaluminum hydride; DIPEA: N,N-diisopropyl Amine; THF: tetrahydrofuran; Boc: tert-butoxycarbonyl; NBS: N-bromosuccinimide; Cbz-Cl: benzyl chloroformate; TFA: trifluoroacetic acid; Et ₂ O: diethyl ether; Ethanol; Dioxane: 1,4-dioxane; TLC: thin layer chromatography; Me: methyl; MTBE: methyl tert-butyl ether; HATU: O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate; DCM: dichloromethane; DBU: diazabicyclo ring; EA: ethyl acetate; TEA: triethylamine; XPhos: 2 - Bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; PE: petroleum ether.

Example 1: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-5-( 1-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3 , 4-tetrahydroisoquinoline-1-carboxamido)benzoic acid formate preparation (TM-1)

First step: tert-butyl 4-(1-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)- Preparation of 3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1-3)

The compound 4-(5-bromo-1,2,3,4-tetrahydroisoquinoline-1-carboxamide) benzoic acid tert-butyl ester hydrochloride (1-1, 20 g, 43 mmol), tert-butyl 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Butyl ester (1-2, 14.6 g, 47.3 mmol), sodium carbonate (29 g, 215 mmol) dissolved in a mixed solvent (180 mL) of 1,4-dioxane/water (5/1 by volume) in Pd(dppf)Cl ₂ (3.1 g, 4.3 mmol) was added under N ₂ atmosphere, and then placed in an oil bath at 120 ° C overnight. After the reaction was cooled to room temperature, the mixture was evaporated. mjjjjjjjjjjj

MS m/z (ESI): 534 [M+H] ⁺

Second step: tert-butyl(S)-4-(1-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-5 Of -3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1-4)

Compound 1-3 (32.6 g) was separated by chiral HPLC (column: IF Column; mobile phase: Hexane/EtOH/HAc=80/20/0.1 (V/V/V); flow rate: 1.0 ml/min; The detection wavelength: 214 nm; retention time: 11.97 min) gave the title compound (1-4, 11.7 g, yield: 35.9%).

MS m/z (ESI): 534 [M+H] ⁺

The third step: ((S)-1-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-2-((R)-3-(3-chloro-2-fluorophenyl)- 4,5-Dihydroisoxazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl Preparation of ester (1-6)

Compound 1-4 (10 g, 19 mmol), (R)-3-(3-chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid (1-5, 4.6 g, 19 mmol Soluble in DMF (25 mL), add DIPEA (7.4 g, 57 mmol) and HATU (8.7 g, 23 mmol), add, stir at room temperature overnight, add water, stir for 10 minutes, filter, filter cake dried and purified by silica gel column The title compound (1-6, 12.6 g, yield: 85.4%) was obtained.

¹ H NMR (500 MHz, DMSO) δ: 10.95-10.92 (s, 1H), 7.87-7.86 (d, 2H), 7.77-7.56 (m, 4H), 7.57-7.56 (d, 1H), 7.36-7.26 (m , 2H), 7.15-7.13 (s, 1H), 5.83 (s, 1H), 5.79-5.75 (s, 1H), 5.63 (s, 1H), 4.29-4.23 (m, 1H), 4.00 (s, 1H) ), 3.91-3.86 (m, 1H), 3.75-3.68 (m, 2H), 3.58 (m, 2H), 3.16-3.10 (m, 1H), 3.00-2.95 (m, 1H), 2.39-2.26 (m , 2H), 2.02 (s, 1H), 1.55 (s, 9H), 1.47 (s, 9H).

MS m/z (ESI): 779 [M+H] ⁺

Fourth step: ((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-5-(1, Preparation of 2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid hydrochloride (1-7)

The compound 1-6 (5 g, 6.4 mmol) was dissolved in tetrahydrofuran (10 mL), and the mixture was cooled to 0° C., and then dropwiselylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylyly Ethyl ether (50 mL) was added, and the mixture was evaporated to dryness.

MS m/z (ESI): 603 [M+H] ⁺

Step 5: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-5-( 1-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3 Of 4-(4-hydrogenisoquinoline-1-carboxamido)benzoic acid formate (TM-1)

Compound 1-7 (505 mg, 0.84 mmol) was dissolved in methanol buffer (30 mL), pH = 4-5, and then D-glucos (1-8, 755 mg, 4.2 mmol) and sodium cyanoborohydride (264 mg, After the addition was completed, the title compound (289 mg, 44.9%) was obtained.

¹ H NMR (400 MHz, DMSO) δ: 10.96-10.86 (s, 1H), 8.23 (s, 1H), 7.89-7.86 (d, 2H), 7.73-7.68 (m, 5H), 7.55-7.52 (d, 1H) ), 7.34-7.23 (m, 2H), 7.12-7.08 (s, 1H), 5.80-5.73 (m, 3H), 5.58 (s, 1H), 4.24 (s, 1H), 3.83 (m, 2H), 3.69-3.60 (m, 5H), 3.50-2.65 (m, 13H), 2.37-2.34 (d, 2H).

MS m/z (ESI): 767 [M+H] ⁺

Example 2: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-5-( 1-((2S,3R,4S,5R)-2,3,4,5,6-pentahydroxyhexyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3 , 4-tetrahydroisoquinoline-1-carboxamido)benzoic acid formate preparation (TM-2)

In the first step of this example, D-galactose was used instead of D-glucose in the fifth step of Example 1, and the title compound was obtained in a similar manner to Example 1.

MS m/z (ESI): 767 [M+H] ⁺

Example 3: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-5-( 1-((2S,3R,4R)-2,3,4,5-tetrahydroxypentyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4- Preparation of tetrahydroisoquinoline-1-carboxamido)benzoic acid formate (TM-3)

In the first step of this example, D-ribose was used instead of D-glucose in the fifth step of Example 1, and the title compound was obtained in a similar manner to Example 1.

MS m/z (ESI): 737 [M+H] ⁺

Example 4: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-5-( 1-((2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2, Preparation of 3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid (TM-4)

Compound 1-7 (105 mg, 0.17 mmol) and gluconolactone (30 mg, 0.17 mmol) were dissolved in methanol (5 mL), and sodium methoxide (28 mg, 0.51 mmol) was added. The title compound (26 mg, yield: 19.6%) was obtained.

MS m/z (ESI): 781 [M+H] ⁺

Example 5: 4-(2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(2-oxo -4((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline Preparation of 1-formylamino)benzoic acid formate (TM-5)

First step: (E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(2-oxo Preparation of piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoate (5-2)

The compound 5-1 (5 g, 6.3 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ° C, and then a solution of hydrochloric acid-1,4 dioxane (4M, 10 mL) was added dropwise, After completion of the reaction, the mixture was evaporated to dryness.

MS m/z (ESI): 645 [M+H] ⁺

Second step: 4-(2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(2-oxo -4((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline Preparation of 1-formylamino)benzoic acid formate (TM-5)

Compound 5-2 (572 mg, 0.84 mmol) was dissolved in methanol buffer (15 mL), pH = 4-5, and then D-glucos (1-8, 755 mg, 4.2 mmol) and sodium cyanoborohydride (264 mg, After the addition was completed, the title compound (165 mg, 24.3%) was obtained.

MS m/z (ESI): 809 [M+H] ⁺

Example 6: 4-(2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(1-( (2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4- Preparation of tetrahydroisoquinoline-1-carboxamido)benzoic acid formate (TM-6)

In the present example, (E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid was used instead of (R)- in the third step of Example 1. 3-(3-Chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboxylic acid, the title compound was obtained.

MS m/z (ESI): 792 [M+H] ⁺

Example 7: 4-((S)-2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5- (2-oxo-4-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)piperazin-1-yl)-1,2,3,4-tetra Preparation of Hydrogen Isoquinoline-1-carboxamido)benzoic Acid Formate (TM-7)

After chiral resolution of 5-1 in this example, the title compound was obtained in a similar manner to Example 5.

MS m/z (ESI): 809 [M+H] ⁺

Example 8: 4-((S)-2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-5- (1-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2, Preparation of 3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid formate (TM-8)

After chiral resolution of 6-2 in this example, the title compound was obtained in a similar manner to Example 6.

MS m/z (ESI): 809 [M+H] ⁺

Pharmacological data

Experimental Example 1 Inhibition of Coagulation Factor XIa

Factor XI activates to become factor XIa, further producing more Xa, thereby amplifying the amount of thrombin formation. The initiation of the endogenous coagulation pathway and the formation of coagulation factor XIa are considered to be important factors in maintaining blood clot integrity. XIa plays a key role in stabilizing thrombus formation, so the inhibitory effect of compounds on factor XIa is critical.

Reagents:

Enzyme: human coagulation factor XIa; manufacturer: Haemtech;

Substrate: Boc-Ile-Glu-Gly-Arg-AMC Acetate salt; Manufacturer: Bachem;

Detection method:

The test compound was dissolved in assay buffer (50 mM HEPES, 145 mM NaCl, 5 mM KCl, 0.1% BSA, pH 7.4) at various concentrations. Coagulation factor XIa and the test compound were added to the well plate, and the mixture was incubated for 10 minutes at room temperature. The reaction was initiated by the addition of a substrate (Boc-Ile-Glu-Gly-Arg-AMC Acetate salt). In the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence signal value. Read once every 30 seconds and continuously read 20 cycles. The inhibition rate of enzyme activity at different concentrations of the compound was calculated during the linear reaction period. Inhibiting concentration IC ₅₀ values with compounds of the fitting half GraphPad Prism 5 software.

Table 1. Inhibition of Factor XIa by Compounds

Compound number	IC 50 mean (nM)
TM-1	0.12±0.01

As can be seen from Table 1, the compound of the present invention has a significant inhibitory effect on coagulation factor XIa.

Experimental Example 2: Selective inhibition of coagulation factor VIIa and coagulation factor Xa enzyme

Reagents:

Enzyme: Human Factor VIIa; manufacturer: Haematologic Technologies;

Substrate: Boc-VPR-AMC; manufacturer: R&D;

Tissue factor: tissue factor F3; manufacturer: Sino Biological;

Enzyme: human coagulation factor Xa; manufacturer: R&D;

Substrate: Mca-RPKPVE-Nval-WRK(Dnp)-NH ₂ ; Manufacturer: R&D;

Detection method for selective inhibition of coagulation factor VIIa enzyme:

The test compound was dissolved in assay buffer (50 mM Hepes, 150 mM NaCl, 5 mM CaCl ₂ , pH 7.4) at a final concentration of 20 μM, 2 μM and 0.2 μM. Coagulation factor VIIa and tissue factor were mixed at an equimolar concentration, and after incubation at 37 ° C for 15 minutes, the test compound was further added for 10 minutes at room temperature, followed by addition of a substrate (Boc-VPR-AMC) to initiate the reaction. Using the enzyme kinetic mode, the excitation light wavelength was 380 nm, and the emission light wavelength was 460 nm to read the fluorescence signal value. Read once every 30 seconds and continuously read 20 cycles. The inhibition rate of enzyme activity at different concentrations of the compound was calculated during the linear reaction period. The range of IC ₅₀ was judged based on the inhibition rate at different concentrations.

Detection method for selective inhibition of coagulation factor Xa activity:

The test compound was dissolved in a detection buffer (50 mM Tris, 150 mM NaCl, 10 mM CaCl ₂ , 0.05% Brij 35, pH 7.5) at a final concentration of 20 μM, 2 μM and 0.2 μM. Coagulation factor Xa and the test compound were added to the well plate, and the mixture was incubated for 10 minutes at room temperature. The reaction was initiated by the addition of a substrate (Mca-RPKPVE-Nval-WRK(Dnp)-NH ₂ ). Using the enzyme kinetic mode, the excitation light wavelength was selected to be 320 nm, and the emission light wavelength was 400 nm to read the fluorescence signal value. Read once every 30 seconds and continuously read 20 cycles. The inhibition rate of enzyme activity at different concentrations of the compound was calculated during the linear reaction period. The range of the IC ₅₀ was judged based on the magnitude of the inhibition at different concentrations.

Table 2. Inhibition of test compounds on factor Xa and VIIa

Compound number	Xa IC 50 (μM)	VIIa IC 50 (μM)
TM-1	~20	>20

"~" means approx.

The compounds of the invention (e.g., TM-1) have no significant inhibitory effect on factor Xa and factor VIIa. As can be seen from Table 1-2, the compound of the present invention (e.g., TM-1) has a good selectivity, and has no inhibitory effect on coagulation factors Xa and VIIa while maintaining and enhancing high affinity for coagulation factor XIa.

Experimental Example 3: Effect of Compounds on Coagulation in Vitro

Reagents:

aPTT reagent (purchased from Sysmex);

PT reagent (purchased from Sysmex);

The coagulation pathway includes the exogenous coagulation pathway and the endogenous coagulation pathway. The parameter associated with the exogenous coagulation pathway is prothrombin time, expressed as PT (prothrombin time); the parameter associated with the endogenous coagulation pathway is activated partial thromboplastin time, expressed as aPTT (activated partial thromboplatin time).

aPTT (activated partial thromboplastin time) and PT (prothrombin time) detection methods:

After anticoagulation of different species (rabbit, human), the upper layer of plasma was collected by centrifugation, and divided into multiple portions, and different test compounds were added to make the final concentration of the test compound 10 μM. After mixing, incubate at 37 ° C, then The sample was placed in a coagulation analyzer for aPTT and PT detection. Blank plasma (without compound) was used as a reference and the ratio of aPTT to PT of all samples to blank plasma was analyzed.

Table 3. Effect of Compound TM-1 on different species aPTT and PT (n=3)

	rabbit	people
aPTT ratio to blank plasma	2.06±0.21	2.63±0.24
PT ratio to blank plasma	1.01±0.01	1.01±0.02

As can be seen from Table 3, the aPTT was significantly prolonged after the addition of the compound TM-1 of the present invention as compared with the blank plasma to which the test compound was not added, indicating that the compound of the present invention achieves an anti-endogenous coagulation effect by selectively inhibiting XIa. There was no significant change in the PT value associated with the exogenous coagulation pathway when the compound of the present invention was added compared to the blank plasma without the addition of the test compound, and the compound of the present invention had no effect on the pathway of exogenous coagulation.

Experimental Example 4: Pharmacokinetics (PK) Study in Rats and Rabbits

The compound of the present invention and the positive compound (BMS-962212) were administered to male SD rats by intravenous injection (IV) to examine the pharmacokinetic characteristics. Blood was collected at various time points after administration, and blood was anticoagulated using EDTA.K ₂ , and plasma samples were obtained after centrifugation and stored at -80 °C. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS.

The pharmacokinetic parameters were calculated using WinNonlin 6.3 software using a non-compartmental model. The experimental results are shown in Table 4.

Table 4 Compound TM-1 rat pharmacokinetic data

The compound of the present invention and the positive compound were administered to male rabbits by intravenous injection (IV) to examine the pharmacokinetic characteristics. Blood was collected at various time points after administration, and blood was anticoagulated using EDTA.K ₂ , and plasma samples were obtained after centrifugation and stored at -80 °C. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS.

The pharmacokinetic parameters were calculated using WinNonlin 6.3 software using a non-compartmental model. The experimental results are shown in Table 5.

Table 5 Compound TM-1 Rabbit Pharmacokinetic Data

As can be seen from Table 4-5, the compound of the present invention (for example, Compound TM-1) has a higher plasma exposure (AUC _last ) in rats, which is equivalent to twice the exposure of the positive compound, AUC _INF data and AUC. _{The last} data has the same trend; the plasma drug concentration (C _max ) is comparable to the positive compound; the T _{1/2 of the} compound of the present invention and the positive compound are 0.30 h and 0.19 h, respectively, indicating that the compound of the present invention has good pharmacokinetic properties. . The plasma exposure (AUC _last ) in rabbits is equivalent to three times the exposure of positive compounds, and the AUC _INF data has the same trend as the AUC _last data; the plasma drug concentration (C _max ) is equivalent to twice the positive compound; the present invention The T _{1/2 of the} compound and the positive compound were 0.62 h and 0.25 h, respectively, indicating that the compound of the present invention has good pharmacokinetic properties. Compared with positive compounds, it has obvious advantages in pharmacokinetics.

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each of the references (including all patents, patent applications, journal articles, books, and any other publications) cited in this application are hereby incorporated by reference in their entirety.

Claims (13)

1. A compound, a pharmaceutically acceptable salt, ester, polymorph or solvate thereof, a stereoisomer, tautomer or mixture thereof, or a stable isotope derivative of said compound a metabolite or prodrug wherein the compound has the structure of formula (I):

   

   among them:

   

   Represents a single or double bond;

   R ₁ is each independently selected from H, halogen, and 5-6 membered heteroaryl at each occurrence, and a plurality of R ₁ may be the same or different from each other;

   R _{2 is} selected from the group consisting of H and O;

   R ₃ is each independently selected from H and a hydroxyl group at each occurrence, a plurality of R ₃ may be the same or different from each other, and at least one R _{3 is} not H;

   R _{4 is} selected from the group consisting of H and C _1-6 alkyl;

   Y is selected from

   

   W is selected from CR ₅ , CR _5a R _5b and C(=O);

   Q is selected from N, C and CR ₆ ;

   R ₅ , R _5a , R _5b and R ₆ are each independently selected from H and C _1-6 alkyl;

   n is selected from any integer between 4-12, inclusive;

   m and r are each independently an integer of 1, 2, 3, 4 or 5.
2. A compound, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer, tautomer or mixture thereof, or a compound of the compound Stable isotope derivatives, metabolites or prodrugs, of which:

   R ₁ is each independently selected from the group consisting of H, fluorine, chlorine, bromine and a 5-membered heteroaryl group, and a plurality of R _{1 's} may be the same or different from each other;

   And / or when

   

   When a single bond is indicated, R ₂ is H;

   

   When representing a double bond, R ₂ is O;

   And/or, W is selected from the group consisting of CH, CH ₂ and C(=O), and Q is selected from C, CH and N.
3. A compound according to claim 1 or 2, a pharmaceutically acceptable salt, ester, polymorph or solvate of said compound, a stereoisomer, tautomer or mixture thereof, or A stable isotopic derivative, metabolite or prodrug of a compound, wherein the compound has the structure of formula (II):

   

   Wherein R ₁ , R ₂ , R ₃ , R ₄ , Y, W, Q, n and r are as defined in any one of claims 1-2;

   Preferably, the compound has the structure of formula (III)

   

   Wherein R ₁ , R ₂ , R ₃ , R ₄ , Y, W, Q, n and r are as defined in any one of claims 1-2.
4. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt, ester, polymorph or solvate of said compound, a stereoisomer, tautomer or mixture thereof, Or a stable isotope derivative, metabolite or prodrug of the compound having one or more of the following characteristics:

   (1) r is an integer of 1, 2 or 3; preferably, r is 1;

   (2)

   

   Selected from

   

   (3) R ₁ is hydrogen or a 5-membered heteroaryl group having 1 to 4 nitrogen atoms;

   (4) R ₃ is each independently selected from H and a hydroxyl group at each occurrence, a plurality of R _{3 's} may be the same or different from each other, and at least one R _{3 is} not H; preferably, R ₃ is a hydroxyl group;

   (5) n is an arbitrary integer between 4-10, inclusive; preferably, n is an integer of 4, 5 or 6; more preferably, n is 5;

   (6) R _{4 is} selected from H and C _1-6 alkyl; preferably, R ₄ is H;

   (7) W is selected from CR ₅ , CR _5a R _5b and C(=O), and R ₅ , R _5a and R _5b are each independently selected from H and C _1-6 alkyl; preferably, W is selected from CH and C(=O); more preferably, W is selected from CH;

   (8) Q is selected from N, C and CR ₆ ; preferably, Q is selected from C and N; more preferably, Q is C;

   (9) Y is

   

   (10) Y is

   
5. A compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer, tautomer of the compound or a mixture, or a stable isotope derivative, metabolite or prodrug of said compound, wherein said compound is selected from the group consisting of

   

   
6. A compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer, tautomer of the compound or a mixture, or a stable isotope derivative, metabolite or prodrug of said compound, wherein said compound is selected from the group consisting of

   
7. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, ester, polymorph or solvate of said compound Isomers, tautomers or mixtures thereof, or stable isotopic derivatives, metabolites or prodrugs of said compounds, preferably said pharmaceutical compositions further comprise pharmaceutically acceptable excipients.
8. The pharmaceutical composition according to claim 7, further comprising one or more active ingredients, and the active ingredient may be a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt or ester of the compound A polymorph or solvate, a stereoisomer, a tautomer or a mixture thereof, or a stable isotope derivative, metabolite or prodrug of the compound.
9. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, ester, polymorph or solvate of said compound, stereoisomers of said compound, mutual An isomer or a mixture thereof, or a stable isotope derivative, metabolite or prodrug of the compound as an active ingredient, the pharmaceutical preparation being a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.
10. A compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, ester, polymorph or solvate of the compound, a stereoisomer, tautomer of the compound or a mixture, or a stable isotope derivative, metabolite or prodrug of the compound or a pharmaceutical composition according to any one of claims 7 or 8, or a pharmaceutical preparation according to claim 9 for use in the treatment of a clotting factor The use of XIa for the inhibition of related diseases;

    Preferably, the disease associated with inhibition of factor XIa is a thromboembolic disorder selected from the group consisting of an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, and a thrombus in the heart chamber. Embolism disorder;

    More preferably, the thromboembolic disorder is selected from the group consisting of unstable angina pectoris, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke , atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and (a) resulting from prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) extracorporeal circulation, (e) hemodialysis, or (f) exposure of blood to artificial surfaces that are prone to thrombosis Thrombosis.
11. A compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, ester, polymorph or solvate of said compound, a stereoisomer, tautomer or mixture thereof, Or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition according to any one of claims 7-8 or a pharmaceutical preparation according to claim 9 for use in the prevention or treatment of inhibition of coagulation factor XIa The disease.
12. A method of preventing or treating a disease associated with inhibition of factor XIa, the method comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1 to 6, said compound being pharmaceutically acceptable a salt, an ester, a polymorph or a solvate, a stereoisomer, a tautomer or a mixture thereof, or a stable isotope derivative, metabolite or prodrug of the compound, or a claim The pharmaceutical composition of any of 7-8, or the formulation of claim 9.
13. A method of preparing a compound according to any one of claims 1 to 6, comprising:

    (1) Preparation of intermediate E:

    

    Wherein X is a boric acid or borate group, preferably -B(OH) ₂ or

    

    R ₁ , Y, W, Q, m and r are as defined in any one of claims 1-6;

    Route 1:

    Step 1: Compound A and Compound B are reacted to form Compound C;

    Step 2: Compound C and Compound D are reacted to form Compound E;

    Route 2:

    Step 3: Compound A and Compound D are reacted to form Compound F;

    Step 4: Compound F and Compound B are reacted to form Compound E;

    (2) Preparation of a compound of formula I:

    

    Wherein R ₁ , R ₂ , R ₃ , R ₄ , Y, W, Q, n, m and r are as defined in any one of claims 1-5;

    Route 1:

    Step 5: Compound E is deprotected under acidic conditions to form compound G;

    Step 6: Compound G is formed into a compound of formula I by a condensation reaction with a carboxylic acid, an amine hydrolysis reaction of an ester, a substitution reaction of a halide or a reductive amination reaction of an aldehyde;

    Route 2:

    Step 7: Compound E selectively removes the protecting group under acidic conditions to form compound J;

    Step 8: Compound J is formed by a condensation reaction with a carboxylic acid, an amine hydrolysis reaction of an ester, a substitution reaction of a halide or a reductive amination reaction of an aldehyde to form a compound K;

    Step 9: Compound K is deprotected under acidic conditions to form a compound of formula I.