WO2019218899A1

WO2019218899A1 - Tetrahydroisoquinoline amide compound containing polyglycol ether and pharmaceutical use thereof

Info

Publication number: WO2019218899A1
Application number: PCT/CN2019/085873
Authority: WO
Inventors: 朱加望; 宋智泉; 宋立强; 吴勇勇; 王利春; 王晶翼
Original assignee: 四川科伦博泰生物医药股份有限公司
Priority date: 2018-05-17
Filing date: 2019-05-07
Publication date: 2019-11-21

Abstract

Disclosed is a tetrahydroisoquinoline amide compound containing polyglycol ether and a pharmaceutical use thereof. In particular, the present disclosure relates to a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, polymorph, a solvate, a prodrug or a stable isotope derivative thereof, or a stereoisomer, tautomer or mixture thereof, and a preparation method thereof, and a use thereof for preventing or treating symptoms associated with an excessive activity of an XIa factor.

Description

Tetrahydroisoquinolinamide compound containing polyglycol ether and its pharmaceutical use

Technical field

The present invention relates to a poly(ethylene glycol ether)-containing tetrahydroisoquinolinamide compound or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or the compound Stereoisomers, tautomers or mixtures thereof, methods of preparing such compounds and use in the prevention or treatment of conditions associated with excessive activity of factor XIa, such as thromboembolic disorders.

Background technique

Thromboembolic diseases have high morbidity, mortality or disability. Myocardial infarction, cerebral infarction and pulmonary infarction caused by thromboembolism are the leading causes of death. Antithrombotic drugs mainly include anticoagulation, antiplatelet and thrombolytic drugs. Traditional anticoagulant drugs (such as warfarin, heparin), and rivaroxaban, clopidogrel, and dabigatran etexilate have good effects on reducing thrombus formation, but they cannot avoid potential bleeding complications. Danger. Therefore, there is an urgent need for clinical anti-thrombotic drugs for improving bleeding side effects.

The coagulation cascade is a process in which a series of coagulation factors are sequentially activated to form fibrin. This cascade reaction is divided into an endogenous pathway and an exogenous pathway. Factor XIa is an endogenous pathway that plays a role in the amplification of cascade reactions. Inhibitor drugs targeting the XIa factor target can block the endogenous pathway and inhibit the amplification of the coagulation cascade, thereby having a better antithrombotic effect. In recent years, the results of anti-embolization experiments show that XIa factor is a new target for anti-thrombosis with low risk of bleeding, and its research and drug development have attracted more and more attention (WO2013093484, WO2013056060, US20160368923, etc.).

Summary of invention

It is an object of the present invention to provide a compound which is potent, safe and/or pharmaceutically effective (e.g., having better solubility) which is a factor XIa inhibitor, or a pharmaceutically acceptable salt, ester or polycrystal thereof. a form, solvate, prodrug or stable isotope derivative, or a stereoisomer, tautomer or mixture of the compounds. In particular, prodrugs of the compounds of the invention have improved oral drug absorption and plasma exposure and are useful in oral pharmaceutical formulations. The invention also provides the compound, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer, tautomer of the compound A method of preparing a construct or a mixture thereof and use in preventing or treating a condition associated with excessive activity of factor XIa, such as a thromboembolic disorder.

Specifically, the present application relates to the following aspects:

In one aspect, the application provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or Stereoisomers, tautomers or mixtures thereof,

among them,

R ^{1 is} selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl and 3-10 membered heterocyclic, wherein said C _1-6 alkyl, C _2-6 The alkenyl group, the C _3-6 cycloalkyl group and the 3-10 membered heterocyclic group are optionally one or more selected from the group consisting of halogen, C _1-6 alkyl, -OH and -O-(C _1-6 alkyl) Substituted by a substituent;

Selected from the following structure:

R ² , R ³ and R ⁴ are each independently selected from the group consisting of: H, halogen, C _1-6 alkyl, -OH, -O-(C _1-6 alkyl), 3-6 membered heterocyclic, phenyl And a 5-6 membered heteroaryl group wherein the C _1-6 alkyl group, -O-(C _1-6 alkyl), 3-6 membered heterocyclic group, phenyl group and 5-6 membered heteroaryl group Optionally substituted with one or more substituents selected from the group consisting of halogen, C _1-6 alkyl, -OH and -O-(C _1-6 alkyl);

Y is selected from the group consisting of C _2-4 alkenylene and 5-6 membered heteroarylene;

Ring A is selected from the following structures:

R ^{5 is} selected from the group consisting of H, C _1-6 alkyl and -C _1-4 alkylene-OC(=O)OC _1-4 alkyl;

n is selected from an integer of 2-9.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound, a method for preparing a tautomer or a mixture thereof, which comprises the following

method one:

In Method 1, R ^L1 and R ^L2 each independently represent a halogen or a C _1-3 alkyl sulfonate group optionally substituted by a halogen (eg, a triflate group); R ^Lx represents =0, Halogen or a C _1-3 alkyl sulfonate group optionally substituted by halogen (for example, a triflate group); PG ¹ , PG ² , PG ³ and PG ⁴ are protecting groups; Z represents a leaving group Preferably, the leaving group is selected from the group consisting of H, halogen, C _1-3 alkyl sulfonate group optionally substituted by halogen, boronic acid group, boronic acid ester group, substituted silicon group or substituted metal group group;

Step 1: Compound S-1 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-1;

Step 2: Compound IM-1 undergoes a coupling reaction to form compound IM-2;

Step 3: Compound IM-2 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-3;

Step 4: Compound IM-3 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride to form compound IM- 4;

Step 5: Compound IM-4 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I).

Those skilled in the art will appreciate that the order of the above processes can be adjusted as desired, or the substitution reaction process in step five can be omitted.

Method Two:

In the second method, R ^L1 , R ^L2 , R ^Lx , PG ¹ , PG ² , PG ³ , PG ⁴ and Z are as defined in the first method;

Step 2: Compound IM-1 undergoes a coupling reaction to form compound IM-2;

Step 3: Compound IM-2 is subjected to chiral resolution to obtain compound IM-5;

Step 4: Compound IM-5 undergoes deprotection reaction and continues to carry out acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-6;

Step 5: Compound IM-6 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -7;

Step 6: Compound IM-7 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I)-1.

Those skilled in the art will appreciate that the order of the above processes can be adjusted as desired, or the substitution reaction process in step six can be omitted.

Method three:

In the third method, R ^L1 , R ^L2 , R ^Lx , PG ³ , PG ⁴ and Z are as defined in the first method;

Step 1: Compound S-2 undergoes a coupling reaction to form compound IM-8;

Step 2: Compounds IM-8, S-3 and S-4 are subjected to Ugi reaction in an alcohol solvent to form compound IM-9;

Step 3: Compound IM-9 undergoes a deprotection reaction, and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -10;

Step 4: Compound IM-10 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I).

Those skilled in the art will appreciate that the order of the above processes can be adjusted as desired, or the substitution reaction process in step four can be omitted.

Method four:

In method four, R ^L1 , R ^L2 , R ^Lx , PG ³ , PG ⁴ and Z are as defined in method one;

Step 1: Compound S-2 undergoes a coupling reaction to form compound IM-8;

Step 4: Compound IM-10 is subjected to chiral resolution to obtain compound IM-11;

Step 5: Compound IM-11 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I)-1.

Method five:

In method five, R ^L1 , R ^L2 , R ^Lx , PG ² , PG ³ and PG ⁴ are as defined in method one;

Step 1: Compound S-5 and S-6 were subjected to a Buckwald coupling reaction to give compound IM-12. In some embodiments, S-5 and piperazine are subjected to a Buckwald coupling reaction and then subjected to a protective reaction to produce compound IM-12;

Step 2: Compound IM-12 is subjected to acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-13;

Step 3: Compound IM-13 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -14;

Step 4: Compound IM-14 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-15;

Step 5: Compound IM-15 is subjected to chiral resolution to obtain compound IM-16;

Step 6: Compound IM-16 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (VI).

In the above method 1, method two, method three or method four, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ring A, Y, W, Q and n are as defined above.

In the above method five, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ring A, Y and n are as defined above.

Another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or Stereoisomers, tautomers or mixtures thereof of the compounds preferably further comprise pharmaceutically acceptable excipients.

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

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound , tautomers or mixtures thereof, or a pharmaceutical composition of the invention, or the use of an agent of the invention in the manufacture of a medicament for the prevention or treatment of a condition associated with excessive activity of factor XIa (eg thromboembolism) Sexual illness). Such thromboembolic disorders include arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders of the heart chamber.

Effect of the invention

The present invention significantly increases the water solubility of the compound by introducing a polyethylene glycol ether substituent on the tetrahydroisoquinoline structure, and at the same time, the compound of the present invention exhibits a good inhibitory activity against the XIa enzyme. Furthermore, the ester derivatives of the compounds of the invention provide an effective prodrug form which can be used in oral administration.

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 "alkyl" is defined as a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, an alkyl group has from 1 to 12 carbon atoms (denoted as "C _1-12 alkyl"), preferably from 1 to 6 carbon atoms (denoted as "C _1-6 alkyl"), It preferably has 1 to 4 carbon atoms (denoted as "C _1-4 alkyl group", and still more preferably has 1 to 3 carbon atoms (denoted as "C _1-3 alkyl group"). For example, as used herein, the term " _C1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl). The term "C _1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl). The term "C _1-3 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 3 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl). In the present invention, "alkyl" is optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl") (for example, -CF _{3 )} , -C ₂ F ₅ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ Cl or -CH ₂ CH ₂ CF _{3 ,} etc.).

The term "alkenyl" refers to a hydrocarbon group containing at least one carbon-carbon double bond. In some embodiments, an alkenyl group has 2 to 12 carbon atoms (denoted as "C _2-12 alkenyl"), preferably 2 to 6 carbon atoms (denoted as "C _2-6 alkenyl"). The alkenyl group may be a linear or branched alkenyl group. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. The alkenyl group may be an unsubstituted alkenyl group or substituted by one or more substituents which may be the same or different, such as a halogen, an alkenyl group, an alkynyl group, an aryl group, a cycloalkyl group, a cyano group, a hydroxyl group or the like. The term "C _2-6 alkenyl" refers to a hydrocarbon group of 2 to 6 carbon atoms containing at least one carbon-carbon double bond (ie, vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl) , n-pentenyl, n-hexenyl, etc.). The term " _C2-4 alkenyl" refers to a hydrocarbon radical of 2 to 4 carbon atoms containing at least one carbon-carbon double bond (ie, vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl) Wait).

The term "alkylene" means a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a linear or branched saturated hydrocarbon group. In some embodiments, the alkylene group contains 1-10 carbon atoms (denoted as "C _1-10 alkylene"), and in other embodiments, the alkylene group contains 1-6 carbons Atom (denoted as "C _1-6 alkylene"), in other embodiments, the alkylene group contains from 1 to 4 carbon atoms (denoted as "C _1-4 alkylene"). Such examples include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), isopropylidene (-CH(CH3)CH2-), and the like, wherein the alkylene group can be independently It is unsubstituted or substituted by one or more of the substituents described herein.

The term "alkenylene" means a divalent group obtained by removing one hydrogen atom from the alkenyl group defined by the present invention. Non-limiting examples of alkenylene include -CH = CH -, - C ( CH 3) = CH-, and -CH = CHCH ₂ -. The term "C _2-4 alkenylene" refers to a divalent group obtained by removing one hydrogen atom from a C _2-4 alkenyl group (i.e., a vinylidene group, a propenylene group, a n-n-butenyl group, a sub-3-methyl group). But-2-enyl group, etc.).

The term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic monocyclic ring (such as a C _3-10 cycloalkyl group, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). , cycloheptyl, cyclooctyl, cyclodecyl) or polycyclic (including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2 .1] an octyl or bicyclo [5.2.0] fluorenyl, decahydronaphthyl, etc.) hydrocarbon ring optionally substituted with one or more (such as 1 to 3) suitable substituents. Wherein the cycloalkyl group has 3 to 15 carbon atoms, preferably 3 to 6 carbon atoms. For example, the term "C _3-6 cycloalkyl" refers to the saturation or unsaturation of 3 to 6 ring-forming carbon atoms. Non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which are optionally suitably prepared by one or more (such as 1 to 3) Substituted by a substituent such as a methyl substituted cyclopropyl group.

The term "heterocyclyl" includes any of those having a carbon atom and at least one heteroatom (eg, O, S, N, P) or a heteroatom moiety (eg, SO ₂ , CO, CONH, COO, PO, PO ₂ ) in the ring. A substituted non-aromatic ring group is selected. In some embodiments, the heterocyclic group has from 3 to 18 ring atoms, preferably from 3 to 10 ring atoms, more preferably from 3 to 6 ring atoms. The heterocyclic group may be a saturated, partially saturated, non-aromatic monocyclic or fused ring group. Examples of the heterocyclic group include a cyclohexylimino group, an imidazolidinyl group, an imidazolinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, a pyridyl group, a pyrrolidinyl group, a thienyl group, and a 4,5-dihydro-1H- group. Imidazolyl, 1,2,3,6-tetrahydropyridyl, 3-oxopiperazine, 4H-1,3-oxazinyl, 5,6-dihydro-4H-1,3-oxazinyl.

Examples of the term "3-10 membered heterocyclic group" include oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrrole Polinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, Thiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperid Azinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxetanyl, thiaheptanyl, oxazepine, diaza Base, thiazepine, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and the like. Examples of the -CH2- group substituted by -C(=O)- in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidone Base, 3,5-dioxopiperidinyl, pyrimidindione.

Examples of the term "3-6 membered heterocyclic group" include oxiranyl group, azetidinyl group, oxetanyl group, thioheterobutyl group, pyrrolidinyl group, 2-pyrroline group, 3-pyrrole group. Polinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, Thiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperid Zinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl.

The term "(sub)heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, preferably having 5, 6, 8, 9, 10, 11 , 12, 13 or 14 ring atoms, in particular containing 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, in each case, may be benzofused. For example, the (sub)heteroaryl group may be selected from (i)thienyl, (i)furanyl, (i)pyrrolyl, (i)oxazolyl, (sub)thiazolyl, (sub)imidazolyl, (Asia) Pyrazolyl, (i)isoxazolyl, (i)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl, etc., and their benzo derivative Or (i)pyridinyl, (i)pyridazinyl, (i)pyrimidinyl, (i)pyrazinyl, (i)triazinyl, and the like, and their benzo derivatives. Examples of the term "5-6 membered heteroaryl" include pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridone), isoxazolyl, isothiazolyl, Oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazinyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl.

The term "protecting group" refers to a chemical group having the following characteristics: i) reactable with a corresponding functional group to form a protected group; ii) stabilize the reaction conditions to which the protected group will be subjected; and iii) The protected group is removed to release the functional group.

The term "anion" means a negatively charged organic or inorganic ion, and specific examples thereof include fluoride ion, chloride ion, bromide ion, iodide ion, sulfate ion, phosphate ion, nitrate ion, carbonate ion, acetate ion, lactate ion, tartaric acid ion, Benzoic acid ion, citrate ion, trifluoroacetic acid ion, methanesulfonate ion, ethanesulfonic acid ion, methyl sulfate ion, benzenesulfonate ion, p-toluenesulfonic acid ion, isethionate ion, adipic acid ion, Ethane-1,2-disulfonic acid ion, 1,5-naphthalene disulfonic acid ion, naphthalene-2-sulfonic acid ion, malate ion, maleic acid ion, malonate ion, fumarate ion, amber Acid ions, 1-hydroxy-2-naphthoic acid ions, phthalic acid ions, sorbic acid ions, oleic acid ions and glucuronic acid ions, among which fluoride, chloride, bromide, iodide, trifluoro Acetate ion, sulfate ion, lactate ion, tartaric acid ion, benzoic acid ion, citrate ion, methanesulfonate ion, benzenesulfonate ion, p-toluenesulfonic acid ion, adipic acid ion, ethane-1,2-disulfonate Acid ion, 1,5-naphthalene Sulfonic acid ion, naphthalene-2-sulfonic acid ion, malate ion, maleic acid ion, malonic acid ion, fumaric acid ion, succinic acid ion, 1-hydroxy-2-naphthoic acid ion or glucuronic acid ion.

Solid lines can be used in this article

Solid wedge

Virtual wedge

The carbon-carbon 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, prodrugs or stable isotope derivatives, in which they 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 administration. 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.

When a bond of a substituent is shown to pass through a bond in the ring without a specified position, such a substituent may be bonded to any suitable ring-forming atom in the substitutable ring.

The invention also includes stable isotopic derivatives (isotopically labeled compounds) of the compounds of the invention, which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but differ in atomic mass or mass number in nature. The atomic substitution of the dominant atomic mass or mass number. 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 by an isotope, and the isotopically substituted crystallization solvent includes 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, for example, be sodium, potassium, calcium, ammonium, aluminum, triethylammonium, acetate, propionate, butyrate, formate, trifluoroacetate, maleic acid. Salt, tartrate, citrate, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, B Sulfonate, 2-hydroxyethanesulfonate, besylate, p-toluenesulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, tris Methylaminomethane salt, salt formed with cysteine, salt formed with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinic acid Salts, oxalates, picrates, thiocyanates, undecanoates, salts with acrylic polymers, salts with carboxyvinyl polymers, and 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.

Pharmaceutically acceptable esters of the compounds of the invention include those resulting from the esterification of an acid group of a compound of the invention with an alcohol.

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 & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

Compound

In one aspect, the application provides a compound represented by the following formula (I), or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or the compound Stereoisomers, tautomers or mixtures thereof,

among them,

R ^{1 is} selected from H, C _1-6 alkyl (e.g., C _1-3 alkyl), C _2-6 alkenyl (e.g., C _2-3 alkenyl), C _3-6 cycloalkyl, and 3-10. a heterocyclic group (for example, a 5-6 membered heterocyclic group) wherein the C _1-6 alkyl group (e.g., C _1-3 alkyl group), C _2-6 alkenyl group (e.g., C _2-3 alkenyl group), C _3-6 cycloalkyl and 3-10 membered heterocyclyl (for example, 5-6 members of a heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S) are optionally selected by one or more Substituents from halogen, C _1-6 alkyl (eg C _1-3 alkyl), -OH and -O-(C _1-6 alkyl) (eg -O-(C _1-3 alkyl)) Replace

Selected from the following structure:

R ² , R ³ and R ⁴ are each independently selected from the group consisting of: H, halogen, C _1-6 alkyl (for example, C _1-3 alkyl), -OH, -O-(C _1-6 alkyl), a 3-6 membered heterocyclic group (for example, a 5-6 membered heterocyclic group having 1 or 2 hetero atoms selected from N, O, and S), a phenyl group, and a 5-6 membered heteroaryl group (for example, 5-6) a heteroaryl group having 1 or 2 hetero atoms selected from N, O, S), wherein the C _1-6 alkyl group (for example, C _1-3 alkyl group), -O-(C _1-6 Alkyl), -O-(C _1-6 alkyl), 3-6 membered heterocyclic group (for example, a heterocyclic group of 5-6 members containing one or two hetero atoms selected from N, O, and S) a phenyl group and a 5-6 membered heteroaryl group (for example, a 5-6 membered heteroaryl group having 1 or 2 hetero atoms selected from N, O, S) is optionally selected from one or more selected from the group consisting of halogens, Substituted with a substituent of a C _1-6 alkyl group (e.g., C _1-3 alkyl), -OH, and -O-(C _1-6 alkyl) (e.g., -O-(C _1-3 alkyl));

Y is selected from a C _2-4 alkenylene group and a 5-6 membered heteroarylene group (for example, a 5-6 membered heteroarylene group having 1 or 2 hetero atoms selected from N, O, S);

Ring A is selected from the following structures:

R ^{5 is} selected from the group consisting of H, C _1-6 alkyl (e.g., C _1-3 alkyl) and -C _1-4 alkylene-OC(=O)OC _1-4 alkyl; n is selected from 2-9 An integer such as 2, 3, 4, 5, 6, 7, 8, or 9. In a preferred embodiment, R ^{1 is} selected from the group consisting of H, C _1-3 alkyl (eg methyl, ethyl, n-propyl, isopropyl) and halo C _1-3 alkyl (eg fluoro C _{1 -3} alkyl groups such as fluoromethyl and fluoroethyl).

In a more preferred embodiment, R ^{1 is} selected from the group consisting of H, CH ₃ , CF ₃ and CH ₂ CF ₃ .

In a preferred embodiment, R ² and R ⁴ are each independently selected from the group consisting of: H, halogen, unsubstituted or tetrazolyl substituted with one halogen atom (for example F, Cl, Br or I).

In a more preferred embodiment, R ² and R ⁴ are each independently selected from:

F, Cl, H,

Preferably, R ^{2 is} selected from the group consisting of: H,

Preferably, R ^{4 is} selected from the group consisting of H, F and Cl.

In a preferred embodiment, R ^{3 is} selected from the group consisting of H and halogen.

In a more preferred embodiment, R ^{3 is} selected from the group consisting of H, F and Cl.

In a preferred embodiment, R ³ is a halogen such as F or Cl.

In a preferred embodiment, Y is selected from the group consisting of vinylidene, propenylene, oxazolyl, oxazolyl, thiazolyl, isoisothiazolyl, imidazolyl, pyrazolyl.

In a preferred embodiment, Y is selected from the group consisting of vinylidene and isoxazolyl.

In a more preferred embodiment, Y is selected from the following structures:

In a preferred embodiment, ring A is

In a preferred embodiment, R ^{5 is} selected from the group consisting of H, C _1-3 alkyl (eg methyl, ethyl, n-propyl, isopropyl) and -C _1-3 alkylene-OC (=O) OC _1-3 alkyl.

In a preferred embodiment, the -C _1-3 alkylene-OC(=O)OC _1-3 alkyl group is

Wherein R ^{6 is} selected from the group consisting of H, -CH ₃ and -CH ₂ CH ₃ ; and R ^{7 is} selected from the group consisting of -CH ₃ , -CH ₂ CH ₃ and -CH(CH ₃ ) ₂ .

In a preferred embodiment, n is selected from an integer from 2 to 4, such as 2, 3 or 4.

In some embodiments, the structure of the compounds of the invention is as follows,

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ring A, n,

And Y are as defined in formula (I).

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,

And Y are as defined in formula (I).

Wherein R ^{6 is} selected from the group consisting of H, -CH ₃ and -CH ₂ CH ₃ ; R ^{7 is} selected from the group consisting of -CH ₃ , -CH ₂ CH ₃ and -CH(CH ₃ ) ₂ ; R ¹ , R ² , R ³ , R ⁴ ,

And Y are as defined in formula (I).

In some embodiments, in the above formula (III),

R ^{1 is} selected from the group consisting of H, C _1-3 alkyl and halo C _1-3 alkyl;

R ^{2 is} selected from the following structures:

R ³ and R ⁴ are each independently selected from the group consisting of H, F and Cl;

Selected from the following structure:

Y is selected from the following structures:

R ^{6 is} selected from the group consisting of H, -CH ₃ and -CH ₂ CH ₃ ; R ^{7 is} selected from the group consisting of -CH ₃ , -CH ₂ CH ₃ and -CH(CH ₃ ) ₂ ;

Wherein R ¹ , R ² , R ³ , R ⁴ ,

And Y as defined by formula (I);

In some embodiments, in the above formula (V),

R ^{2 is} selected from the following structures:

Selected from the following structure:

Y is selected from the following structures:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y and ring A are as defined in formula (I). The present invention encompasses compounds obtained by any combination of the various embodiments. In some embodiments, the structure of the compounds of the invention is as follows:

In some embodiments, the structure of the compounds of the invention is as follows:

In the compound of the present invention, a compound wherein R ⁵ is H is an active ingredient; a compound wherein R ^{5 is} not H is a prodrug, and can be metabolized to a corresponding active ingredient (ie, a compound having R ⁵ is H) in a living body to exert pharmacological effects. effect.

Preparation

The compounds of the invention can 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 below. 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 understand that 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 following routes are as defined above. Those skilled in the art will appreciate that one or more of the following 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.

Another aspect of the present application provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound, a method for preparing a tautomer or a mixture thereof, comprising the following

method one:

Step 2: Compound IM-1 undergoes a coupling reaction to form compound IM-2;

Step 4: Compound IM-3 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -4;

Those skilled in the art will appreciate that the order of the above processes can be adjusted as needed, or the substitution reaction process in step five can be omitted.

Method Two:

Step 2: Compound IM-1 undergoes a coupling reaction to form compound IM-2;

Those skilled in the art will appreciate that the order of the above processes can be adjusted as needed, or the substitution reaction process in step six can be omitted.

Method three:

Step 1: Compound S-2 undergoes a coupling reaction to form compound IM-8;

Those skilled in the art will appreciate that the order of the above processes can be adjusted as needed, or the substitution reaction process in step four can be omitted.

Method four:

Step 1: Compound S-2 undergoes a coupling reaction to form compound IM-8;

Method five:

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 or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stabilizing thereof Isotope derivatives, or stereoisomers, tautomers or mixtures thereof, of the compounds, optionally further comprising one or more pharmaceutically acceptable carriers.

"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.

In the pharmaceutical compositions of the present invention, pharmaceutically acceptable carriers which may be employed include, but are not limited to, sterile liquids such as water and oils, including those oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, Mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline, glucose or an aqueous glycerin solution 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, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 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 condition associated with excessive activity 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 or a pharmaceutically acceptable salt, ester, polymorph, solvate thereof, or a pharmaceutically acceptable salt thereof A drug or stable isotope derivative, or a stereoisomer, tautomer or mixture thereof, 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 or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or Stereoisomers, tautomers or mixtures thereof of the compounds, or pharmaceutical compositions of the invention.

Treatment and use

Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound Use of a tautomer or a mixture thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for preventing or treating a disorder associated with excessive activity of factor XIa.

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

Another object of the present invention is to provide a method for preventing or treating a disorder associated with excessive activity of factor XIa, which comprises administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, An ester, polymorph, solvate, prodrug or stable isotope derivative, or a stereoisomer, tautomer or mixture thereof of the compound, or a pharmaceutical composition of the invention.

According to one embodiment of the invention, the condition associated with excessive activity of factor XIa includes, but is not limited to, a thromboembolic disorder, preferably an arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder , or a thromboembolic disorder in the heart chamber.

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) 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.

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 will add up to about 0.007 mg/day to about 3500 mg/day, for example 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.).

Another aspect of the present application provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound, A tautomer or a mixture thereof, or the use of a pharmaceutical composition of the invention in the preparation of a formulation for modulating (e.g., reducing or inhibiting) the activity of factor XIa in an individual cell.

Another aspect of the present application provides a method of modulating (e.g., reducing or inhibiting) the activity of Factor XIa in an individual cell comprising administering to said cell an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or ester thereof , a polymorph, a solvate, a prodrug or a stable isotope derivative, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutical composition of the invention, or a pharmaceutical composition of the invention Pharmaceutical preparations.

In some embodiments, the formulation is administered to an individual to modulate (eg, reduce or inhibit) the activity of factor XIa in a cell of the subject; or the formulation is administered to an in vitro cell (eg, a cell line or from an individual) Cells) to modulate (eg, reduce or inhibit) the activity of factor XIa in a cell.

The application also relates to the following technical solutions:

A compound represented by the following formula (I): or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate or isotopically labeled compound thereof, particularly Is a prodrug compound,

In the above formula (I),

R ^{1 is} selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl and 3-10 membered heterocyclic, wherein the alkyl, alkenyl, cycloalkyl and hetero The cyclo group is optionally substituted with one or more substituents selected from the group consisting of halogen, C _1-6 alkyl, -OH and -O-(C _1-6 alkyl);

Preferably, R ^{1 is} selected from the group consisting of H, C _1-3 alkyl and halo C _1-3 alkyl;

More preferably, R ^{1 is} selected from the group consisting of H, CH ₃ , CF ₃ and CH ₂ CF ₃ ;

Selected from the following structure:

R ² , R ³ and R ⁴ are each independently selected from the group consisting of: H, halogen, C _1-6 alkyl, -OH, -O-(C _1-6 alkyl), -O-(C _1-6 alkane a 3-6 membered heterocyclic group, a phenyl group, and a 5-6 membered heteroaryl group, wherein the alkyl group, heterocyclic group, phenyl group, and heteroaryl group are optionally selected from one or more selected from the group consisting of halogen, Substituent substitution of C _1-6 alkyl, -OH and -O-(C _1-6 alkyl);

Preferably, R ^{2 is} selected from the group consisting of H, unsubstituted or tetrazolyl substituted with one halogen atom;

More preferably, R ^{2 is} selected from the following structures: H,

Preferably, R ³ and R ⁴ are each independently selected from H, a halogen atom;

More preferably, R ³ and R ⁴ are each independently selected from the group consisting of H, F and Cl; Y is selected from the group consisting of C _2-4 alkenylene and 5-6 membered heteroarylene;

Preferably, Y is selected from the group consisting of vinylidene, propenylene, isoxazolyl, oxazolyl, thiazolyl, isoisothiazolyl, imidazolyl, pyrazolyl;

More preferably, Y is selected from the following structures:

Ring A is selected from the following structures:

Preferably ring A is

Preferably R ^{5 is} selected from the group consisting of H and -C _1-3 alkylene-OC(=O)OC _1-3 alkyl;

n is selected from an integer of 2-9;

Preferably n is an integer selected from 2-4.

Scheme 2. The compound according to Scheme 1, the structure of which is shown below,

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ring A, Q, W and Y are as defined for formula (I) in Scheme 1.

Scheme 3. The compound according to Scheme 1, the structure of which is as follows:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q, W and Y are as defined for formula (I) in Scheme 1.

Scheme 4. The compound according to Scheme 1, the structure of which is as follows:

Wherein R ^{6 is} selected from the group consisting of H, -CH ₃ and -CH ₂ CH ₃ ; R ^{7 is} selected from the group consisting of -CH ₃ , -CH ₂ CH ₃ and -CH(CH ₃ ) ₂ ; R ¹ , R ² , R ³ , R ⁴ , Q, W and Y as defined in formula 1 for formula (I);

Preferably, in the above formula (III),

R ^{2 is} selected from the following structures:

H,

Selected from the following structure:

Y is selected from the following structures:

R ^{6 is} selected from the group consisting of H, -CH ₃ and -CH ₂ CH ₃ ; R ^{7 is} selected from the group consisting of -CH ₃ , -CH ₂ CH ₃ and -CH(CH ₃ ) ₂ .

Scheme 5. A compound according to Scheme 1, the structure of which is as follows:

Wherein R ¹ , R ² , R ³ , R ⁴ , Q, W and Y are as defined for formula (I) in Scheme 1;

Preferably, in the above formula (V),

R ^{2 is} selected from the following structures:

H,

Selected from the following structure:

Y is selected from the following structures:

Scheme 6. The compound according to Scheme 1, the structure of which is shown below,

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and ring A are as defined for formula (I) in Scheme 1.

A pharmaceutical composition according to any one of the items 1 to 6, which is a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, Their metabolite forms, or mixtures thereof, and one or more pharmaceutically acceptable carriers.

A pharmaceutical preparation, wherein the preparation comprises the compound according to any one of the items 1 to 6, a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer thereof, or any crystal form thereof. Or a racemate, a metabolite form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the invention, which is in the form of a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.

The compound of any one of the methods 1 to 6, a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or A mixture thereof, or the pharmaceutical composition according to item 8, or the pharmaceutical preparation according to item 11 for use in the preparation of a medicament for treating a disease associated with inhibition of factor XI.

The use according to claim 9, wherein the thromboembolic disorder comprises an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, and a thromboembolic disorder 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.

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). ^{The 1} H NMR was measured by JEOL Eclipse 400 NMR, and the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), hexamethyl dimethyl sulfoxide (DMSO-d6), and the internal standard was four. Methylsilane (TMS), chemical shift is given in units of 10 ^-6 (ppm),

The abbreviations in the nuclear magnetic resonance (NMR) spectra 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 special description in the examples, and the reaction temperature is room temperature (20 ° C ~ 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 and examples, and intermediate synthesis examples, the meanings of the abbreviations are as follows:

Aq.:aqueous solution HPLC: high performance liquid chromatography

AcOH: acetic acid LC-MS: liquid chromatography-mass spectrometry

BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine MnO ₂ : manganese dioxide

DMF: N,N-dimethylformamide NaCl: sodium chloride

DMP: Dess Martin oxidant NaI: sodium iodide

DABCO: triethylenediamine NaOH: sodium hydroxide

DIEA: diisopropylethylamine NaO ^t Bu: sodium tert-butoxide

THF: tetrahydrofuran NaBH ₃ CN: sodium cyanoborohydride

MeOH: methanol NaBH ₄ : sodium borohydride

MeCN: acetonitrile HATU: O-(7-azabenzotriazol-1-yl)-

Boc: tert-butoxycarbonyl N,N,N',N'-tetramethyluronium hexafluorophosphate

NCS: N-chlorosuccinimide DCM: dichloromethane

TFA: trifluoroacetic acid EA: ethyl acetate

TFAA: Trifluoroacetic anhydride

NH ₂ OH ^. HCl: Hydroxylamine hydrochloride

HCl: hydrogen chloride

EtOH: ethanol

ⁿ BuLi: n-butyllithium

I ₂ : Iodine

E ₃ N: triethylamine

EDCI: 1-(3-dimethylaminopropyl)-3-ethyl

Carbodiimide

Dioxane: 1,4-dioxane

Pd(OAc) ₂ : palladium acetate

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone) dipalladium

HC(OMe) ₃ : Trimethyl orthoformate

K ₂ CO ₃ : potassium carbonate

TMSN ₃ : Azido trimethylsilane

TLC: thin layer chromatography

Example A: Preparation of (R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboxylic acid (Int-A)

First step: Preparation of 3-chloro-2-fluorobenzaldehyde oxime (A-2)

The compound 3-chloro-2-fluorobenzaldehyde (50.0g, 0.32mol) and hydroxylamine hydrochloride (22.2g, 0.32mol) was dissolved in THF (400mL), was added after stirring Et ₃ N (32.3g, 0.32mol) overnight. The reaction mixture was quenched with EtOAc EtOAc EtOAc. MS m/z (ESI): 174 [M+H] ⁺

Second step: Preparation of 3-chloro-2-fluoro-N-hydroxybenzimid chloride (A-3)

The compound 3-chloro-2-fluorobenzaldehyde oxime (28.0 g, 0.16 mol) was dissolved in DMF (200 mL). The organic phase was washed, dried, filtered, evaporated MS m/z (ESI): 208 [M+H] ⁺

Third step: Preparation of 3-(3-chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid tert-butyl ester (A-4)

The compound 3-chloro-imine -N- hydroxybenzamide chloride (37.6g, crude) and tert-butyl acrylate (46g, 0.36mol) was dissolved in dichloromethane (300mL), was added Et ₃ N (27.3 g, 0.27 mol), the reaction mixture was stirred at room temperature overnight, and the reaction was completed by LC-MS. The title compound was obtained (36.7 g, m. MS m/z (ESI): 300 [M+H] ⁺

Fourth step: Preparation of (R)-3-(3-chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid tert-butyl ester (A-5)

3-(3-Chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid tert-butyl ester (18 g) was isolated and purified by chiral HPLC ( instrument model: Shimadzu LC-20AD, Column: IG (IG00CD-UF004) (0.46 cm ID × 15 cm L); column temperature: 35 ° C; flow rate: 1.0 mL / min; detection wavelength: UV 254 nm; mobile phase A: 100% MeOH; retention time: 4.868 The title compound (7.2 g, 40%) was obtained. MS m/z (ESI): 300 [M+H] ⁺

Step 5: Preparation of (R)-3-(3-chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid (Int-A)

The compound (R)-3-(3-chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid tert-butyl ester (5.0 g, 16.68 mmol) was dissolved in dichloromethane (10 mL) Trifluoroacetic acid (10 mL) was added and the mixture was evaporated. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m v MS m/z (ESI): 244 [M+H] ⁺

Example B: Preparation of (E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid (Int-B)

First step: Preparation of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (B-2)

4-Chloro-3-fluoroaniline (450 g, 3.1 mol) and tetrahydrofuran (1 L) were added to a 3 L three-necked flask, and trifluoroacetic anhydride (715 g, 3.4 mol) was slowly added with stirring. The reaction mixture was stirred at room temperature for 3 hr. EtOAc (EtOAc) MS m/z (ESI): 242 [M+H] ⁺

Second step: Preparation of N-(4-chloro-3-fluoro-2-iodophenyl)-2,2,2-trifluoroacetamide (B-3)

Add B-2 (100g, 0.41mol) and tetrahydrofuran (1L) to a 3L three-necked flask, cool to -78 ° C under nitrogen atmosphere, slowly add n-butyl lithium solution (2.5M, 500mL), after the completion of the addition Stir at this temperature for 1 hour. After the addition was completed, a solution of elemental iodine (300 g, 1.18 mol) in THF (600 mL) was slowly added, and after the completion of the dropwise addition, the mixture was stirred at this temperature for 1 hour. After completion of the reaction by LC-MS, the reaction mixture was poured into a 1N hydrochloric acid (1.4 L) solution, and stirred thoroughly, and then saturated sodium thiosulfate solution was added until the solution turned from brown to pale yellow. After extracting three times with ethyl acetate (5 L), EtOAc (EtOAc) MS m/z (ESI): 368 [M+H] ⁺

Third step: Preparation of (E)-3-(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)acrylate tert-butyl ester (B-4)

To a 2 L single-mouth bottle was added compound B-3 (100 g, 272 mmol), tert-butyl acrylate (105 g, 816 mmol), palladium acetate (4.3 g, 19.1 mmol), anhydrous triethylenediamine (180 g, 816 mmol) and DMF ( 500 mL), heated to reflux overnight under nitrogen. The reaction was monitored by LC-MS. After cooling to room temperature, the pH was adjusted to about 3 with dilute hydrochloric acid. The organic layer was combined with EtOAc (3 mL). MS m/z (ESI): 368 [M+H] ⁺

Fourth step: Preparation of (E)-3-(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)acrylic acid (B-5):

Compound B-4 (97 g, 263.8 mmol) was dissolved in anhydrous ethanol (1 L), and then aqueous EtOAc (32.3 g, 79. The reaction was heated to 85 ° C for 16 hours, and the reaction was monitored by LC-MS. Part of the solvent was removed by EtOAc (EtOAc)EtOAc. MS m/z (ESI): 216 [M+H] ⁺

Step 5: Preparation of (E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid (Int-B)

Compound B-5 (60 g, 253 mmol) was dissolved in glacial acetic acid (1. 8L) and then trimethyl orthoformate (410 g, 3790 mmol) After reacting for 4 hours at room temperature, TMSN ₃ (148 g, 1260 mmol) was added, and the mixture was heated to 80 ° C for 18 hours. After completion of the reaction by LC-MS, the reaction mixture was concentrated to dryness, and the residue was dissolved in 3 L of water. It was extracted with EA/THF (1/1). The obtained yellow solid was EtOAc (EtOAc)EtOAc. MS m/z (ESI): 269 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-) δ 12.80 (br, 1 H), 9.87 (s, 1H), 8.03 - 7.78 (m, 1H), 7.67 (dd, J = 8.8, 1.6 Hz, 1H), 6.97 ( d, J = 16.0 Hz, 1H), 6.31 (dd, J = 16.4, 1.6 Hz, 1H).

Example 1: (S,E)-4-(5-(4-(2,5,8,11-tetraoxatridecyl-13-yl)-piperazin-1-yl)-2-( 3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino Preparation of benzoic acid (T-1)

First step: Preparation of 5-(piperazin-1-yl)isoquinoline (1-1)

The compound 5-bromoisoquinoline (25 g, 120 mmol) and piperazine (31 g, 360 mmol) were dissolved in toluene (600 mL), tris(dibenzylideneacetone) dipalladium (1.10 g, 1.20 mmol), BINAP ( 2.2 g, 3.60 mmol) and sodium tert-butoxide (17.3 g, 180 mmol) were reacted at 98 ° C for 4 hours. After completion of the reaction by LC-MS, the reaction solution was cooled to room temperature, and an appropriate amount of water was added. The toluene was evaporated under reduced pressure, and the residue was evaporated, evaporated, evaporated, evaporated 78%). MS m/z (ESI): 214 [M+H] ⁺

Second step: Preparation of 2,2,2-trifluoro-1-(4-(isoquinolin-5-yl)piperazin-1-yl)ethanone (1-2)

Compound 1-1 (20 g, 93.8 mmol) was dissolved in DCM (200 mL), triethylamine (38 g, 375 mmol) and trifluoroacetic acid (39 g, 188 mmol). After the reaction was completed by LC-MS, EtOAc m. MS m/z (ESI): 310 [M+H] ⁺

The third step: 2,2,2-trifluoro-1-(4-(1,2,3,4-tetrahydroisoquinolin-5-yl)piperazin-1-yl)ethanone (1-3 Preparation

Compound 1-2 (27g, 87.3mmol) was dissolved in _{MeOH / CH 3 COOH (1:} 1,270mL) in batches added sodium cyanoborohydride (16.5g, 261.9mmol), at room temperature for 4 hours. After LC-MS was monitored, the reaction mixture was diluted with water (1.35 L), sodium carbonate was slowly added, pH=8 was adjusted, dichloromethane/methanol (10/1) was extracted, and the organic phase was combined. It was dried, concentrated by filtration, and the obtained crude material was used directly. MS m/z (ESI): 314 [M+H] ⁺

Fourth step: Preparation of 1-(4-(3,4-dihydroisoquinolin-5-yl)piperazin-1-yl)-2,2,2-trifluoroethanone (1-4)

Compound 1-3 (32.6 g, 104 mmol) was dissolved in dichloromethane (870 mL), and then MgSO. After the reaction was completed by LC-MS, the reaction mixture was filtered over EtOAc EtOAc (EtOAc). MS m/z (ESI): 312 [M+H] ⁺

Step 5: (E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazolyl-1-yl)phenyl)acryloyl)-5-(4- (2,2,2-Trifluoroacetyl)piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino)benzoic acid tert-butyl ester (1-5) Preparation

Compound 1-4 (10.2 g, 32.6 mmol), Int-B (4.4 g, 16.3 mmol) and 4-iso- cyanobenzoic acid tert-butyl ester (9.3 g, 45.7 mmol) were dissolved in ethanol (320 mL). The mixture was refluxed at 90 ° C for 12 hours. The reaction was completed with EtOAc EtOAc EtOAc. MS m/z (ESI): 783 [M+H] ⁺

Step 6: (E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazolyl-1-yl)phenyl)acryloyl)-5-(piperazine) Of -1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino)benzoic acid tert-butyl ester (1-6)

Compound 1-5 (4.1g, 5.24mmol) was dissolved in MeOH (240mL) was added NaBH ₄ (2.0g, 52.4mmol), the reaction 20 ℃ 30 minutes. The reaction was monitored by LC-MS and concentrated under reduced pressure. MS m/z (ESI): 687 [M+H] ⁺

Step 7: (S,E)-4-(5-(4-(2,5,8,11-tetraoxatridecyl-13-yl)-piperazin-1-yl)-2-( 3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino Preparation of tert-butyl benzoate (1-7)

Compound 1-6 (5.01 g, 7.28 mmol) and 1-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-2-methoxy-ethane (3.95 g, 14.6 mmol) was dissolved in acetonitrile (70 mL), sodium iodide (218 mg, 1.46 mmol) and potassium carbonate (4.02 g, 29.1 mmol) were added and reacted at 75 ° C for 2 hours. The reaction was observed to give EtOAc (m.). The racemic compound was separated by chiral HPLC (instrument model: Shimadzu LC-20AD, column: IC (IC00CD-TB016) (0.46 cm ID × 15 cm L); column temperature: 35 ° C; flow rate: 2.0 mL / min; The detection wavelength: UV 254 nm; mobile phase: MeOH/TEA = 100/0.1 (V/V); retention time: 11.046 min.) afforded the title compound 1-7 (0.85 g, 30%). MS m/z (ESI): 877 [M+H] ⁺

Step 8: (S,E)-4-(5-(4-(2,5,8,11-tetraoxatridecyl-13-yl)-piperazin-1-yl)-2-( 3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino Preparation of benzoic acid (T-1)

To a solution of Compound 1-7 (833 mg, 0.95 mmol The reaction was monitored by EtOAc (EtOAc) elute MS m/z (ESI): 821 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} 12.71 (br, 1H), 10.74 (s, 1H), 9.87 (s, 1H), 8.00-7.92 (m, 1H), 7.90-7.83 (m, 2H), 7.71-7.59 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H), 7.25 - 7.16 (m, 1H), 7.09 (d, J = 16.0 Hz, 1H), 7.02 - 6.89 (m, 2H), 5.73 ( s, 1H), 4.14–4.04 (m, 1H), 3.63–3.45 (m, 12H), 3.44–3.40 (m, 3H), 3.22 (s, 3H), 3.10–2.95 (m, 2H), 2.93– 2.84 (m, 2H), 2.83–2.73 (m, 2H), 2.71–2.52 (m, 6H).

Example 2: 1-((ethoxycarbonyl)oxy)ethyl(S,E)-4-(5-(4-(2,5,8,11-tetraoxatridecane-13-) -(piperazin-1-yl)-2-(3-(3-chloro-2-fluoro-6-(1H-tetrazolyl-1-yl)phenyl)acryloyl)-1,2,3 Of 4-(4-tetrahydroisoquinoline-1-carbonylamido)benzoate (T-2)

To a solution of MeCN T-1 (143mg, 0.17mmol ) of (4mL) was added _{_{K 2 CO 3 (240mg, 1.70mmol}} ), 1- chloroethyl ethyl carbonate (133mg, 0.85mmol) and NaI (26 mg, 0.17 mmol), then stirred at 70 °C. The title compound T-2 (70 mg, 41%) was obtained. MS m/z (ESI): 937 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 9.87 (s, 1H), 8.1 - 7.93 (m, 1H), 7.93 - 7.85 (m, 2H), 7.76 - 7.69 (m, 2H) , 7.67 (dd, J = 8.8, 1.2 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.28 - 7.17 (m, 1H), 7.09 (d, J = 15.6 Hz, 1H), 7.02 - 6.89 (m, 2H), 6.89 - 6.79 (m, 1H), 5.73 (s, 1H), 4.20 - 4.03 (m, 3H), 3.58 (s, 2H), 3.56 - 3.48 (m, 10H), 3.48 - 3.46(m,1H), 3.44–3.40(m,2H), 3.22(s,3H), 3.10–2.95(m,2H),2.96–2.86(m,3H),2.86–2.76(m,2H), 2.76–2.53 (m, 5H), 1.56 (d, J = 5.2 Hz, 3H), 1.20 (t, J = 8.0 Hz, 3H).

Example 3: 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine-4 -yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetra Preparation of hydrogen isoquinoline-1-carbonylamido)benzoic acid (T-3)

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

The compound 4-(5-bromo-1,2,3,4-tetrahydroisoquinoline-1-carboxamide) benzoic acid tert-butyl ester hydrochloride Int-C (20.0 g, 43.0 mmol) (see patent CN107540659A) ), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 ( 2H)-tert-butyl carboxylic acid 3-1 (14.6 g, 47.3 mmol), sodium carbonate (29.0 g, 215 mmol) dissolved in 1,4-dioxane/water (5/1) mixed solvent (180 mL) After the N _{2 was} replaced three times, Pd(dppf)Cl ₂ (3.1 g, 4.3 mmol) was added under a N ₂ atmosphere, and then placed in an oil bath at 120 ° C overnight. After the reaction was completed by LC-MS, EtOAc m. MS m/z (ESI): 534 [M+H] ⁺

Step 2: (S)-4-(1-((4-(tert-Butoxycarbonyl)phenyl)aminocarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl) Preparation of -3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3-3)

The compound tert-butyl 4-(1-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-3, Separation of 6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (32.6 g) by chiral HPLC (column: IF Column; mobile phase: Hexane/EtOH/HAc=80/20/0.1 (V/V/) V); flow rate: 1.0 ml/min; detection wavelength: 214 nm; retention time: 11.97 min) to give the title compound 3-3 (11.7 g, 36%). MS m/z (ESI): 534 [M+H] ⁺

Third step: ((S)-1-((4-(tert-butoxycarbonyl)phenyl)aminocarbonyl)-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 Preparation of butyl ester (3-4)

The compound tert-butyl(S)-4-(1-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-5-yl -3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3-3, 10 g, 19 mmol), (R)-3-(3-chloro-2-fluorobenzene)-4,5 -Dihydroisoxazole-5-carboxylic acid Int-A (4.6 g, 19 mmol) was dissolved in DMF (25 mL), DIPEA (7.4 g, 57 mmol) and HATU (8.7 g, 23 mmol). . After the reaction was completed by LC-MS, the mixture was evaporated,jjjjjjjjjj MS m/z (ESI): 779 [M+H] ⁺

Fourth step: ((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-5-(1 Of 2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoate (3-5)

The compound ((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 ester 3 -4 (700 mg, 0.92 mmol) was dissolved in tetrahydrofuran (18 mL), cooled to EtOAc (EtOAc) After the reaction was completed by EtOAc (EtOAc:EtOAc) MS m/z (ESI): 659 [M+H] ⁺

Step 5: 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine-4 -yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetra Preparation of tert-butyl hydroperyl isoquinoline-1-carbonylamido)benzoate (3-6)

To a solution of compound 3-5 (540 mg, 0.82 mmol) in MeCN (20 mL), 1-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]-2- Methoxy-ethane (444 mg, 1.64 mmol), K ₂ CO ₃ (566 mg, 4.10 mmol), and NaI (49 mg, 0.33 mmol), then stirred at 75 °. The reaction was completed by EtOAc (EtOAc)EtOAc. MS m/z (ESI): 761 [M+H] ⁺

Step 6: 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine-4 -yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetra Preparation of hydrogen isoquinoline-1-carbonylamido)benzoic acid (T-3)

To a solution of compound 3-6 (110.00 mg, 0.13 mmol The reaction was monitored by EtOAc (EtOAc) eluting MS m/z (ESI): 793 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ10.88 (s, 1H), 9.80 (s, 1H), 7.92-7.85 (m, 2H), 7.80-7.66 (m, 4H), 7.63-7.57 (m, 1H) , 7.36–7.27 (m, 2H), 7.19–7.13 (m, 1H), 5.81 (s, 1H), 5.76 (dd, J = 11.6, 7.6 Hz, 1H), 5.62 (s, 1H), 4.31–4.20 (m, 2H), 4.06–3.94 (m, 2H), 3.91–3.76 (m, 4H), 3.76–3.57 (m, 7H), 3.57–3.46 (m, 6H), 3.47–3.37 (m, 4H) , 3.20 (s, 3H),), 3.22–3.10 (m, 1H), 3.08–2.97 (m, 2H).

Example 4: 1-((ethoxycarbonyl)oxy)ethyl 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl) -1,2,3,6-tetrahydropyridin-4-yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5 Of carbonyl-)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoic acid (T-4)

The compound T-3 (100mg, 0.13mmol) was dissolved in MeCN (4mL), was added _{_{K 2 CO 3 (87mg, 0.63mmol}} ), 1- chloroethyl ethyl carbonate (96mg, 0.63mmol) and NaI (9.6mg , 0.06 mmol), then stirred at 70 °C. The reaction was completed by EtOAc (EtOAc) eluting eluting eluting MS m/z (ESI): 909 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ10.96 (s, 1H), 7.99-7.87 (m, 2H), 7.85-7.63 (m, 4H), 7.53 (d, J = 7.6Hz, 1H), 7.32 (t , J = 8.0 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.84 (q, J = 5.4 Hz, 1H), 5.79 (s, 1H) ), 5.74 (dd, J = 11.2, 7.6 Hz, 1H), 5.55 (s, 1H), 4.29 - 4.19 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.86 (dd, J = 17.2, 7.2 Hz, 1H), 3.75–3.62 (m, 2H), 3.62–3.45 (m, 10H), 3.45–3.40 (m, 2H), 3.34–3.30 (m, 4H), 3.22 (s, 3H) , 3.18–3.06 (m, 2H), 3.18–3.06 (m, 2H), 3.01–2.92 (m, 1H), 2.72–2.57 (m, 3H), 2.39–2.20 (m, 2H), 1.56 (d, J = 5.6 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H).

Example 5: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-5- (1-(2-(2-(2-ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline Preparation of 1-(carbonylamido)benzoic acid (T-5a) and 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-di Hydroisoxazole-5-carboyl)-5-(1-(2-(2-(2-ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)- Preparation of methyl 1,2,3,4-tetrahydroisoquinoline-1-carbonylamidobenzoate (T-5b)

First step: Preparation of 2-(2-(2-methoxyethoxy)ethoxy)acetaldehyde (5-2)

The compound 2-(2-(2-methoxyethoxy)ethoxy)ethan-1-ol (5-1, 1.04 g, 6.35 mmol) was dissolved in DCM (20 mL). After adding sodium hydrogencarbonate (2.13 g, 25.4 mmol) to the system at 0 ° C, DMP (5.38 g, 12.7 mmol) was slowly added portionwise, and then the temperature of the system was raised to room temperature to continue the reaction, and the progress of the reaction was monitored by LC-MS. After the reaction was completed, a saturated sodium thiosulfate solution (20 mL) was added to the system to quench the reaction, and the mixture was extracted with DCM (3×30 mL), and the combined organic phase was dried and concentrated to give the residue. MS m/z (ESI): 163 [M+H] ⁺

Second step: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-5- (1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid trifluoroacetate (5-3) Preparation

Compound 3-4 (1.00 g, 1.52 mmol) was dissolved in DCM (10 mL). EtOAc (10 mL) was slowly added dropwise to the system at 0 ° C, then allowed to warm to room temperature for 1 h, and the reaction was monitored by LC-MS. After the completion of the reaction, a large amount of diethyl ether was added to the reaction mixture to give a solid, which was then evaporated, and filtered, and the filter cake was washed with diethyl ether (3×5 mL). The title compound 5-3 (1.07 g, yield: 98%). MS m/z (ESI): 603 [M+H] ⁺

Third step: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-5- (1-(2-(2-(2-ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline Preparation of 1-(carbonylamido)benzoic acid (T-5a) and 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-di Hydroisoxazole-5-carboyl)-5-(1-(2-(2-(2-ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)- Preparation of methyl 1,2,3,4-tetrahydroisoquinoline-1-carbonylamidobenzoate (T-5b)

Compound 5-3 (228 mg, 0.38 mmol) was dissolved in MeOH (15 mL), pH = 4, and the temperature of the system was reduced to 0 ° C, then 2-(2-(2-methoxyethoxy) was added dropwise to the system. Ethyloxy)acetaldehyde (1-2, 306 mg, 1.9 mmol). After the addition was completed, the temperature of the system was raised to 60 ° C, and the progress of the reaction was monitored by LC-MS. After the completion of the reaction, the solvent was evaporated under reduced pressure.

T-5a:

MS m/z (ESI): 749 [M+H] ⁺

T-5b:

MS m/z (ESI): 763 [M+H] ⁺

¹ H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 10.84 (s, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.75 - 7.65 (m, 4H), 7.56 - 7.53 (m) , 1H), 7.34–7.23 (m, 2H), 7.14–7.10 (m, 1H), 6.55 (s, 1H), 5.80 (s, 1H), 5.76–5.70 (m, 1H), 5.62 (s, 1H) ), 4.27–4.19 (m, 1H), 4.15–4.05 (m, 2H), 3.90–3.82 (m, 1H), 3.74–3.61 (m, 4H), 3.55–3.49 (m, 1H), 3.45–3.19 (m, 13H), 3.16–3.07 (m, 1H), 3.01–2.93 (m, 1H), 2.43–2.21 (m, 2H), 2.10–2.04 (m, 3H).

Example 6: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-5- (1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1 Of 2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoic acid (T-6)

First step: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-5- (1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1 ,2,3,4-Tetrahydroisoquinoline-1-carbonylamino)benzoic acid tert-butyl ester (6-1)

Compound 3-5 (100 mg, 0.15 mmol) was dissolved in MeCN (15 mL), the temperature of the system was reduced to 0 ° C, and potassium carbonate (105 mg, 0.76 mmol) and 2-(2-(2-(2-) 2-Bromoethoxy)ethoxy)ethoxy)ethan-1-ol (78 mg, 0.3 mmol), then the temperature of the system was increased to 80 ° C, and the reaction was monitored by LC-MS. After completion of the reaction, the solvent was evaporated to dryness crystals crystals crystals crystals MS m/z (ESI): 835 [M+H] ⁺

Second step: 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-5-( 1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid (T-6)

Compound 6-1 (70 mg, 0.08 mmol) was dissolved in DCM (3 mL). The temperature of the system was reduced to 0 ° C, and trifluoroacetic acid (382 mg, 3.4 mmol) was slowly added dropwise thereto, and then the system temperature was raised to room temperature. The reaction was monitored by LC-MS. After the completion of the reaction, a large amount of diethyl ether (8 mL) was added to the mixture to give a solid crystals. MS m/z (ESI): 779 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ10.82 (s, 1H), 8.19 (s, 1H), 7.87 (d, J = 8.7Hz, 1H), 7.77-7.65 (m, 3H), 7.52 (d, J = 7.3 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 6.9 Hz, 1H), 5.79 (s, 1H), 5.79–5.71(m,1H),5.55(s,1H), 4.24–4.21(m,1H),3.88–3.82(m,1H),3.75–3.66(m,1H),3.58(t,J=5.9 Hz, 2H), 3.53–3.52 (m, 5H), 3.44–3.42 (m, 16H), 3.12 (s, 2H), 2.69–2.67 (m, 2H), 2.63–2.60 (m, 2H).

Example 7: (E)-4-(5-(4-(2,5,8,11-tetraoxatridecyl-13-yl)-piperazin-1-yl)-2-(3- (3-Chloro-2-fluoro-6-(1H-tetrazolyl-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzene Preparation of formic acid (T-22)

T-22 was synthesized in a similar manner to the eighth step of Example 1 except that in the present embodiment, a racemic mixture 7-1 was used instead of 1-7 in Example 1. MS m/z (ESI): 821 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} 12.71 (br, 1H), 10.74 (s, 1H), 9.87 (s, 1H), 8.00-7.92 (m, 1H), 7.90-7.83 (m, 2H), 7.71-7.59 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H), 7.25 - 7.16 (m, 1H), 7.09 (d, J = 16.0 Hz, 1H), 7.02 - 6.89 (m, 2H), 5.73 ( s, 1H), 4.14–4.04 (m, 1H), 3.63–3.45 (m, 12H), 3.44–3.40 (m, 3H), 3.22 (s, 3H), 3.10–2.95 (m, 2H), 2.93– 2.84 (m, 2H), 2.83– 2.73 (m, 2H), 2.71–2.52 (m, 6H).

Example 8: 1-((ethoxycarbonyl)oxy)ethyl (E)-4-(5-(4-(2,5,8,11-tetraoxatridecane-13-yl)) -piperazin-1-yl)-2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4 -Preparation of tetrahydroisoquinoline-1-carbonylamido)benzoate (T-23)

T-23 was synthesized in a similar manner to Example 2 except that T-22 was used instead of T-1 in Example 2 in this example.

MS m/z (ESI): 937 [M+H] ⁺

Example 9: 4-((S)-5-(4-(2,5,8,11-tetraoxatridecyl-13-yl)piperazin-1-yl)-2-((R) -3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino Preparation of benzoic acid (T-8)

First step: 4-((S)-5-(4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2-((R)-3-(3-chloro- 2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoic acid (8-1) Preparation

Compound 1-4 (100 mg, 0.32 mmol), Int-A (54.8 mg, 0.22 mmol) and tert-butyl 4-isocarbonitrilebenzoate (84.9 mg, 0.42 mmol) were dissolved in ethanol (10 mL) under nitrogen It was refluxed at 80 ° C for 24 hours. The reaction was observed to give EtOAc (m.) MS m/z (ESI): 783 [M+H] ⁺

Second step: 4-((S)-5-piperazinyl-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5- Preparation of carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoic acid (8-2)

8-1 (452 mg, 0.58 mmol) was dissolved in MeCN / MeOH (10 mL) and potassium carbonate (807 mg, 5. The LCMS showed that the crude material was evaporated, EtOAc/EtOAc (EtOAc).

Third and fourth steps: 4-((S)-5-(4-(2,5,8,11-tetraoxatridecyl-13-yl)piperazin-1-yl)-2-(( R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carbon Preparation of amido)benzoic acid (T-8)

T-8 was synthesized in a similar manner to the seventh and eighth steps of Example 1 except that in the third step, 8-2 was used instead of 1-6 in the seventh step of Example 1. MS m/z (ESI): 796 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.75 (s, 1H), 10.81 (s, 1H), 7.86 (dd, J = 8.8 Hz, 2H), 7.77 - 7.70 (m, 2H), 7.68 ( Dd, J = 8.8 Hz, 2H), 7.36 - 7.28 (m, 2H), 7.22 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 5.74 (dd, J = 11.2) , 7.2 Hz, 1H), 5.72 (s, 1H), 4.27 - 4.20 (m, 1H), 3.86 (dd, J = 16.0, 7.2 Hz, 1H), 3.68 (dd, J = 16.4, 11.6 Hz, 1H) , 3.62–3.48 (m, 12H), 3.42 (dd, J = 5.2, 2.8 Hz, 2H), 3.23 (s, 3H), 3.13–3.00 (m, 2H), 2.98–2.74 (m, 5H), 2.67 –2.52 (m, 6H).

Example 10: 1-((ethoxycarbonyl)oxy)ethyl 4-((S)-5-(4-(2,5,8,11-tetraoxatridecane-13-yl) -piperazin-1-yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-1,2, Preparation of 3,4-tetrahydroisoquinoline-1-carbonylamido)benzoate (T-9)

T-9 was synthesized in a similar manner to Example 2 except that T-8 was used instead of T-1 in Example 2 in this example.

MS m/z (ESI): 912 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ10.92 (s, 1H), 7.91 (d, J = 8.4Hz, 2H), 7.78-7.65 (m, 4H), 7.36-7.28 (m, 2H), 7.22 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.83 (q, J = 4.8 Hz, 1H), 5.81 - 5.71 (m, 1H), 5.71 (s, 1H) ), 4.30 - 4.21 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.86 (dd, J = 17.6, 7.6 Hz, 1H), 3.68 (dd, J = 11.6, 17.2 Hz, 1H) , 3.65–3.47 (m, 13H), 3.46–3.40 (m, 2H), 3.23 (s, 2H), 3.13–3.00 (m, 2H), 2.93–2.76 (m, 4H), 2.70–2.53 (m) , 6H), 1.56 (d, J = 5.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H).

Example 11: (S,E)-4-(5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine 4-yl)-2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydro Preparation of isoquinoline-1-carbonylamido)benzoic acid (T-10)

T-10 was synthesized in a similar manner to Example 3 except that in the first step, Int-B was used instead of Int-A in the third step of Example 3.

MS m/z (ESI): 818 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.61 (br, 1H), 10.81 (s, 1H), 9.88 (s, 1H), 7.97 (t, J = 8.4Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.77 - 7.60 (m, 3H), 7.55 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.95 (d, J = 16.0 Hz, 1H), 5.85 (s, 1H), 5.54 (s, 1H), 4.15 - 4.05 (m, 1H), 3.71 - 3.45 (m, 13H), 3.44 - 3.39 (m, 2H), 3.22 (s, 3H), 3.16–3.04 (m, 3H), 2.95–2.86 (m, 1H), 2.80–2.54 (m, 4H), 2.31–2.18 (m, 2H).

Example 12: 1-((ethoxycarbonyl)oxy)ethyl 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl) -1,2,3,6-tetrahydropyridin-4-yl)-2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzene Of acryl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoate (T-11)

T-11 was synthesized in a similar manner to Example 2 except that T-10 was used instead of T-1 in Example 2 in this example.

MS m/z (ESI): 934 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ10.93 (s, 1H), 9.88 (s, 1H), 7.97 (t, J = 8.7Hz, 1H), 7.92 (d, J = 8.8Hz, 2H) , 7.74 (d, J = 8.8 Hz, 2H), 7.68 (dd, J = 8.4, 1.2 Hz, 1H), 7.64 - 7.52 (m, 1H), 7.31 - 7.22 (m, 1H), 7.08 - 6.93 (m , 2H), 6.84 (q, J = 5.2 Hz, 1H), 5.81 (s, 1H), 5.58 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 4.12 - 4.04 (m, 1H) , 3.74–3.45 (m, 12H), 3.41 (dd, J=5.2, 3.2 Hz, 2H), 3.34–3.29 (m, 4H), 3.20 (s, 3H), 3.17–3.03 (m, 2H), 3.02 – 2.83 (m, 2H), 2.83–2.54 (m, 3H), 1.56 (d, J = 5.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H).

Experimental Example 1 Inhibition of Coagulation Factor XIa Enzyme

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. Fitting half or compound with GraphPad Prism 5 software SigmaPlot inhibiting concentration ₅₀ value IC (A indicates IC ₅₀ <1nM, B represents 10nM> IC _50> 1nM, C represents 50nM> IC _50> 10nM).

Table 1. Inhibition of Factor XIa by Compounds

化合物编号Compound number	IC ₅₀ IC ₅₀
T-1T-1	AA
T-2T-2	CC
T-3T-3	AA
T-4T-4	BB
T-22T-22	AA
T-8T-8	AA

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, rat PK test

Preparation of the test sample:

Test compounds were prepared according to the method of Table 2

Table 2. Preparation table of test compound to be tested

experiment method:

Male rats were intragastrically administered (po) to the test substance in solution state. The plasma concentrations of the test substances and metabolites in the rats were determined by LC-MS/MS. The main pharmacokinetic parameters were calculated by WinNonlin 6.3 software.

The test design grouping is shown in Table 3 below.

Table 3. Test Design Group Table

test results:

The PK test results of the compounds in rat plasma are shown in Table 4 below.

Table 4. Rat PK test results

The results showed that the compound T-23 of the present invention was used as a prodrug of T-22, T-2 as a prodrug of T-1, and T-9 as a prodrug of T-8, orally administered in a solution state, large The absorption in the mice was good.

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

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

among them,

R 1 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl and 3-10 membered heterocyclic, wherein said C 1-6 alkyl, C 2-6 The alkenyl group, the C 3-6 cycloalkyl group and the 3-10 membered heterocyclic group are optionally one or more selected from the group consisting of halogen, C 1-6 alkyl, -OH and -O-(C 1-6 alkyl) Substituted by a substituent;

Selected from the following structure:

R 2 , R 3 and R 4 are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl, -OH, -O-(C 1-6 alkyl), 3-6 membered heterocyclic group, benzene And a 5-6 membered heteroaryl group, wherein said C 1-6 alkyl group, -O-(C 1-6 alkyl), -O-(C 1-6 alkyl), 3-6 membered heterocyclic ring , phenyl and 5-6 membered heteroaryl optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, -OH and -O- (C 1- 6 alkyl) substituents;

Y is selected from the group consisting of C 2-4 alkenylene and 5-6 membered heteroarylene;

Ring A is selected from the following structures:

R 5 is selected from the group consisting of H, C 1-6 alkyl and -C 1-4 alkylene-OC(=O)OC 1-4 alkyl;

n is selected from an integer of 2-9.
A compound according to claim 1 or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer or tautomer of said compound a conformation or a mixture thereof, wherein

R 1 is selected from the group consisting of H, C 1-3 alkyl and halo C 1-3 alkyl;

Preferably, R 1 is selected from the group consisting of H, CH 3 , CF 3 and CH 2 CF 3 .
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound, Isomers or mixtures thereof, wherein

R 2 and R 4 are each independently selected from: H, halogen, unsubstituted or tetrazolyl substituted with one halogen atom (for example, F, Cl, Br or I);

Preferably, R 2 and R 4 are each independently selected from:

F, Cl,

Preferably, R 2 is selected from the group consisting of

Preferably, R 4 is selected from the group consisting of H, F and Cl.
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or stereoisomerism of said compound a form, a tautomer or a mixture thereof, wherein

R 3 is selected from the group consisting of H and halogen;

Preferably, R 3 is a halogen such as F or Cl.
A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or stereoisomerism of said compound a form, a tautomer or a mixture thereof, wherein

Y is selected from the group consisting of vinylidene, propenylene, isoxazolyl, oxazolyl, thiazolyl, isoisothiazolyl, imidazolyl, pyrazolyl;

Preferably, Y is selected from the following structures:
A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or stereoisomerism of said compound a form, a tautomer or a mixture thereof, wherein

Ring A is
A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of said compound a form, a tautomer or a mixture thereof, wherein

R 5 is selected from the group consisting of H and -C 1-3 alkylene-OC(=O)OC 1-3 alkyl.
A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or stereoisomerism of said compound a form, a tautomer or a mixture thereof, wherein

n is 2, 3 or 4.
A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of said compound a form, a tautomer or a mixture thereof, the structure of the compound being as shown in formula (I)-1,

Wherein R 1 , R 2 , R 3 , R 4 , R 5 , ring A, n,
And Y are as defined in any one of claims 1-8.
A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoscopic form of said compound Isomers, tautomers or mixtures thereof, the structure of which is as shown in formula (II):

Wherein R 1 , R 2 , R 3 , R 4 , R 5 ,
And Y are as defined in any one of claims 1-5, 7.
A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or stereoisomerism of said compound a form, a tautomer or a mixture thereof, the structure of which is as shown in formula (III):

Wherein R 6 is selected from the group consisting of H, -CH 3 and -CH 2 CH 3 ; R 7 is selected from the group consisting of -CH 3 , -CH 2 CH 3 and -CH(CH 3 ) 2 ; R 1 , R 2 , R 3 , R 4 ,
And Y as defined in any one of claims 1-5;

Preferably, among the compounds represented by formula (III),

R 1 is selected from the group consisting of H, C 1-3 alkyl and halo C 1-3 alkyl;

R 2 is selected from the following structures:

R 3 and R 4 are each independently selected from the group consisting of F and Cl;

Selected from the following structure:

Y is selected from the following structures:

R 6 is selected from the group consisting of H, -CH 3 and -CH 2 CH 3 ; R 7 is selected from the group consisting of -CH 3 , -CH 2 CH 3 and -CH(CH 3 ) 2 .
A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or stereoisomerism of said compound a body, a tautomer or a mixture thereof, the structure of which is as follows:

Wherein R 1 , R 2 , R 3 , R 4 ,
And Y as defined in any one of claims 1-5;

Preferably, among the compounds represented by formula (V),

R 1 is selected from the group consisting of H, C 1-3 alkyl and halo C 1-3 alkyl;

R 2 is selected from the following structures:

R 3 and R 4 are each independently selected from the group consisting of F and Cl;

Selected from the following structure:

Y is selected from the following structures:
A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or stereoisomerism of said compound a body, a tautomer or a mixture thereof, the structure of which is as follows:

Wherein R 1 , R 2 , R 3 , R 4 , R 5 , Y and ring A are as defined in any one of claims 1-7.
A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of said compound a form, a tautomer or a mixture thereof, the compound being selected from the group consisting of:
A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of said compound a form, a tautomer or a mixture thereof, the compound being selected from the group consisting of:
A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound, A method of tautomers or mixtures thereof, selected from:

method one:

In Method 1, R L1 and R L2 each independently represent a halogen or a C 1-3 alkyl sulfonate group optionally substituted by a halogen (eg, a triflate group); R Lx represents =0, Halogen or a C 1-3 alkyl sulfonate group optionally substituted by halogen (for example, a triflate group); PG 1 , PG 2 , PG 3 and PG 4 are protecting groups; Z represents a leaving group Preferably, the leaving group is selected from the group consisting of H, halogen, C 1-3 alkyl sulfonate group optionally substituted by halogen, boronic acid group, boronic acid ester group, substituted silicon group or substituted metal group group;

Step 1: Compound S-1 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-1;

Step 2: Compound IM-1 undergoes a coupling reaction to form compound IM-2;

Step 3: Compound IM-2 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-3;

Step 4: Compound IM-3 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -4;

Step 5: Compound IM-4 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I);

Wherein, the order of the above processes can be adjusted as needed;

Method Two:

In the second method, R L1 , R L2 , R Lx , PG 1 , PG 2 , PG 3 , PG 4 and Z are as defined above in the first method;

Step 1: Compound S-1 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-1;

Step 2: Compound IM-1 undergoes a coupling reaction to form compound IM-2;

Step 3: Compound IM-2 is subjected to chiral resolution to obtain compound IM-5;

Step 4: Compound IM-5 undergoes deprotection reaction and continues to carry out acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-6;

Step 5: Compound IM-6 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -7;

Step 6: Compound IM-7 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I)-1;

Wherein, the order of the above processes can be adjusted as needed;

Method three:

In the third method, R L1 , R L2 , R Lx , PG 3 , PG 4 and Z are as defined above in the first method;

Step 1: Compound S-2 undergoes a coupling reaction to form compound IM-8;

Step 2: Compounds IM-8, S-3 and S-4 are subjected to Ugi reaction in an alcohol solvent to form compound IM-9;

Step 3: Compound IM-9 undergoes a deprotection reaction, and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -10;

Step 4: Compound IM-10 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I);

Wherein, the order of the above processes can be adjusted as needed;

Method four:

In the fourth method, R L1 , R L2 , R Lx , PG 3 , PG 4 and Z are as defined above in the first method;

Step 1: Compound S-2 undergoes a coupling reaction to form compound IM-8;

Step 2: Compounds IM-8, S-3 and S-4 are subjected to Ugi reaction in an alcohol solvent to form compound IM-9;

Step 3: Compound IM-9 undergoes a deprotection reaction, and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -10;

Step 4: Compound IM-10 is subjected to chiral resolution to obtain compound IM-11;

Step 5: Compound IM-11 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I)-1;

Method five:

In method five, R L1 , R L2 , R Lx , PG 2 , PG 3 and PG 4 are as defined in method one;

Step 1: Compound S-5 and S-6 are subjected to a Buckwald coupling reaction to form compound IM-12; preferably, S-5 and piperazine are subjected to a Buckwald coupling reaction and then subjected to a protective reaction to produce compound IM-12;

Step 2: Compound IM-12 is subjected to acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-13;

Step 3: Compound IM-13 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -14;

Step 4: Compound IM-14 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-15;

Step 5: Compound IM-15 is subjected to chiral resolution to obtain compound IM-16;

Step 6: Compound IM-16 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (VI);

Those skilled in the art will appreciate that the order of the above processes can be adjusted as needed, and the substitution reaction process in step six can be omitted;

In the above method 1, method 2, method 3 or method 4, R 1 , R 2 , R 3 , R 4 , R 5 , ring A, Y, W, Q and n are as claimed in any one of claims 1 to 13. definition;

In the above method five, R 1 , R 2 , R 3 , R 4 , R 5 , ring A, Y and n are as defined in any one of claims 1 to 13.
A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, Or a stereoisomer, tautomer or mixture thereof of the compound, optionally, further comprising one or more pharmaceutically acceptable carriers.
A pharmaceutical preparation, wherein the preparation comprises: a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof Or a stereoisomer, tautomer or mixture thereof of the compound, as an active ingredient, or a pharmaceutical composition according to claim 17; preferably, the preparation is a solid preparation, a semisolid preparation, a liquid preparation Or in the form of a gaseous preparation.
A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of said compound, Use of a tautomer or a mixture thereof, or a pharmaceutical composition according to claim 17, or a pharmaceutical preparation according to claim 18 for the preparation of a medicament for the treatment of a disorder associated with excessive activity of factor XIa.
The use according to claim 19, wherein the condition associated with excessive activity of factor XIa is a thromboembolic disorder, such as an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, or a thrombus in the heart chamber Embolism disorder;

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) 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.