WO2019205979A1 - Non-natural amino acid derivative, pharmaceutical composition comprising same, method for preparing same, and use of same - Google Patents

Abstract

A non-natural amino acid derivative represented by formula (I), a pharmaceutical composition comprising same, a method for preparing same, and a use of same as an arginase inhibitor. More specifically, the present invention relates to a non-natural amino acid derivative which is capable of inhibiting the hydrolysis of arginine, and therefore can be used for preventing or treating arginase activity-related diseases or conditions.

Description

Non-natural amino acid derivative, pharmaceutical composition containing same, preparation method and use thereof Field of invention

The present invention relates to non-natural amino acid derivatives, pharmaceutical compositions comprising the same, processes for their preparation and their use as arginase inhibitors. More specifically, the present invention relates to a non-natural amino acid derivative capable of inhibiting hydrolysis of arginine, thereby being useful for preventing or treating a disease or condition associated with arginase activity.

Background of the invention

Arginase is a dinuclear manganese metalloenzyme with two subtypes: arginase I (ARG-1), which is expressed in the cytoplasm of cells, mainly in the liver; and arginase II ( ARG-2), expressed in mitochondria, is mainly found in the kidney, small intestine, brain, monocytes and macrophages. In mammalian cells, L-arginine is mainly metabolized by two pathways: one is hydrolysis to L-ornithine and urea by arginase; the other is oxidized by nitric oxide synthase (NOS). L-citrulline and nitric oxide are produced. Arginase and nitric oxide synthase play an important role in regulating cellular nitric oxide levels and pathophysiological diseases. At the same time, the study found that arginase not only participates in the ornithine cycle of the liver, but also affects the immune system of humans and mice, and also reduces the production of nitric oxide by hydrolyzing arginine, thereby triggering fibrosis and tissue regeneration, thereby promoting inflammation. The occurrence and development. In addition, arginine deficiency also inhibits T cell immune responses, particularly inflammation-related immune responses, while pathogens can evade immune responses by synthesizing arginase (Nature, 1996, 383, 554-557; Pharm. Pat .Anal., 2014, 3(1), 65-85; Med. Res. Rev., 2017, 37(3), 475-513).

Arginase inhibitors are potential therapeutic agents for cancer, induced or spontaneous immune disorders, allergic asthma, inflammatory bowel disease, ulcerative colitis, atherosclerosis and hypertension, and others caused by pathogens Treatment of the disease.

Arginine hydrolysis is carried out by divalent manganese ions mediated nucleophilic attack of sulfhydryl carbon atoms via a tetrahedral transition state. Under physiological pH conditions, the organoboronic acid compound is easily changed from sp ² hybridization to sp ³ hybridized negative ion form. This structure is very similar to the tetrahedral transition state of the enzyme-catalyzed substrate, so the organoboric acid compound is used as the arginine. Enzyme inhibitors have been extensively studied.

In 1997, Christianson et al. first reported the inhibition of arginase by 2(S)-amino-6-dihydroxyboronic acid (ABH) (IC ₅₀ =0.8 μM, J.Am.Chem .Soc. 1997, 119, 8107-8108).

WO1999019295 discloses the inhibition of arginase by S-(2-dihydroxyborylethyl)-L-cysteine (BEC).

Furthermore, WO2010062366 reports the structure of another arginine analog, nor-NOHA:

Ilies M et al. (J. Med. Chem. 2010, 53, 4266) discloses an arginine analog A1P containing an aminoimidazole structure having the following structure:

Mars has disclosed a variety of boric acid compounds which have varying degrees of inhibitory activity against arginase. Among them, WO2011133653 discloses the following structure:

Calithera discloses the following structure in WO 2017075363:

At present, most arginine analogs have poor absorption due to their large polarity and have poor pharmacokinetic properties. Novel arginase inhibitors having better pharmacokinetic properties, good absorption, and lower toxic side effects are provided in the present application.

Summary of invention

The present invention provides non-natural amino acid derivatives which have good inhibitory effects on arginase (arginase I and/or arginase II) and have good physicochemical properties (eg solubility, physical and / or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, appropriate half-life and duration of action), improved safety (lower toxicity and / or fewer side effects, wider) The therapeutic window) and other excellent properties.

Some aspects of the invention provide a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein Said compound has the structure of formula (I):

among them:

R ^{1 is} selected from the group consisting of -OR ^a and -NR ^b R ^c ;

R ^{2 is} selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, -OR ^a , -NR ^b R ^c , -C(=O)-R ^a , -S(= O) ₂ -R ^a , -C(=NR ^a )NR ^b R ^c , -C(=O)NR ^b R ^c and -C(=O)CH(NH ₂ )R ^a ;

R ³ and R ⁴ are each independently selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 An aryl group, a 5-14 membered heteroaryl group, a C _6-12 aralkyl group, and -C(=O)-R ^a ; or R ³ and R ⁴ together with a group to which they are attached form a 5-8 membered ring ( E.g

or

);

D is selected from C _2-6 alkylene, -CH ₂ -C _3-10 cycloalkylene, -CH ₂ -(3-10 membered heterocyclylene), -CH ₂ -C _6-10 arylene, C _2-6 alkenylene, C _2-6 alkynylene, saturated or partially unsaturated C _3-10 cycloalkylene, saturated or partially unsaturated 3-10 membered heterocyclylene, C _6-10 An aryl group and a 5-14 membered heteroarylene group, and when D is a C _2-6 alkylene group, a C _2-6 alkenylene group or a C _2-6 alkynylene group, the hydrocarbon chain of the group is optional The ground is separated by one or more of the following groups: -NR"'-, -O-, -S(=O) _p -, saturated or partially unsaturated C _3-10 cycloalkylene, saturated or partially Unsaturated 3-10 membered heterocyclylene, C _6-10 arylene and 5-14 membered heteroarylene;

X, Y and Z are each independently selected from -C(R')(R")-, -C(=O)-, -C(=S)-, -N(R"')-, -O- And -S(=O) _p -;

R' and R" are each independently selected from the group consisting of hydrogen, halogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, saturated or partially unsaturated _C3-10 cycloalkyl, saturated or Partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -OR ^a , -NR ^b R ^c , -OC(=O -C _1-6 alkyl, -C _1-6 alkylene-NR ^b R ^c and -C _1-6 alkylene-CO ₂ -C _1-6 alkyl;

R"' is selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5- 14-membered heteroaryl, C _6-12 aralkyl, -OR ^a , -C(=O)-R ^a , -S(=O) ₂ -R ^a , -C _1-6 alkylene-CO ₂ -C _1-6 alkyl, -C(=O)OC _1-6 alkyl and -C(=O)NHC _1-6 alkyl;

R ^{a is} selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic, C _6-10 aryl, 5-14 Heteroaryl, C _6-12 aralkyl, -C(=O)C _1-6 alkyl, -C(=O)OC _1-6 alkyl, -C(=O)NHC _1-6 alkane And -C _1-6 alkylene-CO ₂ -C _1-6 alkyl;

R ^b and R ^c are each independently selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -OR ^a , -S(=O) ₂ -R ^a , -C _1-6 alkylene-CO ₂ -C _1-6 An alkyl group, -C(=O)C _1-6 alkyl, -C(=O)OC _1-6 alkyl, and -C(=O)NHC _1-6 alkyl;

k, m, n, and p are each independently 0, 1, or 2, provided that k, m, and n are not 0 at the same time;

The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkyl, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl, sub Each of the heteroaryl and aralkyl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH ₂ , nitro, Sulfhydryl, -CO ₂ H, -CO ₂ C _1-6 alkyl, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogen C _1-6 Alkyl, C _3-6 cycloalkyl, halo C _3-6 cycloalkyl, -NH-C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkylene- OH, -C _1-6 alkylene-CN, -C _1-6 alkylene-OC _1-6 alkyl, -C _1-6 alkylene-CO ₂ -C _1-6 alkyl, 3 to A 10-membered heterocyclic group, a C _6-10 aryl group, a 5-14 membered heteroaryl group, and a C _6-12 aralkyl group.

Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N- An oxide, an isotopically labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation or a gaseous formulation.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or Use of a medicament or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with arginase activity.

Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or A medicament or a pharmaceutical composition of the invention for use in preventing or treating a disease or condition associated with arginase activity.

Another aspect of the invention provides a method of preventing or treating a disease or condition associated with arginase activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof , esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.

Another aspect of the invention provides a method of preparing a compound of the invention.

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.

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms. 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, isopentyl, neopentyl or n-hexyl), optionally substituted by one or more (such as 1 to 3) suitable substituents Substituted by halogen (in this case the group is referred to as "haloalkyl") (eg CH ₂ F, CHF ₂ , CF ₃ , CCl ₃ , C ₂ F ₅ , C ₂ Cl ₅ , CH ₂ CF ₃ , CH ₂ Cl) Or -CH ₂ CH ₂ CF _{3 ,} etc.). 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 "alkylene" denotes the corresponding divalent group and includes, for example, "C _1-6 alkylene", "C _2-6 alkylene", "C _1-4 alkylene" and the like, and specific examples include However, it is not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical comprising at least one double bond, for example, having from 2 to 6 carbon atoms ("C _2-6 alkenyl"). The alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 Hexyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the invention contain alkenyl groups, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof. The term "alkenylene" is a corresponding divalent group including, for example, "C _2-6 alkenylene", "C _2-4 alkenylene", and the like, and specific examples thereof include, but are not limited to, vinylidene, arylene A propylene group, a butenylene group, a pentenylene group, a hexylene group, a cyclopentylene group, a cyclohexylene group, and the like.

As used herein, the term "alkynyl" refers to a monovalent hydrocarbon radical containing one or more triple bonds, for example having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl. The term "alkynylene" is a corresponding divalent group including, for example, "C _2-6 alkynylene", "C _2-4 alkynylene" and the like. Examples thereof include, but are not limited to, ethynylene, propynylene, butynylene, pentynylene, and hexynylene.

The term "cycloalkyl" as used herein refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). , cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl Or bicyclo [5.2.0] anthracenyl, decahydronaphthyl, etc.)), which is optionally substituted by one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C _3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl or ring). Hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.

As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to a saturation having, for example, 3 to 10, 3 to 8 or 3 to 6 ring carbon atoms (ie, "sub" Cycloalkyl" and "cycloalkyl") or unsaturated (ie having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings including, but not limited to, (sub) rings Propyl (ring), (sub)cyclobutyl (ring), (sub)cyclopentyl (ring), (sub)cyclohexyl (ring), (sub)cycloheptyl (ring), (sub)cyclooctane A group (ring), a (sub)cyclononyl group (ring), a (sub)cyclohexenyl group (ring), and the like.

The term "heterocyclyl", "heterocyclylene" and "heterocycle" as used herein, mean having, for example, 3-10, 3-8 or 3-6 ring atoms, at least one of which is a ring atom. Is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie having one or more double and/or triple bonds in the ring). A cyclic group. For example, "3-10 membered (sub)heterocyclic (yl)" has 2 to 9 (eg, 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N a saturated or partially unsaturated (sub)heterocyclic ring of one or more (e.g., 1, 2, 3 or 4) heteroatoms of O and S. Examples of the heterocyclylene group and the heterocyclic ring group include, but are not limited to, (meth)oxiranyl, (i)aziridine, (a) azetidinyl, (sub)oxy Oxetanyl, (i)tetrahydrofuranyl, (di)dioxolinyl, (i)pyrrolidinyl, (i)pyrrolidone, (im)imidazolidinyl, (Asia) Pyrazolyl, (i)pyrroline, (i)tetrahydropyranyl, (i)piperidinyl, (y)morpholinyl, (di)dithianyl, (sub) Thimorpholinyl, (i)piperazinyl or (tri)trithianyl. The group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane, etc.). The heterocyclylene group and the heterocyclic ring group may be optionally substituted by one or more (for example, 1, 2, 3 or 4) suitable substituents.

As used herein, the terms "(sub)aryl" and "aryl" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the terms "C _6-10 (sub)aryl" and "C _6-10 aryl" mean an aromatic group containing from 6 to 10 carbon atoms, such as (phenylene)phenyl. (Benzene ring) or (methylene) naphthyl (naphthalene ring).

As used herein, the terms "(sub)heteroaryl" and "heteroaryl" refer to a monocyclic, bicyclic or tricyclic aromatic ring system, for example, having 5, 6, 8, 9, 10, 11, 12 , 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, Nitrogen or sulfur), and, in each case, may be benzofused. In particular, "(sub)heteroaryl" or "heteroaryl" is selected from (i)thienyl, (i)furanyl, (i)pyrrolyl, (i)oxazolyl, (sub)thiazolyl, (i)imidazolyl, (i)pyrazolyl, (i)isoxazolyl, (i)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl And their benzo derivatives; or (i)pyridyl, (pyridazinyl), (i)pyrimidinyl, (i)pyrazinyl, (i)triazinyl, etc., and their benzo derivative.

The term "aralkyl" as used herein preferably denotes an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein. The aryl group, for example, may have 6 to 10 carbon atoms, the heteroaryl group may have, for example, 5 to 10 ring atoms, and the alkyl group may have, for example, 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

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

The term "substituted" means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present. The normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

If a substituent is described as "optionally substituted," the substituent may be unsubstituted or (2) substituted. If the carbon 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 carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. 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 (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same or different from 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 connecting two atoms in the ring, such a substituent may be bonded to any of the ring-forming atoms in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass. Examples of suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium ⁽² H), tritium ⁽³ H)); isotopes of carbon (e.g. ¹¹ C, ¹³ C and ¹⁴ C) Chlorine isotope (eg ³⁶ Cl); fluorine isotopes (eg ¹⁸ F); iodine isotopes (eg ¹²³ I and ¹²⁵ I); nitrogen isotopes (eg ¹³ N and ¹⁵ N); oxygen isotopes (eg ¹⁵ O) , ¹⁷ O and ¹⁸ O); phosphorus isotope (eg ³² P); and sulfur isotope (eg ³⁵ S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (e.g., assays). The radioisotope ruthenium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Substitution with positron emitting isotopes (eg, ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D ₂ O, acetone-d ₆ or DMSO-d ₆ .

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

Solid lines can be used in this article

Solid wedge

Virtual wedge

The chemical bonds of the compounds of the invention are depicted. The use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.). The use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate 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 are intended to 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 certain 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, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof The compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug. Thus, when reference is made herein to a "compound of the invention," it is also intended to encompass the various derivative forms described above for the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, sea benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharide, stearate, succinate, tannic acid, tartrate, toluene Sulfonate, trifluoroacetate and xinofoate.

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

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

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

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. The synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups. Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; ARKatritzky and AJ Boulton, Eds., Academic Press And GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, ARKatritzky and AJ Boulton, Eds., Academic Press.

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, 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 the body or The above compounds can be converted to the compounds 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). 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 T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

detailed description

Compound

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound has the structure of formula (I):

among them:

R ^{1 is} selected from the group consisting of -OR ^a and -NR ^b R ^c ;

R ^{2 is} selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, -OR ^a , -NR ^b R ^c , -C(=O)-R ^a , -S(= O) ₂ -R ^a , -C(=NR ^a )NR ^b R ^c , -C(=O)NR ^b R ^c and -C(=O)CH(NH ₂ )R ^a ;

R ³ and R ⁴ are each independently selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 An aryl group, a 5-14 membered heteroaryl group, a C _6-12 aralkyl group, and -C(=O)-R ^a ; or R ³ and R ⁴ together with a group to which they are attached form a 5-8 membered ring ( E.g

or

);

D is selected from C _2-6 alkylene, -CH ₂ -C _3-10 cycloalkylene, -CH ₂ -(3-10 membered heterocyclylene), -CH ₂ -C _6-10 arylene, C _2-6 alkenylene, C _2-6 alkynylene, saturated or partially unsaturated C _3-10 cycloalkylene, saturated or partially unsaturated 3-10 membered heterocyclylene, C _6-10 An aryl group and a 5-14 membered heteroarylene group, and when D is a C _2-6 alkylene group, a C _2-6 alkenylene group or a C _2-6 alkynylene group, the hydrocarbon chain of the group is optional The ground is separated by one or more of the following groups: -NR"'-, -O-, -S(=O) _p -, saturated or partially unsaturated C _3-10 cycloalkylene, saturated or partially Unsaturated 3-10 membered heterocyclylene, C _6-10 arylene and 5-14 membered heteroarylene;

X, Y and Z are each independently selected from -C(R')(R")-, -C(=O)-, -C(=S)-, -N(R"')-, -O- And -S(=O) _p -;

R' and R" are each independently selected from the group consisting of hydrogen, halogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, saturated or partially unsaturated _C3-10 cycloalkyl, saturated or Partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -OR ^a , -NR ^b R ^c , -OC(=O -C _1-6 alkyl, -C _1-6 alkylene-NR ^b R ^c and -C _1-6 alkylene-CO ₂ -C _1-6 alkyl;

R"' is selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5- 14-membered heteroaryl, C _6-12 aralkyl, -OR ^a , -C(=O)-R ^a , -S(=O) ₂ -R ^a , -C _1-6 alkylene-CO ₂ -C _1-6 alkyl, -C(=O)OC _1-6 alkyl and -C(=O)NHC _1-6 alkyl;

R ^{a is} selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic, C _6-10 aryl, 5-14 Heteroaryl, C _6-12 aralkyl, -C(=O)C _1-6 alkyl, -C(=O)OC _1-6 alkyl, -C(=O)NHC _1-6 alkane And -C _1-6 alkylene-CO ₂ -C _1-6 alkyl;

R ^b and R ^c are each independently selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -OR ^a , -S(=O) ₂ -R ^a , -C _1-6 alkylene-CO ₂ -C _1-6 An alkyl group, -C(=O)C _1-6 alkyl, -C(=O)OC _1-6 alkyl, and -C(=O)NHC _1-6 alkyl;

k, m, n, and p are each independently 0, 1, or 2, provided that k, m, and n are not 0 at the same time;

The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkyl, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl, sub Each of the heteroaryl and aralkyl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH ₂ , nitro, Sulfhydryl, -CO ₂ H, -CO ₂ C _1-6 alkyl, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogen C _1-6 Alkyl, C _3-6 cycloalkyl, halo C _3-6 cycloalkyl, -NH-C _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C _1-6 alkylene- OH, -C _1-6 alkylene-CN, -C _1-6 alkylene-OC _1-6 alkyl, -C _1-6 alkylene-CO ₂ -C _1-6 alkyl, 3 to A 10-membered heterocyclic group, a C _6-10 aryl group, a 5-14 membered heteroaryl group, and a C _6-12 aralkyl group.

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein R ^{a is} selected from the group consisting of hydrogen, C _1-6 alkyl (preferably methyl) and -CH(NH ₂ )CH ₃ .

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein R ^b and R ^c are each independently selected from the group consisting of hydrogen, C _1-6 alkyl (preferably methyl), -C(=O)-CH(NH ₂ )CH ₃ and -CH(CH ₃ )-CO ₂ -CH ₃ .

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein R ¹ is -OH.

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein R ^{2 is} selected from the group consisting of hydrogen and C _1-6 alkyl, preferably R ^{2 is} selected from the group consisting of hydrogen and methyl.

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein R ³ and R ⁴ are both hydrogen.

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein -(X) _k -(Y) _m -(Z) _n - group is selected from -CH ₂ -CR"R"-CH ₂ -, -CH ₂ -CH ₂ -CR'R"-CH ₂ - -CH ₂ -CR'R"-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -NR"'-CH ₂ - and -CH ₂ -NR"'-CH ₂ -CH ₂ -.

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof , wherein R' and R" are each independently selected from the group consisting of hydrogen, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OH, -OCH ₃ ,

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein R' and R" are each independently selected from the group consisting of hydrogen, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -OH, -OCH ₃ ,

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof , where R"' is selected from hydrogen,

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof , where R"' is selected from hydrogen,

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein D is a C _2-6 alkylene group, preferably a butylene group.

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound has the structure of formula (II):

Preferably, the compound has any structure of the formula:

Wherein q is 2, 3, 4, 5 or 6, preferably q is 4.

In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof Wherein the compound is selected from the group consisting of

resolve resolution

In some embodiments, the invention provides a method of preparing a compound of formula (II), comprising the steps of:

among them:

Hal is halogen, preferably chlorine, bromine or iodine;

q' is an integer of q-2;

When R ^a is hydrogen, R ^a is a carboxy protecting group, preferably a C _1-6 alkyl group, such as a methyl group; and when R ^{a is} not hydrogen, R ^a is the same as R ^a ;

When R ² is hydrogen, R ^{2 '} is an amino protecting group such as t-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz); and when R ^{2 is} not hydrogen, R ^{2 '} is the same as R ² ;

When R ³ or R ⁴ is hydrogen, R ^{3 '} or R ^{4 '} are each independently C _1-6 alkyl, or R ^{3 '} and R ^4' together with the group to which they are attached form a 5-8 membered ring. (E.g

or

And when both R ³ and R ^{4 are} not hydrogen, R ^{3 '} and R ^{4 '} are the same as R ³ and R ⁴ , respectively;

The remaining groups are as defined above;

The reaction conditions of each step are as follows:

Step 1: Compound (II)-a and compound Reg-1 in a base (for example, diisopropylethylamine, triethylamine, pyridine, sodium carbonate, potassium acetate, potassium carbonate, potassium hydroxide, cesium carbonate, diiso) Reaction in the presence of lithium propylamide or lithium hexamethyldisilazide to prepare compound (II)-b;

Step 2: optionally adding a phosphine ligand to the compound (II)-b and the compound Reg-2 in the presence of a catalyst/accelerator (preferably a 1,5-cyclooctadiene phosphonium dimer) Preferably 1,2-bis(diphenylphosphino)ethane) is reacted to prepare compound (II)-c;

Step 3: reacting compound (II)-c in the presence of an acid (for example, hydrochloric acid) or a base (for example, lithium hydroxide or sodium hydroxide) to prepare a compound of formula (II), provided that R ^{a '} and R ^a same, ^'are the same and R ² and R ^3' R ² and R ^{4 'are} R ³ and R ⁴ are the same, the three steps do not exist.

Pharmaceutical compositions and methods of treatment

In some embodiments, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, An N-oxide, an isotopically-labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous formulation. In some embodiments, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or use of a prodrug or a pharmaceutical composition or pharmaceutical formulation of the invention in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with arginase activity.

In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug or a pharmaceutical composition or pharmaceutical preparation of the invention for preventing or treating a disease or condition associated with arginase activity.

In some embodiments, the invention provides a method of preventing or treating a disease or condition associated with arginase activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable compound thereof Salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions or pharmaceutical formulations of the invention.

In some embodiments, the disease or condition associated with arginase activity is selected from the group consisting of a cardiovascular condition, a sexual dysfunction, a wound healing disorder, a gastrointestinal disorder, an autoimmune disorder, an immune disorder, an infection, a lung disease, Liver disease, inflammation, hemolytic disease and cancer, preferably cancer, colon cancer, breast cancer and lung cancer (including non-small cell lung cancer), renal cell carcinoma, prostate cancer, multiple myeloma, acute myeloid leukemia, Neuroblastoma, glioblastoma or melanoma.

"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.

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

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

For these routes of administration, the pharmaceutical compositions of the invention may be administered in a suitable dosage form.

The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.

The term "effective amount" as used herein 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). 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 amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.

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 one or more symptoms of such a condition or condition, or Prevention of 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.).

In some embodiments, the pharmaceutical compositions of the invention may also comprise one or more additional therapeutic or prophylactic agents.

Example

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( ¹ H NMR) or mass spectrometry (MS).

The nuclear magnetic resonance spectroscopy ( ¹ H NMR) measuring instrument was a Bruker 400 MHz nuclear magnetic resonance apparatus; the solvent was determined to be heavy water (D ₂ O), deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ) or hexamethylene diene. The sulfoxide (DMSO-d ₆ ); the internal standard substance is tetramethylsilane (TMS).

The meanings of the abbreviations in the NMR spectrum are as follows: s: singlet; d: doublet; t: triplet; q: quartet; dd: doublet; qd: quadruple; ddd: double Peak; ddt: double triplet; dddd: double doublet; m: multiplet; br: broad; J: coupling constant; Hz: Hertz.

The chemical shift (δ) is given in parts per million (ppm).

The mass spectrometer (MS) assay instrument was an Agilent (ESI) mass spectrometer, model number Agilent 6120B.

Example 1: Preparation of 2-(4-dihydroxyborylbutyl)piperidine-2-carboxylic acid (1)

Step 1: Synthesis of 1-tert-butyl 2-methylpiperidine-1,2-dicarboxylate (1-b)

Methyl piperidine-2-carboxylate (1-a) (5.0 g, 34.9 mmol) and di-tert-butyl dicarbonate (7.5 g, 34.4 mmol) were dissolved in 1,4-dioxane at room temperature ( In 50 ml), triethylamine (10.6 g, 104.7 mmol) was further added, followed by reaction at room temperature overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. The solvent was evaporated under reduced pressure, and ethyl acetate (200 ml) was evaporated, and then washed with 0.5N hydrochloric acid (200 ml), saturated sodium hydrogen carbonate (150 ml) and brine (150 mL) dry. The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give 8.2 g. ESI-MS (m/z): 144.2 [M+H] ⁺ .

Step 2: Synthesis of 1-tert-butyl 2-methyl 2-(but-3-en-1-yl)piperidine-1,2-dicarboxylate (1-c)

A solution of the compound (1-b) (7.1 g, 29.18 mmol) in tetrahydrofuran (20 mL) was added dropwise to a solution of lithium diisopropylamide (31 mL, 30.66 mmol) in tetrahydrofuran (50 mL). in. After the dropwise addition, the reaction mixture was stirred for 10 min, then the mixture was heated to 0 ° C for 1 h, and then a solution of 4-bromo-1-butene (5.9 g, 43.77 mmol) in tetrahydrofuran (20 ml) was added dropwise to the reaction mixture, The reaction was stirred at 0 °C overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. Saturated ammonium chloride was added dropwise to the mixture, and the mixture was evaporated to ethyl ether (EtOAc) The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give EtOAc. The crude product was purified by EtOAcqqqqq ESI-MS (m/z): 198.2 [M+H] ⁺ .

Step 3: 1-tert-butyl 2-methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Synthesis of piperidine-1,2-dicarboxylate (1-d)

Compound (1-c) (220 mg, 0.74 mmol), 1,5-cyclooctadiene ruthenium chloride dimer (38 mg, 0.059 mmol) and 1,2-bis(diphenyl) were sequentially subjected to a nitrogen atmosphere. Phosphonium ethane (47 mg, 0.118 mmol) was added to dichloromethane (1 mL). After stirring at room temperature for 1 h, the temperature was lowered to -25 ° C, and pinacol borane (189 mg, 1.48 mmol) was added dropwise, stirred for 10 min, then transferred to room temperature and stirred overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction was diluted with dichloromethane (20 mL), EtOAc (EtOAc)EtOAc. The obtained crude product was purified by ethylamine. ESI-MS (m/z): 326.2 [M+H] ⁺ .

Step 4: Synthesis of 2-(4-dihydroxyborylbutyl)piperidine-2-carboxylic acid (1)

Concentrated hydrochloric acid (2 ml) was added to the compound (1-d) (104 mg, 0.245 mmol), warmed to 120 ° C and then stirred for 48 h. LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction was concentrated directly to remove concentrated hydrochloric acid.

ESI-MS (m/z): 230.2 [M+H] ⁺ ; ¹ H-NMR (400 MHz, D ₂ O) δ 3.28-3.22 (m, 1H), 3.16 (dt, J = 11.2, 3.6 Hz, 1H), 2.26-2.21 (m, 1H), 1.85-1.72 (m, 4H), 1.67-1.55 (m, 2H), 1.47-1.18 (m, 5H), 0.77 (t, J = 8.0 Hz, 2H) .

Example 2: Preparation of 2-(4-dihydroxyborylbutyl)-1-methylpiperidine-2-carboxylic acid (2)

2-(4-Dihydroxyborylbutyl)piperidine-2-carboxylic acid (6 mg, 0.026 mmol) and aqueous formaldehyde (4.7 mg, 0.157 mmol) were dissolved in methanol (1 ml) and stirred for 1 h at room temperature. Further, sodium cyanoborohydride (7 mg, 0.078 mmol) was added, and the mixture was reacted overnight at room temperature. LC-MS detection indicated that the starting material disappeared and the target product was formed. After purification, 7.29 mg of pure product was obtained.

ESI-MS (m/z): 226.2 [M+H-18] ⁺ ; ¹ H NMR (400 MHz, D ₂ O) δ 3.44 - 3.37 (m, 1H), 3.16 - 3.13 (m, 1H), 2.78 (s, 3H), 2.10-2.07 (m, 1H), 1.77-1.62 (m, 6H), 1.41-1.32 (m, 3H), 1.24-1.17 (m, 2H), 0.78-0.72 (m, 2H) .

Example 3: Preparation of 4-amino-2-(4-dihydroxyborylbutyl)pyrrolidine-2-carboxylic acid (32)

Step 1: (2R,4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (32 -b) synthesis

(2R,4R)-1-tert-butyl-2-methyl-4-hydroxypyrrolidine-1,2-dicarboxylate (32-a) (20.0 g, 81.5 mmol), at room temperature Imidazole (22.2 g, 326.2 mmol) and 4-dimethylaminopyridine (996 mg, 8.15 mmol) were dissolved in N,N-dimethylformamide (200 ml), and then t-butyldimethylchlorosilane (13.4) g, 163.0 mmol), and reacted overnight at room temperature. LC-MS detection indicated complete reaction. The reaction mixture was poured into EtOAc (EtOAc) (EtOAc) The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give 22.5 g of crude material, which was directly used for the next reaction.

ESI-MS (m/z): 260.2 [M+H-100] ⁺ .

Step 2: (4R)-1-tert-butyl-2-methyl-2-(but-3-en-1-yl)-4-((tert-butyldimethylsilyl)oxy)pyrrole Synthesis of alkane-1,2-dicarboxylate (32-c)

The compound (32-b) (22.5 g, 62.58 mmol) was dissolved in dry tetrahydrofuran (200 mL), and then, then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Mm). After the dropwise addition, the mixture was stirred for 10 min, and then the mixture was heated to 0 ° C for 1 h, and then a solution of 4-bromo-1-butene (9.29 g, 68.84 mmol) in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the potassium iodide was added thereto. 1.0 g, 6.26 mmol), added to room temperature and stirred overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. To the system, a saturated aqueous solution of ammonium chloride was added dropwise, and the mixture was evaporated to ethyl ether (250 ml). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give 18.3 g of crude material.

ESI-MS (m/z): 314.3 [M+H-100] ⁺ .

Step 3: (4R)-1-tert-butyl-2-methyl-2-(but-3-en-1-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (32-d )Synthesis

Compound (32-c) (4.02 g, 9.72 mmol) and tetrabutylammonium fluoride (2.54 g, 9.72 mmol) were added to tetrahydrofuran (40 ml). LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction mixture was concentrated to give EtOAc (EtOAc) (EtOAcjjjjjjjjj And use it directly for the next reaction.

ESI-MS (m/z):244.1 [M+H-56] ⁺ .

Step 4: Synthesis of 1-tert-butyl-2-methyl-2-(but-3-en-1-yl)-4-oxopyrrolidine-1,2-dicarboxylate (32-e)

Compound (32-d) (3.6 g, 12.03 mmol) was added to dichloromethane <RTI ID=0.0> Then, Dess Martin oxidizing agent (7.65 g, 18.04 mmol) was added in portions, and the mixture was added to the mixture and stirred at room temperature overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. Saturated sodium hydrogen carbonate solution (100 ml) was added to the reaction system, and the mixture was stirred for 1 hour, and then extracted with dichloromethane (100 ml × 2), then the organic phase was washed once with saturated sodium hydrogen carbonate solution (100 ml), and then brine. It was washed with anhydrous sodium sulfate and filtered, and the solvent was evaporated.

ESI-MS (m/z):242.3 [M+H-56] ⁺ .

Step 5: Synthesis of 1-tert-butyl-2-methyl-4-amino-2-(but-3-en-1-yl)pyrrolidine-1,2-dicarboxylate (32-f)

Compound (32-e) (1.5 g, 5.04 mmol) was added to tetrahydrofuran (15 ml), followed by ammonium chloride (539.8 mg, 10.9 mmol) and triethylamine (1.02 g, 10.9 mmol). Stir at room temperature for 3 h. Additional sodium cyanoborohydride (633.6 mg, 10.9 mmol) was added, added and stirred at rt overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. Water (50 ml) was added to the reaction mixture, and ethyl acetate (50 ml × 2) was added, and the organic phase was washed with brine, dried over anhydrous sodium sulfate After purification, 80 mg of pure product was obtained, which was directly used for the next reaction.

ESI-MS (m/z):243.1 [M+H-56] ⁺ .

Step 6: 1-tert-Butyl-2-methyl-2-(but-3-en-1-yl)-4-((S)-2-((tert-butoxycarbonyl)amino)propanamido) Synthesis of pyrrolidine-1,2-dicarboxylate (32-g)

Compound (32-f) (80 mg, 268 μmol), N-tert-butoxycarbonyl-L-alanine (60.9 mg, 321.7 μmol) and 1-hydroxybenzotriazole (72.5 mg, 536.2 μmol) were added to In methyl chloride (2 ml), additional 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (102.8 mg, 536.2 μmol) and N,N-diisopropylethylamine were added. (138.3 mg, 1.07 mmol), added, and stirred at room temperature overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. Water (20 ml) was added to the reaction mixture, and the mixture was evaporated. 79 mg of pure product was obtained which was used directly in the next reaction.

ESI-MS (m/z): 314.1 [M+H-100-56] ⁺ .

Step 7: 1-tert-Butyl-2-methyl-4-((S)-2-((tert-butoxycarbonyl)amino)propionamido)-2-(4-(4,4,5,5) Synthesis of tetrakis-methyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (32-h)

Compound (32-g) (79 mg, 168.2 μmol), 1,5-cyclooctadiene phosphonium chloride dimer (8.71 mg, 13.46 μmol) and 1,2-bis(diphenyl) were sequentially treated under nitrogen atmosphere. Ethylphosphine)ethane (10.72 mg, 26.92 μmol) was added to dichloromethane (1 ml). After stirring at room temperature for 1 h, the temperature was lowered to -25 ° C, and pinacolborane (43.06 mg, 336.48 μmol) was added dropwise, stirred for 10 min, then transferred to room temperature and stirred overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction was diluted with dichloromethane (20 mL), EtOAc (EtOAc)EtOAc. The obtained crude product was purified by preparative liquid chromatography toiel

ESI-MS (m/z): 498.4 [M+H-100] ⁺ .

Step 8: Synthesis of 4-amino-2-(4-dihydroxyborylbutyl)pyrrolidine-2-carboxylic acid (32)

Concentrated hydrochloric acid (2 ml) was added to the compound (32-h) (40 mg, 66.94 μmol), warmed to 120 ° C, and then stirred for 4 h. LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction was concentrated directly to remove concentrated hydrochloric acid.

ESI-MS (m/z): 231.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, D ₂ O) δ 4.21-4.02 (m, 2H), 3.95-3.88 (m, 1H), 3.18-2.98 (m, 0.5H), 2.69-2.53 (m, 1H), 2.23-2.13 (m, 1H), 2.12-2.05 (m, 0.5H), 1.95-1.86 (m, 1H), 1.45-1.21 (m, 4H), 0.78-0.60 (m, 2H).

Example 4: Preparation of 2-(4-dihydroxyborylbutyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid (34)

Step 1: 1-tert-Butyl-2-methyl-2-(but-3-en-1-yl)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylate (34- Synthesis of a)

Compound (32-e) (594 mg, 2.0 mmol) was dissolved in methanol (15 mL), dimethylamine hydrochloride (243 mg, 3.0 mmol), and stirred at room temperature for 10 min. Sodium borohydride (314 mg, 5.0 mmol) was stirred at room temperature for 2.0 h. LC-MS monitoring indicated that the reaction was completed, and water (100 mL) was added to the reaction mixture to quench the reaction, which was extracted with ethyl acetate (50ml × 3), and the organic phase was washed with saturated brine (100ml × 2), anhydrous sulfuric acid The title compound (500 mg) was obtained.

ESI-MS (m/z): 327.2 [M+H] ⁺ .

Step 2: 1-tert-Butyl-2-methyl-4-(dimethylamino)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa) Synthesis of Boronocyclopentan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (34-b)

Compound (34-a) (500 mg, 1.53 mmol), 1,5-cyclooctadiene ruthenium chloride dimer (25.8 mg, 39.8 μmol) and 1,2-bis(diphenyl) were sequentially treated under nitrogen atmosphere. Ethylphosphine)ethane (31.7 mg, 79.6 μmol) was added to dichloromethane (5.0 mL). After stirring at room temperature for 1 h, the temperature was lowered to -25 ° C, and pinacol borane (294 mg, 2.30 mmol) was added dropwise, stirred for 10 min, then transferred to room temperature and stirred overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction was diluted with dichloromethane (20 mL), EtOAc (EtOAc)EtOAc. The obtained crude product was purified by preparative liquid chromatography to afford the title compound (400 mg).

ESI-MS (m/z): 455.2 [M+H] ⁺ .

Step 3: Synthesis of 2-(4-dihydroxyborylbutyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid (34)

Concentrated hydrochloric acid (5 ml) was added to the compound (34-b) (400 mg, 0.88 mmol), warmed to 120 ° C and then stirred for 4 h. LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction mixture was directly concentrated to remove concentrated hydrochloric acid, which was purified by preparative liquid chromatography.

ESI-MS (m/z): 259.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, D ₂ O) δ 4.51-3.75 (m, 2H), 3.62-3.54 (m, 1H), 3.18-2.88 (m, 9H), 2.32-2.13 (m, 2H), 1.83-1.62 (m, 2H), 1.48-1.38 (m, 2H), 1.37-1.19 (m, 2H), 0.78-0.60 (m, 2H) .

Example 5: Preparation of (4R)-2-(4-dihydroxyborylbutyl)-4-hydroxypyrrolidine-2-carboxylic acid (42)

Step one: (4R)-1-tert-butyl-2-methyl-4-((tert-butyldimethylsilyl)oxy)-2-(4-(4,4,5,5- Synthesis of Tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)pyrrolidine-1,2-dicarboxylate (42-a)

Compound (32-c) (660 mg, 1.60 mmol), 1,5-cyclooctadiene ruthenium chloride dimer (82.66 mg, 127.6 μmol) and 1,2-bis(diphenyl) were sequentially treated under a nitrogen atmosphere. Ethylphosphine)ethane (101.7 mg, 255.2 μmol) was added to dichloromethane (7 mL). After stirring at room temperature for 1 h, the temperature was lowered to -25 ° C, and pinacol borane (408.5 mg, 3.19 mmol) was added dropwise, stirred for 10 min, then transferred to room temperature and stirred overnight. LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The obtained crude product was purified by ethylamine.

ESI-MS (m/z): 442.3 [M+H-100] ⁺ .

Step 2: Synthesis of (4R)-2-(4-dihydroxyborylbutyl)-4-hydroxypyrrolidine-2-carboxylic acid (42)

Concentrated hydrochloric acid (2 ml) was added to the compound (42-a) (20 mg, 36.93 μmol), warmed to 120 ° C, and then stirred for 4 h. LC-MS detection indicated that the starting material disappeared and the target product was formed. The reaction was concentrated directly to remove concentrated hydrochloric acid.

ESI-MS (m/z): 232.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, D ₂ O) δ 3.77-3.61 (m, 1H), 3.57-3.36 (m, 1H), 3.24-3.17 (m, 1H), 3.08-2.56 (m, 0.7H), 2.21-1.74 (m, 1H), 1.54-1.13 (m, 8H), 0.80-0.76 (m, 0.3H).

Biological test

The inhibitory activity of the compound on arginase I (ARG-1) was evaluated by the following experiment.

30 μL of 0.33 μg/ml ARG-1 enzyme solution and 10 μL of test compound at different concentrations were added to a 96-well plate and mixed. After incubating for 20 min at room temperature, 10 μL of the reaction substrate was added to the system, mixed, and placed in a 37 ° C incubator for 2 h. After the reaction was completed, 100 μL of urea detection reagent was added, and the mixture was incubated at room temperature for 20 minutes, and the absorbance at 520 nM (OD520 nM) was read by a microplate reader.

The inhibition rate of the test compound against ARG-1 enzyme activity was calculated according to the following formula: IR (% inhibition rate) = (OD solvent control - OD compound) / (OD solvent control - OD negative control) * 100% (solvent control was not added) A control for the compound, the negative control is a control without the addition of the ARG-1 enzyme and the compound). IC ₅₀ was calculated according to the formula single point method _{(IC 50 = (100-Y} ) / Y * X), wherein Y is the inhibition rate, X is the concentration of compound, between 30-80% of the value of Y should be between.

The inhibitory effect of the test compound on ARG-1 enzyme activity is shown in Table 1.

Table 1. Inhibition of ARG-1 Enzyme Activity by Compounds

Compound number	IC 50 (μM)
1	1.6

32

4.3

The results showed that the tested compounds (e.g., Compound 1, Compound 32) had a good inhibitory effect on ARG-1 enzyme activity.

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 (18)

1. a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound has the formula (I) )Structure:

   

   among them:

   R ^{1 is} selected from the group consisting of -OR ^a and -NR ^b R ^c ;

   R ^{2 is} selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, -OR ^a , -NR ^b R ^c , -C(=O)-R ^a , -S(= O) ₂ -R ^a , -C(=NR ^a )NR ^b R ^c , -C(=O)NR ^b R ^c and -C(=O)CH(NH ₂ )R ^a ;

   R ³ and R ⁴ are each independently selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 An aryl group, a 5-14 membered heteroaryl group, a C _6-12 aralkyl group, and -C(=O)-R ^a ; or R ³ and R ⁴ together with a group to which they are attached form a 5-8 membered ring ( E.g

   

   or

   

   );

   D is selected from C _2-6 alkylene, -CH ₂ -C _3-10 cycloalkylene, -CH ₂ -(3-10 membered heterocyclylene), -CH ₂ -C _6-10 arylene, C _2-6 alkenylene, C _2-6 alkynylene, saturated or partially unsaturated C _3-10 cycloalkylene, saturated or partially unsaturated 3-10 membered heterocyclylene, C _6-10 An aryl group and a 5-14 membered heteroarylene group, and when D is a C _2-6 alkylene group, a C _2-6 alkenylene group or a C _2-6 alkynylene group, the hydrocarbon chain of the group is optional The ground is separated by one or more of the following groups: -NR"'-, -O-, -S(=O) _p -, saturated or partially unsaturated C _3-10 cycloalkylene, saturated or partially Unsaturated 3-10 membered heterocyclylene, C _6-10 arylene and 5-14 membered heteroarylene;

   X, Y and Z are each independently selected from -C(R')(R")-, -C(=O)-, -C(=S)-, -N(R"')-, -O- And -S(=O) _p -;

   R' and R" are each independently selected from the group consisting of hydrogen, halogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, saturated or partially unsaturated _C3-10 cycloalkyl, saturated or Partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -OR ^a , -NR ^b R ^c , -OC(=O -C _1-6 alkyl, -C _1-6 alkylene-NR ^b R ^c and -C _1-6 alkylene-CO ₂ -C _1-6 alkyl;

   R"' is selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 aryl, 5- 14-membered heteroaryl, C _6-12 aralkyl, -OR ^a , -C(=O)-R ^a , -S(=O) ₂ -R ^a , -C _1-6 alkylene-CO ₂ -C _1-6 alkyl, -C(=O)OC _1-6 alkyl and -C(=O)NHC _1-6 alkyl;

   R ^{a is} selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclic, C _6-10 aryl, 5-14 Heteroaryl, C _6-12 aralkyl, -C(=O)C _1-6 alkyl, -C(=O)OC _1-6 alkyl, -C(=O)NHC _1-6 alkane And -C _1-6 alkylene-CO ₂ -C _1-6 alkyl;

   R ^b and R ^c are each independently selected from hydrogen, C _1-6 alkyl, saturated or partially unsaturated C _3-10 cycloalkyl, saturated or partially unsaturated 3-10 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, C _6-12 aralkyl, -OR ^a , -S(=O) ₂ -R ^a , -C _1-6 alkylene-CO ₂ -C _1-6 An alkyl group, -C(=O)C _1-6 alkyl, -C(=O)OC _1-6 alkyl, and -C(=O)NHC _1-6 alkyl;

   k, m, n, and p are each independently 0, 1, or 2, provided that k, m, and n are not 0 at the same time;

   The above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkyl, heterocyclyl, heterocyclylene, aryl, arylene, heteroaryl, sub Each of the heteroaryl and aralkyl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH ₂ , nitro, Sulfhydryl, -CO ₂ H, -CO ₂ C _1-6 alkyl, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogen C _1-6 Alkyl, C _3-6 cycloalkyl, halo C _3-6 cycloalkyl, -NH-C _1-6 alkyl, -N-(C _1-6 alkyl) ₂ , -C _1-6 alkylene -OH, -C _1-6 alkylene-CN, -C _1-6 alkylene-OC _1-6 alkyl, -C _1-6 alkylene-CO ₂ -C _1-6 alkyl, 3 To a 10-membered heterocyclic group, a C _6-10 aryl group, a 5-14 membered heteroaryl group, and a C _6-12 aralkyl group.
2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R ^{a is} selected From hydrogen, C _1-6 alkyl (preferably methyl) and -CH(NH ₂ )CH ₃ .
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R ^b and R ^c are each independently selected from the group consisting of hydrogen, C _1-6 alkyl (preferably methyl), -C(=O)-CH(NH ₂ )CH ₃ and -CH(CH ₃ )-CO ₂ -CH ₃ .
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein R ¹ is -OH.
5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof A drug wherein R ^{2 is} selected from the group consisting of hydrogen and C _1-6 alkyl, preferably R ^{2 is} selected from the group consisting of hydrogen and methyl.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein R ³ and R ⁴ are both hydrogen.
7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein -(X) _k -(Y) _m -(Z) _n - group is selected from -CH ₂ -CR'R"-CH ₂ -, -CH ₂ -CH ₂ -CR'R"-CH ₂ -, -CH ₂ -CR'R"-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -NR"'-CH ₂ - and -CH ₂ -NR"'-CH ₂ -CH ₂ -.
8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof a drug, wherein R' and R" are each independently selected from the group consisting of hydrogen, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N (CH _{3 2} , -OH, -OCH ₃ ,

   

   
9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof a drug, wherein R' and R" are each independently selected from the group consisting of hydrogen, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N (CH _{3 2} , -OH, -OCH ₃ ,

   

   
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicine, wherein R"' is selected from hydrogen,

    

    
11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pre- Medicine, wherein R"' is selected from hydrogen,

    

    
12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof A drug wherein D is a C _2-6 alkylene group, preferably a butylene group.
13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein the compound has the structure of formula (II):

    

    Preferably, the compound has any structure of the formula:

    

    Wherein q is 2, 3, 4, 5 or 6, preferably q is 4.
14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Medicament wherein the compound is selected from the group consisting of

    

    

    
15. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N- An oxide, an isotopically labeled compound, a metabolite or a prodrug, and a pharmaceutically acceptable carrier, preferably a solid formulation, a semisolid formulation, a liquid formulation or a gaseous formulation.
16. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or former thereof Use of a medicament or a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the prevention or treatment of a disease or condition associated with arginase activity.
17. The use according to claim 16, wherein the disease or condition is selected from the group consisting of a cardiovascular condition, a sexual dysfunction, a wound healing disorder, a gastrointestinal disorder, an autoimmune disorder, an immune disorder, an infection, a lung disease, a liver disease, an inflammation, a hemolytic disorder And cancer, which is preferably gastric cancer, colon cancer, breast cancer and lung cancer (including non-small cell lung cancer), renal cell carcinoma, prostate cancer, multiple myeloma, acute myeloid leukemia, neuroblastoma, colloidal mother Cell tumor or melanoma.
18. A method of preparing a compound of formula (II) as claimed in claim 13, comprising the steps of:

    

    among them:

    Hal is halogen, preferably chlorine, bromine or iodine;

    q' is an integer of q-2;

    When R ^a is hydrogen, R ^{a '} is a carboxy protecting group, preferably a C _1-6 alkyl group, such as a methyl group; and when R ^{a is} not hydrogen, R ^{a '} is the same as R ^a ;

    When R ² is hydrogen, R ^{2 '} is an amino protecting group such as t-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz); and when R ^{2 is} not hydrogen, R ^{2 '} is the same as R ² ;

    When R ³ or R ⁴ is hydrogen, R ^{3 '} or R ^{4 '} are each independently C _1-6 alkyl, or R ^{3 '} and R ^4' together with the group to which they are attached form a 5-8 membered ring. (E.g

    

    or

    

    And when both R ³ and R ^{4 are} not hydrogen, R ^{3 '} and R ^{4 '} are the same as R ³ and R ⁴ , respectively;

    The remaining groups are as defined in claim 13;

    The reaction conditions of each step are as follows:

    Step 1: reacting compound (II)-a with compound Reg-1 in the presence of a base to prepare compound (II)-b;

    Step 2: reacting compound (II)-b with compound Reg-2 in the presence of a catalyst/accelerator, optionally with a phosphine ligand to prepare compound (II)-c;

    Step 3: The compound (II)-c is reacted in the presence of an acid or a base to prepare a compound of the formula (II), provided that when R ^{a '} is the same as R ^a , R ^{2 '} is the same as R ² and R ^{3 '} and When R ^{4 'is the} same as R ³ and R ⁴ respectively, then step 3 does not exist.