WO2019218904A1 - Unnatural amino acid derivative, preparation method therefor and use thereof - Google Patents

Abstract

Provided are an unnatural amino acid derivative represented by formula (I) (X being a group which binds to arginase; Y being a linking group; and Z being a group which binds to an E3 ubiquitin-protein ligase), a pharmaceutical composition comprising same, a preparation method therefor, and a use thereof in preventing or treating diseases or conditions associated with arginase activity. X-Y-Z (I)

Description

Unnatural amino acid derivative, preparation method and use thereof Field of invention

The present invention relates to a non-natural amino acid derivative, a pharmaceutical composition comprising the same, a process for the preparation thereof and use thereof 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).

Ubiquitin is a small molecule protein consisting of 76 amino acids and having a highly conserved sequence in eukaryotic cells. The main function of ubiquitin is to label the target protein, and the labeled target protein can be recognized and degraded by the proteasome. This process is called ubiquitin/proteasome system (UPS). The ubiquitin-protein ligase (E3) binds directly to the protein and determines the specificity of degradation. The UPS pathway is an important pathway for protein degradation in cells. UPS plays an important role in many metabolic activities of living cells (such as cell growth, signal transduction, DNA repair, antigen presentation). The UPS process mainly includes the following four steps: 1 activation of ubiquitin: the carboxyl residue of ubiquitin is combined with the thiol group of ubiquitin-activating enzyme E1. This step requires ATP as energy to form a ubiquitin and ubiquitin-activating enzyme. Thioester bond between E1; 2 cross-linking of ubiquitin: E1 transfers activated ubiquitin to ubiquitin-binding enzyme E2 through a lactide process; 3E3 binds ubiquitin complex to target protein: ubiquitin-protein The ligase E3 binds the ubiquitin that binds to E2 to the target protein. If ubiquitin is already present on the target protein, the ubiquitin that binds E2 can be directly attached to the target protein; 4 the proteasome completes the degradation: the proteasome recognizes the The labeled target protein, thereby hydrolyzing the target protein into a peptide chain of 7-8 amino acids in length, completes degradation of the target protein.

Proteolysis targeting chimeric molecule (PROTAC) is a bifunctional molecule that binds to both ubiquitin-protein ligase E3 and target proteins, ubiquitinating target proteins that are not capable of binding to E3. Selective degradation by the UPS system controls the level of target proteins in the cells. The PROTAC molecule consists of three parts: a target protein binding group, a ubiquitin-protein ligase binding group, and a linker. Currently, the ubiquitin-protein ligase E3 binding group mainly includes MDM2, cIAP1 (a cytostatic agent of apoptotic protein 1), CRBN (cereblon), and VHL.

Summary of invention

The present invention provides a PROTAC molecule comprising a group that binds to an arginase, a linker, and a group that binds to an E3 ubiquitin-protein ligase, which degrades arginase by targeting ubiquitination, thereby For preventing or treating a disease or condition associated with arginase activity (eg, cancer, induced or spontaneous immune disorder, allergic asthma, inflammatory bowel disease, ulcerative colitis, atherosclerosis or hypertension, etc.).

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:

X is a group that binds to arginase;

Y is a linking group;

Z is a group that binds to the E3 ubiquitin-protein ligase.

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. The term "C _1-6 alkyl" as used herein refers to a linear or branched group of 1 to 6 carbon atoms (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which are optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen Substitution (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 _1-4 alkylene" and the like, and specific examples include, but are not limited to, methylene, ethylene Base, propylene, butylene, pentylene and hexylene.

As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical comprising one double bond and having 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" mean, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6) ring carbons. Atomic saturation (ie, "cycloalkylene" and "cycloalkyl") or unsaturated (ie, having one or more double and/or triple bonds in the ring) a monocyclic or polycyclic hydrocarbon ring, Including but not limited to (sub)cyclopropyl (cyclo), (sub)cyclobutyl (cyclo), (sub)cyclopentyl (cyclo), (sub)cyclohexyl (cyclo), (sub)cycloheptyl ( Ring), (sub)cyclooctyl (ring), (sub)cyclodecyl (ring), (sub)cyclohexenyl (ring), and the like.

As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" mean, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6) a ring atom, wherein at least one of the ring atoms is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie one or more within the ring) Double bond and/or triple bond) 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 "aromatic ring" 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 aromatic ring" mean an aromatic group containing from 6 to 10 carbon atoms, such as (phenylene)phenyl. (Benzene ring) or (methylene) naphthyl (naphthalene ring). The (sub)aryl and aromatic rings are optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO ₂ , C _1-6 alkyl, etc.) .

As used herein, the terms "(sub)heteroaryl" and "heteroaryl" refer to a monocyclic, bicyclic or tricyclic aromatic ring system 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 benzo-fused. 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 denotes an aryl or heteroaryl substituted alkyl group, wherein the aryl, heteroaryl and alkyl are as defined herein. Typically, the aryl group can have from 6 to 10 carbon atoms, the heteroaryl group can have from 5 to 10 ring atoms, and the alkyl group can have from 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 with", 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 selected substituents are optionally 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 independently be independently selected substituent Optionally substituted.

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.

Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts.

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

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

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

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%.

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:

X is a group that binds to arginase;

Y is a linking group;

Z is a group that binds to the E3 ubiquitin-protein ligase.

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 X is

(preferred

);

A is selected from:

U is a C _1-4 alkylene group, preferably a methylene group, an ethylene group, a propylene group or a butylene group;

W is selected from the group consisting of: -CR'R"-, -NR"'- and -O-;

Ring V is a saturated or partially unsaturated 3-10 membered heterocyclic ring or a saturated or partially unsaturated C _3-10 hydrocarbon ring, preferably a pyrrolidine ring, piperidine ring or piperazine ring;

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

);

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 heterocyclyl, 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;

n is 1, 2, 3 or 4;

j is 0 or 1;

The above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon, heterocyclic, heterocyclic, aryl, heteroaryl and aralkyl groups are each optionally one, two, three Or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH ₂ , nitro, fluorenyl, -CO ₂ H, -CO ₂ C _1-6 alkyl, C _{1- 6} alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated C _1-6 alkyl, C _3-6 cycloalkyl, halogenated 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 Alkyl-OC _1-6 alkyl, -C _1-6 alkylene-CO ₂ -C _1-6 alkyl, 3 to 10 membered heterocyclic group, C _6-10 aryl group, 5-14 membered heteroaryl And C _6-12 aralkyl.

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, halogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-6 cycloalkyl, Saturated or partially unsaturated 3-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aralkyl, -OR ^a , -NR ^b R ^c , -OC ( =O)-C _1-3 alkyl, -C _1-3 alkylene-NR ^b R ^c and -C _1-3 alkylene-CO ₂ -C _1-3 alkyl.

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 ,among them,

X is selected from

(preferred

).

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 X is selected from:

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 X is selected from:

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 Y is selected from:

Amino acid, polypeptide, polyethylene glycol, polyhydroxy-substituted alkyl, monosaccharide, polysaccharide, glycoconjugate, quaternary ammonium salt, urea, mercapto, ester (including but not limited to carboxylate, phosphorus (phosphonate) acid Esters, amides (including but not limited to phosphorus (phosphine) amides), phosphorus (phosphine) amide esters, fatty alkyl groups, halogen-substituted alkyl groups, alkyl groups containing heteroatoms such as N, O, S and their oxides, Cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aromatic, heteroaryl rings (including but not limited to triazole compounds).

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 Y is selected from:

among them:

The above group is linked to X by a position marked by 1 or 2, and is connected to Z by another position;

E is selected from H, -NR'R" (preferably -NH ₂ ) and halogen;

G, G ⁰ , G ¹ , G ² and G ³ are each independently selected from each of: C _1-6 alkylene, 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 arylene and 5-14 membered heteroarylene, -O-, -NR "'-, -C(=O)-, -R ^d -C(=O)-, -C(=O)-R ^d -, -R ^d -C(=O)-R ^e - and -C _1-6 alkylene-OC _1-6 alkylene-(preferably -CH ₂ -O-CH ₂ -);

R ^d and R ^e are each independently selected from C _1-6 alkylene, saturated or partially unsaturated C _3-6 cycloalkylene, saturated or partially unsaturated 3-10 membered heterocyclylene, -O- And -NH-;

R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, hydroxy, -NH ₂ , -OC _1-6 alkyl, - NH-C _1-6 alkyl, -N-(C _1-6 alkyl) ₂ , C _6-10 aryl, C _6-12 aralkyl (such as benzyl) and 5-14 membered heteroaryl;

The above alkyl, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkyl, heterocyclic, heterocyclylene, aryl, arylene, heteroaryl, heteroarylene and aromatic The alkyl groups are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH ₂ , nitro, decyl, -CO ₂ H, -CO ₂ C _1-6 alkyl, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated 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 10 membered heterocyclic ring a C _6-10 aryl group, a 5-14 membered heteroaryl group and a C _6-12 aralkyl group; and m, m ⁰ , m ¹ , m ² and m ³ are each independently ⁰ , ¹ , ² , 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

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 Y is selected from:

The above groups are linked to X by the position of the 1 mark, and are connected to Z by the position of the 2 mark.

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 E3 ubiquitin-protein ligase is selected from the group consisting of: von Hippel-Lindau (VHL), CRBN, XIAP, E3A, MDM2, late stage promoting complex (APC), UBR5 (EDD1), SOCS/BC-box /eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3 , PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, WWP1, WWP2, Parkin, A20/TNFAIP3, AMFR/gp78, ARA54, β-TrCP1 /BTRC, BRCA1, CBL, CHIP/STUB1, E6, E6AP/UBE3A, F-Box Protein 15/FBXO15, FBXW7/Cdc4, GRAIL/RNF128, HOIP/RNF31, cIAP-1/HIAP-2, cIAP-2/HIAP -1, cIAP(pan), ITCH/AIP4, KAP1, MARCH8, Mind Bomb 1/MIB1, Mind Bomb 2/MIB2, MuRF1/TRIM63, NDFI P1, NleL, RNF2, RNF8, RNF168, RNF43, SART1, Skp2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32 and ZNRF3;

Preferably, the E3 ubiquitin-protein ligase is selected from the group consisting of VHL, CRBN, cIAP-1, MDM2, APC, EDD1, LNXp80, CBX4, HERC1, HERC2, HERC3, HERC4, PIAS1, PIAS2, PIAS3, PIAS4, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, WWP1, WWP2, CBL, E6, KAP1, N1eL, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, UBR5 (EDD1) and ZNRF3.

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 Z is:

(a group that binds to VHL) (a group that binds to CRBN) (a group that binds to cIAP1) (a group that binds to MDM2);

Preferably, wherein R' is selected from hydrogen, halogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-6 cycloalkyl, saturated or partially unsubstituted Saturated 3-6 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, C _6-10 aralkyl, -OR ^a , -NR ^b R ^c , -OC(=O)- C _1-3 alkyl, -C _1-3 alkylene-NR ^b R ^c and -C _1-3 alkylene-CO ₂ -C _1-3 alkyl; preferably, R' is C _1-4 Alkyl (eg, tert-butyl).

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 ,among them

X is selected from:

Y is selected from:

The above group is linked to X by the position of 1 mark, and is connected to Z by the position of 2 mark;

Z is:

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 ,among them

X is selected from:

Y is selected from:

The above group is linked to X by the position of 1 mark, and is connected to Z by the position of 2 mark;

Z is:

In a preferred embodiment, X is

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

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 the use of a prodrug 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.

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 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 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 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). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.

The 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.

The abbreviations in this article have the following meanings:

abbreviation	meaning
DCM	Dichloromethane
DIEA/DIPEA	N,N-diisopropylethylamine
DMF	N,N-dimethylformamide
EA	Ethyl acetate
EDCI	1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HATU	1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate
H 2 O	water
HOBt	1-hydroxybenzotriazole
LC-MS	Liquid chromatography-mass spectrometry
MeOH	Methanol
NMM	4-methylmorpholine
Pd/C	Palladium/carbon
PE	Petroleum ether
Pre-HPLC	Preparation of high performance liquid chromatography

TFA	Trifluoroacetate
THF	Tetrahydrofuran

Example 1: (3R,4S)-3-Amino-1-((3S,21S)-21-amino-3-((2S,4R)-4-hydroxy-2-((4-(4-A) Thiazole-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5,15-dioxo-7,10,13-trioxa-4, Synthesis of 16-diazadocosin-22-acyl)-4-(3-dihydroxyboronic propyl)pyrrolidine-3-carboxylic acid (5)

Step 1: (S)-6-(Methoxycarbonyl)-2,2-dimethyl-4,12-dioxo-3,14,17,20-tetraoxa-5,11-diaza Synthesis of hetero-docosane-22-acid (5-2)

2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))diacetic acid (222 mg, 1.0 mmol) was weighed and dissolved in DMF (5 mL), cooled To 0 ° C, (t-butoxycarbonyl)-L-lysine methyl ester (260 mg, 1.0 mmol), HOBt (148 mg, 1.1 mmol), EDCI (211 mg, 1.1 mmol) and NMM (111 mg, 1.1 mmol) After the addition, the temperature was kept stirring for 30 min. The title compound (60 mg) was obtained eluted eluting eluting eluting ESI-MS (m/z): 365.2 [M-100].

Step 2: (3S,21S)-21-((tert-Butoxycarbonyl)amino)-3-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl) Benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5,15-dioxo-7,10,13-trioxa-4,16-diaza Synthesis of Dodecane-22-acid methyl ester (5-3)

Compound (5-2) (60 mg, 0.13 mmol) was dissolved in DMF (5 mL) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl) 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (66 mg, 0.14 mmol), HATU (74 mg, 0.19 mmol) and DIEA (50 mg, 0.39 mmol), after adding, keep stirring at this temperature for 30 min. The title compound (65 mg) was obtained eluted eluted eluting eluting eluting ESI-MS (m/z): 877.3 [M+H] ⁺ .

Step 3: (3S, 21S)-21-((tert-Butoxycarbonyl)amino)-3-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl) Benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5,15-dioxo-7,10,13-trioxa-4,16-diaza Synthesis of dodecane-22-acid (5-4)

Compound (5-3) (65 mg, 0.074 mmol) was dissolved in THF / H ₂ O (2.5 mL / 0.5 mL), cooled to 0 ° C, and lithium hydroxide (12 mg, 0.30 mmol) was added. After stirring at 0 ° C for 1 h, the reaction was completed by LC-MS. The pH was adjusted to about 6 with 1N-hydrochloric acid, and the title compound (65 mg) was obtained. ESI-MS (m/z): 863.3 [M+H] ⁺ .

Step 4: (3R,4S)-3-azido-1-((3S,21S)-21-((tert-butoxycarbonyl)amino)-3-((2S,4R)-4-hydroxy-2 -((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5,15-dioxo-7,10 ,13-trioxa-4,16-diazadocosin-22-acyl)-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxo Synthesis of Benzene Heteroborolan-2-yl)propyl)pyrrolidine-3-carboxylate (5-5)

Compound (5-4) (65 mg, 0.075 mmol) was dissolved in DMF (5 mL) and (3R,4S)-3-azido-4-(3-(4,4,5,5- Benzyl methyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxylate (48 mg, 0.090 mmol), HOBt (15 mg, 0.11 mmol), EDCI (22 mg, 0.11 mmol) and DIEA (15 mg, 0.11 mmol) were added and stirred at this temperature for 24 hours. The title compound (50 mg) was obtained after purified by EtOAc. ESI-MS (m/z): 1259.4 [M+H] ⁺ .

Step 5: (3R,4S)-3-Amino-1-((3S,21S)-21-((tert-butoxycarbonyl)amino)-3-((2S,4R)-4-hydroxy-2-((2S,4R)-4-hydroxy-2-() (4-(4-Methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5,15-dioxo-7,10,13 -trioxa-4,16-diazadocosin-22-acyl)-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Synthesis of Heterocyclic Pentane-2-yl)propyl)pyrrolidine-3-carboxylic Acid (5-6)

The compound (5-5) (50 mg, 0.040 mmol) was dissolved in methanol (20 mL), and the mixture was replaced with nitrogen three times, and Pd/C (5 mg) was added, and the hydrogen was replaced three times and reacted under a hydrogen balloon for 2 hours. The reaction was completed by EtOAc (EtOAc) elute ESI-MS (m/z): 1143.3 [M+H] ⁺ .

Step 6: (3R,4S)-3-Amino-1-((3S,21S)-21-amino-3-((2S,4R)-4-hydroxy-2-((4-(4-methyl) Thiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5,15-dioxo-7,10,13-trioxa-4,16 Synthesis of bis-azadocosin-22-acyl)-4-(3-dihydroxyborylpropyl)pyrrolidine-3-carboxylic acid (5)

Compound (5-6) (6 mg, 0.0053 mmol) was dissolved in 4N HCl (4 mL). The reaction was completed by EtOAc (EtOAc):

ESI-MS (m/z): 943.3 [M-17]; ¹ H NMR (400 MHz, heavy water) δ 9.72 (s, 1H), 7.56 - 7.40 (m, 4H), 4.54 (q, J = 8.4, 6.7 Hz, 3H), 4.44 (s, 2H), 4.29 - 4.14 (m, 2H), 4.10 (d, J = 4.4 Hz, 2H), 4.02 - 3.88 (m, 3H), 3.87 - 3.74 (m, 2H) ), 3.70 (d, J = 9.2 Hz, 8H), 3.52 (dd, J = 18.3, 11.5 Hz, 1H), 3.18 (q, J = 6.6, 6.1 Hz, 2H), 2.53 (d, J = 1.4 Hz) , 3H), 2.31 (dd, J = 13.9, 7.6 Hz, 1H), 2.05 (ddd, J = 13.9, 9.9, 4.1 Hz, 1H), 1.85 (s, 2H), 1.64 (d, J = 12.9 Hz, 1H), 1.51 (t, J = 7.3 Hz, 2H), 1.37 (s, 4H), 1.24 (dd, J = 14.4, 6.1 Hz, 2H), 1.16 (d, J = 1.3 Hz, 2H), 0.94 ( s, 9H), 0.75 (p, J = 7.5 Hz, 2H).

Biological test

In vitro enzymatic screening test

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

Add 30 μL of ARG-1 enzyme (dissolved in ddH ₂ O at a working concentration of 5.56 nM (0.2 μg/ml)) to each well of a 96-well plate and 10 μL of different concentrations of test compound (dH ₂ O diluted) and Mix it. After incubating for 20 min at room temperature, 10 μL of the reaction substrate (100 mM arginine, 125 mM glycine, pH 10.5; MnCl ₂ final concentration 1.25 mM; dissolved in ddH ₂ O) was added to the system, mixed, and placed. The plate was incubated for 2 h in a 37 ° C incubator. After the reaction was completed, 100 μL of urea detection reagent (1M H ₂ SO ₄ , 50 mM H ₃ BO ₃ , 0.03% Brij35, 2 mM o-phthalaldehyde, 2 mM N-(1-naphthyl)ethylenediamine dihydrochloride) was added. Incubate for 20 min at room temperature with shaking, and read the absorbance at ₅₂₀ nM (OD ₅₂₀ nM) 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

Example number	IC 50 (μM)
Embodiment 1	3.58±0.37

The results show that the compound of the present invention (for example, the compound of Example 1) has a good inhibitory effect on the ARG-1 enzyme activity.

2. In vitro cell screening test

The inhibitory activity of the compound on the ARG-1 enzyme in the CHOK1-ARG-1 stable cell line was evaluated by the following experiment.

The CHOK1-ARG-1 stable cell line (cultured in 1640 cell culture medium) in logarithmic growth phase was inoculated into a 96-well plate at a seeding density of 10,000 cells per well, and cultured overnight with adherent cells; Dilute to a working concentration with PBS solution (containing 20 mM arginine), add 100 μL of compound dilution to each well in a 96-well plate, and incubate in a cell incubator for 24 hours. After the incubation, transfer 50 μL of the cell culture supernatant to In a 96-well assay plate, add 100 μL of urea detection reagent per well (1M H ₂ SO ₄ , 50 mM H ₃ BO ₃ , 0.03% Brij35, 2 mM o-phthalaldehyde, 2 mM N-(1-naphthyl)ethylenediamine diphosphate The acid salt) was incubated at room temperature for 20 minutes with shaking, and the absorbance at 520 nm (OD520 nm) was read by a microplate reader.

The inhibition rate of the test compound on ARG-1 enzyme activity in the cells 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 Control without added compound, negative control is control without addition of CHOK1-ARG-1 cells and compounds). IC ₅₀ was calculated by fitting a four-parameter method GraphPad software. The results are shown in Table 2.

Table 2. Inhibition of ARG-1 enzyme in CHOK1-ARG-1 stable cell line by compound

Example number	IC 50 (μM)
Embodiment 1	0.56±0.02

The results show that the compound of the present invention (for example, the compound of Example 1) has a good inhibitory effect on the ARG-1 enzyme activity in the stable cell line of CHOK1-ARG-1.

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 (15)

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: X——Y——Z

   (I)

   among them:

   X is a group that binds to arginase;

   Y is a linking group;

   Z is a group that binds to the E3 ubiquitin-protein ligase.
2. A compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein X is

   

   

   A is selected from:

   

   U is a C _1-4 alkylene group, preferably a methylene group, an ethylene group, a propylene group or a butylene group;

   W is selected from the group consisting of: -CR'R"-, -NR"'- and -O-;

   Ring V is a saturated or partially unsaturated 3-10 membered heterocyclic ring or a saturated or partially unsaturated C _3-10 hydrocarbon ring, preferably a pyrrolidine ring, piperidine ring or piperazine ring;

   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

   

   );

   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;

   n is 1, 2, 3 or 4;

   j is 0 or 1;

   The above alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon, heterocyclic, heterocyclic, aryl, heteroaryl and aralkyl groups are each optionally one, two, three Or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH ₂ , nitro, fluorenyl, -CO ₂ H, -CO ₂ C _1-6 alkyl, C _{1- 6} alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated C _1-6 alkyl, C _3-6 cycloalkyl, halogenated 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 Alkyl-OC _1-6 alkyl, -C _1-6 alkylene-CO ₂ -C _1-6 alkyl, 3 to 10 membered heterocyclic group, C _6-10 aryl group, 5-14 membered heteroaryl And C _6-12 aralkyl.
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 X From:

   
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 Medicine, where X is selected from:

   
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 Medicine, where Y is selected from:

   

   

   among them:

   The above group is linked to X by a position marked by 1 or 2, and is connected to Z by another position;

   E is selected from H, -NR'R" (preferably -NH ₂ ) and halogen;

   G, G ⁰ , G ¹ , G ² and G ³ are each independently selected from each of: C _1-6 alkylene, 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 arylene and 5-14 membered heteroarylene, -O-, -NR "'-, -C(=O)-, -R ^d -C(=O)-, -C(=O)-R ^d -, -R ^d -C(=O)-R ^e - and -C _1-6 alkylene-OC _1-6 alkylene-(preferably -CH ₂ -O-CH ₂ -);

   R ^d and R ^e are each independently selected from C _1-6 alkylene, saturated or partially unsaturated C _3-6 cycloalkylene, saturated or partially unsaturated 3-10 membered heterocyclylene, -O- And -NH-;

   R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, 3-10 membered heterocyclyl, hydroxy, -NH ₂ , -OC _1-6 alkyl, - NH-C _1-6 alkyl, -N-(C _1-6 alkyl) ₂ , C _6-10 aryl, C _6-12 aralkyl (such as benzyl) and 5-14 membered heteroaryl;

   The above alkyl, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkyl, heterocyclic, heterocyclylene, aryl, arylene, heteroaryl, heteroarylene and aromatic The alkyl groups are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, hydroxy, oxo, cyano, -NH ₂ , nitro, decyl, -CO ₂ H, -CO ₂ C _1-6 alkyl, C _1-6 alkyl, halo C _1-6 alkyl, -OC _1-6 alkyl, -O-halogenated 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 10 membered heterocyclic ring a group, a C _6-10 aryl group, a 5-14 membered heteroaryl group, and a C _6-12 aralkyl group;

   m, m ⁰ , m ¹ , m ² and m ³ are each independently ⁰ , ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , 14, 15 or 16 .
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 Medicine, where Y is selected from:

   

   The above groups are linked to X by the position of the 1 mark, and are connected to Z by the position of the 2 mark.
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 the E3 ubiquitin-protein ligase is selected from the group consisting of: von Hippel-Lindau (VHL), CRBN, XIAP, E3A, MDM2, late stage promoting complex (APC), UBR5 (EDD1), SOCS/BC- Box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2 PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, WWP1, WWP2, Parkin, A20/TNFAIP3, AMFR/gp78, ARA54, β- TrCP1/BTRC, BRCA1, CBL, CHIP/STUB1, E6, E6AP/UBE3A, F-boxin 15/FBXO15, FBXW7/Cdc4, GRAIL/RNF128, HOIP/RNF31, cIAP-1/HIAP-2, cIAP-2/ HIAP-1, cIAP(pan), ITCH/AIP4, KAP1, MARCH8, Mind Bomb 1/MIB1, Mind Bomb 2/MIB2, MuRF1/TRIM63, NDFIP1, NleL RNF2, RNF8, RNF168, RNF43, SART1, Skp2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32 and ZNRF3;

   Preferably, the E3 ubiquitin-protein ligase is selected from the group consisting of VHL, CRBN, cIAP-1, MDM2, APC, EDD1, LNXp80, CBX4, HERC1, HERC2, HERC3, HERC4, PIAS1, PIAS2, PIAS3, PIAS4, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, WWP1, WWP2, CBL, E6, KAP1, N1eL, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, UBR5 (EDD1) and ZNRF3.
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 Medicine, where Z is:

   
9. The compound of claim 8 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R' is selected From hydrogen, halogen, C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, saturated or partially unsaturated C _3-6 cycloalkyl, saturated or partially unsaturated 3-6 hetero a cyclic group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, a C _6-10 aralkyl group, —OR ^a , —NR ^b R ^c , —OC(=O)—C _1-3 alkyl, -C _1-3 alkylene-NR ^b R ^c and -C _1-3 alkylene-CO ₂ -C _1-3 alkyl; preferably, R' is C _1-4 alkyl (eg t-butyl) ).
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, of which

    X is selected from:

    

    

    Y is selected from:

    

    

    The above group is linked to X by the position of 1 mark, and is connected to Z by the position of 2 mark;

    Z is:

    
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, of which

    X is selected from:

    

    

    Preferably, X is

    

    Y is selected from:

    

    

    

    The above group is linked to X by the position of 1 mark, and is connected to Z by the position of 2 mark;

    Z is:

    
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 Medicament wherein the compound is selected from the group consisting of

    

    

    

    

    
13. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 12, 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.
14. 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 Use of a medicament or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the prevention or treatment of a disease or condition associated with arginase activity.
15. The use according to claim 14, 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 pulmonary 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.