CN110963997A

CN110963997A - Heterocyclic amide compound, pharmaceutical composition containing same, and preparation method and application of heterocyclic amide compound

Info

Publication number: CN110963997A
Application number: CN201910884166.7A
Authority: CN
Inventors: 李桂英; 田强; 钮晓达; 王英; 宋宏梅; 蔡家强; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2018-09-28
Filing date: 2019-09-18
Publication date: 2020-04-07

Abstract

The invention relates to heterocyclic amide compounds, pharmaceutical compositions containing the same, methods for preparing the same, and uses thereof as interferon gene stimulating protein (STING) agonists. More particularly, the present invention relates to heterocyclic amide compounds which are capable of stimulating interferon production and thus useful as immunomodulators in the treatment of STING-mediated diseases or conditions such as cancer, infectious diseases, inflammation, immune-related diseases and the like.

Description

Heterocyclic amide compound, pharmaceutical composition containing same, and preparation method and application of heterocyclic amide compound

Technical Field

Background

STING (stimulants of interferon gene stimulators) is a transmembrane protein, also known as TMEM173, MPYS, MITA or ERIS, which is an important Signaling molecule in immune response, when stimulated by a ligand, such as bacterial-derived Cyclic Dinucleotide (CDN), STING is activated, changes in molecular configuration, thereby up-regulating IRF3 and NF κ B Signaling pathways, in particular, activated STING recruits TANK-binding kinase (TBK1) in cytoplasm, mediates phosphorylation of IRF3 by TBK1, thereby leading to interferon- β and other cytokine production, production of interferon- β is a marker of STING activation, while interferon is a group of active proteins with multiple functions, which have the potential to modulate immune function, enhance antiviral effect, inhibit tumor cell proliferation, induce tumor cell agonism, 674, etc. (Nature, 674, etc., which are a potent agonist for inhibiting tumor cell proliferation, tumor cell proliferation inhibition, tumor cell proliferation, tumor cell proliferation, tumor cell.

In recent years, cyclic dinucleotide analogues have been disclosed by various agencies as STING agonists. Such as MIW-815(ADUS100, formula one), has entered clinical stage 1; WO2017027645 and WO2017093933 report cyclic dinucleotide compounds represented by formula two and formula three, respectively.

Recently, WO2017175147 discloses benzimidazoles and dimeric STiNG-like agonists thereof as shown below, which show good agonistic activity.

Disclosure of Invention

The present invention provides heterocyclic amide compounds which have good agonistic effects on STING, and have excellent properties such as good physicochemical properties (e.g., solubility, physical and/or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window), and the like.

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 the compound has the structure of formula (I):

wherein:

x, Y and Z are each independently selected from C and N;

Q¹and Q²Each independently selected from CR¹⁰And N;

R¹and R¹⁰Each independently selected from hydrogen, -OR⁵、-NR⁶R⁷Cyano, halogen, halogeno C_1-6Alkyl radical, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl group;

R²is selected from-C (═ O) NR⁸R⁹、-C(＝S)NR⁸R⁹、-S(＝O)_mNR⁸R⁹and-C (═ NH) NR⁸R⁹；

R³Selected from a direct bond, -C_1-6Alkylene-, -C_1-6alkylene-O-C_1-6Alkylene-, -C_1-6alkylene-NR⁶-C_1-6Alkylene-, -C_3-6Cycloalkylene-, -3-to 10-membered heterocyclylene-, -C_6-10Arylene-and-5 to 14 membered heteroarylene-;

R⁴selected from hydrogen and C_1-6An alkyl group;

R⁵、R⁶and R⁷Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, - (CH)₂CH₂O)_nCH₂CH₂OR⁸A sugar group, a 3-to 10-membered heterocyclyl group containing a quaternized nitrogen atom, -P (═ O) (OR ') (OR "), and-OP (═ O) (OR') (OR");

R⁸and R⁹Each occurrence independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cyclic hydrocarbyl groups, -P (═ O) (OR ') (OR ") and-OP (═ O) (OR') (OR");

u is selected fromHydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, -C (═ O) OR¹¹、-OC(＝O)R¹¹、-C(＝O)NR¹¹R¹²、-NR¹¹C(＝O)R¹²、-NR¹¹C(＝O)NHR¹²、-S(＝O)_mR¹¹、-S(＝O)₂OR¹¹、-S(＝O)₂NR¹¹R¹²、-OS(＝O)₂R¹¹、-NR¹¹S(＝O)₂R¹²、-NR¹¹S(＝O)₂NHR¹²3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, -P (═ O) (OR ') (OR "), -OP (═ O) (OR') (OR"), -NR¹¹P (═ O) (OR') (OR ") and-OP (═ O) (NR)¹¹R¹²) (OR "), wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally fused to C_6-10An aromatic ring or a 5-to 14-membered heteroaromatic ring;

R¹¹and R¹²Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl, or R¹¹And R¹²Together with the groups to which they are attached form a 4-to 10-membered ring;

a is selected from C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl group;

m is 0, 1 or 2;

n is 0, 1, 2 or 3;

each of the above groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen, hydroxy, oxo, cyano, -NH₂Nitro, mercapto, -CO₂H、-CO₂C_1-6Alkyl radical, C_1-6Alkyl, halo C_1-6Alkyl, -O-C_1-6Alkyl, -O-halo C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_3-6Cycloalkyl, -NH-C_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6alkylene-OH, -C_1-6alkylene-CN, -C_1-6alkylene-O-C_1-6Alkyl, -C_1-6alkylene-CO₂-C_1-6Alkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, 3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, a glycosyl group, -P (═ O) (OR ') (OR "), and-OP (═ O) (OR') (OR"); and is

R 'and R' are each independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl group;

with the proviso that A is not

Wherein:

R^ais C_1-6Alkyl, optionally substituted with one or more substituents selected from the group consisting of: hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxylate, amide, sulfonamide, and carbamate groups;

R^bselected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl and cyclopropyl;

R^cselected from hydrogen, halogen and C_1-4An alkyl group.

Another aspect of 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 (III):

wherein:

Q¹and Q²Each independently selected from CR¹⁰And N;

R¹and R¹⁰Each independently selected from hydrogen、-OR⁵and-NR⁶R⁷；

R²is-C (═ O) NR⁸R⁹；

R³Selected from a direct bond, -C_1-6Alkylene-, -C_1-6alkylene-O-C_1-6alkylene-and-C_1-6alkylene-NR⁶-C_1-6Alkylene-;

R⁴selected from hydrogen and C_1-6An alkyl group;

u is selected from-NR¹¹C(＝O)NHR¹²Optionally fused to C_6-103-to 10-membered heterocyclic group containing quaternized nitrogen atom, 3-to 10-membered nitrogen-containing heterocyclic group containing oxo group, fused to C, of aromatic ring or 5-to 14-membered heteroaromatic ring_6-103-to 10-membered nitrogen-containing heterocyclyl of an aromatic OR 5-to 14-membered heteroaromatic ring, -P (═ O) (OR ') (OR "), -OP (═ O) (OR') (OR"), -NR¹¹P (═ O) (OR') (OR ") and-OP (═ O) (NR)¹¹R¹²)(OR”)；

R¹¹And R¹²Each independently selected from hydrogen and C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl group;

n is 0, 1, 2 or 3;

each of the above groups is optionally substituted by 1, 2, 3 or4 substituents independently selected from the group consisting of: halogen, hydroxy, oxo, cyano, -NH₂Nitro, mercapto, -CO₂H、-CO₂C_1-6Alkyl radical, C_1-6Alkyl, halo C_1-6Alkyl, -O-C_1-6Alkyl, -O-halo C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_3-6Cycloalkyl, -NH-C_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6alkylene-OH, -C_1-6alkylene-CN, -C_1-6alkylene-O-C_1-6Alkyl, -C_1-6alkylene-CO₂-C_1-6Alkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, 3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, a glycosyl group, -P (═ O) (OR ') (OR "), and-OP (═ O) (OR') (OR"); and is

R 'and R' are each independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12An 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, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention or treatment of a STING-mediated disease or condition.

Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of a STING-mediated disease or condition.

Another aspect of the present invention provides a method of preventing or treating a STING-mediated disease or condition, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

Another aspect of the invention provides a process for preparing a compound of the invention.

Drawings

FIG. 1: agonism of compounds on STING signaling pathway.

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent 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 present invention.

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C_1-6Alkyl "refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halo (when the group is referred to as" haloalkyl ") (e.g., CH)₂F、CHF₂、CF₃、CCl₃、C₂F₅、C₂Cl₅、CH₂CF₃、CH₂Cl or-CH₂CH₂CF₃Etc.). The term "C_1-4Alkyl "refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). The term "alkylene" denotes a corresponding divalent radical, including, for example, "C_1-6Alkylene group "," C_1-4Alkylene "and the like, specific examples include, but are 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 containing one double bond and having from 2 to 6 carbon atoms ("C)_2-6Alkenyl "). The alkenyl group is, for example, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. The term "alkenylene" is a corresponding divalent radical, including, for example, "C_2-6Alkenylene group and C₂₄Alkenylene "and the like, specific examples of which include, but are not limited to: vinylene, propenylene, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, and the like. When the compounds of the invention contain an alkenyl or alkenylene group, the compounds may be present in pure E (entgegen) form, in pure Z (zusammen) form or in any mixture thereof.

As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, e.g., having 2, 3, 4, 5 or 6 carbon atoms, e.g., ethynyl or propynyl. The term "alkynylene" is a corresponding divalent radical, including, for example, "C_2-6Alkynylene group and C_2-4Alkynylene "and the like. Examples include, but are not limited to: ethynylene, propynyl, butynyl, pentynyl, hexynyl and the like.

As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring(e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, 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]Nonyl, decalinyl, etc.)), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C_3-6Cycloalkyl "refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6) ring carbon atoms, including, but not limited to, (trimethylene) cyclopropyl (ring), (tetramethylene) cyclobutyl (ring), (tetramethylene) cyclopentyl (ring), (hexamethylene) cycloheptylene (ring), (trimethylene) cyclooctylene (ring), (hexamethylene) nonyl (ring), (cyclohexenyl (ring) and the like.

As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) cyclic groups having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, S and P and the remaining ring atoms are C. For example, a "3 to 10 membered (hetero) heterocycle (ene)" is a saturated or partially unsaturated (hetero) heterocycle (ene) having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclylene and heterocycle include, but are not limited to: oxirane (ene), aziridine (ene), azetidine (azetidinyl) (ene), oxetane (oxirane), (tetramethylene) tetrahydrofurane, (tetramethylene) dioxolyl (dioxalinyl), (tetramethylene) pyrrolidinyl, (tetramethylene) pyrrolidinone, (tetramethylene) imidazolidine, (tetramethylene) pyrazolene, (tetramethylene) pyrrolinyl, (tetramethylene) tetrahydropyranyl, (tetramethylene) piperidene, (tetramethylene) morpholinyl, (tetramethylene) dithianyl, (tetramethylene) thiomorpholinyl, (tetramethylene) piperazinyl, or trithianyl (trithianyl). The group also encompasses bicyclic ring systems, including spiro, fused or bridged systems (such as 8-azaspiro [4.5] decane, 3, 9-diazaspiro [5.5] undecane, 2-azabicyclo [2.2.2] octane, and the like). The heterocyclylene and heterocyclic ring(s) may be optionally substituted with one or more (e.g. 1, 2, 3 or 4) suitable substituents.

As used herein, the terms "(arylene) 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 term "C_6-10(arylene) and C_6-10Aromatic ring "means an aromatic group containing 6 to 10 carbon atoms, such as (phenylene) phenyl (benzene ring) or (phenylene) naphthyl (naphthalene ring). The aryl (ene) and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO)₂、C_1-6Alkyl, etc.).

As used herein, the terms "(arylene) heteroaryl" and "heteroaryl ring" 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 contains at least one heteroatom which may be the same or different (said heteroatom being, for example, oxygen, nitrogen or sulfur), and which, in addition, may be benzo-fused in each case. In particular, "(arylene) heteroaryl" or "heteroaromatic ring" is selected from thienyl (ene), furyl (ene), pyrrolyl (ene), oxazolyl (ene), thiazolyl (ene), imidazolyl (ene), pyrazolyl (ene), isoxazolyl (ene), isothiazolyl (ene), oxadiazolyl (ene), triazolyl (ene), thiadiazolyl (ene), and the like, and benzo derivatives thereof; or pyridyl (ene), pyridazinyl (ene), pyrimidinyl (ene), pyrazinyl (ene), triazinyl (ene), etc., and benzo derivatives thereof.

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

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

As used herein, the term "glycosyl" refers to the sugar moiety in the glycoside molecule that provides the hemiacetal hydroxyl group, examples of which include arabinosyl, fructosyl, fucosyl, galactosyl, N-acetylgalactosanyl, glucosyl, N-acetylglucosyl, and mannosyl.

The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the current circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be optionally replaced individually and/or together with an independently selected substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen present) may each be optionally replaced with an independently selected substituent.

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

When a bond of a substituent is shown through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (g), (b), (c), (d), (²H) Tritium (a)³H) ); isotopes of carbon (e.g. of¹¹C、¹³C and¹⁴C) (ii) a Isotopes of chlorine (e.g. of chlorine)³⁶C1) (ii) a Isotopes of fluorine (e.g. of fluorine)¹⁸F) (ii) a Isotopes of iodine (e.g. of iodine)¹²³I and¹²⁵I) (ii) a Isotopes of nitrogen (e.g. of¹³N and¹⁵n); isotopes of oxygen (e.g. of¹⁵O、¹⁷O and¹⁸o); isotopes of phosphorus (e.g. of phosphorus)³²P); and isotopes of sulfur (e.g. of³⁵S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in drug and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) Are particularly useful for this purpose because of their ease of incorporation and ease of detection. Using positron-emitting isotopes (e.g. of the type¹¹C、¹⁸F、¹⁵O and¹³n) can be used to examine substrate receptor occupancy in Positron Emission Tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent employed previously. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substitutedThose, e.g. D₂O, acetone-d₆Or DMSO-d₆。

The term "stereoisomer" denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

Solid lines may be used herein

Solid wedge shape

Or virtual wedge shape

Chemical bonds of the compounds of the present invention are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown are present. When present in a racemic mixture, solid and dotted wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to be stereoisomeric (which includes cis and trans isomers, optical isomers (e.g., R and R)S enantiomer), diastereoisomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

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

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include 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, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, salicylate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, dihydro, Pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate (xinofoate).

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

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

As used herein, the term "ester" means an ester derived from a compound of the respective general formula in the present application, including physiologically hydrolysable esters (which can be hydrolysed under physiological conditions to release the compound of the invention in free acid or alcohol form). The compounds of the invention may themselves also be esters.

The compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, since the available lone pair is required for oxidation of the nitrogen to the oxide; one skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp 748-750; a.r.katitzky and a.j.boulton, eds., Academic Press; and G.W.H.Cheeseman and E.S.G.Werstuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite thereof.

The present invention further includes within its scope prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which may themselves have little or no pharmacological activity which, when administered into or onto the body, may be converted to the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into 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 be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in h. bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, such as those described in T.W.Greene & P.G.M.Wuts, protectivve Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

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

As used herein, "Ph" represents a phenyl group and "Bn" represents a benzyl group.

In some embodiments, the present 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):

wherein:

x, Y and Z are each independently selected for C and N;

Q¹and Q²Each independently selected from CR¹⁰And N;

R⁴selected from hydrogen and C_1-6An alkyl group;

u is selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, -C (═ O) OR¹¹、-OC(＝O)R¹¹、-C(＝O)NR¹¹R¹²、-NR¹¹C(＝O)R¹²、-NR¹¹C(＝O)NHR¹²、-S(＝O)_mR¹¹、-S(＝O)₂OR¹¹、-S(＝O)₂NR¹¹R¹²、-OS(＝O)₂R¹¹、-NR¹¹S(＝O)₂R¹²、-NR¹¹S(＝O)₂NHR¹²3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, -P (═ O) (OR ') (OR "), -OP (═ O) (OR') (OR"), -NR¹¹P (═ O) (OR') (OR ") and-OP (═ O) (NR)¹¹R¹²) (OR "), wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally fused to C_6-10An aromatic ring or a 5-to 14-membered heteroaromatic ring;

a is selected from C_3-6Cycloalkyl, 3-to 10-membered heteroCyclic group, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl group;

m is 0, 1 or 2;

n is 0, 1, 2 or 3;

each of the above groups (e.g., the above alkylene, alkyl, alkenyl, alkynyl, cycloalkylene, cycloalkyl, heterocyclylene, heterocyclyl, arylene, aryl ring, heteroarylene, heteroaryl ring, and aralkyl) is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: halogen, hydroxy, oxo, cyano, -NH₂Nitro, mercapto, -CO₂H、-CO₂C_1-6Alkyl radical, C_1-6Alkyl, halo C_1-6Alkyl, -O-C_1-6Alkyl, -O-halo C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_3-6Cycloalkyl, -NH-C_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6alkylene-OH, -C_1-6alkylene-CN, -C_1-6alkylene-O-C_1-6Alkyl, -C_1-6alkylene-CO₂-C_1-6Alkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, 3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, a glycosyl group, -P (═ O) (OR ') (OR "), and-OP (═ O) (OR') (OR"); and is

with the proviso that A is not

Wherein:

R^cselected from hydrogen, halogen and C_1-4An alkyl group.

In a preferred embodiment, the present invention provides 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 (II):

wherein:

x and Z are each independently selected from C and N;

Q²selected from the group consisting of CR¹⁰And N;

R¹selected from hydrogen, C_1-4Alkyl, -OR⁵、-NR⁶R⁷Cyano and halogen;

R²is-C (═ O) NR⁸R⁹；

R³Selected from a direct bond, -C_1-4Alkylene-, -C_1-4alkylene-O-C_1-4Alkylene-, -C_1-4alkylene-NR⁶-C_1-4Alkylene-and-3 to 10 membered heterocyclylene-;

R⁴is hydrogen;

R⁵、R⁶and R⁷Each independently selected from hydrogen and C_1-4Alkyl, 3-to 10-membered heterocyclic group, C_3-6Cycloalkyl, - (CH)₂CH₂O)_nCH₂CH₂OR⁸A sugar group, a 3-to 10-membered heterocyclyl group containing a quaternized nitrogen atom, -P (═ O) (OR ') (OR "), and-OP (═ O) (OR') (OR");

R⁸selected from hydrogen and C_1-4An alkyl group;

R⁹is hydrogen;

R¹⁰selected from hydrogen, halogen, cyano, -OR⁵and-NR⁶R⁷；

R¹¹and R¹²Each independently selected from hydrogen and C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl, or R¹¹And R¹²Together with the groups to which they are attached form a 4-to 10-membered ring;

a is selected from 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl group;

m is 0, 1 or 2; and is

n is 0, 1, 2 or 3.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein X is C.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or pro-compound thereofMedicine, in which Q²Is CH.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein Z is N.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein R is¹Is methoxy (-OCH)₃)。

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein R is²is-C (═ O) NH₂。

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein R is³Selected from the group consisting of a direct bond, methylene, ethylene, propylene and-CH₂CH₂OCH₂-, preferably, R³Selected from the group consisting of a direct bond, methylene, ethylene and propylene.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug thereof, wherein a is a 5-to 14-membered heteroaryl, preferably

More preferably

In the preferred aspectsIn an embodiment of (a), the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein U is methyl, ethyl, propyl, butyl, -NHC (═ O) NHPh, -NHC (═ O) NHBn, -NHP (═ O) (OBn)₂、-NHP(＝O)(OBn)(OCH₃)、-P(＝O)(OBn)₂、-P(＝O)(OBn)(OCH₂CH₃)、

Methyl, ethyl, propyl and butyl are preferred.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein

X is C;

Q²is CH;

z is N;

R¹is methoxy;

R²is-C (═ O) NH₂；

R³Selected from the group consisting of a direct bond, methylene, ethylene, propylene and-CH₂CH₂OCH₂-(R³Preferably a direct bond, methylene, ethylene or propylene);

a is selected from

U is selected from methyl, ethyl, propyl and butyl.

In other embodiments, the present 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 (III):

wherein:

Q¹and Q²Each independently selected from CR¹⁰And N;

R¹and R¹⁰Each independently selected from hydrogen, -OR⁵and-NR⁶R⁷；

R²is-C (═ O) NR⁸R⁹；

R⁴selected from hydrogen and C_1-6An alkyl group;

n is 0, 1, 2 or 3;

each of the above groups (e.g., the above alkylene, alkyl, cycloalkyl, heterocyclyl, aryl ring, heteroaryl ring, and aralkyl groups) is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: halogen, hydroxy, oxo, cyano, -NH₂Nitro, mercapto, -CO₂H、-CO₂C_1-6Alkyl radical, C_1-6Alkyl, halo C_1-6Alkyl, -O-C_1-6Alkyl, -O-halo C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_3-6Cycloalkyl, -NH-C_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6alkylene-OH, -C_1-6alkylene-CN, -C_1-6alkylene-O-C_1-6Alkyl, -C_1-6alkylene-CO₂-C_1-6Alkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, 3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, a glycosyl group, -P (═ O) (OR ') (OR "), and-OP (═ O) (OR') (OR"); and is

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein Q¹Is CH.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound thereofA metabolite or prodrug thereof, wherein Q²Is CH.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein R is⁴Is hydrogen.

Wherein:

R^ais C_1-6An alkyl group;

R^cselected from hydrogen, halogen and C_1-4An alkyl group;

each of the above alkyl, alkenyl, alkynyl and cyclopropyl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of: halogen, hydroxy, oxo, cyano, -NH₂Nitro, mercapto, -CO₂H、-CO₂C_1-6Alkyl radical, C_1-6Alkyl, halo C_1-6Alkyl, -O-C_1-6Alkyl, -O-halo C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_3-6Cycloalkyl, -NH-C_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6alkylene-OH, -C_1-6alkylene-CN, -C_1-6alkylene-O-C_1-6Alkyl, -C_1-6alkylene-CO₂-C_1-6Alkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, 3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, a glycosyl group, -P (═ O) (OR ') (OR "), and-OP (═ O) (OR') (OR"); and is

R 'and R' are each independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl group; and is

A is most preferably

In a preferred embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein U is-NHC (═ O) NHPh, -NHC (═ O) NHBn, -NHP (═ O) (OBn)₂、-NHP(＝O)(OBn)(OCH₃)、-P(＝O)(OBn)₂、-P(＝O)(OBn)(OCH₂CH₃)、

preferably-NHC (═ O) NHBn, -NHP (═ O) (OBn)₂、-NHP(＝O)(OBn)(OCH₃)、-P(＝O)(OBn)(OCH₂CH₃)、-P(＝O)(OBn)₂、

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein R is³is-C_1-6alkylene-or-C_1-6alkylene-O-C_1-6Alkylene-, preferably-CH₂CH₂CH₂-or-CH₂CH₂OCH₂-。

In some embodiments, the present 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 any of the following formulae:

wherein U' is fused to C_6-10A 3-to 10-membered nitrogen-containing heterocyclic group of an aromatic ring or a 5-to 14-membered heteroaromatic ring or optionally fused to C_6-10A 3-to 10-membered heterocyclyl containing a quaternized nitrogen atom of an aromatic ring or a 5-to 14-membered heteroaromatic ring;

said C is_6-10Each of the aromatic ring, 5-to 14-membered heteroaromatic ring, 3-to 10-membered nitrogen-containing heterocyclyl group, or 3-to 10-membered heterocyclyl group containing a quaternized nitrogen atom is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: halogen, hydroxy, oxo, cyano, -NH₂Nitro, mercapto, -CO₂H、-CO₂C_1-6Alkyl radical, C_1-6Alkyl, halo C_1-6Alkyl, -O-C_1-6Alkyl, -O-halo C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_3-6Cycloalkyl, -NH-C_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6alkylene-OH, -C_1-6alkylene-CN, -C_1-6alkylene-O-C_1-6Alkyl, -C_1-6alkylene-CO₂-C_1-6Alkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, 3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, a glycosyl group, -P (═ O) (OR ') (OR "), and-OP (═ O) (OR') (OR");

preferably, said C_6-10Each of the aromatic ring, 5-to 14-membered heteroaromatic ring, 3-to 10-membered nitrogen-containing heterocyclyl group, or 3-to 10-membered heterocyclyl group containing a quaternized nitrogen atom is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: -CO₂H、-C_1-6alkylene-OH and-C_1-6alkylene-O-C_1-6An alkyl group.

In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein:

R¹is methoxy;

R²is-C (═ O) NH₂；

R³is-CH₂-CH₂-CH₂-or-CH₂CH₂OCH₂-；

R⁴Is H;

R¹²is Bn;

r 'and R' are each independently selected from methyl, ethyl, and Bn;

a is

U' is

R¹is methoxy;

R²is-C (═ O) NH₂；

R³is-CH₂-CH₂-CH₂-；

R⁴Is H;

R¹²is Bn;

a is

R¹is methoxy;

R²is-C (═ O) NH₂；

R³is-CH₂-CH₂-CH₂-；

R⁴Is H;

R¹²is phenyl;

a is

R¹is methoxy;

R²is-C (═ O) NH₂；

R³is-CH₂-CH₂-CH₂-；

R⁴Is H;

r 'and R' are each independently selected from methyl, ethyl, and Bn;

a is

R¹is methoxy;

R³is-CH₂-CH₂-CH₂-；

A is

U' is

R¹is methoxy;

R²is-C (═ O) NH₂；

R³is-CH₂-CH₂-CH₂-or-CH₂CH₂OCH₂-；

R⁴Is H;

R¹²is Bn;

r 'and R' are each independently selected from methyl, ethyl, and Bn;

a is

U' is

R¹is methoxy;

R³is-CH₂-CH₂-CH₂-or-CH₂CH₂OCH₂-；

A is

U' is

Any combination of the above embodiments is encompassed by the present invention.

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

synthesis method

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

wherein each group is as defined above;

the reaction conditions in each step are as follows:

the method comprises the following steps: subjecting compound (IV-a) to a carbonylation reaction, preferably in a solvent such as dichloromethane, in the presence of a carbonylation reagent such as triphosgene to give compound (IV-b); and

step two: reacting the compound (IV-b) with R¹²-NH₂Reaction under basic conditions (e.g. in the presence of triethylamine, DIPEA) to give the compound of formula (IV), preferably in a solvent (e.g. dichloromethane).

In other embodiments, the present invention provides a method of preparing a compound of formula (IV), comprising the steps of:

wherein each group is as defined above;

the reaction conditions in each step are as follows:

the method comprises the following steps: carbonylating compound (IV-c) in the presence of a carbonylation reagent (e.g. triphosgene), optionally under basic conditions (e.g. in the presence of triethylamine, DIPEA) to give compound (IV-d), preferably in a solvent (e.g. dichloromethane); and

step two: the compound (IV-d) is reacted with the compound (IV-a) under basic conditions (e.g., in the presence of triethylamine, DIPEA) to obtain the compound of formula (IV), preferably in a solvent (e.g., dichloromethane).

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

wherein:

hal is halogen, such as F, Cl, Br or I;

the remaining groups are as defined above;

the reaction conditions in each step are as follows:

the method comprises the following steps: reacting compound (IV-a) with a dihalogen phosphate of formula REG-1 or a monohalogen phosphate of formula REG-2, respectively, under basic conditions (e.g., in the presence of triethylamine, DIPEA) to give compound (V-b) or a compound of formula (V), preferably in a solvent (e.g., tetrahydrofuran, dichloromethane); and

step two: the compound (V-b) is reacted with R "-OH, optionally under basic conditions (e.g. in the presence of triethylamine, DIPEA), to give the compound of formula (V), preferably in a solvent (e.g. tetrahydrofuran).

In some embodiments, the present invention provides a process for preparing a compound of formula (VI), comprising the steps of:

a tool A is provided:

PG¹as carboxyl protecting groups, e.g. C_1-6An alkyl group;

hal is halogen, such as F, Cl, Br or I;

u' is fused to C_6-10A 3-to 10-membered nitrogen-containing heterocyclic group of an aromatic ring or a 5-to 14-membered heteroaromatic ring;

the remaining groups are as defined above;

the reaction conditions in each step are as follows:

the method comprises the following steps: reacting the compound (VI-a) with Hal-R³-NH₂Reaction under basic conditions (e.g. in the presence of potassium carbonate, triethylamine, DIPEA) to give compound (VI-b), preferably in a solvent (e.g. DMF);

step two: reacting compound (VI-b) with U' H under basic conditions (e.g., in the presence of potassium carbonate, triethylamine, DIPEA) to give compound (VI-c), preferably in a solvent (e.g., DMF);

step three: reacting compound (VI-C) under reducing conditions (e.g., Pd/C and hydrogen conditions) to give compound (VI-d), preferably in a solvent (e.g., methanol, ethanol);

step four: reacting compound (VI-d) with cyanogen bromide, preferably in a solvent such as acetonitrile, to give compound (VI-e);

step five: reacting compound (VI-e) with a-C (═ O) OH in the presence of a condensation reagent (e.g. HATU or HOBT + EDCI) under basic conditions (e.g. in the presence of potassium carbonate, triethylamine, DIPEA) to give compound (VI-f), preferably in a solvent (e.g. DMF);

step six: subjecting Compound (VI-f) to deprotection conditions (e.g. when PG is present¹Is C_1-6Alkyl, under acidic conditions such as concentrated hydrochloric acid) to give compound (VI-g); and

step seven: compound (VI-g) is reacted with ammonium chloride in the presence of a condensing agent (e.g. HATU or HOBT + EDCI) under basic conditions (e.g. in the presence of potassium carbonate, triethylamine, DIPEA) to give compound of formula (VI), preferably in a solvent (e.g. DMF).

Pharmaceutical compositions and methods of treatment

In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably in 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 a preferred embodiment, the pharmaceutical composition is preferably administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.

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

In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention for use in the prevention or treatment of a STING-mediated disease or condition.

In some embodiments, the present invention provides a method of preventing or treating a STING-mediated disease or condition, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

In some embodiments, the STING-mediated disease or condition is preferably cancer, inflammation, infectious disease, or immune-related disease; the cancer is preferably a malignant solid tumor, including metastatic solid tumors, recurrent solid tumors, and lymphomas.

By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be employed 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, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's pharmaceutical sciences (1990).

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

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

Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, 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, when administered, will alleviate one or more symptoms of the condition being treated to some extent.

The dosing regimen may be adjusted to provide the best 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 exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

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

As used herein, unless otherwise specified, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

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

Detailed Description

Examples

The present invention is further described below by reference to examples and experimental examples, but these examples are not provided to limit the scope of the present invention.

The structure of the compound is determined by nuclear magnetic resonance spectrum (¹H NMR) or Mass Spectrometry (MS).

Nuclear magnetic resonance spectrum (¹H NMR) isBruker 400MHz nuclear magnetic resonance; determination of the solvent as heavy Water (D)₂O), deuterated methanol (CD)₃OD), deuterated chloroform (CDCl)₃) Or hexadeutero dimethyl sulfoxide (DMSO-d)₆) (ii) a The internal standard substance is Tetramethylsilane (TMS).

Abbreviations in the nuclear magnetic resonance spectrum have the following meanings: s: a single peak; d: a doublet peak; t: a triplet; q: quartering; dd: double doublet; qd: a quartet peak; ddd: double doublet; ddt: double triple peaks; dddd: double doublet; m: multiple peaks; br: broad peak; j: a coupling constant; hz: hertz.

Chemical shifts (δ) are given in parts per million (ppm).

The Mass Spectrometer (MS) was an Agilent (ESI) mass spectrometer model Agilent 6120B.

The abbreviations herein have the following meanings:

abbreviations	Means of
		DIEA/DIPEA	N, N-diisopropylethylamine
DMF	N, N-dimethylformamide
		EDCI	1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
HATU	O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
		HCl	Hydrochloric acid
HOBt	1-hydroxybenzotriazole
		NCS	N-chlorosuccinimide
Pd/C	Palladium/carbon
		THF	Tetrahydrofuran (THF)

The first embodiment is as follows: 1- (3- (3-benzylureido) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (Compound C1)

The method comprises the following steps: synthesis of 1- (3-aminopropyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (C1-2)

Reacting (3- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d]Imidazol-1-yl) propyl) carbamic acid benzyl ester (1.0g, 2.0mmol, synthesis method see WO2017/175156a1) dissolved in tetrahydrofuran (20mL), replaced with nitrogen three times, added Pd/C (100mg), replaced with hydrogen three times and reacted under a hydrogen balloon at room temperature for 2 hours. The reaction was filtered through celite, the filter cake was washed twice with tetrahydrofuran (10ml), and the combined filtrates were concentrated to dryness to give the title compound (600 mg). ESI-MS (m/z): 400.1[ M + H]⁺。

Step two: synthesis of 2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -1- (3-isocyanatopropyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (C1-3)

Compound (C1-2) (50mg, 0.13mmol) was suspended in methylene chloride (5ml), and triphosgene (111mg, 0.38mmol) was added thereto, followed by stirring at room temperature overnight. The reaction was concentrated and dried to give a crude white solid which was used directly in the next reaction.

Step three: synthesis of 1- (3- (3-benzylureido) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (C1)

Compound (C1-3) (50mg, 0.13mmol) was suspended in dichloromethane (5mL), benzylamine (20mg, 0.19mmol) and DIEA (50mg, 0.38mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and separated and purified by Pre-HPLC to give the title compound (35 mg). ESI-MS (m/z): 533.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.84(s，1H)，8.00(s，1H)，7.66(d，J＝1.3Hz，1H)，7.44-7.16(m，7H)，6.67(s，1H)，6.36(t，J＝6.0Hz，1H)，6.04(t，J＝5.9Hz，1H)，4.62(q，J＝7.1Hz，2H)，4.36(t，J＝7.2Hz，2H)，4.19(d，J＝5.9Hz，2H)，3.97(s，3H)，3.11(q，J＝6.6Hz，2H)，2.16(s，3H)，1.97-1.77(m，2H)，1.35(t，J＝7.1Hz，3H).

Example two: (3- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) phosphoramidate dibenzyl ester (Compound C2)

The method comprises the following steps: synthesis of dibenzyl chlorophosphate (C2-2)

NCS (1.8g, 13.4mmol) was weighed, suspended in toluene (25ml), dibenzyl hydrogenphosphite (1.0g, 3.81mmol) was added, the reaction was allowed to proceed overnight at room temperature, and the completion of the reaction was detected by LC-MS. Filtration and concentration of the filtrate dried to give the title compound (1.0 g).

Step two: synthesis of dibenzyl (3- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) phosphoramidate (C2)

Compound (C1-2) (200mg, 0.5mmol) was suspended in tetrahydrofuran (5ml), DIEA (194.13mg, 1.50mmol) and dibenzyl chlorophosphate (163.40mg, 0.55mmol) were added in this order, and the reaction was allowed to react overnight at room temperature and checked for completion by LC-MS. Purification by Pre-HPLC separation afforded the title compound (54 mg). ESI-MS (m/z): 660.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.87(s，1H)，8.01(s，1H)，7.68(d，J＝1.3Hz，1H)，7.40-7.27(m，14H)，6.68(s，1H)，5.34-5.15(m，1H)，5.07(dd，J＝7.2，4.5Hz，1H)，5.02-4.81(m，4H)，4.59(q，J＝7.1Hz，2H)，4.36(t，J＝6.9Hz，2H)，3.93(s，3H)，2.84(dt，J＝13.6，6.9Hz，2H)，2.12(s，3H)，1.90(p，J＝7.1Hz，2H)，1.33(t，J＝7.1Hz，3H).

Example three: (S) -1- (3- (4-benzyl-2, 5-dioxoimidazolidin-1-yl) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (Compound C3)

The method comprises the following steps: synthesis of methyl (S) -2-isocyanato-3-phenylpropionate (C3-2)

L-phenylalanine methyl ester hydrochloride (50mg, 0.28mmol) was suspended in methylene chloride (5mL), and triphosgene (91mg, 0.3mmol) was added to the suspension to conduct a reaction at room temperature for 2 hours. The reaction was directly concentrated to dryness to give the title compound, which was used in the next reaction without further purification.

Step two: synthesis of methyl ((3- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamoyl) -L-phenylalanine (C3-3)

Compound (C3-2) (57mg, 0.28mmol) was suspended in dichloromethane (5ml), and compound (C1-2) (80mg, 0.80mmol) was added and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and separated and purified by Pre-HPLC to give the title compound (35 mg). ESI-MS (m/z): 605.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.82(s，1H)，8.00(s，1H)，7.66(s，1H)，7.37(d，J＝1.5Hz，2H)，7.33-7.07(m，5H)，6.66(s，1H)，6.32-6.10(m，2H)，4.61(d，J＝7.1Hz，2H)，4.45-4.25(m，3H)，3.93(s，3H)，3.57(s，3H)，3.16-2.78(m，4H)，2.17(s，3H)，1.95-1.73(m，2H)，1.34(t，J＝7.1Hz，3H).

Step three: synthesis of (S) -1- (3- (4-benzyl-2, 5-dioxoimidazolidin-1-yl) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (C3)

Compound (C3-3) (10mg, 0.016mmol) was dissolved in THF (1mL), lithium hydroxide (3mg, 0.080mmol) was dissolved in water (0.2mL) and added, and the reaction was stirred at room temperature for 1 hour. No starting material remained as monitored by LC-MS, pH adjusted to 7 with 1N HCl, and purified by Pre-HPLC to give the title compound (5 mg). ESI-MS (m/z): 573.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.83(s，1H)，8.28(s，1H)，8.01(s，1H)，7.66(d，J＝1.5Hz，1H)，7.38(d，J＝1.4Hz，2H)，7.20-7.11(m，4H)，7.10-7.04(m，1H)，6.64(s，1H)，4.60(q，J＝7.1Hz，2H)，4.36(t，J＝4.9Hz，1H)，4.18(dt，J＝18.4，6.9Hz，2H)，3.96(s，3H)，3.28-3.20(m，2H)，2.94(t，J＝5.6Hz，2H)，2.18(s，3H)，1.67(dq，J＝31.2，7.4Hz，2H)，1.35(t，J＝7.1Hz，3H).

Example four: benzyl (3- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) phosphoramidate (Compound C4)

The method comprises the following steps: synthesis of benzyl dichlorophosphate (C4-2)

Phosphorus oxychloride (50mg, 0.33mmol) was dissolved in dichloromethane (5mL), cooled to-30 ℃, benzyl alcohol (35mg, 0.33mmol) and triethylamine (33mg, 0.33mmol) were slowly added dropwise under nitrogen atmosphere, and stirred for 30min while maintaining the temperature to obtain a dichloromethane solution of benzyl dichlorophosphate, which was used directly in the next reaction.

Step two: synthesis of benzyl (3- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) phosphoramidate (C4)

To the reaction solution obtained in step one, compound (C1-2) (83mg, 0.16mmol) was added, stirred at that temperature for 1 hour, methanol (5ml) was added, the reaction solution was concentrated to dryness, and the title compound (5mg) was isolated and purified by Pre-HPLC. ESI-MS (m/z): 584.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.87(s，1H)，8.01(s，1H)，7.67(d，J＝1.3Hz，1H)，7.39(d，J＝1.4Hz，2H)，7.30(d，J＝3.2Hz，5H)，6.67(s，1H)，5.19-5.06(m，1H)，4.86(dd，J＝7.4，3.5Hz，2H)，4.60(q，J＝7.1Hz，2H)，4.36(t，J＝6.9Hz，2H)，3.96(s，3H)，3.54(d，J＝11.1Hz，3H)，2.83(dd，J＝12.1，6.6Hz，2H)，2.15(s，3H)，1.95-1.81(m，2H)，1.34(t，J＝7.1Hz，3H).

Example five: 1- (3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) -2- (1-ethyl-3-methyl-IH-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (Compound C5)

The method comprises the following steps: synthesis of methyl 4- ((3-bromopropyl) amino) -3-methoxy-5-nitrobenzoate (C5-2)

Methyl 4-chloro-3-methoxy-5-nitrobenzoate (2.45g, 5.78mmol) was dissolved in DMF (29mL), 3-bromopropylamine (1.37g, 10mm0l) was added, potassium carbonate (2.78g, 20mmol) was added, and the reaction was allowed to warm to 80 ℃ overnight. Upon completion of the reaction of the starting material as monitored by LC-MS, the reaction mixture was added to 100mL of water to precipitate a large amount of red solid, which was then filtered, washed with water and dried to obtain the title compound (2.0 g). ESI-MS (m/z): 347.2[ M + H]⁺。

Step two: synthesis of methyl 4- ((3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) amino) -3-methoxy-5-nitrobenzoate (C5-3)

Compound (C5-2) (2.0g, 10mmol) was dissolved in DMF (20mL), tetrahydroisoquinoline (0.77g, 5.78mmol) was added, potassium carbonate (1.6g, 11.56mmol) was added, and the reaction was allowed to warm to 80 ℃ overnight. Upon completion of the reaction of the starting material as monitored by LC-MS, the reaction mixture was added to 100mL of water to precipitate a large amount of red solid, which was then filtered, washed with water and dried to obtain the title compound (1.7 g). ESI-MS (m/z): 400.2[ M + H]⁺。

Step three: synthesis of methyl 3-amino-4- ((3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) amino) -5-methoxybenzoate (C5-4)

Compound (C5-3) (1.7g, 4.25mmol) was dissolved in ethanol (17mL), Pd/C (170mg, 10%) was added, and the reaction was carried out overnight under a hydrogen atmosphere. And (5) monitoring by LC-MS, wherein a product is produced. The reaction system was filtered to remove Pd/C, the filtrate was concentrated under reduced pressure and separated by preparative HPLC, and lyophilized to give the title compound (1.0 g). ESI-MS (m/z): 370.2[ M + H]⁺。

Step four: synthesis of methyl 2-amino-1- (3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxylate (C5-5)

Compound (C5-4) (1.0g, 2.70mmol) was dissolved in acetonitrile (20mL), cyanogen bromide (0.57g, 5.4mmol) was added, and the reaction was stirred at room temperature overnight to precipitate a large amount of white solid. And (5) monitoring by LC-MS, and completely reacting the raw materials. The reaction was filtered directly and the filter cake was rinsed with a small amount of acetonitrile and dried to give the title compound (800 mg). ESI-MS (m/z): 395.2[ M + H ]]⁺。

Step five: synthesis of 1- (3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxylic acid methyl ester (C5-6)

Compound (C5-5) (0.8g, 2.0mmol) was dissolved in DMF (20mL), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (303mg, 2.0mmol) was added, HATU (1.14g, 3.0mmol) and DIPEA (780mg, 6.0mmol) were added, and the mixture was heated to 80 ℃ for reaction overnight. And (5) monitoring by LC-MS, and generating a product. The reaction was directly isolated by preparative HPLC to give the title compound (500 mg). ESI-MS (m/z): 531.2[ M + H]⁺。

Step six: synthesis of 1- (3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxylic acid (C5-7)

Compound (C5-6) (500mg, 0.94mmol) was dissolved in concentrated hydrochloric acid (5mL) and reacted at 80 ℃ for 2 h. And (5) monitoring by LC-MS, and generating a product. The reaction was directly concentrated under reduced pressure and isolated by preparative HPLC to give the title compound (50 mg). ESI-MS (m/z): 517.2[ M + H]⁺。

Step seven: synthesis of 1- (3- (3, 4-dihydroisoquinolin-2 (1H) -yl) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (C5)

Mixing compound (C5-7) (50mg, 96.79umol), NH₄Cl (6.21mg, 0.11mmol), HOBt (15.69mg, 0.11mmol), EDCI (22.27mg, 0.12mmol) and DIEA (37.53mg, 0.29mmol) were dissolved in DMF (5mL) and the temperature was raised to 80 ℃ for overnight reaction. The reaction was separated and purified by HPLC to give the title compound (9 mg). ESI-MS (m/z): 516.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.83(s，1H)，8.00(s，1H)，7.65(s，1H)，7.39(d，J＝1.4Hz，1H)，7.37(s，1H)，7.10(d，J＝4.8Hz，3H)，7.02(s，1H)，6.61(s，1H)，4.61(d，J＝7.3Hz，2H)，4.43(s，2H)，3.97(s，3H)，3.56(s，2H)，2.80(s，2H)，2.67-2.63(m，2H)，2.33(d，J＝2.0Hz，1H)，2.14(s，3H)，2.02(s，2H)，1.34(t，J＝7.0Hz，3H).

Example six: 2- (1-Ethyl-3-methyl-IH-pyrazole-5-carboxamido) -7-methoxy-1- (3- (3-phenylureido) propyl) -1H-benzo [ d ] imidazole-5-carboxamide (Compound C6)

The method comprises the following steps: synthesis of phenyl isocyanate (C6-2)

Aniline (93mg, 1.0mmol) was dissolved in dichloromethane (2mL), cooled to 0 ℃, added to a solution of triphosgene (297mg, 1.0mmol) in dichloromethane (2mL), triethylamine (303mg, 3.0mmol) was added dropwise, warmed to room temperature, stirred for reaction for 1 hour, the reaction system was concentrated under reduced pressure to remove the solvent to give the title compound (100mg), which was used directly in the next reaction.

Step two: synthesis of 2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1- (3- (3-phenylureido) propyl) -1H-benzo [ d ] imidazole-5-carboxamide (C6)

Compound (C1-2) (50mg, 0.13mmol) was dissolved in methylene chloride (2mL), and phenylisocyanate (15mg, 0.13mmol) and triethylamine (40mg, 0.39mmol) were added to stir at room temperature for 1 h. The reaction was monitored by LC-MS and the starting material was completely reacted. The reaction system was concentrated under reduced pressure, and then separated and purified by preparative HPLC to give the title compound (18 mg). ESI-MS (m/z): 519.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.85(s，1H)，8.51(s，1H)，8.00(s，1H)，7.67(d，J＝1.3Hz，1H)，7.43-7.31(m，3H)，7.25-7.20(m，2H)，6.96-6.77(m，1H)，6.66(s，1H)，6.26(s，1H)，4.64-4.60(m，2H)，4.40(t，J＝7.3Hz，2H)，3.97(s，3H)，3.22-3.18(m，2H)，3.12-3.08(m，1H)，2.09(s，3H)，1.98-1.90(m2H)，1.34(t，J＝7.1Hz，3H)，1.18(t，J＝7.3Hz，2H).

Example seven: 2- (1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1- (3- (3- (pyridin-4-ylmethyl) ureido) propyl) -1H-benzo [ d ] imidazole-5-carboxamide (Compound C7)

The method comprises the following steps: synthesis of 4- (isocyanatomethyl) pyridine (C7-2)

Pyridine 4-ylmethylamine (108mg, 1.0mmol) was dissolved in dichloromethane (2mL), cooled to 0 ℃, triphosgene (297mg, 1.0mmol) in dichloromethane (2mL) was added, triethylamine (303mg, 3.0mmol) was added dropwise, the reaction was warmed to room temperature and stirred, reacted for 1 hour, and then concentrated under reduced pressure to remove the solvent to give the title compound (110mg), which was used directly in the next reaction.

Step two: synthesis of 2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1- (3- (3- (pyridin-4-ylmethyl) ureido) propyl) -1H-benzo [ d ] imidazole-5-carboxamide (C7)

Compound (C1-2) (50mg, 0.13mmol) was dissolved in dichloromethane (2mL), compound (C7-2) (18mg, 0.13mmol) and triethylamine (40mg, 0.39mmol) were added, the reaction was stirred at room temperature for 1h, and the reaction was monitored by LC-MS and the starting material was completely reacted. The reaction was concentrated under reduced pressure, followed by separation and purification by preparative HPLC to give the title compound (25 mg).

ESI-MS(m/z)：534.3[M+H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ8.45-8.43(m，2H)，8.01(s，1H)，7.67(s，1H)，7.39-7.37(m，2H)，7.21-7.20(m，2H)，6.68(s，1H)，6.51(t，J＝6.1Hz，1H)，6.18(t，J＝5.8Hz，1H)，4.64-4.59(m，2H)，4.36(t，J＝7.3Hz，2H)，4.21(d，J＝6.0Hz，2H)，3.97(s，3H)，3.13-3.11(m，2H)，2.15(s，3H)，1.90-1.86(m，2H)，1.35(t，J＝7.1Hz，3H).

Example eight: 1- (3- (3- (cyclohexylmethyl) ureido) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (Compound C8)

The method comprises the following steps: synthesis of (isocyanatomethyl) cyclohexane (C8-2)

Cyclohexylmethylamine (113mg, 1.0mmol) was dissolved in dichloromethane (2mL), cooled to 0 ℃, a solution of triphosgene (297mg, 1.0mmol) in dichloromethane (2mL) was added, triethylamine (303mg, 3.0mmol) was added dropwise, the reaction was warmed to room temperature and stirred for reaction for 1 hour, then the solvent was removed by concentration under reduced pressure to give the title compound (120mg), which was used directly in the next reaction.

Step two: synthesis of 1- (3- (3- (cyclohexylmethyl) ureido) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (C8)

Compound (C1-2) (50mg, 0.13mmol) was dissolved in dichloromethane (2mL), compound (C8-2) (19mg, 0.13mmol) and triethylamine (40mg, 0.39mmol) were added, the reaction was stirred at room temperature for 1h, and LC-MS monitored until the starting material was completely disappeared. The reaction was concentrated under reduced pressure, followed by separation and purification by preparative HPLC to give the title compound (20 mg).

ESI-MS(m/z)：539.2[M+H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.84(s，1H)，8.00(s，1H)，7.66(s，1H)，7.46-7.25(m，2H)，6.67(s，1H)，5.87-5.83(m，2H)，4.64-4.59(m，2H)，4.36-4.32(t，J＝7.3Hz，2H)，3.98(s，3H)，3.09-3.06(m，1H)，2.81(t，J＝6.3Hz，2H)，2.18(s，3H)，1.90-1.78(m，2H)，1.64-1.61(m，6H)，1.35(t，J＝7.1Hz，3H)，1.30-1.22(m，1H)，1.15-1.12(m，3H)，0.86-0.77(m，2H).

Example nine: n- (1-butyl-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-2-yl) -1-methyl-1H-indazole-3-carboxamide (Compound C9)

Reacting 2-amino-1-butyl-7-methoxy-1H-benzo [ d]Imidazole-5-carboxamide (30mg, 0.11mmol, synthesis method see WO2017/175156a1) was dissolved in DMF (1mL), 1-methyl-1H-indazole-3-carboxylic acid (20mg, 0.11mmol) was added followed by HATU (48mg, 0.13mmol) and N, N-diisopropylethylamine (44mg, 0.33mmol), reacted overnight at room temperature with LC-MS monitoring and the starting material was completely reacted. The reaction was separated and purified by HPLC to give the title compound (15 mg). ESI-MS (m/z): 421.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.88(s，1H)，8.52(d，J＝8.2Hz，1H)，8.01(s，1H)，7.85-7.66(m，2H)，7.57-7.25(m，4H)，4.54-4.12(m，5H)，4.01(s，3H)，1.83(t，J＝7.6Hz，2H)，1.43(d，J＝7.4Hz，2H)，0.96(t，J＝7.3Hz，3H).

Biological experiments

Positive control Compound ADU-S100 used in the following Experimental examples

From MCE (1638750-96-5), GSK53

Synthesized as described in WO2017175156A 1.

EXAMPLE 1 agonism of Compounds on STING-mediated Interferon (IFN) signaling pathway

This experiment evaluates the agonism of compounds on the IFN signaling pathway at the cellular level by measuring the SEAP (secreted embryonic alkaline phosphatase) reporter gene activity regulated by the IFN regulatory factor (interferon regulatory factor). THP1-Blue in logarithmic growth phase^TMISG cells (Invivogen) were centrifuged and then resuspended at 2X 10⁶At a concentration of 50. mu.L/well, to a 96-well cell culture plate (Thermo). Compounds were diluted to 200, 66.67, 22.22, 7.41, 2.47, 0.82, 0.27 and 0 μ M using complete medium, added to the cells at 50 μ L/well and the plates placed in a cell incubator for 16 h. After the cell incubation was completed, 10. mu.L of the cell culture supernatant was transferred to a 96-well plate, and 90. mu.L/well of QUANTI-blue (InvivoGen) solution was added, incubated at 37 ℃ for 3 hours, and the reading at OD 620nm was read using a microplate reader. EC (EC)₅₀Calculated by Graphpad Prism software log (agonist) vs. response-variable slope fit. The results are shown in Table I and show that the test compound is on THP1-Blue^TMThe STING signaling pathway in ISG cells has strong agonism.

TABLE I test Compounds for agonism on Interferon (IFN) signaling pathway

Remarking: e_maxRefers to the highest OD produced by stimulation of a compound₆₂₀A value; EC (EC)₅₀Refers to OD produced by compound stimulation₆₂₀Value up to E_maxHalf the time the concentration of the compound; "E_max% "is the highest OD produced by the compound activating STING₆₂₀The value is compared with the highest OD produced by STING activated by GSK53₆₂₀Percentage of value, E_max% of (GSK53) was 100%.

EXAMPLE 2 agonism of Compounds on IFN- β downstream of STING

This experiment evaluated the agonistic effect of compounds on STING protein at cellular level by detecting changes in the downstream cytokine IFN- β of STING by ELISA assay THP-1 cells (tokyo bai) in logarithmic growth phase were resuspended at a density of 8 × 10⁶Each cell/mL, was inoculated into a 24-well plate (Thermo) at 250. mu.L per well, the example compound was diluted with complete medium to 2 Xworking solution concentration (200, 100, 50, 25, 12.5, 6.25, 3.125. mu.M), 250. mu.L of the diluted compound was added to a 24-well plate (250. mu.L of 2% DMSO medium was added to control wells) and mixed well with the cells, the 24-well plate was placed in a cell incubator for 16h, supernatant was collected by centrifugation at 300 g.times.5 min, 100. mu.L of cell culture was aspirated, primary antibody and secondary antibody labeled with HRP were incubated according to the Human IFN- β ELISA kit (PBL-41410) procedure, developed color was developed, and absorbance at 450nm was read, IFN- β concentration was calculated using Graphpad Prism software according to the standard curve, and EC for agonism of the test compound on IFN- β was calculated₅₀The results are shown in Table II and show that the test compound has a strong promoting effect on the production of the cytokine IFN- β downstream of STING in THP-1 cells.

TABLE II test Compounds for agonism of IFN- β, a cytokine downstream of STING

Remarking: e_maxThe highest IFN- β amount stimulated by the compound, EC₅₀Means that the amount of IFN- β produced by the stimulation of the compound reaches E_maxHalf the time the concentration of the compound; "E_max% is the percentage of the highest amount of IFN- β produced by the compound activating STING to the highest amount of IFN- β produced by GSK53 activating STING, E_max% of (GSK53) was 100%.

EXPERIMENTAL EXAMPLE 3 agonism of Compounds on STING Signaling pathway

The experiment evaluates the agonistic effect of test compounds on STING signaling pathway at cellular level by detecting changes in phosphorylation levels of STING and its downstream proteins TBK1 (TANK-binding kinase 1), IRF3 (interferon regulatory factor 3) by western blotting.

The THP-1 cells in the logarithmic growth phase are centrifugally resuspended, and the cell density is adjusted to 4 x 10⁶Cell suspension was seeded at 0.5 ml/well into 12-well plates. Test compounds were diluted to 2 × working solution concentration: ADU-S10060 gM; GSK 5320 μ M; compound C16, 20, 60 μ M; compound C26, 20, 60 μ M. Adding 0.5ml into the cell suspension, and placing the cell suspension in a cell culture box for incubation for 3 hours; the cells were collected by centrifugation, lysed with 40. mu.l of cell lysate (CST), quantified by BCA, and then 10. mu.l of 5 Xloading buffer was added thereto, and heated at 95 ℃ for 10min to prepare a protein electrophoresis sample for Western blotting. Primary antibody was purchased from CST: sting (D2P2F) rabbit mAb, Phospho-Sting (Ser366) rabbit mAb, Phospho-IRF3(Ser396) (D601M) rabbit mAb, IRF3(D9J5Q) mouse mAb, TBK1/NAK (D1B4) rabbit mAb, Phospho-TBK1/NAK (Ser172) (D52C2)

Rabbit mAb, GAPDH (D16H11) rabbit mAb. Secondary peroxidase-conjugated goat anti-rabbit IgG (H + L) was purchased from Zsgb-bio and rabbit anti-mouse IgG-HRP was purchased from Santa Cruz. The experimental results are shown in figure 1, and the results show that the example I (compound C1) and the example II (compound C2) have strong agonistic effect on the phosphorylation levels of STING and the downstream proteins TBK1 and IRF3 in THP-1 cells.

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

Claims

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 structure of formula (I):

wherein:

x, Y and Z are each independently selected from C and N;

Q¹and Q²Each independently selected from CR¹⁰And N;

R⁴selected from hydrogen and C_1-6An alkyl group;

u is selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl group, 3 to 10A heterocyclic radical, C_6-10Aryl, 5-to 14-membered heteroaryl, C_6-12Aralkyl, -C (═ O) OR¹¹、-OC(＝O)R¹¹、-C(＝O)NR¹¹R¹²、-NR¹¹C(＝O)R¹²、-NR¹¹C(＝O)NHR¹²、-S(＝O)_mR¹¹、-S(＝O)₂OR¹¹、-S(＝O)₂NR¹¹R¹²、-OS(＝O)₂R¹¹、-NR¹¹S(＝O)₂R¹²、-NR¹¹S(＝O)₂NHR¹²3-to 10-membered heterocyclyl containing a quaternized nitrogen atom, -P (═ O) (OR ') (OR "), -OP (═ O) (OR') (OR"), -NR¹¹P (═ O) (OR') (OR ") and-OP (═ O) (NR)¹¹R¹²) (OR "), wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally fused to C_6-10An aromatic ring or a 5-to 14-membered heteroaromatic ring;

m is 0, 1 or 2;

n is 0, 1, 2 or 3;

with the proviso that A is not

Wherein:

R^cselected from hydrogen, halogen and C_1-4An alkyl 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 said compound has the structure of formula (II):

wherein:

x and Z are each independently selected from C and N;

Q²selected from the group consisting of CR¹⁰And N;

R¹selected from hydrogen, C_1-4Alkyl, -OR⁵、-NR⁶R⁷Cyano and halogen;

R²is-C (═ O) NR⁸R⁹；

R⁴is hydrogen;

R⁸selected from hydrogen and C_1-4An alkyl group;

R⁹is hydrogen;

R¹⁰selected from hydrogen, halogen, cyano, -OR⁵and-NR⁶R⁷；

m is 0, 1 or 2; and is

n is 0, 1, 2 or 3.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug thereof, wherein a is a 5-to 14-membered heteroaryl, preferably

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug thereof, wherein U is methyl, ethyl, propyl, butyl, -NHC (═ O) NHPh, -NHC (═ O) NHBn, -NHP (═ O) (OBn)₂、-NHP(＝O)(OBn)(OCH₃)、-P(＝O)(OBn)₂、-P(＝O)(OBn)(OCH₂CH₃)、

5. 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 (III):

wherein:

Q¹and Q²Each independently selected from CR¹⁰And N;

R¹and R¹⁰Each independently selected from hydrogen, -OR⁵and-NR⁶R⁷；

R²is-C (═ O) NR⁸R⁹；

R⁴selected from hydrogen and C_1-6An alkyl group;

R¹¹And R¹²Each independently selected fromHydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-to 14-membered heteroaryl and C_6-12Aralkyl group;

n is 0, 1, 2 or 3;

6. The compound of claim 5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein A is a 5-to 14-membered heteroaryl, preferably

Wherein:

R^ais C_1-6An alkyl group;

R^cselected from hydrogen, halogen and C_1-4An alkyl group;

A is most preferably

7. The compound of claim 5 or 6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein U is-NHC (═ O) NHPh, -NHC (═ O) NHBn, -NHP (═ O) (OBn)₂、-NHP(＝O)(OBn)(OCH₃)、-P(＝O)(OBn)₂、-P(＝O)(OBn)(OCH₂CH₃)、

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R³is-C_1-6alkylene-or-C_1-6alkylene-O-C_1-6Alkylene-, preferably-CH₂CH₂CH₂-or-CH₂CH₂OCH₂-。

9. The compound of any one of claims 1-8, 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 any of the following formulae:

wherein U' is fused to C_6-10A 3-to 10-membered nitrogen-containing heterocyclic group of an aromatic ring or a 5-to 14-membered heteroaromatic ring or optionally fused to C_6-10A 3-to 10-membered heterocyclic group containing a quaternized nitrogen atom of an aromatic ring or a 5-to 14-membered heteroaromatic ring.

10. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein said compound is selected from the group consisting of:

11. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of 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 prodrug thereof, and a pharmaceutically acceptable carrier, preferably said pharmaceutical composition is a solid, semisolid, liquid or gaseous formulation, and said pharmaceutical composition is preferably administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or transdermal route.

12. Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of claim 11, in the manufacture of a medicament for the prevention or treatment of a STING-mediated disease or condition, wherein the STING-mediated disease or condition is preferably cancer, inflammation, infectious disease or immune-related disease; the cancer is preferably a malignant solid tumor, including metastatic solid tumors, recurrent solid tumors, and lymphomas.

13. The preparation method comprises the steps of (1) preparing,

wherein the process is a process for preparing a compound of formula (IV) comprising the steps of:

wherein each group is as defined in any one of claims 1 to 9;

the reaction conditions in each step are as follows:

the method comprises the following steps: subjecting compound (IV-a) to a carbonylation reaction in the presence of a carbonylation reagent to obtain compound (IV-b); and

step two: reacting the compound (IV-b) with R¹²-NH₂Reacting under alkaline conditions to obtain a compound of formula (IV);

or the method comprises the following steps:

wherein each group is as defined in any one of claims 1 to 9;

the reaction conditions in each step are as follows:

the method comprises the following steps: carbonylating compound (IV-c) in the presence of a carbonylating agent, optionally under basic conditions, to obtain compound (IV-d); and

step two: reacting compound (IV-d) with compound (IV-a) under basic conditions to give a compound of formula (IV);

or a process for the preparation of a compound of formula (V) comprising the steps of:

wherein:

hal is halogen, such as F, Cl, Br or I;

the remaining groups are as defined in any one of claims 1 to 9;

the reaction conditions in each step are as follows:

the method comprises the following steps: reacting compound (IV-a) with a dihalogen phosphate of formula REG-1 or a monohalogen phosphate of formula REG-2, respectively, under alkaline conditions to give compound (V-b) or a compound of formula (V); and

step two: reacting compound (V-b) with R "-OH, optionally under basic conditions, to give a compound of formula (V);

or a process for the preparation of a compound of formula (VI) comprising the steps of:

wherein:

PG¹as carboxyl protecting groups, e.g. C_1-6An alkyl group;

hal is halogen, such as F, Cl, Br or I;

the remaining groups are as defined in any one of claims 1 to 9;

the reaction conditions in each step are as follows:

the method comprises the following steps: reacting the compound (VI-a) with Hal-R³-NH₂Reacting under alkaline condition to obtain a compound (VI-b);

step two: reacting the compound (VI-b) with U' H under alkaline conditions to obtain a compound (VI-c);

step three: reacting the compound (VI-c) under reducing conditions to obtain a compound (VI-d);

step four: reacting the compound (VI-d) with cyanogen bromide to obtain a compound (VI-e);

step five: reacting compound (VI-e) with a-C (═ O) OH under basic conditions in the presence of a condensation reagent to give compound (VI-f);

step six: reacting the compound (VI-f) under deprotection conditions to obtain a compound (VI-g); and

step seven: the compound (VI-g) is reacted with ammonium chloride in the presence of a condensing agent under basic conditions to give a compound of the formula (VI).