Tricyclic compounds as GPR84 antagonists

Abstract

The present invention relates to tricyclic compounds for use as GPR84 antagonists, specifically, tricyclic compounds having the structure represented by Formula I, tautomers, stereoisomers, hydrates, solvates, pharma- ceutically acceptable salts, or prodrugs thereof, wherein rings Cy, L 1 , R 1 is as defined in the present invention, and the tricyclic compound exhibits significant GPR84 antagonistic effect, has good drug development potential, and is highly safe. JPEG2024523460000032.jpg6162

Description

Technical Field

[0001] This application claims the priority of Chinese Patent Application No. 2021106855681 with an application date of June 21, 2021. This application incorporates the entire text of the above-mentioned Chinese patent application by reference. The present invention belongs to the field of medicine. Specifically, the present invention relates to tricyclic compounds as GPR84 antagonists.

Background Art

[0002] G protein-coupled receptor 84 (GPR84) is a G protein-coupled receptor that binds to the Gi / o pathway sensitive to pertussis toxin. When activated by binding to a ligand, it inhibits adenylate cyclase activity via the Gi protein, reducing the intracellular cAMP level. GPR84 belongs to the fatty acid receptor family, is mainly expressed in the bone marrow, followed by peripheral leukocytes and the lung, and can be activated by medium-chain saturated fatty acids. Among them, capric acid (C10), undecanoic acid (C11), and lauric acid (C12) have the most excellent agonist activity. In addition to the endogenous ligand medium-chain fatty acids, researchers have also discovered exogenous agonists with better activity, such as diindolylmethane (DIM), 6-n-octylaminouracil (6-OAU), and embelin.

[0003] Under normal physiological conditions, short-chain and medium-chain fatty acids and diindolylmethane in immune cells activate GPR84, upregulating the secretion of the IL-12 P40 subunit and promoting the occurrence of inflammation. Studies have shown that the exogenous agonist 6-OAU activates GPR84, causing a chemotactic reaction, upregulating the AKT, ERK, and nuclear factor κB (NFκB) signaling pathways, increasing the expression levels of inflammatory mediators TNFα, IL-6, IL-12B, CCL2, CCL5, and CXCL1, promoting the release of cytokines (IL-8, IL-12) and tumor necrosis factor α (TNF-α), thereby amplifying the inflammatory response of macrophages at the inflammatory site, exacerbating inflammation, and proving to cause various inflammatory diseases.

[0004] Studies have shown that under fibrotic conditions, higher levels of GPR84 mRNA expression are observed in fibroblasts, podocytes, proximal tubular epithelial cells, and macrophages. In a model of idiopathic pulmonary fibrosis, administration of a GPR84 antagonist (oral, 30 mg / kg, twice daily) for 2 weeks led to a dramatic decrease in the Ashcroft score from day 7. In a mouse model of endotoxemia, upregulation of GPR84 mRNA was observed during acute inflammation. Furthermore, upregulation of GPR84 expression has also been observed in models of chronic inflammation such as diabetes and atherosclerosis. Increased expression of GPR84 has been reported in colonic tissues and blood samples from patients with inflammatory bowel disease (IBD). Transcription of GPR84 mRNA was also increased in liver biopsy tissues from patients with non-alcoholic fatty liver disease (NAFLD). Furthermore, the observation of GPR84 upregulation is not limited to peripheral diseases and has also been demonstrated in neuropathic conditions. Previous studies have shown that GPR84 is expressed at low levels in the brains of healthy adult mice, but it has been reported that inflammatory stimuli such as an endotoxin shock model can induce significant upregulation of GPR84 in central nervous system (CNS) microglia. Tumor necrosis factor α and interleukin-1 are thought to play an important role in the upregulation of GPR84 because the expression of GPR84 in the cerebral cortex is reduced in mice lacking these molecules. Comparatively high levels of GPR84 mRNA expression have also been reported in animal models of other diseases that affect the central nervous system, such as experimental autoimmune encephalomyelitis, a model of multiple sclerosis, cuprizone-induced demyelination and axonal injury, and a mouse model of Alzheimer's disease (APP-PS1).

[0005] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic interstitial lung disease of unknown cause, characterized by progressive scarring or fibrosis localized to the lung interstitium, leading to loss of lung function and ultimately death. IPF is often considered a rare disease because of the high risk of rapid progression and death. The clinical prognosis of IPF patients is poor, with a median survival of about 3 years at the time of diagnosis. Regulatory authorities have approved pirfenidone and nintedanib (INN) as therapeutic agents for IPF. Pirfenidone and nintedanib have slowed the rate of decline in lung function in IPF patients, but neither drug improves lung function, and the majority of patients continue to progress despite treatment. Furthermore, side effects of these therapies include diarrhea, abnormal liver function tests after taking nintedanib, nausea, and rash due to pirfenidone. Therefore, there remains a large unmet medical need, and IPF remains a major cause of morbidity and mortality, and there is a strong need for effective treatment.

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to provide a tricyclic compound, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, which is used for preventing and / or treating GPR84-related diseases or for manufacturing a medicament, a pharmaceutical composition or a preparation for preventing and / or treating GPR84-related diseases as a GPR84 antagonist.

Means for Solving the Problems

[0007] A first aspect of the present invention provides a tricyclic compound, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and the tricyclic compound has a structure represented by Formula I.

[0008]

Chemical Formula

[0009] However, Cy is

[0010] [Chem.]

[0011] and L1 is absent or L1 is C1-C4 alkylene, C2-C4 alkenylene having one double bond or C2-C4 alkynylene having one triple bond, R1 is C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, said R1 is optionally substituted by R 11 and said R 11 is selected from the following substituents: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl and C1-C6 haloalkoxy, when there are a plurality of substituents, said R 11 are the same or different substituents.

[0012] In a preferred embodiment of the present invention, L1 is absent or L1 is -CH2-, -CH=CH- or -C≡C-.

[0013] In a preferred embodiment of the present invention, L1 is absent or L1 is -C≡C-.

[0014] In a preferred embodiment of the present invention, R1 is 3-6 membered cycloalkyl.

[0015] In a preferred embodiment of the present invention, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0016] In a preferred embodiment of the present invention, R1 is

[0017] [Chem.]

[0018] is.

[0019] In a preferred embodiment of the present invention, R 11 is selected from the following substituents: halogen, cyano, C1-C6 alkyl and C1-C6 alkoxy.

[0020] In a preferred embodiment of the present invention, the tricyclic compound is as shown in the following formula.

[0021]

Chemical formula

[0022] The second aspect of the present invention provides an intermediate B having the following structure.

[0023]

Chemical formula

[0024] However, Cy is as defined in the first aspect of the present invention, X is selected from -OTf, -OTs, -OMs, chlorine, bromine or iodine.

[0025] The third aspect of the present invention provides a method for producing the tricyclic compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug according to the first aspect of the present invention. The method includes 1) reacting the intermediate B according to the second aspect of the present invention with the compound H-L1-R1 to obtain the tricyclic compound, However, L1 and R1 are as defined in the first aspect of the present invention.

[0026] In a preferred embodiment of the present invention, the method further includes 2) reacting the intermediate B with the compound H-L1-R1 in the presence of a catalyst, and / or 3) reacting the intermediate B with the compound H-L1-R1 under the protection of an inert gas, and / or 4) including the step of reacting the intermediate B with the compound H-L1-R1 under alkaline conditions.

[0027] In a preferred embodiment of the present invention, the catalyst is a palladium catalyst and / or a copper catalyst.

[0028] In a preferred embodiment of the present invention, the palladium catalyst is selected from Pd(PPh3)2Cl2, Pd(OAc)2, Pd(TFA)2, PdCl2, Pd(PPh3)4 and Pd2(dba)3, and more preferably, the palladium catalyst is Pd(PPh3)2Cl2 or Pd(OAc)2.

[0029] In a preferred embodiment of the present invention, the copper catalyst is a monovalent copper catalyst.

[0030] In a preferred embodiment of the present invention, the copper catalyst is CuI.

[0031] In a preferred embodiment of the present invention, the inert gas is nitrogen gas, helium gas, neon gas or argon gas.

[0032] In a preferred embodiment of the present invention, in the above manufacturing method, according to the differences of each group of the compound, different reaction conditions and intermediates can be selected according to the above embodiments of the present invention. When an active group (such as carboxyl, amino, hydroxyl, etc.) is present in the substituent, the active group can be protected with a protecting group if necessary and then participate in the reaction. After the reaction is completed, the protecting group can be deprotected. Among them, a compound in which one or more reaction sites are blocked by one or more protecting groups (also called protecting groups) is a "protected derivative" of the compound of formula I described in the present invention. For example, suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, isotopes, etc. Suitable amino and amide protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable protecting groups are well known to those skilled in the art.

[0033] In a preferred embodiment of the present invention, in the above manufacturing method, the reaction of each step is preferably carried out in an inert solvent, and an appropriate inert solvent can be selected according to the specific situation. The inert solvent includes, but is not limited to, toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, trichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a composition thereof.

[0034] The fourth aspect of the present invention provides a pharmaceutical composition comprising a tricyclic compound according to the first aspect of the present invention (in a therapeutically effective amount), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier.

[0035] In a preferred embodiment of the present invention, the pharmaceutical composition comprises a tricyclic compound according to the first aspect of the present invention (in a therapeutically effective amount), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and at least one other pharmacological active antagonist and / or inhibitor. Preferably, the other pharmacological active antagonist is a GPR84 antagonist. Preferably, the other pharmacological active inhibitor is a GPR84 inhibitor.

[0036] The fifth aspect of the present invention provides the use of a tricyclic compound according to the first aspect of the present invention, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, or the use of a pharmaceutical composition according to the fourth aspect, wherein the use is acting as a GPR84 antagonist, and / or preventing and / or treating a disease associated with / mediated by GPR84, and / or manufacturing a medicine, a pharmaceutical composition or a preparation for acting as a GPR84 antagonist and / or preventing and / or treating a disease associated with / mediated by GPR84.

[0037] In a preferred embodiment of the present invention, the GPR84-related diseases include inflammatory diseases, lung diseases, neuroinflammatory diseases, infectious diseases, autoimmune diseases, endocrine diseases, and / or metabolic diseases, and / or diseases associated with / mediated by immune dysfunction.

[0038] In a preferred embodiment of the present invention, the lung disease is chronic obstructive pulmonary disease and / or interstitial lung disease. The inflammatory disease is preferably inflammatory bowel disease or vasculitis. The interstitial lung disease is preferably congenital pulmonary fibrosis.

[0039] In a preferred embodiment of the present invention, the interstitial lung disease is preferably congenital pulmonary fibrosis or idiopathic pulmonary fibrosis.

[0040] In a preferred embodiment of the present invention, the autoimmune disease is rheumatoid arthritis.

[0041] The present invention provides a method for preventing and / or treating a disease associated with GPR84 in a subject in need thereof, the method comprising providing to the subject an effective amount of the tricyclic compound, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, prodrug or the pharmaceutical composition thereof.

[0042] In a preferred embodiment of the present invention, in the method for preventing and / or treating a disease associated with GPR84 in a subject in need thereof, the disease associated with GPR84 is as described above.

[0043] In a preferred embodiment of the present invention, for the compound, the isotopic abundance of all atoms is the same as its natural abundance.

[0044] Additional aspects and advantages of the present invention will be given in part in the following description, in part will be apparent from the following description, or can be understood by the practice of the present invention.

Mode for Carrying Out the Invention

[0045] Terms and Definitions Unless otherwise specified, the definitions of the groups and terms described in the specification and claims of the present application include exemplary definitions, illustrative definitions, preferred definitions, definitions described in tables, definitions of specific compounds in examples, etc., and can be arbitrarily combined and joined with each other. The definitions of the groups and the structures of the compounds combined and joined in this way should fall within the scope described in the specification of the present application.

[0046] Unless otherwise defined, all scientific and technical terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed category belongs. Unless otherwise noted, all patents, patent applications, and published materials cited in this specification are hereby incorporated by reference in their entirety. In the case of multiple definitions for terms in this specification, the definitions in this application shall prevail.

[0047] It should be understood that the above brief description and the following detailed description are merely exemplary and explanatory, and do not limit the category of the present invention in any way. In this application, unless otherwise specified, the use of the singular form includes the plural form. It should be noted that unless otherwise clearly stated in the specification, the singular forms used in this specification and the claims include the plural forms of the indicated objects. Also, unless otherwise noted, it should be noted that the "or" used means "and / or". Furthermore, the term "comprising", such as other forms like "including", "included", and "containing", is not limiting.

[0048] For the definitions of standard chemical terms, reference can be made to the references (such as Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4TH ED.” Vols. A (2000) and B (2001), Plenum Press, New York, etc.). Unless otherwise specified, conventional methods within the technical scope of the art are used, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods. Unless a specific definition is given, the terms used in this specification in the relevant descriptions of analytical chemistry, synthetic organic chemistry, pharmaceuticals and medical chemistry are known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical manufacture, formulation and delivery, and treatment of patients. For example, the instructions of the kit manufacturer can be used, or reactions and purification can be carried out by methods known in the art or according to the description in this specification. The above-mentioned techniques and methods can generally be carried out according to conventional methods well-known in the art, as described in various general and more specific documents cited and discussed in this specification. In this specification, the groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds.

[0049] When a substituent is described by the usual chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2. As used in this specification,

[0050]

Chem.

[0051] indicates the bonding site of the group. As used in this specification, “R1”, “R1” and “R 1 ” have the same meaning and can be replaced with each other. Similar definitions also have the same meaning for other symbols such as R2.

[0052] The section headings used in this specification are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are hereby incorporated by reference in their entirety.

[0053] In addition to the above, when used in the specification and claims of this application, unless otherwise specifically stated, the following terms have the meanings set forth below.

[0054] Regarding the numerical ranges described in the specification and claims of this application, when the numerical range is understood as an "integer", it should be understood as describing the two endpoints of the range and each integer within the range. For example, "integers from 0 to 5" should be understood as describing each of the integers 0, 1, 2, 3, 4, and 5.

[0055] In this application, the term "halogen" means fluorine, chlorine, bromine, or iodine, either alone or as part of another substituent.

[0056] As used herein, the term "alkyl", alone or as part of another substituent, consists of only carbon and hydrogen atoms, contains no unsaturated bonds, and has, for example, 1 to 6 carbon atoms, and means a straight-chain or branched-chain hydrocarbon chain group connected to the rest of the molecule by a single bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyl may be unsubstituted or substituted with one or more suitable substituents. Alkyl may also be an isotopic isomer of naturally abundant alkyl that is rich in isotopes of carbon and / or hydrogen (i.e., deuterium or tritium). As used herein, the term "alkenyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0057] The term "C1-C6 alkyl", alone or as part of another substituent, should be understood to mean a straight or branched chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl may be, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc., or their isomers. The term "C1-C5 alkyl" should be understood to mean a straight or branched chain saturated monovalent hydrocarbon group having 1, 2, 3 or 5 carbon atoms. In particular, the group has 1, 2 or 3 carbon atoms ("C1-C3 alkyl") and is, for example, methyl, ethyl, n-propyl or isopropyl.

[0058] The term "C1-C6 alkoxy", alone or as part of another substituent, should be understood to mean a straight or branched chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and an oxygen atom, or the definition of C1-C6 alkyl - O - C1-C6 alkyl is as described herein, and the oxygen atom may be linked to any one carbon atom of the straight or branched chain of C1-C6 alkyl. Methoxy (CH3 - O -), ethoxy (C2H5 - O -), propoxy (C3H7 - O -), butoxy (C4H9 - O -), etc. are included, but not limited thereto.

[0059] Alone or as part of another substituent, the term "halo" is used interchangeably with the term "halogen substitution". "Haloalkyl" or "halogen-substituted alkyl" means a branched or straight-chain saturated aliphatic hydrocarbon group substituted by one or more halogens, containing a specific number of carbon atoms (e.g., -CvFw, where v = 1 to 3 and w = 1 to (2v + 1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0060] Alone or as part of another substituent, the term "alkenylene" refers to a substituent formed by removing two hydrogens from a straight-chain or branched-chain olefin having a specific number of carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds. Here, the carbon-carbon double bond may be located at any position of the alkenylene, and the two hydrogens removed may be present on the same carbon atom or on different carbon atoms (e.g., the two hydrogens removed are each on the terminal carbon atoms). Thus, C2-C4 alkenylene includes C2, C3, or C4 alkenylene, and C2 alkenylene (i.e., vinylene) includes, but is not limited to, -CH=CH-,

[0061]

Chemical formula

[0062] and -C(CH3)=CH-, but is not limited to these. C4 alkenylene includes -CH2-CH=CH-CH2-,

[0063]

Chemical formula

[0064] , including, but not limited to, -CH2=CH-CH2-CH2- and -CH2-CH-CH2=CH2.

[0065] Individually or as part of another substituent, the term "alkynylene" refers to a substituent formed by removing two hydrogens from a straight-chain or branched-chain alkene having a specific number of carbon atoms and containing one or more carbon-carbon triple bonds. Here, the carbon-carbon triple bond may be located at any position of the alkynylene, and the two hydrogens to be removed may be present on the same carbon atom or on different carbon atoms (for example, the two hydrogens to be removed are on the carbon atoms at both ends respectively). Thus, C2-C4 alkynylene includes C2, C3 or C4 alkynylene, and C2 alkynylene (i.e., ethylene) is

[0066] [Chemical formula]

[0067] including, but not limited to, and C3 alkynylene is

[0068] [Chemical formula]

[0069] including, but not limited to, and C4 alkynylene is

[0070] [Chemical formula]

[0071] including, but not limited to.

[0072] Individually or as part of another substituent, the term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms and having a specific number of carbon atoms (for example, C3-C6). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0073] Individually or as part of another substituent, the term "heterocycloalkyl" refers to a cyclic group having a specific number of ring atoms (e.g., 4 to 6 members), a specific number of heteroatoms (e.g., 1, 2, or 3), and a specific type of heteroatoms (one or more of N, O, and S), which is monocyclic, bridged, or spirocyclic, and all rings are saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0074] Individually or as part of another substituent, the term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, where the alkoxy is as defined above.

[0075] The term "inert solvent" includes, but is not limited to, toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, trichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a composition thereof.

[0076] The compounds provided herein, including intermediates that can be used to produce the compounds provided herein, contain reactive functional groups (e.g., but not limited to carboxyl, hydroxyl, and amino moieties), and further include protected derivatives thereof. A "protected derivative" is those compounds in which one or more reactive sites are blocked by one or more protecting groups (also called protecting groups). Suitable protecting groups for carboxyl moieties include benzyl, tert-butyl, and the like, and isotopes, etc. Suitable amino and amide protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable hydroxyl protecting groups include benzyl, and the like. Other suitable protecting groups are well known to those skilled in the art.

[0077] As used herein, "optional" or "optionally" means that the event or circumstance described thereafter may or may not occur, and the description includes both the occurrence and non-occurrence of that event or circumstance. For example, "optionally substituted aryl" means that the aryl may be substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl.

[0078] As used herein, the terms "salt" or "pharmaceutically acceptable salt" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable salt" pertains to those compounds, materials, compositions, and / or dosage forms that are within the scope of reliable medical judgment, suitable for contact with human and animal tissues, and have little to no toxicity, irritation, allergic response, or other problems or complications, and that meet a reasonable benefit / risk ratio.

[0079] "Pharmaceutically acceptable acid addition salts" mean salts formed with inorganic or organic acids that can retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salts" mean salts formed with inorganic or organic bases that can retain the biological effectiveness of the free acid without other side effects. In the present invention, in addition to pharmaceutically acceptable salts, other salts are also considered. These can act as intermediates in the purification of the compound or the production of other pharmaceutically acceptable salts, or can be used in the identification, characterization, or purification of the compounds of the present invention.

[0080] The term "stereoisomer" means isomers resulting from differences in the spatial arrangement of atoms within a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0081] Depending on the choice of starting materials and methods, the compounds of the present invention can exist as one of the possible isomers, or as a mixture thereof, depending on the number of asymmetric carbon atoms, for example, as pure optical isomers, or as a mixture of isomers, for example, as a mixture of racemates and diastereomers. When describing a compound having optical activity, the prefixes D and L, or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or chiral centers) within the molecule. The prefixes D and L, or (+) and (-) are symbols used to specify the rotation of plane-polarized light by a compound, where (-) or L indicates that the compound is levorotatory. A compound with the prefix (+) or D is dextrorotatory.

[0082] When the bond to the chiral carbon in the formula of the present invention is depicted as a straight line, it should be understood that both the (R) and (S) configurations of the chiral carbon, as well as the enantiomerically pure compounds and mixtures thereby obtained, are included within the scope of this general formula. The graphical representations of racemates or enantiomerically pure compounds in this specification are from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of the stereocenter is indicated by a wedge bond and a dashed bond.

[0083] The term "tautomer" means a functional group isomer that results from the rapid movement of atoms within a molecule between two positions. The compounds of the present invention can exhibit the phenomenon of tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the movement of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in an equilibrium state, and attempting to isolate a single tautomer usually results in a mixture whose physicochemical properties are consistent with a mixture of the compounds. The position of the equilibrium depends on the chemical nature within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant, and in phenol, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.

[0084] As used herein, "pharmaceutical composition" means a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert biological activity.

[0085] As used herein, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent approved by the relevant government regulatory agencies as acceptable for human or veterinary use.

[0086] As used in this application, the term "solvate" means that a compound of the present invention or a salt thereof contains a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.

[0087] As used in this application, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by a solvent. The prodrug of the present invention is produced by modifying a functional group in the compound, and this modification can be removed by ordinary operations or in vivo to obtain the parent compound. Prodrugs include compounds formed by binding hydroxyl or amino in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl and free amino, respectively.

[0088] One or more atoms constituting the compound of the present invention may contain unnatural atomic isotopes. For example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14The compounds can be labeled with radioisotopes such as those of (C). Conversion of the isotope composition of the compounds of the present invention is included within the scope of the present invention, whether radioactive or not.

[0089] The term "excipient" means a pharmaceutically acceptable inert ingredient. Examples of types of "excipients" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can improve the handling properties of pharmaceutical formulations, i.e., by enhancing fluidity and / or adhesiveness, making the formulations more suitable for direct compression.

[0090] As used herein, the term "treatment" and other similar synonyms

[0091] (i) preventing the occurrence of a disease or disorder in a mammal, particularly when such a mammal is susceptible to the disease or disorder but has not been diagnosed as having the disease or disorder, (ii) inhibiting a disease or disorder, i.e., preventing its onset, (iii) alleviating a disease or disorder, i.e., causing the condition of the disease or disorder to regress, or (iv) reducing the symptoms caused by the disease or disorder, and includes the meaning of.

[0092] In the reaction of each step, the reaction temperature can be appropriately selected according to the solvent, starting material, reagent, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step is completed, the target compound can be separated and purified from the reaction system according to conventional methods such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. Without affecting the next reaction, it is also possible to directly transfer to the next reaction without separating and purifying the target compound. The reaction of each step of the present invention is preferably carried out in an inert solvent, and the inert solvent includes, but is not limited to, toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, trichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a composition thereof.

[0093] Beneficial effects As a result of extensive and intensive research, the inventors of the present invention unexpectedly developed a tricyclic compound as a GPR84 antagonist, its tautomer, stereoisomer, hydrate, solvate, and pharmaceutically acceptable salt. The tricyclic compound has a strong GPR84 antagonist effect. The compound of the present invention has a high oral exposure amount in mice, exhibits excellent pharmacokinetic properties, has a high free fraction in human plasma, good stability, slow metabolism, high drug discovery potential, low risk of drug interaction, and good safety.

[0094] The compound of the present invention can be used to prevent and / or treat GPR84-related diseases as a GPR84 antagonist, and is used in the manufacture of a medicament, pharmaceutical composition or preparation used as a GPR84 antagonist, and in the manufacture of a medicament, pharmaceutical composition or preparation for preventing and / or treating GPR84-related diseases.

Examples

[0095] The present invention will be further described based on the following specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be regarded as limiting the protection scope of the present invention. Based on a full understanding of the present invention, in the following examples, experimental methods for which specific conditions are not indicated usually follow conventional conditions or the conditions proposed by the manufacturer. Those skilled in the art can make modifications that are not necessary for the technical solution of the present invention, and such modifications should be considered to be included within the protection scope of the present invention.

[0096] In the following examples, DCM represents dichloromethane, MeOH represents methanol, TEA represents triethylamine, DMF represents N,N-dimethylformamide, and EA represents ethyl acetate.

[0097] Example 1: Preparation of Compound I-1 The synthetic route is as shown below:

[0098]

Chemical formula

[0099] Step 1: Synthesis of 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-(allyloxy)-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one

[0100]

Chemical formula

[0101] Under the protection of nitrogen gas, at 0 °C, (2-oxabicyclo[2.1.1]hexan-1-yl)methanol (0.23 g, 2.1 mmol) was dissolved in a solution of anhydrous DCM (100 mL), sodium hydride (0.081 g, 2.1 mmol, 60% content in mineral oil) was added, and the mixture was stirred for 15 minutes. 9-(Allyloxy)-2-chloro-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.5 g, 1.6 mmol) was added, the reaction mixture was stirred, and the temperature was raised to room temperature overnight. Saturated aqueous NH4Cl solution (50 mL) was added for one wash, the organic layer was washed once with water (50 mL), dried over MgSO4, concentrated under reduced pressure to obtain a crude product, and purified by silica gel column to obtain the product 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-(allyloxy)-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.45 g, yield: 79%). LC-MS, M / Z (ESI): 367.2 [M+H] + .

[0102] Step 2: Synthesis of 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-hydroxy-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one

[0103] [Chemical formula]

[0104] Compound 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-(allyloxy)-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.45 g, 1.23 mmol) was placed in a 100 mL single-neck flask, DCM / MeOH (10 mL / 10 mL) was added, K2CO3 (0.34 g, 2.46 mmol) and Pd(PPh3)4 (0.071 g, 0.061 mmol) were added at room temperature, and the mixture was stirred overnight at room temperature. Spot detection was performed. After completion of the reaction, the reaction solvent was concentrated to dryness, the obtained crude product was diluted with EA (20 mL), the organic phase was extracted 3 times with water (20 mL×3), the aqueous phases were combined, adjusted to pH = 4, the aqueous phase was further extracted 3 times with DCM (20 mL×3), the organic phases were combined, the organic phase was washed once with saturated brine (20 mL×1), then dried, filtered, and concentrated to obtain the crude product 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-hydroxy-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.35 g, yield: 87%). LC-MS, M / Z (ESI): 327.3[M+H] + .

[0105] Step 3: Synthesis of 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-9-yl trifluoromethanesulfonate

[0106] [Chemical formula]

[0107] Compound 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-hydroxy-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.35 g, 1.07 mmol) was dissolved in DCM (10 mL), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.46 g, 1.28 mmol) and TEA (0.27 mL, 1.93 mmol) were added, and then the mixture was stirred at room temperature for 5 hours. The solvent was concentrated to dryness to obtain a crude product, which was separated and purified by silica gel column (DCM:MeOH (V / V) = 50:1 - 20:1) to obtain 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-9-yl trifluoromethanesulfonate (0.31 g, yield: 63.4%). LC-MS, M / Z (ESI): 459.1 [M+H] + .

[0108] Step 4: Synthesis of 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-(cyclopropylethynyl)-6,7-dihydro-4H-pyrimidinyl[6,1-α]isoquinolin-4-one

[0109] [Chemical Structure]

[0110] Pd(PPh3)2Cl2 (0.011 g, 0.016 mmol), CuI (0.012 g, 0.065 mmol), and 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-9-yl trifluoromethanesulfonate (0.15 g, 0.33 mmol) were placed in a sealed tube under the protection of nitrogen gas. Cyclopropylacetylene (0.11 g, 1.64 mmol) and triethylamine (0.17 g, 1.64 mmol) were dissolved in anhydrous DMF (3 mL), added to the sealed tube, and stirred at 60 °C overnight. After performing spot detection and ensuring that the raw materials had completely reacted, DMF was removed and concentrated to obtain a crude product, which was separated and purified by silica gel column (dichloromethane:methanol (V / V) = 50:1 - 10:1) to obtain 2-((2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-(cyclopropylethynyl)-6,7-dihydro-4H-pyrimidinyl[6,1-α]isoquinolin-4-one (I-1) (63.6 mg, yield: 51.9%). LC-MS, M / Z (ESI): 375.2 [M+H] + 。

[0111] 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 1H), 7.34 (dd, J = 8.2, 1.5 Hz, 1H), 7.28 (d, J = 1.0 Hz,1H), 6.37 (s, 1H), 4.69 (s, 2H), 4.24 - 4.11 (m, 2H), 3.84 (d, J = 8.8 Hz, 2H), 2.95 (dd, J = 7.2, 4.8 Hz,3H), 1.84 (dt, J = 4.8, 4.3 Hz, 2H), 1.59 (dd, J = 4.7, 1.8 Hz, 2H), 1.47 (tt, J = 8.2, 5.1 Hz, 1H), 0.96 -0.88 (m, 2H), 0.87 - 0.80 (m, 2H).

[0112] Example 2: Preparation of Target Compound I-2

[0113]

Chem.

[0114] The synthetic route of Compound I-2 refers to the synthetic method of I-1. Replace (2-oxabicyclo[2.1.1]hexan-1-yl)methanol with (hexahydrofuro[3,2-b]furan-2-yl)methanol, and obtain 9-(cyclopropylethynyl)-2-((hexahydrofuro[3,2-b]furan-2-yl)methoxy)-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (I-2) through a similar four-step reaction. LC-MS, M / Z (ESI): 405.2 [M+H] + 。

[0115] Example 3: Preparation of the target compound I-3 The synthetic route is as shown below:

[0116]

Chem.

[0117] Step 1: Synthesis of 9-(allyloxy)2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one

[0118]

Chem.

[0119] Under the protection of nitrogen gas, at 0 °C, (4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methanol (0.23 g, 2.1 mmol) was dissolved in anhydrous DCM (100 mL) solution, and sodium hydride (0.081 g, 2.1 mmol, 60% content in mineral oil) was added and stirred for 15 minutes. 9-(Allyloxy)-2-chloro-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.5 g, 1.6 mmol) was added, and the reaction mixture was stirred and warmed to room temperature overnight. Saturated NH4Cl aqueous solution (50 mL) was added for one wash, the organic layer was washed once with water (50 mL), dried over MgSO4, concentrated under reduced pressure to obtain a crude product, and purified by silica gel column to obtain the product 9-(allyloxy)2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.47 g, yield: 80%). LC-MS, M / Z (ESI): 381.2 [M+H] + 。

[0120] Step 2: Synthesis of 2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-hydroxy-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one

[0121]

Chemical formula

[0122] The compound 9-(allyloxy)-2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.45 g, 1.23 mmol) was placed in a 100 mL one-neck flask, DCM / MeOH (10 mL / 10 mL) was added, K2CO3 (0.34 g, 2.46 mmol) and Pd(PPh3)4 (0.071 g, 0.061 mmol) were added at room temperature, and the mixture was stirred at room temperature overnight. Spot detection was performed, and after the reaction was completed, the reaction solvent was concentrated to dryness to obtain the crude product, which was diluted with EA (20 mL), and the organic phase was extracted with water (20 mL x 3) three times, and the aqueous phase was combined, then adjusted to pH = 4, and the aqueous phase was further extracted with DCM (20 mL x 3) three times, and the organic phase was combined, and the organic phase was washed once with saturated brine (20 mL x 1), and then dried, filtered, and concentrated to obtain the crude product 2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-hydroxy-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.35 g, yield: 87%). LC-MS, M / Z (ESI): 341.3[M+H] + .

[0123] Step 3: Synthesis of 2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-9-yl trifluoromethanesulfonate

[0124] [ka]

[0125] Compound 2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-hydroxy-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-4-one (0.35 g, 1.07 mmol) was dissolved in DCM (10 mL), 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.46 g, 1.28 mmol) and TEA (0.27 mL, 1.93 mmol) were added, and then the mixture was stirred at room temperature for 5 hours. The solvent was concentrated and dried to obtain a crude product, which was separated and purified by silica gel column (DCM:MeOH (V / V) = 50:1 - 20:1) to obtain 2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-9-yl trifluoromethanesulfonate (0.31 g, yield: 63.4%). LC-MS, M / Z (ESI): 473.1 [M+H] + .

[0126] Step 4: Synthesis of 2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-(cyclopropylethynyl)-6,7-dihydro-4H-pyrimidinyl[6,1-α]isoquinolin-4-one

[0127] [Chemical formula]

[0128] Pd(PPh3)2Cl2 (0.011 g, 0.016 mmol), CuI (0.012 g, 0.065 mmol), and 2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-4-oxo-6,7-dihydro-4H-pyrimido[6,1-α]isoquinolin-9-yl trifluoromethanesulfonate (0.15 g, 0.33 mmol) were placed in a sealed tube and protected with nitrogen gas. Cyclopropylacetylene (0.11 g, 1.64 mmol) and triethylamine (0.17 g, 1.64 mmol) were dissolved in anhydrous DMF (3 mL), added to the sealed tube, and stirred at 60 °C overnight. After performing spot detection and ensuring that the raw materials had completely reacted, DMF was removed and concentrated to obtain a crude product, which was separated and purified by silica gel column (dichloromethane:methanol (V / V) = 50:1 - 10:1) to obtain 2-((4-methyl-2-oxabicyclo[2.1.1]hexan-1-yl)methoxy)-9-(cyclopropylethynyl)-6,7-dihydro-4H-pyrimidinyl[6,1-α]isoquinolin-4-one (I-3) (63.6 mg, yield: 51.9%). LC-MS, M / Z (ESI): 389.2 [M+H] + 。

[0129] 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H), 7.34 (dd, 1H), 7.28 (d, 1H), 6.37 (s, 1H), 4.69 (s, 2H), 4.24 - 4.11 (m, 2H), 3.63 (s, 2H), 2.95 (t,2H), 1.70-1.61 (m, 4H), 1.47 (dd, 1H), 1.34 (s, 3H), 0.96 -0.88 (m, 2H), 0.87 - 0.80 (m, 2H).

[0130] In the test example of the present invention, the preparation of the control compound referred to the preparation method of compound 122 in Patent WO2013 / 092791Al, and its structure is as follows.

[0131]

Chemical formula

[0132] Test Example 1: Experiment for Measuring the GPR84 Antagonist Effect The measurement of the antagonist effect of the compound against GPR84 was carried out in a stably transfected CHO cell line that highly expresses the human GPR84 receptor. The stably transfected cell line was cultured until 80% confluence, trypsinized to collect the cells, counted, and then inoculated into a 384-well plate at 5 μL / well. A 10× compound working solution was prepared with 1× Stimulation Buffer, 1 μL of the 10× compound was taken and added to the corresponding experimental wells, centrifuged, and then incubated at 37°C for 20 minutes. Next, 4 μL of a 2.5 μM forskolin & 200 nM 6-OAU solution was added, centrifuged, and then incubated at 37°C for 30 minutes. After the reaction ended, the cAMP content in the cells was quantified according to the method described in the cAMP test kit (Perkin Elmer, Cat#TRF0263). The antagonist effect (IC 50 value) of the test compound was calculated.

[0133] [Table 1]

[0134] The results indicate that the compounds of the present invention have a strong GPR84 antagonist effect.

[0135] Test Example 2: Pharmacokinetics Experiment in Mice For the pharmacokinetic experiment of the mouse, male ICR mice weighing 20 - 25 g were used and fasted overnight. Three mice were selected, and 3 mg / kg was administered intragastrically. Blood was collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after administration. The blood samples were centrifuged at 6800 g for 6 minutes at 2 - 8 °C, and the plasma was collected and stored at -80 °C. At each time point, 20 μL of plasma was taken, 200 μL of methanol containing an internal standard of 100 ng / mL was added, vortexed to mix uniformly, and then centrifuged at 18000 g for 7 minutes at 2 - 8 °C. 200 μL was transferred to a 96-well plate, and LC-MS / MS quantitative analysis was performed. The main pharmacokinetic parameters were analyzed by the non-compartmental model of WinNonlin7.0 software.

[0136]

Table 2

[0137] The results indicate that the compound of the present invention has a high oral exposure and good drug discovery potential in mice.

[0138] Test Example 3: Pharmacokinetic Experiment in Dogs For the pharmacokinetic experiment in dogs, three male beagles weighing 8 - 10 kg were used, fasted overnight, and 3 mg / kg was administered orally. Blood was collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after administration. The blood samples were centrifuged at 6800 g for 6 minutes at 2 - 8 °C, and the plasma was collected and stored at -80 °C. Plasma at each time point was taken, an acetonitrile solution containing 3 - 5 times the amount of the internal standard was added and mixed, vortexed for 1 minute to mix, centrifuged at 13000 rpm for 10 minutes at 4 °C, the supernatant was taken, 3 times the amount of water was added and mixed, and an appropriate amount of the mixed solution was taken for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by the non-compartmental model of WinNonlin7.0 software.

[0139] The experimental results indicate that the compound of the present invention exhibits good pharmacokinetic properties in the body of dogs.

[0140] Test Example 4: Pharmacokinetics Experiment in Rats According to the following experimental method, the pharmacokinetic properties of the control compound and the compound of the present invention in rats were measured.

[0141] Three male SD rats were used and administered intragastrically at a dose of 2.5 mg / kg. The solvent was 5% DMSO + 10% Solutol + 85% Saline. They were fasted overnight, and blood was collected before administration and at 15, 30 minutes, and 1, 2, 4, 6, 8, 24 hours after administration. The blood samples were centrifuged at 6800 g for 6 minutes at 2 - 8°C, the plasma was collected and stored at -80°C. 20 μL of plasma was collected at each time point, 200 μL of methanol containing an internal standard of 100 ng / mL was added, vortexed to mix uniformly, and then centrifuged at 18000 g for 7 minutes at 2 - 8°C. 200 μL was transferred to a 96-well plate and LC-MS / MS quantitative analysis was performed. The main pharmacokinetic parameters were analyzed by the non-compartmental model of WinNonlin 7.0 software.

[0142] The experimental results indicate that the compound of the present invention exhibits good pharmacokinetic properties in the body of rats.

[0143] Test Example 5: Plasma Protein Binding Rate of the Compound The plasma protein binding rate of the compound was detected by equilibrium dialysis (HTDialysis, HTD 96b). The compound was prepared as a 0.5 nM stock solution using DMSO and then diluted 25-fold with a 0.05 M sodium phosphate buffer to form a working solution. A blank 96-well plate was taken, 380 μL of plasma was pre-added to each well, and then 20 μL / well of the working solution was added to the plasma and mixed well. The final concentration of the compound was 1 μM, and each well contained 0.2% DMSO.

[0144] 100 μL of 0.05 M sodium phosphate buffer was added to the receiving side of each dialysis chamber (HTD 96b), and then 100 μL of plasma containing the compound was added to the supply side. After covering with a plastic cover, it was placed at 37°C and cultured for 5 hours while shaking.

[0145] After the completion of cultivation, 25 μL of samples were collected from each of the supply side and the receiving side of the dialysis chamber, placed in a blank 96-well plate, the same volume of plasma was added to each of the samples on the supply side, and the same volume of 0.05 M sodium phosphate buffer was added to each of the samples on the receiving side and mixed uniformly. After adding 200 μL of an acetonitrile solution containing an internal standard to each well, the 96-well plate was vortexed at 600 rpm for 10 minutes, shaken, centrifuged at 5594 g for 15 minutes (Thermo Multifuge × 3R), then 50 μL of the supernatant was taken and transferred to a new 96-well plate, and the sample was mixed with 50 μL of ultrapure water to perform LC-MS / MS analysis.

[0146] The plasma protein binding rate and the free fraction were calculated by the following formula: % binding rate = 100 × ([concentration on the supply side] 5h - [concentration on the receiving side] 5h ) / [concentration on the supply side] 5h . % free fraction = 100 - % binding rate

[0147] The experimental results show that the compound of the present invention has a high free fraction in human plasma and has good drug discovery potential.

[0148] Test Example 6: Human Liver Microsome Stability According to the following experimental method, the human liver microsomal stability of the control compound and the compound of the present invention was measured. The liver microsomal stability test of the compound was detected by co-culturing the compound with human liver microsomes in vitro. First, the test compound was prepared as a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted with PBS into microsome / buffer, and this solution was used to dilute the 0.5 mM compound to prepare a working solution. The concentration of the compound in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. A deep well plate was taken, 30 μL of the working solution was added to each well, and then 15 μL of the preheated 6 mM NADPH solution was added to initiate the reaction, and the mixture was cultured at 37 °C. At 0, 5, 15, 30, and 45 minutes after the culture, 135 μL of acetonitrile was added to the corresponding well to stop the reaction. After stopping the reaction with acetonitrile at the last 45-minute time point, the deep well plate was vortexed for 10 minutes, shaken (600 rpm), and then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, purified water was added at a ratio of 1:1, and LC-MS / MS detection was performed to obtain the ratio of the peak area of the compound to the peak area of the internal standard at each time point. The peak area ratio of the compound at 5, 15, 30, and 45 minutes was compared with the peak area ratio at 0 minute to calculate the residual rate of the compound at each time point. T 1 / 2 was calculated.

[0149] The experimental results indicate that the compound of the present invention has good stability, slow metabolism, and high drug discovery potential in human liver microsomes.

[0150] The above shows and describes the embodiments of the present invention. However, the above embodiments are illustrative and should not be construed as limiting the present invention. It should be understood that changes, modifications, substitutions, and variations of the above embodiments can be made by those skilled in the art within the scope of the present invention. (Postscript) The present disclosure includes the following aspects. Item 1: A tricyclic compound having the structure represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

Chem.

Chem.

Chem.

Chem.

Chem.

Claims

1. A tricyclic compound having the structure represented by Formula I, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof. 【Chemical 1】 (However, ring Cy is 【Chemical 2】 and L １ either does not exist, or L １ is C １ to C ４ alkylene, C having one double bond ２ to C ４ alkenylene or C having one triple bond ２ to C ４ alkynylene, R １ is C １ to C ６ alkyl, C １ to C ６ alkoxy, 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, said R １ is optionally substituted by R １１ and Said R １１ is selected from the following substituents: halogen, cyano, hydroxyl, C １ to C ６ alkyl, C １ to C ６ alkoxy, C ３ to C ６ cycloalkyl, C １ to C ６ haloalkyl and C １ to C ６ haloalkoxy, and When there are a plurality of substituents, the R １１ is the same or different substituents.)

2. L １ is absent or L １ is -CH ２ -, -CH=CH- or -C≡C-, and the tricyclic compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt characterized thereby.

3. R １ is a tricyclic compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that it is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

4. R １１ is selected from the following substituents: halogen, cyano, C １ to C ６ alkyl and C １ to C ６ alkoxy, and is characterized in that it is the tricyclic compound according to claim 1, its tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt.

5. The tricyclic compound according to claim 1, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, characterized in that the tricyclic compound is as shown in the following formula. 【Chemical 4】

6. Intermediate B having the following structure. [Chemical Formula 5] (However, Cy is as defined in claim 1, X is selected from -OTf, -OTs, -OMs, chlorine, bromine or iodine.)

7. 1) An intermediate B having the following structure and a compound H-L １ -R １ reacting to obtain the tricyclic compound, and Here, X is selected from -OTf, -OTs, -OMs, chlorine, bromine or iodine, Cy, L １ and R １ A process for producing a tricyclic compound, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that Cy, L, and R are as defined in claim 1.

8. The method further comprises 2) reacting the intermediate B with the compound H-L １ -R １ in the presence of a catalyst, and / or 3) reacting the intermediate B with the compound H-L １ -R １ under the protection of an inert gas, and / or 4) A step of reacting the intermediate B with the compound H-L １ -R １ including reacting them under alkaline conditions, The catalyst is a palladium catalyst and / or a copper catalyst, The palladium catalyst is selected from Pd(PPh ３ ), Pd(OAc ２ ), Pd(TFA ２ ), PdCl ２ ), Pd(PPh ２ ), PdCl ２ ), Pd(PPh ３ ), Pd ４ and Pd ２ (dba ３ ), and The copper catalyst is CuI, The method according to claim 7, characterized in that the inert gas is nitrogen gas, helium gas, neon gas or argon gas.

9. A pharmaceutical composition comprising the tricyclic compound according to any one of claims 1 to 5, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, for treating or preventing a GPR84-related disease selected from inflammatory diseases, lung diseases, neuroinflammatory diseases, infectious diseases, autoimmune diseases, endocrine diseases, and metabolic diseases.

11. The inflammatory disease is inflammatory bowel disease or vasculitis; and / or The lung disease is chronic obstructive pulmonary disease and / or interstitial lung disease; and / or The autoimmune disease is rheumatoid arthritis, characterized in that the pharmaceutical composition according to claim 10.

12. The pharmaceutical composition according to claim 11, characterized in that the interstitial lung disease is congenital pulmonary fibrosis or idiopathic pulmonary fibrosis.

13. Use of the tricyclic compound according to any one of claims 1 to 5, a tautomer, stereoisomer, hydrate, solvate, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament, pharmaceutical composition or formulation for acting as a GPR84 antagonist and / or for preventing and / or treating a GPR84-related disease.

14. The use according to claim 13, wherein the GPR84-related disease is selected from the group consisting of inflammatory diseases, lung diseases, neuroinflammatory diseases, infectious diseases, autoimmune diseases, endocrine diseases, and metabolic diseases.

15. The inflammatory disease is inflammatory bowel disease or vasculitis; and / or The lung disease is chronic obstructive pulmonary disease and / or interstitial lung disease; and / or The use according to claim 14, wherein the autoimmune disease is rheumatoid arthritis.

16. The use according to claim 15, wherein the interstitial lung disease is congenital pulmonary fibrosis or idiopathic pulmonary fibrosis.

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