Asymmetric GPR84 antagonists and their use

Abstract

Asymmetric GPR84 antagonist and its use, the structure of the GPR84 antagonist is represented by formula I. The compound of formula I has antagonistic activity of GPR84, can competitively inhibit the receptor activation effect of GPR84 agonist, and is useful for treating many diseases associated with high expression or excessive excitability of GPR84, such as multiple sclerosis, inflammatory bowel disease, organ fibrosis, arthritis, etc. [Formula 1] JPEG2024526350000045.jpg4145

Description

Technical Field

[0001] The present invention relates to ligand molecules of G protein-coupled receptor 84 (abbreviated as G protein-coupled receptor 84, GPR84). The ligand molecules according to the present invention have antagonist activity against GPR84 and can competitively suppress the receptor activation effect by GPR84 agonists, and are useful for the treatment of many diseases related to the high expression or excessive excitability of GPR84, such as multiple sclerosis, inflammatory bowel disease, organ fibrosis, arthritis and the like.

Background Art

[0002] GPR84 is a G protein-coupled receptor discovered in 2001 that is associated with the Gi pathway and is activated by medium-chain fatty acids (MCFAs) with chain lengths of C9-C14. When GPR84 is activated, adenylyl cyclase is suppressed, reducing cAMP production. GPR84 is expressed in many tissues or organs, such as the heart, lungs, kidneys, liver, bone marrow, and adipose tissue, and is particularly widely expressed in myelin cells associated with the innate immune system, including mononuclear cells, macrophages and neutrophils in peripheral blood, and microglia in the central nervous system. Under physiological conditions, GPR84 expression is low in leukocytes and adipocytes, but acute inflammatory stimuli (e.g., lipopolysaccharide LPS, TNFα, or inflammatory responses associated with many diseases) can induce significant upregulation of GPR84 expression. Activation of GPR84 enhances macrophage phagocytosis, promotes chemotaxis of immune cells, and increases the secretion of pro-inflammatory cytokines (IL-12 p40), thereby amplifying the inflammatory response in the body. On the other hand, knockout of GPR84 leads to a decrease in the secretion of pro-inflammatory cytokines (IL-1, IL-6, and TNF) in macrophages, while simultaneously increasing the secretion of Th2 cytokines (IL-4, IL-5, and IL-13) in T cells. The above studies demonstrated the pro-inflammatory effects of GPR84 on metabolic regulation and immune responses in the body. Subsequent studies revealed that GPR84 is involved in the development and progression of many inflammatory and metabolic diseases, including multiple sclerosis (MS, Glia 2007, 55, 790-800), inflammatory bowel disease (IBD, J. Med. Chem. 2020, 63, 13526-13545), organ fibrosis (J. Clin. Med. 2020, 9, 4, Am. J. Pathol. 2018, 188, 1132-1148), and arthritis (Curr. Opin. Clin. Nutr. Metab. Care 2011, 14, 322-327). Therefore, GPR84 is a potential target for the treatment of the above-mentioned diseases, and GPR84 antagonists are expected to be useful in treating these diseases.

[0003] To date, only patents for GPR84 antagonists from Galapagos (Belgium) and Liminal (Canada) have been reported. Galapagos' compounds have a tetrahydroisoquinopyrimidinone (or pyridinone) structural core (WO2013092791, WO2014095798, WO2015197550, WO2016169911), and a representative compound, GLPG1205, is a highly active GPR84-negative allosteric modulator (J. Med. Chem. 2020, 63, 13526-13545). It progressed to Phase II clinical trials as a candidate for the treatment of inflammatory bowel disease, but the trial was terminated because its therapeutic effect was not significantly different from that of the placebo group. The compound is currently undergoing a second Phase II clinical evaluation for the treatment of idiopathic pulmonary fibrosis. Liminal's PBI-4050 and PBI-4547 are non-selective GPR84 antagonists, structurally 3-n-pentylphenylacetate sodium and 3,5-di-n-pentylphenylacetate sodium, respectively. Both are lipid residue analogs with GPR84 antagonistic activity on the μmol scale and simultaneously agonist activity to both fatty acid receptors GPR40 and GPR120. PBI-4050 has already completed Phase II clinical trials for the treatment of idiopathic pulmonary fibrosis and is currently undergoing Phase II / III clinical studies for the treatment of Alstrom's disease. PBI-4547 is undergoing Phase I clinical studies as a drug candidate for non-alcoholic steatohepatitis.

[0004] Minami Hatsuyuki et al. reported a highly active GPR84 antagonist with a phosphate diester structure (WO2018161831), in which both ester groups have a tricyclic structure. The representative compound XYF573c showed a remarkable alleviating effect on the symptoms of enteritis in mice induced by DSS, and its therapeutic effect was better than that of sulfasalazine at the same dose. Furthermore, in tissue distribution studies, XYF573c was selectively distributed to the intestinal tract (AUC 0-8h = 24447.42 h*ng / mL, oral administration: 5 mg / kg), on the other hand, the exposure in peripheral blood is low (AUC 0-8hSince it was shown that XYF573c has an absorption rate of 666.53 h*ng / mL (oral administration: 5 mg / kg), it appears that XYF573c primarily acts on upregulated GPR84 in intestinal immune cells, thereby suppressing GPR84-mediated inflammatory responses and thus treating colitis. However, its distribution in peripheral blood suggests that it can also exert its effects by partially suppressing the migration of peripheral immune cells. While such GPR84 antagonists are suitable for treating inflammatory bowel disease due to their targeting of intestinal distribution, their use in treating diseases such as organ fibrosis, multiple sclerosis, and arthritis is limited due to poor oral absorption.

[0005] The oral absorption of a compound is closely related to its oil-water partition coefficient (e.g., CLogP, ALogP), and a compound with good drug-like properties needs a CLogP of less than 5 (Lipinski's rule of five). XYF573c has a CLogP of 6.419, indicating significant room for optimization. In the phosphate diester structure of the original GPR84 antagonist, both ester groups are strongly lipophilic tricyclic structures. Such symmetrical structural features limit the expansion of the compound's chemical space and pose a major obstacle to optimizing the compound's drug-like properties (e.g., CLogP, ALogP). [Overview of the project] [Problems that the invention aims to solve]

[0006] The object of the present invention is to provide a novel GPR84 antagonist, as well as a method for producing and using the same. [Means for solving the problem]

[0007] In a first aspect of the present invention, the present invention provides a compound represented by general formula (I), or its enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts thereof. [ka] (In the equation, Y is either O or S.) Z is the conjugate acid of a base such as H, or metal ions such as Li, Na, K, Ca, Mg, Cu, Fe, Zn, Al, Mn, or NH3, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, imidazole. L1 is none, O, S, -CH=CH-, CO, -C(=CH2)-, a substituted or unsubstituted C1-C6 alkylene group, -NH-, -N(C1-C4 alkyl group)-, a C3-C6 cycloalkyl group or a C3-C6 heterocycloalkyl group, and the substitution means having one or more substituents selected from the group consisting of a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen, and a hydroxy group. L2 is none, CH. Rings A and B are each independently a C6-C 10 aromatic ring, a C3-C 10 cycloalkane ring, a C3-C 10 heterocycloalkane ring, a C3-C 10 heteroaromatic ring. n1 and n2 are each independently 0, 1, 2, 3 or 4. R1 and R2 are each independently -OH, -SH, -NH2, F, Cl, Br, I, a substituted or unsubstituted -C r H 2r -L7-C [[ID=2I]] s H 2s+1 , -C r H 2r -N(C t ​​​​​​, a substituted or unsubstituted C1-C6 alkyl group, wherein the substitution means having one or more substituents selected from the group consisting of halogens, hydroxyl groups, amino groups, -COOC1-C6 alkyl groups, and -COOH. L7 is independently O, S, and NH, each r is independently 0, 1, 2, 3, 4, 5, or 6, each s is independently 0, 1, 2, 3, 4, 5, or 6, and each t is independently 1, 2, 3, 4, 5, or 6. L3 and L4 are independently O, none, and -O(C1~C 10 Alkylene group)-,-O(C1~C 10 Alkylene group) NH-, -O(C1~C 10 Alkylene group) O-, -CONH-, -OCO-, -NH-, -NHCOO-, -N(C1~C6 alkyl group)-, or C1~C 10 It is an alkylene group. R3 is H, OH, NH2, SH, -COOH, substituted or unsubstituted C1-C 10 Alkyl alkyl groups, substituted or unsubstituted C2-C 10 Alkenyl group, substituted or unsubstituted C2-C 10 Alkynyl group, substituted or unsubstituted 3-12 membered cycloalkane ring, substituted or unsubstituted C6-C 14 Aromatic rings, substituted or unsubstituted amino groups, substituted or unsubstituted 4-10 membered heterocycloalkane rings, substituted or unsubstituted 4-10 membered heteroaromatic rings, cholic acid, lithocholic acid, deoxycholic acid, isolithocholic acid, isodeoxycholic acid, genodeoxycholic acid, ursodeoxycholic acid, α-mulicoleic acid, β-mulicoleic acid, γ-mulicoleic acid, ω-mulicoleic acid, where the above substitutions refer to amino groups, C1-C1 10 Alkyl alkyl groups, halogens, C6-C 10 Aromatic ring, C1-C6 alkoxy group, 3-12 membered cycloalkane ring, -OC p H 2p -OC q H 2q+1 Nitro group, oxo (=O), hydroxyl group, carboxyl group, -C(O)OC1~C6 alkyl group, -O-C6~C 10It has 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of an aromatic ring, -NH-(4-10 membered heteroaromatic ring), and -NH-(4-10 membered heteroaromatic ring)-CONH2, where each p is independently 1, 2, 3, 4, 5, or 6, and each q is independently 1, 2, 3, 4, 5, or 6. each [ka] (Each represents either a single bond or a double bond.)

[0008] In another preferred example, rings A and B are independently a benzene ring, a C3-C6 cycloalkane ring, a C3-C6 heterocycloalkane ring, and a C3-C6 heteroaromatic ring, respectively. In another preferred example, rings A and B are independently a benzene ring, a thiophene ring, a pyrrole ring, a furan ring, a cyclohexane ring, a cyclopentane ring, or a cycloheptane ring.

[0009] In another preferred example, L1 is independently none, CH2, O, S, -CO-, -NH-, and L2 is independently none, CH. In another preferred example, n1 is 0, 1, or 2, and R1 is F, Cl, Br, I, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, or a trifluoromethoxy group.

[0010] In another preferred example, n2 is 0, 1, or 2, and R2 is F, Cl, Br, I, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, or a trifluoromethoxy group. In another suitable example, L3 is either O or S. In another preferred example, L4 is O, none, -NH-, -OCH2NH-, -OCH2CH2NH-, -OCH2CH2CH2NH-, -N(C1~C4 alkyl group)-, -CH2-, or -CH2CH2-.

[0011] In the present invention, for example, -O(C1~C 10 Alkylene group)-,-O(C1~C10 The linking modes of alkylene groups such as NH-, -CONH-, -OCO-, -NHCOO-, -OCH2NH-, -OCH2CH2NH-, and -OCH2CH2CH2NH- are not particularly restricted and can link from left to right or right to left with linked atoms or groups, for example, C, P, and R3. For example, P-L4-R3 represents P-CONH-R3 or R3-CONH-P when L4 is -CONH-. In another preferred example, if L4 is defined as the above group, the left end of the group is linked to P and the right end is linked to R3.

[0012] In another preferred example, R3 is C1-C with substitution or no substitution. 10 Alkyl alkyl groups, substituted or unsubstituted C2-C 10 Alkenyl group, substituted or unsubstituted C2-C 10 Alkynyl group, substituted or unsubstituted 3-12 membered cycloalkane ring, substituted or unsubstituted C6-C 14 Aromatic rings, substituted or unsubstituted amino groups, substituted or unsubstituted 4-10 membered heterocycloalkane rings, substituted or unsubstituted 4-10 membered heteroaromatic rings, cholic acid, lithocholic acid, deoxycholic acid, isolithocholic acid, isodeoxycholic acid, genodeoxycholic acid, ursodeoxycholic acid, α-mulicoleic acid, β-mulicoleic acid, γ-mulicoleic acid, ω-mulicoleic acid, where the above substitutions refer to amino groups, C1-C1 10 Alkyl alkyl groups, halogens, C6-C 10 Aromatic ring, C1-C6 alkoxy group, 3-12 membered cycloalkane ring, -OC p H 2p -OC q H 2q+1 The molecule has 1, 2, 3, 4, or 5 substituents selected from the group consisting of a nitro group, oxo (=O), hydroxyl group, carboxyl group, -COOC1~C6 alkyl group, and -O-benzene ring, where each p is independently 1, 2, or 3, and each q is independently 1, 2, or 3.

[0013] In another preferred example, the pharmaceutically acceptable salt is a salt obtained by the reaction of a compound having the structure represented by formula I with an inorganic base, and is selected from lithium salts, potassium salts, sodium salts, calcium salts, magnesium salts, copper salts, ferric salts, ferrous salts, zinc salts, aluminum salts, ammonium salts, dermanganese salts, and primorganese salts, or

[0014] The pharmaceutically acceptable salt is a salt obtained by the reaction of a compound having the structure represented by formula I with an organic base compound, and the organic base is selected from the group consisting of NH3, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and imidazole. In another preferred example, the compound is one of the compounds produced in the examples.

[0015] In a second aspect of the present invention, a method for producing the compound described in the first aspect, comprising the following steps, is provided: [ka]

[0016] Compounds of formula S1, S2, and S3 are used as starting materials and reacted to obtain a compound having the structure represented by formula P1. (However, the definitions of R1, R2, R3, L1, L2, L4, L5, Y, n1, n2, rings A and B are as described above.) L3 is O. Each X1 is independently a dimethylamino group, an ethylamino group, or a diisopropylamino group. X2 consists of a cyanoethyl group, an allyl group, a t-butyl group, and a benzyl group.

[0017] A third aspect of the present invention provides a method for producing the compound described in the first aspect, comprising the following steps: [ka]

[0018] Compounds of formula S1, S3, and S4 are used as starting materials and reacted to obtain a compound having the structure represented by formula P1. (However, the definitions of R1, R2, R3, L1, L2, L4, L5, Y, n1, n2, ring A, and B are as described above.) L3 is either O or CH2. Each X is independently F, Cl, Br, or I.

[0019] A fourth aspect of the present invention provides a method for producing the compound described in the first aspect, comprising the following steps: [ka]

[0020] Compounds of formula S1 and S5 are used as starting materials and reacted to obtain a compound having the structure represented by formula P1. (However, the definitions of R1, R2, R3, L1, L2, L4, L5, Y, n1, n2, rings A and B are as described above.) L3 is either O or CH2. Each X is independently F, Cl, Br, or I.

[0021] A fifth aspect of the present invention provides a drug composition comprising the following: Compounds represented by the general formula (I) described in the first aspect, or their enantiomers, diastereomers, racemates or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

[0022] A sixth aspect of the present invention provides the use of the compound described in the first aspect or its enantiomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof, or the drug composition described in the fifth aspect, as follows: (i) Use for the manufacture of GPR84 antagonists; (ii) Use as a GPR84 antagonist; (iii) Use for the manufacture of drugs to treat diseases associated with high expression or excessive excitability of the GPR84 receptor. In another preferred example, the disease is multiple sclerosis, inflammatory bowel disease, fibrosis, neurodegenerative disease, or arthritis.

[0023] A seventh aspect of the present invention provides a method for treating a disorder associated with high expression or excessive excitability of the GPR84 receptor, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein may be used in the methods of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0025] Of course, within the scope of the present invention, it is understood that the above-mentioned technical features of the present invention and the technical features specifically described below (for example, in the examples) can be combined to form new or preferred technical solutions. Due to space limitations, each will not be explained in detail here. [Brief explanation of the drawing]

[0026] [Figure 1] Figure 1 shows the tissue distribution of compounds XYF573c and LSX472a in ICR mice. [Modes for carrying out the invention]

[0027] The inventors of this application, through extensive and in-depth research, have developed a novel GPR84 antagonist with a structure in which one ester group of a phosphate diester is a tricyclic fragment, and the other ester group is a derivative of many structural types, such as a (cyclo)alkyl group or a substituted (cyclo)alkyl group, an aryl group or a substituted aryl group, or a cholic acid derivative. The compound of this application can competitively suppress the activation of the GPR84 receptor by GPR84 agonists and is useful in the production of drugs to treat diseases associated with high expression or excessive excitability of the GPR84 receptor, including multiple sclerosis, inflammatory bowel disease, fibrosis, and arthritis. Furthermore, this asymmetrical structural modification overcomes the structural characteristics of the original symmetric phosphate diester GPR84 antagonist, and by lowering the GLogP of the compound while maintaining GPR84 antagonistic activity, it has better oral absorption and organ distribution characteristics, which is advantageous in the development of drugs to treat diseases such as organ fibrosis, arthritis, multiple sclerosis, and inflammatory bowel disease. Based on this, the present invention was completed.

[0028] term In the present invention, C6~C 10 C3-C6 refers to a group containing 6 to 10 carbon atoms, while C3-C6 refers to a group containing 3 to 6 carbon atoms, and other terms are expressed similarly.

[0029] In this invention, unless otherwise specified, terms such as aromatic ring, cycloalkane ring, alkyl group, alkenyl group, and alkynyl group have the same meanings as those familiar to those skilled in the art. For example, an alkyl group is a saturated linear or branched hydrocarbon group, such as -CH3 or -CH(CH3)2. An alkylene group is the portion remaining after two monovalent hydrogens have been removed from a saturated hydrocarbon group, and includes, but is not limited to, a methylene group (-CH2-) and an ethylene group (-CH2CH2-). An alkoxy group is -O-(alkyl group), and includes, but is not limited to, -OCH3 and -OCH2CH3. A cycloalkane ring and cycloalkyl group are saturated cyclic hydrocarbon groups, such as a cyclohexyl group. A heterocycloalkyl group and heterocycloalkane ring are saturated cyclic hydrocarbon groups containing at least one (for example, 1, 2, 3, or 45) heteroatoms (selected from N, O, or S). A heteroaromatic ring or heteroaryl group is a saturated aromatic ring containing at least one heteroatom (for example, 1, 2, 3, or 4).

[0030] Unless otherwise stated, the aromatic rings, heteroaromatic rings, cycloalkane rings, alkyl groups, alkylene groups, alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, etc., described herein include both substituted and unsubstituted forms, and possible substituents are C1-C1. 10 Alkyl alkyl groups, C2-C 10 Alkenyl group, C2-C 10 Alkynyl group, C3-C 20 Cycloalkyl groups, C3-C 20 Cycloalkenyl group, C1-C 20 Heterocycloalkyl groups, C1-C 20 Heterocycloalkenyl group, C1-C 20 This includes, but is not limited to, alkoxy groups, aryl groups, allyloxy groups, heteroaryl groups, heteroallyloxy groups, amino groups, hydroxyl groups, halogens, mercapto groups, cyano groups, nitro groups, carboxyl groups, and carboxylic acid ester groups.

[0031] GPR84 antagonist The GPR84 antagonist provided by the present invention is a compound having the structure of formula I shown above. The present invention also provides pharmaceutically acceptable salts thereof, including salts obtained by the reaction of a compound of formula I with an inorganic base or an organic base compound. Salts obtained from inorganic bases include, but are not limited to, aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, and zinc salts. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts obtained from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cycloamines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, imidazole, and others.

[0032] The main advantages of this invention are as follows: The inventors have developed a novel GPR84 antagonist in which one ester group of the phosphate diester is a tricyclic fragment, and the other ester group is a derivative of many structural types, such as a (cyclo)alkyl group or a substituted (cyclo)alkyl group, an aryl group or a substituted aryl group, or a cholic acid derivative. Such modifications are beneficial for expanding the chemical space of GPR84 antagonists and are beneficial for the treatment of GPR84-related diseases because they have better oral absorption and organ distribution characteristics by lowering GLogP.

[0033] As described above, the compounds provided by the present invention have better oral absorption and more specific target tissue distribution characteristics while suitably maintaining the antagonistic activity of GPR84, thus offering further potential for development.

[0034] Manufacturing method Compound I can be realized by any of the following schemes 1 to 5. Scheme 1: [ka]

[0035] The first step of the reaction is carried out in dichloromethane or acetonitrile. The activating reagents used are 4,5-dicyanoimidazole, diisopropylammonium tetrazolide, or N-methylimidazole. The reaction temperature is 20°C to 60°C, and the reaction time is approximately 1 to 24 hours. After the reaction is complete, the mixture is neutralized with saturated NaHCO3 or Na2CO3 solution, extracted with solvents such as AcOEt, Et2O, CH2Cl2, or CHCl3, and the concentrate is purified by column chromatography. The second step of the reaction is carried out in dichloromethane or N,N-dimethylformamide, with tetrazole as the activating agent, and the reaction time is approximately 1 to 24 hours. Further oxidation is performed by adding an oxidizing agent, which is t-butyl hydroperoxide or m-chloroperbenzoic acid, and the reaction time is approximately 0.3 to 2 hours. Quenching is performed with saturated Na2SO3, and the mixture is extracted with solvents such as AcOEt, Et2O, CH2Cl2, or CHCl3. The concentrate is then purified by column chromatography. The third step of the reaction is carried out in dichloromethane, and the conditions used by protecting group X2 are catalytic hydrogenation or base catalysis. The catalyst used for catalytic hydrogenation is Pd / C or Pd(OH)2 / C and hydrogen gas at atmospheric pressure, and the base used for base catalysis is triethylamine or 1,8-diazabicycloundecene-7 (DBU). The reaction time is approximately 0.3 to 1 hour. After the reaction is complete, insoluble matter is removed by filtration, neutralized with dilute hydrochloric acid, extracted with solvents such as AcOEt, Et2O, CH2Cl2, and CHCl3, and the concentrate is subjected to column chromatography to obtain the desired product, which is then confirmed by means of NMR or other methods. (However, the definitions of R1, R2, R3, L1, L2, L4, L5, Y, n1, n2, ring A, and B are as described above. L3 is O, each X1 is independently a dimethylamino group, an ethylamino group, or a diisopropylamino group, and X2 is a cyanoethyl group, an allyl group, a t-butyl group, or a benzyl group.)

[0036] Scheme 2: [ka]

[0037] The reaction is carried out in pyridine. The reaction temperature is 60°C to 100°C, and the reaction time is approximately 1 to 24 hours. After the reaction is complete, the mixture is cooled to room temperature, S3 is added, and the reaction is carried out at 60°C to 100°C for 1 to 24 hours. After the reaction is complete, water is added to quench the reaction, and the mixture is extracted with solvents such as AcOEt, Et2O, CH2Cl2, and CHCl3. The concentrate is purified by column chromatography to obtain the desired product, and the obtained product is confirmed by means of NMR or other methods. (However, the definitions of R1, R2, R3, L1, L2, L4, L5, Y, n1, n2, ring A, and B are as described above. L3 is O, S, NH or CH2, and each X is independently F, Cl, Br or I.)

[0038] Scheme 3: [ka]

[0039] The reaction is carried out with pyridine. The reaction temperature is 60°C to 100°C. The reaction time is approximately 1 to 24 hours. After the reaction is complete, the mixture is quenched with H2O, extracted with solvents such as AcOEt, Et2O, CH2Cl2, and CHCl3, washed with saturated brine, dried, and the solvent is removed under low temperature and reduced pressure. The concentrate is subjected to column chromatography to obtain the target product, which is then confirmed by means of NMR or other methods. (However, the definitions of R1, R2, R3, L1, L2, L4, L5, Y, n1, n2, rings A and B are as described above. L3 is either O or CH2, and each X is independently F, Cl, Br, or I.)

[0040] Scheme 4: [ka]

[0041] The raw material P1 is dissolved in ethyl acetate, washed twice with an aqueous solution of a base (conjugate base of M, hydroxide of M, or carbonate compound of M), the aqueous layer is back-extracted with ethyl acetate, the ethyl acetate layer is concentrated, and the crude product is subjected to silica gel column chromatography to obtain product P2.

[0042] M is a metal cation ion such as Li, Na, K, Ca, Mg, Cu, Fe, Zn, Al, Mn, or a conjugate acid of a base such as NH3, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, or imidazole. (However, the definitions of R1, R2, R3, L1, L2, L4, L5, Y, n1, n2, rings A and B are as described above.) L3 is either O or CH2.

[0043] Scheme 5: [ka]

[0044] The reaction is carried out in N,N-dimethylformamide (DMF), with 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and dimethylaminopyridine (DMAP) as activating reagents, and triethylamine or N,N-diisopropylethylamine as the base. The reaction takes place at room temperature for approximately 6 to 24 hours. After the reaction is complete, the solvent is removed under low temperature and reduced pressure, extracted with ethyl acetate, the aqueous phase is back-extracted three times, washed with saturated brine, and the organic phase is concentrated. The desired product is then obtained by column chromatography, and the obtained product is confirmed by means of NMR or other methods.

[0045] (However, the definitions of R1, R2, R3, R4, L1, L2, L4, Y, n1, n2, rings A and B are as described above.) L5 is not independently available, -(CH2) m -,-(CH2)m -CH=CH-, -(CH2) m -C≡C-, -(C2H4O) m -,-(CH2) m -NH-, -(CH2) m The time is -O-, and each m is an independent integer between 0 and 10. R4 is C1-C with substitution or no substitution. 10 Alkyl, substituted or unsubstituted C6-C 10 Aromatic ring, C3~C 10 Cycloalkane ring, C3~C 10 Heterocycloalkane ring, C3~C 10 The heteroaromatic rings, cholic acid, lithocholic acid, deoxycholic acid, isolithocholic acid, isodeoxycholic acid, genodeoxycholic acid, ursodeoxycholic acid, α-mulicoleic acid, β-mulicoleic acid, γ-mulicoleic acid, and ω-mulicoleic acid are examples of the above substitutions, which are defined as having one or more substituents selected from the group consisting of C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, and hydroxyl groups. L3 is either O or CH2.

[0046] Purpose Compound I, as an antagonist of GPR84, can competitively suppress the activation of the GPR84 receptor by a GPR84 agonist and is useful in the manufacture of drugs to treat diseases associated with high expression or excessive excitability of GPR84, including multiple sclerosis, inflammatory bowel disease, organ fibrosis, and arthritis.

[0047] Drug composition The drug composition of the present invention contains a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0048] "Medicinal carrier," "pharmaceutically acceptable carrier," or "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gel substances that are applicable to humans and must be of sufficient purity and sufficiently low toxicity. "Compatible" means that each component in the composition can be compounded with and among itself the active ingredient of the present invention (compound of formula I or a pharmaceutically acceptable salt thereof) without significantly reducing the effect of the active ingredient. Examples of medicinal carrier portions include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., twinol). R These include humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and distilled water from which pyrogenic substances have been removed.

[0049] The compounds and drug compositions of the present invention may take various forms, for example, they may be administered orally in the form of capsules, tablets, granules, solutions, powders, or syrups, or parenterally in the form of injections. The compounds and drug compositions of the present invention may be present in a suitable solid or liquid carrier, or in a suitable disinfectant device for injection or infusion. The above formulations can be manufactured by conventional pharmaceutical methods.

[0050] The compounds and pharmaceutical compositions of the present invention can be used for clinical use in mammals, including humans and animals, and can be administered via routes such as the mouth, nose, or gastrointestinal tract. The most preferred route of administration is oral administration.

[0051] The features described in this invention, or the features described in the examples, can be combined in any way. All features disclosed in this description can be used in combination with any form of composition, and each feature disclosed in the description can be replaced with any homologous, equivalent, or similar substitute feature for the purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0052] The present invention will be further described below with reference to specific examples. These examples are used solely to illustrate the present invention and are not intended to limit its scope. Experimental methods in the following examples where specific conditions are not given will generally follow standard conditions, such as those described in Sambrook et al., "Molecular Cloning: A Laboratory Manual" (New York, Cold Spring Harbor Laboratory Press, 1989), or the manufacturer's recommended conditions. Unless otherwise specified, percentages and parts refer to weight percentages and parts by weight.

[0053] In the following examples, NMR was measured using a Bruker AVANCE III 400M instrument, and the NMR calibration was δH 7.26 ppm (CDCl3), 2.50 ppm (DMSO-d6), and 3.15 ppm (CD3OD). Reagents were mainly supplied by Shanghai Chemical Reagents Co., Ltd. The TLC thin-layer chromatography silica gel plates were produced by Shandong Yantai Huiyou Silica Gel Development Co., Ltd., model number HSGF 254, and the silica gel for normal-phase column chromatography used for compound purification was produced by Shandong Qingdao Marine Chemical Co., Ltd. Branch, model number zcx-11, with a mesh size of 200-300.

[0054] Example 1 Manufacturing of compound LSX448 [ka]

[0055] Synthesis of intermediate G1M. Starting material G1 (200 mg, 0.78 mmol) and 4,5-dicyanoimidazole (184 mg, 1.56 mmol) were dissolved in dry dichloromethane. Bis(diisopropylamino)(2-cyanoethoxy)phosphine (0.495 ml, 1.56 mmol) was added dropwise under the protection of argon gas at 20°C, and the reaction was carried out for 5 hours at 20°C. Saturated NaHCO3 was added to adjust the pH to 7, the mixture was concentrated, extracted with dichloromethane, the aqueous phase was back-extracted three times, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (PE:AcOEt = 15:1~10:1) to obtain intermediate G1M (280 mg, 78%, colorless liquid). [ka]

[0056] Synthesis of compound LSX448. Intermediate G1M is dissolved in dry dichloromethane, tetrazole (43 mg, 0.63 mmol) and G2 (0.097 ml, 0.63 mmol) are added, and the mixture is reacted for 4 hours. Then t-butyl hydroperoxide (70% aqueous solution) (0.094 ml, 0.63 mmol) is added, and the mixture is reacted for 1 hour. The mixture is neutralized with saturated sodium sulfite solution, extracted with ethyl acetate, the aqueous phase is back-extracted three times, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (PE:AcOEt = 10:1~2:1) to obtain intermediate G1N. This is redissolved in dry dichloromethane, 1,8-diazabicycloundecene-7 (0.094 ml, 0.63 mmol) is added, and the mixture is reacted for 30 minutes to obtain a 1 mol / L solution. The pH was adjusted to 7 by adding HCl, and the solution was extracted with ethyl acetate. The aqueous phase was back-extracted three times, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (DCM:MeOH = 15:1~10:1). The solvent was removed by rotary drying to obtain the target compound LSX448 (35 mg, 10%, white solid). 1H NMR (d6-DMSO, 400 MHz): δ 7.46 (d, J = 7.2 Hz, 1H), 7.31-7.20 (m, 6H), 7.08 (d, J = 7.2 Hz, 1H), 3.87 (m, 2H), 3.83(s, 3H), 1.45(m, 2H), 1.24-1.14(m, 10H), 0.78(t, J = 7.6 Hz, 3H).

[0057] The following compounds were synthesized using a similar method. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0058] Example 2 Manufacturing of compound LSX442 [ka]

[0059] Starting material G1 (200 mg, 0.78 mmol) was dissolved in dried pyridine (5 mL), and redistilled POCl3 (0.078 mL, 0.86 mmol) was added dropwise under the protection of argon gas. The reaction was carried out overnight at 80°C. The next day, after cooling to room temperature, G3 (290 mg, 2.34 mmol) was added dropwise to the reaction system. After completion, the reaction system was heated to 80°C and the reaction was carried out for 6 hours. After returning to room temperature, water was added for quenching, and 1 mol / L hydrochloric acid was added to adjust the pH to 7. Extraction was performed with ethyl acetate, and the aqueous phase was back-extracted three times. Washing was done with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (DCM:MeOH = 15:1~10:1). The solvent was removed by rotary drying to obtain the target compound LSX442 (40 mg, 12%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 7.2 Hz, 1H), 7.29-7.04 (m, 9H), 6.78 (d, J = 8.4 Hz, 2H), 3.83(s, 3H), 3.67(s, 3H).

[0060] The following compounds were synthesized using a similar method. [Table 2]

[0061] Example 3 Manufacturing of compound LSX432 [ka] Starting material G1 (200 mg, 0.78 mmol) was dissolved in dried pyridine (5 mL), and G5 (0.480 mL, 2.34 mmol) was added dropwise under the protection of argon gas. The mixture was reacted overnight at 80°C, returned to room temperature, quenched with water, and the pH was adjusted to 7 with 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate, the aqueous phase was back-extracted three times, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (DCM:MeOH = 15:1~10:1). The solvent was removed by rotary drying to obtain the target compound LSX432 (120 mg, 35%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 7.2 Hz, 1H), 7.39 - 7.10 (m, 6H), 7.05 (d, J = 7.2 Hz, 1H), 3.83 (s, 3H), 1.49 - 1.35 (m, 4H), 1.30 - 1.03 (m, 10H), 0.89 - 0.79 (m, 3H).

[0062] Example 4 Manufacturing of compound LSX419 [ka] Intermediate G1M (368 mg, 0.78 mmol) is dissolved in dry dichloromethane, t-butyl hydroperoxide (70% aqueous solution) (0.094 ml, 0.63 mmol) is added, and the mixture is reacted for 1 hour. The mixture is neutralized with saturated sodium sulfite solution, extracted with ethyl acetate, the aqueous phase is back-extracted three times, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (PE:AcOEt = 10:1~2:1) to obtain intermediate G1N. This is dissolved in dry dichloromethane, 1,8-diazabicycloundecene-7 (0.094 ml, 0.63 mmol) is added, and the mixture is reacted for 30 minutes. 1 mol / L HCl is added to adjust the pH to 7, extracted with ethyl acetate, the aqueous phase is back-extracted three times, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (DCM:MeOH = The solvent was removed by rotary drying (15:1 to 10:1) to obtain the target compound LSX419 (120 mg, 18%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 7.2 Hz, 1H), 7.38 - 7.24 (m, 5H), 7.20 (dd, J = 7.2, 1.2 Hz, 1H), 7.13 (dd, J = 7.2, 1.2 Hz, 1H), 3.85 (s, 3H), 3.44 (dp, J = 20.0, 6.8 Hz, 2H), 1.15 (d, J = 6.8 Hz, 12H).

[0063] Example 5 Manufacturing of compound LSX784 [ka]

[0064] Intermediate G1M (920 mg, 0.78 mmol) is dissolved in dry dichloromethane, tetrazole (107 mg, 1.575 mmol) and G6 (0.242 ml, 1.575 mmol) are added, and the mixture is reacted for 4 hours. Then t-butyl hydroperoxide (70% aqueous solution) (0.235 ml, 1.575 mmol) is added, and the mixture is reacted for 1 hour. The mixture is neutralized with saturated sodium sulfite solution, extracted with ethyl acetate, the aqueous phase is back-extracted three times, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (PE:AcOEt = 10:1~2:1) to obtain the intermediate. This intermediate is dissolved in dry dichloromethane, 1,8-diazabicycloundecene-7 (0.235 ml, 1.575 mmol) is added, and the mixture is reacted for 30 minutes to obtain a 1 mol / L solution. The pH was adjusted to 7 by adding HCl, and the solution was extracted with ethyl acetate. The aqueous phase was back-extracted three times, washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated, and subjected to silica gel chromatography (DCM:MeOH = 15:1~10:1). The solvent was removed by rotary drying to obtain an intermediate, which was dissolved in an ethyl acetate solution of hydrogen chloride. The reaction was carried out at room temperature for 2 hours, after which the solvent was removed under low temperature and reduced pressure. After vacuum drying, cholic acid (122 mg, 0.298 mmol), EDCI (86 mg, 0.448 mmol), and DMAP (109 mg, 0.892 mmol) were added, and N,N-dimethylformamide and triethylamine were used as solvents. The reaction was carried out at room temperature for 2 days, after which the solvent was removed under reduced pressure. After concentration, the solution was subjected to silica gel chromatography (DCM:MeOH:AcOH = 10:1:0.1~5:1:0.1) to obtain LSX784 (16 mg, 1.05%, white solid). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 7.6 Hz, 1H), 7.38 - 7.17 (m, 6H), 7.13 - 7.06 (m, 1H), 4.31 (d, J = 4.4 Hz, 1H), 4.16 - 4.06 (m, 1H), 4.00 (d, J = 3.2 Hz, 1H), 3.94 - 3.80 (m, 5H), 3.80 - 3.74 (m, 1H), 3.67 - 3.55 (m, 1H), 3.09 (q, J = 6.8 Hz, 2H), 2.28 - 2.06 (m, 2H), 2.07 - 1.91 (m, 1H), 1.86 - 1.70 (m, 4H), 1.72 - 1.57 (m, 4H), 1.49 - 1.09 (m, 15H), 1.04 - 0.77 (m, 12H), 0.59 (s, 3H).

[0065] Example 6 (1) Experimental Objectives The antagonistic activity of the compound of the present invention was tested for GPR84. (2) Origin of materials Human-derived GPR84 cell lines were obtained by transduction of HEK293 cell lines with plasmids encoding GPR84 and Gα16 proteins. The fluorescent dye Fluo-4 AM was purchased from Invitrogen.

[0066] (3) Principles of testing Within the cell, 2+ Ions are second messengers in the G protein-coupled receptor signaling pathway, and Gα 16 When GPR84, coupled to a protein, binds to the agonist, it triggers a reaction in the cell involving Ca 2+ The ion concentration increases significantly. Fluo-4 is Ca 2+ A fluorescent probe specific to ions, Ca 2+ It can quantitatively bind to ions and emit fluorescence. Therefore, fluorescence detection methods are used to detect the activating or antagonistic activity of compounds in 96-well or 384-well flat-bottom microplates.

[0067] Detection of the inhibitory effect of GPR84 antagonists on the receptor: GPR84 cells were incubated with the fluorescent dye Fluo-4, then antagonist compounds were added at different concentrations and incubated for a set period of time to allow the agonist to establish a binding site with GPR84 (antagonistic binding site). Subsequently, a fixed concentration of agonist (6-n-octylaminouracil, 6-n-octylaminouracil, 6-OAU) was added to create competition for the binding site with the antagonist compound. Simultaneously, the cells were excited with a light source at a wavelength of 485 nm, and the change in the fluorescence intensity of the dye due to changes in intracellular calcium ion concentration was detected at a wavelength of 525 nm. The median inhibitory concentration (IC) of the compound was then measured using GraphPad PRISM software. 50 ) was calculated.

[0068] (4) The experimental process Preparation of HBSS: 0.4 g / L KCl (5.4 mM), 0.12 g / L Na2HPO412H2O (0.3 mM), 0.06 g / L KH2PO4 (0.4 mM), 0.35 g / L NaHCO3 (4.2 mM), 0.14 g / L CaCl2 (1.3 mM), 0.10 g / L MgCl26H2O (0.5 mM), 0.05 g / L MgSO4 (0.6 mM), and 8.0 g / L NaCl (137 mM). Each of the above components was weighed out, dissolved in ultrapure water, and the pH was adjusted to 7.4 with hydrochloric acid or NaOH solution. The solution was filtered and stored at 4°C for 1 month.

[0069] Preparation of calcium-fluid buffer: First, a 560 mM D-glucose (100×) stock aqueous solution and a 250 mM 1,2-diphenyl-4-(2-phenylsulfinyl)ethyl-3,5-pyrazolidinedione (1000×) stock solution were prepared. Furthermore, 0.5 g of BSA, 1 mL of 560 mM D-glucose stock solution, and 100 μL of 250 mM 1,2-diphenyl-4-(2-phenylsulfinyl)ethyl-3,5-pyrazolidinedione stock solution were added to 100 mL of HBSS, and the final concentrations were 0.5% BSA, 5.6 mM D-glucose, and 250 μM 1,2-diphenyl-4-(2-phenylsulfinyl)ethyl-3,5-pyrazolidinedione, respectively. The solutions were then homogeneously mixed and prepared immediately before use.

[0070] Dye preparation: A 1 μL solution of 2 mM Fluo-4 AM (1000X, purchased from Invitrogen) in DMSO and a 10 μL solution of 3% Cremophor EL (100X, purchased from Sigma-Aldrich) in PBS were mixed, and then 1 mL of calcium aqueous solution was added and mixed uniformly.

[0071] Cells 4 × 10 4 The samples were inoculated into a 96-well plate at a density of cells / well and incubated for 24 hours. After discarding the culture medium, 40 μL of Fluo-4 AM fluorescent stain was added to each well and incubated in a 37°C incubator for 40 minutes. After aspirating the dye, 50 μL of the test compound was added and incubated at room temperature for 10 minutes. Then, 25 μL of 6-OAU (the effective concentration after dilution was the EC of the agonist) was measured using a Flex Station III microplate reader. 80 We stimulated the cell by inserting a sample (in the vicinity) and read the change in Fluo-4 AM dye fluorescence intensity in real time due to the change in intracellular calcium ion flow (excitation wavelength 485 nm, detection wavelength 525 nm).

[0072] (5) Experimental results [Table 3-1] [Table 3-2] [Table 3-3]

[0073] a I C 50 : * 1 - 10 μM;** 0.1 - 1 μM;*** < 0.1 μM b The CLogP values ​​were calculated using CambridgeSoft's ChemBioDraw software (version Ultra 12.0). All structures used in the calculation represent the free acid form of the compounds. c ALogP values ​​were calculated using Schrodinger's Maestro software (version 11.2). All compounds were calculated in their ionized state at pH = 7. Among them, compound LSX431 shows significant differences between ALogP and CLogP data due to the protonation of the nitrogen atom of the phosphamide.

[0074] (6)Result analysis From the results in Table 1, the compound of the present invention is IC 50 The values ​​were all less than 10 μM, and the IC5 of some compounds 50 The IC of some compounds is between 0.1 and 1 μM. 50 Although the value was low, less than 100 nM, the compound of the present invention was shown to be useful as a GPR84 antagonist. Furthermore, the existing compound XYF573c(IC) 50 Compared to XYF573c (= 26.2 nM, CLogP = 6.419, ALogP = 6.80), among the compounds, 30 compounds had CLogP between 5 and 6, 37 compounds had CLogP < 5, 47 compounds had ALogP between 5 and 6, and 26 compounds had ALogP < 5, all of which were significantly lower than the CLogP and ALogP of XYF573c.

[0075] Example 7 (1) Experimental Objectives Tissue distribution experiments were conducted in ICR mice to determine the distribution of the compounds XYF573c and LSX472a of the present invention in plasma and organs, and to assess oral exposure levels (AUC). 0-8h ) were compared. (2) Origin of materials The ICR mice were purchased from the Shanghai Municipal Research Center for Experimental Animals. (3) Principles of testing The concentrations of the compound in the plasma and organs of ICR mice were detected by LC-MS.

[0076] (4) The experimental process The mice were fasted for more than 12 hours during the experiment, allowed to drink water freely, and were given food 2 hours after administration. Compounds XYF573c and LSX472a were both administered orally at a dose of 5 mg / kg, with the solvent being DMSO / 0.5% HPMC = 5 / 95, v / v, and N = 3.

[0077] Approximately 20 μL of mouse cardiac blood, portal vein plasma, or 20 mg of liver, lung, and ileum tissue were taken into a clean centrifuge tube 0.5 h, 2 h, and 8 h after oral administration, respectively. 200 μL of MeOH / ACN (50 / 50, v / v) was added, and the mixture was vortexed in a vortex mixer for 1 minute. The mixture was then centrifuged at 15000 rpm for 5 minutes, and 20 μL of the supernatant was taken and mixed with 20 μL of ACN / water (1 / 1, v / v), and quantitative analysis was performed by LC-MS. AUC 0-8h The values ​​were calculated using the trapezoidal method from the concentrations of the compound at 0.5h, 2h, and 8h.

[0078] (5) Experimental results A decrease in cLogP is crucial for the oral absorption of compounds. The compound LSX472a of the present invention had a cLogP of 5.51, which was 0.9 lower than that of XYF573c. Such a change is related to the oral exposure (Plasma AUC) of LSX472a. 0-8hThe results showed a 13-fold improvement compared to XYF573c (Figure 1 and Table 1). Furthermore, LSX472a clearly increased exposure in the intestinal tract (e.g., ileum) compared to XYF573c. Therefore, the development of the structure of the GPR84 antagonist of the present invention improves the drug-like properties of such compounds, increases oral absorption, and is also advantageous for improving the target tissue distribution of the compounds. [Table 4]

[0079] All documents relating to the present invention are cited herein by reference, so that each document may be cited independently. Furthermore, after reading the above, those skilled in the art will understand that various variations and modifications of the present invention may be made, and that equivalent forms thereof are included within the scope of the claims of the present invention.

Claims

1. A compound represented by general formula (I), or its enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, Y is either O or S.) Z is H, a metal ion, or a conjugate acid of a base, where the metal is selected from the group consisting of Li, Na, K, Ca, Mg, Cu, Fe, Zn, Al, and Mn, and the base is NH ３ Selected from the group consisting of arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and imidazole. L １ is O or S, L ２ is CH, Rings A and B are C ６ ~C １０ It is an aromatic ring, n1 and n2 are each independently 0, 1, 2, 3 or 4, and R １ , R ２ are each independently F, Cl, Br, I, a substituted or unsubstituted -L ７ -C ｓ H ２ｓ＋１ , or a substituted or unsubstituted C １ -C ６ alkyl group, and the above substitution means having one or more substituents selected from the group consisting of halogen, a hydroxy group, an amino group, a -COOC １ -C ６ alkyl group, and -COOH. L ７ is either O or S, and s is independently 1, 2, 3, 4, 5, or 6. L ３ is O, L ４ O, none, -O(C) １ ~C １０ Alkylene group) -, -O(C) １ ~C １０ Alkylene group) NH-, -O(C １ ~C １０ Alkylene group) O-, -NH-, or C １ ~C １０ It is an alkylene group. R ３ C is either substituted or unsubstituted. １ ~C １０ Alkyl, substituted, or unsubstituted C ２ ~C １０ Alkenyl group, substituted or unsubstituted C ２ ~C １０ Alkynyl group, substituted or unsubstituted 3-12 membered cycloalkane ring, substituted or unsubstituted C ６ ~C １４ Aromatic rings, substituted or unsubstituted amino groups, substituted or unsubstituted 4-10 membered heterocycloalkane rings, substituted or unsubstituted 4-10 membered heteroaromatic rings, cholic acid, lithocholic acid, deoxycholic acid, isolithocholic acid, isodeoxycholic acid, genodeoxycholic acid, ursodeoxycholic acid, α-mulicoleic acid, β-mulicoleic acid, γ-mulicoleic acid, ω-mulicoleic acid, where the above substitutions refer to amino groups, C １ ~C １０ Alkyl alkyl groups, halogens, C ６ ~C １０ aromatic ring, C １ ~C ６ Alkoxy group, 3-12 membered cycloalkane ring, -O-C ｐ H ２ｐ -O-C ｑ H ２ｑ＋１ Nitro group, =O, hydroxyl group, carboxyl group, -C(O)OC １ ~C ６ Alkyl alkyl group, -O-C ６ ~C １０ Aromatic ring, -NH- (4-10 member heteroaromatic ring), -NH- (4-10 member heteroaromatic ring)-CONH ２ It has one, two, three, four, five, or six substituents selected from the group consisting of the following, where p is independently one, two, three, four, five, or six, and q is independently one, two, three, four, five, or six.

2. L １ is O, L ２ CH is The compound according to feature 1.

3. R ３ C1 to C are either substituted or unsubstituted. １０ Alkyl, substituted, or unsubstituted C ２ ~C １０ Alkenyl group, substituted or unsubstituted C ２ ~C １０ Alkynyl group, substituted or unsubstituted 3-12 membered cycloalkane ring, substituted or unsubstituted C ６ ~C １４ Aromatic rings, substituted or unsubstituted amino groups, substituted or unsubstituted 4-10 membered heterocycloalkane rings, substituted or unsubstituted 4-10 membered heteroaromatic rings, cholic acid, lithocholic acid, deoxycholic acid, isolithocholic acid, isodeoxycholic acid, genodeoxycholic acid, ursodeoxycholic acid, α-mulicoleic acid, β-mulicoleic acid, γ-mulicoleic acid, ω-mulicoleic acid, where the above substitutions refer to amino groups, C １ ~C １０ Alkyl alkyl groups, halogens, C ６ ~C １０ aromatic ring, C １ ~C ６ Alkoxy group, 3-12 membered cycloalkane ring, -O-C ｐ H ２ｐ -O-C ｑ H ２ｑ＋１ Nitro group, =O, hydroxyl group, carboxyl group, -COOC １ ~C ６ The compound according to claim 2, characterized in that it has 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl groups and -O-benzene rings, where p is independently 1, 2, or 3 and q is independently 1, 2, or 3.

4. The compound according to claim 1, characterized in that the compound is selected from the following group. 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】

5. A method for producing the compound described in claim 1, wherein the compound has a structure represented by formula P1, and the method comprises the following steps: 【Transformation 7】 Compounds of formula S1, S2, and S3 are used as starting materials and reacted to obtain a compound having the structure represented by formula P1. (However, R １ , R ２ , R ３ , L １ , L ２ , L ４ The definitions of Y, n1, n2, ring A, and ring B are as described above. L ３ The answer is O. Each X １ These are independently a dimethylamino group, an ethylamino group, and a diisopropylamino group. X ２ These are cyanoethyl, allyl, t-butyl, and benzyl groups.

6. A method for producing the compound described in claim 1, wherein the compound has a structure represented by formula P1, and the method comprises the following steps: 【Transformation 8】 Compounds of formula S1, S3, and S4 are used as starting materials and reacted to obtain a compound having the structure represented by formula P1. (However, R １ , R ２ , R ３ , L １ , L ２ , L ４ The definitions of Y, n1, n2, ring A, and ring B are as described above. L ３ The answer is O. Each X is independently F, Cl, Br, or I.

7. A method for producing the compound described in claim 1, wherein the compound has a structure represented by formula P1, and the method comprises the following steps: 【Chemistry 9】 Compounds of formula S1 and S5 are used as raw materials and reacted to obtain a compound having the structure represented by formula P1. (However, the definitions of R １ , R ２ , R ３ , L １ , L ２ , L ４ , Y, n1, n2, ring A, and ring B are as defined above.) L ３ The answer is O. Each X is independently F, Cl, Br, or I.

8. A drug composition characterized by comprising the following: A compound represented by general formula (I) as described in claim 1, or its enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof; and A pharmaceutically acceptable carrier.

9. Uses of a compound represented by general formula (I) as described in claim 1, or its enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that they are used for the following purposes. (i) Use for the manufacture of GPR84 antagonists; or (ii) Use for the manufacture of drugs to treat diseases associated with high expression or excessive excitability of the GPR84 receptor.

10. The use according to claim 9, characterized in that the disease is multiple sclerosis, inflammatory bowel disease, fibrosis, neurodegenerative disease, or arthritis.

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