Polysubstituted amino / heterocycle-substituted benzothiazole compounds and uses

Abstract

This invention relates to polysubstituted amino / heterocyclic substituted benzothiazole compounds and their uses. Specifically, the compounds of this invention have the structure shown in Formula I, wherein the definitions of each group and substituent are as described in the specification. This invention also discloses methods for preparing the compounds and their uses in the prevention and / or treatment of GPR183-related diseases.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically to benzothiazole compounds with multiple substituted amino / heterocyclic substitutions and their uses. Background Technology

[0002] G protein-coupled receptor 183 (GPR183), also known as Epstein-Barr virus-induced gene 2 (EBI2), was first identified in 1993 as a lymphocyte-specific GPCR highly expressed in EBV-infected cells. In 2011, GPR183 was deorphaned after two simultaneously published papers revealed that hydroxycholesterol (oxysterol) is an endogenous agonist of GPR183, with 7α,25-dihydroxycholesterol (7α,25-OHC) being the most potent endogenous ligand. Subsequently, GPR183 was identified as a chemokine receptor, with 7α,25-dihydroxycholesterol being a potent endogenous ligand. This finding is closely related to the observation that high expression of GPR183 in leukocytes and its differential expression are crucial for the accurate localization of B cells in lymphoid organs. The pharmacological significance of GPR183 as a target stems from its role and that of its endogenous ligands in various diseases, such as B-cell malignancies, inflammatory / autoimmune diseases, and metabolic disorders. Activation of GPR183 plays a crucial role in humoral immune responses, and many autoimmune diseases may be directly or indirectly related to the physiological functions of GPR183. As more important roles of GPR183 in various diseases are revealed, agonists and antagonists hold significant value in further pharmacological research and disease treatment.

[0003] In 2014, Novartis researchers reported a class of brominated cinnamonamide compounds, NIBR189, which exhibited good inhibitory activity against GPR183 (J. Med. Chem. 2014, 57, 3358-3368), but the IC50 of this compound for inhibiting hERG was limited. 50 The concentration was as high as 1.6 μM, indicating a risk of cardiotoxicity (J. Med. Chem. 2024, 67, 3520-3541). Subsequently, researchers from Nanjing Aimeifei (J. Med. Chem. 2023, 66, 15926-15943) and Shanghai Jiao Tong University (J. Med. Chem. 2024, 67, 3520-3541) reported inhibitors 2 and 3, both of which maintained good in vitro and in vivo GPR183 inhibitory activity (IC50). 50 <10 nM), but still has inhibitory effects on cardiotoxicity-related hERG, at 7.9 μM and 8.7 μM, respectively.

[0004]

[0005] Therefore, there is an urgent need in this field to develop a compound that combines excellent GPR183 inhibitory activity with better safety. Summary of the Invention

[0006] The object of this invention is to provide a compound of Formula I and its use in the prevention and / or treatment of GPR183-related diseases.

[0007] In a first aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0008]

[0009] in,

[0010] Q is selected from the following group: 1-3 Rs a Substituted or unsubstituted alkyl groups containing 1-3 heteroatoms selected from N, O or S, or 1-3 R atoms. a Substituted or unsubstituted heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S, or 1-3 R atoms. a Substituted or unsubstituted 4-10 membered spirocyclic heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; C6-C10 aryl groups; 5-6 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; C4-C10 cycloalkyl groups; 1-2 R groups b Substituted amino groups, R b -O-;

[0011] Each R a Each of the following groups is independently selected: deuterium, halogen, hydroxyl, cyano, amino, oxo, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl-(C=O)-NH-, substituted or unsubstituted C1-C4 alkyl-(C=O)-, substituted or unsubstituted C1-C6 alkyl-S(=O)2-; wherein each of the following groups is independently selected: substituted by 1-3 substituents selected from the following groups: halogen, hydroxyl, amino, cyano;

[0012] Each R b Each is independently a C1-C6 alkyl group, and each alkyl group is optionally independently substituted with a halogen and / or deuterium;

[0013] R 1 R 2 R 3Each of the following groups is independently selected: hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C4 alkyl-(C=O)-NH-; wherein each of the substitutions independently refers to substitution by 1-3 substituents selected from the following group: halogen, hydroxyl, amino;

[0014] Or R 1 R 2 Together with the C connected thereto, they form a group selected from the group consisting of 5-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, or C5-C6 cycloalkyl groups; wherein the heterocyclic alkyl or cycloalkyl group is optionally independently substituted by 1-2 substituents selected from the group consisting of halogen, deuterium, hydroxyl, or amino.

[0015] In another preferred example, Q is selected from the following group: 1-3 R a Substituted or unsubstituted 4-7 membered monocyclic heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and 1-3 R atoms. a Substituted or unsubstituted 4-8-membered bridged heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; 1-2 R... b Substituted amino groups;

[0016] Each R a Each is independently selected from the following group: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl.

[0017] Each R b Each is independently a C1-C6 alkyl group, and each alkyl group is independently substituted with a halogen and / or deuterium.

[0018] In another preferred example, Q is selected from the following group:

[0019]

[0020] R a As defined in claim 1;

[0021] m is selected from the following groups: 0, 1, 2, 3.

[0022] In another preferred embodiment, Q is selected from the group consisting of: -N (deuterated C1-C6 alkyl)2, -N (halogenated C1-C6 alkyl)2.

[0023] In another preferred embodiment, Q is -N (fully deuterated C1-C6 alkyl)2.

[0024] In another preferred example, Q is -N(CD3)2.

[0025] In another preferred embodiment, R 1 R 2 Each is independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy;

[0026] Or R 1 R 2 Together with the C connected thereto, they form a group selected from the group consisting of 5-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, or C5-C6 cycloalkyl groups; wherein the heterocyclic alkyl or cycloalkyl group is optionally independently substituted by 1-2 substituents selected from the group consisting of halogen, deuterium, hydroxyl, or amino.

[0027] In another preferred embodiment, R 1 R 2 Each is independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl.

[0028] In another preferred embodiment, R 1 R 2 Each of the following is selected independently: hydrogen, deuterium, halogen, hydroxyl.

[0029] In another preferred embodiment, R 1 R 2 Each is independently selected from the following group: halogens, hydroxyl groups.

[0030] In another preferred embodiment, R 1 R 2 Together with the C to which it is attached, they form a 5-6 membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S; the heterocyclic alkyl group is optionally substituted by 1-2 substituents selected from the group consisting of halogen, deuterium, hydroxyl, and amino.

[0031] In another preferred embodiment, R 1 R 2 Together with the C connected thereto, they form a 5-6 membered heterocyclic alkyl group containing 1-3 O atoms; the heterocyclic alkyl group is optionally substituted by 1-2 substituents selected from the group consisting of halogen, deuterium, hydroxyl, and amino.

[0032] In another preferred embodiment, R 1 R 2 Together with the C atoms to which they are attached, they form a 5-6 membered heterocyclic alkyl group containing two O atoms; the heterocyclic alkyl group is optionally substituted with one or two halogens.

[0033] In another preferred embodiment, R 3Selected from the following group: hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy.

[0034] In another preferred embodiment, R 3 Selected from the following group: hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl.

[0035] In another preferred embodiment, R 3 Selected from the following group: hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl.

[0036] In another preferred embodiment, R 3 Selected from the following group: hydrogen, deuterium, C1-C6 alkyl.

[0037] In another preferred embodiment, the compound is selected from the group consisting of:

[0038]

[0039]

[0040] A second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0041] A third aspect of the invention provides the use of the compound described in the first aspect of the invention, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the prevention and / or treatment of GPR183-related diseases.

[0042] In another preferred embodiment, the drug is used to inhibit GPR183 activity.

[0043] In another preferred embodiment, the GPR183-related diseases are selected from the group consisting of: tumors, inflammation, autoimmune diseases, metabolic diseases, pain, bacterial infections, and viral infections.

[0044] In another preferred embodiment, the tumor is selected from the group consisting of: B-cell malignancies, hematologic malignancies, clear cell renal cell carcinoma, prostate cancer, laryngeal squamous cell carcinoma, head and neck cancer, lung cancer, colon cancer, breast cancer, liver cancer, and pancreatic cancer.

[0045] In another preferred embodiment, the inflammation is selected from the group consisting of: inflammatory bowel disease, osteoarthritis, non-alcoholic fatty liver disease, interstitial cystitis, atherosclerosis, pneumonia, chronic sinusitis, myocarditis, and nephritis.

[0046] In another preferred embodiment, the autoimmune disease is selected from the group consisting of: rheumatoid arthritis, systemic lupus erythematosus, autoimmune encephalomyelitis, vitiligo, type I diabetes, chronic atrophic gastritis, multiple sclerosis, and acute idiopathic polyneuritis.

[0047] In another preferred embodiment, the metabolic disease is selected from the group consisting of: obesity, diabetes, dyslipidemia, osteoporosis, and scurvy.

[0048] In another preferred embodiment, the pain is neuropathic pain.

[0049] In another preferred embodiment, the bacterial infection is selected from the group consisting of: tuberculosis, scarlet fever, and purulent meningitis.

[0050] In another preferred embodiment, the viral infection is selected from the group consisting of: novel coronavirus, influenza virus, measles, mumps, and viral hepatitis.

[0051] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0052] Through long-term and in-depth research, the inventors unexpectedly prepared a novel compound that combines excellent GPR183 inhibitory activity with superior safety by optimizing its structure. Based on this, the inventors completed this invention.

[0053] the term

[0054] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0055] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0056] In this invention, the term "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0057] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0058] In this invention, the term "C2-C6 ynyl" refers to a straight-chain or branched ynyl group having 2-6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0059] In this invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3-8 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Other similar terms have similar meanings.

[0060] In this invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is a C1-C4 alkoxy group.

[0061] In this invention, the term "heterocyclic alkyl" refers to a 4-8 membered heterocyclic alkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, including (but not limited to) the following groups:

[0062] In this invention, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.

[0063] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include: furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0064] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0065] In this invention, the term "deuterium substitution" refers to being replaced by deuterium.

[0066] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0067] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0068] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0069] compound

[0070] This invention provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0071]

[0072] The groups are defined above.

[0073] In another preferred embodiment, in the compound, any one of R1, R2, R3 and Q is independently a group corresponding to the specific compound of the present invention.

[0074] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0075] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0076] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0077] The embodiments of this invention specifically describe methods for preparing compounds of Formula I, but these specific methods do not constitute any limitation on this invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0078] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased commercially unless otherwise specified.

[0079] Pharmaceutical Compositions and Administration

[0080] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0081] Because the compounds of the present invention have excellent antitumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0082] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0083] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0084] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0085] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0086] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0087] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0088] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0089] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0090] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0091] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0092] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0093] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as antitumor drugs).

[0094] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0095] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0096] Compared with the prior art, the present invention has the following main advantages:

[0097] (1) The compounds of the present invention have both excellent GPR183 inhibitory activity and better safety.

[0098] (2) The compounds of the present invention have excellent pharmacokinetic properties.

[0099] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0101] Preparation of compound S1 in Example 1:

[0102]

[0103] Synthesis of Compounds 1-2

[0104] Compound 1-1 (900 mg, 4.84 mmol) and malonic acid (600 mg, 5.32 mmol) were dissolved in 7-8 mL of pyridine, followed by the addition of 0.5 mL of piperidine. After the addition was complete, the mixture was heated to 110 °C and stirred. After reacting for 3 hours, HCl solution (3N) was added to the reaction solution, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was dried in a drying oven to obtain a white powdery solid 1-2.

[0105] Synthesis of compounds 1-3

[0106] Compounds 1-2 (460 mg, 2.00 mmol) and HATU (997 mg, 2.60 mmol) were dissolved in 3 mL of anhydrous N,N-dimethylformamide, and triethylamine (841 μl, 6.10 mmol) was added. The mixture was stirred at room temperature. After 30 minutes, 1-Boc-piperazine (376 mg, 2.00 mmol) was added to the reaction solution, and the mixture was stirred at room temperature. After reacting for 3 hours, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was collected, concentrated, and then subjected to gradient elution by column chromatography to obtain a white powdery solid 1-3.

[0107] Synthesis of compounds 1-4

[0108] Compounds 1-3 (460 mg, 1.16 mmol) were dissolved in 3 mL of dichloromethane, followed by the addition of 3 mL of a 1,4-dioxane solution in hydrochloric acid. The mixture was stirred at room temperature. After half an hour, the reaction solution was concentrated to obtain the crude product of compounds 1-4.

[0109] Synthesis of compounds 1-5

[0110] 2-Chloro-6-benzothiazolium carboxylic acid (107 mg, 0.5 mmol) and HATU (247 mg, 0.65 mmol) were dissolved in 2 mL of anhydrous N,N-dimethylformamide, and triethylamine (208 μl, 1.50 mmol) was added. The mixture was stirred at room temperature. After 30 minutes, compounds 1-4 (198 mg, 0.50 mmol) were added to the reaction solution, and the mixture was stirred at room temperature. After reacting for 3 hours, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, the organic phase was collected, concentrated, and then subjected to gradient elution by column chromatography to obtain a white powdery solid 1-5.

[0111] Preparation of compound S1

[0112] Compounds 1-5 (80 mg, 0.16 mmol) and morpholine (14 μl, 0.16 mmol) were dissolved in 2 mL of anhydrous N,N-dimethylformamide. Anhydrous sodium carbonate (85 mg, 0.33 mmol) and DIPEA (58 μl, 0.33 mmol) were added, and the mixture was heated to 80 °C and stirred. After reacting for 3 hours, the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was collected, concentrated, and subjected to gradient elution by column chromatography to obtain a white powdery solid S1.

[0113] 1 H NMR(400MHz,chloroform-d)δ7.77(d,J=1.4Hz,1H),7.66(d,J=15.3Hz,1H),7.56(d,J=8.3Hz,1H),7.38(dd,J=8.3,1.8Hz,1H),7.27(s, 1H),7.25(d,J=8.2Hz,1H),7.07(d,J=8.2Hz,1H),6.78(d,J=15.3Hz,1H),3.88–3.83(m,4H),3.75(d,J=17.9Hz,7H),3.69–3.62(m,5H).

[0114] Preparation of compound S2 in Example 2:

[0115] The synthesis steps for compound S2 are the same as those for compound S1, except that the substrate morpholine is replaced with 2-cyanomorpholine.

[0116] 1 H NMR(400MHz,chloroform-d)δ7.80(d,J=1.8Hz,1H),7.67(d,J=15.3Hz,1H),7.61(d,J=8. 3Hz,1H),7.41(dd,J=8.3,1.7Hz,1H),7.27(s,1H),7.24(d,J=1.6Hz,1H),7.07(d,J=8.2Hz ,1H),6.78(d,J=15.3Hz,1H),4.77(t,J=3.9Hz,1H),4.21–4.06(m,2H),3.94(dt,J=12.1, 3.9Hz, 1H), 3.83 (dt, J=13.2, 4.5Hz, 3H), 3.74 (s, 7H), 3.57 (ddd, J=12.6, 8.7, 3.4Hz, 1H).

[0117] Preparation of compound S3 in Example 3:

[0118] The synthesis steps for compound S3 are the same as those for compound S1, except that the substrate morpholine is replaced with 3-oxa-8-azabicyclo[3.2.1]octane.

[0119] 1 H NMR(400MHz,chloroform-d)δ7.76(d,J=1.7Hz,1H),7.66(d,J=15.3Hz,1H),7.56(d,J=8.3Hz,1H),7.37(dd,J=8.3,1.8Hz,1H),7.27(s,1H ),7.24(s,1H),7.07(d,J=8.2Hz,1H),6.78(d,J=15.2Hz,1H),4.32(s,2H),3.94(d,J=11.0Hz,2H),3.85–3.59(m,10H),2.23–2.09(m,4H).

[0120] Preparation of compound S4 in Example 4:

[0121] The synthesis steps for compound S4 are the same as those for compound S1, except that the substrate morpholine is replaced with di(trideuteryl)amine hydrochloride.

[0122] 1H NMR (400MHz, CDCl3) δ7.73(s,1H),7.64(d,J=15.4Hz,1H),7.52(d,J=8.2Hz,1H),7.39–7.28 (m,1H),7.23(d,J=11.2Hz,2H),7.05(d,J=8.1Hz,1H),6.76(d,J=15.0Hz,1H),3.70(s,8H).

[0123] Preparation of compound S5 in Example 5:

[0124] The synthesis steps for compound S5 are the same as those for compound S1, except that the substrate morpholine is replaced with 4-methylpiperidin-4-ol.

[0125] 1H NMR(400MHz,chloroform-d)δ7.73(dd,J=1.8,0.5Hz,1H),7.66(d,J=15.3Hz,1H),7.51(dd,J=8.3,0.5Hz,1H),7.35(dd,J=8.3,1.8Hz,1H),7.24(dd,J=10.4,2.1 Hz,2H),7.07(d,J=8.2Hz,1H),6.78(d,J=15.3Hz,1H),3.90(d,J=13.4Hz,2H),3 .73(m,8H),3.61(ddd,J=13.2,10.5,4.3Hz,2H),1.82–1.67(m,4H),1.33(s,3H).

[0126] Preparation of compound S6 in Example 6:

[0127]

[0128] The starting material 1-1 was replaced with 6-1, and the final marin was replaced with di(trideuterium methyl)amine hydrochloride. The synthesis steps of compound S6 were the same as those of compound S1.

[0129] 1 H NMR (400MHz, DMSO) δ10.32(s,1H),7.86(s,1H),7.47(d,J=8.4Hz,1H),7.42(d,J=8.2Hz,1H),7. 34(m,2H),7.16(d,J=7.2Hz,1H),7.12(d,J=7.5Hz,2H),3.72(s,2H),3.59(s,2H),3.52(s,4H).

[0130] Preparation of compound S7 in Example 7:

[0131] The synthesis steps for compound S7 are the same as those for compound S1, except that the substrate morpholine is replaced with 4,4-difluoropiperidine.

[0132] 1 H NMR(400MHz,chloroform-d)δ7.77(d,J=1.7Hz,1H),7.66(d,J=15.3Hz,1H),7.56(d,J=8.3Hz,1H),7.38(dd,J=8.3,1.8Hz ,1H),7.27–7.22(m,2H),7.07(d,J=8.1Hz,1H),6.78(d,J=15.3Hz,1H),3.95–3.49(m,12H),2.15(tt,J=13.0,5.9Hz,4H).

[0133] Preparation of compound S8 in Example 8:

[0134] The synthesis steps for compound S8 are the same as those for compound S1, except that the substrate morpholine is replaced with piperidine.

[0135] 1 H NMR(400MHz,chloroform-d)δ7.75–7.71(m,1H),7.66(d,J=15.3Hz,1H),7.52(d,J=8.2Hz,1H),7.34(dd,J=8.3,1 .8Hz,1H),7.26–7.22(m,2H),7.07(d,J=8.2Hz,1H),6.78(d,J=15.3Hz,1H),3.69(d,J=34.6Hz,12H),1.72(s,6H).

[0136] Experimental Example 1: hERG Cardiotoxicity Test

[0137] 1. Testing method:

[0138] CHO-hERG cells were cultured until the cell density reached 60%-80%. The culture medium was removed, the cells were washed once with 7 mL of PBS, then digested with 3 mL of Detachin, neutralized and centrifuged, the supernatant was removed, and the cells were resuspended in culture medium.

[0139] The 50 mM stock solution of the compound was diluted with DMSO using a Bravo instrument. The highest test concentration of the compound was 40 μM, followed by six concentrations: 40.00, 13.33, 4.44, 1.48, 0.49, and 0.16 μM. The DMSO content in the final test concentration did not exceed 0.2%, and this concentration of DMSO had no effect on the hERG potassium channel.

[0140] The single-cell high-impedance sealing and whole-cell pattern formation processes were all completed automatically by the Qpatch instrument, and the experimental data were analyzed using GraphPad Prism 5.0 software.

[0141] 2. Experimental Results:

[0142] Table 1. Cardiac hERG inhibitory toxicity of some compounds.

[0143]

[0144]

[0145] Table 1 shows that compounds 1, 2, and 3, as reported in the literature, all exhibit strong inhibitory activity against hERG. To further illustrate the significant impact of amino group substitution in the aminothiazole structure on hERG, we also synthesized reference compound 4, which exhibits strong inhibitory activity against hERG (IC50, 1000 mmol / L). 50 The concentration was 9.82 μM. In contrast, in this invention, the representative compounds S4, S5, and S6 showed a significant decrease in their inhibitory activity against hERG, with an IC50 concentration of 9.82 μM. 50 All values ​​were greater than 20.31 μM, indicating that the compounds of this invention have significantly improved safety.

[0146] Experimental Example 2: CYP Enzyme Inhibition Test

[0147] 1. Testing method:

[0148] Preparation of buffer solutions and solutions: Dissolve 8.71 g of potassium hydrogen phosphate in 950 mL of water, adjust the pH to 7.4 with hydrochloric acid solution, add water to 1000 mL, filter, and then store in a refrigerator at 4°C. Prepare stock solutions of terfenadine and tolbutamide (1 mg / mL each) with DMSO, then dilute with acetonitrile to prepare quenching solutions containing 5 / 10 ng / mL (terfenadine and tolbutamide).

[0149] Preparation of liver microsome solution: Before use, thaw the liver microsomes in a water bath at 37°C and prepare the liver microsome solution according to the table below:

[0150]

[0151]

[0152] Prepare a 5 mM NADPH solution using phosphate buffer. Dilute a 10 mM DMSO stock solution of the test compound four times to prepare the test solution. The positive references selected in this experiment are inhibitors of each CYP family member.

[0153] Add 238.5 μL of liver microsome solution to a test tube, followed by 1.5 μL of the analyte solution. Mix thoroughly and incubate at 37°C for 5 minutes. Then, add 60 μL of NADPH solution, mix thoroughly, and incubate with shaking at 37°C for 10 minutes. After incubation, immediately add 500 μL of quenching solution and vortex for 1 minute. Centrifuge the sample at low temperature and high speed for 15 minutes (4,000 pm, 4°C), and aliquot 300 μL of the supernatant for further LC-MS / MS analysis. IC50 50 The values ​​were analyzed using GraphPadPrism software.

[0154] 2. Experimental Results:

[0155] Table 2 shows the CYP enzyme inhibitory toxicity of some compounds.

[0156]

[0157]

[0158] As shown in Table 2, compounds 2 and 3 both exhibit strong inhibitory activity against 2C19. To further illustrate the significant impact of amino group substitution in the aminothiazole structure on 2C19, we also synthesized reference compound 4, which also exhibits strong inhibitory activity against 2C19, with an IC50 value of [missing value]. 50 The concentration was 0.37 μM. In contrast, the representative compounds S4, S5, and S6 of this invention showed a significant decrease in inhibitory activity against 2C19, with an IC50 concentration of 0.37 μM. 50 All values ​​were greater than 10 μM, indicating that the compounds of this invention have significantly improved safety.

[0159] Furthermore, compound S5 was selected for various common CYP enzyme activity tests, and the test results are shown in Table 3. The IC50 values ​​of the compound inhibiting metabolic enzymes were all greater than 10 μM, which also indicates that the compound of the present invention has significantly excellent safety.

[0160] Table 3. Inhibitory activity of representative compound S5 against common CYP enzymes.

[0161]

[0162] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in, Q is selected from the following group: 1-3 Rs a Substituted or unsubstituted alkyl groups containing 1-3 heteroatoms selected from N, O or S, or 1-3 R atoms. a Substituted or unsubstituted heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S, or 1-3 R atoms. a Substituted or unsubstituted 4-10 membered spirocyclic heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; C6-C10 aryl groups; 5-6 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; C4-C10 cycloalkyl groups; 1-2 R groups b Substituted amino groups, R b -O-; Each R a Each of the following groups is independently selected: deuterium, halogen, hydroxyl, cyano, amino, oxo, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl-(C=O)-NH-, substituted or unsubstituted C1-C4 alkyl-(C=O)-, substituted or unsubstituted C1-C6 alkyl-S(=O)2-; wherein each of the following groups is independently selected: substituted by 1-3 substituents selected from the following groups: halogen, hydroxyl, amino, cyano; Each R b Each is independently a C1-C6 alkyl group, and the alkyl group is optionally independently substituted with a halogen and / or deuterium; R 1 R 2 R 3 Each of the following groups is independently selected: hydrogen, deuterium, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C4 alkyl-(C=O)-NH-; wherein each of the substitutions independently refers to substitution by 1-3 substituents selected from the following group: halogen, hydroxyl, amino; Or R 1 R 2 Together with the C connected thereto, they form a group selected from the group consisting of 5-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, or C5-C6 cycloalkyl groups; wherein the heterocyclic alkyl or cycloalkyl group is optionally independently substituted by 1-2 substituents selected from the group consisting of halogen, deuterium, hydroxyl, or amino.

2. The compound according to claim 1, characterized in that, Q is selected from the following group: 1-3 Rs a Substituted or unsubstituted 4-7 membered monocyclic heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and 1-3 R atoms. a Substituted or unsubstituted 4-8-membered bridged heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, or S; 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; 1-2 R... b Substituted amino groups; Each R a Each is independently selected from the following group: deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl. Each R b Each is independently a C1-C6 alkyl group, and each alkyl group is independently substituted with a halogen and / or deuterium.

3. The compound according to claim 1, characterized in that, Q is selected from the following group: R a As defined in claim 1; m is selected from the following groups: 0, 1, 2, 3.

4. The compound according to claim 1, characterized in that, Q is selected from the following group: -N(deuterated C1-C6 alkyl)2, -N(halogenated C1-C6 alkyl)2.

5. The compound according to claim 1, characterized in that, R 1 R 2 Each is independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy; Or R 1 R 2 Together with the C connected thereto, they form a group selected from the group consisting of 5-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, or C5-C6 cycloalkyl groups; wherein the heterocyclic alkyl or cycloalkyl group is optionally independently substituted by 1-2 substituents selected from the group consisting of halogen, deuterium, hydroxyl, or amino.

6. The compound according to claim 1, characterized in that, R 1 R 2 Together with the C atoms to which they are attached, they form a 5-6 membered heterocyclic alkyl group containing two O atoms; the heterocyclic alkyl group is optionally substituted with one or two halogens.

7. The compound according to claim 1, characterized in that, R 3 Selected from the following group: hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy.

8. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

9. A pharmaceutical composition, characterized in that, The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, comprising a pharmaceutically acceptable carrier and a safe and effective amount thereof.

10. Use of the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that, Used to prepare a drug for the prevention and / or treatment of GPR183-related diseases.

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