Tetrahydrobenzothiazole compound and pharmaceutical use thereof

Abstract

The present invention relates to a tetrahydrobenzothiazole compound and a pharmaceutical use thereof. Specifically, the present invention relates to a compound as represented by formula I or a pharmaceutically acceptable salt thereof, wherein the definitions of substituents are as defined in the description.

Description

Tetrahydrobenzothiazole compounds and their pharmaceutical uses Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to tetrahydrobenzothiazole compounds and their pharmaceutical uses. Background Technology

[0002] Asthma is a chronic respiratory disease characterized by airway inflammation, bronchoconstriction, and airway hyperresponsiveness. Eosinophilic asthma (EA) is a subtype of asthma characterized by eosinophilic airway inflammation, typically manifesting as: ① chronic airway inflammation: eosinophils accumulate in the airways and release inflammatory mediators, leading to airway damage and allergic reactions; ② refractory asthma: EA often responds poorly to traditional bronchodilators and low-dose inhaled corticosteroids, requiring stronger anti-inflammatory treatment.

[0003] Pramipexol is a highly selective D2 / D3 receptor agonist, and the dopamine signaling pathway may be involved in regulating immune responses. Dopamine receptors are expressed in eosinophils, T cells, and macrophages and may influence inflammatory responses. Furthermore, activation of the D3 receptor may suppress Th2-type immune responses and reduce eosinophil recruitment.

[0004] In recent years, dextropramivir has been found to be a selective inhibitor of eosinophil maturation and can be used to treat asthma and eosinophil-related diseases. Summary of the Invention

[0005] This disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0006] in:

[0007] R 1a R 1b R 3 Each is independently selected from hydrogen and C. 1-6 Alkyl, 3- to 10-membered cycloalkyl, wherein the alkyl or cycloalkyl is optionally surrounded by one or more R A Replaced;

[0008] R 2a R 2b R 4a R 4b Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R B Replaced;

[0009] R 5 Selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. C replace;

[0010] R A R B R C Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups;

[0011] m is selected from 1, 2, 3, 4, 5, 6;

[0012] b is selected from 0, 1, 2, 3, 4, 5, 6;

[0013] Compound of formula I cannot be

[0014] In some embodiments, the compound represented by formula I is the compound represented by formula II-A.

[0015] in,

[0016] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heteroalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl.

[0017] R a Each group is independently selected from halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, and C groups. 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R D Replaced;

[0018] R D Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups;

[0019] a is selected from 0, 1, 2, 3;

[0020] Compound II-A cannot be

[0021] R 1a R 1b R 2a R 3 R 4a R 4b R 2b b and m are as defined above.

[0022] In some embodiments, ring A is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heteroalkyl, wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R groups. a Replace, R a As defined above.

[0023] In some embodiments, the compound represented by formula I is the compound represented by formula III-A.

[0024] in,

[0025] X is selected from -(CH2)-, -NH-, -S-, and -O-;

[0026] p is selected from 0, 1, 2, 3;

[0027] q is selected from 0, 1, 2, and 3;

[0028] R 1a R 1b R 2a R 3 R 4a R 4b R 2b b, m, R a a is as defined above.

[0029] In some embodiments, the compound represented by Formula I is selected from the compounds represented by Formula II-B or Formula II-C, or pharmaceutically acceptable salts thereof.

[0030] in,

[0031] R 5a R 5b R 6a R 6b R 6c Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 10-membered cycloalkyl, and R5a R 5b R 6a R 6b R 6c At least one of them is independently selected from halogen, cyano, or halogenated C. 1-6 Alkyl, cyano-substituted C 1-6 Alkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally surrounded by one or more R E Replaced;

[0032] Compounds of formula IIB cannot be

[0033] R 2a’ Selected from halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R F Replaced;

[0034] R 5’ Selected from C 1-6 Alkyl, C 1-6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. G replace;

[0035] R E R F R G Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups;

[0036] R 1a R 1b R 2a R 3 R 4a R 4b R 2b b is as defined above.

[0037] In some implementations, R 5’ C 1-6 Alkyl group. In some embodiments, R... 5’ Selected from methyl, ethyl, propyl, and butyl. In some embodiments, R... 5’ It is an ethyl group.

[0038] In some implementations, R 1a R 1b R 2a R 3 R 4a R 4b Each is independently hydrogen.

[0039] In some implementations, m is 1.

[0040] In some embodiments, the compound represented by Formula I is selected from compounds represented by Formula III-A', Formula III-B, or Formula III-C.

[0041] Among them, R 2b b, R a a, X, p, q, R 2a’ R 5a R 5b R 6a R 6b R 6c As defined above.

[0042] In some embodiments, X is selected from -(CH2)- and -O-.

[0043] In some implementations, p is selected from 0, 1, and 2. In some implementations, p is 1.

[0044] In some implementations, q is 0 or 1.

[0045] In some embodiments, the compound represented by formula I is selected from the compounds represented by formulas IV-A.

[0046] Where r is selected from 1, 2, 3, 4,

[0047] R 2b b, R a a is as defined above.

[0048] In some implementations, b is 0.

[0049] In some embodiments, the compound represented by formula I is selected from the compounds represented by formulas V-A.

[0050] Where r and R a a is as defined above.

[0051] In some embodiments, the compound represented by Formula I is selected from compounds represented by Formula VI-A-1, Formula VI-A-2, Formula VI-A-3, or Formula VI-A-4.

[0052] Among them, R a a is as defined above.

[0053] In some implementations, R 5a R 5b R 6a R 6b R 6c At least one of them is independently selected from fluorine, chlorine, bromine, and cyano. In some embodiments, R 5a R 5b R 6a R 6b R 6c At least one of them is independently selected from fluorine or cyano.

[0054] In some implementations, R a Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkyloxy group. In some embodiments, R... a Each group is independently selected from halogen, hydroxyl, mercapto, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy groups. In some embodiments, R... a Each is independently selected from halogen, hydroxyl, cyano, and methyl groups. In some embodiments, R... a Each is independently a methyl group.

[0055] In some implementations, R 2a’ Selected from C 1-6 Alkyl group. In some embodiments, R... 2a’ Selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. In some embodiments, R... 2a’ It is a methyl group.

[0056] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from...

[0057] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from...

[0058] On the other hand, this disclosure also provides a compound or a pharmaceutically acceptable salt thereof, selected from...

[0059] On the other hand, this disclosure also provides a compound or a pharmaceutically acceptable salt thereof, selected from...

[0060] This disclosure also provides isotopic substitutions of the aforementioned compounds or their pharmaceutically acceptable salts or their stereoisomers, rotatimers, or tautomers. In some embodiments, the isotopic substitutions are deuterated derivatives.

[0061] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0062] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0063] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0064] This disclosure also provides the use of the aforementioned compound or its pharmaceutically acceptable salt in the preparation of a medicament for the treatment of asthma.

[0065] In some implementations, the asthma referred to therein is allergic asthma.

[0066] This disclosure also provides the use of the aforementioned compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of eosinophil-related diseases.

[0067] In some embodiments, the eosinophil-related disease is eosinophil-associated asthma.

[0068] This disclosure further provides a kit comprising the compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compounds. In some embodiments, the kit may also comprise a dopamine receptor agonist. In some embodiments, the kit may also comprise an eosinophil-selective inhibitor.

[0069] The pharmaceutically acceptable salts of the aforementioned compounds disclosed herein may be selected from inorganic or organic salts. The inorganic salts are selected from hydrochloride, hydrobromide, phosphate, or sulfate; the organic salts are selected from acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, citrate, maleate, tartrate, fumarate, citrate, or lactate.

[0070] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0071] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0072] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0073] In the chemical structure of the compounds described in this disclosure, the bonds... No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0074] Although all the above structural formulas are shown in some isomer form for simplicity, this disclosure can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers.

[0075] The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, a proton tautomer (also known as a proton transfer tautomer) includes an interconversion via proton transfer, as in the compounds of this disclosure which contain the following tautomeristic changes between A and B:

[0076] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0077] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0078] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0079] Terminology Explanation:

[0080] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0081] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0082] "Pharmaceutical excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0083] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0084] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, including, but not limited to, halogens, hydroxyl, mercapto, carboxyl, amino, cyano, C6, and C7. 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0085] The term "cycloalkyl" or "carbocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 10 carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0086] The cycloalkyl or carbocyclic group may be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable linker, preferably one or more of the following groups, including but not limited to halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0087] The terms "heterocyclic alkyl," "heterocyclic group," or "heterocycle" refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 6 to 10 ring atoms. Examples of monocyclic heterocyclic alkyl groups include, but are not limited to, piperazine rings, piperidine rings, cycloazine rings, ethylene oxide rings, and cyclothioethane rings. Butyl ring, acridine ring, thiobutyl ring, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, tetrahydropyran ring, tetrahydrothiophene ring, etc.; polycyclic cycloalkyl groups include heterocyclic alkyl groups with spirocyclic, fused, and bridged rings.

[0088] Heterocyclic alkyl groups, heterocyclic groups, or heterocycles may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including but not limited to halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, and C6 groups. 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0089] The term "aryl" or "aromatic ring" refers to any stable, monocyclic or bicyclic carbon ring with up to seven atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, biphenyl, or binaphthyl. Unless otherwise specified, the aryl or aromatic ring may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, including but not limited to halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, and C6 groups. 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0090] The term "heteroaryl" or "heteroaromatic ring" refers to a stable monocyclic or bicyclic ring with up to seven atoms in each ring, wherein at least one ring is aromatic and at least one ring contains one to four heteroatoms selected from O, N, and S. Heteroaromatic rings within the scope of this definition include, but are not limited to, pyridine rings, thiazine rings, pyrimidine rings, pyridazine rings, furan rings, pyrrole rings, thiophene rings, imidazole rings, pyrazole rings, oxazole rings, isoxazole rings, thiazole rings, benzofuran rings, isobenzofuran rings, isoindole rings, indole rings, benzothiophene rings, benzimidazole rings, indole rings, benzoxazole rings, benziisoxazole rings, purine rings, benzothiazole rings, quinoline rings, isoquinoline rings, quinazoline rings, quinazolineone rings, and thioquinazolineone rings.

[0091] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, including but not limited to halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0092] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, including but not limited to: halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups.

[0093] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0094] The term "hydroxyl group" refers to -OH.

[0095] The term "amino" refers to -NH2.

[0096] The term "cyano" refers to -CN.

[0097] The term "nitro" refers to -NO2.

[0098] The term "carbonyl" refers to C=O.

[0099] The term "carboxyl group" refers to -C(O)OH.

[0100] The term "halogenation" refers to the substitution of one or more atoms selected from fluorine, chlorine, bromine, and iodine.

[0101] The term "monovalent group" refers to a compound that has "formally" eliminated a single-valent atom or group.

[0102] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. Attached Figure Description

[0103] Figure 1. The efficacy of the compound in a mouse model of asthma. * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001 vs model, ### p<0.001 vs. control compound. Detailed Implementation

[0104] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0105] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0106] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0107] HPLC determination was performed using an Agilent 1100 high-performance liquid chromatograph, a GAS15B DAD UV detector, and a Water Vbridge C18 150*4.6mm 5um column.

[0108] MS measurements were performed using an Agilent 6120 triple quadrupole mass spectrometer with a G1315D DAD detector and a Waters Xbridge C18 4.6*50mm, 5µm column, in positive / negative ion mode, with a mass scan range of 80–1200.

[0109] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.2mm ± 0.03mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm-0.5mm.

[0110] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara One (Biotage).

[0111] Normal column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0112] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bid Pharmaceuticals.

[0113] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0114] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0115] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0116] Hydrogen was produced by the QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instruments Co., Ltd.

[0117] Nitrogen or hydrogen atmospheres are typically evacuated and then filled with nitrogen or hydrogen gas, and this process is repeated three times.

[0118] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0119] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0120] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the different polarities of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0121] Example 1: Preparation of Compound 1

[0122] Compound 1a (500 mg, 2.95 mmol, purchased from Shaoyuan) and allyl bromide (428.87 mg, 3.55 mmol) were dissolved in DMF (4 mL), and DIPEA (763.64 mg, 5.91 mmol) was added. Under nitrogen protection, the mixture was stirred at room temperature until the reaction was complete. The solution was purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%), and then lyophilized in 1N hydrochloric acid (10 mL) to give 360 ​​mg of the hydrochloride salt of compound 1 (yield: 43.18%).

[0123] MS(ESI): m / z 210.1 [M+H] + .

[0124] 1 H NMR (400MHz, D2O): δ5.90-5.80(m,1H),5.49-5.42(m,2H),3.45-3.46(m,3H) ,3.05-3.00(m,1H),2.70-2.63(m,3H),2.27-2.23(m,1H),2.00-1.93(m,1H).

[0125] Example 2 Preparation of Compound 2

[0126] Compound 1a (500 mg, 2.95 mmol) and isobutane iodo (652.36 mg, 3.55 mmol) were dissolved in DMF (4 mL), and DIPEA (763.64 mg, 5.91 mmol) was added. Under nitrogen protection, the mixture was heated to 60 °C and stirred until the reaction was complete. The solution was purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%), and 1N hydrochloric acid (10 mL) was added. The solution was then drained to dryness using an oil pump to give 220 mg of the hydrochloride salt of compound 2 (yield: 24.97%).

[0127] MS(ESI): m / z 226.1 [M+H] + .

[0128] 1 H NMR (400MHz, D2O): δ3.64-3.54(m,1H),3.04-2.99(m,1H),2.93-2.91(m,2H),2 .67-2.53(m,3H),2.29-2.25(m,1H),1.99-1.84(m,2H),0.92(d,J=8.4Hz,6H).

[0129] Example 3 Preparation of Compound 3

[0130] Compound 1a (500 mg, 2.95 mmol) and 3-iodopropionitrile (561.38 mg, 3.10 mmol) were dissolved in DMF (4 mL), and DIPEA (763.64 mg, 5.91 mmol) was added. Under nitrogen protection, the mixture was heated to 60 °C and stirred until the reaction was complete. The solution was purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%), 1N HCl (10 mL) was added, and then diluted with 10 mL of water. The solution was lyophilized to give 400 mg of the hydrochloride salt of compound 3 (yield: 45.86%).

[0131] MS(ESI): m / z 223.1 [M+H] + .

[0132] 1 H NMR (400MHz, D2O): δ3.73-3.65(m,1H),3.46(t,J=5.8Hz,2H),3.06-3.01(m,1H) ,2.95(t,J=5.8Hz,2H),2.71-2.63(m,3H),2.28-2.24(m,1H),2.01-1.91(m,1H).

[0133] Example 4: Preparation of Compound 4

[0134] Step 1:

[0135] Compound 4a (163.64 mg, 1 mmol, purchased from Leyan) was dissolved in 2 mL of 48% hydrobromic acid aqueous solution, cooled to 0°C on an ice bath, and stirred for 15 min. Then, bromine (159.81 mg, 1.00 mmol) and thiourea (76.12 mg, 1.00 mmol) were added, stirred at room temperature, and then heated to 90°C with stirring until the reaction was complete. The reaction solution was cooled to 0°C on an ice bath, the pH was adjusted to 10–14 with 2 M NaOH, filtered, the filtrate was evaporated to dryness, slurried with DCM / MeOH (10 / 1), filtered, the filtrate was evaporated to dryness, slurried with 10 mL of water, filtered, to obtain 68 mg of compound 4b (yield: 37.10%).

[0136] MS(ESI): m / z 183.9 [M+H] + .

[0137] 1 H NMR (400MHz, CD3OD): δ2.62-2.44(m,4H), 1.74-1.71(m,2H), 1.19(s,3H).

[0138] Step 2:

[0139] Compound 4b (990 mg, 2.87 mmol) was dissolved in DMF (10 mL), and DIPEA (1.48 g, 11.48 mmol) was added. The mixture was cooled to 0 °C, and then propionic anhydride (410.68 mg, 3.16 mmol) was added. The mixture was stirred until the reaction was complete. The reaction solution was poured into 100 mL of water, and solid potassium carbonate was added to adjust the pH to 10–14. The solution was then extracted with EA (30 mL x 10). The extracts were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (CH3CN / H2O: 0%–30% for 40 min). The solution was then evaporated to dryness to give 400 mg of compound 4c (yield: 58.26%).

[0140] MS(ESI): m / z 240.1 [M+H]+ .

[0141] Step 3:

[0142] Compound 4c (280 mg, 1.17 mmol) was dissolved in THF (4 mL) under nitrogen protection. 1 M boranetetrahydrofuran (5.85 mL, 5.85 mmol) was added dropwise, and the mixture was heated to 65 °C and stirred until complete. The reaction solution was cooled to 0 °C, methanol was added until no more bubbles appeared, and the pH was adjusted to acidic with 1 N hydrochloric acid. The mixture was then stirred at 70 °C until complete. The reaction solution was cooled to room temperature, 20 mL of saturated potassium carbonate solution was added, and the mixture was extracted with EA (30 mL × 3). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was then prepared by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%) to give 117 mg of crude product. The crude product was dispersed in 10 mL of water, 1 N hydrochloric acid (10 mL) was added, and the solution was evaporated to dryness using an oil pump to give 180 mg of the hydrochloride salt of compound 4 (yield: 51.58%).

[0143] Compound 4 was chirally resolved (ChiralPak AD, 250×30mm ID, 10μm, Mobile phase: A for CO2 and B for Ethanol (0.1% NH3H2O), Gradient: B 20%, Flow rate: 120mL / min) to give 30mg of compound 4A hydrochloride and 45mg of compound 4B hydrochloride. The structures of compounds 4A and 4B are as follows:

[0144] Compound 4A:

[0145] MS(ESI): m / z 226.3 [M+H] + .

[0146] 1 H NMR (400MHz, CD3OD): δ3.13-2.64(m,6H), 2.15-2.12(m,2H), 1.81-1.72(m,2H), 1.45(s,3H), 1.07(t,J=7.2Hz,3H).

[0147] Compound 4B:

[0148] MS(ESI): m / z 226.3 [M+H] + .

[0149] 1H NMR (400MHz, CD3OD): δ3.15-2.72(m,6H), 2.18-2.15(m,2H), 1.84-1.74(m,2H), 1.48(s,3H), 1.09(t,J=7.2Hz,3H).

[0150] Example 5: Preparation of Compound 5

[0151] Compound 1a (500 mg, 2.95 mmol) was dispersed in ethanol (10 mL), and 2-butanone (271.79 mg, 3.77 mmol) was added. After stirring, sodium triacetylborohydride (1.88 g, 8.86 mmol) was added, and the reaction was stirred until complete. The reaction solution was placed in an ice bath at 0 °C, and the pH was adjusted to approximately 10 with saturated potassium carbonate. The solution was extracted with EA (30 mL × 3), and the extracts were combined, washed with Brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by HPLC (0.5% NH4HCO3 H2O: ACN = 0-95%), and 1N hydrochloric acid (10 mL) was added. The solution was then dried using an oil pump to give 260 mg of the hydrochloride salt of compound 5 (yield: 29.51%).

[0152] Compound 5 was chirally resolved (ChiralCel OX, 250 × 30 mm ID, 10 μm, Mobile phase: A for CO2 and B for Methanol (0.1% NH3H2O), Gradient: B 30%, Flow rate: 120 mL / min) to give 51 mg of compound 5A hydrochloride and 72 mg of compound 5B hydrochloride. The structures of compounds 5A and 5B are as follows:

[0153] Compound 5A:

[0154] MS(ESI): m / z 226.1 [M+H] + .

[0155] 1 H NMR (400MHz, D2O): δ3.79-3.68(m,1H),3.41-3.31(m,1H),3.02-2.95(m,1H),2.70-2.55(m,3H),2.27-2.22( m,1H),1.94-1.84(m,1H),1.81-1.70(m,1H),1.57-1.42(m,1H),1.25(d,J=6.4Hz,3H),0.90(t,J=7.6Hz,3H).

[0156] Compound 5B:

[0157] MS(ESI): m / z 226.1 [M+H] + .

[0158] 1 H NMR (400MHz, D2O): δ3.80-3.67(m,1H),3.39-3.27(m,1H),3.05-2.94(m,1H),2.71-2.53(m,3H),2.26-2.15( m,1H),1.97-1.84(m,1H),1.78-1.66(m,1H),1.56-1.43(m,1H),1.24(d,J=6.8Hz,3H),0.89(t,J=7.6Hz,3H).

[0159] Example 6 Preparation of Compound 6

[0160] Step 1:

[0161] Compound 6a (259 mg, 3.01 mmol, purchased from Adamas) and DIEA (305 mg, 3.01 mmol) were dissolved in DCM (5 mL) and stirred at 0 °C. HATU (1.27 g, 3.31 mmol) was added, and the mixture was brought to room temperature and reacted until complete. The mixture was then cooled in an ice-water bath. Compound 1a (509 mg, 3.01 mmol) was dissolved in DCM (5 mL) and DIEA (305 mg, 3.01 mmol) and added to the above mixture cooled in an ice-water bath. The mixture was brought to room temperature and stirred until complete. The organic phase was concentrated to dryness, and the residue was dissolved in ethyl acetate (20 mL) and water (120 mL). The organic phase was separated, and the aqueous phase was extracted again with ethyl acetate (20 mL × 2). The combined organic phases were concentrated and recrystallized from EA to give 502 mg of compound 6b (yield: 70.28%).

[0162] MS(ESI): m / z 238.1 [M+H] + .

[0163] Step 2:

[0164] Compound 6b (400 mg, 1.69 mmol) was dissolved in anhydrous THF (10 mL), and BH3·THF (1 M, 8.43 mmol, 8.43 mL) was added. The reaction was heated until complete. MeOH (5 mL) was added under an ice-water bath until no more bubbles were produced. HCl (1 N, 10 mL) was added, and the reaction was stirred until complete. The mixture was concentrated, and the pH was adjusted to approximately 10 with saturated potassium carbonate solution. Extraction was performed using EA (20 mL × 3). The organic phases were combined, concentrated, and purified by HPLC (0.5% NH4HCO3H2O:ACN = 0-95%). The solution was then lyophilized with 1 N hydrochloric acid (10 mL) to give 200 mg of the hydrochloride salt of compound 6 (yield: 53.13%).

[0165] MS(ESI): m / z 224.1 [M+H] + .

[0166] 1 H NMR (400MHz, D2O): δ3.76-3.69(m,1H),3.11-3.04(m,3H),2.76-2.68(m,3H),2.36-2. 30(m,1H),2.06-1.98(m,1H),1.13-1.06(m,1H),0.73-0.68(m,2H),0.40-0.35(m,2H).

[0167] Example 7 Preparation of Compound 7

[0168] Compound 7a (300 mg, 3.00 mmol, purchased from Leyan) and DIEA (607 mg, 6.00 mmol, purchased from Anaiji) were dissolved in DCM (10 mL) and stirred at 0°C. HATU (1.26 g, 3.30 mmol) was added, and the mixture was brought to room temperature and stirred until complete. The mixture was then cooled in an ice-water bath until ready for use. Compound 1a (508 mg, 3.00 mmol, purchased from Shaoyuan) was dissolved in DCM (10 mL) and DIEA (607 mg, 6.00 mmol), and added dropwise to the above mixture in the ice-water bath. The mixture was brought to room temperature and stirred until complete. The organic phase was concentrated to dryness, and the residue was compound 7b. Step 2:

[0169] Compound 7b (500 mg, 1.99 mmol) was dissolved in anhydrous THF (10 mL), and BH3·THF (9.95 mmol, 0.995 mL) was added. The reaction was heated until complete. MeOH (5 mL) was added under an ice-water bath until no more bubbles were produced. 1N HCl (10 mL) was added, and the mixture was stirred until complete. The mixture was concentrated, and the pH was adjusted to approximately 10 with saturated potassium carbonate solution. Extraction was performed using EA (20 mL × 3). The organic phases were combined, concentrated, and purified by HPLC (0.5% NH4HCO3H2O:ACN = 0-95%). The solution was lyophilized with 1N hydrochloric acid (10 mL) to give 170 mg of the hydrochloride salt of compound 7 (yield: 36.00%).

[0170] MS(ESI): m / z 238.1 [M+H] + .

[0171] 1 H NMR(400MHz,D2O): δ3.68-3.66(m,1H),3.12-3.02(m,3H),2.76-2.68(m,3 H),2.38-2.34(m,1H),2.02-1.98(m,1H),1.17(s,1H),0.61-0.54(m,4H).

[0172] Example 8: Preparation of Compound 8

[0173] Step 1:

[0174] Compound 8a (306 mg, 3.00 mmol, purchased from Jiangsu Aikon) and DIEA (607 mg, 6.00 mmol) were dissolved in DCM (5 mL) and stirred at 0°C. HATU (1.26 g, 3.30 mmol) was added, and the mixture was heated to room temperature until complete. The mixture was then cooled in an ice-water bath for later use. Compound 1a (507 mg, 3.00 mmol, purchased from Shaoyuan) was dissolved in a mixed solvent of DCM (5 mL) and DIEA (607 mg, 6.00 mmol). This solution was added dropwise to the above ice-water bath mixture, and the mixture was heated to room temperature and stirred until complete. The organic phase was concentrated to dryness, and the residue was dissolved in ethyl acetate (20 mL) and water (10 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were concentrated and recrystallized from EA to give 510 mg of compound 8b (yield: 67.17%).

[0175] MS(ESI): m / z 254.1 [M+H] + .

[0176] Step 2:

[0177] Compound 8b (510 mg, 2.01 mmol) was dissolved in anhydrous THF (10 mL), and BH3·THF (10.05 mmol, 10.05 mL) was added. The reaction was heated until complete. MeOH (5 mL) was added under an ice-water bath until no more bubbles were produced. 1N HCl (10 mL) was added, and the reaction was stirred until complete. The mixture was concentrated, and the pH was adjusted to approximately 10 with saturated potassium carbonate solution. The mixture was extracted with EA (20 mL × 3), the organic phases were combined, concentrated, and purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%) to give 170 mg of compound 8 (yield: 35.28%).

[0178] MS(ESI): m / z 240.1 [M+H] + .

[0179] 1 H NMR (400MHz, CD3OD): δ5.25-4.65(m,2H), 4.63-4.20(m,2H), 3.45-1.96(m,9H), 1.80-1.45(m,1H).

[0180] Example 9: Preparation of Compound 9

[0181] Compound 1a (425 mg, 2.51 mmol) and acetic acid (151 mg, 2.51 mmol) were dissolved in methanol (5 mL) and cooled in an ice-water bath. Compound 9a (275 mg, 3.26 mmol, purchased from Nanjing Pharmaceutical) was dissolved in methanol and added dropwise to the above mixture in the ice-water bath. The mixture was then heated to room temperature and stirred until the reaction was complete. The mixture was cooled again in an ice-water bath, and sodium cyanoborohydride (316 mg, 5.02 mmol) was added. The mixture was then heated to room temperature and stirred until the reaction was complete. The organic phase was concentrated to dryness, and the residue was dissolved in saturated potassium carbonate solution (15 mL). The residue was extracted with EA (20 mL × 3), the organic phases were combined, concentrated, and purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%). The purified solution was then lyophilized with 1N hydrochloric acid (10 mL) to give 210 mg of the hydrochloride salt of compound 9 (yield: 35.23%).

[0182] Compound 9 was resolved (ChiralPak IG, 250×30mm ID, 10μm, Mobile phase: A for CO2 and B for Isopropanol (0.1% NH3H2O), Gradient: B 40%, Flow rate: 120mL / min) to yield 219 mg of compound 9A hydrochloride and 57 mg of compound 9B hydrochloride. The structures of compounds 9A and 9B are as follows:

[0183] Compound 9A:

[0184] MS(ESI): m / z 238.1 [M+H] + .

[0185] 1 H NMR (400MHz, D2O): δ4.18-4.05(m,1H),3.70-3.60(m,1H),3.05-3.01(m,1H) ,2.72-2.67(m,3H),2.60-2.20(m,4H),2.10-1.74(m,3H),1.17-1.16(m,3H).

[0186] Compound 9B:

[0187] MS(ESI): m / z 238.1 [M+H] + .

[0188] 1 H NMR(400MHz,D2O): δ3.79-3.75(m,1H),3.70-3.60(m,1H),3.05-3.01(m,1H) ,2.72-2.67(m,3H),2.60-2.20(m,4H),2.10-1.74(m,3H),1.10-1.08(m,3H).

[0189] Example 10: Preparation of Compound 10

[0190] Step 1:

[0191] Compound 1a (3.5 g, 20.68 mmol) was dissolved in dioxane (40 mL) and water (30 mL). Sodium bicarbonate (3.47 g, 41.36 mmol) and Boc anhydride (5.42 g, 24.82 mmol) were added, and the mixture was stirred until complete. The mixture was extracted with ethyl acetate (40 mL × 3), the organic phase was concentrated, and the residue was dissolved in dichloromethane (30 mL). Triethylamine (3.83 g, 37.87 mmol) and acetyl chloride (2.23 g, 28.4 mmol) were added, and the mixture was stirred until complete. The mixture was washed with water, the organic phase was directly concentrated, and the crude product was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature until complete. The solution was concentrated and purified by column chromatography (H₂O:ACN = 0-95%) to give 3.0 g of compound 10a (yield: 75%).

[0192] MS(ESI): m / z 212.1 [M+H] + .

[0193] Step 2:

[0194] Compound 10a (806 mg, 3.81 mmol) was dissolved in ethanol (34 mL). Acetic acid (1.06 g, 3.81 mmol), tetraisopropoxytitanium (1.08 g, 3.81 mmol, 1.14 mL, purchased from Alfa), and compound 10b (1.33 g, 11.44 mmol, purchased from Bide) were added under ice bath cooling. The reaction mixture was heated until complete. Sodium cyanoborohydride (479.46 mg, 7.63 mmol) was added, and the mixture was stirred until complete. The reaction solution was concentrated to dryness, and the pH was adjusted to approximately 10 with saturated potassium carbonate solution. Extraction was performed using EA (30 mL × 3). The organic phases were combined and concentrated to give compound 10c (yield: 100%).

[0195] MS(ESI): m / z 294.1 [M+H] + .

[0196] Step 3:

[0197] Compound 10c (0.9 g, 3.07 mmol) was dissolved in methanol (9 mL), and 6 M HCl (9 mL) was added. The reaction mixture was heated until complete. The reaction solution was concentrated and purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%). The solution was then lyophilized with 1 N hydrochloric acid (10 mL) to give 230 mg of the hydrochloride salt of compound 10 (yield: 26.25%).

[0198] MS(ESI): m / z 252.1 [M+H] + .

[0199] 1 H NMR (400MHz, D2O): δ4.09-4.03(m,2H), 3.82-3.76(m,1H), 3.15-3.10(m,1H), 2.79-2.70(m,3H), 2.40-2.36(m,1H), 2.08-1.99(m,3H).

[0200] Example 11: Preparation of compound 11:

[0201] Step 1:

[0202] Compound 11a (1.0 g, 8.77 mmol, purchased from BDI) was dissolved in dichloromethane (10 mL), cooled in an ice-water bath, and pyridine (5.6 g, 70.8 mmol) and p-toluenesulfonyl chloride (2.0 g, 10.5 mmol) were added. The reaction was allowed to proceed to completion at room temperature. Ethyl acetate (100 mL) was added, and the organic phase was washed successively with water (30 mL) and saturated sodium chloride (30 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, purified by column chromatography (PE:EA = 10:1–3:1), and lyophilized to give 1.2 g of compound 11b (yield: 51.27%).

[0203] MS(ESI): m / z 269.1 [M+H] + .

[0204] Step 2:

[0205] Compound 11b (0.79 g, 2.95 mmol) and compound 1a (0.5 g, 2.95 mmol) were dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (0.61 g, 4.43 mmol) and potassium iodide (0.74 g, 4.43 mmol) were added. The mixture was then heated to 80 °C until complete. After cooling, the mixture was filtered and purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%). The purified solution was then lyophilized in 1N hydrochloric acid (10 mL) to give 0.31 g of the hydrochloride salt of compound 11 (yield: 33.81%).

[0206] MS(ESI): m / z 266.1 [M+H] + .

[0207] 1 H NMR(400MHz,D2O): δ3.69-3.64(m,1H),3.42-3.38(t,J=7.2Hz,2H),3.06-3.0 0(dd,J=16.0Hz,1H),2.27-2.57(m,4H),2.28-2.25(m,1H),2.00-1.91(m,1H).

[0208] Example 12: Preparation of compound 12:

[0209] Step 1:

[0210] Compound 12a (0.4 g, 4.14 mmol, purchased from BDI) was dissolved in dichloromethane (10 mL), cooled in an ice-water bath, and pyridine (2.66 g, 33.61 mmol) and p-toluenesulfonyl chloride (0.95 g, 5.00 mmol) were added. The reaction was allowed to proceed to completion at room temperature. Ethyl acetate (100 mL) was added, and the organic phase was washed successively with water (30 mL) and saturated sodium chloride (30 mL). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 10:1–3:1) to give 0.81 g of compound 12b (yield: 77.74%).

[0211] MS(ESI): m / z 251.1 [M+H] + .

[0212] Step 2:

[0213] Compounds 12b (0.45 g, 2.66 mmol) and 1a (0.66 g, 2.66 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (0.55 g, 3.99 mmol) and potassium iodide (0.66 g, 3.99 mmol) were added. The mixture was then heated to 80 °C until complete. After cooling, the mixture was filtered and purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%). The purified solution was then lyophilized in 1N hydrochloric acid (10 mL) to give 0.35 g of the hydrochloride salt of compound 12 (yield: 53.81%).

[0214] MS(ESI): m / z 248.1 [M+H] + .

[0215] 1 H NMR (400MHz, D2O): δ6.20-5.90(m,1H),3.67-3.62(m,1H),3.33-3.29(t,J=7.2Hz,2H), 3.05-3.00(dd,J=15.2Hz,1H),2.70-2.61(m,3H),2.36-2.22(m,3H),1.98-1.93(m,1H).

[0216] Example 13: Preparation of compound 13:

[0217] Step 1: Compound 13a (1.3 g, 11.81 mmol, purchased from B&D) was dissolved in dichloromethane (20 mL) and cooled in an ice-water bath. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.49 g, 11.82 mmol) and triethylamine (2.39 g, 23.63 mmol) were added. The reaction mixture was stirred in an ice-water bath until complete. A solution of compound 1a (2.0 g, 11.82 mmol) and triethylamine (2.39 g, 23.63 mmol) in N,N-dimethylformamide (20 mL) was added, and the reaction was allowed to proceed to completion at room temperature. The solution was concentrated and purified by column chromatography (5-50% MeCN:H2O) to give 1.4 g of compound 13b (yield: 33.53%).

[0218] MS(ESI): m / z 262.1 [M+H] + .

[0219] Step 2:

[0220] Compound 13b (0.73 g, 2.76 mmol) was dissolved in tetrahydrofuran (7 mL). Borane tetrahydrofuran solution (16.5 mL, 1.0 M) was added dropwise under nitrogen protection, followed by heating to 65 °C until the reaction was complete. The reaction solution was cooled to 0 °C, methanol was added until no more bubbles appeared, then 1 N dilute hydrochloric acid (10 mL) was added, and the reaction was stirred at 70 °C until complete. A saturated potassium carbonate solution (60 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%), and lyophilized in 1 N hydrochloric acid (10 mL) to give 0.42 g of compound 13 hydrochloride (yield: 61.78%).

[0221] MS(ESI): m / z 248.1 [M+H] + .

[0222] 1 H NMR (400MHz, D2O): δ3.73-3.63 (m, 3H), 3.07-3.02 (dd, J = 15.2Hz, 1H), 2.71-2. 61(m,3H),2.32-2.28(m,1H),2.00-1.91(m,1H),1.75-1.66(t,J=19.2Hz,3H).

[0223] Example 14: Preparation of compound 14:

[0224] Compound 14a (0.68 g, 3.55 mmol, purchased from Bidet) and compound 1a (0.5 g, 2.95 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (0.81 g, 5.92 mmol) was added. The mixture was heated to 80 °C until the reaction was complete. After cooling, the mixture was filtered and purified by HPLC (0.5% NH4HCO3 H2O:ACN = 0-95%). The purified solution was then lyophilized in 1N hydrochloric acid (10 mL) to give 0.31 g of the hydrochloride salt of compound 14 (yield: 44.98%).

[0225] MS(ESI): m / z 234.1 [M+H] + .

[0226] 1 H NMR (400MHz, D2O): δ6.41-6.14(m,1H), 3.75-3.58(m,3H), 3.07-3.02(dd,J=15.6Hz,1H), 2.71-2.62(m,3H), 2.32-2.23(m,1H), 2.01-1.93(m,1H).

[0227] Example 15 Preparation of Compound 15

[0228] Step 1:

[0229] Compound 15a (500 mg, 2.26 mmol, purchased from Bioderm), Boc anhydride (1.97 g, 9.04 mmol, purchased from Titan), and DMAP (55.2 mg, 0.45 mmol) were dissolved in acetonitrile (20 mL), and triethylamine (343 mg, 3.39 mmol) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction solution was concentrated and purified by column chromatography (PE:EA = 100:0–50:50) to give 982 mg of compound 15b (yield: 100%).

[0230] MS(ESI): m / z 422.2 [M+H] + .

[0231] Step 2:

[0232] Compound 15b (590 mg, 1.4 mmol) was dissolved in methanol (30 mL) and stirred. 10% palladium on carbon (247 mg) was added, and the mixture was purged with hydrogen three times. The mixture was stirred until the reaction was complete. The mixture was filtered, and the filter cake was washed three times with methanol (10 mL). The filtrate was concentrated to give 540 mg of compound 15c (yield: 98.54%).

[0233] MS(ESI): m / z 392.2 [M+H] + .

[0234] Step 3:

[0235] Compound 15c (500 mg, 1.28 mmol) was dissolved in DMF (20 mL), and propionic anhydride (182 mg, 1.4 mmol) and DIEA (330 mg, 2.55 mmol) were added. The mixture was stirred until the reaction was complete. 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was collected, dried, and concentrated to give 550 mg of the hydrochloride salt of compound 15d (yield: 96.22%).

[0236] MS(ESI): m / z 448.2 [M+H] + .

[0237] Step 4:

[0238] Compound 15d (550 mg, 1.23 mmol) was dissolved in 10 mL of THF, cooled in an ice-water bath, and a boranetetrahydrofuran complex (6.14 mL, 1 M in THF) was added. The mixture was heated to 60 °C and stirred until the reaction was complete. The reaction was quenched with methanol, and 5 mL of 2 M HCl was added. The mixture was heated to 70 °C and stirred until the reaction was complete. 30 mL of water was added, and the mixture was extracted with methyl tert-butyl ether (30 mL × 2). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE:EA = 100:0–50:50) to give 332 mg of compound 15e (yield: 62.31%).

[0239] MS(ESI): m / z 434.2 [M+H] + .

[0240] Step 5:

[0241] At room temperature, 8 mL of 4 M dioxane hydrochloride was added to compound 15e (332 mg, 765 μmol), and the mixture was stirred until the reaction was complete. The mixture was concentrated, and 10 mL of ethyl acetate was added to the residue and stirred for 5 minutes. The mixture was then filtered, and the filter cake was washed with 10 mL of ethyl acetate. The filter cake was collected and dried to give 183 mg of compound 15 (yield: 78.03%).

[0242] 1 H NMR (400MHz, D2O): δ7.67-7.65(m,1H),7.60-7.56(m,2H),7.44-7.41(m,1 H),7.01(s,1H),3.31-3.36(m,2H),1.71-1.52(m,2H),0.93-0.89(m,3H).

[0243] Example 16 Preparation of the control compound

[0244] It was prepared according to the method disclosed in patent WO2013096816A1.

[0245] Biological evaluation

[0246] Test Example 1: Efficacy of the disclosed compound in an asthmatic mouse model

[0247] This study evaluated the efficacy of the disclosed compounds in an ovalbumin (OVA)-induced mouse asthma model. Six- to eight-week-old female BALB / c mice were randomly divided into five groups: negative control (NC), OVA-induced asthma model (Model), OVA-induced and control compound 100 mg / kg administration group, OVA-induced and compound 7 100 mg / kg administration group, and OVA-induced and compound 2 100 mg / kg administration group. Administration occurred from Day 0 to Day 42. Sensitization was achieved by intraperitoneal injection of 400 μg OVA / Al(OH)3 on Days 14 and 21. Challenge was performed by nebulization with 3% OVA solution from Days 36 to 42. Whole blood was collected 4 hours after the final challenge, and eosinophil counts were performed using a hematology analyzer.

[0248] The results are shown in Figure 1. On Day 42, compared with the negative control group (NC), the number of eosinophils in the blood of the model group (Model) was significantly increased (p<0.01), indicating that the model was successfully constructed. Compared with the model group, the number of eosinophils in the control compound, compound 2, and compound 7 administration groups was significantly reduced, and compound 7 was more effective than the control compound (p<0.001).

[0249] Test Example 2: Distribution test of the disclosed compound in rat bone marrow

[0250] The mechanism by which the control compound reduces eosinophils in the blood is by inhibiting the maturation of eosinophils in the bone marrow. Therefore, this study evaluated the distribution of the disclosed compound in rat bone marrow. Male SD rats were administered 30 mg / kg of the control compound and compound 7 by gavage, respectively. Plasma and bone marrow samples were collected at 0.5, 2, and 8 h after administration to determine drug concentrations.

[0251] The results are shown in Table 1. The exposure of compound 7 in rat plasma was twice that of the control compound, and the exposure in bone marrow was 2.7 times that of the control compound, consistent with significantly better efficacy.

[0252] Table 1. Rat bone marrow distribution data

[0253] Test Example 3: PK Characterization of the Disclosed Compound in Canine Plasma

[0254] The control compound was administered twice daily (BID) in asthmatic patients. This study evaluated the pharmacokinetic (PK) characteristics of the disclosed compound in Beagle dog plasma. The control compound and compound 7 were administered by single gavage at a dose of 10 mg / kg. Venous blood samples were collected before administration and at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after administration to detect drug concentrations.

[0255] The results are shown in Table 2, with the control compound showing t in dogs. 1 / 2 For 5.44 hours, MRT 0-∞ The t-hours of compound 7 in dogs were 8.26 h. 1 / 2 For 10.015h, MRT 0-∞ The terminal elimination half-life of compound 7 was 13.85 h, approximately twice that of the control compound, and its average residence time in dogs was approximately 1.7 times that of the control compound. Compound 7 shows promise for extending the dosing interval and has potential for QD (quantitative dose) administration.

[0256] Table 2 Pharmacokinetic parameters of the compounds in canine plasma

Claims

1. A compound of formula I ###0001### or a pharmaceutically acceptable salt thereof. in: R 1a , R 1b , R 3 are each independently selected from the group consisting of hydrogen, C 1-6 1-6C-alkyl, 3- to 10-membered cycloalkyl, said alkyl, cycloalkyl being optionally substituted by one or more R A ; R 2a R 2b R 4a R 4b Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R B Replaced; R 5 Selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3- to 10-membered cycloalkyl, 3- to 10-membered heteroalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more R groups. C replace; R A R B R C Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups; m is selected from 1, 2, 3, 4, 5, 6; b is selected from 0, 1, 2, 3, 4, 5, 6; The compounds of formula I cannot be 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of Formula I is a compound of Formula II-A, in, Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heteroalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R a Each group is independently selected from halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, and C groups. 1-6 Alkyl, C 1-6 alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally surrounded by one or more R D Replaced; R D Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 10-membered cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl may optionally be substituted with one or more halogens, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, or cyano groups; a is selected from 0, 1, 2, 3; The compound of formula II-A cannot be R 1a , R 1b , R 2a , R 3 , R 4a , R 4b , R 2b , b, m are as defined in claim 1.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring A is 3- to 10-membered cycloalkyl or 3- to 10-membered heteroalkyl, said cycloalkyl, heterocyclyl optionally substituted with one or more R a substituents, R a As defined in claim 2.

4. The compound according to any one of claims 1 to 3, wherein the compound of Formula I is selected from the group consisting of Formula III-A, or a pharmaceutically acceptable salt thereof. in, X is selected from -(CH2)-, -NH-, -S-, and -O-; p is selected from 0, 1, 2, 3; q is selected from 0, 1, 2, and 3; R 1a , R 1b , R 2a , R 3 , R 4a , R 4b , R 2b , b, m are as defined in claim 1, R a , a is as defined in claim 2.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1a R 1b R 2a R 3 R 4a R 4b Each is hydrogen independently.

6. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein m is 1.

7. The compound according to any one of claims 1 to 6, wherein the compound of Formula I is selected from the group consisting of a compound of Formula III-A', or a pharmaceutically acceptable salt thereof, wherein R 2b , b is as defined in claim 1, R a , a is as defined in claim 2, X, p, q are as defined in claim 4.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 7, wherein X is selected from -(CH2)-, -O-, preferably -(CH2)-.

9. The compound or its pharmaceutically acceptable salt according to any one of claims 4 to 8, wherein p is selected from 0, 1, and 2.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 9, wherein q is 0 or 1.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 4 to 10, wherein the compound of Formula I is selected from the group consisting of a compound of Formula IV-A, wherein r is selected from 1, 2, 3, and 4. R 2b , b is as defined in claim 1, R a , a is as defined in claim 2.

12. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein r is 1.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein b is 0.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, wherein R a Each is independently selected from halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy groups, preferably halogen, hydroxyl, mercapto, amino, cyano, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy, and more preferably halogen, hydroxyl, cyano, or methyl.

15. A compound of formula I ###0002### or a pharmaceutically acceptable salt thereof, selected from the group consisting of ###0003### 16. A compound of formula I ###0002### or a pharmaceutically acceptable salt thereof, selected from the group consisting of ###0003### 17. The compound according to any one of claims 1 to 16, or an isotope-substituted product of the pharmaceutically acceptable salt thereof, preferably, the isotope-substituted product is a deuterated product.

18. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in claim 17, and a pharmaceutically acceptable excipient.

19. Use of the compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or an isotope substitute as described in claim 17, or a pharmaceutical composition as described in claim 18, in the preparation of a medicament for treating asthma.

20. The use according to claim 19, wherein the asthma is allergic asthma.

21. Use of the compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or an isotope substitute as claimed in claim 17, or a pharmaceutical composition as claimed in claim 18, in the preparation of a medicament for treating eosinophil-related diseases.

22. The use as described in claim 21, wherein the eosinophil-related disease is eosinophil-associated asthma.

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