TLR7 and TLR8 inhibitors, and preparation method, pharmaceutical composition and application thereof

Abstract

A compound of formula (I), a deuterated substance thereof, or pharmaceutically acceptable salts thereof, methods of preparation, pharmaceutical compositions and uses thereof. The compound can be used for preventing and / or treating inflammatory diseases, autoimmune diseases and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to TLR7 and TLR8 inhibitors, pharmaceutical compositions containing the inhibitors, and their uses, as well as methods for preparing the inhibitors. The compounds and pharmaceutical compositions can be used to prevent and / or treat inflammatory or autoimmune diseases, etc. Background Art

[0002] Toll-like receptors (TLRs) are a class of molecular pattern recognition receptors that are widely distributed in different tissues. They monitor and recognize different pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and play an important role in both innate and acquired immunity (Kawai T. et al., Nature Immunol., 11, 2010, 373-384).

[0003] TLRs are expressed in various immune cells and can be divided into two categories according to their expression sites: TLRs expressed on the cell membrane (TLR1, 2, 4, 5, 6) and TLRs expressed on the endosomal membrane (TLR3, 7, 8, 9), which recognize different components and molecules in PAMPs. Among them, TLR7, 8, and 9 are mainly highly expressed in DC cells and B cells. TLR7 and 8 mainly recognize ssRNA, and TLR9 mainly recognizes CpG-DNA.

[0004] TLR7 and TLR8 are most similar in sequence and function. A large number of studies have shown that the activation of TLR7 and 8 can trigger type I interferon responses and various inflammatory responses. In the case of autoimmune disorders such as systemic lupus erythematosus (SLE), abnormal and persistent activation of TLR7 and 8 leads to the deterioration of the disease state. Therefore, the development of compounds with selective and potent inhibitory activity is expected to become a new method for preventing and / or treating inflammatory and autoimmune diseases by antagonizing TLR7 and 8 and inhibiting over-activated immune responses. Summary of the invention

[0005] Provided herein is a novel TLR7 and TLR8 inhibitor (or antagonist), which can be used to prevent and / or treat inflammatory or autoimmune diseases, etc.

[0006] According to one aspect herein, there is provided a compound represented by formula (I), a deuterated substance thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] A is selected from a 5-10 membered heteroaromatic group or a benzene ring group containing 1-5 ring heteroatoms;

[0010] B is selected from a benzene ring group, a benzene ring and C 3-7 A fused ring group fused to a saturated or unsaturated non-aromatic carbon ring, a fused ring group fused to a benzene ring and a 3-7-membered saturated or unsaturated non-aromatic heterocyclic ring containing 1-3 ring heteroatoms, a fused ring group fused to a benzene ring and a 5-10-membered heteroaromatic ring containing 1-3 ring heteroatoms, a fused ring group fused to a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms, and a 5-6-membered monocyclic heteroaromatic group containing 1-3 ring heteroatoms;

[0011] X is selected from a cyclobutane group, an oxetane group, and an azetidine group, and A and B are ortho or para to each other on X;

[0012] When A and B are fused ring groups, the substituents on A and B are independently located on any ring of the fused ring group; and A and B can be independently connected to X through C or heteroatoms on any ring of the fused ring group;

[0013] R1 is independently selected from H, halogen, CN, -OR4, =O, -N(R4)R5, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl, and 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl are each independently optionally substituted with one or more groups selected from F, Cl, Br, OH, CN, NH2, and =O;

[0014] R2 is selected from -C 1-4 Alkylene (R4) R5, -OC 0-4 Alkylene-R5, -SC 0-4 Alkylene-R5, -C(O)-C 0-4 Alkylene-R5, -C(O)C 0-4 Alkylene -OR5, -C(O)C 0-4 Alkylene-N(R4)-C 0-4 Alkylene-R5, -N(R4)-C 0-4 Alkylene-R5, -N(R4)C(O)-C 0-4 Alkylene-R5, -N(R4)S(O)2-C 0-4 Alkylene-R5, -S(O)2R5, -S(O)2N(R4)-C 0-4Alkylene-R5; 3-7 membered monocyclic heterocycloalkyl containing 1-3 ring heteroatoms, 5-10 membered heteroaryl containing 1-3 ring heteroatoms, 5-11 membered heterobridged cycloalkyl containing 1-3 ring heteroatoms; the alkylene, monocyclic heterocycloalkyl, heteroaryl, heterobridged cycloalkyl are each independently optionally substituted by one or more selected from F, Cl, Br, OH, CN, NH2, R8, -C 1-4 Alkylene (R4) R5, -OR4, -N(R4) R5, -C(O) R5, -C(O)C 0-4 Alkylene -N(R4)R5, -N(R4)C(O)R5;

[0015] R3 is independently selected from H, halogen, OH, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms, -N(R4)-C 0-4 Alkylene-R5, -C(O)-C 0-4 Alkylene-R5, -C(O)C 0-4 Alkylene OR5, -C(O)C 0-4 Alkylene-N(R4)-C 0-4 Alkylene R5, -N(R4)C(O)-C 0-4 Alkylene-R5, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and alkylene are each independently optionally substituted with one or more groups independently selected from F, Cl, Br, OH, CN, NH2;

[0016] R4 and R5 are each independently selected from H, OH, NH2, C 1-4 Alkyl, C 3-7 Monocyclic alkyl, 3-7 membered monocyclic heterocyclic alkyl containing 1-3 ring heteroatoms, C 5-8a fused ring group consisting of a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a 3-7-membered saturated carbocycle fused to a fused ring group; a fused ring group consisting of a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a fused ring group consisting of a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a fused ring group consisting of a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms and a fused ring group consisting of a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms and a 3-7-membered saturated carbocycle fused to a fused ring group consisting of The alkyl, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, heterobridged cycloalkyl, condensed ring group, and spirocyclic group are each independently substituted by one or more groups selected from the following: F, Cl, Br, OH, CN, NH2, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered 1-4 Alkylene-S(O)2-C 1-4 Alkyl, C 1-4 Alkanoyl-substituted 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms-carbonyl C 0-4 Alkyl, -C(O)-C 1-4 alkyl, C optionally substituted by one or more groups selected from F, Cl, Br, OH, CN or NH2 1-4 alkyl;

[0017] When R4 and R5 are connected to the same C or N, R4 and R5 can also form a 3-7 membered aromatic or non-aromatic ring group containing 0-3 ring heteroatoms together with the C or N to which they are connected;

[0018] m and n are each independently selected from integers of 0-4, such as 0, 1, 2, 3, 4;

[0019] The ring heteroatoms are independently selected from N, O, or S;

[0020] The alkyl group and the alkylene group are linear or branched.

[0021] Preferably, in formula (I), A is selected from a fused ring group consisting of a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms, or a fused ring group consisting of a benzene ring and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms;

[0022] R1 is independently selected from H, halogen, CN, =O, or C 1-4Alkyl; said alkyl being optionally substituted with one or more F, Cl, or Br;

[0023] R2 is selected from -C 1-4 Alkylene (R4) R5, -C(O)N(R4) R5, -N(R4) R5, 5-11 membered heterobridged cycloalkyl containing 1-3 ring heteroatoms;

[0024] R3 is independently selected from H, halogen, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)-C 1-4 Alkyl, -C(O)NH-C 1-4 Alkyl; the alkyl or alkoxy groups are each independently optionally substituted with one or more F, Cl, or Br;

[0025] R4 is H; or C 1-4 alkyl;

[0026] R5 is selected from C 3-7 Monocyclic alkyl; 3-7 membered monocyclic heterocyclic alkyl containing 1-3 ring heteroatoms; 5-11 membered heterobridged cycloalkyl containing 1-3 ring heteroatoms; spirocyclic group consisting of 3-7 membered saturated heterocyclic ring containing 1-3 ring heteroatoms and 3-7 membered saturated carbocyclic ring; the monocyclic alkyl, monocyclic heterocyclic alkyl, heterobridged cycloalkyl, and spirocyclic group are each independently substituted by one or more groups selected from the following: -NH2, -C 1-4 Alkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms, -C 1-4 Alkylene-S(O)2-C 1-4 Alkyl, C 1-4 Alkanoyl-substituted 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms-carbonyl C 0-4 Alkyl, -C(O)-C 1-4 alkyl, C optionally substituted by one or more groups selected from F, Cl, Br, OH, and CN 1-4 alkyl;

[0027] m and n are each independently selected from 0, 1, or 2.

[0028] Preferably, in formula (I), A is selected from a thieno[2,3-d]pyrimidine group, a thieno[2,3-b]pyridine group, a pyrazolo[3,4-d]pyrimidine group, a pyrazolo[3,4-b]pyridine group, a quinazoline, a quinoline, a pyrazolo[4,3-b]pyridine group, and a pyrazolo[4,3-d]pyrimidine group;

[0029] X is selected from a cyclobutane group and an azetidine group, and A and B are ortho or para to each other on X, preferably para to each other;

[0030] B is selected from a benzene ring group, a pyridine group, a 1,3-dihydroisoindole group, an indazole group, a benzimidazole group, a benzocyclopentane group, a benzofuran group, a 2,3-dihydrobenzofuran group, a 2,3-dihydroindole group, an indole group, an imidazo[1,2-a]pyridine group, a 1,2,3,4-tetrahydroisoquinoline group, a 1,2-dihydroisoquinoline group, a quinazoline group, a thieno[3,2-b]thiophene group, an imidazo[2,1-b]thiazole group, and a benzo[d]thiazole group;

[0031] R1 each independently represents H, halogen, CN, =O, methyl, ethyl, or trifluoromethyl;

[0032] R2 is selected from 8-azabicyclo[3.2.1]octan-3-yl, N-(8-azabicyclo[3.2.1]octan-3-yl)-N-methyl-carbamoyl, N-(8-azabicyclo[3.2.1]octan-3-yl)-N-methyl-amino, N-(8-azabicyclo[3.2.1]octan-3-yl)-methyl, N-(9-azabicyclo[3.3.1 ]nonan-3-yl)-N-methyl-carbamoyl, N-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-N-methyl-carbamoyl, N-(2-azabicyclo[2.2.1]heptane-5-yl)-N-methyl-carbamoyl, N-(2-azabicyclo[2.2.2]octan-5-yl)-N-methyl-carbamoyl, N-(3 -azabicyclo[3.2.1]octan-8-yl)-N-methyl-carbamoyl, N-(4-aminocyclohexyl)-N-methyl-carbamoyl, N-(piperidin-3-yl)-N-methyl-carbamoyl, N-(3-azabicyclo[3.1.0]hexane-6-yl)-N-methyl-carbamoyl, N-(4-azaspiro[2,5]octan-6-yl)-N-methyl-carbamoyl, wherein the 8-nitrogen position of 8-azabicyclo[3.2.1]octan-3-yl in the above groups is optionally substituted with methyl, ethyl, trifluoroethyl, cyanomethyl, tetrahydropyran-4-yl, hydroxyisobutyl, tetrahydropyrrol-2-ylformyl, methylsulfonylethyl, oxetan-3-yl, N-acetylpiperidin-4-yl, morpholin-4-ylcarbonylmethyl, or acetyl;

[0033] R3 is each independently selected from H, halogen, -OH, methyl, methoxy, or trifluoromethyl.

[0034] Preferably, in formula (I), A is selected from a fused ring group consisting of a 5-7 membered heteroaromatic ring containing 1-3 ring heteroatoms and a 5-7 membered heteroaromatic ring containing 1-3 ring heteroatoms;

[0035] R1 is independently selected from H, halogen, or C1-4 alkyl;

[0036] R2 is selected from -C(O)N(R4)R5, a 5-11 membered heterobridged cycloalkyl group containing 1-3 ring heteroatoms;

[0037] R3 are each independently selected from H, halogen, C 1-4 alkyl;

[0038] R4 is H; or C 1-4 alkyl;

[0039] R5 is selected from 5-11 membered hetero-bridged cycloalkyl containing 1-3 ring heteroatoms; the hetero-bridged cycloalkyl is independently optionally substituted by one or more groups selected from the following: -C 1-4 Alkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms, -C 1-4 Alkylene-S(O)2-C 1-4 Alkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms-carbonyl C 0-4 alkyl, C optionally substituted by one or more groups selected from F, Cl, Br, OH, and CN 1-4 alkyl;

[0040] m and n are each independently selected from 0, 1, or 2.

[0041] Preferably, in formula (I), A is selected from a thieno[2,3-d]pyrimidine group, a thieno[2,3-b]pyridine group, a pyrazolo[3,4-d]pyrimidine group, a pyrazolo[3,4-b]pyridine group, a pyrazolo[4,3-b]pyridine group, and a pyrazolo[4,3-d]pyrimidine group;

[0042] X is selected from a cyclobutane group and an azetidine group, and A and B are ortho or para to each other on X, preferably para to each other;

[0043] B is selected from a benzene ring group, a pyridine group, a 1,3-dihydroisoindole group, an indazole group, and a benzimidazole group;

[0044] R1 each independently represents H, halogen or methyl;

[0045] R2 is selected from 8-azabicyclo[3.2.1]octan-3-yl or N-(8-azabicyclo[3.2.1]octan-3-yl)-N-methyl-carbamoyl, wherein the 8-azabicyclo[3.2.1]octan-3-yl in the above groups is optionally substituted with methyl, isopropyl, trifluoroethyl, cyanomethyl, tetrahydropyran-4-yl, hydroxyisobutyl, tetrahydropyrrol-2-ylformyl, and methylsulfonylethyl at the 8-position N;

[0046] R3 are each independently selected from H, or halogen.

[0047] The ring heteroatoms are independently selected from N, O, or S.

[0048] Preferably, the compound represented by formula (I) is selected from, but not limited to, the following compounds:

[0049]

[0050]

[0051] In another aspect, provided herein is a method for preparing the compound represented by the above formula (I), its deuterated product, or a pharmaceutically acceptable salt thereof.

[0052] For example, it can be prepared by the method of Scheme 1 as follows:

[0053]

[0054] The definitions of the groups in each formula are as described above. Compound 1-a as shown in Scheme 1 can be prepared by any method known in the art and / or commercially available. As shown in Scheme 1, compound 1-a and trichloroacetyl chloride react in the presence of an organic solvent and zinc to obtain compound 1-b; compound 1-b is reduced in the presence of zinc to obtain compound 1-c, which is further reduced to obtain compound 1-d; compound 1-d is hydroxylated in the presence of an organic solvent and triphenylphosphine to obtain compound 1-e, which is then reacted with a halogenated heteroaryl compound. The reaction is carried out in the presence of a nickel catalyst to obtain compound 1-f; the ester is then hydrolyzed to obtain compound 1-g, and compound 1-g is subjected to amide condensation with HN(R4)R5 to obtain the final product compound 1-h.

[0055]

[0056] As shown in Scheme 2, compound 2-a prepared by any method known in the art and / or commercially purchased is reacted with tert-butyl 3-iodoazetidine-1-carboxylate in the presence of an organic solvent and a nickel catalyst to generate compound 2-b; after deprotection, compound 2-c is obtained, and compound 2-c is reacted with a halogenated heteroaryl compound Compound 2-d is obtained through coupling reaction; compound 2-d is subjected to ester hydrolysis to obtain compound 2-e, and compound 2-e is subjected to amide condensation with HN(R4)R5 to obtain the final product compound 2-f.

[0057]

[0058] As shown in Scheme 3, compound 3-a prepared by any method known in the art and / or commercially purchased is reacted with tert-butyl 3-iodoazetidine-1-carboxylate to produce compound 3-b; compound 3-b is deprotected to obtain compound 3-c, which is then reacted with A coupling reaction is performed to obtain compound 3-d; compound 3-d is subjected to ester hydrolysis reaction to obtain compound 3-e; compound 3-e is subjected to amide condensation with HN(R4)R5 to obtain the final product compound 3-f.

[0059]

[0060] As shown in Scheme 4, compound 4-a prepared by any method known in the art and / or commercially purchased is reacted with (3-bromopropyl)triphenylphosphonium bromide to obtain 4-b; compound 4-b is oxidized by m-CPBA to obtain 4-c, which is then reacted with a trifluoromethanesulfonic acid reagent (such as sodium bis(trimethylsilyl)amide) to generate 4-d; palladium catalysis is used to convert it into 4-e, which is then reacted with a halogenated heteroaryl compound.

[0061] Compound 4-f is obtained through coupling reaction; compound 4-f is reduced and hydrolyzed to obtain 4-h, which is subjected to amide condensation with HN(R4)R5 to obtain the final product compound 4-i.

[0062] On the other hand, a pharmaceutical composition is provided, comprising a compound represented by the above formula (I), a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The composition can be used to prevent and / or treat inflammatory diseases or autoimmune diseases. The inflammatory diseases and autoimmune diseases include, for example, Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allogeneic transplant rejection, chronic obstructive pulmonary disease, Graves' disease, rheumatoid arthritis, systemic lupus erythema, lupus nephritis, cutaneous lupus, psoriasis, Sjögren's syndrome, psoriasis, etc.

[0063] On the other hand, the present invention provides the use of the compound represented by the above formula (I), its deuterated substance, or their pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of a drug for preventing and / or treating inflammatory diseases or autoimmune diseases. The inflammatory diseases and autoimmune diseases include, for example, Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allogeneic transplant rejection, chronic obstructive pulmonary disease, Graves' disease, rheumatoid arthritis, systemic lupus erythema, lupus nephritis, cutaneous lupus, psoriasis, Sjögren's syndrome, psoriasis, etc.

[0064] On the other hand, a method for preventing and / or treating an inflammatory disease or an autoimmune disease is provided, comprising administering to an individual in need thereof a preventive and / or therapeutically effective amount of a compound represented by the above formula (I), a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition. The inflammatory disease and autoimmune disease include, for example, Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allogeneic transplant rejection, chronic obstructive pulmonary disease, Graves' disease, rheumatoid arthritis, systemic lupus erythema, lupus nephritis, cutaneous lupus, psoriasis, Sjögren's syndrome, psoriasis, etc.

[0065] In this article,

[0066] Ring heteroatoms are independently selected from N, O, or S.

[0067] Examples of the "halogen" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0068] “C 0-4 "Alkylene", when the number of C atoms is 0, it means that the alkylene does not exist. For example, -OC 0-4 Alkylene-R5, when the number of carbon atoms in the alkylene is 0, represents -O-R5.

[0069] The "alkylene group" includes a linear or branched alkylene group, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

[0070] “C 2-4 Examples of the "alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.

[0071] “C 2-4 Examples of the “alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 2-methyl-1-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

[0072] “C 1-4 Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0073] “C 1-4 Examples of the "alkanoyl group" include acetyl, propionyl, butyryl, and 2-methylpropionyl.

[0074] “C 3-7 Examples of the "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0075] The “5-10 membered heteroaryl group containing 1 to 5 ring heteroatoms” include pyrrole, imidazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyridine, pyrimidine, pyrimidine, pyridazine, pyridazine, pyrazine, pyrazine, triazine, benzofuran, benzothiophene, indole, indazole, isoindazole, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, benzotriazole , benzoxadiazole, benzothiadiazole, benzopyridine, benzopyrimidine, benzotriazine, pyridofuran, pyridothiophene, pyridopyrrole, pyridopyrazole, pyridoimidazole, pyridothiazole, pyridisothiazole, pyridoxazole, pyridisoxazole, pyridoxadiazole, pyridothiadiazole, pyridopyridine, pyridopyrimidine, pyridotriazine, furopyrrole, thiazolopyrimidine, pyrimidoimidazole, pyrimidopyrazole, pyridotriazole, pyrimidotriazole, etc.;

[0076] "Benzene ring and C 3-7 The "fused ring group fused to a saturated or unsaturated non-aromatic carbon ring" may include, for example, benzocyclobutane, benzocyclopentane, benzocyclopentene, benzocyclohexane, benzocyclohexene, etc.;

[0077] The “fused ring group in which a benzene ring is fused to a 3-7-membered saturated or unsaturated non-aromatic heterocyclic ring containing 1-3 ring heteroatoms” includes, for example, dihydrobenzofuran, dihydroisobenzofuran, indoline, isoindoline, benzo β-lactam ring, benzo β-lactone, benzoxadiole, tetrahydroquinoxaline, dihydrobenzoxazine, etc.;

[0078] Examples of the “fused ring group in which a benzene ring is fused to a 5-10 membered heteroaromatic ring containing 1-3 ring heteroatoms” include benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, benzotriazole, benzooxadiazole, benzothiadiazole, benzopyridine, benzopyrimidine, and benzotriazine;

[0079] Examples of the “fused ring group in which a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms is fused to a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms” include thienothiophene, pyridofuran, pyridothiophene, pyridopyrrole, pyridopyrazole, pyridoimidazole, pyridothiazole, pyridisothiazole, pyridoxazole, pyridisoxazole, pyridoxadiazole, pyridothiadiazole, pyridopyridine, pyridopyrimidine, pyridotriazine, furopyrrole, thiazolopyrimidine, pyrimidoimidazole, pyrimidopyrazole, pyridotriazole and the like;

[0080] Examples of the “5-6 membered monocyclic heteroaromatic group containing 1-3 ring heteroatoms” include pyrrole, imidazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, 1,2,3-triazole, 1,2,4-triazole, pyrazole, pyridine, pyrimidine, pyrimidine, pyridazine, pyridazine, pyrazine, pyrazine, triazine, and the like;

[0081] The “3-7 membered heterocycloalkyl group containing 1-3 ring heteroatoms” include pyrrolidine, tetrahydrofuran, morpholine, tetrahydropyran, dioxane, piperidine, piperazine, homopiperidine, homopiperazine, oxirane, oxetane, azetidine, thietane, thiomorpholine, thiotetrahydropyran, thioxane, dithiane, azepane, oxepane, thiepane, oxazepane, thiepane, thiazepane and the like;

[0082] “C 5-8 Examples of the "bridged cycloalkyl" include bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[3.1.1]heptane, etc.;

[0083] Examples of the “5- to 11-membered heterobridged cycloalkyl group containing 1 to 3 ring heteroatoms” include 1-azabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 2-oxabicyclo[2.2.2]octane, 2-oxabicyclo[2.1.1]hexane, 1-azabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 2-oxabicyclo[2.2.2]octane, 2-oxabicyclo[2.1.1]hexane, azabicyclo[3.2.2]nonane, 3,6-diazabicyclo[3.1.1]heptane, 3-aza-6-oxabicyclo[3.1.1]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 3-aza-8-oxabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2]octane, etc.;

[0084] The “spirocyclic group consisting of a 3-7-membered saturated heterocyclic ring containing 1-3 ring heteroatoms and a 3-7-membered saturated carbon ring” includes azaspirohexane, azaspiroheptane, azaspirooctane, azaspironane, oxaspirohexane, oxaspiroheptane, oxaspirooctane, oxaspirononane, etc.;

[0085] Examples of the “spirocyclic group consisting of a 3-7-membered saturated heterocyclic ring containing 1-3 ring heteroatoms and a 3-7-membered saturated heterocyclic ring containing 1-3 ring heteroatoms” include diazaheptane, diazaoctane, diazanonane, diazadecane, diazaundecane, oxazaheptane, oxazaoctane, oxazanonane, oxazadecane, oxazaundecane, and the like;

[0086] The compound shown in the above-mentioned formula (I), its deuterated substance or their pharmaceutically acceptable salts include various optical stereoisomers. The compound of the present invention can be asymmetric, for example, having one or more chiral centers. All optical stereoisomers, such as enantiomers and diastereomers, are included within the scope of the present invention unless otherwise specified. In the present invention, the compound containing the asymmetrically substituted carbon atom can be separated in any optically active form or racemic form. Various methods for preparing optically active forms are known in the art, for example, by resolving the racemic mixture or by stereoselective synthesis.

[0087] The present invention also includes all forms of the compounds whose atoms are various isotopes. Isotopes include all atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium.

[0088] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0089] Herein, the term "pharmaceutically acceptable salt" refers to salts formed with bases, such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, etc., when the compound has an acidic functional group; and to salts formed with acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, bisulfate, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, undecanoic acid, palmitic acid, stearic acid, oleic acid, malonic acid, adipic acid, lactic acid, malic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, ascorbic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, phthalic acid, p-toluenesulfonic acid, gluconic acid, galacturonic acid, dodecyl sulfuric acid, and various amino acids, etc. DETAILED DESCRIPTION

[0090] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content recorded in the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms fall within the scope of the present invention equally.

[0091] Intermediate 1. (1R,3s,5S)-3-(Methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0092] Synthesis of tert-butyl (1R,3s,5S)-3-(((benzyloxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (2)

[0093]

[0094] Dissolve (1R, 3s, 5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.0 g, 8.84 mmol) in dichloromethane (DCM) (10 mL), then add sodium bicarbonate (1.1 g, 13.27 mmol), then add water (10 mL), and finally add benzyl chloroformate (CbzCl) (2.3 g, 13.27 mmol), and stir the reaction solution at 25 ° C for 4 hours. The reaction solution was diluted with water (20 mL), then extracted three times with dichloromethane (30 mL), the organic phases were combined, and washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100: 1 to 5: 1) to obtain a white solid (2.4 g, yield: 75%). LC-MS: [M+Na] + :383.1.

[0095] Synthesis of tert-butyl (1R,3s,5S)-3-(((benzyloxy)carbonyl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (3)

[0096]

[0097] At 0°C, tert-butyl (1R, 3s, 5S) 3-(((benzyloxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 6.66 mmol) was dissolved in N,N-dimethylformamide (DMF) (20 mL), and then sodium hydride (60%, mineral oil) (479.0 mg, 11.98 mmol) was added. After stirring for half an hour, iodomethane (MeI) (1.1 g, 7.99 mmol) was added, and finally the reaction solution was stirred at 25°C for 1 hour. The reaction solution was diluted with water (50 mL), and then ethyl acetate (30 mL) was added for extraction three times. The organic phases were combined and washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 100: 1 to 5: 1) to obtain a white oil (2.4 g, yield: 96%).

[0098] LC-MS: [M+Na] + :397.2.

[0099] Synthesis of tert-butyl (1R,3s,5S)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (4)

[0100]

[0101] Tert-butyl (1R,3s,5S)-3-(((benzyloxy)carbonyl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 6.41 mmol) was dissolved in methanol (30 mL), and then 10% palladium carbon (136.0 mg) was added. The reaction solution was stirred at 25°C for 16 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude colorless oil (1.5 g, yield: 97%).

[0102] Example 1. N-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-N-methyl-4-((1r,3r)-3-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzamide (Compound 1)

[0103]

[0104] Synthesis of methyl 4-(2,2-dichloro-3-oxocyclobutyl)benzoate (2):

[0105]

[0106] 4-vinyl-benzoic acid methyl ester (2.50 g, 15.41 mmol) was dissolved in anhydrous ether (25 mL), and then zinc particles (5.0 g, 77.00 mmol) and trichloroacetyl chloride (13.1 g, 77.00 mmol) were added in sequence. After nitrogen degassing and replacement three times, the nitrogen system was maintained and the reaction solution was stirred at 50° C. for 16 hours. After LCMS monitoring of the reaction of the raw materials was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (4.2 g, yield: 100%), which was directly used in the next step.

[0107] LC-MS: [M+H] + :272.8.

[0108] Synthesis of methyl 4-(3-oxocyclobutyl)benzoate (3):

[0109]

[0110] Methyl 4-(2,2-dichloro-3-oxocyclobutyl)benzoate (4.2 g, 15.38 mmol) was dissolved in acetic acid (100 mL), and then zinc particles (2.0 g, 30.8 mmol) were added. The reaction solution was heated to 100 ° C for 16 hours. After the reaction of the raw materials was complete, the reaction solution was cooled to room temperature, and then slowly added to the reaction solution dropwise into a saturated sodium bicarbonate solution (400 mL), extracted three times with ethyl acetate (400 mL), and the organic phases were combined and washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1 to 3 / 1) to obtain a yellow oil (1.0 g, yield: 32%).

[0111] LC-MS: [M+H] + :205.1.

[0112] Synthesis of methyl 4-(3-hydroxycyclobutyl)benzoate (4)

[0113]

[0114] 4-(3-oxocyclobutyl)benzoic acid methyl ester (2.1g, 10.28mmol) was dissolved in methanol (15mL) and tetrahydrofuran (15mL), and sodium borohydride (1.95g, 51.40mmol) was slowly added at 0°C. After nitrogen degassing and replacement three times, the nitrogen system was maintained, and the reaction solution was finally warmed to 25°C and stirred for 2 hours. After LCMS monitoring of the reaction of the raw materials was complete, a saturated sodium chloride solution (15mL) was slowly added to the reaction solution to quench, and then extracted three times with ethyl acetate (15mL), the organic phase was combined, and washed three times with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain a yellow oil (1.0g, yield: 47%).

[0115] LC-MS: [M+H] + :207.1.

[0116] Synthesis of methyl 4-(3-iodocyclobutyl)benzoate (5):

[0117]

[0118] 4-(3-hydroxycyclobutyl) benzoic acid methyl ester (1.0g, 4.85mmol) is dissolved in tetrahydrofuran (10mL), then iodine (2.5g, 9.70mmol), imidazole (660.0mg, 9.70mmol) and triphenylphosphine (PPh3) (2.5g, 9.70mmol) are added successively, after nitrogen degassing is replaced three times, nitrogen system is kept, and finally reaction solution is stirred at 25 ℃ for 16 hours. After LCMS monitoring raw material reaction is complete, reaction solution is filtered and concentrated under reduced pressure to obtain crude product. Crude product is purified by rapid silica gel column (petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to obtain colorless oil (1.1g, yield: 72%).

[0119] LC-MS: [M+H] + :316.7.

[0120] Synthesis of methyl 4-((1r,3r)-3-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzoate (6):

[0121]

[0122] Methyl 4-(3-iodocyclobutyl)benzoate (1.1 g, 3.48 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then 4-chloro-2-methylthiophene[2,3-d]pyrimidine (771.0 mg, 4.18 mmol), ethylene glycol dimethyl ether nickel bromide (NiBr2(DME)) (59.0 mg, 0.19 mmol), palladium dichloride (34.0 mg, 0.19 mmol), 1,3-bis(diphenylphosphino)propane (dppp) (79.0 mg, 0.19 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (dbbpy) (51.0 mg, 0.19 mmol), zinc particles (455.0 mg, 6.96 mmol) and potassium bromide (828.0 mg, 6.96 mmol), after nitrogen degassing and replacement three times, the nitrogen system was maintained and the reaction solution was stirred at 80 ° C for 16 hours. After LCMS monitoring of the complete reaction of the raw materials, the reaction solution was poured into water (15 mL) for dilution, extracted three times with ethyl acetate (15 mL), the organic phases were combined, and washed three times with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel plate (petroleum ether / ethyl acetate = 2:1) to obtain a white solid (107.0 mg, yield: 9%).

[0123] LC-MS: [M+H] + :339.0.

[0124] Synthesis of 4-((1r,3r)-3-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzoic acid (7):

[0125]

[0126] Methyl 4-((1r,3r)-3-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzoate (107.0 mg, 0.32 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), and then lithium hydroxide (15.0 mg, 0.63 mmol) was added, and the reaction solution was stirred at 25°C for 8 hours. 1N hydrochloric acid solution was added to the reaction solution to adjust the pH to 5, and then extracted three times with ethyl acetate (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product (103.0 mg, yield: 100%), which was used directly in the next step without purification.

[0127] LC-MS: [M+H] + :325.0.

[0128] Synthesis of tert-butyl (1R,3s,5S)-3-(N-methyl-4-((1r,3r)-3-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (8):

[0129]

[0130] 4-((1r,3r)-3-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzoic acid (103.0 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then (1R,3s,5S)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (91.3 mg, 0.38 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (145.0 mg, 0.38 mmol) and N,N-diisopropylethylamine (DIEA) (0.1 mL, 0.64 mmol) were added in sequence, and the reaction solution was stirred at 25 ° C for 16 hours. The reaction solution was poured into ice water (15 mL) for dilution, extracted three times with ethyl acetate (15 mL), the organic phases were combined, washed three times with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil (67.0 mg, yield: 39%).

[0131] LC-MS: [M+H]+ :547.0.

[0132] Synthesis of N-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-N-methyl-4-((1r,3r)-3-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzamide (Compound 1):

[0133]

[0134] Tert-butyl (1R, 3s, 5S)-3-(N-methyl-4-((1r, 3r)-3-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (67.0 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and then (trimethylsilyl)methyl trifluoromethanesulfonate (TMSOTf) (54.5 mg, 0.25 mmol) and bis(trimethylsilyl)amine (HMDS) (0.05 mL, 0.25 mmol) were added in sequence, and the mixed reaction solution was stirred at 25 ° C for 1 hour. Water (1 mL) was added to quench, and the mixture was directly spin-dried. The mixture was purified by preparation to obtain a white solid (13.96 mg, yield: 26%).

[0135] LC-MS: [M+H] + :447.0.

[0136] 1 H NMR (400MHz, Methanol-d4) δ7.65(d,J=6.0Hz,1H),7.55(d,J=6.0Hz,1H),7.44(s,2H),7.35(d,J=7.8Hz,2H),4.24-4 .13(m,1H),4.04-3.40(m,4H),2.90(dd,J=18.4,9.5Hz,5H),2.78(s,3H),2.68(q,J=10.5Hz,2H),2.04-1.13(m,8H).

[0137] Example 2. N-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-N-methyl-4-(3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)benzamide (Compound 2)

[0138]

[0139] Synthesis of tert-butyl 3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidine-1-carboxylate (2):

[0140]

[0141] 4-Chloro-2-methylthiophene[2,3-d]pyrimidine (1.0 g, 5.42 mmol) was dissolved in N,N-dimethylformamide (20 mL), and then tert-butyl 3-iodoazetidine-1-carboxylate (2.0 g, 7.04 mmol), ethylene glycol dimethyl ether nickel bromide (92.0 mg, 0.30 mmol), palladium dichloride (53.0 mg, 0.30 mmol), 1,3-bis(diphenylphosphino)propane (123.0 mg, 0.30 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (80.0 mg, 0.30 mmol), zinc particles (708.0 mg, 10.83 mmol) and potassium bromide (1.3 g, 10.83 mmol) were added in sequence. After degassing and replacing with nitrogen three times, the nitrogen system was maintained and the reaction solution was stirred at 60°C for 16 hours. The reaction solution was diluted with water (60 mL), extracted twice with ethyl acetate (40 mL), the organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 50:1 to 3:1) to obtain a yellow solid (730.0 mg, yield: 44%).

[0142] LC-MS: [M+H] + :306.1.

[0143] Synthesis of 4-(azetidin-3-yl)-2-methylthieno[2,3-d]pyrimidine (3):

[0144]

[0145] 3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidine-1-carboxylic acid tert-butyl ester (680.0 mg, 2.23 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (0.5 mL) was added and stirred at 25 ° C for 16 hours. LCMS showed that the raw material was completely reacted. 3N sodium bicarbonate solution was slowly added to the reaction solution until the pH reached 9, and then extracted twice with ethyl acetate (40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography (dichloromethane / methane = 10:1) to obtain a white solid (283.0 mg, yield: 62%).

[0146] LC-MS: [M+H] + :206.1.

[0147] Synthesis of methyl 4-(3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)benzoate (4):

[0148]

[0149] 4-(Azetidine-3-yl)-2-methylthieno[2,3-d]pyrimidine (220.0 mg, 1.07 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then methyl 4-bromobenzoate (254.0 mg, 1.18 mmol), potassium carbonate (296.0 mg, 2.14 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (Ruphos Pd G3) (90.0 mg, 0.11 mmol) were added in sequence. After degassing and replacing with nitrogen three times, the nitrogen system was maintained and the reaction solution was stirred at 100°C for 4 hours. The reaction solution was diluted with water (40 mL), extracted with ethyl acetate (80 mL), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 30:1 to 3:1) to obtain a yellow solid 4 (118.0 mg, yield: 32%).

[0150] LC-MS: [M+H] + :340.0.

[0151] Synthesis of 4-(3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)benzoic acid (5):

[0152]

[0153] Methyl 4-(3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)benzoate (118.0 mg, 0.35 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and then lithium hydroxide (8.3 mg, 0.35 mmol) was added, and the reaction solution was stirred at 25 ° C for 16 hours. 1M aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to 3, and then extracted with ethyl acetate (80 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was used directly in the next step without purification.

[0154] LC-MS: [M+H] + :326.1.

[0155] Synthesis of (1R,3s,5S)-3-(N-methyl-4-(3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)benzamido)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6):

[0156]

[0157] 4-(3-(2-Methylthieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)benzoic acid (160.0 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then (1R,3s,5S)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (142.0 mg, 0.59 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (206.0 mg, 0.54 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.2 mL, 0.98 mmol) were added in sequence, and the mixed reaction solution was stirred at 25°C for 16 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (80 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography (dichloromethane / methane = 50:1 to 10:1) to obtain a white solid (253.0 mg, yield: 94%).

[0158] LC-MS: [M+H] + :548.1.

[0159] Synthesis of N-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-N-methyl-4-(3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)benzamide (Compound 2):

[0160]

[0161] Tert-butyl (1R, 3s, 5S)-3-(N-methyl-4-(3-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-1-yl)benzamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (250.0 mg, 0.46 mmol) was dissolved in dichloromethane (5 mL), and then (trimethylsilyl)methyl trifluoromethanesulfonate (0.2 mL, 0.91 mmol) and bis(trimethylsilyl)amine (0.3 mL, 1.37 mmol) were added in sequence, and the reaction solution was stirred at 25 ° C for 2 hours. Water (0.2 mL) was added to quench the mixture, and the mixture was directly spin-dried. The crude product was purified by preparation to obtain a white solid (169.0 mg, yield: 83%).

[0162] LC-MS: [M+H] + :448.0.

[0163] 1 H NMR (400MHz, Methanol-d4) δ7.73(d,J=5.9Hz,1H),7.58(dd,J=6.1,1.3Hz,1H),7.33(d,J=8.1Hz,2H),6.62(d,J=8.1Hz,2H),4.68(q,J=7 .2Hz,1H),4.47(t,J=7.8Hz,2H),4.34(t,J=6.7Hz,2H),4.16(s,1H),3.59(s,2H),2.94(s,3H),2.81(d,J=1.3Hz,3H),2.23-1.14(m,8H).

[0164] Example 3. N-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-N-methyl-4-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-3-yl)benzamide (Compound 3)

[0165]

[0166] Synthesis of tert-butyl 3-(4-(methoxycarbonyl)phenyl)azetidine-1-carboxylate (2):

[0167]

[0168] (4-(Methoxycarbonyl)phenyl)boronic acid (500.0 mg, 2.78 mmol) was dissolved in 1,4-dioxane (30 mL), and tert-butyl 3-iodoazetidine-1-carboxylate (1.6 g, 5.56 mmol), nickel nitrate hexahydrate (40.4 mg, 0.14 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (dbbpy) (37.3 mg, 0.14 mmol) and potassium carbonate (1.2 g, 8.33 mmol) were added in sequence. The reaction mixture was stirred at 80 ° C for 16 hours in a nitrogen system. After the reaction was completed by LCMS monitoring, it was poured into water (100 mL), extracted with ethyl acetate (100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate=10:1 / 1:1) to give a white solid (400.0 mg, yield: 49%).

[0169] Synthesis of methyl 4-(azetidin-3-yl)benzoate (3):

[0170]

[0171] Tert-butyl 3-(4-(methoxycarbonyl)phenyl)azetidine-1-carboxylate (400.0 mg, 1.37 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (TFA) (0.6 mL) was added under ice bath, and the reaction mixture was stirred at 0° C. for 30 minutes under nitrogen system. After the reaction was completed as monitored by LCMS, the reaction solution was concentrated under reduced pressure to obtain a crude light yellow oil (220.0 mg, yield: 84%).

[0172] LC-MS: [M+H] + :192.2.

[0173] Synthesis of methyl 4-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-3-yl)benzoate (4):

[0174]

[0175] 4-Chloro-2-methylthieno[2,3-d]pyrimidine (202.0 mg, 1.05 mmol) was dissolved in acetonitrile (ACN) (20 mL), and 4-(azetidin-3-yl)benzoic acid methyl ester (130.0 mg, 0.70 mmol) and potassium carbonate (292.0 mg, 2.11 mmol) were added successively, and the reaction mixture was stirred at 60 ° C for 2 hours in a nitrogen system. After the reaction was completed by LCMS monitoring, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 100: 1 / 1: 1) to obtain a white solid (200.0 mg, yield: 84%).

[0176] LC-MS: [M+H] + :340.0.

[0177] Synthesis of 4-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-3-yl)benzoic acid (5):

[0178]

[0179] Methyl 4-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-3-yl)benzoate (200.0 mg, 0.59 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide (16.9 mg, 0.71 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours in a nitrogen system. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with water (50 mL), and the pH of the reaction solution was adjusted to acidic with 1M dilute hydrochloric acid, then extracted with ethyl acetate (200 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a white solid (100.0 mg, yield: 52%).

[0180] LC-MS: [M+H] + :326.1.

[0181] Synthesis of tert-butyl (1R,3s,5S)-3-(N-methyl-4-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-3-yl)benzamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (6):

[0182]

[0183] 4-(1-(2-Methylthieno[2,3-d]pyrimidin-4-yl)azetidin-3-yl)benzoic acid (150.0 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (4 mL), and tert-butyl (1R,3s,5S)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (144.0 mg, 0.60 mmol), N,N-diisopropylethylamine (0.2 mL, 0.92 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (210.0 mg, 0.55 mmol) were added in sequence. The reaction mixture was stirred at 25 °C for 16 hours under a nitrogen system. After the reaction was completed as monitored by LCMS, the mixture was poured into water (50 mL), extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 10:1 / 0:1) to obtain a white solid (150.0 mg, yield: 61%).

[0184] LC-MS: [M+H] + :548.0.

[0185] Synthesis of N-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-N-methyl-4-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-3-yl)benzamide (Compound 3):

[0186]

[0187] Tert-butyl (1R, 3s, 5S)-3-(N-methyl-4-(1-(2-methylthieno[2,3-d]pyrimidin-4-yl)azetidin-3-yl)benzamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (150.0 mg, 0.27 mmol) was dissolved in dichloromethane (4 mL), hexamethyldisilazane (0.6 mL, 0.55 mmol) and trimethylsilyl trifluoromethanesulfonate (0.2 mL, 0.82 mmol) were added in sequence, and the reaction mixture was stirred at 25 ° C for 1 hour in a nitrogen system. After the reaction was completed by LCMS monitoring, the preparation was purified to obtain a white solid (50.0 mg, yield: 41%).

[0188] LC-MS: [M+H] + :448.1.

[0189] 1H NMR (400MHz, Methanol-d4) δ7.61(d,J=8.6Hz,2H),7.49-7.41(m,3H),7.39(d,J=5.9Hz,1H),5.00(s,2H),4.50(s,2H),4.21(s,1H),3.97(s,1 H),3.76(s,1H),3.56(s,1H),2.93(d,J=37.5Hz,3H),2.56(s,3H),1.97(td,J=12.3,2.9Hz,4H),1.67(d,J=48.6Hz,3H),1.17(d,J=8.5Hz,1H).

[0190] Example 4. N-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-N-methyl-4-((Rel-1S,2S)-2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzamide (Compound 4)

[0191]

[0192] Synthesis of methyl 4-(cyclopropylidenemethyl)benzoate (2):

[0193]

[0194] In a three-necked round-bottom flask, a solution of (3-bromopropyl)triphenylphosphonium bromide (29.2 g, 260 mmol) in tetrahydrofuran (500 mL) was added to a solution of potassium tert-butoxide (50.0 g, 130 mmol) in tetrahydrofuran (500 mL). The reaction mixture was stirred at 70 ° C for 1 hour, and then a solution of methyl paraformylbenzoate (21.4 g, 130 mmol) in tetrahydrofuran (200 mL) was added. The reaction mixture was then stirred at 25 ° C for 3 days. After LCMS showed that the reaction was complete, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (petroleum ether: ethyl acetate = 100: 1 to 20: 1) to obtain a white solid (11.0 g, yield: 45%).

[0195] Synthesis of methyl 4-(2-oxocyclobutyl)benzoate (3):

[0196]

[0197] Meta-chloroperbenzoic acid (15.1 g, 87.66 mmol) was added to a solution of methyl 4-(cyclopropylidenemethyl)benzoate (11.0 g, 58.44 mmol) in dichloromethane (150 mL) at 0 ° C. The reaction mixture was stirred at 25 ° C for 16 hours. After LCMS showed that the reaction was completed, the reaction mixture was quenched by adding ammonium chloride (20 mL). The reaction mixture was then poured into water (100 mL), extracted with dichloromethane (300 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (petroleum ether: ethyl acetate = 100: 1 to 3: 1) to give a colorless oil (5.2 g, yield: 44%).

[0198] LC-MS: [M+H] + :205.1.

[0199] Synthesis of methyl 4-(2-(((trifluoromethyl)sulfonyl)oxy)cyclobut-1-en-1-yl)benzoate (4):

[0200]

[0201] In a three-necked round-bottom flask, a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (9.8mL, 1N) was added to a tetrahydrofuran solution of methyl 4-(2-oxocyclobutyl)benzoate (1.0g, 4.90mmol) at -78°C in tetrahydrofuran (10mL). The reaction mixture was stirred at -78°C for 1 hour, and then a tetrahydrofuran (10mL) solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.1g, 5.88mmol) was added. The reaction mixture was then stirred at 25°C for 16 hours. After LCMS showed that the reaction was complete, the reaction mixture was quenched by adding ammonium chloride (20mL). The reaction mixture was then poured into water (60mL), extracted with ethyl acetate (90mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 10:1) to give a colorless oil (1.2 g, yield: 73%).

[0202] LC-MS: [M+H] + :337.1.

[0203] Synthesis of methyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclobut-1-en-1-yl)benzoate (5):

[0204]

[0205] Methyl 4-(2-(((trifluoromethyl)sulfonyl)oxy)cyclobut-1-ene-1-yl)benzoate (1.0 g, 2.97 mmol), biboronic acid pinacol ester (1.5 g, 5.94 mmol), potassium acetate (873.0 g, 8.91 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (219.0 mg, 0.30 mmol) were added to dioxane (20 mL), purged with nitrogen three times, and then the mixture was stirred at 90 ° C for 16 hours. After LCMS showed that the reaction was complete, the reaction mixture was poured into water (90 mL), extracted with ethyl acetate (90 mL), and the organic phases were combined. It was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue (600 mg) The crude product was directly used in the next step.

[0206] LC-MS: [M+H] + :315.1.

[0207] Synthesis of methyl 4-(2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobut-1-en-1-yl)benzoate (6):

[0208]

[0209] Methyl 4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclobut-1-ene-1-yl)benzoate (600.0 mg, 1.91 mmol), 4-chloro-2-methylthieno[2,3-d]pyrimidine (326.0 mg, 1.91 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (139.0 mg, 0.19 mmol) and potassium carbonate (527.0 mg, 3.82 mmol) were dissolved in a mixture of dioxane (10 mL) and water (2 mL), purged with nitrogen three times, and then the mixture was stirred at 100 ° C for 16 hours. After LCMS showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was poured into water (40 mL), extracted with ethyl acetate (60 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 3:1) to give a light yellow solid (380.0 mg, yield: 59%).

[0210] LC-MS: [M+H] + :337.1.

[0211] Synthesis of methyl 4-(2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzoate (7):

[0212]

[0213] 4-(2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobut-1-ene-1-yl)benzoic acid methyl ester (380.0 mg, 1.13 mmol) was added to a methanol (10 mL) solution, 10% palladium on carbon (40.0 mg) was added, the mixture was ventilated with hydrogen three times, and stirred at 25 ° C for 2 days. After LCMS showed that the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by thin layer silica gel plate (petroleum ether: ethyl acetate = 3: 1) to give a white solid (144.0 mg, yield: 38%).

[0214] LC-MS: [M+H] + :339.1.

[0215] Synthesis of 4-((Rel-1S,2S)-2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzoic acid (8):

[0216]

[0217] Methyl 4-(2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzoate (144.0 mg, 0.43 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL), and then lithium hydroxide (30.6 mg, 1.28 mmol) was added, and the reaction solution was stirred at 25°C for 2 hours. 1N hydrochloric acid solution was added to the reaction solution to adjust the pH to 5, and then extracted three times with ethyl acetate (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product (70.0 mg, yield: 51%), which was used directly in the next step without purification.

[0218] LC-MS: [M+H] + :325.0.

[0219] Synthesis of (1R,3s,5S)-3-(N-methyl-4-((Rel-1S,2S)-2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzamido)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (9):

[0220]

[0221] 4-((Rel-1S,2S)-2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzoic acid (70.0 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (3 mL), and then (1R,3s,5S)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (57.1 mg, 0.24 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91.0 mg, 0.24 mmol) and N,N-diisopropylethylamine (57.0 mg, 0.44 mmol) were added in sequence, and the reaction solution was stirred at 25°C for 16 hours. The reaction solution was poured into ice water (15 mL) for dilution, extracted three times with ethyl acetate (15 mL), the organic phases were combined, washed three times with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer silica gel plate (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil (65.0 mg, yield: 55%).

[0222] LC-MS: [M+H] + :547.0.

[0223] Synthesis of N-((1R,3s,5S)-8-azabicyclo[3.2.1]oct-3-yl)-N-methyl-4-((Rel-1S,2S)-2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzamide (Compound 4):

[0224]

[0225] (1R, 3s, 5S)-3-(N-methyl-4-((Rel-1S, 2S)-2-(2-methylthieno[2,3-d]pyrimidin-4-yl)cyclobutyl)benzamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (65.0 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), and then (trimethylsilyl)methyl trifluoromethanesulfonate (54.5 mg, 0.25 mmol) and bis(trimethylsilyl)amine (0.05 mL, 0.25 mmol) were added in sequence, and the mixed reaction solution was stirred at 25 ° C for 2 hours. Water (1 mL) was added to quench, and the mixture was directly spin-dried. The mixture was purified by preparation to obtain a white solid (30 mg, yield: 57%).

[0226] LC-MS: [M+H] + :447.3.

[0227] 1H NMR (400 MHz, Methanol-d4) δ 7.53 (d, J = 6.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.28 (dd, J = 11.0, 7.0 Hz, 3H), 4.26–4.12 (m, 2H), 3.94–3.41 (m, 3H), 2.80 (s, 6H), 2.58 (s, 1H), 2.46–2.33 (m, 3H), 1.95–1.47 (m, 7H), 1.10–0.99 (m, 1H). Example 5.

[0228] The following compounds were prepared according to the methods of Schemes 1 to 3 and Examples 1 to 3:

[0229]

[0230]

[0231] Activity Example HEK-Blue-hTLR7 Cell Inhibition Assay

[0232] 1. HEK-BLUE-hTLR7 cells were seeded in 384-well plates, 10,000 cells per well, 40 μL, and maintained in DMEM medium containing 10 μg / ml blasticidin and 100 μg / ml bleomycin, and incubated in a 37°C & 5% CO2 incubator overnight.

[0233] 2. The compounds were prepared in DMSO at a starting concentration of 5 μM and diluted in DMEM medium containing 10 μg / ml blasticidin and 100 μg / ml bleomycin.

[0234] 3. HEK-BLUE-hTLR7 cells treated with DMSO were used as the blank control group, HEK-BLUE-hTLR7 cells treated with R848 alone were used as the positive control group, and HEK-BLUE-hTLR7 cells treated with the test compound and R848 were used as the test group, with 2 parallel wells for each group.

[0235] 4. Using the echo sonic pipetting system, add 80 nl of compound solutions of different concentrations. After incubation in the incubator for 30 min, add 40 nl of R848 solution (10 μM) diluted in the same culture medium to ensure that the final DMSO concentration is not higher than 0.3%.

[0236] 5. After adding the test compound and R848, the culture plate was placed in a 37°C & 5% CO2 incubator and incubated for 24 hours.

[0237] 6. Equilibrate the Quanti-Blue detection reagent to room temperature and take 18 μl into a new 384-well plate. Take out the 384-well plate that has been incubated for 24 hours, equilibrate it to room temperature, and transfer 2 μL of cell supernatant to 18 μl of Quanti-Blue reagent.

[0238] Centrifuge at 7.500 rpm for 3 min, incubate in a 37°C & 5% CO2 incubator for two hours. Use a BMG microplate reader to read the absorbance signal at 620 nM and record the data.

[0239] 8. Calculate cell inhibition rate = (1-(OD test group-OD blank group) / (OD positive group-OD blank group)) x 100%, and calculate relative IC by curve fitting 50 (half inhibitory concentration). The results are shown in Table 1 below:

[0240] Table 1: IC values ​​of representative compounds for TLR7 50 (nM) value

[0241] Compound No. <![CDATA[TLR7 IC 50 ]]> Example 1 236.9 Example 3 185.3

[0242] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound represented by formula (I) or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof: in, A is selected from a 5-10 membered heteroaryl group containing 1-5 ring heteroatoms, and a benzene ring group; B is selected from a benzene ring group, a benzene ring and C 3-7 A fused ring group fused to a saturated or unsaturated non-aromatic carbon ring, a fused ring group fused to a benzene ring and a 3-7-membered saturated or unsaturated non-aromatic heterocyclic ring containing 1-3 ring heteroatoms, a fused ring group fused to a benzene ring and a 5-10-membered heteroaromatic ring containing 1-3 ring heteroatoms, a fused ring group fused to a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms, and a 5-6-membered monocyclic heteroaromatic group containing 1-3 ring heteroatoms; X is selected from a cyclobutane group, an oxetane group, and an azetidine group, and A and B are ortho or para to each other on X; When A and B are fused ring groups, the substituents on A and B are independently located on any ring of the fused ring group; and A and B can be independently connected to X through C or a heteroatom on any ring of the fused ring group; R1 is independently selected from H, halogen, CN, -OR4, =O, -N(R4)R5, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl, and 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl are each independently optionally substituted with one or more groups selected from F, Cl, Br, OH, CN, NH2, and =O; R2 is selected from -C 1-4 Alkylene (R4) R5, -OC 0-4 Alkylene-R5, -SC 0-4 Alkylene-R5, -C(O)-C 0-4 Alkylene-R5, -C(O)C 0-4 Alkylene -OR5, -C(O)C 0-4 Alkylene-N(R4)-C 0-4 Alkylene-R5, -N(R4)-C 0-4 Alkylene-R5, -N(R4)C(O)-C 0-4 Alkylene-R5, -N(R4)S(O)2-C 0-4 Alkylene-R5, -S(O)2R5, -S(O)2N(R4)-C 0-4 Alkylene-R5; 3-7 membered monocyclic heterocycloalkyl containing 1-3 ring heteroatoms, 5-10 membered heteroaryl containing 1-3 ring heteroatoms, and 5-11 membered heterobridged cycloalkyl containing 1-3 ring heteroatoms; the alkylene, monocyclic heterocycloalkyl, heteroaryl, heterobridged cycloalkyl are each independently optionally substituted by one or more selected from F, Cl, Br, OH, CN, NH2, R8, -C 1-4 Alkylene (R4) R5, -OR4, -N(R4) R5, -C(O) R5, -C(O)C 0-4 Alkylene -N(R4)R5, and -N(R4)C(O)R5; R3 is independently selected from H, halogen, OH, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms, -N(R4)-C 0-4 Alkylene-R5, -C(O)-C 0-4 Alkylene-R5, -C(O)C 0-4 Alkylene OR5, -C(O)C 0-4 Alkylene-N(R4)-C 0-4 Alkylene R5, -N(R4)C(O)-C 0-4 Alkylene-R5, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and alkylene are each independently optionally substituted with one or more groups independently selected from F, Cl, Br, OH, CN, NH2; R4 and R5 are each independently selected from H, OH, NH2, C 1-4 Alkyl, C 3-7 Monocyclic alkyl, 3-7 membered monocyclic heterocyclic alkyl containing 1-3 ring heteroatoms, C 5-8 The invention relates to a bridged cycloalkyl group, a 5-11-membered heterobridged cycloalkyl group containing 1-3 ring heteroatoms, a fused ring group of a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a 3-7-membered saturated carbocycle, a fused ring group of a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms, a fused ring group of a 3-7-membered saturated heterocycle containing 1-3 ring heteroatoms and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms, a fused ring group of a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms and a 3-7-membered saturated carbocycle, and a fused ring group of a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms and a 3-7-membered saturated carbocycle. The alkyl, cycloalkyl, heterocycloalkyl, bridged cycloalkyl, heterobridged cycloalkyl, condensed ring group, and spirocyclic group are each independently substituted by one or more groups selected from the following: F, Cl, Br, OH, CN, NH2, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, -C(O)NH2, 3-7-membered 1-4 Alkylene-S(O)2-C 1-4 Alkyl, C 1-4 Alkanoyl-substituted 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms-carbonyl C 0-4 Alkyl, -C(O)-C 1-4 alkyl, C optionally substituted by one or more groups selected from F, Cl, Br, OH, CN or NH2 1-4 alkyl; When R4 and R5 are connected to the same C or N, R4 and R5 can also form a 3-7 membered aromatic or non-aromatic ring group containing 0-3 ring heteroatoms together with the C or N to which they are connected; m and n are each independently selected from integers of 0-4, such as 0, 1, 2, 3, 4; The ring heteroatoms are independently selected from N, O, or S; The alkyl group and the alkylene group are linear or branched.

2. The compound represented by formula (I) according to claim 1, its deuterated substance, or a pharmaceutically acceptable salt thereof, wherein: In formula (I), A is selected from a fused ring group consisting of a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms, and a fused ring group consisting of a benzene ring and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms; R1 is each independently selected from H, halogen, CN, =O, and C 1-4 Alkyl; said alkyl being optionally substituted with one or more F, Cl, or Br; R2 is selected from -C 1-4 Alkylene (R4) R5, -C(O)N(R4) R5, -N(R4) R5, and 5-11 membered heterobridged cycloalkyl containing 1-3 ring heteroatoms; R3 is independently selected from H, halogen, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)-C 1-4 Alkyl, and -C(O)NH-C 1-4 Alkyl; the alkyl or alkoxy groups are each independently optionally substituted with one or more F, Cl, or Br; R4 is H; or C 1-4 alkyl; R5 is selected from C 3-7 Monocyclic alkyl; 3-7 membered monocyclic heterocyclic alkyl containing 1-3 ring heteroatoms; 5-11 membered heterobridged cycloalkyl containing 1-3 ring heteroatoms; and a spirocyclic group consisting of a 3-7 membered saturated heterocyclic ring containing 1-3 ring heteroatoms and a 3-7 membered saturated carbocyclic ring; the monocyclic alkyl, monocyclic heterocyclic alkyl, heterobridged cycloalkyl, and spirocyclic group are each independently optionally substituted by one or more groups selected from the following: -NH2, -C 1-4 Alkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms, -C 1-4 Alkylene-S(O)2-C 1-4 Alkyl, C 1-4 Alkanoyl-substituted 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms, 3-7-membered heterocycloalkyl containing 1-3 ring heteroatoms-carbonyl C 0-4 Alkyl, -C(O)-C 1-4 alkyl, C optionally substituted by one or more groups selected from F, Cl, Br, OH, and CN 1-4 alkyl; m and n are each independently selected from 0, 1, or 2.

3. The compound represented by formula (I) according to claim 1 or 2, its deuterated substance, or a pharmaceutically acceptable salt thereof, wherein: In formula (I), A is selected from a thieno[2,3-d]pyrimidine group, a thieno[2,3-b]pyridine group, a pyrazolo[3,4-d]pyrimidine group, a pyrazolo[3,4-b]pyridine group, a quinazoline, a quinoline, a pyrazolo[4,3-b]pyridine group, and a pyrazolo[4,3-d]pyrimidine group; X is selected from a cyclobutane group and an azetidine group, and A and B are ortho or para to each other on X, preferably para to each other; B is selected from a benzene ring group, a pyridine group, a 1,3-dihydroisoindole group, an indazole group, a benzimidazole group, a benzocyclopentane group, a benzofuran group, a 2,3-dihydrobenzofuran group, a 2,3-dihydroindole group, an indole group, an imidazo[1,2-a]pyridine group, a 1,2,3,4-tetrahydroisoquinoline group, a 1,2-dihydroisoquinoline group, a quinazoline group, a thieno[3,2-b]thiophene group, an imidazo[2,1-b]thiazole group, and a benzo[d]thiazole group; R1 each independently represents H, halogen, CN, =O, methyl, ethyl, or trifluoromethyl; R2 is selected from 8-azabicyclo[3.2.1]octan-3-yl, N-(8-azabicyclo[3.2.1]octan-3-yl)-N-methyl-carbamoyl, N-(8-azabicyclo[3.2.1]octan-3-yl)-N-methyl-amino, N-(8-azabicyclo[3.2.1]octan-3-yl)-methyl, N-(9-azabicyclo[3.3.1]nonan-3-yl)-N-methyl-carbamoyl, N-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-N-methyl-carbamoyl, N-(2-azabicyclo[2.2.1]heptane-5-yl)-N-methyl-amino, N-(8-azabicyclo[3.2.1]octan-3-yl)-methyl -yl)-N-methyl-carbamoyl, N-(2-azabicyclo[2.2.2]octan-5-yl)-N-methyl-carbamoyl, N-(3-azabicyclo[3.2.1]octan-8-yl)-N-methyl-carbamoyl, N-(4-aminocyclohexyl)-N-methyl-carbamoyl, N-(piperidin-3-yl)-N-methyl-carbamoyl, N-(3-azabicyclo[3.1.0]hexane-6-yl)-N-methyl-carbamoyl, and N-(4-azaspiro[2,5]octan-6-yl)-N-methyl-carbamoyl, wherein the 8-azabicyclo in the above groups is [3.2.1] The 8-position N of the octane-3-yl group may be substituted with methyl, ethyl, trifluoroethyl, cyanomethyl, tetrahydropyran-4-yl, hydroxyisobutyl, tetrahydropyrrol-2-ylformyl, methylsulfonylethyl, oxetan-3-yl, N-acetylpiperidin-4-yl, morpholin-4-ylcarbonylmethyl or acetyl; R3 is each independently selected from H, halogen, -OH, methyl, methoxy, or trifluoromethyl.

4. The compound according to claim 1 or 2, its deuterated substance, or a pharmaceutically acceptable salt thereof, wherein: In formula (I), A is selected from a fused ring group consisting of a 5-7 membered heteroaromatic ring containing 1-3 ring heteroatoms and a 5-7 membered heteroaromatic ring containing 1-3 ring heteroatoms; R1 is independently selected from H, halogen, or C 1-4 alkyl; R2 is selected from -C(O)N(R4)R5, and a 5-11 membered heterobridged cycloalkyl group containing 1-3 ring heteroatoms; R3 are each independently selected from H, halogen, C 1-4 alkyl; R4 is H; or C 1-4 alkyl; R5 is selected from 5-11 membered hetero-bridged cycloalkyl containing 1-3 ring heteroatoms; the hetero-bridged cycloalkyl is independently optionally substituted by one or more groups selected from the following: -C 1-4 Alkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms, -C 1-4 Alkylene-S(O)2-C 1-4 Alkyl, 3-7 membered heterocycloalkyl containing 1-3 ring heteroatoms-carbonyl C 0-4 alkyl, C optionally substituted by one or more groups selected from F, Cl, Br, OH, and CN 1-4 alkyl; m and n are each independently selected from 0, 1, or 2.

5. The compound according to any one of claims 1 to 4, its deuterated substance, or a pharmaceutically acceptable salt thereof, wherein: In formula (I), A is selected from a thieno[2,3-d]pyrimidine group, a thieno[2,3-b]pyridine group, a pyrazolo[3,4-d]pyrimidine group, a pyrazolo[3,4-b]pyridine group, a pyrazolo[4,3-b]pyridine group, and a pyrazolo[4,3-d]pyrimidine group; X is selected from a cyclobutane group and an azetidine group, and A and B are ortho or para to each other on X, preferably para to each other; B is selected from a benzene ring group, a pyridine group, a 1,3-dihydroisoindole group, an indazole group, and a benzimidazole group; R1 each independently represents H, halogen or methyl; R2 is selected from 8-azabicyclo[3.2.1]octan-3-yl and N-(8-azabicyclo[3.2.1]octan-3-yl)-N-methyl-carbamoyl, wherein the 8-azabicyclo[3.2.1]octan-3-yl in the above groups is optionally substituted with methyl, isopropyl, trifluoroethyl, cyanomethyl, tetrahydropyran-4-yl, hydroxyisobutyl, tetrahydropyrrol-2-ylformyl, or methylsulfonylethyl at the 8-N position; R3 are each independently selected from H, and halogen.

6. The compound according to any one of claims 1 to 5, its deuterated substance, or a pharmaceutically acceptable salt thereof, wherein: The compound represented by the formula (I) is the following compound:

7. A method for preparing the compound according to any one of claims 1 to 6, its deuterated substance, or a pharmaceutically acceptable salt thereof, the method being selected from one of the following schemes 1 to 4: The scheme 1 comprises the following steps: a1) reacting compound (1-a) with trichloroacetyl chloride in the presence of an organic solvent and zinc to obtain compound (1-b); b1) reducing compound (1-b) in the presence of zinc to obtain compound (1-c), and then reducing it again to obtain compound (1-d); c1) subjecting compound (1-d) to hydroxyhalogenation in the presence of an organic solvent and triphenylphosphine to obtain compound (1-e), and then Reaction in the presence of a nickel catalyst to obtain compound (1-f); d1) subjecting compound (1-f) to ester hydrolysis to obtain compound (1-g); and e1) subjecting compound (1-g) to amide condensation with HN(R4)R5 to obtain the final product compound (1-h); The scheme 2 comprises the following steps: a2) reacting compound (2-a) with tert-butyl 3-iodoazetidine-1-carboxylate in the presence of an organic solvent and a nickel catalyst to produce compound (2-b); b2) deprotecting compound (2-b) to obtain compound (2-c), and then Carrying out coupling reaction to obtain compound (2-d); c2) subjecting compound (2-d) to an ester hydrolysis reaction to obtain compound (2-e); d2) subjecting compound (2-e) to amide condensation with HN(R4)R5 to obtain the final product compound (2-f); The scheme 3 comprises the following steps: a3) reacting compound (3-a) with tert-butyl 3-iodoazetidine-1-carboxylate to produce compound (3-b); b3) deprotecting compound (3-b) to obtain compound (3-c), and then Carrying out coupling reaction to obtain compound (3-d); c3) subjecting compound (3-d) to ester hydrolysis to obtain compound (3-e); d3) subjecting compound (3-e) to amide condensation with HN(R4)R5 to obtain the final product compound (3-f); The scheme 4 comprises the following steps: a4) reacting compound (4-a) with (3-bromopropyl)triphenylphosphonium bromide to produce compound (4-b); b4) subjecting compound (4-b) to oxidation with m-CPBA to obtain compound (4-c), and then reacting with a triflation reagent to obtain compound (4-d); c4) subjecting compound (4-d) to a palladium-catalyzed reaction to obtain compound (4-e), and then Compound (4-f) is obtained through coupling reaction; d4) subjecting compound (4-f) to reduction reaction to obtain compound (4-g), hydrolyzing compound (4-h), and subjecting compound (4-h) to amide condensation with HN(R4)R5 to obtain the final product compound (4-i); The definitions of A, B, R1, R4, R5 and m in the above compounds are the same as those in the compound of formula (I) according to any one of claims 1 to 6.

8. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 6, its deuterated product, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. Use of the compound of formula (I) according to any one of claims 1 to 6, its deuterated product, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating inflammatory diseases or autoimmune diseases.

10. The use according to claim 9, wherein The inflammatory and autoimmune diseases are selected from Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allogeneic transplant rejection, chronic obstructive pulmonary disease, Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, Sjögren's syndrome, and psoriasis.

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