Pyrimidino aromatic ring compound and application thereof in medicine

Abstract

The invention relates to a pyrimidino aromatic ring compound and application thereof in medicines, in particular to application of the pyrimidino aromatic ring compound as a TLR8 agonist. Specifically, the invention relates to a compound as shown in a general formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and application of the compound as a drug, especially application of the compound as a TLR8 agonist. Wherein the variables are defined in the specification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine. In particular, it relates to a kind of pyrimidine and aromatic ring compound and its use as a drug, especially as TLR8 agonist.The present application also relates to the composition of these pyrimidine and aromatic ring compounds with other therapeutic agents, and its use as a drug, especially as TLR8 agonist. BACKGROUND

[0002] Toll-like receptors (TLRs) are an important pattern recognition receptor of innate immune response, widely distributed in mammalian myeloid dendritic cells, monocytes and mononuclear macrophages. On the one hand, TLRs can recognize specific microbial PAMPs (such as: lipopolysaccharide, flagellin, single / double-stranded RNA, etc.), thereby triggering the body's innate immunity; on the other hand, different TLRs can induce specific functional region gene expression, thereby triggering the body's antigen-specific adaptive immune response.

[0003] In mammals, 13 TLR members have been found, of which TLR1-TLR9, TLR11 are common to humans and mice, and TLR10, TLR12 and TLR13 are specific to mice. TLR8 is a member of the TLRs 3, 7, 8 and 9 subgroups, which is limited to the endosomal compartment of cells that specifically recognize non-self nucleic acids. TLR8 is mainly expressed by monocytes, NK cells and myeloid dendritic cells (mDC) in humans. TLR8 agonists can cause the release of various pro-inflammatory cytokines, such as IL-6, IL-12, TNF-α and IFN-γ.

[0004] TLR8 activation mediates the clearance of virus-infected cells and tumor cells in the body, and its agonists can be used as independent immunotherapeutic drugs or immunoadjuvants, showing important clinical application prospects in immunotherapy. TLR8 activation is closely related to anti-infective innate immune response, and can mediate the occurrence and development of viral infection diseases such as HBV, HCV, HIV and herpes virus, tumors, autoimmune diseases, and metabolic diseases.

[0005] Currently, TLR8 and TLR7 dual agonists have been reported in many patents. In view of the wide therapeutic potential of TLR8 agonist drugs, there is still a need for new TLR8 agonist drugs, especially those with high selectivity for TLR8 for the treatment and / or prevention of hepatitis B virus. SUMMARY

[0006] The present application relates to novel pyrimidoaromatic compounds, and pharmaceutically acceptable compositions thereof, which have good activation effect on TLR8, and have good selective activation effect on TLR8, and they also have the advantages of substantially no induction effect on liver enzymes, substantially no inhibition effect on liver enzymes, and substantially no toxicity to heart. In addition, they also have good solubility, good stability and very good pharmacokinetic properties. The compounds of the present application can be used to treat and / or prevent various diseases related to TLR8 activity, and have good application prospect in anti-hepatitis B virus (HBV).

[0007] In one aspect, the present application relates to a compound as shown in formula (I) or a stereoisomer, a tautomer, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the compound as shown in formula (I),

[0008]

[0009] wherein each R 1 and R 2 is independently C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxy, cyano, amino and C 1-4 alkyl;

[0010] Q1 is a fused bicyclic heteroaryl group consisting of 7-12 ring atoms, a fused bicyclic heterocyclyl group consisting of 7-12 ring atoms or a C 6-12 aryl group, wherein the fused bicyclic heteroaryl group consisting of 7-12 ring atoms, the fused bicyclic heterocyclyl group consisting of 7-12 ring atoms and the C 6-12 aryl group are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents of R w1 ;

[0011] L is a bond, -CH2-, -(CH2)2-, -(CH2)3-, -C(=O)- or -S(=O) 0-2 -;

[0012] Q2 is a heterocyclyl group consisting of 5 ring atoms, a heterocyclyl group consisting of 6 ring atoms, a heteroaryl group consisting of 5-6 ring atoms or a phenyl group, wherein the heterocyclyl group consisting of 5 ring atoms, the heterocyclyl group consisting of 6 ring atoms, the heteroaryl group consisting of 5-6 ring atoms and the phenyl group are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents of R w2 ;

[0013] each R w1 and R w2independently deuterium, F, Cl, Br, I, =0, hydroxyl, cyano, amino, C 1-4 alkylamino, C 1-4 alkoxy, C 1-4 alkyl or C 1-4 haloalkyl.

[0014] In some embodiments of the application, Q1as described herein is a 9-10 membered fused bicyclic heteroaryl, a 9-10 membered fused bicyclic heterocyclyl, a phenyl or a naphthyl, wherein each of said 9-10 membered fused bicyclic heteroaryl, 9-10 membered fused bicyclic heterocyclyl, phenyl and naphthyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R 1 and R 2 each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl or n-hexyl, wherein each of said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl and n-hexyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and sec-butyl.

[0015] In some embodiments of the application, Q1as described herein is a 9-10 membered fused bicyclic heteroaryl, a 9-10 membered fused bicyclic heterocyclyl, a phenyl or a naphthyl, wherein each of said 9-10 membered fused bicyclic heteroaryl, 9-10 membered fused bicyclic heterocyclyl, phenyl and naphthyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R w1 .

[0016] In some embodiments of the application, Q1as described herein is a 9 membered fused bicyclic heteroaryl, a 10 membered fused bicyclic heteroaryl, a 9 membered fused bicyclic heterocyclyl, a 10 membered fused bicyclic heterocyclyl, a phenyl or a naphthyl, wherein each of said 9 membered fused bicyclic heteroaryl, 10 membered fused bicyclic heteroaryl, 9 membered fused bicyclic heterocyclyl, 10 membered fused bicyclic heterocyclyl, phenyl and naphthyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R w1 .

[0017] In some embodiments of the application, Q1as described herein is

[0018] In some embodiments of the application, Q2of the present application is aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl, wherein each of said aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, and phenyl is independently unsubstituted or substituted with 1, 2, 3, or 4 R w2 substituents.

[0019] In some embodiments of the application, R w1 and R w2 are each independently deuterium, F, CI, Br, I, =0, hydroxyl, cyano, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, methoxy, ethoxy, 1 -propoxy, 2-propoxy, 1 -butoxy, 2-methyl- 1 -propoxy, 2-butoxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, -CH2F, -CH2CI, -CF3, -CHF2, -CHC12, -CH2CH2F, -CH2CH2CI, -CH2CHF2, -CH2CHC12, -CHFCH2F, -CHC1CH2CI, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, or -CH2CH2CF3.

[0020] In some embodiments of the application, the compound of the present application comprises the structure of one of the following:

[0021]

[0022] or a stereoisomer, tautomer, nitroso, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0023] In another aspect, the present application also provides a pharmaceutical composition comprising the compound of the present application and a pharmaceutically acceptable excipient.

[0024] In some embodiments, the pharmaceutical composition of the present application further comprises one or more additional therapeutic agents, wherein the therapeutic agent is an HBV DNA polymerase inhibitor, a toll-like receptor 7 modulator, a toll-like receptor 8 modulator, a toll-like receptor 7 and 8 modulator, a toll-like receptor 3 modulator, an interferon a ligand, an HBsAg inhibitor, a compound targeting HbcAg, a cyclophilin inhibitor, an HBV therapeutic vaccine, an HBV prophylactic vaccine, an HBV viral entry inhibitor, an NTCP inhibitor, an antisense oligonucleotide targeting viral mRNA, a short interfering RNA (siRNA), a hepatitis B virus E antigen inhibitor, an HBx inhibitor, a cccDNA inhibitor, an HBV antibody, a thymosin agonist, a cytokine, a nucleoprotein inhibitor, a retinoic acid-inducible gene 1 stimulator, a NOD2 stimulator, a recombinant thymosin a-1, a hepatitis B virus replication inhibitor, a hepatitis B surface antigen (HBsAg) secretion or assembly inhibitor, an IDO inhibitor, or a combination thereof.

[0025] In some embodiments, the pharmaceutical composition of the present application, wherein the one or more additional therapeutic agents is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, Alfaferone, Alloferon, simodalin, cladrin, emtricitabine, famciclovir, interferon, Bovogen CP, Inotefin, interleukin-2, miv-otefe, nitazoxanide, ribavirin, rozital-A, sizofiran, Euforavac, Ampligen, Phosphazid, Heplisav, recombinant human interleukin-2, levamisole, or propagermanium.

[0026] In some embodiments, the pharmaceutical composition of the present application, wherein the other therapeutic agent(s) is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, Alfaferone, Alloferon, Celmolex, Cravacit, Emtricitabine, Famciclovir, Bovogen CP, Infergen, Interferon alfa-1b, Interferon alfa, Interferon alfa-2a, Interferon beta-1a, Interferon alfa-2, Interleukin-2, Miv-501, Nitazoxanide, Peginterferon alfa-2a, Ribavirin, Roferon-A, Silicore, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon alfa-2b, Recombinant human interleukin-2, Levamisole or Progultin.

[0027] In another aspect, the present application also provides uses of the compound or the pharmaceutical composition of the present application in activating TLR8.

[0028] In another aspect, the present application also provides uses of the compound or the pharmaceutical composition of the present application in the manufacture of a medicament for activating TLR8.

[0029] In another aspect, the present application also provides uses of the compound or the pharmaceutical composition of the present application in the manufacture of a medicament for preventing, treating, managing or alleviating a TLR8-mediated disease in a patient.

[0030] In some embodiments, the TLR8-mediated disease is hepatitis B virus infection, hepatitis C virus infection, influenza virus infection, herpes virus infection, HIV infection, allergic disease, rheumatoid arthritis, allergic asthma, chronic fatigue, type II diabetes, hay fever, lupus erythematosus, multiple sclerosis, melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer or thyroid cancer.

[0031] In another aspect, the present application also provides uses of the compound or the pharmaceutical composition of the present application in the manufacture of a medicament for treating or preventing an immune regulation system disease.

[0032] In another aspect, the present application also provides uses of the compound or the pharmaceutical composition of the present application in the manufacture of a medicament for treating or preventing a viral infection or a tumor.

[0033] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for treating or preventing hepatitis B virus infection, hepatitis C virus infection, influenza virus infection, herpes virus infection, HIV infection, allergic disease, rheumatoid arthritis, allergic asthma, chronic fatigue, type II diabetes, hay fever, lupus erythematosus, multiple sclerosis, melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, stomach cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

[0034] Another aspect of the present application relates to the methods of preparing, isolating and purifying the compounds of Formula (I).

[0035] The present application also relates to the use of the compounds of the present application and their pharmaceutically acceptable salts for the manufacture of a medicament for the effective treatment of the diseases described herein. The compounds of the present application are also used for the manufacture of a medicament for the reduction, prevention, control or treatment of the conditions of the diseases described herein in a patient.

[0036] Unless otherwise stated, all stereoisomers, tautomers, nitroso forms, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present application are within the scope of the application.

[0037] The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically, associated with other components of the formulation and the mammal being treated therewith.

[0038] The salts of the compounds of the present application also include salts of intermediates used in making or purifying the compounds of Formula (I) or the isolated enantiomers of the compounds of Formula (I), but are not necessarily pharmaceutically acceptable.

[0039] If the compounds of the present application are basic, salts can be prepared from them using any appropriate method provided in the literature, for example, using inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid and the like. Or using organic acids, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid; pyranosidic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids, such as citric acid and tartaric acid; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic acid and cinnamic acid; sulfonic acids, such as p-toluenesulfonic acid, benzene sulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid and the like or combinations thereof.

[0040] If the compounds of the present application are acidic, it is intended that salt can be prepared from inorganic or organic bases such as, for example, ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium hydroxides, N + (R 14 )4, and alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts prepared from amino acids such as glycine and arginine, ammonia, such as primary, secondary, and tertiary amines, N + (R 14 )4, such as R 14 is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates, and aromatic sulfonates.

[0041] The foregoing outlines some aspects of the present application, but is not limited to such aspects. Additional aspects will be set forth in more detail in the description that follows.

[0042] Detailed Description of the Invention

[0043] Definitions and General Terminology

[0044] The present application will be described with particular reference to the accompanying figures and examples, which are set forth to illustrate, but not to limit, the application. The present application contemplates all alternatives, modifications, and variations of the described methods and materials that can be reasonably expected to fall within the scope of the present application as defined by the claims. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The present application is not intended to be limited to the methods and materials described. Many documents and similar materials are cited throughout the specification. The citation of any document or similar material is not intended to be an admission that the present application is not entitled to antedate such material by virtue of prior application. The citation of documents and similar materials is intended to be an admission that such documents and similar materials are pertinent to the patentability of the present application.

[0045] The following definitions will be employed, unless otherwise indicated. For purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific gravity is to be determined in accordance with ASTM thEd, 1994. In addition, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, Michael B., and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0046] As described herein, the compounds of the application can optionally be substituted with one or more substituents, such as described herein for the compounds of the formulae above, or as described in particular examples, subgroups, and classes of compounds embraced by the application.

[0047] Also, it should be noted that the descriptive terms "each," "each independent," and "each respective" are used interchangeably herein throughout the specification and are to be interpreted broadly to mean that the specific options expressed by the same symbol between different groups are independent of each other, and that the specific options expressed by the same symbol within the same group are independent of each other, unless otherwise explicitly noted.

[0048] Throughout various sections of the specification, substituents of compounds of the application are presented grouped by a common characteristic. It is specifically intended that the application include each and every independent combination of substituents specifically indicated herein. 1-6 "alkyl" specifically refers to the individually disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0049] As used herein, the term "alkyl" includes saturated straight or branched chain monovalent hydrocarbon radicals of from 1 to 20 carbon atoms, where the alkyl group can be independently optionally substituted with one or more substituents as described herein. In some embodiments, the alkyl group contains from 1 to 12 carbon atoms; in other embodiments, the alkyl group contains from 1 to 10 carbon atoms; in other embodiments, the alkyl group contains from 1 to 8 carbon atoms; in other embodiments, the alkyl group contains from 1 to 6 carbon atoms; in other embodiments, the alkyl group contains from 1 to 4 carbon atoms; in other embodiments, the alkyl group contains from 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0050] The term "alkylene" denotes a saturated, divalent or polyvalent hydrocarbon radical resulting from the removal of two or more hydrogen atoms from a saturated straight chain or branched chain hydrocarbon radical. Unless otherwise specifically indicated, an alkylene group contains 1 to 12 carbon atoms. In some embodiments, an alkylene group contains 1 to 6 carbon atoms; in other embodiments, an alkylene group contains 1 to 4 carbon atoms; in yet other embodiments, an alkylene group contains 1 to 3 carbon atoms; in still other embodiments, an alkylene group contains 1 to 2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), i-propylene (-CH(CH3)CH2-), and the like.

[0051] The term "alkenyl" denotes a straight chain or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is a C-C sp 2 The term "alkenyl" denotes a straight chain or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is a C-C sp

[0052] The term "alkynyl" denotes a straight chain or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is a C-C sp

[0053] The terms "haloalkyl", "haloalkenyl", or "haloalkoxy" indicate that an alkyl, alkenyl, or alkoxy group is substituted by one or more halogen atoms, wherein the alkyl, alkenyl, and alkoxy groups have the meanings described herein. Examples of such groups include, but are not limited to, difluoroethyl (-CH2CHF2,-CF2CH3,-CHFCH2F), trifluoroethyl (-CH2CF3,-CF2CH2F,-CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), fluorovinyl (-CH=CHF,-CF=CH2), and so on.

[0054] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in still other embodiments, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention.

[0055] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0056] The term "aryl" may be used alone or as a subset of "aranyl," "aranalkoxy," or "aranoxyalkyl," referring to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14 carbon atoms, or 9-12 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 carbon atoms and has one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic cyclic ring," as aryl may include phenyl, naphthyl, and anthracene. The aryl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0057] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system containing 5-16 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system comprises a ring of 5-7 ring atoms and has one or more attachment sites connected to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound," which includes monocyclic heteroaryl, fused bicyclic heteroaryl, or polycyclic fused heteroaryl. In some embodiments, a heteroaryl is a heteroaryl comprising 5-14 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, a heteroaryl is a heteroaryl comprising 5-12 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a fused bicyclic heteroaryl group consisting of 7-12 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a fused bicyclic heteroaryl group consisting of 9-10 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a fused bicyclic heteroaryl group consisting of 5-10 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a fused bicyclic heteroaryl group consisting of 8-10 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-7 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a monocyclic heteroaryl group consisting of 5-6 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 6 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0058] Other embodiments include, but are not limited to, the following monocyclic groups: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 2-pyridyl, 3- Pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (also known as tetrazolyl, e.g., 5H-tetrazole, 2H-tetrazole), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl) (e.g., pyrazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also The heteroaryl group includes, but is not limited to, the following bicyclic or tricyclic groups: benzimidazolyl, benzofuranyl, benzothiopheneyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), phenoxathioyl, dibenzimidazolyl, dibenzofuranyl, dibenzothiopheneyl, etc. The heteroaryl group may optionally be substituted by one or more substituents described in this invention.

[0059] The term "composed of M-M1 ring atoms" indicates that the cyclic group is composed of M-M1 ring atoms, including carbon atoms and / or heteroatoms such as O, N, S, and P. For example, "a heteroaryl group composed of 5-10 ring atoms" means that it comprises a heteroaryl group composed of 5, 6, 7, 8, 9, or 10 ring atoms.

[0060] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein, referring to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms, and the ring system has one or more bonding sites connected to the remainder of the molecule. The term "heterocyclic group" includes monocyclic heterocyclic groups, bicyclic fused heterocyclic groups, or polycyclic fused heterocyclic groups, spirocyclic heterocyclic groups, or bridged heterocyclic groups, and also includes polycyclic ring systems in which the heterocycle may be fused with one or more non-aromatic carbocyclic rings or heterocycles or one or more aromatic rings or combinations thereof, wherein the bonding group or site is on the heterocycle. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spirobicyclic heterocyclic groups. Unless otherwise stated, the -CH2- group of the heterocyclic group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclic group is a ring system composed of 3-12 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 4-7 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 3-7 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 4-6 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 3-6 ring atoms; in some embodiments, the heterocyclic group is a monocyclic heterocyclic group composed of 5-6 ring atoms; in some embodiments, the heterocyclic group is a bicyclic heterocyclic group composed of 7-12 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group composed of 7-12 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group composed of 9-10 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group composed of 7-10 ring atoms; in some embodiments, the heterocyclic group is a fused bicyclic heterocyclic group composed of 8-10 ring atoms. The heterocyclic group is, in some embodiments, a bridged bicyclic heterocyclic group consisting of 6-10 ring atoms; in other embodiments, a ring system consisting of 3-8 ring atoms; in other embodiments, a ring system consisting of 3-6 ring atoms; in other embodiments, a ring system consisting of 5-7 ring atoms; in other embodiments, a ring system consisting of 5-8 ring atoms; in other embodiments, a ring system consisting of 6-8 ring atoms; a ring system consisting of 3 ring atoms; in other embodiments, a ring system consisting of 4 ring atoms; in other embodiments, a ring system consisting of 5 ring atoms; in other embodiments, a ring system consisting of 6 ring atoms; in other embodiments, a ring system consisting of 7 ring atoms; and in other embodiments, a ring system consisting of 8 ring atoms.

[0061] Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxyl, piperazinyl, homopiperazinyl, aziridine, oxacyclobutyl, thiohexacyclobutyl, thiohexacyclobutyl, homopiperidinyl, oxacyclopropyl, aziridine heptyl, oxacycloheptyl, thioheptyl, oxazonyl, diazacyclobutyl, thioazonyl, 2-pyrrolidinyl, 3-pyrrolidinyl The following compounds are used: pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxacyclopentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothienyl, pyrazolinyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholino; wherein examples of carbon atoms on the ring being replaced by oxo (=O) groups include, but are not limited to, pyrimidinidone, 1,2,4-thiadiazole-5(4H)-keto, 1,2,4-oxadiazole-5(4H)-keto, 1H-1,2,4-triazole-5(4H)-keto, etc.; wherein examples of carbon atoms on the ring being replaced by =S groups include, but are not limited to, 1,2,4-oxadiazole-5(4H)-thionol, 1,3,4-oxadiazole-2(3H)-thionol, etc. The heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0062] The term "fused bicyclic" refers to a monovalent or polyvalent, saturated, partially unsaturated or fully unsaturated non-aromatic or aromatic ring system in which the two rings share two adjacent ring atoms.

[0063] The terms “spirocyclic,” “spirocyclic,” “spirobicyclic,” or “spirobicyclic” are used interchangeably here to refer to a monovalent or polyvalent, saturated or partially unsaturated, non-aromatic ring system in which one ring originates from a specific ring carbon atom on the other ring, and the two rings share only one atom.

[0064] For example, as described by formula a below, rings B and B′ are referred to as “fused bicyclic”, while rings A′ and B share a single carbon atom and are referred to as “spirocyclic” or “spirobicyclic”. Each ring in a fused bicyclic or spirobicyclic group can be a carbocyclic or heterocyclic group, and each ring may optionally be substituted by one or more substituents described in this invention.

[0065]

[0066] The terms "fused bicyclic heterocyclic group" and "bicyclic fused heterocyclic group" are used interchangeably to refer to a monovalent, saturated or partially unsaturated, non-aromatic fused-ring system. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain an aromatic ring or aromatic heterocyclic ring (although aromatics can be used as substituents thereon). Each ring in the ring system comprises 3-7 atoms, and at least one ring comprises one or more heteroatoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2. In some embodiments, the fused bicyclic heterocyclic group is a fused bicyclic heterocyclic group consisting of 7-10 ring atoms; in some embodiments, the fused bicyclic heterocyclic group is a fused bicyclic heterocyclic group consisting of 8-10 ring atoms. Examples of such groups include, but are not limited to, 3-aza-fused [3.1.0]hexane, 3-aza-bicyclic [3.3.0]octane, hexahydro-furan [3,4-c]pyrrole, hexahydro-thiophene [3,4-c]pyrrole, 3,4,5,6-tetrahydro-cyclopentane [c]thiophene, etc. The fused bicyclic heterocyclic group is optionally substituted by one or more substituents described in this invention.

[0067] The term "bridged bicyclic group" or "bridged bicyclic" refers to a saturated or partially unsaturated non-aromatic bridged ring system, as shown in formula b, where ring A1 and ring A2 share a common alkane chain, heteroatom, or heteroalkane chain, where j is 1, 2, 3, or 4, and X... 3 The system may be an alkyl chain, a heteroatom, or a heteroalkyl chain. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain an aromatic ring or a heterocyclic ring (although aromatics may be used as substituents thereon). Each ring, such as A1 or A2, contains 3-7 atoms, and examples include, but are not limited to, bicyclic [2.2.1]heptyl, 2-methyl-diazabicyclo[2.2.1]heptyl, etc. The bridged bicyclic group may optionally be substituted by one or more substituents described in this invention.

[0068]

[0069] The term "bridged bicyclic heterocyclic group" refers to a saturated or partially unsaturated non-aromatic bridged bicyclic system, wherein each ring comprises 3-7 atoms, and at least one ring comprises one or more heteroatoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to obtain a group like SO, SO2, PO, PO2. In some embodiments, the bridged bicyclic heterocyclic group is a bridged bicyclic heterocyclic group consisting of 6-10 ring atoms. Examples of such groups include, but are not limited to, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2-thio-5-azabicyclo[2.2.1]heptyl, 2-oxo-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, and 2-methyl-2,5-diazabicyclo[2.2.1]heptyl. The bridged bicyclic heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0070] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 ring carbon atoms, with one or more linkages to the rest of the molecule, including monocyclic, bicyclic, or polycyclic fused, spirocyclic, or bridged ring systems. In some embodiments, the cycloalkyl group is a spirobicycloalkyl group consisting of 6-10 atoms; in other embodiments, the cycloalkyl group is a fused bicycloalkyl group consisting of 6-10 atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 3-10 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 3-8 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 3-7 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 5-8 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 3-6 ring carbon atoms; in other embodiments, the cycloalkyl group is a cyclic system containing 5-6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and said cycloalkyl groups may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0071] The terms "alkylamino" and "alkanoamino" are used interchangeably, including "N-alkylamino" and "N,N-dialkylamino," wherein the hydrogen atom in the amino group is independently replaced by one or two alkyl groups. In some embodiments, the alkylamino group has one or two C24 groups. 1-12 The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In other embodiments, the alkylamino group has one or two C atoms. 1-6 The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In other embodiments, the alkylamino group has one or two C atoms. 1-4The alkyl group is attached to a lower-order alkylamino group formed on the nitrogen atom. In some other embodiments, the alkylamino group has one or two carbon atoms. 1-3 An alkyl group is attached to a nitrogen atom to form a lower-order alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples of alkylamino groups include, but are not limited to, N-methylamino (-NHCH3), N-ethylamino (-NHCH2CH3), N,N-dimethylamino (-N(CH3)2), N,N-diethylamino (-N(CH2CH3)2), etc.

[0072] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0073] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0074] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0075] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0076] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name compounds whose plane polarization is rotated. (-) or l indicates the compound is levorotatory, while (+) or d indicates it is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures differ. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0077] The terms "tautomer" or "tautomer form" refer to isomers of different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerization between keto-enol and imine-enamine forms. Valence tautomers include interconversions involving the recombination of bonding electrons. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0078] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C... 1-8 Sulfonates and aromatic sulfonates.

[0079] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0080] The term "protecting group" or "Pg" refers to a substituent that, when reacting with other functional groups, is typically used to block or protect specific functionalities. For example, a "protecting group for an amino group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenemethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect its functionality; suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect its functionality. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphine)ethyl, nitroethyl, and so on. For a general description of protecting groups, please refer to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0081] Pharmaceutical compositions, formulations, administration, and uses of the compounds and pharmaceutical compositions of the present invention.

[0082] According to another aspect, the pharmaceutical composition of the present invention comprises a compound represented by formula (I), a compound listed in the present invention, or a compound of the examples, and a pharmaceutically acceptable excipient.

[0083] The compounds in the pharmaceutical compositions of the present invention are effective for the treatment of TLR8-mediated diseases. The areas of disease treatment that may be mentioned for the compounds or pharmaceutical compositions of the present invention include, for example, immune diseases, diseases caused by viral infections, and tumors, such as hepatitis B virus infection, hepatitis C virus infection, influenza virus infection, herpes virus infection, HIV infection, allergic diseases, rheumatoid arthritis, allergic asthma, chronic fatigue, type II diabetes, hay fever, lupus erythematosus, multiple sclerosis, melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumors, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer, and thyroid cancer.

[0084] The present invention includes pharmaceutical preparations containing, in addition to non-toxic, inert, pharmaceutically suitable excipients, one or more compounds of formula (I) of the present invention or pharmaceutical compositions thereof.

[0085] The above-mentioned pharmaceutical preparations may also contain other active pharmaceutical ingredients besides the compound shown in formula (I).

[0086] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0087] As described in this invention, the pharmaceutical compositions of this invention comprise any compound of formula (I) of this invention, further comprising pharmaceutically acceptable excipients, such as those used in this invention, including any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are summarized herein demonstrate that various excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional excipients that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0088] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0089] The pharmaceutical compositions of the compounds of the present invention can be administered in any of the following ways: oral administration, inhalation via aerosol, local administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intrasternal, or intracranial injection or infusion, or administration via an external reservoir. Preferred methods are oral administration, intramuscular injection, intraperitoneal administration, or intravenous injection.

[0090] The compounds or pharmaceutical compositions thereof of the present invention may be administered in unit dose form. The dosage form may be a liquid or other dosage form. Liquid dosage forms may be true solutions, colloids, microparticles, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders for injection, inclusion complexes, implants, patches, and liniments.

[0091] Oral tablets and capsules may contain excipients such as binders, like syrup, gum arabic, sorbitol, astragalus gum, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated using pharmaceutically known methods.

[0092] Oral liquids can be formulated as hydrated oil suspensions, solutions, emulsions, syrups, or elixirs, or as dry products to be replenished with water or other suitable media before use. These liquid formulations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelling agents, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils, emulsifiers such as lecithin, sorbitan monooleate, and gum arabic; or non-aqueous excipients (which may contain edible oils such as almond oil), fats such as glycerin, ethylene glycol, or ethanol; preservatives such as methylparaben or propylparaben, and sorbic acid. Flavorings or colorings may be added if desired.

[0093] Suppositories may contain a conventional suppository base, such as cocoa butter or other glycerides.

[0094] For external administration, liquid dosage forms are typically made from a compound and a sterilized excipient. Water is the preferred excipient. Depending on the excipient and drug concentration, the compound can be either dissolved in the excipient or prepared as a suspension. When preparing an injectable solution, the compound is first dissolved in water, filtered, sterilized, and then packaged into sealed bottles or ampoules.

[0095] When applied topically to the skin, the compounds of the present invention can be formulated into suitable ointments, lotions, or creams, wherein the active ingredient is suspended or dissolved in one or more excipients. Excipients that may be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water. Excipients that may be used in lotions and creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0096] The amount of active ingredient that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended therapeutic target and the specific method of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 to 1000 mg of the active substance formulated with a suitable and convenient amount of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients vary between about 5% to about 95% (by weight) of the total composition.

[0097] The compounds disclosed in this invention, such as those represented by formula (I), can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, for example, at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or longer. In one variant, the compound is administered on a daily or intermittent schedule throughout the individual's lifespan.

[0098] The dosage or frequency of administration of the compounds disclosed in this invention may be adjusted during treatment based on the physician's judgment.

[0099] The compound can be applied to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is applied once daily.

[0100] In some embodiments, a method for treating or preventing human diseases or conditions is provided, comprising administering to a human a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. Since TLR-8 agonists can be used to treat a wide variety of diseases or symptoms, the specific identity of the additional therapeutic agents will depend on the specific disease or condition being treated.

[0101] The compound represented by formula (I) may be administered by any useful route and manner, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound represented by formula (I) is from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, for example, from about 0.0001 mg / kg body weight / day to about 10 mg / kg / day or from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day or for example, from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day.

[0102] The therapeutically effective amount of the compound represented by Formula (I) is from about 0.01 mg / dose to about 1000 mg / dose, for example, from about 0.01 mg / dose to about 100 mg / dose, or for example, from about 0.1 mg / dose to about 100 mg / dose, or for example, from about 1 mg / dose to about 100 mg / dose, or for example, from about 1 mg / dose to about 10 mg / dose. Other therapeutically effective amounts of the compound represented by Formula (I) are about 1 mg / dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 mg / dose. Other therapeutically effective amounts of the compound represented by formula (I) are about 100 mg / dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or 500 mg / dose. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered every hour, every 2, 3, 4, 6, 8, 12, 16 hours, or every 24 hours. A single dose may also be administered every day, every 2, 3, 4, 5, 6 days, or every 7 days. A single dose may also be administered every week, every 2, 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly.

[0103] The frequency of administration of the compound shown in Formula (I) will be determined by the individual patient's needs, for example, once daily or twice daily or more. For example, depending on the length of time required for continuous treatment of HBV or HCV infection, the compound shown in Formula (I) can be administered to people infected with HBV or HCV for a period of 20 to 180 days, or for a period of 20 to 90 days, or for a period of 30 to 60 days.

[0104] Administration can be intermittent, in which a patient receives a daily dose of the compound represented by formula (I) for a period of several days or more, followed by a period of several days or more in which the patient does not receive the daily dose of the compound. For example, a patient may receive a dose of the compound every other day or three times a week. Again, as an example, a patient may receive a daily dose of the compound for a period of 1 to 14 days, followed by a period of 7 to 21 days in which the patient does not receive the dose of the compound, followed by a subsequent period in which the patient receives the daily dose of the compound again (e.g., from 1 to 14 days). The administration of the compound, followed by periods of non-administration, can be repeated according to the clinical requirements of the patient being treated.

[0105] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0106] In one embodiment, a kit is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0107] In some embodiments, the compound disclosed in this invention or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more other therapeutic agents. In some embodiments, the compound disclosed in this invention or a pharmaceutically acceptable salt thereof is combined with two other therapeutic agents. In other embodiments, the compound disclosed in this invention or a pharmaceutically acceptable salt thereof is combined with three other therapeutic agents. In still other embodiments, the compound disclosed in this invention or a pharmaceutically acceptable salt thereof is combined with four other therapeutic agents. The one, two, three, four, or more other therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0108] In some embodiments, when the compounds disclosed in this invention are combined with one or more other therapeutic agents described herein, the components of the composition are administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or more applications.

[0109] In some embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents in a single dosage form for simultaneous administration to a patient, such as as a solid dosage form for oral administration.

[0110] In some embodiments, the compounds disclosed herein are administered together with one or more other therapeutic agents. Administering the compounds disclosed herein together with one or more other therapeutic agents generally means administering the compounds disclosed herein and one or more other therapeutic agents simultaneously or sequentially, such that therapeutically effective amounts of both the compounds disclosed herein and the one or more other therapeutic agents are present in the patient.

[0111] Co-application includes applying a unit dose of the compound disclosed in this invention before or after applying a unit dose of one or more other therapeutic agents, for example, applying the compound disclosed in this invention within seconds, minutes, or hours after applying one or more other therapeutic agents. For example, in some embodiments, a unit dose of the compound disclosed in this invention is applied first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is applied first, followed by a unit dose of the compound disclosed in this invention within seconds or minutes. In some embodiments, a unit dose of the compound disclosed in this invention is applied first, followed by a unit dose of one or more other therapeutic agents after a period of several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is applied first, followed by a unit dose of the compound disclosed in this invention after a period of several hours (e.g., 1-12 hours).

[0112] The pharmaceutical compositions provided by this invention comprise a compound represented by formula (I) of this invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and further comprise one or more other therapeutic agents. The therapeutic agents are HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, toll-like receptor 7 and 8 modulators, toll-like receptor 3 modulators, interferon α ligands, HBsAg inhibitors, compounds targeting HbcAg, cyclic protein inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV virus entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA), hepatitis B virus E antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies, thymosin agonists, cytokines, nucleoprotein inhibitors, retinoic acid-induced gene 1 stimulators, NOD2 stimulators, recombinant thymosin α-1 and hepatitis B virus replication inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, IDO inhibitors, or combinations thereof.

[0113] The one or more therapeutic agents mentioned are lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, Alfaferone, Alloferon, simmointerleukin, clavudine, emtricitabine, faxclovir, interferon, bacalan CP, interferon α-1b, interferon α, interferon α-2a, interferon β-1a, interferon α-2, interleukin-2, mirtovalidone, nitrozonide, pegylated interferon α-2a, ribavirin, rointerferon-A, cizonan, eufovac, amprigin, phosphazid, heplisav, interferon α-2b, recombinant human interleukin-2, levamisole, or propafenone.

[0114] Another aspect of this invention relates to the use of the compounds or pharmaceutical compositions of this invention in the preparation of medicaments for immune diseases, diseases caused by viral infections, and tumors, particularly the use of medicaments for the prevention, treatment, or relief of hepatitis B disease in patients, including administering medication to patients at a pharmaceutically acceptable and effective dose. Hepatitis B disease refers to liver diseases caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute hepatitis B virus infection can be asymptomatic or present with symptoms of acute hepatitis. Patients with chronic viral infection have active disease that can develop into cirrhosis and liver cancer.

[0115] General synthesis methods

[0116] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following synthetic schemes and examples are provided to further illustrate the content of the present invention.

[0117] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0118] In the examples described below, all temperatures are specified in degrees Celsius (°C) unless otherwise stated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0119] Silica gel columns were used, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy used CDCl3, DMSO-d6, CD3OD, or acetone-d6 as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiplets were observed, the following abbreviations were used: s (singlet), q (quartet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), ddd (double doublet), tt (triple triplet), br.s (broadened singlet). The coupling constant J was expressed in Hertz (Hz).

[0120] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0121] Low-resolution mass spectrometry (MS) data were also determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30°C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0122] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase consisted of 0.1% formic acid-acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B). Gradient elution conditions are shown in Table a: Table a: Gradient Elution Conditions

[0123]

[0124]

[0125] Compound purification was evaluated using an Agilent 1100 series high-performance liquid chromatography (HPLC) system with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column (2.1 × 30 mm, 4 μm), a flow rate of 0.6 mL / min for 10 min, and a concentration of 5-95% (0.1% formic acid acetonitrile solution) or (0.1% formic acid aqueous solution) at a column temperature of 40 °C.

[0126] The following abbreviations are used throughout this invention:

[0127] MeOH, Methanol, IPA, Isopropanol

[0128] MeOH-d4 Deuterated methanol TBAF Tetrabutylammonium fluoride

[0129] MsCl Methylsulfonyl chloride TBSCl tert-butyldimethylchlorosilane

[0130] EtOH Ethanol (TfO)2NPh 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)

[0131] DIAD (Diisopropyl Azodicarbonate Methanesulfonamide)

[0132] DCM,CH2Cl2 dichloromethane NaBH(OAc)3 sodium triacetoxyborohydride

[0133] DCE dichloroethane t-BuOH tert-butanol

[0134] PdCl2(dppf)[1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride DMBNH2 2,4-dimethoxybenzylamine

[0135] CDC13 is a solution of deuterated chloroform in HCl / EA and HCl / EtOAc in ethyl acetate.

[0136] Boc tert-Butoxycarbonyl HAUT 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexadecyl

[0137] (Boc)₂O ditert-butyl dicarbonate fluorophosphate

[0138] PE petroleum ether NBS N-bromosuccinimide

[0139] EtOAc,EA (ethyl acetate) ACN (acetonitrile)

[0140] 1 atm 101.325 kPa DIPEA N,N-diisopropylethylamine

[0141] h hours DMF N,N-dimethylformamide

[0142] RT,rt EDCI at room temperature 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0143] DME (ethylene glycol dimethyl ether) DMAP (4-dimethylaminopyridine)

[0144] B2Pin2 Pinanediol Boronate (AIBN)

[0145] TFA (trifluoroacetic acid, Et3N), TEA (triethylamine)

[0146] KOAc potassium acetate mL, ml

[0147] MeNH2 methylamine THF tetrahydrofuran

[0148] t-BuOK Potassium tert-butoxide DMSO Dimethyl sulfoxide

[0149] BRETTPHOS PD G3 Methanesulfonic acid (2-dicyclohexylAc2O Acetic anhydride)

[0150] Phosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-aminot 1 / 2 half life

[0151] -1,1'-biphenyl-2-yl)palladium(II) Rt retention time

[0152] Synthesis method

[0153] The following synthetic scheme outlines the experimental steps for preparing the compounds disclosed in this invention. Wherein, each R... 1 R 2 Q1, Q2 and L have the meanings as described in this invention.

[0154] Synthesis Scheme 1

[0155]

[0156] The compound described in formula (I) can be synthesized by the method disclosed in synthetic scheme 1. First, compound 1-12 reacts with compound A-1 in the presence of a base (such as sodium bicarbonate, potassium carbonate, potassium acetate, etc.) and a catalyst (such as PdCl2dppf, etc.) to generate compound A-2; then, compound... A-2 Hydrolysis under alkaline conditions (such as lithium hydride) yields compound A-3; then, compound A-3 and compound A-4 undergo a condensation reaction under condensing agent (such as HATU) and alkaline conditions (such as DIPEA) to yield compound A-5; finally, compound A-5 is deprotected under acidic conditions (such as a solution of 1,4-dioxane with hydrogen chloride) to yield the compound described in formula (I). Detailed Implementation

[0157] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0158] Preparation Examples

[0159] In the following preparation examples, the inventors have described in detail the preparation process of the compounds of the present invention using some of the compounds as examples. Furthermore, in the following preparation examples, when there is a discrepancy between the compound name and the compound structure, the compound structure shall prevail.

[0160] Example 1: Synthesis of Compound 1

[0161]

[0162] Step 1 : Synthesis of compound 1-2

[0163]

[0164] Compound 1-1 (50.0 g, 116 mmol) was dissolved in tetrahydrofuran (400 mL), purged with nitrogen three times, cooled to -40 °C, and stirred for 10 min. A tetrahydrofuran solution of isopropyl magnesium chloride (87 mL, 174 mmol, 2.0 mol / L) was added dropwise over approximately 20 min, and the reaction was continued with stirring for 1 h. DMF (11.7 mL, 151 mmol) was added, and the mixture was cooled to room temperature and stirred for another 4 h. The reaction was quenched by slowly adding 10% ammonium chloride solution (15.5 g, 290 mmol), followed by extraction with ethyl acetate (250 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was slurried in a mixture of isopropanol and petroleum ether (200 mL, IPA / PE (V / V) = 1 / 1) to give compound 1-2 as a grayish-white solid (21 g, yield 54.3%).

[0165] Step 2: Synthesis of compound 1-3

[0166]

[0167] Compounds 1-2 (11.67 g, 35.02 mmol) were dissolved in 1,4-dioxane (35 mL), and concentrated hydrochloric acid (58.35 mL, 12 mol / L) was added. The mixture was reacted at 90 °C for 13 h. After cooling to room temperature, water (100 mL) was added, and a solid precipitated. The solid was filtered, and the filter cake was washed with water (100 mL) to give a reddish-brown solid compound. The solid compound was purified by silica gel column chromatography (PE / EA(V / V) = 5 / 1) to give title compound 1-3 as a white solid compound (8.0 g, yield 94%).

[0168] MS(ESI,pos.ion)m / z:243.0[M+H] + .

[0169] Step 3: Synthesis of compound 1-4

[0170]

[0171] At -10°C, compounds 1-3 (8.5 g, 35 mmol) were dissolved in dichloromethane (85 mL), and triethylamine (7.3 mL, 52 mmol) and DMAP (0.43 g, 3.5 mmol) were added. Acetic anhydride (5.0 mL, 53 mmol) was slowly added dropwise. After the addition was complete, the mixture was moved to room temperature and reacted for 1 h. The reaction was quenched by adding ammonium chloride (100 mL). The aqueous phase was extracted with DCM (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated. The residue was purified by silica gel column chromatography (PE / EA (V / V) = 5 / 1) to give the title compounds 1-4 as white solids (10 g, 100% yield).

[0172] Step 4: Synthesis of compound 1-5

[0173]

[0174] Compounds 1-4 (10 g, 35.08 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.673 g, 1.85 mmol), cesium carbonate (22.9 g, 70.2 mmol), NH2Boc (6.268 g, 52.44 mmol), and 1,4-dioxane (100 mL) were added to the reaction flask, and the reaction was carried out at 100 °C for 14 h under nitrogen protection. The reaction solvent was concentrated, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH / Et3N(V / V / V)=15 / 1 / 0.003) to obtain a light crude product. The crude product was then slurried with ethanol (70 mL) to obtain the title compounds 1-5 as yellow solids (9.4 g, yield 96%).

[0175] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.79(s,1H),7.57(s,1H),4.56(t,J=8.3Hz,2H),3.49–3.43(m,2H),1.47(s,9H).

[0176] Step 5: Synthesis of compound 1-6

[0177]

[0178] Compounds 1-5 (0.60 g, 2.1 mmol) were dissolved in dichloromethane (12 mL) at -10 °C. Triethylamine (0.45 mL, 3.2 mmol) and DMAP (0.027 g, 0.22 mmol) were added, followed by the slow addition of acetic anhydride (0.30 mL, 3.2 mmol). After the addition was complete, the reaction mixture was moved to room temperature and reacted for 2.5 h. The solvent was concentrated, and the residue was purified by silica gel column chromatography (PE / EA(V / V) = 5 / 1) to give the title compounds 1-6 as a yellow solid (0.512 g, yield 74%).

[0179] MS(ESI,pos.ion)m / z:222.1[M-Boc+H] +

[0180] Step 6: Synthesis of compound 1-7

[0181]

[0182] Compound 1-6 (5.8 g, 18 mmol), ethyl 3-cyano-2-(triphenylphosphine)acrylate (10 g, 25.81 mmol), and toluene (58 mL) were added to a single-necked flask, and the mixture was heated under reflux for 11 h. The solvent was concentrated, and the residue was purified by silica gel column chromatography (PE / EA(V / V) = 5 / 1) to give the title compound as a pale white solid (7.2 g, 93% yield).

[0183] 1 H NMR (400MHz, CDCl3) δ7.67(s,1H),7.35(s,1H),6.06(s,1H),4.64(t,J=8.7Hz,2H),4.37(q,J=7 .1Hz,2H),3.23(s,2H),3.11(t,J=8.6Hz,2H),2.30(s,3H),1.46(s,9H),1.39(t,J=7.1Hz,3H).

[0184] Step 7: Synthesis of compound 1-8

[0185]

[0186] Compound 1-7 (7.5 g, 17 mmol) and HCl / EtOH (58 mL, 174 mmol, 3 mol / L) were added to a reaction flask and reacted at room temperature for 24 h. The solvent was concentrated, and the resulting residue was slurried with methyl ether (30 mL) to give the title compound as a white solid (4.87 g, yield 96.95%).

[0187] 1H NMR (400MHz, DMSO-d6) δ10.55(s,1H),9.80(s,1H),8.77(s,1H),7.61(s,1H),6.78(s,1H),4.61( t,J=8.8Hz,2H),4.25(q,J=7.0Hz,2H),3.42(s,2H),3.29(t,J=8.8Hz,2H),1.29(t,J=7.1Hz,3H).

[0188] Step 8: Synthesis of compound 1-9

[0189]

[0190] Compounds 1-8 (4.2 g, 13 mmol), TBSCl (2.5 g, 16 mmol), and imidazole (2.3 g, 32 mmol) were dissolved in DMF (21 mL) and reacted at 35 °C for 3 h. Ethyl acetate (100 mL) was added, and a solid precipitated. The solid was filtered, and the filter cake was washed with ethyl acetate (100 mL) to give the title compound as a white solid (6.8 g, yield 116%).

[0191] Step 9: Synthesis of compound 1-10

[0192]

[0193] Compounds 1-9 (5.5 g, 13 mmol) and triethylamine (5.2 mL, 38 mmol) were dissolved in DCM (55 mL), and then Boc anhydride (7.2 mL, 31 mmol) was added. The mixture was stirred at room temperature for 2 h. The solvent was concentrated, and the resulting residue was purified by silica gel column chromatography (PE / EA(V / V) = 5 / 1) to give the title compound as a yellow solid (6.0 g, yield 87%).

[0194] Step 10: Synthesis of compound 1-11

[0195]

[0196] Compound 1-10 (1.6 g, 3.2 mmol) and a tetrahydrofuran solution of tetrabutylammonium fluoride (4.8 mL, 4.8 mmol, 1 mol / L) were added to a reaction flask and the mixture was stirred at room temperature for 1.7 h. Water (30 mL) was added, followed by extraction with EA (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 2 / 1) to give the title compound as a yellow solid (1.0 g, yield 81%).

[0197] Step 11 : Synthesis of compound 1-12

[0198]

[0199] Compound 1-11 (1.50 g, 3.86 mmol) was dissolved in dichloromethane (30.0 mL), followed by the addition of DBU (0.928 g, 5.79 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.07 g, 5.80 mmol). The mixture was stirred at room temperature for 1 h. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography (PE / EA(v / v) = 5 / 1) to give the title compound as a yellow foamy solid (1.83 g, yield 91.0%).

[0200] Step 12: Synthesis of compound 1-14

[0201]

[0202] Compound 1-13 (0.40 g, 1.8 mmol), 2-(chloromethyl)pyrimidine (0.35 g, 2.1 mmol), cesium carbonate (1.7 g, 5.2 mmol), and DMF (4.8 mL) were added to a reaction flask, and the mixture was stirred at 50 °C for 5 h. After cooling to room temperature, the mixture was poured into water (20 mL), filtered, and the filter cake was collected. The filter cake was washed successively with water and petroleum ether, and dried under reduced pressure to give the title compound as a white solid (0.407 g, yield 72%).

[0203] MS(ESI,pos.ion)m / z:317.1[M+H] + .

[0204] Step 13: Synthesis of compound 1-15

[0205]

[0206] Compound 1-14 (400 mg, 1.261 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1,3,2-dioxaborane (pinacol diboronate, 0.480 g, 1.89 mmol), KOAc (0.371 g, 3.78 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.015 g, 0.018 mmol), and 1,4-dioxane (8.0 mL) were added to a reaction flask. The reaction mixture was reacted at 80 °C for 5 h. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was slurried with isopropyl ether (10 mL) to give the title compound as a yellow solid (0.44 g, 96% yield).

[0207] MS(ESI,pos.ion)m / z:365.2[M+H]+ .

[0208] Step 14: Synthesis of compound 1-16

[0209]

[0210] Compound 1-15 (0.489 g, 1.34 mmol), compound 1-12 (350 mg, 0.67 mmol), sodium bicarbonate (0.178 g, 2.01 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (0.086 g, 0.10 mmol), DME (5 mL), and water (1 mL) were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 65 °C for 13 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 30 / 1) to give the title compound as a yellow solid (0.280 g, yield 68.4%).

[0211] MS(ESI,pos.ion)m / z:609.2[M+H] + .

[0212] Step 15: Synthesis of compound 1-17

[0213]

[0214] Compound 1-16 (0.260 g, 0.427 mmol), H₂O (0.52 mL), MeOH (2.60 mL), and LiOH·H₂O (0.089 g, 2.1 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 6 h. The mixture was concentrated, and the residue was adjusted to pH 6 with citric acid (8 mL, 1 M). The residue was extracted with DCM (20 mL × 3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 15 / 1) to give the title compound as a yellow solid (0.063 g, yield 25%).

[0215] MS(ESI,pos.ion)m / z:581.3[M+H] + .

[0216] Step 16: Synthesis of compound 1-18

[0217]

[0218] DMF (2 mL) was added to the reaction flask, followed by the sequential addition of compound 1-17 (0.063 g, 0.11 mmol), DIPEA (0.035 g, 0.27 mmol), n-dipropylamine (0.022 g, 0.22 mmol), and HATU (0.11 g, 0.28 mmol) at 0 °C. The resulting reaction mixture was transferred to room temperature and stirred for 1 h. The reaction solution was poured into water (10 mL), and then extracted with DCM (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (0.077 g, yield 107%).

[0219] MS(ESI, pso.ion) m / z: 664.2 [M+H] + .

[0220] Step 17: Synthesis of compound 1

[0221]

[0222] Compound 1-18 (0.077 g, 0.12 mmol) and a 1,4-dioxane solution of HCl (5 mL, 20 mmol, 4 mol / L) were added to a reaction flask, and the mixture was stirred at room temperature for 19 h. The solvent was concentrated, and the pH was adjusted to 9 with sodium bicarbonate solution. The mixture was then extracted with DCM (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 10 / 1) to give a crude product. The crude product was recrystallized from isopropyl ether to give the title compound as a yellow solid (36 mg, yield 55%).

[0223] MS(ESI,pos.ion)m / z:563.6[M+H] + ;

[0224] 1 H NMR(400MHz, CDCl3) δ8.68(d,J=4.9Hz,2H),8.46(d,J=8.2Hz,1H),8.26(s,1H) ,8.17(s,1H),8.14(d,J=3.2Hz,1H),7.34(s,1H),7.17(t,J=4.8Hz,1H),6.69( s,1H),5.70(s,2H),4.74(t,J=8.7Hz,2H),3.69–3.58(m,1H),3.52–3.33(m,4H ),3.29(t,J=8.7Hz,2H),3.10(s,1H),1.70–1.62(m,4H),0.93(t,J=7.0Hz,6H);

[0225] HR-MS (ESI): 564.2710 [M+H] + .

[0226] Example 2: Synthesis of Compound 2

[0227]

[0228] Using 6-bromo-2H-isoquinoline-1-one, 2-chloromethylpyrimidine hydrochloride, di-n-propylamine and compounds 1-12 as starting materials, the title compound was obtained as a yellow solid (97 mg, yield 62%) by referring to the synthesis method in steps 12-17 of Example 1.

[0229] MS,(ESI,pos.ion)m / z:563.3[M+H] + ;

[0230] 1 H NMR(400MHz, CDCl3) δ8.68(d,J=4.9Hz,2H),8.44(d,J=8.4Hz,1H),7.93(s, 1H),7.87(d,J=8.5Hz,1H),7.32(s,1H),7.21–7.15(m,2H),6.69(s,1H),6.5 9(d,J=7.3Hz,1H),5.43(s,2H),4.71(t,J=8.8Hz,2H),3.52–3.33(m,4H),3 .27(t,J=8.7Hz,2H),2.84(s,2H),1.73–1.60(m,4H),0.93(t,J=7.0Hz,6H);

[0231] HR-MS (ESI): 563.2745 [M+H] + .

[0232] Example 3: Synthesis of Compound 3

[0233]

[0234] Using 6-bromo-2H-isoquinoline-1-one, 2-chloromethylthiazole, di-n-propylamine and compounds 1-12 as starting materials, and following the synthetic method in steps 12-17 of Example 1, the title compound was obtained as a yellow solid (30 mg, yield 35%).

[0235] MS(ESI,pos.ion)m / z:568.3[M+H] + ;

[0236] 1H NMR (400MHz, CDCl3) δ8.46(d,J=8.7Hz,1H),7.84(d,J=7.7Hz,2H),7.75(d,J=3.2Hz,1H),7.53(s,1H),7.33(d,J=3.2Hz,1H),7.29(d,J=7.3Hz,1H),6 .74(s,1H),6.60(d,J=7.4Hz,1H),5.49(s,2H),4.75(t,J=8.8Hz,2H),3.49 –3.35(m,4H),3.33–3.20(m,4H),1.69–1.63(m,4H),0.93(t,J=7.2Hz,6H);

[0237] HR-MS (ESI): 568.2357 [M+H] + .

[0238] Example 4: Synthesis of Compound 4

[0239]

[0240] Using compounds 1-13, 2-chloromethylthiazole, di-n-propylamine and compounds 1-12 as raw materials, the title compound was obtained as a yellow solid (60 mg, yield 70.56%) according to the synthesis method in steps 12-17 of Example 1.

[0241] MS(ESI,pos.ion)m / z:569.3[M+H] + ;

[0242] 1 H NMR (400MHz, CDCl3) δ8.49(d,J=8.4Hz,1H),8.28(s,1H),8.18(d,J=8.5Hz,1H),8.14(s,1H),7.78(d,J=3.3Hz,1H),7.42(s,1H),7.32(d,J=3.3Hz,1 H),6.73(s,1H),5.77(s,2H),4.78(t,J=8.7Hz,2H),3.54–3.38(m,4H),3. 32(t,J=8.8Hz,2H),3.01(s,2H),1.75–1.66(m,4H),0.96(t,J=7.3Hz,6H).

[0243] HR-MS (ESI): 569.2323 [M+H] + .

[0244] Example 5: Synthesis of Compound 5

[0245]

[0246] Using compounds 1-13, 2-chloromethyloxazole, di-n-propylamine and compounds 1-12 as raw materials, the title compound was obtained as a yellow solid (22 mg, yield 26%) by referring to the synthesis method in steps 12-17 of Example 1.

[0247] MS(ESI,pos.ion)m / z:553.5[M+H] + ;

[0248] 1 H NMR (400MHz, CDCl3) δ8.49(d,J=8.4Hz,1H),8.28(s,1H),8.18(d,J=8.5Hz,1H),8.14(s,1H),7.78(d,J=3.3Hz,1H),7.42(s,1H),7.32(d,J=3.3Hz,1 H),6.73(s,1H),5.77(s,2H),4.78(t,J=8.7Hz,2H),3.54–3.38(m,4H),3. 32(t,J=8.8Hz,2H),3.01(s,2H),1.75–1.66(m,4H),0.96(t,J=7.3Hz,6H);

[0249] HR-MS (ESI): 553.2552 [M+H] + .

[0250] Example 6: Synthesis of Compound 6

[0251]

[0252] Using 4-(pyrrolidine-1-carbonyl)phenylboronic acid pinacol ester, di-n-propylamine and compounds 1-12 as starting materials, the title compound was obtained as a yellow solid (27 mg, yield 43%) by referring to the synthesis method in steps 14-17 of Example 1.

[0253] MS(ESI,pos.ion)m / z:501.4[M+H] + ;

[0254] 1H NMR (400MHz, DMSO-d6) δ7.75(d,J=8.2Hz,2H),7.56(d,J=8.2Hz,2H),7.03(s,1H),6.61(s,1H),6.59(s,1H),4.61(t,J=8.7Hz,2 H),3.50–3.42(m,4H),3.31–3.27(m,3H),3.23(t,J=8.7Hz,2H),1.93–1.78(m,4H),1.64–1.50(m,4H),1.10(s,3H),0.84(m,6H);

[0255] HR-MS (ESI): 501.2826 [M+H] + .

[0256] Biological tests

[0257] Test 1: Assessment of agonistic activity against human TLR7 and TLR8

[0258] Experimental objective: To apply HEK-Blue TM hTLR7 and HEK-Blue TM The agonistic and cytotoxic activities of compounds on hTLR7 and hTLR8 cells were detected in hTLR8 cells.

[0259] The experimental steps are as follows:

[0260] 1) Compound preparation: The compound was first prepared into a 20 mM stock solution using DMSO. Then, the compound was serially diluted 3-fold and added to 96-well plates, resulting in 10 concentrations, with each concentration in duplicate. 0.5 μL of DMSO was added to each well for the negative control. The final DMSO concentration was 0.5%.

[0261] 2) HEK-Blue TM hTLR7 or HEK-Blue TM hTLR8 cells were suspended in culture medium and then seeded into 96-well plates containing the compound, with 50,000 cells per well. The compound and cells were co-incubated at 37°C and 5% CO2 for 24 hours.

[0262] 3) QUANTI-Blue detection solution: Take 1 mL of QB reagent and 1 mL of QB buffer, add 98 mL of sterile water, mix well to dissolve, and let stand at room temperature for 10 min.

[0263] 4) Compound activity assay: Take 20 μL of the culture supernatant from step 2) from each well and add it to a 96-well plate containing 180 μL of QUANTI-Blue detection solution. Incubate at 37°C for 1 h, and then measure the absorbance (OD) at 650 nm using a Flextation III microplate reader. 650 ).

[0264] 5) Cell viability assay: Perform the procedure according to the Celltiter-Glo instruction manual. Detect the chemiluminescence signal (RLU) using a Flextation III multi-functional microplate reader.

[0265] 6) Data Analysis

[0266] Compound activity: OD 650 The values ​​were analyzed using GraphPad Prism software, and the dose-response curves of the compounds were fitted to calculate the EC50 of the compounds. 50 value.

[0267] Cell viability assay: The formula for calculating cell viability % is as follows. Cell viability % values ​​were analyzed using GraphPad Prism software, and a compound dose-response curve was fitted to calculate the compound's CC effect on cells. 50 value.

[0268] Cell activity % = RLU 化合物 / RLU DMSOControl *100%

[0269] The compounds of this invention exhibit good agonistic activity against hTLR8 and good selective activation of hTLR8. The test results of the agonistic activity of the compounds of this invention against human TLR7 and TLR8 are shown in Table A. Furthermore, the compounds of this invention have low cytotoxicity; for example, the CC value of cytotoxicity in Example 2 is shown. 50 >100 (μM).

[0270] Table A: Agonistaltic activity of the compounds of this invention against human TLR7 and TLR8

[0271]

[0272] Conclusion: Experimental data show that Examples 1 and 2 of the present invention have good agonistic activity against hTLR8 and good selective activation of hTLR8.

[0273] Test 2: Inhibitory effect of the compound of this invention on human liver microsomal CYP enzyme

[0274] Experimental objective: To evaluate the inhibitory effects of compounds on the major metabolic enzymes CYP1A2, CYP2C19, CYP2D6 and CYP3A4 in human liver microsomes using a human liver microsome system.

[0275] Experimental Methods: The test compound was incubated at a concentration of 10 μM in the final incubation system with human liver microsomal suspensions containing cytochrome P450 enzymes CYP1A2, CYP2C19, CYP2D6, and CYP3A4, respectively. The substrates were known to be metabolized by the corresponding single enzymes to produce specific metabolites, which were determined by UPLC-MS / MS. The relative inhibition rate (%) was calculated by testing the percentage reduction in metabolite formation between the compound and the solvent DMSO over the same time period.

[0276] Relative inhibition rate % = (1-(N) +inh / N veh ))×100

[0277] N represents the concentration of the probe substrate metabolite, and it is assumed that at 0 min, the blood product concentration is 0 in both the group with and without inhibitor. +inh To increase the metabolite concentration in the inhibitor group, N veh The concentration of metabolites is shown in the group without inhibitors.

[0278] Conclusion: The experimental data of liver drug-metabolizing enzyme inhibition test show that the compound of the present invention has virtually no inhibitory effect on major liver drug-metabolizing enzymes.

[0279] Test 4: The induction effect of the compound of this invention on human liver microsomal CYP enzyme

[0280] Experimental objective: To evaluate the induction effects of the test substances on CYP1A2, CYP2B6 and CYP3A4 at both the enzyme activity and mRNA levels using frozen human hepatocytes as the test system.

[0281] Experimental Methods: Twenty-four hours after cell plating, induction was initiated by adding culture medium containing the test compounds (concentrations of 10, 1, and 0.1 μM). The medium was replaced with fresh drug-containing medium every 24 hours. After 72 hours of induction, the medium was replaced with medium containing CYP1A2, CYP2B6, and CYP3A4 specific substrates and incubated for 30 minutes. 100 μL of the culture was then used for treatment, and the labeled metabolites of the substrates were detected to evaluate enzyme activity levels. Finally, cells were lysed, reverse transcribed, and the expression levels of CYP1A2, CYP2B6, and CYP3A4 genes in the cells were assessed using real-time quantitative PCR.

[0282] The fold induction rate of the test compound compared to the blank control, and the percentage induction rate of the test compound compared to the positive control, were used as the criteria for evaluating the inducing potential of the test compound. The positive control for CYP1A2 was omeprazole; the positive control for CYP2B6 was phenobarbital; and the positive control for CYP3A4 was rifampin.

[0283] Conclusion: The experimental data of liver drug-metabolizing enzyme induction test showed that the compound of the present invention had virtually no inducing effect on liver drug-metabolizing enzymes CYP1A2, CYP2B6 and CYP3A4.

[0284] Test 5: Pharmacokinetic experiments of the compounds of this invention in beagle dogs, mice, rats or cynomolgus monkeys.

[0285] (1) Beagle PK test experiment

[0286] The PK determination method of the compound of this invention in beagle dogs (purchased from Hunan Slack Jingda Experimental Animal Co., Ltd., weighing 10-12kg, male, aged 10-12 months, 3 dogs per group orally and 3 dogs per group intravenously) is as follows:

[0287] Beagles were administered the test compound orally at doses of 2.5 mg / kg or 5 mg / kg, or intravenously at doses of 0.5 mg / kg, 1 mg / kg, or 2 mg / kg.

[0288] Following drug administration, venous blood samples were collected at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours) and deposited into EDTA-K2 anticoagulant tubes. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed using a triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode. Pharmacokinetic parameters were calculated using a non-compartmental model with WinNonlin 6.3 software.

[0289] Conclusion: Pharmacokinetic experimental data show that the compound of this invention has good pharmacokinetic properties in beagle dogs and has good application prospects in anti-HBV.

[0290] (2) Mouse PK test experiment:

[0291] The pharmacokinetic (PK) assay of the compound of this invention in ICR mice (purchased from Hunan Slack Jingda Experimental Animal Co., Ltd., weighing 20-25g, male, aged 45-60 days, 3 mice per group orally and 3 mice per group intravenously) is as follows:

[0292] ICR mice were administered the test compound orally at 10 mg / kg or via tail vein injection at 2 mg / kg or 10 mg / kg.

[0293] Blood samples were collected from the orbital vein at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours) after drug administration and collected in anticoagulant tubes containing EDTA-K2. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed using a triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode. Pharmacokinetic parameters were calculated using a non-compartmental model with WinNonlin 6.3 software.

[0294] Conclusion: Pharmacokinetic data show that the compound of this invention has good pharmacokinetic properties in mice and has good application prospects in anti-HBV.

[0295] (3) PK test experiment of SD rats:

[0296] The pharmacokinetic (PK) assay of the compound of this invention in SD rats (purchased from Hunan Slack Jingda Experimental Animal Co., Ltd., weighing 200-250g, male, aged 2-3 months, 3 rats per group orally and 3 rats per group intravenously) is as follows:

[0297] Rats were administered the test compound orally by gavage at 2.5 mg / kg or 5 mg / kg or intravenously by injection at 1 mg / kg.

[0298] Following drug administration, venous blood samples were collected at time points (0.083, 0.25, 0.5, 1, 2, 5, 7, and 24 hours) and collected in anticoagulant tubes containing EDTA-K2. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed using a triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode. Pharmacokinetic parameters were calculated using a non-compartmental model with WinNonlin 6.3 software.

[0299] Conclusion: Pharmacokinetic experimental data show that the compound of the present invention has a large exposure level in SD rats, indicating that the compound of the present invention is well absorbed in SD rats and has good bioavailability, and has good application prospects in anti-HBV.

[0300] (4) Crab-eating macaque PK test experiment:

[0301] The pharmacokinetic (PK) assay method for the compounds of this invention in cynomolgus monkeys (purchased from Guangdong Chunsheng Biotechnology Development Co., Ltd., male, weighing 3-6 kg, aged 4-6 years, 3 monkeys per group orally and 3 monkeys per group intravenously) is as follows:

[0302] Crab-eating macaques were administered the test compound orally at 2.5 mg / kg or 5 mg / kg, or intravenously at 0.5 mg / kg or 1 mg / kg.

[0303] Following drug administration, venous blood samples were collected at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours) and deposited into EDTA-K2 anticoagulant tubes. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed using a triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode. Pharmacokinetic parameters were calculated using a non-compartmental model with WinNonlin 6.3 software.

[0304] Conclusion: Pharmacokinetic experimental data show that the compound of this invention has good pharmacokinetic properties in cynomolgus monkeys and has good application prospects in anti-HBV.

[0305] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A compound, which is a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, of formula (I). in, Each R 1 and R 2 Independently for C 1-6 Alkyl, wherein the C 1-6 The alkyl group is unsubstituted or is composed of 1, 2, 3, or 4 independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, and C. 1-4 Alkyl substituents; Q1 is a fused bicyclic heteroaryl group composed of 7-12 ring atoms, a fused bicyclic heterocyclic group composed of 7-12 ring atoms, or C. 6-12 aryl, wherein the fused bicyclic heteroaryl group composed of 7-12 ring atoms, the fused bicyclic heterocyclic group composed of 7-12 ring atoms, and C 6-12 Each aryl group is independent and unsubstituted or occupied by 1, 2, 3 or 4 R groups. w1 Substituents of the substituents; L represents a bond, -CH2-, -(CH2)2-, -(CH2)3-, -C(=O)-, or -S(=O). 0-2 -; Q2 is a heterocyclic group consisting of 5 ring atoms, a heterocyclic group consisting of 6 ring atoms, a heteroaryl group consisting of 5-6 ring atoms, or a phenyl group, wherein the heterocyclic group consisting of 5 ring atoms, the heterocyclic group consisting of 6 ring atoms, the heteroaryl group consisting of 5-6 ring atoms, and the phenyl group are each independently unsubstituted or converted by 1, 2, 3, or 4 R atoms. w2 Substituents of the substituents; Each R w1 and R w2 Independently, it can be deuterium, F, Cl, Br, I, =O, hydroxyl, cyano, amino, or C. 1-4 Alkylamino, C 1-4 Alkoxy, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

2. The compound according to claim 1, wherein, Each R 1 and R 2 The group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl groups are each independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl groups.

3. The compound according to claim 1 or 2, wherein, Q1 is a fused bicyclic heteroaryl group composed of 9-10 ring atoms, a fused bicyclic heterocyclic group composed of 9-10 ring atoms, a phenyl group, or a naphthyl group, wherein the fused bicyclic heteroaryl group composed of 9-10 ring atoms, the fused bicyclic heterocyclic group composed of 9-10 ring atoms, the phenyl group, and the naphthyl group are each independently unsubstituted or converted by 1, 2, 3, or 4 R groups. w1 Substituents; or Q1 is a fused bicyclic heteroaryl group composed of 9 ring atoms, a fused bicyclic heteroaryl group composed of 10 ring atoms, a fused bicyclic heterocyclic group composed of 9 ring atoms, or a fused bicyclic heterocyclic group composed of 10 ring atoms, a phenyl group, or a naphthyl group, wherein the fused bicyclic heteroaryl group composed of 9 ring atoms, the fused bicyclic heteroaryl group composed of 10 ring atoms, the fused bicyclic heterocyclic group composed of 9 ring atoms, or the fused bicyclic heterocyclic group composed of 10 ring atoms, the phenyl group, and the naphthyl group are each independently unsubstituted or replaced by 1, 2, 3, or 4 R groups. w1 Substituents are substituted.

4. The compound according to any one of claims 1-3, wherein, Q1 is 5. The compound according to any one of claims 1-4, wherein, Q2 is aziridine, aziridine, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl, wherein the aziridine is... Azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, pyrazolyl, imidazoyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazoyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thiophenyl, pyrazinyl, pyridazinyl, pyrimidinyl, and phenyl are each independently unsubstituted or substituted with 1, 2, 3, or 4 R groups. w2 Substituents are substituted.

6. The compound according to any one of claims 1-5, wherein each R w1 and R w2 Independently, it is deuterium, F, Cl, Br, I, =O, hydroxyl, cyano, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CH2Cl, -CF3, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2 or -CH2CH2CF3.

7. The compound according to any one of claims 1-6, comprising one of the following structures: Or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof.

8. A pharmaceutical composition comprising the compound of any one of claims 1-7, and pharmaceutically acceptable excipients thereof.

9. The pharmaceutical composition of claim 8, further comprising one or more other therapeutic agents, wherein the therapeutic agents are lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, Alfaferone, Alloferon, simvastatin, clavudine, emtricitabine, faxclovir, interferon, bacalin CP, interferon, interleukin-2, mirtovitezide, nitrozonide, ribavirin, interferon-A, cizonan, eufolavac, amplivir, phosphazid, heplisav, recombinant human interleukin-2, levamisole, or propafenone.

10. Use of the compound of any one of claims 1-7 or the pharmaceutical composition of any one of claims 8-9 in the preparation of a medicament for the prevention, treatment, or relief of a patient with a TLR8-mediated disease, wherein the TLR8-mediated disease is hepatitis B virus infection, hepatitis C virus infection, influenza virus infection, herpes virus infection, HIV infection, allergic diseases, rheumatoid arthritis, allergic asthma, chronic fatigue, type II diabetes, hay fever, lupus erythematosus, multiple sclerosis, melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer, or thyroid cancer.

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