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 lead to 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 for treating and / or preventing various diseases related to TLR8 activity, and have good application prospects 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 Q is one of the following structural formulae:

[0010]

[0011] wherein X is N or CR 4 ;

[0012] each R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 6a , R 7a and R 8a are independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkylamino, C 1-6 alkoxy or C 1-6 alkyl, wherein the C 1-4 alkylamino, C 1-6 alkoxy and C 1-6 alkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino and C 1-4 alkyl;

[0013] Y is O or S;

[0014] R 3 is -C 1-6 alkylene-OH, wherein the -C 1-6 alkylene-OH is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino and C 1-6alkylene- is unsubstituted or substituted by 1, 2, 3, 4 or 5 R w1 substituted;

[0015] R is H, deuterium or C 1-6 alkyl;

[0016] each R 9 and R 9a is independently H, -L-NR a R b , F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkylamino, C 1-6 alkoxy or C 1-6 alkyl, wherein said C 1-4 alkyl, C 1-6 alkyl and C 1-6 alkyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-4 alkyl and C

[0017] L is -C 1-6 alkylene- or -C(=0)-, wherein said -C 1-6 alkylene- is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, methyl, ethyl, n-propyl or i-propyl;

[0018] each R a and R b is independently hydrogen, deuterium, C 1-12 alkyl, C 2-12 alkenyl or C 2-12 alkynyl, wherein said C 1-12 alkyl, C 2-12 alkenyl and C 2-12 alkynyl are each independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R w2 substituted;

[0019] or, R a , R b together with the N atom to which they are attached form a 3- to 8-membered heterocyclyl, wherein said 3- to 8-membered heterocyclyl is unsubstituted or substituted by 1, 2, 3 or 4 R w3 substituted;

[0020] each R w1 , R w2 and R w3 is independently deuterium, F, Cl, Br, I, =0, hydroxyl, cyano, amino, C 1-6 alkylamino, C1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(=O)-C 1-4 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-6 Cycloalkyl, heterocyclic groups consisting of 3-6 ring atoms, heteroaryl groups consisting of 5-6 ring atoms, or C 6-10 aryl, wherein the amino group, C 1-6 Alkylamino, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(=O)-C 1-4 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-6 Cycloalkyl groups, heterocyclic groups consisting of 3-6 ring atoms, heteroaryl groups consisting of 5-6 ring atoms, and C 6-10 Each aryl group is independently unsubstituted or is independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 Alkyl and C 1-4 Substituents of alkylamino groups.

[0021] In some embodiments of the present invention, each R 1 R 2 R 4 R 5 R 6 R 7 R 8 R 6a R 7a and R 8a Independently, it is hydrogen, deuterium, F, Cl, Br, I, 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, n-pentyl, or n-hexyl, wherein the N-methylamino, N-ethylamino, and N,N-dimethylamino groups are... 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, n-pentyl, and n-hexyl 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;

[0022] R can be H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl.

[0023] In some embodiments of the present invention, R 3 The derivatives are -CH2-OH, -(CH2)2-OH, -(CH2)3-OH, -CH(CH3)CH2-OH, -CH2CH(CH3)-OH, or -(CH2)4-OH, wherein the -CH2- in -CH2-OH, the -(CH2)2- in -(CH2)2-OH, the -(CH2)3- in -(CH2)3-OH, the -CH(CH3)CH2- in -CH(CH3)CH2-OH, the -CH2CH(CH3)- in -CH2CH(CH3)-OH, and the -(CH2)4- in -(CH2)4-OH are each independently unsubstituted or substituted by 1, 2, 3, 4, or 5 R groups. w1 replace;

[0024] Among them, each R w1 It has the meaning described in this invention.

[0025] In some embodiments of the present invention, each R 9 and R 9a Independently for H, -L-NR a R b F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 Alkylamino, C 1-4 Alkoxy or C 1-4 Alkyl, wherein the C 1-4 Alkylamino, C 1-4 Alkoxy and C 1-4 The alkyl groups are each independently unsubstituted or composed of 1, 2, 3, or 4 independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 Alkoxy and C 1-4 Substituents of alkyl groups;

[0026] L is -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH(CH3)-, -CH(CH3)CH2-, -(CH2)4- or -C(=O)-, wherein -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH(CH3)-, -CH(CH3)CH2- and -(CH2)4- are each independently unsubstituted or substituted by 1, 2, 3 or 4 independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, methyl, ethyl, n-propyl or isopropyl;

[0027] Among them, each R a and Rb have the meaning indicated in the present application.

[0028] In some embodiments of the present application, each R 9 and R 9a are independently H, -L-NR a R b , F, CI, Br, I, hydroxy, 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, sec-butyl, or t-butyl, wherein each of said 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, sec-butyl, and t-butyl is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, CI, Br, I, hydroxy, cyano, amino, methoxy, ethoxy, 1 -propoxy, 2-propoxy, 1 -butoxy, 2-methyl- 1 -propoxy, 2-butoxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl; wherein each R a and R b have the meaning indicated in the present application.

[0029] In some embodiments of the present application, each R a and R b are independently hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein each of said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R w2 ;

[0030] or, R a , R b , and the N atom to which they are attached form a 3- to 6-membered heterocyclyl, wherein said 3- to 6-membered heterocyclyl is unsubstituted or substituted with 1, 2, 3, or 4 R w3 ;

[0031] wherein each R w2 and R w3 have the meaning indicated in the present application.

[0032] In some embodiments of the present application, each R aand R b independently hydrogen, deuterium, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -CºCH, -CH2CºCH, -CºC-CH3, -CH2CH2CºCH, -CH2CºCCH3, or -CºCCH2CH3, wherein each of said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -CºCH, -CH2CºCH, -CºC-CH3, -CH2CH2CºCH, -CH2CºCCH3, and -CºCCH2CH3 is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, -CN, -NO2, -NHR w2 , -NR

[0033] or, R a , R b and R w3 together with the N atom to which they are attached form an aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein each of said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl is independently unsubstituted or substituted with 1, 2, 3, or 4 R w2 substituents;

[0034] wherein each R w3 has the meaning described herein.

[0035] In some embodiments of the application, each R w1 , R w2 , and R w3independently deuterium, F, Cl, 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, -CH2C1, -CF3, -CHF2, -CHC12, -CH2CH2F, -CH2CH2C1, -CH2CHF2, -CH2CHC12, -CHFCH2F, -CHC1CH2C1, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirdinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl, wherein said 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, -CH2C1, -CF3, -CHF2, -CHC12, -CH2CH2F, -CH2CH2C1, -CH2CHF2, -CH2CHC12, -CHFCH2F, -CHC1CH2C1, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirdinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl is optionally substituted with one to three substituents selected from the group consisting ofN,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, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, 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 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, -N(CH3)2, -NHCH3, -N(CH2CH3)2, -N(CH3)CH2CH3, and -NHCH2CH3.

[0036] In another aspect, the present application also provides a pharmaceutical composition comprising the compound of the present application and a pharmaceutically acceptable excipient.

[0037] In some embodiments, the pharmaceutical composition described herein 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.

[0038] In some embodiments, the pharmaceutical composition described herein, 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, Celmoleus, Crisantasp, Emtricitabine, Famicolovir, Interferon, Bovogen CP, Infergen, Interleukin-2, Miv-501, Nitazoxanide, Ribavirin, Roferon-A, Zanamivir, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon a-2b, Levamisole, or Propagermanium.

[0039] In some embodiments, the pharmaceutical composition described herein, 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, Celmoleus, Crisantasp, Emtricitabine, Famicolovir, Bovogen CP, Infergen, Interferon a-1b, Interferon a, Interferon a-2a, Interferon b-1a, Interferon a-2, Interleukin-2, Miv-501, Nitazoxanide, Peginterferon a-2a, Ribavirin, Roferon-A, Zanamivir, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon a-2b, recombinant human Interleukin-2, Levamisole, or Propagermanium.

[0040] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for activating TLR8.

[0041] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for preparing a kit for activating TLR8.

[0042] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for preparing a medicament for preventing, treating, managing or alleviating a TLR8-mediated disease in a patient.

[0043] 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, stomach cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer or thyroid cancer.

[0044] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for preparing a medicament for treating or preventing an immune regulation system disease.

[0045] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for preparing a medicament for treating or preventing a viral infection or a tumor.

[0046] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for preparing a medicament 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.

[0047] Another aspect of the present application relates to a method for preparing, isolating and purifying the compound of formula (I).

[0048] 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.

[0049] Detailed description of the application

[0050] Definitions and general terminology

[0051] The present application will be illustrated in detail by listing the documents to which the specific embodiments correspond, the examples being accompanied by structural formulas and chemical formulas. The present application is intended to encompass all alternatives, variations and equivalents that can be included within the present inventive field 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 application is not intended to be limited to the methodologies and materials described. There are many documents and similar materials that are distinct from, or contrary to, the present application application, including, but not limited to, definitions of terms, usage of terms, described techniques, or the scope as controlled by the present application application.

[0052] The following definitions will be applied as the application is described, unless otherwise explicitly provided. 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, 75thEd., inside cover, and specific gravity is as reported therein. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5thEd., Ed.: Smith, Michael B, and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference. th Ed, 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0053] As described herein, the compounds of the present application can be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as particular examples, subgeneric classes, and generic classes of compounds encompassed by the present application in the examples.

[0054] Also, it should be noted that the descriptive terms "each and every," "each and every independently," and "each and every respectively independently" are used interchangeably throughout this document and should be interpreted broadly, as meaning that the recited options expressed by the same symbol in different groups are independent of each other, and also as meaning that the recited options expressed by the same symbol in the same group are independent of each other, unless explicitly indicated otherwise.

[0055] Throughout the specification, substituents of compounds of the application are disclosed by reference to groups of atoms or ranges of atoms. It is specifically intended that the application include each and every individual subcombination of the various members of the groups and ranges. For example, the term "C1-C6alkyl" specifically includes each and every individual subcombination of the individual alkyl groups C1, C2, C3, C4, C5, and C6. It is further specifically intended that the application include each and every individual subcombination of the various members of the groups and ranges. 1-6 "alkyl" specifically includes the individual groups methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl.

[0056] 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.

[0057] 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.

[0058] 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

[0059] 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

[0060] The term "haloalkyl," "haloalkenyl," or "haloalkoxy" means an alkyl, alkenyl, or alkoxy group, respectively, substituted by one or more halogen atoms, wherein alkyl, alkenyl, and alkoxy have the meaning as described herein. Examples of such include, but are not limited to, difluoroethyl (-CH2CHF2, -CF2CH3, -CHFCH2F), trifluoroethyl (-CH2CF3, -CF2CH2F, -CFHCHF2), trifluoromethyl (-CF3), trifluoromethoxy (-OCF3), fluoroethenyl (-CH=CHF, -CF=CH2), and the like.

[0061] The term "alkoxy" means an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein alkyl has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms; in other embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in yet other embodiments, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group can optionally be substituted by one or more substituents as described herein.

[0062] 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), and the like.

[0063] The term "aryl" can be used alone or as part of "aralkyl," "aralkoxy," or "aryloxyalkyl" and refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members, and has one or more attachment points for attachment to the remainder of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring system," such as aryl can include phenyl, naphthyl, and anthryl. The aryl groups can be independently unsubstituted or substituted with one or more substituents described herein.

[0064] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring 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 contains 5-7 ring members, and has one or more attachment points for attachment to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound," and includes monocyclic heteroaryl, fused bicyclic heteroaryl, or polycyclic fused heteroaryl. In some embodiments, the heteroaryl is a 5-14 ring atom containing heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 5-12 ring atom containing heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 5-10 ring atom containing heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 8-10 ring atom containing fused bicyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 5-8 ring atom containing heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 5-7 ring atom containing heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 5-6 ring atom containing monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 5 ring atom containing heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a 6 ring atom containing heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0065] In other embodiments, the heteroaryl group includes, but is not limited to, monocyclic groups such as 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 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-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-l,2,4-triazolyl, 1H-l,2,4-triazolyl, 1,2,3-triazolyl), 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-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; and bicyclic or tricyclic groups such as benzimidazolyl, benzofuranyl, benzothiophenyl, 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), phenoxathiinyl, dibenzimidazolyl, dibenzofuranyl, dibenzothiophenyl, and the like. The heteroaryl groups are optionally substituted with one or more substituents as described herein.

[0066] The term "comprising M to M1 ring atoms" means that the ring group consists of M to M1 ring atoms, which include carbon atoms and / or O, N, S, P, and the like heteroatoms. For example, "heteroaryl group comprising 5 to 10 ring atoms" means a heteroaryl group comprising 5, 6, 7, 8, 9, or 10 ring atoms.

[0067] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring systems containing 3-12 ring atoms, at least one of which is a nitrogen, sulfur, and oxygen atom, and having one or more points of attachment to the rest of the molecule. The term "heterocyclyl" includes monocyclic heterocyclyl, bicyclic fused heterocyclyl or polycyclic fused heterocyclyl, spirocyclic heterocyclyl or bridged heterocyclyl groups, and also includes polycyclic ring systems in which a heterocycle can be fused with one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, with the point of attachment being on the heterocycle. Bicyclic heterocyclyl groups include bridged bicyclic heterocyclyl, fused bicyclic heterocyclyl and spiro bicyclic heterocyclyl groups. Unless otherwise specified, -CH2- groups of heterocyclyl groups can optionally be replaced with -C(=O)- groups. Sulfur atoms of rings can optionally be oxidized to S-oxides. Nitrogen atoms of rings can optionally be oxidized to N-oxides. In some embodiments, the heterocyclyl group is a ring system of 3-12 ring atoms; in some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group of 4-7 ring atoms; in some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group of 3-7 ring atoms; in some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group of 4-6 ring atoms; in some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group of 3-6 ring atoms; in some embodiments, the heterocyclyl group is a monocyclic heterocyclyl group of 5-6 ring atoms; in some embodiments, the heterocyclyl group is a bicyclic heterocyclyl group of 7-12 ring atoms; in some embodiments, the heterocyclyl group is a fused bicyclic heterocyclyl group of 7-12 ring atoms; in some embodiments, the heterocyclyl group is a fused bicyclic heterocyclyl group of 7-10 ring atoms; in some embodiments, the heterocyclyl group is a fused bicyclic heterocyclyl group of 8-10 ring atoms; in some embodiments, the heterocyclyl group is a bridged bicyclic heterocyclyl group of 6-10 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 3-8 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 3-6 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 5-7 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 5-8 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 6-8 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 3 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 4 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 5 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 6 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 7 ring atoms; in other embodiments, the heterocyclyl group is a ring system of 8 ring atoms.

[0068] Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolizinyl, quinolizinyl, and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl; examples in which a ring carbon atom is replaced by an oxo (=0) group include, but are not limited to, pyrimidinedionyl, 1,2,4-thiadiazol-5(4H)-onyl, 1,2,4-oxadiazol-5(4H)-onyl, 1H-1,2,4-triazol-5(4H)-onyl, and the like; examples in which a ring carbon atom is replaced by an =S group include, but are not limited to, 1,2,4-oxadiazol-5(4H)-thionyl, 1,3,4-oxadiazol-2(3H)-thionyl, and the like. The heterocyclyl groups can be optionally substituted with one or more substituents described herein.

[0069] The terms "spirocyclyl", "spirocycle", "spirobicyclyl", or "spirobicycle" are used interchangeably herein to refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic ring system in which one ring is derived from a specific ring carbon atom of another ring and the two rings share only one atom.

[0070] For example, as depicted in formula a below, rings B and B' are referred to as "fused bicyclic", while ring A' and ring B share a carbon atom and are referred to as "spirocyclic" or "spirobicyclic". Each ring of a fused bicyclic group and a spirobicyclic group can be carbocyclyl or heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.

[0071]

[0072] The terms "fused bicyclic heterocyclyl" and "bicyclic fused heterocyclyl" are used interchangeably to mean a saturated or partially unsaturated, non-aromatic annular system. Such a system can contain independent or conjugated unsaturation, but the core structure does not contain an aromatic or heteroaromatic ring (although aromaticity can be a substituent thereon). Each ring in the ring system contains 3-7 atoms, and at least one ring contains one or more heteroatoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2. In some embodiments, the fused bicyclic heterocyclyl is a fused bicyclic heterocyclyl of 7-10 ring atoms; in some embodiments, the fused bicyclic heterocyclyl is a fused bicyclic heterocyclyl of 8-10 ring atoms; examples of which include, but are not limited to, 3-azafused [3.1.0] hexane, 3-azabicyclo[3.3.0]octane, hexahydro-furo[3,4-c]pyrrolyl, hexahydro-thieno[3,4-c]pyrrolyl, 3,4,5,6-tetrahydro-cyclopentane[c]thiophenyl, and the like. The fused heterobicyclic group is optionally substituted with one or more substituents described herein.

[0073] The term "bridged bicyclic group" or "bridged bicyclic ring" means a saturated or partially unsaturated, non-aromatic bridged ring system, as shown in formula b, i.e., ring Ai and ring A2share an alkyl chain, a heteroatom, or a heteroalkyl chain, where j is 1, 2, 3, or 4, X 3 is an alkyl chain, a heteroatom, or a heteroalkyl chain. Such a system can contain independent or conjugated unsaturation, but the core structure does not contain an aromatic or heteroaromatic ring (although aromaticity can be a substituent thereon). Each ring, such as Ai or A2, contains 3-7 atoms, examples of which include, but are not limited to, bicyclo[2.2.1]heptane, 2-methyl-diazabicyclo[2.2.1]heptane, and the like. The bridged bicyclic group is optionally substituted with one or more substituents described herein.

[0074]

[0075] The term "bridged bicyclic heterocyclyl" denotes a saturated or partially unsaturated non-aromatic bridged bicyclic ring system, wherein each ring contains 3-7 atoms, and at least one ring contains one or more heteroatoms, i.e., contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2. In some embodiments, the bridged bicyclic heterocyclyl is a 6-10 membered bridged bicyclic heterocyclyl, examples of which include, but are not limited to, 2-oxo-5-azabicyclo[2.2.1]heptanyl, 2-thioxo-5-azabicyclo[2.2.1]heptanyl, 2-oxo-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-methyl-2,5-diazabicyclo[2.2.1]heptanyl. The bridged bicyclic heterocyclyl groups are optionally substituted by one or more substituents described herein.

[0076] The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic ring system, saturated, containing 3-12 ring carbon atoms, having one or more points of attachment to the rest of the molecule, including monocyclic, bicyclic or polycyclic fused, spiro or bridged ring ring systems. In some embodiments, the cycloalkyl is a 6-10 membered spiro bicycloalkyl; in other embodiments, the cycloalkyl is a 6-10 membered fused bicycloalkyl; in other embodiments, the cycloalkyl is a ring system containing 3-10 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system containing 3-8 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system containing 3-7 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system containing 5-8 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system containing 3-6 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system containing 5-6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and the cycloalkyl groups can independently be unsubstituted or substituted by one or more substituents described herein.

[0077] The terms "alkylamino" and "alkylamino" are used interchangeably and include "N-alkylamino" and "N,N-dialkylamino" wherein one or both of the hydrogen atoms in the amino group are replaced by one or two alkyl groups, respectively. In some embodiments, the alkylamino is one or two C 1-12 In other embodiments, the alkylamino is one or two C 1-6 In other embodiments, the alkylamino is one or two C 1-4lower alkylamino groups formed by the attachment of an alkyl group to a nitrogen atom. In still other embodiments, alkylamino is one or two C 1-3 lower alkylamino groups formed by the attachment of an alkyl group to a nitrogen atom. Suitable alkylamino groups can be monoalkylamino or dialkylamino, 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), and the like.

[0078] Unless otherwise stated, the chemical structures depicted herein include all tautomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): e.g., the R, S configuration about an asymmetric center, the (Z), (E) isomers about a double bond, and the (Z), (E) conformational isomers. Thus, individual stereochemical isomers or mixtures thereof, or enantiomeric, diastereomeric, or geometric (or conformational) mixtures of the compounds of the present application are within the scope of the present application.

[0079] The term "prodrug" as used herein refers to a compound that is converted into a compound of Formula (I) in vivo. Such conversion is effected by hydrolysis or enzymatic conversion in blood or tissue of the prodrug to the parent structure. The prodrug compounds of the present application can be esters, and among the esters useful as prodrugs in the present application are benzoate esters, aliphatic (C 1-24esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the application containing a hydroxyl group can be acylated to yield a prodrug form of the compound. Other prodrug forms include phosphates, such as those compounds which are phosphorylated on a hydroxyl group of the parent. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium 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 S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0080] Unless otherwise stated, all tautomeric forms of the compounds of the application are encompassed within the scope of the application. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include one or more isotopically enriched atoms.

[0081] "Metabolites" refers to the products resulting from metabolism of a particular compound or salt thereof in the body. Metabolites of a compound can be identified using techniques known in the art and their activity can be characterized using assays described herein. Such products can be oxidized, reduced, hydrolyzed, amidated, deamidated, esterified, deesterified, enzymatically cleaved, and the like. Accordingly, the application includes metabolites of compounds of the application, including those produced in vivo upon administration of the compound to a mammal.

[0082] The use of the terms "stereochemically isomeric forms" is meant to encompass both enantiomeric forms and racemates. The definitions and conventions used in this application for describing the stereochemistry of compounds follow 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 the present application can contain asymmetrically centers or chiral centers and therefore exist in different stereoisomers. All stereoisomers of the compounds of the present application, including but not limited to, diastereomers, enantiomers, atropisomers, and their mixtures, such as racemates, form part of the present application. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D, L or R, S are used to denote the absolute configuration of the molecule. The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, (-) or 1 meaning that the compound is levorotatory, and the prefix (+) or d meaning that the compound is dextrorotatory. The chemical structures of these stereoisomers are identical but their orientations in the solid state differ. A specific stereoisomer can be referred to as an enantiomer if its structure is not superimposable on that of the mirror image. A mixture of enantiomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can result from racemic synthesis or from resolution of an enantiomeric mixture. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric forms lacking optical activity.

[0083] The term "tautomer" or "tautomeric forms" refers to structural isomers that exist in equilibrium. For example, proton tautomers (i.e., proton-shift tautomers) include tautomers that interconvert by a shift in a proton, such as keto-enol and imine-enamine isomerization. Atom-valence tautomers include tautomers that interconvert by a rearrangement of bonding electrons. Unless otherwise specified, all tautomeric forms of the compounds of the application are within the scope of the application.

[0084] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the application. Pharmaceutically acceptable salts are well known in the art, as described in detail in S. M. Berge et al., "Pharmaceutical Salts," J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable non-toxic salts of an acid include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, and organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, malonic, and other salts as are well known in the art. Other pharmaceutically acceptable salts include adipate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl)4 salts. The present application also contemplates the quaternization of any basic nitrogen-containing groups of the compounds of the application by salts of inorganic or organic acids, for example and without limitation, hydrochloric, hydrobromic, sulfuric, phosphoric, sulfamic, sulfonic, nitric, maleic, fumaric, toluenesulfonic, methanesulfonic, acetic, naphthalenesulfonic, benzenesulfonic, naphthalenedisulfonic, oxalic, and other acids as are well known in the art. Other pharmaceutically acceptable salts include, but are not limited to, those derived from the following: caffeine, rabeprazole, cinnamoic, citic, cyclamic, dicalcic, fumaric, galact, glutamic, glucuronic, glycerophosphoric, glycolic, hemisulfuric, heptanoic, hexanoic, hydroxymaleic, hydroxynaphthoic, iodistic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, metaphosphoric, mesylic, metho- sulfonic, mucic, naphthalic, nitric, nitroso, pamoic, pantothenic, pectic, persulfuric, phenylacetic, propionic, pyroglutamic, salicylic, sorbic, stearic, succinic, sulfamic, sulfanilic, sulfonic, tannic, urea, and zirconic acids. 1-8

[0085] The "solvate" of the present application refers to an association or complex of one or more solvent molecules with a compound of the present application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to the complex that contains solely water as the solvent.

[0086] ​The term "protecting group" or "Pg" refers to a substituent that is commonly employed to block or protect the functionality of a particular group while undergoing subsequent reactions. For example, "amino-protecting group" refers to a substituent attached to an amino group that blocks or protects the functionality of the amino group while making other functional group transformations (e.g., acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the functionality of the hydroxy group while making other functional group transformations (e.g., acetyl and silyl). "Carboxy-protecting group" refers to a substituent of a carboxylic acid group that blocks or protects the functionality of the carboxylic acid group while making other functional group transformations (e.g., -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like). For a general description of protecting groups, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0087] Description of the compounds of the present application

[0088] The compounds of the present application, and their pharmaceutically acceptable compositions, are effective in activating TLR8 and inhibiting HBV infection.

[0089] In one aspect, the present application relates to a compound of formula (I) or a stereoisomer, a tautomer, a N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

[0090]

[0091] wherein each R 1 , R 2 , R 3 , R 5 , R 6 , Q and X have the meanings described herein.

[0092] In some embodiments of the present application, Q is one of the following structural formulae:

[0093] wherein each Y, R, R 7 , R 8 , R 6a , R7a R 8a R 9 R 9a have the meanings described herein.

[0094] In some embodiments of the application, X is N or CR 4 ; wherein R 4 have the meanings described herein.

[0095] In some embodiments of the application, each R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 6a , R 7a and R 8a are independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkylamino, C 1-6 alkoxy or C 1-6 alkyl, wherein said C 1-4 alkylamino, C 1-6 alkoxy and C 1-6 alkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino and C 1-4 alkyl.

[0096] In some embodiments of the application, Y is O or S.

[0097] In some embodiments of the application, R 3 is -C 1-6 alkylene-OH, wherein the -C 1-6 alkylene- of said -C 1-6 alkylene-OH is unsubstituted or substituted with 1, 2, 3, 4 or 5 R w1 ;

[0098] wherein each R w1 has the meanings described herein.

[0099] In some embodiments of the application, R is H, deuterium or C 1-6 alkyl.

[0100] In some embodiments of the application, each R 9 and R 9a is independently H, -L-NR a R b , F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4alkyl, C 1-6 alkoxy or C 1-6 alkyl, C 1-4 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-4 alkyl, C

[0101] In some embodiments of the application, L is -C 1-6 alkylene- or -C(=O)-, wherein the -C 1-6 alkylene- is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, CI, Br, I, hydroxyl, cyano, amino, methyl, ethyl, n-propyl or i-propyl.

[0102] In some embodiments of the application, each R a and R b is independently hydrogen, deuterium, C 1-12 alkyl, C 2-12 alkenyl or C 2-12 alkynyl, wherein the C 1-12 alkyl, C 2-12 alkenyl and C 2-12 alkynyl is each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R w2 substituents;

[0103] or, R a , R b form, together with the N atom to which they are attached, a 3- to 8-membered heterocyclyl, wherein the 3- to 8-membered heterocyclyl is unsubstituted or substituted with 1, 2, 3 or 4 R w3 substituents;

[0104] wherein each R w2 and R w3 has the meaning given in the present application.

[0105] In some embodiments of the application, each R w1 , R w2 and R w3 is independently deuterium, F, CI, Br, I, =0, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, -C(=O)-C 1-4 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or C 6-10 aryl, wherein said amino, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, -C(=O)-C 1-4 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and C 6-10 aryl are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkyl, and C 1-4 alkylamino.

[0106] In some embodiments of the application, each R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 6a , R 7a , and R 8a is independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, cyano, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, methoxy, ethoxy, 1-propyloxy, 2-propyloxy, 1-butyloxy, 2-methyl-l- propyloxy, 2-butyloxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, or n-hexyl, wherein said N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, methoxy, ethoxy, 1-propyloxy, 2-propyloxy, 1-butyloxy, 2-methyl-l- propyloxy, 2-butyloxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl are each 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 s-butyl.

[0107] In some embodiments of the application, R is H, deuterium, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, or n-hexyl.

[0108] In some embodiments of the application, R 3-CH2-OH, -(CH2)2-OH, -(CH2)3-OH, -CH(CH3)CH2-OH, -CH2CH(CH3)-OH, or -(CH2)4-OH, wherein each of the -CH2- of -CH2-OH, -(CH2)2- of -(CH2)2-OH, -(CH2)3- of -(CH2)3-OH, -CH(CH3)CH2- of -CH(CH3)CH2-OH, -CH2CH(CH3)- of -CH2CH(CH3)-OH, and -(CH2)4- of -(CH2)4-OH is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R w1 substituted;

[0109] wherein each R w1 has the meaning described herein.

[0110] In some embodiments of the application, each R 9 and R 9a are independently H, -L-NR a R b , F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkylamino, C 1-4 alkoxy, or C 1-4 alkyl, wherein each of the C 1-4 alkylamino, C 1-4 alkoxy, and C 1-4 alkyl is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkylamino, C 1-4 alkoxy, and C

[0111] wherein each R a and R b has the meaning described herein.

[0112] In some embodiments of the application, L is -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH(CH3)-, -CH(CH3)CH2-, -(CH2)4-, or -C(=O)-, wherein each of the -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH(CH3)-, -CH(CH3)CH2-, and -(CH2)4- 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, or isopropyl.

[0113] In some embodiments of the application, each R 9 and R 9aindependently H, -L-NR a R b F, Cl, Br, I, hydroxy, 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, sec-butyl or t-butyl, wherein each of said 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, sec-butyl and t-butyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxy, cyano, amino, methoxy, ethoxy, 1 -propoxy, 2-propoxy, 1 -butoxy, 2-methyl- 1 -propoxy, 2-butoxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl; wherein each R a and R b have the meaning described herein.

[0114] In some embodiments of the present application, each R a and R b is independently hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein each of said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R w2 ;

[0115] or, R a , R b and the N atom to which they are attached form a 3- to 6-membered heterocyclyl ring, wherein said 3- to 6-membered heterocyclyl ring is unsubstituted or substituted with 1, 2, 3 or 4 R w3 ;

[0116] wherein each R w2 and R w3 have the meaning described herein.

[0117] In some embodiments of the present application, each R a and R bindependently hydrogen, deuterium, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -CºCH, -CH2CºCH, -CºC-CH3, -CH2CH2CºCH, -CH2CºCCH3, or -CºCCH2CH3, wherein each of said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -CºCH, -CH2CºCH, -CºC-CH3, -CH2CH2CºCH, -CH2CºCCH3, and -CºCCH2CH3is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R w2 substituents;

[0118] or, R a , R b and the N atom to which they are attached form an aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein each of said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl is independently unsubstituted or substituted with 1, 2, 3, or 4 R w3 substituents;

[0119] wherein each R w2 and R w3 has the meaning described herein.

[0120] In some embodiments of the application, each R w1 , R w2 and R w3independently deuterium, F, Cl, 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, -CH2C1, -CF3, -CHF2, -CHC12, -CH2CH2F, -CH2CH2C1, -CH2CHF2, -CH2CHC12, -CHFCH2F, -CHC1CH2C1, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirdinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl, wherein said 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, -CH2C1, -CF3, -CHF2, -CHC12, -CH2CH2F, -CH2CH2C1, -CH2CHF2, -CH2CHC12, -CHFCH2F, -CHC1CH2C1, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirdinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl is optionally substituted with one to three substituents selected from the group consisting ofN-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, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirdinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, 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 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, -N(CH3)2, -NHCH3, -N(CH2CH3)2, -N(CH3)CH2CH3, and -NHCH2CH3.

[0121] In one embodiment, the present application comprises a compound having one of the following structures:

[0122]

[0123]

[0124] In another aspect, the present application also provides a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable excipient.

[0125] 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.

[0126] In some embodiments, the pharmaceutical composition of the present application further comprises one or more additional therapeutic agents, wherein the therapeutic agent is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, Alfaferone, Alloferon, Cymelgo, Cravitecan, Emtricitabine, Famicolovir, Interferon, Bovogen CP, Inatepharm, Interleukin-2, Mivotice, Nitazoxanide, Ribavirin, Rovisomycin-A, Zidovudine, Euforavac, Ampligen, Phosphazid, Heplisav, Recombinant human interleukin-2, Levamisole, or Propagermanium.

[0127] In some embodiments, the interferon of the present application is interferon a-1b, interferon a, interferon a-2a, interferon b-1a, interferon a-2, peginterferon a-2a, or interferon a-2b.

[0128] In another aspect, the present application provides use of the compound or the pharmaceutical composition of the present application in activating TLR8.

[0129] In another aspect, the present application provides use of the compound or the pharmaceutical composition of the present application in preparing a kit for activating TLR8.

[0130] In another aspect, the present application provides use of the compound or the pharmaceutical composition of the present application in preparing a medicament for preventing, treating, managing, or alleviating a TLR8-mediated disease in a patient.

[0131] In some embodiments, the TLR8-mediated disease is a hepatitis B virus infection, a hepatitis C virus infection, an influenza virus infection, a herpes virus infection, an HIV infection, an 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, or thyroid cancer.

[0132] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for the preparation of a medicament for treating or preventing an immune regulation system disease.

[0133] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for the preparation of a medicament for treating or preventing a viral infection or a tumor.

[0134] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for the preparation of a medicament for treating or preventing a hepatitis B virus infection, a hepatitis C virus infection, an influenza virus infection, a herpes virus infection, an HIV infection, an 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.

[0135] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating an immune regulation system disease, which comprises administering to a patient an effective therapeutic amount of the compound or the pharmaceutical composition of the present application.

[0136] In another aspect, the present application also provides a method for preventing, treating or alleviating a TLR8-mediated disease in a patient, which comprises administering to the patient an effective amount of the compound of the present application.

[0137] In another aspect, the present application also provides a method for treating or preventing viral infection or tumor using the compound or the pharmaceutical composition, which comprises administering to a patient a pharmaceutically effective amount of the pharmaceutical composition containing the compound of the present application.

[0138] In another aspect, the present application also provides a method 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 using the compound or the pharmaceutical composition, which comprises administering to a patient a pharmaceutically effective amount of the pharmaceutical composition containing the compound of the present application.

[0139] In another aspect, the present application also provides a method for preventing, treating or alleviating immune system disease in a patient using the compound or the pharmaceutical composition, which comprises administering to a patient a therapeutically effective amount of the compound or the pharmaceutical composition of the present application.

[0140] In another aspect, the present application also provides a pharmaceutical composition for preventing, treating or alleviating TLR8-mediated disease in a patient using the compound or the pharmaceutical composition of the present application.

[0141] In another aspect, the present application also provides a pharmaceutical composition for preventing, treating or alleviating immune system disease in a patient using the compound or the pharmaceutical composition of the present application.

[0142] In another aspect, the present application also provides a pharmaceutical composition for treating or preventing viral infection or tumor using the compound or the pharmaceutical composition of the present application.

[0143] In another aspect, the present application also provides the use of the compounds or the pharmaceutical compositions described in the present application as a medicament 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.

[0144] In some embodiments, the patient is a mammal, and in other embodiments, the patient is a human. In other embodiments, the use further comprises contacting a cell with the therapeutic agent.

[0145] Another aspect of the present application relates to methods of preparing, isolating and purifying the compounds of Formula (I).

[0146] The present application also relates to the use of the compounds of the present application and pharmaceutically acceptable salts thereof 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 reducing, preventing, controlling or treating the symptoms of the diseases described herein in a patient.

[0147] 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 present application.

[0148] The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically, with respect to the other components of the formulation and the mammal being treated therewith.

[0149] Salts of the compounds of the present application also include salts of intermediates used in making or purifying the compounds of Formula (I) or salts of isolated enantiomers of the compounds of Formula (I), but are not necessarily pharmaceutically acceptable salts.

[0150] If the compounds of the present application are basic, salts of the compounds encompassed by the present application are prepared from any appropriate acid, as 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; pyranosic 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, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid and the like, or combinations thereof.

[0151] If the compounds of the present application are acidic, salts of the compounds encompassed by the present application are prepared from any appropriate base, as provided in the literature, for example, using inorganic or organic bases, such as ammonia (primary, secondary and tertiary amines), alkali metal hydroxides, ammonium hydroxides, N + (R 14 )4salts and alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary amines, N + (R 14 )4salts, such as R 14 is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl and the like, and cyclic amines, such as piperidine, morpholine and piperazine and the like, and inorganic salts derived 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.

[0152] Pharmaceutical compositions, formulations, administration and use of the compounds and pharmaceutical compositions of the present application

[0153] According to another aspect, the pharmaceutical compositions of the present application include a compound of Formula (I), a compound listed in the present application, or an example compound, and a pharmaceutically acceptable excipient.

[0154] The compounds of the present application are effective in the treatment of TLR8 mediated diseases in the pharmaceutical compositions of the present application. The areas of disease treatment that can be mentioned for the compounds or pharmaceutical compositions of the present application are, 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 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.

[0155] The present application includes pharmaceutical preparations containing one or more compounds of the present application of the formula (I) or pharmaceutical compositions thereof in addition to nontoxic, inert, pharmaceutically suitable excipients.

[0156] The above-mentioned pharmaceutical preparations can also contain other active pharmaceutical ingredients in addition to the compounds of the formula (I).

[0157] The compounds of the present application exist in free form or in suitable, pharmaceutically acceptable derivatives. According to the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative which upon administration to a patient is capable of providing (directly or indirectly) a compound as described herein, a metabolite or residue thereof.

[0158] 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.

[0159] 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.

[0160] The pharmaceutical compositions of the compounds of the present application can be administered in any of the foregoing ways, for example, by oral, spray, topical, rectal, nasal, local, vaginal, parenteral, e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intraocular injection or infusion, or by means of an implanted reservoir. Preferably, the compositions are administered orally, intramuscularly, intraperitoneally or intravenously.

[0161] The compounds of the present application or their pharmaceutical compositions can be administered in a unit dosage form. The dosage form can be a liquid dosage form or other dosage form. The liquid dosage form can be a true solution, a gel, a microparticle, a suspension. Other dosage forms such as tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder, inclusion compounds, implants, patches, liniments, and the like.

[0162] Oral tablets and capsules can contain excipients such as binders, e.g., syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, e.g., lactose, sucrose, corn starch, calcium phosphate, sorbitol, amino acid; lubricants, e.g., magnesium stearate, talc, polyethylene glycol, silica; disintegrants, e.g., potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated with pharmaceutically acceptable substances as is well known in the art.

[0163] Oral liquids can be prepared in the form of aqueous or non-aqueous solutions, suspensions, emulsions, syrups, or elixirs, or can be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can contain components conventional in the art, such as suspending agents, sorbitol, cellulose gum, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated vegetable oil, emulsifying agents such as lecithin, sorbitan monooleate, acacia; or non-aqueous vehicles (which can contain edible oils) such as almond oil, oily esters such as glycerol, propylene glycol, or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate, sorbic acid. If desired, flavoring or coloring agents can be added.

[0164] Suppositories can contain conventional suppository excipients such as cocoa butter or other glycerides.

[0165] For parenteral administration, fluid dosage forms generally comprise the compound in a pharmaceutically acceptable aqueous or non-aqueous solution, dispersion, suspension, emulsion, or ointment. The active compound can be dissolved in or mixed with the selected carrier, e.g., saline, calamarine, glycerol, water, or the like, and if desired, other accessories such as a flavoring or coloring agent. The pH and exact concentration of the solution or suspension can be adjusted according to the particular mode of administration and the subject to be treated. Injectable forms can be sterilized, e.g., by filtration, prior to packaging.

[0166] When administered topically to the skin, the compounds of the present application can be formulated into suitable ointments, creams, or lotions, in which the active ingredient is suspended or dissolved, or can be delivered by an atomizer or used in conjunction with an iontophoretic device. Suitable excipients for ointments, creams, and lotions include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, and water. Ointments can, if desired, contain both a solvent and a cream base; creams may, if desired, contain both a solvent and an emulsifying agent.

[0167] The amount of active ingredient that can be combined with the inactive ingredients to produce a dosage form will vary depending upon the host and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to a human can contain between about 1 to 1000 mg of active substance, formulated with suitable and convenient amounts of pharmaceutically-acceptable excipients. In certain embodiments, the pharmaceutically-acceptable excipients vary from about 5% to about 95% (weight:weight) of the total composition.

[0168] The compounds disclosed herein, e.g., a compound of Formula (I), can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, e.g., for at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In one variation, the compound is administered on a daily or intermittent schedule over the lifetime of the individual.

[0169] The dosage or frequency of administration of the compounds disclosed herein can be adjusted during the course of treatment based on the judgment of the administering medical practitioner.

[0170] A compound can be administered to an individual (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once per day.

[0171] In certain embodiments, methods are provided for treating or preventing a disease or condition in a human comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. Because agonists of TLR-8 are useful in the treatment of a variety of diseases or conditions, the particular identity of the additional therapeutic agent will depend on the particular disease or condition being treated.

[0172] The compounds of Formula (I) can be administered by any useful route and means, for example, by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound of 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 / g body weight / day or, for example, from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day.

[0173] A therapeutically effective amount of a compound of 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 a compound of 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 a compound of Formula (I) are about 100 mg / dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or 500 mg / dose. Single doses can be administered every hour, every day, or every week. For example, single doses can be administered once every 1 hour, once every 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. Single doses can also be administered once every 1 day, once every 2, 3, 4, 5, 6 days, or once every 7 days. Single doses can also be administered once every 1 week, once every 2, 3 weeks, or once every 4 weeks. In certain embodiments, single doses can be administered once per week. Single doses can also be administered once per month.

[0174] The frequency of administration of a compound of Formula (I) will be determined by the needs of the individual patient, for example, it can be once per day or twice or more per day. For example, administration of a compound can be for a period of time from 20 days to 180 days, or, for example, from 20 days to 90 days, or, for example, from 30 days to 60 days, to a human infected with HBV or HCV, as required by the length of time necessary to treat the HBV or HCV infection.

[0175] Administration can be intermittent, where the patient receives a daily dose of the compound of Formula (I) for a period of several days or more, followed by a period of several days or more where the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day or three times per week. By way of further example, the patient can receive a dose of the compound every day for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound. Administration of the compound followed by a period of non-administration of the compound can be repeated as clinically indicated to treat the patient.

[0176] In one embodiment, a pharmaceutical composition 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 and a pharmaceutically acceptable excipient.

[0177] 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.

[0178] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0179] In certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents described herein, the components of the combination are administered in a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0180] In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, e.g., as a solid dosage form for oral administration.

[0181] In certain embodiments, the presently disclosed compounds are administered with one or more additional therapeutic agents. Co-administration of the presently disclosed compounds with one or more additional therapeutic agents generally means that the presently disclosed compounds and the one or more additional therapeutic agents are administered concurrently or sequentially, such that therapeutically effective levels of both the presently disclosed compounds and the one or more additional therapeutic agents are present in the patient.

[0182] Co-administration includes administration of a unit dose of the presently disclosed compounds prior to or following administration of a unit dose of the one or more additional therapeutic agents, e.g., administration of the presently disclosed compounds within seconds, minutes, or hours of administration of the one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the presently disclosed compounds is administered first, followed within seconds or minutes by administration of a unit dose of the one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of the one or more additional therapeutic agents is administered first, followed within seconds or minutes by administration of a unit dose of the presently disclosed compounds. In some embodiments, a unit dose of the presently disclosed compounds is administered first, followed after a period of several hours (e.g., 1-12 hours) by administration of a unit dose of the one or more additional therapeutic agents. In other embodiments, a unit dose of the one or more additional therapeutic agents is administered first, followed after a period of several hours (e.g., 1-12 hours) by administration of a unit dose of the presently disclosed compounds.

[0183] The pharmaceutical composition provided by the present application comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and further comprises one or more therapeutic agents. 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 alpha 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), an 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 alpha-1, and a hepatitis B virus replication inhibitor, an inhibitor of hepatitis B surface antigen (HBsAg) secretion or assembly, an IDO inhibitor, or a combination thereof.

[0184] The one or more therapeutic agents are lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, Alfaferone, Alloferon, Celmoleus, Cravacit, Emtricitabine, Famicolovir, Interferon, 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.

[0185] Another aspect of the present application relates to use of a compound or a pharmaceutical composition of the present application for the manufacture of a medicament for the prevention, treatment or alleviation of hepatitis B disease in a patient, which comprises administering to the patient an effective amount of the compound or the pharmaceutical composition. Hepatitis B disease refers to liver disease 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 as symptoms of acute hepatitis. Patients with chronic viral infection have active disease and can progress to cirrhosis and liver cancer.

[0186] General synthetic methods

[0187] In general, the compounds of the present application can be prepared by the methods described herein, unless otherwise indicated, where the substituents are as defined in Formula (I). The following synthetic schemes and examples are intended to further illustrate the present application.

[0188] One skilled in the art will recognize that the chemical reactions described herein can be used to prepare many of the other compounds of the present application, and that other methods for preparing the compounds of the present application are also within the scope of the present application. For example, the synthesis of those compounds of the present application which are not illustrated herein can be successfully effected by those skilled in the art using methods analogous to those described herein, suitably selected by protection of interfering groups, by using other known reagents instead of those described herein, or by making routine modifications of reaction conditions. In addition, the reactions or known reaction conditions disclosed herein are recognized to be applicable to the preparation of other compounds of the present application.

[0189] Unless otherwise indicated, all temperatures are set forth in degrees Celsius (°C). Reagents can be purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and used without further purification, unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Reagent Company, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemicals Co. Ltd., Qingdao Tenglong Chemical Reagent Co. Ltd., and Qingdao Haian Chemical Factory.

[0190] Chromatography was performed on silica gel columns, and silica gel (200-300 mesh) was purchased from Qingdao Haian Chemical Factory. NMR spectra were recorded in CDC13, DMSO-d6, CD3OD or acetone-d6 (reported in ppm) with TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiplets were present, 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 (doublet of doublet of doublets), tt (triplet of triplets), br.s (broadened singlet). Coupling constants, J, are reported in Hertz (Hz).

[0191] Low resolution mass spectrometry (MS) data were determined by a spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was kept at 30 °C) of Agilent 6320 series LC-MS, a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied for the LC-MS spectrometer.

[0192] Low resolution mass spectrometry (MS) data were also determined by a spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was kept at 30 °C) of Agilent 6120 series LC-MS, a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied for the LC-MS spectrometer.

[0193] Both of the above spectrometers were equipped with Agilent Zorbax SB-C18 column, 2.1 x 30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peaks were recorded by UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table a: Table a: Gradient elution conditions

[0194]

[0195]

[0196] Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, Zorbax SB-C18 column, 2.1 x 30 mm, 4 μm, 10 min, 0.6 mL / min flow rate, 5-95% (0.1% formic acid in acetonitrile) (0.1% formic acid in water), column temperature maintained at 40 °C.

[0197] The following abbreviations are used throughout this application:

[0198]

[0199] Synthetic methods

[0200] The following synthetic schemes list the experimental procedures for preparing the compounds disclosed in the present application. In each of the schemes, each R 1 , R 2 , R 3 , R 5 , R 6 , X and Q have the meanings as described in the present application, and X1is Cl, Br or I.

[0201] Synthetic Scheme 1

[0202]

[0203] Compounds (I) can be synthesized by the methods disclosed in Synthetic Scheme 1. First, compound A (compound A can be prepared according to the preparation method of Synthetic Scheme 2 in CN116693527A, or by the technical knowledge commonly known in the art) reacts with compound B in the presence of a base (such as potassium carbonate, potassium acetate, etc.) and a catalyst (such as [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, etc.) to generate compound C . Then, compoundC Under acidic conditions (such as trifluoroacetic acid), the 2,4-dimethoxybenzyl protecting group on the amino group is removed to obtain compound (I). Detailed Implementation

[0204] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0205] Preparation Examples

[0206] 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.

[0207] Example 1: (R)-2-((2-amino-7-(3-((butyl-3-en-1-yl(methyl)amino)methyl)pyridin-4-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexane-1-ol

[0208]

[0209] Step 1: tert-Butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate

[0210] (2R)-2-amino-2-methylhexanoate (11.86 g, 65.29 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen protection, and a tetrahydrofuran solution of borane (196.00 mL, 195.87 mmol, 1 M) was slowly added dropwise at 0 °C with stirring. The mixture was transferred to room temperature and stirred for about 3 hours, then transferred to 60 °C and stirred for about 2 hours. A 100 mL solution of sodium hydroxide (13.06 g, 326.45 mmol) in water was then added dropwise at 0 °C with stirring. The resulting reaction mixture was transferred to a 60 °C oil bath and heated with stirring for about 3 hours. Boc anhydride (15.68 g, 71.82 mmol) was then added dropwise while stirring continued for about 3 hours. The reaction was stopped, diluted with water (200 mL), and extracted with ethyl acetate (120 mL × 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA(V / V) = 10 / 1) to give the title compound as a colorless oily liquid (15.10 g, yield 99.98%).

[0211] MS(ESI,pos.ion)m / z:254.2[M+Na] + .

[0212] Step 2: (R)-2-((7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2- methylhexan-1-ol

[0213] Tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate (1.44 g, 6.22 mmol) was added to a solution of hydrochloric acid in 1,4-dioxane (4 M, 20 mL) and stirred at room temperature for about 1 h, the solvent was removed by concentration under reduced pressure, 7-bromo-2,4-dichloropyrido[3,2-d]pyrimidine (1.73 g, 6.20 mmol), tetrahydrofuran (30 mL) and DIPEA (4.01 g, 31.00 mmol) were added to the concentrate, the mixture was reacted at 60 °C for 12 h, the solvent was removed by concentration under reduced pressure, the residue was purified by silica gel column chromatography (PE / EA (V / V) = 5 / 1) to obtain the title compound as a yellow solid (1.63 g, yield 70.08%).

[0214] MS (ESI, pos.ion) m / z: 375.0 [M+H] + .

[0215] Step 3: Synthesis of (R)-2-((7-bromo-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2- d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol Step 4: (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2- yl)amino)pyrido[3,2-d]pyrimidin-7-yl)boronic acid

[0216] (R)-2-((7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (1.53 g, 4.09 mmol), 2,4-dimethoxybenzylamine (0.79 g, 4.70 mmol) and potassium carbonate (1.13 g, 8.18 mmol) were added to 1,4-dioxane (50 mL) respectively, and reacted at 100 °C for 25 h, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (PE / EA (V / V) = 3 / 1) to obtain the title compound as a light yellow solid (2.02 g, yield 97.8%).

[0217] Step 5: 1-(4-bromopyridin-3-yl)-N-methylmethanamine Step 6: N-((4-bromopyridin-3-yl)methyl)-N-methyl-3-en-1-amine

[0218] (R)-2-((7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (1.53 g, 4.09 mmol), 2,4-dimethoxybenzylamine (0.79 g, 4.70 mmol) and potassium carbonate (1.13 g, 8.18 mmol) were added to 1,4-dioxane (50 mL) respectively, and reacted at 100 °C for 25 h, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (PE / EA (V / V) = 3 / 1) to obtain the title compound as a light yellow solid (2.02 g, yield 97.8%).

[0219] MS (ESI, pos. ion) m / z: 470.4 [M+H] + .

[0220] Step 7: (R)-2-((7-(3-((butyl-3-en-1-yl(methyl)amino)methyl)pyridin-4-yl)-2-((2,4- dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

[0221] To a solution of 4-bromopyridine-3-carbaldehyde hydrobromide (5.00 g, 18.73 mmol) in methanol (100 mL) was added dropwise a solution of methylamine in methanol (93.65 mL, 2 mol / L, 187.3 mmol) at 0 °C under nitrogen protection and stirring. The reaction was continued for 1.5 h. Sodium borohydride (1.06 g, 28.09 mmol) was added in portions. After the addition was completed, the reaction was continued at room temperature for 1 h. The reaction was stopped, and the solvent was removed by concentration. Water (100 mL) was added to dilute the solution, which was extracted with EA (100 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid product (3.10 g, yield 82.32%).

[0222] MS (ESI, pos. ion) m / z: 201.1 [M+H] + .

[0223] Step 8: (R)-2-((2-amino-7-(3-((butyl-3-en-1-yl(methyl)amino)methyl)pyridin-4-yl) pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

[0224] To a solution of 4-bromopyridine-3-carbaldehyde hydrobromide (5.00 g, 18.73 mmol) in methanol (100 mL) was added dropwise a solution of methylamine in methanol (93.65 mL, 2 mol / L, 187.3 mmol) at 0 °C under nitrogen protection and stirring. The reaction was continued for 1.5 h. Sodium borohydride (1.06 g, 28.09 mmol) was added in portions. After the addition was completed, the reaction was continued at room temperature for 1 h. The reaction was stopped, and the solvent was removed by concentration. Water (100 mL) was added to dilute the solution, which was extracted with EA (100 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid product (3.10 g, yield 82.32%).

[0225] MS (ESI, pos. ion) m / z: 201.1 [M+H] + .

[0226] Step 1: (R)-2-((7-(3-((butyl(methyl)amino)methyl)pyridin-4-yl)-2-((2,4-dimethoxy- benzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol Step 2: (R)-2-((2-amino-7-(3-((butyl(methyl)amino)methyl)pyridin-4-yl)pyrido[3,2- d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

[0227] N-((4-bromopyridin-3-yl)methyl)-N-methyl-3-en-1-amine (134 mg, 0.53 mmol), (R)-2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)boronic acid (298 mg, 0.64 mmol), potassium carbonate (219.75 mg, 1.59 mmol), Pd(dppf)2Cl2dichloromethane complex (43.28 mg, 0.053 mmol) and 1,4-dioxane / water (V / V) = 5 / 1 mixture solvent (20 mL) were added to the reaction bottle in turn, the reaction mixture was protected by nitrogen, and stirred at 100 °C for 7.5 h. The reaction was stopped, the solvent was dried, and the residue was separated by silica gel column chromatography (DCM / MeOH (V / V) = 10 / 1) to obtain the product (0.25 g, yield 79.37%).

[0228] MS (ESI, pos.ion) m / z: 600.3 [M+H] + .

[0229] Step 1: 1-(4-bromopyridin-3-yl)-N,N-dimethylmethanamine Step 2: Synthesis of (R)-2-((2-amino-7-(3-((dimethylamino)methyl)pyridin-4-yl)pyrido[3,2- d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

[0230] (R)-2-((7-(3-((butyl-3-en-1-yl(methyl)amino)methyl)pyridin-4-yl)-2-((2,4- dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (0.26 g, 0.46 mmol) and TFA (2 mL) were added to the reaction bottle in turn, and the reaction mixture was stirred at room temperature for 2.5 h. The reaction was stopped, 50 ml of saturated sodium bicarbonate was added for dilution, then extracted with DCM (50 ml x 3), the organic phase was combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by HPLC to obtain the product as a light yellow solid (0.14 g, yield 74.32%).

[0231] MS (ESI, pos.ion) m / z: 450.5 [M+H] + ;

[0232] 1H NMR (400 MHz, CD3OD) δ 9.30 - 8.80 (m, 2H), 8.67 (s, 1H), 8.04 (s, 1H), 7.66 (s, 1H), 5.81 - 5.62 (m, 1H), 5.21 - 5.10 (m, 2H), 4.60 (s, 2H), 4.01 (d, J = 11.2 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.20 - 3.08 (m, 2H), 2.66 (s, 3H), 2.43 (d, J = 7.1 Hz, 2H), 2.14 (d, J = 14.5 Hz, 1H), 2.07 - 1.91 (m, 1H), 1.59 (s, 3H), 1.47 - 1.33 (m, 4H), 0.95 (t, J = 6.0 Hz, 3H).

[0233] HR-MS (ESI): 450.30 [M+H] + .

[0234] Example 2: (R)-2-((2-amino-7-(3-((butyl(methyl)amino)methyl)pyridin-4-yl)pyrido[3,2- d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

[0235]

[0236] Step 1: (R)-2-((7-bromo-2-((2,4-dimethoxybenzyl)amino)quinazolin-4-yl)amino)-2- methylhexan-1-ol Step 2: (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino) quinazolin-7-yl)boronic acid

[0237] Step 3: (R)-2-((2-amino-7-(3-((dimethylamino)methyl)pyridin-4-yl)quinazolin-4-yl)amino)- 2-methylhexan-1-ol

[0238] (R)-2-((7-(3-((butyl-3-en-1-yl(methyl)amino)methyl)pyridin-4-yl)-2-((2,4- dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (0.42 g, 0.70 mmol) and Pd / C (0.075 g, 0.07 mmol, wt 10%) were added into a reaction flask, dissolved in methanol (20 mL), the reaction mixture was stirred at room temperature for 14 h under hydrogen atmosphere. The reaction was stopped, the palladium carbon was removed by filtration, the filtrate was rotary evaporated, the residue was separated by silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) to obtain the yellow solid product (0.22 g, yield 52.23%).

[0239] MS (ESI, pos.ion) m / z: 602.4 [M+H] + .

[0240] Step 1: N-((4-bromopyridin-3-yl)methyl)-2-methoxy-N-methylethan-1-amine Step 2: (R)-2-((2-amino-7-(3-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-4-yl) quinazolin-4-yl)amino)-2-methylhexan-1-ol

[0241] (R)-2-((7-(3-((butyl(methyl)amino)methyl)pyridin-4-yl)-2-((2,4- dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (0.22 g, 0.37 mmol) was added to a reaction flask, followed by TFA (2 mL), and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was blown dry under nitrogen, and the product was obtained as a white solid (158 mg, 95.7% yield) by reverse-phase liquid chromatography.

[0242] MS (ESI, pos.ion) m / z: 452.3. [M+H] + ;

[0243] 1 H NMR (400 MHz, CD3OD) δ 9.06 (s, 1H), 8.88 (s, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 7.66 (s, 1H), 4.57 (s, 2H), 4.00 (d, J = 11.1 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.03 (s, 2H), 2.66 (s, 3H), 2.21 - 2.07 (s, 1H), 2.07 - 1.91 (m, 1H), 1.64 - 1.47 (d, J = 18.6 Hz, 5H), 1.46 - 1.27 (m, 6H), 0.98 - 0.85 (m, 6H);

[0244] HR-MS (ESI): 452.3147 [M+H] + .

[0245] Example 3: (R)-2-((2-amino-7-(3-((dimethylamino)methyl)pyridin-4-yl)pyrido[3,2- d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

[0246] ​

[0247] Dissolve 1-(4-bromopyridin-3-yl)-N-methylmethanamine (1.00 g, 4.97 mmol) in DMF (10 mL), then add iodomethane (847 mg, 5.96 mmol) and cesium carbonate (2.43 g, 7.46 mmol) successively, and stir the reaction at room temperature for 4.5 h. After the reaction is complete, dilute with 100 mL of water, extract with EA (100 mL x 3), wash the combined organic phases with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) to obtain the product (420 mg, yield 39.29%) as yellow oil. MS (ESI, pos.ion) m / z: 215.0 [M+H] + .

[0248] ​ ​

[0249] With 1-(4-bromopyridin-3-yl)-N,N-dimethylmethanamine and (R)-(2-((2,4- dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)boronic acid as raw materials, reference is made to the synthetic method of steps 7-8 in Example 1, and the title compound is obtained as a light yellow solid (0.14 g, yield 74.32%).

[0250] MS (ESI, pos.ion) m / z: 410.1 [M+H] +

[0251] 1 H NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.85 (s, 1H), 8.67 (s, 1H), 8.03 (s, 1H), 7.65 (d, J = 4.6 Hz, 1H), 4.57 (s, 2H), 4.01 (d, J = 11.2 Hz, 1H), 3.76 (d, J = 11.2 Hz, 1H), 2.75 (s, 6H), 2.21 - 2.09 (m, 1H), 2.00 (dd, J = 15.0, 9.3 Hz, 1H), 1.59 (s, 3H), 1.39 (s, 4H), 0.96 (t, J = 6.6 Hz, 3H).

[0252] HR-MS (ESI): 410.2669 [M+H] + .

[0253] Example 4: (R)-2-((2-amino-7-(3-((dimethylamino)methyl)pyridin-4-yl)quinazolin-4- yl)amino)-2-methylhexan-1-ol

[0254] ​ ​

[0255] The title compound was prepared as yellow solid (0.31 g, yield 63.48%) using tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate and 7-bromo-2,4-dichloroquinazoline as starting materials, following the synthetic method of Example 1, step 2-3.

[0256] ​ ​

[0257] The title compound was prepared as brown foam solid (0.60 g, yield 99.31%) using (R)-2-((7-bromo-2-((2,4-dimethoxybenzyl)amino)quinazolin-4-yl)amino)-2- methylhexan-1-ol as starting material, following the synthetic method of Example 1, step 4, with the reaction temperature at 110 °C. MS (ESI, pos.ion) m / z: 469.1 [M+H] + .

[0258] ​ ​

[0259] The title compound was prepared as yellow solid (60 mg, yield 58.75%) using 1-(4-bromopyridin-3-yl)-N,N-dimethylmethanamine and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1- hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)boronic acid as starting materials, following the synthetic method of Example 1, step 7-8.

[0260] MS (ESI, pos.ion) m / z: 409.3 [M+H] + ;

[0261] 1H NMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.81 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 4.3 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.54 (s, 2H), 4.21 (d, J = 11.3 Hz, 1H), 3.73 (d, J = 11.3 Hz, 1H), 2.72 (s, 6H), 2.29 (t, J = 10.4 Hz, 1H), 1.84 (t, J = 10.6 Hz, 1H), 1.57 (s, 3H), 1.45 - 1.33 (m, 4H), 0.94 (t, J = 6.9 Hz, 3H). HR-MS (ESI): 409.2720 M+H] + .

[0262] Example 5: (R)-2-((2-amino-7-(3-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-4- yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

[0263]

[0264] ​

[0265] (4-bromopyridin-3-yl)(hydroxy)methanamine hydrobromide (2.00 g, 7.49 mmol) and (2-methoxyethyl)(methyl)amine (1.40 g, 15.73 mmol) were added into a reaction flask, 1,2-dichloroethane (50 mL) was added at 0 °C, stirred for 10 min, then acetic acid (2.70 g, 44.94 mmol) was added, stirred at room temperature, then sodium triacetoxyborohydride (2.22 g, 10.49 mmol) was added, continued to react at room temperature for 4 h. After the reaction was completed, saturated sodium bicarbonate (100 mL) was added for dilution, extracted with DCM (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, the solvent was rotary evaporated, and the residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) to obtain a light yellow solid product (0.72 g, yield 37.10%).

[0266] MS (ESI, pos.ion) m / z: 259.1 [M+H] + .

[0267] ​ Pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

[0268] The title compound was prepared as a yellow solid (0.15 g, yield 82.68%) using N-((4-bromopyridin-3-yl)methyl)-2-methoxy-N-methylethan-1-amine and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)boronic acid as starting materials by following the synthetic procedure of step 7-8 of example 1.

[0269] MS (ESI, pos.ion) m / z: 454.4 [M+H] + .

[0270] 1 H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 8.85 (s, 1H), 8.67 (s, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 4.62 (s, 2H), 4.01 (d, J = 11.1 Hz, 1H), 3.74 (d, J = 11.1 Hz, 1H), 3.63 (s, 2H), 3.30 (d, J = 7.7 Hz, 5H), 2.72 (s, 3H), 2.13 (d, J = 14.0 Hz, 1H), 2.06 - 1.93 (m, 1H), 1.58 (s, 3H), 1.38 (s, 4H), 0.94 (s, 3H).

[0271] HR-MS (ESI): 454.2929 [M+H] + .

[0272] Example 6: (R)-2-((2-amino-7-(3-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-4- yl)quinazolin-4-yl)amino)-2-methylhexan-1-ol

[0273]

[0274] The title compound was prepared as a yellow solid (30 mg, yield 16.57%) using (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7- yl)boronic acid and N-((4-bromopyridin-3-yl)methyl)-2-methoxy-N-methylethan-1-amine as starting materials by following the synthetic procedure of step 7-8 of example 1.

[0275] MS (ESI, pos.ion) m / z: 453.4 [M+H] +

[0276] 1HNMR (400 MHz, CD3OD) δ 8.95 (s, 1H), 8.81 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 5.0 Hz, 1H), 7.55 (s, 1H), 7.52 - 7.46 (m, 1H), 4.60 (s, 2H), 4.22 (d, J = 11.3 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.65 - 3.59 (m, 2H), 3.31 (s, 3H), 3.28 - 3.23 (m, 2H), 2.69 (s, 3H), 2.36 - 2.25 (m, 1H), 1.85 (t, J = 10.7 Hz, 1H), 1.58 (s, 3H), 1.44 - 1.32 (m, 4H), 0.95 (t, J = 6.9 Hz, 3H).

[0277] HR-MS (ESI): 453.2981 [M+H] + .

[0278] Example 7: (R)-4-(2-amino-4-((l-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)-3-(methoxymethyl)pyridin-2(lH)-one

[0279]

[0280] Step 1: 3-(Bromomethyl)-2-chloro-4-iodopyridine

[0281] To a reaction flask were added 2-chloro-4-iodo-3-methylpyridine (11.10 g, 43.79 mmol), NBS (8.57 g, 48.17 mmol) and AIBN (0.72 g, 4.38 mmol), carbon tetrachloride (60 mL) was added, and the mixture was heated to 78 °C for 10 h under nitrogen protection. The reaction mixture was cooled to room temperature, saturated sodium thiosulfate solution (200 mL) was added, and the mixture was separated. The aqueous phase was back-extracted with DCM (100 x 2 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EA (V / V) = 10 / 1) to give the title compound (10.00 g, yield 68.71%).

[0282] MS (ESI, pos.ion) m / z: 332.0 [M+H] + .

[0283] Step 2: 2-Chloro-4-iodo-3-(methoxymethyl)pyridine

[0284] Into the reaction flask was added 3-bromomethyl-2-chloro-4-iodopyridine (2.00 g, 6.02 mmol), sodium methoxide in methanol (1.63 g, 30.10 mmol, 5 mol / L) successively, and the reaction was allowed to proceed at room temperature for about 4 h; the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 10 / 1) to obtain the title compound as a light yellow solid (1.74 g, yield 102%).

[0285] MS (ESI, pos.ion) m / z: 284.1 [M+H] + .

[0286] Step 3: 4-Iodo-3-(methoxymethyl)pyridin-2(1H)-one

[0287] 2-Chloro-4-iodo-3-(methoxymethyl)pyridine (1.60 g, 5.64 mmol) and potassium tert-butoxide (3.17 g, 28.22 mmol) were added to tert-butanol (30 mL) respectively, and the reaction was allowed to proceed at 70 °C for about 22 h. After cooling to room temperature, the solvent was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) to obtain the title compound as a light yellow solid (1.31 g, yield 87.63%).

[0288] MS (ESI, pos.ion) m / z: 265.9 [M+H] + .

[0289] Step 4: (R)-4-(2-Amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-yl)-3- (methoxymethyl)pyridin-2(1H)-one Step 1: N-((2-Chloro-4-iodopyridin-3-yl)methyl)-2-methoxy-N-methylethan-1-amine

[0290] The title compound was prepared as a light yellow solid (0.18 g, yield 99.18%) using 4-iodo-3-(methoxymethyl)pyridin-2(1H)-one and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-yl)boronic acid as the raw materials according to the synthetic method of Reference Example 1, steps 7-8.

[0291] MS (ESI, pos.ion) m / z: 413.4 [M+H] + .

[0292] 1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 7.99 (s, 1H), 7.57 (d, J = 6.7 Hz, 1H), 6.45 (d, J = 6.7 Hz, 1H), 4.22 (s, 2H), 4.02 (d, J = 11.2 Hz, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.37 (s, 3H), 2.21 - 2.09 (m, 1H), 2.02 - 1.91 (m, 1H), 1.59 (s, 3H), 1.47 - 1.34 (m, 4H), 0.95 (t, J = 6.3 Hz, 3H).

[0293] HR-MS (ESI): 413.2300 [M+H] + .

[0294] Example 8: (R)-4-(2-amino-4-((l-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)-3- (methoxymethyl)pyridin-2(lH)-one

[0295]

[0296] The title compound was prepared as yellow solid (85 mg, yield 50.38%) from 4-iodo-3- (methoxymethyl)pyridin-2(lH)-one and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((l- hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)boronic acid as starting material, following the synthetic procedure of step 7-8 in Example 1.

[0297] MS (ESI, pos.ion) m / z: 412.5 [M+H] + .

[0298] 1 H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 7.99 (s, 1H), 7.57 (d, J = 6.7 Hz, 1H), 6.45 (d, J = 6.7 Hz, 1H), 4.22 (s, 2H), 4.02 (d, J = 11.2 Hz, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.37 (s, 3H), 2.21 - 2.09 (m, 1H), 2.02 - 1.91 (m, 1H), 1.59 (s, 3H), 1.47 - 1.34 (m, 4H), 0.95 (t, J = 6.3 Hz, 3H).

[0299] HR-MS (ESI): 412.2344. [M+H] + .

[0300] Example 9: (R)-4-(2-amino-4-((l-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)-3-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-2(lH)-one

[0301]

[0302] Step 2: 4-Iodo-3-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-2(1H)-one

[0303] Into a reaction bottle were added 3-(bromomethyl)-2-chloro-4-iodopyridine (1.00 g, 3.01 mmol), (2-methoxyethyl)(methyl)amine (0.46 g, 5.12 mmol) and DCM (50 mL) successively, followed by the addition of DIEA (3.89 g, 30.10 mmol), and the mixture was allowed to react at room temperature for 16.5 h. After concentration, the residue was purified by silica gel column chromatography (PE / EA (V / V) = 2 / 1) to obtain the product as a light yellow solid 0.93 g in a yield of 90.72%.

[0304] MS (ESI, pos.ion) m / z: 341.2 [M+H] + .

[0305] Step 3: (R)-4-(2-Amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)-3-(((2-methoxyethyl)(methyl)amino)methyl)

[0306] Into a reaction bottle were added N-((2-chloro-4-iodopyridin-3-yl)methyl)-2-methoxy-N- methylethan-1-amine (2, 0.93 g, 2.73 mmol), potassium tert-butoxide (1.23 g, 10.92 mmol) and tert-butanol (10 mL) successively, and the mixture was allowed to react at 85 °C for 24 h under nitrogen protection. After cooling to room temperature, the pH of the reaction system was adjusted to 2-3 with a hydrochloric acid solution in 1,4-dioxane (4 mol / L), and the mixture was stirred for 30 min. Then, the pH of the solution was adjusted to 8-9 with a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with DCM (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) to obtain the product as a white solid (0.48 g, yield 54.58%). Pyridin-2(1H)-one Step 1: N-((4-Bromopyridin-3-yl)methyl)-N-methylbutan-1-amine Step 2: (R)-2-((2-Amino-7-(3-((butyl(methyl)amino)methyl)pyridin-4-yl)quinazolin-4-yl)amino)-2- methylhexan-1-ol

[0307] Step 1: 3-(Bromomethyl)-2-chloro-4-iodopyridine

[0308] The title compound was prepared as a yellow solid (85 mg, yield 69.77%) from 4-iodo-3-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-2(lH)-one and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((l-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)boronic acid following the synthetic method of step 7-8 in example 1.

[0309] MS (ESI, pos.ion) m / z: 469.5 [M+H] + ;

[0310] 1 H NMR (400 MHz, CD3OD) δ 8.42 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 6.7 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 6.7 Hz, 1H), 4.46 (d, J = 13.8 Hz, 1H), 4.21 (d, J = 11.2 Hz, 1H), 4.15 (d, J = 13.8 Hz, 1H), 3.70 (dd, J = 16.3, 7.5 Hz, 3H), 3.36 (s, 4H), 3.25 (s, 1H), 2.76 (s, 3H), 2.28 (dd, J = 16.2, 8.7 Hz, 1H), 1.84 (t, J = 10.8 Hz, 1H), 1.57 (s, 3H), 1.46 - 1.28 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H);

[0311] HR-MS (ESI): 469.2929 [M+H] + .

[0312] Example 10: (R)-4-(2-amino-4-((l-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)-3-((2-methoxyethyl)(methyl)amino)methyl)pyridin-2(lH)-one

[0313]

[0314] The title compound was prepared as a yellow solid (85 mg, yield 69.77%) from 4-iodo-3-(((2-methoxyethyl)(methyl)amino)methyl)pyridin-2(lH)-one and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((l-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)boronic acid following the synthetic method of step 7-8 in example 1.

[0315] MS (ESI, pos.ion) m / z: 470.4 [M+H] + ;

[0316] 1 H NMR (400 MHz, CD3OD) δ 8.60 (d, J = 1.2 Hz, 1H), 7.94 (s, 1H), 7.75 (d, J = 6.7 Hz, 1H), 6.54 (d, J = 6.7 Hz, 1H), 4.49 (d, J = 13.4 Hz, 1H), 4.17 (d, J = 14.0 Hz, 1H), 4.01 (d, J = 11.2 Hz, 1H), 3.71 - 3.64 (m, 3H), 3.44 - 3.34 (m, 4H), 3.29 - 3.18 (m, 1H), 2.77 (s, 3H), 2.18 - 2.07 (m, 1H), 2.04 - 1.94 (m, 1H), 1.58 (s, 3H), 1.46 - 1.32 (m, 4H), 0.95 (t, J = 6.7 Hz, 3H);

[0317] HR-MS (ESI): 470.2882 [M+H] + .

[0318] Example 11: (R)-2-((2-amino-7-(3-((butyl(methyl)amino)methyl)pyridin-4-yl)quinazolin-4- yl)amino)-2-methylhexan-1-ol

[0319] Step 2: 1-(2-Chloro-4-iodopyridin-3-yl)-N,N-dimethylmethanamine

[0320] (4-bromopyridin-3-yl)(hydrogen)methyl alcohol hydrobromide (1.00 g, 3.75 mmol) and butyl(methyl)amine (0.69 g, 7.88 mmol) were added into a reaction flask, placed at 0 °C, then DCE (50 mL) was added, stirred for 1 h, then acetic acid (1.35 g, 22.5 mmol) was added, stirred at room temperature for 10 min, sodium triacetoxyborohydride (1.11 g, 5.25 mmol) was added, and stirring was continued for 28.5 h. After the reaction was completed, saturated sodium bicarbonate (100 mL) was added, DCM was extracted (100 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) to obtain a white solid product (0.24 g, yield 24.89%).

[0321] MS (ESI, pos.ion) m / z: 470.4 [M+H] + .

[0322] Step 3: 3-((Dimethylamino)methyl)-4-iodopyridin-2(1H)-one Step 4: (R)-4-(2-Amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)-3-((dimethylamino)methyl)pyridin-2(1H)-one

[0323] The title compound was prepared from N-((4-bromopyridin-3-yl)methyl)-N- methylbutan-1 -amine and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1 -hydroxy-2- methylhexan-2-yl)amino)quinazolin-7-yl)boronic acid as a yellow solid (100 mg, yield 47.22%) according to the synthetic method of step 7-8 of example 1.

[0324] MS (ESI, pos.ion) m / z: 451.4 [M+H] + ;

[0325] 1 HNMR (400 MHz, CD3OD) δ 8.97 (s, 1H), 8.81 (d, J = 3.9 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 5.1 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 4.56 (s, 2H), 4.21 (d, J = 11.3 Hz, 1H), 3.73 (d, J = 11.3 Hz, 1H), 2.98 (s, 2H), 2.67 (s, 3H), 2.35 - 2.23 (m, 1H), 1.92 - 1.80 (m, 1H), 1.57 (s, 3H), 1.52 - 1.44 (m, 2H), 1.43 - 1.32 (m, 4H), 1.29 - 1.21 (m, 2H), 0.94 (t, J = 6.8 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H);

[0326] HR-MS (ESI): 451.3188 [M+H] + .

[0327] Example 12: (R)-4-(2-amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)- 3-((dimethylamino)methyl)pyridin-2(1H)-one

[0328] Step 1: 2-Chloro-4-iodo-3-(piperidin-1-ylmethyl)pyridine

[0329] Into a reaction flask, 2-chloro-4-iodo-3-methylpyridine (11.10 g, 43.79 mmol), NBS (8.57 g, 48.17 mmol), AIBN (0.72 g, 4.38 mmol) and CCl4(60 mL) were added successively, and the reaction mixture was stirred at 78 °C for 22 h under nitrogen protection. After cooling to room temperature, 200 mL of saturated sodium thiosulfate solution was added, and the mixture was separated. The aqueous phase was extracted with DCM (100 mL x 2) again, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE / EA (V / V) = 10 / 1) to give the product as a white solid (10.00 g, yield 68.71 %). MS (ESI, pos.ion) m / z: 332.0 [M+H] + .

[0330] Step 2: 4-Iodo-3-(piperidin-1-ylmethyl)pyridin-2(1H)-one

[0331] Into a reaction flask, 3-(bromomethyl)-2-chloro-4-iodopyridine (1.00 g, 3.01 mmol), a THF solution of dimethylamine (0.23 g, 5.12 mmol, 2 mol / L) and DCM (50 mL) were added successively, and after dissolution, DIPEA (3.89 g, 30.10 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was concentrated, and the residue was purified by column chromatography on silica gel (PE / EA (V / V) = 2 / 1) to give the product as a light yellow solid (0.86 g, yield 96.35 %). MS (ESI, pos.ion) m / z: 297.0 [M+H] + .

[0332] Step 3: (R)-4-(2-Amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)-3-(piperidin-1-ylmethyl)pyridin-2(1H)-one

[0333] Into a reaction flask, 1-(2-chloro-4-iodopyridin-3-yl)-N,N-dimethylmethanamine (0.86 g, 2.90 mmol), potassium tert-butoxide (1.30 g, 11.6 mmol) and tert-butanol (10 mL) were added, and the reaction mixture was stirred at 85 °C for 39.5 h under nitrogen protection. After cooling to room temperature, the pH of the reaction system was adjusted to 2-3 with a 1,4-dioxane solution of hydrochloric acid (4 mol / L), and the mixture was stirred for 30 min. Then, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with DCM (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH (V / V) = 10 / 1) to give the product as a light yellow solid (0.47 g, yield 58.28 %).

[0334] MS (ESI, pos.ion) m / z: 279.0 [M+H] + .

[0335] Step 1: 1-(6-Fluoro-4-iodopyridin-3-yl)-N-methylmethanamine Step 2: N-((6-Fluoro-4-iodopyridin-3-yl)methyl)-N-methylbut-3-en-1-amine

[0336] The title compound was prepared as yellow solid (67 mg, yield 29.78%) from (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)boronic acid and 3-((dimethylamino)methyl)-4-iodopyridin-2(1H)-one following the synthetic procedure of step 7-8 in example 1.

[0337] MS (ESI, pos.ion) m / z: 425.4 [M+H] + .

[0338] 1 HNMR (400 MHz, CD3OD) δ 8.41 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 6.7 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 6.7 Hz, 1H), 4.25 - 4.15 (m, 3H), 3.72 (d, J = 11.3 Hz, 1H), 2.76 (s, 6H), 2.29 (t, J = 10.2 Hz, 1H), 1.84 (t, J = 10.6 Hz, 1H), 1.57 (s, 3H), 1.38 (dd, J = 11.0, 5.4 Hz, 4H), 0.94 (t, J = 6.9 Hz, 3H).

[0339] HR-MS (ESI): 425.2668 [M+H] + .

[0340] Example 13: (R)-4-(2-amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)-3-((dimethylamino)methyl)pyridin-2(1H)-one

[0341]

[0342] The title compound was prepared as yellow solid (67 mg, yield 29.78%) from (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)boronic acid and 3-((dimethylamino)methyl)-4-iodopyridin-2(1H)-one following the synthetic procedure of step 7-8 in example 1.

[0343] MS (ESI, pos.ion) m / z: 426.4 [M+H]+ ;

[0344] 1 HNMR (400 MHz, CD3OD) δ 8.59 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 6.7 Hz, 1H), 6.51 (d, J = 6.7 Hz, 1H), 4.20 (s, 2H), 4.01 (d, J = 11.2 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 2.77 (s, 6H), 2.19 - 2.08 (d, J = 14.3 Hz, 1H), 2.07 - 1.94 (m, 1H), 1.59 (s, 3H), 1.39 (s, 4H), 0.95 (t, J = 6.6 Hz, 3H);

[0345] HR-MS (ESI): 426.2612 [M+H] + .

[0346] Example 14: (R)-4-(2-amino-4-((l-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)-3- (piperidin-l-ylmethyl)pyridin-2(lH)-one

[0347] Step 3: 5-((But-3-en-1-yl(methyl)amino)methyl)-4-iodopyridin-2(1H)-one

[0348] Into a reaction bottle was added 3-bromomethyl-2-chloro-4-iodopyridine (1.00 g, 3.01 mmol), piperidine (1 mL), DIPEA (5 mL) and dichloromethane (50 mL) successively, the reaction mixture was reacted at room temperature for about 30 minutes, the solvent was spin dried, and the residue was purified by silica gel column chromatography (PE / EA (V / V) = 10 / 1) to obtain the title compound as a light yellow solid (1.00 g, 98.70%).

[0349] MS (ESI, pos.ion) m / z: 337.0 [M+H] + .

[0350] Step 4: 5-((But-3-en-1-yl(methyl)amino)methyl)-1-(2-(dimethylamino)ethyl)-4-iodopyridin-2(1H)-one

[0351] 2-chloro-4-iodo-3-(piperidin-l-ylmethyl)pyridine (1.00 g, 2.97 mmol) and potassium tert-butoxide (1.67 g, 14.85 mmol) were added to tert-butanol (30 mL) respectively, and reacted at 70 °C under nitrogen protection for about 21 h. Concentration under reduced pressure, then silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) was used for separation and purification to obtain the title compound as a light yellow solid (0.93 g, yield 98.42%).

[0352] MS (ESI, pos. ion) m / z: 319.0 [M+H] + .

[0353] Step 5: (R)-4-(2-Amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-yl)-5-((but-3-en-1-yl(methyl)amino)methyl)-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one ​

[0354] The title compound was prepared from (R)-4-iodo-3-(piperidin-1-ylmethyl)pyridin- 2(1H)-one and (2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)quinazolin-7-yl)boronic acid as a yellow solid (218 mg, yield 79.53%) according to the method described in step 7-8 of example 1.

[0355] MS (ESI, pos. ion) m / z: 465.5 [M+H] + ;

[0356] 1 HNMR (400 MHz, CD3OD) δ 8.46 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 6.5 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 6.5 Hz, 1H), 4.20 (d, J = 11.5 Hz, 3H), 3.73 (d, J = 11.3 Hz, 1H), 3.43 (d, J = 11.0 Hz, 2H), 2.88 (t, J = 10.8 Hz, 2H), 2.33 - 2.20 (m, 1H), 1.91 - 1.68 (m, 6H), 1.57 (s, 3H), 1.52 - 1.18 (m, 5H), 0.93 (t, J = 6.6 Hz, 3H);

[0357] HR-MS (ESI): 465.2980 [M+H] + .

[0358] Example 15: (R)-4-(2-amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)-3-(piperidin-1-ylmethyl)pyridin-2(1H)-one

[0359]

[0360] The title compound was prepared as a yellow solid (163 mg, yield 60.36%) using 4-iodo-3-(piperidin-1-ylmethyl)pyridin-2(1H)-one (synthesized in Reference Example 14) and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-yl)boronic acid (synthesized in Reference Example 1) as starting materials following the synthetic procedure of steps 7-8 in Reference Example 1.

[0361] MS (ESI, pos.ion) m / z: 466.5 [M+H] + ;

[0362] 1 H NMR (400 MHz, CD3OD) d 8.62 (s, 1H), 7.98 (s, 1H), 7.76 (d, J = 5.8 Hz, 1H), 6.53 (d, J = 5.6 Hz, 1H), 4.24 (s, 2H), 4.01 (d, J = 11.2 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.44 (d, J = 10.4 Hz, 2H), 2.89 (t, J = 14.0 Hz, 2H), 2.19 - 2.08 (m, 1H), 2.03 - 1.92 (m, 1H), 1.91 - 1.70 (m, 5H), 1.58 (s, 3H), 1.51 - 1.34 (s, 5H), 0.94 (d, J = 6.1 Hz, 3H);

[0363] HR-MS (ESI): 466.2939 [M+H] + .

[0364] Example 16: (R)-4-(2-amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)-5-((but-3-en-1-yl(methyl)amino)methyl)-1-(2-(dimethylamino)ethyl)pyridin- 2(1H)-one

[0365]

[0366] ​

[0367] To the flask was added 5-(bromomethyl)-2-fluoro-4-iodopyridine (6.01 g, 19.02 mmol), methylamine (5.97 g, 192.3 mmol) and methanol (120 mL) and stirred at room temperature for about 1.5 hours. The reaction was completed and the solvent was evaporated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution (200 mL) and then extracted with dichloromethane (200 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as a yellow oil (5.04 g, yield 99.60%).

[0368] MS (ESI, pos.ion) m / z: 266.9 [M+H] + .

[0369] ​

[0370] To the flask was added 5-(bromomethyl)-2-fluoro-4-iodopyridine (6.01 g, 19.02 mmol), methylamine (5.97 g, 192.3 mmol) and methanol (120 mL) and stirred at room temperature for about 1.5 hours. The reaction was completed and the solvent was evaporated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution (200 mL) and then extracted with dichloromethane (200 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as a yellow oil (5.04 g, yield 99.60%). + .

[0371] ​

[0372] To the flask was added 5-(bromomethyl)-2-fluoro-4-iodopyridine (6.01 g, 19.02 mmol), methylamine (5.97 g, 192.3 mmol) and methanol (120 mL) and stirred at room temperature for about 1.5 hours. The reaction was completed and the solvent was evaporated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution (200 mL) and then extracted with dichloromethane (200 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as a yellow oil (5.04 g, yield 99.60%).

[0373] MS (ESI, pos.ion) m / z: 266.9 [M+H] + .

[0374] ​ ​

[0375] Dissolve 5-((but-3-en-1-yl(methyl)amino)methyl)-4-iodopyridin-2(1H)-one (0.35 g, 1.1 mmol), 2-(dimethylamino)ethan-1-ol (0.10 g, 1.10 mmol) and triphenylphosphine (0.43 g, 1.65 mmol) in anhydrous tetrahydrofuran (10 mL), replace with nitrogen for three times, cool the reaction to 0 °C, add DIAD (0.33 g, 1.65 mmol), after addition, move the reaction mixture to room temperature and react for 15 h. Concentrate the solvent, purify the residue by silica gel column chromatography (DCM / MeOH (V / V) = 10 / 1) to obtain the title compound as a yellow oily compound (0.351 g, yield 81.97 %). MS (ESI, pos.ion) m / z: 390.1 [M+H] + .

[0376] ​ ​

[0377] ​

[0378] Prepare the title compound as a white solid (71 mg, yield 47.25 %) from 5-((but-3-en-1-yl(methyl)amino)methyl)-1-(2-(dimethylamino)ethyl)-4-iodopyridin-2(1H)-one and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-yl)boronic acid by referring to the synthetic method of step 7-8 in Example 1.

[0379] MS (ESI, pos.ion) m / z: 537.6 [M+H] + ;

[0380] 1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 6.65 (s, 1H), 5.74 - 5.59 (m, 1H), 5.15 - 5.05 (m, 2H), 4.51 (t, J = 5.9 Hz, 2H), 4.25 (s, 2H), 3.99 (d, J = 11.2 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 3.65 (t, J = 5.9 Hz, 2H), 3.33 (d, J = 15.5 Hz, 2H), 3.12 - 2.97 (m, 8H), 2.65 (s, 3H), 2.40 - 2.29 (m, 2H), 2.16 - 2.06 (m, 1H), 2.03 - 1.92 (m, 1H), 1.57 (s, 3H), 1.43 - 1.31 (m, 4H), 0.93 (t, J = 6.1 Hz, 3H).

[0381] Example 17: (R)-2-((2-amino-7-(2-methoxypyridin-4-yl)pyrido[3,2-d]pyrimidin-4- yl)amino)-2-methylhexan-1-ol

[0382]

[0383] The title compound was prepared (130 mg, yield 64.13%) as a white solid from 4-bromo-2-methoxypyridine and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1- hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-yl)boronic acid as the starting material by referring to the synthetic methods of step 7-8 in example 1.

[0384] MS (ESI, pos.ion) m / z: 383.2 [M+H] + .

[0385] 1 H NMR (400 MHz, CD3OD) δ 8.93 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 5.3 Hz, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 5.3 Hz, 1H), 7.21 (s, 1H), 4.01 (d, J = 9.9 Hz, 4H), 3.76 (d, J = 11.3 Hz, 1H), 2.21 - 2.09 (m, 1H), 2.02 - 1.90 (m, 1H), 1.59 (s, 3H), 1.47 - 1.34 (m, 4H), 0.95 (t, J = 6.6 Hz, 3H).

[0386] HR-MS (ESI): 383.2206 [M+H]+ .

[0387] Example 18: (R)-4-(2-amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)-1-methylpyridin-2(1H)-one

[0388] Step 1: 4-bromo-1-methylpyridin-2(1H)-one

[0389] A mixture of 4-bromo-1,2-dihydropyridin-2-one (0.50 g, 2.87 mmol) was dissolved in DMF (5 mL), and then iodomethane (0.49 g, 3.45 mmol) and cesium carbonate (1.40 g, 4.30 mmol) were added successively. The reaction mixture was stirred at room temperature for 1.5 h. The reaction was stopped, diluted with water (50 mL), and then extracted with EA (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The resulting residue was purified by column chromatography on silica gel (PE / EA (V / V) = 1 / 2) to give the product as a yellow solid (0.52 g, yield 96.36%). MS (ESI, pos.ion) m / z: 188.20 [M+H] + .

[0390] Step 2: (R)-4-(2-amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)-1-methylpyridin-2(1H)-one Step 2: (R)-4-(2-amino-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyrido[3,2- d]pyrimidin-7-yl)-1-methylpyridin-2(1H)-one

[0391] The title compound was prepared as a white solid (130 mg, yield 64.13%) from 4-bromo-1-methylpyridin-2(1H)-one and (R)-(2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxy-2-methylhexan-2-yl)amino)pyridyl[3,2-d]pyrimidin-7-yl)boronic acid as starting material according to the synthetic method of steps 7-8 in Example 1.

[0392] MS (ESI, pos.ion) m / z: 383.3 [M+H] + .

[0393] 1H NMR (400 MHz, CD3OD) δ 8.89 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 7.85 (d, J = 7.0 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 6.79 (dd, J = 7.0, 1.7 Hz, 1H), 4.01 (d, J = 11.2 Hz, 1H), 3.76 (d, J = 11.3 Hz, 1H), 3.65 (s, 3H), 2.19 - 2.08 (m, 1H), 2.02 - 1.90 (m, 1H), 1.58 (s, 3H), 1.38 (s, 4H), 0.95 (t, J = 6.7 Hz, 3H).

[0394] HR-MS (ESI): 383.2202 [M+H] + .

[0395] Example 19: (R)-N-(2-((2-amino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4- yl)amino)-2-methylhexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0396]

[0397] Step 1: (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoic acid

[0398] A reaction bottle was added with (2R)-2-amino-2-methylhexanoic acid hydrochloride (20.00 g, 110.10 mmol), THF (100 mL) and a solution of sodium hydroxide (14.53 g, 363.33 mmol) in water (400 mL), stirred to dissolve at room temperature, slowly added dropwise a solution of Boc anhydride (28.84 g, 132.12) in THF (100 mL), and stirred at room temperature for 12 h after dropping. The reaction was stopped, the pH of the reaction solution was adjusted to 4-5 with a saturated citric acid solution; extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a light yellow solid (22.50 g, yield 83.30%).

[0399] 1 H NMR (400 MHz, CDCl3) δ 1.86 - 1.79 (m, 1H), 1.56 - 1.54 (m, 4H), 1.46 (d, J = 6.2 Hz, 9H), 1.38 - 1.28 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H).

[0400] Step 2: tert-butyl (R)-(1-amino-2-methyl-1-oxohexan-2-yl)carbamate

[0401] Into a reaction flask was placed (R)-2-((tert-butoxycarbonyl)amino)-2- methylhexanoic acid (19.40 g, 79.08 mmol), triethylamine (10.40 g, 102.80 mmol) and tetrahydrofuran (130 mL), and ethyl chloroformate (10.30 g, 94.90 mmol) was added dropwise slowly at -10 °C. After the dropwise addition was completed, the reaction mixture was stirred at -10 °C for about 2 h, then cooled to -20 °C and stirred under an ammonia atmosphere for about 2 h, and then stirred at room temperature for 5 h. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oily liquid (19.32 g, yield 99.99%).

[0402] MS (ESI, pos.ion) m / z: 145.1 [M-Boc+H] + .

[0403] Step 3: tert-butyl (R)-(1-amino-2-methylhexan-2-yl)carbamate

[0404] To a solution of 1 M lithium aluminum hydride in tetrahydrofuran (9.00 g, 237.21 mmol) was added dropwise slowly a solution of tert-butyl (R)-(1-amino-2-methyl-1- oxohexan-2-yl)carbamate (19.32 g, 79.07 mmol) in tetrahydrofuran (100 mL) at 0 °C, and the dropwise addition was completed. The reaction mixture was stirred at room temperature for 3 h, then heated to 60 °C for 5 h. After the reaction was completed, 15% sodium hydroxide solution (20 mL) was added to the reaction mixture, and then extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a colorless oily liquid (12.65 g, yield 69.45%).

[0405] MS (ESI, pos.ion) m / z: 231.2 [M+H] + .

[0406] Step 4: tert-butyl (R)-(2-methyl-1-(1-methyl-1H-pyrazole-4-carboxamido)hexan-2- yl)carbamate Step 4: tert-butyl (R)-(2-methyl-1-(1-methyl-1H-pyrazole-4-carboxamido)hexan-2- yl)carbamate

[0407] Tert-butyl (R)-(2-methyl-1-(1-methyl-1H-pyrazole-4-carboxamido)hexan-2-yl)carbamate (3.17 g, 9.37 mmol) was added to a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 30 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (2.23 g, 99.86% yield).

[0408] MS (ESI, pos.ion) m / z: 239.2 [M-Boc+H] + .

[0409] Step 5: (R)-N-(2-((7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2- methylhexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0410] Tert-butyl (R)-(2-methyl-1-(1-methyl-1H-pyrazole-4-carboxamido)hexan-2-yl)carbamate (3.17 g, 9.37 mmol) was added to a solution of hydrochloric acid in 1,4-dioxane (4 mol / L, 30 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (2.23 g, 99.86% yield).

[0411] Step 5: (R)-N-(2-((7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2- methylhexyl)-1-methyl-1H-pyrazole-4-carboxamide Step 6: (R)-N-(2-((7-bromo-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4- yl)amino)-2-methylhexyl)-1-methyl-1H-pyrazole-4-carboxamide

[0412] A reaction bottle was charged with (R)-N-(2-amino-2-methylhexyl)-1-methyl-1H-pyrazole-4- carboxamide (2.23 g, 9.36 mmol), 7-bromo-2,4-dichloropyrido[3,2-d]pyrimidine (2.61 g, 9.36 mmol), DIPEA (6.04 g, 46.77 mmol), and tetrahydrofuran (50 mL). The reaction mixture was stirred at 60 °C for 24 h under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE / EA (V / V) = 1 / 1) to give the title compound as a light yellow solid (1.51 g, 33.55% yield).

[0413] MS (ESI, pos.ion) m / z: 482.0 [M+H] + .

[0414] Step 7: (R)-N-(2-((2-amino-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-4-yl)amino)-2- methylhexyl)-1-methyl-1H-pyrazole-4-carboxamide ​

[0415] (R)-N-(2-((7-bromo-2-chloropyridino[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)-1-methyl-1H-pyrazole-4-carboxamide (1.51 g, 3.14 mmol), 2,4-dimethoxybenzylamine (0.79 g, 4.71 mmol), potassium carbonate (1.30 g, 9.49 mmol), and 1,4-dioxane (30 mL) were added to the reaction flask. The reaction mixture was reacted at 100 °C for about 20 h, concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (DCM / MeOH (V / V) = 15 / 1) to give the title compound as a pale yellow solid (1.51 g, yield 78.64%).

[0416] MS(ESI,pos.ion)m / z:611.1[M+H] + .

[0417] ​ ​

[0418] (R)-N-(2-((7-bromo-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)-1-methyl-1H-pyrazole-4-carboxamide (0.33 g, 0.54 mmol) and a methanol solution of hydrochloric acid (4 mol / L, 20 mL) were added to a reaction flask. The reaction mixture was reacted at room temperature (2 MPa) under a hydrogen atmosphere for approximately 23 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Trifluoroacetic acid (7.65 g, 67.09 mmol) was added to the concentrated residue, and the mixture was stirred at room temperature for approximately 2 h. The solvent was dried under nitrogen, and the mixture was purified by reversed-phase HPLC (elution with 15%-50% acetonitrile / water for 30 min, containing 1‰ TFA) to give the title compound as a brownish-yellow solid (0.07 g, yield 33.54%).

[0419] MS(ESI,pos.ion)m / z:387.4[M+H] + ;

[0420] 1H NMR (400 MHz, DMSO-d6) d (ppm) 12.15 (s, 1H), 8.17 (s, 1H), 8.11 (t, J = 6.1 Hz, 1H), 7.87 (s, 1H), 7.17 (s, 2H), 6.96 (s, 1H), 3.85 (s, 3H), 3.76 (dd, J = 13.7, 5.8 Hz, 1H), 3.53 - 3.43 (m, 1H), 3.10 (t, J = 5.3 Hz, 2H), 2.54 (d, J = 6.2 Hz, 2H), 2.09 - 1.97 (m, 1H), 1.82 - 1.74 (m, 2H), 1.36 (s, 3H), 1.28 - 1.14 (m, 4H), 0.85 (t, J = 6.9 Hz, 3H);

[0421] HR-MS (ESI): 387.2615 [M+H] + .

[0422] Biological tests

[0423] Test 1: Test of agonistic activity on human TLR7 and TLR8 and cytotoxic activity

[0424] Purpose of the experiment: application of HEK-Blue TM hTLR7 and HEK-Blue TM hTLR8 cells to detect the agonistic activity and cytotoxic activity of the compounds on hTLR7 and hTLR8.

[0425] The experimental procedure is as follows:

[0426] 1) Compound preparation: the compound is first prepared into a 20 mM stock solution with DMSO, then the compound is diluted by 3 times gradient and added to the 96-well plate, a total of 10 concentrations, each concentration with double duplicate wells. The negative control well is added with 0.5 μL DMSO per well. The final concentration of DMSO is 0.5%.

[0427] 2) HEK-Blue TM hTLR7 or HEK-Blue TM hTLR8 cells are suspended in culture solution and then seeded into the 96-well plate containing the compound, with a cell number of 50,000 per well. The compound and cells are incubated at 37°C, 5% CO2 for 24 h.

[0428] 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 stand at room temperature for 10 min.

[0429] 4) Compound activity test: 20 μL of culture supernatant in step 2) was taken per well and added to a 96-well plate containing 180 μL of QUANTI-Blue detection solution, and incubated at 37°C for 1 h, and then the absorbance value at 650 nm (OD650) was detected using a multifunctional enzyme label instrument Flextation III. 650 ).

[0430] 5) Cell activity test: The method was operated according to the Celltiter-Glo instruction, and the chemiluminescence signal (RLU) was detected using a multifunctional enzyme label instrument Flextation III.

[0431] 6) Data analysis

[0432] Compound activity: The OD650value was analyzed using GraphPad Prism software, and the compound dose-effect curve was fitted, and the EC50value of the compound was calculated. 650 50 value.

[0433] Cell activity test: The cell activity % was calculated according to the following formula. The cell activity % value was analyzed using GraphPad Prism software, and the compound dose-effect curve was fitted, and the CC50value of the compound to the cell was calculated. 50

[0434] Cell activity % = RLU 化合物 / RLU DMSOControl * 100%

[0435] The compound of the present application has good agonistic activity to hTLR8, and has good selective activation effect on hTLR8. The test results of the agonistic activity of the compound of the present application to human TLR7 and TLR8 are shown in Table A, and the toxicity of the compound of the present application to cells is small. The toxicity results of the compound of the present application to cells are shown in Table A-1.

[0436] Table A: Agonistic activity of the compound of the present application to human TLR7 and TLR8

[0437]

[0438] Table A-1: Toxicity of the compound of the present application to cells

[0439]

[0440]

[0441] Test 2: Inhibition of the compound of the present application to human liver microsomal CYP enzyme

[0442] ​​Objective: To evaluate the inhibition of the major metabolic enzymes CYP1A2, CYP2C19, CYP2D6 and CYP3A4 in microsomes by the test compound.

[0443] Method: The test compound was incubated with the cytochrome P450 enzymes CYP1A2, CYP2C19, CYP2D6 and CYP3A4 in human liver microsomes at a final concentration of 10 μM. The known substrates were metabolized by the respective enzymes to specific metabolites, which were determined by UPLC-MS / MS. The relative inhibition (%) was calculated by the percentage decrease of metabolite formation of the test compound compared to the solvent DMSO.

[0444] Relative inhibition (%) = (1 - (N +inh / N veh )) x 100

[0445] N is the concentration of the metabolite of the probe substrate and is assumed to be 0 at 0 min with or without inhibitor. N +inh is the metabolite concentration with inhibitor, N veh is the metabolite concentration without inhibitor. The results of the liver enzyme inhibition test of the compounds of the present application are shown in Table C.

[0446] Table C: Experimental data of the liver enzyme inhibition test of the compounds of the present application

[0447]

[0448] Conclusion: The experimental data of the liver enzyme inhibition test show that the compounds of the present application have no inhibition on the major liver enzymes.

[0449] Test 3: Induction of the CYP enzymes in human liver microsomes by the compounds of the present application

[0450] Objective: To evaluate the induction of CYP1A2, CYP2B6 and CYP3A4 by the test compound from both enzyme activity and mRNA level using cryopreserved human hepatocytes as test system.

[0451] Experimental method: 24 hours after cell plating, induction was started by adding culture medium containing the test compound (test concentration: 10, 1 and 0.1 μM), and fresh drug-containing culture medium was replaced every 24 hours. After 72 hours of induction, the culture medium was replaced with culture medium containing specific substrates of CYP1A2, CYP2B6 and CYP3A4 for 30 minutes of incubation, 100 μL was taken for processing, and the labeled metabolites of the substrates were detected to evaluate the enzyme activity level. Finally, the cells were lysed, reverse transcribed, and the expression amount of CYP1A2, CYP2B6 and CYP3A4 genes in the cells was evaluated by real-time quantitative PCR method.

[0452] The test compound induction fold compared with the blank control and the test compound induction percentage compared with the positive control were taken as the basis for evaluating the induction potential of the test compound. The CYP1A2 positive control was omeprazole, the CYP2B6 positive control was phenobarbital, and the CYP3A4 positive control was rifampicin. The results of the liver enzyme induction test are shown in Table D.

[0453] Table D: Liver enzyme induction test data

[0454]

[0455] Note: The comparative compound is (R)-2-((2-amino-7-fluoropyrido [3, 2-d] pyrimidin-4-yl) amino)-2-methylhexan-1-ol

[0456] Conclusion: The liver enzyme induction test data show that the compound of the present application has no induction effect on liver enzymes CYP1A2, CYP2B6 and CYP3A4.

[0457] Test 4: Pharmacokinetic experiment of the compound of the present application in beagle dogs, mice, rats or cynomolgus monkeys

[0458] (1) Beagle dog PK test experiment

[0459] The PK determination experiment method of the compound of the present application in beagle dogs (purchased from Hunan Slike Jingda Experimental Animal Co., Ltd., body weight 10-12 kg, male, age 10-12 months, oral administration of 3 in each group, intravenous injection of 3 in each group):

[0460] Beagle dogs were orally administered with 2.5 mg / kg or 5 mg / kg of the test compound or intravenously injected with 0.5 mg / kg or 1 mg / kg or 2 mg / kg of the test compound.

[0461] Blood samples were collected at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours) after administration into the orbit venous, and collected in anticoagulant tubes with EDTA-K2. The plasma samples were extracted by liquid-liquid extraction, and then quantitatively analyzed by multiple reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. The pharmacokinetic parameters were calculated by non-compartment model method using WinNonlin 6.3 software.

[0462] Conclusion: The pharmacokinetic experimental data show that the compound has good pharmacokinetic properties in beagle dogs, and has good application prospect in anti-HBV.

[0463] (2) Mouse PK test experiment:

[0464] The PK determination experiment method of the compound in ICR mice (purchased from Hunan Slike Jingda Experimental Animal Co., Ltd., weighing 20-25 g, male, age 45-60 days, 3 per group orally, 3 per group intravenously) is as follows:

[0465] ICR mice are orally administered with 10 mg / kg of the test compound or intravenously injected with 2 mg / kg or 10 mg / kg of the test compound.

[0466] Blood samples were collected at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours) after administration into the orbit venous, and collected in anticoagulant tubes with EDTA-K2. The plasma samples were extracted by liquid-liquid extraction, and then quantitatively analyzed by multiple reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. The pharmacokinetic parameters were calculated by non-compartment model method using WinNonlin 6.3 software.

[0467] Conclusion: The pharmacokinetic experimental data show that the compound has good pharmacokinetic properties in mice, and has good application prospect in anti-HBV.

[0468] (3) SD rat PK test experiment:

[0469] The PK determination experiment method of the compound in SD rats (purchased from Hunan Slike Jingda Experimental Animal Co., Ltd., weighing 200-250 g, male, age 2-3 months, 3 per group orally, 3 per group intravenously) is as follows:

[0470] Rats are orally administered with 2.5 mg / kg or 5 mg / kg of the test compound or intravenously injected with 1 mg / kg of the test compound.

[0471] Blood samples were collected at time points (0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours) after administration into EDTA-K2 anticoagulant tubes. The plasma samples were extracted by liquid-liquid extraction, and then were quantitatively analyzed by multiple reaction monitoring (MRM) on a triple quadrupole tandem mass spectrometer. The pharmacokinetic parameters were calculated by non-compartment model method using WinNonlin 6.3 software.

[0472] Conclusion: The pharmacokinetic experimental data show that the compound of the present application has a large exposure in SD rats, indicating that the compound of the present application is well absorbed in SD rats and has good bioavailability, and has a good application prospect in the aspect of anti-HBV.

[0473] (4) Cynomolgus monkey PK test experiment:

[0474] The PK determination experiment method of the compound of the present application in cynomolgus monkeys (purchased from Guangdong Chunsheng Biotechnology Development Co., Ltd., weighing 3-6 kg, male, aged 4-6 years, orally administered 3 in each group, and intravenously injected 3 in each group):

[0475] The cynomolgus monkeys were orally administered with 2.5 mg / kg or 5 mg / kg of the test compound or intravenously injected with 0.5 mg / kg or 1 mg / kg of the test compound.

[0476] Blood samples were collected at time points (0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours) after administration into EDTA-K2 anticoagulant tubes. The plasma samples were extracted by liquid-liquid extraction, and then were quantitatively analyzed by multiple reaction monitoring (MRM) on a triple quadrupole tandem mass spectrometer. The pharmacokinetic parameters were calculated by non-compartment model method using WinNonlin 6.3 software.

[0477] Conclusion: The pharmacokinetic experimental data show that the compound of the present application has good pharmacokinetic properties in cynomolgus monkeys, and has a good application prospect in the aspect of anti-HBV.

[0478] Although the present application has been described in detail in the foregoing description with general principles, specific embodiments and experiments, some modifications or improvements can be made on the basis of the present application, which is obvious to those skilled in the art. Therefore, these modifications or improvements made on the basis of not deviating from the spirit of the present application, all belong to the scope of protection claimed by the present application.

Claims

1. A compound, which is a compound of Formula (I) or a stereoisomer, a tautomer, a nitroso, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound of Formula (I), wherein Q is one of the following structural formulas: wherein X is N or CR 4 ; each R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 6a , R 7a and R 8a are independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkylamino, C 1-6 alkoxy or C 1-6 alkyl, wherein said C 1-4 alkylamino, C 1-6 alkoxy and C 1-6 alkyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino and C 1-4 alkyl; Y is O or S; R 3 -C 1-6 alkylene-OH, wherein said -C 1-6 alkylene-OH is -C 1-6 alkylene-unsubstituted or substituted by 1, 2, 3, 4 or 5 R w1 substituents; R is H, deuterium, or C 1-6 alkyl; Each R 9 and R 9a Independently for H, -L-NR a R b F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 Alkylamino, C 1-6 Alkoxy or C 1-6 Alkyl, wherein the C 1-4 Alkylamino, C 1-6 Alkoxy and C 1-6 The alkyl groups are each independently unsubstituted or composed of 1, 2, 3, or 4 independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, C 1-6 Alkoxy and C 1-4 Alkyl substituents; L is -C 1-6 alkylene- or -C(=O)-, wherein said -C 1-6 alkylene- is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl or i-propyl; each R a and R b is independently hydrogen, deuterium, C 1-12 alkyl, C 2-12 alkenyl, or C 2-12 alkynyl, wherein said C 1-12 alkyl, C 2-12 alkenyl, and C 2-12 alkynyl are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R w2 substituents; or, R a or, R b with the N atom to which they are attached form a 3-8 membered heterocyclyl group, wherein said 3-8 membered heterocyclyl group is unsubstituted or substituted with 1, 2, 3, or 4 R w3 substituents; each R w1 , R w2 , and R w3 is independently deuterium, F, Cl, Br, I, =0, hydroxyl, cyano, amino, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, -C(=0)-C 1-4 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, or C 6-10 aryl, wherein said amino, C 1-6 alkylamino, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 haloalkyl, -C(=0)-C 1-4 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and C 6-10 aryl are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkyl, and C 1-4 alkylamino.

2. The compound of claim 1, wherein, each R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 6a , R 7a and R 8a are independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, cyano, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, methoxy, ethoxy, 1 -propyloxy, 2-propyloxy, 1 -butoxy, 2-methyl- 1 -propyloxy, 2-butoxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl or n-hexyl, wherein each of said N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, methoxy, ethoxy, 1 -propyloxy, 2-propyloxy, 1 -butoxy, 2-methyl- 1 -propyloxy, 2-butoxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-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 s-butyl; R is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl or n-hexyl.

3. The compound of claim 1 or 2, wherein, R 3 is -CH2-OH, -(CH2)2-OH, -(CH2)3-OH, -CH(CH3)CH2-OH, -CH2CH(CH3)-OH, or -(CH2)4-OH, wherein each of the -CH2- of -CH2-OH, the -(CH2)2- of -(CH2)2-OH, the -(CH2)3- of -(CH2)3-OH, the -CH(CH3)CH2- of -CH(CH3)CH2-OH, the -CH2CH(CH3)- of -CH2CH(CH3)-OH, and the -(CH2)4- of -(CH2)4-OH is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R w1 substituents.

4. The compound of claim 1, wherein, Each R 9 and R 9a Independently for H, -L-NR a R b F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 Alkylamino, C 1-4 Alkoxy or C 1-4 Alkyl, wherein the C 1-4 Alkylamino, C 1-4 Alkoxy and C 1-4 The alkyl groups are each independently unsubstituted or composed of 1, 2, 3, or 4 independently selected from F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 Alkoxy and C 1-4 Substituents of alkyl groups; L is -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH(CH3)-, -CH(CH3)CH2-, -(CH2)4- or -C(=O)-, wherein each of said -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH(CH3)-, -CH(CH3)CH2- and -(CH2)4- 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 or isopropyl; or each R 9 and R 9a independently H, -L-NR a R b F, CI, Br, I, 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, sec-butyl, or t-butyl, wherein each of said 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, sec-butyl, and t-butyl is independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, CI, Br, I, hydroxyl, cyano, amino, methoxy, ethoxy, 1 -propoxy, 2-propoxy, 1 -butoxy, 2-methyl- 1 -propoxy, 2-butoxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl.

5. The compound of claim 1, wherein, each R a and R b is independently hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R w2 substituents; or, R a , R b together with the N atom to which they are attached form a 3-6 membered heterocyclyl group, wherein said 3-6 membered heterocyclyl group is unsubstituted or substituted with 1, 2, 3, or 4 R w3 substituents.

6. The compound of claim 1, wherein, Each R a and R b Independently, it is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3 or -C≡CCH2CH3, wherein the methyl group, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, and -C≡CCH2CH3 are each independently unsubstituted or substituted by 1, 2, 3, 4, or 5 R groups. w2 replace; or, R a or, R b together with the N atom to which they are attached form an aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein each of said aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl is independently unsubstituted or substituted with 1, 2, 3, or 4 R w3 substituents.

7. The compound of claim 1, wherein, each R w1 , R w2 , and R w3 independently deuterium, F, Cl, 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, -CH2C1, -CF3, -CHF2, -CHC12, -CH2CH2F, -CH2CH2C1, -CH2CHF2, -CH2CHC12, -CHFCH2F, -CHC1CH2C1, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirdinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl, wherein said 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, -CH2C1, -CF3, -CHF2, -CHC12, -CH2CH2F, -CH2CH2C1, -CH2CHF2, -CH2CHC12, -CHFCH2F, -CHC1CH2C1, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirdinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl is optionally substituted with one to three substituents selected from the group consisting ofN-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, -CH2Cl, -CHF2, -CHCl2, -CH2CH2F, -CH2CH2Cl, -CH2CHF2, -CH2CHCl2, -CHFCH2F, -CHClCH2Cl, -CH2CF3, -CH(CF3)2, -CF2CH2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH2CH2CH=CH2, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2CH2C≡CH, -CH2C≡CCH3, -C≡CCH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azirdinyl, 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, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, and phenyl are each 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, -N(CH3)2, -NHCH3, -N(CH2CH3)2, -N(CH3)CH2CH3, and -NHCH2CH3.

8. A compound, which comprises one of the following structures: or stereoisomers, tautomers, nitroso, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof.

9. A pharmaceutical composition, comprising the compound of any one of claims 1-9, and a pharmaceutically acceptable excipient thereof. Optionally, the pharmaceutical composition 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 alpha 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, 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 alpha-1, a hepatitis B virus replication inhibitor, a hepatitis B surface antigen secretion or assembly inhibitor, an IDO inhibitor, or a combination thereof, or further comprises one or more additional therapeutic agents, wherein the therapeutic agent 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, mivotin, nitazoxanide, ribavirin, rozosin-A, sizofiran, Euforavac, Ampligen, Phosphazid, Heplisav, recombinant human interleukin-2, levamisole or propagermanium.

10. Use of a compound of any one of claims 1-8 or a pharmaceutical composition of claim 9 for the manufacture of a medicament for preventing, managing, treating or lessening a TLR8-mediated disease in a patient, the TLR8-mediated disease being a hepatitis B virus infection, a hepatitis C virus infection, an influenza virus infection, a herpes virus infection, an HIV infection, an 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, or thyroid cancer.

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