CN116768883A

CN116768883A - Pyrimido aromatic ring compounds and application thereof in medicines

Info

Publication number: CN116768883A
Application number: CN202210222697.1A
Authority: CN
Inventors: 任青云; 颜光华; 张英俊; 赖庆莹
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2022-03-09
Filing date: 2022-03-09
Publication date: 2023-09-19

Abstract

The invention relates to a pyrimido aromatic ring compound and application thereof in medicines, in particular to application of the pyrimido aromatic ring compound serving as a TLR8 agonist. In particular, the invention relates to compounds of formula (I) or stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and their use as medicaments, in particular as TLR8 agonists. Wherein the variables are as defined in the specification.

Description

Pyrimido aromatic ring compounds and application thereof in medicines

Technical Field

The invention belongs to the field of medicines. In particular to a pyrimido aromatic ring compound and application thereof as a medicine, in particular to application thereof as a TLR8 agonist. The invention also relates to compositions of these pyrimidoaromatic compounds with other therapeutic agents, and their use as pharmaceuticals, particularly as TLR8 agonists.

Background

Toll-like receptors (TLRs) are an important pattern recognition receptor for the innate immune response, and are widely distributed in mammalian myeloid dendritic cells, monocytes and monocytes macrophages. In one aspect, TLRs recognize specific microbial PAMPs (e.g., lipopolysaccharide, flagellin, single/double stranded RNA, etc.), thereby eliciting innate immunity in the body; on the other hand, different TLRs are able to induce gene expression in specific functional regions, thereby eliciting an antigen-specific adaptive immune response in the body.

In mammals, 13 members of TLRs have been found, with TLR1-TLR9, TLR11 being common to humans and mice, and TLR10, TLR12 and TLR13 being unique to mice. TLR8 is a member of the TLRs subgroup (TLRs 3, 7, 8 and 9), limited to endosomal compartments of cells that specifically recognize non-nucleic acids. TLR8 is expressed in humans primarily by monocytes, NK cells and myeloid dendritic cells (mDC). TLR8 agonists can result in the release of a variety of different pro-inflammatory cytokines, such as IL-6, IL-12, TNF- α and IFN- γ.

After TLR8 is activated, inflammation immunity is mediated to promote the elimination of virus-infected cells and tumor cells in vivo, and the agonist can be used as an independent immunotherapy drug or an immune adjuvant, so that the agonist has important clinical application prospect in immunotherapy. TLR8 activation is closely related to anti-infective natural immune response, and can mediate the occurrence and development of viral infectious diseases such as HBV, HCV, HIV, herpesvirus, etc., tumors, autoimmune diseases, metabolic diseases, etc.

Currently dual agonists of TLR8 and TLR7 are reported in many patents, and in view of the broad therapeutic potential of TLR8 agonist drugs, there remains a need for new TLR8 agonist drugs, particularly for use as agonists with higher selectivity for TLR8 for the treatment and/or prevention of hepatitis b virus.

Disclosure of Invention

The invention relates to novel pyrimido aromatic ring compounds and pharmaceutically acceptable compositions thereof, which have good activation effect on TLR8 and good selective activation effect on TLR8, and at the same time have the advantages of basically no induction effect on liver enzymes, basically no toxicity on hearts and the like, and in addition, have good solubility, good stability and very good pharmacokinetic properties. The compound of the invention can treat and/or prevent various diseases related to TLR8 activity, and has good application prospect especially in the aspect of resisting Hepatitis B Virus (HBV).

In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),

wherein X is N or CR ⁷ ；

Y is N or CR ⁴ ；

Each R is ¹ 、R ² 、R ⁵ 、R ⁶ And R is ⁷ Independently hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, C _1-4 Alkylamino, C _1-6 Alkoxy or C _1-6 Alkyl, wherein, C _1-4 Alkylamino, C _1-6 Alkoxy and C _1-6 Alkyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from F, cl, br, I, hydroxy, cyano, amino and C _1-4 Substituted by alkyl;

r is heteroaryl consisting of 5-6 ring atoms or-C (=O) -R ³ Wherein the heteroaryl group consisting of 5 to 6 ring atoms is unsubstituted or substituted with 1, 2 or 3 groups independently selected from F, cl, br, I, hydroxy, cyano, amino, C _1-4 Alkyl, -C (=o) -OH and-C (=o) -O-C _1-4 Substituted by alkyl;

R ³ is C _3-6 Cycloalkyl, phenyl, heteroaryl of 5 to 10 ring atoms or fused bicyclic heterocyclyl of 7 to 10 ring atoms, wherein the phenyl, heteroaryl of 5 to 10 ring atoms and fused bicyclic heterocyclyl of 7 to 10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w1 Substituted by substituents of said C _3-6 Cycloalkyl is substituted with 1, 2, 3 or 4 groups independently selected from F, cl, br, I, hydroxy, cyano, amino and C _1-4 Substituted by alkyl;

R ⁴ is hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, heteroaryl of 5 ring atoms, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkyl and C _3-6 Cycloalkyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4R ^w2 Substituted by substituents of said 5 ring atoms consisting of heteroaryl, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl and pyrimidinylEach independently is 1 or 2R ⁸ Is substituted by a substituent of (2);

each R is ⁸ Independently a heteroaryl group consisting of 5 to 10 ring atoms or a heterocyclic group consisting of 3 to 12 ring atoms, wherein the heteroaryl group consisting of 5 to 10 ring atoms and the heterocyclic group consisting of 3 to 12 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w3 Is substituted by a substituent of (2);

each R is ^w1 、R ^w2 And R is ^w3 Independently deuterium, F, cl, br, I, = O, R ^7a -C (=o) -, hydroxy, cyano, amino, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _6-10 Aryl, HOOC-phenyl-or HOOC-C _1-6 Alkylene-, wherein said C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkyl, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, C _6-10 Aryl, phenyl in HOOC-phenyl-and HOOC-C _1-6 C in alkylene radical _1-6 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from F, cl, br, I, HOOC-, hydroxy, cyano, amino and C _1-4 Substituted by alkyl;

R ^7a is OH, amino, C _1-6 Alkoxy, C _1-6 Alkyl or C _1-6 An alkylamino group.

In some embodiments, each R ¹ 、R ² 、R ⁵ 、R ⁶ And R is ⁷ Independently hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-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, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethylThe group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl each independently being unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl;

r is furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or-C (=O) -O-R ³ Wherein the furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -C (=o) -OH, -C (=o) -O-methyl, -C (=o) -O-ethyl, -C (=o) -O-n-propyl, -C (=o) -O-isopropyl, -C (=o) -O-n-butyl, -C (=o) -O-isobutyl and-C (=o) -O-sec-butyl; wherein R is ³ Having the meaning described in the present invention.

In some embodiments, the R ³ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, a monocyclic heteroaryl group consisting of 5 to 6 ring atoms, a fused bicyclic heteroaryl group consisting of 8 to 10 ring atoms or a fused bicyclic heterocyclyl group consisting of 8 to 10 ring atoms, wherein the phenyl, the monocyclic heteroaryl group consisting of 5 to 6 ring atoms, the fused bicyclic heteroaryl group consisting of 8 to 10 ring atoms and the fused bicyclic heterocyclyl group consisting of 8 to 10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w1 Wherein each R is substituted with a substituent of ^w1 Having the meaning according to the invention, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl radicals are each independently selected from the group consisting of F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl by 1, 2, 3 or 4Is substituted by a substituent of (2).

In some embodiments, the R ³ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, and,Or a fused bicyclic heterocyclic group consisting of 8 to 10 ring atoms, wherein the phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or->And fused bicyclic heterocyclic groups consisting of 8 to 10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w1 Is substituted by a substituent of (2); wherein each R ^w1 Having the meaning stated in the description, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each independently substituted by 1, 2, 3 or 4 substituents independently selected from F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl.

In some embodiments, the R ⁴ Is hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, C _1-4 Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said C _1-4 Alkylamino, methoxy, ethoxy1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl each independently being unsubstituted or substituted with 1, 2, 3 or 4R ^w2 Substituted with substituents of said furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being substituted with 1 or 2R ⁸ Is substituted by a substituent of (2); wherein each R ⁸ Having the meaning described in the present invention.

In some embodiments, each R ⁸ Independently a monocyclic heteroaryl group of 5 to 6 ring atoms, a fused bicyclic heteroaryl group of 7 to 10 ring atoms, a monocyclic heterocyclyl group of 3 to 6 ring atoms or a fused bicyclic heterocyclyl group of 8 to 10 ring atoms, wherein the monocyclic heteroaryl group of 5 to 6 ring atoms, the fused bicyclic heteroaryl group of 7 to 10 ring atoms, the monocyclic heterocyclyl group of 3 to 6 ring atoms and the fused bicyclic heterocyclyl group of 8 to 10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w3 Is substituted by a substituent of (2); wherein each R ^w3 Having the meaning described in the present invention.

In some embodiments, the R ⁸ Is furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or Wherein the furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl and isoxazoleA group, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl andeach independently is unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w3 Is substituted by a substituent of (2); wherein each R ^w3 Having the meaning described in the present invention.

In some embodiments, each R ^w1 、R ^w2 And R is ^w3 Independently deuterium, F, cl, br, I, = O, R ^7a -C (=o) -, hydroxy, cyano, amino, C _1-4 Alkylamino, C _1-4 Alkoxy, C _1-4 Alkyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, HOOC-phenyl-or HOOC-C _1-4 Alkylene-, wherein said C _1-4 Alkylamino, C _1-4 Alkoxy, C _1-4 Alkyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl in HOOC-phenyl-and HOOC-C _1-4 C in alkylene radical _1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, cl, br, I, HOOC-, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl;

R ^7a is OH, amino, C _1-4 Alkoxy, C _1-4 Alkyl or C _1-4 An alkylamino group.

In some embodiments, each R ^w1 、R ^w2 And R is ^w3 Independently deuterium, F, cl, br, I, = O, R ^7a -C (=o) -, hydroxy, cyano, amino, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxyGroup, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂ F、-CH ₂ Cl、-CF ₃ 、-CHF ₂ 、-CHCl ₂ 、-CH ₂ CH ₂ F、-CH ₂ CH ₂ Cl、-CH ₂ CHF ₂ 、-CH ₂ CHCl ₂ 、-CHFCH ₂ F、-CHClCH ₂ Cl、-CH ₂ CF ₃ 、-CH(CF ₃ ) ₂ 、-CF ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CHF ₂ 、-CH ₂ CH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, HOOC-phenyl-, HOOC-CH ₂ -、HOOC-(CH ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ -、、HOOC-C(CH ₃ ) ₂ Or HOOC-C (CH) ₃ ) ₂ CH ₂ -, wherein said N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂ F、-CH ₂ Cl、-CHF ₂ 、-CHCl ₂ 、-CH ₂ CH ₂ F、-CH ₂ CH ₂ Cl、-CH ₂ CHF ₂ 、-CH ₂ CHCl ₂ 、-CHFCH ₂ F、-CHClCH ₂ Cl、-CH ₂ CF ₃ 、-CH(CF ₃ ) ₂ 、-CF ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CHF ₂ 、-CH ₂ CH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl in HOOC-phenyl-, HOOC-CH ₂ -CH in ₂ -、HOOC-(CH ₂ ) ₂ - (CH) in- ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ - (CH) in- ₂ ) ₃ -、HOOC-C(CH ₃ ) ₂ -C (CH) ₃ ) ₂ -and HOOC-C (CH) ₃ ) ₂ CH ₂ -C (CH) ₃ ) ₂ CH ₂ -each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, cl, br, I, HOOC-, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

R ^7a is OH, amino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-methylamino, N-ethylamino, N-dimethylamino or N, N-diethylamino.

On the other hand, the invention also provides a pharmaceutical composition which comprises the compound and pharmaceutically acceptable auxiliary materials.

In some embodiments, the pharmaceutical composition of the invention 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 that targets HbcAg, a cyclophilin inhibitor, an HBV therapeutic vaccine, an HBV prophylactic vaccine, an HBV viral entry inhibitor, an NTCP inhibitor, an antisense oligonucleotide that targets 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-induced gene 1 stimulator, a NOD2 stimulator, recombinant thymosin alpha-1 and a hepatitis b virus replication inhibitor, a hepatitis b surface antigen (HBsAg) secretion or assembly inhibitor, an IDO inhibitor, or a combination thereof.

In some embodiments, the pharmaceutical composition of the invention, wherein the other therapeutic agent or agents is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, alfaferone, alloferon, cet Mo Baijie, claddine, emtricitabine, famciclovir, interferon, baganine CP, due's, interleukin-2, miltefosinate, nitazoxanide, ribavirin, luo Raosu-a, sirzopyran, euforavac, an Puli near, phosphazid, heplisav, recombinant human interleukin-2, levamisole or propigermanium.

In some embodiments, the pharmaceutical composition of the invention wherein the other therapeutic agent or agents is lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, alfaferone, alloferon, cet Mo Baijie, claddine, emtricitabine, famciclovir, baganin CP, idofenadine, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, miltefoster, nitazoxanide, polyethylene glycol interferon alpha-2 a, ribavirin, luo Raosu-a, cizopran, euforavic, an Puli, phosphazid, heplisav, interferon alpha-2 b, recombinant human leukocyte alpha-2, levamisole or propigermanium.

In another aspect, the invention also provides the use of a compound or pharmaceutical composition of the invention for activating TLR8.

In another aspect, the invention also provides the use of a compound or pharmaceutical composition of the invention in the preparation of a kit for activating TLR8.

In another aspect, the invention also provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for preventing, treating or alleviating a TLR 8-mediated disorder in a patient.

In some embodiments, the TLR 8-mediated disease is a hepatitis b virus infection, a hepatitis c virus infection, an influenza virus infection, a herpes virus infection, an aids virus 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, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer, or thyroid cancer.

In another aspect, the invention also provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the treatment or prophylaxis of a disease of the immune modulating system.

In another aspect, the invention also provides the use of the compound or pharmaceutical composition in the manufacture of a medicament for the treatment or prophylaxis of viral infections or tumours.

In another aspect, the invention also provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the treatment or prophylaxis of 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 cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below.

Detailed description of the invention

Definitions and general terms

The invention will be described in detail with reference to certain specific details, examples of which are provided with illustrations of structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the art of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The invention is in no way limited to the description of methods and materials. There are numerous documents and similar substances which differ or contradict the present application, including but in no way limited to the definition of terms, the use of terms, the described techniques, or the scope of control as per the present application.

The invention will apply to the following definitions unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in terms of the periodic table of the elements, CAS version and handbook of chemicals, 75, ^th Ed, 1994. In addition, the general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, university Science Books, sausalato 1999,and"March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March, john Wiley&Sons, new York:2007, hereby incorporated by reference in its entirety.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, for example, for compounds of the general formula above, or for particular examples, subclasses, and classes of compounds encompassed by the invention, as described herein.

In addition, unless explicitly indicated otherwise, the descriptions used throughout this document "… and … are each independently", "… and … are each independently" and "… and … are each independently" are interchangeable, "and are to be understood in a broad sense to mean that the particular items expressed between the same symbols in different groups do not affect each other, or that the particular items expressed between the same symbols in the same groups do not affect each other.

In the various parts of the present specification, substituents of the compounds of the invention are disclosed in terms of the type or scope of groups. It is specifically intended that the present invention includes each of these group species and ranges Each independent sub-combination of members. For example, the term "C _1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl and C ₆ An alkyl group.

In the various parts of the present specification, substituents of the compounds of the invention are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl and C ₆ An alkyl group.

The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon radicals of 1 to 20 carbon atoms, wherein the alkyl radicals may independently be optionally substituted by one or more substituents as described herein. Some of these are alkyl groups containing 1 to 12 carbon atoms; still other embodiments are alkyl groups containing 1 to 10 carbon atoms; still other embodiments are alkyl groups containing 1 to 8 carbon atoms; still other embodiments are alkyl groups containing 1 to 6 carbon atoms; still other embodiments are alkyl groups containing 1 to 4 carbon atoms; still other embodiments are alkyl groups containing 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methylpropyl or isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-butyl (t-Bu, -C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) N-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2, 3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3, 3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ ) N-heptyl, n-octyl, and the like.

The term "alkylene" refers to a saturated divalent or polyvalent hydrocarbyl radical resulting from the removal of two or more hydrogen atoms from a saturated straight or branched chain hydrocarbyl radical. Unless otherwise specified, alkylene groups contain 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1 to 6 carbon atoms; in other embodiments, the alkylene group contains 1 to 4 carbon atoms; in some embodiments, the alkylene group contains 1 to 3 carbon atoms; in still other embodiments, the alkylene group contains 1 to 2 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), ethylene (-CH) ₂ CH ₂ (-) n-propylene (-CH) ₂ CH ₂ CH ₂ (-), isopropylidene (-CH (CH) ₃ )CH ₂ (-), etc.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more groupsSubstituted by halogen atoms, wherein alkyl and alkoxy have the meaning described herein. Examples include, but are not limited to, difluoroethyl (-CH) ₂ CHF ₂ ,-CF ₂ CH ₃ ,-CHFCH ₂ F) Trifluoroethyl group (-CH) ₂ CF ₃ ,-CF ₂ CH ₂ F,-CFHCHF ₂ ) Trifluoromethyl (-CF) ₃ ) Trifluoromethoxy (-OCF) ₃ ) Etc.

The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 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 still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) ₃ ) Ethoxy (EtO, -OCH) ₂ CH ₃ ) 1-propoxy (n-PrO, n-propoxy, -OCH) ₂ CH ₂ CH ₃ ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) ₃ ) ₂ ) 1-butoxy (n-BuO, n-butoxy, -OCH) ₂ CH ₂ CH ₂ CH ₃ ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) ₂ CH(CH ₃ ) ₂ ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) ₃ )CH ₂ CH ₃ ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ) 1-pentoxy (n-pentoxy, -OCH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentoxy (-OCH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentoxy (-OCH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butoxy (-OC (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butoxy (-OCH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-l-butoxy (-OCH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-l-butoxy (-OCH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) Etc.

The term "aryl" may be used alone or as part of an "aralkyl", "aralkoxy" or "aryloxyalkyl" group, to denote monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, or from 6 to 10 carbon atoms, wherein at least one ring system is aromatic, wherein each ring system contains a ring of from 3 to 7 carbon atoms, and wherein one or more attachment points are attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be unsubstituted or substituted with one or more substituents described herein.

The term "heteroaryl" means a monocyclic, bicyclic or tricyclic ring system containing 5 to 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 a ring of 5 to 7 ring atoms and has one or more attachment points attached to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or "heteroaromatic compound" and includes monocyclic heteroaryl, fused bicyclic heteroaryl, or polycyclic fused heteroaryl. In some embodiments, heteroaryl is a heteroaryl consisting of 5-14 ring atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl group consisting of 5-12 ring atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl group consisting of 5 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a fused bicyclic heteroaryl consisting of 8-10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl group consisting of 5 to 8 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl group consisting of 5-7 ring atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl group consisting of 5-6 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a fused bicyclic heteroaryl consisting of 7-10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a heteroaryl group consisting of 5 ring atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl is a heteroaryl group consisting of 6 ring atoms comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Still other embodiments are heteroaryl groups including, but not limited to, the following monocyclic groups: 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, such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 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-thiodiazoyl, 1,3, 4-thiodiazoyl, 1,2, 5-thiodiazoyl, pyrazinyl, 1,3, 5-triazinyl; also included are the following bi-or tricyclic groups, but in no way limited to these groups: benzimidazolyl, benzofuranyl, benzothienyl, 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), phenoxathianyl, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl 、Etc. The heteroaryl group is optionally substituted with one or more substituents described herein.

The term "M-M ₁ "consisting of atoms" means that the cyclic group consists of M-M ₁ And the ring atoms comprise carbon atoms and/or O, N, S, P and other hetero atoms. For example, "heteroaryl of 5-10 atoms" represents heteroaryl of 5, 6, 7, 8, 9 or 10 atoms.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, at least one of which is selected from the group consisting of nitrogen, sulfur and oxygen atoms, and which has one or more points of attachment to the remainder of the molecule. The term "heterocyclyl" includes monocyclic heterocyclyl, bicyclic or polycyclic fused heterocyclyl, spiroheterocyclyl or bridged heterocyclyl, and also includes polycyclic ring systems in which the heterocycle may be fused to one or more non-aromatic carbocycles or combinations thereof, wherein the attached radicals or points are on the heterocycle. Bicyclic heterocyclyl groups include bridged bicyclic heterocyclyl groups, fused bicyclic heterocyclyl groups, and spiro bicyclic heterocyclyl groups. Unless otherwise indicated, -CH for heterocyclyl ₂ The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclyl is a ring system consisting of 3 to 12 ring atoms; in some embodiments, the heterocyclyl is a monocyclic heterocyclyl consisting of 4 to 7 ring atoms; in some embodiments, the heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 7 ring atoms; in some embodiments, the heterocyclyl is a monocyclic heterocyclyl consisting of 4 to 6 ring atoms; in some embodiments, the heterocyclyl is a monocyclic heterocyclyl consisting of 3 to 6 ring atoms; in some embodiments, the heterocyclyl is a monocyclic heterocyclyl consisting of 5 to 6 ring atoms; in some embodiments, the heterocyclyl is a bicyclic heterocyclyl consisting of 7-12 ring atoms; in some embodimentsThe heterocyclic group is a condensed bicyclic heterocyclic group consisting of 7-12 ring atoms; in some embodiments, the heterocyclyl is a fused bicyclic heterocyclyl consisting of 7-10 ring atoms; in some embodiments, the heterocyclyl is a fused bicyclic heterocyclyl consisting of 8-10 ring atoms; in some embodiments, the heterocyclyl is a bridged bicyclic heterocyclyl consisting of 6 to 10 ring atoms; in other embodiments, the heterocyclyl is a ring system of 3 to 8 ring atoms; in other embodiments, the heterocyclyl is a ring system of 3 to 6 ring atoms; in other embodiments, the heterocyclyl is a ring system of 5 to 7 ring atoms; in other embodiments, the heterocyclyl is a ring system of 5 to 8 ring atoms; in other embodiments, the heterocyclyl is a ring system of 6 to 8 ring atoms; in other embodiments, the heterocyclyl is a ring system of 3 ring atoms; in other embodiments, the heterocyclyl is a ring system of 4 ring atoms; in other embodiments, the heterocyclyl is a ring system of 5 ring atoms; in other embodiments, the heterocyclyl is a ring system of 6 ring atoms; in other embodiments, the heterocyclyl is a ring system of 7 ring atoms; in other embodiments, the heterocyclyl is a ring system of 8 ring atoms.

Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazalkyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl, azepanyl, oxepinyl, thiepanyl, oxaazepinyl, diazaperzinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxacyclopentyl, pyrazolinyl, dithianyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 3-azabicyclo [ 3.1.0:]hexyl, 3-azabicyclo [4.1.0]Heptyl and azabicyclo [2.2.2]Hexyl, 3H-indolylquinazolinesAn oxazinyl group,And N-pyridylurea. Examples of heterocyclic groups also include 1, 1-dioxothiomorpholinyl; examples where the ring carbon atom is substituted with an oxo (=o) group include, but are not limited to, pyrimidinedione, 1,2, 4-thiadiazole-5 (4H) -one, 1,2, 4-oxadiazole-5 (4H) -one, 1H-1,2, 4-triazole-5 (4H) -one, and the like >Etc.; examples where the ring carbon atom is substituted with an = S group include, but are not limited to, 1,2, 4-oxadiazole-5 (4H) -thione, 1,3, 4-oxadiazole-2 (3H) -thione, and the like. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

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

The terms "spirocyclic", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic ring system in which one ring originates from a specific ring carbon atom on the other ring, and both rings share that ring carbon atom.

For example, as described in formula a below, rings B and B 'are referred to as "fused bicyclic" rings, while rings a' and B share one carbon atom, referred to as "spiro" or "spirobicyclic". Each ring of the fused bicyclic and spirobicyclic groups may be carbocyclyl or heterocyclyl, and each ring is optionally substituted with one or more substituents described herein.

The terms "fused bicyclic heterocyclyl" and "bicyclic fused heterocyclyl" are used interchangeably and denote monovalent satietyAnd or a partially unsaturated non-aromatic ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (but the aromatic may be a substituent thereon). Each ring of the ring system comprises 3 to 7 atoms and at least one ring comprises one or more heteroatoms, i.e. comprises 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a ring like SO, SO ₂ ，PO，PO ₂ In some embodiments, the fused bicyclic heterocyclyl is a fused bicyclic heterocyclyl consisting of 7 to 10 ring atoms; in some embodiments, the fused bicyclic heterocyclyl is a fused bicyclic heterocyclyl consisting of 8-10 ring atoms; examples include, but are not limited to, 3-aza-fusions [3.1.0]Hexane, 3-azabicyclo [3.3.0 ]]Octane, hexahydro-furan [3,4-c]Pyrrolyl, hexahydro-thiophene [3,4-c ]]Pyrrolyl, 3,4,5, 6-tetrahydro-cyclopentane [ c]Thienyl, and the like. The fused heterobicyclic group is optionally substituted with one or more substituents described herein.

The term "bridged bicyclic group" or "bridged bicyclic ring" denotes a saturated or partially unsaturated, non-aromatic bridged ring system, as shown in formula b, i.e., ring A1 shares an alkyl chain, heteroatom or a heteroalkyl chain with ring A2, where j is 1, 2, 3 or 4, X ³ Is an alkyl chain, a heteroatom or a heteroalkyl chain. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (but the aromatic may be a substituent thereon). Wherein each ring, such as A1 or A2, contains 3-7 atoms, examples of which include, but are not limited to, bicyclo [2.2.1]Heptyl, 2-methyl-diazabicyclo [2.2.1]Heptyl, and the like. The bridged bicyclic group is optionally substituted with one or more substituents described herein.

The term "bridged bicyclic heterocyclyl" denotes a saturated or partially unsaturated, non-aromatic bridged bicyclic ring system, whereinEach ring comprising 3 to 7 atoms and at least one ring comprising one or more heteroatoms, i.e. comprising 1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a ring like SO, SO ₂ ，PO，PO ₂ In some embodiments, bridged bicyclic heterocyclyl is a bridged bicyclic heterocyclyl consisting of 6-10 ring atoms, examples of which include, but are not limited to, 2-oxo-5-azabicyclo [2.2.1 ] ]Heptyl, 2-thio-5-azabicyclo [2.2.1]Heptyl, 2-oxo-5-azabicyclo [2.2.1]Heptyl, 2, 5-diazabicyclo [2.2.1]Heptyl, 2-methyl-2, 5-diazabicyclo [2.2.1]A heptyl group. The bridged bicyclic heterocyclyl is optionally substituted with one or more substituents described herein.

The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring carbon atoms that is saturated, and includes monocyclic, bicyclic or polycyclic fused, spiro or bridged ring systems, having one or more points of attachment to the remainder of the molecule. Some of these embodiments, cycloalkyl is spirobicycloalkyl of 6-10 atoms; in other embodiments, cycloalkyl is a fused bicycloalkyl of 6 to 10 atoms; in other embodiments, cycloalkyl is a ring system containing 3 to 10 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3 to 8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3 to 7 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5 to 8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5 to 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 may independently be unsubstituted or substituted with one or more substituents described herein.

The terms "alkylamino" and "alkylamino" are used interchangeably and include "N-alkylamino" and "N, N-dialkylamino" in which the hydrogen atoms in the amino groups are each independently substituted with one or two alkyl groups. Of which some are realEmbodiments are those wherein the alkylamino group is one or two C _1-12 Alkyl groups are attached to lower alkylamino groups formed on the nitrogen atom. In other embodiments, the alkylamino group is one or two C _1-6 Alkyl groups are attached to lower alkylamino groups formed on the nitrogen atom. In other embodiments, the alkylamino group is one or two C _1-4 Alkyl groups are attached to lower alkylamino groups formed on the nitrogen atom. In still other embodiments, the alkylamino group is one or two C _1-3 Alkyl groups are attached to lower alkylamino groups formed on the nitrogen atom. Suitable alkylamino groups may be mono-or di-alkylamino, examples of alkylamino groups include, but are not limited to, N-methylamino (-NHCH) ₃ ) N-ethylamino (-NHCH) ₂ CH ₃ ) N, N-dimethylamino (-N (CH) ₃ ) ₂ ) N, N-diethylamino (-N (CH) ₂ CH ₃ ) ₂ ) Etc.

Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.

The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, e.g. those phosphate compounds are the parent hydroxy groupsAnd (3) phosphorylating the groups. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14of 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.

All tautomeric forms of the compounds of the invention are included within the scope of the invention unless otherwise indicated. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

The definition and use of stereochemistry in the present invention is generally referred to in the following documents: 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 invention may contain asymmetric or chiral centers and thus exist as different stereoisomers. All stereoisomeric forms of the compounds of the invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to name the sign of the compound plane polarization rotation, where (-) or l means that the compound is left-handed and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereoisomers are different. The particular stereoisomer may be an enantiomer, and the mixture of isomers is commonly referred to as an enantiomeric mixture. 50: mixtures of enantiomers of 50 are referred to as racemic mixtures or racemates, which may result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

The term "tautomer" or "tautomeric form" refers to isomers of structures of different energies that can be interconverted by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include tautomerism by proton shift, such as keto-enol and imine-enamine isomerisation. Valency (valence) tautomers include tautomers that reorganize into bond electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange To obtain these salts. Other pharmaceutically acceptable salts include adipic acid salts, malic acid salts, 2-hydroxypropionic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, boric acid salts, butyric acid salts, camphoric acid salts, camphorsulfonic acid salts, cyclopentylpropionates, digluconate salts, dodecylsulfate salts, ethanesulfonic acid salts, formate salts, fumaric acid salts, glucoheptonate salts, glycerophosphate salts, gluconate salts, hemisulfate salts, heptanoate salts, caproate salts, hydroiodic acid salts, 2-hydroxy-ethanesulfonic acid salts, lactobionic acid salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, malonic acid salts, methanesulfonic acid salts, 2-naphthalenesulfonic acid salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, propionate salts, stearates, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl group ₄ Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations that are resistant to counter ion formation, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C _1-8 Sulfonate and aromatic sulfonate.

"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.

The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with another functional group. For example, "protection of amino groupsThe group "refers to the functionality of one substituent attached to an amino group to block or protect the amino group in a compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: t W.Greene, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。

Description of the Compounds of the invention

The invention relates to novel pyrimido aromatic ring compounds and pharmaceutically acceptable compositions thereof, which have good activation effect on TLR8 and good selective activation effect on TLR 8. The compounds of the invention and pharmaceutically acceptable compositions thereof are useful in the preparation of a medicament for preventing, treating or alleviating TLR 8-mediated diseases in a patient, wherein the TLR 8-mediated diseases include, but are not limited to, HBV infection, cancer, influenza virus infection, inflammation, diabetes, allergic disease, and the like.

wherein X is N or CR ⁷ ；

Y is N or CR ⁴ ；

R ⁴ is hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, heteroaryl of 5 ring atoms, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said C _1-6 Alkylamino, C _1-6 Alkoxy, C _1-6 Alkyl and C _3-6 Cycloalkyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4R ^w2 Substituted by substituents of said 5 ring atoms, each of said 5 ring atoms consisting of heteroaryl, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl and pyrimidinyl being independently substituted by 1 or 2R ⁸ Is substituted by a substituent of (2);

R ^7a is OH, amino, C _1-6 Alkoxy, C _1-6 Alkyl or C _1-6 An alkylamino group.

In some embodiments, each R ¹ 、R ² 、R ⁵ 、R ⁶ And R is ⁷ Independently hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-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, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, N-propyl, isopropylN-butyl, isobutyl, sec-butyl, tert-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, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl.

In some embodiments, R is furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or-C (=o) -O-R ³ Wherein the furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -C (=o) -OH, -C (=o) -O-methyl, -C (=o) -O-ethyl, -C (=o) -O-n-propyl, -C (=o) -O-isopropyl, -C (=o) -O-n-butyl, -C (=o) -O-isobutyl and-C (=o) -O-sec-butyl; wherein R is ³ Having the meaning described in the present invention.

In some embodiments, the R ³ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, a monocyclic heteroaryl group consisting of 5 to 6 ring atoms, a fused bicyclic heteroaryl group consisting of 8 to 10 ring atoms or a fused bicyclic heterocyclyl group consisting of 8 to 10 ring atoms, wherein the phenyl, the monocyclic heteroaryl group consisting of 5 to 6 ring atoms, the fused bicyclic heteroaryl group consisting of 8 to 10 ring atoms and the fused bicyclic heterocyclyl group consisting of 8 to 10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w1 Wherein each R is substituted with a substituent of ^w1 Having the meaning according to the invention, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl radicals are each independently selected from the group consisting of F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl by 1, 2, 3 or 4The substituents of the radicals are substituted.

In some embodiments, the R ⁴ Is hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, C _1-4 Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said C _1-4 Alkylamino, methoxy, ethoxyGroup, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl each independently being unsubstituted or substituted with 1, 2, 3 or 4R ^w2 Substituted with substituents of said furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being substituted with 1 or 2R ⁸ Is substituted by a substituent of (2); wherein each R ⁸ Having the meaning described in the present invention.

In some embodiments, the R ⁸ Is furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or Wherein the furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl and isoxazoleOxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and piperazinylEach independently is unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w3 Is substituted by a substituent of (2); wherein each R ^w3 Having the meaning described in the present invention.

In some embodiments, each R ^w1 、R ^w2 And R is ^w3 Independently deuterium, F, cl, br, I, = O, R ^7a -C (=o) -, hydroxy, cyano, amino, C _1-4 Alkylamino, C _1-4 Alkoxy, C _1-4 Alkyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, HOOC-phenyl-or HOOC-C _1-4 Alkylene-, wherein said C _1-4 Alkylamino, C _1-4 Alkoxy, C _1-4 Alkyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl in HOOC-phenyl-and HOOC-C _1-4 C in alkylene radical _1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, cl, br, I, HOOC-, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl; wherein each R ^7a Having the meaning described in the present invention.

In some embodiments, R ^7a Is OH, amino, C _1-4 Alkoxy, C _1-4 Alkyl or C _1-4 An alkylamino group.

In some embodiments, each R ^w1 、R ^w2 And R is ^w3 Independently deuterium, F, cl, br, I, = O, R ^7a -C (=o) -, hydroxy, cyano, amino, N-methylamino, N-ethylamino, N-dimethylamino, N-di-Ethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂ F、-CH ₂ Cl、-CF ₃ 、-CHF ₂ 、-CHCl ₂ 、-CH ₂ CH ₂ F、-CH ₂ CH ₂ Cl、-CH ₂ CHF ₂ 、-CH ₂ CHCl ₂ 、-CHFCH ₂ F、-CHClCH ₂ Cl、-CH ₂ CF ₃ 、-CH(CF ₃ ) ₂ 、-CF ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CHF ₂ 、-CH ₂ CH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, HOOC-phenyl-, HOOC-CH ₂ -、HOOC-(CH ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ -、HOOC-C(CH ₃ ) ₂ Or HOOC-C (CH) ₃ ) ₂ CH ₂ -, wherein said N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂ F、-CH ₂ Cl、-CHF ₂ 、-CHCl ₂ 、-CH ₂ CH ₂ F、-CH ₂ CH ₂ Cl、-CH ₂ CHF ₂ 、-CH ₂ CHCl ₂ 、-CHFCH ₂ F、-CHClCH ₂ Cl、-CH ₂ CF ₃ 、-CH(CF ₃ ) ₂ 、-CF ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CHF ₂ 、-CH ₂ CH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl in HOOC-phenyl-, HOOC-CH ₂ -CH in ₂ -、HOOC-(CH ₂ ) ₂ - (CH) in- ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ - (CH) in- ₂ ) ₃ -、HOOC-C(CH ₃ ) ₂ -C (CH) ₃ ) ₂ -and HOOC-C (CH) ₃ ) ₂ CH ₂ -C (CH) ₃ ) ₂ CH ₂ Each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, cl, br, I, HOOC-, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

In some embodiments, R ^7a Is OH, amino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-methylamino, N-ethylamino, N-dimethylamino or N, N-diethylamino.

In some embodiments, the invention relates to compounds of one of the following, or stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, but in no way limited to these compounds:

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In some embodiments, the interferon described herein is interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, polyethylene glycol interferon alpha-2 a, or interferon alpha-2 b.

In another aspect, the invention provides the use of a compound or pharmaceutical composition of the invention for activating TLR8.

In another aspect, the invention provides the use of a compound or pharmaceutical composition of the invention in the preparation of a kit for activating TLR8.

In another aspect, the invention also provides the use of the compound or pharmaceutical composition in the manufacture of a medicament for preventing, treating or alleviating a TLR 8-mediated disease in a patient.

In another aspect, the invention also provides the use of the compound or pharmaceutical composition in the manufacture of a medicament for the treatment or prophylaxis of diseases of the immune modulating system.

In another aspect, the invention also provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the treatment or prophylaxis of hepatitis b virus infection, hepatitis c virus infection, influenza virus infection, herpes virus infection, hiv infection, allergic disease, rheumatoid arthritis, allergic asthma, chronic fatigue, type II diabetes, hay fever, lupus erythematosus, multiple sclerosis, melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

In another aspect, the invention also provides the use of the compound or pharmaceutical composition in the manufacture of a medicament for the prevention, treatment or alleviation of a disease of the immune modulating system, comprising administering to a patient a therapeutically effective amount of the compound of the invention or the pharmaceutical composition of the invention.

In another aspect, the invention also provides a method of preventing, treating or alleviating a TLR 8-mediated disease in a patient using a compound of the invention in an amount effective to treat the disease in the patient.

In another aspect, the invention also provides a method of treating or preventing a viral infection or tumor by the compound or pharmaceutical composition, the method comprising administering to a patient a pharmaceutically acceptable effective dose of a pharmaceutical composition comprising a compound of the invention.

In another aspect, the invention also provides a method of 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, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer, and thyroid cancer in a patient, the method comprising administering to the patient a pharmaceutically effective dose of a pharmaceutical composition comprising a compound of the invention.

In another aspect, the invention provides a method of preventing, treating or alleviating a disease in the immune system of a patient comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention.

In another aspect, the invention also provides the use of a compound or pharmaceutical composition of the invention as a medicament for preventing, treating or alleviating a TLR 8-mediated disease in a patient.

In another aspect, the invention also provides the use of a compound or pharmaceutical composition of the invention as a medicament for preventing, treating or alleviating a disease of the immune system in a patient.

In another aspect, the invention also provides the use of a compound or pharmaceutical composition of the invention as a medicament for the treatment or prophylaxis of viral infections or neoplasms.

In another aspect, the invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention as a medicament for the treatment or prophylaxis of hepatitis b virus infection, hepatitis c virus infection, influenza virus infection, herpes virus infection, hiv infection, allergic disease, rheumatoid arthritis, allergic asthma, chronic fatigue, type II diabetes, hay fever, lupus erythematosus, multiple sclerosis, melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

Some of these embodiments are mammals, and other examples are humans. In other embodiments, the use further comprises contacting the cell with a therapeutic agent.

The invention also relates to the use of the compounds of the invention and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical product for the effective treatment of the diseases described herein. The compounds of the invention are also useful for the manufacture of a medicament for alleviating, preventing, managing or treating a condition of the disease of the invention in a patient.

Unless otherwise indicated, all stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the invention are within the scope of the invention.

The term "pharmaceutically acceptable" includes substances or compositions that must be suitable for chemical or toxicological treatment, in relation to the other components that make up the formulation and the mammal being treated.

Salts of the compounds of the present invention also include salts of intermediates used in the preparation or purification of the compounds of formula (I) or isolated enantiomers of the compounds of formula (I), but are not necessarily pharmaceutically acceptable salts.

If the compounds of the present invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or 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; pyranose 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-toluene sulfonic acid, benzene sulfonic acid, methane sulfonic acid, ethane sulfonic acid, trifluoromethane sulfonic acid, and the like, or combinations thereof.

If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, for example, using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium, N ⁺ (R ¹⁴ ) ₄ Salts 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 Tertiary ammonia, N ⁺ (R ¹⁴ ) ₄ Salts of (A), e.g. R ¹⁴ Is H, C _1-4 Alkyl, C _6-10 Aryl, C _6-10 Aryl C _1-4 Alkyl, etc., and cyclic amines such as piperidine, morpholine, piperazine, etc., and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Also included are suitable, nontoxic ammonium, quaternary ammonium salts and amine cations resistant to counter ion formation, e.g. halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C _1-8 Sulfonate and aromatic sulfonate.

Pharmaceutical compositions, formulations, administration and use of the compounds and pharmaceutical compositions of the invention

According to another aspect, the pharmaceutical composition of the present invention comprises a compound of formula (I), a compound listed herein, or a compound of the examples, and a pharmaceutically acceptable adjuvant.

The compounds in the pharmaceutical compositions of the invention are useful in the treatment of TLR8 mediated diseases. For the compounds or pharmaceutical compositions of the invention, the areas of disease treatment that may be mentioned are, for example: immune diseases, diseases and tumors caused by viral infection, 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, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer, and thyroid cancer.

The invention comprises a pharmaceutical preparation which comprises one or more compounds shown as the formula (I) or a pharmaceutical composition thereof or one or more compounds shown as the formula (I) or a pharmaceutical composition thereof except nontoxic and inert pharmaceutically suitable auxiliary materials.

The pharmaceutical preparation may also contain other active pharmaceutical ingredients other than the compounds of formula (I).

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

The pharmaceutical compositions of the present invention, as described herein, comprise any of the compounds of formula (I) of the present invention, further comprising pharmaceutically acceptable excipients, such as, for example, any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersing agent, flavoring or suspending agent, surfactant, isotonizing agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as used herein, as appropriate for the particular target dosage form. As described in the following documents: 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, in combination with the teachings of the literature herein, shows that different excipients can be used In the preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. In addition to the extent to which any conventional adjuvant is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.

Substances that may be pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum proteins; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; a partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate; a wax; polyethylene-polyoxypropylene-block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the clothing material; a sweetener; a flavoring agent; a perfume; preservatives and antioxidants.

The pharmaceutical composition of the compounds of the invention may be administered in any of the following ways: oral administration, spray inhalation, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or administration by means of an explanted reservoir. The preferred mode is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.

The compounds of the present invention or pharmaceutical compositions thereof may be administered in unit dosage form. The dosage form may be a liquid dosage form or other dosage form. The liquid dosage form can be true solution, colloid, microparticle, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, implant, patch, liniment, etc.

Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated by methods known in the pharmaceutical arts.

Oral liquids may be formulated as suspensions, solutions, emulsions, syrups or elixirs with water as an oil, or as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gelatin, hydrogenated edible fats and oils, emulsifying agents such as lecithin, sorbitan monooleate, acacia; or non-aqueous adjuvants (possibly containing edible oils) such as almond oil, fats and oils such as glycerol, ethylene glycol, or ethanol; preservatives, such as methyl or propyl parahydroxybenzoate, sorbic acid. Flavoring or coloring agents may be added as desired.

Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.

For parenteral administration, liquid dosage forms are generally prepared from the compound and a sterile adjuvant. The auxiliary material is water. According to the different concentrations of selected auxiliary materials and medicines, the compound can be dissolved in the auxiliary materials or prepared into suspension solution, and when the injection solution is prepared, the compound is dissolved in water, filtered and sterilized and then filled into a sealed bottle or ampoule.

When topically applied to the skin, the compounds of the present invention may be formulated in the form of an appropriate ointment, lotion, or cream wherein the active ingredient is suspended or dissolved in one or more excipients, which may be used in the ointment formulation include, but are not limited to: mineral oil, liquid vaseline, white vaseline, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; adjuvants that may be used in lotions and creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The amount of active ingredient that can be combined with the inactive ingredient to create a dosage form can vary depending upon the intended subject of treatment and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to a human may contain about 1 to 1000mg of active agent formulated with a suitable and convenient amount of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutically acceptable excipients vary from about 5% to about 95% (weight: weight) of the total composition.

The presently disclosed compounds, e.g., compounds of formula (I), may be administered to an individual for a desired period or duration of time, e.g., 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 longer, according to an effective dosing regimen. In one variation, the compound is administered on a daily or intermittent schedule during the lifetime of the individual.

The dosage or frequency of administration of the disclosed compounds can be adjusted during the course of treatment based on the judgment of the administering physician.

The compound can be administered to an individual (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once daily.

In certain embodiments, methods for treating or preventing a disease or disorder in a human are provided, comprising administering to the human a therapeutically effective amount of a disclosed compound of the invention, 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. Since agonists of TLR-8 are useful for treating various diseases or conditions, the particular identity of the additional therapeutic agent will depend on the particular disease or condition being treated.

The compounds of formula (I) may be administered by any useful route and manner, for example, orally or parenterally (e.g., intravenously). The therapeutically effective amount of the compound of formula (I) is from about 0.00001mg/kg body weight/day to about 10mg/kg body weight/day, such as from about 0.0001mg/kg body weight/day to about 10mg/kg body weight/day or from about 0.001mg/kg body weight/day to about 1mg/kg body weight/day, or such as from about 0.01mg/kg body weight/day to about 1mg/g body weight/day or such as from about 0.05mg/kg body weight/day to about 0.5mg/kg body weight/day.

The therapeutically effective amount of the 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 10 mg/dose. Other therapeutically effective amounts of the compounds 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 the compounds 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. A single dose may be administered hourly, daily or weekly. For example, a single dose may be administered every 1 hour, every 2, 3, 4, 6, 8, 12, 16 hours, or every 24 hours. A single dose may also be administered once every 1 day, once every 2, 3, 4, 5, 6 or 7 days. A single dose may also be administered once every 1 week, once every 2, 3 or 4 weeks. In certain embodiments, a single dose may be administered once a week. A single dose may also be administered once a month.

The frequency of administration of the compound of formula (I) will be determined by the needs of the individual patient and may be, for example, once a day or two or more times a day. For example, the compound may be administered to a person infected with HBV or HCV for a period of 20 to 180 days, or for example for a period of 20 to 90 days, or for example for a period of 30 to 60 days, depending on the length of time required for continuous treatment of HBV or HCV infection.

Administration may be intermittent, wherein the patient receives a daily dose of the compound of formula (I) for a period of days or more, followed by a period of days or more wherein the patient does not receive a daily dose of the compound. For example, the patient may receive doses of the compound every other day or three times a week. For another example, the patient may receive a dose of the compound daily 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 receives a daily dose of the compound again. The administration of the compound followed by the period of no administration of the compound may be repeated according to the clinical requirements of the patient being treated.

In one embodiment, a pharmaceutical composition is provided comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

In one embodiment, a kit is provided comprising a compound of the present disclosure, 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.

In certain embodiments, a compound of the present disclosure, 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 of the present disclosure, 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 may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.

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

In certain embodiments, the presently disclosed compounds are 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.

In certain embodiments, the presently disclosed compounds are administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of the disclosed compound of the present invention and one or more additional therapeutic agents such that a therapeutically effective amount of both the disclosed compound of the present invention and the one or more additional therapeutic agents are present in the patient.

Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, e.g., within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a disclosed compound is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of the unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of the unit dose of one or more additional therapeutic agents after a period of several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of the unit dose of a compound of the present disclosure after a period of several hours (e.g., 1-12 hours).

The pharmaceutical composition provided by the invention comprises a compound shown as the formula (I) or pharmaceutically acceptable salt thereof, pharmaceutically acceptable excipient and one or more other therapeutic agents. Wherein the therapeutic agent is an HBV DNA polymerase inhibitor, a toll-like receptor 7 modulator, a toll-like receptor 8 modulator, toll-like receptor 7 and 8 modulators, 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), 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 stimulator of retinoic acid-induced gene 1, a NOD2 stimulator, a recombinant thymosin alpha 1 and hepatitis b virus replication inhibitor, a hepatitis b surface antigen (HBsAg) secretion or assembly inhibitor, an IDO inhibitor, or a combination thereof.

The one or more therapeutic agents are lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, alfaferone, alloferon, cil Mo Baijie, cladribine, emtricitabine, famciclovir, interferon, baganine CP, idofenane, interferon alpha-1 b, interferon alpha-2 a, interferon beta-1 a, interferon alpha-2, interleukin-2, miltefoster, nitazoxanide, polyethylene glycol interferon alpha-2 a, ribavirin, luo Raosu-a, cizovan, euforavac, an Puli proximal, phosphazid, heplisav, interferon alpha-2 b, recombinant human interleukin-2, levamisole or propigermanium.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of immune disorders, disorders caused by viral infections and tumors, in particular for the prevention, treatment or alleviation of hepatitis b disease in a patient, comprising administering to the patient a pharmaceutically acceptable effective dose. Hepatitis B refers to liver diseases caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma. Acute hepatitis b virus infection may be asymptomatic or may be manifested as symptoms of acute hepatitis. Patients with chronic viral infections suffer from active disease and can develop cirrhosis and liver cancer.

General synthetic method

In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following synthetic schemes and examples are provided to further illustrate the teachings of the present invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.

The examples described below are given unless otherwise indicated that all temperatures are set to degrees celsius (c). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. The general reagents were purchased from Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin Chemie, inc., qingdao Tenglong chemical Co., ltd., and Qingdao ocean chemical works.

The chromatographic column uses silica gel column, and silica gel (200-300 mesh) is purchased from Qingdao ocean chemical plant. Nuclear magnetic resonance spectroscopy with CDC1 ₃ ,DMSO-d ₆ ,CD ₃ OD or acetone-d ₆ TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard for the solvent (reported in ppm). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, multiplet), m (multiplet ), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet), ddd (doublet), tt (triplet), br.s (broadened singlet, broad singlet). Coupling constant J, in units of hertz (Hz).

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

Low resolution Mass Spectrometry (MS) data were also determined by a spectrometer of the Agilent 6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

Both spectrometers were equipped with a Agilent Zorbax SB-C18 column, 2.1X130 mm,5 μm format. The injection volume is determined by the sample concentration; the flow rate is 0.6mL/min; the peak of the HPLC was read by recording the UV-Vis wavelengths at 210nm and 254 nm. The mobile phase was a 0.1% acetonitrile formate solution (phase a) and a 0.1% ultrapure formate solution (phase B). Gradient elution conditions are shown in table 1:

table 1: gradient elution conditions

Time (min)	A(CH ₃ CN,0.1％HCOOH)	B(H ₂ O,0.1％HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm on a Zorbax SB-C18 column, 2.1X130 mm,4 μm,10 min, flow rate of 0.6mL/min,5-95% (0.1% aqueous formic acid in acetonitrile) and column temperature maintained at 40 ℃.

The following abbreviations are used throughout the present invention:

MeOH methanol

Ethyl acetate solution of HCl/EA, HCl/EtOAc hydrogen chloride

MeOH-d ₄ Deuterated methanol

DIPEA N, N-diisopropylethylamine

DCM,CH ₂ Cl ₂ Dichloromethane (dichloromethane)

DMF N, N-dimethylformamide

DMAP 4-dimethylaminopyridine

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

CDC1 ₃ Deuterated chloroform

EtOH ethanol

Boc

Et ₃ N, TEA triethylamine

(Boc) ₂ Di-tert-butyl O dicarbonate

mL, mL milliliter

PE Petroleum ether

THF tetrahydrofuran

EtOAc, EA ethyl acetate

TEA triethylamine

1atm 101.325kPa

DMSO dimethyl sulfoxide

h hours

Ac ₂ O acetic anhydride

MsCl methanesulfonyl chloride

t _1/2 Half-life period

RT, RT room temperature

Rt retention time

TFA trifluoroacetic acid

Synthesis method

The following synthetic schemes list the experimental procedures for preparing the compounds disclosed in the present invention. Wherein each R ¹ 、R ² 、R ³ 、R ^w2 、R ⁵ 、R ⁶ 、R ⁸ R, X and Y have the meaning as described in the present invention. Wherein each X ₁ And X ₂ Independently Cl or Br.

Synthesis scheme 1

Intermediate (1-1) can be prepared by the method described in scheme 1. First, the compound (1-a) is reacted with a reducing agent (e.g., BH ₃ Tetrahydrofuran solution, etc.), and carrying out reduction reaction to obtain a compound (1-b); then, the compound (1-b) is subjected to oxidation reaction under the action of an oxidant (such as a dessert-Martin reagent and the like) to obtain a compound (1-c); reacting the compound (1-c) with benzylamine, and reducing the reaction product by a reducing agent (such as sodium borohydride) to obtain a compound (1-d); removing benzyl protecting group from the compound (1-d) to obtain a compound (1-e); reacting the compound (1-e) with the compound (1-f) under basic conditions (e.g., triethylamine, etc.), to obtain a compound (1-g); finally, the Boc protecting group of compound (1-g) is removed under acidic conditions (e.g., 1, 4-dioxane solution of hydrogen chloride) to afford intermediate (1-1).

Synthesis scheme 2

The compound (1-2) can be produced by the method described in synthetic scheme 2. Firstly, reacting the compound (1-h) or a salt thereof with the compound (1-i) under alkaline conditions (such as DIPEA and the like) to obtain a compound (1-j); then, the compound (1-j) reacts with (2, 4-dimethoxyphenyl) benzylamine under alkaline conditions (such as potassium carbonate and the like) to obtain a compound (1-k); finally, the amino protecting group DMB (i.e., 2, 4-dimethoxybenzyl) is removed from the compound (1-k) to give the objective compound (1-2).

Synthesis scheme 3

A kind of electronic device with high-pressure air-conditioning systemD2The compounds shown can be synthesized by the methods disclosed in synthesis scheme 3. Wherein R is ^x Is C _1-6 Alkyl, C _3-6 Cycloalkyl, heteroaryl of 5 ring atoms, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said C _1-6 Alkyl and C _3-6 Cycloalkyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4R ^w2 Substituted by substituents of said 5 ring atoms, each of said 5 ring atoms consisting of heteroaryl, 1,3, 5-triazinyl, pyrazinyl, pyridazinyl and pyrimidinyl being independently substituted by 1 or 2R ⁸ Is substituted by a substituent of (2).

Under basic conditions (e.g., N-diisopropylethylamine, etc.), the compoundC1And a compoundBOr its salt to obtain the compoundC2. Then, under the action of alkali (such as potassium carbonate, sodium carbonate, etc.), the compoundC2Reacting with 2, 4-dimethoxy benzylamine to obtain the compoundC3. Finally, the catalyst (e.g., [1,1' -bis (diphenylphosphino) ferrocene) in the presence of a base (e.g., potassium acetate)]Palladium dichloride dichloromethane complex, etc.), pinacol diboronate and compoundsC3Reacting to obtain the compoundCAnd/orC-1The method comprises the steps of carrying out a first treatment on the surface of the Compounds of formula (I)COr (b)C-1In the presence of a base (e.g. potassium carbonate, etc.)Catalysts (e.g. [1,1' -bis (diphenylphosphine) ferrocene)]Palladium dichloride dichloromethane complex, etc.), with a compound AReacting to obtain the compoundD1. Then, the compoundD1Removing the 2, 4-dimethoxy benzyl protecting group on the amino group under acidic condition (such as trifluoroacetic acid, etc.), to obtain compound (D2).

Detailed Description

The following examples are illustrative of the invention and are not intended to limit the scope of the invention.

Preparation example

In the following preparation examples, the inventors have described in detail the preparation of the compounds of the present invention, taking some of the compounds of the present invention as examples. In addition, in the following production examples, in the case where there is no correspondence between the compound name and the compound structure, the compound structure is taken into consideration.

Example 1: (R) -N- (2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) isoxazole-3-carboxamide

Step 1: (R) - (1-hydroxy-2-methylhex-2-yl) carbamic acid tert-butyl ester

To the reaction flask were added (R) -2-amino-2-methylhexanoic acid (5 g,34.435 mmol) and THF (50 mL), followed by dropwise addition of BH thereto ₃ Is stirred at room temperature for 1 hour after the addition of THF (68.87 mL,68.87mmol,1 mol/L), and then transferred to 70℃for 8 hours. After the reaction, 10% NaOH aqueous solution (68.87 g,172.2 mmol) was slowly added dropwise to the flask to quench the reaction, the temperature was then raised to 80℃for 1h, the temperature was then lowered to 60℃and Boc was added ₂ O (7.515 g,34.43 mmol) was reacted further for 3h. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (50 mL) and saturated brine (50 mL) were added thereto, and the mixture was separated, and the organic phase was concentrated with anhydrous sulfuric acidSodium was dried, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) =5/1) to give the title compound as a colorless oil (4.06 g,17.6mmol, yield 51.0%). MS (ESI, pos.ion) m/z 176.3[ M+H ]] ⁺ 。

Step 2: (R) - (2-methyl-1-oxohex-2-yl) carbamic acid tert-butyl ester

Tert-butyl (R) - (1-hydroxy-2-methylhex-2-yl) carbamate (4.06 g,17.6 mmol) was dissolved in DCM (100 mL) and dess-martin reagent (11.2 g,26.4 mmol) was added and the reaction stirred at room temperature for 4h. After completion of the reaction, a saturated aqueous solution of sodium thiosulfate (60 mL) was added to the reaction flask, and after stirring for 10min, insoluble solids were removed by filtration, and the filtrate was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (V/V) =5/1) to give the title compound as a pale yellow oil (3.332 g,14.53mmol, yield 82.8%). MS (ESI, pos.ion) m/z 130.3[ M+H ]] ⁺ 。

Step 3: (R) - (1- (benzylamino) -2-methylhex-2-yl) carbamic acid tert-butyl ester

To the reaction flask was added tert-butyl (R) - (2-methyl-1-oxohex-2-yl) carbamate (3.332 g,14.53 mmol), meOH (30 mL) and benzylamine (1.557 g,14.53 mmol), and the mixture was stirred at 40℃for 12h and then cooled to room temperature, naBH was added ₄ (0.85 g,22.5 mmol) and the reaction was continued for 1h. After completion of the reaction, the solvent was concentrated under reduced pressure, the residue was dissolved with EA (100 mL), and the resultant mixture was washed with sodium hydroxide solution (100 mL, 1M) and 10% aqueous citric acid solution (100 mL), respectively, and saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oily product, which was directly used for the next reaction.MS(ESI,pos.ion)m/z:321.3[M+H] ⁺ 。

Step 4: (R) - (1-amino-2-methylhex-2-yl) carbamic acid tert-butyl ester

To the autoclave were added tert-butyl (R) - (1- (benzylamino) -2-methylhex-2-yl) carbamate (4.657 g,14.53 mmol), etOH (100 mL) and Pd (OH) ₂ C (2.7 g,1.5 mmol). The reaction mixture was heated to 70℃under a hydrogen atmosphere of 1MPa for reaction for 12h. After completion of the reaction, it was filtered through celite, and the filtrate was dried to give the title compound as a white solid (3.245 g,14.09mmol, yield 96.95%) which was used directly in the next reaction. MS (ESI, pos.ion) m/z 231.3[ M+H ]] ⁺ 。

Step 5: (R) - (1- (isoxazole-3-carboxamido) -2-methylhex-2-yl) carbamic acid tert-butyl ester

To the reaction flask were added isoxazole-3-carbonyl chloride (0.6 g,5 mmol) and DCM (3 mL), followed by tert-butyl (R) - (1-amino-2-methylhex-2-yl) carbamate (0.443 g,1.92 mmol) and TEA (0.9 g,9 mmol) dropwise. The reaction mixture was stirred at room temperature for 8h. After the completion of the reaction, the reaction mixture was washed with 10% aqueous citric acid (10 mL), saturated sodium bicarbonate (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =20/1) to give the title compound as a pale yellow oily liquid (0.2 g,0.6mmol, yield 10%). MS (ESI, pos.ion) m/z 226.2[ M+H ]] ⁺ 。

Step 6: (R) -N- (2-amino-2-methylhexyl) isoxazole-3-carboxamide

To the reaction flask was added tert-butyl (R) - (1- (isoxazole-3-carboxamido) -2-methylhex-2-yl) carbamate (0.208 g,0.639 mmol) and a solution of HCl in 1, 4-dioxane (5 mL, 4M) and the addition was completed and stirred at room temperature for 1h. The solvent was concentrated under reduced pressure to give the title compound as a yellow oil, which was used directly in the next reaction.

Step 7: (R) -N- (2- ((2-chloropyrido [3, 2-d)]Pyrimidin-4-yl) amino) -2-methylhexyl) isoxazoles 3-carboxamide

To the reaction flask was added (R) -N- (2-amino-2-methylhexyl) isoxazole-3-carboxamide (0.144 g,0.550 mmol), THF (10 mL), 2, 4-dichloropyrido [3, 2-d) ]Pyrimidine (0.110 g,0.550 mmol) and DIPEA (0.284 g,2.20 mmol) and the reaction mixture was heated to 75 ℃ for 12h. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (V/V) =2/1) to give the title compound as a yellowish green oil (0.131 g,0.337mmol, yield 61.2%). MS (ESI, pos.ion) m/z 389.1[ M+H ]] ⁺ 。

Step 8: (R) -N- (2- ((2, 4-dimethoxy benzyl) amino) pyrido [3, 2-d)]Pyrimidin-4-yl) ammonia Phenyl) -2-methylhexyl) isoxazole-3-carboxamide

Into a reaction flask was added (R) -N- (2- ((2-chloropyrido [3, 2-d)]Pyrimidin-4-yl) amino) -2-methylhexyl-isoxazole-3-carboxamide (0.125 g,0.322 mmol), K ₂ CO ₃ (0.088 g,0.64 mmol), 1, 4-dioxane (5 mL) and (2, 4-dimethoxy) benzylamine (0.059 g,0.35 mmol), and the reaction mixture was heated to 90℃for 12h. After completion of the reaction, the mixture was concentrated under reduced pressure, methylene chloride (10 mL) and water (10 mL) were added to the flask, the mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered,the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =10/1) to give the title compound as a pale yellow oil (0.165 g,0.318mmol, yield 98.8%).

Step 9: (R) -N- (2- ((2-aminopyrido [3, 2-d)]Pyrimidin-4-yl) amino) -2-methylhexyl) isoxazole Azole-3-carboxamide

To the reaction flask was added (R) -N- (2- ((2, 4-dimethoxybenzyl) amino) pyrido [3, 2-d)]Pyrimidin-4-yl) amino) -2-methylhexyl-isoxazole-3-carboxamide (0.165 g,0.318 mmol) and TFA (2 mL) were reacted with stirring at room temperature for 1h. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution was added dropwise to the reaction flask for neutralization, followed by extraction with methylene chloride (20 mL) and separation. The organic phase was filtered to remove insoluble solids, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =10/1) to give the title compound as a white solid (78 mg,0.2112mmol, yield 66.5%). MS (ESI, pos.ion) m/z 370.2[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)10.67(s,1H),8.49(s,1H),8.36(s,1H),7.75(d,J＝7.9Hz,1H),7.55–7.42(m,2H),6.89(s,1H),6.52(s,2H),3.82–3.68(m,2H),2.02(t,J＝12.4Hz,1H),1.85–1.72(m,1H),1.55–1.46(m,3H),1.42–1.25(m,4H),0.89(t,3H)。

The following examples 2 to 11 are prepared by the preparation method of reference example 1:

example 2: (R) -N- (2- ((2-aminopyrido [3, 2-d)]Pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide

MS(ESI,pos.ion)m/z:383.4[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.48–8.41(m,1H),8.07–8.00(m,1H),7.83(s,1H),7.80–7.71(m,2H),7.54–7.45(m,1H),7.12(s,2H),4.05(dd,J＝13.9,6.0Hz,1H),3.89(dd,J＝14.1,6.6Hz,1H),3.85(s,3H),2.24–2.12(m,1H),1.70(d,J＝12.6Hz,1H),1.51(s,3H),1.46–1.37(m,1H),1.33–1.23(m,4H),0.91–0.84(m,3H)。

Example 3: (R) -N- (2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) thiazole-2-carboxamide

MS(ESI,pos.ion)m/z:386.2[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)10.84(s,1H),8.43(d,J＝4.2Hz,1H),7.92(d,J＝3.1Hz,1H),7.82(d,J＝8.4Hz,1H),7.64(d,J＝3.1Hz,1H),7.62–7.53(m,2H),7.30(s,2H),3.80(d,J＝5.7Hz,2H),2.03(dd,J＝18.0,7.9Hz,1H),1.81(dd,J＝17.5,7.8Hz,1H),1.52(s,3H),1.50–1.31(m,4H),0.91(t,J＝6.9Hz,3H)。

Example 4: (R) -N- (2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -5-methylisoxazole-3-carboxamide

MS:(ESI,pos.ion)m/z:384.3[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)10.42(s,1H),8.49–8.42(m,1H),7.87(d,J＝8.3Hz,1H),7.68(s,1H),7.58(dd,J＝8.5,4.3Hz,1H),7.34(s,2H),6.54(s,1H),3.83–3.70(m,2H),2.53(s,3H),2.10–1.97(m,1H),1.90–1.77(m,1H),1.52(d,J＝12.4Hz,3H),1.49–1.43(m,1H),1.42–1.32(m,3H),0.93(t,J＝6.9Hz,3H)。

Example 5: (R) -N- (2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-3-carboxamide

MS(ESI,pos.ion)m/z:383.1[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.97(s,1H),8.42–8.38(m,1H),7.78(d,J＝8.4Hz,1H),7.55–7.48(m,2H),7.39(d,J＝2.1Hz,1H),6.86(d,J＝2.1Hz,2H),3.93(s,3H),3.77(d,J＝5.8Hz,2H),2.95(s,1H),2.08–1.95(m,1H),1.86–1.69(m,1H),1.48(s,3H),1.46–1.28(m,4H),0.89(t,J＝7.0Hz,3H)。

Example 6: (R) -N- (2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-1, 2, 4-triazole-3-carboxamide

MS(ESI,pos.ion)m/z:384.3[M+H] ⁺ ； ¹ H NMR(400MHz,CD ₃ OD)δ(ppm)8.62(d,J＝3.8Hz,1H),8.47(s,1H),7.87(d,J＝8.3Hz,1H),7.76(dd,J＝8.4,4.4Hz,1H),4.13(d,J＝14.1Hz,1H),4.00(s,3H),3.81(d,J＝14.2Hz,1H),2.27(t,J＝10.5Hz,1H),1.94(dd,J＝16.0,8.4Hz,1H),1.62(s,3H),1.52–1.24(m,4H),0.94(t,J＝6.5Hz,3H)。

Example 7: (R) -N- (2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -1H-1,2, 4-triazole-3-carboxamide

MS(ESI,pos.ion)m/z:370.3[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)11.11(s,1H),8.48–8.37(m,2H),8.12(s,1H),8.02(d,J＝8.3Hz,1H),7.78(s,2H),7.65–7.52(m,2H),3.88–3.77(m,2H),2.13–1.98(m,1H),1.90–1.77(m,1H),1.55(s,3H),1.39–1.35(m,2H),1.28–1.25(m,2H),0.91(t,J＝6.8Hz,3H)。

Example 8: (R) -N- (2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) pyrazine-2-carboxamide

MS(ESI,pos.ion)m/z:381.3[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)10.28(s,1H),9.53(s,1H),8.84(d,J＝2.4Hz,1H),8.54(s,1H),8.45(d,J＝4.2Hz,1H),7.83(d,J＝8.4Hz,1H),7.57(dd,J＝8.6,4.3Hz,2H),6.56(s,2H),3.91(dd,J＝5.9,1.9Hz,2H),2.14–2.00(m,1H),1.80(dd,J＝17.3,7.9Hz,1H),1.53(s,3H),1.43–1.31(m,3H),1.27(s,1H),0.92(t,J＝6.9Hz,3H)。

Example 9: (R) -N- (2- ((2-amino-7-fluoropyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide

MS(ESI,pos.ion)m/z:401.6[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.22(d,J＝2.4Hz,1H),7.86(s,1H),7.78(s,1H),7.52(s,1H),7.30(d,J＝14.3Hz,1H),7.13(s,1H),5.17(s,2H),3.91(s,3H),3.88–3.77(m,2H),1.80–1.68(m,1H),1.51(s,3H),1.38–1.25(m,5H),0.91(t,J＝6.9Hz,3H)。

Example 10: (R) -N- (2- ((2-amino-7-fluoroquinazolin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide

MS:(ESI,pos.ion)m/z:400.6[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.33(s,1H),8.45(s,1H),8.23(s,1H),8.14(dt,J＝17.9,8.9Hz,1H),8.05(s,1H),7.11(s,1H),7.03(s,1H),5.30(2,J＝2.2Hz,2H),4.04–3.94(m,1H),3.89(s,3H),3.24–3.13(m,1H),1.39–1.13(m,9H),0.81(t,J＝6.0Hz,3H)。

Example 11: (R) -N- (2- ((2-amino-7-fluoropyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole-3-carboxamide

MS:(ESI,pos.ion)m/z:427.7[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.24(s,1H),7.77(s,1H),7.37(d,J＝9.0Hz,1H),7.28–7.25(m,1H),6.98(s,1H),5.40(s,2H),4.14(t,J＝7.1Hz,2H),3.97(dd,J＝13.8,5.4Hz,1H),3.88–3.77(m,1H),3.08–2.99(m,2H),2.64(dt,J＝14.7,7.3Hz,2H),1.76(d,J＝11.9Hz,1H),1.51(s,3H),1.34(dd,J＝24.7,18.1Hz,5H),0.91(t,J＝6.8Hz,3H)。

Example 12: (R) -2- ((2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) hexyl) amino) thiazole-4-carboxylic acid ethyl ester

Step 1: (R) - (1-hydroxyhexan-2-yl) carbamic acid tert-butyl ester

To a 250mL reaction flask were added lithium aluminum hydride (5.79 g,153 mmol) and tetrahydrofuran (100 mL), and (2R) -2-aminocaproic acid (10.00 g,76.24 mmol) was slowly added in portions while ice-cooling, and the reaction was carried out at about 70℃for about 6 hours. Cooling to about 0 ℃, slowly dropwise adding water (10 mL), quenching reaction by tetrahydrofuran (50 mL) and NaOH (5 mL, 2M), filtering by diatomite, washing a filter cake by tetrahydrofuran (25 mL) to obtain colorless filtrate, slowly adding Boc anhydride (17.00 g,76.33 mmol) into the filtrate, and stirring the mixture at room temperature after adding reaction for about 11 hours. The reaction solution was then concentrated under reduced pressure, the resulting concentrated residue was diluted with acetone (50 mL), the reaction diluted solution was stirred at room temperature for about 4 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) =5/1) to give the title colorless oil (9.75 g, yield 58.9%). MS (ESI, pos.ion) m/z 118.2[ M-Boc+H ] ⁺ 。

Step 2: (4R) -4-butyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide

Into a 250mL reaction flask were added tert-butyl (R) - (1-hydroxyhexane-2-yl) carbamate (9.00 g,41.4 mmol) and acetonitrile (70 mL), cooled to about-40℃and a solution of thionyl chloride (7.51 mL,104 mmol) in acetonitrile (30 mL) was added dropwise, pyridine (16.7 mL,207 mmol) was added slowly, and the mixture was transferred to room temperature and stirred for reaction for about 3.5 hours. The solvent was removed by concentration, diluted with water (50 mL) and ethyl acetate (100 mL), then washed with saturated brine (50 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated to give the title compound as a tan oil (10.09 g, 92.5% yield).

Step 3: (R) -4-butyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2, 2-oxide

In a 500mL reaction flask were charged (4R) -4-butyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester-2-oxide (10.09 g,38.31 mmol), acetonitrile (100 mL) and RuCl ₃ (795 mg,3.83 mmol), cooled to about 0deg.C, and a solution of sodium periodate (12.3 g,57.4 mmol) in water (100 mL) was added dropwise, and reacted at room temperature for about 18.5 hours. After completion of the reaction, suction filtration, washing the cake with ethyl acetate (50 mL), diluting the filtrate with ethyl acetate (100 mL), washing with saturated brine (100 ml×2), concentrating the organic phase, and purifying the obtained residue by silica gel column chromatography (PE/EA (V/V) =20/1) to give the title compound as a colorless oil (5.94 g, yield 55.5%).

Step 4:2- ((tert-Butoxycarbonyl) amino) thiazole-4-carboxylic acid ethyl ester

In a 50mL reaction flask were charged ethyl 2-aminothiazole-4-carboxylate (2.00 g,11.6 mmol), methylene chloride (20 mL), and 4-lutidine (142 mg,1.16 mmol)) Boc anhydride (2.72 g,12.2 mmol) was slowly added in ice bath and the reaction was stirred at room temperature for about 18.5 hours after the addition, boc anhydride (1.29 g,5.79 mmol) was added and the reaction was continued for about 7 hours. The reaction solution was washed with water (10 ml×2) and saturated brine (10 mL), the organic phase was concentrated, and the residue was separated and purified by silica gel column chromatography (PE/EA (V/V) =5/1) to give the title compound as a white solid (2.34 g, yield 74.0%). MS (ESI, pos.ion) m/z 217.1[ M-Boc+H] ⁺ 。

Step 5: (R) -2- ((tert-Butoxycarbonyl) (2- ((tert-Butoxycarbonyl) amino) hexyl) amino) thiazole-4-carboxylic acid Ethyl ester

Into a 100mL reaction flask, ethyl 2- ((tert-butoxycarbonyl) amino) thiazole-4-carboxylate (1.00 g,3.67 mmol), cesium carbonate (2.39 g,7.34 mmol) and DMF (30 mL) were added, the temperature was raised to about 50℃and a solution of tert-butyl (R) -4-butyl-1, 2, 3-oxathiazolidine-3-carboxylate-2, 2-oxide (1.33 g,4.76 mmol) in DMF (10 mL) was added dropwise, and the reaction was continued at about 50℃for about 2 hours after the addition. Cooled to room temperature, suction filtered, the filter cake was washed with ethyl acetate (25 mL), the filtrate was diluted with ethyl acetate (25 mL), then saturated brine was washed (25 ml×2), HCl (25 mL,1 m) was added to the washed ethyl acetate solution, vigorously stirred at room temperature for about 10 minutes, the aqueous phase was discarded, the organic phase was washed with saturated brine (25 ml×2), and the organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) =5/1) to give the title compound as a colorless oil (1.71 g, yield 98.7%). MS (ESI, pos.ion) m/z 472.3[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.77(s,1H),4.88(d,J＝8.9Hz,1H),4.36(q,J＝7.1Hz,2H),4.33–4.23(m,1H),4.10–4.02(m,2H),1.61(s,9H),1.54–1.47(m,2H),1.46–1.41(m,2H),1.41–1.36(m,5H),1.28(s,9H),0.91(t,J＝6.8Hz,3H)。

Step 6: (R) -2- ((2-aminohexyl) amino) thiazole-4-carboxylic acid ethyl ester dihydrochloride

In a 25mL single flask, ethyl (R) -2- ((tert-butoxycarbonyl) (2- ((tert-butoxycarbonyl) amino) hexyl) amino) thiazole-4-carboxylate (1.71 g,3.63 mmol), ethyl acetate (3 mL) and HCl/EtOAc (10 mL,40mmol,4 mol/L) were added and the reaction was stirred at room temperature for about 16 hours with a gradual precipitation of a white solid. Suction filtration, filter cake washing with ethyl acetate (15 mL) and filter cake spin drying at 40℃for about 30 minutes gave the title compound as a white solid (1.23 g, 98.5% yield). MS (ESI, pos.ion) m/z 272.1[ M+H ]] ⁺ 。

Step 7: (R) -2- ((2- ((2-chloropyrido [3, 2-d)]Pyrimidin-4-yl) amino) hexyl) amino) thiazole-4-carboxylic acid Acid ethyl ester

In a 100mL single vial was added (R) -2- ((2-aminohexyl) amino) thiazole-4-carboxylic acid ethyl ester dihydrochloride (1.23 g,3.57 mmol), 2, 4-dichloropyrido [3, 2-d)]Pyrimidine (0.72 g,3.6 mmol), tetrahydrofuran (25 mL), and diisopropylethylamine (3.1 mL,18 mmol) were reacted at 75℃for about 15.5 hours. Cooled to room temperature, then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) =2/1) to give the title compound as an off-white solid (915 mg, yield 58.9%). MS (ESI, pos.ion) m/z 435.0[ M+H ] ] ⁺ 。

Step 8: (R) -2- ((2- ((2- ((2, 4-dimethoxy benzyl) amino) pyrido [3, 2-d)]Pyrimidin-4-yl) ammonia Hexyl) amino) thiazole-4-carboxylic acid ethyl ester

In a 50mL reaction flask was added (R) -2- ((2- ((2-chloropyrido [3, 2-d)]Pyrimidin-4-yl-amino) hexyl) amino) thiazole-4-carboxylic acid ethyl ester (900 mg,2.07 mmol), (2, 4-dimethoxybenzyl)) Ammonia (692 mg,4.14 mmol), potassium carbonate (867 mg,6.21 mmol) and 1, 4-dioxane (10 mL) were reacted at about 90℃for about 16 hours. The heating was turned off, cooled to room temperature, dichloromethane (10 mL) was added, washed with water (10 mL), and the organic phase was concentrated and purified by column chromatography on silica gel (DCM/MeOH (V/V) =50/1) to give the title compound as a pale brown solid (1.14 g, yield 97.4%). MS (ESI, pos.ion) m/z 566.1[ M+H ]] ⁺ 。

Step 9: (R) -2- ((2- ((2-aminopyrido [3, 2-d)]Pyrimidin-4-yl) amino) hexyl) amino) thiazole-4- Carboxylic acid ethyl ester

In a 50mL reaction flask was added (R) -2- ((2- ((2- ((2, 4-dimethoxybenzyl) amino) pyrido [3, 2-d)]Pyrimidin-4-yl-amino) hexyl) amino) thiazole-4-carboxylic acid ethyl ester (1.09 g,1.93 mmol), methylene chloride (3 mL) and trifluoroacetic acid (9 mL) were reacted at room temperature with stirring for about 4 hours. The solvent was removed by concentration under reduced pressure, the residue was diluted with water (10 mL) and ethyl acetate (20 mL), then the pH was adjusted to about 7 with saturated sodium bicarbonate solution, the aqueous phase was discarded, the organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (DCM/MeOH (V/V) =20/1) to give the title compound as a white solid (800 mg, yield 99.9%). MS (ESI, pos.ion) m/z 416.1[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.38(d,J＝4.2Hz,1H),8.24(s,1H),7.82(t,J＝8.5Hz,2H),7.52(dd,J＝8.4,4.4Hz,1H),7.21(s,1H),4.74–4.54(m,1H),4.32(q,J＝7.0Hz,2H),3.75–3.54(m,2H),1.88–1.65(m,2H),1.54–1.19(m,9H),0.93(t,J＝6.9Hz,3H)。

Example 13: (R) -2- ((2- ((2-aminopyrido [3,2-d ] pyrimidin-4-yl) amino) hexyl) amino) thiazole-4-carboxylic acid

In a 50mL single-necked flaskAdding (R) -2- ((2- ((2-aminopyrido [3, 2-d)]Pyrimidin-4-yl-amino) hexyl) amino) thiazole-4-carboxylic acid ethyl ester (450 mg,1.08 mmol), tetrahydrofuran (2 mL), methanol (2 mL), and sodium hydroxide (118 mg,2.95 mmol) in water (6 mL), and the reaction was stirred at room temperature for about 16 hours. The solvent was removed mostly by concentration, the concentrate was diluted with additional water (10 mL), then the pH was adjusted to around 7 with 1M hydrochloric acid, a large amount of white solid was precipitated, stirring was continued at room temperature for about 30 minutes, suction filtration was performed, the filter cake was washed with water (20 mL), and vacuum drying was performed at 50 ℃ for about 4 hours to give the title compound as a white solid (403 mg, yield 96.03%). MS (ESI, pos.ion) m/z 388.5[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.34(d,J＝4.3Hz,1H),7.97(d,J＝9.0Hz,1H),7.81(s,1H),7.65-7.52(m,2H),7.38(s,1H),6.60(s,2H),4.52-4.43(m,1H),3.59-3.46(m,2H),1.77-1.62(m,2H),1.40-1.25(m,4H),0.85(t,J＝6.9Hz,3H)。

Example 14: (R) -N- (2- ((2-amino-7- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) pyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide

Step 1: (R) -N- (2- ((7-bromo-2- ((2, 4-dimethoxybenzyl) amino) pyrido [3, 2-d)]Pyrimidine-4-) Group) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide

With (R) -2-amino-2-methylhexanoic acid and 7-bromo-2, 4-dichloropyridine [3,2-d ] ]Pyrimidine as starting material the title compound was synthesized as a tan foam solid in a yield of 2.5% with reference to example 1, steps 1 to 8. MS (ESI, pos.ion) m/z 611.0[ M+H ]] ⁺ 。

Step 2: (R) - (2- ((2, 4-dimethoxybenzyl) amino) -4- ((2-methyl-1- (1-methyl-1H-pyrazole-4-) Carboxamide) hexane-2-yl)Amino) pyrido [3,2-d]Pyrimidin-7-yl) boronic acids

The dried reaction flask was charged with (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 (100 mg,0.16 mmol), pinacol biborate (83 mg,0.33 mmol), potassium acetate (49 mg,0.49 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (20 mg,0.024 mmol) and ethylene glycol dimethyl ether (5 mL), nitrogen substitution three times, temperature rise to 80℃under nitrogen protection, and stirring for about 2 hours. The residue was dissolved in methylene chloride (15 mL) by suction filtration through celite, spin-drying the filtrate, and the resulting mixture was washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to give the title compound as a tan foam (107 mg, yield 100%). MS (ESI, pos.ion) m/z 577.1[ M+H ] ] ⁺ 。

Step 3: 5-bromo-2- (4-methylpiperazin-1-yl) pyrimidine

1-methylpiperazine (541 mg,5.40 mmol) was dissolved in 1, 4-dioxane (10 mL), then 5-bromo-2-chloropyrimidine (520 mg,2.69 mmol) was added, and the temperature was raised to reflux and the reaction was stirred. Stirring was continued for about 5 hours, heating was turned off, stirring was stopped, and the solvent was dried, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =40/1) to give the title compound as a white brown solid (603 mg, yield 87.23%). MS (ESI, pos.ion) m/z 257.0[ M+H ]] ⁺ 。

Step 4: (R) -N- (2- ((2, 4-dimethoxybenzyl) amino) -7- (2- (4-methylpiperazin-1-yl) pyrimidine-5- Radical) pyrido [3,2-d]Pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide

Into a dry reaction flask was added (R) - (2- ((2, 4-dimethoxybenzyl) amino) -4- ((2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamido) hexane-2-yl) amino) pyrido [3,2-d ]]Pyrimidine-7-yl) boronic acid (107 mg,0.16 mmol), 5-bromo-2- (4-methylpiperazin-1-yl) pyrimidine (50 mg,0.19 mmol), potassium carbonate (34 mg,0.25 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (20 mg,0.024 mmol), 1, 4-dioxane (10 mL) and water (2 mL), the reaction mixture was replaced with nitrogen three times, warmed to 80℃under nitrogen protection, and stirred for about 5 hours. The residue was dissolved in dichloromethane (15 mL) and then washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, and the resulting residue was purified by thin layer chromatography (DCM/MeOH (V/V) =15/1) to give the title compound as a brown solid product (73 mg, yield 63.38%). MS (ESI, pos.ion) m/z 709.2[ M+H ] ] ⁺ 。

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

Into a dry reaction flask was added (R) -N- (2- ((2, 4-dimethoxybenzyl) amino) -7- (2- (4-methylpiperazin-1-yl) pyrimidin-5-yl) pyridinyl [3, 2-d)]Pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide (70 mg,0.099 mmol) and dichloromethane (2 mL) were dissolved by stirring, and trifluoroacetic acid (2 mL) was then added and the reaction mixture was stirred for about 5 hours. Stirring was stopped, the solvent was removed by spin-drying, methylene chloride (10 mL) was added to dilute, and then the pH of the solution was adjusted to about 8 with saturated sodium bicarbonate solution. Removing insoluble substances by suction filtration, collecting filtrate, separating, collecting lower organic phase, extracting aqueous phase with dichloromethane (10 mL), mixingAnd the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying, and the resulting residue was purified by thin layer chromatography (DCM/MeOH (V/V) =10/1) to give the title compound as a yellow solid (40 mg, yield 72.51%). MS (ESI, pos.ion) m/z 280.6[ M/2+H ]] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.59(s,1H),8.51(s,1H),7.88(s,1H),7.78(s,1H),7.75(s,1H),7.57(t,J＝4.7Hz,1H),7.35(s,1H),7.26(s,1H),5.68(s,2H),4.03–3.92(m,5H),3.86(s,3H),3.84–3.75(m,1H),2.58–2.50(m,4H),2.37(s,3H),2.22–2.11(m,1H),1.79–1.65(m,1H),1.50(s,3H),1.45–1.26(m,4H),0.88(t,J＝6.8Hz,3H)。

Example 15:4- ((S) -7- (5- (2-amino-4- (((R) -2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamide) hexan-2-yl) amino) pyrido [3,2-d ] pyrimidin-7-yl) pyrimidin-2-yl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) benzoic acid

Step 1: (R) -2- (4- (ethoxycarbonyl) phenyl) -3-oxohexahydroimidazo [1,5-a]Pyrazine-7 (1H) -carbonitriles Acid tert-butyl ester

Into a dry reaction flask was charged (R) -3-oxohexahydroimidazo [1,5-a ]]Pyrazine-7 (1H) -carboxylic acid tert-butyl ester (900 mg,3.73 mmol), ethyl p-iodobenzoate (1.00 g,3.62 mmol), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (176 mg,0.36 mmol), palladium acetate (41 mg,0.18 mmol), cesium carbonate (2.36 g,7.24 mmol) and 1, 4-dioxane (20 mL) were replaced with nitrogen three times, and the reaction was stirred at 90℃until it was warmed. Stirring for about 13 hours, closing heating, cooling to room temperature, adding dichloromethane (30 mL) for dilution, stirring for 30 minutes, performing diatomite suction filtration, spin-drying the filtrate to obtain a white brown solid crude product, adding ethyl acetate (20 mL), stirring and pulping at room temperature for about 7 hours, performing suction filtration, and performing ethyl acetate (4 mL)) The filter cake was washed, and the filter cake was collected and dried under reduced pressure to give the product as a white solid (1.16 g, yield 82.2%). MS (ESI, pos.ion) m/z 334.1[ M-56+H] ⁺ 。

Step 2 (S) -4- (3-oxo-hexahydroimidazo [1, 5-a)]Pyrazin-2 (3H) -yl) benzoic acid ethyl ester hydrochloride

(R) -2- (4- (ethoxycarbonyl) phenyl) -3-oxo hexahydroimidazo [1,5-a]Pyrazine-7 (1H) -carboxylic acid tert-butyl ester (1.16 g,3.73 mmol) was dissolved in dichloromethane (5 mL), a solution of 1, 4-dioxane (5 mL,4 mol/L) of hydrogen chloride was added, and the reaction mixture was stirred at room temperature for about 15 hours. The stirring was stopped, and concentrated under reduced pressure to give a brown solid crude product, which was added with methyl tert-butyl ether (10 mL), stirred and slurried at room temperature for about 2 hours, suction filtered, the filter cake was washed with methyl tert-butyl ether (5 mL), and the filter cake was collected and dried under reduced pressure to give the title compound as a yellow solid (938 mg, yield 96.6%). MS (ESI, pos.ion) m/z 290.4[ M+H ] ] ⁺ 。

Step 3: (S) -4- (7- (5-bromopyrimidin-2-yl) -3-oxohexahydroimidazo [1, 5-a)]Pyrazin-2 (3H) -yl Benzoic acid ethyl ester

(S) -4- (3-oxo hexahydroimidazo [1, 5-a)]Ethyl pyrazin-2 (3H) -yl) benzoate hydrochloric acid (505 mg,1.55 mmol) was dissolved in acetonitrile (10 mL), then 5-bromo-2-chloropyrimidine (300 mg,1.55 mmol) and potassium carbonate (643 mg,4.65 mmol) were added, the reaction mixture was warmed to 80℃and stirred for about 17 hours, the heating was turned off, stirring was stopped, and the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (DCM/EA (V/V) =9/1) to give the title compound as a white solid (566 mg, yield 81.77%). MS (ESI, pos.ion) m/z 446.0[ M+H ]] ⁺ 。

Step 4:4- ((S) -7- (5-(2-amino-4- (((R) -2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamide) Yl) hexane-2-yl) amino) pyrido [3,2-d]Pyrimidin-7-yl) pyrimidin-2-yl) -3-oxohexahydroimidazo [1,5-a]Piirae-type pyridine Oxazine-2 (3)H) -group) benzoic acid

(S) -4- (7- (5-bromopyrimidin-2-yl) -3-oxo-hexahydroimidazo [1, 5-a)]Pyrazin-2 (3H) -yl) benzoic acid ethyl ester and (R) - (2- ((2, 4-dimethoxybenzyl) amino) -4- ((2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamido) hexane-2-yl) amino) pyrido [3,2-d]Pyrimidin-7-yl) boronic acid the synthesis procedure of example 14, steps 4 to 5, was followed to give the title compound as a white solid in 51% yield. MS (ESI, pos.ion) m/z 720.2[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ /CD ₃ COOD)δ(ppm)8.74–8.67(m,2H),8.64–8.58(m,1H),8.07–7.92(m,4H),7.89–7.79(m,1H),7.69–7.57(m,2H),5.14–4.98(m,1H),4.96–4.87(m,1H),4.16–3.99(m,3H),3.91–3.81(m,3H),3.81–3.71(m,1H),3.70–3.45(m,1H),3.15–3.02(m,2H),3.02–2.86(m,1H),2.24–2.14(m,1H),2.08–1.98(m,1H),1.87–1.71(m,1H),1.60–1.50(m,3H),1.45–1.25(m,4H),0.96–0.71(m,3H)。

Example 16: n- ((R) -2- ((2-amino-7- (2- ((R) -3-oxohexahydroimidazo [1,5-a ] pyrazin-7 (1H) -yl) pyrimidin-5-yl) pyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide

By (R) -3-oxo-hexahydroimidazo [1,5-a ]]Pyrazine-7 (1H) -carboxylic acid tert-butyl ester and (R) - (2- ((2, 4-dimethoxybenzyl) amino) -4- ((2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamido) hexane-2-yl) amino) pyrido [3,2-d]Pyrimidine-7-yl) boronic acid as starting material the procedure of reference example 15 gives the title compound as a white solid in yield32％。MS(ESI,pos.ion)m/z:600.2[M+H] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.63(s,2H),8.53(d,J＝1.8Hz,1H),7.88(s,1H),7.82–7.73(m,2H),4.92(dd,J＝13.1,2.8Hz,1H),4.85(d,J＝10.1Hz,1H),3.96–3.86(m,5H),3.84–3.74(m,2H),3.62(t,J＝8.7Hz,1H),3.16(dd,J＝9.0,5.2Hz,1H),3.03-2.90(m,3H),2.22–2.12(m,1H),1.76(t,J＝10.7Hz,1H),1.52(s,3H),1.41–1.28(m,4H),0.89(t,J＝6.9Hz,3H)。

Example 17: n- ((R) -2- ((2-amino-7- (2- ((S) -2-isobutyl-3-oxohexahydroimidazo [1,5-a ] pyrazin-7 (1H) -ylpyrimidin-5-yl) pyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole-4-carboxamide

Step 1 (R) -2-isobutyl-3-oxohexahydroimidazo [1,5-a]Pyrazine-7 (1H) -carboxylic acid tert-butyl ester

Sodium hydride (250 mg,6.25mmol, 60%) and N, N-dimethylformamide (10 mL) were added to the dried reaction flask, transferred to 0deg.C, and (R) -3-oxohexahydroimidazo [1,5-a was added]Pyrazine-7 (1H) -carboxylic acid tert-butyl ester (500 mg,2.07 mmol), after stirring the reaction mixture for about 30 minutes, iodoisobutane (0.5 mL,4 mmol) was added and the mixture was transferred to room temperature and stirred for about 42 hours. Stirring was stopped, water (15 mL) and ethyl acetate (20 mL) were added, the upper organic phase was collected, the aqueous phase was extracted with ethyl acetate (15 mL), the organic phases were combined, the combined organic phases were washed with water (20 mL) and then washed with saturated sodium chloride solution (15 ml×2), and concentrated under reduced pressure, and the obtained residue was isolated and purified by means of a column chromatography on regular silica gel (PE/EA (V/V) =1/1) to give the title compound as a white solid (138 mg, yield 22.39%). MS (ESI, pos.ion) m/z 242.1[ M-56+H ] ⁺ 。

Step 2N- ((R) -2- ((2-amino-7- (2- ((S) -2-isobutyl-3-oxy)Hexahydroimidazo [1,5-a ] s]Piirae-type pyridine Oxazin-7 (1H) -ylpyrimidin-5-yl) pyrido [3,2-d]Pyrimidin-4-yl) amino) -2-methylhexyl) -1-methyl-1H-pyrazole 4-carboxamide

(R) -2-isobutyl-3-oxohexahydroimidazo [1,5-a]Pyrazine-7 (1H) -carboxylic acid tert-butyl ester and (R) - (2- ((2, 4-dimethoxybenzyl) amino) -4- ((2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamido) hexane-2-yl) amino) pyrido [3,2-d]Pyrimidin-7-yl) boric acid as a starting material, the title compound was obtained as a white solid in 28% yield by the synthesis method of example 15. MS (ESI, pos.ion) m/z 656.4[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.63(s,2H),8.53(d,J＝1.4Hz,1H),7.90(s,1H),7.82–7.77(m,2H),7.58(t,J＝5.3Hz,1H),7.41(s,1H),5.77(s,2H),4.90(dd,J＝12.7,2.6Hz,1H),4.85–4.77(m,1H),4.04–3.92(m,2H),3.88(s,3H),3.83(dd,J＝14.0,6.1Hz,1H),3.74–3.65(m,1H),3.55–3.48(m,1H),3.14–2.97(m,5H),2.92–2.85(m,1H),2.26–2.12(m,1H),1.89(dt,J＝13.6,6.9Hz,1H),1.75(t,J＝10.4Hz,1H),1.53(s,3H),1.41–1.28(m,4H),1.00–0.86(m,9H)。

Example 18:3- ((S) -7- (5- (2-amino-4- (((R) -2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamide) hexan-2-yl) amino) pyrido [3,2-d ] pyrimidin-7-yl) pyrimidin-2-yl) -3-oxohexahydroimidazo [1,5-a ] pyrazin-2 (3H) -yl) -2, 2-dimethylpropionic acid

Step 1: di-tert-butyl (R) -2- (((3-methoxy-2, 2-dimethyl-3-oxopropyl) amino) methylpiperazine- 1, 4-dicarboxylic acid ester

Tert-butyl (R) -2- (aminomethyl) piperazine-1, 4-dicarboxylate (1.32 g,4.20 mmol) was dissolved in methanol (10 mL), followed by addition of methyl 2, 2-dimethyl-3-oxopropionate (420 mg,3.23 mmol) and acetic acid (0.1 mL,2 mmol). The reaction mixture was stirred at room temperature for about 1 hour, transferred to an ice-water bath, sodium cyanoborohydride (620 mg,9.67 mmol) was added, and the reaction was continued with stirring at room temperature for about 19 hours. The stirring was stopped, the solvent was removed under reduced pressure, then dichloromethane (30 mL) was added to dissolve the residue, saturated sodium bicarbonate solution (20 mL) was added, the lower organic phase was collected, the aqueous phase was extracted with dichloromethane (30 mL), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (V/V) =4/1) to give the title compound as a pale yellow oil (0.99 g, yield 71.0%). MS (ESI, pos.ion) m/z 430.2[ M+H ] ] ⁺ 。

Step 2: (R) -methyl 2, 2-dimethyl-3- ((piperazin-2-ylmethyl) amino) propanoate dihydrochloride

A dry reaction flask was charged with (R) -2- (((3-methoxy-2, 2-dimethyl-3-oxopropyl) amino) methyl) piperazine-1, 4-dicarboxylic acid tert-butyl ester (985 mg,2.29 mmol) and a dioxane solution of hydrogen chloride (8 mL, 4M), the reaction mixture was stirred at room temperature for about 23 hours, stirring was stopped, and concentrated under reduced pressure to give the title compound as a yellow viscous solid, 693mg, for the next reaction. MS (ESI, pos.ion) m/z 230.5[ M+H ]] ⁺ 。

Step 3: (R) -3- (((3-methoxy-2, 2-dimethyl-3-oxopropyl) amino) methyl) piperazine-1-carboxylic acid tert-butyl ester Butyl ester

Methyl (R) -2, 2-dimethyl-3- ((piperazin-2-ylmethyl) amino) propionate hydrochloride (693 mg,2.29 mmol) was dissolved in dichloromethane (25 mL), cooled to 0deg.C, triethylamine (1.6 mL,12 mmol) was added, and stirred for about 10 minutes. A solution of Boc anhydride (505 mg,2.29 mmol) in dichloromethane (10 mL) was slowly added dropwise, the reaction mixture stirred at 0deg.C for about 13 hours, the reaction stopped, water (30 mL) was added for dilution, the lower organic phase was collected, the aqueous phase was extracted with dichloromethane (30 mL), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a pale yellow oil (713 mg, yield 94.40%). MS (ESI, pos.ion) m/z 330.6[ M+H ] ] ⁺ 。

Step 4: (R) -2- (3-methoxy-2, 2-dimethyl-3-oxopropyl) -3-oxohexahydroimidazo [1,5-a] Pyrazine-7 (1H) -carboxylic acid tert-butyl ester

(R) -3- (((3-methoxy-2, 2-dimethyl-3-oxopropyl) amino) methyl) piperazine-1-carboxylic acid tert-butyl ester (710 mg,2.16 mmol) was dissolved in dichloromethane (20 mL), N-diisopropylethylamine (1.07 mL,6.47 mmol) was added, cooled to 0 ℃, a solution of triphosgene (320 mg,1.08 mmol) in dichloromethane (10 mL) was added dropwise, the reaction was allowed to warm to room temperature with stirring for about 18 hours after the dropwise addition, stirring was stopped, the pH of the solution was adjusted to about 5 with 1M hydrochloric acid, the dichloromethane solvent was removed under reduced pressure, the residue was diluted with ethyl acetate (60 mL) and then washed with 1M hydrochloric acid (30 mL. Times.3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EA (V/V) =1/1) to give the title compound as a white solid (660 mg, yield 86.16%). MS (ESI, pos.ion) m/z 356.1[ M+H ]] ⁺ 。

Step 5: (S) -2, 2-dimethyl-3- (3-oxohexahydroimidazo [1, 5-a)]Pyrazin-2 (3H) -yl) propionic acid methyl ester Hydrochloride salt

Into a dry reaction flask was added (R) -2- (3-methoxy-2, 2-dimethyl-3-oxopropyl) -3-oxohexahydroimidazo [1,5-a ]Pyrazine-7 (1H) -carboxylic acid tert-butyl ester (660 mg,1.86 mmol) and hydrogen chloride dioxane solution (6 mL,24mmol,4 mol/L) were reacted at room temperature with stirring for about 15 hours. Stirring was stopped, the solvent was removed under reduced pressure, methyl tert-butyl ether (10 mL) was added to the residue, stirred and slurried for about 1 hour, followed by suction filtration, and the cake was collected and dried under reduced pressure to give the title compound as an off-white solid (403 mg, yield 74.38%). MS (ESI, pos.ion) m/z 256.1[ M+H ]] ⁺ 。

Step 6: (S) -3- (7- (5-bromopyrimidin-2-yl) -3-oxohexahydroimidazo [1, 5-a)]Pyrazin-2 (3H) -yl) 2, 2-Dimethylpropanoic acid methyl ester

(S) -2, 2-dimethyl-3- (3-oxo hexahydroimidazo [1, 5-a)]Methyl pyrazin-2 (3H) -yl) propionate hydrochloride (313 mg,1.07 mmol) was dissolved in acetonitrile (10 mL), 5-bromo-2-chloropyrimidine (207 mg,1.07 mmol) and potassium carbonate (445 mg,3.22 mmol) were added in this order, and the reaction mixture was warmed to 80℃and stirred for about 16 hours. The heating was turned off, stirring was stopped, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EA (V/V) =1/1) to give the title compound as a pale yellow oily product (350 mg, yield 79.13%). MS (ESI, pos.ion) m/z 412.5[ M+H ]] ⁺ 。

Step 7:3- ((S) -7- (5- (2-amino-4- (((R) -2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamide) Yl) hexane-2-yl) amino) pyrido [3,2-d]Pyrimidin-7-yl) pyrimidin-2-yl) -3-oxohexahydroimidazo [1,5-a]Piirae-type pyridine Oxazin-2 (3H) -yl) -2, 2-dimethylpropionic acid

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(S) -3- (7- (5-bromopyrimidin-2-yl) -3-oxo-hexahydroimidazo [1, 5-a)]Pyrazin-2 (3H) -yl) -2, 2-dimethylpropionic acid methyl ester and (R) - (2- ((2, 4-dimethoxybenzyl) amino) -4- ((2-methyl-1- (1-methyl-1H-pyrazole-4-carboxamido) hexane-2-yl) amino) pyrido [3,2-d]Pyrimidin-7-yl) boric acid as a starting material, the synthesis procedure of example 14, steps 4 to 5, was followed to give the title compound as a white solid in 11% yield. MS (ESI, pos.ion) m/z 700.3[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.56(d,J＝1.7Hz,1H),8.54(s,2H),7.93(s,1H),7.90(s,1H),7.78(s,1H),4.74(d,J＝10.4Hz,1H),4.61(d,J＝9.9Hz,1H),4.00–3.92(m,2H),3.89(s,3H),3.83–3.77(m,1H),3.60–3.44(m,3H),3.28(dd,J＝9.1,3.2Hz,1H),3.23(d,J＝13.9Hz,1H),3.04–2.90(m,3H),2.08–1.97(m,1H),1.86–1.77(m,1H),1.54(s,3H),1.37–1.32(m,4H),0.94–0.80(m,9H)。

Example 19: (R) -1-amino-N- (2- ((2-amino-7-fluoropyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhexyl) cyclopropane-1-carboxamide

Step 1:1- (((benzyloxy) carbonyl) amino) cyclopropane-1-carboxylic acid

To the reaction flask were added 1-aminocyclopropylcarboxylic acid (1.00 g,9.90 mmol), 1, 4-dioxane (10 mL), water (20 mL), sodium carbonate (3.10 g,29.00 mmol) and benzyl chloroformate (1.70 mL,12.00 mmol), and the reaction was stirred at room temperature for about 20 hours. To the flask were added water (20 mL) and ethyl acetate (20 mL), the organic phase was removed, and the aqueous phase was further washed with ethyl acetate (20 mL). Then dilute hydrochloric acid was added dropwise to the aqueous phase to adjust the pH to acidity, ethyl acetate (20 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (DCM/MeOH (V/V) =10/1) to give the title compound as a white solid (1.45 g, yield 62%).

Step 2: (R) - (1- (1- (((benzyloxy) carbonyl) amino) cyclopropane-1-carboxamide) -2-methylhexane-2- Radical) -carbamic acid tert-butyl ester

To the reaction flask was added tert-butyl (R) - (1-amino-2-methylhexan-2-yl) carbamate (0.27 g,1.18 mmol), dichloromethane (5 mL), EDCI (0.34 g,1.77 mmol), DIPEA (0.23 g,1.77 mmol) and 1- (((benzyloxy) carbonyl) amino) cyclopropane-1-carboxylic acid (0.36 g,1.53 mmol), and the reaction mixture was stirred at room temperature overnight. To the reaction flask was added 10% potassium carbonate solution (20 mL), stirred for about 1 hour, the solution was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was separated and purified by a silica gel column (DCM/MeOH (V/V) =10/1) to give the title compound as a pale yellow solid (0.53 g, yield 100%). MS (ESI, pos.ion) m/z 348.0[ M+H ]] ⁺ 。

Step 3: (R) - (1- ((2-amino-2-methylhexyl) carbamoyl) cyclopropyl) carbamic acid benzyl ester

To the reaction flask was added tert-butyl (R) - (1- (1- (((benzyloxy) carbonyl) amino) cyclopropane-1-carboxamide) -2-methylhexane-2-yl) -carbamate (0.53 g,1.18 mmol) and HCl/1, 4-dioxane (5 mL, 4M) and the reaction was stirred at room temperature for about 1 hour. Then concentrated under reduced pressure to give the title compound as a yellow oil, which was used directly in the next reaction.

Step 4: (R) - (1- ((2- ((2-chloro-7-fluoropyrido [3, 2-d))]Pyrimidin-4-yl) amino) -2-methylhexyl Carbamoyl) cyclopropyl) carbamic acid benzyl ester

To the reaction flask was added benzyl (R) - (1- ((2-amino-2-methylhexyl) carbamoyl) cyclopropyl) carbamate (0.41 g,1.07 mmol), tetrahydrofuran (5 mL), 2, 4-dichloro-7-fluoropyrido [3, 2-d)]Pyrimidine (0.23 g,1.06 mmol) and DIPEA (0.55 g,4.26 mmol), and the reaction mixture was heated to 75 ℃ to react overnight. Concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (PE/EA (V/V) =1/1) to give the title compound as a yellow oil (0.53 g, yield 93.2%). MS (ESI, pos.ion) m/z 528.9[ M+H ]] ⁺ 。

Step 5: (R) - (1- ((2, 4-dimethoxybenzyl) amino) -7-fluoropyrido [3, 2-d)]Pyrimidin-4-yl Amino) -2-methylhexyl) carbamoyl) cyclopropyl) carbamic acid benzyl ester

Add (R) - (1- ((2- ((2-chloro-7-fluoropyridine) [3, 2-d) to the reaction flask]Pyrimidine-4-yl) amino) -2-methylhexyl) carbamoyl) cyclopropyl carbamate (0.53 g,0.99 mmol), potassium carbonate (0.27 g,1.98 mmol), dioxane (5 mL) and 2, 4-dimethoxybenzylamine (0.33 g,1.99 mmol), the reaction mixture was warmed to 90 ℃ and reacted overnight, concentrated under reduced pressure, and the resulting residue was isolated and purified by silica gel column chromatography (DCM/MeOH (V/V) =20/1) to give the title compound as a yellow solid (0.46 g, 69.9%). MS (ESI, pos.ion) m/z 660.4[ M+H ] ] ⁺ 。

Step 6: (R) - (1- ((2- ((2-amino-7-fluoropyrido [3, 2-d))]Pyrimidin-4-yl) amino) -2-methylhexan Group) carbamoyl) cyclopropyl) benzyl carbamate

To the reaction flask was added (R) - (1- ((2, 4-dimethoxybenzyl) amino) -7-fluoropyrido [3, 2-d)]Pyrimidine-4-yl) amino) -2-methylhexyl) carbamoyl) cyclopropyl) carbamate (0.15 g,0.23 mmol) and TFA (1 mL), and the reaction mixture was stirred at room temperature for about 2 hours. To the reaction solution was added dropwise saturated sodium bicarbonate solution to adjust the pH to 8-9, dichloromethane (10 mL) was added for dilution, the filtrate was separated by celite, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a pale yellow solid (0.12 g, yield 100%). MS (ESI, pos.ion) m/z 510.0[ M+H ]] ⁺ 。

Step 7: (R) -1-amino-N- (2- ((2-amino-7-fluoropyrido [3, 2-d)]Pyrimidin-4-yl]Amino) -2-methyl Hexyl) cyclopropane-1-carboxamide

Add (R) - (1- ((2- ((2-amino-7-fluoropyrido [3, 2-d)) to a reaction flask]Pyrimidine-4-yl) amino) -2-methylhexyl-carbamoyl) cyclopropyl) carbamate (0.12 g,0.23 mmol), methanol (3 mL), tetrahydrofuran (3 mL) were added and dissolved, 10% Pd/C (0.024 g,0.023 mmol) was added and reacted at room temperature under a hydrogen atmosphere for about 5 hours. The residue was isolated and purified by silica gel column chromatography (DCM/MeOH (V/V) =1/1) to give the title compound as a white solid (0.051 g, yield 60%). MS (ESI, pos.ion) m/z 376.3[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.56–8.43(m,1H),8.27(d,J＝2.5Hz,1H),7.36(dd,J＝10.6,2.4Hz,1H),7.17(s,1H),6.59(s,2H),3.73(dd,J＝13.5,6.1Hz,1H),3.46(dd,1H),2.07–1.93(m,1H),1.85–1.73(m,1H),1.39(s,3H),1.32–1.16(m,5H),1.11–1.01(m,2H),0.90–0.71(m,5H)。

Biological testing

Test 1: testing of agonistic Activity of humanized TLR7 and TLR8

The purpose of the experiment is as follows: using HEK-Blue ^TM hTLR7 and HEK-Blue ^TM hTLR8 cell detection compounds for hTLR7 and hTLR8 agonistic activity and cellsToxic activity.

The experimental procedure was as follows:

1) Compound preparation: compounds were first prepared in 20mM stock solution using DMSO and then 3-fold gradient dilutions of the compounds were added to 96-well plates for a total of 10 concentrations, each concentration being double multiplexed. Negative control wells were added with 0.5 μl DMSO per well. The final DMSO concentration was 0.5%.

2) HEK-Blue ^TM hTLR7 or HEK-Blue ^TM hTLR8 cells were suspended in culture and seeded into 96-well plates containing the compound at 50,000 cells per well. Compounds and cells at 37 ℃,5% co ₂ Co-incubation was carried out for 24h under the conditions.

3) QUANTI-Blue detection solution: taking 1mL of QB reagent and 1mL of QB buffer, adding 98mL of sterile water, uniformly mixing and dissolving, and standing at room temperature for 10min.

4) Compound activity assay: mu.L of the culture supernatant obtained in step 2) was added to a 96-well plate containing 180. Mu.L of QUANTI-Blue detection solution, incubated at 37℃for 1 hour, and the absorbance at 650nm was measured by a multifunctional microplate reader Flextion III (OD ₆₅₀ )。

5) Cell activity detection: chemiluminescent signals (RLU) were detected using a multifunctional microplate reader Flextion III, operating according to the Celltiter-Glo specification method.

6) Data analysis

Compound activity: OD (optical density) ₆₅₀ Values were analyzed using GraphPad Prism software and compound dose response curves fitted to calculate EC for the compounds ₅₀ Values.

Cell activity detection: the% cell activity was calculated as follows. Cell% activity values were analyzed using GraphPad Prism software and compound dose response curves fitted to calculate compound-to-cell CC ₅₀ Values.

Cell activity% = RLU _{Compounds of formula (I)} /RLU _DMSO _Control *100％

The compound has better agonistic activity to hTLR8 and better selective activating effect to hTLR8, the test result of the agonistic activity of the compound to human TLR7 and TLR8 is shown in table A, the toxicity of the compound to cells is small, and the toxicity of the compound to cells is shown in table A-1. Table a: agonistic activity of the compounds of the application on human hTLR7 and hTLR8

Examples numbering	TLR8 EC ₅₀ (μM)	TLR7 EC ₅₀ (μM)
			1	0.041	31.07
2	0.005	9.12
			3	0.285	N/A
4	0.067	16.03
			5	0.066	N/A
6	0.101	39.6
			7	0.043	＞100
8	0.066	＞100
			9	0.09	42.52
10	0.013	35.95
			11	0.039	22.33
14	0.046	＞100
			16	0.655	＞100
19	0.168	＞100

Conclusion: experimental data show that the compound has better agonistic activity on hTLR8 and better selective activation on hTLR 8.

Table a-1: toxicity results of the inventive Compounds on cells

Conclusion: experimental data indicate that the compounds of the application have low toxicity to cells.

Test 2: automated patch clamp detection of compound effects on hERG channel currents expressed by HEK293 cell stability

The purpose of the experiment is as follows: the risk of inhibition of the cardiac hERG potassium channel was assessed by measuring the concentration effect of compounds blocking the hERG channel using patch clamp technology and HEK-293 cell lines stably expressing the hERG channel.

The experimental method comprises the following steps: hERG cells are clamped by patch clamp technology, membrane rupture is carried out after high-resistance sealing is formed, hERG current is recorded in a whole cell recording mode, and each drug concentration is set to be twice administration for at least 5 minutes. Test concentrations were 0.3 μΜ,1 μΜ,3 μΜ,10 μΜ and 30 μΜ, and the test compounds were observed for changes in hERG current.

Conclusion: the hERG test experimental data shows that the compounds of the invention have low toxicity to the heart.

Test 3: inhibition of human liver microsomal CYP enzymes by the compounds of the invention

The purpose of the experiment is as follows: the inhibition of the primary metabolizing enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 in the microsomes by the test compounds was evaluated using the human liver microsome system.

The experimental method comprises the following steps: the concentration of the test substance in the final incubation system was 10. Mu.M, and incubated with human liver microsome suspensions containing cytochrome P450 enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4, respectively. Substrates are known to be metabolically converted by the corresponding single enzymes to specific metabolites, and the metabolites are determined by the UPLC-MS/MS method. The relative inhibition (Relative Inhibition (%)) was calculated by testing the percent reduction in metabolite production of the compound and solvent DMSO over the same time period. Relative inhibition% ＝(1-(N _+inh /N _veh ))×100

N is the concentration of the probe substrate metabolite and is assumed to be 0 for the blood-borne products of the inhibitor group with or without 0 min. N (N) _+inh To add inhibitor group metabolite concentration, N _veh Is the metabolite concentration of the inhibitor-free group. The structure of the compound liver drug enzyme inhibition test is shown in Table B.

Table B: experimental data for liver drug enzyme inhibition test of the compound of the invention

Conclusion: the liver drug enzyme inhibition test experimental data show that the compound of the invention has no inhibition effect on main liver drug enzyme

Test 4: induction of human liver microsomal CYP enzymes by the compounds of the invention

The purpose of the experiment is as follows: the induction of CYP1A2, CYP2B6 and CYP3A4 by the test substances is evaluated from the two aspects of enzyme activity and mRNA level respectively by using frozen human liver cells as a test system.

The experimental method comprises the following steps: the induction was started 24 hours after cell plating by adding the medium containing the compound to be tested (test concentrations of 10, 1 and 0.1. Mu.M), fresh drug-containing medium was changed every 24 hours, after 72 hours of induction, the medium was changed to medium containing CYP1A2, CYP2B6 and CYP3A4 specific substrates for 30 minutes of incubation, 100. Mu.L was taken for treatment, and the enzyme activity level was evaluated by detecting the labeled metabolites of the substrates. Finally, the cells are lysed and reverse transcribed, and the expression levels of CYP1A2, CYP2B6 and CYP3A4 genes in the cells are estimated by a real-time quantitative PCR method.

The induction times of the test compound compared with the blank control and the induction percentage of the test compound compared with the positive control are used as the basis for evaluating the induction potential of the test compound. Among them, the CYP1A2 positive control is: omeprazole; the CYP2B6 positive control was: phenobarbital; the CYP3A4 positive control was: rifampicin. The results of the liver drug enzyme induction test are shown in Table C.

Table C: experimental data of liver drug enzyme induction test

The following is noted: the comparative compound was (R) -2- ((2-amino-7-fluoropyrido [3,2-d ] pyrimidin-4-yl) amino) -2-methylhex-1-ol

Conclusion: experimental data of liver drug enzyme induction test show that the compound has no induction effect on liver drug enzymes CYP1A2, CYP2B6 and CYP3A 4.

Test 5: pharmacokinetic experiments of the Compounds of the invention in beagle dogs, mice, rats or cynomolgus monkeys

(1) Pigeon PK test experiment

PK assay of compounds in beagle dogs (ex tslycra laboratory animals inc, henna, weight 10-12kg, male, age 10-12 months, 3 per group orally, 3 per group intravenously):

beagle dogs were given 2.5mg/kg or 5mg/kg or 0.5mg/kg or 1mg/kg or 2mg/kg of test compound by oral gavage.

Intravenous blood was collected at time points (0.083, 0.25,0.5,1,2,4,6,8 and 24 hours) after administration and collected at EDTA-K addition ₂ Is arranged in the anticoagulation tube. After liquid-liquid extraction, the plasma samples were quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. And calculating pharmacokinetic parameters by a non-atrioventricular model method by using WinNonlin 6.3 software.

Conclusion: the drug generation experimental data show that the compound has better pharmacokinetic property in beagle bodies and has good application prospect in anti-HBV aspect.

(2) Mouse PK test experiment:

PK assay of compounds in ICR mice (ex mala laboratory animals inc, glauca, henna, weight 20-25g, male, age 45-60 days, 3 per group orally, 3 per group intravenously):

ICR mice were given 10mg/kg by oral gavage or 2mg/kg by tail vein injection of the test compound or 10 mg/kg.

Blood was collected from orbital veins at time points (0.083,0.25,0.5,1,2,4,6,8 and 24 hours) after administration and collected at EDTA-K addition ₂ Is arranged in the anticoagulation tube. After liquid-liquid extraction, the plasma samples were quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. And calculating pharmacokinetic parameters by a non-atrioventricular model method by using WinNonlin 6.3 software.

Conclusion: the drug generation experimental data show that the compound has better pharmacokinetic property in mice and has good application prospect in anti-HBV aspect.

(3) SD rat PK test experiment:

PK assay of compounds in SD rats (ex malaysia schrader laboratory animals inc., weight 200-250g, male, age 2-3 months, 3 per group orally, 3 per group intravenously):

rats are given 2.5mg/kg or 5mg/kg by oral gavage or 1mg/kg by intravenous injection of test compound.

Intravenous blood was collected at time points (0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours) after administration and collected on EDTA-K ₂ Is arranged in the anticoagulation tube. After liquid-liquid extraction, the plasma samples were quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. And calculating pharmacokinetic parameters by a non-atrioventricular model method by using WinNonlin 6.3 software.

Conclusion: the drug generation experimental data show that the compound of the invention has better in vivo exposure of SD rats, which indicates that the compound of the invention has good in vivo absorption in SD rats, good bioavailability and good application prospect in anti-HBV aspect.

(4) Cynomolgus monkey PK test experiment:

PK assay of compounds in cynomolgus monkeys (purchased from guangdong spring biosciences development limited, weight 3-6kg, male, age 4-6 years, 3 per group orally, 3 per group intravenously):

the cynomolgus monkey is administered 2.5mg/kg or 5mg/kg orally and parenterally or 0.5mg/kg or 1mg/kg of test compound.

Intravenous blood was collected at time points (0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours) after administration and collected at EDTA-K addition ₂ Is arranged in the anticoagulation tube. After liquid-liquid extraction, the plasma samples were quantitatively analyzed by multiplex reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer. And calculating pharmacokinetic parameters by a non-atrioventricular model method by using WinNonlin 6.3 software.

Conclusion: the pharmaceutical generation experimental data show that the compound has good pharmacokinetic properties in the bodies of the cynomolgus monkeys and has good application prospect in the aspect of HBV resistance.

While the invention has been described in detail in the foregoing general description, embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.

Claims

1. A compound which is a compound represented by the formula (I) or a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein X is N or CR ⁷ ；

Y is N or CR ⁴ ；

R ^7a is OH, amino, C _1-6 Alkoxy, C _1-6 Alkyl or C _1-6 An alkylamino group.

2. The compound of claim 1, wherein each R ¹ 、R ² 、R ⁵ 、R ⁶ And R is ⁷ Independently hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, N-pentyl or N-hexyl, wherein said N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-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 with 1, 2, 3 or 4 groups independently selected from F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, N-propyl, isopropyl, N-butyl and sec-butyl Substituted by radicals;

r is furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or-C (=O) -R ³ Wherein the furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -C (=o) -OH, -C (=o) -O-methyl, -C (=o) -O-ethyl, -C (=o) -O-n-propyl, -C (=o) -O-isopropyl, -C (=o) -O-n-butyl, -C (=o) -O-isobutyl and-C (=o) -O-sec-butyl.

3. The compound of claim 1, wherein R ³ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, a monocyclic heteroaryl group consisting of 5 to 6 ring atoms, a fused bicyclic heteroaryl group consisting of 8 to 10 ring atoms or a fused bicyclic heterocyclyl group consisting of 8 to 10 ring atoms, wherein the phenyl, the monocyclic heteroaryl group consisting of 5 to 6 ring atoms, the fused bicyclic heteroaryl group consisting of 8 to 10 ring atoms and the fused bicyclic heterocyclyl group consisting of 8 to 10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w1 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl each independently substituted with 1, 2, 3, or 4 substituents independently selected from F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.

4. The compound of claim 1, wherein R ³ Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, and the like,Isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl,Or a fused bicyclic heterocyclic group consisting of 8 to 10 ring atoms, wherein the phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, or->And fused bicyclic heterocyclic groups consisting of 8 to 10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w1 The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl each independently substituted with 1, 2, 3, or 4 substituents independently selected from F, cl, br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.

5. The compound of claim 1, wherein R ⁴ Is hydrogen, deuterium, F, cl, br, I, hydroxy, cyano, amino, C _1-4 Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said C _1-4 Alkylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independentlyUnsubstituted or substituted by 1, 2, 3 or 4R ^w2 Substituted with substituents of said furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently being substituted with 1 or 2R ⁸ Is substituted by a substituent of (2).

6. The compound of claim 1, wherein each R ⁸ Independently a monocyclic heteroaryl group of 5 to 6 ring atoms, a fused bicyclic heteroaryl group of 7 to 10 ring atoms, a monocyclic heterocyclyl group of 3 to 6 ring atoms or a fused bicyclic heterocyclyl group of 8 to 10 ring atoms, wherein the monocyclic heteroaryl group of 5 to 6 ring atoms, the fused bicyclic heteroaryl group of 7 to 10 ring atoms, the monocyclic heterocyclyl group of 3 to 6 ring atoms and the fused bicyclic heterocyclyl group of 8 to 10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w3 Is substituted by a substituent of (2).

7. The compound of claim 1, wherein R ⁸ Is furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or Wherein the furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolylAlkyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl and +.>Each independently is unsubstituted or substituted with 1, 2, 3, 4 or 5R ^w3 Is substituted by a substituent of (2).

8. The compound of claim 1, wherein each R ^w1 、R ^w2 And R is ^w3 Independently deuterium, F, cl, br, I, = O, R ^7a -C (=o) -, hydroxy, cyano, amino, C _1-4 Alkylamino, C _1-4 Alkoxy, C _1-4 Alkyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, HOOC-phenyl-or HOOC-C _1-4 Alkylene-, wherein said C _1-4 Alkylamino, C _1-4 Alkoxy, C _1-4 Alkyl, C _1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl in HOOC-phenyl-and HOOC-C _1-4 C in alkylene radical _1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, cl, br, I, HOOC-, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl;

R ^7a is OH, amino, C _1-4 Alkoxy, C _1-4 Alkyl or C _1-4 An alkylamino group.

9. The compound of claim 1, wherein each R ^w1 、R ^w2 And R is ^w3 Independently deuterium, F, cl, br, I, = O, R ^7a -C (=o) -, hydroxy, cyano, amino, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butylRadical, tert-butyl radical, -CH ₂ F、-CH ₂ Cl、-CF ₃ 、-CHF ₂ 、-CHCl ₂ 、-CH ₂ CH ₂ F、-CH ₂ CH ₂ Cl、-CH ₂ CHF ₂ 、-CH ₂ CHCl ₂ 、-CHFCH ₂ F、-CHClCH ₂ Cl、-CH ₂ CF ₃ 、-CH(CF ₃ ) ₂ 、-CF ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CHF ₂ 、-CH ₂ CH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, HOOC-phenyl-, HOOC-CH ₂ -、HOOC-(CH ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ -、HOOC-C(CH ₃ ) ₂ Or HOOC-C (CH) ₃ ) ₂ CH ₂ -, wherein said N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-l-propoxy, 2-butoxy, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, -CH ₂ F、-CH ₂ Cl、-CHF ₂ 、-CHCl ₂ 、-CH ₂ CH ₂ F、-CH ₂ CH ₂ Cl、-CH ₂ CHF ₂ 、-CH ₂ CHCl ₂ 、-CHFCH ₂ F、-CHClCH ₂ Cl、-CH ₂ CF ₃ 、-CH(CF ₃ ) ₂ 、-CF ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ F、-CH ₂ CH ₂ CHF ₂ 、-CH ₂ CH ₂ CF ₃ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl in HOOC-phenyl-, HOOC-CH ₂ -CH in ₂ -、HOOC-(CH ₂ ) ₂ - (CH) in- ₂ ) ₂ -、HOOC-(CH ₂ ) ₃ - (CH) in- ₂ ) ₃ -、HOOC-C(CH ₃ ) ₂ -C (CH) ₃ ) ₂ -and HOOC-C (CH) ₃ ) ₂ CH ₂ -C (CH) ₃ ) ₂ CH ₂ -each ofIndependently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, cl, br, I, HOOC-, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

10. The compound of claim 1 comprising the structure of one of:

or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1-10, and pharmaceutically acceptable excipients thereof.

12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 in the manufacture of a medicament for preventing, treating or alleviating a TLR 8-mediated disorder in a patient.

13. Use of a compound according to any one of claims 1-10 or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment or prophylaxis of hepatitis b virus infection, hepatitis c virus infection, influenza virus infection, herpes virus infection, hiv infection, allergic diseases, rheumatoid arthritis, allergic asthma, chronic fatigue, type II diabetes, hay fever, lupus erythematosus, multiple sclerosis, melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.