WO2017219931A1 - 二氢蝶啶酮类衍生物、其制备方法及其用途 - Google Patents

二氢蝶啶酮类衍生物、其制备方法及其用途 Download PDF

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WO2017219931A1
WO2017219931A1 PCT/CN2017/088785 CN2017088785W WO2017219931A1 WO 2017219931 A1 WO2017219931 A1 WO 2017219931A1 CN 2017088785 W CN2017088785 W CN 2017088785W WO 2017219931 A1 WO2017219931 A1 WO 2017219931A1
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alkyl
compound
group
membered
alkoxy
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French (fr)
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刘钢
于华
陈强强
康熙伟
罗小勇
蒋语涵
曾宏
宋宏梅
刘瑞红
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN201780003780.7A priority Critical patent/CN108290893B/zh
Publication of WO2017219931A1 publication Critical patent/WO2017219931A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of medicine and relates to a TLR7 agonist, in particular to a dihydrodisc ketone derivative, a preparation method thereof and use thereof.
  • TLRs Toll-like receptors
  • PRR pattern recognition receptor
  • TLR7 is one of the TLRs family, mainly expressed in the lung, placenta, heart, bone marrow, lymph nodes and other tissues; the cells expressing TLR7 are mainly immune cells, including pulp-like dendritic cells (pDCs) and bone marrow-like dendritic cells (mDCs). ), B lymphocytes, macrophages, etc. (especially with dendritic cells).
  • TLR7 is primarily activated by viral single-stranded RNA. Activation of serous dendritic cells plays an important role in the innate response to the virus, and these cells are responsible for the production of type I interferon (IFN) in the acute phase of most viral infections. Induction of the production and secretion of endogenous interferons (such as alpha-interferon and beta-interferon) promotes an effective adaptive immune response.
  • IFN type I interferon
  • Hepatitis B is an infectious disease caused by hepatitis B virus (HBV) and mainly characterized by liver inflammation. HBV infection is worldwide. According to the World Health Organization, about 2 billion people worldwide have been infected with HBV, of which 350 million are chronic HBV infections. About 1 million people die each year from liver failure, liver cirrhosis and primary hepatocellular carcinoma caused by HBV infection. .
  • the genotyping of hepatitis B is mainly divided into A, B, C, D, E, F, G, and H types. Different genotyping of HBV is associated with the condition and antiviral therapy of patients with hepatitis B.
  • the main prevention and treatment methods for hepatitis B virus are hepatitis B vaccine prevention, interferon and nucleoside analogues.
  • Administration of exogenous alpha interferon eg, recombinant alpha-interferon or pegylated IFN-a
  • HBV chronic hepatitis B virus
  • HBV chronic hepatitis B virus
  • TLR7 is down-regulated in HBV-infected patients compared with healthy subjects, and HBV infection can directly down-regulate TLR7 expression.
  • the response mechanism of TLR7 agonist GS-9620 may be high intestinal absorption, promoting local activation of TLR7 in dendritic cells of intestinal lymphoid tissue/liver, and local activation further activates the systemic immune system.
  • TLR7 agonists mainly exert immunological antiviral effects by stimulating the response of endogenous interferon type I (INF- ⁇ / ⁇ ) and enhancing the expression of interferon downstream signaling interferon regulatory genes (ISGs), TLR7
  • ISGs interferon downstream signaling interferon regulatory genes
  • the present invention provides a class of TLR7 agonists, a process for their preparation and their use in the preparation of a disease associated with low expression of TLR7.
  • a first aspect of the invention provides a compound of formula I or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof or any polymorph or racemate thereof , or their metabolite forms, and mixtures thereof,
  • X is -O-, -NH-, -S-, -C(O)- or -S(O) 2 -;
  • R 1 is C 1-6 alkyl, 3-8 membered cycloalkyl-C 0-6 alkyl or 3-8 membered heterocycloalkyl-C 0-6 alkyl, wherein said C 1-6 alkyl a 3-8 membered cycloalkyl-C 1-6 alkyl group or a 3-8 membered heterocycloalkyl-C 1-6 alkyl group which is unsubstituted or independently one or more (for example 1, 2, 3) Or 4) substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl And C 2-6 alkynyl;
  • L is -(CH 2 ) n -, wherein n is 1, 2, 3, 4, 5 or 6;
  • Ring A is a benzene ring, a pyridine, a pyrimidine, a piperazine, a pyrazine, a pyridazine, a 3-8 membered cycloalkyl group or a 5-membered heterocyclic group (for example, a 5-membered heterocycloalkyl group or a 5-membered heteroaryl group);
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, and C 1-6 alkoxy;
  • R 4 is absent or is 5-9 membered heterocyclyl-C 0-6 alkyl, 6-9 membered heterospiro-C 0-6 alkyl, 6-9 membered heterocyclo-C 0-6 An alkyl group or a 6-9 membered heterocyclic ring-C 0-6 alkyl group, wherein the 5-9 membered heterocyclyl-C 0-6 alkyl group, 6-9 membered heterospiro-C 0-6 Alkyl, 6-9 membered heterocyclo-C 0-6 alkyl or 6-9 membered heterocyclic-C 0-6 alkyl is unsubstituted or each independently one or more (eg 1, 2, 3 or 4) substituents selected from the group consisting of: hydroxy, halogen, carbonyl, oxo, carboxy, C 1-6 alkoxycarbonyl, C 1-6 alkyl, halo C 1-6 alkyl , C 1-6 alkoxy, C 1-6 alkylamino, di C
  • R 1 is selected from propyl or butyl
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, F, C 1-6 alkyl and C 1-6 alkoxy;
  • R 4 is a substituted or unsubstituted 5-9 membered heteroaryl-C 0-6 alkyl group (e.g., tetrazolium), 6-9 membered heterospiro-C 0-6 alkyl group, 6-9 membered hetero And a cyclo-C 0-6 alkyl group or a 6-9 membered heterobridged ring-C 0-6 alkyl group, or a substituted 5 membered heterocycloalkyl-C 0-6 alkyl group, wherein the substituted 5 -9 membered heteroaryl-C 0-6 alkyl (eg tetrazolium), 6-9 membered heterospiro-C 0-6 alkyl, 6-9 membered heterocyclo-C 0-6 alkane a 6-9 membered heterocyclic ring-C 0-6 alkyl group or a 5 membered heterocycloalkyl-C 0-6 alkyl group means the 5-9 membered heteroaryl-C
  • R 1 is selected from
  • C 1-6 alkyl group wherein the C 1-6 alkyl group is substituted by one or more (eg 1, 2, 3 or 4) cyano, C 2-6 alkenyl or C 2-6 alkynyl groups .
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy, and 2-dimethylaminoethoxy;
  • R 4 is absent or is 6-9 membered heterospiro-C 0-6 alkyl, 6-9 membered heterocyclo-C 0-6 alkyl, 6-9 membered heterocyclic ring-C 0- 6 alkyl, 5-membered heterocycloalkyl-C 0-6 alkyl, piperidinyl-C 0-6 alkyl, piperazinyl-C 0-6 alkyl, piperazinone-C 0-6 alkyl , 4-oxo-[1,4]azaphosphoryl or 1,2,3,6-tetrahydropyridyl-C 0-6 alkyl, wherein the 6-9 membered heterospiro-C 0 -6 alkyl, 6-9 membered heterocyclo-C 0-6 alkyl, 6-9 membered heterocyclic ring-C 0-6 alkyl, 5-membered heterocycloalkyl-C 0-6 alkyl, piperidinyl-C 0-6 alkyl, piperazinyl
  • the X is selected from the group consisting of -O-, -NH-, -S-, and -C(O)-; preferably, the X is selected from the group consisting of -O- and -S-; Preferably, said X is -O-.
  • the L is -(CH 2 ) n -, and n is 1 or 5.
  • Ring A is a benzene ring
  • L and R 4 are meta to each other.
  • Ring A is pyridine
  • L and R 4 are para to each other.
  • the compound has the structure shown below,
  • R 1 is selected from propyl or butyl
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, F, C 1-6 alkyl and C 1-6 alkoxy; preferably, both R 2 and R 3 are hydrogen;
  • R 4 is a substituted or unsubstituted 5-9 membered heteroaryl-C 0-6 alkyl group (e.g., tetrazolium), 6-9 membered heterospiro-C 0-6 alkyl group, 6-9 membered hetero And a cyclo-C 0-6 alkyl group or a 6-9 membered heterobridged ring-C 0-6 alkyl group, or a substituted 5 membered heterocycloalkyl-C 0-6 alkyl group, wherein the substituted 5 -9 membered heteroaryl-C 0-6 alkyl (eg tetrazolium), 6-9 membered heterospiro-C 0-6 alkyl, 6-9 membered heterocyclo-C 0-6 alkane a 6-9 membered heterocyclic ring-C 0-6 alkyl group or a 5 membered heterocycloalkyl-C 0-6 alkyl group means the 5-9 membered heteroaryl-C
  • the alkyl group is a 6-9 membered heterospiro-C 0-6 alkyl group containing a pyrrolidine ring, a 6-9 membered heterocycloalkyl-C 0-6 alkyl group containing a pyrrolidine ring or a pyrrolidine ring-containing group.
  • 6-9 membered heterocyclic ring-C 0-6 alkyl group for example, 6-9 membered heterospiro-methyl group containing a pyrrolidine ring, 6-9 membered heterocyclo-methyl group or 6-9 member Hybrid bridge ring-methyl, for example,
  • the 5-9 membered heteroaryl-C 0-6 alkyl group is a 5-9 membered heteroaryl group, such as oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazo Azolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc.;
  • the 5-membered heterocycloalkyl-C 0-6 alkyl group is a 5-membered heterocycloalkyl-methyl group, for example, a pyrrolidinylmethyl or pyrrolidone methyl group.
  • the substituent is selected from the group consisting of a hydroxyl group, a carboxyl group, a C1-6 alkoxycarbonyl group (e.g., methoxycarbonyl or ethoxycarbonyl), a methylol group, a methoxy group, a dimethylamino group, a fluorine group.
  • the compound has the structure shown below,
  • X is -O-, -NH-, -S-, -C(O)- or -S(O) 2 -; preferably, X is -O-, -NH-, -S- or -C(O More preferably, X is -O- or -S-; more preferably, X is -O-;
  • R 1 is selected from
  • substituted or unsubstituted C 1-6 alkyl group wherein the substituted C 1-6 alkyl group means that the C 1-6 alkyl group is one or more (for example 1, 2, 3 or 4) a substituent substituted from a cyano group, a C 2-6 alkenyl group, and a C 2-6 alkynyl group;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, and C 1-6 alkoxy;
  • R 1 is an unsubstituted C 1-6 alkyl group
  • R 2 and R 3 are not hydrogen at the same time
  • R 1 is selected from
  • the compound has the structure shown below,
  • R 1 is selected from an alkyl group
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, and di C 1-6 alkyl substituted amino-C 1-6 alkoxy;
  • R 4 is absent or is 6-9 membered heterospiro-C 0-6 alkyl, 6-9 membered heterocyclo-C 0-6 alkyl, 6-9 membered heterocyclic ring-C 0- 6 alkyl, 5-membered heterocycloalkyl-C 0-6 alkyl, piperidinyl-C 0-6 alkyl, piperazinyl-C 0-6 alkyl, piperazinone-C 0-6 alkyl , 4-oxo-[1,4]azaphosphoryl or 1,2,3,6-tetrahydropyridyl-C 0-6 alkyl, wherein the 6-9 membered heterospiro-C 0 -6 alkyl, 6-9 membered heterocyclo-C 0-6 alkyl, 6-9 membered heterocyclic ring-C 0-6 alkyl, 5-membered heterocycloalkyl-C 0-6 alkyl, piperidinyl-C 0-6 alkyl, piperazinyl
  • R 4 When R 4 is absent, one of R 2 and R 3 is 2-dimethylaminoethoxy;
  • R 1 is selected from a C 1-6 alkyl group (e.g., butyl or pent-2-yl);
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy, and 2-dimethylaminoethoxy;
  • R 4 is absent or is 6-9 membered heterospiro-C 0-6 alkyl, 6-9 membered heterocyclo-C 0-6 alkyl, 6-9 membered heterocyclic ring-C 0- 6 alkyl, 5-membered heterocycloalkyl-C 0-6 alkyl, piperidinyl-C 0-6 alkyl, piperazinyl-C 0-6 alkyl, piperazinone-C 0-6 alkyl , 4-oxo-[1,4]azaphosphoryl or 1,2,3,6-tetrahydropyridyl-C 0-6 alkyl, wherein the 6-9 membered heterospiro-C 0 -6 alkyl, 6-9 membered heterocyclo-C 0-6 alkyl, 6-9 membered heterocyclic ring-C 0-6 alkyl, 5-membered heterocycloalkyl-C 0-6 alkyl, piperidinyl-C 0-6 alkyl, piperazinyl
  • R 4 When R 4 is absent, one of R 2 and R 3 is 2-dimethylaminoethoxy;
  • X is -O-, -NH-, -S- or -C(O), preferably -O-, -NH- or -S-, further preferably -O- or -S-, more preferably -O -;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy, and 2-dimethylaminoethoxy;
  • R 4 is absent or is piperidinyl-C 0-6 alkyl, piperazinyl-C 0-6 alkyl or 1,2,3,6-tetrahydropyridyl-C 0-6 alkyl, wherein Said piperidinyl-C 0-6 alkyl, piperazinyl-C 0-6 alkyl or 1,2,3,6-tetrahydropyridyl-C 0-6 alkyl unsubstituted or independently One or more (for example, 1, 2, 3 or 4) substituents selected from the group consisting of: hydroxy, halogen, C 1-6 alkyl, C 1-6 alkylamino, di C 1-6 Alkyl substituted amino.
  • the compound has the structure shown below,
  • R 1 is selected from the group consisting of butyl and pent-2-yl
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkoxy and 2-dimethylaminoethoxy; preferably, both R 2 and R 3 are hydrogen, or R 2 is hydrogen R 3 Is 2-dimethylaminoethoxy or fluorine;
  • R 4 is absent or represents 6-9 membered heterospiro-C 0-6 alkyl, 6-9 membered heterocyclo-C 0-6 alkyl (eg, 1-pyrrolidino[3,4- c]pyrrolidinyl), 6-9 membered heterobridged-C 0-6 alkyl, 5-membered heterocycloalkyl-C 0-6 alkyl (eg, 1-pyrrolidinyl or 1-pyrrolidine) , piperidinyl, piperazinyl, piperazinone-C 0-6 alkyl, 4-oxo-[1,4]azaphosphoryl or 1,2,3,6-tetrahydropyridyl, Wherein the 6-9 membered heterospiro-C 0-6 alkyl group, 6-9 membered heterocyclo-C 0-6 alkyl group, 6-9 membered heterocyclic ring group-C 0-6 alkyl group , 5-membered heterocycloalkyl-C 0-6 alkyl, pipe
  • the compound of Formula I-3A wherein R 4 is absent or is piperidinyl-C 0-6 alkyl, piperazinyl-C 0-6 alkyl or 1, 2,3,6-tetrahydropyridyl-C 0-6 alkyl, wherein the piperidinyl-C 0-6 alkyl, piperazinyl-C 0-6 alkyl or 1,2,3,6 - tetrahydropyridyl-C 0-6 alkyl is unsubstituted or each independently substituted with one or more (for example 1, 2, 3 or 4) substituents selected from the group consisting of hydroxy, halogen An amino group substituted with a C 1-6 alkyl group, a C 1-6 alkylamino group, or a di C 1-6 alkyl group.
  • R 4 is selected from the group consisting of piperazinyl, 4-methylpiperazinyl, 4-isopropylpiperazinyl, N-methyl- 1,2,3,6-tetrahydropyridin-4-yl, N-methylpiperidinyl, piperazinone-C 0-6 alkyl, 4-oxo-[1,4]azaphosphoryl, 4-hydroxypiperidinyl and dimethylaminopiperidine.
  • R 4 is selected from the group consisting of piperazinyl, 4-methylpiperazinyl, 4-isopropylpiperazinyl, N-methyl- 1,2,3,6-tetrahydropyridin-4-yl, N-methylpiperidinyl, piperazinone-C 0-6 alkyl, 4-oxo-[1,4]azaphosphoryl, 4-hydroxypiperidinyl and 4-dimethylaminopiperidine.
  • R 4 is selected from the group consisting of piperazinyl, 4-methylpiperazinyl, 4-isopropylpiperazinyl, N-methyl- 1,2,3,6-tetrahydropyridin-4-yl, N-methylpiperidinyl, piperazinone-C 0-6 alkyl, 4-oxo-[1,4]azaphosphoryl and 4-hydroxypiperidinyl.
  • R 1 is selected from butyl
  • R 2 and R 3 are both hydrogen, or R 2 is hydrogen R 3 is 2-dimethylaminoethoxy or fluorine;
  • R 4 is absent or is selected from the group consisting of 4-methylpiperazinyl, N-methylpiperidinyl, N-methyl-1,2,3,6-tetrahydropyridin-4-yl.
  • the compound has the structure shown below,
  • R 3 is 2-dimethylaminoethoxy, R 4 is absent; or R 3 is hydrogen, and R 4 is selected from the group consisting of 4-methylpiperazinyl, N-methylpiperidinyl, N-methyl- 1,2,3,6-tetrahydropyridin-4-yl.
  • R 1 is an alkyl group
  • R 3 is hydrogen, halogen or C 1-4 alkyl
  • R 4 is selected from piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, C 1-6 alkylamino-C 1-6 alkoxy and di C 1-6 alkyl substituted amino -C 1-6 alkoxy, said piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl optionally substituted or polysubstituted with hydroxy, halogen, C 1 -6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di C 1-6 alkyl substituted amino, C 1-6 alkoxy-C 1 -6 alkyl and cyano substituted C 1-6 alkyl.
  • R 1 is C 1-6 alkyl
  • R 3 is hydrogen or halogen
  • R 4 is selected from the group consisting of piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl and di-C 1-6 alkyl Amino-C 1-6 alkoxy, the piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl optionally
  • the ground is mono- or polysubstituted by a substituent: a hydroxy group, a C 1-6 alkyl group, and a di C 1-6 alkyl group-substituted amino group.
  • R 1 is C 1-4 alkyl
  • R 3 is hydrogen, fluorine, chlorine or bromine
  • R 4 is selected from the group consisting of piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl and di-C 1-4 alkyl Amino-C 1-4 alkoxy, the piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl optionally The ground is mono- or polysubstituted by the following substituents: hydroxy, methyl, ethyl, propyl and dimethylamino.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
  • R 3 is hydrogen or fluorine
  • R 4 is selected from the group consisting of piperazin-1-yl, 4-dimethylaminopiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-methylpiperazin-1-yl, N-methylpiperidine 4-yl, N-methyl-1,2,3,6-tetrahydropyridin-4-yl and 2-dimethylaminoethoxy.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
  • R 3 is hydrogen
  • R 4 is selected from the group consisting of 4-methylpiperazin-1-yl, N-methylpiperidin-4-yl, N-methyl-1,2,3,6-tetrahydropyridin-4-yl and 2-di Methylaminoethoxy.
  • R 1 is C 1-6 alkyl, preferably C 1-4 alkyl, for example, R 1 is methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • the compound wherein R 1 is methyl.
  • the compound wherein R 1 is ethyl.
  • the compound wherein R 1 is n-propyl.
  • the compound wherein R 1 is isopropyl.
  • the compound wherein R 1 is n-butyl.
  • the compound wherein R 1 is isobutyl.
  • the compound wherein R 1 is sec-butyl.
  • the compound wherein R 1 is tert-butyl.
  • the compound wherein R 3 is hydrogen, fluoro, chloro, bromo, iodo, or C 1-4 alkyl.
  • the compound wherein R 3 is hydrogen.
  • the compound wherein R 3 is fluorine.
  • the compound wherein R 3 is bromine.
  • the compound wherein R 3 is iodine.
  • the compound wherein R 3 is methyl.
  • the compound wherein R 3 is ethyl.
  • the compound wherein R 3 is n-propyl.
  • the compound wherein R 3 is isopropyl.
  • the compound wherein R 3 is n-butyl.
  • the compound wherein R 3 is isobutyl.
  • the compound wherein R 3 is sec-butyl.
  • the compound wherein R 3 is tert-butyl.
  • R 4 is selected from the group consisting of piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridyl, C 1-6 alkylamino-C 1-6 Alkoxy and di-C 1-6 alkyl-substituted amino-C 1-6 alkoxy.
  • the piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl is optionally mono- or polysubstituted with a hydroxy group: , halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di C 1-6 alkyl substituted amino, C 1-6 alkane An oxy-C 1-6 alkyl group and a cyano substituted C 1-6 alkyl group.
  • the piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl is optionally mono- or polysubstituted by a hydroxy group, a methyl group, Ethyl, propyl and dimethylamino are mono- or polysubstituted.
  • the compound: R 4 is piperazinyl.
  • the compound: R 4 is piperidinyl.
  • R 4 is 1,2,3,6-tetrahydropyridyl.
  • R 4 is C 1-6 alkylamino-C 1-6 alkoxy.
  • R 4 is di C 1-6 alkyl substituted amino-C 1-6 alkoxy.
  • R 4 is selected from the group consisting of piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridine 4-yl and di-C 1-4 alkyl-substituted amino-C 1-4 alkoxy.
  • the compound: R 4 is a piperazin-1-yl.
  • the compound: R 4 is piperidin-1-yl.
  • the compound: R 4 is piperidin-4-yl.
  • R 4 is 1,2,3,6-tetrahydropyridin-4-yl.
  • R 4 is di C 1-4 alkyl substituted amino-C 1-4 alkoxy.
  • the piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridine-4 The group is optionally mono- or polysubstituted with a hydroxy group, a halogen, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylamino group, Di-C 1-6 alkyl-substituted amino, C 1-6 alkoxy-C 1-6 alkyl and cyano substituted C 1-6 alkyl.
  • the piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 1,2,3,6-tetrahydropyridine-4 The -yl group is optionally mono- or polysubstituted by the following substituents: hydroxy, methyl, ethyl, propyl and dimethylamino.
  • R 4 is 4-dimethylaminopiperidin-1-yl.
  • the compound: R 4 is 4-hydroxy-piperidin-1-yl.
  • R 4 is 4-methylpiperazin-1-yl.
  • R 4 is N-methylpiperidin-4-yl.
  • R 4 is N-methyl-1,2,3,6-tetrahydropyridin-4-yl.
  • R 4 is 2-dimethylaminoethoxy.
  • the compound has the structure shown below,
  • L is -(CH 2 ) n -, wherein n is 1, 2, 3, 4, 5 or 6, preferably n is 1 or 5;
  • Ring A is selected from 3-6 membered cycloalkyl, 5-membered heterocycloalkyl (eg pyrrolidine), 5-membered heteroaryl (oxazole, isoxazole, thiazole, pyrazole or imidazole) or piperazine;
  • 5-membered heterocycloalkyl eg pyrrolidine
  • 5-membered heteroaryl oxazole, isoxazole, thiazole, pyrazole or imidazole
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl, and C 1-6 alkoxy, and R 4 is absent; or,
  • R 2 and R 3 are both hydrogen and R 4 represents a 5-6 membered heterocycloalkyl-C 0-1 alkyl group, wherein the 5-6 membered heterocycloalkyl-C 0-1 alkyl group is unsubstituted or Substituted by one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of oxo, hydroxy, halo, C 1-6 alkyl, halo C 1-6 alkyl, C 1 -6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxy-C 1-6 alkyl;
  • R 2 is hydrogen
  • R 3 is selected from the group consisting of fluorine, methyl, trifluoromethyl and difluoromethyl, and R 4 is absent; or
  • R 2 and R 3 are both hydrogen, and R 4 represents a piperidinyl group or a piperidinyl group substituted by a methyl group.
  • n 5;
  • Ring A is selected from a 5-membered heterocycloalkyl group (e.g., pyrrolidine) or piperazine;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl and C 1-6 alkoxy; preferably, R 2 is hydrogen and R 3 is fluorine Or methyl;
  • R 4 does not exist.
  • L is a methylene group
  • Ring A is cyclopropyl or cyclobutyl
  • R 2 and R 3 are both hydrogen
  • R 4 is 4-methylpiperazinyl.
  • the compound is selected from the group consisting of
  • the invention further provides a process for the preparation of a compound according to any of the first aspects of the invention, wherein the compound of formula I can be prepared by the following reaction route:
  • Step 1 Compound SM-5 is reacted with cyanamide to give compound IN-23;
  • Step 2 Compound IN-23 reacts with R 1 -XH to form compound IN-24;
  • Step 3 Compound IN-24 ring closure reaction to give compound IN-25;
  • Step 4 nitration of compound IN-25 to give compound IN-26;
  • Step 5 chlorination of compound IN-26 to give compound IN-27;
  • Step 6 Compound IN-27 is reacted with amine IN-28 to give compound IN-29;
  • Step 7 Compound IN-29 is reduced by nitro reduction and cyclized to give the compound of formula I.
  • the compound of formula 1-1 can be prepared by the following reaction scheme:
  • Step 1 Compound SM-1 is reacted with ethyl aminoacetate to form compound compound IN-1;
  • Step 2 Compound IN-1 is reacted with 2-methylthio-5-nitro-6-chloro-4-pyrimidinamine to give compound IN-2;
  • Step 3 Compound IN-2 is oxidized to obtain compound IN-3;
  • Step 4 R 1 -OH is reacted with compound IN-3 to form compound compound IN-4;
  • Step 5 Compound IN-5 is obtained after cyclization of compound IN-4;
  • Step 6 Reduction of compound IN-5 to give compound IN-6;
  • Step 7 Compound IN-6 is subjected to reductive amination to form a compound of formula I-1;
  • the Formula I-2 can be prepared by the following reaction route:
  • Step 1 Compound SM-3 is reacted with ethyl aminoacetate to form compound IN-12;
  • Step 2 Compound IN-12 is reacted with 2-methylthio-5-nitro-6-chloro-4-pyrimidinamine to give compound IN-13;
  • Step 3 Compound IN-13 is oxidized to give compound IN-14;
  • Step 4 Compound IN-14 is reacted with R 1 -XH to form compound IN-15;
  • Step 5 cyclization of compound IN-15 to give a compound of formula I-2;
  • the Formula I-3 can be prepared by the following reaction route:
  • the first step the compound SM-2 reacts with R 4 H to form the compound IN-7;
  • Step 2 Compound IN-7 is reacted with ethyl aminoacetate to form compound IN-8;
  • the third step the compound IN-8 is reacted with 2-methylthio-5-nitro-6-chloro-4-pyrimidinamine to form the compound IN-9;
  • the fourth step the compound IN-9 is oxidized to obtain the compound IN-10;
  • Step 5 Compound IN-10 is reacted with R 1 -XH to form compound IN-11;
  • Step 6 cyclization of compound IN-11 to obtain a compound of formula I-3;
  • Lg in SM-2 is a leaving group of a nucleophilic substitution reaction (e.g., halogen, -OTs, -OCOR, R is an alkyl group), and the remaining atoms or substituents are as defined in formula I-3.
  • a nucleophilic substitution reaction e.g., halogen, -OTs, -OCOR, R is an alkyl group
  • the Formula I-3A can be prepared by the following reaction route:
  • the first step the compound SM-2A reacts with R 4 H to form the compound IN-7A;
  • the second step the compound IN-7A is reacted with ethyl aminoacetate to form the compound IN-8A;
  • the third step the compound IN-8A and 2-methylthio-5-nitro-6-chloro-4-pyrimidinamine are reacted to form the compound IN-9A;
  • the fourth step the compound IN-9A is oxidized to obtain the compound IN-10A;
  • the fifth step the compound IN-10A reacts with R 1 -OH to form the compound IN-11A;
  • Step 6 cyclization of compound IN-11A to obtain a compound of formula I-3A;
  • Lg in SM-2A is a leaving group of a nucleophilic substitution reaction (e.g., halogen, -OTs, -OCOR, R is an alkyl group), and the remaining atoms or substituents are as defined in formula I-3A.
  • a nucleophilic substitution reaction e.g., halogen, -OTs, -OCOR, R is an alkyl group
  • the Formula I-3A-1 can be prepared by the following reaction scheme:
  • the first step the compound SM-2A-1 reacts with R 4 H to form the compound IN-7A-1;
  • the second step the compound IN-7A-1 is reacted with ethyl aminoacetate to form the compound IN-8A-1;
  • the third step the compound IN-8A-1 is reacted with 2-methylthio-5-nitro-6-chloro-4-pyrimidinamine to form the compound IN-9A-1;
  • the fourth step the compound IN-9A-1 is oxidized to obtain the compound IN-10A-1;
  • the fifth step the compound IN-10A-1 reacts with CH 3 (CH 2 ) 3 OH to form the compound IN-11A-1;
  • Step 6 cyclization of compound IN-11A-1 to obtain a compound of formula I-3A-1;
  • Lg in SM-2A-1 is a leaving group of a nucleophilic substitution reaction (eg, halogen, -OTs, -OCOR, R is an alkyl group), and the remaining atoms or substituents are defined as Formula I-3A-1 Said in the middle.
  • a nucleophilic substitution reaction eg, halogen, -OTs, -OCOR, R is an alkyl group
  • the compound of formula 1-4 can be prepared by the following reaction scheme:
  • Step 1 The hydroxyl group of compound SM-4 is protected as its silyl ether compound IN-16;
  • Step 2 Compound IN-16 is reacted with ethyl bromoacetate to give compound IN-17;
  • Step 3 Compound IN-17 is reacted with 2-methylthio-5-nitro-6-chloro-4-pyrimidinamine to give compound IN-18;
  • Step 4 oxidation of the thioether of compound IN-18 to methylene sulfone compound IN-19;
  • Step 5 Compound IN-19 reacts with n-butanol to form IN-20;
  • Step 6 activation of the hydroxyl group of compound IN-20 to its mesylate compound IN-21;
  • Step 7 Compound IN-21 is reacted with Ring A to give compound IN-22;
  • Step 8 the nitro group of compound IN-22 is reduced to form a compound of formula I-4;
  • the atoms in the compounds of the invention may be replaced by their isotopes.
  • 12 C can be replaced by its isotope 13 C or 14 C;
  • 1 H can be replaced by 2 H (D, ⁇ ) or 3 H (T, ⁇ );
  • 31 P can be replaced by 32 P or 33 P, and the like.
  • the invention includes compounds of formula I and compounds obtained by isotopic substitution of any of the compounds of formula I.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of any one of the first aspects of the present invention or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof or any of them Forms or racemates, or their metabolite forms, and mixtures thereof, and the like, and optionally, one or more pharmaceutically acceptable carriers or excipients.
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
  • the carriers described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plants.
  • the excipient refers to an addenda other than the main drug in the pharmaceutical preparation. Its nature is stable, no compatibility with the main drug, no side effects, no effect on the effect, not easy to deform, chapped, mildew, insects, harmless to the human body, no physiological effects at room temperature, does not produce chemical or physical with the main drug The effect does not affect the determination of the content of the main drug.
  • a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof or any polymorph or racemate thereof, or a metabolite thereof, and mixtures thereof Administration can be by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes or as an inhalant.
  • the pharmaceutical composition may optionally be administered in combination with other agents that have at least some effect in the treatment of various diseases.
  • a compound of the present invention or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof or any polymorph or racemate thereof, or a metabolite thereof, and mixtures thereof
  • Various suitable dosage forms can be formulated according to the route of administration.
  • the pharmaceutical composition or a suitable dosage form according to the invention may contain from 0.01 mg to 1000 mg of the compound of the invention, suitably from 0.1 mg to 800 mg, preferably from 0.5 to 500 mg, more preferably from 1 to 350 mg, particularly preferably from 5 to 250 mg.
  • a compound of the invention or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof, or any polymorph or racemate thereof, or a metabolite thereof, when administered orally, and Mixtures and the like of these may be formulated into any orally acceptable preparation including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule formulation generally comprises lactose and dried cornstarch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension.
  • some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.
  • a compound of the invention or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof, or any polymorph or racemate thereof, or a metabolite form thereof, when applied topically to the skin, And mixtures thereof and the like can be prepared in the form of a suitable ointment, lotion or cream preparation in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which may be used in ointment preparations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; and detergents or creams which may be used include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the medicament can be administered in the form of a sterile injectable preparation, including sterile injectable water or an oil suspension or a sterile injectable solution.
  • a sterile injectable preparation including sterile injectable water or an oil suspension or a sterile injectable solution.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • suitable in vitro or in vivo assays are performed to determine the efficacy of the pharmaceutical compositions of the invention and whether the administration is suitable for treating a disease or medical condition in a subject. Examples of such assays are described below in connection with specific diseases or medical treatments in non-limiting embodiments.
  • an effective amount of a composition of the invention sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day.
  • the dosage is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the dosage may range from about 0.01 to 1000 mg/kg of subject weight per day, every two days or every three days, more typically from 0.1 to 500 mg/kg of subject weight.
  • An exemplary treatment regimen is once every two days or once a week or once a month.
  • the formulation is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly or yearly.
  • the formulation may be administered in the form of a sustained release formulation, in which case less dosing frequency is required.
  • the dosage and frequency will vary depending on the half-life of the formulation in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment. In preventive applications, Relatively low doses are administered over a relatively long period of time. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, and preferably until the individual exhibits partial or complete improvement in the symptoms of the disease, after which the patient can be administered Prevention program.
  • the invention further provides a compound of any one of the first aspects of the invention, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof, or any polymorph or racemate thereof, or Use of their metabolite forms, and mixtures thereof, and the like, or pharmaceutical compositions thereof, in the preparation of a TLR agonist, preferably, the TLR agonist is a TLR7 agonist.
  • the invention further provides a compound of any one of the first aspects of the invention, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof, or any polymorph or racemate thereof, or The use of their metabolite forms, and mixtures thereof, and the like, or pharmaceutical compositions thereof, for the preparation of a medicament as a TLR agonist, preferably, the TLR agonist is a TLR7 agonist.
  • the invention further provides a compound of any one of the first aspects of the invention, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof, or any polymorph or racemate thereof, or Use of their metabolite forms, as well as mixtures thereof and the like, or pharmaceutical compositions thereof, for the manufacture of a medicament for the treatment of a disease associated with TLR7.
  • the TLR7-related disease is selected from the group consisting of hepatitis (eg, hepatitis B (HBV) or hepatitis C (HCV)), asthma, allergic rhinitis, dermatomyositis, malaria, psoriasis, Actinic keratosis, solid tumors (such as bladder cancer or non-Hodgkin's lymphoma (NHL)), hematological tumors, melanoma, and autoimmune diseases (such as systemic lupus erythematosus (SLE), AIDS (HIV)).
  • HBV hepatitis B
  • HCV hepatitis C
  • the invention further provides a compound of any one of the first aspects of the invention, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, isotopic compound thereof, or any polymorph or racemate thereof, or Their metabolite forms, as well as mixtures thereof and the like, or pharmaceutical compositions thereof, for the treatment of diseases associated with TLR7.
  • the TLR7-related disease is selected from the group consisting of hepatitis (eg, hepatitis B (HBV) or hepatitis C (HCV)), asthma, allergic rhinitis, dermatomyositis, malaria, psoriasis, Actinic keratosis, solid tumors (such as bladder cancer or non-Hodgkin's lymphoma (NHL)), hematological tumors, melanoma, and autoimmune diseases (such as systemic lupus erythematosus (SLE), AIDS (HIV)).
  • HBV hepatitis B
  • HCV hepatitis C
  • the invention also provides a method of treating a disease associated with TLR7 comprising administering to a subject in need thereof an effective amount of a compound of any one of the first aspects of the invention, or a pharmaceutically acceptable salt, ester, or solvent thereof Compounds, hydrates, isomers, isotopic compounds or any polymorph or racemate thereof, or metabolite forms thereof, and mixtures thereof, and the like, or pharmaceutical compositions thereof.
  • the TLR7-related disease is selected from the group consisting of hepatitis (eg, hepatitis B (HBV) or hepatitis C (HCV)), asthma, allergic rhinitis, dermatomyositis, malaria, psoriasis, Actinic angle Diseases, solid tumors (such as bladder cancer or non-Hodgkin's lymphoma (NHL)), hematological tumors, melanoma, and autoimmune diseases (such as systemic lupus erythematosus (SLE), AIDS (HIV)).
  • HBV hepatitis B
  • HCV hepatitis C
  • C 1-6 alkyl as used in the present invention means a straight or branched alkyl group having 1 to 6 carbon atoms, such as a C 1-4 alkyl group, a C 1-2 alkyl group, a C 1 alkyl group, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl or C 6 alkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • C 0 alkyl as used in the present invention means that the alkyl group is absent, for example when the 3-8 membered cycloalkyl-C 0-6 alkyl group is a 3-8 membered cycloalkyl-C 0 alkyl group.
  • the C 0 alkyl moiety is absent, and thus the 3-8 membered cycloalkyl-C 0 alkyl group is a 3-8 membered cycloalkyl group.
  • halogenated C 1-6 alkyl means a group obtained by substituting the above C 1-6 alkyl group with one or more halogens, for example, a halogenated C 1-4 alkyl group, a halogenated C 1 group. -2 alkyl, halo C 1 alkyl, halo C 2 alkyl, halo C 3 alkyl, halo C 4 alkyl, halo C 5 alkyl or halo C 6 alkyl.
  • the halogen is selected from the group consisting of F, Cl, Br and I, preferably the halogen is F or Cl, more preferably the halogen is F.
  • Specific examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoropropyl, fluoroisopropyl, fluoro-n-butyl, fluoroisobutyl, fluoro Sub-sec-butyl, fluoro-tert-butyl, fluoro-n-pentyl, fluoro-n-hexyl, chloromethyl, chloroethyl, chloropropyl, chloroisopropyl, chloro-n-butyl, chloroform Butyl, chloro-sec-butyl, chloro-tert-butyl, chloro-n-pentyl, chloro-n-hexyl and the like.
  • C 1-6 alkoxy as used in the present invention means a group having a "C 1-6 alkyl-O-" structure in which a C 1-6 alkyl group has the same meaning as described above.
  • Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, 2-butoxy, isopropoxy, sec-butoxy, tert-butoxy, n-pentyloxy, Is n-hexyloxy and the like.
  • C 1-6 alkylamino as used in the present invention means a group having a structure of "C 1-6 alkyl-NH-" wherein the C 1-6 alkyl group has the same meaning as defined above.
  • C 1-4 alkylamino, C 1-2 alkylamino, C 1 alkylamino, C 2 alkylamino, C 3 alkylamino, C 4 alkylamino, C 5 alkylamino or C 6 alkylamino for example, C 1-4 alkylamino, C 1-2 alkylamino, C 1 alkylamino, C 2 alkylamino, C 3 alkylamino, C 4 alkylamino, C 5 alkylamino or C 6 alkylamino.
  • Specific examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, 2-butylamino, sec-butylamino, isobutylamino, t-butylamino, n-pentylamino, n-hexylamino and the like.
  • di-C 1-6 alkyl-substituted amino as used in the present invention means having A structural group in which a C 1-6 alkyl group has the same meaning as defined above, and two C 1-6 alkyl groups bonded to an N atom may be the same or different.
  • a di-C 1-4 alkyl-substituted amino group or a di-C 1-2 alkyl-substituted amino group for example, a di-C 1-4 alkyl-substituted amino group or a di-C 1-2 alkyl-substituted amino group.
  • Specific examples include, but are not limited to, dimethylamino, diethylamino, methylethylamino, methylisopropylamino, ethylisopropylamino, methyl-tert-butylamino, ethyl-tert-butylamino, and the like. .
  • C 2-6 alkenyl as used in the present invention means a straight or branched hydrocarbon group having 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds, preferably containing one carbon-carbon double bond.
  • C 2-6 alkenyl For example, C 2-4 alkenyl, C 2 alkenyl, C 3 alkenyl, C 4 alkenyl, C 5 alkenyl or C 6 alkenyl.
  • Specific examples include, but are not limited to, ethenyl, propenyl, 2-propenyl, butenyl, 2-butenyl, 2-methyl-propenyl, butadienyl, pentenyl, 2-methyl- Butenyl, 3-methyl-butenyl, 1,3-pentadienyl, 1,4-pentadienyl, hexenyl, 2-ethyl-butenyl, 3-methyl-pentyl Alkenyl, 4-methyl-pentenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl and the like.
  • C 2-6 alkynyl as used in the present invention means a straight or branched hydrocarbon group having 2 to 6 carbon atoms and one, two or three carbon-carbon triple bonds, preferably containing a carbon-carbon triple bond.
  • C 2-6 alkynyl For example, C 2-4 alkynyl, C 2 alkynyl, C 3 alkynyl, C 4 alkynyl, C 5 alkynyl or C 6 alkynyl.
  • Specific examples include, but are not limited to, ethynyl, propynyl, 2-propynyl, butynyl, 2-butynyl, 2-methyl-propynyl, butadiynyl, pentynyl, 2- Methyl-butynyl, 3-methyl-butynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, hexynyl, 2-ethyl-butynyl, 3-methyl A pentynynyl group, a 4-methyl-pentynyl group, a 1,3-hexadiynyl group, a 1,4-hexadiynyl group, a 1,5-hexadiynyl group, and the like.
  • cycloalkyl refers to a saturated or partially saturated monocyclic alkyl group.
  • a 3-8 membered cycloalkyl group is preferred, such as a 3 membered, 4 membered, 5 membered, 6 membered, 7 membered or 8 membered cycloalkyl group.
  • Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • heterocyclyl refers to an aliphatic or aromatic ring containing at least 1 up to 4 (for example 1, 2, 3 or 4) heteroatoms selected from N, O and S, such as a heterocyclic ring. Alkyl or heteroaryl.
  • heterocycloalkyl refers to a saturated or partially saturated heteroatom containing at least 1 up to 4 (eg 1, 2, 3 or 4) heteroatoms selected from N, O and S.
  • a cycloalkyl group as defined above, preferably, said heterocycloalkyl group contains at least one N.
  • the N and S can optionally be oxidized, and the N can optionally be quaternized.
  • a 3-8 membered heterocycloalkyl group a 5-6 membered heterocycloalkyl group, a 3-, 4-, 5-, 6-, 7- or 8-membered heterocycloalkyl group.
  • Specific examples include, but are not limited to, ethylene oxide, oxocyclobutane, pyrrolidine, pyrrolidone, tetrahydrofuran, 4,5-dihydro-1H-pyrazole, piperidine, piperazine, morpholine, thiomorpho, and the like. .
  • heteroaryl refers to an aromatic ring containing at least 1 up to 4 (for example 1, 2, 3 or 4) heteroatoms selected from N, O and S.
  • a 5-8 membered heteroaryl group a 5-6 membered heteroaryl group, a 5-membered, 6-membered, 7-membered or 8-membered heteroaryl group.
  • Specific examples include, but are not limited to, pyrrole, furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, and the like.
  • heterospiro means, respectively, containing at least 1 up to 4 (for example 1, 2, 3 or 4) selected from N, O.
  • the heterospiro, heterocyclo and hetero bridged ring groups contain 5-15 atoms, more preferably 5-10 atoms, more preferably 6-9 atoms, such as 6, 7, 8, 9 Heterospiro, heterocyclo and hetero bridged ring groups.
  • Specific examples include, but are not limited to, 1-pyrrolidino[3,4-c]pyrrolidinyl, 3-aza-bicyclo[3.1.0]hexyl, 2-aza-bicyclo[3.1.0]hexyl, six Hydrogen-furo[3,4-c]pyrrole, 2-oxa-6-aza-spiro[3.4]octane, octahydro-cyclopenta[c]pyrrole, 2-aza-spiro[4.4 ] decane, 6-aza-spiro[3.4]octane, 5-aza-spiro[2.4]heptane, and the like.
  • alkoxycarbonyl as used in the present invention means a group having an "alkyl-OC(O)-" structure having the same definition as described above.
  • the alkoxycarbonyl group is preferably a C 1-6 alkoxycarbonyl group, more preferably a C 1-4 alkoxycarbonyl group. Specific examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl t-butoxycarbonyl, and the like.
  • optical isomer includes all possible optical isomer forms (e.g., enantiomers, diastereomers, etc.) of the compounds of formula I of the present invention.
  • the compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof may also form a solvate such as a hydrate, an alcoholate or the like.
  • the compounds of the formula I according to the invention may also be in the form of prodrugs or in which the active ingredient is released after metabolic changes in the body.
  • suitable prodrug derivatives are well known to those skilled in the art.
  • the compounds of the formula I according to the invention may also be in a chemically protected form which protects the active groups of the compounds, such as amino groups, which are metabolized in vivo to release the active ingredient.
  • a chemically protected form which protects the active groups of the compounds, such as amino groups, which are metabolized in vivo to release the active ingredient.
  • pharmaceutically acceptable salt includes conventional salts formed with a pharmaceutically acceptable inorganic or organic acid, or an inorganic or organic base.
  • suitable acid addition salts include salts of hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, succinic acid, glycolic acid, pamoic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid, and the like.
  • suitable base addition salts include sodium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, N-methylglucamine, and procaine. Salt.
  • an effective amount refers to an amount sufficient to achieve the desired therapeutic effect, for example, to achieve an amount that reduces the symptoms associated with the condition to be treated.
  • treatment is intended to alleviate or eliminate the disease state or condition being addressed. If the subject receives a therapeutic amount of a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, the subject exhibits one or more indications and symptoms Observable and/or detectable reduction or improvement, the subject is successfully "treated”. It will also be appreciated that the treatment of the disease state or condition includes not only complete treatment, but also failure to achieve complete treatment, but achieving some biological or medical related results.
  • TLR7 agonist of the invention can be taken orally, and the liver is quickly absorbed, allowing absorption from the intestinal tract into the hepatic portal vein (hepatic and intestinal circulation), and the low dose can exert good pharmacological effects and reduce adverse events; 2. Can and go Adrenaline (NA) is combined with a single tablet; 3. TLR7 is highly selective but does not activate the TLR8 pathway, reducing the side effects of TNF- ⁇ activation; 4. Similar to the injection of IFN, oral TLR agonist induces IFN production, exerts efficacy .
  • NA Adrenaline
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS).
  • 1 H NMR was measured by JEOL Eclipse 400 NMR, and the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexamethylene dimethyl sulfoxide (DMSO-d6), internal standard was four.
  • Methylsilane (TMS) chemical shifts are given in units of 10 -6 (ppm);
  • the MS was measured using an Agilent (ESI) mass spectrometer
  • the thin-layer chromatography silica gel plate was prepared by thin-layer chromatography using an aluminum plate (20 ⁇ 20 cm) manufactured by Merck, and the specification was GF 254.
  • reaction was monitored by thin layer chromatography (TLC) or LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • TLC thin layer chromatography
  • LCMS LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • the polarity is adjusted differently or adjusted by adding triethylamine or the like.
  • the microwave reaction was carried out using a Biotage Initiator + (400 W, RT ⁇ 300 ° C) microwave reactor.
  • Column chromatography generally uses 200 to 300 mesh silica gel as a carrier.
  • the system of the eluent includes: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.
  • reaction temperature is room temperature (20 ° C ⁇ 35 ° C);
  • the reagents used in the present invention were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebe Chemical.
  • the compound 3-(pyrrolidin-1-methyl)benzonitrile (61 g, 0.328 mol) was added to a 1 L three-necked flask, and 200 mL of MeOH, MeOH/NH 3 solution and Raney-Ni were added thereto, and hydrogen was introduced thereto, and the reaction was carried out at 25 ° C for 48 hours.
  • the reaction was completed by LC-MS, and Raney-Ni (with celite) was filtered off, and the filter cake was washed with MeOH (50 mL ⁇ 2).
  • the title compound (59 g, yield 94%) was obtained.
  • the third step preparation of N-(3-(pyrrolidin-1-methyl)benzyl)glycine ethyl ester
  • Step 5 Preparation of N-(6-Amino-2-methanesulfonyl-5-nitropyrimidin-4-yl)-N-(3-(pyrrolidin-1-methyl)benzyl)glycine ethyl ester
  • Second step Preparation of N-(6-amino-2-methylthio-5-nitropyrimidin-4-yl)-N-(3-cyanobenzyl)glycine ethyl ester
  • the starting material 5-nitro-2-methylthio-4,6-dichloropyrimidine 120 g, 0.5 mol was added to a three-necked flask, dissolved in 600 mL of THF, and a solution of triethylamine and ammonia methanol (86 mL, 0.6 mol) was added.
  • the reaction was stirred at room temperature for 1 hour; the reaction was completed by TLC.
  • the reaction mixture was poured into 2 L of water and filtered with suction. The filter cake was washed successively with purified water (500 mL ⁇ 2) petroleum ether (400 mL) and dried to give the desired product 95 g, yield 86% .
  • the nitro compound (100 mg, 0.2 mmol) was added to a mixed system of 5 mL of ethanol and 5 mL of water, and the powder was added, and the mixture was heated to 80 ° C to stir the reaction. After 30 minutes, TLC showed the reaction was complete, and the reaction solution was poured into about 20 mL of saturated hydrogen carbonate. The mixture was extracted with aq. EtOAc (EtOAc)EtOAc.
  • Second step 4-(5-((ethoxycarbonylmethyl-amino)methyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester
  • the third step 4-(5-((N-(6-amino-2-methylthio-5-nitropyrimidin-4-yl)-N--ethoxycarbonylmethylamino)methyl)pyridine- 2-yl) piperazine-1-carboxylic acid tert-butyl ester
  • Step 4 4-(5-((N-(6-Amino-2-methylsulfonyl-5-nitropyrimidin-4-yl)-N--ethoxycarbonylmethyl-amino)methyl)pyridine -2-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 5 4-(5-((N-(6-Amino-2-butoxy-5-nitropyrimidin-4-yl)-N--ethoxycarbonylmethyl-amino)methyl)pyridine -2-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 6 4-(5-((4-Amino-2-butoxy-6-oxo-6,7-dihydropteridin-8(5H)-yl)methyl)pyridin-2-yl Piperazine-1-carboxylic acid tert-butyl ester
  • Step 7 4-Amino-2-butoxy-8-((6-(piperazin-1-yl)pyridin-3-yl)methyl)-7,8-dihydropteridin-6 (5H )-ketone
  • Step 8 4-Amino-2-butoxy-8-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)methyl)-7,8-dihydropteridine -6(5H)-one (Compound 14)
  • the compound 69-C was obtained in a yield (53%) by the method similar to that described in the third step of Example 2, using 69-B instead of 61-B of the third step of Example 2.
  • Compound 69 was prepared in a similar manner to that described in the fourth step of Example 2, using 69-C instead of 61-C of the fourth step of Example 2, yield (27%).
  • the second step 2-(((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)methyl)amino)acetate
  • the third step 2-(N-(6-amino-2-methylthio-5-nitropyrimidin-4-yl)-N-((6-(4-hydroxypiperidin-1-yl)pyridine- 3-base) Methyl)-amino)ethyl acetate
  • Example 2 Prepared using a third-step synthesis procedure similar to Example 1, using 2-(((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)methyl)amino)acetic acid ethyl ester instead of Example 1 4-(5-((Ethoxycarbonylmethyl-amino)methyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester in the third step.
  • the fourth step 2-(N-(6-amino-2-methanesulfonyl-5-nitropyrimidin-4-yl)-N-((6-(4-hydroxypiperidin-1-yl)pyridine- 3-yl)methyl)amino)ethyl acetate
  • Step 5 2-(N-(6-Amino-2-butoxy-5-nitropyrimidin-4-yl)-N-((6-(4-hydroxypiperidin-1-yl)pyridine- 3-yl)methyl)-amino)ethyl acetate
  • Step 6 4-Amino-2-butoxy-8-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)methyl)-7,8-dihydropteridine- 6(5H)-ketone (compound 15)
  • Second step 2-(((6-(4-(Dimethylamino)piperidin-1-yl)pyridin-3-yl)methyl)amino)acetate
  • the third step 2-(N-(6-amino-2-methylthio-5-nitropyrimidin-4-yl)-N-((6-(4-(dimethylamino))piperidine-1- Ethyl pyridin-3-yl)methyl)-amino)ethyl acetate
  • Step 4 2-(N-(6-Amino-2-methanesulfonyl-5-nitropyrimidin-4-yl)-N-((6-(4-(dimethylamino))piperidine-1- Ethyl pyridin-3-yl)methyl)-amino)ethyl acetate
  • Step 5 2-(N-(6-Amino-2-butoxy-5-nitropyrimidin-4-yl)-N-((6-(4-(dimethylamino))piperidine-1- Ethyl pyridin-3-yl)methyl)-amino)ethyl acetate
  • Step 6 4-Amino-2-butoxy-8-((6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)methyl)-7,8-di Hydropteridine-6(5H)-one (16)
  • the preparation method was the same as in the first to seventh steps of Example 1, to give the title compound.
  • the compound 72-C was obtained in a yield (72%) by the procedure similar to that described in the third step of Example 2, using 72-B instead of 61-B of the third step of Example 2.
  • Test Example 1 NF-kB reporter gene assay:
  • TLR7 For antiviral drugs, it is generally desired to have high activity against TLR7 and weak activity against TLR8, or it is preferable for TLR7 to have selectivity over TLR8.
  • Human embryonic kidney cell HEK293 (Nanjing Kezhen Biotechnology Co., Ltd.) stably expressing TLR7 and NF- ⁇ b luciferase reporter gene system was cultured in DMEM medium containing 10% FBS (Gibco, 10099-141) (Gibco, cat. 12100-046). The cells were trypsinized, resuspended, counted, and seeded in well plates. Different concentrations of the test compound were configured in DMSO, and 10 ⁇ L of different concentrations of the test compound were added to the well plate.
  • the final concentration of the test compound in each well was 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03. ⁇ M, 0 ⁇ M, final concentration of DMSO 0.5%.
  • the group in which the concentration of the test compound was 0 ⁇ M was a blank control group.
  • Cells were incubated with test compound at 37 °C, 5% CO 2 incubator, an equal volume Brigh-Glo TM detection reagent (Promega, cat.E2620), rt.
  • the relative chemiluminescence unit value (RLU) was read and the EC 50 and E max were fitted under a multi-function fully automated microplate reader (Thermo Varioskan Flash). The results are shown in Table 1.
  • Compound Table 1 EC 50 of TLR7 in HEK293 cells
  • the compounds of the invention of formula I-3 series is lower than the EC 50 value of the positive control was A 50 values of TLR7 EC HEK293 cells, and below Formula I-1, compound I-2, I-4 of It is to be noted that the compound of the formula I-3 of the present invention has a significantly higher activation effect on TLR7 than the positive control A, and is higher than the compounds of the formulae I-1, I-2, and I-4.
  • the compounds of the formula I-3 of the invention show better activation activity on HEK293 cell TLR7.
  • the compound of the formula I-3 of the present invention has an Emax of generally greater than 600% for HEK293 cells TLR7 and has excellent activating activity.
  • Human embryonic kidney cells HEK293 were cultured in DMEM medium containing 10% FBS.
  • the pcDNA5/FRT-AN-LUC-hTLR8 plasmid (Nanjing Kezhen Biotechnology Co., Ltd.) was transfected to express the hTLR8 and NF- ⁇ b luciferase reporter genes.
  • the cells were trypsinized, resuspended, counted, and seeded in well plates. Different concentrations of the test compound were configured in DMSO, and 10 ⁇ L of different concentrations of the test compound were added to the well plate.
  • the final concentration of the test compound in each well was 600 ⁇ M, 300 ⁇ M, 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0 ⁇ M, DMSO. The final concentration is 1%.
  • the group in which the concentration of the test compound was 0 ⁇ M was a blank control group.
  • the compounds of the invention were significantly less active against TLR8 than the positive control A, compounds of formula I-1, I-2, I-4.
  • the compound of the formula I-3 of the present invention showed higher activation activity against HEK293 cell TLR7 relative to the positive control A, and the compound of the formula I-1, I-2, I-4, and the HER293 cell TLR8.
  • the weak activation activity is shown, indicating that the compounds of the formula I-3 of the present invention show better activation selectivity for TLR7.
  • Test Example 2 Detection of activation of human peripheral blood mononuclear cells (PBMC):
  • TLR7 activation The main biological effect of TLR7 activation is to stimulate cells to secrete IFN ⁇ and chemokine regulated by IFN ⁇ . This pathway is a major mechanism of antiviral drugs; the main biological effect of TLR8 activation is to stimulate cells to secrete inflammatory cells.
  • Factors include: TNF ⁇ , IL-6, IL-12 (eg, IL-12p40), IL-1 ⁇ , and the like.
  • antiviral drugs it is generally expected that the drug has high activity against TLR7 and weak activity against TLR8, or is more selective for TLR7 than TLR8.
  • Detection method Human PMBC cells were inoculated in a well plate and incubated. Different concentrations of the compounds of the invention were added to well plates containing PBMC and incubation continued for 24 h. The wells were centrifuged and the supernatant was collected, and the concentrations of the cytokines IFN ⁇ , IL-12p40, IL-1 ⁇ , IL-6, TNF ⁇ were measured by ELISA. The results are shown in Table 2-1 and Table 2-2.
  • the compound 14 of the present invention stimulated PBMC cells to secrete IFN ⁇ at a concentration of 3000 nM, and the inflammatory cytokines IL-12p40, IL-1 ⁇ , IL- were more potent.
  • the stimulatory effect of 6 and TNF ⁇ secretion was significantly weaker than that of the positive control A, indicating that the compound 14 of the present invention has a better selectivity for TLR7.
  • the compound 14 of the present invention stimulated PBMC cells to be more active in secreting IFN ⁇ at a compound concentration of 1000 nM as compared with the positive control A.
  • the stimulatory effect of the compound 14 of the present invention on the secretion of the inflammatory cytokines IL-12p40 and IL-1 ⁇ was significantly weaker than that of the positive control A. It is shown that the compound 14 of the present invention is more selective for TLR7 than TLR8 at a concentration of 1000 nM.
  • the compound 14 of the present invention is more active in stimulating PBMC cells to secrete IFN ⁇ at a compound concentration of 300 nM and 100 nM; in addition, the compound 14 of the present invention acts on the inflammatory cytokine IL.
  • the stimulatory effect of -12p40 secretion was significantly weaker than that of the positive control, indicating that the compound 14 of the present invention is more selective for TLR7 at concentrations of 300 nM and 100 nM, and the compound of the present invention 14 is also more effective at low concentrations.
  • Test Example 3 Detection of changes in plasma IFN- ⁇ levels in cynomolgus monkeys
  • the compounds of the invention are TLR7 agonists for the treatment of chronic hepatitis B virus (HBV) infection, which induce an in vivo type I interferon (IFN-alpha) dependent antiviral innate immune response.
  • IFN- ⁇ is a type I interferon that induces pDCs to develop resistance to viral infection by interfering with viral gene transcription or translation of viral protein components, thereby preventing or limiting viral infection.
  • antiviral drugs it is generally desirable to have high activity against TLR7 to increase IFN-[alpha] expression levels.
  • Detection method cynomolgus monkeys (purchased from Hainan Jingang Biotechnology Co., Ltd.) were grouped by weight. After fasting overnight, 1 mg/kg of positive control compound A and the compound of the present invention were administered by single gavage, before administration, At the 1h, 2h, 4h, 6h, 8h, and 24h after the drug, 1.5ml of blood was collected, anticoagulated by heparin sodium, and centrifuged at 4000 rpm for 10 minutes. After separating the plasma, the IFN- ⁇ content at different time points was determined according to the ELISA kit method. The area under the plasma IFN- ⁇ curve (AUC) of crab monkeys (unit: pg.h/mL), and the results are shown in Table 3.
  • AUC area under the plasma IFN- ⁇ curve
  • the compounds of the present invention 14, 61, 69, 71 were more stimulating the secretion of IFN- ⁇ in the cynomolgus monkey at a dose of 1 mg/kg compared to the positive control A, indicating that the compounds of the present invention 14, 61 69, 71 have better antiviral activity.
  • the compound of the present invention is a TLR7 agonist which is both active and selective.

Abstract

公开了式I所示二氢蝶啶酮类衍生物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其制备方法及在制备治疗与TLR7相关疾病的药物中的用途。

Description

[根据细则37.2由ISA制定的发明名称]　二氢蝶啶酮类衍生物、其制备方法及其用途 技术领域
本发明属于医药领域，涉及TLR7激动剂，具体涉及二氢碟啶酮类衍生物、其制备方法及其用途。
背景技术
Toll样受体(Toll-like receptors，TLR)是参与非特异性免疫(天然免疫)的一类重要蛋白，也是连接非特异性免疫和特异性免疫的桥梁。TLR是单个的跨膜非催化性蛋白质，属模式识别受体(Pattern recognition receptor，PRR)家族，能快速应答病原体。TLR7作为TLRs家族之一，主要表达在肺、胎盘、心、骨髓、淋巴结等组织；表达TLR7的细胞主要为免疫细胞，包括类浆树突状细胞(pDCs)、骨髓样树突状细胞(mDCs)、B淋巴细胞、巨噬细胞等(尤以树突细胞为著)。TLR7主要是由病毒单链RNA激活。类浆树突状细胞的激活在对病毒的先天性应答中起着重要作用，而这些细胞负责大部分的病毒感染急性期的I型干扰素(IFN)的生产。诱导内源性干扰素(譬如α-干扰素和β-干扰素)的产生与分泌能促进有效的适应性免疫反应。
乙型病毒性肝炎是由乙型肝炎病毒(HBV)引起的，以肝脏炎症为主要表现的传染病。HBV感染呈世界性流行。据世界卫生组织报道，全球约20亿人曾感染过HBV，其中3.5亿人为慢性HBV感染者，每年约有100万人死于HBV感染所致的肝衰竭、肝硬化和原发性肝细胞癌。乙肝的基因分型主要分为A、B、C、D、E、F、G、H型。HBV的不同基因分型与乙肝患者的病情和抗病毒治疗有关。
乙型病毒性肝炎目前主要防治手段为乙肝疫苗预防、干扰素和核苷类似物等药物治疗。外源性α-干扰素(例如，重组α-干扰素或聚乙二醇化的IFN-a)的施用对慢性乙型肝炎病毒(HBV)和肝炎病毒感染的患者提供了治疗益处。证据表明，诱导免疫调节和一个缓慢的具有保护性的抗病毒免疫反应可以有效地控制病毒。
文献显示，与健康者相比，HBV感染者中TLR7低表达，HBV感染可直接下调TLR7表达。另据文献研究表明，TLR7激动剂GS-9620响应机制可能是肠道高吸收，在肠道淋巴组织/肝脏的树突状细胞中促进TLR7局部活化，其局部活化进一步激活全身免疫系统作用。
由于TLR7激动剂主要是通过刺激调节内源性I型干扰素(INF-α/β)的响应，提高干扰素下游信号干扰素调节基因(ISGs)的表达等发挥免疫性抗病毒作用，因此TLR7激动剂的作用机制是通过活化自身免疫系统抗病毒，对乙肝的不同基因型无选择性抑制。
US2010/0143301公开了一种结构如下所示的TLR7激动剂。
Figure PCTCN2017088785-appb-000001
本领域亟需开发具有较好活性以及选择性的TLR7激动剂。
发明内容
本发明提供一类TLR7激动剂，其制备方法及其在制备治疗与TLR7低表达相关疾病中的用途。
具体的，本发明的第一方面提供一种式I所示化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等，
Figure PCTCN2017088785-appb-000002
其中，
X为-O-、-NH-、-S-、-C(O)-或-S(O)2-；
R1为C1-6烷基、3-8元环烷基-C0-6烷基或3-8元杂环烷基-C0-6烷基，其中所述C1-6烷基、3-8元环烷基-C1-6烷基或3-8元杂环烷基-C1-6烷基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自下述的取代基取代：卤素、羟基、氰基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C2-6烯基和C2-6炔基；
L为-(CH2)n-，其中n为1、2、3、4、5或6；
环A为苯环、吡啶、嘧啶、哌嗪、吡嗪、哒嗪、3-8元环烷基或5元杂环基(例如5元杂环烷基或5元杂芳基)；
R2和R3各自独立地选自氢、卤素、氰基、C1-6烷基、卤代C1-6烷基和C1-6烷氧基；
R4不存在或为5-9元杂环基-C0-6烷基、6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基或6-9元杂桥环基-C0-6烷基，其中所述5-9元杂环基-C0-6烷基、6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基或6-9元杂桥环基-C0-6烷基未被取代或各自独立地被一个或多个(例如1、2、3或4个)选自下述的取代基取代：羟基、卤素、羰基、氧代、羧基、C1-6烷氧羰基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基、羟基取代的C1-6烷基和氰基取代的C1-6烷基。
在本发明的部分实施方案中，当所述式I化合物为
Figure PCTCN2017088785-appb-000003
时，
R1选自丙基或丁基；
R2和R3各自独立地选自氢、F、C1-6烷基和C1-6烷氧基；
R4为取代或未取代的5-9元杂芳基-C0-6烷基(例如四氮唑)、6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基或6-9元杂桥环基-C0-6烷基、或取代的5元杂环烷基-C0-6烷基，其中所述取代的5-9元杂芳基-C0-6烷基(例如四氮唑)、6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基或5元杂环烷基-C0-6烷基是指所述5-9元杂芳基-C0-6烷基(例如四氮唑)、6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基或5元杂环烷基-C0-6烷基各自独立地被一个或多个(例如1、2、3或4个)选自下述的取代基取代：羟基、羧基、C1-6烷氧羰基、羟基取代的C1-6烷基、C1-6烷氧基、二C1-6烷基取代的氨基、卤素、C1-6烷基和C1-6烷氧基-C1-6烷基，并且，当所述取代基为两个甲基时，其取代在一个碳原子上。
在本发明的部分实施方案中，当
Figure PCTCN2017088785-appb-000004
为
Figure PCTCN2017088785-appb-000005
且X为-O-、-S-或-NH-时，
R1选自
Figure PCTCN2017088785-appb-000006
Figure PCTCN2017088785-appb-000007
和C1-6烷基，其中所述C1-6烷基被一个或多个(例如1、2、3或4个)氰基、C2-6烯基或C2-6炔基取代。
在本发明的部分实施方案中，当
Figure PCTCN2017088785-appb-000008
为
Figure PCTCN2017088785-appb-000009
时，
R2和R3各自独立地选自氢、卤素、C1-6烷氧基和2-二甲氨基乙氧基；
R4不存在或为6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基，其中所述6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基；且 当R4不存在时，R2和R3中有一个为2-二甲氨基乙氧基。
在本发明的部分实施方案中，所述X选自-O-、-NH-、-S-和-C(O)-；优选地，所述X选自-O-和-S-；更优选地，所述X为-O-。
在本发明的部分实施方案中，所述L为-(CH2)n-，n为1或5。
在本发明的部分实施方案中，当所述环A为苯环时，L和R4互为间位。
在本发明的部分实施方案中，当所述环A为吡啶时，L和R4互为对位。
在本发明的部分实施方案中，所述化合物具有如下所示的结构，
Figure PCTCN2017088785-appb-000010
其中，
R1选自丙基或丁基；
R2和R3各自独立地选自氢、F、C1-6烷基和C1-6烷氧基；优选地，R2和R3均为氢；
R4为取代或未取代的5-9元杂芳基-C0-6烷基(例如四氮唑)、6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基或6-9元杂桥环基-C0-6烷基、或取代的5元杂环烷基-C0-6烷基，其中所述取代的5-9元杂芳基-C0-6烷基(例如四氮唑)、6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基或5元杂环烷基-C0-6烷基是指所述5-9元杂芳基-C0-6烷基(例如四氮唑)、6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基或5元杂环烷基-C0-6烷基各自独立地被一个或多个(例如1、2、3或4个)选自下述的取代基取代：氧代、羟基、羧基、C1-6烷氧羰基、羟基取代的C1-6烷基、C1-6烷氧基、二C1-6烷基取代的氨基、卤素、C1-6烷基和C1-6烷氧基-C1-6烷基，并且，当所述取代基为两个甲基时，其取代在一个碳原子上；优选地，所述取代基选自羟基、羧基、C1-6烷氧羰基(例如甲氧羰基或乙氧羰基)、羟甲基、甲氧基、二甲氨基、氟、甲基、乙基、异丙基和甲氧甲基；
优选地，所述6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基或6-9元杂桥环基-C0-6烷基为含吡咯烷环的6-9元杂螺环基-C0-6烷基、含吡咯烷环的6-9元杂并环基-C0-6烷基或含吡咯烷环的6-9元杂桥环基-C0-6烷基，例如含吡咯烷环的6-9元杂螺环基-甲基、6-9元杂并环基-甲基或6-9元杂桥环基-甲基，例如，
Figure PCTCN2017088785-appb-000011
优选地，所述5-9元杂芳基-C0-6烷基为5-9元杂芳基，例如噁唑基、噻唑基、咪唑基、吡唑基、三氮唑基、四氮唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基等；
优选地，所述5元杂环烷基-C0-6烷基为5元杂环烷基-甲基，例如，吡咯烷甲基或吡咯烷酮甲基。
在本发明的优选实施方案中，所述取代基选自羟基、羧基、C1-6烷氧羰基(例如甲氧羰基或乙氧羰基)、羟甲基、甲氧基、二甲氨基、氟、甲基、乙基、异丙基和甲氧甲基，当所述取代基为甲基时，其为单取代或双取代。
在本发明的部分实施方案中，所述化合物具有如下所示结构，
Figure PCTCN2017088785-appb-000012
其中，
X为-O-、-NH-、-S-、-C(O)-或-S(O)2-；优选地，X为-O-、-NH-、-S-或-C(O)-；更优选地，X为-O-或-S-；更优选地，X为-O-；
R1选自
Figure PCTCN2017088785-appb-000013
和取代或未取代的C1-6烷基，其中所述取代的C1-6烷基是指所述C1-6烷基被一个或多个(例如1、2、3或4个)选自氰基、C2-6烯基和C2-6炔基的取代基取代；
R2和R3各自独立地选自氢、卤素和C1-6烷氧基；
当R1为未取代的C1-6烷基时，R2和R3不同时为氢；
优选地，R1选自
Figure PCTCN2017088785-appb-000014
在本发明的部分实施方案中，所述化合物具有如下所示结构，
Figure PCTCN2017088785-appb-000015
R1选自烷基；
R2和R3各自独立地选自氢、卤素、C1-6烷基、C1-6烷氧基和二C1-6烷基取代的氨基-C1-6烷氧基；
R4不存在或为6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基，其中所述6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：氧代、羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基；并且，
当R4不存在时，R2和R3中有一个为2-二甲氨基乙氧基；
其余原子或取代基如式I-1中所述。
在本发明的部分实施方案中，式I-3所示化合物，其中：
R1选自C1-6烷基(例如丁基或戊-2-基)；
R2和R3各自独立地选自氢、卤素、C1-6烷氧基和2-二甲氨基乙氧基；
R4不存在或为6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基，其中所述6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：氧代、羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基；并且，
当R4不存在时，R2和R3中有一个为2-二甲氨基乙氧基；
其余原子或取代基如式I-1中所述。
在本发明的部分实施方案中，式I-3所示化合物，其中：
X为-O-、-NH-、-S-或-C(O)，优选为-O-、-NH-或-S-，进一步优选为-O-或-S-，更优选为-O-；
R2和R3各自独立地选自氢、卤素、C1-6烷氧基和2-二甲氨基乙氧基；
R4不存在或为哌啶基-C0-6烷基、哌嗪基-C0-6烷基或1,2,3,6-四氢吡啶基-C0-6烷基，其中所述哌啶基-C0-6烷基、哌嗪基-C0-6烷基或1,2,3,6-四氢吡啶基-C0-6烷基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代： 羟基、卤素、C1-6烷基、C1-6烷氨基、二C1-6烷基取代的氨基。
在本发明的部分实施方案中，所述化合物具有如下所示结构，
Figure PCTCN2017088785-appb-000016
其中，
R1选自丁基和戊-2-基；
R2和R3各自独立地选自氢、卤素、C1-6烷氧基和2-二甲氨基乙氧基；优选地，R2和R3均为氢，或R2为氢R3为2-二甲氨基乙氧基或氟；
R4不存在或代表6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基(例如，1-吡咯烷并[3,4-c]吡咯烷基)、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基(例如，1-吡咯烷基或1-吡咯烷甲基)、哌啶基、哌嗪基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基，其中所述6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基、哌嗪基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：氧代、羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基；优选地，所述取代基选自二甲氨基、甲基、乙基、异丙基、羟基、甲氧乙基和氰甲基。
在本发明的部分优选实施方案中，式I-3A所示化合物，其中，R4不存在或为哌啶基-C0-6烷基、哌嗪基-C0-6烷基或1,2,3,6-四氢吡啶基-C0-6烷基，其中所述哌啶基-C0-6烷基、哌嗪基-C0-6烷基或1,2,3,6-四氢吡啶基-C0-6烷基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：羟基、卤素、C1-6烷基、C1-6烷氨基、二C1-6烷基取代的氨基。
在本发明的部分优选实施方案中，式I-3A所示化合物，其中：R4选自哌嗪基、4-甲基哌嗪基、4-异丙基哌嗪基、N-甲基-1,2,3,6-四氢吡啶-4-基、N-甲基哌啶基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基，4-羟基哌啶基和二甲氨基哌啶。
在本发明的部分优选实施方案中，式I-3A所示化合物，其中：R4选自哌嗪基、4-甲基哌嗪基、4-异丙基哌嗪基、N-甲基-1,2,3,6-四氢吡啶-4-基、N-甲基哌啶基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基，4-羟基哌啶基和4-二甲氨基哌啶。
在本发明的部分优选实施方案中，式I-3A所示化合物，其中：R4选自哌嗪基、4-甲基哌嗪基、4-异丙基哌嗪基、N-甲基-1,2,3,6-四氢吡啶-4-基、N-甲基哌啶基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基和4-羟基哌啶基。
在本发明的部分优选实施方案中，式I-3A所示化合物，其中：
R1选自丁基；
R2和R3均为氢，或R2为氢R3为2-二甲氨基乙氧基或氟；
R4不存在或选自4-甲基哌嗪基、N-甲基哌啶基、N-甲基-1,2,3,6-四氢吡啶-4-基。
在本发明的部分优选实施方案中，所述化合物具有如下所示结构，
Figure PCTCN2017088785-appb-000017
其中：R3为2-二甲氨基乙氧基，R4不存在；或者R3为氢，R4选自4-甲基哌嗪基、N-甲基哌啶基、N-甲基-1,2,3,6-四氢吡啶-4-基。
在本发明的部分优选实施方案中，所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其具有式I-3B所示结构，
Figure PCTCN2017088785-appb-000018
其中：R1为烷基；
R3为氢、卤素或C1-4烷基；
R4选自哌嗪基、哌啶基、1,2,3,6-四氢吡啶基、C1-6烷氨基-C1-6烷氧基和二C1-6烷基取代的氨基-C1-6烷氧基，所述哌嗪基、哌啶基、1,2,3,6-四氢吡啶基任选地被以下取代基单取代或多取代：羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基。
在本发明的部分优选实施方案中，式I-3B所示化合物，其中：
R1为C1-6烷基；
R3为氢或卤素；
R4选自哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基和二C1-6烷基取代的氨基-C1-6烷氧基，所述哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基任选地被以下取代基单取代或多取代：羟基、C1-6烷基和二C1-6烷基取代的氨基。
在本发明的部分优选实施方案中，式I-3B所示化合物，其中：
R1为C1-4烷基；
R3为氢、氟、氯或溴；
R4选自哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基和二C1-4烷基取代的氨基-C1-4烷氧基，所述哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基任选地被以下取代基单取代或多取代：羟基、甲基、乙基、丙基和二甲氨基。
在本发明的部分优选实施方案中，式I-3B所示化合物，其中：
R1为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基；
R3为氢或氟；
R4选自哌嗪-1-基、4-二甲氨基哌啶-1-基、4-羟基哌啶-1-基、4-甲基哌嗪-1-基、N-甲基哌啶-4-基、N-甲基-1,2,3,6-四氢吡啶-4-基和2-二甲氨基乙氧基。
在本发明的部分优选实施方案中，式I-3B所示化合物，其中：
R1为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基；
R3为氢；
R4选自4-甲基哌嗪-1-基、N-甲基哌啶-4-基、N-甲基-1,2,3,6-四氢吡啶-4-基和2-二甲氨基乙氧基。
在本发明的部分实施方案中，所述化合物中R1为C1-6烷基，优选为C1-4烷基，例如R1为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。
在本发明的部分实施方案中，所述化合物中R1为甲基。
在本发明的部分实施方案中，所述化合物中R1为乙基。
在本发明的部分实施方案中，所述化合物中R1为正丙基。
在本发明的部分实施方案中，所述化合物中R1为异丙基。
在本发明的部分实施方案中，所述化合物中R1为正丁基。
在本发明的部分实施方案中，所述化合物中R1为异丁基。
在本发明的部分实施方案中，所述化合物中R1为仲丁基。
在本发明的部分实施方案中，所述化合物中R1为叔丁基。
在本发明的部分实施方案中，所述化合物中R3为氢、氟、氯、溴、碘或C1-4烷基。
在本发明的部分实施方案中，所述化合物中R3为氢。
在本发明的部分实施方案中，所述化合物中R3为氟。
在本发明的部分实施方案中，所述化合物中R3为氯。
在本发明的部分实施方案中，所述化合物中R3为溴。
在本发明的部分实施方案中，所述化合物中R3为碘。
在本发明的部分实施方案中，所述化合物中R3为甲基。
在本发明的部分实施方案中，所述化合物中R3为乙基。
在本发明的部分实施方案中，所述化合物中R3为正丙基。
在本发明的部分实施方案中，所述化合物中R3为异丙基。
在本发明的部分实施方案中，所述化合物中R3为正丁基。
在本发明的部分实施方案中，所述化合物中R3为异丁基。
在本发明的部分实施方案中，所述化合物中R3为仲丁基。
在本发明的部分实施方案中，所述化合物中R3为叔丁基。
在本发明的部分实施方案中，所述化合物中：R4选自哌嗪基、哌啶基、1,2,3,6-四氢吡啶基、C1-6烷氨基-C1-6烷氧基和二C1-6烷基取代的氨基-C1-6烷氧基。
在本发明的部分实施方案中，所述化合物中：所述哌嗪基、哌啶基、1,2,3,6-四氢吡啶基任选地被以下取代基单取代或多取代：羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基。在本发明的部分实施方案中，所述哌嗪基、哌啶基、1,2,3,6-四氢吡啶基任选地被以下取代基单取代或多取代：被羟基、甲基、乙基、丙基和二甲氨基单取代或多取代。
在本发明的部分实施方案中，所述化合物中：R4为哌嗪基。
在本发明的部分实施方案中，所述化合物中：R4为哌啶基。
在本发明的部分实施方案中，所述化合物中：R4为1,2,3,6-四氢吡啶基。
在本发明的部分实施方案中，所述化合物中：R4为C1-6烷氨基-C1-6烷氧基。
在本发明的部分实施方案中，所述化合物中：R4为二C1-6烷基取代的氨基-C1-6烷氧基。
在本发明的部分实施方案中，所述化合物中：R4选自哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基和二C1-4烷基取代的氨基-C1-4烷氧基。
在本发明的部分实施方案中，所述化合物中：R4为哌嗪-1-基。
在本发明的部分实施方案中，所述化合物中：R4为哌啶-1-基。
在本发明的部分实施方案中，所述化合物中：R4为哌啶-4-基。
在本发明的部分实施方案中，所述化合物中：R4为1,2,3,6-四氢吡啶-4-基。
在本发明的部分实施方案中，所述化合物中：R4为二C1-4烷基取代的氨基-C1-4烷氧基。
在本发明的部分实施方案中，所述化合物中：所述哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基任选地被以下取代基单取代或多取代：羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基。在本发明的部分实施方案中，所述化合物中：所述哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基任选地被以下取代基单取代或多取代：羟基、甲基、乙基、丙基和二甲氨基。
在本发明的部分实施方案中，所述化合物中：R4为4-二甲氨基哌啶-1-基。
在本发明的部分实施方案中，所述化合物中：R4为4-羟基哌啶-1-基。
在本发明的部分实施方案中，所述化合物中：R4为4-甲基哌嗪-1-基。
在本发明的部分实施方案中，所述化合物中：R4为N-甲基哌啶-4-基。
在本发明的部分实施方案中，所述化合物中：R4为N-甲基-1,2,3,6-四氢吡啶-4-基。
在本发明的部分实施方案中，所述化合物中：R4为2-二甲氨基乙氧基。
在本发明的部分实施方案中，所述化合物具有如下所示结构，
Figure PCTCN2017088785-appb-000019
其中，
L为-(CH2)n-，其中n为1、2、3、4、5或6，优选地，n为1或5；
环A选自3-6元环烷基、5元杂环烷基(例如吡咯烷)、5元杂芳基(噁唑、异噁唑、噻唑、吡唑或咪唑)或哌嗪；
R2和R3各自独立地选自氢、卤素、C1-6烷基、卤代C1-6烷基和C1-6烷氧基，R4不存在；或者，
R2和R3均为氢，R4代表5-6元杂环烷基-C0-1烷基，其中所述5-6元杂环烷基-C0-1烷基未被取代或被一个或多个(例如1、2、3或4个)选自下述的取代基取代：氧代、羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、C1-6烷氧基-C1-6烷基；
优选地，R2为氢，R3选自氟、甲基、三氟甲基和二氟甲基，R4不存在；或者，
R2和R3均为氢，R4代表哌啶基或被甲基取代的哌啶基。
在本发明的部分具体实施方案中，
n为5；
环A选自5元杂环烷基(例如吡咯烷)或哌嗪；
R2和R3各自独立地选自氢、卤素、C1-6烷基、卤代C1-6烷基和C1-6烷氧基；优选地，R2为氢，R3为氟或甲基；
R4不存在。
在本发明的部分具体实施方案中，
L为亚甲基；
环A为环丙基或环丁基；
R2和R3均为氢；
R4为4-甲基哌嗪基。
在本发明的部分实施方案中，所述化合物选自
Figure PCTCN2017088785-appb-000020
Figure PCTCN2017088785-appb-000021
Figure PCTCN2017088785-appb-000022
Figure PCTCN2017088785-appb-000023
本发明还提供本发明第一方面任一项所述化合物的制备方法，其中，所述式I化合物可通过如下反应路线制备得到：
Figure PCTCN2017088785-appb-000024
第1步：化合物SM-5与氰胺反应得到化合物IN-23；
第2步：化合物IN-23与R1-X-H反应生成化合物IN-24；
第3步：化合物IN-24关环反应得到化合物IN-25；
第4步：化合物IN-25硝基化得到化合物IN-26；
第5步：化合物IN-26氯化反应得到化合物IN-27；
第6步：化合物IN-27与胺IN-28反应得到化合物IN-29；
第7步：化合物IN-29经硝基还原后合环得到所述式I化合物。
在本发明的一些实施方案中，所述式I-1化合物可通过如下反应路线制备得到：
Figure PCTCN2017088785-appb-000025
步骤1：化合物SM-1与氨基乙酸乙酯反应生成化合物化合物IN-1；
步骤2：化合物IN-1与2-甲硫基-5-硝基-6-氯-4-嘧啶胺反应生成化合物IN-2；
步骤3：化合物IN-2氧化后得到化合物IN-3；
步骤4：R1-OH与化合物IN-3反应生成化合物化合物IN-4；
步骤5：化合物IN-4环化后得到化合物IN-5；
步骤6：化合物IN-5还原得到化合物IN-6；
步骤7：化合物IN-6经还原胺化反应生成式I-1化合物；
其中，各原子或取代基定义如式I-1中所述。
在本发明的一些实施方案中，所述式I-2可通过如下反应路线制备得到：
Figure PCTCN2017088785-appb-000026
第1步：化合物SM-3与氨基乙酸乙酯反应生成化合物IN-12；
第2步：化合物IN-12与2-甲硫基-5-硝基-6-氯-4-嘧啶胺反应生成化合物IN-13；
第3步：化合物IN-13氧化后得到化合物IN-14；
第4步：化合物IN-14与R1-X-H反应生成化合物IN-15；
第5步：化合物IN-15环化后得到式I-2化合物；
其中各原子或取代基定义如式I-2中所述。
在本发明的一些实施方案中，所述式I-3可通过如下反应路线制备得到：
第一步：化合物SM-2与R4H反应生成化合物IN-7；
第二步：化合物IN-7与氨基乙酸乙酯反应生成化合物IN-8；
第三步：化合物IN-8与2-甲硫基-5-硝基-6-氯-4-嘧啶胺反应生成化合物IN-9；
第四步：化合物IN-9氧化得到化合物IN-10；
第五步：化合物IN-10与R1-X-H反应生成化合物IN-11；
第六步：化合物IN-11环化后得到式I-3化合物；
其中，SM-2中的Lg为亲核取代反应的离去基团(例如卤素、-OTs、-OCOR，R为烷基)，其余各原子或取代基定义如式I-3中所述。
在本发明的一些实施方案中，所述式I-3A可通过如下反应路线制备得到：
Figure PCTCN2017088785-appb-000028
第一步：化合物SM-2A与R4H反应生成化合物IN-7A；
第二步：化合物IN-7A与氨基乙酸乙酯反应生成化合物IN-8A；
第三步：化合物IN-8A与2-甲硫基-5-硝基-6-氯-4-嘧啶胺反应生成化合物IN-9A；
第四步：化合物IN-9A氧化得到化合物IN-10A；
第五步：化合物IN-10A与R1-OH反应生成化合物IN-11A；
第六步：化合物IN-11A环化后得到式I-3A化合物；
其中，SM-2A中的Lg为亲核取代反应的离去基团(例如卤素、-OTs、-OCOR，R为烷基)，其余各原子或取代基定义如式I-3A中所述。
在本发明的一些实施方案中，所述式I-3A-1可通过如下反应路线制备得到：
Figure PCTCN2017088785-appb-000029
第一步：化合物SM-2A-1与R4H反应生成化合物IN-7A-1；
第二步：化合物IN-7A-1与氨基乙酸乙酯反应生成化合物IN-8A-1；
第三步：化合物IN-8A-1与2-甲硫基-5-硝基-6-氯-4-嘧啶胺反应生成化合物IN-9A-1；
第四步：化合物IN-9A-1氧化得到化合物IN-10A-1；
第五步：化合物IN-10A-1与CH3(CH2)3OH反应生成化合物IN-11A-1；
第六步：化合物IN-11A-1环化后得到式I-3A-1化合物；
其中，SM-2A-1中的Lg为亲核取代反应的离去基团(例如卤素、-OTs、-OCOR，R为烷基)，其余各原子或取代基定义如式I-3A-1中所述。
在本发明的一些实施方案中，所述式I-4化合物可通过如下反应路线制备得到：
Figure PCTCN2017088785-appb-000030
第1步：化合物SM-4的羟基保护成其硅醚化合物IN-16；
第2步：化合物IN-16与溴代乙酸乙酯反应得到化合物IN-17；
第3步：化合物IN-17与2-甲硫基-5-硝基-6-氯-4-嘧啶胺反应生成化合物IN-18；
第4步：化合物IN-18的硫醚氧化成亚甲砜化合物IN-19；
第5步：化合物IN-19与正丁醇反应生成IN-20；
第6步：化合物IN-20的羟基活化成其甲磺酸酯化合物IN-21；
第7步：化合物IN-21与A环反应得到化合物IN-22；
第8步：化合物IN-22的硝基还原后合环得到式I-4化合物；
其中各原子或取代基定义如式I-4中所述。
上述各反应步骤的具体条件为本领域公知，对此本发明不作具体限定。根据本发明的教导结合本领域公知常识，本领域技术人员可以对通式中的各取代基进行选择替换以制备得到不同的化合物，这些选择和替换均在本发明的保护范围之内。
本发明所述化合物中的原子可以被其同位素替代。例如12C可被其同位素13C或14C替代；1H可被2H(D，氘)或3H(T，氚)替代；31P可被32P或33P替代等。本发明包括式I所述化合物以及式I化合物中的任意原子经其同位素替换后得到的化合物。
本发明还提供一种药物组合物，其包含本发明第一方面任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等，以及任选地，一种或多种药学上可接受的载体或赋形剂。
所述药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
这里所述的载体包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。
所述赋形剂是指在药物制剂中除主药以外的附加物。其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。
本发明的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等可以通过以下途径给药：胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。所述药物组合物可以任选地与在治疗各种疾病中至少有一定效果的其它试剂联合给药。
本发明的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等可根据给药途径配成各种适宜的剂型。
本发明所述的药物组合物或适宜的剂型可以含有0.01mg至1000mg的本发明化合物，适宜含有0.1mg至800mg，优选含有0.5-500mg，更优选含有1至350mg，特别优选5-250mg。
当口服用药时，本发明化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当皮肤局部施用时，本发明化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
本发明化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
在本发明的实施方案中，进行合适的体外或体内测定来确定本发明药物组合物的效果以及给药是否适用于治疗个体所患疾病或医学疾病状态。这些测定的实例在下文非限制性实施例结合具体疾病或医学治疗进行了描述。通常，足以实现预防或治疗效果的本发明组合物的有效量为约0.001mg/千克体重/天至约10,000mg/千克体重/天。合适的情况下，剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。剂量范围可以为每天、每两天或每三天约0.01至1000mg/kg受试者体重，更通常为0.1至500mg/kg受试者体重。示例性的治疗方案为每两天一次或每周一次或每月一次给药。通常多次给予所述制剂，单次剂量之间的间隔可以是每天、每周、每月或每年。或者，可以以缓释制剂的形式给予所述制剂，在这种情况下，需要较少的给药频率。剂量和频率根据制剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以 相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。
本发明还提供本发明第一方面任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等或其药物组合物在制备TLR激动剂中的用途，优选地，所述TLR激动剂为TLR7激动剂。
本发明还提供本发明第一方面任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等或其药物组合物在制备作为TLR激动剂的药物中的用途，优选地，所述TLR激动剂为TLR7激动剂。
本发明还提供本发明第一方面任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等或其药物组合物在制备治疗与TLR7相关的疾病的药物中的用途。
在本发明的部分实施方案中，所述与TLR7相关的疾病选自肝炎(例如乙型肝炎(HBV)或丙型肝炎(HCV))、哮喘、过敏性鼻炎、皮肌炎、疟疾、牛皮癣、光化角化病、实体瘤(例如膀胱癌或非霍奇金淋巴瘤(NHL))、血液肿瘤、黑色素瘤和自身免疫疾病(例如全身性红斑狼疮(SLE),艾滋病(HIV))。
本发明还提供本发明第一方面任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等或其药物组合物，其用于治疗与TLR7相关的疾病。
在本发明的部分实施方案中，所述与TLR7相关的疾病选自肝炎(例如乙型肝炎(HBV)或丙型肝炎(HCV))、哮喘、过敏性鼻炎、皮肌炎、疟疾、牛皮癣、光化角化病、实体瘤(例如膀胱癌或非霍奇金淋巴瘤(NHL))、血液肿瘤、黑色素瘤和自身免疫疾病(例如全身性红斑狼疮(SLE),艾滋病(HIV))。
本发明还提供一种治疗与TLR7相关的疾病的方法，其包括向有需要的受试者施用有效量的本发明第一方面任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等或其药物组合物。
在本发明的部分实施方案中，所述与TLR7相关的疾病选自肝炎(例如乙型肝炎(HBV)或丙型肝炎(HCV))、哮喘、过敏性鼻炎、皮肌炎、疟疾、牛皮癣、光化角 化病、实体瘤(例如膀胱癌或非霍奇金淋巴瘤(NHL))、血液肿瘤、黑色素瘤和自身免疫疾病(例如全身性红斑狼疮(SLE),艾滋病(HIV))。
以下对本发明的术语进行解释，对于特定的术语，如果本发明中的含义与本领域技术人员通常理解的含义不一致，以本发明中的含义为准；如果在本发明中没有定义，则其具有本领域技术人员通常理解的含义。除非有相反陈述，本发明中使用的术语具有下述含义：
本发明所用术语“C1-6烷基”是指具有1-6个碳原子的直链或支链烷基，例如C1-4烷基、C1-2烷基、C1烷基、C2烷基、C3烷基、C4烷基、C5烷基或C6烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
本发明所用术语“C0烷基”表示所述烷基不存在，例如当所述3-8元环烷基-C0-6烷基为3-8元环烷基-C0烷基时，C0烷基部分不存在，因此所述3-8元环烷基-C0烷基为3-8元环烷基。
本发明所用术语“卤代C1-6烷基”是指上述C1-6烷基被一个或多个卤素取代后得到的基团，例如卤代C1-4烷基、卤代C1-2烷基、卤代C1烷基、卤代C2烷基、卤代C3烷基、卤代C4烷基、卤代C5烷基或卤代C6烷基。其中所述卤素选自F、Cl、Br和I，优选地，所述卤素为F或Cl，更优选地，所述卤素为F。具体的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氟乙基、氟代丙基、氟代异丙基、氟代正丁基、氟代异丁基、氟代仲丁基、氟代叔丁基、氟代正戊基、氟代正己基、氯甲基、氯乙基、氯代丙基、氯代异丙基、氯代正丁基、氯代异丁基、氯代仲丁基、氯代叔丁基、氯代正戊基、氯代正己基等。
本发明中所用术语“C1-6烷氧基”是指具有“C1-6烷基-O-”结构的基团，其中C1-6烷基具有前述相同的含义。例如C1-4烷氧基、C1-2烷氧基、C1烷氧基、C2烷氧基、C3烷氧基、C4烷氧基、C5烷氧基或C6烷氧基。具体的实例包括但不限于甲氧基、乙氧基、丙氧基、正丁氧基、2-丁氧基、异丙氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基等。
本发明中所用术语“C1-6烷氨基”是指具有“C1-6烷基-NH-”结构的基团，其中C1-6烷基具有前述相同的含义。例如C1-4烷氨基、C1-2烷氨基、C1烷氨基、C2烷氨基、C3烷氨基、C4烷氨基、C5烷氨基或C6烷氨基。具体的实例包括但不限于甲氨基、乙氨基、丙氨基、异丙氨基、正丁氨基、2-丁氨基、仲丁氨基、异丁氨基、叔丁氨基、正戊氨基、正己氨基等。
本发明中所用术语“二C1-6烷基取代的氨基”是指具有
Figure PCTCN2017088785-appb-000031
结构的基团，其中C1-6烷基具有前述相同的含义，连接在N原子上的两个C1-6烷基可以相同也可以不同。例如二C1-4烷基取代的氨基或二C1-2烷基取代的氨基。具体的实例包括但不限于二甲氨基、二乙胺基、甲基乙基氨基、甲基异丙基氨基、乙基异丙基氨基、甲基叔丁基氨基、乙基叔丁基氨基等。
本发明中所用术语“C2-6烯基”是指含有2-6个碳原子以及一个、两个或三个碳碳双键的直链或支链烃基，优选含有一个碳碳双键的C2-6烯基。例如C2-4烯基、C2烯基、C3烯基、C4烯基、C5烯基或C6烯基。具体的实例包括但不限于乙烯基、丙烯基、2-丙烯基、丁烯基、2-丁烯基、2-甲基-丙烯基、丁二烯基、戊烯基、2-甲基-丁烯基、3-甲基-丁烯基、1,3-戊二烯基、1,4-戊二烯基、己烯基、2-乙基-丁烯基、3-甲基-戊烯基、4-甲基-戊烯基、1,3-己二烯基、1,4-己二烯基、1,5-己二烯基等。
本发明中所用术语“C2-6炔基”是指含有2-6个碳原子以及一个、两个或三个碳碳三键的直链或支链烃基，优选含有一个碳碳三键的C2-6炔基。例如C2-4炔基、C2炔基、C3炔基、C4炔基、C5炔基或C6炔基。具体的实例包括但不限于乙炔基、丙炔基、2-丙炔基、丁炔基、2-丁炔基、2-甲基-丙炔基、丁二炔基、戊炔基、2-甲基-丁炔基、3-甲基-丁炔基、1,3-戊二炔基、1,4-戊二炔基、己炔基、2-乙基-丁炔基、3-甲基-戊炔基、4-甲基-戊炔基、1,3-己二炔基、1,4-己二炔基、1,5-己二炔基等。
本发明中所用术语“环烷基”是指饱和或部分饱和的单环烷基。优选3-8元环烷基，例如3元、4元、5元、6元、7元或8元环烷基。具体的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
本发明中所用术语“杂环基”是指含有至少1个至多4个(例如1、2、3或4个)选自N、O和S的杂原子的脂肪环或芳香环，例如杂环烷基或杂芳基。
具体地，本发明中所用术语“杂环烷基”是指含有至少1个至多4个(例如1、2、3或4个)选自N、O和S的杂原子的饱和或部分饱和的单如上述定义的环烷基，优选地，所述杂环烷基至少含有一个N。所述N和S任选地可被氧化，所述N可任选地被季铵化。例如3-8元杂环烷基、5-6元杂环烷基、3元、4元、5元、6元、7元或8元杂环烷基。具体的实例包括但不限于环氧乙烷、氧代环丁烷、吡咯烷、吡咯烷酮、四氢呋喃、4,5-二氢-1H-吡唑、哌啶、哌嗪、吗啉、硫吗啉等。
具体地，本发明中所用术语“杂芳基”是指含有至少1个至多4个(例如1、2、3或4个)选自N、O和S的杂原子的芳香环。例如5-8元杂芳基、5-6元杂芳基、5元、6元、7元或8元杂芳基。具体的实例包括但不限于吡咯、呋喃、噻吩、吡啶、嘧啶、吡嗪、哒嗪等。
本发明中所用术语“杂螺环基”、“杂并环基”和“杂桥环基”分别指含有至少1个至多4个(例如1、2、3或4个)选自N、O和S的杂原子的螺环基、并环基或桥环基。优选 地，所述杂螺环基、杂并环基和杂桥环基含有5-15个原子，更优选5-10个原子，更优选6-9个原子，例如6、7、8、9元杂螺环基、杂并环基和杂桥环基。具体的实例包括但不限于1-吡咯烷并[3,4-c]吡咯烷基、3-氮杂-双环[3.1.0]己基、2-氮杂-双环[3.1.0]己基、六氢-呋喃并[3,4-c]吡咯、2-氧杂-6-氮杂-螺[3.4]辛烷、八氢-环戊烷并[c]吡咯、2-氮杂-螺[4.4]壬烷、6-氮杂-螺[3.4]辛烷、5-氮杂-螺[2.4]庚烷等。
本发明中所用术语“烷氧羰基”是指具有“烷基-O-C(O)-”结构的基团，所述烷基具有与前述相同的定义。所述烷氧羰基优选C1-6烷氧羰基，更优选C1-4烷氧羰基。具体的实例包括但不限于甲氧羰基、乙氧羰基、丙氧羰基叔丁氧羰基等。
本发明所用术语“光学异构体”包括本发明式I化合物的所有可能的光学异构体形式(例如对映异构体、非对映异构体等)。
本发明式I化合物或其药学可接受的盐还可以形成溶剂合物，例如水合物、醇合物等。
本发明式I化合物还可以是前药或以或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。
本发明式I化合物还可以是化学保护的形式，所述保护基可保护在化合物的活性基团(如氨基)上，所述保护基可在体内代谢释放出活性成分。选择和制备适当的化学保护的形式是本领域技术人员公知技术。
本发明所用术语“药学上可接受的盐”包括与药学上可以接受的无机酸或者有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括氢溴酸、硫酸、磷酸、高氯酸、琥珀酸、羟基乙酸、扑酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括钠、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、N-甲基葡糖胺和普鲁卡因等形成的盐。
本文所用术语“有效量”是指足以实现所需治疗效果的量，例如，实现减轻与待治疗疾病相关的症状的量。
本文所用的术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、其光学异构体或其药学上可接受的盐或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
发明的有益效果
本发明TLR7激动剂的优势：1.可口服，且肝脏快速吸收，允许从肠道吸收进入肝门静脉(肝肠循环)，低剂量就能够发挥良好的药效，降低不良事件；2.可以和去甲肾上腺素(NA)配合成单药片服用；3.TLR7高选择性而不激活TLR8通路，减少TNF-α激活的副作用；4.与注射IFN类似，口服TLR激动剂诱导IFN产生，发挥药效。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
化合物的结构是通过核磁共振(1HNMR)或质谱(MS)来确定的。1HNMR的测定是用JEOL Eclipse 400核磁仪，测定溶剂为氘代甲醇(CD3OD)、氘代氯仿(CDCl3)，六氘代二甲基亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出；
MS的测定用Agilent(ESI)质谱仪；
制备高效液相使用岛津LC-8A制备液相色谱仪。
薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层层析分离纯化采用的规格是GF 254。
反应的监测采用薄层色谱法(TLC)或LCMS，使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节或者加入三乙胺等进行调节。
微波反应使用BiotageInitiator+(400W,RT～300℃)微波反应器。
柱层析一般使用200～300目硅胶为载体。洗脱剂的体系包括：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。
实施例中无特殊说明，反应的温度为室温(20℃～35℃)；
本发明所使用的试剂购自Acros Organics，Aldrich Chemical Company，特伯化学等公司。
在常规的合成法以及实施例、和中间体合成例中，各缩写的意思如以下所示。
Figure PCTCN2017088785-appb-000032
制备例1：N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯(中间体1)的制备
Figure PCTCN2017088785-appb-000033
第一步：3-(吡咯烷-1-甲基)苯腈的制备
将3-氰基苯甲醛(60g，0.458mol)加入到三口瓶中，加入THF(500mL)溶解，并加入吡咯和醋酸；冰水浴冷却，加入NaBH(OAc)3(145g，0.687mol)，加毕，缓慢升至室温并搅拌过夜(约20小时)；TLC检测反应完全，将反应液加入1.5L水中，加入NaHCO3溶液将水溶液pH值调制8-9；加入EA(500mL×1，300mL×2)萃取水层，合并EA，加饱和食盐水洗涤，无水硫酸钠干燥。浓缩EA得目标化合物(62g，收率73％)。
第二步：3-(吡咯烷-1-甲基)苄胺的制备
将化合物3-(吡咯烷-1-甲基)苯腈(61g，0.328mol)加入1L三口瓶中，加入200mLMeOH、MeOH/NH3溶液和Raney-Ni，通入氢气，25℃下反应48小时；LC-MS检测反应完全，抽滤掉Raney-Ni(加硅藻土)，滤饼用MeOH(50mL×2)洗涤；浓缩甲醇得目标化合物(59g，收率94％)。
第三步：N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯的制备
将化合物3-(吡咯烷-1-甲基)苄胺(59g，0.310mol)加入到1L三口瓶中，加入400mL THF、三乙胺86mL，滴加溴乙酸乙酯(57g，0.341mol)，室温搅拌24小时。TLC检测反应完全，将反应液加入2L水中，EA萃取，合并有机相，饱和食盐水洗涤两次，无水硫酸钠干燥；浓缩得目标产物(64g，收率74％)。
第四步：N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯的制备
将化合物N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯(58g，0.210mol)和6-氨基-5-硝基-2-甲硫基-4-氯嘧啶(44g，0.200mol)依次加入500mL THF中，滴加Et3N(61g，0.6mol)，室温反应4小时；TLC反应完全后，将反应液缓慢加入到2L水中，EA萃取，合并EA，饱和食盐水洗，无水硫酸钠干燥。浓缩EA析出固体，过滤，得目标产物(64g，收率69％)。
第五步：N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯的制备
将化合物N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯(4.6g，0.010mol)加入50mL乙腈中滴加30mL过硫酸氢钾复合盐水溶液(6.72g，0.04mol)，冰水浴下搅拌2小时，LC-MS显示反应完全，加入200mL水，二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥(3.5g，收率68％)。
制备例2：3-(4-氨基-2-丁氧基-6-氧代-6,7-二氢蝶啶-8(5H)-基)甲基-苯甲醛(中间体2)的制备：
Figure PCTCN2017088785-appb-000034
第一步N-(3-氰基苄基)甘氨酸乙酯的制备
将间氰基苯甲醛(80g，0.61mol)与甘氨酸乙酯盐酸盐(94g，0.67mol)加入到2L三口瓶中，加入1.2L甲醇、三乙胺和NaBH3CN，室温搅拌反应6小时；TLC检测反应完全，将反应液加入4L水和EA(1L x 1，500mL×2)萃取水层，合并EA，加饱和食盐水洗涤，无水硫酸钠干燥。浓缩EA得到产品112g，收率84％。
第二步：N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-(3-氰基苄基)甘氨酸乙酯的制备
将(3-氰基苄基)甘氨酸乙酯和6-氨基-5-硝基-2-甲硫基-4-氯嘧啶加入到2L三口瓶中，加入THF(1L)、三乙胺(100mL)，室温反应24小时；将反应液过滤，滤液加入3L纯净水中，EA(1L×1，500mL×2)萃取，合并EA加饱和食盐水(300mL×2)洗涤，无水硫酸钠干燥1小时；浓缩EA析出固体，过滤，母液中加入石油醚重结晶，过滤，洗涤，合并滤饼，干燥得75.5g目标化合物，收率43.5％。
第三步N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-(3-氰基苄基)甘氨酸乙酯的制备
将N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-(3-氰基苄基)甘氨酸乙酯(66g，0.164mol)加入到2L三口瓶中，加入DCM(1.8L)和m-CPBA(70.7g，0.41mol)，室温反应20小时；TLC反应完全后，过滤，滤饼用DCM洗涤，滤液依次用亚硫酸氢钠溶液(0.8L×2)，饱和食盐水(300mL×2)洗涤后无水硫酸钠干燥1小时；纯化得到产品60.5g，收率85％。
第四步N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N-(3-氰基苄基)甘氨酸乙酯的制备
将N-(6-氨基-2-(甲磺酰基)-5-硝基嘧啶-4-基)-N-(3-氰基苄基)甘氨酸乙酯(60g，0.138mol)加入到1L三口瓶中然后加入600mL正丁醇溶解，加入对甲苯磺酸13g，升温至80℃反应4小时。TLC反应完全后，过滤，滤饼用正丁醇洗涤，抽干干燥得53g，收率89％。
第五步3-(4-氨基-2-丁氧基-6-氧代-6,7-二氢蝶啶-8(5H)-基)甲基-苯腈的制备
将N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N-(3-氰基苄基)甘氨酸乙酯(53g，0.123mol)加入到1L三口瓶中加入450mL乙醇，加入保险粉的水溶液，升温至80℃反应6小时。TLC反应完全后，过滤，洗涤滤饼，干燥得产品30g，收率68％。
第六步3-(4-氨基-2-丁氧基-6-氧代-6,7-二氢蝶啶-8(5H)-基)甲基-苯甲醛的制备
将3-(4-氨基-2-丁氧基-6-氧代-6,7-二氢蝶啶-8(5H)-基)甲基-苯腈(33g，0.093mol)加入到1L三口瓶中加入800mL甲酸，加入Raney-Ni，加毕，通入氢气升温至80℃反应1小时。LC-MS显示反应完全后，反应液过滤(加硅藻土)，滤液浓缩后加入200mL乙醇搅拌析晶，抽滤，干燥得到产品25g，收率75％。
制备例3：6-氯-2-甲硫基-5-硝基嘧啶-4-胺(中间体3)的制备
Figure PCTCN2017088785-appb-000035
将原料5-硝基-2-甲硫基-4,6-二氯嘧啶(120g，0.5mol)加入三口瓶中加入600mL THF溶解，加入三乙胺和氨甲醇(86mL，0.6mol)溶液，室温搅拌反应1小时；TLC检测反应完全，将反应液加入到2L水中，抽滤，滤饼依次用纯化水(500mL×2)石油醚(400mL)洗涤后干燥得到目标产物95g，收率86％。
制备例4：在本发明的实施方案中，磺酰化物与醇可通过以下方法连接
方法1：
Figure PCTCN2017088785-appb-000036
将化合物N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯(1.0g，2mmol)加入10mL醇(R1-OH)中，加入TFA(0.5mL，6mmol)，升温至90℃搅拌反应，LC-MS显示反应完全后，将反应液倒入约20mL饱和NaHCO3水溶液中，DCM萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩得粗品，用制备板分离得纯品。
方法2：
Figure PCTCN2017088785-appb-000037
将化合物N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯(1.0g，2mmol)加入10mL DME中，加入醇(R1-OH，1mL)，TFA(0.5mL，6mmol)，升温至90℃搅拌反应，LC-MS显示反应完全后，放置至室温，将反应液倒入约20mL 饱和NaHCO3水溶液中，DCM萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩得粗品，用制备板分离得纯品。
方法3：
Figure PCTCN2017088785-appb-000038
将化合物N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-(3-(吡咯烷-1-甲基)苄基)甘氨酸乙酯(1.0g,2mmol)加入10mL DCM中，加入醇(R1-OH，1mL)，室温搅拌反应，LC-MS显示反应完全后，加入20mL DCM稀释，饱和食盐水洗两次，无水硫酸钠干燥，浓缩得粗品，用制备板分离得纯品。
制备例5：在本发明的实施方案中，可通过以下关环方案得到本发明的二氢蝶啶酮
方法4：
Figure PCTCN2017088785-appb-000039
将硝基化合物(100mg，0.2mmol)加入5mL乙醇和5mL水的混合体系中，加入保险粉，升温至80℃搅拌反应，30分钟后TLC显示反应完全，将反应液倒入约20mL饱和碳酸氢钠水溶液中，DCM萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩得粗品，用少量甲醇搅洗，过滤得纯品。
实施例A：
8-(3-(2-氮杂二环[3.1.0]己烷-2-基甲基)苄基)-4-氨基-2-丁氧基-7,8-二氢蝶啶-6(5H)-酮(化合物1)的制备
Figure PCTCN2017088785-appb-000040
将3-(4-氨基-2-丁氧基-6-氧代-6,7-二氢蝶啶-8(5H)-基)甲基-苯甲醛(中间体2)(40mg，0.113mmol)加入5mL甲醇的体系中，加入2-氮杂二环[3.1.0]己烷盐酸盐(30mg，0.251mmol)和氰基硼氢化钠(30mg，0.477mmol)，升温至60℃搅拌反应，4小时后TLC显示反应完全，将反应液倒入约20mL饱和碳酸氢钠水溶液中，DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得粗品38mg，HPLC纯化得化合物1(15mg，收率42.9％)。
MS m/z(ESI):423[M+H]+；
1HNMR(400MHz,CD3OD)δ:7.63-7.44(m,4H),4.88(s,2H),4.48-4.31(m,4H),4.17-4.14(m,2H),3.55-3.44(m,2H),3.23-3.10(m,2H),2.24-2.13(m,1H),2.07-1.96(m,2H),1.80-1.64(m,2H),1.48-1.38(m,1H),0.94(t,3H,J＝8Hz),0.6-0.4(m,2H).
实施例B：
(S)-4-氨基-2-丁氧基-8-(3-((3-氟吡咯烷-1-基)甲基)苄基)-7,8-二氢蝶啶-6(5H)-酮(化合物12)的制备
Figure PCTCN2017088785-appb-000041
使用类似实施例A方法制备，用(S)-3-氟吡咯烷代替实施例1中的2-氮杂二环[3.1.0]己烷盐酸盐，得到标题化合物。
MS m/z(ESI):429[M+H]+；
1HNMR(400MHz,CD3OD)δ:7.63-7.44(m,4H),4.88(s,2H),4.48-4.31(m,5H),4.17-4.14(m,2H),3.55-3.44(m,2H),3.23-3.10(m,3H),2.24-2.13(m,2H),2.07-1.96(m,2H),1.25-1.17(m,1H),0.94(t,3H,J＝8Hz).
实施例C：
4-氨基-2-丁氧基-8-(3-((3,3-二甲基吡咯烷-1-基)甲基)苄基)-7,8-二氢蝶啶-6(5H)-酮(化合物51)的制备
Figure PCTCN2017088785-appb-000042
使用类似实施例A的方法制备，用3,3-二甲基吡咯烷代替实施例1中的2-氮杂二环[3.1.0]己烷盐酸盐，得到标题化合物。
MS m/z(ESI):439[M+H]+；
1HNMR(400MHz,CD3OD)δ:7.63-7.44(m,4H),4.88(s,2H),4.17-4.14(m,2H),3.98(s,2H),3.63(s,2H),2.54-2.43(m,2H),2.07-1.96(m,2H),1.80-1.64(m,2H),1.48-1.38(m,4H),0.99(s,6H),0.90(t,3H,J＝8Hz).
实施例1：4-氨基-2-丁氧基-8-((6-(4-甲基哌嗪-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物14)的制备
Figure PCTCN2017088785-appb-000043
第一步：4-(5-甲酰基吡啶-2-基)哌嗪-1-羧酸叔丁酯
将化合物6-溴烟醛(1.0g，5.376mmol)，N-Boc-哌嗪(1.0g，5.376mmol)和DIEA(2.5mL)加入到10mL的DME中，升温至120℃搅拌反应，6.5小时后TLC显示原料反应完全；加入水，用EA进行萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后得到黄色固体1.4g(收率89.7％)。
第二步：4-(5-((乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯
将化合物4-(5-甲酰基吡啶-2-基)哌嗪-1-羧酸叔丁酯(1.2g，4.12mmol)，甘氨酸乙酯盐酸盐(1.2g，8.60mmol)和氰基硼氢化钠(0.6g，9.548mmol)加入30mL甲醇体系中，20℃下搅拌反应，3小时后LC-MS显示原料反应完全，停止反应，加入水后，用EA进行萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后得到淡黄色固体1.5g，粗品直接用于下一步反应。
第三步：4-(5-((N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N--乙氧羰基甲基氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯
将化合物4-(5-((乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(1.0g，2.65mmol)和6-氯-2-甲硫基-5-硝基嘧啶-4-胺(0.6g，2.70mmol)加入10mL的四氢呋喃体系中，加入0.8mL三乙胺，室温下搅拌，3小时后TLC显示反应完全，加入水，用DCM进行萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后得到黄色固体1.3g(收率87.3％)。
第四步：4-(5-((N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N--乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯
将化合物4-(5-((N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N--乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(30mg，0.051mmol)和KHSO5(25.73mg，0.153mmol)加入到6mL的乙腈体系中，室温下搅拌反应，1小时后LC-MS显示原料反应完全，将反应液倒入冰浴中的饱和碳酸氢钠溶液，用DCM进行萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后得到类白色固体16mg(粗品)，直接用于下一步反应。
MS m/z(ESI):427[M+H]+；
第五步：4-(5-((N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N--乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯
将化合物16 4-(5-((N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)--N-乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(200mg，0.337mmol)，Cs2CO3(132mg,0.4mmol)和0.6mL正丁醇加入10mL DCM体系中，室温搅拌反应，20分钟后LC-MS显示原料反应完全，将反应液倒入水中，用DCM进行萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后得到粗品200mg，制备板纯化后得到纯品80mg(收率40.1％)。
第六步：4-(5-((4-氨基-2-丁氧基-6-氧代-6,7-二氢蝶啶-8(5H)-基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯
将化合物17 4-(5-((N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N--乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(60mg，0.102mmol)，Na2S2O4(180mg，1.02mmol)加入5mL的乙醇和5mL水的混合体系中，升温至90℃反应1小时，TLC显示原料反应完全，将反应液倒入20mL的饱和碳酸氢钠溶液中，DCM进行多次萃取，合并有机相后加入5mL甲醇，无水硫酸钠充分干燥后浓缩得到60mg粗品，用甲醇进行打浆处理，最后得到白色固体30mg(收率60％)。
第七步：4-氨基-2-丁氧基-8-((6-(哌嗪-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮
将化合物184-(5-((4-氨基-2-丁氧基-6-氧代-6,7-二氢蝶啶-8(5H)-基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(300mg，0.615mmol)加入到4M的盐酸二氧六环体系中，室温搅拌，5分钟后LC-MS显示原料反应完全，直接浓缩后得到白色固体270mg(收率98％)。
第八步：4-氨基-2-丁氧基-8-((6-(4-甲基哌嗪-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物14)
将化合物19 4-氨基-2-丁氧基-8-((6-(哌嗪-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(100mg，0.223mmol)溶解于甲醇和DCM(10mL/10mL)的混合体系中，加入0.5mL甲醛水溶液和NaBH3CN(100mg，1.59mmol)，搅拌室温反应，40分钟后LC-MS显示原料反应完全，向体系中加入20mL的DCM后，用水洗涤，有机相加入5mL MeOH后用无水硫酸钠充分干燥，浓缩后制备色谱分离纯化得到纯品30mg(收率32％).
MS m/z(ESI):427[M+H]+；
1HNMR(400MHz,DMSO-d6)δ:9.69(brs,1H),8.16-8.13(m,1H),7.71-7.64(m,1H),6.82-6.76(m,1H),6.23(brs,2H),4.59(s,2H),4.14-4.10(m,2H),3.84(s,2H),3.61-3.48(m, 4H),2.61-2.52(m,4H),2.23(s,3H),1.65-1.57(m,2H),1.41-1.33(m,2H),0.90(t,3H,J＝8Hz).
实施例2：
4-氨基-2-丁氧基-8-((6-(2-(二甲基氨基)乙氧基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物61)的制备
Figure PCTCN2017088785-appb-000044
第一步：化合物61-A的制备
将2-溴吡啶-5-甲醛(370mg,2mmol)和N,N-二甲基乙醇胺溶于DMF(5ml)中，冰水浴冷却下加入NaH(160mg,4mmol)，然后升至室温搅拌，16小时后，将反应液倒入约20ml水中，后处理得化合物61-A粗品300mg直接用于下一步反应。产率(77.1％)
第二步：化合物61-B的制备
将化合物61-A(300mg,1.5mmol)溶于1,2-二氯乙烷(10ml)中，加入甘氨酸乙酯盐酸盐(500mg,4mmol)，无水硫酸镁(1g)，三乙胺(400mg,4mmol)，加毕，室温搅拌4小时后，过滤，滤液冰水浴冷却，加入三乙酰基硼氢化钠(1g,4mmol)，加毕，搅拌十分钟后，缓慢滴入冰乙酸(0.5ml),滴毕，室温搅拌过夜后，后处理得化合物61-B粗品350mg，直接用于下一步反应。产率(83.1％)
第三步：化合物61-C的制备
将化合物61-B(350mg,1.2mmol)和59-F(460mg,1.2mmol)依次加入THF(10ml)中，搅拌下滴入三乙胺(200mg,2mmol),室温搅拌反应过夜后，将反应液倒入约50ml水中，后处理得化合物61-C，400mg.产率(67.7％)
第四步：化合物61的制备
将化合物61-B(100mg,0.2mmol)溶于甲醇(5ml)中，加入催化量的兰尼镍，氢气保护下搅拌反应1小时，后处理得到化合物61.产率(28％)MS m/z(ESI):416[M+H]+；
1HNMR(400MHz,DMSO-d6)δ:9.69(brs,1H),8.16-8.13(m,1H),7.69-7.66(m,1H),6.82-6.76(m,1H),6.23(brs,2H),4.59(s,2H),4.34-4.30(m,2H),4.12(t,2H,J＝6.4Hz),3.84(s,2H),2.61-2.58(m,2H),2.20(s,6H),1.65-1.57(m,2H),1.41-1.33(m,2H),0.90(t,3H, J＝8Hz).
实施例3：
4-氨基-2-丁氧基-8-((1'-甲基-1',2',3',6'-四氢-[2,4'-二吡啶]-5-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物69)的制备
Figure PCTCN2017088785-appb-000045
第一步：化合物69-A的制备
将2-溴吡啶-5-甲醛(1g,5mmol)和硼酸酯(1.3g,6mol)溶于二氧六环(20ml)中，加入10％NaCO3水溶液(5ml)和Pd(dppf)Cl2，在氮气保护下，100℃搅拌反应16小时，后处理得化合物69-A粗品1g直接用于下一步反应。产率(98％)
第二步：化合物69-B的制备
用69-A代替实施例2中第二步的61-A，采用与实施例2中第二步所描述类似的方法制备化合物69-B，产率(85.6％)。
第三步：化合物69-C的制备
用69-B代替实施例2中第三步的61-B，采用与实施例2中第三步所描述类似的方法制备化合物69-C，产率(53％)。
第四步：化合物69的制备
用69-C代替实施例2中第四步的61-C，采用与实施例2中第四步所描述类似的方法制备化合物69，产率(27％)。
MS m/z(ESI):425[M+H]+；
1HNMR(400MHz,CD3OD)δ:8.55(s,1H),7.65-7.45(m,2H),6.82-6.72(m,1H),4.88(s,2H),4.17-4.14(m,2H),3.98(s,2H),3.09-3.01(m,2H),2.49-2.39(m,2H),2.27(s,3H),2.09-2.01(m,2H),1.88-1.64(m,2H),1.48-1.26(m,2H),0.94(t,3H,J＝8Hz).
实施例4：
4-氨基-2-丁氧基-8-((6-(1-甲基哌啶-4-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物71)的制备
Figure PCTCN2017088785-appb-000046
第一步：化合物71的制备
将化合物69-C(100mg)溶于甲醇(5ml)中，加入催化量Raney Ni,氢气保护下保持40℃左右搅拌反应120小时，后处理得到30mg化合物71.产率(29％)
MS m/z(ESI):426[M+H]+；
1HNMR(400MHz,CD3OD)δ:8.55(s,1H),7.65-7.45(m,2H),4.88(s,2H),4.17-4.14(m,2H),3.98(s,2H),2.81-2.74(m,3H),2.49-2.39(m,2H),2.25(s,3H),2.09-2.01(m,2H),1.88-1.64(m,4H),1.48-1.26(m,2H),0.94(t,3H,J＝8Hz).
实施例5：
4-氨基-2-丁氧基-8-((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物15)的制备
Figure PCTCN2017088785-appb-000047
第一步：6-(4-羟基哌啶-1-基)烟醛
将化合物6-溴烟醛(2.0g，10.75mmol)，碳酸钾(2.5g，18.12mmol)和哌啶-4-醇(1.5g，14.82mmol)溶解于50mL的DMSO中，升温至90℃，12小时后TLC显示原料反应完全，向体系中加入水，用DCM进行萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后得到黄色固体1.6g(收率72.7％)。
第二步：2-(((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)氨基)醋酸乙酯
使用类似实施例1的第二步合成方法制备，用6-(4-羟基哌啶-1-基)烟醛代替实施例1第二步中的4-(5-甲酰基吡啶-2-基)哌嗪-1-羧酸叔丁酯。
第三步：2-(N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-((6-(4-羟基哌啶-1-基)吡啶-3-基) 甲基)-氨基)醋酸乙酯
使用类似实施例1的第三步合成方法制备，用2-(((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)氨基)醋酸乙酯代替实施例1第三步中的4-(5-((乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯。
第四步：2-(N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)氨基)醋酸乙酯
使用类似实施例1的第四步合成方法制备，用2-(N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯代替实施例1第四步中的4-(5-((N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯。
第五步：2-(N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N-((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯
使用类似实施例1的第五步合成方法制备用2-(N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯代替实施例1第五步中的4-(5-((N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)--N-乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯。
第六步：4-氨基-2-丁氧基-8-((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物15)
使用类似实施例1的第六步合成方法制备，用2-(N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N-((6-(4-羟基哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯代替实施例1第六步中的4-(5-((N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N--乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯。
MS m/z(ESI):428[M+H]+；
1HNMR(400MHz,DMSO-d6)δ:9.69(brs,1H),8.16-8.13(m,1H),7.71-7.64(m,1H),6.82-6.76(m,1H),6.23(brs,2H),4.59(s,2H),4.14-4.10(m,2H),3.84(s,2H),3.61-3.48(m,4H),2.61-2.52(m,2H),1.75-1.57(m,6H),1.41-1.33(m,2H),0.90(t,3H,J＝8Hz).
实施例6：
4-氨基-2-丁氧基-8-((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物16)的制备。
Figure PCTCN2017088785-appb-000048
第一步：6-(4-(二甲氨基)哌啶-1-基)烟醛
使用类似实施例5的第一步合成方法制备，用N,N-二甲基哌啶-4-胺取代实施例15第一步中的哌啶-4-醇。
第二步：2-(((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)氨基)醋酸乙酯
使用类似实施例1的第二步合成方法制备，用6-(4-(二甲氨基)哌啶-1-基)烟醛代替实施例1第二步中的4-(5-甲酰基吡啶-2-基)哌嗪-1-羧酸叔丁酯。
第三步：2-(N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯
使用类似实施例1的第三步合成方法制备，用2-(((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)氨基)醋酸乙酯代替实施例1第三步中的4-(5-((乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯。
第四步：2-(N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯
使用类似实施例1的第四步合成方法制备，用2-(N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N-((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯代替实施例1第四步中的4-(5-((N-(6-氨基-2-甲硫基-5-硝基嘧啶-4-基)-N--乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯。
第五步：2-(N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N-((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯
使用类似实施例1的第五步合成方法制备，用2-(N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)-N-((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯代替实施例1第五步中的4-(5-((N-(6-氨基-2-甲磺酰基-5-硝基嘧啶-4-基)--N-乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯。
第六步：4-氨基-2-丁氧基-8-((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(16)
使用类似实施例1的第六步合成方法制备，用2-(N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N-((6-(4-(二甲氨基)哌啶-1-基)吡啶-3-基)甲基)-氨基)醋酸乙酯代替实施例1第六步中的4-(5-((N-(6-氨基-2-丁氧基-5-硝基嘧啶-4-基)-N--乙氧羰基甲基-氨基)甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯。
MS m/z(ESI):455[M+H]+；
1HNMR(400MHz,DMSO-d6)δ:9.69(brs,1H),8.16-8.13(m,1H),7.71-7.64(m,1H),6.82-6.76(m,1H),6.23(brs,2H),4.59(s,2H),4.14-4.10(m,2H),3.84(s,2H),3.11-3.03(m,2H),2.61-2.52(m,3H),2.22(s,6H),1.75-1.57(m,6H),1.41-1.33(m,2H),0.90(t,3H,J＝8Hz).
实施例7：
4-氨基-2-丁氧基-8-((6-(哌嗪-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物42)的制备
Figure PCTCN2017088785-appb-000049
制备方法与实施例1第一步至第七步相同，得到标题化合物。
MS m/z(ESI):412[M+H]+；
1HNMR(400MHz,DMSO-d6)δ:9.69(brs,1H),8.16-8.13(m,1H),7.71-7.64(m,1H),6.82-6.76(m,1H),6.23(brs,2H),4.59(s,2H),4.14-4.10(m,2H),3.84(s,2H),3.61-3.48(m,4H),2.61-2.52(m,4H),1.93(brs,1H),1.65-1.57(m,2H),1.41-1.33(m,2H),0.90(t,3H,J＝8Hz).
实施例8：
4-氨基-2-丁氧基-8-((5-氟-6-(4-甲基哌嗪-1-基)吡啶-3-基)甲基)-7,8-二氢蝶啶-6(5H)-酮(化合物72)的制备
Figure PCTCN2017088785-appb-000050
第一步：化合物72-A的制备
将2-溴-3-氟-吡啶-5-甲醛(1g,5mmol)和N-甲基哌嗪(2g,20mmol)加入到DMF(20ml)中，升温至100℃，反应16小时，LC-MS显示反应完全，将反应液倒入约100ml 10％碳酸钾水溶液中，乙酸乙酯萃取三次，合并乙酸乙酯相，饱和食盐水洗，无水硫酸钠干燥，浓缩后得粗品1g直接用于下一步反应。产率(98％)。
第二步：化合物72-B的制备
用72-A代替实施例2中第二步的61-A，采用与实施例2中第二步所描述类似的方法制备化合物72-B，产率(76％)。
第三步：化合物72-C的制备
用72-B代替实施例2中第三步的61-B，采用与实施例2中第三步所描述类似的方法制备化合物72-C，产率(72％)。
第四步：化合物72的制备
用72-C代替实施例2中第四步的61-C，采用与实施例2中第四步所描述类似的方法制备化合物72，产率(26％)。
MS m/z(ESI):445[M+H]+
1HNMR(400MHz,CD3OD)δ:7.79(s,1H),7.35-7.25(m,1H),4.88(s,2H),4.17-4.14(m,2H),3.98(s,2H),3.71-3.61(m,4H),2.49-2.39(m,4H),2.25(s,3H),1.88-1.64(m,2H),1.48-1.26(m,2H),0.94(t,3H,J＝8Hz)
试验例1：NF-kB报告基因检测：
对于抗病毒药物，一般期望对TLR7具有高活性而对TLR8具有弱活性，或者是对TLR7具有强于TLR8的选择性为佳。
1.TLR7激动剂细胞水平药效筛选方法
稳定表达TLR7和NF-κb荧光素酶报告基因系统的人胚胎肾细胞HEK293(南京科佰生物科技有限公司)培养于含有10％FBS(Gibco，10099-141)的DMEM培养基(Gibco，cat.12100-046)中。将细胞用胰蛋白酶消化、重悬，计数，接种于孔板中。用DMSO配置不同浓度的待测化合物，将10μL不同浓度待测化合物加入孔板中，每孔中待测化合 物的终浓度分别为100μM，30μM，10μM，3μM，1μM，0.3μM，0.1μM，0.03μM，0μM，DMSO终浓度为0.5％。其中待测化合物浓度为0μM的组为空白对照组。待测化合物与细胞在37℃、5％CO2培养箱中孵育，加入等体积Brigh-GloTM检测试剂(Promega，cat.E2620)，室温反应。在多功能全自动酶标仪(Thermo Varioskan Flash)下读取相对化学发光单位值(RLU)并拟合EC50和Emax。结果见表1。
表1化合物对HEK293细胞TLR7的EC50
Figure PCTCN2017088785-appb-000051
由表1可见，本发明的式I-3系列化合物对HEK293细胞TLR7的EC50值低于阳性对照物A的EC50值，并且低于式I-1、I-2、I-4的化合物，说明本发明的式I-3系列化合物对TLR7的激活作用明显高于阳性对照物A，同时高于式I-1、I-2、I-4的化合物。本发明的式I-3系列化合物对HEK293细胞TLR7显示更好的激活活性。
另外，本发明的式I-3系列化合物对HEK293细胞TLR7的Emax一般大于600％，具有优异的激活活性。
2.TLR8选择性筛选方法
人胚胎肾细胞HEK293培养于含有10％FBS的DMEM培养基中。转染pcDNA5/FRT-AN-LUC-hTLR8质粒(南京科佰生物科技有限公司)，使其高表达hTLR8和NF-κb荧光素酶报告基因。将细胞用胰蛋白酶消化、重悬，计数，接种于孔板中。用DMSO配置不同浓度的待测化合物，将10μL不同浓度待测化合物加入孔板中，每孔中待测化合物的终浓度分别为600μM，300μM，100μM，30μM，10μM，3μM，1μM，0μM，DMSO终浓度为1％。其中待测化合物浓度为0μM的组为空白对照组。待测化合物与细胞在37℃、5％CO2培养箱中共孵育6h后，加入1/2体积Brigh-GloTM检测试剂(Promega，cat.E2620)，室温反应5min。在多功能全自动酶标仪(Thermo Varioskan Flash)化学发光检测模式下读取相对化学发光单位值(RLU)，用GraphPad Prism 5软件拟合EC50和Emax。
结果显示，本发明式I-3化合物对HEK293细胞TLR8的EC50值,例如：化合物14，EC50>600μM高于阳性对照物A的EC50值44.66μM，同时也高于式I-1，I-2，I-4的化合物，例如：化合物1EC50＝293，说明本发明式I-3化合物对TLR8的激活作用明显弱于阳性对照物A，同时也弱于式I-1，I-2，I-4的化合物。
本发明式I-3系列化合物对HEK293细胞TLR8的Emax值，例如：化合物14，未到活性平台期，无拟合Emax；化合物61，Emax为115％明显低于阳性对照物A的Emax值1286％，同时也低于式I-1，I-2，I-4的化合物，例如：化合物1Emax为810％，说明本发明式I-3系列化合物对TLR8的最大活性效应明显弱于阳性对照物A，同时也弱于式I-1，I-2，I-4的化合物。说明本发明化合物针对TLR8的活性均显著弱于阳性对照物A，式I-1，I-2，I-4的化合物。
综上，相对于阳性对照物A，及式I-1，I-2，I-4的化合物，本发明式I-3系列化合物对HEK293细胞TLR7显示更高的激活活性，同时对HEK293细胞TLR8显示弱的激活活性，说明，本发明式I-3系列化合物对TLR7显示较好的激活选择性。
本发明的式I-3系列其它化合物对HEK293细胞TLR7也显示与上述式I-3系列化合物基本类似的激活活性和选择性。
试验例2：人外周血单个核细胞(PBMC)激活检测：
TLR7被激活的主要生物学效应是刺激细胞分泌IFNα和受IFNα调控的趋化因子，这一途径是药物抗病毒的一种主要机制；TLR8被激活的主要生物学效应是刺激细胞分泌炎性细胞因子，包括：TNFα、IL-6、IL-12(例如IL-12p40)、IL-1β等。对于抗病毒药物，一般期望药物对TLR7具有高活性而对TLR8具有弱活性，或者是对TLR7具有强于TLR8的选择性为佳。
检测方法：将人PMBC细胞接种于孔板中孵育。将不同浓度的本发明化合物加入含有PBMC的孔板中，继续孵育24h。将孔板离心并收集上清，用ELISA测试细胞因子IFNα、IL-12p40、IL-1β、IL-6、TNFα的浓度。结果见表2-1、表2-2。
表2-1
Figure PCTCN2017088785-appb-000052
由表2-1可见，与阳性对照物A相比，本发明化合物14在浓度为3000nM时，刺激PBMC细胞分泌IFNα的活性更强，对炎性细胞因子IL-12p40、IL-1β、IL-6和TNFα分泌的刺激作用显著弱于阳性对照物A，表明本发明化合物14对TLR7的选择性较好。
表2-2
Figure PCTCN2017088785-appb-000053
由表2-2可见，与阳性对照物A相比，本发明化合物14在化合物浓度为1000nM时，刺激PBMC细胞分泌IFNα的活性更强。
本发明化合物14对炎性细胞因子IL-12p40和IL-1β分泌的刺激作用显著弱于阳性对照物A。表明本发明化合物14在浓度为1000nM时对TLR7的选择性较TLR8更高。
表2-3
Figure PCTCN2017088785-appb-000054
由表2-3可见，与阳性对照物A相比：本发明化合物14在化合物浓度为300nM和100nM时，刺激PBMC细胞分泌IFNα的活性更强；另外，本发明化合物14对炎性细胞因子IL-12p40分泌的刺激作用显著弱于阳性对照物，表明本发明化合物14在浓度为300nM和100nM时对TLR7的选择性更好，本发明化合物14在低浓度下也具有较良好的有效性。
试验例3：食蟹猴血浆IFN-α含量变化检测
本发明化合物为治疗慢性乙型肝炎病毒(HBV)感染的TLR7激动剂，可诱导体内I型干扰素(IFN-α)依赖性抗病毒先天免疫应答。IFN-α为I型干扰素，能诱导pDCs细胞对病毒感染产生抗性，其通过干扰病毒基因转录或病毒蛋白组分的翻译，从而阻止或限制病毒感染。对于抗病毒药物，一般期望对TLR7具有高活性从而增加IFN-α表达水平。
检测方法：食蟹猴(购自海南金港生物技术股份有限公司)按体重分组，禁食过夜后，单次灌胃给予1mg/kg的阳性对照化合物A以及本发明化合物，于给药前，给药后1h、2h、4h、6h、8h、24h采血1.5ml，肝素钠抗凝，4000转*10min离心，分离血浆后，按ELISA试剂盒方法测定不同时间点的IFN-α的含量，计算食蟹猴血浆IFN-α曲线下面积(AUC)(单位：pg.h/mL)，结果见表3。
表3
化合物编号 IFN-α(AUC)
阳性对照物A 22783
化合物14 92591
化合物61 66848
化合物69 41960
化合物71 102643
由表3可见，与阳性对照物A相比，本发明化合物14、61、69、71在1mg/kg剂量下在食蟹猴体内更能刺激IFN-α的分泌，说明本发明化合物14、61、69、71具有更好的抗病毒活性。
由以上可见，本发明的化合物是一个兼具活性和选择性的TLR7激动剂。
上述实验例中，阳性对照物A结构为：
Figure PCTCN2017088785-appb-000055
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解，根据已经公开的所有教导，可以对本发明的细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (20)

  1. 式I-3所示化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，或它们的混合物，其中：
    Figure PCTCN2017088785-appb-100001
    X为-O-、-NH-、-S-、-C(O)-或-S(O)2-；
    R1选自烷基；
    R2和R3各自独立地选自氢、卤素、C1-6烷基、C1-6烷氧基和二C1-6烷基取代的氨基-C1-6烷氧基；
    R4不存在或为6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基，其中所述6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：氧代、羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基；并且，
    当R4不存在时，R2和R3中有一个为2-二甲氨基乙氧基。
  2. 权利要求1所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，或它们的混合物，其中：
    R1选自C1-6烷基(例如丁基或戊-2-基)；
    R2和R3各自独立地选自氢、卤素、C1-6烷氧基和2-二甲氨基乙氧基；
    R4不存在或为6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基-C0-6烷基，其中所述6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基-C0-6烷基、哌嗪基-C0-6烷基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6- 四氢吡啶基-C0-6烷基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：氧代、羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基；并且，
    当R4不存在时，R2和R3中有一个为2-二甲氨基乙氧基。
  3. 权利要求1或2所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，或它们的混合物，其中：
    X为-O-、-NH-、-S-或-C(O)，优选为-O-、-NH-或-S-，进一步优选为-O-或-S-，更优选为-O-；
    R2和R3各自独立地选自氢、卤素、C1-6烷氧基和2-二甲氨基乙氧基；
    R4不存在或为哌啶基-C0-6烷基、哌嗪基-C0-6烷基或1,2,3,6-四氢吡啶基-C0-6烷基，其中所述哌啶基-C0-6烷基、哌嗪基-C0-6烷基或1,2,3,6-四氢吡啶基-C0-6烷基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：羟基、卤素、C1-6烷基、C1-6烷氨基、二C1-6烷基取代的氨基。
  4. 权利要求1至3任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其具有式I-3A所示结构，
    Figure PCTCN2017088785-appb-100002
    其中，
    R1选自丁基和戊-2-基；
    R2和R3各自独立地选自氢、卤素、C1-6烷氧基和2-二甲氨基乙氧基；优选地，R2和R3均为氢，或R2为氢，R3为2-二甲氨基乙氧基或氟；
    R4不存在或代表6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基(例如，1-吡咯烷并[3,4-c]吡咯烷基)、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基(例如，1-吡咯烷基或1-吡咯烷甲基)、哌啶基、哌嗪基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基，其中所述6-9元杂螺环基-C0-6烷基、6-9元杂并环基-C0-6烷基、6-9元杂桥环基-C0-6烷基、5元杂环烷基-C0-6烷基、哌啶基、哌嗪基、哌嗪酮-C0-6烷基、 4-氧代-[1,4]氮杂磷酰基或1,2,3,6-四氢吡啶基未被取代或各自独立地被一个或多个(例如1个、2个、3个或4个)选自下述的取代基取代：氧代、羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基；优选地，所述取代基选自二甲氨基、甲基、乙基、异丙基、羟基、甲氧乙基和氰甲基。
  5. 权利要求1至4任一项所述的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等，其中，R4选自哌嗪基、4-甲基哌嗪基、4-异丙基哌嗪基、N-甲基-1,2,3,6-四氢吡啶-4-基、N-甲基哌啶基、哌嗪酮-C0-6烷基、4-氧代-[1,4]氮杂磷酰基和4-羟基哌啶基。
  6. 权利要求1至5任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其具有式I-3B所示结构，其中：
    Figure PCTCN2017088785-appb-100003
    R1为烷基；
    R3为氢、卤素或C1-4烷基；
    R4选自哌嗪基、哌啶基、1,2,3,6-四氢吡啶基、C1-6烷氨基-C1-6烷氧基和二C1-6烷基取代的氨基-C1-6烷氧基，所述哌嗪基、哌啶基、1,2,3,6-四氢吡啶基任选地被以下取代基单取代或多取代：羟基、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6烷氨基、二C1-6烷基取代的氨基、C1-6烷氧基-C1-6烷基和氰基取代的C1-6烷基。
  7. 权利要求6所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中：
    R1为C1-6烷基；
    R3为氢或卤素；
    R4选自哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基和二C1-6烷基取 代的氨基-C1-6烷氧基，所述哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基任选地被以下取代基单取代或多取代：羟基、C1-6烷基和二C1-6烷基取代的氨基。
  8. 权利要求6所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中：
    R1为C1-4烷基；
    R3为氢、氟、氯或溴；
    R4选自哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基和二C1-4烷基取代的氨基-C1-4烷氧基，所述哌嗪-1-基、哌啶-1-基、哌啶-4-基、1,2,3,6-四氢吡啶-4-基任选地被以下取代基单取代或多取代：羟基、甲基、乙基、丙基和二甲氨基。
  9. 权利要求6所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中：
    R1为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基；
    R3为氢或氟；
    R4选自哌嗪-1-基、4-二甲氨基哌啶-1-基、4-羟基哌啶-1-基、4-甲基哌嗪-1-基、N-甲基哌啶-4-基、N-甲基-1,2,3,6-四氢吡啶-4-基和2-二甲氨基乙氧基。
  10. 权利要求6所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其中：
    R1为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基；
    R3为氢；
    R4选自4-甲基哌嗪-1-基、N-甲基哌啶-4-基、N-甲基-1,2,3,6-四氢吡啶-4-基和2-二甲氨基乙氧基。
  11. 权利要求1-10任一项所述的化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，其选自以下化合物，
    Figure PCTCN2017088785-appb-100004
    Figure PCTCN2017088785-appb-100005
  12. 权利要求1-3任一项所述化合物的制备方法，其包括以下步骤：
    Figure PCTCN2017088785-appb-100006
    第一步：化合物SM-2与R4H反应生成化合物IN-7；
    第二步：化合物IN-7与氨基乙酸乙酯反应生成化合物IN-8；
    第三步：化合物IN-8与2-甲硫基-5-硝基-6-氯-4-嘧啶胺反应生成化合物IN-9；
    第四步：化合物IN-9氧化得到化合物IN-10；
    第五步：化合物IN-10与R1-X-H反应生成化合物IN-11；
    第六步：化合物IN-11环化后得到式I-3化合物；
    其中，化合物SM-2中的Lg为亲核取代反应的离去基团(例如卤素、-OTs、-OCOR，R为烷基)，其余各原子或取代基定义如权利要求1－3所述。
  13. 权利要求4所述化合物的制备方法，其包括以下步骤：
    Figure PCTCN2017088785-appb-100007
    第一步：化合物SM-2A与R4H反应生成化合物IN-7A；
    第二步：化合物IN-7A与氨基乙酸乙酯反应生成化合物IN-8A；
    第三步：化合物IN-8A与2-甲硫基-5-硝基-6-氯-4-嘧啶胺反应生成化合物IN-9A；
    第四步：化合物IN-9A氧化得到化合物IN-10A；
    第五步：化合物IN-10A与R1-OH反应生成化合物IN-11A；
    第六步：化合物IN-11A环化后得到式I-3A化合物；
    其中，SM-2A中的Lg为亲核取代反应的离去基团(例如卤素、-OTs、-OCOR，R为烷基)，其余各原子或取代基定义如权利要求4中所述。
  14. 药物组合物，其包含权利要求1-11任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，以及任选地，一种或多种药学上可接受的载体或赋形剂。
  15. 权利要求1-11任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等或权利要求14的药物组合物在制备作为TLR激动剂(优选TLR7激动剂)的药物中的用途。
  16. 权利要求1-11任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物等或权利要求14的药物组合物在制备用于治疗与TLR7相关的疾病的药物中的用途。
  17. 权利要求16的用途，其中所述与TLR7相关的疾病选自肝炎(例如乙型肝炎(HBV)或丙型肝炎(HCV))、哮喘、过敏性鼻炎、皮肌炎、疟疾、牛皮癣、光化角化病、实体瘤(例如膀胱癌或非霍奇金淋巴瘤(NHL))、血液肿瘤、黑色素瘤和自身免疫疾病(例如全身性红斑狼疮(SLE)，艾滋病(HIV))。
  18. 权利要求1-11任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物，或权利要求14的药物组合物，其用于治疗与TLR7相关的疾病；
    优选地，所述与TLR7相关的疾病选自肝炎(例如乙型肝炎(HBV)或丙型肝炎(HCV))、哮喘、过敏性鼻炎、皮肌炎、疟疾、牛皮癣、光化角化病、实体瘤(例如膀胱癌或非霍奇金淋巴瘤(NHL))、血液肿瘤、黑色素瘤和自身免疫疾病(例如全身性红斑狼疮(SLE)，艾滋病(HIV))。
  19. 一种治疗与TLR7相关的疾病的方法，其包括向有需要的受试着施用有效量的权利要求1-11任一项所述化合物或其药学可接受的盐、酯、溶剂化物、水合物、异构体，同位素化合物或它们的任意多晶型或消旋物，或它们的代谢物形式，以及它们的混合物或权利要求14的药物组合物。
  20. 权利要求19所述的治疗方法，其中所述与TLR7相关的疾病选自肝炎(例如乙型肝炎(HBV)或丙型肝炎(HCV))、哮喘、过敏性鼻炎、皮肌炎、疟疾、牛皮癣、光化角化病、实体瘤(例如膀胱癌或非霍奇金淋巴瘤(NHL))、血液肿瘤、黑色素瘤和自身免疫疾病(例如全身性红斑狼疮(SLE)，艾滋病(HIV)。
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