CN114805392A - Macrocyclic TLR7 agonist, preparation method thereof, pharmaceutical composition and application thereof - Google Patents

Macrocyclic TLR7 agonist, preparation method thereof, pharmaceutical composition and application thereof Download PDF

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CN114805392A
CN114805392A CN202210054984.6A CN202210054984A CN114805392A CN 114805392 A CN114805392 A CN 114805392A CN 202210054984 A CN202210054984 A CN 202210054984A CN 114805392 A CN114805392 A CN 114805392A
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alkylene
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唐国志
黄孟炜
马大为
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Shanghai Weishen Pharmaceutical Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention discloses a macrocyclic TLR7 agonist, a preparation method thereof, a pharmaceutical composition and application thereof. The macrocyclic TLR7 agonist disclosed by the invention is a compound shown in a formula I. The compound has novel structure, good activity and good application prospect.

Description

Macrocyclic TLR7 agonist, preparation method thereof, pharmaceutical composition and application thereof
Technical Field
The invention relates to a macrocyclic TLR7 agonist, a preparation method thereof, a pharmaceutical composition and application thereof.
Background
Toll-like receptors (TLRs) are a class of structurally conserved proteins that form a first barrier in innate immune responses. TLRs can recognize endogenous molecules released following invasive microbial and tissue injury or non-physiological cell death and activate signaling cascades that lead to the production of proinflammatory cytokines by recognizing various conserved pathogen-associated molecular patterns (PAMPs). The inflammatory process is critical to the development and progression of a variety of diseases, such as type I diabetes, sepsis, cancer, viral infectious diseases, and the like. Strategies for the manipulation of inflammatory responses by small molecule modulators of TLRs to treat related diseases are therefore promising.
There are 10 known members of the family of human TLRs, which are type I transmembrane proteins characterized by a leucine-rich extracellular domain and a cytoplasmic tail containing a conserved Toll/interleukin-1 receptor (IL) -1receptor (TIR) domain. Within this family, TLR3, TLR7, TLR8 and TLR9 are located in endosomal compartments. (Vijay K., Int immunopharmacol.,2018, 59, 391-
TLR7 recognizes single-stranded rna (ssrna) fragments. TLR7 is expressed primarily in plasmacytoid dendritic cells and B cells. TLR7 stimulation primarily induces the production of type I interferons, including interferon-alpha (IFN- α), and causes transcription of interferon-stimulated genes (ISGs). (Gorden KB., J Immunol.,2005,174, 1259-S1268; Shah M., Expert Opin Investig Drugs,2016,25, 437-S453) interferon alpha is one of the major Drugs for treating chronic hepatitis B or C. Therefore, the development of TLR7 agonists for the treatment of viral infectious diseases is of great clinical significance.
Studies have also reported the treatment of cancer with TLR7 agonists. WO201772662 reports the treatment of HER2 positive cancers with TLR7 agonist-anti-HER 2 conjugates. Yosuke Ota et al found that intravenous injection of the TLR7 agonist DSP-0509 and anti-PD-1 antibodies had a synergistic effect on the anti-tumor immune response (AACR 2018 meeting book: Abstract 4726).
There are currently several related TLR7 agonist patent applications, but there is still a continuing need to develop highly active, safer and therapeutically highly effective TLR7 agonists.
Disclosure of Invention
The invention aims to solve the technical problem that the existing TLR7 agonist has a single structure, and provides a macrocyclic TLR7 agonist, a preparation method thereof, a pharmaceutical composition and application thereof.
The invention provides a compound shown as a formula I, a solvate, a prodrug, a metabolite, or a pharmaceutically acceptable salt of the compound shown as the formula I:
Figure BDA0003476093400000021
wherein Y is N or CR Y ；
R Y Is cyano or halogen substituted C 1 ～C 4 An alkyl group;
a is O, S, -S (═ O) 2 、-S(＝O)(＝NH)、NR 4 Or CR 6 R 7 ；R 4 、R 6 And R 7 Independently is H or C 1 ～C 6 An alkyl group;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated alkylene radical, R 1-1 Substituted C 2 ～C 10 Alkylene radical, R 1-1 Substituted C 2 ～C 10 Unsaturated hydrocarbylene, -Z 1 -NH-C(＝O)-Z 2 -、-Z 3 -NH-C(＝O)-Z 4 -L 1 -、-Z 5 -L 2 -、-Z 6 -O-Z 7 -、-Z 8 -O-Z 9 -L 3 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 1 、L 2 、L 3 And L 4 Independently isO、S、S(＝O) 2 、NR 8 ，R 8 Is H or C 1 ～C 6 An alkyl group;
-L 5 -is C 3 ～C 6 Cycloalkylene, halogen-substituted C 3 ～C 6 Cycloalkylene, 3-6 membered heterocycloalkylene with 1-3 heteroatoms selected from N, O and S, or halogen-substituted heteroatom selected from N, O and S, 3-6 membered heterocycloalkylene with 1-3 heteroatoms;
n and r are independently 1,2 or 3;
-Z 1 -、-Z 2 -、-Z 3 -、-Z 4 -、-Z 6 -、-Z 7 -、-Z 8 -and-Z 9 -independently is C 1 ～C 6 Alkylene radical, C 2 ～C 6 Unsaturated alkylene radical, R 1-2 Substituted C 1 ～C 6 Alkylene or R 1-2 Substituted C 2 ～C 6 An unsaturated alkylene group;
-Z 5 -is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated alkylene group, R 1-3 Substituted C 2 ～C 10 Alkylene or R 1-3 Substituted C 2 ～C 10 An unsaturated alkylene group;
R 1-1 、R 1-2 and R 1-3 Independently is OH, CN, NH 2 Halogen, C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy or COOR 1-1-1 ；R 1 -1-1 Is H or C 1 ～C 3 An alkyl group;
R 1 、R 2 and R 3 Independently of one another H, halogen, C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 An alkyl group;
or alternatively, "R 1 And R 2 "or" R 2 And R 3 R is a 4-7 membered heterocycloalkyl group having 1-3 hetero atoms and one or more hetero atoms selected from N, O and S 1-4 The substituted 'hetero atom is one or more selected from N, O and S, 4-7 membered heterocycloalkylene with 1-3 hetero atoms', C 4 ～C 7 Cycloalkylene or R 1-5 Substituted C 4 ～C 7 A cycloalkylene group; or alternatively, "R 1 And R 2 "or" R 2 And R 3 "the hetero atom (S) together with the carbon atom (S) to which they are bonded is (are) one or more members selected from the group consisting of N, O and S, a 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms", or R 1-4 The "hetero atom" in the substituted "hetero atom is selected from one or more of N, O and S, and the 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms" is selected from one or more of N, O and S, and 1 or 2 or more arbitrary methylene groups in the 4-to 7-membered heterocycloalkyl group having 1 to 3 hetero atoms "are independently substituted with a carbonyl group or S (═ O) 2 Replacement;
R 1-4 and R 1-5 Independently OH, halogen, CN, C 1 ～C 6 Alkyl radical, R 1-6 Substituted C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy radical, R 1-9 Substituted C 1 ～C 6 Alkoxy, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、NR 1-10 R 1-11 、COOR 1-12 、SR 1-13 、C 3 ～C 7 Cycloalkyl radical, R 1-19 Substituted C 3 ～C 7 Cycloalkyl, one or more of N, O and S as hetero atoms, 4-to 7-membered heterocycloalkyl with 1 to 3 hetero atoms, and R 1-20 The substituted ' hetero atom is selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 hetero atoms ', ' hetero atom is selected from one or more of N, O and S, and C with 1-4 hetero atoms 1 ～C 10 Heteroaryl', R 1-21 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 Heteroaryl "or-G (CR) 1-14 R 1-15 ) u -COOR 1-16 (ii) a G is O, S, S (═ O) 2 Or NH; u is 1,2 or 3;
R 1-6 and R 1-9 Independently of each otherIs halogen, amino, CN, OH, -COOR 1-17 、-S(＝O) 2 R 1-31 、-C(＝O)NH 2 、-S(＝O) 2 NH 2 、C 1 ～C 3 Alkoxy radical, C 3 ～C 7 Cycloalkyl radical, COOR 1-18 Substituted C 3 ～C 7 Cycloalkyl, 4-7 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S and 1-3 heteroatoms, and R 1-22 The substituted ' hetero atom is selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 hetero atoms ', ' hetero atom is selected from one or more of N, O and S, and C with 1-4 hetero atoms 1 ～C 10 Heteroaryl "or R 1-23 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 Heteroaryl ";
R 1-7 and R 1-8 Independently is C 1 ～C 3 Alkyl radical, C 3 ～C 7 Cycloalkyl radical, R 1-24 Substituted C 3 ～C 7 Cycloalkyl, 4-7 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S and 1-3 heteroatoms, and R 1-25 The substituted ' hetero atom is selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 hetero atoms ', ' hetero atom is selected from one or more of N, O and S, and C with 1-4 hetero atoms 1 ～C 10 Heteroaryl', R 1-26 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 Heteroaryl ", C 6 ～C 10 Aryl radical, R 1-27 Substituted C 6 ～C 10 Aryl or-NR 1-28 R 1-29 ；
R 1-10 、R 1-11 、R 1-12 、R 1-16 、R 1-17 、R 1-18 、R 1-28 And R 1-29 Independently is H or C 1 ～C 3 An alkyl group; r 1-31 Is C 1 ～C 3 An alkyl group;
R 1-13 is H, C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 An alkyl group;
R 1-14 and R 1-15 Independently H, C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 An alkyl group;
R 1-19 、R 1-20 、R 1-21 、R 1-22 、R 1-23 and R 1-24 Independently OH, halogen, amino, CN, C 1 ～C 6 An alkyl group;
R 5 is H, CN, halogen, C 3 ～C 5 Cycloalkyl radical, C 1 ～C 6 Alkyl or C 1 ～C 6 An alkoxy group;
R 13 is H, -CONR 14 R 15 、-C(＝O)R 16 or-COOR 17 ，R 14 、R 15 、R 16 And R 17 Independently is C 1 ～C 6 Alkyl or R 13-1 Substituted C 1 ～C 6 An alkyl group; r 13-1 Is CN, halogen, C 1 ～C 6 Alkoxy or- (CH) 2 CH 2 O) q -R 13-2 ，R 13-2 Is C 1 ～C 6 And q is an integer of 0 to 460.
In some embodiments, in the compounds represented by formula I, solvates, prodrugs, metabolites, or pharmaceutically acceptable salts thereof, certain groups may be defined as follows, and the remaining groups may be defined as in any of the above embodiments (hereinafter referred to as "in some embodiments"):
a is O;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 2 And L 4 Independently is O;
-L 5 -is C 3 ～C 6 A cycloalkylene group;
-Z 5 -is C 2 ～C 10 An alkylene group;
R 1 、R 2 and R 3 Independently is H;
or, R 1 And R 2 Together with the carbon atom to which they are attached form a "4-to 7-membered heterocycloalkylene group with 1 to 3 hetero atoms selected from one or more of N, O and S" or R 1-4 Substituted '4-7 membered heterocycloalkylene with 1-3 hetero atoms selected from one or more of N, O and S';
R 1-4 independently is C 1 ～C 6 Alkyl radical, R 1-6 Substituted C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or 4-7 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
R 1-6 independently represents one or more heteroatoms selected from N, O and S, and C with 1-4 heteroatoms 1 ～C 10 Heteroaryl ";
R 1-7 and R 1-8 Independently is C 1 ～C 3 An alkyl group;
R 5 is H;
R 13 is H, -C (═ O) R 16 or-COOR 17 ，R 16 And R 17 Independently is C 1 ～C 6 An alkyl group.
In some embodiments, in the compounds represented by formula I, solvates, prodrugs, metabolites, or pharmaceutically acceptable salts thereof, certain groups may be defined as follows, and the remaining groups may be defined as in any of the above embodiments (hereinafter referred to as "in some embodiments"):
a is O;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated alkylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 2 And L 4 Independently is O;
-L 5 -is C 3 ～C 6 A cycloalkylene group;
-Z 5 -is C 2 ～C 10 An alkylene group;
R 1 and R 2 Together with the carbon atom to which they are attached form a "4-to 7-membered heterocycloalkylene group with 1 to 3 hetero atoms selected from one or more of N, O and S" or R 1-4 Substituted '4-7 membered heterocycloalkylene with 1-3 hetero atoms selected from one or more of N, O and S';
R 1-4 independently is C 1 ～C 6 Alkyl radical, R 1-6 Substituted C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or 4-7 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
R 1-6 independently represents one or more heteroatoms selected from N, O and S, and C with 1-4 heteroatoms 1 ～C 10 Heteroaryl ";
R 1-7 and R 1-8 Independently is C 1 ～C 3 An alkyl group;
R 3 is H;
R 5 is H;
R 13 is H, -C (═ O) R 16 or-COOR 17 ，R 16 And R 17 Independently is C 1 ～C 6 An alkyl group.
In some of the embodiments described herein, the first and second,
a is O;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 2 And L 4 Independently is O;
-L 5 -is C 3 ～C 6 A cycloalkylene group;
-Z 5 -is C 2 ～C 10 An alkylene group;
R 1 and R 2 Together with the carbon atom to which they are attached form a "4-to 7-membered heterocycloalkylene group with 1 to 3 hetero atoms selected from one or more of N, O and S" or R 1-4 Substituted '4-7 membered heterocycloalkylene with 1-3 hetero atoms selected from one or more of N, O and S';
R 1-4 independently is C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or 4-7 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
R 1-7 and R 1-8 Independently is C 1 ～C 3 An alkyl group;
R 3 is H; r 5 Is H;
R 13 is H.
In some of the embodiments described herein, the first and second,
a is O;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 - (e.g. B is n-pentylene, pentenylene, -O-n-propylene-or
Figure BDA0003476093400000051
(
Figure BDA0003476093400000052
The structural fragment representation has trans-butylene fragment, the following
Figure BDA0003476093400000053
All such meanings of structural fragments);
L 2 and L 4 Independently is O;
-L 5 -is C 3 ～C 6 Cycloalkylene (e.g., butylene);
-Z 5 -is C 2 ～C 10 Alkylene (e.g., n-propylene);
R 1 and R 2 Together with the carbon atom to which they are attached form a "4-to 7-membered heterocycloalkylene group with 1 to 3 hetero atoms selected from one or more of N, O and S" or R 1-4 The substituted 'hetero atom is one or more selected from N, O and S, 4-7 membered heterocycloalkylene with 1-3 hetero atoms', C 4 ～C 7 Cycloalkylene or R 1-5 Substituted C 4 ～C 7 Cycloalkylene radicals (e.g. R) 1 And R 2 And the carbon atoms to which they are attached together form a piperidinyl group or substituted piperidinyl group);
R 1-4 independently is C 1 ～C 6 Alkyl, -C (═ O) R 1-8 、C 3 ～C 7 Cycloalkyl or "4-to 7-membered heterocycloalkyl having 1 to 3 hetero atoms selected from N, O and S (for example, R) 1-4 Independently is isopropyl, -C (═ O) CH 3 Cyclobutyl or tetrahydropyranyl); when R is Y Is halogen-substituted C 1 ～C 4 When it is alkyl, said R 1-4 Is C 1 ～C 6 Alkyl (e.g., isopropyl);
R 1-8 independently is C 1 ～C 3 Alkyl (e.g., methyl);
R 3 is H;
R 13 is H;
R 5 is H.
In some embodiments, Y is N.
In some embodiments, R Y Is cyano.
In some embodiments, a is O.
In some embodiments, B is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -, or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -, preferably C 2 ～C 10 Alkylene or C 2 ～C 10 An unsaturated alkylene group.
In some aspects, L 2 And L 4 Is O.
In some embodiments, -L 5 -is C 3 ～C 6 Cycloalkylene radicals.
In some embodiments, -L 5 -is a cyclobutyl group.
In some embodiments, -Z 5 -is C 2 ～C 10 An alkylene group.
In some embodiments, -Z 5 -is n-propylene.
In some embodiments, n and r are 1.
In some embodiments, B is n-pentylene, pentenylene (e.g.
Figure BDA0003476093400000061
(e.g. in
Figure BDA0003476093400000062
And/or
Figure BDA0003476093400000063
) -, - (O-O) -is n-pentylene or
Figure BDA0003476093400000064
(e.g. in
Figure BDA0003476093400000065
) Preferably, B is n-pentylene or pentenylene.
In some embodiments, R 1 And R 2 Together with the carbon atom to which they are attached form a "4-to 7-membered heterocycloalkylene group with 1 to 3 hetero atoms selected from one or more of N, O and S" or R 1-4 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3 4-7 membered heterocycloalkylene.
In some embodiments, R 1-4 Is C 1 ～C 6 Alkyl radical, R 1-6 Substituted C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1 -8 、C 3 ～C 7 Cycloalkyl or "one or more hetero atoms selected from N, O and S, 4-to 7-membered heterocycloalkyl having 1 to 3 hetero atoms", preferably C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or "4-to 7-membered heterocycloalkyl having 1 to 3 hetero atoms selected from N, O and S, and more preferably C 1 ～C 6 Alkyl or "4-7 membered heterocycloalkyl in which the heteroatom is selected from N, O and S, and the number of heteroatoms is 1-3".
In some embodiments, R 1-6 Is' one or more of hetero atoms selected from N, O and S, and C with 1-4 hetero atoms 1 ～C 10 Heteroaryl group ".
In some embodiments, R 1-7 And R 1-8 Is C 1 ～C 3 An alkyl group.
In some embodiments, R 1 And R 2 Together with the carbon atom to which they are attached form
Figure BDA0003476093400000066
Figure BDA0003476093400000067
In some embodiments, R 3 Is H.
In some embodiments, R 5 Is H.
In some embodiments, R 13 Is H, -C (═ O) R 16 or-COOR 17 Preferably, H is used.
In some embodiments, R 16 And R 17 Is C 1 ～C 6 An alkyl group.
In some embodiments, R 13 Is H,
Figure BDA0003476093400000071
Preferably H.
In some of the embodiments described herein, the first and second,
Figure BDA0003476093400000072
is composed of
Figure BDA0003476093400000073
Figure BDA0003476093400000074
In some of the embodiments described herein, the first and second,
Figure BDA0003476093400000075
is composed of
Figure BDA0003476093400000076
In some embodiments, -A-B-is
Figure BDA0003476093400000077
Figure BDA0003476093400000078
In some embodiments, when B is C 2 ～C 10 Alkylene or R 1-1 Substituted C 2 ～C 10 When it is alkylene, said C 2 ～C 10 Alkylene and said R 1-1 Substituted C 2 ～C 10 C in alkylene 2 ～C 10 Alkylene is independently C 4 ～C 6 Alkylene (e.g. n-butylene, n-pentylene or n-hexylene), preferably n-pentylene.
In some embodiments, when B is C 2 ～C 10 Unsaturated alkylene or R 1-1 Substituted C 2 ～C 10 When unsaturated alkylene is mentioned, C 2 ～C 10 Unsaturated alkylene and said R 1-1 Substituted C 2 ～C 10 C in unsaturated alkylene 2 ～C 10 Unsaturated hydrocarbylene radicals being independently C 4 ～C 6 Alkenyl, more preferably
Figure BDA0003476093400000081
(e.g.) "
Figure BDA0003476093400000082
(type E) and
Figure BDA0003476093400000083
(Z type) ", a,
Figure BDA0003476093400000084
Figure BDA0003476093400000085
)。
In some embodiments, when R 8 Is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is C 1 ～C 3 An alkyl group.
In some embodiments, when-L 5 -is C 3 ～C 6 Cycloalkylene or halogen substituted C 3 ～C 6 When cycloalkylene, said C 3 ～C 6 Cycloalkylene and said halogen-substituted C 3 ～C 6 C in cycloalkylene 3 ～C 6 Cycloalkylene is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, preferably cyclobutylene (for example
Figure BDA0003476093400000086
)。
In some embodiments, when-Z 1 -、-Z 2 -、-Z 3 -、-Z 4 -、-Z 6 -、-Z 7 -、-Z 8 -and-Z 9 -independently is C 1 ～C 6 Alkylene or R 1-2 Substituted C 1 ～C 6 When it is alkylene, said C 1 ～C 6 Alkylene and said R 1-2 Substituted C 1 ～C 6 C in alkylene 1 ～C 6 Alkylene is independently C 1 ～C 3 An alkylene group.
In some embodiments, when-Z 1 -、-Z 2 -、-Z 3 -、-Z 4 -、-Z 6 -、-Z 7 -、-Z 8 -and-Z 9 -independently is C 2 ～C 6 Unsaturated alkylene or R 1-2 Substituted C 2 ～C 6 When unsaturated alkylene is mentioned, C 2 ～C 6 Alkylene and R 1-2 Substituted C 2 ～C 6 C in unsaturated alkylene 2 ～C 6 The unsaturated alkylene groups are independently C 2 ～C 4 An unsaturated alkylene group.
In some embodiments, when-Z 5 -is C 2 ～C 10 Alkylene or R 1-3 Substituted C 2 ～C 10 When alkylene, C 2 ～C 10 Alkylene and said R 1-3 Substituted C 2 ～C 10 C in alkylene 2 ～C 10 Alkylene is independently C 3 ～C 6 Alkylene (e.g. n-propylene, n-butylene, n-pentylene or n-hexylene), preferably n-butylene.
In some embodiments, -Z 5 -is C 2 ～C 10 Unsaturated alkylene or R 1-3 Substituted C 2 ～C 10 When unsaturated alkylene is mentioned, C 2 ～C 10 Unsaturated alkylene and said R 1-3 Substituted C 2 ～C 10 C in unsaturated alkylene 2 ～C 10 The unsaturated hydrocarbylene groups are independently C 3 ～C 6 An unsaturated alkylene group.
In some embodiments, -Z 5 -L 2 -is of
Figure BDA0003476093400000087
In some aspects, - (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -is of
Figure BDA0003476093400000088
(e.g. in
Figure BDA0003476093400000089
)。
In some embodiments, when R 1-1 、R 1-2 And R 1-3 When independently halogen, the halogen is independently F, Cl, Br or I.
In some embodiments, when R 1-1 、R 1-2 And R 1-3 Independently is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is independently C 1 ～C 3 An alkyl group.
In some embodiments, when R 1-1 、R 1-2 And R 1-3 Independently is C 1 ～C 6 At alkoxy, said C 1 ～C 6 Alkoxy is independently C 1 ～C 3 An alkoxy group.
In some embodiments, when R 1 、R 2 And R 3 Independently halogen or halogen substituted C 1 ～C 6 When alkyl, said halogen and said halogen substituted C 1 ～C 6 The halogen in the alkyl group is independently F, Cl, Br or I.
In some embodiments, when R 1 、R 2 And R 3 Independently is C 1 ～C 6 Alkyl and halogen substituted C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl and said halogen substituted C 1 ～C 6 In alkyl radical C 1 ～C 6 Alkyl is independently C 1 ～C 3 An alkyl group.
In some embodiments, when "R" is 1 And R 2 "or" R 2 And R 3 "together with the carbon atom to which they are attached" form a hetero atom selected from one or more of N, O and S, a 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms "or R 1-4 When the substituted "hetero atom is one or more selected from N, O and S, and the hetero atom number is 1-3, 4-to 7-membered heterocycloalkylene", the "hetero atom is one or more selected from N, O and S, and the hetero atom number is 1-3, 4-to 7-membered heterocycloalkylene", and R 1-4 Substituted "hetero atomsOne or more selected from N, O and S, wherein the "hetero atom" in the 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms "is one or more selected from N, O and S, wherein the" 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms "is independently" a 5-to 6-membered heterocycloalkylene group having 1 hetero atom and N ", and is more preferably a piperidylene group, for example
Figure BDA0003476093400000091
In some embodiments, when "R" is 1 And R 2 "or" R 2 And R 3 "taken together with the carbon atom to which they are attached form R 1-4 When the substituted' hetero atom is one or more selected from N, O and S, and the number of hetero atoms is 1-3, and the number of hetero atoms is 4-7 membered heterocycloalkylene 1-4 Is 1,2 or 3, preferably 1.
In some embodiments, when "R" is 1 And R 2 "or" R 2 And R 3 "taken together with the carbon atom to which they are attached form R 1-4 When the substituted' hetero atom is one or more selected from N, O and S, and the number of hetero atoms is 1-3, and the number of hetero atoms is 4-7 membered heterocycloalkylene 1-4 The substitution position(s) is (are) on said heteroatom.
In some embodiments, when R 1-4 And R 1-5 Independently halogen, the halogen is F, Cl, Br or I.
In some embodiments, when R 1-4 And R 1-5 Independently is C 1 ～C 6 Alkyl or R 1-6 Substituted C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl and said R 1-6 Substituted C 1 ～C 6 C in alkyl 1 ～C 6 Alkyl is independently C 1 ～C 4 An alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), and further preferably a methyl group or an isopropyl group.
In some embodiments, when R 1-4 And R 1-5 Independently is C 1 ～C 6 Alkoxy or R 1-9 Substituted C 1 ～C 6 At alkoxy, said C 1 ～C 6 Alkoxy and R 1-9 Substituted C 1 ～C 6 C in alkoxy 1 ～C 6 Alkoxy is independently C 1 ～C 4 An alkoxy group.
In some embodiments, when R 1-4 And R 1-5 Independently is C 3 ～C 7 Cycloalkyl or R 1-19 Substituted C 3 ～C 7 When there is a cycloalkyl group, said C 3 ～C 7 Cycloalkyl and R 1-19 Substituted C 3 ～C 7 C in cycloalkyl 3 ～C 7 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclobutyl.
In some embodiments, when R 1-6 And R 1-9 Independently represents one or more heteroatoms selected from N, O and S, and C with 1-4 heteroatoms 1 ～C 10 Heteroaryl "or R 1-23 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 When the heteroaryl is adopted, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1-4C 1 ～C 10 Heteroaryl "and R 1-21 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 The hetero atom in the heteroaryl is selected from one or more of N, O and S, and the number of hetero atoms is 1-4C 1 ～C 10 Heteroaryl is "independently" C having 1 heteroatom which is N 4 ～C 6 Heteroaryl ", more preferably pyridyl (e.g. pyridyl)
Figure BDA0003476093400000101
)。
In some embodiments, when R 1-4 Is R 1-6 Substituted C 1 ～C 6 When it is alkyl, said R 1-6 Is 1,2 or 3, preferably 1.
In some embodiments, when R 1-4 Is R 1-6 Substituted C 1 ～C 6 When it is alkyl, said R 1-6 Substituted C 1 ～C 6 Alkyl is
Figure BDA0003476093400000102
In some embodiments, when R 1-13 、R 1-14 And R 1-15 Independently is C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 C in alkyl 1 ～C 6 Alkyl is independently C 1 ～C 3 An alkyl group.
In some embodiments, when R 1-13 、R 1-14 And R 1-15 Independently halogen substituted C 1 ～C 6 When alkyl, said halogen being substituted by C 1 ～C 6 The halogen in the alkyl group is independently F, Cl, Br or I.
In some embodiments, when R 1-19 、R 1-20 、R 1-21 、R 1-22 、R 1-23 And R 1-24 When independently halogen, the halogen is independently F, Cl, Br or I.
In some embodiments, when R 1-19 、R 1-20 、R 1-21 、R 1-22 、R 1-23 And R 1-24 Independently is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is independently C 1 ～C 3 An alkyl group.
In some embodiments, R is 1-4 The substituted "hetero atom is one or more selected from N, O and S, and the 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms" is
Figure BDA0003476093400000103
Figure BDA0003476093400000104
In some embodiments, when R 5 Is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is C 1 ～C 3 An alkyl group.
In some embodiments, when R 5 Is C 1 ～C 6 When alkoxy, said C 1 ～C 6 Alkoxy is C 1 ～C 3 An alkoxy group.
In some embodiments, when R 14 、R 15 、R 16 And R 17 Independently is C 1 ～C 6 Alkyl or R 13-1 Substituted C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl and said R 13-1 Substituted C 1 ～C 6 C in alkyl 1 ～C 6 Alkyl is independently C 1 ～C 4 An alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl), and further preferably an n-propyl group or an n-butyl group.
In some embodiments, when R 13-1 When the halogen is F, Cl, Br or I.
In some embodiments, when R 13-1 Is C 1 ～C 6 At alkoxy, said C 1 ～C 6 Alkoxy is C 1 ～C 3 An alkoxy group.
In some embodiments, when R 13-1 Is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is C 1 ～C 3 An alkyl group.
In some embodiments, when R 13-2 Is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is C 1 ～C 3 An alkyl group.
In some embodiments, the compound of formula I is any one of the following:
Figure BDA0003476093400000111
the invention also provides a compound shown as the formula II:
Figure BDA0003476093400000121
wherein R is A And R B Independently is H or an amino protecting group, and R A And R B Not H at the same time; y, A, B, R 1 、R 2 、R 3 And R 5 As defined above.
In some embodiments, the compound of formula II is any one of the following:
Figure BDA0003476093400000122
the invention also provides a preparation method of the compound shown in the formula I, which is a method 1 or a method 2:
the method 1 comprises the following steps: carrying out deprotection reaction on a compound shown as a formula II to obtain R 13 A compound of formula I which is H;
Figure BDA0003476093400000131
wherein R is A 、R B 、A、B、Y、R 1 、R 2 、R 3 And R 5 As defined above;
the method 2 comprises the following steps: obtaining R by the method 1 13 Carrying out acylation reaction on a compound shown as a formula I and a compound III which are H to obtain R 13 is-CONR 14 R 15 、-C(＝O)R 16 or-COOR 17 The compound shown in the formula I;
Figure BDA0003476093400000132
wherein R is A 、R B 、A、B、Y、R 1 、R 2 、R 3 And R 5 As defined above.
In method 1, the operation and conditions of the deprotection reaction may be conventional in the art, for example, heating in trifluoroacetic acid.
In method 1, the operation and conditions of the acylation reaction may be conventional in the art, and may be carried out, for example, under the action of a base (e.g., pyridine and triethylamine, pyridine and DIPEA, DMAP and triethylamine, or DMAP and DIPEA).
The invention also provides a pharmaceutical composition, which comprises the compound shown in the formula I, a solvate, a prodrug, a metabolite or pharmaceutically acceptable salts of the compound and the solvate, the prodrug and the metabolite, and a pharmaceutical adjuvant.
The invention also provides the compound shown in the formula I, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or an application of the pharmaceutical composition in preparing a medicament, wherein the medicament is used for treating or preventing tumors or infection caused by viruses.
In some embodiments, the virus is preferably one or more of HBV, HCV, HIV, and influenza.
The invention also provides application of the compound shown as the formula I, a solvate, a prodrug, a metabolite or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparation of a TLR7 agonist.
In such applications, the TLR7 agonist is useful in a mammalian organism; also useful in vitro, primarily for experimental purposes, for example: provide an alignment as a standard or control, or be made into a kit according to the conventional method in the field, and provide a rapid detection for the TLR7 inhibition effect.
Unless otherwise defined, the terms used in the present invention have the following meanings:
herein, attached to an olefinic or alicyclic ring
Figure BDA0003476093400000141
Refers to the olefin or the alicyclic cis-trans isomer or a mixture of both. The cis-trans isomer may be according to cisTrans-isomeric nomenclature (i.e., cis-trans nomenclature) or Z-E nomenclature. For example
Figure BDA0003476093400000142
To represent
Figure BDA0003476093400000143
(Z-configuration olefin) and/or
Figure BDA0003476093400000144
(E configuration olefins); also for example
Figure BDA0003476093400000145
To represent
Figure BDA0003476093400000146
(trans-cyclobutyl) and/or
Figure BDA0003476093400000147
(cis-cyclobutylidene).
As used herein, the terms preceded and/or followed may be supplemented with a single dash "-" or double dash "-" indicating the bond sequence of the named substituent to the parent moiety, with a single dash representing a single bond and a double dash representing a double bond. In the absence of a single dash or double dash, it is believed that a single bond is formed between the substituent and its parent moiety; further, substituents are read "left to right" or "top to bottom" unless otherwise indicated. For example, "-Z 5 -L 2 - "represents Z 5 To A, L 2 And B is connected.
The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by the patient. The "patient" is preferably a mammal, more preferably a human.
The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.
The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).
The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.
The term "prodrug" refers to a derivative of a compound of the invention that, when administered to a warm-blooded animal (e.g., a human), is converted to a compound of the invention (drug). Typical examples of prodrugs include compounds having biologically labile protecting groups on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
The term "metabolite" refers to a product of degradation of a compound of the invention by one or more metabolic processes, which exerts a desired biological activity.
The terms "compound," "solvate," "prodrug," "metabolite," and "pharmaceutically acceptable salt" can exist in crystalline or amorphous form. The term "crystal form" refers to a form in which ions or molecules are arranged strictly periodically in a three-dimensional space in a defined manner and have a periodic recurring pattern at a distance; due to the above described periodic arrangement, various crystal forms, i.e. polymorphism, may exist. The term "amorphous" refers to a state in which ions or molecules are distributed in a disordered manner, i.e., the ions and molecules do not have a periodic arrangement.
The terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt", when present as stereoisomers, may exist as a single stereoisomer or as a mixture thereof (e.g., as a racemate). The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound according to the invention is not less than 95% relative to all stereoisomers of the compound.
The terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt", if present as tautomers, may be present as single tautomers or mixtures thereof, preferably as more stable tautomers. For example, and tautomers of each other.
The atoms in the terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt" may be present in their natural or non-natural abundance. In the case of hydrogen atoms, in its natural abundance, it is understood that about 99.985% is protium and about 0.015% is deuterium; in its unnatural abundance, it is meant that about 95% thereof is deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" can be an atom that is present in a non-natural abundance.
When any variable (e.g. R) 1-1 ) In the definition of a compound, the occurrence at each position of the variable is defined multiple times independently of the occurrence at the remaining positions, and their meanings are independent of each other and independent of each other. Thus, if a group is substituted by 1,2 or 3R 1-1 Substituted by radicals, i.e. the radical may be substituted by up to 3R 1-1 Substituted in the position R 1-1 Is defined by the definition of (1) and the remaining positions R 1-1 Are defined independently of each other. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms, and generally refers to a saturated alkyl group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term "alkylene" refers to a divalent group of straight or branched chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. The two valencies may be concentrated on the same atom, e.g. methylene (-CH) 2 -) ethylene (-CHCH) 3 -, the two valencies may also be attached to two atoms, respectively, for example 1, 2-ethylene (-CH) 2 CH 2 -)。
The term "unsaturated hydrocarbylene" refers to a divalent group of straight or branched chain aliphatic hydrocarbon groups having the indicated number of carbon atoms containing one or more units of unsaturation, e.g., -CH 2 CH 2 CH＝CHCH 2 -。
The term "alkoxy" refers to the group-O-RX, wherein RX is alkyl as defined above.
The term "cycloalkyl" refers to a monovalent saturated cyclic alkyl group, examples of which are: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.
The term "cycloalkylene" refers to a divalent radical of a saturated cyclic alkylene, exemplified by cycloalkylene: cyclopropylene radical
Figure BDA0003476093400000161
Cyclobutylene (e.g. of
Figure BDA0003476093400000162
) Cyclopentylene (e.g. cyclopentylene)
Figure BDA0003476093400000163
Or cyclohexylene, and the like.
The term "heterocycloalkyl" refers to a saturated monocyclic group having a heteroatom. Examples of heterocycloalkyl groups are: tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, and the like.
The term "heterocycloalkylene" refers to a divalent group having a saturated monocyclic group of heteroatoms. Of heterocycloalkylene groupsExamples are: piperidylidene radicals (e.g. as
Figure BDA0003476093400000164
) Tetrahydrofurylene, tetrahydropyrylene, tetrahydrothienyl, tetrahydropyrylene, tetrahydropyrrolylene, etc.
The term "aryl" refers to C 6 -C 10 Aryl, such as phenyl or naphthyl.
The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably an aromatic 5-6 membered monocyclic or 9-10 membered bicyclic ring containing 1,2 or 3 members independently selected from nitrogen, oxygen and sulfur, when bicyclic, at least one ring is aromatic, e.g., furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl and the like.
The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances in a pharmaceutical formulation, except for the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition)
The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.
The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention provides a series of macrocyclic compounds, which have good TLR7 agonistic activity and can be used for treating or preventing tumors or infections caused by viruses.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The compounds of the invention were prepared using the following procedure:
scheme 1
Figure BDA0003476093400000171
In the process 1, a starting compound IIa or IIb or IIc and a compound III are subjected to substitution reaction to obtain a compound IV; carrying out substitution reaction on the compound IV and the compound V to generate a compound A1; subjecting the compound A1 to olefin metathesis reaction to obtain a macrocyclic compound A2; and deprotecting a group of the compound A2 to obtain a target compound Ib, or catalytically hydrogenating the compound A2 to obtain a compound A3, and deprotecting a group of the compound A3 to obtain a target compound Ia.
And (2) a flow scheme:
Figure BDA0003476093400000181
in the process 2, the initial compound IIa or IIb or IIc and the compound III are subjected to substitution reaction to obtain a compound IV, and the compound IV and the compound VI are subjected to substitution reaction to generate a compound B1; subjecting the compound B1 to olefin metathesis reaction to obtain a macrocyclic compound B2; deprotection of compound B2 to obtain target compound Id or catalytic hydrogenation of compound B2 to obtain compound B3, and deprotection of compound B3 to obtain target compound Ic.
And (3) a flow path:
Figure BDA0003476093400000191
in the process 3, a starting compound C1 and a compound C2 are subjected to substitution reaction to obtain a compound C3; the compound C3 and the compound IId are subjected to substitution reaction to obtain a compound C4; removing the protecting group of the compound C4 to obtain a compound C5, and performing oxidation reaction on the compound C5 to obtain a compound C6; carrying out substitution reaction on the compound C6 to obtain a macrocyclic compound C7; deprotection of the group from compound C7 affords target compound Ie.
And (4) a flow chart:
Figure BDA0003476093400000201
Figure BDA0003476093400000202
in the process 4, the starting compound C1 is substituted to obtain a compound D1; carrying out substitution reaction on the compound D1 and the compound IId to obtain a compound D2; removing the protecting group of the compound D2 to obtain a compound D3, and performing oxidation reaction on the compound D3 to obtain a compound D4; carrying out substitution reaction on the compound D4 to obtain a macrocyclic compound D5; deprotection of the group from compound D5 affords the target compound If.
And (5) a flow chart:
Figure BDA0003476093400000203
in scheme 5, compound I is acylated to give compound Ig, R 13 Is CONR 14 R 15 、C(＝O)R 16 Or COOR 17 )。
In the above schemes 1 to 5, LG is-OH, halogen, -OS (O) 2 (C 1 -C 4 Alkyl), the substituents in each compound are as defined aboveAny one of the above.
In the following examples, the structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) at 10 -6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
The SHIMADZU LC system (column:
Figure BDA0003476093400000211
CSH TM Prep-C18, 19 x 150mm, liquid handler LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% aqueous trifluoroacetic acid).
LC/MS spectra of the compounds were obtained using LC/MS (Agilent Technologies 1200 Series). LC/MS conditions were as follows (run time 10 min):
acid conditions: a: 0.05% trifluoroacetic acid in water; b: 0.05% trifluoroacetic acid in acetonitrile;
alkaline conditions: a: 0.05% NH 3 ·H 2 An aqueous solution of O; b: acetonitrile
Neutral conditions are as follows: a: 10mM NH 4 An aqueous solution of OAC; b: acetonitrile
In the following examples, the intermediate and the final compound were purified by silica gel column chromatography or used
Figure BDA0003476093400000212
CSH TM Prep-C18(5μm，OBD TM 19 x 150mm) chromatography column or using xbridge (tm) Prep Phenyl (5 μm, OBD) TM 30 x 100mm) was purified by preparative HPLC on a reverse phase chromatography column.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).
The silica gel plate used in the Thin Layer Chromatography (TLC) detection product adopts a silica gel plate with the specification of 0.15 mm-0.2 mm, and the silica gel plate used in the thin layer chromatography separation and purification product adopts the specification of 0.4 mm-0.5 mm.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
Abbreviation: ac of 2 O: acetic anhydride; AIBN: azobisisobutyronitrile; BH 3 : borane; boc 2 O: tert-butyloxycarbonyl carbonate; CBr 4 : carbon tetrabromide; CH (CH) 3 I (MeI): methyl iodide; con.H 2 SO 4 : concentrated sulfuric acid; con. HNO 3 : concentrated nitric acid; cs 2 CO 3 : cesium carbonate; CH (CH) 3 SNa is sodium methyl mercaptide; DCM: dichloromethane; the DIAD: diisopropyl azodicarboxylate; DIBAL-H: diisobutylaluminum hydride; DIEA: n, N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; DMSO, DMSO: dimethyl sulfoxide; h 2 SO 4 : sulfuric acid; HOAc; acetic acid; k 2 CO 3 : potassium carbonate; k 3 PO 4 : potassium phosphate; LiAlH 4 : lithium aluminum hydride; LiHMDS: bis-trimethylsilyl amido lithium; LiOH: lithium hydroxide; mCPBA: m-chloroperoxybenzoic acid; MeOH: methanol; n, N-diethyllaniline: n, N-diethylaniline; NaCNBH 3 : sodium cyanoborohydride; NaH: sodium hydride; NaHCO 2 3 : sodium bicarbonate; NBS: n-bromosuccinimide; NH (NH) 3 : ammonia; NIS: n-iodosuccinimide; PCy 3: tricyclohexylphosphine; pd (dppf) Cl 2 : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; pd (OAc) 2 : palladium acetate; Pd/C: palladium on carbon; pd 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium; POCl 3 : phosphorus oxychloride; PPh 3 : triphenylphosphine; SOCl 2 : thionyl chloride; TBAF: tetrabutylammonium fluoride; TBDPSCl: tert-butyldiphenylchlorosilane; TBSCl: tert-butyldimethylsilyl chloride; t-BuOK: potassium tert-butoxide; TEA: triethylamine; TES: triethyl phosphateSilane; TFA: trifluoroacetic acid; TFAA: trifluoroacetic anhydride; TfOH: trifluoromethanesulfonic acid; THF: tetrahydrofuran; TLC: thin layer chromatography; TMP: trimethyl phosphate; XantPhos: 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; zn: zinc; zn (CN) 2 Zinc cyanide
PREPARATION EXAMPLE 1 intermediate A1
Figure BDA0003476093400000221
Step 1: preparation of intermediate A1-2
Intermediate a1-1(2 g, 5.04 mmol), DIEA (1.95 g, 15.11 mmol) and bis (4-methoxybenzyl) amine (1.56 g, 6.1 mmol) were dissolved in dichloromethane (20 ml) and the reaction was mixed and stirred at 20 degrees for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate a1-2(2.43 g, 78.0%) as a colorless oil. MS:618.8(M + H) + 。
Step 2: preparation of intermediate A1-3
Intermediate A1-2(2.4 g, 3.9 mol) and potassium tert-butoxide (871.5 mg, 7.7 mmol) were dissolved in 3-buten-1-ol (20 mL) and the reaction was allowed to mix and stir at 90 ℃ for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate a1-3(2.53 g, 99.6%) as a colorless oil. 1 H NMR(400MHz,CDCl 3 )δ7.17(d,J＝8.6Hz,4H),6.86(d,J＝8.7Hz,4H),6.26(s,1H),5.94–5.79(m,1H),5.55(s,2H),5.15–4.99(m,2H),4.81(s,4H),4.36(t,J＝7.1Hz,2H),3.80(d,J＝2.7Hz,6H),3.67–3.57(m,2H),2.61–2.47(m,2H),0.95–0.89(m,2H),0.02–0.06(m,9H)。
And step 3: preparation of intermediate A1-4
Intermediate A1-3(2.5 g, 3.9 mmol)) Zinc cyanide (637 mg, 7 mmol), zinc powder (455 mg, 7 mmol) and palladium acetate (156 mg, 0.7 mmol) were dissolved in DMF (10 ml) and the reaction was mixed and stirred at 100 ℃ for 8 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a1-4(1.8 g, 78%) as a colorless oil. MS 600.5(M + H) + 。
And 4, step 4: preparation of intermediate A1
Intermediate a1-4(1.7 g, 2.8 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (20 ml) and the reaction was mixed and stirred at 25 ℃ for 5 hours. The reaction mixture was concentrated to dryness and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a1(1.28 g, 98%) as a white solid. MS:469.9(M + H) + 。
Preparation example 2 intermediate A2
Figure BDA0003476093400000231
Step 1: preparation of intermediate A2-2
Intermediate a2-1(2.0 g, 10.6 mmol), TEA (1.6 g, 15.9 mmol) and bis (4-methoxybenzyl) amine (4.06 g, 12.7 mmol) were dissolved in dichloromethane (20 ml) and the reaction was mixed and stirred at 20 degrees for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate a2-2(4.0 g, 92%) as a yellow oil. MS:410.2(M + H) + 。
Step 2: preparation of intermediate A2
Intermediate A2-2(4 g, 9.8 mmol) and sodium thiomethoxide (2.05 g, 29.3 mmol) were dissolved in DMF (30 mL) and the reaction was mixed and stirred at 110 deg.CShould be 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a2(2.8 g, 68%) as a yellow solid. MS:422.2(M + H) + 。
Preparation example 3 intermediate A3
Figure BDA0003476093400000232
Intermediate A2-2(2.0 g, 4.9 mmol) and potassium tert-butoxide (5.5 g, 48.8 mmol) were dissolved in 3-buten-1-ol (20 mL) and the reaction was mixed and reacted for 12 hours with stirring at 90 degrees. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a3(1.5 g, 69%) as a yellow solid. MS 446.3(M + H) + 。
Preparation example 4 intermediate A4
Figure BDA0003476093400000233
Step 1: preparation of intermediate A4-2
Intermediate A4-1(11.3 g, 60 mmol) was dissolved in dichloromethane (240 mL) and CF was added with 0 deg.C stirring 3 SO 3 Na (28.2 g, 180 mmol) and water (96 ml) and the reaction stirred at 0 ℃ for 10 min. t-BuOOH (42 ml) was added to the above reaction solution with stirring at 0 ℃ and the reaction mixture was reacted with stirring at room temperature for 72 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a4-2(1.9 g, 13%) as a colorless oil. MS:256.1(M + H) + 。
Step 2: preparation of intermediate A4-3
Intermediate a4-2(1.9 g, 7.5 mmol) and bis (4-methoxybenzyl) amine (1.9 g, 7.5 mmol) and DIEA (1.9 g, 14.9 mmol) were dissolved in isopropanol (20 ml) and the reaction was mixed and stirred at 130 degrees for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate a4-3(900 mg, 25%) as a yellow oil. MS:477.0(M + H) + 。
And step 3: preparation of intermediate A4-4
Intermediate a4-3(0.9 g, 1.8 mol) and sodium hydrogen (117 mg, 2.9 mmol) were dissolved in tetrahydrofuran (10 ml) and the reaction was allowed to mix and stir at 0 degrees for 0.5 hours. SEMCl (366 mg, 2.2 mmol) was then added to the reaction mixture and the reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate a4-4(600 mg, 67%) as a colorless oil. MS:608.0(M + H) + 。
And 4, step 4: preparation of intermediate A4-5
Intermediate A4-4(500 mg, 0.82 mmol) and potassium tert-butoxide (185 mg, 1.6 mmol) were dissolved in 3-buten-1-ol (10 mL) and the reaction was allowed to mix and stir at 110 ℃ for 12 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic phase was washed with saturated sodium thiosulfate solution, water and brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate a4-5(300 mg, 57%) as a colorless oil.
And 5: preparation of intermediate A4
Intermediate a4-5(300 mg, 0.46 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (2 ml) and the reaction was mixed and stirred at 25 ℃ for 15 h. The reaction mixture was concentrated to dryness and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution andthe crude product was purified by silica gel column chromatography to give intermediate a4(230 mg) as a white solid. MS:513.1(M + H) + 。
PREPARATION EXAMPLE 5 intermediate B1
Figure BDA0003476093400000251
Step 1: preparation of intermediate B1-2
Intermediate B1-1(3.3 g, 14.5 mmol) was dissolved in 15 ml of dichloromethane, and trifluoroacetic anhydride (6.1 g, 29.0 mmol) was added dropwise to the reaction mixture with stirring at 0 ℃. The reaction mixture was then allowed to warm to room temperature and stirring was continued for 3 hours. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate B1-2 as a colorless oil (4.0 g, 96% yield). MS:288.1(M + H) + 。
Step 2: preparation of intermediate B1-3
Intermediate B1-2(5.0 g, 17.4 mmol) was dissolved in trifluoroacetic acid (40 mL) and NIS (7.8 g, 34.8 mmol) and concentrated H were added sequentially with stirring at 0 deg.C 2 SO 4 (0.37 g, 3.8 mmol). The reaction mixture was allowed to warm to room temperature and the reaction was continued with stirring for 12 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate B1-3(3.7 g, yield 51%) as a white solid. MS:414.5(M + H) + 。
And step 3: preparation of intermediate B1-4
Intermediate B1-3(1.7 g, 4.1 mmol) was suspended in methanol 20 ml and aqueous potassium carbonate (1.14 g in 2.5 ml water) was added to the mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was used in the next reaction without purification as intermediate B1-4.
And 4, step 4: preparation of intermediate B1-5
Intermediate B1-4(1.3 g, 4.1 mmol) was dissolved in ethyl acetate (20 ml) and water (20 ml), followed by the addition of di-tert-butyl dicarbonate (1.1 g, 4.9 mmol) and sodium bicarbonate (464 mg, 5.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate and extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by silica gel column chromatography to give intermediate B1-5(1.5 g, yield 87%) as a colorless oil.
And 5: preparation of intermediate B1-6
Intermediate B1-5(1.0 g, 2.4 mmol), allylboronic acid pinacol ester (4.0 g, 24 mmol), tris (dibenzylideneacetone) dipalladium (0.44 g, 0.48 mmol), tricyclohexylphosphine (0.13 g, 0.48 mmol) and potassium phosphate (1.5 g, 7.3 mmol) were dissolved in DMF (10 ml) under nitrogen. The reaction mixture was stirred at 80 ℃ for 2 hours, followed by extraction with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate B1-6(700 mg, yield 88%) as a yellow oil.
Step 6: preparation of intermediate B1
Intermediate B1-6(600 mg, 1.8 mmol) was dissolved in THF (15 ml) under nitrogen and 1.5M DIBAL-H toluene solution (3.6 ml, 5.4 mmol) was added with stirring at 0 ℃. The reaction mixture was then stirred at 0 ℃ for 2 hours, quenched by addition of methanol, and then extracted by dilution with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B1(130 mg, 24% yield) as a yellow oil.
PREPARATION EXAMPLE 6 INTERMEDIATE B2
Figure BDA0003476093400000261
Step 1: preparation of intermediate B2-2
Intermediate B2-1(5.0 g, 22 mmol) was dissolved in dichloromethane (120 ml), trifluoroacetic anhydride (6.1 ml, 43.9 mmol) was added dropwise at 0 ℃, and the reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate B2-2(5.9 g, yield 93%) as a white solid. MS:288.1(M + H) + 。 1 H NMR(CDCl 3 ,400MHz)δ7.91-7.86(m,2H),7.24-7.19(m,1H),4.82(d,J＝20Hz,2H),3.92(s,3H),3.87(t,J＝6.0Hz,2H),3.03-2.99(m,2H)。
Step 2: preparation of intermediate B2-3
Intermediate B2-2(5.9 g, 20.5 mmol) was dissolved in trifluoroacetic acid (40 ml) and NIS (7.8 g, 34.8 mmol) and concentrated sulfuric acid (4 ml) were added sequentially with stirring at 0 ℃. The reaction mixture was warmed to room temperature and reacted for 12 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B2-3 as a white solid (7.0 g, yield 83%). 1 H NMR(CDCl 3 ,400MHz)δ8.39(s,1H),7.83(s,1H),4.69-4.68(m,2H),3.92(s,3H),3.90-3.82(m,2H),3.01-2.95(m,2H)。
And step 3: preparation of intermediate B2-4
Intermediate B2-3(7.0 g, 16.9 mmol) was suspended in methanol (20 ml) and potassium carbonate solution (4.7 g in 10 ml water) was added. The reaction mixture was stirred at room temperature for 3 hours, and then the reaction mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was used in the next reaction without purification as intermediate B2-4. MS:318.1(M + H) + 。
And 4, step 4: preparation of intermediate B2-5
Intermediate B2-4(5.4 g, 16.9 mmol) was dissolved in ethyl acetate (60 mL) and water (60 mL) and sodium bicarbonate (1.7 g, 20 mmol) and di-tert-butyl dicarbonate (4.5 g, 20.3 mmol) were added at 0 deg.C in ethyl acetateLiquid (20 ml). The reaction mixture was warmed to room temperature and stirred for further 12 hours, and the reaction mixture was then extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B2-5(5.8 g, yield 82%) as a colorless oil. MS:403.1(M-55+41) + 。 1 H NMR(CDCl 3 ,400MHz)δ8.34(s,1H)7.79(s,1H),4.47(s,2H),3.91(s,3H),3.63(t,J＝5.6Hz,2H),2.85(t,J＝5.6Hz,2H),1.50(s,9H)。
And 5: preparation of intermediate B2-6
Intermediate B2-5(1.0 g, 2.4 mmol), allylboronic acid pinacol ester (4.0 g, 24 mmol), tris (dibenzylideneacetone) dipalladium (0.44 g, 0.48 mmol), tricyclohexylphosphine (0.13 g, 0.48 mmol) and potassium phosphate (1.5 g, 7.3 mmol) were dissolved in DMF (15 ml) under nitrogen protection and the reaction mixture was stirred at 80 ℃ for 2 h. The reaction mixture was diluted with ethyl acetate and extracted, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography to give intermediate B2-6(608 mg, yield 77%) as a yellow oil. MS:317.2(M-55+41) + 。
Step 6: preparation of intermediate B2
Intermediate B2-6(1.1 g, 3.2 mmol) was dissolved in 40 ml of dry THF under nitrogen, 1.5M DIBAL-H toluene solution (6.4 ml, 9.6 mmol) was added with 0 degree stirring and the reaction was continued for 30 minutes with stirring, followed by quenching with saturated aqueous ammonium chloride (30 ml) and extraction with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B2(480 mg, yield 49%) as a colorless oil. 1 H NMR(CDCl 3 ,400MHz)δ7.03(s,2H),5.97-5.87(m,1H),5.11-5.03(m,2H),4.63(s,2H),4.53(s,2H),3.61(t,J＝5.6Hz,2H),3.33(d,J＝5.6Hz,2H),2.84(t,J＝5.6Hz,2H),1.48(s,9H)。
Preparation example 7 intermediate B3
Figure BDA0003476093400000271
Step 1: preparation of intermediate B3-1
Intermediate B1-5(10 g, 27.0 mmol) and pinacol diboron (13.7 g, 54.0 mmol) were dissolved in 1, 4-dioxane (200 mL) followed by PdCl 2 (dppf) (2 g, 2.7 mmol), potassium acetate (8 g, 81 mmol), and the reaction mixture was stirred at 80 ℃ for 2 hours. The reaction was quenched with water and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B3-1 as a yellow solid (10.5 g, 93% yield). MS:418.3(M + H) + 。
Step 2: preparation of intermediate B3
Intermediate B3-1(10.5 g, 25.2 mmol) was dissolved in ethanol (50 ml) and water (25 ml) and m-chloroperbenzoic acid (5.2 g, 30.2 mmol) was added at 0 ℃. And the reaction mixture was warmed to room temperature and stirred for 1 hour, then quenched by the addition of ice water and extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine and water, respectively, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B3 as a white solid (7.5 g, 97% yield). MS:308.2(M + H) + 。
Preparation 8 intermediate B4
Figure BDA0003476093400000281
Step 1: preparation of intermediate B4-2
Intermediate B4-1 (trans configuration, 5.0 g, 4.7 mmol) was dissolved in THF (50 ml) and 2.5M lithium aluminum hydride THF solution (69.2 ml, 173 mmol) was added dropwise with stirring at 0 ℃. The reaction mixture was warmed to room temperature and reacted for 12 hours. Then, the reaction was quenched dropwise with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine and water, respectively, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B4-2 as a colorless oil (2.0 g, yield 50%).
Step 2: preparation of intermediate B4-3
Intermediate B4-2(2.0 g) was dissolved in THF (15 ml) and sodium hydrogen (124 mg, 5.2 mmol) was added at 0 ℃. After the reaction mixture was stirred at room temperature for 30 minutes, diphenyl tert-butylchlorosilane (1.2 g, 4.3 mmol) was added, and stirring was continued at room temperature for 1 hour. The reaction was then quenched by addition of ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine and water, respectively, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B4-3 as a colorless oil (110 mg, yield 72%).
And step 3: preparation of intermediate B4-4
Intermediate B4-3(3 g, 8.5 mmol) was dissolved in dichloromethane (50 ml) and then triphenylphosphine (3.3 g, 12.7 mmol) and carbon tetrabromide (4.2 g, 12.7 mmol) were added and the reaction mixture was reacted at room temperature for 2 hours. The reaction was then quenched by addition of ice water and extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine and water, respectively, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B4-4 as a colorless oil (3.2 g, 91% yield). 1 H NMR(400MHz,CDCl 3 )δ7.66(d,J＝6.9Hz,4H),7.41(dd,J＝10.7,7.0Hz,6H),3.60-3.70(m,2H),3.49(dd,J＝9.7,6.5Hz,1H),3.38(t,J＝8.8Hz,1H),2.56(h,J＝8.0Hz,1H),2.25(d,J＝7.0Hz,1H),2.03(q,J＝11.1,9.9Hz,1H),1.85(q,J＝10.0,9.2Hz,1H),1.60-1.80(m,,2H),1.06(s,9H)。
And 4, step 4: preparation of intermediate B4-5
Intermediate B3(1 g, 3.25 mmol) and intermediate B4-4(1.4 g, 3.3 mmol) were dissolved in DMF (10 ml) followed by cesium carbonate (2.1 g, 6.5 mmol). The reaction mixture was reacted at 100 ℃ for 1 hour. The reaction was then quenched by addition of ice water and extracted with ethyl acetate. The organic phase was treated with saturated sodium bicarbonate solution and saturated brineAnd water, dried, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate B4-5(1.4 g, yield 67%) as a colorless oil. MS:644.4(M + H) + 。
And 5: preparation of intermediate B4-6
Intermediate B4-5(1.4 g, 2.2 mmol) was dissolved in tetrahydrofuran (20 ml) and a THF solution of lithium aluminum hydride (2.5M THF solution, 0.87 ml, 2.2 mmol) was added dropwise at 0 ℃. The reaction mixture solution was stirred at 0 ℃ for 30 minutes, followed by quenching the reaction dropwise with ice water and extraction with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine and water, respectively, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B4-6 (trans configuration, 1.1 g, yield 82%) as a colorless oil. MS:616.4(M + H) + 。
Step 6: preparation of intermediate B4
Intermediate B4-6(615 mg, 1.0 mmol) was dissolved in dichloromethane (20 ml), triphenylphosphine (526 mg, 2.0 mmol) and carbon tetrabromide (915 mg, 2.8 mmol) were added dropwise at 20 ℃, and the reaction mixture was stirred at 20 ℃ for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate B4(550 mg, 81%) as a colorless oil.
Preparation of example 9 intermediate B5
Figure BDA0003476093400000291
Step 1: preparation of intermediate B5-1
4-bromo-1-butanol (5 g, 32.3 mmol) was dissolved in DMF (80 mL) and NaH (1.6 g, 39.5 mmol) was added at 0 ℃. The reaction mixture was then stirred at room temperature for 30 minutes, followed by the addition of diphenyl tert-butylchlorosilane (10.9 g, 39.5 mmol), and stirring of the reaction at room temperature was continued for 2 hours. The reaction was quenched with ice-water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine and water, respectively, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B5-1 as a colorless oil (3.0 g, yield 22%).
Step 2: preparation of intermediate B5-2
Intermediate B3(1 g, 3.3 mmol) and intermediate B5-1(1.2 g, 3.3 mmol) were dissolved in DMF (10 ml) followed by addition of cesium carbonate (2.1 g, 6.5 mmol). The reaction mixture was stirred at 100 ℃ for 1 hour. After cooling, the reaction was quenched with ice-water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine and water, respectively, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B5-2 as a colorless oil (1.5 g, yield 75%). MS:618.4(M + H) + 。
And step 3: preparation of intermediate B5-3
Intermediate B5-2(0.7 g, 1.2 mmol) was dissolved in tetrahydrofuran (20 ml), a THF solution of lithium aluminum hydride (2.5M THF solution, 0.46 ml, 2.3 mmol) was added dropwise at 0 ℃ and the reaction was stirred at 0 ℃ for 30 minutes, quenched by dropwise addition of ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine and water, respectively, dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate B5-3 as a colorless oil (0.55 g, yield 82%). MS:590.4(M + H) + 。
And 4, step 4: preparation of intermediate B5
Intermediate B5-3(1.1 g, 1.8 mmol) was dissolved in dichloromethane (20 ml), triphenylphosphine (740 mg, 2.8 mmol) and carbon tetrabromide (915 mg, 2.8 mmol) were added dropwise at 20 ℃, and the reaction mixture was stirred at 20 ℃ for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate B5(850 mg, 71%) as a colorless oil.
PREPARATION EXAMPLE 10 intermediate B6
Figure BDA0003476093400000301
Step 1: preparation of intermediate B6-1
Synthesis of intermediate B6-1 with reference to intermediate B2, intermediate B6-1 was prepared by using methyl 3-bromobenzoate in place of intermediate B2-5.
And 2, step: preparation of intermediate B6
Synthesis of intermediate B6 referring to intermediate B5, intermediate B6 was prepared by using intermediate B6-1 ester instead of intermediate B5-3.
Example 1
Compound I-1
Figure BDA0003476093400000311
Step 1: preparation of intermediate I-1-1
Intermediate I-12-1(411 mg, 1.1 mmol), intermediate a1(500 mg, 1.1 mmol) and cesium carbonate (548 mg, 1.7 mmol) were dissolved in DMF (10 ml) and the reaction mixture was stirred at 25 ℃ for 15 h. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate I-1-1(490 mg, 60%) as a yellow solid. MS:731.4(M + H) + 。
Step 2: preparation of intermediate I-1-2
Intermediate I-1-1(490 mg, 0.67 mmol) was dissolved in dichloromethane (200 ml) under nitrogen, followed by the addition of Grubbs' second generation catalyst (114 mg, 0.13 mmol) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate I-1-2(120 mg, 26%) as a yellow solid. MS:703.4(M + H) + 。
And step 3: preparation of intermediate I-1
Intermediate I-1-2(40 mg, 0.057 mmol) was dissolved in trifluoroacetic acid (5 ml) and the reaction mixture was stirred at 110 ℃ for 1 hour. The reaction was cooled, the reaction mixture was concentrated to dryness and extracted by dissolving in ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dried sodium sulfate, then filtered and concentrated to give a crude product, which was separated by preparative liquid chromatography to give compound I-1(10 mg, 37%) as a white solid. MS:363.2(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.18(s,2H),8.08(s,1H),7.91(s,1H),7.08(s,1H),5.81-5.76(m,1H),5.50-5.40(m,1H),5.29(s,2H),4.88-4.85(m,2H),4.22-4.18(m,2H),3.72-3.69(m,2H),3.37-3.28(m,2H),3.07(d,J＝7.2Hz,2H),2.79-2.75(m,2H)。
Example 2
Compound I-2
Figure BDA0003476093400000312
Step 1: preparation of intermediate I-2-1
Intermediate I-1-2(40 mg, 0.057 mmol) was dissolved in ethyl acetate (10 ml) under nitrogen, followed by addition of palladium on carbon (20 mg) with stirring at room temperature, followed by stirring of the reaction mixture under hydrogen at room temperature for 4 hours. The reaction mixture was filtered and concentrated to give intermediate I-2-1(40 mg, 100%) as a yellow solid. MS 705.2(M + H) + 。
Step 2: preparation of intermediate I-2
Intermediate I-2-1(40 mg, 0.057 mmol) was dissolved in trifluoroacetic acid (5 ml), and the reaction mixture was stirred at 110 ℃ for 1 hour. The reaction was cooled, the reaction mixture was concentrated to dryness and extracted by dissolving in ethyl acetate, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was separated by preparative liquid chromatography to give compound I-2(15 mg, 55%) as a white solid. MS 365.2(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.87(s,2H),7.91(s,1H),7.69(s,1H),6.86(s,1H),5.32(s,2H),4.43-4.36(m,2H),4.18-4.12(m,2H),3.36-3.30(m,2H),2.85-2.80(m,2H),2.65-2.59(m,2H),1.75-1.68(m,2H),1.49-1.42(m,2H),1.37-1.28(m,2H)。
Example 3
Compound I-3
Figure BDA0003476093400000321
Step 1: preparation of intermediate I-3-1
Intermediate a2(350 mg, 0.83 mmol), intermediate B5(676 mg, 1 mmol) and cesium carbonate (406 mg, 1.2 mmol) were dissolved in DMF (10 ml) and the reaction mixture was stirred at 25 ℃ for 2 h. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give intermediate I-3-1(550 mg, 65%) as a yellow oil. MS:993.5(M + H) + 。
Step 2: preparation of intermediate I-3-2
Intermediate I-3-1(120 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5 ml) and a 1M solution of TBAF in tetrahydrofuran (0.2 ml, 0.2 mmol), and the reaction mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate I-3-2(80 mg, 80%) as a white solid. MS:755.4(M + H) + 。
And step 3: preparation of intermediate I-3-3
Intermediate I-3-2(350 mg, 0.45 mmol) was dissolved in dichloromethane (10 ml), m-chloroperoxybenzoic acid (93 mg, 0.54 mmol) was added to the reaction mixture with 0 degree stirring, and the reaction mixture was stirred at 25 ℃ for 2 hours. Extracting the reaction mixture with ethyl acetate, washing the organic phase with saturated brine, drying over anhydrous dry sodium sulfate, filtering, concentrating to obtain crude product, and purifying the crude product by silica gel column chromatography to obtain yellowIntermediate I-3-3(340 mg, 95%) was obtained as a colored solid. MS 771.4(M + H) + 。
And 4, step 4: preparation of intermediate I-3-4
A solution of intermediate I-3-3(340 mg, 0.43 mmol) and potassium tert-butoxide (96 mg, 0.85 mmol) in tetrahydrofuran (10 ml) was stirred at 25 ℃ for 2 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate I-3-4(200 mg, 64%) as a yellow solid. MS:707.4(M + H) + 。
And 5: preparation of intermediate I-3
Synthesis of Compound I-3 referring to Compound I-2, Compound I-3 was prepared as a white solid by substituting intermediate I-2-1 with intermediate I-3-4. MS:367.2(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.86(s,2H),7.95(s,1H),7.89-7.87(m,1H),7.56(s,1H),6.77(s,1H),5.30(s,2H),4.72-4.65(m,2H),4.40-4.32(m,2H),4.18-4.12(m,2H),3.32-3.28(m,2H),2.74-2.70(m,2H),1.65-1.57(m,4H)。
Example 4
Compound I-4
Figure BDA0003476093400000331
Synthesis of Compound I-4 with reference to Compound I-2, Compound I-4 was prepared as a white solid by using intermediate B6 in place of intermediate I-12-1. MS:310.2(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ7.97(s,1H),7.65(s,1H),7.16-7.10(m,1H),7.05-7.10(m,1H),6.90-6.87(m,1H),5.36(s,2H),4.36-4.28(m,2H),2.68-2.62(m,2H),1.75-1.67(m,2H),1.35-1.28(m,4H)。
Example 5
Compound I-5
Figure BDA0003476093400000332
Synthesis of Compound I-5 with reference to Compound I-3, Compound I-5 was prepared as a white solid by using intermediate B4 in place of intermediate B5. MS 393.3(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.91(s,1H),8.81(s,1H),7.86(d,J＝2.2Hz,1H),7.62(s,1H),6.73(s,1H),5.30-5.27(m,2H),4.17-4.13(m,4H),3.75-3.71(m,2H),3.35-3.31(m,2H),2.78-2.74(m,2H),2.42-2.36(m,2H),1.90-1.85(m,1H),1.84-1.75(m,1H),1.73-1.68(m,2H)。
Example 6
Compound I-6
Figure BDA0003476093400000341
Step 1: preparation of intermediate I-6-1
Intermediate I-5-4(732 mg, 1 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (3 ml) and the reaction mixture was stirred at 20 ℃ for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography to give intermediate I-6-1(588 mg, 93%) as a colorless oily intermediate. MS:632.2(M + H) + 。
Step 2: preparation of intermediate I-6-2
Intermediate I-6-1(88.5 mg, 140 micromoles) was dissolved in methanol (5 ml), and then acetone (40.6 mg, 699.8 micromoles) and acetic acid (8.4 mg, 140 micromoles) were added to the above reaction mixture and stirred at room temperature for 1 hour. Adding NaCNBH 3 (44.1 mg, 699.8 micromoles) was added to the reaction mixture and the reaction mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was quenched with ice water and extracted by dilution with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate I-6-2(48 mg, 51%) as a yellow solid. MS:675.1(M + H) + 。
And step 3: preparation of Compound I-6
Intermediate I-6-2(48 mg, 71.2 micromoles) was dissolved in trifluoroacetic acid (5 ml) and the reaction mixture was stirred at 110 ℃ for 1 hour. The reaction was cooled, the reaction mixture was concentrated to dryness and extracted by dissolving in ethyl acetate, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was separated by preparative liquid chromatography to give compound I-6(11 mg, 36%) as a white solid. MS:435.3(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ7.87(d,J＝1.9Hz,1H),7.63(s,1H),6.74(s,1H),5.30(s,2H),4.62-4.58(m,1H),4.30-4.25(m,2H),3.75-3.70(m,2H),3.45-3.38(m,1H),3.23-3.18(m,1H),2.95-2.90(m,1H),2.85-2.78(m,1H),2.48-2.34(m,3H),1.92-1.87(m,1H),1.82-1.78(m,1H),1.70-1.64(m,2H),1.27(dd,J＝6.6,4.8Hz,6H)。
Example 7
Compound I-7
Figure BDA0003476093400000351
Synthesis of Compound I-7 referring to Compound I-6, Compound I-7 was prepared as a white solid by using cyclobutanone instead of acetone. MS:447.3(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ7.86(s,1H),7.64(s,1H),6.75(s,1H),5.29(s,2H),4.57-4.52(m,1H),4.38–4.27(m,1H),4.09-4.04(m,2H),3.76-3.72(m,1H),3.09-3.05(m,1H),2.91(d,J＝18.7Hz,1H),2.82-2.76(m,1H),2.44-2.38(m,2H),2.29-2.11(m,5H),1.92-1.65(s,7H)。
Example 8
Compound I-8
Figure BDA0003476093400000352
Synthesis of Compound I-8 with reference to Compound I-6, Compound I-8 was prepared as a white solid by using intermediate I-3-4 in place of intermediate I-5-4. MS:409.3(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.42(s,1H),7.96(d,J＝1.4Hz,1H),7.86(s,1H),6.77(d,J＝1.2Hz,1H),5.32(s,2H),4.68(s,2H),4.38(t,J＝6.5Hz,2H),4.28(d,J＝4.9Hz,2H),3.60-3.55(m,2H),3.24-3.15(m,1H),2.91-2.87(m,1H),2.77-2.74(m,1H),1.63-1.58(m,4H),1.29-1.25(m,6H)。
Example 9
Compound I-9
Figure BDA0003476093400000353
Synthesis of Compound I-9 referring to Compound I-6, Compound I-9 was prepared as a white solid by using intermediate I-3-4 in place of intermediate I-5-4 and cyclobutanone in place of acetone. MS:421.3(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.81(s,1H),7.98(s,1H),7.86(s,1H),6.78(s,1H),5.31(s,2H),4.70-6.64(m,2H),4.40-4.33(m,2H),4.06-4.01(m,1H),3.75-3.70(m,2H),3.07(s,1H),2.90-2.68(m,2H),2.22-2.05(m,4H),1.77-1.53(m,7H)。
Example 10
Compound I-10
Figure BDA0003476093400000361
Step 1: preparation of intermediate I-10-3
Synthesis of intermediate I-10-3 with reference to Compound I-2, intermediate I-11-1 was used instead of intermediate I-12-1 to prepare intermediate I-10-3 as a white solid. MS:705.3(M + H) + 。
Step 2: preparation of Compound I-10
Synthesis of Compound I-10 referring to Compound I-6, Compound I-10 was prepared as a white solid by substituting intermediate I-10-3 for intermediate I-5-4. MS:407.3(M + H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.49(s,1H),7.91(s,1H),7.70(s,1H),6.92(s,1H),5.34(d,J＝1.7Hz,2H),4.49-4.46(m,1H),4.42-4.38(m,1H),4.26-4.23(m,2H),3.65-3.52(m,2H),3.16-3.00(m,2H),2.96-2.92(m,1H),2.65-2.60(m,2H),1.76-1.73(m,2H),1.53-1.49(m,2H),1.30(dd,J＝6.6,3.7Hz,8H)。
Example 11
Compound I-11
Figure BDA0003476093400000362
Step 1: preparation of intermediate I-11-1
Intermediate B2(0.4 g, 1.3 mmol) was dissolved in dichloromethane (10 ml), triphenylphosphine (785.9 mg, 3.0 mmol) and carbon tetrabromide (991.8 mg, 3.0 mmol) were added dropwise at 20 ℃, and the reaction mixture was stirred at 20 ℃ for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate I-11-1(0.23 g, 31%) as a colorless oil. MS 309.9[ M + H-56 ]] + 。
Step 2: preparation of intermediate I-11-2
Intermediate I-11-1(0.23 g, 619.7 micromoles), intermediate B1(320.1 mg, 681.7 micromoles) and cesium carbonate (403.8 mg, 1.2 mmol) were dissolved in DMF (4 ml) and the reaction mixture was stirred at 90 ℃ for 5 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate I-11-2(0.4 g, 86%) as a yellow solid. MS 755.2(M + H) + 。
And step 3: preparation of intermediate I-11-3
Intermediate I-11-2(0.4 g, 529.9 micromoles) was dissolved in dichloromethane (200 ml) under nitrogen, followed by addition of Grubbs' second generation catalyst (20 mg, 529.9 micromoles) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give intermediate I-11-3(0.20 g, 51%) as a yellow solid. MS 727.2(M + H) + 。
And 4, step 4: preparation of intermediate I-11-4
Intermediate I-11-3(0.12 g, 165.1 micromoles) was dissolved in ethyl acetate (10 ml) under nitrogen, followed by addition of palladium on carbon (60 mg) with stirring at room temperature, and the reaction mixture was stirred at room temperature under hydrogen for 4 hours. The reaction mixture was filtered and concentrated to yield intermediate I-11-4(0.12 g, 99.7%) as a yellow solid. MS:729.2(M + H) + 。
And 5: preparation of intermediate I-11-5
Intermediate I-11-4(0.12 g, 164.6 micromoles) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (2 ml) and the reaction mixture was stirred at 20 ℃ for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give intermediate I-11-5(88 mg, 85%) as a colorless oily intermediate. MS:629.2(M + H) + 。
Step 6: preparation of intermediate I-11-6
Intermediate I-11-5(88 mg, 140 micromoles) was dissolved in methanol (5 ml), and then acetone (40.6 mg, 699.8 micromoles) and acetic acid (8.4 mg, 140 micromoles) were added to the above reaction mixture and stirred at room temperature for 1 hour. Adding NaCNBH 3 (44.1 mg, 699.8 micromoles) was added to the reaction mixture and the reaction mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was quenched with ice water and extracted by dilution with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate I-11-6(44 mg, 47%) as a yellow solid. MS:671.1(M + H) + 。
And 7: preparation of Compound I-11
Intermediate I-11-6(44 mg, 65.6. mu. mol) was dissolved in trifluoroacetic acid (5 ml), and the reaction mixture was stirred at 110 ℃ for 1 hour. Cooling, evaporating reaction mixture, dissolving in ethyl acetate, extracting, washing organic phase with saturated sodium bicarbonate solution and saturated saline, drying with anhydrous dry sodium sulfate, filtering,concentration gave a crude product which was isolated by preparative liquid chromatography to give compound I-11 as a white solid (6.25 mg, 22%). MS:431.0(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.70(s,1H),7.50(br,2H),7.37(s,1H),6.87(s,1H),5.20(s,2H),4.42(s,2H),4.25(s,2H),3.65(dd,J＝28.1,21.5Hz,2H),3.01(s,3H),2.63(s,2H),1.74(s,2H),1.55–1.40(m,2H),1.33–1.28(m,8H)。
Example 12
Compound I-12
Figure BDA0003476093400000381
Step 1: preparation of intermediate I-12-1
Synthesis of intermediate I-12-1 with reference to intermediate I-11-1, intermediate I-12-1 was prepared by using intermediate B1 instead of intermediate B2. MS 309.9[ M + H-56 ]] + 。
Step 2: preparation of intermediate I-12-3
Synthesis of intermediate I-12-3 referring to intermediate I-11-3, intermediate I-12-3 was prepared by using intermediate I-12-1 instead of intermediate I-11-1. MS 727.2(M + H) + 。
And step 3: preparation of Compound I-12
Intermediate I-12-3(100 mg, 137.6. mu. mol) was dissolved in trifluoroacetic acid (5 ml), and the reaction mixture was stirred at 110 ℃ for 1 hour. The reaction was cooled, the reaction mixture was concentrated to dryness and extracted by dissolving in ethyl acetate, the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was isolated by preparative liquid chromatography to give compound I-12(4.91 mg, 8.4%) as a white solid. MS:387.1(M + H) + 。 1 H NMR(400MHz,DMSO)δ8.15(s,1H),7.55(br,2H),7.29(s,1H),7.04(s,1H),5.74(dd,J＝14.7,7.8Hz,1H),5.44(dd,J＝15.3,7.8Hz,1H),5.19(s,2H),4.83(s,2H),4.27(s,2H),3.36(s,2H),3.08(d,J＝6.9Hz,2H),2.78(s,2H),2.49–2.44(m,2H),2.40(s,1H)。
Example 13
Compound I-13 and compound I-14
Figure BDA0003476093400000391
Step 1: preparation of intermediate I-13-1
Intermediate I-11-3(100 mg, 137.6 micromoles) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (2 ml) and the reaction mixture was stirred at 20 ℃ for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give intermediate I-13-1(80 mg, 93%) as a colorless oily intermediate. MS 627.2(M + H) + 。
Step 2: preparation of intermediate I-13-2
Intermediate I-13-1(88 mg, 127.6 micromole) was dissolved in methanol (5 ml), and then acetone (40.6 mg, 699.8 micromole) and acetic acid (8.4 mg, 140 micromole) were added to the above reaction mixture and stirred at room temperature for 1 hour. Adding NaCNBH 3 (40.2 mg, 638.2. mu. mol) was added to the above reaction mixture, and the reaction mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was quenched with ice water and extracted by dilution with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product which was purified by silica gel column chromatography to give intermediate I-13-2(45 mg, 53%) as a yellow oil. MS:669.1(M + H) + 。
And 3, step 3: preparation of Compound I-13 and Compound I-14
Intermediate I-13-2(18.4 mg, 27.5 micromole) was dissolved in trifluoroacetic acid (5 ml) and the reaction mixture was stirred at 110 ℃ for 1 hour. Cooling for reaction, concentrating the reaction mixture, evaporating to dryness, dissolving and extracting with ethyl acetate, washing the organic phase with saturated sodium bicarbonate solution and saturated saline, drying with anhydrous dry sodium sulfate, filtering, concentrating to obtain crude product, and separating the crude product by preparative liquid chromatography to obtain compound I-13 and compound I-14 which are white solids.
Compound I-13(2.8 mg). MS 429.0(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.99(s,1H),7.50(br,2H),7.28(s,1H),6.93(s,1H),5.83–5.68(m,1H),5.41(dt,J＝15.3,7.5Hz,1H),5.14(s,2H),4.83(s,2H),3.48(s,2H),3.01(d,J＝6.7Hz,2H),2.91–2.82(m,1H),2.75(s,2H),2.62(d,J＝5.2Hz,2H),2.47(d,J＝6.3Hz,2H),1.02(t,J＝8.1Hz,6H)。
Compound I-14(2.8 mg). MS 429.0(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.68(s,1H),7.54(br,2H),7.31(s,1H),6.89(s,1H),5.70(t,J＝8.3Hz,1H),5.66–5.56(m,1H),5.12(s,2H),4.61–4.50(m,2H),3.55(s,2H),3.15(d,J＝7.4Hz,2H),2.92–2.83(m,1H),2.74(s,2H),2.61(d,J＝5.0Hz,2H),2.34(s,2H),1.04(d,J＝6.5Hz,6H)。
Example 14
Compound I-15
Figure BDA0003476093400000401
Step 1: preparation of intermediate I-15-2
Synthesis of intermediate I-15-2 reference intermediate I-11-5 was prepared by using intermediate I-12-3 instead of intermediate I-11-3 to give intermediate I-15-2. MS:629.2(M + H) + 。
Step 2: preparation of intermediate I-15-3
Intermediate I-15-2(39 mg, 0.06 mmol) and TEA (35 mg, 0.34 mmol) were dissolved in tetrahydrofuran (5 ml), acetyl chloride (10 mg, 0.13 mmol) was added to the reaction mixture with stirring at 0 ℃ and stirring continued at room temperature for 2 hours. The reaction mixture was quenched with ice water and extracted by dilution with ethyl acetate. The organic phase was washed with brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give intermediate I-15-3(11 mg, 15%) as a colorless oil. MS:671.2(M + H) + 。
And step 3: preparation of Compound I-15
Synthesis of Compound I-15 reference intermediate I-2 was prepared by substituting intermediate I-15-3 for intermediate I-12-3 to give a white solid compoundSubstance I-15. MS:431.2(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.61(s,1H),7.50(br,2H),7.36(s,1H),6.80(s,1H),5.17(s,2H),4.56(s,1H),4.49(s,1H),4.39-4.36(m,2H),3.61-3.58(m,2H),2.72-2.61(m,4H),2.03(s,3H),1.70(br,2H),1.45(br,2H),1.31(br,2H)。
Example 15
Compound I-16
Figure BDA0003476093400000402
Synthesis of Compound I-16 referring to Compound I-11, Compound I-16 was prepared as a white solid by using intermediate I-15-2 instead of intermediate I-11-5 and tetrahydro-4H-pyran-4-one instead of acetone. MS:473.2(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.53(s,1H),7.50(br,2H),7.35(s,1H),6.65(s,1H),5.13(s,2H),4.39-4.36(m,2H),3.87-3.86(m,2H),3.57(s,2H),3.32-3.24(m,2H),2.71-2.62(m,6H),1.74-1.71(m,4H),1.45-1.24(m,7H)。
Example 16
Compound I-17
Figure BDA0003476093400000411
Synthesis of Compound I-17 with reference to Compound I-15, Compound I-17 was prepared as a white solid by using 4- (bromomethyl) pyridine in place of acetyl chloride. MS:480.1(M + H) + 。 1 H NMR(400MHz,DMSO)δ8.50(s,2H),7.58(s,1H),7.50(br,2H),7.34-7.33(m,3H),6.62(s,1H),5.13(s,2H),4.42-4.39(m,2H),3.61(s,2H),3.48(s,2H),2.70-2.55(m,6H),1.70(br,2H),1.47-1.44(m,2H),1.31-1.24(m,2H)。
Example 17
Compound I-18
Figure BDA0003476093400000412
Synthesis of Compound I-18 reference Compound I-11 was made by using intermediate I-15-2 instead of the intermediateCompound I-18 was prepared as a white solid from form I-11-5. MS:431.1(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.57-7.41(m,3H),7.36(s,1H),6.68(s,1H),5.15(s,2H),4.37(t,J＝6.5Hz,2H),3.68(s,2H),2.94(s,1H),2.80(s,2H),2.68(s,2H),2.59(s,2H),1.69(s,2H),1.41(d,J＝6.2Hz,2H),1.34(d,J＝6.2Hz,2H),1.06(d,J＝6.3Hz,6H)。
Example 18
Compound I-19
Figure BDA0003476093400000413
Synthesis of Compound I-19 referring to Compound I-11, white solid Compound I-19 was prepared by using intermediate I-15-2 instead of intermediate I-11-5 and cyclobutanone instead of acetone. MS:443.0(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.54(br,3H),7.35(s,1H),6.64(s,1H),5.14(s,2H),4.38(s,2H),3.29(s,2H),2.76(s,1H),2.60(s,4H),2.45(s,2H),2.00(d,J＝7.1Hz,2H),1.80(s,2H),1.68(s,4H),1.42-1.38(m,2H),1.33-1.28(m,2H)。
Example 19
Compound I-20
Figure BDA0003476093400000421
Compound I-19(15 mg, 33.9 micromole), TEA (10.3 mg, 101.7 micromole) and butyryl chloride (7.2 mg, 67.8 micromole) were dissolved in dichloromethane (5 ml) and the reaction mixture was stirred at 40 ℃ for 16 hours. The reaction mixture was quenched with ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was isolated by preparative liquid chromatography to give compound I-20(2.9 mg, 17%) as a white solid. MS:513.3(M + H) + 。 1 H NMR(400MHz,DMSO)δ10.97(s,1H),7.64(s,1H),7.54(s,1H),6.64(s,1H),5.24(s,2H),4.45(s,2H),2.75(s,1H),2.62(s,4H),2.46(d,J＝7.2Hz,4H),2.00(d,J＝7.5Hz,3H),1.80(s,2H),1.72–1.53(m,6H),1.39–1.28(m,5H),0.90(t,J＝7.4Hz,3H)。
Example 20
Compound I-21
Figure BDA0003476093400000422
Compound I-19(15 mg, 33.9 micromoles) was dissolved in tetrahydrofuran (5 ml), sodium hydride (4.1 mg, 101.7 micromoles) was added to the reaction solution with stirring at 0 degrees, and the reaction was continued for 1 hour with stirring. Chlorobutyl carbonate (23.2 mg, 169.5 micromoles) was then added to the above reaction solution at 0 degrees, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was isolated by preparative liquid chromatography to give compound I-21(4 mg, 22%) as a white solid. MS:543.3(M + H) + 。 1 H NMR(400MHz,DMSO)δ10.81(s,1H),8.38(s,1H),7.65(s,1H),7.55(s,1H),6.64(s,1H),5.23(s,2H),4.45(t,J＝6.6Hz,2H),4.14(t,J＝6.6Hz,2H),3.28(s,2H),2.81–2.70(m,1H),2.61(d,J＝4.6Hz,4H),2.44(t,J＝5.7Hz,2H),1.99(d,J＝3.8Hz,2H),1.78–1.71(m,2H),1.69(s,2H),1.66–1.55(m,4H),1.39–1.21m,6H),0.91(t,J＝7.4Hz,3H)。
Example 21
Compound I-22
Figure BDA0003476093400000431
Synthesis of Compound I-22 referring to Compound I-15, Compound I-22 was prepared as a white solid by using methanesulfonyl chloride instead of acetyl chloride. MS:467.1(M + H) + 。 1 H NMR(400MHz,DMSO)7.63(s,1H),7.50(br,2H),7.36(s,1H),6.78(s,1H),5.17(s,2H),4.40-4.36(m,2H),4.26(s,2H),3.38-3.35(m,2H),2.88(s,3H),2.76(br,2H),2.62(br,2H),1.70(br,2H),1.45(br,2H),1.33(br,2H)。
Example 22
Compound I-23
Figure BDA0003476093400000432
Synthesis of Compound I-23 with reference to Compound I-11, Compound I-23 was prepared as a white solid by using intermediate A4 in place of intermediate A1. MS:474.1(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.46(s,1H),7.34(br,2H),7.13(s,1H),6.64(s,1H),5.13(s,2H),4.29(br,2H),3.53(s,2H),2.91-2.82(m,1H),2.65(br,2H),2.56(br,4H),1.66(br,2H),1.36(br,4H),1.03(d,J＝8Hz,6H)。
Example 23
Compound I-24
Figure BDA0003476093400000433
Synthesis of Compound I-24 with reference to Compound I-19, Compound I-24 was prepared as a white solid by using intermediate A4 in place of intermediate A1. MS 486.1(M + H) + 。 1 H NMR(400MHz,DMSO)δ7.46(s,1H),7.35(br,2H),7.13(s,1H),6.57(s,1H),5.13(s,2H),4.25(br,2H),3.25(s,2H),2.77-2.73(m,1H),2.62(br,4H),2.49-2.43(m,2H),1.99(br,2H),1.85-1.70(m,2H),1.64(br,4H),1.34(br,4H)。
Test example 1: evaluation of drug efficacy at cellular level
Test example 1 assay of human TLR7 agonistic Activity of the Compound of the present invention
Compound of the invention p HEK-Blue TM The stable expression of hTLR7 agonistic activity of TLR7 in human TLR7 cell line was tested as follows:
1. the compounds to be tested were weighed out and formulated in DMSO (Sigma) to a concentration of 10 mM. The compounds to be assayed were diluted in DMSO in 3.16-fold gradients for a total of 10 concentration gradients with a maximum concentration of 1 mM.
2. The test compound, DMSO control, was diluted 10-fold using DPBS buffer (Gibco) and then added to a volume of 20 μ L to a 96-well cell culture plate (Corning).
3. Digestion of HEK-Blue with cell separation (Gibco) TM hTLR7 cell(Invivogen) and cell counting (TC-20 cell counter, Bio-rad) was performed. The cells were diluted to 4.4E 5/ml using DMEM cell culture medium (Gibco). Add 180. mu.L to a 96 well cell culture plate. At 37 ℃ 5% CO 2 Incubate in incubator for 16-22 hours.
4. QUANTI-Blue detection reagent (Invivogen) was prepared and 180. mu.L was added to a new 96-well plate. mu.L of cell culture supernatant was removed from the cell culture plate and added to a 96-well plate and incubated at 37 ℃ for 1-3 hours.
Measurement of light absorption at 630nm with a Neo2 multifunctional microplate reader (Bio-tek), and calculation of half effective concentration EC of drug by GraphPad Prism 50 。
TABLE 1 EC of compounds of the invention for agonism of human TLR7 50 Value of
Compound (I) EC 50 (nM) Compound (I) EC 50 (nM)
Compound I-1 51 Compound I-2 85
Compound I-3 368 Compound I-5 279
Compound I-6 367 Compound I-7 237
Compound I-8 136 Compound I-9 148
Compound I-10 77 Compound I-11 14
Compound I-12 7 Compound I-13 9
Compound I-14 5 Compound I-15 503
Compound I-16 76 Compound I-17 1695
Compound I-18 72 Compound I-19 100
Compound I-22 974 Compound I-23 69
Compound I-24 778

Claims (11)

1. A compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0003476093390000011
wherein Y is N or CR Y ；
R Y Is cyano or halogen substituted C 1 ～C 4 An alkyl group;
a is O, S, -S (═ O) 2 、-S(＝O)(＝NH)、NR 4 Or CR 6 R 7 ；R 4 、R 6 And R 7 Independently is H or C 1 ～C 6 An alkyl group;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated alkylene radical, R 1-1 Substituted C 2 ～C 10 Alkylene radical, R 1-1 Substituted C 2 ～C 10 Unsaturated hydrocarbylene, -Z 1 -NH-C(＝O)-Z 2 -、-Z 3 -NH-C(＝O)-Z 4 -L 1 -、-Z 5 -L 2 -、-Z 6 -O-Z 7 -、-Z 8 -O-Z 9 -L 3 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 1 、L 2 、L 3 And L 4 Independently O, S, S (═ O) 2 、NR 8 ，R 8 Is H or C 1 ～C 6 An alkyl group;
-L 5 -is C 3 ～C 6 Cycloalkylene, halogen-substituted C 3 ～C 6 Cycloalkylene, 3-6 membered heterocycloalkylene with 1-3 heteroatoms selected from N, O and S, or halogen-substituted heteroatom selected from N, O and S, 3-6 membered heterocycloalkylene with 1-3 heteroatoms;
n and r are independently 1,2 or 3;
-Z 1 -、-Z 2 -、-Z 3 -、-Z 4 -、-Z 6 -、-Z 7 -、-Z 8 -and-Z 9 -independently is C 1 ～C 6 Alkylene radical, C 2 ～C 6 Unsaturated alkylene radical, R 1-2 Substituted C 1 ～C 6 Alkylene or R 1-2 Substituted C 2 ～C 6 An unsaturated alkylene group;
-Z 5 -is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated alkylene radical, R 1-3 Substituted C 2 ～C 10 Alkylene or R 1-3 Substituted C 2 ～C 10 An unsaturated alkylene group;
R 1-1 、R 1-2 and R 1-3 Independently is OH, CN, NH 2 Halogen, C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy or COOR 1-1-1 ；R 1-1 - 1 Is H or C 1 ～C 3 An alkyl group;
R 1 、R 2 and R 3 Independently of one another H, halogen, C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 An alkyl group;
or alternatively, "R 1 And R 2 "or" R 2 And R 3 R is a 4-7 membered heterocycloalkyl group having 1-3 hetero atoms and one or more hetero atoms selected from N, O and S 1-4 Substituted "heteroatoms selected from N, O and SOne or more of 4-to 7-membered heterocycloalkylene' having 1 to 3 hetero atoms and C 4 ～C 7 Cycloalkylene or R 1-5 Substituted C 4 ～C 7 A cycloalkylene group; or alternatively, "R 1 And R 2 "or" R 2 And R 3 "the hetero atom (S) together with the carbon atom (S) to which they are bonded is (are) one or more members selected from the group consisting of N, O and S, a 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms", or R 1-4 The "hetero atom" in the substituted "hetero atom is selected from one or more of N, O and S, and the 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms" is selected from one or more of N, O and S, and 1 or 2 or more arbitrary methylene groups in the 4-to 7-membered heterocycloalkyl group having 1 to 3 hetero atoms "are independently substituted with a carbonyl group or S (═ O) 2 Replacement;
R 1-4 and R 1-5 Independently OH, halogen, CN, C 1 ～C 6 Alkyl, R 1-6 Substituted C 1 ～C 6 Alkyl radical, C 1 ～C 6 Alkoxy radical, R 1-9 Substituted C 1 ～C 6 Alkoxy, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、NR 1-10 R 1-11 、COOR 1-12 、SR 1-13 、C 3 ～C 7 Cycloalkyl radical, R 1-19 Substituted C 3 ～C 7 Cycloalkyl, 4-7 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S and 1-3 heteroatoms, and R 1-20 The substituted 'hetero atom is selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 hetero atoms, the' hetero atom is selected from one or more of N, O and S, and C with 1-4 hetero atoms 1 ～C 10 Heteroaryl', R 1-21 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 Heteroaryl "or-G (CR) 1-14 R 1-15 ) u -COOR 1-16 (ii) a G is O, S, S (═ O) 2 Or NH; u is 1,2 or 3;
R 1-6 and R 1-9 Independently halogen, amino, CN, OH, -COOR 1-17 、-S(＝O) 2 R 1-31 、-C(＝O)NH 2 、-S(＝O) 2 NH 2 、C 1 ～C 3 Alkoxy radical, C 3 ～C 7 Cycloalkyl radical, COOR 1-18 Substituted C 3 ～C 7 Cycloalkyl, 4-7 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S and 1-3 heteroatoms, and R 1-22 The substituted ' hetero atom is selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 hetero atoms ', ' hetero atom is selected from one or more of N, O and S, and C with 1-4 hetero atoms 1 ～C 10 Heteroaryl "or R 1-23 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 Heteroaryl ";
R 1-7 and R 1-8 Independently is C 1 ～C 3 Alkyl radical, C 3 ～C 7 Cycloalkyl radical, R 1-24 Substituted C 3 ～C 7 Cycloalkyl, 4-7 membered heterocycloalkyl having one or more heteroatoms selected from N, O and S and 1-3 heteroatoms, and R 1-25 The substituted ' hetero atom is selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 hetero atoms ', ' hetero atom is selected from one or more of N, O and S, and C with 1-4 hetero atoms 1 ～C 10 Heteroaryl', R 1-26 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 Heteroaryl ", C 6 ～C 10 Aryl radical, R 1-27 Substituted C 6 ～C 10 Aryl or-NR 1- 28 R 1-29 ；
R 1-10 、R 1-11 、R 1-12 、R 1-16 、R 1-17 、R 1-18 、R 1-28 And R 1-29 Independently is H or C 1 ～C 3 An alkyl group; r 1-31 Is C 1 ～C 3 An alkyl group;
R 1-13 is H, C 1 ～C 6 Alkyl or halogen substitutedC 1 ～C 6 An alkyl group;
R 1-14 and R 1-15 Independently H, C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 An alkyl group;
R 1-19 、R 1-20 、R 1-21 、R 1-22 、R 1-23 and R 1-24 Independently OH, halogen, amino, CN, C 1 ～C 6 An alkyl group;
R 5 is H, CN, halogen, C 3 ～C 5 Cycloalkyl radical, C 1 ～C 6 Alkyl or C 1 ～C 6 An alkoxy group;
R 13 is H, -CONR 14 R 15 、-C(＝O)R 16 or-COOR 17 ，R 14 、R 15 、R 16 And R 17 Independently is C 1 ～C 6 Alkyl or R 13 - 1 Substituted C 1 ～C 6 An alkyl group; r 13-1 Is CN, halogen, C 1 ～C 6 Alkoxy or- (CH) 2 CH 2 O) q -R 13-2 ，R 13-2 Is C 1 ～C 6 And q is an integer of 0 to 460.
2. A compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein is any one of the following schemes:
scheme 1:
a is O;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 2 And L 4 Independently is O;
-L 5 -is C 3 ～C 6 A cycloalkylene group;
-Z 5 -is C 2 ～C 10 An alkylene group;
R 1 、R 2 and R 3 Independently is H;
or, R 1 And R 2 Together with the carbon atom to which they are attached form a "4-to 7-membered heterocycloalkylene group with 1 to 3 hetero atoms selected from one or more of N, O and S" or R 1-4 Substituted '4-7 membered heterocycloalkylene with 1-3 hetero atoms selected from one or more of N, O and S';
R 1-4 independently is C 1 ～C 6 Alkyl radical, R 1-6 Substituted C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or 4-7 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
R 1-6 independently represents one or more heteroatoms selected from N, O and S, and C with 1-4 heteroatoms 1 ～C 10 Heteroaryl ";
R 1-7 and R 1-8 Independently is C 1 ～C 3 An alkyl group;
R 5 is H;
R 13 is H, -C (═ O) R 16 or-COOR 17 ，R 16 And R 17 Independently is C 1 ～C 6 An alkyl group;
scheme 2:
a is O;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 2 And L 4 Independently is O;
-L 5 -is C 3 ～C 6 A cycloalkylene group;
-Z 5 -is C 2 ～C 10 An alkylene group;
R 1 and R 2 Together with the carbon atom to which they are attachedForm one or more of N, O and S, 4-7 membered heterocycloalkylene with 1-3 hetero atoms or R 1-4 Substituted '4-7 membered heterocycloalkylene with 1-3 hetero atoms selected from one or more of N, O and S';
R 1-4 independently is C 1 ～C 6 Alkyl radical, R 1-6 Substituted C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or 4-7 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
R 1-6 independently represents one or more heteroatoms selected from N, O and S, and C with 1-4 heteroatoms 1 ～C 10 Heteroaryl ";
R 1-7 and R 1-8 Independently is C 1 ～C 3 An alkyl group;
R 3 is H;
R 5 is H;
R 13 is H, -C (═ O) R 16 or-COOR 17 ，R 16 And R 17 Independently is C 1 ～C 6 Alkyl radical
Scheme 3:
a is O;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 2 And L 4 Independently is O;
-L 5 -is C 3 ～C 6 A cycloalkylene group;
-Z 5 -is C 2 ～C 10 An alkylene group;
R 1 and R 2 Together with the carbon atom to which they are attached form a "4-to 7-membered heterocycloalkylene group with 1 to 3 hetero atoms selected from one or more of N, O and S" or R 1-4 Substituted "hetero atomsOne or more selected from N, O and S, and 4-7 membered heterocycloalkylene with 1-3 hetero atoms;
R 1-4 independently is C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or 4-7 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
R 1-7 and R 1-8 Independently is C 1 ～C 3 An alkyl group;
R 3 is H; r is 5 Is H;
R 13 is H;
scheme 4:
a is O;
b is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -；
L 2 And L 4 Independently is O;
-L 5 -is C 3 ～C 6 A cycloalkylene group;
-Z 5 -is C 2 ～C 10 An alkylene group;
R 1 and R 2 Together with the carbon atom to which they are attached form a "4-to 7-membered heterocycloalkylene group with 1 to 3 hetero atoms selected from one or more of N, O and S" or R 1-4 The substituted 'hetero atom is one or more selected from N, O and S, 4-7 membered heterocycloalkylene with 1-3 hetero atoms', C 4 ～C 7 Cycloalkylene or R 1-5 Substituted C 4 ～C 7 A cycloalkylene group;
R 3 is H;
R 1-4 independently is C 1 ～C 6 Alkyl, -C (═ O) R 1-8 、C 3 ～C 7 Cycloalkyl or 4-7 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S; when R is Y Is halogenSubstituted by elements C 1 ～C 4 When it is alkyl, said R 1-4 Is C 1 ～C 6 Alkyl (e.g., isopropyl);
R 1-8 independently is C 1 ～C 3 An alkyl group;
R 3 is H;
R 13 is H;
R 5 is H.
3. The compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1, wherein Y is N;
and/or, R Y Is cyano;
and/or, A is O;
and/or B is C 2 ～C 10 Alkylene radical, C 2 ～C 10 Unsaturated hydrocarbylene, -Z 5 -L 2 -, or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -, preferably C 2 ～C 10 Alkylene or C 2 ～C 10 An unsaturated alkylene group;
and/or, L 2 And L 4 Is O;
and/or-L 5 -is C 3 ～C 6 A cycloalkylene group;
and/or-Z 5 -is C 2 ～C 10 An alkylene group;
and/or n and r are 1;
and/or, R 1 And R 2 Together with the carbon atoms to which they are bonded form a 4-to 7-membered heterocycloalkylene group containing 1 to 3 heteroatoms selected from N, O and S 1-4 Substituted '4-7 membered heterocycloalkylene with 1-3 hetero atoms selected from one or more of N, O and S';
and/or, R 1-4 Is C 1 ～C 6 Alkyl radical, R 1-6 Substituted C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or "one or more hetero atoms selected from N, O and S, 4-to 7-membered heterocycloalkyl having 1 to 3 hetero atoms", preferably C 1 ～C 6 Alkyl, -S (═ O) 2 R 1-7 、-C(＝O)R 1-8 、C 3 ～C 7 Cycloalkyl or "4-to 7-membered heterocycloalkyl having 1 to 3 hetero atoms selected from N, O and S, and more preferably C 1 ～C 6 Alkyl or 4-7 membered heterocycloalkyl with 1-3 heteroatoms selected from N, O and S;
and/or, R 1-6 Is' one or more of hetero atoms selected from N, O and S, and C with 1-4 hetero atoms 1 ～C 10 Heteroaryl ";
and/or, R 1-7 And R 1-8 Is C 1 ～C 3 An alkyl group;
and/or, R 3 Is H;
and/or, R 5 Is H;
and/or, R 13 Is H, -C (═ O) R 16 or-COOR 17 Preferably, it is H;
and/or, R 16 And R 17 Is C 1 ～C 6 An alkyl group.
4. The compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1,
Figure FDA0003476093390000051
is composed of
Figure FDA0003476093390000052
Figure FDA0003476093390000053
And/or the presence of a gas in the gas,
Figure FDA0003476093390000061
is composed of
Figure FDA0003476093390000062
and/or-A-B-is
Figure FDA0003476093390000063
5. The compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1, wherein when B is C 2 ～C 10 Alkylene or R 1-1 Substituted C 2 ～C 10 When it is alkylene, said C 2 ～C 10 Alkylene and said R 1-1 Substituted C 2 ～C 10 C in alkylene 2 ～C 10 Alkylene is independently C 4 ～C 6 Alkylene, preferably n-pentylene
And/or, when B is C 2 ～C 10 Unsaturated alkylene or R 1-1 Substituted C 2 ～C 10 When unsaturated alkylene is mentioned, C 2 ～C 10 Unsaturated alkylene and said R 1-1 Substituted C 2 ～C 10 C in unsaturated alkylene 2 ～C 10 Unsaturated hydrocarbylene radicals being independently C 4 ～C 6 Alkenyl, preferably
Figure FDA0003476093390000064
And/or when R 8 Is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is C 1 ～C 3 An alkyl group;
and/or when-L 5 -is C 3 ～C 6 Cycloalkylene or halogen substituted C 3 ～C 6 When cycloalkylene, said C 3 ～C 6 Cycloalkylene and said halogen-substituted C 3 ～C 6 Sub-ringC in alkyl 3 ～C 6 Cycloalkylene is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, preferably cyclobutylene;
and/or when-Z 1 -、-Z 2 -、-Z 3 -、-Z 4 -、-Z 6 -、-Z 7 -、-Z 8 -and-Z 9 -independently is C 1 ～C 6 Alkylene or R 1-2 Substituted C 1 ～C 6 When it is alkylene, said C 1 ～C 6 Alkylene and said R 1-2 Substituted C 1 ～C 6 C in alkylene 1 ～C 6 Alkylene is independently C 1 ～C 3 An alkylene group;
and/or when-Z 1 -、-Z 2 -、-Z 3 -、-Z 4 -、-Z 6 -、-Z 7 -、-Z 8 -and-Z 9 -independently is C 2 ～C 6 Unsaturated alkylene or R 1-2 Substituted C 2 ～C 6 When unsaturated alkylene is mentioned, C 2 ～C 6 Alkylene and R 1-2 Substituted C 2 ～C 6 C in unsaturated alkylene 2 ～C 6 The unsaturated hydrocarbylene groups are independently C 2 ～C 4 An unsaturated alkylene group;
and/or when-Z 5 -is C 2 ～C 10 Alkylene or R 1-3 Substituted C 2 ～C 10 When alkylene, C 2 ～C 10 Alkylene and said R 1-3 Substituted C 2 ～C 10 C in alkylene 2 ～C 10 Alkylene is independently C 3 ～C 6 Alkylene, preferably n-butylene;
and/or-Z 5 -is C 2 ～C 10 Unsaturated alkylene or R 1-3 Substituted C 2 ～C 10 When unsaturated alkylene is mentioned, C 2 ～C 10 Unsaturated alkylene and said R 1-3 Substituted C 2 ～C 10 C in unsaturated alkylene 2 ～C 10 The unsaturated hydrocarbylene groups are independently C 3 ～C 6 An unsaturated alkylene group;
and/or when R 1-1 、R 1-2 And R 1-3 When independently halogen, said halogen is independently F, Cl, Br or I;
and/or when R 1-1 、R 1-2 And R 1-3 Independently is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is independently C 1 ～C 3 An alkyl group;
and/or when R 1-1 、R 1-2 And R 1-3 Independently is C 1 ～C 6 At alkoxy, said C 1 ～C 6 Alkoxy is independently C 1 ～C 3 An alkoxy group;
and/or when R 1 、R 2 And R 3 Independently halogen or halogen substituted C 1 ～C 6 When alkyl, said halogen and said halogen substituted C 1 ～C 6 Halogen in the alkyl group is independently F, Cl, Br or I;
and/or when R 1 、R 2 And R 3 Independently is C 1 ～C 6 Alkyl and halogen substituted C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl and said halogen substituted C 1 ～C 6 In alkyl radical C 1 ～C 6 Alkyl is independently C 1 ～C 3 An alkyl group;
and/or, when "R" is 1 And R 2 "or" R 2 And R 3 "together with the carbon atom to which they are attached" form a hetero atom selected from one or more of N, O and S, a 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms "or R 1-4 When the substituted "hetero atom is one or more selected from N, O and S, and the hetero atom number is 1-3, 4-to 7-membered heterocycloalkylene", the "hetero atom is one or more selected from N, O and S, and the hetero atom number is 1-3, 4-to 7-membered heterocycloalkylene", and R 1-4 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom is 1-3 in 4-7 membered heterocycloalkyleneOne or more selected from N, O and S, wherein 4-to 7-membered heterocycloalkylene having 1 to 3 hetero atoms is "independently" 5-to 6-membered heterocycloalkylene having 1 hetero atom and N hetero atom ", more preferably piperidylene, such as
Figure FDA0003476093390000071
And/or, when "R" is 1 And R 2 "or" R 2 And R 3 "taken together with the carbon atom to which they are attached form R 1-4 When the substituted' hetero atom is one or more selected from N, O and S, and the number of hetero atoms is 1-3, and the number of hetero atoms is 4-7 membered heterocycloalkylene 1-4 1,2 or 3, preferably 1;
and/or, when "R" is 1 And R 2 "or" R 2 And R 3 "taken together with the carbon atom to which they are attached form R 1-4 When the substituted' hetero atom is one or more selected from N, O and S, and the number of hetero atoms is 1-3, and the number of hetero atoms is 4-7 membered heterocycloalkylene 1-4 The substitution position of (a) is on said heteroatom;
and/or when R 1-4 And R 1-5 Independently halogen, said halogen is F, Cl, Br or I;
and/or, R 1-4 And R 1-5 Independently is C 1 ～C 6 Alkyl or R 1-6 Substituted C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl and said R 1-6 Substituted C 1 ～C 6 C in alkyl 1 ～C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or isopropyl;
and/or when R 1-4 And R 1-5 Independently is C 1 ～C 6 Alkoxy or R 1-9 Substituted C 1 ～C 6 When alkoxy, said C 1 ～C 6 Alkoxy and R 1-9 Substituted C 1 ～C 6 C in alkoxy 1 ～C 6 Alkoxy is independently C 1 ～C 4 An alkoxy group;
and/or when R 1-4 And R 1-5 Independently is C 3 ～C 7 Cycloalkyl or R 1-19 Substituted C 3 ～C 7 When there is a cycloalkyl group, said C 3 ～C 7 Cycloalkyl and R 1-19 Substituted C 3 ～C 7 C in cycloalkyl 3 ～C 7 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclobutyl;
and/or when R 1-6 And R 1-9 Independently represents one or more heteroatoms selected from N, O and S, and C with 1-4 heteroatoms 1 ～C 10 Heteroaryl "or R 1-23 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 When the heteroaryl is adopted, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1-4C 1 ～C 10 Heteroaryl "and R 1-21 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-4C 1 ～C 10 The hetero atom in the heteroaryl is selected from one or more of N, O and S, and the number of hetero atoms is 1-4C 1 ～C 10 Heteroaryl is "independently" C having 1 heteroatom which is N 4 ～C 6 Heteroaryl ", preferably pyridyl, e.g.
Figure FDA0003476093390000081
And/or when R 1-4 Is R 1-6 Substituted C 1 ～C 6 When it is alkyl, said R 1-6 1,2 or 3, preferably 1;
and/or when R 1-13 、R 1-14 And R 1-15 Independently is C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl or halogen substituted C 1 ～C 6 C in alkyl 1 ～C 6 Alkyl is independentlyC 1 ～C 3 An alkyl group;
and/or when R 1-13 、R 1-14 And R 1-15 Independently halogen substituted C 1 ～C 6 When alkyl, said halogen being substituted by C 1 ～C 6 Halogen in the alkyl group is independently F, Cl, Br or I;
and/or when R 1-19 、R 1-20 、R 1-21 、R 1-22 、R 1-23 And R 1-24 When independently halogen, said halogen is independently F, Cl, Br or I;
and/or when R 1-19 、R 1-20 、R 1-21 、R 1-22 、R 1-23 And R 1-24 Independently is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is independently C 1 ～C 3 An alkyl group;
and/or when R 5 Is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is C 1 ～C 3 An alkyl group;
and/or when R 5 Is C 1 ～C 6 At alkoxy, said C 1 ～C 6 Alkoxy is C 1 ～C 3 An alkoxy group;
and/or when R 14 、R 15 、R 16 And R 17 Independently is C 1 ～C 6 Alkyl or R 13-1 Substituted C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl and said R 13-1 Substituted C 1 ～C 6 C in alkyl 1 ～C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably n-propyl or n-butyl;
and/or when R 13-1 When the halogen is F, Cl, Br or I;
and/or when R 13-1 Is C 1 ～C 6 At alkoxy, said C 1 ～C 6 Alkoxy is C 1 ～C 3 An alkoxy group;
and/or when R 13-1 Is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is C 1 ～C 3 An alkyl group;
and/or when R 13-2 Is C 1 ～C 6 When alkyl, said C 1 ～C 6 Alkyl is C 1 ～C 3 An alkyl group.
6. The compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 5, wherein-Z is 5 -L 2 -is of
Figure FDA0003476093390000082
And/or, - (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 -is of
Figure FDA0003476093390000083
For example
Figure FDA0003476093390000084
And/or when R 1-4 Is R 1-6 Substituted C 1 ～C 6 When it is alkyl, said R 1-6 Substituted C 1 ～C 6 Alkyl is
Figure FDA0003476093390000085
And/or, said R 1-4 The substituted "hetero atom is one or more selected from N, O and S, and the 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms" is
Figure FDA0003476093390000091
7. The compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1, wherein said compound of formula I is any one of the following compounds:
Figure FDA0003476093390000092
Figure FDA0003476093390000101
8. a compound of formula II:
Figure FDA0003476093390000102
wherein R is A And R B Independently is H or an amino protecting group, and R A And R B Not H at the same time; y, A, B, R 1 、R 2 、R 3 And R 5 Is as defined in any one of claims 1 to 6.
9. The compound of formula II according to claim 8, wherein said compound of formula II is any one of the following compounds:
Figure FDA0003476093390000103
Figure FDA0003476093390000111
10. a pharmaceutical composition comprising a compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, and a pharmaceutically acceptable adjuvant.
11. Use of a compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, or a pharmaceutical composition thereof, as claimed in claim 10, in the manufacture of a medicament for the treatment or prevention of a tumour or an infection caused by a virus;
preferably, the virus is one or more of HBV, HCV, HIV and influenza virus;
preferably, the TLR7 agonist is for use in vivo in a mammalian organism or for use in vitro.
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