CN115119508A - 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 PDFInfo
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- CN115119508A CN115119508A CN202280002672.9A CN202280002672A CN115119508A CN 115119508 A CN115119508 A CN 115119508A CN 202280002672 A CN202280002672 A CN 202280002672A CN 115119508 A CN115119508 A CN 115119508A
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- substituted
- alkyl
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- alkylene
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 86
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- 125000005842 heteroatom Chemical group 0.000 claims description 192
- 229910052717 sulfur Inorganic materials 0.000 claims description 115
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- 125000000217 alkyl group Chemical group 0.000 claims description 98
- 125000002947 alkylene group Chemical group 0.000 claims description 73
- 229910052736 halogen Chemical group 0.000 claims description 64
- 150000002367 halogens Chemical class 0.000 claims description 50
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 48
- -1 C 6 Halogen Chemical class 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
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- 239000002207 metabolite Substances 0.000 claims description 23
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 22
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
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- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
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- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
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- 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
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- 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
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- 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
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- 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
A macrocyclic TLR7 agonist, its preparation method, pharmaceutical composition and its application are provided. The macrocyclic TLR7 agonist is a compound shown in a formula I. The compound has novel structure, good activity and good application prospect.
Description
This application claims priority to chinese patent application 2021100758546, filed on 20/1/2021. The present application refers to the above-mentioned chinese patent application in its entirety.
The invention relates to a macrocyclic TLR7 agonist, a preparation method thereof, a pharmaceutical composition and application thereof.
Toll-like receptors (TLRs) are a class of structurally conserved proteins that form the 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. Therefore, strategies for the manipulation of inflammatory response therapy-related diseases by small molecule modulators of TLRs are 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 induces mainly the production of type I interferons, including interferon-alpha (IFN- α), and causes the 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:
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 group, 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 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 formed together with the carbon atom to which they are bonded "is one or more selected from N, O and S, a 4-to 7-membered heterocycloalkylene group having 1 to 3 hetero atoms" or the 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 Replacing;
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 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, one or more of N, O and S as hetero atoms, 4-to 7-membered heterocycloalkyl with 1 to 3 hetero atoms, and R 1-22 The substituted 'hetero atom is selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 hetero atoms, 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 "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 or C 1 ~C 6 An alkyl group;
R 5 is H, CN, halogen, C 3 ~C 5 Cycloalkyl, 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 compound represented by formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, certain groups may be defined as follows, and the remaining groups may be defined as described in any of the above embodiments (hereinafter referred to as "in some embodiments" in this paragraph):
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, wherein the hetero atoms are one or more selected from N, O and S;
R 1-4 independently is C 1 ~C 6 Alkyl, 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 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';
R 1-4 independently is C 1 ~C 6 Alkyl radical, R 1-6 Substituted C 1 ~C 6 Alkyl radical、-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 heteroatom (S) selected from one or more of N, O and S, with 1 to E3 of 4 to 7 membered heterocycloalkylene;
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 alkylene, -Z 5 -L 2 -or- (CH) 2 ) n -L 5 -(CH 2 ) r -L 4 - (for example B is n-pentylene, pentenylene, -O-n-propylene-or( The structural fragment representation has trans-butylene fragment, the followingAll such meanings of structural fragments);
L 2 and L 4 Independently is O;
-L 5 -is C 3 ~C 6 Cycloalkylene radical(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 alkylene, -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.(e.g. in the case of ) n-pentylene-O-), -or(e.g. in) 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 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, 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 group and said R 1-1 Substituted C 2 ~C 10 C in unsaturated hydrocarbylene 2 ~C 10 Unsaturated hydrocarbylene radicals being independently C 4 ~C 6 Alkenyl, more preferably(e.g.) "(form E) and(Z type) "、 )。
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)。
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 hydrocarbylene 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, 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 is present, theC of (A) 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 The "hetero atom" in the substituted "hetero atom is selected from one or more of N, O and S, and the" hetero atom "in 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 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 of N, and is more preferably a piperidylene group, for example
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 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3 4-7-membered heteroWhen cycloalkyl is said to be R 1-4 The substitution position(s) is (are) on said heteroatom.
In some embodiments, when R 1-4 And R 1-5 Independently, 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 In the case of heteroaryl, the "heteroatom" is one or more selected from N, O and S, C having 1 to 4 heteroatoms 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))。
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
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 the alkyl group is used, the alkyl group,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
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 At 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:
the invention also provides a compound shown as the formula II:
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:
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;
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 of formula I;
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 acylation reaction may be conducted under conditions conventional in the art, 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 application of the compound shown as the formula I, the solvate, the prodrug, the metabolite or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing medicines 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 can be used in a mammalian organism; also useful in vitro, primarily for experimental purposes, for example: provide comparison as a standard sample or a control sample, or be prepared into a kit according to a conventional method in the field, and provide rapid detection for the inhibition effect of TLR 7.
The present invention also provides a method for preventing or treating tumors or infections caused by viruses, which comprises administering to a subject a therapeutically effective amount of the above-mentioned compound represented by formula I, its solvate, its prodrug, its metabolite, their pharmaceutically acceptable salts or the above-mentioned pharmaceutical composition.
In the treatment method, the virus is preferably one or more of HBV, HCV, HIV and influenza virus.
Unless otherwise defined, the terms used in the present invention have the following meanings:
herein, attached to an olefinic or alicyclic ringRefers to the olefin or the alicyclic cis-trans isomer or a mixture of both. Cis-trans isomers may be named according to the cis-trans isomeric nomenclature (i.e., cis-trans nomenclature) or the Z-E nomenclature. For example, inTo represent(Z-configuration olefin) and/or(E configuration olefins); also for exampleTo represent(trans-cyclobutyl) and/or(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, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), and the like. When 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 certain intervals; due to the above 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", when 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 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. Two prices can be integrated into the sameOn one 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 radicalCyclobutylene (e.g. of) Cyclopentylene (e.g. cyclopentylene)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 saturated monocyclic group of two with heteroatomsA valence group. Examples of heterocycloalkylene are: piperidylidene radicals (e.g. as) Tetrahydrofurylene, tetrahydropyrylene, tetrahydrothiophenylene, 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.
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
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; deprotecting a group of a 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 the target compound Ia.
And (2) a flow scheme:
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; and deprotecting the compound B2 to obtain a target compound Id or catalytically hydrogenating the compound B2 to obtain a compound B3, and deprotecting the compound B3 to obtain a target compound Ic.
And (3) a flow path:
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 a 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 compound C7 affords the target compound Ie.
And (4) a flow chart:
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 a 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.
Scheme 5:
in the scheme 5, the compound I is subjected to acylation reaction to obtain a 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), each substituent in each compound is as defined in any one of the preceding.
In the following examples, the structures of the compounds were 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:CSH TM Prep-C18, 19 × 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 usedCSH TM Prep-C18(5μm,OBD TM 19 x 150mm) chromatography column or using xbridge (tm) Prep Phenyl(5μm,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 wakame 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 for the present invention can be synthesized using 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 (dimethylsulfoxide): dimethyl sulfoxide; h 2 SO 4 : sulfuric acid; HOAc; acetic acid; k 2 CO 3 : potassium carbonate; k is 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 : a thionyl chloride; TBAF: tetrabutylammonium fluoride; TBDPSCl: tert-butyldiphenylchlorosilane; TBSCl: tert-butyldimethylsilyl chloride; t-BuOK: potassium tert-butoxide; TEA: triethylamine; TES: triethylsilane; 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
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. Organic compoundsThe phases were 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 dust (455 mg, 7 mmol) and palladium acetate (156 mg, 0.7 mmol) were dissolved in DMF (10 ml) and the reaction was mixed at 100 ℃ with stirring for 8 h. 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
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 degrees for 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
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 with stirring at 90 degrees for 12 hours. 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
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 stirring at 0 ℃ 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 3, 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 mixed and stirred at 0 ℃ for 0.5 h. 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 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 a4(230 mg) as a white solid. MS:513.1(M + H) + 。
PREPARATION EXAMPLE 5 intermediate B1
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 a crude product, which was purified by silica gel column chromatography to give intermediate B1-2 as a colorless oil (4.0 g, yield 96%). MS:288.1(M + H) + 。
And 2, step: 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 stirred for an additional 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
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 ℃, 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. Washing the organic phase with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and purifying the crude product by silica gel column chromatography to obtain white solid intermediateForm B2-3(7.0 g, 83% yield). 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 3, 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 a solution of sodium bicarbonate (1.7 g, 20 mmol) and di-tert-butyl dicarbonate (4.5 g, 20.3 mmol) in ethyl acetate (20 ml) was added at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for an additional 12 hours, after which the reaction mixture was extracted with ethyl acetate. 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 B2-5 as a colorless oil (5.8 g, yield 82%). 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 concentratedThe crude product was purified by silica gel column chromatography to give intermediate B2-6(608 mg, 77% yield) as a yellow oil. MS:317.2(M-55+41) + 。
And 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 ℃ stirring and the reaction was stirred for 30 minutes, then quenched with saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate. 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 B2 as a colorless oil (480 mg, yield 49%). 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
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) andto water (25 ml) was added m-chloroperbenzoic acid (5.2 g, 30.2 mmol) 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
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, 50% yield).
And 2, step: 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), 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 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 B4-5 as a colorless oil (1.4 g, yield 67%). 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 to react, followed by dropwise addition of ice water to quench the reaction, 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
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 was continued at room temperature 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, 22% yield).
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 3, 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
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.
Step 2: preparation of intermediate B6
Synthesis of intermediate B6 referring to intermediate B5, intermediate B6 was prepared by using the intermediate B6-1 ester instead of intermediate B5-3.
Example 1
Compound I-1
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, 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-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
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
Step 1: preparation of intermediate I-3-1
Intermediate A2(350 mg, 0.83 mmol), intermediateBody 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 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 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. 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-3-3(340 mg, 95%) as a yellow 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 a yellow solid intermediateBody I-3-4(200 mg, 64%). 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
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
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
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 h. 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. mu. mol) was dissolved in trifluoroacetic acid (5 ml), and the reaction mixture was stirred at 110 ℃ for 1 hour. Cooling, concentrating, evaporating, dissolving in ethyl acetate, extracting, washing the organic phase with saturated sodium bicarbonate solution and saturated saline, and drying sulfur without waterSodium salt was dried, then filtered and concentrated to give the crude product, which was isolated 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
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
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
Synthesis of Compound I-9 with reference to Compound I-6, Compound I-9 was prepared as a white solid by using intermediate I-3-4 instead of intermediate I-5-4 and cyclobutanone instead 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
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
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 the addition of Grubbs' secondary 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
In nitrogenIntermediate I-11-3(0.12 g, 165.1 micromole) was dissolved in ethyl acetate (10 ml) under a blanket of gas, followed by addition of palladium on carbon (60 mg) with stirring at room temperature, and the reaction mixture was subsequently stirred under hydrogen at room temperature 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 a 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 the reaction mixture to dryness, dissolving and extracting with ethyl acetate, washing the organic phase with saturated sodium bicarbonate solution and saturated saline, and drying sulfuric acid without waterSodium was dried, then filtered and concentrated to give the 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
Step 1: preparation of intermediate I-12-1
Synthesis of intermediate I-12-1 referring 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 3, 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
Step 1: preparation of intermediate I-13-1
Intermediate I-11-3(100 mg, 137.6 micromole) 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. Reacting 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 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 and reacting, concentrating and evaporating reaction mixed liquid, dissolving and extracting by using ethyl acetate, washing an organic phase by using saturated sodium bicarbonate solution and saturated saline, drying by using anhydrous dry sodium sulfate, filtering, concentrating to obtain a crude product, and separating the crude product by using preparative liquid chromatography to obtain a compound I-13 and a 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
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, filtered and concentrated to give intermediate I-15-3(11 mg, 15%)。MS:671.2(M+H) + 。
And step 3: preparation of Compound I-15
Synthesis of Compound I-15 referring to intermediate I-2, Compound I-15 was prepared as a white solid by substituting intermediate I-15-3 for intermediate I-12-3. 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
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
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
Synthesis of Compound I-18 referring to Compound I-11, Compound I-18 was prepared as a white solid by substituting intermediate I-15-2 for intermediate 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
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
Compound I-19(15 mg, 33.9. mu.M), TEA (10.3 mg, 101.7. mu.M) and butyryl chloride (7.2 mg, 67.8. mu.M) were dissolved in dichloromethane (5 mL) and the reaction mixture was stirred at 40 deg.CStirring and reacting 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(400 MHz,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
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 ℃ 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
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
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
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 hTLR7 stably expresses the agonistic activity of TLR7 in a human TLR7 cell strain and is tested by the following method:
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 with DPBS buffer (Gibco) and added to a 20 μ L volume to a 96-well cell culture plate (Corning).
3. Digestion of HEK-Blue with cell separation (Gibco) TM hTLR7 cells (Invivogen) and cell counts were performed (TC-20 cell counter, Bio-rad). The cells were diluted to 4.4E 5/ml using DMEM cell culture medium (Gibco). Add 180 μ L to 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 the 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 (12)
- A compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof: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 subHydrocarbyl 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 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" formed together with the carbon atom to which they are attached "is one or more selected from the group consisting of N, O and SA plurality of 4-to 7-membered heterocycloalkylene 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 Replacing;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, 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, 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 "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, one or more of N, O and S as hetero atoms, 4-to 7-membered heterocycloalkyl with 1 to 3 hetero atoms, and R 1-25 The substituted 'hetero atom is selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 hetero atoms, 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 1-26 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, 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 or 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.
- A compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof or a pharmaceutically acceptable salt thereof according to 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, wherein the hetero atoms are one or more selected from N, O and S;R 1-4 independently is C 1 ~C 6 Alkyl, 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 is a heteroOne or more atoms selected from N, O and S, and 1-4 hetero atoms of C 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 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 Alkyl radicalScheme 3: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 The substituted heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1-34 to 7 membered heterocycloalkylene of (a);R 1-4 independently is C 1 ~C 6 Alkyl, aryl, heteroaryl, and heteroaryl, - 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 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 An alkyl group;R 3 is H;R 13 is H;R 5 is H.
- 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 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, wherein the hetero atoms are one or more selected from 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, H;and/or, R 16 And R 17 Is C 1 ~C 6 An alkyl group.
- As claimed in claim 1, of formula IA compound of (a), a solvate thereof, a prodrug thereof, a metabolite thereof or a pharmaceutically acceptable salt thereof, 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-pentyleneAnd/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 group and said R 1-1 Substituted C 2 ~C 10 C in unsaturated hydrocarbylene 2 ~C 10 Unsaturated hydrocarbylene radicals independently being C 4 ~C 6 Alkenyl, preferablyAnd/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 it is 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 cyclohexyleneA group, preferably a cyclobutyl group;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 hydrocarbylene 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 hydrocarbylene 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 When 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 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 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 "hetero atom" in the substituted "hetero atom is selected from one or more of N, O and S, and the" hetero atom "in 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 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 of N, and is more preferably a piperidylene group, for exampleAnd/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 Is 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 The substituted heteroatom is one or more selected from N, O and S, and the heteroatom number is 1-3 4-7-membered heterocycloalkaneWhen is "said R 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 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;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 a cycloalkyl group is said to be 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 Independent of each otherThe ground is' one or more of C with 1-4 hetero atoms selected from N, O and S 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 In the case of heteroaryl, the "heteroatom" is one or more selected from N, O and S, C having 1 to 4 heteroatoms 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.And/or 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;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 independently C 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 Alkyl radicalWhen said halogen is substituted 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 it is halogenThe 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.
- 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 ofAnd/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
- 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.
- Use of a compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 10, as claimed in any one of claims 1 to 7, in the manufacture of a medicament for the treatment or prevention of a tumor or an infection caused by a virus or a TLR7 agonist;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.
- A method for preventing or treating tumors or infections caused by viruses, which comprises administering to a subject a therapeutically effective amount of a compound of formula I, solvate thereof, prodrug thereof, metabolite thereof, pharmaceutically acceptable salt thereof or pharmaceutical composition thereof as claimed in any one of claims 1 to 7;in the treatment method, the virus is preferably one or more of HBV, HCV, HIV and influenza virus.
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Application publication date: 20220927 Assignee: Suzhou Shentuo Pharmaceutical Technology Co.,Ltd. Assignor: Shanghai Weishen Pharmaceutical Co.,Ltd. Contract record no.: X2023990000874 Denomination of invention: Macrocyclic TLR7 agonist, its preparation method, drug composition, and its use License type: Common License Record date: 20231016 |