CN108727369B - Influenza virus replication inhibitors and uses thereof - Google Patents

Influenza virus replication inhibitors and uses thereof Download PDF

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CN108727369B
CN108727369B CN201810335919.4A CN201810335919A CN108727369B CN 108727369 B CN108727369 B CN 108727369B CN 201810335919 A CN201810335919 A CN 201810335919A CN 108727369 B CN108727369 B CN 108727369B
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CN108727369A (en
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任青云
唐昌华
殷俊俊
易凯
雷义波
王叶俊
张英俊
聂飚
许娟
严欢
陈建萍
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention provides a compound serving as an influenza virus replication inhibitor, a method for preparing the compound, a pharmaceutical composition containing the compound and application of the compound and the pharmaceutical composition thereof in treating influenza.

Description

Influenza virus replication inhibitors and uses thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to novel compounds serving as influenza virus replication inhibitors, a method for preparing the novel compounds, a pharmaceutical composition containing the novel compounds and application of the novel compounds and the pharmaceutical composition in treating influenza. More specifically, the compounds of the present invention are useful as inhibitors of influenza RNA polymerase.
Background
Influenza (hereinafter referred to as influenza) is an acute respiratory infectious disease seriously harming human health, is caused by influenza virus, and has the characteristics of high prevalence, wide epidemic and rapid transmission. Influenza viruses cause severe symptoms such as pneumonia or heart and lung failure in the elderly and children with weak immunity and in patients with some immunological disorders. Influenza virus was first discovered in 1933 by Wilson Smith (Wilson Smith), who was named H1N1.H represents hemagglutinin; n represents neuraminidase; the numbers represent different types. Influenza viruses have been found to have caused multiple pandemics worldwide, with an outbreak of epidemics around ten years or so, causing significant losses worldwide. Influenza virus epidemics can result in 25 to 50 dying cases, 300 to 500 thousand cases, and about 5 to 15% of all people worldwide are infected each year. Each pandemic occurs due to the presence of a new strain of virus in humans. Typically, these new strains are caused by the spread of existing influenza viruses from other animal species to humans.
Influenza viruses are RNA viruses of the Orthomyxoviridae family (Orthomyxoviridae), belonging to the genus influenza. Influenza viruses are mainly classified into three types A, B, C, namely, a type a, a type b and a type c, according to the antigenic property and the genetic property of the virus particle Nucleoprotein (NP) and the matrix protein (M). The three viruses have similar biochemical and biological characteristics. The virus particles are 80-120nm in diameter and are generally approximately spherical, but may take on a filiform form. The virus consists of three layers, the inner layer is a virus nucleocapsid, and the inner layer contains Nucleoprotein (NP), P protein and RNA. NPs are soluble antigens (S antigens), have type-specific, and are antigenically stable. The P proteins (P1, P2, P3) may be the polymerase required for RNA transcription and replication. The middle layer is a virus envelope and consists of a layer of lipoid and a layer of Membrane Protein (MP), and the MP has stable antigenicity and type specificity. The outer layer is a radial protrusion of two different glycoproteins, namely hemagglutinin (H) and neuraminidase (N). H can cause erythrocyte agglutination, is a tool for adsorbing viruses on the surface of sensitive cells, N can hydrolyze mucin, and hydrolyze N-acetylneuraminic acid at the tail end of glycoprotein with specificity of cell surface receptor, and is a tool for separating viruses from the surface of cells after the replication of the viruses is completed. Both H and N have variant properties, so only strain-specific antigenicity and antibodies thereof have protective effects.
Influenza a viruses have 1 species. Wild water birds are a natural host for a large number of influenza a viruses. Sometimes, viruses spread to other species and can cause destructive outbreaks in poultry or cause human influenza pandemic. Among the 3 influenza types, type a virus is the most virulent human pathogen causing most severe diseases, can be transmitted to other species, and produces a large-area epidemic of human influenza. Influenza a viruses can be subdivided into different serotypes based on the antibody response to these viruses. The confirmed human serotypes, ranked by known number of human pandemic deaths, are: H1N1 (1918 causes spanish influenza), H2N2 (1957 causes asian influenza), H3N2 (1968 causes hong gang influenza), H5N1 (pandemic in 2007-08 influenza), H7N7 (with rare zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N3 and H10N7.
Influenza B viruses, which are of 1 species, often cause local epidemics of influenza, do not cause large outbreaks of worldwide influenza, and are found only in humans and seals. This type of influenza virus mutates at a rate 2-3 times slower than type a, and therefore has low genetic diversity, with only one type B influenza serotype. Because of this lack of antigen diversity, humans often acquire a degree of influenza B immunity in the early years. However, mutations in influenza B viruses are sufficient to make it impossible to permanently immunize, but their rate of antigen change is low, combined with limited host changes (suppression of cross-species antigen transitions), and thus the spread scale is relatively small and no influenza B pandemic occurs.
Influenza C viruses are 1 species, are mostly in a sporadic form, mainly attack infants, generally do not cause influenza epidemics, and can infect humans and pigs.
It is unusual for viruses to have a nucleic acid whose genome is not a single fragment; in contrast, the genome contains 7 or 8 fragments of negative sense RNA. Influenza a genome encodes 11 proteins: hemagglutinin (H), neuraminidase (N), nucleoprotein (NP), M1, M2, NS1, NS2 (NEP), PA, PB1-F2 and PB2.H and N are macromolecular glycoproteins that are external to the viral particle. HA is a lectin that mediates the binding of viruses to target cells and entry of the viral genome into target cells, while NA involves the release of progeny viruses from infected cells by cleavage of sugars bound to mature viral particles. Thus, these proteins have been the target of antiviral drugs. Moreover, these proteins are antigens of antibodies that can be raised. Influenza a viruses are classified into subtypes based on antibody responses to H and N, forming the basis for the distinction of H and N in H5N1, for example.
Vaccination and the use of antiviral drugs are important means to cope with influenza pandemics, however, mass production of vaccines is essentially impossible before pandemic due to the strong ability of influenza virus antigens to mutate. Among the antiviral therapeutic agents currently available are the M2 ion channel blockers amantadine and rimantadine, and the neuraminidase inhibitors Oseltamivir (Oseltamivir), zanamivir (Zanamivir), peramivir (Peramivir), and Laninamivir (laninavir). However, influenza viruses have developed resistance to all of these drugs. Thus, there is a continuing need for new anti-influenza therapeutics.
A new anti-influenza agent, faviravir (Favipiravir), has been marketed which targets inhibition of viral gene replication by inhibiting RNA polymerase of influenza virus, thereby achieving antiviral effects, but its therapeutic effect and resistance of influenza virus to it are yet to be demonstrated, and therefore other compounds for treating influenza by this mechanism of action remain urgent for scientists to develop.
Summary of The Invention
The invention provides a novel compound serving as an influenza virus RNA polymerase inhibitor, and the compound and the composition thereof can be used for preparing medicines for preventing, treating or relieving virus infection diseases of patients.
In one aspect, the present invention relates to a compound which is a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Figure BDA0001629238560000021
wherein ring A, U 5 、U 6 、U 7 、R 9 、R 10 And W has the definition as described herein.
In some embodiments, wherein ring a is of the formula:
Figure BDA0001629238560000022
wherein: u (U) 1 Is N or CR 1 ；U 2 Is N or CR 2 ；U 3 Is N or CR 3 ；U 4 Is N or CR 4 ；
U 5 Is N or CR 5 ；U 6 Is N or CR 6 ；U 7 Is N or CR 7 The method comprises the steps of carrying out a first treatment on the surface of the Provided that 1) when U 5 When N is N, U 6 、Y 7 At the same time N, 2) when U 5 Is CR (CR) 5 When U 6 Is CR (CR) 6 And U is 7 Is CR (CR) 7 ；
R 1 、R 2 、R 3 、R 4 And R is 8 Each independently H, D, F, cl, br, I, CN, NO 2 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from D, F, cl, br, I, CN, -OR b 、-NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, R b O-C 1-4 Alkylene or R d R c N-C 1-4 An alkylene group;
R 5 、R 6 and R is 7 Each independently H, D, F, cl, br, I, CN, NO 2 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 An alkylene group, wherein the R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms and (heteroaryl of 5-10 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted; provided that R 5 、R 6 And R is 7 At least 2 are not H;
R 9 is-OR b 、C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclyl, C 3-12 carbocyclyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-16 atoms or (heteroaryl of 5-16 atoms) -C 1-4 Alkylene group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclyl, C 3-12 carbocyclyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-16 atoms and (heteroaryl of 5-16 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted;
each R is x D, F, cl, br, I, CN, NO independently 2 、-OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, -C (=o) R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 3 to 8 atoms, (heterocyclyl of 3 to 8 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 An alkylene group, wherein the R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 3 to 8 atoms, (heterocyclyl of 3 to 8 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms and (heteroaryl of 5-10 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、-OR b 、-NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, R b O-C 1-4 Alkylene or R d R c N-C 1-4 An alkylene group;
or two adjacent R x Together with the carbon atoms to which they are attached, form C 3-6 Carbocycle, heterocycle of 5-6 atoms, C 6-10 An aromatic ring or a heteroaromatic ring of 5 to 6 atoms, wherein C 3-6 Carbocycle, heterocycle of 5-6 atoms, C 6-10 The aromatic ring and the heteroaromatic ring consisting of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、-OR b 、-NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, R b O-C 1-4 Alkylene or R d R c N-C 1-4 An alkylene group;
R 10 for H, D or optionally by 1, 2, 3 or 4 independently selected from D, F, cl, br, I, CN, NO 2 OR-OR b C substituted by substituent(s) 1-6 An alkyl group;
w is C 1-8 Alkyl, C 3-12 Carbocyclyl or 3-12 atomsHeterocyclyl, wherein said C 1-8 Alkyl, C 3-12 Carbocyclyl and heterocyclyl of 3 to 12 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4R w Substituted;
each R is w D, F, cl, br, I, CN, NO independently 2 、-C(＝O)R a 、-C(＝O)OR b 、-NR e C(＝O)R a 、-NR e C(＝O)NR c R d 、-S(＝O) 2 R f 、-S(＝O) 2 NR e C(＝O)R a 、-S(＝O) 2 NR c R d 、(R b O) 2 P(＝O)-C 0-2 Alkylene, -OR b 、R b O-C 1-2 Alkylene, R d R c N-C 1-2 Alkylene, C 1-6 Alkyl, heteroaryl of 5-6 atoms or heterocyclyl of 5-6 atoms, wherein said C 1-6 Alkyl, heteroaryl of 5-6 atoms and heterocyclyl of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, N 3 、＝O、NO 2 、-OR b 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R a 、R b 、R c 、R d 、R e and R is f Each independently is H, D, hydroxy, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 3-6 carbocyclyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 Alkylene group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 3-6 carbocyclyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (3-12 primordia)Heterocylic group) -C of the sub-composition 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms and (heteroaryl of 5-10 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, CN, OH, NH 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group;
or R is c 、R d And together with the nitrogen atom to which they are attached, form a 3-8 atom-containing heterocyclic ring or a 5-8 atom-containing heteroaryl ring, wherein the 3-8 atom-containing heterocyclic ring and the 5-8 atom-containing heteroaryl ring are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, CN, OH, NH 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group.
In other embodiments, wherein ring a is of the formula:
Figure BDA0001629238560000041
in other embodiments, wherein ring a is of the formula:
Figure BDA0001629238560000042
in other embodiments, R 1 、R 2 、R 3 、R 4 And R is 8 Each independently H, D, F, cl, br, I, CN, NO 2 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-OR b 、-NR c R d Methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents Substitution, said substituents being independently selected from D, F, cl, br, I, CN, -OR b 、-NR c R d Or C 1-3 A haloalkyl group.
In other embodiments, R 5 、R 6 And R is 7 Each independently H, D, F, cl, br, I, CN, NO 2 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-OR b 、-NR c R d 、C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C 1-4 Alkylene group, wherein the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted; provided that R 5 、R 6 And R is 7 At least 2 are not H.
In other embodiments, R 9 is-OR b 、C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclyl, C 3-6 carbocyclyl-C 1-4 Alkylene, heterocyclyl of 5-10 atoms, (heterocyclyl of 5-10 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 Alkylene group, wherein the C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclyl, C 3-6 carbocyclyl-C 1-4 Alkylene, heterocyclyl of 5-10 atoms, (heterocyclyl of 5-10 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms and (heteroaryl of 5-10 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted.
In other embodiments, R x D, F, cl, br, I, CN, NO independently 2 、-OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, -C (=o) R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-2 Alkylene, phenyl-C 1-2 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C 1-2 An alkylene group, wherein the R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-2 Alkylene, phenyl-C 1-2 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、-OR b 、-NR c R d Methyl, ethyl, n-propyl or isopropyl;
or two adjacent R x Together with the carbon atoms to which they are attached, form C 5-6 Carbocycles, benzene rings, or heteroaromatic rings of 5-6 atoms, wherein C 5-6 Carbocyclic ring, benzene ring and heteroaromatic ring composed of 5-6 atomsEach independently being unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、-OR b 、-NR c R d Methyl, ethyl, n-propyl or isopropyl.
In other embodiments, R 10 H, D, CF of a shape of H, D, CF 3 Methyl, ethyl, n-propyl or isopropyl.
In other embodiments, W is C 1-6 Alkyl, C 5-8 Carbocyclyl or heterocyclyl of 5-8 atoms, wherein said C 1-6 Alkyl, C 5-8 Carbocyclyl and heterocyclyl consisting of 5-8 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4R w Substituted.
In other embodiments, each R w D, F, cl, br, I, CN, NO of a shape of D, F, cl, br, I, CN, NO 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)OH、-NHC(＝O)R a 、-NHC(＝O)NR c R d 、-S(＝O) 2 R f 、-S(＝O) 2 NHC(＝O)R a 、-S(＝O) 2 NR c R d 、(R b O) 2 P(＝O)-C 0-2 Alkylene, -OR b Methyl, ethyl, n-propyl, isopropyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or heterocyclyl of 5 to 6 atoms, wherein the methyl, ethyl, n-propyl, isopropyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and heterocyclyl of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, N 3 、＝O、NO 2 、-OCH 3 、C 1-3 Alkyl or C 1-3 A haloalkyl group.
In other embodiments, R a 、R b 、R c 、R d 、R e And R is f Each independently H, D, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, methoxy, ethoxy, C 3-6 Carbocyclyl, heterocyclyl of 5-6 atoms, phenyl, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C 1-4 Alkylene, wherein the methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, methoxy, ethoxy, C 3-6 Carbocyclyl, heterocyclyl of 5-6 atoms, phenyl, heteroaryl of 5-6 atoms, and (heteroaryl of 5-6 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, CN, OH, NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl or methoxy;
or R is c 、R d And together with the nitrogen atom to which they are attached, form a 5-6 atom-containing heterocyclic ring or a 5-6 atom-containing heteroaryl ring, wherein the 5-6 atom-containing heterocyclic ring and the 5-6 atom-containing heteroaryl ring are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, CN, OH, NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl or methoxy.
In other embodiments, R 9 is-OR b Ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4,5,6, 7-tetrahydrobenzofuranyl, 1,2,3, 4-tetrahydroisoquinolyl, phenyl, naphthyl, furyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, benzothiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl or isoquinolinyl, whereinThe ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4,5,6, 7-tetrahydrobenzofuranyl, 1,2,3, 4-tetrahydroisoquinolyl, phenyl, naphthyl, furyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, benzothiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl and isoquinolinyl each independently of which is unsubstituted or substituted with 1,2,3,4 or 5R x Substituted.
In other embodiments, W is of the formula:
Figure BDA0001629238560000051
wherein: n is 0, 1, 2, 3 or 4.
In other embodiments, the invention relates to a compound of the structure of formula (II) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000061
wherein ring A, R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (III) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000062
wherein ring A, R 5 、R 6 、R 7 、R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (IV) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000063
wherein ring A, R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (V) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000064
Wherein ring A, R 5 、R 6 、R 7 、R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (VI) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000071
wherein ring A, R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (VII) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000072
wherein ring A, R 5 、R 6 、R 7 、R 9 And R is w With the definition according to the invention.
In another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention.
In some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or combination thereof.
In some embodiments, the pharmaceutical compositions provided herein further comprise one or more additional therapeutic agents.
In still other embodiments, the additional therapeutic agent is selected from an anti-influenza virus agent or vaccine.
In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
In other embodiments, the pharmaceutical compositions of the invention wherein the other therapeutic agent involved is Amantadine, rimantadine, oseltamivir (Oseltamivir), zanamivir (Zanamivir), peramivir (Peramivir), laninavir (laninavir), lanamivir octanoate hydrate (Laninamivir Octanoate Hydrate), fampicvir (Favipiravir), arbidol (Arbidol), ribavirin (Ribavirin), stavafrine, ingavirin (Ingavirin), influenza enzyme (flash), CAS No. 1422050-75-6, JNJ-872, S-033188, influenza vaccine (FluMist)
Figure BDA0001629238560000073
Quadrivalent、
Figure BDA0001629238560000074
Quadrivalent、/>
Figure BDA0001629238560000075
Or->
Figure BDA0001629238560000076
) Or a combination thereof.
In another aspect, the invention provides the use of said compound or said pharmaceutical composition for the manufacture of a medicament for the prevention, treatment, therapy or alleviation of a viral infectious disease in a patient.
In some embodiments, the viral infection is an influenza viral infection.
In other embodiments, the invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.
Unless otherwise indicated, the present invention encompasses all stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention.
In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
The compounds of the present invention also include the salt forms thereof, which are not necessarily pharmaceutically acceptable salts, but may be used in the preparation and/or purification of the compounds of the present invention and/or in intermediates for the isolation of enantiomers of the compounds of the present invention.
The compounds of the present invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); thus, the present invention also includes solvated and unsolvated forms thereof.
On the other hand, the compounds of the invention may contain several asymmetric centers or in the form of a mixture of racemates as generally described. The invention further comprises a racemic mixture, a portion of the racemic mixture, and the separated enantiomers and diastereomers.
The compounds of the present invention may exist as one of the possible isomers, rotamers, atropisomers, tautomers or as a mixture thereof, and the present invention may further comprise isomers, rotamers, atropisomers, mixtures of tautomers, or partial mixtures of isomers, rotamers, atropisomers, tautomers or isolated isomers, rotamers, atropisomers, tautomers of the compounds of the present invention.
In another aspect, the compounds of the invention include compounds defined herein labeled with various isotopes, e.g., where a radioisotope, such as 3 H， 14 C and C 18 F, or in which non-radioactive isotopes are present, e.g 2 H and 13 a compound of C.
In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds comprised by formula (I).
The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise indicated, all patent publications cited throughout the disclosure of this invention are incorporated by reference in their entirety.
The invention will apply to the following definitions unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in terms of the periodic table of the elements, CAS version and handbook of chemicals, 75, th ed, 1994. In addition, the general principles of organic chemistry are found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, and "March's Advanced Organic Chemistry", by Michael B.Smith and Jerry March, john Wiley&Sons, new York, 2007, the disclosure of which is hereby incorporated by reference in its entirety.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject is also a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
The terms "subject" and "patient" as used herein are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds or mammals such as chickens, quails, or turkeys), particularly "mammals" (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), more particularly humans, including non-primates. In one embodiment, the subject is a non-human animal, such as a livestock (e.g., horse, cow, pig, or sheep) or a companion animal (e.g., dog, cat, guinea pig, or rabbit). In other embodiments, "patient" refers to a human.
The invention also includes isotopically-labelled compounds of the invention which are identical to those recited in the invention except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H， 3 H， 13 C， 14 C， 15 N， 16 O， 17 O， 31 P， 32 P， 36 S， 18 F and F 37 Cl。
The compounds of the invention containing the aforementioned isotopes and/or other isotopes of other atoms, and pharmaceutically acceptable salts of such compounds, are included within the scope of the invention. Isotopically-labelled compounds of the invention, e.g. radioactive isotopes, e.g 3 H and 14 c incorporation into the compounds of the present invention may be useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 h, and carbon-14, i.e 14 C, isotopes are particularly preferred. Furthermore, with heavy isotopes, e.g. deuterium, i.e 2 H substitution may provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.
The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attopiomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as mixtures of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in cis or trans (cis-or trans-) configuration.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attospimers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Unless otherwise indicated, structures described herein are also meant to include all isomeric (e.g., enantiomer, diastereomeric atropisomer (attiosomer) and geometric (or conformational)) forms of such structures; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, individual stereochemical isomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (or conformational) isomer mixtures of the compounds of the invention are all within the scope of the invention.
The term "stereoisomer" refers to a compound having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
As used herein, "nitroxide" refers to the oxidation of 1 or more than 1 nitrogen atom to form an N-oxide when the compound contains several amine functionalities. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514), in which an amine compound is reacted with 3-chloroperoxybenzoic acid (m-CPBA), for example in an inert solvent, for example methylene chloride.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are known in the artDomains are well known as the literature: S.M. Berge et al describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionic aldehyde salts, lactate salts, laurate salts, lauryl sulfate, malate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, propionate salts, stearate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl group 4 Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1-8 Sulfonate and aromatic sulfonate.
The term "as used herein"Prodrug ", represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14 of the A.C.S. symposium Series, edward B.Roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al, prodrug: design and Clinical Applications, nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al, prodrugs of Phosphates and Phosphonates, journal of Medicinal Chemistry,2008,51,2328-2345.
Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in racemic or enantiomerically enriched form, for example, in the form of the (R) -, (S) -, (R, R) -, (S, S) -, (S, R) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. The substituents on the atoms having unsaturated double bonds may be present in the form of- (Z) -or- (E) -if possible.
Thus, as described herein, the compounds of the present invention may exist as one of the possible isomers, rotamers, atropisomers, tautomers or as a mixture thereof, for example as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or as a mixture thereof.
Any of the resulting isomer mixtures may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, based on the physicochemical differences of the components, for example by chromatography and/or fractional crystallization.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Pressure Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis (e.g., jacques, et al, enantiomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；and Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)。
The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. It will be appreciated that the terms "optionally substituted" and "unsubstituted or substituted with … … substituents" and "substituted or unsubstituted" may be used interchangeably. The terms "optionally," "optional," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, the term "optionally" whether or not preceding the term "substituted" means that one or more hydrogen atoms in a given structure are unsubstituted or substituted with a particular substituent. An optional substituent may be present in each of the groups unless otherwise indicated Substitution is performed at a substitutable position. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to D, F, cl, br, I, CN, N 3 、OH、NH 2 、NO 2 Oxo (=o), -C (=o) R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-NR e C(＝O)R a 、-S(＝O) 2 R f 、-S(＝O) 2 NR e C(＝O)R a 、-S(＝O) 2 NR c R d 、(R b O) 2 P(＝O)-C 0-2 Alkylene, -OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-12 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkyl-C 1-4 Alkylene, C 3-12 Carbocyclyl, C 3-12 carbocyclyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-16 atoms or (heteroaryl of 5-16 atoms) -C 1-4 Alkylene, wherein each R a 、R b 、R c 、R d 、R e And R is f Having the definition according to the invention.
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 Alkyl "means in particular methyl, ethyl, C, independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group; the term "heteroaryl of 5 to 10 atoms" refers in particular to the independently disclosed heteroaryl of 5 atoms, heteroaryl of 6 atoms, heteroaryl of 7 atoms, heteroaryl of 8 atoms, heteroaryl of 9 atoms and heteroaryl of 10 atoms.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein refers to a saturated straight or branched chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms; some of these are alkyl groups containing 1 to 12 carbon atoms; some of these are alkyl groups containing 1 to 10 carbon atoms; still other embodiments are alkyl groups containing 1 to 9 carbon atoms; still other embodiments are alkyl groups containing 1 to 8 carbon atoms; still other embodiments are alkyl groups containing 1 to 6 carbon atoms; still other embodiments are alkyl groups containing 1 to 4 carbon atoms, and still other embodiments are alkyl groups containing 1 to 3 carbon atoms; still other embodiments are alkyl groups containing 1-2 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like, wherein the alkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains.
The term "alkylene" means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight or branched saturated hydrocarbon group. Unless otherwise specified, an alkylene group contains from 1 to 10 carbon atoms, and in other embodiments an alkylene group contains from 1 to 6 carbon atoms, and in other embodiments an alkylene group contains from 1 to 4 carbon atoms, and in other embodiments an alkylene group contains from 1 to 2 carbon atoms. Examples of this include methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), isopropylidene (-CH (CH) 3 )CH 2 -)，-CH(C(CH 3 ) 3 )CH 2 -and the like, wherein the alkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "alkenyl" means a straight or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position C-C is sp 2 Double bonds, wherein the alkenyl groups may be independently unsubstituted or substituted with one or more substituents described herein, include the positioning of groups having "cis", "trans" or "Z", "E", specific examples of which include, but are not limited to, vinyl (-ch=ch) 2 ) Allyl (-CH) 2 CH＝CH 2 ) Etc.
The term "alkynyl" means a straight or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein C-C in at least one position is an sp triple bond, wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described herein, specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) Etc.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain from 1 to 20 carbon atoms, some embodiments are alkoxy groups containing from 1 to 10 carbon atoms, some embodiments are alkoxy groups containing from 1 to 8 carbon atoms, some embodiments are alkoxy groups containing from 1 to 6 carbon atoms, some embodiments are alkoxy groups containing from 1 to 4 carbon atoms, some embodiments are alkoxy groups containing from 1 to 3 carbon atoms, and some embodiments are alkoxy groups containing from 1 to 2 carbon atoms.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And the like, wherein the alkoxy groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms. Some of these embodiments are "haloalkyl", "haloalkenyl" or "haloalkoxy" containing from 1 to 10 carbon atoms; still other embodiments are "haloalkyl", "haloalkenyl" or "haloalkoxy" groups containing from 1 to 8 carbon atoms; still other embodiments are "haloalkyl", "haloalkenyl" or "haloalkoxy" groups containing from 1 to 6 carbon atoms; still other embodiments are where the "haloalkyl", "haloalkenyl" or "haloalkoxy" groups contain from 1 to 4 carbon atoms, and still other embodiments are where the "haloalkyl", "haloalkenyl" or "haloalkoxy" groups contain from 1 to 3 carbon atoms; still other embodiments are "haloalkyl", "haloalkenyl" or "haloalkoxy" groups containing from 1 to 2 carbon atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl group having one or more hydroxy substituents, wherein the alkyl group has the meaning as described herein. In some embodiments, the hydroxyalkyl group contains 1 to 6 carbon atoms; in other embodiments, the hydroxyalkyl group contains from 1 to 4 carbon atoms; in still other embodiments, the hydroxyalkyl group contains from 1 to 3 carbon atoms; in still other embodiments, the hydroxyalkyl group contains from 1 to 2 carbon atoms. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl (-CH) 2 CH 2 OH), 1-hydroxyethyl (-CHOHCH) 3 ) 1, 2-dihydroxyethyl (-CHOHCH) 2 OH), 2, 3-dihydroxypropyl (-CH 2 CHOHCH 2 OH), 1-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl, 3-hydroxypropyl, hydroxybutyl, and the like. The hydroxyalkyl group may be optionally substituted with one or more substituents described herein.
The term "carbocyclyl" may be used alone or as a majority of "carbocyclylalkyl" or "carbocyclylalkoxy" to refer to a non-aromatic carbocyclic ring system containing 3 to 14 ring carbon atoms, saturated or containing one or more unsaturated units. The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein. In some embodiments, the number of ring carbon atoms of the carbocyclic ring is 3-12; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is 3 to 10; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is 3 to 8; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is 3 to 6; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is 5 to 6; in other embodiments, the number of ring carbon atoms of the carbocyclic ring is from 5 to 8. In other embodiments, the number of ring carbon atoms of the carbocyclic ring is from 6 to 8. The term "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl, and spiro bicyclic carbocyclyl, the "fused" bicyclic ring system comprising two rings sharing 2 adjacent ring atoms. The bridge Lian Shuanghuan group includes two rings sharing 3 or 4 adjacent ring atoms. The spiro ring system shares 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexanedienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridged carbocyclyl groups include, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, and the like.
The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring carbon atoms that is saturated and has one or more points of attachment to the remainder of the molecule. In some embodiments, cycloalkyl is a ring system containing 3 to 10 ring carbon atoms, e.g., C 3-10 Cycloalkyl; in other embodiments, cycloalkyl is a ring system containing 3 to 8 ring carbon atoms, e.g., C 3-8 Cycloalkyl; in still other embodiments, cycloalkyl is a ring system containing 5 to 8 ring carbon atoms, e.g., C 5-8 Cycloalkyl; in still other embodiments, cycloalkyl groups are ring systems containing 3 to 6 ring carbon atoms, e.g., C 3-6 Cycloalkyl; in still other embodiments, cycloalkyl groups are ring systems containing 5 to 6 ring carbon atoms, e.g., C 5-6 Cycloalkyl; examples of cycloalkyl groups includeBut are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.
The term "heterocyclyl" may be used alone or as a major part of a "heterocyclylalkyl" or "heterocyclylalkoxy" group, means a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms, wherein said heterocyclyl is non-aromatic and does not contain any aromatic rings, and wherein the ring system has one or more points of attachment to the rest of the molecule. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclyl groups include bridged bicyclic heterocyclyl groups, fused bicyclic heterocyclyl groups, and spiro bicyclic heterocyclyl groups. Unless otherwise indicated, a heterocyclic group may be a carbon or nitrogen group, and-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclyl is a ring system consisting of 3 to 8 ring atoms; in other embodiments, the heterocyclyl is a ring system of 3 to 6 ring atoms; in other embodiments, the heterocyclyl is a ring system of 5 to 7 ring atoms; in other embodiments, the heterocyclyl is a ring system of 5 to 8 ring atoms; in other embodiments, the heterocyclyl is a ring system of 6 to 8 ring atoms; in other embodiments, the heterocyclyl is a ring system of 5 to 6 ring atoms; in other embodiments, the heterocyclyl is a ring system of 4 ring atoms; in other embodiments, the heterocyclyl is a ring system of 5 ring atoms; in other embodiments, the heterocyclyl is a ring system of 6 ring atoms; in other embodiments, the heterocyclyl is a ring system of 7 ring atoms; in other embodiments, the heterocyclyl is a ring system of 8 ring atoms.
Heterocyclic ringExamples of bases include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazanyl, homopiperazinyl, homopiperidinyl, oxaheptanyl, thietanyl. In heterocyclic groups-CH 2 Examples of the substitution of the-group by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, pyrimidinedionyl. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane groups and 1, 1-dioxothiomorpholinyl groups. Bridged heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.2.1]Octyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
The term "bridge" refers to a bond, atom or chain of unbranched atoms connecting two different parts of a molecule. Two atoms connected by a bridge (typically but not always two tertiary carbon atoms) are denoted "bridgehead".
The term "spiro" refers to an atom (typically a quaternary carbon atom) having one common atom as the only one between two rings.
The term "consisting of m atoms," where m is an integer, typically describes the number of ring-forming atoms in a molecule where the number of ring-forming atoms is m. For example, piperidinyl is a 6-atom-composed heterocyclyl group, while 1,2,3, 4-tetrahydronaphthyl is a 10-atom-composed carbocyclyl group.
The term "heteroatom" refers to any oxidation state form of O, S, N, P, B, and Si, including N, S, and P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" refers to F, cl, br or I.
The term "N 3 "means an azide structure. Such groups may be linked to other groups, for example, to a methyl group to form azidomethane (MeN 3 ) Or with a phenyl group to form an azidobenzene (PhN) 3 )。
The term "aromatic" generally means a cyclic closed conjugated system, pi electrons are highly delocalized, have delocalized energy, and are relatively stable with low system energy.
The term "aryl" may be used alone or as a majority of "arylalkyl" or "arylalkoxy" to denote monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, each ring contains 3 to 7 ring atoms, and one or more attachment points are attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "heteroaryl" may be used alone or as a majority of a "heteroarylalkyl" or "heteroarylalkoxy" group, to denote a monocyclic, bicyclic, and tricyclic aromatic system containing 5-16 ring atoms, or containing 5-14 ring atoms, or containing 5-12 ring atoms, or containing 5-10 ring atoms, or a monocyclic system containing 5-8 ring atoms, or containing 5-7 ring atoms, or containing 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms, and wherein the heteroaryl group has one or more attachment points attached to the remainder of the molecule. When the-CH is present in the heteroaryl group 2 -said-CH, when a group is 2 The group may optionally be replaced by-C (=o) -. Unless otherwise indicated, the heteroaryl groupsThe group may be attached to the remainder of the molecule (e.g., the host structure in the formula) by any reasonable site (which may be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a 5-14 atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 5-12 atom heteroaryl group comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a 5-10 atom heteroaryl group comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a 5-8 atom heteroaryl group comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a 5-7 atom heteroaryl group comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a 5-6 atom heteroaryl group comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, the heteroaryl is a 5-atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, the heteroaryl is a 6-atom composition heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
Still other embodiments are heteroaryl groups including, but not limited to, the following monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiodiazolyl, 1,3, 4-thiodiazolyl, 1,2, 5-thiodiazolyl, pyrazinyl, 1,3, 5-triazinyl; also included are the following bi-or tricyclic groups, but in no way limited to these groups: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 4,5,6, 7-tetrahydrobenzofuranyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), phenoxathianyl, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl,
Figure BDA0001629238560000151
The heteroaryl group is optionally substituted with one or more substituents described herein.
The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means-CO 2 H。
The term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", means- (C=O) -.
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. Some of these are, for example, alkylamino groups of one or two C 1-6 Lower alkylamino groups wherein the alkyl group is attached to the nitrogen atom. Other embodiments are where the alkylamino group is C 1-3 Lower alkylamino groups of (a). Suitable alkylamino groups may be mono-or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, and the like.
The term "arylamino" refers to the substitution of an amino group with one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. Some of these examples are those wherein the aromatic ring on the arylamino group may be further substituted.
The term "aminoalkyl" includes C substituted with one or more amino groups 1-10 Linear or branched alkyl groups. Some of these are C wherein the aminoalkyl group is substituted with one or more amino groups 1-6 Examples of "lower aminoalkyl" include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
As described herein, a ring system in which substituents are attached to a central ring by a bond represents that the substituents may be substituted at any substitutable position on the ring, including monocyclic, bicyclic or polycyclic ring systems. For example, formula a represents that substituent R may be substituted at any position in the ring system that may be substituted, as shown in formulas b-1 to b-8:
Figure BDA0001629238560000152
as described herein, a ring system formed by a bond attached to the center of a ring represents that the bond may be attached to the remainder of the molecule at any available position on the ring system. For example, formula c represents that the group may be attached to the remainder of the molecule through any possible attachment position on the ring, as shown in formulas d-1 and d-2.
Figure BDA0001629238560000153
The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The terms "comprising" or "including" are used in an open-ended fashion, i.e., including the teachings described herein, but not excluding additional aspects.
The term "pharmaceutically acceptable carrier" as used herein includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, all of which are known to those of skill in the art (as described in Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990,pp.1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
The term "inhibiting replication of influenza virus" as used herein includes reducing the amount of viral replication (e.g., by at least 10%) and preventing viral replication altogether (i.e., 100% reducing the amount of viral replication). In some embodiments, influenza virus replication is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.
The term "effective amount" of a compound of the invention refers to the amount that causes the desired biological response. In the present invention, it is contemplated that the biological response is inhibition of influenza virus replication, reduction of the amount of influenza virus or reduction or amelioration of the severity, duration, progression or onset of influenza virus infection, prevention of spread of influenza virus infection, prevention of recurrence, evolution, onset or progression of symptoms associated with influenza virus infection, or enhancement of the prophylactic or therapeutic effect of another anti-influenza infection therapy used. The exact amount of the compound to be administered to a subject will depend on the mode of administration, the type and severity of the infection, and the characteristics of the subject, such as health, age, sex, weight and tolerance to drugs. The skilled artisan will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other antiviral agents, such as in combination with anti-influenza drugs, the "effective amount" of the second agent will depend on the type of drug used. Suitable dosages of approved agents are known and the skilled artisan can adjust depending on the condition of the subject, the type of condition being treated, and the amount of the compound of the invention used. In cases where amounts are not explicitly indicated, an effective amount should be taken. For example, the compounds of the invention may be administered to a subject in a dosage range of about 0.01-100 mg/body weight/day for therapeutic or prophylactic treatment.
The term "treatment" as used herein refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or ameliorating the progression, severity, and/or duration of an influenza virus-mediated condition, or ameliorating one or more symptoms (particularly, one or more discernible symptoms) of an influenza virus-mediated condition as a result of administration of one or more therapies (e.g., one or more therapeutic agents (e.g., compounds and compositions of the invention).
The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound, suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, p-toluenesulfonyl (Ts), trityl (Trt), t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: t W.Greene, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
Description of the Compounds of the invention
The invention provides a novel compound serving as an influenza virus RNA polymerase inhibitor, and the compound and the composition thereof can be used for preparing medicines for preventing, treating or relieving virus infection diseases of patients.
In one aspect, the present invention relates to a compound which is a compound of formula (I) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
Figure BDA0001629238560000161
wherein ring A, U 5 、U 6 、U 7 、R 9 、R 10 And W has the definition as described herein.
In some embodiments, wherein ring a is of the formula:
Figure BDA0001629238560000171
wherein: u (U) 1 Is N or CR 1 ；U 2 Is N or CR 2 ；U 3 Is N or CR 3 ；U 4 Is N or CR 4 ；
U 5 Is N or CR 5 ；U 6 Is N or CR 6 ；U 7 Is N or CR 7 The method comprises the steps of carrying out a first treatment on the surface of the Provided that 1) when U 5 When N is N, U 6 、Y 7 At the same time N, 2) when U 5 Is CR (CR) 5 When U 6 Is CR (CR) 6 And U is 7 Is CR (CR) 7 ；
R 1 、R 2 、R 3 、R 4 And R is 8 Each independently H, D, F, cl, br, I, CN, NO 2 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl groups are each independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from D, F, cl, br, I, CN, -OR b 、-NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, R b O-C 1-4 Alkylene or R d R c N-C 1-4 An alkylene group;
R 5 、R 6 and R is 7 Each independently H, D, F, cl, br, I, CN, NO 2 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 An alkylene group, wherein the R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms and (heteroaryl of 5-10 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted; provided that R 5 、R 6 And R is 7 At least 2 are not H;
R 9 is-OR b 、C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclyl, C 3-12 carbocyclyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-16 atoms or (heteroaryl of 5-16 atoms) -C 1-4 Alkylene group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclyl, C 3-12 carbocyclyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-16 atoms and (heteroaryl of 5-16 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted;
each R is x D, F, cl, br, I, CN, NO independently 2 、-OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, -C (=o) R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 3 to 8 atoms, (heterocyclyl of 3 to 8 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 An alkylene group, wherein the R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 3 to 8 atoms, (heterocyclyl of 3 to 8 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms and (heteroaryl of 5-10 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、-OR b 、-NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, R b O-C 1-4 Alkylene or R d R c N-C 1-4 An alkylene group;
or two adjacent R x Together with the carbon atoms to which they are attached, form C 3-6 Carbocycle, heterocycle of 5-6 atoms, C 6-10 An aromatic ring or a heteroaromatic ring of 5 to 6 atoms, wherein C 3-6 Carbocycle, heterocycle of 5-6 atoms, C 6-10 The aromatic ring and the heteroaromatic ring consisting of 5 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、-OR b 、-NR c R d 、C 1-6 Alkyl, C 1-6 Haloalkyl, R b O-C 1-4 Alkylene or R d R c N-C 1-4 An alkylene group;
R 10 for H, D or optionally by 1, 2, 3 or 4 independently selected from D, F, cl, br, I, CN, NO 2 OR-OR b C substituted by substituent(s) 1-6 An alkyl group;
w is C 1-8 Alkyl, C 3-12 Carbocyclyl or heterocyclyl of 3 to 12 atoms, wherein said C 1-8 Alkyl, C 3-12 Carbocyclyl and heterocyclyl of 3 to 12 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4R w Substituted;
each R is w D, F, cl, br, I, CN, NO independently 2 、-C(＝O)R a 、-C(＝O)OR b 、-NR e C(＝O)R a 、-NR e C(＝O)NR c R d 、-S(＝O) 2 R f 、-S(＝O) 2 NR e C(＝O)R a 、-S(＝O) 2 NR c R d 、(R b O) 2 P(＝O)-C 0-2 Alkylene, -OR b 、R b O-C 1-2 Alkylene, R d R c N-C 1-2 Alkylene, C 1-6 Alkyl, heteroaryl of 5-6 atoms or heterocyclyl of 5-6 atoms, wherein said C 1-6 Alkyl, heteroaryl of 5-6 atoms and heterocyclyl of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, N 3 、＝O、NO 2 、-OR b 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
R a 、R b 、R c 、R d 、R e and R is f Each independently is H, D, hydroxy, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 3-6 carbocyclyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 Alkylene group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 3-6 carbocyclyl-C 1-4 Alkylene, 3-12 atom heterocyclyl, (3-12 atom heterocyclyl) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms and (heteroaryl of 5-10 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, CN, OH, NH 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group;
or R is c 、R d And together with the nitrogen atom to which they are attached, form a 3-8 atom-containing heterocyclic ring or a 5-8 atom-containing heteroaryl ring, wherein the 3-8 atom-containing heterocyclic ring and the 5-8 atom-containing heteroaryl ring are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, CN, OH, NH 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 An alkylamino group.
In other embodiments, the invention relates to a compound of the structure of formula (I-a) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000181
wherein ring A, R 9 、R 10 And W has the definition as described herein.
In other embodiments, the invention relates to a compound of the structure of formula (I-b) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000182
Wherein ring A, R 5 、R 6 、R 7 、R 9 、R 10 And W has the definition as described herein.
In other embodiments, wherein ring a is of the formula:
Figure BDA0001629238560000191
in other embodiments, wherein ring a is of the formula:
Figure BDA0001629238560000192
in other embodiments, R 1 、R 2 、R 3 、R 4 And R is 8 Each independently H, D, F, cl, br, I, CN, NO 2 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-OR b 、-NR c R d Methyl, ethyl, n-propyl OR isopropyl, wherein each of said methyl, ethyl, n-propyl and isopropyl is independently unsubstituted OR substituted with 1, 2, 3 OR 4 substituents independently selected from D, F, cl, br, I, CN, -OR b 、-NR c R d Or C 1-3 A haloalkyl group.
In other embodiments, R 5 、R 6 And R is 7 Each independently H, D, F, cl, br, I, CN, NO 2 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、-OR b 、-NR c R d 、C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C 1-4 Alkylene group, wherein the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted; provided that R 5 、R 6 And R is 7 At least 2 are not H.
In other embodiments, R 9 is-OR b 、C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclyl, C 3-6 carbocyclyl-C 1-4 Alkylene, heterocyclyl of 5-10 atoms, (heterocyclyl of 5-10 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms or (heteroaryl of 5-10 atoms) -C 1-4 Alkylene group, wherein the C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclyl, C 3-6 carbocyclyl-C 1-4 Alkylene, heterocyclyl of 5-10 atoms, (heterocyclyl of 5-10 atoms) -C 1-4 Alkylene, C 6-10 Aryl, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5-10 atoms and (heteroaryl of 5-10 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted.
In other embodiments, each R x D, F, cl, br, I, CN, NO independently 2 、-OR b 、-NR c R d 、R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, -C (=o) R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-2 Alkylene, phenyl-C 1-2 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C 1-2 An alkylene group, wherein the R b O-C 1-4 Alkylene, R d R c N-C 1-4 Alkylene, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms)-C 1-2 Alkylene, phenyl-C 1-2 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、-OR b 、-NR c R d Methyl, ethyl, n-propyl or isopropyl;
or two adjacent R x Together with the carbon atoms to which they are attached, form C 5-6 Carbocycles, benzene rings, or heteroaromatic rings of 5-6 atoms, wherein C 5-6 Carbocycle, benzene ring and heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、-OR b 、-NR c R d Methyl, ethyl, n-propyl or isopropyl.
In other embodiments, each R x D, F, cl, br, I, CN, NO independently 2 、OH、-OCH 3 、-OCH 2 CH 3 、-NH 2 HO-methylene-, HO-ethylene-, H 2 N-C 1-4 Alkylene, -C (=o) R a 、-C(＝O)OR b 、-C(＝O)NR c R d Methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-2 Alkylene, phenyl-C 1-2 Alkylene, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C 1-2 Alkylene, wherein the methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 cycloalkyl-C 1-2 Alkylene, heterocyclyl of 5-6 atoms, (heterocyclyl of 5-6 atoms) -C 1-2 Alkylene, phenyl-C 1-2 Alkylene, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-2 Alkylene groups are each independently unsubstitutedOr substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、-NH 2 Methyl, ethyl, n-propyl or isopropyl;
or two adjacent R x Together with the carbon atoms to which they are attached, form C 5-6 Carbocycles, benzene rings, or heteroaromatic rings of 5-6 atoms, wherein C 5-6 Carbocycle, benzene ring and heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, NO 2 、OH、-NH 2 Methyl, ethyl, n-propyl or isopropyl.
In other embodiments, R 10 H, D, CF of a shape of H, D, CF 3 Methyl, ethyl, n-propyl or isopropyl.
In other embodiments, W is C 1-6 Alkyl, C 5-8 Carbocyclyl or heterocyclyl of 5-8 atoms, wherein said C 1-6 Alkyl, C 5-8 Carbocyclyl and heterocyclyl consisting of 5-8 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4R w Substituted.
In other embodiments, each R w D, F, cl, br, I, CN, NO of a shape of D, F, cl, br, I, CN, NO 2 、-C(＝O)OCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)OH、-NHC(＝O)R a 、-NHC(＝O)NR c R d 、-S(＝O) 2 R f 、-S(＝O) 2 NHC(＝O)R a 、-S(＝O) 2 NR c R d 、(R b O) 2 P(＝O)-C 0-2 Alkylene, -OR b Methyl, ethyl, n-propyl, isopropyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl or heterocyclyl of 5-6 atoms, wherein the methyl, ethyl, n-propyl, isopropyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thia Oxazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and heterocyclyl consisting of 5-6 atoms each independently being unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, br, I, CN, N 3 、＝O、NO 2 、-OCH 3 、C 1-3 Alkyl or C 1-3 A haloalkyl group.
In other embodiments, R a 、R b 、R c 、R d 、R e And R is f Each independently H, D, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, methoxy, ethoxy, C 3-6 Carbocyclyl, heterocyclyl of 5-6 atoms, phenyl, heteroaryl of 5-6 atoms or (heteroaryl of 5-6 atoms) -C 1-4 Alkylene, wherein the methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, methoxy, ethoxy, C 3-6 Carbocyclyl, heterocyclyl of 5-6 atoms, phenyl, heteroaryl of 5-6 atoms and (heteroaryl of 5-6 atoms) -C 1-4 Alkylene groups are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, CN, OH, NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl or methoxy;
or R is c 、R d And together with the nitrogen atom to which they are attached, form a 5-6 atom-containing heterocyclic ring or a 5-6 atom-containing heteroaryl ring, wherein the 5-6 atom-containing heterocyclic ring and the 5-6 atom-containing heteroaryl ring are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, cl, CN, OH, NH 2 、C 1-3 Alkyl, C 1-3 Haloalkyl or methoxy.
In other embodiments, R 9 is-OR b Acetylene, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4,5,6,7-Tetrahydrobenzofuranyl, 1,2,3, 4-tetrahydroisoquinolinyl, phenyl, naphthyl, furanyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, benzothiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl or isoquinolinyl, wherein the ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4,5,6, 7-tetrahydrobenzofuranyl, 1,2,3, 4-tetrahydroisoquinolyl, phenyl, naphthyl, furyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, benzothiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl and isoquinolinyl are each independently unsubstituted or substituted with 1,2,3,4 or 5R x Substituted.
In other embodiments, W is of the formula:
Figure BDA0001629238560000211
wherein: n is 0, 1, 2, 3 or 4.
In other embodiments, the invention relates to a compound of the structure of formula (II) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000212
wherein ring A, R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (III) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000213
wherein ring A, R 5 、R 6 、R 7 、R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (IV) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000214
wherein ring A, R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (V) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000221
Wherein ring A, R 5 、R 6 、R 7 、R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (VI) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000222
wherein ring A, R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (VII) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000223
wherein ring A, R 5 、R 6 、R 7 、R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (VIII) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000224
/>
wherein ring A, R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (IX) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000231
Wherein ring A, R 5 、R 6 、R 7 、R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure of formula (X) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000232
wherein ring A, R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to a compound of the structure shown in formula (XI) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001629238560000233
wherein ring A, R 5 、R 6 、R 7 、R 9 And R is w With the definition according to the invention.
In other embodiments, the invention relates to compounds of one of the following or stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, but in no way limited to these compounds:
Figure BDA0001629238560000234
Figure BDA0001629238560000241
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Figure BDA0001629238560000251
/>
Figure BDA0001629238560000261
/>
Figure BDA0001629238560000271
in another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention.
In some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or combination thereof.
In some embodiments, the pharmaceutical compositions provided herein further comprise one or more additional therapeutic agents.
In still other embodiments, the additional therapeutic agent is selected from an anti-influenza virus agent or vaccine.
In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.
In other embodiments, the pharmaceutical compositions of the invention wherein the other therapeutic agent involved is Amantadine, rimantadine, oseltamivir (Oseltamivir), zanamivir (Zanamivir), peramivir (Peramivir), laninavir (laninavir), lanamivir octanoate hydrate (Laninamivir Octanoate Hydrate), fampicvir (Favipiravir), arbidol (Arbidol), ribavirin (Ribavirin), stavafrine, ingavirin (Ingavirin), influenza enzyme (flash), CAS No. 1422050-75-6, JNJ-872, S-033188, influenza vaccine (FluMist)
Figure BDA0001629238560000272
Quadrivalent、
Figure BDA0001629238560000273
Quadrivalent、/>
Figure BDA0001629238560000274
Or->
Figure BDA0001629238560000275
) Or a combination thereof.
In another aspect, the invention provides the use of said compound or said pharmaceutical composition for the manufacture of a medicament for the prevention, treatment, therapy or alleviation of a viral infectious disease in a patient.
In some embodiments, the viral infection is an influenza viral infection.
In other embodiments, the invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.
In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be used as intermediates for preparing and/or purifying the compounds of the present invention and/or for separating enantiomers of the compounds of the present invention.
Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodite/iodide, isethionate, lactate, lactoaldehyde, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactoate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts may be derived include, for example, ammonium salts and metals of groups I to XII of the periodic Table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts may be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (choline), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine and tromethamine.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxides, carbonates, bicarbonates, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).
Moreover, the compounds of the present invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include both solvated and unsolvated forms.
Any formulae given herein are also intended to represent unlabeled as well as isotopically-labeled forms of these compounds. Isotopically-labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H， 3 H， 11 C， 13 C， 14 C， 15 N， 18 F， 31 P， 32 P， 36 S， 37 Cl or 125 I。
In another aspect, the compounds of the invention include compounds defined herein which are labeled with various isotopes, e.g., where a radioisotope, such as 3 H， 14 C and C 18 F, or in which non-radioactive isotopes are present, e.g 2 H and 13 C. such isotopically-labeled compounds are useful in metabolic studies (using 14 C) Reaction kinetics studies (using, for example 2 H or 3 H) Detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays, or may be used in radiation therapy of a patient. 18 F-labeled compounds are particularly desirable for PET or SPECT studies. Isotopically-labelled compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation of the present invention as using a suitable isotopically-labelled reagent in place of the originally-used unlabelled reagent。
In addition, heavier isotopes are in particular deuterium (i.e., 2 substitution of H or D) may provide certain therapeutic advantages, which are brought about by a higher metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in this context is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those wherein the crystallization solvent may be isotopically substituted, e.g. D 2 O, acetone-d 6 Or DMSO-d 6 Those solvates of (a).
Compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition, which comprises a compound shown as a formula (I), a formula (I-a) or a formula (I-b) or a stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate of the compound. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle.
The pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or have no other adverse effects or side effects once administered to a patient. Standard pharmaceutical techniques may be employed.
The pharmaceutical or pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle as described herein, as used herein, including any solvents, diluents, liquid vehicles, dispersing agents, suspending agents, surfactants, isotonicity agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like, suitable for the particular target dosage form. Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York discloses various carriers for use in formulating pharmaceutically acceptable compositions and methods of making same as are well known. In addition to conventional carrier vehicles that are incompatible with the compounds of the present invention, for example, may produce adverse biological effects or may interact deleteriously with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and use thereof is also contemplated by the present invention.
Some examples of materials that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropyl methylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol or polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, ringer's solution (Ringer's solution), ethanol and phosphate buffers, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants according to the judgment of the formulator, anti-sticking agents, coating agents, sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
The compounds or compositions of the invention may be administered by any suitable means, and the compounds and pharmaceutically acceptable compositions described above may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), orally as an oral or nasal spray, etc., depending on the severity of the infection being treated.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable formulations may be formulated, for example, into sterile injectable aqueous or oleaginous suspensions using suitable dispersing or wetting agents and suspending agents according to known techniques. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, u.s.p. And isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any odorless, non-volatile oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used to prepare injectables.
For example, injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by the addition of sterilizing agents which are in the form of sterile solid compositions which are soluble or dispersible in sterile water or other sterile injectable medium prior to use.
To prolong the effect of the compounds or compositions of the present invention, it is often desirable to slow down the absorption of the compounds by subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of a compound then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a matrix of microcapsules of the compound in a biodegradable polymer such as polylactide-polyglycolide acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycols or suppository waxes, which are solid at the ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or bulking agents such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerin, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as, for example, paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of similar type can also be used as fillers in soft and hard gel capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, troches, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes. Solid compositions of similar type can also be used as fillers in soft and hard gel capsules using lactose or milk sugar, high molecular weight polyethylene glycols and other excipients.
The active compounds may also be in microencapsulated form with one or more of the above-described excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical arts. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. In general, such dosage forms may also contain additional substances other than inert diluents, such as tabletting lubricants and other tabletting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
Topical or transdermal administration forms of the compounds of the invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compounds are combined with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated as falling within the scope of the present invention. In addition, the present invention contemplates the use of skin patches that have the added advantage of providing controlled delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate may be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
The compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or by implantation of a kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the composition is administered orally, intraperitoneally, or intravenously.
The sterile injectable form of the compositions of the invention may be an aqueous or oleaginous suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents, following techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any odorless, non-volatile oil may be used, including synthetic mono-or diglycerides. In addition, as in particular in polyoxyethylated form, natural pharmaceutically acceptable oils, such as olive oil or castor oil, fatty acids, such as octadecenoic acid and its glyceride derivatives, are used for the preparation of injectables. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, spans, and other emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.
The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, common carriers include, but are not limited to, lactose and starch. A lubricant, such as magnesium stearate, is also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavoring agents or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing the agent with a non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of the present invention may also be administered topically, especially when the therapeutic target includes topical instillation in readily accessible areas or organs, including ocular, skin, or lower intestinal disorders. Suitable topical formulations are readily prepared for each of these regions or organs.
Local instillation into the lower intestinal tract can be achieved with rectal suppository formulations (see above) or with suitable enema formulations. Topical skin patches may also be used.
For topical application, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the invention include, but are not limited to, mineral oil, petroleum jelly, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH adjusted, sterile saline, or in particular as a solution in isotonic, pH adjusted, sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.
The pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical arts and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The compounds used in the methods of the invention may be formulated in unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be administered in a single daily dose or in one of a plurality of daily doses (e.g., about 1-4 times or more a day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.
Use of the compounds and compositions of the invention
The compounds and the pharmaceutical compositions provided by the invention can be used for preparing medicines for preventing, treating or relieving viral infectious diseases of patients, and preferably, the viral infection is influenza virus infection.
The invention also provides application of the compound or the pharmaceutical composition thereof in preparing influenza virus RNA polymerase inhibitor medicines.
The present invention provides a method for treating, preventing or delaying infection caused by a virus, the method comprising administering to a patient in need of treatment a therapeutically effective amount of the above compound or a pharmaceutical composition thereof. Wherein the virus is an influenza virus. Also, the above-mentioned compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents. The administration may be simultaneous, sequential or at intervals.
The dosage of a compound or pharmaceutical composition required to effect a therapeutic, prophylactic or delay action, etc., will generally depend on the particular compound being administered, the patient, the particular disease or disorder and its severity, the route and frequency of administration, etc., and will be determined by the attending physician on a case-by-case basis. For example, in the case of administration of a compound or pharmaceutical composition provided herein by intravenous route, administration may be performed once a week or even at longer intervals.
In summary, the present invention provides a novel compound which is useful as an influenza virus RNA polymerase inhibitor. The compound of the invention is suitable for preparing medicines with various dosage forms, and can be widely used for treating seasonal influenza, avian influenza, swine influenza and influenza virus mutant strains with drug resistance to duffy.
The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
Drawings
FIG. 1 is a schematic illustration of a process according to the invention(+/-) -trans-3- ((4- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl)) 6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 1) 1 H NMR spectrum;
FIG. 2 is a schematic illustration of a preparation according to the present invention(+/-) -trans-3- ((4- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl)) 6-phenyl-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 2) 1 H NMR spectrum;
FIG. 3 is a schematic illustration of a preparation of the invention(+/-) -trans-3- ((4- (5, 7-difluoro-1H-indol-3-yl) -6- (furan-2-yl) Phenyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 3) 1 H NMR spectrum;
FIG. 4 is a schematic illustration of a preparation according to the present invention(+/-) -trans-3- ((4- (5, 7-difluoro-1H-indol-3-yl) -6-phenyl-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 4) 1 H NMR spectrum;
FIG. 5 is a schematic illustration of a preparation of the invention(+/-) -trans-3- ((4- (5, 7-difluoro-1H-indol-3-yl) -6-phenyl-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 4) 13 C NMR spectrum;
FIG. 6 is a schematic illustration of a preparation of the invention(+/-) -trans-3- ((4- (2-chloro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 5) 1 H NMR spectrum;
FIG. 7 is a schematic illustration of a preparation of the invention(2S, 3S) -3- ((4- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -6- (2- Furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 6) 1 H NMR spectrum;
FIG. 8 is a schematic representation of a preparation according to the present invention(2S, 3S) -3- ((4- (2-furyl) -6- (7H-pyrrolo [2, 3-d)]Pyrimidine-5-complexes Phenyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 7) 1 H NMR spectrum;
FIG. 9 is a schematic illustration of a preparation of the present invention(2S, 3S) -3- ((4- (6-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (2- Furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid(example 8) 1 H NMR spectrum.
General synthetic procedure
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
In this specification, a structure is dominant if there is any difference between a chemical name and a chemical structure.
In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated, wherein the substituents are as defined for formula (I), formula (I-a) or formula (I-b). The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company, J & K Scientific ltd, and used without further purification unless otherwise indicated. General reagents were purchased from Shandong Guangdong chemical plant, guangzhou chemical plant, tianjin good-apartment chemical Co., tianjin Fuchen chemical plant, wuhan Xinhua Yuan technology development Co., ltd., qingdao Tenglong chemical Co., qingdao ocean chemical plant, beijing coupling technology Co., ltd., shanghai Tebert chemical Co., ltd., shanghai Tech.
Anhydrous tetrahydrofuran, 1, 4-dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.
The test conditions of the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum are as follows: nuclear magnetic instrument of 400MHz or 600MHz of Bruker (Bruker) under room temperature condition, CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet), m (multiplet ), br (broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constants, expressed as J, are given in hertz (Hz).
The test conditions for low resolution Mass Spectrometry (MS) data were: agilent 6120 Quadragole HPLC-MS (column model: zorbax SB-C18, 2.1X130 mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O), UV detection at 210nm/254nm, electrospray ionization mode (ESI).
The test conditions for high resolution Mass Spectrometry (MS) data were: agilent 6530 QTOF HPLC-MS (direct injection on two passes, 1min, flow rate 0.6mL/min, mobile phase 80% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O), using electrospray ionization mode (ESI).
The characterization mode of the purity of the compound is as follows: agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column type: NOVASEP,50/80mm, DAC) was detected at 210nm/254nm with UV.
The following abbreviations are used throughout the present invention:
AcOH,HAc,HOAc,CH 3 COOH acetic acid, acetic acid
AcOK,KOAc,CH 3 COOK potassium acetate
BnOH benzyl alcohol
Bu 4 NF tetrabutylammonium fluoride
BOC, boc t-Butoxycarbonyl
(Boc) 2 Di-tert-butyl O dicarbonate
n-BuOH n-butanol
CHCl 3 Chloroform (chloroform)
CDCl 3 Deuterated chloroform
CD 3 OD deuterated methanol
CH 2 Cl 2 DCM dichloromethane
CH 3 CN, meCN acetonitrile
CH 3 Cl chloromethane
CH 3 I methyl iodide
CH 3 SO 2 Cl, msCl methylsulfonyl chloride
Cbz benzyloxycarbonyl
DIEA,DIPEA,iPr 2 Net N, N-diisopropylethylamine
DMF N, N-dimethylformamide, dimethylformamide
DME dimethyl ether
DMAP 4-dimethylaminopyridine
DMSO dimethyl sulfoxide
DMSO-d 6 Deuterated dimethyl sulfoxide
DPPA diphenyl azide phosphate
EC 50 Half effective concentration
EtOAc, EA ethyl acetate
Et 3 N, TEA triethylamine
Et 2 O-diethyl ether
EtOH ethanol
Et 3 SiH triethylsilane
g
h hours
HATU 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate
H 2 Hydrogen gas
H 2 O water
HCl hydrogen chloride
H 2 O 2 Hydrogen peroxide
H 3 PO 4 Phosphoric acid
H 2 SO 4 Sulfuric acid
HNO 3 Nitric acid
HCOOK Potassium formate
HCOONH 4 Ammonium formate
HPLC high performance liquid chromatography
High Performance Thin Layer Chromatography (HPTLC)
HRMS high resolution mass spectrometry
Hexane n-Hexane
I 2 Iodine
Fe iron
2-MeTHF 2-methyltetrahydrofuran
MgSO 4 Magnesium sulfate
MeOH,CH 3 OH methanol
MeI,CH 3 I methyl iodide
mL, mL milliliter
min
M, mol/L
N 2 Nitrogen gas
NH 3 Ammonia gas
NMP N-methylpyrrolidone
NaHCO 3 Sodium bicarbonate
NaBH 4 Sodium borohydride
NaBH 3 CN cyano sodium borohydride
NaOMe,NaOCH 3 ,CH 3 ONa sodium methoxide
NaOH sodium hydroxide
NaCl sodium chloride
NaH 2 PO 4 Sodium dihydrogen phosphate
NaH sodium hydride
NaI sodium iodide
Na 2 SO 4 Sodium sulfate
Na 2 S 2 O 3 Sodium thiosulfate
NBS N-bromosuccinimide
NIS N-iodosuccinimide
NCS N-chlorosuccinimide
NH 4 Cl ammonia chloride
NH 2 OH HCl hydroxylamine hydrochloride
Ph phenyl
psi pounds per square inch
Pd/C palladium/carbon
Pd(OAc) 2 Palladium acetate
Pd(OH) 2 Palladium hydroxide
Pd(PPh 3 ) 4 Tetrakis (triphenylphosphine) palladium
Pd(PPh 3 ) 2 Cl 2 Bis (triphenylphosphine) palladium dichloride
Pd(dppf)Cl 2 ,PdCl 2 (dppf) 1,1' -bis (diphenylphosphino) ferrocene Palladium dichloride
Pd(dppf)Cl 2 ·CH 2 Cl 2 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane complex
Pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium
P(t-Bu) 3 Tri (t-butyl) phosphine
Pd(dtbpf)Cl 2 1,1' -bis (di-t-butylphosphino) ferrocene palladium dichloride
PE petroleum ether (60-90 ℃ C.)
POCl 3 Phosphorus oxychloride
Ph 3 CCl triphenylchloromethane
K 2 CO 3 Potassium carbonate
K 3 PO 4 Potassium phosphate
KOH potassium hydroxide
KOAc potassium acetate
RT, RT, r.t. room temperature
Rt retention time
SOCl 2 Thionyl chloride
SI therapeutic index
t-BuOK potassium tert-butoxide
THF tetrahydrofuran
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
TBAI tetrabutylammonium iodide
TBS (Tunnel boring system) tris buffer saline
TsCl p-toluenesulfonyl chloride
TrtCl triphenylchloromethane
Ts p-toluenesulfonyl group
Trt trityl radical
ZnCl 2 TMEDA chlorine (N, N, N, N-tetramethyl ethylene diamine) zinc
X-Phos 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl
Apparent distribution volume of Vss
Zn zinc
Mu L microliters
The following synthetic schemes list the experimental procedures for preparing the compounds disclosed in the present invention. Wherein U is 1 、U 2 、U 3 、U 4 、U 5 、U 6 、U 7 、R 8 And R is 9 PG is a protecting group, such as Trt (trityl), ts (p-toluenesulfonyl), etc., having the definition as described herein.
Synthesis scheme 1
Figure BDA0001629238560000361
A kind of electronic device with high-pressure air-conditioning system(4)The intermediates shown can be synthesized by the methods disclosed in scheme 1. First, the compound(1)With a suitable protecting agent (such as TsCl (p-toluenesulfonyl chloride), trtCl (triphenylchloromethane)) under alkaline conditions to form compounds(2). ThenCompounds of formula (I)(2)And a compound(3)Under the action of Pd catalyst, the coupling reaction is carried out to generate an intermediate(4)。
Synthesis scheme 2
Figure BDA0001629238560000362
A kind of electronic device with high-pressure air-conditioning system(10)The intermediates shown can be synthesized by the methods disclosed in scheme 2. First, the compound(5)And a compound(6)Reacting in the dark to obtain the compound(7). Then, the compound(7)Ring-opening under the action of alkali (such as sodium methoxide) to obtain compound(8). Next, the compound(8)And DPPA and benzyl alcohol are subjected to rearrangement reaction under alkaline condition to generate a compound(9). Finally, the compound(9)Removal of protecting groups from amino groups under reducing conditions to form intermediates(10)。
Synthesis scheme 3
Figure BDA0001629238560000363
A kind of electronic device with high-pressure air-conditioning system(16)The compounds shown can be prepared by the methods described in synthetic scheme 3. First, the compound(11)With boric acid compounds(12)Generating a compound through Suzuki coupling reaction(13). Then, the compound(13)And a compound(10)Reacting under alkaline condition to produce compound(14). Next, the compound(14)And a compound(4)Under the action of Pd catalyst, suzuki coupling reaction is carried out to generate a compound (15). Finally, the compound(15)Removing protecting group under the action of alkali to obtain compound(16)。
Synthesis scheme 4
Figure BDA0001629238560000371
A kind of electronic device with high-pressure air-conditioning system(16)The compounds shown can also be prepared by the methods described in scheme 4Obtained. First, the compound(11)And a compound(10)Reacting under alkaline condition to produce compound(17). Then, the compound(17)With boric acid compounds(12)Generating a compound through Suzuki coupling reaction(14). Next, the compound(14)And a compound(4)Under the action of Pd catalyst, suzuki coupling reaction is carried out to generate a compound(15). Finally, the compound(15)Removing protecting group under the action of alkali to obtain compound(16)。
Synthesis scheme 5
Figure BDA0001629238560000372
A kind of electronic device with high-pressure air-conditioning system(22)The compounds shown can be prepared by the methods described in synthetic scheme 5. First, the compound(18)AND (COCl) 2 (oxalyl chloride) reaction to give the compound(19). Then, the compound(19)And a compound(13)Condensation reaction takes place to produce compound(20). Next, the compound(20)And a compound(4)Under the action of Pd catalyst, suzuki coupling reaction is carried out to generate a compound(21). Finally, the compound(21)Removing protecting group under the action of alkali to obtain compound(22)。
Synthesis scheme 6
Figure BDA0001629238560000381
A kind of electronic device with high-pressure air-conditioning system(27)The compounds shown can also be prepared by the methods described in synthetic scheme 6. First, the compound(11)And a compound(23)Reacting under alkaline condition to produce compound (24). Then, the compound(24)With boric acid compounds(12)Generating a compound through Suzuki coupling reaction(25). Next, the compound(25)And a compound(4)Under the action of Pd catalyst, suzuki coupling reaction is carried out to generate a compound(26). Finally, the compound(26)Removing protecting group under the action of alkali to obtain compound(27)。
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Preparation example
In the following preparation examples, the inventors have described in detail the preparation of the compounds of the present invention, taking some of the compounds of the present invention as examples.
Example 1 (+/-) -trans-3- ((4- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl)) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid
Figure BDA0001629238560000382
Step 1) (+/-) -endo-bicyclo [2.2.2]Oct-5-ene-2, 3-dicarboxylic anhydride
Figure BDA0001629238560000383
Maleic anhydride (100 g,1.02 mol) and chloroform (1000.0 mL) were sequentially added to a 2000mL dry reaction flask, the mixture was cooled to 0 ℃, then 1, 3-cyclohexadiene (112.5 mL,1.12 mol) was added dropwise thereto, and after the addition was completed, the reaction mixture was transferred to room temperature and reacted overnight in the absence of light. After the completion of the reaction, the solvent was dried under reduced pressure, and methanol (700.0 mL) was added to the resulting residue, and the resulting mixture was heated to 50 ℃ and stirred for 10 minutes, then cooled to 0 ℃ and stirred for 30 minutes. Suction filtration and vacuum drying of the filter cake at 45 ℃ gave the title compound as a white solid (147 g, 81%).
MS(ESI,pos.ion)m/z:179.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):6.28(dd,J＝4.2,3.4Hz,2H),3.29(s,2H),3.04(s,2H),1.61(d,J＝7.9Hz,2H),1.22(d,J＝7.6Hz,2H)。
Step 2) (+/-) -trans-3- (methoxycarbonyl) bicyclo [2.2.2]Oct-5-ene-2-carboxylic acid
Figure BDA0001629238560000391
In a dry reaction flask was added (+/-) -endo-bicyclo [2.2.2] oct-5-ene-2, 3-dicarboxylic anhydride (33.50 g,188.01 mmol), then a methanol solution of sodium methoxide (5M, 300.8 mL) was added dropwise to the flask at 0℃after which the reaction mixture was transferred to room temperature and the reaction was continued to be stirred for 4 days, then part of the methanol (about 120 mL) was distilled off under reduced pressure, the remaining reaction solution was slowly added to an aqueous hydrochloric acid solution (277 mL, 18%) at 0℃with a white precipitate generated, the methanol was distilled off under reduced pressure, the remaining residue was stirred at 0℃for 30 minutes, then filtered off with suction, and the filter cake was washed with water (30 mL. Times.3) and dried under vacuum to give the title compound as a white solid (37.19 g, 94%).
MS(ESI,neg.ion)m/z:209.0[M-H] - ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm):12.28(s,1H),6.34(s,1H),6.17(s,1H),3.65(s,3H),2.94(s,1H),2.91(d,J＝4.4Hz,1H),2.86(d,J＝2.4Hz,1H),2.72(s,1H),1.48–1.58(m,1H),1.34–1.44(m,1H),1.26–1.16(m,1H),1.09–0.99(m,1H)。
Step 3) (+/-) -trans-3- (((benzyloxy) carbonyl) amino) bicyclo [2.2.2]Oct-5-ene-2-carboxylic acid methyl ester
Figure BDA0001629238560000392
The compound (+/-) -trans-3- (methoxycarbonyl) bicyclo [2.2.2] oct-5-ene-2-carboxylic acid (6.0 g,29 mmol) was dissolved in toluene (50 mL), the resulting solution was replaced with nitrogen 3 times, diphenyl azide phosphate (7.0 mL,32 mmol) and triethylamine (4.0 mL,29 mmol) were then sequentially added thereto by syringe, the mixture was heated to 90℃and stirred for 2 hours, benzyl alcohol (3.0 mL,29 mmol) was then added dropwise to the reaction solution by syringe, and the reaction was continued at this temperature for 3 days. The reaction solution was cooled to room temperature, ethyl acetate (60 mL) was then added to dilute the reaction solution, and then the resulting mixture was washed with saturated aqueous sodium hydrogencarbonate (60 ml×2) and saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =8/1) to give the title compound as a yellow oil (8.25 g, 92%).
MS(ESI,pos.ion)m/z:316.1[M+H] + 。
Step 4) (+/-) -trans-3-aminobicyclo [2.2.2]Octane-2-carboxylic acid methyl ester
Figure BDA0001629238560000393
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To the autoclave was added (+/-) -trans-3- (((benzyloxy) carbonyl) amino) bicyclo [2.2.2] oct-5-ene-2-carboxylic acid methyl ester (8.21 g,26.0 mmol) at room temperature, and the compound was dissolved by further adding tetrahydrofuran (20 mL) and methanol (20 mL), and then Pd/C (10%, 1.40 g) was added to the resulting solution, and the reaction solution was reacted at room temperature under 40psi hydrogen pressure overnight. The reaction was filtered off the catalyst through celite, the filter cake was washed with methanol (20 mL) and ethyl acetate (20 mL) in turn, the filtrate was concentrated under reduced pressure to give a colorless oil, which was purified by silica gel column chromatography (DCM/MeOH (v/v) =20/1-10/1) to give the title compound as a colorless oil (3.95 g, 83%).
MS(ESI,neg.ion)m/z:184.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):3.68(s,3H),3.31(d,J＝6.7Hz,1H),2.11(d,J＝6.7Hz,1H),1.98–1.91(m,1H),1.83–1.71(m,1H),1.60–1.33(m,10H)。
Step 5) (+/-) -trans-3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2- Methyl formate
Figure BDA0001629238560000394
2,4, 6-trichloro-1, 3, 5-triazine (5.00 g,27.00 mmol) and sodium bicarbonate (2.70 g,32.13 mmol) were suspended in acetone (100 mL) and then cooled to 0deg.C, and a solution of (+/-) -trans-3-aminobicyclo [2.2.2] octane-2-carboxylic acid methyl ester (5.00 g,27.00 mmol) in acetone (30 mL) was slowly added dropwise and stirring was continued at 0deg.C for 3 hours. After completion of the reaction, water (100 mL) was added, the aqueous phase was extracted with ethyl acetate (100 ml×2), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =10/1) to give the title compound as a pale yellow solid (7.20 g, 80%).
MS(ESI,pos.ion)m/z:331.0[M+H] + 。
Step 6) (+/-) -trans-3- ((4-chloro-6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester
Figure BDA0001629238560000401
(+/-) -trans-3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester (2.50 g,7.55 mmol), 2-furanboronic acid (850 mg,7.55 mmol), potassium acetate (2.30 g,22.60 mmol) and Pd (dppf) Cl 2 (620 mg,0.755 mmol) was mixed in 1, 4-dioxane (50 mL), water (5 mL) was added, then warmed to 100deg.C under nitrogen and stirred for 4 hours. After the reaction was completed, the reaction solution was directly filtered to remove solid impurities, and the solvent was removed, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =15/1) to give a white solid (520 mg, 19%).
MS(ESI,pos.ion)m/z:363.2[M+H] + 。
Step 7) 3-bromo-5-fluoro-1H-pyrrolo [2,3-b]Pyridine compound
Figure BDA0001629238560000402
5-fluoro-1H-pyrrolo [2,3-b]Pyridine (1 g,7.34 mmol) was dissolved in DMF (10 mL), then bromine (0.75 mL,14.5 mmol) was added dropwise thereto, and the reaction was stirred at room temperature for 4 hours. Adding saturated sodium thiosulfate aqueous solutionThe reaction was quenched (100 mL), the resulting mixture was extracted with ethyl acetate (100 ml×2), the combined organic phases were washed with saturated brine (100 ml×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =4/1) to give the title compound as a yellow powder (0.6 g, 40%). MS (ESI, pos.ion) m/z 216.90[ M+H ] ] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.23(s,1H),8.35–8.21(m,1H),7.81(d,J＝2.7Hz,1H),7.71(dd,J＝8.9,2.6Hz,1H)。
Step 8) 3-bromo-5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b]Pyridine compound
Figure BDA0001629238560000403
3-bromo-5-fluoro-1H-pyrrolo [2,3-b ] pyridine (0.74 g,3.44 mmol) was dissolved in THF (5 mL), naH (127 mg,3.0 mmol) was added thereto at 0deg.C and stirred at this temperature for 30 min, then TsCl (458 mg,2.4 mmol) was added, and the mixture was transferred to room temperature and stirred further overnight. The reaction was quenched with water (50 mL), the aqueous phase was extracted with ethyl acetate (50 ml×2), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =4/1) to give the title compound as a yellow solid (740 mg, 83%).
MS(ESI,pos.ion)m/z:370.80[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.32(s,1H),8.06(d,J＝8.3Hz,2H),7.84(s,1H),7.47(dd,J＝7.8,2.6Hz,1H),7.29(d,J＝8.3Hz,2H),2.38(s,3H)。
Step 9) 5-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl- 1H-pyrrolo [2,3-b]Pyridine compound
Figure BDA0001629238560000411
3-bromo-5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b]Pyridine (175 mg,0.22 mmol), pd (dppf) Cl 2 (70 mg,0.09 mmol) and KOAc (144 mg,1.47 mmol) were suspended in DME (5 mL), the suspension was purged with nitrogen, and then pinacol diboronate (190 mg,0.71 mmol) was added thereto, the tube was capped and reacted at 105℃for 2 hours under microwave conditions. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, then the resulting mixture was suction-filtered through celite, the cake was washed with ethyl acetate (20 ml×2), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v) =4/1) to give the title compound as a yellow solid (130 mg, 65.9%).
MS(ESI,pos.ion)m/z:417.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.27(d,J＝1.2Hz,1H),8.19(s,1H),8.08(d,J＝8.3Hz,2H),7.89(dd,J＝8.5,2.7Hz,1H),7.30(s,1H),7.28(s,1H),2.39(s,3H),1.37(s,12H)。
Step 10) (+/-) -trans-3- ((4- (5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridine-3- Phenyl) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino-bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester
Figure BDA0001629238560000412
5-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (545 mg,0.79mmol, 60%), potassium carbonate (380 mg,2.74 mmol), palladium acetate (17 mg,0.07 mmol), X-Phos (68 mg,0.14 mmol) and (+/-) -trans-3- ((4-chloro-6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (250 mg,0.69 mmol) were mixed in THF (10 mL), water (0.5 mL) was added, and then heated to 66℃under nitrogen protection under reflux for stirring for 12 hours. The solid impurities were removed by direct filtration after the reaction, and the solvent was removed, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =8/1) to give a pale yellow solid (225 mg, 53%).
MS(ESI,pos.ion)m/z:617.2[M+H] + 。
Step 11) (+/-) -trans-3- ((4- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (furan-2- Phenyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid
Figure BDA0001629238560000413
(+/-) -trans-3- ((4- (5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (225 mg,0.36 mmol) was dissolved in a mixed solution of THF/MeOH (v/v=8 mL/4 mL), then NaOH (150 mg,3.6 mmol) was weighed into water (2 mL), the above reaction solution was added and stirred overnight at room temperature. Water (10 mL) was added, acidified to pH 3-4 with hydrochloric acid (1M), the aqueous phase extracted with ethyl acetate (20 mL. Times.3), the organic phase washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure, and the resulting residue purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1-5/1) to give the title compound as a white solid (70 mg, 42.79%).
MS(ESI,pos.ion)m/z:449.3[M+H] + ；
HRMS(ESI,pos.ion)m/z:449.1741[M+H] + ,(C 23 H 22 FN 6 O 3 )[M+H] + Theoretical value 449.1737;
1 H NMR(400MHz,DMSO-d 6 ) Delta (ppm) 12.77-12.34 (m, 1H), 8.52 (dd, j=31.2, 18.8hz, 1H), 8.38-8.15 (m, 1H), 7.97 (d, j=10.3 hz, 1H), 6.87 (s, 1H), 6.68 (d, j=41.0 hz, 1H), 4.53 (d, j=53.3 hz, 1H), 2.67 (dd, j=29.0, 5.6hz, 1H), 2.04-1.83 (m, 2H), 1.47 (dd, j=27.2, 12.4hz, 3H), 1.38 (d, j=21.5 hz, 5H), 1.19 (m, 2H); the title compound 1 H NMR(400MHz,DMSO-d 6 ) The spectrum is shown in figure 1.
Example 2 (+/-) -trans-3- ((4- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl)) -6-phenyl-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid
Figure BDA0001629238560000421
Step 1) (+/-) -trans-3- ((4-chloro-6-phenyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octyl Alkyl-2-carboxylic acid methyl ester
Figure BDA0001629238560000422
(+/-) -trans-3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester (4.0 g,12.1 mmol), phenylboronic acid (1.50 g,12.1 mmol), potassium carbonate (5.0 g,36.2 mmol) and Pd (PPh) 3 ) 4 (1.40 g,1.21 mmol) was mixed in THF (80 mL), water (8 mL) was added, and then the mixture was stirred under nitrogen at 70℃for 9 hours. The solid impurities were removed by direct filtration after the reaction was completed, and purified by silica gel column chromatography (PE/EtOAc (v/v) =20/1) after removal of the solvent to give yellow solid (930mg, 21%).
MS(ESI,pos.ion)m/z:373.1[M+H] + 。
Step 2) (+/-) -trans-3- ((4- (5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b) ]Pyridine-3- Phenyl) -6-phenyl-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester
Figure BDA0001629238560000423
5-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (1.1 g,1.60mmol, 60%), potassium carbonate (400 mg,2.89 mmol), palladium acetate (50 mg,0.22 mmol), X-Phos (112 mg,0.23 mmol) and (+/-) -trans-3- ((4-chloro-6-phenyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (500 mg,1.34 mmol) were mixed in THF (10 mL), water (0.5 mL) was added, and then heated to 66℃under nitrogen protection under reflux stirring for 12 hours. After the reaction was completed, the solid impurities were removed by direct filtration, and the solvent was removed, and the obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =8/1) to give a pale yellow solid (240 mg, 28.55%).
MS(ESI,pos.ion)m/z:627.2[M+H] + 。
Step 3) (+/-) -trans-3- ((4- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6-phenyl-1, 3,5- Triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid
Figure BDA0001629238560000431
(+/-) -trans-3- ((4- (5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6-phenyl-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid methyl ester (240 mg,0.38 mmol) was dissolved in a mixed solution of THF/MeOH (v/v=8 mL/4 mL), then NaOH (150 mg,3.8 mmol) was weighed and dissolved in water (2 mL), added to the above reaction solution and stirred at room temperature overnight. Water (10 mL) was added, acidified to pH 3-4 with hydrochloric acid (1M), the aqueous phase extracted with ethyl acetate (20 mL. Times.3), the combined organic phases washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure, and the resulting residue purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1-5/1) to give the title compound as a white solid (80 mg, 45.56%).
MS(ESI,pos.ion)m/z:459.3[M+H] + ；
HRMS(ESI,pos.ion)m/z:459.2010[M+H] + ,(C 25 H 24 FN 6 O 2 )[M+H] + Theoretical value 459.1945;
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.59(d,J＝24.7Hz,1H),8.66–8.58(m,1H),8.50(dd,J＝15.1,6.7Hz,2H),8.34(s,1H),8.05(dd,J＝27.3,6.8Hz,1H),7.58(d,J＝7.3Hz,3H),4.71–4.53(m,1H),2.71(dd,J＝30.9,6.1Hz,1H),2.00(s,1H),1.77(d,J＝30.9Hz,2H),1.67–1.50(m,3H),1.48–1.33(m,5H),1.22(d,J＝23.3Hz,2H)；
the title compound 1 H NMR(400MHz,DMSO-d 6 ) The spectrum is shown in figure 2.
Example 3 (+/-) -trans-3- ((4- (5, 7-difluoro-1H-indol-3-yl) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid
Figure BDA0001629238560000432
Step 1) (+/-) -trans-3- ((4-chloro-6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester
Figure BDA0001629238560000433
(+/-) -trans-3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester (2.50 g,7.55 mmol), 2-furanboronic acid (850 mg,7.55 mmol), potassium acetate (2.30 g,22.60 mmol) and Pd (dppf) Cl 2 (620 mg,0.848 mmol) was mixed in 1, 4-dioxane (50 mL) and water (5 mL), and the resulting mixture was warmed to 100℃under nitrogen and stirred for 4 hours. The solid impurities were removed by direct filtration after the reaction, and the solvent was removed, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =15/1) to give a white solid (520 mg, 19%).
MS(ESI,pos.ion)m/z:363.2[M+H] + 。
Step 2) (2-bromo-4, 6-difluorophenyl) carbamic acid methyl ester
Figure BDA0001629238560000441
Compound 2-bromo-4, 6-difluoroaniline (10.00 g,48.07 mmol) and potassium carbonate (19.93 g,144.20 mmol) were suspended in acetonitrile (80 mL), methyl chloroformate (22.29 mL,288.46 mmol) was slowly added dropwise thereto at room temperature, and after the addition was completed, the resulting mixture was stirred at room temperature for 10 minutes and then heated to 60℃for reaction for 1 hour. After the reaction, water (80 mL) was added to the reaction system, the solution was separated, the resulting aqueous phase was extracted with ethyl acetate (80 mL), the combined organic phases were washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1 to 3/1) to give the title compound as a white solid (11.68 g, 91%).
MS(ESI,pos.ion)m/z:267.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.24–7.17(m,1H),6.93(td,J＝9.3,2.7Hz,1H),6.10(s,1H),3.81(s,3H)。
Step 3) (2, 4-difluoro-6- ((trimethylsilyl) ethynyl) phenyl) carbamic acid methyl ester
Figure BDA0001629238560000442
Methyl (2-bromo-4, 6-difluorophenyl) carbamate (10.8 g,40.6 mmol) was dissolved in acetonitrile (11.6 mL) followed by the sequential addition of triethylamine (11.3 mL), pd (PPh) 3 ) 2 Cl 2 (5.76 g,8.12 mmol) and cuprous iodide (773 mg,4.06 mmol) were then slowly added to the reaction system under nitrogen protection, the mixture after the addition was stirred at 80 ℃ overnight under nitrogen protection, then saturated ammonium chloride solution (100 mL) was added to the reaction solution for dilution, the resultant mixture was extracted with ethyl acetate (100 ml×3), the combined organic phases were washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness under reduced pressure, and the resultant residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =10/1) to give the title compound as a brown solid (9.53 g, 83%).
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.03–6.97(m,1H),6.93–6.86(m,1H),6.27(s,1H),3.80(s,3H),0.28(s,9H)。
Step 4) 5, 7-difluoro-1H-indole
Figure BDA0001629238560000443
Methyl (11.02 g,38.88 mmol) of compound (2, 4-difluoro-6- ((trimethylsilyl) ethynyl) phenyl) carbamate (11.02 g,38.88 mmol) was dissolved in ethanol (100 mL), then an ethanol solution of sodium ethoxide (61 mL,155.5 mmol) was added thereto, the resulting mixture was stirred under nitrogen for 1.5 hours at room temperature and then heated to 80 ℃ and the reaction was continued with stirring for 3 hours, then cooled to room temperature, the solvent was removed by concentration under reduced pressure, ethyl acetate (100 mL) was added to the resulting residue, which was dissolved, and the resulting mixture was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) =10/1) to give the title compound as a white solid (4.76 g, 80%).
1 H NMR(600MHz,CDCl 3 )δ(ppm):9.62(s,1H),8.16(d,J＝2.2Hz,1H),7.42–7.33(m,1H),6.53(dd,J＝3.1,2.1Hz,1H),2.53(d,J＝1.0Hz,3H)。
Step 5) 5, 7-difluoro-1-p-toluenesulfonyl-1H-indole
Figure BDA0001629238560000444
The compound 5, 7-difluoro-1H-indole (4.76 g,31.1 mmol) was dissolved in toluene (120 mL), then a sodium hydride solution (50% (mass fraction), 2.6mg,62 mmol), p-toluenesulfonyl chloride (8.89 g,46.6 mmol) and tetrabutylammonium bisulfate (1.06 g,3.11 mmol) were added sequentially, the resulting mixture was stirred at room temperature for reaction overnight, then ethyl acetate (100 mL) was added for dilution, the resulting mixture was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the residue which was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) =10/1) to give the title compound as a yellow solid (8.31 g, 87%).
MS(ESI,pos.ion)m/z:308.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.24(s,1H),8.06(d,J＝8.3Hz,2H),7.81(s,1H),7.31(d,J＝8.2Hz,2H),2.68(d,J＝1.3Hz,3H),2.40(s,3H)。
Step 6) 3-bromo-5, 7-difluoro-1-p-toluenesulfonyl-1H-indole
Figure BDA0001629238560000451
The compound 5, 7-difluoro-1-p-toluenesulfonyl-1H-indole (4.3 g,14.0 mmol) was dissolved in dichloromethane (100 mL) and then NBS (3.3 g,18.0 mmol) was added thereto in portions, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate solution (100 mL), the organic phase was washed with saturated brine (100 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (n-hexane/EtOAc (v/v) =10/1) to give the title compound as a tan solid (5.23 g, 97%).
MS(ESI,pos.ion)m/z:386.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.90–7.81(m,3H),7.33(d,J＝8.2Hz,2H),7.03(dd,J＝7.8,2.1Hz,1H),6.84(ddd,J＝11.5,9.1,2.2Hz,1H),2.42(s,3H)。
Step 7) 5, 7-difluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluene sulfonyl-1H-indoles
Figure BDA0001629238560000452
Into a one-necked flask, 3-bromo-5, 7-difluoro-1-p-toluenesulfonyl-1H-indole (5.23 g,13.5 mmol), dipentamethylenediboron (5.16 g,20.3 mmol), potassium acetate (3.99 g,40.6 mmol), pd (dppf) Cl 2 ·CH 2 Cl 2 (2.21 g,2.71 mmol) and 1, 4-dioxane (20 mL) and the resulting mixture was stirred under nitrogen at 80deg.C for 16 h. The reaction was cooled to room temperature, filtered through celite, the filter cake was washed with ethyl acetate (50 mL) and the filtrate was concentrated to dryness and the resulting residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) =10/1) to give the title compound as a white solid (4.89 g, 83%).
MS(ESI,pos.ion)m/z:434.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.21(s,1H),7.82(t,J＝7.9Hz,4H),7.30(s,2H),2.40(s,3H),1.38(s,12H)。
Step 8) (+/-) -trans-3- ((4- (5, 7-difluoro-1-p-toluenesulfonyl-1H-indol-3-yl) -6- (furo f) Pyran-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester
Figure BDA0001629238560000453
5, 7-difluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl-1H-indole (600 mg,0.85mmol, 60%), potassium phosphate (500 mg,2.31 mmol), pd (dtbpf) Cl 2 (50 mg,0.077 mmol), (+/-) -trans-3- ((4-chloro-6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2 ]Methyl octane-2-carboxylate (280 mg,0.77 mmol) was mixed in 1, 4-dioxane (10 mL) and water (1 mL), and the resulting mixture was warmed to 100 ℃ under nitrogen and stirred for 4 hours. The solid impurities were removed by direct filtration after the reaction, and the solvent was removed, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =8/1) to give a pale yellow solid (420 mg, 86%).
MS(ESI,pos.ion)m/z:634.3[M+H] + 。
Step 9) (+/-) -trans-3- ((4- (5, 7-difluoro-1H-indol-3-yl) -6- (furan-2-yl) -1,3, 5-tris Oxazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid
Figure BDA0001629238560000461
(+/-) -trans-3- ((4- (5, 7-difluoro-1-p-toluenesulfonyl-1H-indol-3-yl) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid methyl ester (420 mg,0.66 mmol) was dissolved in THF/MeOH (v/v=8 mL/4 mL), then a solution of NaOH (265 mg,6.6 mmol) in water (2 mL) was added to the reaction solution and the resulting mixture was stirred overnight at room temperature. Water (20 mL) was added, the reaction was acidified with hydrochloric acid (1M) to pH approximately 3-4, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1-5/1) to give the title compound as a white solid (200 mg, 65%).
MS(ESI,pos.ion)m/z:466.3[M+H] + ；
HRMS(ESI,pos.ion)m/z:466.1702[M+H] + ,(C 24 H 23 F 2 N 5 O 3 )[M+H] + Theoretical value 466.1691;
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.66–12.31(m,1H),8.52(dd,J＝31.2,18.8Hz,1H),8.36–8.15(m,1H),7.97(d,J＝10.3Hz,1H),7.45(d,J＝2.9Hz,1H),6.87(s,1H),6.68(d,J＝41.0Hz,1H),2.50(s,1H),2.18(s,2H),1.98(s,1H),1.82–1.61(m,3H),1.63–1.36(m,5H),1.19(dd,J＝24.2,13.6Hz,2H)；
the title compound 1 H NMR(400MHz,DMSO-d 6 ) The spectrum is shown in figure 3.
Example 4 (+/-) -trans-3- ((4- (5, 7-difluoro-1H-indol-3-yl) -6-phenyl-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid
Figure BDA0001629238560000462
Step 1) (+/-) -trans-3- ((4- (5, 7-difluoro-1-p-toluenesulfonyl-1H-indol-3-yl) -6-phenyl-) 1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester
Figure BDA0001629238560000463
5, 7-difluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl-1H-indole (680 mg,0.94mmol, 60%), potassium phosphate (550 mg,2.57 mmol), pd (dtbpf) Cl 2 (85mg,0.13mmol) and (+/-) -trans-3- ((4-chloro-6-phenyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Methyl octane-2-carboxylate (320 mg,0.85 mmol) was mixed in 1, 4-dioxane (10 mL) and water (1 mL), and the resulting mixture was warmed to 100 ℃ under nitrogen and stirred for reaction for 12 hours. The solid impurities were removed by direct filtration after the reaction, and the solvent was removed, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =8/1) to give pale yellow solid (320 mg, 58%). MS (ESI, pos.ion) m/z 644.3[ M+H ]] + 。
Step 2) (+/-) -trans-3- ((4- (5, 7-difluoro-1H-indol-3-yl) -6-phenyl-1, 3, 5-triazine-2-propanoic acid) Radical) amino) bicyclo [2.2.2 ]Octane-2-carboxylic acid
Figure BDA0001629238560000471
(+/-) -trans-3- ((4- (5, 7-difluoro-1-p-toluenesulfonyl-1H-indol-3-yl) -6-phenyl-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid methyl ester (320 mg,0.49 mmol) was dissolved in THF/MeOH (v/v=8 mL/4 mL), then a solution of NaOH (200 mg,5.00 mmol) in water (2 mL) was added thereto, and the resulting reaction solution was stirred at room temperature overnight. Water (10 mL) was added, the reaction was acidified with hydrochloric acid (1M) to pH approximately 3-4, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1-5/1) to give the title compound as a white solid (70 mg, 30%).
MS(ESI,pos.ion)m/z:476.1[M+H] + ；
HRMS(ESI,pos.ion)m/z:476.1895[M+H] + ,(C 23 H 22 ClN 6 O 3 )[M+H] + Theoretical value 476.1898;
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.56(d,J＝18.3Hz,1H),12.27(s,1H),8.51(dd,J＝15.1,7.8Hz,3H),8.23(dd,J＝56.3,9.4Hz,1H),8.04(dd,J＝23.4,6.6Hz,1H),7.60–7.55(m,2H),7.13(s,1H),4.76–4.46(m,1H),2.73(dd,J＝24.0,5.6Hz,1H),1.96(d,J＝36.7Hz,2H),1.79(dd,J＝30.5,11.2Hz,3H),1.66–1.39(m,5H),1.21(t,J＝15.9Hz,2H)；
13 C NMR(101MHz,DMSO-d 6 )δ(ppm):175.97,175.76,169.96,169.87,169.65,169.21,165.62,137.05,134.16,132.11,128.74,128.31,103.78,98.18,97.89,50.89,48.44,40.97,39.38,28.37,26.11,24.10,21.84,19.14。
the title compound 1 H NMR(400MHz,DMSO-d 6 ) The spectrogram is shown in figure 4;
the title compound 13 C NMR(101MHz,DMSO-d 6 ) The spectrum is shown in FIG. 5.
Example 5 (+/-) -trans-3- ((4- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid
Figure BDA0001629238560000472
Step 1) 5-chloro-3- ((trimethylsilyl) ethynyl) pyrazin-2-amine
Figure BDA0001629238560000473
3-bromo-5-chloropyrazin-2-amine (200 mg,0.96 mmol), triethylamine (290 mg,2.88 mmol), cuprous iodide (5 mg,0.33 mmol) and bis (triphenylphosphine) palladium dichloride (13 mg,0.02 mmol) were dissolved in tetrahydrofuran (5 mL), the reaction solution was stirred at room temperature, and then trimethylethynyl silicon (0.15 mL,1.06 mmol) was slowly added dropwise to the reaction solution, and after the addition was completed, the reaction solution was heated to 55℃and continued to react for 1 hour. After the reaction system was cooled to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EA (v/v) =30/1) to give the title compound as a pale yellow solid (208 mg, 96%).
MS(ESI,pos.ion)m/z:227.00[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.98(s,1H),5.11(s,2H),0.31(s,9H)。
Step 2) 2-chloro-5H-pyrrolo [2,3-b]Pyrazine compounds
Figure BDA0001629238560000481
5-chloro-3- ((trimethylsilyl) ethynyl) pyrazin-2-amine (100 mg,0.44 mmol) was dissolved in THF (8 mL), the resulting solution was stirred at room temperature, then potassium tert-butoxide (59 mg,0.53 mmol) was added thereto, the tube was capped and the reaction was carried out at 120 ℃ for 1 hour. The reaction was stopped, cooled to room temperature, the reaction solution was diluted with ethyl acetate (80 mL), filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EA (v/v) =3/1) to give the title compound as a pale yellow solid (40 mg, 59%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):8.29(s,1H),7.98(d,J＝3.5Hz,1H),6.62(d,J＝3.5Hz,1H),5.75(s,1H)。
Step 3) 2-chloro-7-iodo-5H-pyrrolo [2,3-b]Pyrazine compounds
Figure BDA0001629238560000482
2-chloro-5H-pyrrolo [2,3-b ] pyrazine (80 mg,1.82 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL), to which was added NIS (4571 mg,2.00 mmol), and the resulting reaction solution was allowed to react overnight at room temperature. The reaction was quenched with saturated sodium thiosulfate (50 mL), separated, the aqueous phase was extracted with ethyl acetate (50 ml×2), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =20/1-4/1) to give the title compound as a yellow solid (458 mg, 89%).
MS(ESI,pos.ion)m/z:280.00[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 )δ(ppm):12.81(s,1H),8.36(s,1H),8.21(d,J＝2.7Hz,1H)。
Step 4) 2-chloro-7-iodo-5-trityl-5H-pyrrolo [2,3-b]Pyrazine compounds
Figure BDA0001629238560000483
2-chloro-7-iodo-5H-pyrrolo [2,3-b]Pyrazine (1.76 g,6.30 mmol), K 2 CO 3 (1.74 g,12.60 mmol) and triphenylchloromethane (1.93 g,6.93 mmol) were dissolved in DMF (8 mL), the resulting reaction solution was stirred at room temperature overnight, the reaction solution was added to water (100 mL), the resulting mixture was extracted with ethyl acetate (100 mL. Times.3), the combined organic phases were washed with saturated brine (180 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) =20/1) to give the title compound as a pale yellow solid (2.96 g, 90%).
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.92(s,1H),7.65(s,1H),7.35–7.30(m,10H),7.17(dd,J＝6.5,3.0Hz,5H)。
Step 5) 2-chloro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5-trityl- 5H-pyrrolo [2,3-b]Pyrazine compounds
Figure BDA0001629238560000491
2-chloro-7-iodo-5-trityl-1H-pyrrolo [2,3-b ] pyrazine (500 mg,0.96 mmol) and isopropyl alcohol pinacol borate (231 mg,1.25 mmol) were dissolved in THF (10 mL), the resulting solution was cooled to-27℃under nitrogen protection, and then isopropyl magnesium chloride (2M, 0.70 mL) was slowly added dropwise thereto, and the reaction was stirred at-27℃for 1.5 hours after the completion of the dropwise addition. The reaction was stopped, the reaction solution was added to saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (100 ml×3), and the combined organic phases concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10/1) to give the title compound as a yellow solid (210 mg, 42%).
Step 6) (+/-) -trans-3- ((4- (2-chloro-5-trityl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester
Figure BDA0001629238560000492
2-chloro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5-trityl-5H-pyrrolo [2,3-b ] pyrazine (226 mg,0.303mmol, 70%), potassium carbonate (152 mg,1.10 mmol), palladium acetate (12 mg,0.05 mmol), X-Phos (52 mg,0.11 mmol), and methyl (+/-) -trans-3- ((4-chloro-6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg,0.275 mmol) were mixed in tetrahydrofuran (5 mL) and water (0.5 mL), and the resulting mixture was warmed to reflux under nitrogen protection and stirred for 12 hours. The solid impurities were removed by direct filtration after the reaction, and the solvent was removed, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =8/1) to give a pale yellow solid (70 mg, 35%).
Step 7) (+/-) -trans-3- ((4- (2-chloro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (furan-2- Phenyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid
Figure BDA0001629238560000493
(+/-) -trans-3- ((4- (2-chloro-5-trityl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (furan-2-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (70 mg,0.10 mmol) was dissolved in dichloromethane (10 mL), triethylsilane (1.53 g,13.46 mmol) and trifluoroacetic acid (0.78 g,6.26 mmol) were then added, the resulting mixture was stirred at room temperature overnight, the reaction mixture was concentrated to give a crude THF/MeOH (v/v=8 mL/4 mL) solution, then NaOH (38 mg,1.0 mmol) in water (2 mL) was added thereto, and the resulting mixture was left to stir at room temperature overnight. Water (20 mL) was added, the reaction was acidified with hydrochloric acid (1M) to pH approximately 3-4, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1-5/1) to give the title compound as a pale yellow solid (26 mg, 58%).
MS(ESI,pos.ion)m/z:466.0[M+H] + ；
HRMS(ESI,pos.ion)m/z:465.1387[M+H] + ,(C 22 H 21 ClN 7 O 3 )[M+H] + Theoretical value 466.1394;
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):13.02(s,1H),12.21(s,1H),8.78(s,1H),8.41(s,1H),7.97(d,J＝11.8Hz,1H),7.46(d,J＝13.5Hz,1H),6.87(s,2H),6.74(s,1H),6.64(s,1H),4.52(d,J＝25.2Hz,1H),2.67(s,1H),1.97(s,2H),1.47(d,J＝36.6Hz,5H),1.23(s,1H)；
the title compound 1 H NMR(400MHz,DMSO-d 6 ) The spectrum is shown in FIG. 6.
Example 6 (2S, 3S) -3- ((4- (5-chloro-1H-pyrazolo [3,4-b ] pyridin-3-yl) -6- (2-furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid
Figure BDA0001629238560000501
Step 1) (2S, 3S) -3-aminobicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester hydrochloride
Figure BDA0001629238560000502
The preparation of the title compound is described in reference to the preparation described in patent WO 2015073491 and the relevant content thereof is incorporated in its entirety into the present invention.
Step 2) (2S, 3S) -3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid methyl ester Acid ethyl ester
Figure BDA0001629238560000503
2,4, 6-trichloro-1, 3, 5-triazine (3.00 g,16.26 mmol) was dissolved in acetone (60 mL), cooled to 0deg.C, sodium bicarbonate (4.59 g,54.64 mmol) was added, and (2S, 3S) -3-aminobicyclo [2.2.2] octane-2-carboxylate hydrochloride (3.80 g,19.26 mmol) was slowly added and the reaction stirred at 0deg.C for 3 hours. To the reaction solution was added water (60 mL), the resulting mixture was extracted with ethyl acetate (60 mL. Times.3), and the combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =20/1) to give the title compound as a yellow oil (3.91 g, 59%).
MS(ESI,pos.ion)m/z:345.1[M+1] + 。
Step 3) (2S, 3S) -3- ((4-chloro-6- (2-furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] Octane-2-carboxylic acid ethyl ester
Figure BDA0001629238560000504
Taking (2S, 3S) -3- ((4, 6-dichloro-1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Ethyl octane-2-carboxylate (50 mg,0.14 mmol), tetrahydrofuran (4 mL), pd (dppf) Cl 2 (10 mg,0.01 mmol), 2-furanboronic acid (61 mg,0.55 mmol), potassium carbonate (60 mg,0.43 mmol) and water (0.1 mL) were reacted in a microwave tube with heating to 80℃under nitrogen protection for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =5/1) to give the title compound as a white solid (40 mg, 73%).
MS(ESI,pos.ion)m/z:377.2[M+H] + 。
Step 4) 2, 5-dichloro nicotinamide
Figure BDA0001629238560000505
2, 5-Dichloronicotinic acid (810.30 mg, 4.2)2 mmol) was dissolved in dichloromethane (8.0 mL), oxalyl chloride (0.80 mL,9.50 mmol) was added to the reaction under nitrogen, DMF (0.03 mL,0.40 mmol) was then slowly added dropwise to the reaction system and the reaction was stirred at room temperature for 2 hours. The DCM was then removed by concentrating under reduced pressure at 30deg.C, and THF (5 mL) was added thereto, the ice bath was cooled to 0deg.C, and concentrated aqueous ammonia (6.2 mL, 26%) was added thereto, followed by transferring to room temperature and stirring the reaction for 2 hours. Ethyl acetate (20 mL) was added to dilute the reaction solution, which was then extracted with ethyl acetate (80 ml×3), and the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (780 mg, 97%). MS (ESI, pos.ion) m/z 191.1[ M+H ] ] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)8.56(d,J＝2.6Hz,1H),8.12(d,J＝2.6Hz,2H),7.87(s,1H)。
Step 5) 2, 5-dichloro nicotinonitrile
Figure BDA0001629238560000511
2, 5-Dichloronicotinamide (180 mg,0.94 mmol) was dissolved in DCM (8.0 mL) to which TFAA (0.16 mL,1.20 mmol) and Et were then added sequentially 3 N (0.30 mL,2.20 mmol) and the resulting mixture was reacted at room temperature for 1.5 hours, after the reaction was completed, the reaction solution was added to water (50 mL), the resulting mixture was extracted with dichloromethane (80 mL. Times.3), the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (155 mg, 95%) by purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1).
MS(ESI,pos.ion)m/z:196.1[M+Na] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.58(d,J＝2.5Hz,1H),8.01(d,J＝2.5Hz,1H)。
Step 6) 5-chloro-1H-pyrazolo [3,4-b]Pyridin-3-amines
Figure BDA0001629238560000512
2, 5-Dichloronicotinonitrile (160 mg,0.92 mmol) was dissolved in n-butanol (15.0 mL), and then hydrazine hydrate (0.4 mL,15 mmol) was added thereto, and the resulting mixture was reacted at 120℃for 7 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a white solid (86 mg, 55%).
MS(ESI,pos.ion)m/z:169.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.33(s,1H),8.29(s,1H),5.69(s,2H)。
Step 7) 3-bromo-5-chloro-1H-pyrazolo [3,4-b]Pyridine compound
Figure BDA0001629238560000513
/>
5-chloro-1H-pyrazolo [3,4-b ] pyridin-3-amine (694 mg,4.12 mmol) was dissolved in bromoform (5 mL) and tert-butyl nitrite (1.2 mL,10.0 mmol) was added thereto, and the resulting mixture was reacted at 61℃for 1 hour and then transferred to 90℃for another 1 hour. The reaction was stopped, the bromoform was distilled off under reduced pressure, the residue was dissolved with ethyl acetate, then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a yellow powder (471 mg, 49%).
MS(ESI,pos.ion)m/z:233.9[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):14.03(d,J＝206.4Hz,1H),8.61(dd,J＝18.1,1.7Hz,1H),8.28(dd,J＝10.7,2.0Hz,1H)。
Step 8) 3-bromo-5-chloro-1-trityl-1H-pyrazolo [3,4-b]Pyridine compound
Figure BDA0001629238560000521
3-bromo-5-chloro-1H-pyrazolo [3,4-b]Pyridine (471 mg,2.03 mmol) was dissolved in DMF (5 mL) to which K was added at 0deg.C 2 CO 3 (98 mg,6.11 mmol) and stirred at this temperature for 30 minutes, then triphenylchloromethane (677 mg,2.43 mmol) was added and the mixture was transferred to room temperature and stirred overnight. The reaction was quenched with water (50 mL), the aqueous phase was extracted with ethyl acetate (80 ml×2), the combined organic phases were washed with saturated brine (80 ml×3), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4/1) to give the title compound as a yellow solid (425 mg, 44%).
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.38(d,J＝2.3Hz,1H),8.26(d,J＝2.3Hz,1H),7.31–7.19(m,15H)。
Step 9) 5-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl- 1H-pyrazolo [3,4-b]Pyridine compound
Figure BDA0001629238560000522
3-bromo-5-chloro-1-trityl-1H-pyrazolo [3,4-b]Pyridine (500 mg,1.05 mmol), pd (dppf) Cl 2 (158 mg,0.21 mmol) and KOAc (310 mg,3.16 mmol) were suspended in DME (10 mL), the air in the suspension was purged with nitrogen, and then pinacol diboronate (401 mg,1.58 mmol) was added thereto, and the resulting mixture was heated to 105℃under nitrogen and stirred for 2 hours. After the reaction solution was cooled to room temperature, ethyl acetate (20 mL) was added, and then the resulting mixture was suction-filtered through celite, and the cake was washed with ethyl acetate (20 ml×2), and the filtrate was concentrated under reduced pressure to give a brown oily viscous liquid (335 mg, 61%) which was used directly in the next step without further purification.
Step 10) (2S, 3S) -3- ((4- (5-chloro-1-trityl-pyrazolo [3, 4-b)]Pyridin-3-yl) -6- (2-furo Pyranyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acidEthyl ester
Figure BDA0001629238560000523
5-chloro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-trityl-1H-pyrazolo [3,4-b]Pyridine (322 mg,0.37mmol, 60%), (2S, 3S) -3- ((4-chloro-6- (2-furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Ethyl octane-2-carboxylate (100 mg,0.27 mmol), potassium phosphate (110 mg,0.52 mmol), pd (dtbpf) Cl 2 (43 mg,0.07 mmol) in 1, 4-dioxane (3 mL) and water (0.2 mL), the resulting mixture was evacuated with nitrogen bubbling for 10 min, then the tube was capped, heated to 110℃and stirred for 2 h. The reaction was filtered (celite-assisted filtration), the filter cake was washed with ethyl acetate (50 mL), the resulting filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) =5/1) to give the title compound as a yellow solid (69 mg, 35%).
Step 11) (2S, 3S) -3- ((4- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -6- (2-furyl) -1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester
Figure BDA0001629238560000531
(2S, 3S) -3- ((4- (5-chloro-1-trityl-pyrazolo [3, 4-b)]Pyridin-3-yl) -6- (2-furyl) -1,3, 5-triazin-2-yl) amino bicyclo [2.2.2]Ethyl octane-2-carboxylate (69 mg,0.09 mmol) was dissolved in DCM (4 mL), then trifluoroacetic acid (0.07 mL,0.94 mmol) and triethylsilane (0.15 mL,0.94 mmol) were added to the reaction solution, and the resulting mixture was stirred at 30℃overnight. To the reaction solution was added saturated sodium bicarbonate solution (10 mL), and the separated organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1) to give the title compound as a yellow solid (21 mg, 45%). MS (ESI),pos.ion)m/z:494.3[M+H] + 。
Step 12) (2S, 3S) -3- ((4- (5-chloro-1H-pyrazolo [3, 4-b)]Pyridin-3-yl) -6- (2-furyl) -1, 3, 5-triazin-2-yl]Amino group]Bicyclo [2.2.2]Octane-2-carboxylic acid
Figure BDA0001629238560000532
Ethyl (2 s,3 s) -3- ((4- (5-chloro-1H-pyrazolo [3,4-b ] pyridin-3-yl) -6- (2-furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (21 mg,0.04 mmol) was dissolved in a THF/MeOH mixed solvent (v/v=1/1, 4 ml), then an aqueous solution of NaOH (4 m,0.10ml,0.40 mmol) was added to the reaction solution and the resulting mixture was stirred overnight at 30 ℃. The mixture was acidified to pH of about 5.5 with hydrochloric acid (1M), extracted with ethyl acetate (20 ml×3), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1) to give the title compound as a yellow solid (18 mg, 91%).
MS(ESI,pos.ion)m/z:466.1[M+H] + ；
HRMS(ESI,pos.ion)m/z:466.1396[M+H] + ,(C 22 H 21 ClN 7 O 3 )[M+H] + Theoretical value 466.1394;
the title compound 1 H NMR(400MHz,DMSO-d 6 ) The spectrum is shown in FIG. 7.
Example 7 (2S, 3S) -3- ((4- (2-furyl) -6- (7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid
Figure BDA0001629238560000533
Step 1) 5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d]Pyrimidine
Figure BDA0001629238560000541
5-bromo-7H-pyrrolo [2,3-d ] pyrimidine (1.00 g,5.05 mmol) was dissolved in dry tetrahydrofuran (20 mL), sodium hydride (404 mg,16.83 mmol) was added thereto at 0deg.C, stirring was continued at 0deg.C for 30min after the addition was completed, p-toluenesulfonyl chloride (1.16 g,6.06 mmol) was further added, the resulting mixture was transferred to room temperature and reacted overnight with stirring, the reaction was quenched with water (100 mL), the separated liquid, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) =5/1) to give the title compound as a yellow solid (1.40 g, 79%).
MS(ESI,pos.ion)m/z:351.9[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):9.08(s,1H),8.92(s,1H),8.12(d,J＝8.3Hz,2H),7.80(s,1H),7.35(d,J＝8.1Hz,2H),2.43(s,3H)。
Step 2) 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-p-toluenesulfonyl-7H-) Pyrrolo [2,3-d]Pyrimidine
Figure BDA0001629238560000542
Into a single vial was added 5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d]Pyrimidine (500 mg,1.42 mmol), pinacol diboronate (540 mg,2.13 mmol), potassium acetate (218 mg,2.84 mmol), pd (dppf) Cl 2 (115 mg,0.14 mmol) and 1, 4-dioxane (5 mL) and the resulting mixture was heated to 90 ℃ under nitrogen and allowed to react overnight, then cooled to room temperature, the reaction solution was filtered (celite-assisted) and the cake was washed with ethyl acetate (10 mL) and the filtrate was concentrated to dryness and the resulting residue purified by column chromatography on silica gel (PE/EtOAc (v/v) =5/1) to give the title compound as a white solid (284 mg, 50%).
MS(ESI,pos.ion)m/z:400.0[M+H] + 。
Step 3) (2S, 3S) -3- ((4- (2-furyl) -6- (7-p-toluenesulfonyl-7H-pyrrolo [2, 3-d)]Azoxystrobin Pyridin-5-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester
Figure BDA0001629238560000543
5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-p-toluenesulfonyl-7H-pyrrolo [2,3-d]Pyrimidine (148 mg,0.37 mmol), (2S, 3S) -3- ((4-chloro-6- (2-furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Ethyl octane-2-carboxylate (100 mg,0.27 mmol), potassium phosphate (110 mg,0.47 mmol), pd (dtbpf) Cl 2 (43 mg,0.07 mmol), 1, 4-dioxane (3 mL), and water (0.2 mL) were reacted in a closed tube at 110℃for 3 hours under nitrogen. The reaction was filtered (celite-assisted) and the filter cake was washed with ethyl acetate (50 mL). The resulting filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) =5/1) to give the title compound as a yellow solid (110 mg, 68%).
MS(ESI,pos.ion)m/z:614.2[M+H] + 。
Step 4) (2S, 3S) -3- ((4- (2-furyl) -6- (7H-pyrrolo [2, 3-d)]Pyrimidin-5-yl) -1,3, 5-triodes Oxazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid
Figure BDA0001629238560000551
/>
(2S, 3S) -3- ((4- (2-furyl) -6- (7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ethyl ester (110 mg,0.18 mmol) was dissolved in a mixed solvent of THF/MeOH (v/v=1/1, 4 mL), then an aqueous solution of NaOH (4M, 0.45mL,1.80 mmol) was added to the reaction solution, and the resulting mixture was stirred overnight at 30 ℃. The mixture was acidified to pH of about 5.5 with hydrochloric acid (1M), extracted with ethyl acetate (20 ml×3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after evaporation of the solvent under reduced pressure was purified by column chromatography over silica gel (dichloromethane/methanol (v/v) =10/1) to give the title compound as a yellow solid (56 mg, 71%).
MS(ESI,pos.ion)m/z:432.1[M+H] + ；
HRMS(ESI,pos.ion)m/z:432.1790[M+H] + ,(C 22 H 22 N 7 O 3 )[M+H] + Theoretical value 432.1784;
the title compound 1 H NMR(400MHz,DMSO-d 6 ) The spectrum is shown in FIG. 8.
Example 8 (2S, 3S) -3- ((4- (6-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6- (2-furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid
Figure BDA0001629238560000552
Step 1) 3-bromo-6-fluoro-1H-pyrrolo [2,3-b ]Pyridine compound
Figure BDA0001629238560000553
6-fluoro-1H-pyrrolo [2,3-b ] pyridine (2.50 g,18.36 mmol) was dissolved in DMF (50 mL), cooled to 0℃and then a solution of bromine (3.20 g,20.00 mmol) in DMF (20 mL) was added dropwise thereto, and after the addition, the resultant reaction mixture was stirred at room temperature for 2 hours, then water (100 mL) was added, a large amount of solid was precipitated, filtered under reduced pressure, and the cake was washed with water (30 mL. Times.2) and then dried under vacuum at 60℃for 24 hours to give the title compound as a white solid (3.44 g, 87%).
MS(ESI,pos.ion)m/z:217.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.20(s,1H),8.04–7.95(m,1H),7.67(d,J＝2.5Hz,1H),6.94(t,J＝9.7Hz,1H)。
Step 2) 3-bromo-6-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b]Pyridine compound
Figure BDA0001629238560000554
3-bromo-6-fluoro-1H-pyrrolo [2,3-b ] pyridine (3.44 g,16.00 mmol) was dissolved in tetrahydrofuran (68 mL), sodium hydride (1.30 g,32.00mmol, 60%) was added thereto at 0deg.C, the reaction was stirred at this temperature for 30 minutes, then TsCl (4.58 g,24.00 mmol) was added, and after the addition was completed, the mixture was transferred to room temperature and the stirring reaction was continued for 3 hours. The reaction was quenched with water (200 mL), the separated liquid, the aqueous phase extracted with ethyl acetate (100 mL. Times.2), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a brown solid (5.70 g, 97%).
MS(ESI,pos.ion)m/z:369.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm):8.11(d,J＝8.2Hz,2H),7.88(t,J＝7.8Hz,1H),7.75(s,1H),7.34(d,J＝7.8Hz,2H),6.91(d,J＝8.3Hz,1H),2.41(s,3H)。
Step 3) 6-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl- 1H-pyrrolo [2,3-b]Pyridine compound
Figure BDA0001629238560000561
3-bromo-6-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (5.70 g,15.00 mmol), tetrakis (triphenylphosphine) palladium (1.80 g,1.50 mmol) and potassium acetate (4.50 g,46.00 mmol) were suspended in 1, 4-dioxane (120 mL), to which was then added pinacol biborate (5.90 g,23.00 mmol), and the resulting mixture was warmed to 100℃under nitrogen and stirred for 24 hours. Ethyl acetate (50 mL) was added to dilute the reaction, then the resulting mixture was suction filtered through celite, the filter cake was washed with ethyl acetate (20 ml×2), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =40/1) to give the title compound as a yellow solid (3.50 g, 54%).
MS(ESI,pos.ion)m/z:417.30[M+H] + 。
Step 4) (2S, 3S) -3- ((4- (6-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) 6- (2-furyl) -1,3, 5-triazin-2-yl) amino-bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester
Figure BDA0001629238560000562
The compound (2S, 3S) -3- ((4-chloro-6- (2-furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester (100 mg,0.27 mmol), 6-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ]Pyridine (303 mg,0.72 mmol), potassium carbonate (110 mg,0.80 mmol), pd (dtbpf) Cl 2 (43 mg,0.07 mmol), 1, 4-dioxane (3 mL) and water (0.2 mL) were reacted in a closed tube under nitrogen at 110℃for 3 hours. The resulting mixture was filtered (celite-assisted) and the filter cake was washed with ethyl acetate (50 mL). The resulting filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) =5/1) to give the title compound as a yellow solid (23 mg, 14%).
Step 5) (2S, 3S) -3- ((4- (6-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (2-furyl) -1, 3, 5-triazin-2-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid
Figure BDA0001629238560000563
(2S, 3S) -3- ((4- (6-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6- (2-furyl) -1,3, 5-triazin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (23 mg,0.04 mmol) was dissolved in a mixed solvent of THF/MeOH (v/v=1/1, 4 mL), and then an aqueous solution of NaOH (4M, 0.10mL,0.40 mmol) was added to the reaction solution and stirred overnight at 30 ℃. The mixture was acidified to pH of about 5.5 with hydrochloric acid (1M), extracted with ethyl acetate (20 ml×3), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the residue after evaporation of the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane/methanol (v/v) =10/1) to give the title compound as a yellow solid (15 mg, 90%).
MS(ESI,pos.ion)m/z:449.1[M+H] + ；
HRMS(ESI,pos.ion)m/z:449.1752[M+H] + ,(C 23 H 22 FN 6 O 3 )[M+H] + Theoretical value 449.1737;
the title compound 1 H NMR(400MHz,DMSO-d 6 ) The spectrum is shown in FIG. 9.
Test examples of Activity
In the following examples, the inventors take some of the compounds of the present invention as examples, and examined the antiviral activity and cytotoxicity and pharmacokinetic properties of the compounds of the present invention.
Example a: cytopathic effect assay (CPE assay):
compounds were tested at the in vitro cellular level for their ability to inhibit viral H1N1A/Weiss/43 Cytopathic (CPE).
The experimental steps are as follows: MDCK cells (Madin-Darby canine kidney cells, canine kidney epithelial continuous cell line) were seeded at 2000 cells/well in 384 well plates at 37℃in 5% CO 2 Culturing overnight under the condition; the next day, fresh medium containing both the test compound and influenza virus H1N1A/Weiss/43 (capable of producing a multiplicity of infection of 80-95% CPE) at different concentrations was changed. The highest detection concentration of the compound is 100nM, 3-fold gradient dilution, 8 concentration gradients are in turn: 100nM,33.33nM,11.11nM,3.70nM,1.23nM,0.41nM,0.14nM,0.05nM. And simultaneously setting a virus control group without adding medicine and a cell control group without virus infection without adding medicine. The cytotoxicity test group was replaced with the medium without adding virus. Two complex holes are arranged. 37 ℃,5% CO 2 Under the condition of incubationAnd culturing for 5 days. The cell activity was measured using the CCK-8 kit and the measurement data was used to calculate the antiviral effect of the compounds and cytotoxicity to infected viral cells. GraphPad Prism analysis data, CPE inhibition rate calculation, and EC acquisition according to a fitting curve 50 Values.
CPE inhibition = (absorbance of dosing wells-virus control Kong Xiguang)/(cell control Kong Xiguang-virus control Kong Xiguang) ×100% of
Table 1 shows experimental data for the inhibitory activity of some compounds of the invention against influenza virus (A/Weiss/43 (H1N 1)).
Table 1:
example number EC 50 (nM)
Example 1 2.149
Example 2 0.533
Example 3 3.121
Example 4 1.235
Example 5 0.397
Example 6 2.538
As can be seen from Table 1, the compounds of the present invention have excellent anti-influenza virus activity.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (14)

1. A compound which is a compound represented by the formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by the formula (I),
Figure QLYQS_1
wherein:
ring a is of the sub-structural formula:
Figure QLYQS_2
wherein: u (U) 1 Is N or CR 1 ；U 2 Is N or CR 2 ；U 3 Is N or CR 3 ；U 4 Is N or CR 4 ；
U 5 Is N; u (U) 6 Is N; u (U) 7 Is N;
R 1 、R 2 、R 3 、R 4 and R is 8 Each independently is H, D, F, cl, br, I or C 1-6 An alkyl group;
R 9 is C 6-10 Aryl or heteroaryl of 5-10 atoms, wherein said C 6-10 Aryl and heteroaryl consisting of 5 to 10 atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted;
each R is x D, F, cl, br, I, CN, NO independently 2 、-OR b 、R b O-C 1-4 Alkylene, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, heterocyclyl of 3-8 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms; wherein the heterocyclic group consisting of 3 to 8 atoms is non-aromatic and does not contain any aromatic ring;
R 10 H, D, CF of a shape of H, D, CF 3 Methyl, ethyl, n-propyl or isopropyl;
w is
Figure QLYQS_3
(W-4) wherein: n is 1;
each R is w independently-C (=o) OH;
R b h, D or C 1-6 An alkyl group.
2. The compound of claim 1, wherein ring a is of the formula:
Figure QLYQS_4
3. the compound of claim 1, wherein ring a is of the formula:
Figure QLYQS_5
4. a compound according to any one of claims 1-3, wherein R 1 、R 2 、R 3 、R 4 And R is 8 Each independently H, D, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl.
5. A compound according to any one of claims 1-3, wherein each R x D, F, cl, br, I, CN, NO independently 2 、-OR b 、R b O-C 1-4 Alkylene, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, heterocyclyl of 5-6 atoms, phenyl or heteroaryl of 5-6 atoms; wherein the heterocyclic group consisting of 5 to 6 atoms is non-aromatic and does not contain any aromatic ring.
6. A compound according to any one of claims 1-3, wherein R b H, D, methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl.
7. A compound according to any one of claims 1-3, wherein R 9 Is phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, benzothiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl or isoquinolinyl, wherein the phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, benzothiazolyl, thienyl, benzothienyl, pyrazinyl The radicals, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl and isoquinolinyl are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5R x Substituted.
8. The compound of claim 1, having a structure of formula (II):
Figure QLYQS_6
9. the compound of claim 1 having the structure of one of:
Figure QLYQS_7
/>
Figure QLYQS_8
Figure QLYQS_9
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-9, optionally, further comprising a pharmaceutically acceptable adjuvant, vehicle, or combination thereof.
11. The pharmaceutical composition of claim 10, further comprising one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from an anti-influenza virus agent or vaccine.
12. The pharmaceutical composition of claim 10, further comprising one or more additional therapeutic agents, wherein the additional therapeutic agents are amantadine, rimantadine, oseltamivir, zanamivir, peramivir, ranimivir octanoate hydrate, famprivir, arbidol, ribavirin, stavafil, infloresin, influenza enzymes, drugs with CAS numbers 1422050-75-6, JNJ-872, S-033188, influenza vaccines, or combinations thereof.
13. Use of a compound according to any one of claims 1-9 or a pharmaceutical composition according to any one of claims 10-12 for the manufacture of a medicament for the prevention, treatment, therapy or alleviation of a viral infectious disease in a patient;
wherein the viral infection is an influenza virus infection.
14. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 12 for the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102458408A (en) * 2009-06-17 2012-05-16 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
WO2013184985A1 (en) * 2012-06-08 2013-12-12 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
CN103492382A (en) * 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
CN103562205A (en) * 2010-12-16 2014-02-05 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
WO2016020526A1 (en) * 2014-08-08 2016-02-11 Janssen Sciences Ireland Uc Indoles for use in influenza virus infection
WO2016037953A1 (en) * 2014-09-08 2016-03-17 Janssen Sciences Ireland Uc Pyrrolopyrimidines for use in influenza virus infection

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102458408A (en) * 2009-06-17 2012-05-16 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
CN103492382A (en) * 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
CN103562205A (en) * 2010-12-16 2014-02-05 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
WO2013184985A1 (en) * 2012-06-08 2013-12-12 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
WO2016020526A1 (en) * 2014-08-08 2016-02-11 Janssen Sciences Ireland Uc Indoles for use in influenza virus infection
WO2016037953A1 (en) * 2014-09-08 2016-03-17 Janssen Sciences Ireland Uc Pyrrolopyrimidines for use in influenza virus infection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Aminopyrimidinone Cdc7 Kinase Inhibitors;Keith W. Woods et al.;《Bioorganic & Medicinal Chemistry Letters》;20120125;第22卷(第5期);第1940-1943页；Supplementary Material *

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