CN113620948B

CN113620948B - Cap-dependent endonuclease inhibitors

Info

Publication number: CN113620948B
Application number: CN202010372597.8A
Authority: CN
Inventors: 林助强; 陈宏铨
Original assignee: Taijing Pharmaceutical Research And Development Beijing Co ltd
Current assignee: Taijing Pharmaceutical Research And Development Beijing Co ltd
Priority date: 2020-05-06
Filing date: 2020-05-06
Publication date: 2022-11-25
Anticipated expiration: 2040-05-06
Also published as: CN113620948A

Abstract

The present invention provides a compound of formula (I), a pharmaceutically acceptable salt, metabolite or prodrug thereof, for use in inhibiting influenza virus replication:

Description

Cap-dependent endonuclease inhibitors

Technical Field

The present invention relates to the field of medicinal chemistry, in particular to heterocyclic compounds having cap-dependent endonuclease inhibitory activity, prodrugs thereof, and uses thereof for the treatment of influenza.

Background

The RNA polymerase of influenza virus contains a cap-dependent endonuclease (cap-dependent endonuclease) domain that cleaves host mRNA to produce capped RNA fragments that serve as primers for initiating viral mRNA synthesis.

Translation of viral mRNA by host ribosomes requires the 5 'cap end of the mRNA, which can be achieved in influenza virus-infected cells by a cap-snatching mechanism in which a cap-dependent endonuclease cleaves the 5' cap end from the host mRNA, which then serves as transcription primers (10 to 13 nucleotides) that are used to synthesize mRNA encoding the viral proteins.

Inhibition of cap-dependent endonuclease activity can lead to inhibition of influenza virus proliferation, and thus, cap-dependent endonucleases are considered to be important biological targets for effective anti-influenza drugs.

Although different heterocyclic compounds have been used as cap-dependent endonuclease inhibitors. However, influenza has a strong ability to spread, is wide-ranging, and is liable to cause serious complications, and has posed a serious threat to global public health, and therefore, there is still a demand for novel compounds as effective cap-dependent endonuclease inhibitors.

Disclosure of Invention

The present invention provides a novel cap-dependent endonuclease inhibitor.

In a first aspect of the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, metabolite or prodrug thereof:

in the formula,

R ₁ selected from the group consisting of: hydrogen, deuterium, halogen, cyano, hydroxy, carboxy, amino, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _1-6 An alkoxy group;

each R ₂ Independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, hydroxy, carboxy, amino, formyl, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy radical, C _2-6 An alkenyloxy group;

each R ₃ Independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, NO ₂ Oxo, hydroxy, carboxy, amino, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy radical, C _1-6 Alkylamine, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C _6-12 Aryl or 5-12 membered heteroaryl; or any two R ₃ May form C together with the atoms adjacent thereto _3-12 Cycloalkyl, C _3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C _6-12 Aryl or 5-12 membered heteroaryl;

ring A is C _3-12 A cycloalkyl group;

ring B is C _10-30 Carbocyclyl or 10-30 membered heterocyclyl;

m is 0, 1,2 or 3;

n is 0, 1,2, 3, 4 or 5;

wherein, the carboxyl, amino and C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy radical, C _2-6 Alkenyloxy radical, C _1-6 Alkylamine, C _3-12 Cycloalkyl, C _3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C _6-12 Aryl, 5-12 membered heteroAryl radical, C _10-30 H in the carbocyclyl and 10-30 membered heterocyclyl may be optionally substituted with 1 to 5 groups selected from: deuterium, halogen, hydroxy, cyano, amino, nitro, carboxy, C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkyl, halo C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Alkyl radical (C) _3-12 Carbocyclyl), C _1-6 Alkyl (3-12 membered heterocyclyl), C _1-6 Alkoxy (C) _3-12 Carbocyclyl), C _1-6 Alkoxy (3-12 membered heterocyclic group), C _3-12 Cycloalkyl radical, C _3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C _6-12 Aryl or 5-12 membered heteroaryl;

with the proviso that: when the ring A is a cyclopropyl group,

when n is 0 or 1, ring B is not

n is 2, 3, 4 or 5 and ring B is

When there are two arbitrary R ₃ Together with the atoms to which they are attached form C _3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C _6-12 Aryl or 5-12 membered heteroaryl, wherein, said C _3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C _6-12 The aryl and 5-12 membered heteroaryl groups may each be optionally substituted with 1 to 4 groups selected from: deuterium, halogen, hydroxy, cyano, NO ₂ Amino group, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _1-6 Alkoxy, halo C _1-6 Alkyl or halo C _1-6 An alkoxy group.

In another preferred embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, metabolite, or prodrug thereof, has the structure of formula (II):

wherein,

R ₁ 、R ₂ 、R ₃ rings B, m and n are as defined above,

with the proviso that:

when n is 0 or 1, ring B is not

When n is 2, 3, 4 or 5 and ring B is

In another preferred embodiment, any two R ₃ May form, together with the adjacent atoms, a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, oxiranyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, tetrahydrofuryl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, phenyl group, furanyl group, pyrrolyl group, pyridyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, oxadiazolyl group, 1,3, 5-triazinyl group, thiazolyl group, thienyl group, pyrazinyl group, pyridazinyl group or pyrimidinyl group, wherein said cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, oxiranyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, tetrahydrofuryl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, phenyl group, furyl group, pyrrolyl group, pyridyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, oxadiazolyl group, 1,3, 5-triazinyl group, thiazolyl group, thiophene groupOptionally substituted with 1 to 4 groups selected from the group consisting of: halogen, deuterium, cyano, NO ₂ Hydroxy, amino, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl or C _1-6 Alkoxy substitution.

In another preferred embodiment, the compound, or a pharmaceutically acceptable salt, metabolite or prodrug thereof, wherein ring B is selected from the group consisting of:

in a further preferred embodiment of the method,

the moiety is selected from the group consisting of:

in another preferred embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, metabolite, or prodrug thereof, has the structure of formula (III):

wherein R is ₁ 、R ₂ 、R ₃ Ring A, m and n are as defined above;

U ₁ is CH or N;

ring D is C _3-12 Cycloalkyl radical, C _3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C _6-12 Aryl and 5-12 membered heteroaryl.

In another preferred embodiment, R ₁ Independently hydrogen, deuterium, cyano, halogen,Hydroxy, C _1-6 Alkyl or C _1-6 An alkoxy group; preferably, R ₁ Independently hydrogen, deuterium or C _1-6 An alkyl group; more preferably, R ₁ Is hydrogen.

In another preferred embodiment, each R ₂ Independently hydrogen, deuterium, halogen, hydroxy, carboxy, amino, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylcarbonyl group, C _1-6 Alkoxycarbonyl group, C _3-12 Cycloalkyl or C _3-12 A heterocycloalkyl group; preferably, each R ₂ Independently hydrogen, deuterium, halogen, C _1-6 Alkyl or C _1-6 An alkoxy group; more preferably, R ₂ Is hydrogen.

In another preferred embodiment, each R ₃ Independently hydrogen, deuterium, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _1-6 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Cycloalkenyl radical, C _3-12 Heterocycloalkyl, C _3-12 Heterocycloalkenyl, aryl or C _5-12 A heteroaryl group; preferably, each R ₃ Independently hydrogen, deuterium, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-12 Cycloalkyl radical, C _3-12 Heterocycloalkyl, aryl, or C _5-12 A heteroaryl group; more preferably, each R ₃ Independently hydrogen, deuterium, halogen, C _1-6 Alkyl or C _1-6 An alkoxy group; more preferably, at least one R is ₃ Is halogen, e.g. having at least one R ₃ Is fluorine.

In another preferred embodiment, ring a is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; preferably, ring a is cyclopropyl.

In another preferred embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, metabolite, or prodrug thereof, has the structure shown in formula (IV):

in the formula,

R ₁ hydrogen, deuterium, halogen;

each R ₂ Independently hydrogen, deuterium, halogen, C _1-6 An alkyl group;

each R ₃ Independently hydrogen, deuterium, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _1-6 Alkoxy radical, C _3-12 A cycloalkyl group;

U ₁ is CH or N;

ring D is C _3-12 Cycloalkyl, C _3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C _6-12 Aryl or 5-12 membered heteroaryl;

m is 1,2 or 3;

n is 1,2, 3, 4 or 5;

wherein, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, C _3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C _6-12 H in aryl or 5-12 membered heteroaryl may be optionally substituted with 1 to 3 groups selected from: deuterium, halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkyl, halo C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, C _3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C _6-12 Aryl or 5-12 membered heteroaryl.

In another preferred embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, metabolite, or prodrug thereof, has the structure shown in formula (V):

in the formula,

R ₁ 、R ₂ 、R ₃ m and n are as defined above.

In another preferred embodiment, in formula (V), it has one or more characteristics selected from the group consisting of:

R ₁ hydrogen, deuterium, halogen;

each R ₂ Independently hydrogen, deuterium, halogen, C _1-6 An alkyl group;

m is 1,2 or 3;

n is 1,2, 3, 4 or 5;

wherein, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _1-6 Alkoxy radical, C _3-12 The cycloalkyl group may be optionally substituted with 1 to 3 groups selected from: deuterium, halogen, C _1-6 Alkyl, halo C _1-6 Alkyl, halo C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C _6-12 Aryl or 5-12 membered heteroaryl.

R ₁ hydrogen and deuterium;

each R ₂ Independently hydrogen, deuterium, halogen, C _1-6 An alkyl group;

each R ₃ Independently hydrogen, deuterium, halogen, C _1-6 Alkyl radical, C _1-6 An alkoxy group;

m is 1,2 or 3;

n is 1,2, 3, 4 or 5;

wherein, said C _1-6 Alkyl radical, C _1-6 Alkoxy may be optionally substituted with 1 to 3 groups selected from: deuterium, halogen, C _1-6 Alkyl, halo C _1-6 Alkyl, halo C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C _6-12 Aryl or 5-12 membered heteroaryl.

R ₁ hydrogen and deuterium;

each R ₂ Independently hydrogen, deuterium;

each R ₃ Independently hydrogen, deuterium, halogen, C _1-6 An alkyl group;

m is 1,2 or 3;

n is 1,2, 3, 4 or 5;

wherein, said C _1-6 The alkyl group may be optionally substituted with 1 to 3 groups selected from: deuterium, halogen, C _1-6 Alkyl, halo C _1-6 Alkyl, halo C _1-6 Alkoxy radical, C _3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C _6-12 Aryl or 5-12 membered heteroaryl.

In another preferred embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, metabolite or prodrug thereof, is selected from the group consisting of:

in another preferred embodiment, the compound, or a pharmaceutically acceptable salt, metabolite or prodrug thereof is selected from the group consisting of:

in another preferred embodiment, the compound, or a pharmaceutically acceptable salt, metabolite, or prodrug thereof, wherein the prodrug has the structure shown in formula IV:

in the formula,

g is selected from the group consisting of:

a)—C(＝O)—R ₅ ；

b)—C(＝O)—R ₆ ；

c)—C(＝O)—L—R ₆ ；

d)—C(＝O)—L—O—R ₆ ；

e)—C(＝O)—L—O—L—O—R ₆ ；

f)—C(＝O)—L—O—C(＝O)—R ₆ ；

g)—C(＝O)—O—R ₇ ；

h)—C(＝O)—N(—K)(R ₇ )；

i)—C(＝O)—O—L—O—R ₇ ；

j)—C(R ₈ ) ₂ —O—R ₉ ；

k)—C(R ₈ ) ₂ —O—L—O—R ₉ ；

l)—C(R ₈ ) ₂ —O—C(═O)—R ₉ ；

m)—C(R ₈ ) ₂ —O—C(═O)—O—R ₉ ；

n)—C(R ₈ ) ₂ —O—C(═O)—N(—K)—R ₉ ；

o)—C(R ₈ ) ₂ —O—C(═O)—O—L—O—R ₉ ；

p)—C(R ₈ ) ₂ —O—C(═O)—O—L—N(R ₉ ) ₂ ；

q)—C(R ₈ ) ₂ —O—C(═O)—N(—K)—L—O—R ₉ ；

r)—C(R ₈ ) ₂ —O—C(═O)—N(—K)—L—N(R ₉ ) ₂ ；

s)—C(R ₈ ) ₂ —O—C(═O)—O—L—O—L—O—R ₉ ；

t)—C(R ₈ ) ₂ —O—C(═O)—O—L—N(—K)—C(═O)—R ₉ ；

u)—C(R ₈ ) ₂ —O—P(═O)(—R ₁₀ ) ₂ ；

v)—C(R ₈ ) ₂ —R ₁₁ ；

w)—C(═N ⁺ (R ₁₂ ) ₂ )(—N(R ₁₂ ) ₂ )；

x)—C(R ₈ ) ₂ —C(R ₈ ) ₂ —C(═O)—O—R ₇ ；

y)—C(R ₈ ) ₂ —N(—K)—C(═O)—O—R ₇ ；

z)—P(═O)(—R ₁₃ )(—R ₁₄ )；

aa)—S(═O) ₂ —R ₁₅ ；

ab)—R ₁₆ and

ac)—C(R ₈ ) ₂ —C(R ₈ ) ₂ —O—R ₇ ；

wherein L is a linear or branched C _1-6 Alkylene or C _2-6 An alkenylene group;

k is hydrogen or C which is optionally substituted by a substituent E _1-6 An alkyl group;

R ₅ is C which may optionally be substituted by a substituent E _1-6 Alkyl or C _2-6 An alkenyl group;

R ₆ is C which may optionally be substituted by a substituent E _3-12 Carbocyclyl, 3-12 membered heterocyclyl, C _1-6 Alkylamino or C _1-6 An alkylthio group;

R ₇ is trialkylsilyl or C which is optionally substituted by a substituent E _1-6 Alkyl radical, C _3-12 Carbocyclyl, 3-12 membered heterocyclyl, C _3-12 Carbocyclylalkyl or 3-12 membered heterocyclylalkyl;

R ₈ is hydrogen or C _1-6 An alkyl group;

R ₉ is trialkylsilyl or C which is optionally substituted by a substituent E _1-6 Alkyl radical, C _3-12 Carbocyclyl, 3-12 membered heterocyclyl, C _1-6 Alkylamino radical, C _3-12 Carbocyclylalkyl or 3-12 membered heterocyclylalkyl;

R ₁₀ is hydroxy or OBn;

R ₁₁ is C which may optionally be substituted by a substituent E _3-12 Carbocyclyl or 3-12 membered heterocyclyl;

R ₁₂ is C which may optionally be substituted by a substituent E _1-6 An alkyl group;

R ₁₃ is C which may optionally be substituted by a substituent E _1-6 An alkoxy group;

R ₁₄ is optionally substituted by a substituent EC _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _3-12 Carbocyclic oxy, 3-12 membered heterocyclic oxy, C _3-12 Carbocyclic amino or 3-12 membered heterocyclic amino;

or R is ₁₃ And R ₁₄ May form, together with the adjacent phosphorus atom, a heterocyclic group which may be optionally substituted by a substituent E;

R ₁₅ is C which may optionally be substituted by a substituent E _1-6 Alkyl radical, C _3-12 Carbocyclyl, 3-12 membered heterocyclyl, C _3-12 Carbocyclylalkyl or 3-12 membered heterocyclylalkyl;

R ₁₆ is C which may optionally be substituted by a substituent E _1-6 Alkyl radical, C _1-6 Alkenyl radical, C _3-12 Carbocyclyl or 3-12 membered heterocyclyl;

wherein the substituents E are independently selected from the group consisting of: oxo radical, C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino, C _1-6 Alkylamino radical, C _3-12 Carbocyclyl, 3-12 membered heterocyclyl, C _3-12 Carbocycloalkyl, C _1-6 Alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, C _1-6 Alkoxy, cyano, nitro, azido, C _1-6 Alkylsulfonyl, trialkylsilyl and phospho groups;

R ₁ 、R ₂ 、R ₃ ring A, ring B, m and n are as defined above.

In another preferred embodiment, R ₁₁ Is phenyl or 5-10 membered heteroaryl, which may be optionally substituted with substituent E; wherein the substituents E are independently selected from the group consisting of: oxo radical, C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino, C _1-6 Alkylamino radical, C _1-6 Alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, C _1-6 Alkoxy, cyano, nitro, azido, alkaneAlkylsulfonyl, trialkylsilyl and phospho groups.

In another preferred embodiment, G is selected from the group consisting of:

in a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect, or a pharmaceutically acceptable salt, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier.

In a third aspect of the invention, there is provided the use of a compound of the first aspect, or a pharmaceutically acceptable salt, metabolite or prodrug thereof, or a pharmaceutical composition of the second aspect, for the manufacture of a medicament or pharmaceutical composition for the treatment of influenza.

In a fourth aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) as described in the first aspect, or a pharmaceutically acceptable salt, metabolite or prodrug thereof, comprising the steps of:

in the formula,

p is a hydroxyl protecting group;

x is halogen;

ring A, ring B, R ₁ 、R ₂ 、R ₃ M and n are as defined above;

(i) An aldehyde is provided

(ii) Reacting the aldehyde with a carbonyl compound in an inert solvent in the presence of a base

Reacting to obtain a first intermediate

(iii) Reacting the first intermediate with a diamine compound in an inert solvent, and then obtaining a second intermediate under the action of a reducing agent

(iv) In an inert solvent 1, the second intermediate is reacted with

Reaction is carried out, and then the protecting group is removed under the conditions of inert solvent 2 and acid conditions, so as to obtain the compound shown in the formula (I).

In another preferred embodiment, P is benzyl.

In another preferred embodiment, in step (ii), the inert solvent is selected from: DMSO, DMF, ACN.

In another preferred embodiment, in step (ii), the base is selected from: pyrrolidine, sodium hydroxide and strong potassium oxide.

In another preferred embodiment, in step (iii), the inert solvent is selected from: methanol, ethanol and/or water.

In another preferred embodiment, in step (iii), the diamine compound is NH ₂ NHCOCF ₃ 。

In another preferred embodiment, in step (iii), the reducing agent is selected from: naBH ₄ And sodium triacetoxyborohydride.

In another preferred embodiment, in step (iv), the inert solvent 1 is selected from: ACN and DMF.

In another preferred embodiment, in step (iv), the inert solvent 2 is selected from: methanol, ethanol, acetone.

In another preferred embodiment, in step (iv), the acid is selected from: hydrochloric acid, sulfuric acid.

In a fifth aspect of the invention, there is provided a method of treating influenza, comprising administering to a subject in need thereof an effective amount of a compound as described above, or a pharmaceutically acceptable salt, metabolite or prodrug thereof, or a pharmaceutical composition as described in the second aspect.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be repeated herein, depending on the space.

Detailed Description

The present inventors have extensively and intensively studied to find a heterocyclic compound having a novel structure, which has a good inhibitory effect on cap-dependent endonuclease. On the basis of this, the present invention has been completed.

Term(s) for

The term "halogen" refers to fluoro, chloro, bromo or iodo groups.

The term "hydroxy" refers to-OH.

The term "cyano" refers to — CN.

The term "amino" refers to the group-NH ₂ 。

The term "nitro" means-NO ₂ 。

The term "carboxy" refers to-COOH.

The term "formyl" refers to-CHO.

The term "alkyl" (which may be used alone or in combination with other terms) or "C _1-6 Alkyl "(used alone or in combination with other terms) refers to a branched or straight chain saturated aliphatic hydrocarbon group containing 1 to 6 (e.g., 1 to 4, i.e., 1,2, 3, or 4) carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and the like.

The term "alkenyl" (which may be used alone or in combination with other terms) or "C _2-6 Alkenyl "(used alone or in combination with other terms) refers to a straight or branched chain hydrocarbon group containing 2 to 6 (e.g., 2 to 4, i.e., 2, 3, or 4) carbon atoms and one or more double bonds. Examples of alkenyl groups include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprenyl, butadienyl, pentenyl, isopentenyl, isoprenyl, and the like.

The term "C _2-6 Alkynyl "(can)Alone or in combination with other groups) means a straight-chain or branched hydrocarbon radical containing 2 to 6 (e.g. 2 to 4) carbon atoms and one or more triple bonds, C _2-6 Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like.

The term "C _1-6 Alkoxy "(alone OR in combination with other groups) means a-OR group, wherein R is C as described above _1-6 An alkyl group. C _1-6 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The term "C _2-6 Alkenyloxy "(alone OR in combination with other groups) means the group-OR, where R is C as described above _2-6 An alkenyl group.

The term "C _1-6 Alkylamine "(used alone or in combination with other groups) refers to the-NHR group, where R is C as described above _1-6 An alkyl group. C _1-6 Examples of the alkylamine include a methylamino group, an ethylamino group, or an isopropylamino group.

The term "C _3-12 Cycloalkyl "(used alone or in combination with other groups) refers to a saturated cyclic hydrocarbon group containing 3 to 12 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing from 3 to 8 carbon ring atoms (i.e., C) _3-8 ) More usually 3 to 6 carbon ring atoms (i.e., C) _3-6 ) More typically containing 5 to 6 carbon ring atoms (i.e., C) _5-6 ). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl. Alternatively, the cycloalkyl group can also be polycyclic.

The term "C _3-12 Cycloalkenyl "(used alone or in combination with other groups) refers to a partially saturated cyclic hydrocarbon group containing from 3 to 12 carbon ring atoms. Cycloalkenyl groups can be monocyclic, typically containing from 3 to 8 carbon ring atoms (i.e., C) _3-8 ) More usually 3 to 6 carbon ring atoms (i.e., C) _3-6 ) More typically containing 5 to 6 carbon ring atoms (i.e., C) _5-6 ). Examples of monocyclic cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, or cyclohexadienyl. Or alternativelyCycloalkenyl groups can also be polycyclic.

The term "aryl" (which may be used alone or in combination with other groups) refers to an aromatic carbocyclic group containing from 6 to 14 carbon ring atoms. The aryl group may be monocyclic or polycyclic. In the case of polycyclic aromatic rings, the polycyclic ring system requires only one ring to be unsaturated, while the remaining rings can be saturated, partially saturated, or unsaturated. In the present invention, "C _6-12 Aryl "refers to an aromatic carbocyclic group containing from 6 to 12 carbon ring atoms, and examples of aryl include phenyl, naphthyl, indenyl, indanyl, tetrahydroindenyl, fluorenyl, or adamantyl.

The term "3-12 membered heterocycloalkyl" refers to C as defined above _3-12 One or more ring atoms in the cycloalkyl group are selected from the group consisting of: examples of heteroatoms, heterocycloalkyl, of O, N, or S include, but are not limited to, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thioxolinyl, piperazinyl, pyrazolidinyl, imidazolinyl, pyrrolyl.

The term "3-12 membered heterocycloalkenyl" refers to C as defined above _3-12 One or more ring atoms of the cycloalkenyl group are selected from the group consisting of: examples of heteroatoms, heterocycloalkenyl groups of O, N or S include, but are not limited to, pyranyl, dihydrobenzimidazolyl and 1, 3-dihydrospirobenzo [ d]Imidazole-2, 1' -cyclopentan-4-yl.

The term "heteroaryl" refers to a monocyclic or polycyclic ring system comprising one or more aromatic rings and one or more ring atoms in the aromatic ring is selected from the group consisting of: o, N or S, and in the present invention, "5-12 membered heteroaryl" means an aromatic ring system comprising 5 to 12 (i.e., 5, 6, 7, 8, 9, 10, 11, 12) ring atoms, and examples of heteroaryl include, but are not limited to, thienyl, furyl, pyridyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl and thiadiazole.

The term "carbocyclyl" (used alone or in combination with other groups) refers to a cyclic ring containing the indicated number of carbon atoms (e.g., C) _3-12 、C _10-30 ) Saturated cyclic (i.e., "cycloalkyl"),a partially saturated cyclic (i.e., "cycloalkenyl") or a fully unsaturated cyclic (i.e., "aryl") hydrocarbon group. The term "C _10-30 Carbocyclyl "(which may be used alone or in combination with other groups) refers to a saturated cyclic (i.e.," cycloalkyl "), partially saturated cyclic (i.e.," cycloalkenyl "), or fully unsaturated cyclic (i.e.," aryl ") hydrocarbon group containing from 10 to 30 carbon ring atoms. Carbocyclyl, among other things, can also be polycyclic (i.e., contain two or more rings selected from "cycloalkyl", "cycloalkenyl", and "aryl"). Examples of polycyclic carbocyclyl groups include bridged, fused or spirocyclic carbocyclyl groups. In a bridged carbocyclyl, the rings share at least two common and non-adjacent atoms. In fused carbocyclic groups, two or more rings may be fused together such that the two rings share a common bond. Preferably, carbocyclyl is C _3-20 Carbocyclic group, more preferably C _6-18 A carbocyclic group.

The term "heterocyclyl" (which may be used alone or in combination with other groups) refers to a saturated cyclic (i.e., "heterocycloalkyl"), partially saturated cyclic (i.e., "heterocycloalkenyl"), or fully unsaturated cyclic (i.e., "heteroaryl") hydrocarbon group containing the indicated number of ring atoms (3-12 members, 10-30 members). The term "C _10-30 Heterocyclyl "(alone or in combination with other groups) refers to a saturated (i.e.," heterocycloalkyl "), partially saturated (i.e.," heterocycloalkenyl "), or fully unsaturated (i.e.," heteroaryl ") cyclic group containing 10 to 30 carbon ring atoms, wherein at least one carbon ring atom is selected from the group consisting of: hetero atoms of O, N or S. Alternatively, the heterocyclyl moiety may be a polycyclic structure. Examples of polycyclic heterocyclic groups include bridged, fused, or spirocyclic heterocyclic groups. In bridged heterocyclyl groups, the rings share at least two common non-adjacent atoms. In fused heterocyclyl groups, two or more rings (e.g., bicyclic heterocyclyl or tricyclic heterocyclyl) can be fused together such that the two rings share a common bond.

R

RSi

The term "trialkylsilyl" refers to R, wherein each R is independently C as defined above _1-6 An alkyl group.

The term "C _1-6 Alkylamino radical "Is referred to as C _1-6 Alkyl NH-.

The term "alkoxycarbonyl" refers to R-C (= O) -, where R is alkoxy as defined above.

The term "alkylcarbonylamino" refers to R-C (= O) -NH-, R being alkyl as defined above.

The term "alkylcarbonylaminoalkyl" refers to R-C (= O) -NR '-R-, where R is alkyl as described above and R' is H or alkyl as described above.

The term "alkylaminoalkyl" refers to R-NR '-R-, wherein R is an alkyl group as described above and R' is H or an alkyl group as described above.

The term "alkylaminocarbonyloxy" refers to R-NR '-C (= O) -O-, wherein R is an alkyl group as described above and R' is H or an alkyl group as described above.

The term "alkylsulfonyl" refers to R-S (O) ₂ -, R is an alkyl group as defined above.

The term "phospho" refers to-P (O) ₂ 。

The term "azido" refers to-N ₃ 。

"optionally substituted by 8230\8230means substituted or unsubstituted.

Active ingredient

As used herein, "compounds of the invention" refers to compounds of formula I or a pharmaceutically acceptable salt, metabolite, or prodrug thereof.

Wherein A, B, R1, R2, R3, m and n are as defined above.

Preferably, the compound of formula (I) has the structure of formula (II):

wherein R is ₁ 、R ₂ 、R ₃ Ring B, m and n are as defined above, with the proviso that:

when n is 0 or 1, ring B is not

When n is 2, 3, 4 or 5 and ring B is

Preferably, the compound of formula (I) has the structure of formula (III):

wherein R is ₁ 、R ₂ 、R ₃ Ring A, ring D, U ₁ M and n are as defined above.

Preferably, the compound of formula (I) has the structure of formula (IV):

wherein R is ₁ 、R ₂ 、R ₃ Ring D, U ₁ M and n are as defined above.

Preferably, the compound of formula (I) has the structure of formula (V):

wherein R is ₁ 、R ₂ 、R ₃ M and n are as defined above.

Prodrugs

The above compounds can be converted into prodrugs represented by the following general formula:

in this formula, examples of G include, but are not limited to

a)—C(＝O)—R ₅ ；

b)—C(＝O)—R ₆ ；

c)—C(＝O)—L—R ₆ ；

d)—C(＝O)—L—O—R ₆ ；

e)—C(＝O)—L—O—L—O—R ₆ ；

f)—C(＝O)—L—O—C(＝O)—R ₆ ；

g)—C(＝O)—O—R ₇ ；

h)—C(＝O)—N(—K)(R ₇ )；

i)—C(＝O)—O—L—O—R ₇ ；

j)—C(R ₈ ) ₂ —O—R ₉ ；

k)—C(R ₈ ) ₂ —O—L—O—R ₉ ；

l)—C(R ₈ ) ₂ —O—C(═O)—R ₉ ；

m)—C(R ₈ ) ₂ —O—C(═O)—O—R ₉ ；

n)—C(R ₈ ) ₂ —O—C(═O)—N(—K)—R ₉ ；

o)—C(R ₈ ) ₂ —O—C(═O)—O—L—O—R ₉ ；

p)—C(R ₈ ) ₂ —O—C(═O)—O—L—N(R ₉ ) ₂ ；

q)—C(R ₈ ) ₂ —O—C(═O)—N(—K)—L—O—R ₉ ；

r)—C(R ₈ ) ₂ —O—C(═O)—N(—K)—L—N(R ₉ ) ₂ ；

s)—C(R ₈ ) ₂ —O—C(═O)—O—L—O—L—O—R ₉ ；

t)—C(R ₈ ) ₂ —O—C(═O)—O—L—N(—K)—C(═O)—R ₉ ；

u)—C(R ₈ ) ₂ —O—P(═O)(—R ₁₀ ) ₂ ；

v)—C(R ₈ ) ₂ —R ₁₁ ；

w)—C(═N ⁺ (R ₁₂ ) ₂ )(—N(R ₁₂ ) ₂ )；

x)—C(R ₈ )2—C(R ₈ )2—C(═O)—O—R ₇ ；

y)—C(R ₈ )2—N(—K)—C(═O)—O—R ₇ ；

z)—P(═O)(—R ₁₃ )(—R ₁₄ )；

aa)—S(═O) ₂ —R ₁₅ ；

ab)—R ₁₆ And

ac)—C(R ₈ ) ₂ —C(R ₈ ) ₂ —O—R ₇ ；

k is hydrogen or C optionally substituted by a substituent E _1-6 An alkyl group;

R ₈ is hydrogen or C _1-6 An alkyl group;

R ₁₀ is hydroxy or OBn;

R ₁₄ is C which may optionally be substituted by a substituent E _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _3-12 Carbocyclic oxy, 3-12 membered heterocyclic oxy, C _3-12 Carbocyclic amino or 3-12 membered heterocyclic amino;

or R is ₁₃ And R ₁₄ May form, together with the adjacent phosphorus atom, a heterocyclic group which may be optionally substituted by substituent E;

wherein the substituents E are independently selected from the group consisting of: oxo radical, C _1-6 Alkyl, hydroxy C _1-6 Alkyl, amino, C _1-6 Alkylamino radical, C _3-12 Carbocyclyl, 3-12 membered heterocyclyl, C _3-12 Carbocycloalkyl, C _1-6 Alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkaneOxycarbonylalkyl, alkoxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, C _1-6 Alkoxy, cyano, nitro, azido, C _1-6 Alkylsulfonyl, trialkylsilyl and phospho groups;

R ₁ 、R ₂ 、R ₃ ring a, ring B, m and n are as defined above.

Exemplary G groups are

Under physiological conditions in vivo, the OG group is converted to-OH in formula (I) by a decomposition reaction caused by drug metabolizing enzymes, hydrolases, gastric acid, enterobacteria, etc. Upon administration, the prodrug becomes the parent compound having inhibitory activity in vivo against cap-dependent endonucleases.

The compounds of the invention having a chiral center may exist in stereoisomeric forms. Stereoisomers of compounds of formula (I) may include cis and trans isomers, optical isomers, such as (R) and (S) enantiomers, diastereomers, geometric isomers, rotamers, atropisomers, conformational isomers, and tautomers of the compounds, including compounds exhibiting more than one isomerism, as well as mixtures thereof (e.g., racemates and diastereomers). All isomeric forms are included. Furthermore, tautomerism may occur in the compounds of formula (I) of the present invention.

The scope of the invention also includes pharmaceutical compositions containing one or more of the above compounds, salts, metabolites or prodrugs thereof, which are useful in the treatment of influenza.

As used herein, "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed with acids from the compounds of the present invention. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.

Process for the preparation of compounds

The invention also includes a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, metabolite or prodrug thereof; the method comprises the following steps:

(i) Providing an aldehyde

P is a protecting group;

(ii) Reacting the aldehyde with a carbonyl compound in an inert solvent (e.g., DMSO) in the presence of a base (e.g., pyrrolidine, sodium hydroxide, strong potassium oxide, etc.)

Reacting to obtain a first intermediate

(iii) Reacting the first intermediate with a diamine compound (e.g., NH) in an inert solvent (e.g., methanol and/or water) ₂ NHCOCF ₃ ) Reacted, then in a reducing agent (e.g., naBH) ₄ Sodium triacetoxyborohydride, etc.) to obtain a second intermediate

(iv) Reacting the second intermediate with an inert solvent 1 (e.g., ACN)

The reaction is carried out in an inert solvent 2 (such as acetone) and under acidic conditions (such as hydrochloric acid)Removing protecting group to obtain the compound of formula (I) or pharmaceutically acceptable salt and metabolite thereof,

optionally (v) in an inert solvent (e.g. DMA), a catalyst (e.g. K) ₂ CO ₃ Ext> andext> KIext>)ext> compoundext> ixext> isext> reactedext> withext> compoundext> Gext> -ext> aext> inext> theext> presenceext> ofext> KIext>)ext> toext> giveext> aext> prodrugext> ofext> compoundext> iext>,ext> whereinext> aext> isext> selectedext> fromext>:ext> OH, halogen, and the like.

Wherein X is halogen; A. b, R ₁ 、R ₂ 、R ₃ M and n are as defined above.

Preferably, the compounds of the present invention can be synthesized by the following steps

In the formula,

p is a hydroxyl protecting group;

x is halogen;

A、B、G、R ₁ 、R ₂ 、R ₃ m and n are as defined above;

(i-1) reacting the compound i with the compound ii in an inert solvent (e.g., DMSO) in the presence of a base (e.g., pyrrolidine, sodium hydroxide, potassium hydroxide, etc.) to give an intermediate iii;

(ii-1) reacting intermediate iii with a diamine compound (e.g. NH) in an inert solvent (e.g. methanol and/or water) ₂ NHCOCF ₃ ) Reacting to obtain an intermediate iv;

(iii-1) in an inert solvent (e.g., methanol, ethanol, etc.) in a reducing agent (e.g., naBH) ₄ Sodium triacetoxyborohydride, etc.), the intermediate iv undergoes a reduction reaction to obtain an intermediate v;

(iv-1) reacting the intermediate v with the compound vi in an inert solvent (such as ACN, DMF, etc.) under the condition of alkalinity (such as cesium carbonate, sodium hydroxide, strong potassium oxide, etc.) to obtain an intermediate vii;

(v-1) in an inert solvent (e.g., CH) ₂ Cl ₂ ) In the presence of an oxidant, carrying out an oxidation reaction on the intermediate vii to obtain an intermediate viii;

(vi-1) deprotecting intermediate viii in an inert solvent (e.g. acetone) under acidic (e.g. hydrochloric acid) conditions to give target compound ix;

optionally (vii-1) in an inert solvent (e.g., DMA), a catalyst (e.g., K) ₂ CO ₃ Ext> andext> KIext>)ext> compoundext> ixext> isext> reactedext> withext> compoundext> Gext> -ext> aext> inext> theext> presenceext> ofext> KIext>)ext> toext> giveext> compoundext> xext>,ext> whereinext> aext> isext> selectedext> fromext>:ext> OH, halogen, and the like.

Unless otherwise indicated, all reagents and solvents were purchased from commercial sources or were available synthetically from the literature.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention has an excellent cap-dependent endonuclease inhibitory activity, the compound of the present invention or a stereoisomer or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug or a solvate thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment (stabilization, alleviation or cure) of influenza.

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and between the compounds of the present invention without significantly diminishing the pharmaceutical effectiveness of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil etc.), polyols (e.g. propylene glycol, glycerol, glycerineMannitol, sorbitol, etc.), emulsifier (e.g., sorbitol, etc.)

) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).

The term "treatment" refers to the administration of one or more compounds, or salts, metabolites, or prodrugs thereof, to an individual suffering from the above-mentioned disease (i.e., influenza, or having one symptom of influenza, or susceptible to influenza) for the purpose of conferring a therapeutic effect, e.g., a cure, alleviation, alteration, amelioration, or prevention of the above-mentioned disease or of the symptoms of the disease or predisposition to the disease. An "effective amount" refers to the amount of active compound, or a salt, metabolite, or prodrug thereof, administered to produce a therapeutic effect. As will be appreciated by those skilled in the art, effective dosages will vary depending upon the type of condition being treated, the route of administration, the use of excipients, and the possibility of co-use with other treatments.

To practice the methods of the present invention, compositions comprising one or more of the above-described compounds, or salts, metabolites or prodrugs thereof, can be administered parenterally, orally, nasally, rectally, topically or orally. The term "parenteral" refers to subcutaneous, intradermal, intravenous, intraperitoneal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional or intracranial injection, as well as any other suitable injection technique.

The sterile injectable composition may 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. Acceptable carriers and solvents can be mannitol, ringer's solution and isotonic sodium chloride solution. In addition, conventionally employed non-volatile oils are often employed as a solvent or suspending medium (e.g., synthetic mono-or diglycerides). Fatty acids (such as oleic acid and its glyceride derivatives) are useful in the preparation of injectables, as are natural medicinal oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants (e.g., tweens or Spans) or other similar emulsifying agents or bioavailability enhancers which are commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for manufacturing purposes.

Compositions for oral administration may be in any orally acceptable dosage form including, but not limited to, capsules, lozenges, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring or coloring agents may be added.

Nasal aerosol or inhalation compositions may be prepared according to techniques known in the art of pharmaceutical formulation. For example, the composition may be prepared as a solution by dissolving in saline, employing a composition comprising benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other well known solutions or dispersions.

The carrier of the pharmaceutical composition must be "acceptable" in the sense of being compatible with the other active ingredients of the composition (and preferably capable of stabilizing the active ingredients) and not deleterious to the individual to whom it is to be administered. One or more solubilizing agents can be used as excipients to deliver active dibenzylidene acetone. Examples of other pharmaceutical carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D & C yellow No. 10.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds may be used simultaneously, separately or sequentially with the compound of the invention for the prevention and/or treatment of influenza.

When using pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment at a dosage that is pharmaceutically considered to be effective, typically 1 to 2000mg, preferably 20 to 500mg per day for a human of 60kg body weight. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The main advantages of the invention are:

1. the compound of the invention has novel structure;

2. the compound of the present invention has an excellent cap-dependent endonuclease inhibitory action.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Unless otherwise indicated, all reagents and solvents were purchased from commercial sources and used without further purification. All reactions were carried out under dry nitrogen or argon by using Merck Silica Gel 60F ₂₅₄ Thin Layer Chromatography (TLC) monitoring of the glass backing plate. Column chromatography was performed by Merck Silica Gel 60 (0.040 to 0.063mm,230 to 400 mesh). Measurement by Varian Mercury-300 and Varian Bruker AVIII-500 spectrometers ¹ H NMR and ¹³ c NMR spectra, and chemical shifts (δ) are reported in parts per million (ppm) relative to the solvent resonance peak. The following abbreviations are used to indicate multiplicity:s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet) or br (broad). Low resolution mass spectra were measured by the HP Hewlett Packard 1100 series.

Example 1: synthesis and characterization of Compound 1

(i) Synthesis of Compound I-3

Compound I-3 was first prepared in the manner shown above from commercially available 3-benzyloxy-4-oxo-4H-pyran-2-carbaldehyde, followed by intermediates I-1 and I-2.

Pyrrolidine (30.9g, 434 mmole) was added to a solution of 3- (benzyloxy) -4-oxo-4H-pyran-2-carbaldehyde (100g, 434 mmole) and cyclopropanecarboxaldehyde (91.3g, 1.30mmole) in the solvent DMSO (1 liter), and the mixture was stirred at 50 ℃ for 23 to 24 hours and then cooled to room temperature. Dissolving the mixture in CH ₂ Cl ₂ In (1 liter), with 1N HCl _(aq) (1 liter) and saturated NaHCO ₃ The aqueous solution (1 l) was washed, followed by further washing with saturated brine (1 l). The organic phase was separated and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a residue (133 g). The residue thus obtained was dissolved in EtOAc (1L) and washed with saturated NaHCO ₃ The aqueous solution (1 l) was washed, then with a saturated aqueous solution of sodium chloride (1 l), and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure to give a black crude product (106 g). The resulting crude material was purified by column chromatography (hexane/EtOAc = 7/3) followed by recrystallization (hexane/EtOAc = 1/1) to give compound I-1 as a yellow-green solid (87g, 66%).

Reacting NH ₂ NHCOCF ₃ (8.23g, 64mmole) was added to a solution of Compound I-1 (9.65g, 32mmole) in methanol (145 ml) and water (73 ml). The reaction mixture was stirred at 50 ℃ for 20 hours. After cooling to room temperature, the solvent was removed under reduced pressure. Dissolving the solid residue in CH ₂ Cl ₂ (500 ml x 3) and washed with saturated aqueous sodium chloride (200 ml). The organic phase was separated and dried over anhydrous magnesium sulfate. ReducingThe solvent was removed under pressure and the crude product was washed with MTBE (250 mL) to give product I-2 (8.6 g, 90%).

At 0 deg.C, adding NaBH ₄ (1.05g, 27.8 mmole) was slowly added to a solution of Compound I-2 (4.32g, 13.9 mmole) in methanol (38 ml). The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, water (10 ml) was added to the reaction solution, and the solvent was removed under reduced pressure. Dissolving the solid residue in CH ₂ Cl ₂ (250 ml. Times.3) and washed with saturated aqueous sodium chloride (100 ml). The organic phase was separated, dried over anhydrous magnesium sulfate and removed under reduced pressure to give product I-3 (4.47 g).

(ii) Synthesis of Compound I-4

Compound I-4 was prepared from 5-fluoro-thiadibenzo [ e, h ] azulen-8-one by the route shown below:

5-fluoro-thiadibenzo [ e, h ] was stirred in THF/MeOH (2]Azulen-8-one (177 mg, 0.63 mmole) and NaBH ₄ (119 mg, 3.16 mmole) and then allowed to stand at room temperature for 16 hours. After completion of the reaction, quench with water and use CH ₂ Cl ₂ Extracting, and collecting organic layer with MgSO ₄ Dried and concentrated under reduced pressure to give 180 mg of a crude residue, which was used in the next step without purification. At 0 ℃, the crude residue is then mixed with SOCl ₂ (0.2 mL, 2.76 mmole) in CH ₂ Cl ₂ (10 ml) and then allowed to warm to room temperature. After the reaction was completed, concentration was performed under reduced pressure to obtain crude compound I-4, which was used as it was without any purification.

(iii) Synthesis of Compound 1

Compound 1 was prepared from intermediates I-3 to I-6 via the following procedure.

A solution of Compound I-3 (100 mg, 0.34 mmole), cesium carbonate (328 mg, 1.01 mmole) and Compound I-4 (265 mg, 1.0 mmole) was stirred in ACN (5 mL) for 16 hours at room temperature. With CH ₂ Cl ₂ Diluting, washing with water, and using MgS for organic layerO ₄ Drying, concentrating under reduced pressure, purifying the residue by silica gel chromatography to obtain CH ₂ Cl ₂ MeOH =39, 1, to give compound I-5 (160 mg, 0.28mmole, 85% yield).

A solution of Compound I-5 (160 mg, 0.28 mmole) and Dess-Martin oxidizer (Dess-Martinperiodinane) (165 mg, 0.39 mmole) in CH at room temperature ₂ Cl ₂ (16 ml) was stirred for 5 hours. The reaction was washed with water and the organic layer was MgSO ₄ Drying, concentrating under reduced pressure, and purifying the residue by silica gel chromatography to obtain

CH ₂ Cl ₂ MeOH =39 to give compound I-6 (120 mg,0.21mmole, 75% yield).

A solution of Compound I-6 (120mg, 0.21mmole) and LiCl (591 mg) was stirred in DMA (2 mL) at 100 ℃ for 1 hour. Then, after cooling to 0 ℃, acetone (2 ml), 0.5N hydrochloric acid (20 ml) and water (10 ml) were added, and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration and recrystallized from acetone and hexane to give compound 1 (64 mg, 0.14mmole, 64% yield). MS M/z 471.1 (M + H) ⁺ ； ¹ H NMR(d-DMSO)δ7.82-7.72(m,3H),7.69-7.55(m,2H),7.51-7.50(m,1H),7.42-7.07(m,3H),6.40(dd,1H),5.72(s,1H),5.56(dd,1H),3.63(d,1H),3.55(br,1H),2.33(d,1H),1.85-1.84(m,1H),1.27-1.23(m,1H),0.88-0.83(m,2H)。

The compound 1 can also be subjected to separation of isomers through a chiral separation column to obtain a compound 1-a and a compound 1-b.

Compound 1-a: MS M/z 470.9 (M + H) ⁺ ； ¹ H NMR(d-DMSO)δ7.83-7.73(m,3H),7.69-7.55(m,2H),7.51-7.48(m,1H),7.42-7.07(m,3H),6.40(dd,1H),5.72(s,1H),5.57(dd,1H),3.64(d,1H),3.39(br,1H),2.34(d,1H),1.85-1.84(m,1H),1.27-1.23(m,1H),0.85-0.80(m,2H)。

Compound 1-b: MS M/z 470.9 (M + H) ⁺ ； ¹ H NMR(d-DMSO)δ7.83-7.73(m,3H),7.69-7.56(m,2H),7.51-7.48(m,1H),7.43-7.07(m,3H),6.40(dd,1H),5.72(s,1H),5.57(dd,1H),3.64(d,1H),3.34(br,1H),2.34(d,1H),1.88-1.84(m,1H),1.28-1.24(m,1H),0.85-0.80(m,2H)。

Example 2: synthesis and characterization of Compound 2

(i) Synthesis of Compound I-3

Compound I-3 was synthesized in the manner shown in example 1.

(ii) Synthesis of Compound II-1

Compound II-1 was prepared from 2-carboxy-5-fluorophenylboronic acid by the route shown below:

at 0 deg.C, adding SOCl ₂ (1.3 mL, 17.8 mmole) was added to a solution of 2-carboxy-5-fluorophenylboronic acid (2.18 g, 11.9 mmole) in MeOH (47 mL) and the mixture was stirred at 0 deg.C for 3.5 hours. After the reaction was complete, concentration was carried out under reduced pressure to give crude compound II-1-1 (3.3 g), which was used as such without any purification.

Pd (PPh) ₃ ) ₂ Cl ₂ (696 mg, 0.99 mmole) at RT and N _2(g) Under the conditions of (1), compound II-1-1 (2.35 g, 11.9 mmole), compound II-1-2 (2.37 g, 0.99 mmole) and K were added ₂ CO ₃ (4.1 g) in a solution of water (6 ml) and THF (55 ml) followed by N _2(g) Next, the mixture was stirred at 70 ℃ for 15 hours. After cooling to room temperature, the mixture was poured into water and extracted twice with EA. The combined organic layers were washed with brine, over anhydrous MgSO ₄ Drying, concentration under reduced pressure, and purification of the residue by silica gel chromatography (5% ea in hexanes) gave compound II-1-3 (1.574 g, 51%).

2N sodium hydroxide (25 ml) was added to a solution of compound II-1-3 (1.57 g, 5.04 mmole) in THF/MeOH (50 ml) at 90 deg.C for 15 hours, after completion of the reaction, the mixture was cooled to room temperature, concentrated under reduced pressure to remove THF and MeOH, water was added, the mixture was acidified to pH =7 with 1N hydrochloric acid, and the solid was collected by filtration to give compound II-1-4 (1.51 g, 101%).

II-1-4 (1.51 g, 5.06 mmole) was stirred in PPA (29 g) at 90 ℃ for 17 hours, then the mixture was poured into ice water and the solid was collected by filtration to give compound II-1-5 (1.42 g, 100%).

At 0 deg.C, adding NaBH ₄ (230 mg, 6.08 mmole) was added to a solution of Compound II-1-5 (1.42 g, 5.07 mmole) in MeOH/THF (25 ml) and left at room temperature for 1.5 hours, after the reaction was complete, quenched with water, then with CH ₂ Cl ₂ Extracting, and separating the organic layer with anhydrous MgSO ₄ Drying, concentration under reduced pressure, and purification of the residue by silica gel chromatography eluting with hexane: EA =12 to give compound II-1-6 (629 mg, 45%).

At room temperature, adding SOCl ₂ (0.09 mL, 1.22 mmole) was added to compound II-1-6 (172 mg, 6.09 mmole) in CH ₂ Cl ₂ (6 ml) the mixture was stirred at 40 ℃ for 1 hour, after the reaction was complete, concentrated under reduced pressure to give crude compound II-1, which was used directly without any purification.

(II-1) Synthesis of Compound II-1-2

Compound II-1-2 was prepared from thiophene-3-boronic acid and bromobenzene by the pathway shown below:

pd (PPh) ₃ ) ₂ Cl ₂ (4.4 g, 3.82 mmole) at room temperature and N _2(g) To thiophene-3-boronic acid (3.67 g, 28.7 mmole), bromobenzene (3 g, 19.1 mmole) and 2N Na ₂ CO ₃ In aqueous THF (4.8 ml) followed by N _2(g) The mixture was stirred at 70 ℃ for 21 hours. After cooling to room temperature, the mixture was poured into water and extracted twice with EA. The combined organic layers were washed with brine, anhydrous MgSO ₄ Drying, concentrating under reduced pressure,the residue was purified by silica gel chromatography (5% EA in hexanes) to give compound II-1-2-a (2.83 g, 92%).

A solution of NBS (3.12 g, 17.5 mmole) in DMF (20 ml) was added dropwise to a solution of Compound II-1-2-a in DMF (38 ml) at-5 ℃ and stirred at 0 ℃ for 17.5 hours. By reaction with Na ₂ S ₂ O ₃ Quench, extract twice with EA, wash the organic layer with brine, and dry MgSO ₄ Drying, concentration under reduced pressure, and purification of the residue by silica gel chromatography (1% ea in hexanes) gave compound II-1-2 (4.084 g, 97%).

(iii) Synthesis of Compound 2

Compound 2 was synthesized via the following steps, via intermediates I-3 and II-1 through II-2, and then through II-3.

A solution of compound I-3 (164 mg, 0.55 mmole), cesium carbonate (595 mg, 1.83 mmole), potassium iodide (101 mg, 0.61 mmole) and compound II-1 (0.61 mmole) was stirred in ACN (6 ml) for 42 hours at room temperature. With CH ₂ Cl ₂ Diluting, washing with brine, separating the organic layer, and reacting with MgSO ₄ Drying, concentrating under reduced pressure, and purifying the residue by silica gel chromatography to obtain CH ₂ Cl ₂ MeOH =39 to give compound II-2 (127 mg, 37%).

A solution of Compound II-2 (127 mg, 0.23 mmole) and Dess-Martin oxidizer (Dess-Martinperiodinane) (172 mg, 0.41 mmole) in CH at room temperature ₂ Cl ₂ (4.5 ml) for 15 hours. With CH ₂ Cl ₂ Diluting with NaHCO ₃ The reaction was washed with saturated solution, then with saturated NaCl solution, and MgSO ₄ Drying, concentrating under reduced pressure, purifying the residue by PLC, and purifying with CH ₂ Cl ₂ MeOH =39 to give compound II-3 (118 mg, 93%).

LiCl (89 mg, 2.10 mmole) was added to a solution of Compound II-3 (118 mg,0.21 mmole) in DMA (2.1 ml), and the mixture was stirred at 100 ℃ for 1 hour, then cooled to 0 ℃. Acetone (2 ml), 0.5N hydrochloric acid (5 ml) and water (10 ml) were added to the mixture, stirred at room temperature for 1 hour, the solid was collected by filtration and acetone was usedAnd hexane to give compound 2 (78 mg, 79% yield). MS M/z 471.1 (M + H) ⁺ ； ¹ H NMR(d-DMSO)δ7.86-7.66(m,4H),7.51-7.14(m,5H),6.42(dd,1H),5.73(d,1H),5.60(dd,1H),3.64(d,1H),3.44(br,1H),2.35(q,2H),1.87(m,1H),1.27-1.25(m,1H),0.86-0.83(m,2H)。

Example 3: synthesis and characterization of Compound 3

(i) Synthesis of Compound I-3

Compound I-3 was synthesized in the manner shown in example 1.

(ii) Synthesis of Compound IV-1

Compound IV-1 was prepared from methyl2-bromo-3-methylbenzoate (methyl 2-bromo-3-methylbenzonate) and pinacol diboron:

a solution of methyl2-bromo-3-methylbenzoate (3.0 g, 13.1 mmole), pinacol diboride (10.0 g, 39.4 mmole), potassium acetate (3.9 g, 39.7 mmole) and bis (triphenylphosphine) palladium (ii) dichloride (1.1 g, 1.35 mmole) in 1, 2-dioxane (66 ml) was added and stirred under nitrogen at 100 ℃ for 16 hours. Cooling to room temperature, filtering, and using CH to filter cake ₂ Cl ₂ Washing, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel chromatography, eluting with 5% EA in hexane to obtain compound IV-1-a (13.1 mmole).

At 70 deg.C, compound IV-1-a (13.1 mmole), compound II-1-2 (1.6 g, 6.7 mmole), bis (triphenylphosphine) palladium (II) dichloride (470 mg, 0.67 mmole), water (4 ml) and K were added ₂ CO ₃ A solution of (2.77 g, 20.0 mmole) in THF (37 ml) was stirred under nitrogen for 16 hours. After cooling to room temperature, the mixture was poured into water and extracted twice with EA. The organic layer was washed with brine, over MgSO ₄ Drying, concentrating under reduced pressure, and purifying the residue by silica gel chromatography, eluting with 5% EA in hexane, to give compound IV-1-b (470 mg, 1.52 mmole).

Compound IV-1-b (470 mg, 1.52 mmole) and excess NaOH as a liquid in THF/MeOH were added and stirred at 90 deg.C. After completion of the reaction, cooled to room temperature, concentrated under reduced pressure to remove THF and MeOH, then after addition of water, the mixture was acidified to pH =7 with 1N hydrochloric acid, and the solid was collected by filtration to give compound IV-1-c (300 mg, 1.02 mmole).

A solution of compound IV-1-c (300 mg, 1.02 mmole) and excess PPA (20 g) was added and stirred for 16 hours at 100 ℃. It was then poured into ice water, extracted with EA, washed with brine, and MgSO ₄ Dry to concentrate, and purify the residue by silica gel chromatography, eluting with hexane: EA =9, to give compound IV-1-d (180 mg, 0.65mmole, 64% yield).

At 0 deg.C, compound IV-1-d (100 mg, 0.65 mmole) and NaBH are added ₄ (123 mg, 3.25 mmole) in THF/MeOH (15 ml) was stirred and then allowed to stand at room temperature for 3 hours. After the reaction is complete, quench with water and CH ₂ Cl ₂ Extracting, and separating the organic layer with MgSO ₄ Drying, concentration under reduced pressure, and purification of the residue by silica gel chromatography eluting with hexane: EA =9 to give compound IV-1-e (82 mg, 0.29mmole, yield 45%).

At 0 deg.C, compound IV-1-e (82 mg, 0.29 mmole) and SOCl were added ₂ (0.2 mL, 2.76 mmole) of CH ₂ Cl ₂ The solution (10 ml) was stirred and then allowed to warm to room temperature. After the reaction is completed, concentrating under reduced pressure to obtain crude compound IV-1, which can be directly used without any purification.

(iii) Synthesis of Compound 3

Compound IV-1 was followed by intermediate I-3, IV-2 to IV-3 to synthesize Compound 3.

A solution of Compound I-3 (75 mg, 0.25 mmole), cesium carbonate (500 mg, 1.53 mmole), potassium iodide (42 mg, 0.25 mmole) and Compound IV-1 (0.295 mmole) was stirred in ACN (3 ml) at room temperature for 16 hWhen the user wants to use the device. With CH ₂ Cl ₂ Diluting, washing with water, separating organic layer, and MgSO ₄ Drying, concentrating under reduced pressure, and purifying the residue by silica gel chromatography to obtain CH ₂ Cl ₂ MeOH =39, 1, to give compound IV-2 (97 mg, 0.17mmole, 69% yield).

A solution of Compound IV-2 (97 mg, 0.17 mmole) and Dess-Martinctoridine (Dess-Martinperodine) (130 mg, 0.31 mmole) in CH at room temperature ₂ Cl ₂ (20 ml) was stirred for 3 hours. The reaction was washed with water and MgSO ₄ Drying, concentrating under reduced pressure, and purifying the residue by silica gel chromatography to obtain CH ₂ Cl ₂ MeOH =39, 1, to give compound IV-3 (87 mg, 0.16mmole, 92% yield).

A solution of LiCl (600 mg) and Compound IV-3 (118 mg,0.21 mmole) in DMA (2 ml) was added at 100 ℃ and stirred for 1 hour, followed by cooling to 0 ℃. Acetone (2 ml), 0.5N hydrochloric acid (20 ml) and water (10 ml) were added to the mixture, stirred at room temperature for 1 hour, the solid was collected by filtration and CH was used ₂ Cl ₂ And hexane to give compound 3 (13 mg, 0.03mmole, 18% yield). MS M/z 466.9 (M + H) ⁺ ； ¹ H NMR(d-DMSO)δ7.78-7.61(m,4H),7.56-7.41(m,2H),7.38-7.17(m,2H),7.11-7.08(m,1H),6.42(dd,1H),5.61-5.20(m,2H),3.63(d,1H),3.57(br,1H),2.36(m,4H),1.87-1.85(m,1H),1.27-1.24(m,1H),0.85-0.84(m,2H)

Example 4: prodrug preparation method of compound 1

At 80 deg.C, compound 1 (30 mg, 0.064 mmole), K are added ₂ CO ₃ A solution of DMA (1 mL) in (30 mg), KI (30 mg) and chloromethyl dimethyl carbonate (35 mg) was stirred for 3 hours, then cooled to 0 deg.C, 1N hydrochloric acid was added, extracted with EA, washed with brine, and MgSO ₄ Drying and concentrating, using CH ₂ Cl ₂ And hexane, and the solid was collected by filtration to give Compound 1-c (26 mg, 0.047 m)mole, 73% yield).

Prodrugs of other compounds of the invention may be prepared in a similar manner to that of example 4.

Example 5: cytopathic Effect inhibition Assay (CPE) Reduction Assay)

CPE inhibition assays were performed as follows to evaluate the efficacy of test compounds to inhibit cap-dependent endonuclease activity.

MDCK cells in 96-well tissue culture plates were cultured with test compounds and influenza a or influenza B virus at low infection rates for 72 hours at 37 ℃. The plates were fixed by adding 0.5% formaldehyde and then stained with 0.5% crystal violet. Subsequently, the absorbance at 570nm was measured with a microplate analyzer (Multiskan Ascent, thermo). The concentration of test compound required to reduce virus-induced CPE by 50%, expressed as the 50% effective dose (EC), relative to the virus control group ₅₀ )。

Test compounds evaluated in the CPE-inhibition assay showed EC of 0.45. Mu.M, 0.51. Mu.M and 2.38. Mu.M for influenza A virus (A/PR/8/34) infection for compounds 1,2 and 3, respectively ₅₀ The value is obtained.

In addition, compounds 1,2 and 3 showed EC of 0.19. Mu.M, 0.14. Mu.M and 0.89. Mu.M, respectively, for influenza B virus (B/LEE/40) infection ₅₀ The value is obtained.

The results show that: the compound has excellent effect of inhibiting influenza viruses, particularly A-type influenza viruses and B-type influenza viruses, and has great potential to be applied to infection of the A-type influenza viruses and the B-type influenza viruses.

Other embodiments

All features disclosed in the description may be combined in any combination. Various features disclosed in the specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

From the foregoing description, one skilled in the art can easily ascertain the characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, other equivalent embodiments are within the scope of the following claims.

Claims

1. A compound of formula (V):

in the formula,

R ₁ selected from the group consisting of: hydrogen, deuterium, halogen, C _1-6 An alkyl group;

R ₂ selected from the group consisting of: hydrogen, deuterium, halogen, C _1-6 An alkyl group;

R ₃ selected from the group consisting of: hydrogen, deuterium, halogen, C _1-6 An alkyl group;

m is 0, 1,2 or 3;

n is 0, 1,2, 3, 4 or 5.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

3. a pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. Use of a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 3, for the preparation of a medicament or pharmaceutical composition for the treatment of influenza.