CN110117285B - Inhibitors of influenza virus replication and uses thereof - Google Patents

Abstract

The invention provides compounds serving as inhibitors of influenza virus replication, a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds and the pharmaceutical composition thereof in treating influenza.

Description

Inhibitors of influenza virus replication and uses thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to novel compounds serving as an influenza virus replication inhibitor, a preparation method of the novel compounds, a pharmaceutical composition containing the novel compounds, and application of the novel compounds and the pharmaceutical composition in treatment of influenza. More specifically, the compounds of the present invention are useful as inhibitors of influenza virus 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 morbidity, wide epidemic and quick spread. Influenza virus causes severe symptoms such as pneumonia or cardiopulmonary failure in the elderly and children with weak immunity and some patients with immune disorders. Influenza virus was first discovered in 1933 by Wilson Smith (Wilson Smith) in the english man, and was called H1N1.H represents hemagglutinin; n represents neuraminidase. The numbers represent different types. Influenza viruses have caused numerous pandemics worldwide since their discovery, with one outbreak occurring in about ten years, causing enormous losses worldwide. Influenza epidemics can cause 25 to 50 million deaths per year, with 300 to 500 million cases, with a total of about 5 to 15% of people infected worldwide. Each pandemic is due to the emergence of new virus strains in humans. Typically, these new strains result from the transmission of existing influenza viruses from other animal species to humans.

The influenza virus is an RNA virus of Orthomyxoviridae (Orthomyxoviridae) and belongs to the genus influenza virus. Influenza viruses are mainly classified into types A, B and C, also called types A, B and C, according to the antigenic characteristics and genetic characteristics of virus particle Nucleoprotein (NP) and matrix protein (M). The three types of viruses have similar biochemical and biological characteristics. The virus particles are 80-120nm in diameter and are usually approximately spherical, but filamentous forms may occur. The virus is composed of three layers, the inner layer is the virus nucleocapsid, containing Nucleoprotein (NP), P protein and RNA. NP is a soluble antigen (S antigen), has type specificity, and is antigenically stable. The P proteins (P1, P2, P3) may be polymerases required for RNA transcription and replication. The middle layer is virus envelope composed of one lipoid and one Membrane Protein (MP), and the MP has stable antigenicity and type specificity. The outer layer is a radial protuberance made of two different glycoproteins, hemagglutinin (H) and neuraminidase (N). H can cause erythrocyte agglutination, is a tool for adsorbing viruses on the surfaces of sensitive cells, N can hydrolyze mucin, and N-acetylneuraminic acid at the tail end of a receptor specific glycoprotein on the cell surface is a tool for separating the viruses from the cell surface after the replication of the viruses is finished. H and N both have variation characteristics, so that only the specific antigenicity of the strain exists, and the antibody has a protection effect.

Influenza a virus belongs to 1 species, influenza a virus. Wild waterfowl is a natural host for a large number of influenza a viruses. Sometimes, the virus spreads to other species and can cause devastating outbreaks in poultry or cause influenza pandemics in humans. Of the 3 influenza types, the type a virus is the most virulent human pathogen causing most serious diseases, can be transmitted to other species, and produces a large pandemic of human influenza. Influenza a viruses can be subdivided into different serotypes based on antibody responses to these viruses. In the order of known human pandemic deaths, human serotypes have been identified as: H1N1 (causing spanish influenza in 1918), H2N2 (causing asian influenza in 1957), H3N2 (causing hong kong influenza in 1968), H5N1 (pandemic threat in the 2007-08 influenza season), H7N7 (with rare potential for zoonotic diseases), H1N2 (endemic epidemics in humans and pigs), H9N2, H7N3 and H10N7.

Influenza B virus belongs to 1 species, and influenza B virus, which often causes local influenza epidemics and does not cause major influenza outbreaks worldwide, is found only in humans and seals. This type of influenza mutates at a rate 2-3 times slower than type a, and therefore has low genetic diversity, with only one influenza B serotype. Due to this lack of antigenic diversity, humans typically acquire some degree of immunity to influenza B early in life. However, influenza B mutations are sufficient to make durable immunization impossible. But with low antigenic change rates, incorporating their restricted host changes (inhibiting cross-species antigenic shift) to ensure that influenza B pandemics do not occur.

Influenza C viruses belong to 1 species, and influenza C viruses, which are mostly present in a scattered form, mainly attack infants, generally do not cause influenza epidemics, and can infect humans and pigs.

Unusual for viruses, nucleic acids whose genomes are not single fragments; in contrast, the genome contains 7 or 8 segments of negative-sense RNA. The 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 outside the virion. HA is a lectin that mediates binding of the virus to the target cell and entry of the viral genome into the target cell, while NA is involved in releasing progeny virus by cleaving sugars that bind to mature viral particles to infect the cell. Therefore, these proteins have been targets for antiviral drugs. Moreover, these proteins are antigens of antibodies that can be produced. Influenza a viruses are classified into subtypes based on antibody responses to H and N, forming the basis of H and N discrimination in, for example, H5N 1.

Vaccination and the use of antiviral drugs are important means to cope with influenza pandemics, however, due to the strong antigenic variation capacity of influenza viruses, it is essentially impossible to produce vaccines on a large scale before pandemics. The currently available antiviral therapeutics, the M2 ion channel blockers amantadine and rimantadine, as well as the neuraminidase inhibitors Oseltamivir (Oseltamivir), zanamivir (Zanamivir), peramivir (Peramivir) and ranimivir (Laninamivir). However, influenza viruses have developed resistance to all of these drugs. Thus, there is a continuing need for new anti-influenza therapeutic agents.

A novel anti-influenza agent, piravir (Favipiravir), having a novel mechanism of action, which achieves antiviral effects by inhibiting RNA polymerase of influenza virus to thereby target viral gene replication, is marketed, but its therapeutic effects and resistance to influenza virus remain to be demonstrated, and other compounds for treating influenza by this mechanism of action are still urgently needed to be developed by scientists.

Summary of The Invention

The invention provides a novel compound serving as an influenza virus RNA polymerase inhibitor, and application of the compound and a composition thereof in preparing a medicament for preventing, treating or relieving virus infection diseases of patients.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),

wherein the ring A and the ring U ₅ 、R ⁷ 、R ⁸ 、R ⁹ And W has the definition as described in the present invention.

In some embodiments, ring a is of the substructure:

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 ；

R ¹ 、R ² 、R ³ 、R ⁴ And R ⁶ Each independently is H, D, F, cl, br, 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 radical, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Alkyl radical, C _2-6 Alkenyl or C _2-6 Alkynyl, wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl and C _2-6 Alkynyl is independently unsubstituted OR substituted with 1,2,3 OR 4 substituents independently selected from D, F, cl, br, CN, -OR ^b 、-NR ^c R ^d 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, R ^b O-C _1-4 Alkylene or R ^d R ^c N-C _1-4 An alkylene group;

l is- (CR) ^L1 R ^L2 ) _t -、-C(＝O)-(CR ^L1 R ^L2 ) _q -、-S(＝O)-(CR ^L1 R ^L2 ) _q -、-S-(CR ^L1 R ^L2 ) _q -or-O- (CR) ^L1 R ^L2 ) _q -；

t is 0, 1,2,3,4, 5 or 6;

q is 0, 1,2,3,4, 5 or 6;

R ^L1 and R ^L2 Each independently is H, D, F, cl, br, 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 radical, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Alkyl radical, C _2-6 Alkenyl or C _2-6 Alkynyl; or R ^L1 、R ^L2 And withThe carbon atoms to which they are attached together form a carbonyl group; or R ^L1 、R ^L2 Together with the carbon atom to which they are attached form C _3-6 A carbocyclic ring or a heterocyclic ring of 3 to 6 atoms;

R ^S is F, cl, br, CN, NO ₂ 、-OR ^S2 、-NR ^S3 R ^S4 、-OC(＝O)R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 、-C(＝O)OR ^S2 、-C(＝O)NR ^S3 R ^S4 、-NR ^S5 C(＝O)R ^S1 、-OP(＝O)(OR ^S2 ) ₂ 、-OP(＝O)(O-C _1-6 alkylene-OC (= O) R ^S1 ) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene, 5-to 8-membered heteroaryl or (5-to 8-membered heteroaryl) -C _1-4 Alkylene, wherein, the C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group of 3 to 8 atoms, (heterocyclic group of 3 to 8 atoms) -C _1-4 Alkylene, 5-to 8-membered heteroaryl or (5-to 8-membered heteroaryl) -C _1-4 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5 substituents R ^x Substituted with the proviso that R ^S Is not tetrahydropyranyl;

R ^S1 、R ^S2 、R ^S3 、R ^S4 and R ^S5 Each independently of the other is H, D, sodium, potassium, OH, NH ₂ 、C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, 5-to 8-membered heteroaryl or (5-to 8-membered heteroaryl) -C _1-4 Alkylene oxideWherein said C is _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group of 3 to 8 atoms, (heterocyclic group of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 8 atoms and (heteroaryl of 5 to 8 atoms) -C _1-4 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5 substituents R ^x Substituted;

or R ^S3 、R ^S4 And together with the nitrogen atom to which they are attached, form a 3-8 atom heterocyclic ring or a 5-8 atom heteroaromatic ring, wherein the 3-8 atom heterocyclic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3,4 or 5 substituents R ^x Substituted;

R ⁵ and R ⁸ Each independently is H, D, F, cl, br, 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 radical, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group of 3 to 8 atoms, (heterocyclic group of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 8 atoms or (heteroaryl of 5 to 8 atoms) -C _1-4 Alkylene, wherein R is ^b O-C _1-4 Alkylene radical, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene radical5-8 atom-constituting heteroaryl and (5-8 atom-constituting heteroaryl) -C _1-4 Each alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Substituted;

R ⁷ is-OR ^b 、C _2-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 Carbocyclyl, C _3-12 carbocyclyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 16 atoms or (heteroaryl of 5 to 16 atoms) -C _1-4 Alkylene, wherein said C _2-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 Carbocyclic radical, C _3-12 carbocyclyl-C _1-4 Alkylene, heterocyclic group of 3 to 12 atoms, (heterocyclic group of 3 to 12 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 16 atoms and (heteroaryl of 5 to 16 atoms) -C _1-4 Each alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Substituted;

or R ⁵ 、R ⁷ Together with the carbon atom to which they are each attached, or R ⁷ 、R ⁸ And together with the carbon atom to which they are each attached, form C _3-12 Carbocyclic ring, heterocyclic ring of 3-12 atoms, C _6-10 An aromatic ring or a heteroaromatic ring of 5 to 10 atoms, wherein C is _3-12 Carbocyclic ring, heterocyclic ring of 3-12 atoms, C _6-10 The aromatic ring and the 5-10 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^y Substituted;

each R ^x And R ^y Independently D, F, cl, br, CN, NO ₂ 、＝O、-OR ^b 、-NR ^c R ^d 、R ^b O-C _1-4 Alkylene radical, 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 radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group of 3 to 8 atoms, (heterocyclic group of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 8 atoms or (heteroaryl of 5 to 8 atoms) -C _1-4 Alkylene, wherein said C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 8 atoms and (heteroaryl of 5 to 8 atoms) -C _1-4 Each alkylene is independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, CN, NO ₂ 、＝O、-OR ^b 、-NR ^c R ^d 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, R ^b O-C _1-4 Alkylene or R ^d R ^c N-C _1-4 An alkylene group;

R ⁹ is H, D or optionally substituted by 1,2,3 or 4 groups independently selected from D, F, cl, br, CN, NO ₂ OR-OR ^b C substituted by a substituent of (3) _1-6 An alkyl group;

w is the following subformula:

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

each R ^w Independently D, F, cl, br, CN, NO ₂ 、＝O、-C(＝O)R ^a 、-C(＝O)OR ^g 、-C(＝O)O-C _1-6 alkylene-OC (= O) R ^h 、-C(＝O)O-C _1-6 alkylene-OC (= O) OR ^g 、-C(＝O)NR ^c R ^d 、-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 radical, C _1-6 Alkyl, heteroaryl of 5-6 atoms or heterocyclyl of 5-6 atoms, wherein said C _1-6 Each of alkyl, heteroaryl of 5-6 atoms and heterocyclyl of 5-6 atoms is independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, 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 、R ^f 、R ^g and R ^h Each independently of the other is H, D, sodium, potassium, hydroxy, C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Carbocyclyl, C _3-6 carbocyclyl-C _1-4 Alkylene, heterocyclic group of 3 to 6 atoms, (heterocyclic group of 3 to 6 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C _1-4 Alkylene, wherein said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Carbocyclic radical, C _3-6 carbocyclyl-C _1-4 Alkylene, heterocyclic group of 3 to 6 atoms, (heterocyclic group of 3 to 6 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C _1-4 Each alkylene is 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 radical, C _1-6 Alkoxy or C _1-6 An alkylamino group;

or R ^c 、R ^d And together with the nitrogen atom to which they are attached, form a 3-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 3-6 atom heterocyclic ring and the 5-6 atom heteroaromatic 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 radical, C _1-6 Alkoxy or C _1-6 An alkylamino group.

In other embodiments, ring a is of the subformula:

in still other embodiments, ring a is of the substructure:

in other embodiments, R ^S Is F, cl, br, CN, NO ₂ 、-OR ^S2 、-NR ^S3 R ^S4 、-OC(＝O)R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 、-C(＝O)OR ^S2 、-C(＝O)NR ^S3 R ^S4 、-NR ^S5 C(＝O)R ^S1 、-OP(＝O)(OR ^S2 ) ₂ 、-OP(＝O)(O-C _1-4 alkylene-OC (= O) R ^S1 ) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene, 5-6-membered heteroaryl or (5-6-membered heteroaryl) -C _1-2 Alkylene, wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C _1-2 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^x Substituted with the proviso that R ^S Is not tetrahydropyranyl;

R ^S1 、R ^S2 、R ^S3 、R ^S4 and R ^S5 Each independently H, D, sodium, potassium, OH, NH ₂ 、C _1-4 Haloalkyl, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C _1-2 Alkylene, wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C _1-2 Each alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5R ^x Substituted;

or R ^S3 、R ^S4 And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3,4, or 5R ^x And (4) substituting.

In still other embodiments, R ^S Is F, cl, br, CN, NO ₂ 、-OR ^S2 、-NR ^S3 R ^S4 、-OC(＝O)R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 、-C(＝O)OR ^S2 、-C(＝O)NR ^S3 R ^S4 、-NHC(＝O)R ^S1 、-OP(＝O)(OR ^S2 ) ₂ 、-OP(＝O)(O-CH ₂ -OC(＝O)R ^S1 ) ₂ 、-OP(＝O)(O-CH ₂ CH ₂ -OC(＝O)R ^S1 ) ₂ Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1, 3-dioxolen-2-one, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1, 3-dioxol-2-one, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, pyridazinyl, and pyrimidinyl, each of which is unsubstituted or substituted by 4 or 4R ^x Substituted;

R ^S1 、R ^S2 、R ^S3 、R ^S4 and R ^S5 Each independently H, D, sodium, potassium, OH, NH ₂ Trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, tert-butyl, cyclopentyl, or tert-butyl cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, and the like morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl-methylene, imidazolyl-sulfinylEthyl, pyrazolyl-ethylene or pyridyl-ethylene, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl-methylene, imidazolyl-ethylene, pyrazolyl-ethylene and pyridyl-ethylene are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^x And (4) substitution.

In other embodiments, R ⁷ is-OR ^b 、C _2-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Carbocyclyl, C _3-6 carbocyclyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 10 atoms, (heterocyclic group consisting of 5 to 10 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C _1-2 Alkylene, wherein said C _2-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Carbocyclyl, C _3-6 carbocyclyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 10 atoms, (heterocyclic group consisting of 5 to 10 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C _1-2 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Substituted;

R ⁵ and R ⁸ Each independently is H, D, F, cl, br, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OR ^b 、-NR ^c R ^d 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C _1-2 Alkylene, wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, 5-6-atom heteroaryl and (5-6-atom heteroaryl) -C _1-2 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Substituted;

or R ⁵ 、R ⁷ Together with the carbon atom to which they are each attached, or R ⁷ 、R ⁸ Together with the carbon atom to which they are each 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 is _3-6 Carbocycle, heterocycle of 5-6 atoms, C _6-10 The aromatic ring or the 5-6 atom heteroaromatic ring is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^y And (4) substitution.

In still other embodiments, R ⁷ 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-tetrahydroisoquinolinyl, phenyl, naphthyl, furanyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, benzothiazolyl, thienyl, benzothienyl, pyrazinyl(iii) yl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl, or isoquinolinyl, wherein said 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-tetrahydroisoquinolinyl, phenyl, naphthyl, furanyl, benzofuranyl, pyrrolyl, pyridyl, 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 1,2,3,4, or 5R ^y Substituted;

R ⁵ and R ⁸ Each independently is H, D, F, cl, br, CN, NO ₂ Methyl, ethyl, n-propyl or isopropyl;

or R ⁵ 、R ⁷ Together with the carbon atom to which they are each attached, or R ⁷ 、R ⁸ And together with the carbon atom to which they are each attached, form C _5-6 A carbocycle, a heterocycle of 5-6 atoms, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1,3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine or pyrimidine, wherein said C is _5-6 A carbocyclic ring, a 5-6 atom heterocycle, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1,3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine and pyrimidine are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^y And (4) substituting.

In other embodiments, each R is ^x And R ^y Independently D, F, cl, br, CN, NO ₂ 、＝O、-OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, 5-6 atomsSub-group consisting of heterocyclic radicals, phenyl-C _1-2 Alkylene or heteroaryl of 5 to 6 atoms, wherein said C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, 5-6 member heterocyclic radical, phenyl-C _1-2 Alkylene and heteroaryl 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, CN, NO ₂ 、-OR ^b 、＝O、-NR ^c R ^d Methyl, ethyl, n-propyl or isopropyl.

In yet other embodiments, each R is ^x And R ^y Independently D, F, cl, br, CN, NO ₂ 、＝O、-OH、-OCH ₃ 、-OCH ₂ CH ₃ 、-NH ₂ 、-C(＝O)OH、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)NH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1, 3-dioxol-2-one, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1, 3-dioxol-2-one, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3 or 4 substituentsAnd the substituents are independently selected from D, F, cl, br, CN, NO ₂ 、-OH、＝O、-NH ₂ Methyl, ethyl, n-propyl or isopropyl.

In some embodiments, R ¹ 、R ² 、R ³ 、R ⁴ And R ⁶ Each independently is H, D, F, cl, br, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OH、-C(＝O)NH ₂ 、-OH、-NH ₂ Methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, CN, -OH, -NH ₂ Methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R ⁹ Is H, D, CF ₃ Methyl, ethyl, n-propyl or isopropyl.

In other embodiments, each R is ^w Independently D, F, cl, br, CN, NO ₂ 、＝O、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH(CH ₃ ) ₂ 、-C(＝O)OPh、-C(＝O)OCH ₂ Ph、-C(＝O)OH、-C(＝O)ONa、-C(＝O)O-CH ₂ -OC(＝O)CH ₃ 、-C(＝O)O-CH ₂ -OC(＝O)C(CH ₃ ) ₃ 、-C(＝O)O-CH ₂ -OC(＝O)OCH ₃ 、-C(＝O)O-CH ₂ -OC(＝O)OCH ₂ CH ₃ 、-C(＝O)NR ^c R ^d 、-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 a heterocyclic group consisting of 5 to 6 atoms, wherein the methyl, ethyl, n-propyl, isopropyl, pyridyl, pyrazolyl, oxadiazolyl, thiazyl, pyrazinyl, pyridazinyl, pyrimidinyl or heterocyclic group is a heterocyclic group having at least one of the following atoms, and a pharmaceutically acceptable salt thereofFuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl and a heterocyclic group 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, CN, N ₃ 、＝O、NO ₂ 、-OCH ₃ Methyl, ethyl, n-propyl, isopropyl or trifluoromethyl.

In other embodiments, R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g And R ^h Each independently is H, D, sodium, potassium, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, C _3-6 Carbocyclyl, heterocyclyl of 5-6 atoms, phenyl or heteroaryl of 5-6 atoms, wherein said methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, C _3-6 Carbocyclyl, 5-6 atom heterocyclyl, phenyl and 5-6 atom heteroaryl are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl or methoxy;

or R ^c 、R ^d And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl or methoxy.

In other embodiments, the present invention relates to a compound having a structure represented by formula (II), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

wherein U is ₁ 、U ₂ 、U ₃ 、U ₄ 、U ₅ 、L、R ^S 、R ⁶ 、R ⁷ 、R ⁸ And R ^w Having the definitions as described in the present invention.

In other embodiments, the invention relates to a compound having a structure according to formula (III) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

wherein U is ₁ 、U ₂ 、U ₃ 、U ₄ 、U ₅ 、L、R ^S 、R ⁶ 、R ⁷ 、R ⁸ And R ^w Having the definitions as described herein.

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 a vaccine.

In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray dosage form.

In still other embodiments, the pharmaceutical compositions of the invention, wherein the additional therapeutic agent is Amantadine (Amantadine), rimantadine (Rimantadine), oseltamivir (Oseltamivir), zanamivir (Zanamivir), peramivir (Pe)ramivir), laninavir (laninavir), laninavir Octanoate Hydrate (laninavir octoate Hydrate), favipiravir (Favipiravir), arbidol (Arbidol), ribavirin (Ribavirin), stafurin, ingavirin (Ingavirin), influenza enzyme (Fludase), drugs with CAS number 1422050-75-6, JNJ-872 (pimovir), S-033188, influenza vaccine (FluMist)

Quadrivalent、

Quadrivalent、

Or

) Or a combination thereof.

In another aspect, the invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a viral infectious disease in a patient.

In some embodiments, the viral infection is an influenza viral infection.

In some embodiments, the influenza virus is H1N 1A/Weiss/43.

In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.

Unless otherwise indicated, the present invention encompasses stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts and pharmaceutically acceptable prodrugs of all of the compounds of the present 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 salts, which are not necessarily pharmaceutically acceptable salts, but which may be used in the preparation and/or purification of the compounds of the present invention and/or intermediates for the isolation of the enantiomers of the compounds of the present invention.

The compounds of the 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, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the invention also includes solvated and unsolvated forms thereof.

Alternatively, the compounds of the invention may contain several asymmetric centers or their racemic mixtures as generally described. The invention further comprises racemic mixtures, partial racemic mixtures and isolated enantiomers and diastereomers.

The compound of the present invention may exist in the form of one of possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, and the present invention may further comprise isomers, rotamers, atropisomers, tautomers or mixtures of isomers of the compound of the present invention, or isomers, rotamers, atropisomers, tautomers or partial mixtures or separated isomers, rotamers, atropisomers, tautomers.

In another aspect, the compounds of the invention include compounds as defined herein that are labelled with various isotopes, e.g. wherein a radioactive isotope is present, e.g. ³ H， ¹⁴ C and ¹⁸ those compounds of F, or in which a non-radioactive isotope is present, e.g. ² H and ¹³ a compound of C.

In another aspect, the invention relates to methods of preparation, isolation and purification of compounds encompassed by formula (I), formula (II) or formula (III).

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described 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 by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. One 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 that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further 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 subcombination.

Unless defined otherwise, all patent publications cited throughout the disclosure of the invention are incorporated herein by reference in their entirety for all purposes.

The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75, ^th ed, 1994. In addition, general principles of Organic Chemistry are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausaltito: 1999, and March's Advanced Organic Chemistry ", by Michael B.Smith and Jerry March, john Wiley&Sons, new York, 2007, hereby incorporated by reference in its entirety.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. 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" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In other embodiments, the "patient" refers to a human.

The present invention also includes isotopically-labeled compounds of the present invention which are identical to those recited in the present 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 usually found 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 ³⁷ Cl。

compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of such compounds, are included within the scope of the present invention. Isotopically-labelled compounds of the invention, e.g. radioisotopes, e.g. ³ H and ¹⁴ incorporation of C into the compounds of the invention may be useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ h, and carbon-14, i.e ¹⁴ C, an isotope is particularly preferred. This is achieved byIn addition, heavy isotopes, e.g. deuterium, are used, 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 (atropisomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are 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 often referred to as mixtures of enantiomers. A 50.

Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as the pure optical isomer, or as a mixture of isomers, for example as a mixture of racemic and non-corresponding isomers, 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 substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may be in the 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 (atropisomers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric atropisomer, and geometric (or conformational)) forms of the structure; 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, diastereomeric, and geometric (or conformational) isomeric mixtures of the compounds of the invention are intended to be within the scope of the invention.

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), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism 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" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent, e.g., hydrogen peroxide or a peracid, e.g., peroxycarboxylic acid, to form the N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxide may be prepared by the method of l.w. ready (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 such as dichloromethane.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description pharmaceutical acceptable salts in detail in Jal Sciences,1977, 66. Pharmaceutically acceptable non-toxic acid 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 salts obtained by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valeric acid salts, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl radical) ₄ A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 Sulfonates and aromatic sulfonates.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I), formula (II) or formula (III). Such a conversion receptor prodrug is water in bloodTo relieve the effects of conversion to the parent structure by enzymes in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and can be phenyl ester, aliphatic (C) _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, 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: T.Higuchi and V.Stella, pro-drugs as Novel Delivery Systems, vol.14 of the A.C.S.Symphosis Series, edward B.Roche, ed., bioreversible Carriers in Drug designs, american Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, prodrugs: design and Clinical Applications, nature Review Drug Discovery,2008,7,255-270, and S.J.Hecker et al, prodrugs of pharmaceuticals and pharmaceuticals, journal of chemical Chemistry,2008, 2328-5.

Any asymmetric atom (e.g., carbon, etc.) of a compound of the invention can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -, (R, R) -, (S, S) -, (S, R) -or (R, S) -configurations. 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, R) -, (S, S) -, (S, R) -or (R, S) -configuration. The substituents on the atoms having an unsaturated double bond may be present in the- (Z) -or- (E) -form, if possible.

Thus, as described herein, the compounds of the present invention may exist as one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

Any resulting mixture of isomers may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates on the basis of the physicochemical differences of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., high Pressure Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by Asymmetric Synthesis (e.g., jacques, et al, enantiomers, racemes and solutions (Wiley Interscience, new York, 1981); principles of asymmetry 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)。

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the above general formula, or as specified in the examples, subclasses, and groups encompassed by the present invention. It is understood that the terms "optionally substituted", "unsubstituted or substituted by 8230; \8230; substituted by a substituent" and "substituted or unsubstituted" are 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 preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are unsubstituted or substituted with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be selected from a particular groupAnd (b) is substituted with one or more substituents, the substituents may be substituted at various positions, identically or differently. Wherein the substituent can be, but is not limited to, D, F, cl, br, 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, -OR ^S2 、-NR ^S3 R ^S4 、-OC(＝O)R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 、-C(＝O)OR ^S2 、-C(＝O)NR ^S3 R ^S4 、-NR ^S5 C(＝O)R ^S1 、-OP(＝O)(OR ^S2 ) ₂ 、-OP(＝O)(O-C _1-6 alkylene-OC (= O) R ^S1 ) ₂ 、-C(＝O)OR ^g 、-C(＝O)O-C _1-6 alkylene-OC (= O) R ^h 、-C(＝O)O-C _1-6 alkylene-OC (= O) OR ^g 、R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene radical, C _3-12 Carbocyclyl, C _3-12 carbocyclyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 16 atoms or (heteroaryl of 5 to 16 atoms) -C _1-4 Alkylene, wherein each R is ^S1 、R ^S2 、R ^S3 、R ^S4 、R ^S5 、R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g And R ^h Has the following advantagesThe definition is clear.

In addition, unless otherwise explicitly indicated, the descriptions of "each of the 8230, independently" and "\8230" ", independently" are used interchangeably in the present invention and should be understood in a broad sense to mean that the specific options expressed between the same symbols in different groups do not affect each other, or that the specific options expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically contemplated that each separate subcombination of the various members of these groups and ranges is encompassed by the invention. For example, the term "C _1-6 Alkyl "in particular denotes independently disclosed C ₁ Alkyl (methyl), C ₂ Alkyl (ethyl), C ₃ Alkyl radical, C ₄ Alkyl radical, C ₅ Alkyl and C ₆ An alkyl group; the term "heteroaryl of 5-10 atoms" especially refers to 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, which are independently disclosed.

In each of the parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for this variable recites "alkyl" or "aryl," it is to be understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms; in some of these embodiments, the alkyl group contains 1 to 12 carbon atoms; in some of these embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl groupThe radicals contain 1 to 9 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C _1-6 An alkyl group; in other embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C _1-4 An alkyl group; in other embodiments, the alkyl group contains 1-3 carbon atoms, i.e., C _1-3 An alkyl group; in other embodiments, the alkyl group contains 1-2 carbon atoms, i.e., C _1-2 An alkyl group.

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 can be independently unsubstituted or substituted with one or more substituents described herein.

The term "alkyl" and its prefix "alkane", as used herein, are intended to encompass both straight and branched saturated carbon chains.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon radical. Unless otherwise specified, the alkylene group contains from 1 to 10 carbon atoms, in other embodiments the alkylene group contains from 1 to 6 carbon atoms, and in other embodiments the alkylene group contains from 1 to 4 carbon atoms, i.e., C _1-4 An alkylene group; in other embodiments, the alkylene group contains 1 to 2 carbon atoms, i.e., C _1-2 An alkylene group. Examples of this include methylene (-CH) ₂ -, ethylene (-CH) ₂ CH ₂ -, isopropylidene (-CH (CH) ₃ )CH ₂ -)，-CH(C(CH ₃ ))CH ₂ -and the like, wherein the alkylene groups may independently be unsubstituted or substituted with one or more substituents as described herein.

The term "alkenyl" denotes 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 the C-C in at least one position is sp ² Double bonds in which the alkenyl group may be independently unsubstituted or substituted with one or more substituents as described herein, including the positioning of the groups as "cis", "trans" or "Z" and "E", with specific examples including, but not limited to, vinyl (-CH = CH) ₂ ) Allyl (-CH) ₂ CH＝CH ₂ ) And so on.

The term "alkynyl" denotes 2-12 carbon atoms, or 2-8Carbon atoms, or a straight or branched monovalent hydrocarbon group of 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein the C-C in at least one position is a sp triple bond, wherein the alkynyl group may independently be unsubstituted or substituted with one or more substituents as described herein, specific examples including, but not limited to, ethynyl (-C.ident.CH), propargyl (-CH) ₂ C [ identical to ] CH), 1-propynyl (-C [ identical to ] C-CH) ₃ ) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 20 carbon atoms, some examples of which are alkoxy groups containing 1 to 10 carbon atoms, other examples of which are alkoxy groups containing 1 to 8 carbon atoms, and yet other examples of which are alkoxy groups containing 1 to 6 carbon atoms, i.e., C _1-6 An alkoxy group; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms, i.e., C _1-4 An alkoxy group; in other embodiments, the alkoxy group contains 1 to 3 carbon atoms, i.e., C _1-3 An alkoxy group; in other embodiments, the alkoxy group contains 1-2 carbon atoms, i.e., C _1-2 An alkoxy group.

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-pentyloxy (n-pentyloxy, -OCH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyloxy (-OCH (CH)) ₃ )CH ₂ CH ₂ CH ₃ ) 3-Pentoxy (-OCH (CH)) ₂ CH ₃ ) ₂ ) 2-methyl-2-butoxyRadical (-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 group may independently be unsubstituted or substituted with one or more substituents described herein.

The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms. In some of these embodiments, the haloalkyl group contains 1 to 10 carbon atoms; in still other embodiments, the haloalkyl group contains 1 to 8 carbon atoms; in other embodiments, the haloalkyl group contains 1 to 6 carbon atoms, i.e., C _1-6 A haloalkyl group; in other embodiments, the haloalkyl group contains 1 to 4 carbon atoms, i.e., C _1-4 A haloalkyl group; in other embodiments, the haloalkyl group contains 1 to 3 carbon atoms, i.e., C _1-3 A haloalkyl group; in other embodiments, the haloalkyl group contains 1-2 carbon atoms, i.e., C _1-2 A haloalkyl group. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, trifluoroethyl (e.g., 2-trifluoroethyl), trifluoromethoxy, and the like.

The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein and all refer to a non-aromatic carbocyclic ring system containing 3 to 12 ring carbon atoms that is saturated or contains one or more units of unsaturation, and does not contain any aromatic rings, i.e., C _3-12 Carbocyclic ring (radical). In other embodiments, the number of carbon atoms ranges from 3 to 10; in other embodiments, the number of carbon atoms is from 3 to 8; in other embodiments, the number of carbon atoms ranges from 3 to 6; in other embodiments, the number of carbon atoms is from 5 to 6; in other embodiments, the number of carbon atoms is from 5 to 8. In other embodiments, the number of carbon atoms is from 6 to 8. Such "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclesA ring system. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spirobicyclic carbocyclyl, and a "fused" bicyclic ring system contains two rings that share 2 contiguous ring atoms. The bridged bicyclic group includes two rings that share 3,4, or 5 adjacent ring atoms. Spiro ring systems share 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, cyclohexadienyl, 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, having one or more points of attachment to the rest of the molecule. In some of these embodiments, cycloalkyl is a ring system containing from 3 to 10 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 3 to 8 ring carbon atoms; in still other embodiments, cycloalkyl groups are ring systems containing from 5 to 8 ring carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3 to 6 ring carbon atoms, i.e. C _3-6 A cycloalkyl group; in other embodiments, cycloalkyl is a ring system containing 5 to 6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl groups can independently be unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, nonaromatic, monocyclic, bicyclic, or tricyclic ring system containing from 3 to 12 ring atoms wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl is nonaromatic, does not contain any aromatic rings, and wherein the ring system has one or more points of attachment and/or detachmentThe remainder of the children are connected. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH ₂ The-group may optionally be replaced by-C (= O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 to 8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.

Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxazolidinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl. In heterocyclic radicals-CH ₂ Examples of the substitution of the-group by-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, 1, 3-dioxolen-2-one. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Bridging heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2] s]Octyl, 3-azabicyclo [3.2.1]Octyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "m-atomic" where m is an integer typically describes the number of ring-forming atoms in the molecule, which is m. For example, piperidinyl is a 6 atom heterocyclyl group, while 1,2,3, 4-tetrahydronaphthyl is a 10 atom carbocyclyl group.

The term "heteroatom" refers to O, S, N, P, B and Si, including any oxidation state forms of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a 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, R being a substituent as described herein).

The term "halogen" refers to F, cl, br or I.

The term "N ₃ "represents an azide structure. Such groups may be linked to other groups, e.g. to a methyl group to form azidomethane (Men) ₃ ) Or linked to a phenyl group to form azidobenzene (PhN) ₃ )。

The term "aryl" used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbon 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, wherein each ring system contains 3 to 7 atoms forming a ring and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and refers to monocyclic, bicyclic, and tricyclic systems containing 5 to 16 ring atoms, or 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 8 ring atoms, or 5 to 7 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. When a heteroaryl group is present-CH ₂ When said radical is-CH ₂ -the group is optionally replaced by-C (= O) -. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is 5-14 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-12 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-8 atom consisting of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-7 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 5-6 atom heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 5 atom heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

Another oneIn some embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 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), thienyl (e.g., 2-thienyl), pyrazolyl (e.g., 1, 2-thiazolyl, 3-oxadiazolyl, 2, 3-thiazolyl, 5-oxadiazolyl, 2, 3-oxadiazolyl (e.g., 1,2, 3-thiazolyl, 2, 3-oxadiazolyl, 2, 3-thiazolyl, 5-oxadiazolyl), pyrazinyl, 1,3, 5-triazinyl; the following bi-or tricyclic groups are also included, 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), phenoxathiyl, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl,

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", denotes-CO ₂ H。

The term "carbonyl", whether used alone or in combination with other terms such as "aminocarbonyl" or "acyloxy", denotes- (C = O) -.

The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C _1-6 Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C _1-3 Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

As described herein, the ring system formed by a substituent on a ring having a bond to the center represents that the substituent may be substituted at any substitutable position on the ring, including monocyclic, bicyclic or polycyclic ring systems. For example, the substituent R represented by formula a may be substituted at any possible position in the system as shown in formulas b-1 to b-8:

as described herein, a ring system formed by a bond to the center of the ring represents that the bond can be attached to the rest of the molecule at any point on the ring system that is attachable. For example, formula c represents any position on the ring that may be attached to the rest of the molecule, as shown in formulas d-1 and d-2.

As described in the present invention, a structureIn the formula, when two or more substituent groups represented by the same letter, number or symbol are present, the substituent groups are independent of each other. For example, as shown in formula e, each R ^w Have the meaning as indicated in the invention, and each R ^w Are independent of each other, do not affect each other and can be the same or different groups.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

As used herein, the term "pharmaceutically acceptable carrier" 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, which are known to those skilled in the art (e.g., 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.

As used herein, the term "inhibiting the replication of influenza virus" includes both reducing the amount of viral replication (e.g., by at least 10%) and completely preventing viral replication (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 an amount that elicits the desired biological response. In the present invention, the biological response is expected to be inhibition of influenza virus replication, reduction in 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 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, body 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 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 can be adjusted by the skilled artisan according to the condition of the subject, the type of condition being treated and the amount of the compound described herein being used. In the case where amounts are not explicitly specified, an effective amount should be taken. For example, a compound of the invention may be administered to a subject at a dosage in the 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" isRefers to the reaction of a substituent with other functional groups, which is usually used to block or protect a particular functionality. For example, a "protecting group for an amino group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, p-toluenesulfonyl (Ts), tert-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-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 descriptions of protecting groups can be found in the literature: 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 application of the compound and a composition thereof in preparing a medicament for preventing, treating or relieving virus infection diseases of patients.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I),

wherein the ring A and the ring U ₅ 、R ⁷ 、R ⁸ 、R ⁹ And W has the definition as described in the present invention.

In some embodiments, ring a is of the substructure:

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 ；

R ¹ 、R ² 、R ³ 、R ⁴ And R ⁶ Each independently is H, D, F, cl, br, 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 radical, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Alkyl radical, C _2-6 Alkenyl or C _2-6 Alkynyl, wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl and C _2-6 Alkynyl is independently unsubstituted OR substituted with 1,2,3 OR 4 substituents independently selected from D, F, cl, br, CN, -OR ^b 、-NR ^c R ^d 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, R ^b O-C _1-4 Alkylene or R ^d R ^c N-C _1-4 An alkylene group;

l is- (CR) ^L1 R ^L2 ) _t -、-C(＝O)-(CR ^L1 R ^L2 ) _q -、-S(＝O)-(CR ^L1 R ^L2 ) _q -、-S-(CR ^L1 R ^L2 ) _q -or-O- (CR) ^L1 R ^L2 ) _q -；

t is 0, 1,2,3,4, 5 or 6;

q is 0, 1,2,3,4, 5 or 6;

R ^L1 and R ^L2 Each independently is H, D, F, cl, br, 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 radical, C _1-6 Alkyl radical, C _2-6 Alkenyl or C _2-6 An alkynyl group; or R ^L1 、R ^L2 And the carbon atoms to which they are attached form a carbonyl group; or R ^L1 、R ^L2 Together with the carbon atom to which they are attached form C _3-6 A carbocyclic ring or a heterocyclic ring of 3 to 6 atoms;

R ^S is F, cl, br, CN, NO ₂ 、-OR ^S2 、-NR ^S3 R ^S4 、-OC(＝O)R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 、-C(＝O)OR ^S2 、-C(＝O)NR ^S3 R ^S4 、-NR ^S5 C(＝O)R ^S1 、-OP(＝O)(OR ^S2 ) ₂ 、-OP(＝O)(O-C _1-6 alkylene-OC (= O) R ^S1 ) ₂ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene, 5-to 8-membered heteroaryl or (5-to 8-membered heteroaryl) -C _1-4 Alkylene, wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene, 5-to 8-membered heteroaryl or (5-to 8-membered heteroaryl) -C _1-4 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5 substituents R ^x Substituted with the proviso that R ^S Is not tetrahydropyranyl;

R ^S1 、R ^S2 、R ^S3 、R ^S4 and R ^S5 Each independently of the other is H, D, sodium, potassium, OH, NH ₂ 、C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, 3-8 atomsHeterocyclyl group of (3-8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 8 atoms or (heteroaryl of 5 to 8 atoms) -C _1-4 Alkylene, wherein said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group of 3 to 8 atoms, (heterocyclic group of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, 5-8 atom-composed heteroaryl and (5-8 atom-composed heteroaryl) -C _1-4 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5 substituents R ^x Substituted;

or R ^S3 、R ^S4 And together with the nitrogen atom to which they are attached, form a 3-8 atom heterocyclic ring or a 5-8 atom heteroaromatic ring, wherein the 3-8 atom heterocyclic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3,4 or 5 substituents R ^x Substituted;

R ⁵ and R ⁸ Each independently is H, D, F, cl, br, 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 radical, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, 5-to 8-membered heteroaryl or (5-to 8-membered heteroaryl) -C _1-4 Alkylene, wherein R is ^b O-C _1-4 Alkylene, R ^d R ^c N-C _1-4 Alkylene radical, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, 5-8 atom-composed heteroaryl and (5-8 atom-composed heteroaryl) -C _1-4 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Substituted;

R ⁷ is-OR ^b 、C _2-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 Carbocyclyl, C _3-12 carbocyclyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 16 atoms or (heteroaryl of 5 to 16 atoms) -C _1-4 Alkylene, wherein said C _2-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-12 Carbocyclic radical, C _3-12 carbocyclyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 16 atoms and (heteroaryl of 5 to 16 atoms) -C _1-4 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Substituted;

or R ⁵ 、R ⁷ Together with the carbon atom to which they are each attached, or R ⁷ 、R ⁸ Together with the carbon atom to which they are each attached, form C _3-12 Carbocyclic ring, heterocyclic ring of 3-12 atoms, C _6-10 An aromatic ring or a heteroaromatic ring of 5 to 10 atoms, wherein C is _3-12 Carbocyclic ring, heterocyclic ring of 3-12 atoms, C _6-10 The aromatic ring and the 5-10 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^y Substituted;

each R ^x And R ^y Independently D, F, cl, br, CN, NO ₂ 、＝O、-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 radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group of 3 to 8 atoms, (heterocyclic group of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, 5-to 8-membered heteroaryl or (5-to 8-membered heteroaryl) -C _1-4 Alkylene, wherein said C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, heteroaryl of 5 to 8 atoms and (heteroaryl of 5 to 8 atoms) -C _1-4 Each alkylene is independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, CN, NO ₂ 、＝O、-OR ^b 、-NR ^c R ^d 、C _1-6 Alkyl radical, C _1-6 Haloalkyl, R ^b O-C _1-4 Alkylene or R ^d R ^c N-C _1-4 An alkylene group;

R ⁹ is H, D or optionally substituted by 1,2,3 or 4 groups independently selected from D, F, cl, br, CN, NO ₂ OR-OR ^b C substituted by a substituent of (3) _1-6 An alkyl group;

w is the following sub-structure:

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

each R ^w Independently D, F, cl, br, CN, NO ₂ 、＝O、-C(＝O)R ^a 、-C(＝O)OR ^g 、-C(＝O)O-C _1-6 alkylene-OC (= O) R ^h 、-C(＝O)O-C _1-6 alkylene-OC (= O) OR ^g 、-C(＝O)NR ^c R ^d 、-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 radical, R ^d R ^c N-C _1-2 Alkylene radical, 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, 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 、R ^f 、R ^g and R ^h Each independently is H, D, sodium, potassium, hydroxyl, C _1-6 Haloalkyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Carbocyclic radical, C _3-6 carbocyclyl-C _1-4 Alkylene, heterocyclic group of 3 to 6 atoms, (heterocyclic group of 3 to 6 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, 5-6-membered heteroaryl or (5-6-membered heteroaryl) -C _1-4 Alkylene, wherein said C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Carbocyclic radical, C _3-6 carbocyclyl-C _1-4 Alkylene, heterocyclic group consisting of 3 to 6 atoms, (heterocyclic group consisting of 3 to 6 atoms) -C _1-4 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-4 Alkylene, 5-6 atomsAnd (5-6 atom-constituting heteroaryl) -C _1-4 Each alkylene is 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 radical, C _1-6 Alkoxy or C _1-6 An alkylamino group;

or R ^c 、R ^d And together with the nitrogen atom to which they are attached, form a 3-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 3-6 atom heterocyclic ring and the 5-6 atom heteroaromatic 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 radical, C _1-6 Alkoxy or C _1-6 An alkylamino group.

In other embodiments, ring a is of the substructure:

wherein said U is ₁ 、U ₂ 、U ₃ 、U ₄ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ^S And L has the definitions set forth herein.

In still other embodiments, ring a is of the substructure:

wherein said R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁶ 、R ^S And L has the meaning according to the invention.

In other embodiments, R ^S Is F, cl, br, CN, NO ₂ 、-OR ^S2 、-NR ^S3 R ^S4 、-OC(＝O)R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 、-C(＝O)OR ^S2 、-C(＝O)NR ^S3 R ^S4 、-NR ^S5 C(＝O)R ^S1 、-OP(＝O)(OR ^S2 ) ₂ 、-OP(＝O)(O-C _1-4 alkylene-OC (= O) R ^S1 ) ₂ 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C _1-2 Alkylene, wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group of 5 to 6 atoms, (heterocyclic group of 5 to 6 atoms) -C _1-2 Alkylene, 5-6-atom heteroaryl and (5-6-atom heteroaryl) -C _1-2 Alkylene is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^x Substituted with the proviso that R ^S Is not tetrahydropyranyl, wherein R is ^S1 、R ^S2 、R ^S3 、R ^S4 、R ^S5 And R ^x Having the definitions set out in the present invention.

In still other embodiments, R ^S Is F, cl, br, CN, NO ₂ 、-OR ^S2 、-NR ^S3 R ^S4 、-OC(＝O)R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 、-C(＝O)OR ^S2 、-C(＝O)NR ^S3 R ^S4 、-NHC(＝O)R ^S1 、-OP(＝O)(OR ^S2 ) ₂ 、-OP(＝O)(O-CH ₂ -OC(＝O)R ^S1 ) ₂ 、-OP(＝O)(O-CH ₂ CH ₂ -OC(＝O)R ^S1 ) ₂ Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1, 3-dioxol-2-one, furanyl, pyrrolyl, pyridinyl, pyranylOxazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1, 3-dioxol-2-one, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^x Is substituted, wherein R is ^S1 、R ^S2 、R ^S3 、R ^S4 And R ^x Having the definitions set forth herein.

In some embodiments, R ^S1 、R ^S2 、R ^S3 、R ^S4 And R ^S5 Each independently H, D, sodium, potassium, OH, NH ₂ 、C _1-4 Haloalkyl, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C _1-2 Alkylene, wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C _1-2 Each alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5R ^x Substituted;

or R ^S3 、R ^S4 And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocycle or a 5-6 atom heteroaryl ring, wherein the 5-6 atom heterocycle and 5-6 atom heteroaryl ring are each independently unsubstituted or substituted with 1,2,3,4, or 5R ^x Is substituted, wherein R is ^x Having the definitions set forth herein.

In still other embodiments, R ^S1 、R ^S2 、R ^S3 、R ^S4 And R ^S5 Each independently H, D, sodium, potassium, OH, NH ₂ Trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl-methylene, imidazolyl-ethylene, pyrazolyl-ethylene or pyridyl-ethylene, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl-methylene, imidazolyl-ethylene, pyrazolyl-ethylene and pyridyl-ethylene are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^x Substituted wherein R is ^x Having the definitions set forth herein.

In other embodiments, R ⁷ is-OR ^b 、C _2-4 Alkyl, aryl, heteroaryl, and heteroaryl,C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Carbocyclyl, C _3-6 carbocyclyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 10 atoms, (heterocyclic group consisting of 5 to 10 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, 5-to 10-atom heteroaryl or (5-to 10-atom heteroaryl) -C _1-2 Alkylene, wherein said C _2-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Carbocyclyl, C _3-6 carbocyclyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 10 atoms, (heterocyclic group consisting of 5 to 10 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C _1-2 Each alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Substituted wherein R is ^b And R ^y Having the definitions set out in the present invention.

In still other embodiments, R ⁷ 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-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 said 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-tetrahydroisoquinolinyl, phenyl, naphthyl, furanyl, benzofuran, or furanyl groupPyranyl, pyrrolyl, pyridyl, 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 ^y Is substituted, wherein R is ^b And R ^y Having the definitions set out in the present invention.

In other embodiments, R ⁵ And R ⁸ Each independently is H, D, F, cl, br, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、-OR ^b 、-NR ^c R ^d 、C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 6 atoms or (heteroaryl of 5 to 6 atoms) -C _1-2 Alkylene, wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl radical, C _3-6 cycloalkyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C _1-2 Each alkylene is independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Is substituted, wherein R is ^a 、R ^b 、R ^c 、R ^d And R ^y Having the definitions set forth herein.

In still other embodiments, R ⁵ And R ⁸ Each independently is H, D, F, cl, br, CN, NO ₂ Methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R ⁵ 、R ⁷ Together with the carbon atom to which they are each attached, or R ⁷ 、R ⁸ Together with the carbon atom to which they are each 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 is _3-6 Carbocyclic ring, heterocyclic ring of 5-6 atoms, C _6-10 The aromatic ring or 5-6 atom heteroaromatic ring is each independently unsubstituted or substituted by 1,2,3,4 or 5R ^y Substituted wherein R is ^y Having the definitions set out in the present invention.

In still other embodiments, R ⁵ 、R ⁷ Together with the carbon atom to which they are each attached, or R ⁷ 、R ⁸ And together with the carbon atom to which they are each attached, form C _5-6 A carbocycle, a heterocycle of 5-6 atoms, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1,3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine or pyrimidine, wherein said C is _5-6 A carbocyclic ring, a 5-6 atom heterocycle, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1,3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine and pyrimidine are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^y Is substituted, wherein R is ^y Having the definitions set forth herein.

In other embodiments, each R is ^x And R ^y Independently D, F, cl, br, CN, NO ₂ 、＝O、-OR ^b 、-NR ^c R ^d 、-C(＝O)R ^a 、-C(＝O)OR ^b 、-C(＝O)NR ^c R ^d 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, 5-6 member heterocyclic radical, phenyl-C _1-2 Alkylene or heteroaryl of 5 to 6 atoms, wherein said C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, 5-6 member heterocyclic radical, phenyl-C _1-2 Alkylene and 5-6-membered heteroaryl are each independently unsubstituted or substituted with 1,2,3 or 4 substituentsThe substituents are independently selected from D, F, cl, br, CN, NO ₂ 、＝O、-OR ^b 、-NR ^c R ^d Methyl, ethyl, n-propyl or isopropyl, wherein R is ^a 、R ^b 、R ^c And R ^d Having the definitions set out in the present invention.

In some embodiments, each R is ^x And R ^y Independently D, F, cl, br, CN, NO ₂ 、＝O、-OH、-OCH ₃ 、-OCH ₂ CH ₃ 、-NH ₂ 、-C(＝O)OH、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)NH ₂ Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1, 3-dioxol-2-one, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1, 3-dioxol-2-one, phenyl, furyl, triazolyl, pyrazolyl, pyridyl, thiazolyl, tetrazolyl, 1,3, pyridazinyl, 1,3, 5-triazinyl or pyrimidinyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of NO, br, and NO, cl, br ₂ 、＝O、-OH、-NH ₂ Methyl, ethyl, n-propyl or isopropyl.

In other embodiments, R ¹ 、R ² 、R ³ 、R ⁴ And R ⁶ Each independently is H, D, F, cl, br, 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 _1-2 Alkylene radical, R ^d R ^c N-C _1-2 Alkylene radical, C _1-4 Alkyl radical, C _2-4 Alkenyl or C _2-4 Alkynyl, wherein said C _1-4 Alkyl radical, C _2-4 Alkenyl and C _2-4 Alkynyl is independently unsubstituted OR substituted with 1,2,3 OR 4 substituents independently selected from D, F, cl, br, CN, -OR ^b 、-NR ^c R ^d 、C _1-4 Alkyl radical, C _1-4 Haloalkyl, R ^b O-C _1-2 Alkylene or R ^d R ^c N-C _1-2 Alkylene, wherein R is ^a 、R ^b 、R ^c And R ^d Having the definitions set forth herein.

In still other embodiments, R ¹ 、R ² 、R ³ 、R ⁴ And R ⁶ Each independently is H, D, F, cl, br, CN, NO ₂ 、-C(＝O)R ^a 、-C(＝O)OH、-C(＝O)NH ₂ 、-OH、-NH ₂ Methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, br, CN, -OH, -NH ₂ Methyl, ethyl, n-propyl or isopropyl, wherein R is ^a Having the definitions set out in the present invention.

In other embodiments, R ⁹ Is H, D or optionally substituted by 1,2,3 or 4 groups independently selected from D, F, cl, br, CN, NO ₂ OR-OR ^b C substituted by a substituent of (3) _1-4 Alkyl, wherein R is ^b Having the definitions set forth herein.

In still other embodiments, R ⁹ Is H, D, CF ₃ Methyl, ethyl, n-propyl or isopropyl.

In other embodimentsEach R ^w Independently D, F, cl, br, CN, NO ₂ 、＝O、-C(＝O)R ^a 、-C(＝O)OR ^g 、-C(＝O)O-C _1-6 alkylene-OC (= O) R ^h 、-C(＝O)O-C _1-6 alkylene-OC (= O) OR ^g 、-C(＝O)NR ^c R ^d 、-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 radical, C _1-4 Alkyl, heteroaryl of 5-6 atoms or heterocyclyl of 5-6 atoms, wherein said C _1-4 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, CN, N ₃ 、＝O、NO ₂ 、-OR ^b 、C _1-4 Alkyl or C _1-4 Haloalkyl, wherein said R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g And R ^h Having the definitions set out in the present invention.

In yet other embodiments, each R is ^w Independently D, F, cl, br, CN, NO ₂ 、＝O、-C(＝O)OCH ₃ 、-C(＝O)OCH ₂ CH ₃ 、-C(＝O)OCH(CH ₃ ) ₂ 、-C(＝O)OPh、-C(＝O)OCH ₂ Ph、-C(＝O)OH、-C(＝O)ONa、-C(＝O)O-CH ₂ -OC(＝O)CH ₃ 、-C(＝O)O-CH ₂ -OC(＝O)C(CH ₃ ) ₃ 、-C(＝O)O-CH ₂ -OC(＝O)OCH ₃ 、-C(＝O)O-CH ₂ -OC(＝O)OCH ₂ CH ₃ 、-C(＝O)NR ^c R ^d 、-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 a heterocyclic group 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 the heterocyclic group 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, CN, N, and Br ₃ 、＝O、NO ₂ 、-OCH ₃ Methyl, ethyl, n-propyl, isopropyl or trifluoromethyl, wherein R is ^a 、R ^b 、R ^c 、R ^d And R ^f Having the definitions set out in the present invention.

In other embodiments, R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g And R ^h Each independently is H, D, sodium, potassium, hydroxyl, C _1-4 Haloalkyl, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Carbocyclic radical, C _3-6 carbocyclyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, 5-6-membered heteroaryl or (5-6-membered heteroaryl) -C _1-2 Alkylene, wherein said C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Carbocyclyl, C _3-6 carbocyclyl-C _1-2 Alkylene, heterocyclic group consisting of 5 to 6 atoms, (heterocyclic group consisting of 5 to 6 atoms) -C _1-2 Alkylene radical, C _6-10 Aryl radical, C _6-10 aryl-C _1-2 Alkylene, heteroaryl of 5 to 6 atoms and (heteroaryl of 5 to 6 atoms) -C _1-2 Each alkylene is independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, CN, OH, NH ₂ 、C _1-4 Alkyl radical, C _1-4 Alkoxy or C _1-4 An alkylamino group;

or R ^c 、R ^d And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic 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 _1-4 Alkyl radical, C _1-4 Alkoxy or C _1-4 An alkylamino group.

In still other embodiments, R ^a 、R ^b 、R ^c 、R ^d 、R ^e 、R ^f 、R ^g And R ^h Each independently is H, D, sodium, potassium, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, C _3-6 Carbocyclyl, heterocyclyl of 5 to 6 atoms, phenyl or heteroaryl of 5 to 6 atoms, wherein said methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, methoxy, ethoxy, C _3-6 Carbocyclyl, 5-6 atom heterocyclyl, phenyl and 5-6 atom heteroaryl are each independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, cl, CN, OH, NH ₂ Methyl, ethyl, n-propyl, isopropyl or methoxy;

or R ^c 、R ^d And together with the nitrogen atom to which they are attached, form a 5-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 5-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from D, F, cl, CN, OH, NH ₂ Methyl, ethylN-propyl, isopropyl or methoxy.

In other embodiments, the invention relates to a compound having a structure according to formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,

wherein U is ₁ 、U ₂ 、U ₃ 、U ₄ 、U ₅ 、L、R ^S 、R ⁶ 、R ⁷ 、R ⁸ And R ^w Having the definitions as described in the present invention.

In other embodiments, the present invention relates to a compound having the structure shown in formula (III) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein U is ₁ 、U ₂ 、U ₃ 、U ₄ 、U ₅ 、L、R ^S 、R ⁶ 、R ⁷ 、R ⁸ And R ^w Having the definitions as described in the present invention.

In other embodiments, the present invention relates to compounds, or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, of one of the following, but in no way limited to these compounds:

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 some further embodiments, the therapeutic agent is selected from an anti-influenza virus agent or a vaccine.

In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray dosage form.

In still other embodiments, the pharmaceutical composition of the invention, wherein the additional therapeutic agent is Amantadine (Amantadine), rimantadine (Rimantadine), oseltamivir (Oseltamivir), zanamivir (Zanamivir), peramivir (Peramivir), laninamivir (Laninamivir), laninamivir Octanoate Hydrate (Laninamivir Octanoate Hydrate), favipiravir (Favipiravir), arbidol (Arbidol), ribavirin (ribivirin), stafurin, ingavirin (Ingavirin), influenza (flu), CAS 1420-75-6, JNJ-872 (pimoivir), S-033188, influenza vaccine (flumit mix), or a pharmaceutical composition of the invention

Quadrivalent、

Quadrivalent、

Or

) Or a combination thereof.

In another aspect, the invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a viral infectious disease in a patient.

In some embodiments, the viral infection is an influenza viral infection.

In some embodiments, the influenza virus is H1N 1A/Weiss/43.

In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition for 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 useful as intermediates for the preparation and/or purification of the compounds of the present invention and/or for the isolation of the enantiomers of the compounds of the present invention.

Pharmaceutically acceptable acid addition salts can 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, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrophosphate/dihydrogenphosphate, polysilconate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can 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 can be derived include, for example, ammonium salts and metals from groups I to XII of the periodic Table. In certain embodiments, the salts are 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 can 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 (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present 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 the appropriate base (e.g., na, ca, mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In the fields of, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002) may find some additional lists of suitable Salts.

Furthermore, 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, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent unlabeled forms of these compounds as well as isotopically labeled forms. Isotopically labelledThe compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having the atomic mass or mass number selected. 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 as defined herein labelled with various isotopes, for example, wherein a radioactive isotope is present, e.g. ³ H， ¹⁴ C and ¹⁸ those compounds of F, or in which a non-radioactive isotope is present, e.g. ² H and ¹³ C. the isotope labeled compound can be used for metabolic research (use) ¹⁴ C) Reaction kinetics study (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 measurement of the tissue distribution of drugs or substrates, or in radiation therapy of patients. ¹⁸ F-labelled compounds are particularly desirable for PET or SPECT studies. Isotopically-labelled compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by using suitable isotopically-labelled reagents in place of the original non-labelled reagents described in the examples and preparations of this invention.

In addition, heavier isotopes are, in particular, deuterium (i.e., ² substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in this context is to be taken as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If the substituents of the compounds of the invention are specifiedAs 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 in which 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 (II) or a formula (III) or a stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or a solvate thereof. 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.

Pharmaceutically acceptable carriers 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 free of other adverse or side effects once administered to a patient. Standard pharmaceutical techniques may be employed.

The pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or excipient, as described herein, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular intended dosage form, as used herein. The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, lippincott Williams and Wilkins, philadelphia, and Encyclopedia of Pharmaceutical technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, marcel Dekker, new York disclose various carriers for use in formulating pharmaceutically acceptable compositions and well known methods for their preparation. In addition to conventional carrier vehicles which are incompatible with the compounds of the present invention, e.g., may produce undesirable biological effects or may deleteriously interact with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and its use are contemplated by the present invention.

Some examples of substances that can 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, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methyl cellulose, hydroxypropyl methyl cellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch) cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, 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, ethanol and phosphate buffers, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, detackifying agents, gelling agents, and the like, as judged by the formulator, coating agents, sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.

The compounds or compositions of the present invention may be administered by any suitable means, and the above-described compounds and pharmaceutically acceptable compositions may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally as an oral or nasal spray, and the like, 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 compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example, sterile injectable aqueous or oleaginous suspensions. 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 bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injections.

For example, injectable formulations can be sterilized by filtration through a bacteria retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed 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 the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microcapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound 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, for example cocoa butter, polyethylene glycol or a suppository wax, which are solid at 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 mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, 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 paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, 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 a similar type may also be employed as fillers in soft and hard gel capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. 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 a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols.

The active compound may also be in microencapsulated form with one or more of the above-mentioned 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 mixed with at least one inert diluent, for example sucrose, lactose or starch. In general, such dosage forms may also contain additional substances in addition to the inert diluents, such as tableting lubricants and other tableting 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.

Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers as may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of dermal patches with the added advantage of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can 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, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, 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 composition of the invention may be an aqueous or oily 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 bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids, such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections. 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 formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, spans, and other emulsifying agents or bioavailability enhancers which are 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, carriers which are commonly used include, but are not limited to, lactose and 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 are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring 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 may 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, particularly when the target of treatment includes topical application to an easily accessible area or organ, including the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical instillation to the lower intestinal tract may be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Topical skin patches may also be used.

For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream 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, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or solutions in isotonic pH adjusted sterile saline in particular, with or without preservatives 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 spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art 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 for use in the methods of the invention may be formulated in unit dosage form. 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 can be administered as a single daily dose or as one of a plurality of daily doses (e.g., about 1-4 or more times per 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 compound and the pharmaceutical composition provided by the invention can be used for preparing medicines for preventing, treating or relieving virus infectious diseases of patients, and preferably, the virus infection is influenza virus infection.

The invention also provides application of the compound or the pharmaceutical composition thereof in preparation of influenza virus RNA polymerase inhibitor drugs.

The present invention provides a method for the treatment, prevention or delay of infection by a virus, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as described above or a pharmaceutical composition thereof. Wherein the virus is an influenza virus. Also, the above-described 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 of action or the like will generally depend on the particular compound, patient, particular disease or condition being administered and its severity, route and frequency of administration, etc., and will be decided by the attending physician as the case may be. For example, when a compound or pharmaceutical composition provided by the present invention is administered by intravenous route, administration may be performed once a week or even at longer intervals.

In summary, the present invention provides a novel compound that can be used as an influenza virus RNA polymerase inhibitor. The compound of the invention is suitable for being prepared into 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 tamiflu.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Other examples of animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents other than those described herein, or by some routine modification of the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, all temperatures are set forth 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 were used without further purification unless otherwise indicated. General reagents were purchased from Shantou West Long chemical plant, guangdong Guanghua chemical reagent plant, guangzhou chemical reagent plant, tianjin Haojiyu chemical Co., ltd, tianjin Shunhun chemical reagent plant, wuhan Xin Huayuan scientific development Co., ltd, qingdao Tenglong chemical reagent Co., ltd, qingdao Haiyanhua Co., ltd, beijing coupled technology Co., ltd, shanghai Tebo chemical technology Co., ltd, and Shao Yuan technology (Shanghai) Co., ltd.

The anhydrous tetrahydrofuran, 1, 4-dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used dried over anhydrous sodium sulfate in advance.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao oceanic plants.

The test conditions of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: brookfield (Bruker) nuclear magnetic instrument at 400MHz or 600MHz in CDC1 at room temperature 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 (singlets),d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, expressed in J, are given in Hertz (Hz).

The test conditions for low resolution Mass Spectrometry (MS) data were: agilent 6120 Quadrupole HPLC-MS (column model: zorbax SB-C18, 2.1X 30mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH with 0.1% formic acid) ₃ CN) in (H containing 0.1% formic acid) ₂ O)) at 210nm/254nm by UV detection using electrospray ionization mode (ESI).

The test conditions for high resolution Mass Spectrometry (MS) data were: agilent 6530 QTOF HPLC-MS (direct sample introduction by two-way, 1min, flow rate of 0.6mL/min, mobile phase of 80% (CH containing 0.1% formic acid) ₃ CN) in (H containing 0.1% formic acid) ₂ O) using electrospray ionization mode (ESI).

The purity of the compound is characterized in a manner that: agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP,50/80mm, DAC) with UV detection at 210nm/254 nm.

The following acronyms are used throughout the invention:

the following synthetic schemes set forth the experimental procedures for preparing the compounds disclosed in the present invention. Wherein, U ₁ 、U ₂ 、U ₃ 、U ₄ 、R ⁶ 、R ⁷ 、R ⁸ 、R ^y 、R ^g 、R ^S And L has the definition as described in the present invention. X is Br or I, LG is a leaving group, PG is an amino protecting group, and ring M is C _3-12 Carbocyclic ring, heterocyclic ring of 3-12 atoms, C _6-10 An aromatic ring or a heteroaromatic ring of 5 to 10 atoms.

Synthesis scheme 1

Formula (II)(9)The intermediates shown can be synthesized by the methods disclosed in scheme 1. First, the compound(1)Under the action of Pd catalyst, with compound(2)Reacting to form a compound(3). Compound (I)(3)Generating a ring reaction under the action of alkali to generate a compound(4). Then, the compound(4)Halogenated reaction to generate compound(5). Next, the compound(5)Reacting with amino protective agent under alkaline condition to generate compound(6). Finally, the compounds(6)And compounds(7)Or a compound(8)Coupling reaction is carried out to generate an intermediate(9)。

Synthesis scheme 2

Formula (II)(12)The intermediates shown can be synthesized by the methods disclosed in scheme 2. First, the compound(5)And compounds(10)Reacting to form a compound(11). Then, the compound(11)And compounds(37)Coupling reaction is carried out to generate an intermediate(12)。

Synthesis scheme 3

Formula (II)(13)The intermediates shown can be synthesized by the methods disclosed in scheme 3. First, the compound(5)And compounds(10)Reacting to form a compound(11). Then, the compound(11)And compounds(7)The coupling reaction is carried out to generate an intermediate(13)。

Synthesis scheme 4

Formula (II)(20)Intermediate of the formula(21)Intermediate or formula(23)The intermediates shown can be prepared by the methods described in scheme 4. First, the compound(14)And compounds(15)Or a compound(16)Carrying out Suzuki coupling reaction to generate a compound(17). Then, the compound(17)And compounds(18)Reacting under alkaline condition to generate compound(19). Compound (I)(19)Reacting with HBr to generate compound(20). Next, the compound(20)Removing the protecting group on the carboxyl under the action of alkali to obtain a compound(21). Finally, the compounds(21)And compounds(22)React to form the compound(23)。

Synthesis scheme 5

Is of the formula(27)The compounds shown can be prepared by the methods described in FIG. 5. First, the compound(20)And intermediates(9)The Suzuki coupling reaction is carried out under the action of Pd catalyst to generate compound(24). Then, the compound(24)In acid and Et ₃ Removing the protecting group on the amino group under the action of SiH to generate a compound(25). Next, the compound(25)And compounds(10)Reacting to form a compound(26). Finally, the compounds(26)Removing the protecting group on the carboxyl under the action of alkali to obtain a compound(27)。

Synthesis scheme 6

Formula (II)(27)The compounds shown can also be prepared by the methods described in FIG. 6. Compound (I)(21)And intermediates(13)The Suzuki coupling reaction is carried out under the action of Pd catalyst to generate compound(27)。

Synthesis scheme 7

Formula (II)(27)The compounds shown can also be prepared by the methods described in FIG. 7. Compound (I)(21)And intermediates(12)The Suzuki coupling reaction is carried out under the action of Pd catalyst to generate compound(27)。

Synthesis scheme 8

Formula (II)(28)The compounds shown can be prepared by the methods described in FIG. 8. Compound (I)(23)And intermediates(12)Generating a compound by Suzuki coupling reaction under the action of a Pd catalyst(28)。

Synthesis scheme 9

Is of the formula(28)The compounds shown can also be prepared by the methods described in FIG. 9. Compound (I)(23)And intermediates(13)Generating a compound by Suzuki coupling reaction under the action of a Pd catalyst(28)。

Synthesis scheme 10

Formula (II)(31)The compounds shown can be prepared by the methods described in scheme 10. First, the compound(25)Reacting with 3-bromopropionic acid to produce a compound(29). Then, the compound(29)With tetrahydropyrroleReacting to form a compound(30). Finally, the compounds(30)Removing the protecting group on the carboxyl under alkaline condition to obtain the compound(31)。

Synthesis scheme 11

Formula (II)(33)The compounds shown can also be prepared by the methods described in FIG. 11. Compound (I)(32)And intermediates(12)The Suzuki coupling reaction is carried out under the action of Pd catalyst to generate compound(33)。

FIG. 12 Synthesis scheme

Formula (II)(35)A compound of the formula(36)The compounds shown can be prepared by the methods described in FIG. 12. Compound (I)(34)And compounds(10)Nucleophilic reaction to produce the compound(35). Compound (I)(35)And compounds(22)React to form the compound(36)。

Detailed Description

The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.

Preparation examples

In the following preparation examples, the inventors described in detail the preparation of the compounds of the present invention by taking some of the compounds of the present invention as examples.

Example 1 (2S, 3S) -3- ((2- (2-chloro-5-methyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3-aminobicyclo [2.2.2]Octane-2-carboxylic acidEthyl ester hydrochloride

The title compound can be prepared by reference to the synthetic methods disclosed in patent application WO 2015073491.

Step 2) 2, 4-dichloro-5-fluoro-6- (thien-2-yl) pyrimidine

Thiophene (300mg, 3.57mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to-15 deg.C, n-butyllithium (1.4 mL,3.57mmol,2.5 mol/L) was added, and after stirring at this temperature for 1 hour, znCl was added ₂ TMEDA (300mg, 1.18mmol), after stirring at room temperature for 1 hour, palladium dichloride (65mg, 0.36mmol), triphenylphosphine (188mg, 0.71mmol) and 5-fluoro-2, 4, 6-trichloropyrimidine (790mg, 3.92mmol) were further added, and the resulting mixture was heated to 55 ℃ under nitrogen atmosphere for reaction overnight. Water (50 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether) to give the title compound as a white solid (366mg, 41%).

MS(ESI,pos.ion)m/z:250.9[M+H] ⁺ 。

Step 3) (2S, 3S) -3- ((2-chloro-5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Pungent food Alkyl-2-carboxylic acid ethyl ester

2, 4-dichloro-5-fluoro-6- (thien-2-yl) pyrimidine (366mg, 1.47mmol), (2S, 3S) -3-aminobicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester hydrochloride (412mg, 1.76mmol) and K ₂ CO ₃ (508mg, 3.68mmol) was suspended in DMF (5 mL), and the resulting mixture was stirred at room temperature for reaction overnight. Addition of H ₂ The reaction was quenched with O (100 mL), extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5/1) to give the title compound as a white solid (388mg, 64%).

MS(ESI,pos.ion)m/z:410.20[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):7.84(s,1H),7.57(d,J＝4.8Hz,1H),7.18(t,J＝4.2Hz,1H),5.34(s,1H),4.53(s,1H),4.24(m,2H),2.41(d,J＝5.5Hz,1H),2.05(d,J＝10.7Hz,2H),1.93–1.77(m,3H),1.69(d,J＝9.2Hz,5H),1.29(t,J＝5.2Hz,3H)。

Step 4) (2S, 3S) -3- ((2-bromo-5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Pungent food Alkyl-2-carboxylic acid ethyl ester

The compound (2S, 3S) -3- ((2-chloro-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester (1.0 g, 2.24mol) was dissolved in hydrobromic acid acetic acid solution (20mL, 120mmol, 33%), the resulting mixture was stirred at room temperature for reaction for 2 hours, the reaction solution was poured into ice water (30 mL) and extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were washed successively with saturated aqueous sodium bicarbonate (80 mL. Times.2) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid (1.04g, 93%). MS (ESI, pos.ion) m/z of 454.0[ M ] +H] ⁺ 。

Step 5) 5-chloro-3- ((trimethylsilyl) ethynyl) pyrazin-2-amine

3-bromo-5-chloropyrazine-2-amine (200mg, 0.96mmol), triethylamine (290mg, 2.88mmol), cuprous iodide (5mg, 0.33mmol) and bis (triphenylphosphine) palladium dichloride (13mg, 0.02mmol) were dissolved in tetrahydrofuran (5 mL), the reaction solution was stirred at room temperature, trimethylethynyl silicon (0.15ml, 1.06mmol) was slowly added dropwise to the reaction solution, and after the dropwise addition, the reaction solution was transferred to 55 ℃ for further reaction for 1 hour. After the reaction system was cooled to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 30/1) to give the title compound as a pale yellow solid (208mg, 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 6) 2-chloro-5H-pyrrolo [2,3-b]Pyrazine esters

5-chloro-3- ((trimethylsilyl) ethynyl) pyrazin-2-amine (100mg, 0.44mmol) was dissolved in THF (8 mL), and the resulting solution was stirred at room temperature, then potassium tert-butoxide (59mg, 0.53mmol) was added thereto, the tube was sealed, 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, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 3/1) to give the title compound as a pale yellow solid (40mg, 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 7) 2-chloro-7-iodo-5H-pyrrolo [2,3-b]Pyrazine

2-chloro-5H-pyrrolo [2,3-b ] pyrazine (80mg, 1.82mmol) was dissolved in 2-methyltetrahydrofuran (10 mL), NIS (451mg, 2.00mmol) was added thereto, and the resulting reaction mixture was allowed to stand at room temperature overnight. The reaction was quenched with saturated sodium thiosulfate (50 mL), the layers were 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, the solvent was evaporated 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 (456 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 8) 2-chloro-7-iodo-5-trityl-5H-pyrrolo [2,3-b ]]Pyrazine

2-chloro-7-iodo-5H-pyrrolo [2,3-b ]]Pyrazine (1.76g, 6.30mmol), K ₂ CO ₃ (1.74g, 12.60mmol) and triphenylchloromethane (1.93g, 6.93mmol) were dissolved in DMF (8 mL), the resulting reaction solution was left to stand at room temperature overnight with stirring, 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, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatographyPurification by chromatography (PE/EA (v/v) = 20/1) gave the title compound as a light yellow solid (2.96g, 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 9) 2-chloro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5-trityl-5H- Pyrrolo [2,3-b]Pyrazine esters

2-chloro-7-iodo-5-trityl-1H-pyrrolo [2,3-b ] pyrazine (500mg, 0.96mmol) and isopropylenepinacol borate (231mg, 1.25mmol) were dissolved in THF (10 mL), and the resulting solution was cooled to-27 ℃ under nitrogen, to which isopropylmagnesium chloride (2M, 0.70mL) was slowly added dropwise, after which the reaction was stirred at-27 ℃ for 1.5 hours. The reaction was stopped, the reaction solution was added to a saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (100 mL × 3), 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) = 10/1) to give the title compound as a yellow solid (210mg, 42%).

Step 10) (2S, 3S) -3- ((2- (2-chloro-5-trityl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -5- Fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Reacting 2-chloro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5-trityl-5H-pyrrolo [2,3-b ]]Pyrazine (2.53g, 2.90mmol, 60%), potassium carbonate (1.50g, 11mmol), pdCl ₂ (dppf) (390mg, 0.53mmol) and (2S, 3S) -3- ((2-bromo-5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester (1.20g, 2.60mmol) was mixed in 1, 4-dioxane (15 mL) and water (1 mL), and the resulting mixture was evacuated by bubbling nitrogen gas for 10 minutes, followed by heating to 115 ℃ with a sealed tube and stirring for reaction for 3 hours. After the reaction was completed and the solid impurities were removed by direct filtration, the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1-5/1) to obtain the title compound as a white solid (1.85g, 91%).

Step 11) (2S, 3S) -3- ((2- (2-chloro-5H)-pyrrolo [2,3-b]Pyrazin-7-yl) -5-fluoro-6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Reacting (2S, 3S) -3- ((2- (2-chloro-5-trityl-5H-pyrrolo [2,3-b ]]Pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester (282mg, 0.37mmol) was dissolved in DCM (5 mL), and Et was added ₃ SiH (0.60mL, 3.67mmol) and TFA (0.30mL, 3.67mmol), and the resulting mixture was stirred at room temperature overnight. The reaction was stopped, the reaction solution was added to a saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (60 mL × 3), the combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a white solid (75mg, 39%).

MS(ESI,pos.ion)m/z:528.05[M+H] ⁺ 。

Step 12) (2S, 3S) -3- ((2- (2-chloro-5-methyl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3- ((5-fluoro-2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (500mg, 0.94mmol), iodomethane (270mg, 1.89mmol) and potassium carbonate (400mg, 2.84mmol) were suspended in DMF (10 mL), and the resulting mixture was heated to 55 ℃ and reacted overnight with stirring. Water (30 mL) was added, extraction was performed with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the residue after removal of the solvent under reduced pressure was purified by silica gel column chromatography (PE/EA (v/v) = 10/1-4/1) to give the title compound as a white solid (505mg, 98%).

MS(ESI,pos.ion)m/z:541.3[M+H] ⁺ 。

Step 13) (2S, 3S) -3- ((2- (2-chloro-5-methyl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -5-fluoro-6- (Thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2- (2-chloro-5-methyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (505mg, 0.93mmol) was dissolved in ethanol (10 mL) and water (5 mL), then NaOH (190mg, 4.66mmol) was added in portions, and the resulting mixture was stirred at room temperature overnight. Water (30 mL) was added to the reaction, acidified to pH ≈ 6 with hydrochloric acid (1M), and the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the residue after removal of the solvent under reduced pressure was purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1 to 5/1) to obtain the title compound as a white solid (460mg, 96%).

MS(ESI,pos.ion)m/z:513.3[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:513.1268,(C ₂₄ H ₂₃ ClFN ₆ O ₂ S)[M+H] ⁺ Theoretical value 513.1276;

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm):8.61(s,1H),8.42(s,1H),7.88(dd,J＝6.6,4.4Hz,2H),7.69(d,J＝6.4Hz,1H),7.32–7.28(m,1H),4.67(t,J＝6.6Hz,1H),3.97(s,3H),2.87(d,J＝7.1Hz,1H),2.09(s,1H),2.01(s,2H),1.74(d,J＝8.4Hz,2H),1.59–1.38(m,5H)。

example 2 (2S, 3S) -3- ((2- (5- ((2, 2-dimethylpropionyloxy) methyl) -2-fluoro-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino ] bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) 5-bromo-3- ((trimethylsilyl) ethynyl) pyrazin-2-amine

3, 5-dibromopyrazin-2-amine (2.00g, 7.91mmol) was dissolved in THF (24 mL), and triethylamine (3.3mL, 24mmol), cuprous iodide (151mg, 0.79mmol) and Pd (PPh) were added ₃ ) ₂ Cl ₂ (561mg, 0.79mmol), cooling the resulting mixture to-5 deg.C under nitrogen, then adding trimethylsilylacetylene (1.07mL, 7.50mmol) dropwise slowlyThe completed mixture was warmed to 0 ℃ for 1.5 hours. The reaction solution was concentrated 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 black oil (2.00g, 94%).

MS(ESI,pos.ion)m/z:272.00[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):8.04(s,1H),5.14(s,2H),0.30(s,9H)。

Step 2) 2-bromo-5- (p-toluenesulfonyl) pyrrolo [2,3-b ]]Pyrazine esters

5-bromo-3- (2-trimethylsilylacetylene) pyrazin-2-amine (1.22g, 4.52mmol) was dissolved in anhydrous DMF (10 mL), cooled to 0 deg.C, sodium hydride (253mg, 6.33mmol, 60%) was added, the resulting mixture was stirred at 0 deg.C for 15 minutes, p-toluenesulfonyl chloride (865mg, 4.51mmol) was added, and the resulting mixture was warmed to room temperature and allowed to react for 3 hours. The mixture was extracted with ethyl acetate (30 mL × 3), the separated organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated 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 yellow solid (624 mg, 39.2%).

Step 3) N- (5- (p-toluenesulfonyl) pyrrolo [2,3-b]Pyrazin-2-yl) carbamic acid tert-butyl ester

2-bromo-5- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyrazine (624mg, 1.77mmol) was dissolved in 1, 4-dioxane (10 mL), tert-butyl carbamate (311mg, 2.65mmol), potassium carbonate (734mg, 5.31mmol), xanthphos (209mg, 0.35mmol) and palladium acetate (41mg, 0.17mmol) were added, and the resulting mixture was heated to 105 ℃ under nitrogen and stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a white solid (513mg, 75%).

Step 4) 5- (p-toluenesulfonyl) pyrrolo [2,3-b ]]Pyrazin-2-amines

N- (5- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyrazin-2-yl) carbamic acid tert-butyl ester (513mg, 1.32mmol) was dissolved in phosphoric acid (5mL, 85.97mmol), and the resulting mixture was heated to 70 ℃ and stirred for reaction for 2 hours. To the reaction solution was added a saturated sodium bicarbonate solution (30 mL), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the separated organic phase was washed with a saturated saline (50 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated 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 (200mg, 53%).

MS(ESI,pos.ion)m/z:289.4[M+H] ⁺ 。

Step 5) 2-fluoro-5- (p-toluenesulfonyl) pyrrolo [2,3-b]Pyrazine esters

Reacting 5- (p-toluenesulfonyl) pyrrolo [2,3-b ]]Pyrazine-2-amine (50mg, 0.17mmol) and copper powder (1mg, 0.02mmol) were suspended in HBF ₄ To the resulting mixture was stirred at room temperature for 10 minutes, then sodium nitrite (12mg, 0.2mmol) was slowly added at-5 ℃, and the suspension was stirred at room temperature to 0 ℃ for reaction for 15 minutes, and then stirred at room temperature for reaction for 6 hours. The reaction mixture was cooled to 0 ℃, neutralized with saturated sodium carbonate solution to pH =6. The resulting mixture was extracted with ethyl acetate (30 mL × 2), the separated organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated 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 white solid (25mg, 49%).

MS(ESI,pos.ion)m/z:292.2[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):8.19(d,J＝6.9Hz,1H),8.09–8.03(m,3H),7.34(d,J＝8.1Hz,2H),6.75(d,J＝4.1Hz,1H),2.42(s,3H)。

Step 6) 2-fluoro-5H-pyrrolo [2,3-b ]]Pyrazine

2-fluoro-5- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyrazine (100mg, 0.34mmol) was dissolved in TBAF in THF (0.42mL, 0.42mmol, 1mol/L), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, the resulting mixture was diluted with saturated sodium bicarbonate (20 mL), the resulting mixture was extracted with ethyl acetate (20 mL × 3), the separated organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated 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 (42mg, 89%).

MS(ESI,pos.ion)m/z:138.1[M+H] ⁺ ；

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.31(s,1H),8.20(d,J＝6.9Hz,1H),7.96(d,J＝3.5Hz,1H),6.58(d,J＝3.5Hz,1H)。

Step 7) 2-fluoro-7-iodo-5H-pyrrolo [2,3-b]Pyrazine esters

2-fluoro-5H-pyrrolo [2,3-b ] pyrazine (423mg, 3.09mmol) was dissolved in 2-MeTHF (10 mL), and NIS (787 mg, 3.39mmol) was weighed and added thereto, and the resulting mixture was allowed to react at room temperature overnight. 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, the filtrate was evaporated under reduced pressure to remove the solvent, 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 white solid (814mg, 100%).

MS(ESI,neg.ion)m/z:262.1[M-H] ^- 。

Step 8) (2-fluoro-7-iodo-pyrrolo [2, 3-b)]Pyrazin-5-yl) methyl-2, 2-methylpropionate

2-fluoro-7-iodo-5H-pyrrolo [2,3-b ] pyrazine (2.05g, 7.79mmol) was dissolved in DMF (10 mL), cooled to 0 deg.C, naH (405mg, 10.1mmol) was added in portions, the resulting mixture was stirred at 0 deg.C for 30 minutes, chloromethyl pivalate (1.35mL, 9.35mmol) was slowly added dropwise, the resulting mixture was warmed to room temperature and stirred for reaction for 3 hours. The reaction was quenched by adding water (40 mL) to the reaction solution, the resulting mixture was extracted with ethyl acetate (50 mL × 3), the combined organic phases were washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white solid (2.05g, 70%).

MS(ESI,pos.ion)m/z:378.0[M+H] ⁺ 。

Step 9) (2-fluoro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan)Pentan-2-yl) pyrrolo [2,3-b] Pyrazin-5-yl) pivalic acid methyl ester

Methyl (2-fluoro-7-iodo-pyrrolo [2,3-b ] pyrazin-5-yl) pivalate (2.05g, 5.44mmol) and isopropanopinacolborate (1.32g, 7.07mmol) were dissolved in THF (20 mL), the resulting mixture was cooled to-30 ℃ and isopropyl magnesium chloride (2m, 3.26ml) was slowly added dropwise to the above reaction system, and after completion of the addition, the reaction was stirred at-30 ℃ for 1.5 hours. The reaction solution was added to a saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting 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 (1.78g, 87%).

MS(ESI,pos.ion)m/z:378.3[M+H] ⁺ 。

Step 10) (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Pungent food Alkane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (3.25g, 7.15mmol) was suspended in THF (20 mL), methanol (10 mL) and water (10 mL), followed by addition of sodium hydroxide (2.87g, 71.8mmol) in portions, and the resulting mixture was heated to 50 ℃ and stirred for reaction overnight. Water (40 mL) was added to the reaction solution, the resulting mixture was extracted with hydrochloric acid (1M) to adjust pH =6,2-methyltetrahydrofuran (50 mL × 3), the combined organic phases were washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow solid (3.01g, 99%).

Step 11) (2S, 3S) -3- ((2- (5- (((2, 2-dimethylpropionyl) oxy) methyl) -2-fluoro-pyrrolo [2, 3-b]pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino]Bicyclo [2.2.2]Octane-2-carboxylic acid

Reacting (2-fluoro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2, 3-b)]Pyrazin-5-yl) pivalic acid methyl ester (634mg, 1.01mmol, 60mass%), (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thia-t-hia-s-e)Thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid (410mg, 0.96mmol), H ₂ O (0.2mL, 10mmol), 1, 4-dioxane (10 mL), potassium carbonate (531mg, 3.85mmol), and Pd (dppf) Cl ₂ (157mg, 0.19mmol) was added to the microwave tube and the resulting mixture was bubbled with nitrogen for 10 minutes, then microwaved to 110 ℃ and the reaction stirred for 2 hours. The reaction solution was concentrated 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 yellow solid (219mg, 38%).

MS(ESI,pos.ion)m/z:597.3[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:597.2119,(C ₂₉ H ₃₁ F ₂ N ₆ O ₄ S)[M+H] ⁺ Theoretical value: 597.2096;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.68(s,1H),8.38(s,1H),7.86(d,J＝11.4Hz,2H),7.71(s,1H),7.28(s,1H),6.36(s,2H),5.74(s,1H),4.66(s,1H),3.93(s,1H),2.88(s,1H),2.09(s,1H),2.00(s,2H),1.74(s,2H),1.52-1.43(m,4H),1.08(d,J＝6.1Hz,9H)。

example 3 (2S, 3S) -3- ((2- (2-chloro-5- (2-hydroxyethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3- ((2- (2-chloro-5- (2-hydroxyethyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -5- Fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3- ((5-fluoro-2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (500mg, 0.94mmol), 2-bromoethanol (240mg, 1.90mmol) and potassium carbonate (400mg, 2.84mmol) were dissolved in DMF (10 mL) and added to a reaction flask and stirred overnight at 55 ℃. Water (30 mL) was added to the reaction solution, extraction was performed with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the residue after removal of the solvent under reduced pressure was purified by silica gel column chromatography (PE/EA (v/v) = 10/1-4/1) to obtain the title compound as a white solid (520mg, 96%).

MS(ESI,pos.ion)m/z:571.1[M+H] ⁺ 。

Step 2) (2S, 3S) -3- ((2- (2-chloro-5- (2-hydroxyethyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -5- Fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2- (2-chloro-5- (2-hydroxyethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (520mg, 0.91mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (5 mL), then NaOH (190mg, 4.55mmol) was added in portions, and the resulting mixture was heated to reflux and stirred for reaction for 4 hours. The reaction was acidified to pH ≈ 6 with hydrochloric acid (1M), extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (DCM/MeOH (v/v) = 10/1-5/1) to obtain the title compound as a white solid (200mg, 40%).

MS(ESI,pos.ion)m/z:543.3[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:543.1403,(C ₂₅ H ₂₅ FClN ₆ O ₃ S)[M+H] ⁺ Theoretical value: 543.1381;

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm):8.61(s,1H),8.39(s,1H),7.87(m,2H),7.68(s,1H),7.29(s,1H),4.67(s,1H),4.43(s,2H),3.82(s,2H),2.87(s,1H),2.10(s,1H),2.00(s,2H),1.75(s,2H),1.47(m,5H)。

example 4 (2S, 3S) -3- ((2- (2-chloro-5- (((ethoxycarbonyl) oxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro 6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3- ((2- (2-chloro-5- (((ethoxycarbonyl) oxy) methyl) -5H-pyrrolo [2, 3-b)]Pyridine (II) Oxazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (592mg, 1.18mmol), ethyl chloroacetate (150mg, 1.06mmol) and potassium carbonate (490mg, 3.56mmol) were suspended in DMF (10 mL), and the resulting mixture was stirred at room temperature overnight. Water (30 mL) was added, the pH was adjusted to 5 to 6 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 8/1-2/1) to obtain the title compound as a white solid (300mg, 42%).

MS(ESI,pos.ion)m/z:601.3[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:601.1403,(C ₂₇ H ₂₇ ClFN ₆ O ₅ S)[M+H] ⁺ Theoretical value: 601.1436;

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm):8.71(s,1H),8.50(s,1H),7.88(s,2H),7.74(s,1H),7.29(s,1H),6.36(s,2H),4.67(s,1H),4.16(dd,J＝13.7,6.7Hz,2H),2.87(d,J＝6.5Hz,1H),2.08(s,1H),2.00(s,2H),1.74(s,2H),1.42(m,5H),1.21–1.14(m,3H)。

example 5 (2S, 3S) -3- ((2- (2-chloro-5-cyclopropyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3- ((2- (2-chloro-5-cyclopropyl-5H-pyrrolo [2, 3-b)]Pyrazine-7-yl) -5-fluoro-6- (Thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3- ((5-fluoro-2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) -4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (400mg, 0.75mmol), cyclopropylboronic acid (130mg, 1.54mmol), 2' -bipyridine (130mg, 0.83mmol), copper acetate (151mg, 0.83mmol) and anhydrous sodium carbonate (400mg, 2.27mmol) were suspended in 1, 2-dichloroethane (20 mL), and the resulting mixture was heated to 70 ℃ under an oxygen atmosphere and stirred for reaction overnight. The reaction solution was filtered through celite, and after removing the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (PE/EA (v/v) = 10/1-4/1) to obtain the title compound as a white solid (370mg, 85%).

MS(ESI,pos.ion)m/z:567.0[M+H] ⁺ 。

Step 2) (2S, 3S) -3- ((2- (2-chloro-5-cyclopropyl-5H-pyrrolo [2, 3-b)]Pyrazine-7-yl) -5-fluoro-6- (Thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2- (2-chloro-5-cyclopropyl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (420mg, 0.74mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (5 mL), naOH (150mg, 3.70mmol) was added in portions, and the resulting mixture was heated to 80 ℃ and stirred for reaction for 4 hours. To the reaction solution was added water (30 mL), acidified to pH ≈ 6 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1-5/1) to obtain the title compound as a white solid (350mg, 87%).

MS(ESI,pos.ion)m/z:539.3[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:539.1448,(C ₂₆ H ₂₅ ClFN ₆ O ₂ S)[M+H] ⁺ Theoretical values are as follows: 539.1432;

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm):12.19(s,1H),8.41(s,2H),7.90(d,J＝3.4Hz,1H),7.85(d,J＝4.9Hz,1H),7.64(d,J＝6.2Hz,1H),7.30–7.26(m,1H),4.64(t,J＝6.5Hz,1H),3.72(s,1H),2.84(d,J＝7.0Hz,1H),2.10(s,1H),1.98(m,2H),1.74(dd,J＝21.8,10.2Hz,2H),1.62–1.38(m,5H),1.17(d,J＝4.3Hz,2H),1.13(dd,J＝6.6,4.3Hz,2H)。

example 6 (2S, 3S) -3- ((2- (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) 2-chloro-7-iodo-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b]Pyrazine

2-chloro-7-iodo-5H-pyrrolo [2,3-b ] pyrazine (200mg, 0.72mmol) was dissolved in anhydrous DMF (4 mL), cooled to-15 deg.C, sodium hydride (35mg, 0.88mmol, 60%) was added, the resulting mixture was stirred at-15 deg.C for 15 minutes, chloromethyl pivalate (0.13mL, 0.90mmol) was added, then warmed to room temperature and stirred overnight. The reaction solution was added to water (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, 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) to give the title compound as a pale yellow solid (220mg, 78%).

MS(ESI,pos.ion)m/z:394.10[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):8.31(s,1H),7.90(s,1H),6.20(s,2H),1.18(s,9H)。

Step 2) (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) boronic acids

2-chloro-7-iodo-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine (100mg, 0.25mmol) and isopropanol pinacol borate (62mg, 0.33mmol) were dissolved in THF (4 mL), stirred at-27 deg.C, and isopropyl magnesium chloride (2M, 0.17mL, 0.34mmol) was added dropwise slowly to the above reaction system. After the dropwise addition was completed, the reaction was stopped by reacting at-27 ℃ for 1 hour, the reaction solution was added to a saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were concentrated under reduced pressure to give the title compound as a black oil which was used in the next reaction without further purification.

MS(ESI,pos.ion)m/z:312.00[M+H] ⁺ 。

Step 3) (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Pungent food Alkane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (1.90g, 4.18mmol) was dissolved in a mixed solution of THF/MeOH (v/v =10mL/5 mL), followed by addition of a solution of NaOH (1.68g, 42.00mmol) in water (5 mL), and the resulting mixture was stirred at room temperature overnight. The reaction was acidified with dilute hydrochloric acid (1M) to pH ≈ 6, the resulting mixture was extracted with 2-methyltetrahydrofuran (30 mL × 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a pale yellow solid (1.80g, 100%).

MS(ESI,pos.ion)m/z:426.1[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):7.85(d,J＝3.7Hz,1H),7.59(d,J＝5.0Hz,1H),7.21–7.15(m,1H),4.38(d,J＝2.0Hz,1H),2.51–2.47(m,1H),2.14(d,J＝2.5Hz,1H),1.94(d,J＝2.7Hz,1H),1.87(m,1H),1.80–1.62(m,6H)。

Step 4) (2S, 3S) -3- ((2- (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine- 7-yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Reacting (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) boronic acid (80%, 0.53g, 1.10mmol), K ₂ CO ₃ (0.52g，3.80mmol)、Pd(dppf)Cl ₂ (0.16g, 0.21mmol) and (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid (0.45g, 1.10 mmol) was mixed with 1, 4-dioxane (20 mL) and H ₂ O (1 mL), the resulting mixture was purged with nitrogen by bubbling for 10 minutes, and then heated to 115 ℃ with a sealed tube and the reaction was stirred for 4 hoursThen (c) is performed. The reaction was stopped, the reaction mixture was cooled to room temperature, the solvent was removed by concentration under reduced pressure, 2-methyltetrahydrofuran (30 mL) was added to dissolve the reaction mixture, the pH was adjusted to about 6 with dilute hydrochloric acid (1M), the reaction mixture was filtered, the filtrate was separated, the aqueous layer was extracted with 2-methyltetrahydrofuran (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the filtrate was freed of the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to obtain the title compound as a pale yellow solid (0.23g, 36%).

MS(ESI,pos.ion)m/z:613.3[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:613.1789,(C ₂₉ H ₃₁ ClFN ₆ O ₄ S)[M+H] ⁺ The theoretical value is as follows: 613.1800;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.69(s,1H),8.50(s,1H),7.87(s,1H),7.73(d,J＝6.3Hz,1H),7.33–7.26(m,1H),6.35(s,2H),4.67(t,J＝6.5Hz,1H),2.88(d,J＝7.1Hz,1H),2.08(s,1H),2.01(s,1H),1.74(s,2H),1.59–1.35(m,5H),1.09(s,9H).

¹³ C NMR(101MHz,DMSO-d ₆ )δ(ppm):177.51,176.04,155.11,155.03,153.66,152.69,152.58,143.99,141.02,140.42,140.34,140.12,138.41,138.25,138.18,137.43,136.73,136.49,130.56,129.82,129.72,129.00,114.80,67.77,51.50,47.85,38.77,28.78,28.59,27.00,25.89,24.15,21.69,19.59。

example 7 (2S, 3S) -3- ((2- (5- (((2, 2-dimethylpropionyl) oxy) methyl) -2-fluoro-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ethoxycarbonyloxymethyl ester

Step 1) (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Pungent food Alkyl-2-carboxylic acid ((ethoxycarbonyl) oxy) methyl ester

(2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2.00g, 4.69mmol) was dissolved in DMF (20 mL), potassium carbonate (2.02g, 14.20mmol) and chloromethyl ethyl carbonate (0.79g, 5.70mmol) were added, the resulting mixture was stirred at room temperature overnight, water (50 mL) was added to the reaction solution, extraction was then performed with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with saturated brine (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5/1) to give the title compound as a pale yellow solid (1.70g, 69%).

MS(ESI,pos.ion)m/z:527.7[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):7.84–7.81(m,1H),7.57(d,J＝5.0Hz,1H),7.20–7.14(m,1H),6.02(d,J＝5.7Hz,1H),5.77(d,J＝5.6Hz,1H),4.45(d,J＝5.2Hz,1H),4.24(q,J＝7.1Hz,2H),2.50(d,J＝5.4Hz,1H),2.03(d,J＝2.3Hz,1H),1.91(d,J＝2.4Hz,1H),1.81(m,1H),1.72(m,4H),1.65–1.57(m,2H),1.33(t,J＝7.1Hz,3H)。

Step 2) (2s, 3s) -3- ((2- (5- (((2, 2-dimethylpropionyl) oxy) methyl) -2-fluoro-pyrrolo [2, 3-b]pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethoxycarbonyl Oxymethyl ester

Taking (2-fluoro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2, 3-b)]Pyrazin-5-yl) methyl 2, 2-methylpropionate (468mg, 0.75mmol, 60mass%), (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethoxycarbonyloxymethyl ester (375mg, 0.71mmol), H ₂ O (0.2mL, 10mmol), 1, 4-dioxane (10 mL), potassium carbonate (294mg, 2.13mmol) and Pd (dppf) Cl ₂ (116mg, 0.14mmol) was placed in a microwave tube, purged with nitrogen bubbling for 10 minutes, and then heated by microwave to 110 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (350mg, 71%).

MS(ESI,pos.ion)m/z:698.8[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:699.2431,(C ₃₃ H ₃₇ F ₂ N ₆ O ₇ S)[M+H] ⁺ Theoretical values are as follows: 699.2412;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.68(s,1H),8.39(d,J＝6.9Hz,1H),7.90–7.83(m,2H),7.79(d,J＝5.9Hz,1H),7.29(s,1H),6.36(s,2H),5.70(dd,J＝13.4,5.7Hz,2H),4.69(s,1H),4.06(d,J＝4.6Hz,2H),3.04(d,J＝6.8Hz,1H),2.09(s,1H),1.99(s,2H),1.77(s,2H),1.55–1.38(m,4H),1.10(s,12H)；

¹³ C NMR(151MHz,DMSO-d ₆ )δ(ppm):177.53,173.38,158.94,157.36,155.16,155.11,153.66,152.49,152.41,140.53,139.85,138.79,138.19,138.15,137.37,133.09,132.99,130.65,129.89,129.82,129.07,125.94,125.64,114.51,82.42,67.95,64.76,51.08,47.59,38.78,28.75,28.57,27.00,25.68,25.13,23.80,21.32,19.40,14.24。

example 8 (2S, 3S) -3- ((2- (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (pivaloyloxy) methyl ester

Step 1) (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Pungent food Alkyl-2-carboxylic acid (pivaloyloxy) methyl ester

(2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (0.50g, 1.20mmol) was dissolved in anhydrous DMF (10 mL), cooled to-15 ℃, and sodium hydride (95mg, 2.38mmol, 60%) was added thereto, the resulting mixture was stirred at-15 ℃ for reaction for 15 minutes, chloromethyl pivalate (0.20mL, 1.40mmol) was then added thereto, the resulting mixture was stirred at room temperature overnight, water (30 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (30 mL. Times.3), the combined organic phases were washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5/1) to obtain the title compound as a pale yellow solid (0.58g, 92%).

MS(ESI,pos.ion)m/z:539.8[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):7.81(d,J＝3.7Hz,1H),7.56(d,J＝5.0Hz,1H),7.19–7.14(m,1H),6.02(d,J＝5.5Hz,1H),5.77(d,J＝5.5Hz,1H),4.45(s,1H),2.48(d,J＝5.5Hz,1H),1.97(d,J＝2.4Hz,1H),1.91(d,J＝2.5Hz,1H),1.80(m,1H),1.74–1.59(m,6H),1.21(s,9H)。

Step 2) (2S, 3S) -3- ((2- (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazine- 7-yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid (pivaloyloxy) methyl ester

Reacting (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) boronic acid (0.54g, 1.10mmol, 80%), K ₂ CO ₃ (0.53g,3.80mmol)、Pd(dppf)Cl ₂ (0.16g, 0.21mmol) and (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid (pivaloyloxy) methyl ester (0.58g, 1.11mmol) was mixed with 1, 4-dioxane (20 mL), and H was added ₂ O (1 mL), the resulting mixture was purged with nitrogen by bubbling for 10 minutes, the tube was sealed, and the reaction was carried out at 115 ℃ for 4 hours. The reaction was stopped, the reaction solution was cooled to room temperature, filtered, and the solvent was removed from the filtrate, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) to obtain the title compound as a yellow solid (0.40g, 51%).

MS(ESI,pos.ion)m/z:726.8[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:727.2487,(C ₃₃ H ₃₇ ClFN ₆ O ₇ S)[M+H] ⁺ The theoretical value is as follows: 727.2481;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.68(s,1H),8.50(s,1H),7.88(s,1H),7.80(d,J＝6.4Hz,1H),7.32–7.26(m,1H),6.35(s,2H),5.75(d,J＝5.8Hz,1H),5.66(d,J＝5.8Hz,1H),4.70(s,1H),3.03(d,J＝7.0Hz,1H),2.07(s,1H),1.95(s,1H),1.77(s,2H),1.62–1.50(m,3H),1.46–1.36(m,2H),1.10(s,9H),1.02(s,9H)；

¹ H NMR(151MHz,DMSO-d ₆ )δ(ppm):177.51,176.55,173.36,170.82,155.09,155.03,152.52,152.44,143.99,140.53,140.09,138.79,138.17,138.13,137.40,136.76,136.48,134.63,130.63,129.88,129.81,129.08,114.71,102.37,79.57,67.77,60.23,51.12,47.51,38.77,38.54,28.71,28.68,26.98,26.78,25.67,24.03,21.29,21.21,19.41,14.53。

example 9 ((ethoxycarbonyl) oxy) methyl (2S, 3S) -3- ((2- (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

Reacting (2-chloro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) boronic acid (80%, 0.41g, 1.04mmol), K ₂ CO ₃ (0.30g,2.20mmol)、Pd(dppf)Cl ₂ (0.16g, 0.21mmol) and (2S, 3S) -3- ((2-bromo-5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ((ethoxycarbonyl) oxy) methyl ester (0.37g, 0.70mmol) was mixed with 1, 4-dioxane (20 mL) and H ₂ O (1 mL), the resulting mixture was purged with nitrogen bubbling for 10 minutes, then heated to 115 ℃ with a sealed tube and the reaction was stirred for 4 hours. The reaction was stopped, cooled to room temperature, filtered, and the filtrate was freed of solvent, and the resulting 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 (0.25g, 50%).

MS(ESI,pos.ion)m/z:715.3[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:715.2107,(C ₃₃ H ₃₇ ClFN ₆ O ₇ S)[M+H] ⁺ Theoretical values are as follows: 715.2117;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.55(s,1H),8.33(s,1H),7.94(d,J＝3.4Hz,1H),7.59(d,J＝4.8Hz,1H),7.24–7.19(m,1H),6.31(dd,J＝22.9,10.7Hz,2H),5.81(d,J＝5.7Hz,1H),5.72(d,J＝5.7Hz,1H),4.77(s,1H),4.02(m,2H),2.55(d,J＝4.4Hz,1H),2.10(s,1H),1.95(s,1H),1.87–1.67(m,6H),1.54–1.46(m,1H),1.18(s,9H),1.10(t,J＝7.1Hz,3H)。

example 10 (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) 3-bromo-5-fluoro-1H-pyrrolo [2,3-b]Pyridine compound

5-fluoro-1H-pyrrolo [2,3-b ] pyridine (1g, 7.34mmol) was dissolved in DMF (10 mL), followed by dropwise addition of bromine (0.75mL, 14.5 mmol), and the reaction was stirred at room temperature for 4 hours. The reaction was quenched by adding saturated aqueous sodium thiosulfate solution (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 (petroleum ether/ethyl acetate (v/v) = 4/1) to give the title compound as a yellow powder (0.6g, 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 2) 3-bromo-5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridine compound

3-bromo-5-fluoro-1H-pyrrolo [2,3-b ] pyridine (0.74g, 2.0mmol) was dissolved in THF (5 mL), naH (127mg, 3.0mmol) was added thereto at 0 ℃ and stirred at this temperature for 30 minutes, then TsCl (458mg, 2.4mmol) was further added, and the mixture was transferred to room temperature and stirred overnight. The reaction was quenched with water (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, the solvent was evaporated 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 (740 mg, 90%).

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 3) 5-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl- 1H-pyrrolo [2,3-b]Pyridine compound

Reacting 3-bromo-5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridine (175mg, 0.22mmol), pd (dppf) Cl ₂ (70mg, 0.09mmol) and KOAc (144mg, 0.47mmol) were suspended in DME (5 mL), air was purged from the suspension with nitrogen, and then pinacol diboron (190mg, 0.71mmol) was added thereto, the tube was sealed, and the reaction was carried out under microwave conditions at 105 ℃ for 2 hours. After completion of the reaction, ethyl acetate (20 mL) was added to dilute the reaction solution, and 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) = 4/1) to give the title compound as a yellow solid (130mg, 66%).

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 4) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b)]Pyridine-3- Yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Reacting 5-fluoro-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ]]Pyridine (1.52g, 2.56mmol, 70%), K ₂ CO ₃ (1.35g, 9.76mmol), palladium acetate (54mg, 0.24mmol), X-Phos (233mg, 0.48mmol) and (2S, 3S) -3- ((2-chloro-5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Ethyl octane-2-carboxylate (1.00g, 2.44mmol) was mixed in THF (15 mL) and water (1 mL), and the resulting mixture was heated to reflux under nitrogen and stirred to reactAnd (4) at night. After the reaction was completed and the solid impurities were removed by direct filtration, the solvent was removed, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1-5/1) to obtain the title compound as a white solid (1.50g, 92%).

Step 5) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (1.50g, 2.26mmol) was dissolved in TBAF (20mL, 20mmol, 1mmol/L), and the resulting mixture was stirred at room temperature for 2 hours. The reaction was stopped, the reaction solution was added to a saturated sodium bicarbonate solution (100 mL), extracted with dichloromethane (60 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a light yellow solid (780 mg, 67%).

MS(ESI,pos.ion)m/z:510.1[M+H] ⁺ 。

Step 6) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (Thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

(2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ethyl ester (780mg, 1.53mmol), iodomethane (450mg, 3.06mmol) and potassium carbonate (630mg, 4.59mmol) were dissolved in DMF (10 mL), and the resulting mixture was heated to 55 ℃ and stirred for reaction overnight. Water (30 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 10/1-4/1) to give the title compound as a white solid (680mg, 84%).

MS(ESI,pos.ion)m/z:524.3[M+H] ⁺ 。

Step 7) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (Thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (680mg, 1.29mmol) was dissolved in ethanol (10 mL) and water (5 mL), naOH (260mg, 6.49mmol) was added in portions, and the resulting mixture was heated to 40 ℃ and stirred for reaction overnight. Water (30 mL) was added to the reaction solution, acidified to pH ≈ 6 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was freed of the solvent under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =10/1 to 5/1) to obtain the title compound as a white solid (550mg, 85%).

MS(ESI,pos.ion)m/z:496.1[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:496.1607,(C ₂₅ H ₂₄ F ₂ N ₅ O ₂ S)[M+H] ⁺ Theoretical values are as follows: 496.1619;

¹ H NMR(600MHz,DMSO-d ₆ )δ(ppm):12.28(s,1H),8.60(dd,J＝9.7,2.7Hz,1H),8.36(s,1H),8.32(s,1H),7.87(d,J＝5.0Hz,1H),7.84(d,J＝3.3Hz,1H),7.67(d,J＝6.6Hz,1H),7.32–7.29(m,1H),4.68(t,J＝6.4Hz,1H),3.94(s,3H),2.87(d,J＝6.7Hz,1H),2.02(s,1H),1.97(s,1H),1.81(s,3H),1.51(m,5H)。

example 11 (2S, 3S) -3- ((2- (1- (2, 2-dimethylpropionyloxymethyl) -5-fluoro-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-6- (2-thiophen) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2, 3-b)]Pyridine-3- Base) -6- (2-thiophene)Pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Reacting 5-fluoro-1- (p-toluenesulfonyl) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2, 3-b)]Pyridine (725mg, 7.22mmol, 70%), (2S, 3S) -3- ((2-chloro-5-fluoro-6- (2-thiophene) pyrimidin-4-yl) amino) bicyclo [ 2.2.2%]Octane-2-carboxylic acid ethyl ester (500mg, 1.22mmol), potassium carbonate (337mg, 2.44mmol), X-phos (124mg, 0.26mmol) and Pd (OAc) ₂ (27mg, 0.12mmol) was suspended in H ₂ O (0.5 mL) and 1, 4-dioxane (10 mL), and the resulting mixture was purged with nitrogen bubbling for 10 minutes, then the reaction was stirred for 2 hours with microwave heating to 110 ℃. The reaction solution was filtered through celite, the filtrate was concentrated 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 yellow oil (700mg, 86%).

Step 2) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (2-thiophenes Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl) -6- (2-thiophen) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (700mg, 1.06mmol) was dissolved in a mixed solution of TBAF/THF (4.22mL, 4.22mmol, 1mol/L), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution (20 mL) was added to the obtained residue, the obtained mixture was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with a saturated saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to obtain the title compound as a white solid (400mg, 74%).

Step 3) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (2-thiophenes Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Reacting (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-3-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester (100mg, 0.20mmol) was dissolvedIn THF/MeOH/H ₂ O (v/v/v =1mL/1 mL), naOH (39mg, 0.98mmol) was then added in portions, and the resulting mixture was stirred at room temperature overnight. To the reaction was added saturated brine (10 mL), acidified to pH ≈ 6 with dilute hydrochloric acid (1M), the resulting mixture was extracted with 2-MeTHF (20 mL × 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain a residue, which was purified by thin layer preparative chromatography (DCM/MeOH (v/v) = 15/1) to obtain the title compound as a pale yellow solid (71mg, 75%).

MS(ESI,pos.ion)m/z:482.2[M+H] ⁺ 。

Step 4) (2S, 3S) -3- ((2- (1- (2, 2-dimethylpropionyloxymethyl) -5-fluoro-pyrrolo [2, 3-b)]Pyridine (II) Pyridin-3-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (80mg, 0.17mmol) was dissolved in DMF (3 mL), cooled to 0 ℃ and NaH (15mg, 0.38mmol, 60mass%) was added, and the resulting mixture was stirred at 0 ℃ for about 0.5 hour, then chloromethyl pivalate (28mg, 0.19mmol) was added, and the resulting mixture was stirred at room temperature overnight. Water (20 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (20 mL × 3), the separated organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white solid (45 mg, 45%).

HRMS(ESI,pos.ion)m/z:596.2157,(C ₃₀ H ₃₂ F ₂ N ₅ O ₄ S)[M+H] ⁺ Theoretical values are as follows: 596.2143;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.33(s,1H),8.63(dd,J＝9.4,2.6Hz,1H),8.43(s,2H),7.88(d,J＝5.0Hz,1H),7.85(s,1H),7.79(d,J＝6.6Hz,1H),7.33–7.28(m,1H),6.35(s,2H),4.69(s,1H),2.90(d,J＝5.7Hz,1H),2.02(s,1H),1.96(s,1H),1.84-1.46(m,8H),1.10(s,9H)。

example 12 (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1- (thiazol-2-ylmethyl) pyrrolo [2,3-b ] pyridin-3-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1- (thien-2-ylmethyl) pyrrolo [2, 3-b)]Pyrimidine-3- Yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyrimidin-3-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (80mg, 0.16mmol) was dissolved in anhydrous DMF (1 mL), cooled to 0 ℃, then sodium hydride (18mg, 0.45mmol, 60%) and 2- (bromomethyl) thiazolehydrobromate (40mg, 0.15mmol) were added, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (10 mL), the resulting mixture was extracted with ethyl acetate (10 mL × 3), the separated organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated 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 colorless oil (22mg, 23%).

MS(ESI,pos.ion)m/z:607.0[M+H] ⁺ 。

Step 2) (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1- (thiophen-2-ylmethyl) pyrrolo [2, 3-b)]Pyridine-3- Yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((5-fluoro-2- (5-fluoro-1- (thiophen-2-ylmethyl) pyrrolo [2,3-b ] pyridin-3-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (22mg, 0.03mmol) was dissolved in a mixed solvent of ethanol (1 mL) and water (1 mL), followed by addition of sodium hydroxide (7mg, 0.11mmol) in portions, and the resulting mixture was stirred at room temperature overnight. The reaction solution was diluted with water (10 mL), adjusted to pH =4 with dilute hydrochloric acid (1M), and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The separated organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a white solid (15mg, 71%).

HRMS(ESI,pos.ion)m/z:579.1451,(C ₂₈ H ₂₅ F ₂ N ₆ O ₂ S ₂ )[M+H] ⁺ Theoretical values are as follows: 579.1448;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.30(s,1H),8.66–8.62(m,1H),8.50(s,1H),8.37(s,1H),7.88(d,J＝5.1Hz,1H),7.85(s,1H),7.75(t,J＝6.9Hz,2H),7.66(d,J＝3.1Hz,1H),7.32–7.29(m,1H),5.97(s,2H),4.69(s,1H),2.89(d,J＝6.5Hz,1H),2.06–1.92(m,4H),1.64–1.41(m,6H)。

example 13 (2S, 3S) -3- ((2- (2-chloro-5- (3-oxo-3- (pyrrolidin-1-yl) propyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) 3- (2-chloro-7- (4- (((2S, 3S) -3- (ethoxycarbonyl) bicyclo [ 2.2.2)]Octane-2-yl) amines Yl) -5-fluoro-6- (thien-2-yl) pyrimidin-2-yl) -5H-pyrrolo [2,3-b]Pyrazin-5-yl) propionic acid

Ethyl (2S, 3S) -3- ((5-fluoro-2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (250mg, 0.47mmol), 3-bromopropionic acid (230mg, 1.42mmol) and potassium carbonate (330mg, 2.37mmol) were suspended in DMF (10 mL), and the resulting mixture was heated to 50 ℃ and stirred overnight. Water (30 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) =10/1 to 4/1) to obtain the title compound as a white solid (280mg, 98%).

MS(ESI,pos.ion)m/z:599.1[M+H] ⁺ 。

Step 2) (2S, 3S) -3- ((2- (2-chloro-5- (3-oxo-3- (pyrrolidin-1-yl) propyl) -5H-pyrrolo [2, 3-b]pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

3- (2-chloro-7- (4- (((2S, 3S) -3- (ethoxycarbonyl) bicyclo [2.2.2] octan-2-yl) amino) -5-fluoro-6- (thien-2-yl) pyrimidin-2-yl) -5H-pyrrolo [2,3-b ] pyrazin-5-yl) propionic acid (100mg, 0.16mmol), tetrahydropyrrole (23mg, 0.33mmol), pybop (68mg, 0.33mmol) and DIPEA (64mg, 0.50mmol) were dissolved in THF (10 mL), and the resulting mixture was stirred at room temperature overnight. Water (30 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (PE/EA (v/v) = 4/1-1/1) to give the title compound as a white solid (70mg, 64%).

MS(ESI,pos.ion)m/z:652.4[M+H] ⁺ 。

Step 3) (2S, 3S) -3- ((2- (2-chloro-5- (3-oxo-3- (pyrrolidin-1-yl) propyl) -5H-pyrrolo [2, 3-b]pyrazin-7-yl) -6- (thiophen-2-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- (2- (2-chloro-5- (3-oxo-3- (pyrrolidin-1-yl) propyl) -5H-pyrrolo [2,3-b ] pyrazin-7 yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (70mg, 0.10 mmol) was dissolved in a mixed solvent of ethanol (5 mL) and water (2 mL), then NaOH (21mg, 0.53mmol) was added in portions, and the resulting mixture was heated under reflux and stirred for reaction for 4 hours. To the reaction was added water (20 mL), acidified to pH ≈ 6 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 solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1-5/1) to obtain the title compound as a white solid (46mg, 68%).

MS(ESI,pos.ion)m/z:624.2[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:624.1951,(C ₃₀ H ₃₂ ClFN ₇ O ₃ S)[M+H] ⁺ Theoretical value: 624.1960;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.20(s,1H),8.63(s,1H),8.41(s,1H),7.86(m,2H),7.65(d,J＝5.8Hz,1H),7.29(m,1H),4.62(dd,J＝13.6Hz,7.0,3H),3.28(m,4H),2.90(t,J＝6.2Hz,2H),2.85(d,J＝7.0Hz,1H),2.09(s,1H),2.00(s,1H),1.78(m,6H),1.51(m,4H)。

example 14 (2S, 3S) -3- ((2- (2-chloro-5- (2-oxo-2- (pyridin-2-yl) ethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -5-fluoro-6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (700mg, 1.32mmol) was dissolved in ethanol (10 mL) and water (5 mL), then NaOH (265mg, 6.64mmol) was added in portions, and the resulting mixture was heated to reflux and stirred for reaction for 4 hours. Water (30 mL) was added to the reaction solution, acidified to pH ≈ 6 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the residue obtained after removing the solvent from the filtrate under reduced pressure was purified by column chromatography (DCM/MeOH (v/v) =10/1 to 5/1) to obtain the title compound as a white solid (592 mg, 89%).

MS(ESI,pos.ion)m/z:499.0[M+H] ⁺ 。

Step 2) (2S, 3S) -3- ((2- (2-chloro-5- (2-oxo-2- (pyridin-2-yl) ethyl) -5H-pyrrolo [2,3- b]Pyrazin-7-yl) -6- (thiophen-2-yl) -5-fluoro-pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (60mg, 0.12mmol), 2-chloro-1- (pyridin-2-yl) ethanone (29mg, 0.18mmol) and potassium carbonate (50mg, 0.36mmol) were suspended in DMF (5 mL) and the resulting mixture was stirred at room temperature overnight. To the reaction solution was added water (30 mL), the pH was adjusted to 6 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 8/1-1/1) to obtain the title compound as a white solid (20mg, 26%).

MS(ESI,pos.ion)m/z:618.0[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:618.1480,(C ₃₀ H ₂₆ ClFN ₇ O ₃ S)[M+H] ⁺ Theoretical value: 618.1490;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):8.80(s,1H),8.67(s,1H),8.23(s,1H),8.07(d,J＝7.6Hz,1H),7.91(t,J＝7.5Hz,1H),7.80(s,1H),7.66(d,J＝4.3Hz,1H),7.62(d,J＝4.4Hz,1H),7.20(s,1H),6.18(d,J＝5.1Hz,2H),4.62(s,1H),2.68(s,1H),2.05(s,1H),1.98(s,1H),1.76(m,2H),1.65(m,5H)。

example 15 (2S, 3S) -3- ((2- (2-chloro-5- (4, 4-dimethyl-3-oxopentyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

(2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (60mg, 0.12mmol), 1-bromo-4, 4-dimethylpent-3-one (34mg, 0.18mmol) and potassium carbonate (50mg, 0.36mmol) were suspended in DMF (5 mL) and the resulting mixture was stirred at room temperature overnight. To the reaction solution was added water (30 mL), the pH was adjusted to 5 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 8/1-1/1) to give the title compound as a white solid (20mg, 27%).

MS(ESI,pos.ion)m/z:611.2[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:611.1997,(C ₃₀ H ₃₃ ClFN ₆ O ₃ S)[M+H] ⁺ Theoretical values are as follows: 611.2007;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):8.72(s,1H),8.25(s,1H),7.96(d,J＝3.4Hz,1H),7.60(d,J＝4.9Hz,1H),7.22(m,1H),5.46(d,J＝3.5Hz,1H),4.68(m,2H),3.62(ddd,J＝18.4,10.3,4.0Hz,1H),2.89(m,1H),2.57(s,1H),2.11(d,J＝2.3Hz,1H),1.91(m,4H),1.72(m,6H),1.31(m,9H)。

example 16 (2S, 3S) -3- ((2- (2-chloro-5- (cyanomethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

(2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (50mg, 0.10 mmol), bromoacetonitrile (12.5 mg,0.10 mmol), and potassium carbonate (36mg, 0.30mmol) were dissolved in DMF (5 mL), and the resulting mixture was stirred at room temperature overnight. To the reaction solution was added water (30 mL), the pH was adjusted to 5 to 6 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 8/1-2/1) to obtain the title compound as a white solid (24mg, 44%).

MS(ESI,pos.ion)m/z:538.3[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:538.1217,(C ₂₅ H ₂₂ ClFN ₇ O ₂ S)[M+H] ⁺ Theoretical values are as follows: 538.1228;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):9.56(s,1H),8.44(d,J＝2.6,1H),8.30(s,1H),7.94(d,J＝3.3Hz,1H),7.59(d,J＝4.9Hz,1H),7.22(m,1H),5.35(t,J＝8.0Hz,1H),4.72(d,J＝15.6Hz,1H),4.54(d,J＝15.6Hz,1H),2.60(d,J＝4.8Hz,1H),2.10(s,2H),1.94(t,J＝10.4Hz,1H),1.73(m,7H)。

example 17 (2S, 3S) -3- ((2- (5- (carboxymethyl) -2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2- (2-chloro-5- (cyanomethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (60mg, 0.10 mmol) was dissolved in ethanol (5 mL), then NaOH (20mg, 0.53mmol) was weighed and dissolved in water (2 mL) and the above reaction solution was added, and the resulting mixture was heated to reflux with stirring for reaction for 4 hours. To the reaction was added water (20 mL), acidified to pH ≈ 6 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1-5/1) to obtain the title compound as a white solid (52mg, 88%).

MS(ESI,pos.ion)m/z:557.1[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:557.1162,(C ₂₅ H ₂₃ ClFN ₆ O ₄ S)[M+H] ⁺ Theoretical values are as follows: 557.1174;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.67(s,1H),8.41(s,1H),7.93–7.83(m,2H),7.68(d,J＝5.9Hz,1H),7.30(d,J＝3.8Hz,1H),5.22(s,2H),4.69(s,1H),2.88(d,J＝6.5Hz,1H),2.09(s,1H),2.01(s,2H),1.75(s,2H),1.59–1.34(m,5H)。

example 18 (2S, 3S) -3- ((2- (2-chloro-5- (pivaloylaminomethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1 (2S, 3S) -3- ((2- (2-chloro-5- (pivaloylaminomethyl) -5H-pyrrolo [2, 3-b)]Pyrazine-7- Yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3- ((5-fluoro-2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (60mg, 0.11mmol), N- (chloromethyl) -2, 2-dimethylpropionamide (37mg, 0.22mmol), and potassium carbonate (50mg, 3.4mmol) were suspended in DMF (5 mL), and the resulting mixture was stirred at room temperature overnight. Water (30 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and after removing the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (PE/EA (v/v) =10/1 to 4/1) to obtain the title compound as a white solid (68mg, 93%).

MS(ESI,pos.ion)m/z:640.2[M+H] ⁺ 。

Step 2 (2S, 3S) -3- ((2- (2-chloro-5- (pivaloylaminomethyl) -5H-pyrrolo [2, 3-b)]Pyrazine-7- Yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2- (2-chloro-5- (pivaloylaminomethyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (68mg, 0.10 mmol) was dissolved in ethanol (5 mL) and water (2 mL), followed by addition of sodium hydroxide (42mg, 1.06mmol) in portions, and the resulting mixture was stirred under reflux for 4 hours. To the reaction solution was added water (30 mL), acidified to pH ≈ 6 with hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (DCM/MeOH (v/v) = 10/1-5/1) to obtain the title compound as a white solid (34mg, 52%).

MS(ESI,pos.ion)m/z:612.2[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:612.1951,(C ₂₉ H ₃₂ ClFN ₇ O ₃ S)[M+H] ⁺ Theoretical value: 612.1960;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.22(s,1H),8.89(s,1H),8.57(s,1H),8.46(s,1H),7.86(d,J＝4.4Hz,3H),7.70(d,J＝6.4Hz,1H),7.33–7.26(m,1H),5.65(d,J＝3.4Hz,2H),4.66(t,J＝6.6Hz,1H),2.88(d,J＝7.2Hz,1H),2.06(s,1H),2.01(s,2H),1.74(s,2H),1.46(ddd,J＝22.0,12.3,6.4Hz,5H),1.12(s,9H).

example 19 (2S, 3S) -3- ((2- (2-chloro-5- (1H-imidazol-2-ylmethyl) pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

(2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (120mg, 0.24mmol) was dissolved in DMF (3 mL), and potassium carbonate (166mg, 1.20mmol) and 2- (bromomethyl) -1H-imidazole (55mg, 0.31mmol) were added to stir the resulting mixture at 80 ℃ for reaction overnight. Water (10 mL) was added to dilute the mixture, pH =5 was adjusted with dilute hydrochloric acid (1M), and the resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a white solid (6 mg, 4%).

MS(ESI,pos.ion)m/z:580.1[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:579.1451,(C ₂₇ H25ClFN ₈ O ₂ S)[M+H] ⁺ Theoretical value: 579.1494;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.67(s,1H),8.42(s,1H),8.21(s,1H),7.86(d,J＝5.6Hz,1H),7.67(s,1H),7.32–7.27(m,1H),6.99(s,1H),5.63(s,2H),4.62(s,1H),2.84(s,1H),2.07(s,1H),1.99(s,2H),1.75(s,4H),1.56(s,4H)。

example 20 (2S, 3S) -3- ((2- (2-chloro-5- (thiazol-2-ylmethyl) pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

(2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (100mg, 0.20mmol) was dissolved in anhydrous DMF (3 mL), and cooled to 0 ℃ followed by addition of sodium hydride (32mg, 0.80mmol, 60mass%) and 2- (bromomethyl) thiazole (67mg, 0.26mmol), and the resulting mixture was stirred at room temperature overnight. Water (10 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (10 mL × 3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a pale yellow solid (28mg, 23%).

MS(ESI,pos.ion)m/z:596.30[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:596.1099,(C ₂₇ H ₂₄ ClFN ₇ O ₂ S ₂ )[M+H] ⁺ Theoretical value: 596.1105;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.23(s,1H),8.78(s,1H),8.44(s,1H),7.87(dd,J＝8.3,4.1Hz,2H),7.76(d,J＝3.2Hz,1H),7.70(d,J＝3.1Hz,2H),7.31–7.27(m,1H),6.01(s,2H),4.67(s,1H),2.88(d,J＝7.3Hz,1H),2.05(d,J＝31.2Hz,4H),1.75(s,2H),1.60–1.45(m,4H)。

example 21 (2S, 3S) -3- ((2- (2-chloro-5- (oxazol-2-ylmethyl) pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3- ((2- (2-chloro-5- (oxazol-2-ylmethyl) pyrrolo [2, 3-b)]Pyrazin-7-yl) -5- Fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid (oxazol-2-yl) methyl ester

(2S, 3S) -3- ((2- (2-chloro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (50mg, 0.10mmol) was dissolved in anhydrous DMF (3 mL), cooled to 0 ℃ and then sodium hydride (6mg, 0.15mmol, 60mass%) and 2- (bromomethyl) thiazole (15mg, 0.13mmol) were added in this order, and the resulting mixture was stirred at room temperature overnight. Water (10 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (10 mL × 3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a white solid (55mg, 83%).

MS(ESI,pos.ion)m/z:661.1[M+H] ⁺ 。

Step 2) (2S, 3S) -3- ((2- (2-chloro-5- (oxazol-2-ylmethyl) pyrrolo [2, 3-b)]Pyrazin-7-yl) -5- Fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((2- (2-chloro-5- (oxazol-2-ylmethyl) pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (oxazol-2-yl) methyl ester (55mg, 0.08mmol) was dissolved in a mixed solvent of ethanol (1 mL) and water (1 mL), sodium hydroxide (5mg, 0.13mmol) was further added, and the resulting mixture was stirred at room temperature for reaction overnight. The solvent was concentrated under reduced pressure, then water (10 mL) was added, pH =5 was adjusted with dilute hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (10 mL × 3), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to obtain the title compound as a white solid (13mg, 27%).

MS(ESI,pos.ion)m/z:580.1[M+H] ⁺ ；

HRMS (ESI, pos.ion) M/z:580.1320, (C27H 24ClFN7O 3S) [ M + H ] + theoretical: 580.1334;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.22(s,1H),8.73(s,1H),8.43(s,1H),8.10(s,1H),7.87(d,J＝9.7Hz,2H),7.70(d,J＝6.1Hz,1H),7.29(s,1H),7.18(s,1H),5.84(s,2H),4.67(s,1H),2.88(d,J＝7.4Hz,1H),2.09(s,1H),2.01(s,2H),1.75(s,2H),1.53-143(m,4H)。

example 22 (2S, 3S) -3- ((2- (2-chloro-5- (2, 2-dimethylpropionyloxymethyl) pyrrolo [2,3-b ] pyrazin-7-yl) -7-isopropyl-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (2S, 3S) -3-aminobicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester hydrochloride

The title compound can be prepared by reference to the synthesis method disclosed in patent application WO 2015073491.

Step 2) 2, 4-dichloro-7-isopropyl-7H-pyrrolo [2,3-d ]]Pyrimidines

Reacting 2, 4-dichloro-7H-pyrrolo [2,3-d ]]Pyrimidine (500mg, 2.66mmol) was dissolved in DMF (5 mL), naH (130mg, 3.19mmol, 60%) was added thereto at 0 deg.C, the resulting mixture was stirred at 0 deg.C for 30 minutes, isopropyl iodide (904 mg, 5.32mmol) was added thereto, and the resulting mixture was transferred to room temperature and stirred overnight. The reaction was quenched with water (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, the filtrate was evaporated under reduced pressure to remove the solvent, 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 (460mg, 75%). MS (ESI, pos.ion) m/z of 232.0[ 2], [ M + H ]] ⁺ 。

Step 3) (2S, 3S) -3- ((2-chloro-7-isopropyl-7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) bicyclic ring [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3-aminobicyclo [2.2.2] octane-2-carboxylate hydrochloride (1.26g, 5.40mmol) and 2, 4-dichloro-7-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine (1.10g, 5.40mmol) were dissolved in tetrahydrofuran (5 mL), and potassium carbonate (1.87g, 13.50mmol) was further added to stir the resulting mixture at room temperature overnight. The reaction was stopped, the reaction was quenched with water (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, the filtrate was evaporated under reduced pressure to remove the solvent, and the resulting 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 (979mg, 50%).

Step 4) (2S, 3S) -3- ((2-chloro-7-isopropyl-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) bicyclic ring [2.2.2]Octane-2-carboxylic acid

Ethyl (2S, 3S) -3- ((2-chloro-7-isopropyl-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (1.00g, 2.56mmol) was dissolved in a mixed solvent of EtOH (2 mL) and water (2 mL), then NaOH (512mg, 12.80mmol) was added in portions, and the resulting mixture was stirred at room temperature for reaction overnight. The reaction solution was concentrated under reduced pressure, the resulting mixture was added with water (20 mL), pH =5 to 6 was adjusted with dilute hydrochloric acid (1M), the resulting mixture was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to obtain the title compound as a white solid (928mg, 100%).

MS(ESI,pos.ion)m/z:363.3[M+H] ⁺ 。

Step 5) (2S, 3S) -3- ((2-bromo-7-isopropyl-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) bicyclic ring [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((2-chloro-7-isopropyl-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.00g, 2.76mmol) was dissolved in hydrobromic acid acetic acid solution (3mL, 33%), and the reaction was stirred at room temperature for 2 hours. To the reaction solution was added ice water (20 mL), the resulting mixture was extracted with ethyl acetate (20 mL × 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated 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 yellow solid (800mg, 71%).

MS(ESI,pos.ion)m/z:406.3[M+H] ⁺ 。

Step 6) (2S, 3S) -3- ((2- (2-chloro-5- (2, 2-dimethylpropionyloxymethyl) pyrrolo [2, 3-b)]Pyridine (II) Oxazin-7-yl) -7-isopropyl-pyrrolo [2,3-d]Pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Reacting (2-chloro-5- (2, 2-dimethylpropionyloxymethyl) pyrrolo [2,3-b ]]Pyrazin-7-yl) boronic acid (511mg, 0.98mmol, 60%), (2S, 3S) -3- ((2-bromo-7-isopropyl-pyrrolo [2,3-d ])]Pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid (590 mg, 1.45mmol), H ₂ O (0.2mL, 10mmol), 1, 4-dioxane (3 mL), potassium carbonate (371mg, 2.68mmol), and Pd (dppf) Cl ₂ (146mg, 0.179mmol) was added to the microwave tube and the resulting mixture was bubbled with nitrogen gas for 10 minutes, then the reaction was stirred with microwave heating to 115 deg.C for 2 hours. The reaction solution was filtered through celite, extracted with ethyl acetate (30 mL), the combined organic phases were washed successively with dilute hydrochloric acid (1M) (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (450mg, 52%).

MS(ESI,pos.ion)m/z:594.2[M+H] ⁺ 。

HRMS(ESI,pos.ion)m/z:594.2619，(C ₃₀ H ₃₇ ClN ₇ O ₄ )[M+H] ⁺ Theoretical values are as follows: 594.2596;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.21(s,1H),8.65(s,1H),8.46(s,1H),7.26(d,J＝2.6Hz,2H),6.65(s,1H),6.35(s,2H),5.76(s,1H),5.04–4.96(m,1H),4.74(s,1H),3.93(s,1H),2.71(d,J＝6.4Hz,1H),2.16(s,1H),2.00(s,2H),1.79–1.69(m,2H),1.57(s,4H),1.50(t,J＝6.1Hz,6H),1.10(s,9H)。

example 23 (2S, 3S) -3- ((2- (5- (acetoxymethyl) -2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) 2-fluoro-7-iodo-5-trityl-5H-pyrrolo [2,3-b ]]Pyrazine esters

2-fluoro-7-iodo-5H-pyrrolo [2,3-b ] pyrazine (834mg, 3.17mmol) was dissolved in DMF (10 mL), cooled to 0 deg.C, naH (152mg, 3.80mmol, 60%) was added, and stirred at 0 deg.C for about 0.5H. Additional triphenylchloromethane (972mg, 3.49mmol) was added, and the resulting mixture was stirred at room temperature for about 3 hours. The reaction was quenched by adding water (40 mL), the resulting mixture was extracted with ethyl acetate (30 mL × 2), the separated organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a white solid (1.6g, 100%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.03(d,J＝7.0Hz,1H),7.72(s,1H),7.32(dd,J＝9.2,7.1Hz,10H),7.16(d,J＝6.8Hz,5H)。

Step 2) 2-fluoro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5-trityl- 5H-pyrrolo [2,3-b]Pyrazine esters

2-fluoro-7-iodo-5-trityl-5H-pyrrolo [2,3-b ] pyrazine (500mg, 0.99mmol) and isopropanol pinacol borate (231mg, 1.24mmol) were dissolved in THF (10 mL), the resulting mixture was cooled to-27 deg.C, a tetrahydrofuran solution of isopropyl magnesium chloride (2M, 0.58mL) was slowly added dropwise to the reaction solution with vigorous stirring, the reaction was continued for 1.5 hours with stirring after completion of the dropwise addition, the reaction solution was added to a saturated sodium bicarbonate solution (40 mL), extraction was performed with ethyl acetate (30 mL. Times.3), 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) = 10/1) to give the title compound as a yellow solid (500mg, 100%).

MS(ESI,pos.ion)m/z:506.1[M+H] ⁺ 。

Step (ii) of3) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) - 6- (Thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Reacting 2-fluoro-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5-trityl-5H-pyrrolo [2,3-b ]]Pyrazine (1.34g, 1.33mmol, 50%), (2S, 3S) -3- ((2-bromo-5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl]Aminobicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester (500mg, 1.10mmol), potassium carbonate (456mg, 3.30mmol), pd (dppf) Cl ₂ (1799mg, 0.220mmol) was suspended in water (0.2mL, 10mmol) and 1, 4-dioxane (10 mL), and the resulting mixture was purged with nitrogen bubbling and then heated to 110 ℃ by microwave to stir the reaction for 2 hours. The reaction solution was filtered through celite, the filtrate was concentrated 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 yellow solid (820 mg, 99%).

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):8.32(s,1H),8.02(d,J＝7.5Hz,1H),7.83(d,J＝5.0Hz,2H),7.70(d,J＝6.7Hz,1H),7.35(dd,J＝10.1,7.2Hz,10H),7.18(d,J＝7.0Hz,5H),4.55(t,J＝7.0Hz,1H),4.06–4.01(m,2H),2.89(d,J＝7.4Hz,1H),1.95(s,1H),1.89(s,1H),1.72(d,J＝7.2Hz,2H),1.49(m,6H),1.12(t,J＝7.1Hz,3H)。

Step 4) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Reacting (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2, 3-b))]Pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester (820mg, 1.09mmol) was dissolved in DCM (10 mL), and Et was added sequentially ₃ SiH (1.74ml, 10.9 mmol) and trifluoroacetic acid (0.81mL, 10.9 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction solution was added to a saturated sodium bicarbonate solution (40 mL), extracted with dichloromethane (30 mL. Times.3), and 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 to give the title compound as a yellow solid (460mg, 83%).

MS(ESI,pos.ion)m/z:511.3[M+H] ⁺ ；

¹ H NMR(400MHz,CDCl ₃ )δ(ppm):9.21(s,1H),8.55(d,J＝3.1Hz,1H),8.13(d,J＝7.0Hz,1H),7.95(d,J＝3.6Hz,1H),7.58(d,J＝5.0Hz,1H),7.24–7.19(m,1H),5.29(d,J＝5.7Hz,1H),4.78(s,1H),4.23–4.10(m,2H),2.45(d,J＝5.8Hz,1H),2.10(s,1H),2.06(s,1H),1.94(d,J＝13.4Hz,1H),1.85–1.63(m,6H),1.52(d,J＝13.7Hz,1H),1.15(t,J＝7.1Hz,3H)。

Step 5) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Reacting (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Ethyl octane-2-carboxylate (460mg, 0.90mmol) in THF/MeOH/H ₂ To O (v/v/v =1/1/1,3 ml), naOH (360mg, 9.00mmol) was added, and the resulting mixture was stirred at room temperature overnight. To the reaction solution was added saturated brine (20 mL), acidified to pH ≈ 6 with dilute hydrochloric acid (1M), the resulting mixture was extracted with 2-MeTHF (15 mL × 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (DCM/MeOH (v/v) = 15/1) to give the title compound as a pale yellow solid (350mg, 81%).

MS(ESI,pos.ion)m/z:482.9[M+H] ⁺ ；

HRMS(ESI,pos.ion)m/z:483.1416,(C ₂₃ H ₂₁ F ₂ N ₆ O ₂ S)[M+H] ⁺ Theoretical value: 483.1415;

¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm):12.74(s,1H),8.52(s,1H),8.27(d,J＝7.3Hz,1H),7.89(d,J＝3.0Hz,1H),7.84(d,J＝4.9Hz,1H),7.62(d,J＝6.2Hz,1H),7.32–7.24(m,1H),4.65(d,J＝6.3Hz,1H),2.85(d,J＝7.0Hz,1H),2.11(s,1H),1.98(d,J＝14.1Hz,2H),1.84–1.29(m,8H)；

¹³ C NMR(151MHz,DMSO-d ₆ )δ(ppm):176.19,158.21,156.64,155.93,155.88,152.54,152.46,140.90,140.38,140.33,140.29,138.65,138.45,138.41,134.94,132.43,132.33,130.48,130.46,129.72,129.65,128.98,125.03,124.73,113.79,51.36,48.03,28.82,28.49,25.91,23.99,21.67,19.56。

step 6) (2S, 3S) -3- ((2- (5- (acetoxymethyl) -2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazine-7- Yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.0g, 2.1mmol), DMF (10 mL) and potassium carbonate (0.57g, 4.1mmol) were added to a reaction flask, and the resulting mixture was cooled to 0 ℃ and stirred for 15min, and chloromethyl acetate (0.25g, 2.2mmol) was added thereto, reacted at 0 ℃ for 15min, and then allowed to stand at room temperature for reaction overnight. After completion of the reaction, water (50 mL) and ethyl acetate (50 mL) were added to the reaction, the mixture was extracted, the aqueous phase was further extracted with ethyl acetate (20 mL), the combined organic phases were washed with water (50 mL), the organic phase was spin-dried, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 4/1) to give the title compound as a pale yellow solid (0.54g, 47%).

HRMS(ESI,pos.ion)m/z:555.20,(C ₂₆ H ₂₅ F ₂ N ₆ O ₄ S)[M+H] ⁺ Theoretical value: 555.16;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.73(s,1H),8.15(d,J＝7.0Hz,1H),7.95(d,J＝3.5Hz,1H),7.58(d,J＝4.9Hz,1H),7.22–7.18(m,1H),6.38(d,J＝10.9Hz,1H),6.22(d,J＝10.9Hz,1H),5.47(s,1H),4.46(s,1H),2.58(s,1H),2.14(s,3H),2.10(s,1H),1.92(s,1H),1.76–1.68(m,4H),1.50(d,J＝12.4Hz,2H),1.26(d,J＝8.5Hz,2H).

example 24 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- (((methoxycarbonyl) oxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

(2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.0g, 2.1mmol), DMF (10 mL) and potassium carbonate (0.57g, 4.1mmol) were added to a reaction flask, and after cooling to 0 ℃, chloromethyl dimethyl carbonate (0.28g, 2.2mmol) was added, and after reacting at 0 ℃ for 20min, the reaction was left to stand at room temperature overnight. The reaction was stopped, water (50 mL) and ethyl acetate (50 mL) were added to the reaction, the layers were separated by extraction, the aqueous phase was further extracted with ethyl acetate (20 mL), the combined organic phases were washed with water (50 mL), the organic phase was spun off, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 4/1) to give the title compound as a pale yellow solid (0.44g, 37%).

HRMS(ESI,pos.ion)m/z:571.15,(C ₂₆ H ₂₅ F ₂ N ₆ O ₅ S)[M+H] ⁺ Theoretical values are as follows: 571.16, respectively;

¹ H NMR(600MHz,CDCl ₃ )δ(ppm)8.75(s,1H),8.15(d,J＝7.0Hz,1H),7.95(d,J＝3.6Hz,1H),7.57(d,J＝5.0Hz,1H),7.22–7.19(m,1H),6.34–6.30(m,2H),5.46(d,J＝2.9Hz,1H),4.45(d,J＝2.8Hz,1H),3.82(s,3H),2.57(s,1H),2.09(d,J＝2.6Hz,1H),1.92(d,J＝2.3Hz,1H),1.85(s,1H),1.84(s,1H),1.75–1.68(m,4H),1.51–1.47(m,1H),1.25(t,J＝7.1Hz,1H)。

example 25 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- ((((2-methoxyethoxy) carbonyl) oxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) chloromethyl-2-methoxyethyl carbonate

DCM (20 mL) and ethylene glycol methyl ether (2.1mL, 27mmol) were added sequentially to the reaction flask, cooled to 0 deg.C, to which was added dropwise a solution of chloromethyl chloroformate (2.3 mL, 26mmol) in DCM (20 mL) and pyridine (2.3 mL, 29mmol) in DCM (10 mL), after the addition was complete, the reaction was allowed to warm for 10min and allowed to proceed overnight at room temperature. The reaction mixture was washed with water (50 mL. Times.3), allowed to stand for separation, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated by rotary evaporation at 45 ℃ to give the title compound as a colorless liquid (3.8g, 85%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)5.63(s,2H),4.28–4.19(m,2H),3.54–3.49(m,2H),3.26(d,J＝4.0Hz,3H)。

Step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- ((((2-methoxyethoxy) carbonyl) oxy) methyl) - 5H-pyrrolo [2,3-b]Pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2.0 g,4.1 mmol) was dissolved in N, N-dimethylformamide (20 mL), and chloromethyl-2-methoxyethyl carbonate (1.0 g, 5.9mmol) and potassium carbonate (1.7 g, 12mmol) were further added thereto, and the resulting mixture was reacted at room temperature overnight. Water (30 mL) was added to the reaction solution, and the mixture was quenched, extracted with ethyl acetate (50 mL. Times.2), the combined organic phases were washed with saturated brine (50 mL. Times.2), allowed to stand for separation, and the upper organic phase was taken and concentrated by rotary evaporation at 50 ℃. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 200/1) to give the title compound as an off-white solid (300mg, 10%).

MS(ESI,pos.ion)m/z:615.5[M+H] ⁺ 。

HRMS(ESI,pos.ion)m/z:615.1833,(C ₂₈ H ₂₈ F ₂ N ₆ O ₆ S)[M+H] ⁺ Theoretical value: 615.1837;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.74(s,1H),8.15(d,J＝7.0Hz,1H),7.95(d,J＝3.5Hz,1H),7.58(d,J＝5.0Hz,1H),7.22–7.18(m,1H),6.33(s,2H),5.46(s,1H),4.47(s,1H),4.34–4.28(m,2H),3.60–3.56(m,2H),3.32(s,3H),2.56(s,1H),2.09(d,J＝2.2Hz,1H),1.92(s,1H),1.83(s,3H),1.75–1.68(m,4H),1.25(s,1H)。

example 26 (2S, 3S) -3- ((2- (5- (((cyclohexyloxy) carbonyl) oxy) methyl-2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -5-fluoro-6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) chloromethyl cyclohexyl carbonate

Cyclohexanol (1.2 g, 12mmol) and DCM (10 mL) were added to the reaction flask, cooled to 0 ℃ and a solution of chloromethyl chloroformate (1.5 g, 12mmol) in DCM (10 mL) was added dropwise, and the reaction was continued for 5min with incubation. Pyridine (1.0 g, 13mmol) in DCM (10 mL) was added dropwise thereto, and the reaction was continued for 10min with warming to room temperature for 4 hours. Water (50 mL) was added to the reaction solution for washing, the aqueous phase was further extracted with DCM (10 mL), the layers were separated, and the combined organic phases were washed with water (50 mL. Times.2), separated, and the organic phase dried to give the title compound as a light brown liquid (1.3 g, 58%).

Step 2) (2S, 3S) -3- ((2- (5- (((cyclohexyloxy) carbonyl) oxy) methyl-2-fluoro-5H-pyrrolo [2, 3-b]pyrazin-7-yl) -5-fluoro-6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.2g, 2.49mmol), DMF (15 mL) and potassium carbonate (0.41g, 3.0mmol) were added to a reaction flask, stirred in an ice-water bath for 15min, a solution of chloromethyl cyclohexyl carbonate (0.25g, 2.2mmol) in DMF (5 mL) was added thereto, and after completion of the addition, the reaction was allowed to proceed for 10min, and then the reaction was left at room temperature for 3 hours. EA (50 mL) and water (50 mL) were added to the reaction solution for extraction, liquid separation was performed, the aqueous phase was further subjected to liquid separation by EA (20 mL), the organic phases were combined, water (100 mL × 2) was further washed, liquid separation was performed by spin-drying, the obtained residue was purified by silica gel column chromatography (DCM/MeOH (v/v) =1/0 to 200/1), the obtained pale yellow crude product was purified by preparative chromatography, the obtained preparation was extracted with EA (100 mL), liquid separation was performed, the aqueous phase was further extracted with EA (50 mL × 2), the combined organic phases were washed with saturated saline (100 mL), liquid separation was performed, and the organic phase was dried by spin-drying to obtain the title compound as a pale yellow solid (0.37g, 23%).

HRMS(ESI,pos.ion)m/z:639.2217,(C ₂₉ H ₂₈ F ₂ N ₆ O ₆ S)[M+H] ⁺ Theoretical values are as follows: 639.2204.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.53(s,1H),8.05(d,J＝6.7Hz,1H),7.85(s,1H),7.60(d,J＝4.9Hz,1H),7.23–7.19(m,1H),5.78(d,J＝5.6Hz,1H),5.72(d,J＝5.6Hz,1H),4.72(s,1H),4.57(dd,J＝8.7,4.3Hz,1H),2.71(s,1H),2.16–2.01(m,4H),1.86(d,J＝9.6Hz,6H),1.75(s,2H),1.60(s,2H),1.50(d,J＝10.3Hz,3H),1.27(d,J＝7.1Hz,4H)。

example 27 ((2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- (2-oxo-5-phenyl-1, 3-dioxol-4-yl) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) 1-propiophenone

1-phenylpropanol (20g, 146.85mmol), tert-butanol (150 mL), potassium carbonate (40.5g, 293mmol) and elemental iodine (74.5g, 294mmol) were added to a reaction flask, and the mixture was heated to 90 ℃ for reaction for 12 hours under nitrogen substitution protection. After completion of the reaction, the reaction was allowed to cool to room temperature, EA (400 mL) and saturated aqueous sodium thiosulfate (400 mL) were added to the reaction, the aqueous phase was separated by extraction, the aqueous phase was further extracted with EA (100 mL), the combined organic phases were washed with water (200 mL × 2), the organic phases were separated, the organic phase was dried by spinning, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 1/0-50/1) to give the title compound as a pale yellow liquid (14.9g, 75.6%).

Step 2) 2-Bromophenylacetone

1-propiophenone (7g, 52.1699 mmol) and DCM (50 mL) were added to the reaction flask, the mixture was cooled to 0 ℃ and a solution of bromine (7.98g, 52.2mmol) in DCM (20 mL) was added dropwise, after the addition was complete, the mixture was allowed to warm for 20min and allowed to warm to room temperature for reaction overnight. To the reaction was added saturated sodium thiosulfate solution (300 mL) for extraction, the layers were separated, the organic phase was washed with water (300 mL × 2), dried and spun dry to give the title compound as a light brown liquid (10.3g, 92.7%).

Step 3) 2-hydroxybenzeneAcetone (II)

2-Bromophenylacetone (10.3g, 48.3mmol), methanol (50 mL) and sodium formate (13.1g, 193mmol) were added to the reaction flask, and the mixture was heated under reflux for 13 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, EA (200 mL) and water (200 mL) were added, the aqueous phase was separated by extraction, EA (200 mL) was further added to the aqueous phase for extraction, the combined organic phases were washed with water (200 mL × 2), and the separated liquid was dried to give the title compound as a light brown liquid (5.5 g, 76%).

Step 4) 4-methyl-5-phenyl-1, 3-dioxol-2-one

2-Hydroxypropiophenone (4.50g, 30.0mmol), toluene (50 mL) and triphosgene (3.4g, 11mmol) were added to a reaction flask, cooled to 0 ℃, a solution of N, N-dimethylaniline (8.0g, 66mmol) in toluene (2 mL) was added dropwise, and after the dropwise addition, the mixture was allowed to stand for 20min, and the mixture was allowed to stand at room temperature for reaction for 3 hours. Heating to reflux reaction for 4h; after completion of the reaction, the reaction mixture was cooled to room temperature, EA (50 mL) and water (50 mL) were added, the reaction mixture was extracted, the organic phase was further washed with 1M HCl (25 mL), separated and dried, the organic phase was spin-dried, and the obtained residue was purified by silica gel column chromatography (PE/EA (v/v) = 40/1) to obtain the title compound as a pale yellow solid (1.7g, 32%).

MS(ESI,pos.ion)m/z:177.05[M+H] ⁺ 。

Step 5) 4- (bromomethyl) -5-phenyl-1, 3-dioxol-2-one

4-methyl-5-phenyl-1, 3-dioxol-2-one (1.70g, 9.65mmol), chlorobenzene (40 mL), NBS (1.72g, 9.66mmol) and AIBN (0.16g, 0.98mmol) were added to a reaction flask and heated to 80 ℃ for 11h. After completion of the reaction, the reaction was cooled to room temperature, water (50 mL) and DCM (50 mL) were added to the reaction and extracted, the organic phase was successively washed with water (50 mL × 2), dried, the organic phase was spin-dried, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 60/1) to give the title compound as a pale yellow solid (1.6 g, 65%).

Step 6) ((2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- (2-oxo-5-phenyl-1, 3-dioxole-4-) Yl) methyl) -5H-pyrrolo [2,1,3-b]Pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] Octane-2-carboxylic acid

(2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.2g, 2.49mmol), DMF (15 mL) and potassium carbonate (0.41g, 3.0mmol) were added to a reaction flask, the mixture was cooled to 0 ℃ and a solution of 4- (bromomethyl) -5-phenyl-1, 3-dioxol-2-one (0.70, 2.7mmol) in DMF (5 mL) was added dropwise, and the reaction was carried out at this temperature for 2H after completion of the addition. The pH of the reaction was adjusted to 3 with hydrochloric acid (2M), the resulting mixture was extracted with EA (50 mL) and water (50 mL), the aqueous phase was separated, the aqueous phase was further extracted with EA (50 mL), the combined organic phases were washed with water (100 mL × 2), the separated phases were spun off, the organic phase was spun off, the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 1/0-200/1) to give a pale yellow solid, which was further purified by preparative chromatography to give the title compound as a pale yellow solid (0.40g, 24%).

HRMS(ESI,pos.ion)m/z:657.20,(C ₃₃ H ₂₇ F ₂ N ₆ O ₅ S)[M+H] ⁺ Theoretical value: 657.17;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.40(s,1H),8.47(s,1H),8.09(d,J＝7.0Hz,1H),7.91(d,J＝3.2Hz,1H),7.56(d,J＝4.9Hz,1H),7.42–7.37(m,2H),7.34(d,J＝5.2Hz,3H),7.21–7.18(m,1H),5.33(s,1H),5.16(d,J＝14.0Hz,1H),4.89(d,J＝14.0Hz,1H),4.82(s,1H),2.55(d,J＝5.5Hz,1H),2.08(s,2H),2.04(s,1H),1.66(s,4H),1.28(d,J＝3.4Hz,1H),1.26(s,2H)。

example 28 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- (((1-methoxy-2-methyl-1-oxoprop-2-yl) oxy) carbonyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step by stepStep 1) methyl 2- ((chlorocarbonyl) oxy) -2-methylpropionate

Triphosgene (1.3g, 4.38mmol) and THF (10 mL) were added to the reaction flask, the temperature was reduced to 0 deg.C, a solution of methyl 2-hydroxy-2-methylpropionate (1.5g, 12.7mmol) and pyridine (1.0g, 13mmol) in THF (5 mL) was added dropwise, and the reaction was continued at 0 deg.C for 3.5h after dropping. The reaction was filtered, the filter cake was washed with THF (10 mL) and the filtrate was rotary dried to give the title compound as a light brown liquid (1.6 g, 70%).

Step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- (((1-methoxy-2-methyl-1-oxoprop-2-yl) oxy) Yl) carbonyl) -5H-pyrrolo [2,3-b]Pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Pungent food Alkane-2-carboxylic acid

A reaction flask was charged with (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (0.5g, 1.0 mmol) and THF (15 mL), followed by addition of methyl 2- ((chlorocarbonyl) oxy) -2-methylpropionate (0.22g, 1.2 mmol), cooling to 0 deg.C, dropwise addition of a solution of triethylamine (0.29g, 2.1 mmol) in THF (5 mL), reaction at 0 deg.C for 10min after completion of dropwise addition, and warming to room temperature for 4H. The reaction was stopped, EA (30 mL) and brine (30 mL) were added to the reaction and extracted, the aqueous phase was further extracted with EA (10 mL), the combined organic phases were washed with saturated brine (30 mL × 2), separated, dried over anhydrous sodium sulfate, filtered, the filtrate was freed of solvent, and the resulting residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (0.33g, 51%).

HRMS(ESI,pos.ion)m/z:627.25,(C ₂₉ H ₂₈ F ₂ N ₆ O ₆ S)[M+H] ⁺ Theoretical value: 627.18;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.88(s,1H),8.28(d,J＝7.3Hz,1H),7.94(d,J＝3.3Hz,1H),7.58(d,J＝4.9Hz,1H),7.21(t,J＝4.3Hz,1H),5.48(d,J＝3.5Hz,1H),4.51(s,1H),3.83(s,3H),2.55(s,1H),2.11(s,1H),2.00(s,1H),1.89(d,J＝7.1Hz,6H),1.81(d,J＝5.9Hz,3H),1.70(s,3H),1.25(s,2H).

example 29 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- (((5-methyl-2-oxo-1, 3-dioxol-4-yl) methoxy) carbonyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Step 1) (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl (4-nitrophenyl) carbonate

4- (hydroxymethyl) -5-methyl-1, 3-dioxol-2-one (3.00g, 23.1mmol) was dissolved in DCM (25 mL), pyridine (2.01g, 25.4 mmol) was added thereto, and the mixture was stirred at 0 ℃. A solution of (4-nitrophenyl) chloroformate (5.11g, 25.4mmol) in DCM (25 mL) was added dropwise thereto, and after reacting at 0 ℃ for 10min, the mixture was allowed to shift to room temperature overnight. After completion of the reaction, the reaction solution was washed with 1% sodium hydroxide solution (50 mL) and 1M hydrochloric acid (50 mL) in this order. The mixture was allowed to stand for separation, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (v/v) = 10/1) to obtain an off-white solid. The resulting solid was added to toluene (40 mL) and stirred at room temperature overnight. Suction was performed, and the filter cake was rinsed with toluene (10 mL) and then spin-dried at 60 ℃ to give the title compound as an off-white solid (2.90g, 42.6%).

1H NMR(600MHz,CDCl3)δ8.32–8.27(m,2H),7.42–7.37(m,2H),5.03(s,2H),2.22(s,3H).

Step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- (((5-methyl-2-oxo-1, 3-dioxole-4-) Yl) methoxy) carbonyl) -5H-pyrrolo [2,3-b]Pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclic ring [2.2.2]Octane-2-carboxylic acid

(2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (2.0 g,4.1 mmol) and (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl (4-nitrophenyl) carbonate (1.5g, 5.1 mmol) were added to anhydrous DMF (20 mL) and stirred at room temperature for 30min. Triethylamine (1.8mL, 13mmol) was added to the reaction system, and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the reaction mixture was adjusted to acidic pH with 1mol/L hydrochloric acid, extracted with ethyl acetate (50 mL × 2), the upper organic phase was washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 200/1) to give the title compound as a pale pink solid (377mg, 14%).

HRMS(ESI,pos.ion)m/z:639.2[M+H] ⁺ ,(C ₂₈ H ₂₈ F ₂ N ₆ O ₆ S)[M+H] ⁺ Theoretical values are as follows: 639.1473;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.75(s,1H),8.29(d,J＝7.2Hz,1H),7.92(s,1H),7.58(d,J＝4.8Hz,1H),7.24–7.14(m,1H),5.50(d,J＝4.5Hz,1H),5.28(s,2H),4.58(s,1H),2.52(s,1H),2.29(s,3H),2.15(s,1H),2.04(s,1H),1.79(s,3H),1.70(s,3H),1.48(d,J＝12.0Hz,1H),1.25(s,2H).

example 30 Ethyl (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

Step 1) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-pyrrolo [2, 3-b)]Pyrazine-7-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

(2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.0g, 1.4mmol) and ethanol (0.13g, 2.8mmol) were added to a reaction flask and dissolved in DCM (15 mL) and cooled to 0 ℃; then, a solution of DCC (0.34g, 1.6 mmol) and DMAP (0.04g, 0.3 mmol) in DCM (5 mL) was added thereto, stirring was continued at 0 ℃ for 10min, the reaction was allowed to warm to room temperature overnight, the cake was washed with DCM (10 mL), the filtrate was washed with water (30 mL), the organic phase was separated, the organic phase was successively washed with water (30 mL), separated and spin-dried, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 15/1) to obtain the title compound as a pale yellow solid (0.82g, 79%).

HRMS(ESI,pos.ion)m/z:753.2963,(C ₄₄ H ₃₉ F ₂ N ₆ O ₂ S)[M+H] ⁺ Theoretical value: 753.2823.

step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester

Ethyl (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (0.80g, 1.1 mmol) and trifluoroacetic acid (4 mL) were added to a reaction flask and reacted at room temperature for 3H. After completion of the reaction, water (30 mL) was added to the reaction solution and washed, the aqueous phase was further extracted with DCM (10 mL), the combined organic phases were washed with water (30 mL × 2), separated, the organic phase was spin-dried, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to give the title compound as a pale yellow solid (0.38g, 74%).

HRMS(ESI,pos.ion)m/z:511.1929,(C ₂₅ H ₂₅ F ₂ N ₆ O ₂ S)[M+H] ⁺ Theoretical values are as follows: 511.1728;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.53(s,1H),8.52(d,J＝3.0Hz,1H),8.10(d,J＝7.0Hz,1H),7.92(d,J＝3.5Hz,1H),7.55(d,J＝5.0Hz,1H),7.22–7.16(m,1H),5.27(d,J＝5.6Hz,1H),4.76(s,1H),4.16(dq,J＝10.8,7.1Hz,1H),4.01(dq,J＝10.8,7.1Hz,1H),2.43(d,J＝5.7Hz,1H),2.08(s,1H),2.03(s,1H),1.92(d,J＝12.9Hz,1H),1.76(s,1H),1.60(d,J＝11.0Hz,1H),1.50(d,J＝13.1Hz,1H),1.25(s,1H),1.13(t,J＝7.1Hz,3H).

example 31 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid isopropyl ester

Step 1) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) - 6- (Thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid

Will (a) to2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ethyl ester (0.83g, 1.1 mmol) dissolved in THF/MeOH/H ₂ To O (v/v/v =1/1/1,3 ml), naOH (400mg, 10.00mmol) was added, and the resulting mixture was stirred at room temperature overnight. To the reaction solution was added saturated brine (20 mL), acidified to pH ≈ 6 with dilute hydrochloric acid (1M), the resulting mixture was extracted with 2-MeTHF (15 mL × 3), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was freed of the solvent under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (DCM/MeOH (v/v) = 15/1) to give the title compound as a pale yellow solid (640mg, 81%).

MS(ESI,pos.ion)m/z:725.6[M+H]+。

Step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-pyrrolo [2, 3-b)]Pyrazine-7-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid isopropyl ester

A reaction flask was charged with (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (0.58g, 0.8mmol), isopropanol (0.10g, 1.6mmol) and DCM (10 mL) to dissolve, and a solution of DCC (0.30g, 1.5mmol) and DMAP (0.03g, 0.2mmol) in DCM (5 mL) was added and the mixture was stirred for 10min and warmed to room temperature for 4H. After the reaction was completed, the reaction solution was filtered, the cake was washed with DCM (10 mL), the filtrate was washed with water (30 mL), the organic layer was separated, the organic layer was successively washed with water (30 mL), the organic layer was separated, the organic layer was spin-dried, 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 (0.45g, 73%).

HRMS(ESI,pos.ion)m/z:767.3128,(C ₄₄ H ₃₉ F ₂ N ₆ O ₂ S)[M+H] ⁺ Theoretical value: 767.2980.

step 3) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophene-2- Yl) pyrimidin-ethyl-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid isopropyl ester

To a reaction flask was added (2s, 3s) -3- ((5-fluoro-2- (2-fluoro-5-trityl-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid isopropyl ester (0.43g, 0.56mmol), DCM (12 mL) was added and dissolved, further trifluoroacetic acid (2.2 mL) was added, and the resulting mixture was reacted at room temperature for 10 hours. After the reaction was completed, water (30 mL) was added to the reaction and washed, the aqueous phase was extracted with DCM (10 mL), the combined organic phases were washed with water (30 mL × 2), the organic phase was spin-dried, and the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to give the title compound as a pale yellow solid (0.22g, 76%).

HRMS(ESI,pos.ion)m/z:525.2037,(C ₂₆ H ₂₇ F ₂ N ₆ O ₂ S)[M+H] ⁺ Theoretical values are as follows: 525.1884.

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.72(s,1H),8.51(d,J＝3.0Hz,1H),8.09(d,J＝7.0Hz,1H),7.91(d,J＝3.5Hz,1H),7.54(d,J＝4.9Hz,1H),7.21–7.16(m,1H),5.27(d,J＝5.6Hz,1H),5.01(dq,J＝12.6,6.3Hz,1H),4.77(s,1H),2.40(d,J＝5.6Hz,1H),2.08(d,J＝2.2Hz,1H),2.02(d,J＝2.1Hz,1H),1.92(d,J＝12.7Hz,1H),1.70(d,J＝10.2Hz,2H),1.60(d,J＝11.3Hz,1H),1.50(d,J＝13.0Hz,1H),1.42(s,1H),1.26(t,J＝7.1Hz,1H),1.17(d,J＝6.2Hz,3H),1.02(d,J＝6.3Hz,3H),0.91–0.81(m,1H)。

example 32 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid phenyl ester

Step 1) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid phenyl ester

(2S, 3S) -3- [ [ 5-fluoro-2- (2-fluoro-5-tritylpyrrolo [2,3-b ] pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-amino ] bicyclo [2.2.2] octane-2-carboxylic acid (1.0g, 1.4 mmol) was dissolved in DCM (20 mL), and the mixture was stirred at 0 ℃ and then phenol (0.24mL, 2.7 mmol), DMAP (0.04g, 0.3mmol) and DCC (0.35g, 1.7 mmol) were added. The resulting mixture was stirred at 0 ℃ for 20min and then transferred to room temperature for 4h. The reaction solution was filtered, and the filtrate was collected. Washed with water (30 mL), allowed to stand for separation, and the lower organic phase was taken out and purified by silica gel column chromatography (PE/EA (v/v) = 15/1) to give the title compound as a pale yellow solid (1.01g, 91%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.41(s,1H),7.92(d,J＝3.7Hz,1H),7.78(d,J＝7.3Hz,1H),7.56(d,J＝4.9Hz,1H),7.29(s,3H),7.28(s,9H),7.24(s,1H),7.22(d,J＝3.1Hz,1H),7.17(dd,J＝6.5,2.6Hz,5H),6.97(d,J＝7.7Hz,2H),5.24(d,J＝7.3Hz,1H),4.78(d,J＝6.9Hz,1H),2.63(d,J＝6.6Hz,1H),2.26(s,1H),2.09(s,1H),1.79(d,J＝10.1Hz,3H),0.88(dd,J＝12.6,5.9Hz,5H).

Step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid phenyl ester

Phenyl (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (0.65g, 0.81mmol) and trifluoroacetic acid (3 mL) were added to a reaction flask and reacted at room temperature for 3.5h. The reaction solution was extracted with DCM (20 mL), and the organic phase was washed with water (20 mL × 2), and the organic phase was separated by standing, and purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to give the title compound as a pale yellow solid (0.38g, 76%).

HRMS(ESI,pos.ion)m/z:559.1737,(C ₂₈ H ₂₈ F ₂ N ₆ O ₆ S)[M+H] ⁺ Theoretical values are as follows: 559.1728;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)9.54(s,1H),8.30(d,J＝2.9Hz,1H),8.06(d,J＝6.9Hz,1H),7.96(d,J＝3.4Hz,1H),7.58(d,J＝4.8Hz,1H),7.23–7.18(m,1H),7.09(t,J＝7.4Hz,2H),7.04(d,J＝7.0Hz,1H),6.80(d,J＝7.5Hz,2H),5.44(d,J＝5.0Hz,1H),4.71(s,1H),2.72(d,J＝4.1Hz,1H),2.22(s,1H),1.87(d,J＝15.2Hz,2H),1.82–1.74(m,3H),1.70(s,2H),1.58(t,J＝11.8Hz,1H),1.26(t,J＝7.1Hz,1H).

example 33 benzyl (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate

Step 1) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid benzyl ester

(2S, 3S) -3- [ [ 5-fluoro-2- (2-fluoro-5-tritylpyrrolo [2,3-b ] pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-amino ] bicyclo [2.2.2] octane-2-carboxylic acid (1.0g, 1.4 mmol) and DCM (20 mL) were charged into a reaction flask, and after cooling to stirring, benzyl alcohol (0.29mL, 2.8mmol), DCC (0.35g, 1.7mmol) and DMAP (0.04g, 0.3mmol) were added, and the resulting mixture was reacted at 0 ℃ for 20min and then transferred to room temperature to react for 4h. The reaction solution was filtered, and the filtrate was washed with water (30 mL), allowed to stand for layer separation, and the organic phase was purified by silica gel column chromatography (PE/EA (v/v) = 15/1) to give the title compound as a pale yellow solid (1.02g, 91%).

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.42(s,1H),7.88(d,J＝3.5Hz,1H),7.77(d,J＝7.3Hz,1H),7.54(d,J＝4.9Hz,1H),7.32–7.26(m,9H),7.22(s,5H),7.21–7.16(m,7H),5.08(d,J＝12.4Hz,2H),5.00(d,J＝12.4Hz,1H),4.64(t,J＝7.1Hz,1H),2.40(d,J＝7.2Hz,1H),2.06(d,J＝13.7Hz,2H),1.69(d,J＝8.3Hz,3H),1.26(s,5H).

Step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid benzyl ester

Benzyl (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (1.0g, 1.2mmol) was dissolved in DCM (10 mL), glacial acetic acid (1.4mL, 24mmol) was added, and the resulting mixture was reacted at room temperature for 2.5h, and then transferred to 40 ℃ and stirred for reaction overnight. The reaction solution was washed with water (20 mL × 2), allowed to stand for layer separation, the organic phase was concentrated by rotary evaporation at 45 ℃, trifluoroacetic acid (4 mL) was added to the dried solid, reacted at room temperature for 5 hours, DCM (20 mL) was added to the reaction solution and washed with water (20 mL × 2), allowed to stand for layer separation, and the organic phase was purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to obtain the title compound as a pale yellow solid (0.40g, 65%).

HRMS(ESI,pos.ion)m/z:572.1912,(C ₂₈ H ₂₈ F ₂ N ₆ O ₆ S)[M+H] ⁺ Theoretical value: 572.1806;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.56(s,1H),8.01(d,J＝6.7Hz,1H),7.76(d,J＝2.9Hz,1H),7.60(d,J＝4.9Hz,1H),7.20(d,J＝8.4Hz,6H),5.19(d,J＝12.5Hz,1H),5.04(d,J＝12.5Hz,1H),4.81(s,1H),2.69(s,1H),2.10(s,2H),1.95(s,1H),1.79(d,J＝14.5Hz,1H),1.73(d,J＝8.7Hz,1H),1.67–1.54(m,4H),1.47(d,J＝12.4Hz,1H),1.26(t,J＝7.0Hz,1H),0.90–0.77(m,1H).

example 34 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (acetoxy) methyl ester

Step 1) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) - 6- (Thien-2-one) yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid (acetoxy) methyl ester

To a reaction flask were added (2s, 3s) -3- ((5-fluoro-2- (2-fluoro-5-tritylpyrrolo [2,3-b ] pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-amino ] bicyclo [2.2.2] octane-2-carboxylic acid (1.2 g,1.7 mmol), DMF (10 mL) and potassium carbonate (0.46g, 3.3mmol), stirred for 10min, added chloromethyl acetate (0.36g, 3.3mmol), reacted overnight at room temperature, to the reaction was added water (50 mL) and partitioned EA (50 mL) for extraction, the aqueous phase was further extracted with EA (20 mL), the combined organic phase was washed with water (50 mL), partitioned, dried over anhydrous sodium sulfate, and after spin-drying, the resulting residue was purified by silica gel column chromatography (PE/EA (v/v) =10/1 to 8/1), to give the title compound as a pale yellow solid (1.g, 76%).

Step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid (acetoxy) methyl ester

To a reaction flask were added (2S, 3S) -acetoxymethyl-3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-one) yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.0 g,1.3 mmol) and trifluoroacetic acid (3 mL) and reacted at room temperature for 3H. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction, the liquid was separated by extraction, the aqueous phase was extracted with ethyl acetate (20 mL), the combined organic phases were washed with water (50 mL), the organic phase was dried, and after spin-drying, purification by silica gel column chromatography (PE/EA (v/v) = 4/1) gave the title compound as a pale yellow solid (0.54g, 78%).

HRMS(ESI,pos.ion)m/z:555.20,(C ₂₆ H ₂₅ F ₂ N ₆ O ₄ S)[M+H] ⁺ Theoretical value: 555.16;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.61(s,1H),8.00(d,J＝6.6Hz,1H),7.76(d,J＝2.9Hz,1H),7.62(d,J＝4.9Hz,1H),7.25–7.19(m,1H),5.81(d,J＝5.6Hz,1H),5.66(d,J＝5.6Hz,1H),4.80(s,1H),2.73(s,1H),2.09(d,J＝15.1Hz,2H),1.95(s,3H),1.79(t,J＝10.6Hz,2H),1.63(dd,J＝22.1,11.6Hz,4H),1.51(d,J＝11.7Hz,1H),1.26(dd,J＝11.9,4.7Hz,2H),0.87(d,J＝7.4Hz,1H).

example 35 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ((methoxycarbonyl) oxy) methyl ester

Step 1) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2, 3-b)]Pyrazine-7-yl) -substituted acids 6- (thien-2-yl)) Pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ((methoxycarbonyl) oxy) methyl ester

To a reaction flask were added (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5-tritylpyrrolo [2,3-b ] pyrazin-7-yl) -6- (2-thienyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.2g, 1.66mmol), DMF (10 mL) and potassium carbonate (0.46g, 3.3mmol), stirred for 10min, chloromethyl dimethyl carbonate (0.43g, 3.3mmol) was added, and the resulting mixture was reacted at room temperature overnight. To the reaction solution were added water (20 mL) and EA (20 mL) for extraction and liquid separation, the aqueous phase was extracted with EA (20 mL), the combined organic phases were washed with water (40 mL), liquid separation and organic phase drying were carried out, and the obtained residue was purified by silica gel column chromatography (PE/EA (v/v) = 10/1-8/1) to obtain the title compound as a pale yellow solid (0.95g, 71%).

Step 2) (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2, 3-b)]Pyrazin-7-yl) -6- (thiophene-2- Yl) pyrimidin-4-yl) amino) bicyclo [2.2.2]Octane-2-carboxylic acid ((methoxycarbonyl) oxy) methyl ester

To a reaction flask were added (2s, 3s) - ((methoxycarbonyl) oxy) methyl-3- ((5-fluoro-2- (2-fluoro-5-trityl-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (0.95g, 1.2 mmol) and trifluoroacetic acid (3 mL) and the resulting mixture was reacted at room temperature for 3H. Water (50 mL) and ethyl acetate (30 mL) were added to the reaction, the mixture was extracted, the aqueous phase was further extracted with ethyl acetate (20 mL), the combined organic phases were washed with water (50 mL), dried, and the resulting residue was spin-dried and then purified by silica gel column chromatography (PE/EA (v/v) = 4/1-2/1) to give the title compound as a pale yellow solid (0.53g, 79%).

HRMS(ESI,pos.ion)m/z:571.10,(C ₂₆ H ₂₅ F ₂ N ₆ O ₅ S)[M+H] ⁺ Theoretical value of 571.16;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.59(s,1H),8.01(d,J＝6.6Hz,1H),7.79(s,1H),7.63(d,J＝4.8Hz,1H),7.23(t,J＝4.3Hz,1H),5.80(d,J＝5.7Hz,1H),5.71(d,J＝5.7Hz,1H),4.78(s,1H),3.70(s,3H),2.78(s,1H),2.12(s,1H),2.06(s,1H),1.94(s,1H),1.79(dd,J＝26.5,12.6Hz,2H),1.68(s,1H),1.63(d,J＝10.4Hz,1H),1.59(s,1H),1.51(d,J＝11.9Hz,1H),1.26(dd,J＝12.0,4.8Hz,2H).

example 36 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ((methoxycarbonyl) oxy) methyl ester

To a reaction flask were added (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (0.60g, 1.0 mmol), potassium carbonate (0.42g, 3.0 mmol), and chloromethyl dimethyl carbonate (0.19mL, 2.0 mmol), and reacted at room temperature for 4H. The reaction mixture was added with water (10 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated brine (20 mL × 2), allowed to stand for layer separation, and the organic phase was purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to give the title compound as a pale yellow solid (0.54g, 78%).

HRMS(ESI,pos.ion)m/z:685.2250,(C ₂₈ H ₂₈ F ₂ N ₆ O ₆ S)[M+H] ⁺ Theoretical value of 685.2256;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.53(s,1H),8.14(d,J＝7.0Hz,1H),7.93(d,J＝3.5Hz,1H),7.56(d,J＝5.0Hz,1H),7.23–7.17(m,1H),6.30(dd,J＝26.0,10.7Hz,2H),5.73(dd,J＝35.2,5.7Hz,2H),5.32(d,J＝5.4Hz,1H),4.74(s,1H),3.54(s,3H),2.53(s,1H),2.07(d,J＝2.4Hz,2H),1.93(d,J＝10.9Hz,1H),1.78(d,J＝9.6Hz,1H),1.70(s,1H),1.58(s,4H),1.26(s,1H),1.16(s,9H).

example 37 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (acetoxy) methyl ester

To a reaction flask were added (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- ((pivaloyloxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (0.65g, 1.1mmol), potassium carbonate (0.45g, 3.3mmol) and chloromethyl acetate (0.20mL, 2.2mmol), and reacted at room temperature for 3.5H. Water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (25 mL. Times.2), and the combined organic phases were washed with 30mL of saturated brine (30 mL. Times.2). The organic phase was collected by standing for separation, and purified by silica gel column chromatography (PE/EA (v/v) = 3/1) to obtain the title compound as an off-white solid (0.38g, 52%).

HRMS(ESI,pos.ion)m/z:669.20,(C ₂₈ H ₂₈ F ₂ N ₆ O ₆ S)[M+H] ⁺ Theoretical value: 669.2307;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.55(s,1H),8.15(d,J＝7.0Hz,1H),7.93(d,J＝3.5Hz,1H),7.56(d,J＝5.0Hz,1H),7.22–7.18(m,1H),6.35–6.27(m,2H),5.82(d,J＝5.6Hz,1H),5.63(d,J＝5.6Hz,1H),5.30(s,1H),4.77(s,1H),2.49(d,J＝5.5Hz,1H),2.08(d,J＝13.4Hz,2H),1.90(s,3H),1.71(d,J＝11.1Hz,4H),1.56(s,6H),1.25(s,2H),1.17–1.10(m,9H).

example 38 (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5- (((methoxycarbonyl) oxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thien-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid ((methoxycarbonyl) oxy) methyl ester

To a reaction flask were added (2S, 3S) -3- ((5-fluoro-2- (2-fluoro-5H-pyrrolo [2,3-b ] pyrazin-7-yl) -6- (thiophen-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid (1.0g, 2.1mmol), DMF (20 mL) and potassium carbonate (0.86g, 6.2mmol), and after stirring for 10min, chloromethyl dimethyl carbonate (0.65g, 5.2mmol) was added and reacted at room temperature overnight. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction, the liquid was separated by extraction, the aqueous phase was further extracted with ethyl acetate (20 mL), the combined organic phases were washed with water (50 mL), dried, separated by preparative chromatography, the preparative liquid was decanted to remove most of the acetonitrile and then extracted with ethyl acetate (200 mL), the aqueous phase was further extracted with ethyl acetate (100 mL × 2), the combined organic phases were washed with water (300 mL × 2), the liquid was separated, the organic phases were dried, and spun dried to give the title compound as an off-white solid (0.90g, 33%).

HRMS(ESI,pos.ion)m/z:659.10,(C ₂₉ H ₂₉ F ₂ N ₆ O ₈ S)[M+H] ⁺ Theoretical value: 659.17;

¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.54(s,1H),8.13(d,J＝7.0Hz,1H),7.89(d,J＝2.8Hz,1H),7.53(d,J＝4.9Hz,1H),7.16(t,J＝4.2Hz,1H),6.37–6.28(m,2H),5.76(d,J＝5.7Hz,1H),5.68(d,J＝5.7Hz,1H),5.34(d,J＝5.2Hz,1H),4.69(s,1H),3.80(s,3H),3.53(s,3H),2.51(s,1H),2.03(d,J＝3.7Hz,2H),1.85(d,J＝16.9Hz,3H),1.68(d,J＝11.7Hz,3H),1.64(s,1H),1.46(t,J＝11.4Hz,1H).

activity test examples

In the following examples, the inventors examined the antiviral activity and cytotoxicity and pharmacokinetic properties of the compounds of the present invention, using a part of the compounds of the present invention as an example.

Example A: cytopathic effect experiment (CPE assay))：

The ability of the compounds of the invention to inhibit viral H1N 1A/Weiss/43 Cytopathic (CPE) was tested at the cellular level in vitro.

The experimental steps are as follows: MDCK cells (Madin-Darby Canine Kidney cells, continuous cell line of Canine Kidney epithelium) were seeded at a density of 2000/well in 384-well plates at 37 ℃ and 5% CO ₂ Culturing overnight under the condition; the following day, the replacement contained different concentrations of test compound and influenza H1N 1A/Weiss/43 (titer 1 TCID) ₉₀ Per well or multiplicity of infection that can produce cpe 80-95%) of fresh culture fluid. The highest concentration detected for the compound was 50nm, 3-fold gradient dilution, 8 concentration gradients, in order: 50nM,16.67nM,5.56nM,1.85nM,0.62nM,0.21nM,0.069nM,0.023nM. The cytotoxicity test group was identical to the above test conditions, but no influenza virus was added. And simultaneously setting a virus control group without medicine and a cell control group without medicine for virus infection.Two complex holes are arranged. 37 ℃ C., 5% CO ₂ Incubate under conditions for 5 days. The CCK-8 kit is used for detecting the activity of the cells, and the detection data are used for calculating the antiviral effect of the compound and the cytotoxicity to the infected virus cells. GraphPad Prism analyzes data, calculates CPE inhibition rate and cell survival rate, and obtains EC according to a fitted curve ₅₀ And CC ₅₀ The value is obtained.

CPE inhibition = (drug-well absorbance-virus control well absorbance)/(cell control well absorbance-virus control well absorbance) × 100%

Cell survival rate = (drug-added well absorbance-culture medium control well absorbance)/(cell control well absorbance-culture medium control well absorbance) × 100%

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: data on inhibitory Activity of partial Compounds of the invention against influenza Virus (A/Weiss/43 (H1N 1))

Example No. 2	EC 50 (nM)
		Example 6	0.306
Example 13	9.02
		Example 14	0.14
Example 16	0.52
		Example 17	6.17

As can be seen from Table 1, the compounds of the present invention have very good anti-influenza virus activity.

Example B: evaluation of pharmacokinetics after intravenous or oral dosing of the Compounds of the invention

Pharmacokinetic studies of the compounds of the invention in beagle dogs were evaluated. The compounds of the invention are administered in saline solution at 5% DMSO +5% Kolliphor HS 15+90% Saline. For intravenous (iv) administration, animals were given a dose of 1mg/kg, bled (0.3 mL) at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours, and centrifuged at 3,000 or 4,000rpm for 10 minutes. For oral (po) administration, animals were given a dose of 5mg/kg, bled (0.3 mL) at time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours, and centrifuged at 3,000 or 4,000rpm for 10 minutes. The plasma solutions were collected and stored at-20 ℃ or-70 ℃ until the LC/MS/MS analysis described above was performed. The test results are shown in table 2.

TABLE 2 pharmacokinetic data of partial compounds of the invention in beagle dogs

Remarking:

AUC _last -AUC over 0-24 hours;

AUC _INF -AUC from 0 to infinity.

As can be seen from table 2, the compound of the present invention, whether administered intravenously or orally, was exposed in beagle dogs in a large amount, absorbed well, and had good pharmacokinetic properties.

In the description of the specification, reference to the description of "one embodiment," "some embodiments," "an example," "a specific example," or "some examples" or the like 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 invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer 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. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.

Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (16)

1. A compound which is a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt of a compound of formula (I),

wherein:

ring a is of the sub-structure:

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;

R ¹ 、R ² 、R ³ 、R ⁴ and R ⁶ Each independently is H, D, F, cl, br, CN, NO ₂ Or C _1-6 An alkyl group;

l is- (CR) ^L1 R ^L2 ) _t -；

t is 1,2,3,4, 5 or 6;

R ^L1 and R ^L2 Each independently is H or D;

R ^S is CN, -OC (= O) R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 OR-C (= O) OR ^S2 ；

R ^S1 And R ^S2 Each independently is H, D, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 5-6 atom heterocyclic radical, C _6-10 Aryl or heteroaryl of 5 to 6 atoms, wherein said C _1-4 Alkyl radical, C _3-6 Cycloalkyl, heterocyclic radical of 5-6 atoms, C _6-10 Aryl and 5-6-membered heteroaryl are each independently unsubstituted or substituted by 1,2,3,4 or 5R ^x Substituted; wherein said 5-6 member heterocyclyl is a saturated or partially unsaturated, non-aromatic, monocyclic ring system containing 5-6 ring atoms, at least one of which is selected from nitrogen, sulfur and oxygen, wherein said 5-6 member heterocyclyl is non-aromatic and does not contain any aromatic rings, and wherein said ring system has one or more attachment points to the remainder of the molecule;

R ⁸ is H, D, F, cl, br, CN, NO ₂ Or C _1-6 An alkyl group;

R ⁷ is phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl are each independently unsubstituted or substituted with 1,2,3,4 or 5R ^y Substituted;

each R ^x And R ^y Independently is D, -OR ^b 、C _1-6 Alkyl or C _1-6 A haloalkyl group;

R ⁹ is H, D or C _1-6 An alkyl group;

w is the following subformula:

n is 1;

each R ^w independently-C (= O) OH;

R ^b is H, D, C _1-6 Haloalkyl or C _1-6 An alkyl group.

2. The compound of claim 1, wherein ring a is of the sub-formula:

3. the compound of claim 1, wherein R is ^S Is CN, -OC (= O) R ^S1 、-OC(＝O)OR ^S2 、-C(＝O)R ^S1 OR-C (= O) OR ^S2 ；

R ^S1 And R ^S2 Each independently is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein the methyl, ethyl, n-propyl isopropyl, n-butyl,Isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3, 5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl and pyrimidinyl each independently unsubstituted or substituted by 1,2,3,4 or 5R ^x And (4) substituting.

4. The compound of claim 1, wherein

R ⁸ Each independently is H, D, F, cl, br, CN, NO ₂ Or C _1-4 An alkyl group.

5. The compound of claim 1 or 4, wherein the

R ⁸ Is H, D, F, cl, br, CN, NO ₂ Methyl, ethyl, n-propyl or isopropyl.

6. The compound of claim 1, wherein each R is ^x And R ^y Independently is D, -OR ^b 、C _1-4 Alkyl or C _1-4 A haloalkyl group.

7. The compound of claim 1 or 6, wherein each R is ^x And R ^y Independently is D, -OH, -OCH ₃ 、-OCH ₂ CH ₃ Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl or difluoromethyl.

8. The compound of claim 1, wherein R is ¹ 、R ² 、R ³ 、R ⁴ And R ⁶ Each independently is H, D, F, cl, br, CN, NO ₂ Methyl, ethyl, n-propyl or isopropyl;

R ⁹ is H, D, methyl, ethyl, n-propyl or isopropyl.

9. The compound of claim 1, wherein said R ^b Is H, D, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl.

10. The compound of claim 1, having the structure of formula (II):

11. a compound having the structure of one of:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-11, optionally further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle, or combination thereof.

13. The pharmaceutical composition of claim 12, further comprising one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from anti-influenza virus agents or vaccines.

14. The pharmaceutical composition of claim 12, further comprising one or more additional therapeutic agents, wherein the additional therapeutic agent is amantadine, rimantadine, oseltamivir, zanamivir, peramivir, lanimivir caprylate hydrate, faviravir, abidol, ribavirin, stafosweilin, ingavirin, influenzase, a drug with CAS number 1422050-75-6, JNJ-872, S-033188, an influenza vaccine, or a combination thereof.

15. Use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to any one of claims 12 to 14 for the manufacture of a medicament for inhibiting the RNA polymerase of an influenza virus; or for use in the prevention, treatment or alleviation of a viral infectious disease in a patient, wherein said viral infection is an influenza viral infection.

16. The use of claim 15, wherein the influenza virus is H1N 1A/Weiss/43.