RU2792726C2 - 2,3-dihydro-1h-pyrrolisine-7-formamide derivative and its applications - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,3-dihydro-1H-pyrrolysin-7-formamide derivative as a nucleoprotein inhibitor.

EFFECT: new compounds with formula (II) have been obtained, which can be used in the preparation of a drug for the treatment of diseases associated with HBV.

20 cl, 12 tbl, 39 ex, 2 dwg

Description

Link to related applications

The present application claims advantage and priority according to China Patent Application No. 201810528259.1 filed with the National Intellectual Property Office of the People's Republic of China on May 25, 2018, China Patent Application No. 201810843225.1 filed with the National Intellectual Property Office of the People's Republic of China on July 27, 2018, and Chinese Patent Application No. 201811189801.1 filed with the National Intellectual Property Administration of the People's Republic of China on October 12, 2018, the contents of each of which are hereby incorporated by reference in their entirety.

Technical field

The present application relates to a 2,3-dihydro-1H-pyrrolysine-7-formamide derivative as a nucleoprotein inhibitor and its use in the preparation of a medicament for the treatment of diseases associated with hepatitis B virus (HBV). In particular, the present application relates to a compound represented by formula (II), a compound represented by formula (II-A), a compound represented by formula (II-B), a compound represented by formula (I), or stereoisomers or pharmaceutically acceptable salts thereof. , and their use in the preparation of a medicament for the treatment of diseases associated with HBV.

Background of the invention

Hepatitis B is an inflammatory condition caused by hepatitis B virus invasion. It is characterized by a tendency to fibrosis and cirrhosis of the liver and is the direct cause of 80% of primary liver cancers worldwide.

Hepatitis B is a global public health problem. Currently, there is no specific medicine for the treatment of hepatitis B. Nucleosides and interferons dominate the global hepatitis B drug market and are the main first-line drugs for the treatment of hepatitis B. However, treatment with nucleosides or interferons is characterized by such disadvantages as high cost, high probability of recurrence and the like. Therefore, there is a need to develop a new drug against hepatitis B.

Brief description of the invention

The present application provides a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

,

,

Where

m is 1 or 2;

;L selected from

;

T ₁ is selected from the group consisting of N and C (R ₄₃ );

R ₂ is selected from the group consisting of H and C _1-6 -alkyl, and C _1-6 -alkyl optionally has 1, 2 or 3 substituents R _b ;

R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , C _1-6 -alkyl and C _1-3 -alkoxy, with C _1-6 -alkyl and C _1-3 - alkoxy optionally have 1, 2 or 3 substituents R _c ;

each of R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ and R ₄₅ is independently selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 -alkyl, and C _1-3 -alkyl optionally has 1, 2 or 3 R _d substituents;

R ₅ is selected from the group consisting of R ₅₁ , C _3-10 cycloalkyl and 3-6 membered heterocycloalkyl, wherein C _3-10 cycloalkyl and 3-6 membered heterocycloalkyl optionally have 1, 2 or 3 R ₁ substituents;

R ₅₁ is selected from the group consisting of C _1-10 alkyl and C _1-6 heteroalkyl, with C _1-10 alkyl and C _1-6 heteroalkyl optionally having 1, 2 or 3 R _e substituents;

each R ₁ is independently selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-6 -alkyl, -COO-C _1-6 -alkyl and -C _{1- 3} -alkyl-COO-C _1-6 -alkyl, and C _1-6 -alkyl, -COO-C _1-6 -alkyl and -C _1-3 -alkyl-COO-C _1-6 -alkyl optionally have 1 , 2 or 3 substituents R _a ;

each R _a is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-3 alkyl, and C _1-3 alkoxy, with C _1-3 optionally having 1, 2 or 3 substituents R;

each R _b is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each R _c is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 alkyl, with C _1-3 alkyl optionally having 1, 2 or 3 R substituents ;

each R _d is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each Re _is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each R is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each of C _1-6 heteroalkyl and 3-6 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of -NH-, -O-, -S- and N.

In some embodiments of a compound represented by formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R _a is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN , COOH and -OCH ₃ and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R _c is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, each of the above R ₁ is independently selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-3 -alkyl, -COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl, and C _1-3 -alkyl, - COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl optionally have 1, 2, or 3 R _a substituents, and the remaining variables are as defined herein.

и

, причем CH₃, Et,

и

необязательно имеют 1, 2 или 3 заместителя R_a, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, each of the above R ₁ is independently selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, CH ₃ , Et,

And

, and CH ₃ , Et,

And

optionally have 1, 2, or 3 _{R a} substituents, and the remaining variables are as defined herein.

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, each of the above R ₁ is independently selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, CH ₃ , CF ₃ , Et, -CH ₂ -COOH, -CH ₂ -OCH ₃ , -(CH ₂ ) ₂ -COOH,

And

, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₂ is selected from the group consisting of H and C _1-3 alkyl, wherein C _1-3 is alkyl optionally has 1, 2, or 3 R _b substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₂ is selected from the group consisting of H, CH ₃ and Et, and the remaining variables are as follows: defined in this document.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ and C _1-3 -alkyl, with C _1-3 -alkyl optionally having 1, 2 or 3 substituents R _c , and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CH ₃ , CF ₃ and Et, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, each of the aforementioned R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ and R ₄₅ is independently selected from the group consisting of of H, Cl, F, Br, I, OH, NH ₂ , CN and -COOH, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of C _1-7 alkyl and C _1-6 heteroalkyl, wherein C _1-7 alkyl and C _1-6 heteroalkyl optionally have 1, 2, or 3 R _e substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of C _1-7 alkyl and C _1-3 heteroalkyl, wherein C _1-7 alkyl and C _1-3 heteroalkyl optionally have 1, 2, or 3 R _e substituents, and the remaining variables are as defined herein.

,

и

, причем метил, этил, пропил, изопропил,

,

и

необязательно имеют 1, 2 или 3 заместителя R_e, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of methyl, ethyl, propyl, isopropyl,

,

And

, and methyl, ethyl, propyl, isopropyl,

,

And

optionally have 1, 2, or 3 R _e substituents, and the remaining variables are as defined herein.

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of

,

,

And

, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ , C _3-8 -cycloalkyl, and 5-6- membered heterocycloalkyl, with C _3-8 -cycloalkyl and 5-6-membered heterocycloalkyl optionally having 1, 2 or 3 substituents R ₁ and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ , cyclohexyl, tetrahydropyranyl, piperidinyl, and bicyclo[2.2.2 ]octyl, wherein cyclohexyl, tetrahydropyranyl, piperidinyl, and bicyclo[2.2.2]octyl optionally have 1, 2, or 3 R ₁ substituents, and the remaining variables are as defined herein.

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ ,

,

,

And

, and the remaining variables are as defined in this document.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

, and the remaining variables are as defined in this document.

выбрана из группы, состоящей из

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned structural unit

selected from the group consisting of

,

,

And

, and the remaining variables are as defined in this document.

The compound represented by formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described above is selected from the compound represented by formula (II-A) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

,

,

Where

m is 1 or 2;

;L selected from

;

T ₁ is selected from the group consisting of N and C (R ₄₃ );

R ₂ is selected from the group consisting of H and C _1-6 -alkyl, and C _1-6 -alkyl optionally has 1, 2 or 3 substituents R _b ;

R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , C _1-6 -alkyl and C _1-3 -alkoxy, with C _1-6 -alkyl and C _1-3 - alkoxy optionally have 1, 2 or 3 substituents R _c ;

each of R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ and R ₄₅ is independently selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 -alkyl, and C _1-3 -alkyl optionally has 1, 2 or 3 R _d substituents;

R ₅ is selected from the group consisting of R ₅₁ , C _3-10 cycloalkyl and 3-6 membered heterocycloalkyl, wherein C _3-10 cycloalkyl and 3-6 membered heterocycloalkyl optionally have 1, 2 or 3 R ₁ substituents;

R ₅₁ is selected from the group consisting of C _1-7 -alkyl and C _1-6 -heteroalkyl, and C _1-7 -alkyl and C _1-6 -heteroalkyl optionally have 1, 2 or 3 Deputy R _e ;

R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-6 -alkyl, -COO-C _1-6 -alkyl and -C _1-3 - alkyl-COO-C _1-6 -alkyl, and C _1-6 -alkyl, -COO-C _1-6 -alkyl and -C _1-3 -alkyl-COO-C _1-6 -alkyl optionally have 1, 2 or 3 substituents R _a ;

each R _a is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-3 alkyl, and C _1-3 alkoxy, with C _1-3 optionally having 1, 2 or 3 substituents R;

each R _b is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each R _c is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 alkyl, with C _1-3 alkyl optionally having 1, 2 or 3 R substituents ;

each R _d is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each Re _is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each R is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each of C _1-6 heteroalkyl and 3-6 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of -NH-, -O-, -S- and N.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R _a is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH and -OCH ₃ and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R _c is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-3 -alkyl, -COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl, and C _1-3 -alkyl, - COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl optionally have 1, 2, or 3 R _a substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, CH ₃ and Et, with CH ₃ and Et optionally having 1, 2 or 3 R _a substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, CH ₃ , Et, -CH ₂ -COOH, -CH ₂ -OCH ₃ and -(CH ₂ ) ₂ -COOH, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₂ is selected from the group consisting of H and C _1-3 alkyl, wherein C _{1 -3} -alkyl optionally has 1, 2, or 3 R _b substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₂ is selected from the group consisting of H, CH ₃ and Et, and the remaining variables are as follows. as defined in this document.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ and C _1-3 -alkyl, with C _1-3 -alkyl optionally having 1, 2 or 3 R _c substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CH ₃ , CF ₃ and Et and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, each of the aforementioned R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ and R ₄₅ is independently selected from the group , consisting of H, Cl, F, Br, I, OH, NH ₂ , CN and -COOH, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of C _1-6 -alkyl and C _1-3 - heteroalkyl, with C _1-6 -alkyl and C _1-3 -heteroalkyl optionally having 1, 2 or 3 substituents R _e , and the remaining variables are as defined herein.

и

, причем метил, этил, пропил, изопропил,

и

необязательно имеют 1, 2 или 3 заместителя R_e, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of methyl, ethyl, propyl, isopropyl,

And

, and methyl, ethyl, propyl, isopropyl,

And

optionally have 1, 2, or 3 R _e substituents, and the remaining variables are as defined herein.

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of

,

And

, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ , C _3-8 cycloalkyl, and 5- 6-membered heterocycloalkyl, and C _3-8 -cycloalkyl and 5-6-membered heterocycloalkyl optionally have 1, 2 or 3 substituents R ₁ and other variables are as defined herein.

In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ , cyclohexyl, tetrahydropyranyl, piperidinyl, and bicyclo[2.2 .2]octyl, wherein cyclohexyl, tetrahydropyranyl, piperidinyl, and bicyclo[2.2.2]octyl optionally have 1, 2, or 3 R ₁ substituents, and the remaining variables are as defined herein.

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ ,

,

,

And

, and the remaining variables are as defined in this document.

,

,

,

,

,

,

,

,

,

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of

,

,

,

,

,

,

,

,

,

,

,

And

, and the remaining variables are as defined in this document.

выбрана из группы, состоящей из

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned structural unit

selected from the group consisting of

,

,

And

, and the remaining variables are as defined in this document.

The compound represented by formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described above is selected from the compound represented by formula (II-B) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

,

,

Where

m is 1 or 2;

;L selected from

;

T ₁ is selected from the group consisting of N and C (R ₄₃ );

R ₂ is selected from the group consisting of H and C _1-6 -alkyl, and C _1-6 -alkyl optionally has 1, 2 or 3 substituents R _b ;

R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , C _1-6 -alkyl and C _1-3 -alkoxy, with C _1-6 -alkyl and C _1-3 - alkoxy optionally have 1, 2 or 3 substituents R _c ;

each of R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ and R ₄₅ is independently selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 -alkyl, and C _1-3 -alkyl optionally has 1, 2 or 3 R _d substituents;

R ₅ is selected from the group consisting of R ₅₁ , C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl, with 5-6 membered cycloalkyl and 3-6 membered heterocycloalkyl optionally having 1, 2 or 3 R ₁ substituents;

R ₅₁ is selected from the group consisting of C _1-6 -alkyl and C _1-6 -heteroalkyl, and C _1-6 -alkyl and C _1-6 -heteroalkyl optionally have 1, 2 or 3 Deputy R _e ;

R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-6 -alkyl, -COO-C _1-6 -alkyl and -C _1-3 - alkyl-COO-C _1-6 -alkyl, and C _1-6 -alkyl, -COO-C _1-6 -alkyl and -C _1-3 -alkyl-COO-C _1-6 -alkyl optionally have 1, 2 or 3 substituents R _a ;

each R _a is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-3 alkyl, and C _1-3 alkoxy, with C _1-3 optionally having 1, 2 or 3 substituents R;

each R _b is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each R _c is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 alkyl, with C _1-3 alkyl optionally having 1, 2 or 3 R substituents ;

each R _d is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each Re _is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each R is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

each of C _1-6 heteroalkyl and 3-6 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from the group consisting of -NH-, -O-, -S- and N.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R _a is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH and -OCH ₃ and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R _c is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-3 -alkyl, -COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl, and C _1-3 -alkyl, - COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl optionally have 1, 2, or 3 R _a substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, CH ₃ and Et, with CH ₃ and Et optionally having 1, 2 or 3 R _a substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, CH ₃ , Et, -CH ₂ -COOH and -CH ₂ -OCH ₃ and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₂ is selected from the group consisting of H and C _1-3 alkyl, wherein C _{1 -3} -alkyl optionally has 1, 2, or 3 R _b substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₂ is selected from the group consisting of H, CH ₃ and Et, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ and C _1-3 -alkyl, with C _1-3 -alkyl optionally having 1, 2 or 3 R _c substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CH ₃ , CF ₃ and Et and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, each of the aforementioned R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ and R ₄₅ is independently selected from the group , consisting of H, Cl, F, Br, I, OH, NH ₂ , CN and -COOH, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of C _1-3 -alkyl and C _1-3 - heteroalkyl, with C _1-3 -alkyl and C _1-3 -heteroalkyl optionally having 1, 2 or 3 substituents R _e , and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is selected from the group consisting of methyl, ethyl, propyl, and isopropyl, wherein methyl, ethyl , propyl, and isopropyl optionally have 1, 2, or 3 R _e substituents, and the remaining variables are as defined herein.

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅₁ is

, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ , C _5-6 cycloalkyl, and 5- 6-membered heterocycloalkyl, wherein the 5-6 membered cycloalkyl and 5-6-membered heterocycloalkyl optionally have 1, 2 or 3 R ₁ substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ , cyclohexyl, tetrahydropyranyl, and piperidinyl, wherein cyclohexyl, tetrahydropyranyl and piperidinyl optionally have 1, 2, or 3 R ₁ substituents, and the remaining variables are as defined herein.

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of R ₅₁ ,

,

And

, and the remaining variables are as defined in this document.

,

,

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₅ is selected from the group consisting of

,

,

,

,

And

, and the remaining variables are as defined in this document.

выбрана из группы, состоящей из

,

,

и

, а остальные переменные являются такими, как определено в настоящем документе.In some embodiments of a compound represented by formula (II-B), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned structural unit

selected from the group consisting of

,

,

And

, and the remaining variables are as defined in this document.

The compound represented by formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

,

,

Where

;L selected from

;

E ₁ is selected from the group consisting of -O-, -S- and -NH-;

R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-6 -alkyl, -COO-C _1-6 -alkyl and -C _1-3 - alkyl-COO-C _1-6 -alkyl, and C _1-6 -alkyl, -COO-C _1-6 -alkyl and -C _1-3 -alkyl-COO-C _1-6 -alkyl optionally have 1, 2 or 3 substituents R _a ;

R ₂ is selected from the group consisting of H and C _1-6 -alkyl, and C _1-6 -alkyl optionally has 1, 2 or 3 substituents R _b ;

R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , C _1-6 -alkyl and C _1-3 -alkoxy, with C _1-6 -alkyl and C _1-3 - alkoxy optionally have 1, 2 or 3 substituents R _c ;

each of R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ and R ₄₅ is independently selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 -alkyl, and C _1-3 -alkyl optionally has 1, 2 or 3 R _d substituents;

R _a is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 alkyl, with C _1-3 optionally having 1, 2 or 3 R substituents;

R _b is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

R _c is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN, COOH and C _1-3 alkyl, with C _1-3 optionally having 1, 2 or 3 R substituents;

each R _d is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH;

and each R is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R _a is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R _c is selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, C _1-3 -alkyl, -COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl, and C _1-3 -alkyl, -COO- C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl optionally have 1, 2 or 3 substituents R _a , and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, CH ₃ and Et, with CH ₃ and Et optionally having 1, 2 or 3 substituents R _a , and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₁ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CN, COOH, CH ₃ and Et, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₂ is selected from the group consisting of H and C _1-3 alkyl, wherein C _1-3 -alkyl optionally has 1, 2, or 3 R _b substituents, and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₂ is selected from the group consisting of H, CH ₃ and Et, and the remaining variables are as follows: defined in this document.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ and C _1-3 -alkyl, with C _1-3 -alkyl optionally having 1, 2 or 3 substituents R _c , and the remaining variables are as defined herein.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, the aforementioned R ₃ is selected from the group consisting of H, Cl, F, Br, I, OH, NH ₂ , CH ₃ and Et, and the remaining variables are as defined in this document.

In some embodiments of a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, each of the aforementioned R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ and R ₄₅ is independently selected from the group consisting of of H, Cl, F, Br, I, OH, NH ₂ , CN and -COOH, and the remaining variables are as defined herein.

Some other embodiments of the present application are obtained as a result of any combination of the variables described above.

In some embodiments of the present application, the compounds described above or their stereoisomers or pharmaceutically acceptable salts are selected from the group consisting of

,

,

,

,

,

,

,

,

,

,

,

,

,

,

Where

R ₁ , R ₂ , R ₃ , R ₄₁ , R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ and R ₅₁ are as defined herein.

This application further provides compounds represented by the following formulas, or stereoisomers or pharmaceutically acceptable salts thereof:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

.

In some embodiments of the present application, the compounds described above or their stereoisomers or pharmaceutically acceptable salts are selected from the group consisting of

,

,

,

,

,

,

,

,

,

,

и

.

,

,

,

,

,

,

,

,

,

,

And

.

The present application further provides a pharmaceutical composition containing a therapeutically effective amount of the compounds described above or their stereoisomers or pharmaceutically acceptable salts as an active ingredient and a pharmaceutically acceptable carrier.

The present application further provides the use of the compounds described above, or stereoisomers or pharmaceutically acceptable salts thereof, in the preparation of a nucleoprotein inhibiting medicament.

The present application further proposes the use of the compounds described above or their stereoisomers or pharmaceutically acceptable salts as a nucleoprotein inhibitor.

The present application further provides a method for inhibiting a nucleoprotein, comprising administering to a mammal, preferably a human in need of such treatment or prevention, a therapeutically effective amount of the compounds described above or their stereoisomers or pharmaceutically acceptable salts or a pharmaceutical composition containing them.

The present application further provides the compounds described above, their stereoisomers or pharmaceutically acceptable salts or a pharmaceutical composition containing them for use as a nucleoprotein inhibitor.

In some embodiments of the present application, the aforementioned use is characterized in that the pharmaceutical nucleoprotein inhibitor is a drug for use in the treatment or prevention of diseases associated with HBV infection.

The present application further provides the use of the compounds described above, or stereoisomers or pharmaceutically acceptable salts thereof, in the preparation of a medicament for the treatment or prevention of diseases associated with HBV infection.

The present application further provides the use of the compounds described above, or stereoisomers or pharmaceutically acceptable salts thereof, for the treatment or prevention of diseases associated with HBV infection.

The present application further provides a method for treating diseases associated with HBV infection, comprising administering to a mammal in need of such treatment or prevention, preferably a human, a therapeutically effective amount of the compounds described above or their stereoisomers or pharmaceutically acceptable salts or a pharmaceutical composition containing them.

The present application further provides the compounds described above or their stereoisomers or pharmaceutically acceptable salts or a pharmaceutical composition containing them for use in the treatment or prevention of diseases associated with HBV infection.

Technical results

As a novel hepatitis B drug, the compounds described herein have a marked inhibitory effect on HBV. The compounds disclosed herein exhibit good pharmacokinetic properties in terms of absorption, in vivo distribution, metabolism, etc., eg good in vivo liver targeting. The compounds disclosed herein have a low level of toxic side effects.

Definitions and Description

Unless otherwise noted, the following terms and phrases used in this document have the following meanings. A particular term or a particular phrase, unless expressly stated otherwise, should not be construed as vague or obscure, but should be construed according to its general meaning. When a trade name is mentioned, it is meant to refer to the respective commercial product or its active ingredient.

In the context of this document, the term "pharmaceutically acceptable" is used in relation to those compounds, materials, compositions and/or dosage forms that, from a medical point of view, are suitable for use in contact with human and animal tissues, do not cause excessive toxicity, irritation, allergic response or other problems or complications and are in line with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention as disclosed herein, which is derived from a compound containing certain substituents disclosed herein and a relatively non-toxic acid or base. If a compound disclosed herein contains a relatively acidic functionality, then a base addition salt can be prepared by contacting the neutral form of such compound with a sufficient amount of a base in pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or the like. If a compound disclosed herein contains a relatively basic functional group, then an acid addition salt can be prepared by contacting the neutral form of such compound with a sufficient amount of an acid in pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc. .; as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids (eg, arginine, etc.) and salts of organic acids such as glucuronic acid. Certain specific compounds disclosed herein contain both basic and acidic functional groups that allow the compounds to be converted to either base or acid addition salts.

The compounds described herein may be in the form of a geometric isomer or a stereoisomer. All such compounds are contemplated herein, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)-isomers, (L)- isomers and racemic mixtures and other mixtures thereof, such as an enantiomerically or diastereomerically enriched mixture, all of which are within the scope of this application. Substituents such as alkyl may have an additional asymmetric carbon atom. All such isomers and mixtures thereof are within the scope of this application.

Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" describes the consequence of the inability to freely rotate the double or single bond of the ring carbon atom.

Unless otherwise indicated, the term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of each other.

Unless otherwise noted, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemization.

) и клиновидной пунктирной связью (

), а относительная конфигурация стереогенного центра представлена прямой сплошной связью (

) и прямой пунктирной связью (

). Волнистая линия (

) обозначает клиновидную сплошную связь (

) или клиновидную пунктирную связь (

), или волнистой линией (

) обозначает прямую сплошную связь (

) и прямую пунктирную связь (

).Unless otherwise noted, the absolute configuration of a stereogenic center is represented by a wedge-shaped solid bond (

) and a wedge-shaped dotted bond (

), and the relative configuration of the stereogenic center is represented by a straight line (

) and a direct dotted link (

). Wavy line (

) denotes a wedge-shaped continuous bond (

) or wedge-shaped dotted connection (

), or a wavy line (

) denotes a direct solid connection (

) and a direct dotted connection (

).

), это означает, что соединение существует в форме изомера (Z)-типа, изомера (E)-типа или смеси двух изомеров. Например, представленная далее формула (A) означает, что соединение существует в форме одного изомера, представленного формулой (A-1) или формулой (A-2), или в форме смеси обоих изомеров, представленных формулой (A-1) и формулой (А-2); представленная далее формула (B) означает, что соединение существует в форме одного изомера, представленного формулой (B-1) или формулой (B-2), или в форме смеси обоих изомеров, представленных формулой (B-1) и формулой (В-2); а представленная далее формула (C) означает, что соединение существует в форме одного изомера, представленного формулой (C-1) или формулой (C-2), или в форме смеси обоих изомеров, представленных формулой (C-1) и формулой (C-2).Unless otherwise noted, if a compound has a double bond structure such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each double bond atom is bonded to two different substituents (in a double bond that includes an atom nitrogen, the lone pair of electrons on the nitrogen atom is considered as the substituent to which the nitrogen atom is bonded), if the atom on the double bond of the compound and its substituents are connected using a wavy line (

), which means that the compound exists in the form of a (Z)-type isomer, an (E)-type isomer, or a mixture of two isomers. For example, the following formula (A) means that the compound exists in the form of a single isomer represented by formula (A-1) or formula (A-2), or in the form of a mixture of both isomers represented by formula (A-1) and formula ( A-2); the following formula (B) means that the compound exists in the form of a single isomer represented by formula (B-1) or formula (B-2), or in the form of a mixture of both isomers represented by formula (B-1) and formula (B- 2); and the following formula (C) means that the compound exists in the form of a single isomer represented by formula (C-1) or formula (C-2), or in the form of a mixture of both isomers represented by formula (C-1) and formula (C -2).

(A)

(A-1)

(A-2)

(A)

(A-1)

(A-2)

(B)

(B-1)

(B-2)

(B)

(B-1)

(B-2)

(C)

(C-1)

(C-2)

(C)

(C-1)

(C-2)

The compounds disclosed herein may be present in a specific form. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that the various functional isomers are in dynamic equilibrium at room temperature and can easily be converted into each other. If tautomers are possible (for example, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, a protic tautomer, also known as a prototropic tautomer, includes proton transfer interconversions such as keto-enol isomerization and imine-enamine isomerization. The valence isomer includes an interconversion by rearranging some of the electrons involved in bond formation. A specific example of keto-enol tautomerism is the interconversion between two tautomers: pentan-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise specified, the term "be enriched in one isomer", "enriched in an isomer", "be enriched in one enantiomer", or "enriched in an enantiomer" means that the content of one of the isomers or enantiomers is less than 100% and greater than or equal to 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9 %.

Unless otherwise indicated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomeric or enantiomeric excess ("ee") is 80%.

Optically active (R)- and (S)-isomers and D- and L-isomers can be obtained using chiral synthesis or chiral reagents, or other conventional techniques. The enantiomer of a certain compound of this application described herein can be obtained by asymmetric synthesis or derivatization using a chiral auxiliary, separating the resulting mixture of diastereomers and cleaving off the auxiliary group to obtain the desired pure enantiomer. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), the compound is reacted with the corresponding optically active acid or the corresponding optically active base to form a salt of the diastereoisomer, which is then subjected to diastereomeric separation by conventional in the present field of technology methods to obtain a pure enantiomer. In this case, as a rule, the enantiomer and the diastereoisomer are isolated by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (for example, the formation of carbamate from amines).

A compound disclosed herein may contain an unnatural proportion of an atomic isotope at one or more of the atoms that make up the compound. For example, a compound can be labeled with a radioisotope such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), or C-14 ( ¹⁴ C). In another example, hydrogen can be replaced with deuterium to form a deuterated drug, and the bond formed by deuterium and carbon will be stronger than the bond formed by ordinary hydrogen and carbon. Compared with a non-deuterated drug, a deuterated drug has a number of advantages, which include reduced toxic side effects, increased stability, increased efficacy, increased biological half-life, etc. The scope of this application covers all isotopic variants of the compound described herein, regardless of whether whether they are radioactive or not.

"Optional" or "optional" means that the event or circumstance described below may, but need not, occur, and the description includes cases where such an event or circumstance occurs and cases when it does not.

The term "substituted" means that one or more hydrogen atoms on a particular atom are replaced by substituents, which include options with deuterium and hydrogen, provided that the valence of a particular atom is normal, and the compound after substitution is stable. If the substituent is oxygen (i.e. =O), this means that two hydrogen atoms have been replaced. In aromatic groups, substitution by oxygen does not occur. The term "optionally substituted" means that an atom may or may not be substituted with a substituent. Unless otherwise indicated, the type and amount of substituent may be arbitrary, as long as it is chemically achievable.

When any variable (for example, R) appears in the composition or structure of the compound more than once, the definition of such a variable in each case is independent. Thus, for example, if a group has 0-2 R substituents, the group may optionally be substituted with up to two Rs, and the definition of R is independent in each case. In addition, a combination of a substituent and/or a variant thereof is only acceptable if such a combination can lead to a stable compound.

If there is no substitute, this means that the substitute does not exist. For example, if there is no X in A-X, the A-X structure is in fact of the form A. Unless it is specified by which atom a listed substituent is linked to the group to be substituted, a substituent may be linked through any atom of that group. For example, pyridinyl as a substituent may be linked to the group to be substituted through any carbon atom on the pyridine ring.

представляет собой -M-W-, -M-W- может либо связывать кольцо A и кольцо B с образованием

в направлении, аналогичном порядку чтения слева направо, либо связывать кольцо A и кольцо B с образованием

в направлении, противоположном порядку чтения слева направо. Сочетание замещающей группы, заместителя и/или его варианта допустимо лишь в том случае, если такое сочетание может привести к получению стабильного соединения.If no linking direction is specified for the specified linking group, the linking direction is arbitrary. For example, if the linking group L contained in

is -MW-, -MW- can either link ring A and ring B to form

in a direction similar to the reading order from left to right, or link ring A and ring B to form

in the opposite direction of the reading order from left to right. The combination of a substituent group, a substituent and/or a variant thereof is only acceptable if such a combination can lead to a stable compound.

Unless otherwise stated, the number of atoms in a ring is generally defined as the number of ring members. For example, "5-7 membered ring" refers to a "ring" on which 5 to 7 atoms are arranged in a circle.

Unless otherwise indicated, "3-10 membered ring" refers to cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl consisting of 3-10 ring atoms. The ring may be monocyclic, bicyclic or polycyclic, wherein the bicyclic or polycyclic system includes a spiro ring, a fused ring, an internally bridged ring, and the like. Unless otherwise indicated, the ring optionally contains 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N. A 3-10 membered ring may be 3-10 membered, 3-9 membered, 3- 8-membered, 3-7-membered, 3-6-membered, 3-5-membered, 4-10-membered, 4-9-membered, 4-8-membered, 4-7-membered, 4-6- 4-5-membered, 5-10-membered, 5-9-membered, 5-8-membered, 5-7-membered, 5-6-membered, 6-10-membered, 6-9-membered, 6-8-membered or 6-7-membered ring or the like. The term "5-7 membered heterocycloalkyl" includes piperidinyl and the like, but does not include phenyl. The term "ring" also includes a ring system containing at least one ring, in which each "ring" independently corresponds to the above definition.

Unless otherwise indicated, "5-6 membered ring" refers to cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl consisting of 5-6 ring atoms. The ring may be monocyclic or bicyclic, wherein the bicyclic ring system includes a spiro ring, a fused ring, an internally bridged ring, and the like. Unless otherwise indicated, the ring optionally contains 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N. A 5-6 membered ring includes a 5-membered ring, a 6-membered ring, and the like. "5-6 membered ring" includes, for example, phenyl, pyridinyl, piperidinyl and the like. On the other hand, the term "5-6 membered heterocycloalkyl" includes piperidinyl and the like, but does not include phenyl. The term "ring" also includes a ring system containing at least one ring, in which each "ring" independently corresponds to the above definition.

Unless otherwise indicated, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" may be used interchangeably herein. The term "5-6 membered heteroaryl" refers to a monocyclic group that consists of 5-6 ring atoms and has a pi-electron conjugated system, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from the group , consisting of O, S and N, while the rest are carbon atoms. The nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatom is optionally oxidized (ie NO and S(O) _p where p is 1 or 2). The 5-6 membered heteroaryl may be linked to the rest of the molecule via a heteroatom or carbon atom. 5-6 membered heteroaryl includes 5-membered heteroaryl and 6-membered heteroaryl. Examples of 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.). ), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc. ), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc. .), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl ( including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl, 4 -pyridinyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

Unless otherwise indicated, the term "alkyl" refers to a linear or branched saturated hydrocarbon group. In some embodiments, alkyl is C _1-12 alkyl. In other embodiments, alkyl is C _1-6 alkyl. In still other embodiments, alkyl is C _1-3 alkyl. The alkyl may be monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methenyl). Examples of alkyl include methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like. For example, the term "C _1-10 -alkyl" refers to a linear or branched saturated hydrocarbon group consisting of 1-10 carbon atoms. C _1-10 -alkyl includes, without limitation, C _1-10 -, C _1-9 -, C _1-8 -, C _1-6 -, C _1-5 -, C _1-4 -, C _1-3 -, C _1-2 -, C _2-6 -, C _2-4 -, C ₁₀ -, C ₈ -, C ₇ -, C ₆ - and C ₅ -alkyl and the like, and it may be monovalent ( eg methyl), divalent (eg methylene) or polyvalent (eg methenyl). Examples of C _1-12 alkyl include, without limitation, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl ), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, heptyl, octyl, and the like. For example, the term "C _1-6 -alkyl" refers to a linear or branched saturated hydrocarbon group consisting of 1-6 carbon atoms. C _1-6 -alkyl includes, without limitation, C _1-5 -, C _1-4 -, C _1-3 -, C _1-2 -, C _2-6 -, C _2-4 -, C ₆ - and C ₅ -alkyl and the like, and it can be monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methenyl). Examples of C _1-6 alkyl include, without limitation, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl ), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, and the like. For example, the term "C _1-3 -alkyl" refers to a linear or branched saturated hydrocarbon group consisting of 1-3 carbon atoms. C _1-3 -alkyl includes without limitation C _1-2 - and C _2-3 -alkyl and the like, and it can be monovalent (for example, methyl), divalent (for example, methylene) or polyvalent (for example, methenyl) . Examples of C _1-3 alkyl include, without limitation, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

The term "heteroalkyl", by itself or in combination with another term, refers to a stable linear or branched alkyl radical, or a combination thereof, consisting of a specified number of carbon atoms and at least one heteroatom or at least one heteroatomic group. In some embodiments, the heteroatom is selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatomic group is selected from the group consisting of -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N (H)-. In some embodiments, the heteroalkyl is C _1-6 heteroalkyl. In other embodiments, the heteroalkyl is C _1-3 heteroalkyl. The heteroatom or heteroatomic group may be located at any internal position of the heteroalkyl, including the position where the alkyl is bonded to the rest of the molecule. However, the terms "alkoxy", "alkylamino", and "alkylthio" (or thioalkoxy) are commonly used expressions and refer to those alkyl groups that are bonded to the rest of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Examples of heteroalkyl include, without limitation -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ (CH ₃ ) ₂ , -CH ₂ -CH ₂ -O-CH ₃ , -NHCH ₃ , -N (CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )- CH ₃ , -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ , - S(=O)-CH ₃ and -CH ₂ -CH ₂ -S(=O) ₂ -CH ₃ . A maximum of two heteroatoms can go in series, for example -CH ₂ -NH-OCH ₃ .

Unless otherwise indicated, the term "alkoxy" refers to those alkyl groups, each of which is connected to the rest of the molecule through an oxygen atom. Unless otherwise indicated, C _1-6 -alkoxy includes C ₁ -, C ₂ -, C ₃ -, C ₄ -, C ₅ - and C ₆ -alkoxy. In some embodiments, the alkoxy is C _1-3 alkoxy. Examples of alkoxy include, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, and S-pentyloxy. For example, the term "C _1-3 -alkoxy" refers to those alkyl groups each containing 1-3 carbon atoms and linked to the rest of the molecule through an oxygen atom. C _1-3 -alkoxy includes, without limitation, C _1-2 -, C _2-3 -, C ₃ - and C ₂ -alkoxy and the like. Examples of C _1-3 alkoxy include, without limitation, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise stated, C _n-n+m or C _n -C _n+m includes any particular case involving n to n+m carbohydrates (e.g., C _1-12 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ ) or any case involving a range between n and n+m, (e.g. C _1-12 includes C _1-3 , C _1-6 , C _1-9 , C _3-6 , C _3-9 , C _3-12 , C _6-9 , C _6-12 , C _9-12 and the like). Similarly, n-membered - n+m-membered suggests that the number of atoms per ring is between n and n+m. For example, a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, 11-membered ring and 12-membered ring. Also, n-term - n+m-term includes any occurrence of any range between n and n+m. For example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, 6- to 10-membered ring and the like.

Unless otherwise indicated, the term "cycloalkyl" includes any stable cyclic alkyl, which may be a monocyclic, bicyclic, or tricyclic system, with bicyclic and tricyclic systems including a spiro ring, a fused ring, and an internally bridged ring. In some embodiments, cycloalkyl is C _3-8 cycloalkyl. In other embodiments, the cycloalkyl is C _3-6 cycloalkyl. In still other embodiments, the cycloalkyl is C _5-6 cycloalkyl. Cycloalkyl may be monovalent, divalent or polyvalent. Examples of cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like. For example, "C _3-10 cycloalkyl" refers to a saturated cyclic hydrocarbon group of 3-10 carbon atoms, and it can be a monocyclic, bicyclic, or tricyclic system, wherein the bicyclic and tricyclic systems include a spiro ring, a fused ring, and an inner ring. bridge. C _3-10 -cycloalkyl includes, without limitation, C _3-8 -, C _3-6 -, C _3-5 -, C _4-10 -, C _4-8 -, C _4-6 -, C _4-5 - , C _5-8 - and C _5-6 -cycloalkyl and the like, and it may be monovalent, divalent or polyvalent. Examples of C _3-10 cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like. For example, "C _3-8 cycloalkyl" refers to a saturated cyclic hydrocarbon group of 3-8 carbon atoms, and it can be a monocyclic or bicyclic system, the bicyclic system including a spiro ring, a fused ring, and an internally bridged ring. C _3-8 -cycloalkyl includes, without limitation, C _3-6 -, C _3-5 -, C _4-8 -, C _4-6 -, C _4-5 -, C _5-8 - or C _5-6 - cycloalkyl or the like, and it may be monovalent, divalent or polyvalent. Examples of C _3-8 cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

Unless otherwise indicated, the term "heterocycloalkyl", by itself or in combination with other terms, refers to a cyclized "heteroalkyl" and it can be a monocyclic, bicyclic, or tricyclic system, with bicyclic and tricyclic systems including a spiro ring, a fused ring, and a ring with internal bridge. In addition, with respect to "heterocycloalkyl", the heteroatom may occupy a position where the heterocycloalkyl is bonded to the rest of the molecule. In some embodiments, heterocycloalkyl is 4-6 membered heterocycloalkyl. In other embodiments, heterocycloalkyl is 5-6 membered heterocycloalkyl. Examples of heterocycloalkyl include, without limitation, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.) , morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or oxacycloheptanyl. For example, the term "3-6 membered heterocycloalkyl", by itself or in combination with other terms, refers to a saturated cyclic group consisting of 3-6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, independently selected from the group consisting of O, S, and N, with the remainder being carbon atoms. The nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie NO and S(O) _p where p is 1 or 2). The "3-6 membered heterocycloalkyl" may be a monocyclic or bicyclic system, wherein the bicyclic system includes a spiro ring, a fused ring, and an internally bridged ring. Moreover, with respect to "3-6 membered heterocycloalkyl", the heteroatom may occupy the position where the heterocycloalkyl is bonded to the rest of the molecule. 3-6-membered heterocycloalkyl includes, without limitation, 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl and the like. Examples of 3-6 membered heterocycloalkyl include, without limitation, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl and etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianil, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl etc. For example, the term "4-6 membered heterocycloalkyl", by itself or in combination with other terms, refers to a saturated cyclic group consisting of 4-6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. , independently selected from the group consisting of O, S, and N, with the rest being carbon atoms. The nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie NO and S(O) _p where p is 1 or 2). The "4-6 membered heterocycloalkyl" may be a monocyclic or bicyclic system, wherein the bicyclic system includes a spiro ring, a fused ring, and an internally bridged ring. Moreover, with respect to "4-6 membered heterocycloalkyl", the heteroatom may occupy the position where the heterocycloalkyl is bonded to the rest of the molecule. 4-6 membered heterocycloalkyl includes, without limitation, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl and the like. Examples of 4-6 membered heterocycloalkyl include, without limitation, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl and etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianil, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl etc. For example, the term "5-6 membered heterocycloalkyl", by itself or in combination with other terms, refers to a saturated cyclic group of 5-6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. , independently selected from the group consisting of O, S, and N, with the rest being carbon atoms. The nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie NO and S(O) _p where p is 1 or 2). The "5-6 membered heterocycloalkyl" may be a monocyclic or bicyclic system, wherein the bicyclic system includes a spiro ring, a fused ring, and an internally bridged ring. Moreover, with respect to "5-6 membered heterocycloalkyl", the heteroatom may occupy the position where the heterocycloalkyl is bonded to the rest of the molecule. 5-6 membered heterocycloalkyl includes 5-membered heterocycloalkyl and 6-membered heterocycloalkyl. Examples of 5-6 membered heterocycloalkyl include, without limitation, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl and etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.

The term "pharmaceutically acceptable carrier" refers to any agent or any carrier medium that is capable of delivering an effective amount of the active substance disclosed herein, does not adversely affect the biological activity of the active substance, and does not cause a toxic side effect on the individual or patient receiving them. . Typical carriers include water, oil, vegetable and mineral, cream base, lotion base, ointment base, and the like. These bases include a suspending agent, a thickening agent, a penetration enhancer, and the like. Formulations containing them are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

The term "adjuvant" generally refers to a carrier, diluent and/or vehicle that is necessary to formulate an effective pharmaceutical composition.

The word "comprise" and its variants such as "comprises" or "comprising" are to be understood in an open, non-exclusive sense, i.e. "including without limitation".

The term "treatment" means the administration of a compound or formulation as described herein to relieve or eliminate a disease or one or more of the symptoms associated with that disease, and includes:

(i) suppression of the disease or disease state, ie. stop its development;

(ii) alleviate the disease or disease state, i. e. induction of his regression.

The term "prevention" means administering a compound or formulation as described herein to prevent a disease or one or more of the symptoms associated with that disease, and includes preventing the onset of a disease or condition in a mammal, especially when such mammal is predisposed to developing the disease but is still he was not diagnosed.

In the case of drugs and pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to the amount of drug or drug product that is sufficient to achieve the desired effect, but is not toxic. With regard to the oral dosage form disclosed herein, an "effective amount" of one active ingredient in a composition is the amount necessary to achieve the desired effect when the active agent is used in combination with another active agent in the composition. The result of determining the effective amount varies for different people depending on the age and general condition of the subject, as well as depending on the specific active substance. In one case, a suitable effective amount can be determined by a person skilled in the art based on the results of standard tests.

The term “active ingredient,” “therapeutic agent,” “active ingredient,” or “active agent” refers to a chemical that is effective in treating the target disorder, disease, or condition.

The compounds disclosed herein can be prepared by a number of synthetic routes that are well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combinations with other chemical synthesis methods, and their equivalents known to those skilled in the art. Preferred embodiments include, without limitation, the examples disclosed herein.

The solvent used herein may be commercially available. In this application, the following abbreviations are used: aq. means water; HATU is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC means N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA means 3-chloroperoxybenzoic acid; equiv. means equivalent or equivalence; CDI means carbonyldiimidazole; DCM means dichloromethane; PE stands for petroleum ether; DIAD means diisopropyl azodiformate; DMF means N,N-dimethylformamide; DMSO means dimethyl sulfoxide; EtOAc means ethyl acetate; EtOH means ethanol; MeOH means methanol; CBz is benzyloxycarbonyl, an amino protecting group; BOC is t-butoxycarbonyl, which is an amino protecting group; HOAc means acetic acid; NaCNBH ₃ is sodium cyanoborohydride; k.t. means room temperature; O/N means during the night; THF means tetrahydrofuran; Boc ₂ O is di-tert-butyl dicarbonate; TFA means trifluoroacetic acid; DIPEA means diisopropylethylamine; SOCl ₂ means thionyl chloride; CS ₂ means carbon disulfide; TsOH means p-toluenesulfonic acid; NFSI means N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS means N-chlorosuccinimide; n-Bu ₄ NF means tetrabutylammonium fluoride; iPrOH means 2-propanol; mp is the melting point; LDA means lithium diisopropylamide; POCl ₃ means phosphorus oxychloride; LiHMDS means lithium hexamethyldisilazide; DCE means dichloroethane; DIEA means N,N-diisopropylethylamine; MTBE means methyl tert-butyl ether; TEA means triethylamine; DIPEA means N,N-diisopropylethylamine; and LLOQ is the lower limit of quantitation.

Brief description of the drawings

Fig. 1: Plasma levels of HBV DNA;

Fig. 2: HBV DNA levels in the liver.

Detailed description

The present application is described in more detail below with the help of examples. However, this is in no way intended to prejudice the scope of the present application. Although the present application has been described in detail herein, and specific examples have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to these specific examples without departing from the spirit and scope of the present application.

Example 1

Synthesis path:

Stage 1

A solution of acetic anhydride (150 ml) in formic acid (100 ml) was added to a solution of compound 1-1 (15 g, 130.29 mmol, 1 eq.) in formic acid (150 ml) at 0°C. The mixture was stirred at 25° C. for 16 hours. The reaction solution was concentrated under reduced pressure to give compound 1-2, which was used directly in the next step.

¹ H NMR (400 MHz, MeOH-d4) δ = 11.51 (br s, 1H), 8.40-7.97 (m, 1H), 4.64-4.36 (m, 1H), 3 .78-3.46 (m, 2H), 2.38-2.13 (m, 2H), 2.10-1.89 (m, 2H).

Stage 2

Methyl propionate (35.24 g, 419.17 mmol, 34.89 ml, 6 eq.) in a 250 ml flask was added to a solution of compound 1-2 (10 g, 69.86 mmol, 1 eq.) in acetic anhydride ( 100 ml). The mixture was stirred at 130° C. for 6 hours. The reaction solution was concentrated under reduced pressure to obtain compound 1-3. MS (ESI) m/z: 165.8 [M+H] ⁺ .

¹ H NMR (400 MHz, MeOH-d4) δ = 6.61 (d, J=2.8 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 3.97 (t, J =7.2 Hz, 2H), 3.79 (s, 3H), 3.06 (t, J=7.4 Hz, 2H), 2.54 (quin, J=7.3 Hz, 2H).

Stage 3

Oxalyl chloride (535.10 mg, 4.22 mmol, 369.03 μl, 2 eq.) was added to a solution of compound 1-3 (500 mg, 2.11 mmol, 1 eq.) in dichloromethane (5 ml) at 0° C under nitrogen atmosphere, and then added N,N-dimethylformamide (0.05 ml). The mixture was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 1-4, which was used directly in the next step.

Stage 4

Triethylamine (870.23 mg, 8.60 mmol, 1.20 ml, 4 eq.) was added to a solution of compound 1-4 (550 mg, 2.15 mmol, 1 eq.) in dichloromethane (10 ml) and then compound 1-5 (247.62 mg, 2.15 mmol, 1 eq.) was added. The mixture was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was separated using a COMBI-FLASH automatic chromatography system (petroleum ether:ethyl acetate = 100:0 to 80:20, v/v) to obtain compound 1-6. MS (ESI) m/z: 357.2 [M+Na] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.23 (s, 1H), 7.10 (br s, 1H), 4.28 (t, J=7.3 Hz, 2H), 3.73 (s, 3H), 3.69-3.66 (m, 2H), 3.60-3.52 (m, 2H), 3.05 (t, J=7.7 Hz, 2H), 2, 52 (q, J=7.5 Hz, 2H), 2.06 (br d, J=13.8 Hz, 2H), 1.68 (m, 2H), 1.42 (s, 3H).

Stage 5

A solution of lithium hydroxide monohydrate (131.78 mg, 3.14 mmol, 3 eq.) in H ₂ O (1 ml) was added to a solution of compound 1-6 (350 mg, 1.05 mmol, 1 eq.) in tetrahydrofuran ( 5 ml). The mixture was stirred at 30° C. for 12 hours. The reaction solution was adjusted to pH=1-2 with 2 mol/l diluted hydrochloric acid and extracted with ethyl acetate (10 ml×2). The combined organic phases were washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 1-7. MS (ESI) m/z: 343.2 [M+Na] ⁺ .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 7.89 (s, 1H), 4.37 (br d, J=7.0 Hz, 2H), 3.70-3.63 (m, 2H), 3.14-3.10(m, 2H), 2.66-2.52(m, 4H), 2.25-2.19(m, 2H), 1.73-1.67( m, 2H), 1.49 (s, 3H).

Stage 6

Oxalyl chloride (237.74 mg, 1.87 mmol, 163.96 μl, 2 eq.) was added to a solution of compound 1-7 (300 mg, 936.51 μmol, 1 eq.) in dichloromethane (3 ml) at 0° C under nitrogen atmosphere, and then added N,N-dimethylformamide (0.01 ml). The mixture was stirred at 20°C for 1 h to obtain compound 1-8.

Stage 7

Triethylamine (358.42 mg, 3.54 mmol, 493.01 μl, 4 eq.) was added to a solution of compound 1-8 (300 mg, 885.52 μmol, 1 eq.) in dichloromethane (5 ml) under atmospheric conditions nitrogen, and then compound 1-9 (114.33 mg, 885.52 µmol, 1 eq.) was added. The mixture was stirred at 20° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated using a COMBI-FLASH automatic chromatography system (petroleum ether: ethyl acetate = 100:0 to 50:50, v/v .) to give compound 1. MS (ESI) m/z: 432.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.18 (s, 1H), 7.73-7.64 (m, 1H), 7.59 (s, 1H), 7.23 (s, 1H ), 7.09-7.02 (m, 2H), 4.31 (t, J=7.3 Hz, 2H), 3.71 (td, J=4.3, 12.0 Hz, 2H) , 3.62-3.52 (m, 2H), 3.21-3.12 (m, 2H), 2.63-2.50 (m, 2H), 2.07 (br d, J=14 .1 Hz, 2H), 1.70 (ddd, J=4.3, 9.9, 14.0 Hz, 2H), 1.43 (s, 3H).

Example 2

Synthesis path:

Stage 1

N-chlorosuccinimide (77.87 mg, 583.19 µmol, 1.3 eq) was added to a solution of compound 1-6 (150 mg, 448.61 µmol, 1 eq) in acetonitrile (10 ml). The mixture was stirred at 40° C. for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was separated using a COMBI-FLASH automatic chromatography system (petroleum ether:ethyl acetate = 100:0 to 80:20, v/v) to obtain compound 2-1. MS (ESI) m/z: 369.1 [M+H] ⁺ .

Stage 2

A solution of lithium hydroxide monohydrate (34.13 mg, 813.42 µmol, 5 eq.) in H ₂ O (0.5 ml) was added to a solution of compound 2-1 (60 mg, 162.68 µmol, 1 eq.) in ethanol (2 ml). The mixture was stirred at 40°C for 3 hours. The reaction solution was adjusted to pH = 1-2 with 2 mol/l diluted hydrochloric acid and extracted with ethyl acetate (10 ml×2). The combined organic phases were washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound 2-2. MS (ESI) m/z: 377.1 [M+Na] ⁺ .

Stage 3

Oxalyl chloride (28.62 mg, 225.49 µmol, 19.74 µl, 2 equiv.) was added to a solution of compound 2-2 (40 mg, 112.74 µmol, 1 equiv.) in dichloromethane (2 ml) at 0° C under nitrogen atmosphere, and then added N,N-dimethylformamide (0.01 ml). The mixture was stirred at 25° C. for 45 minutes. The reaction solution was concentrated under reduced pressure to obtain compound 2-3.

Stage 4

Triethylamine (43.38 mg, 428.69 µmol, 59.67 µl, 4 eq) was added to a solution of compound 2-3 (40 mg, 107.17 µmol, 1 eq) in dichloromethane (3 ml) under atmospheric conditions nitrogen. Compound 1-9 (13.84 mg, 107.17 µmol, 1 eq) was then added. The mixture was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative HPLC (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: water (containing 0.225% formic acid )-acetonitrile, % acetonitrile: 73%-83%, 7 min) to give compound 2. MS (ESI) m/z: 466.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.40 (s, 1H), 7.72-7.61 (m, 1H), 7.11-6.99 (m, 2H), 6.23 (s, 1H), 4.25 (t, J=7.4Hz, 2H), 3.80-3.57 (m, 4H), 3.19 (t, J=7.7Hz, 2H) , 2.46 (quin, J=7.5 Hz, 2H), 2.08 (br d, J=14.1 Hz, 2H), 1.73 (ddd, J=4.4, 9.6, 13.9 Hz, 2H), 1.48(s, 3H).

Example 3

Synthesis path:

Stage 1

Compound 1-6 (300 mg, 897.22 µmol, 1 eq) and acetonitrile (3 mL) were added to a fluted-necked bottle, followed by N-bromosuccinimide (191.62 mg, 1.08 mmol, 1. 2 eq.). The mixture was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was separated using a COMBI-FLASH automatic chromatography system (petroleum ether:ethyl acetate = 100:0 to 80:20, v/v) to obtain compound 3-1. MS (ESI) m/z: 435.0 [M+Na] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.30 (t, J=7.4 Hz, 2H), 3.83 (s, 3H), 3.80-3.67 (m, 4H), 3.13 (t, J=7.7 Hz, 2H), 2.50 (q, J=7.5 Hz, 2H), 2.15 (d, J=14.1 Hz, 2H), 1, 78 (m, 2H), 1.55 (s, 3H).

Stage 2

Compound 3-1 (100 mg, 241.98 µmol, 1 eq.), methylboric acid (28.97 mg, 483.95 µmol, 2 eq.), potassium carbonate (100 .33 mg, 725.93 µmol, 3 eq.), 1,4-dioxane (2.5 ml) and water (0.5 ml), and then Pd(dppf)Cl ₂ (17.71 mg, 24 .20 µmol, 0.1 eq.). The mixture was stirred at 80° C. for 2 hours. Water (5 ml) was added to the reaction solution and extracted with ethyl acetate (10 ml×3). The combined organic phases were washed with dilute hydrochloric acid (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 3-2. MS (ESI) m/z: 348.9 [M+H] ⁺ .

Stage 3

Compound 3-2 (80 mg, 229.63 µmol, 1 eq.) and ethanol (2 ml) were added to a fluted bottle, followed by sodium hydroxide solution (27.56 mg, 688.88 µmol, 3 eq. ) in water (0.5 ml). The mixture was stirred at 25° C. for 12 hours. Water (5 ml) was added to the reaction solution and washed with ethyl acetate (5 ml). The aqueous phase was adjusted to pH = 1-2 with 2 mol/l dilute hydrochloric acid and extracted with ethyl acetate (10 ml x 2). The combined organic phases were washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 3-3.

Stage 4

Oxalyl chloride (26.57 mg, 209.35 µmol, 18.33 µl, 1 eq.) was added to a solution of compound 3-3 (70 mg, 209.35 µmol, 1 eq.) in dichloromethane (3 ml) at 0° C and then N,N-dimethylformamide (15.30 mg, 209.35 µmol, 16.11 µl, 1 eq.) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 3-4.

Stage 5

Triethylamine (86.04 mg, 850.31 µmol, 118.35 µl, 4 eq.) was added to a solution of compound 3-4 (75 mg, 212.58 µmol, 1 eq.) in dichloromethane (3 ml) and then compound 1-9 (27.45 mg, 212.58 µmol, 1 eq) was added. The mixture was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was separated by preparative HPLC chromatography (column: Boston Green ODS 150 mm × 30 mm × 5 μm; mobile phase: water (containing 0.075% trifluoroacetic acid)-acetonitrile; % acetonitrile content: 47% - 67%, 7 min) c obtaining compound 3. MS (ESI) m/z: 446.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.76-7.66 (m, 1H), 7.37 (s, 1H), 7.19-7.05 (m, 1H), 6.64 -6.46 (m, 1H), 6.56 (s, 1H), 4.30 (t, J=7.3 Hz, 2H), 3.87-3.76 (m, 2H), 3, 75-3.66 (m, 2H), 3.15 (t, J=7.5 Hz, 2H), 2.62-2.52 (m, 5H), 2.15 (d, J=13, 8 Hz, 2H), 1.81 (m, 2H), 1.56 (s, 3H).

Example 4

Synthesis path:

Stage 1

Diisopropylamine (49.91 g, 493.22 mmol, 69.71 ml, 1.2 eq.) was dissolved in tetrahydrofuran (1000 ml) and then n-butyllithium (2.5 M, 197.29 ml, 1, 2 equiv.) at -78°C. After stirring for 0.5 h, compound 4-1 (100 g, 411.02 mmol, 1 eq.) was added at -78°C. After stirring for another 0.5 h, iodomethane (58.34 g, 411.02 mmol, 25.59 ml, 1 eq.) was added at -78°C. The reaction system was stirred at 25° C. for 16 hours. The reaction solution was poured into 1 L of saturated ammonium chloride solution to stop the reaction, and extracted with ethyl acetate (500 ml×4). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4-2.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.79-3.73 (m, 2H), 3.70 (s, 3H), 2.99 (t, J=11.2 Hz, 2H), 2.07-2.04 (m, 2H), 1.45 (s, 9H), 1.40-1.33 (m, 2H), 1.20 (s, 3H).

Stage 2

Compound 4-2 (107 g, 415.81 mmol, 1 eq.) was dissolved in water (500 ml) and ethanol (1000 ml) and then potassium hydroxide (116.65 g, 2.08 mol, 5 eq. ). The reaction system was stirred at 25°C for 16 hours. According to the results of TLC (dichloromethane : methanol = 20:1) it was seen that the compound 4-2 was completely consumed and new spots were obtained. The reaction solution was concentrated under reduced pressure at 40° C. to remove the solvent, and the residue was extracted with 500 ml of ethyl acetate. The aqueous phase was adjusted to pH = 3-5 with 1 M hydrochloric acid and extracted with ethyl acetate (1 L×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4-3.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 3.77 (td, J=4.0, 13.8 Hz, 2H), 3.02 (s, 2H), 2.05-2.00 (m, 2H), 1.45 (s, 9H), 1.38-1.31 (m, 2H), 1.22 (s, 3H).

Stage 3

Compound 4-3 (10 g, 41.10 mmol, 1 eq) was dissolved in toluene (100 ml) and then triethylamine (4.99 g, 49.32 mmol, 6.87 ml, 1.2 eq) was added. ) and benzyl alcohol (6.67 g, 61.65 mmol, 6.41 ml, 1.5 eq.). Diphenylphosphoryl azide (16.97 g, 61.65 mmol, 13.36 ml, 1.5 eq.) was then added at 25° C. under nitrogen atmosphere. The reaction system was stirred at 110° C. for 3 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that compound 4-3 was completely consumed and new spots were obtained. The reaction solution was poured into 100 ml of a saturated ammonium chloride solution to stop the reaction, and then extracted with ethyl acetate (50 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 5:1, v/v). The purified product was concentrated under reduced pressure to give compound 4-4.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.34-7.30 (m, 3H), 7.20-7.17 (m, 2H), 4.70-4.64 (m, 2H) , 3.64 (s, 2H), 3.37-3.21 (m, 2H), 1.95 (s, 2H), 1.62-1.51 (m, 2H), 1.46 (s , 9H), 1.38 (s, 3H).

Stage 4

Compound 4-4 (14 g, 40.18 mmol, 1 eq.) was dissolved in methanol (150 ml) and then a wet carbon-supported palladium catalyst (5 g, 10% content) was added. The reaction system was stirred at 25° C. for 6 hours under hydrogen atmosphere (50 psi). According to the results of TLC (dichloromethane : methanol = 10:1) it was seen that the compound 4-4 was completely consumed and new spots were obtained. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica gel, pore size 100-200 mesh, dichloromethane:methanol = 10:1 to 5:1, v/v) and concentrated under reduced pressure to obtain compound 4-5.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.02 (br s, 2H), 3.59-3.49 (m, 4H), 1.98-1.51 (m, 4H), 1, 46-1.44 (m, 12H).

Stage 5

Compound 1-3 (20 g, 121.07 mmol, 1 eq) was dissolved in DCM (400 mL) in a single-necked dry flask. Compound 4-6 (29.66 g, 242.15 mmol, 22.30 ml, 2 eq.) was added dropwise at 0° C. under nitrogen atmosphere. The reaction system was stirred at 20° C. for 16 hours. According to the results of LCMS, it was seen that the reaction was complete. The reaction solution was poured into 100 ml of water. Then the aqueous phase was extracted with DCM (20 ml x3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 1:1, v/v) to obtain compound 4-7. MS(ESI) m/s: 252.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.76 (s, 1H), 4.38 (t, J=7.6 Hz, 2H), 3.93 (s, 3H), 3.82 ( s, 3H), 3.14-3.10 (m, 2H), 2.62-2.55 (m, 2H).

Stage 6

Compound 4-7 (5 g, 19.90 mmol, 1 eq.) in a dry 50 ml single neck flask was dissolved in acetonitrile (100 ml) and then N-chlorosuccinimide (3.59 g, 26.87 mmol) was added , 1.35 equiv.). The reaction system was stirred at 40° C. for 16 hours. According to the results of LCMS and TLC (petroleum ether : ethyl acetate = 3:1) it was seen that the reaction was complete. The reaction solution was poured into a saturated sodium bicarbonate solution (200 ml) and then concentrated under reduced pressure to remove acetonitrile. The aqueous phase was extracted with dichloromethane (50 ml×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 3:1, v/v) to give compound 4-8. MS(ESI) m/s: 286.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.40 (t, J=7.6 Hz, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.15 ( t, J=7.6 Hz, 2H), 2.59-2.49 (m, 2H).

Stage 7

Compound 4-8 (2.5 g, 8.75 mmol, 1 eq.) was added to a mixture of tetrahydrofuran (40 ml), ethanol (10 ml) and water (10 ml) at 20°C, and then the reaction system was added potassium carbonate (3.63 g, 26.25 mmol, 3 eq.). The reaction system was stirred at 45° C. for 12 hours. TLC (petroleum ether:ethyl acetate = 2:1) showed that the reaction was complete. 100 ml of water was added to the reaction solution, adjusted to pH=3 with 1 mol/l hydrochloric acid, and extracted with ethyl acetate (50 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4-9.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.29 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.05 (t, J=7.6 Hz, 2H), 2.48-2.40 (m, 2H).

Stage 8

Compound 4-9 (0.4 g, 1.47 mmol, 1 eq.), N,N-diisopropylethylamine (380.61 mg, 2.94 mmol, 512.95 µl, 2 eq.) and O-( 7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (1.68 g, 4.42 mmol, 3 eq.) was dissolved in tetrahydrofuran (10 ml). After stirring for 0.5 h, compound 4-5 (473.34 mg, 2.21 mmol, 1.5 eq.) was added. The reaction system was stirred at 25° C. for 1 hour. TLC (petroleum ether:ethyl acetate = 1:1) showed that compound 4-9 was completely consumed and new spots were obtained. The results of LCMS confirmed the receipt of compound 4-10. The reaction solution was poured into a saturated ammonium chloride solution (20 ml) to stop the reaction, and then extracted with ethyl acetate (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 1:1, v/v) and concentrated under reduced pressure to obtain compound 4-10. MS(ESI) m/s: 412.1 [M+H-(tert-Bu)] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.03 (s, 1H), 4.32 (t, J=7.2 Hz, 2H), 3.85 (s, 3H), 3.70 ( s, 2H), 3.25-3.12 (m, 4H), 2.54-2.47 (m, 2H), 1.69-1.62 (m, 4H), 1.52 (s, 3H), 1.47(s, 9H).

Stage 9

Compound 4-10 (0.5 g, 1.07 mmol, 1 eq.) was dissolved in a mixture of methanol (5 ml), tetrahydrofuran (5 ml) and water (5 ml), and then lithium hydroxide monohydrate (134.52 mg, 3.21 mmol, 3 eq.). The reaction system was stirred at 25°C for 3 hours. According to the results of TLC (dichloromethane : methanol = 10:1) it was seen that the compound 4-10 was completely consumed and new spots were obtained. The reaction solution was adjusted to pH = 1-3 with 1 mol/l hydrochloric acid and extracted with ethyl acetate (15 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4-11.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 4.36 (t, J=7.2 Hz, 2H), 3.72-3.67 (m, 2H), 3.24 (s, 2H ), 3.13 (t, J=4.4 Hz, 2H), 2.56-2.48 (m, 2H), 2.20 (d, J=13.6 Hz, 2H), 1.60 -1.53(m, 2H), 1.49(s, 3H), 1.46(s, 9H).

Stage 10

Compound 4-11 (0.38 g, 837.16 µmol, 1 eq.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (954.94 mg, 2.51 mmol, 3 eq.) and triethylamine (254.14 mg, 2.51 mmol, 349.57 μl, 3 eq.) were dissolved in N,N-dimethylformamide (10 ml). After stirring at 25° C. for 0.5 h, compound 1-9 (216.17 mg, 1.67 mmol, 2 eq.) was added. The reaction system was stirred at 55° C. for 5 h, then heated to 70° C. and stirred for 1 h. TLC (petroleum ether : ethyl acetate = 1:1) showed that compound 4-11 was completely consumed and new spots were obtained. The LCMS results confirmed that compound 4-11 was completely consumed and compound 4-12 was obtained. The reaction was stopped with 20 ml of water, and then the reaction solution was extracted with ethyl acetate (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 1:1, v/v) and concentrated under reduced pressure to obtain compound 4-12. MS(ESI) m/s: 465.1 [M-Boc+H] ⁺ .

Stage 11

Compound 4-12 (0.3 g, 530.97 µmol, 1 eq) was dissolved in ethyl acetate (15 ml) and then hydrochloric acid/ethyl acetate (4 mol/l, 5 ml, 37.67 eq) was added. The reaction system was stirred at 25° C. for 0.5 h. TLC (petroleum ether:ethyl acetate = 1:1) showed that compound 4-12 was completely consumed and new spots were obtained. The reaction solution was concentrated under reduced pressure to obtain compound 4-13.

Stage 12

Compound 4-13 (0.2 g, 430.21 µmol, 1 eq.) was dissolved in tetrahydrofuran (10 ml) and then triethylamine (174.13 mg, 1.72 mmol, 239.52 µl, 4 eq. ) and compound 4-14 (83.91 mg, 430.21 µmol, 63.57 µl, 1 eq.). The reaction system was stirred at 25° C. for 1 hour. LCMS showed that compound 4-13 was completely consumed and compound 4-15 was obtained. 20 ml of water was added to the reaction solution to stop the reaction, and extracted with ethyl acetate (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4-15. MS(ESI) m/s: 579.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.49 (s, 1H), 7.77-7.72 (m, 1H), 7.15-7.09 (m, 2H), 6.20 (s, 1H), 4.33 (t, J=7.6 Hz, 2H), 3.27 (t, J=7.2 Hz, 2H), 3.14 (s, 2H), 2.78 -2.75 (m, 2H), 2.57-2.44 (m, 4H), 2.20-2.16 (m, 2H), 1.89-1.84 (m, 2H), 1 .52 (s, 3H), 1.47 (s, 9H).

Stage 13

Compound 4-15 (0.2 g, 345.40 µmol, 1 eq.) was dissolved in dichloromethane (10 ml) and then trifluoroacetic acid (7.70 g, 67.53 mmol, 5 ml, 195.51 eq. .). The reaction system was stirred at 25°C for 0.5 h. The results of LCMS and HPLC confirmed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Xtimate C18 150 mm×25 mm×5 µm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 22% - 42% , 10.5 min) to give compound 4. MS(ESI) m/s: 523.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.95 (s, 1H), 8.40 (s, 1H), 7.87-7.82 (m, 1H), 7.43-7 .39 (m, 2H), 4.29 (t, J=7.2 Hz, 2H), 3.18 (s, 2H), 3.09 (t, J=7.6 Hz, 2H), 2 .88-2.71 (m, 4H), 2.46-2.43 (m, 2H), 2.18 (d, J=14.0 Hz, 2H), 1.73 (t, J=10 .0 Hz, 2H), 1.39 (s, 3H).

Example 5

Synthesis path:

Stage 1

Compound 2-2 (0.13 g, 366.42 µmol, 1 eq.), triethylamine (55.62 mg, 549.63 µmol, 76.50 µl, 1.5 eq.) and O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (167.19 mg, 439.70 µmol, 1.2 eq.) was dissolved in N,N-dimethylformamide (3 ml). After stirring at 25° C. for 0.5 h, compound 5-1 (99.76 mg, 732.84 µmol, 2 eq.) was added. The reaction system was heated to 70°C and stirred for 3 hours. The results of LCMS and HPLC confirmed that compound 2-2 was completely consumed and compound 5 was obtained. 2 drops of water were added to the reaction solution to stop the reaction, and then filtered. The filtrate was purified by preparative HPLC (neutral system; column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 30% - 50%, 5 min) to give compound 12. MS(ESI) m/s: 473.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.05 (s, 1H), 8.42 (s, 1H), 8.18 (dd, J=2.8, 5.8 Hz, 1H ), 7.97 (ddd, J=2.8, 5.0, 9.2 Hz, 1H), 7.52 (t, J=9.2 Hz, 1H), 4.30 (t, J= 7.2 Hz, 2H), 3.65-3.53 (m, 4H), 3.10 (t, J=7.6 Hz, 2H), 2.48-2.41 (m, 2H), 2.07 (d, J=13.6 Hz, 2H), 1.56 (ddd, J=4.8, 8.8, 13.6 Hz, 2H), 1.40 (s, 3H).

Example 6

Synthesis path:

Stage 1

Compound 6-1 (10 g, 77.43 mmol, 1 eq) was dissolved in a mixture of acetic anhydride (40 ml) and formic acid (60 ml). The reaction mixture was reacted at 100° C. for 16 h under nitrogen atmosphere. Compound 6-2 was observed by LCMS. The reaction solution was immediately concentrated under reduced pressure to obtain compound 6-2.

Stage 2

Compound 6-2 (12.10 g, 77 mmol, 1 eq.) was dissolved in acetic anhydride (120 ml) and then methyl propiolate (32.37 g, 385.00 mmol, 32.05 ml, 5 equiv.). The entire reaction system was reacted at 120° C. for 16 h under nitrogen atmosphere. Compound 6-3 was observed by LCMS. The reaction solution was immediately concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 50:1 to 5:1, v/v) to give the compound 6-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.36 (d, J=3.2 Hz, 1H), 6.30 (d, J=3.2 Hz, 1H), 3.95-3, 90 (m, 2H), 3.78 (s, 3H), 3.10-3.05 (m, 2H), 1.96-1.93 (m, 2H), 1.85-1.83 ( m, 2H).

Stage 3

Compound 6-3 (0.5 g, 2.79 mmol, 1 eq.) was added to a corrugated bottle with dichloroethane (5 ml). The reaction system was cooled to 0°C, and then methyl oxalyl chloride (512.69 mg, 4.18 mmol, 385.48 μl, 1.5 eq.) was added dropwise to the reaction system. The reaction in the reaction system was carried out at 0° C. for 1 hour, and according to the results of TLC (petroleum ether:ethyl acetate = 3:1), it was seen that the compound 6-3 was almost completely consumed. The reaction solution was poured into ice-cold saturated sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (20 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 100:0 to 10:1, v/v) to obtain compound 6-4. MS(ESI) m/s: 266.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.68 (s, 1H), 4.40 (t, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.84 ( s, 3H), 3.17 (t, J=6.0 Hz, 2H), 2.05-1.94 (m, 2H), 1.91-1.81 (m, 2H).

Stage 4

Compound 6-4 (0.3 g, 1.13 mmol, 1 eq.) was added to a corrugated bottle with ethanol (5 ml) and water (2 ml) at 25°C, and then potassium carbonate was added to the reaction system (468.93 mg, 3.39 mmol, 3 eq.). The reaction system was stirred at 25° C. for 1 hour. TLC (petroleum ether:ethyl acetate = 2:1) showed that compound 6-4 was completely consumed. The reaction solution was extracted with methyl tert-butyl ether (20 ml×2), adjusted to pH=3 with 1 M hydrochloric acid, and then extracted with ethyl acetate (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 6-5.

Stage 5

Compound 1-5 (55.01 mg, 477.64 µmol, 1.2 eq.) was added to a flask with dichloroethane (3 ml) at 20°C, and then hexafluorophosphate O-(7-azabenzotriazole-1 -yl)-N,N,N',N'-tetramethyluronium (227.02 mg, 597.05 µmol, 1.5 eq) and N,N-diisopropylethylamine (154.33 mg, 1.19 mmol, 207 .99 µl, 3 eq.). After this, the reaction was carried out in the reaction system at 0°C for 10 min, compound 6-5 (0.1 g, 398.03 μmol, 1 eq.) was dissolved in dichloroethane (3 ml) and added dropwise to the reaction system. The resulting reaction system was reacted at 20°C for 20 min, and the results of LCMS showed the receipt of compound 6-6. The reaction solution was washed with saturated ammonium chloride solution (10 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1, v/v) to give compound 6-6.

MS(ESI) m/s: 349.1 [M+H] ⁺ .

Stage 6

Compound 6-6 (0.1 g, 287.03 µmol, 1 eq.) was added to a fluted bottle with tetrahydrofuran (2 ml), ethanol (2 ml) and water (2 ml), and then the reaction system was added lithium hydroxide monohydrate (48.18 mg, 1.15 mmol, 4 eq.). The reaction system was stirred at 20° C. for 1 hour. TLC (petroleum ether:ethyl acetate = 2:1) showed that compound 6-6 was completely consumed. The reaction solution was diluted with 10 ml of water, adjusted to pH=3 with 1 M hydrochloric acid, and extracted with ethyl acetate (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 6-7.

Stage 7

Compound 1-9 (42.28 mg, 327.49 µmol, 1.5 eq.) was added to a dichloromethane (2 ml) fluted bottle at 20°C, and then the reaction system was cooled to 0°C. Then O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (107.92 mg, 283.82 µmol, 1.3 eq) and N,N -diisopropylethylamine (84.65 mg, 654.97 µmol, 114.08 µl, 3 eq.). Thereafter, the reaction system was stirred at 0° C. for 10 min, compound 6-7 (73 mg, 218.32 μmol, 1 eq.) was dissolved in dichloromethane (2 ml) and added dropwise to the reaction system. The resulting reaction system was reacted at 0°C for 20 min, then heated to 70°C and stirred for 12 h. and LCMS showed that compound 6 was obtained. The reaction solution was washed with saturated ammonium chloride (10 ml) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 45% - 65 %, 10.5 min) to give compound 6.

MS(ESI) m/s: 446.2 [M+H] ⁺ .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 8.04 (s, 1H), 7.79-7.69 (m, 1H), 7.38-7.30 (m, 1H), 7 .26-7.16 (m, 1H), 4.42 (t, J=6.8 Hz, 2H), 3.79-3.62 (m, 4H), 3.20 (t, J=6 .8 Hz, 2H), 2.23 (m, 2H), 2.00 (m, 2H), 1.88 (m, 2H), 1.71 (m, 2H), 1.50 (s, 3H ).

Example 7

Synthesis path:

Stage 1

Compound 7-1 (36.17 mg, 281.33 µmol, 1.5 eq) and triethylamine (56.94 mg, 562.65 µmol, 78.32 µl, 3 eq) were dissolved in dichloromethane (5 ml) and then compound 2-3 (70 mg, 187.55 µmol, 1 eq.) dissolved in dichloromethane (5 ml) was added at 0°C. The reaction system was stirred at 25°C for 2 hours. According to the results of LCMS and HPLC, it was seen that the reaction was complete. The reaction was stopped with 15 ml of water, and then the reaction solution was extracted with dichloromethane (15 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Xtimate C18 150 mm × 25 mm × 5 μm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 28% - 58% , 10.5 min) to give compound 7. MS(ESI) m/s: 465.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.28 (s, 1H), 8.42 (s, 1H), 8.29 (d, J=5.6 Hz, 1H), 7, 81 (d, J=1.6Hz, 1H), 7.62-7.60 (m, 1H), 4.30 (t, J=7.2Hz, 2H), 3.63-3.57 (m, 4H), 3.10 (t, J=7.2 Hz, 2H), 2.47-2.45 (m, 2H), 2.07 (d, J=13.2 Hz, 2H) , 1.59-1.53 (m, 2H), 1.41 (s, 3H).

Example 8

Synthesis path:

Stage 1

A solution of sodium hydrochloride (87.11 mg, 2.18 mmol, 3 eq.) in water (2 ml) was added to a solution of compound 3-1 (300 mg, 725.93 μmol, 1 eq.) in tetrahydrofuran (5 ml) and the mixture was stirred at 40° C. for 12 hours. The reaction solution was adjusted to pH=1-2 with 2 mol/l dilute hydrochloric acid and extracted with ethyl acetate (10 ml×3). The combined organic phases were washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 8-1. MS m/s (ESI): 398.9 [M+H] ⁺ .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 4.34 (t, J=7.2 Hz, 2H), 3.82-3.70 (m, 4H), 3.15 (t, J =7.8Hz, 2H), 2.50-2.48(m, 2H), 2.22(d, J=13.8Hz, 2H), 1.77-1.65(m, 2H) , 1.55 (s, 3H).

Stage 2

Thionyl chloride (166.88 mg, 1.40 mmol, 101.75 μl, 2 eq.) was added dropwise to a solution of compound 8-1 (280 mg, 701.34 μmol, 1 eq.) in dichloromethane (5 ml) at 0° C. under nitrogen atmosphere, and then N,N-dimethylformamide (25.63 mg, 350.67 µmol, 26.98 µl, 0.5 eq.) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 8-2, which was used directly in the next step.

Stage 3

Triethylamine (290.72 mg, 2.87 mmol, 399.89 μl, 4 eq.) was added to a solution of compound 8-2 (300 mg, 718.25 μmol, 1 eq.) in dichloromethane (5 ml), followed by compound 1-9 (92.73 mg, 718.25 µmol, 1 eq) was added. The mixture was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was separated by column chromatography (silica gel pore size 100-200 mesh, petroleum ether:ethyl acetate = 100:0 to 40:60, v/v) and then preparative HPLC (column: Xtimate C18 150 mm × 25 mm × 5 µm, mobile phase: water (containing 0.225% formic acid)-acetonitrile, % acetonitrile content: 48% - 68%, 7 min) to give compound 8. MS m/s (ESI): 510.0 [M+ H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.54 (s, 1H), 7.73-7.62 (m, 1H), 7.11-7.01 (m, 2H), 6.30 (s, 1H), 4.25 (t, J=7.4Hz, 2H), 3.76-3.57 (m, 4H), 3.21 (t, J=7.8Hz, 2H) , 2.46-2.43(m, 2H), 2.08(d, J=13.8Hz, 2H), 1.74(m, 2H), 1.49(s, 3H).

Example 9

Synthesis path:

Stage 1

Methylfluorosulfonyl difluoroacetate (180.70 mg, 940.57 µmol, 119.67 µl, 6 eq.) and hexamethylphosphoric acid triamide (28.09 mg, 156.76 µmol, 27.54 µl, 1 eq.) were added to a solution of compound 8 (80 mg, 156.76 µmol, 1 eq.) in DMF (3 ml). After three purges with nitrogen, copper(I) iodide (29.86 mg, 156.76 µmol, 1 eq.) was added. The mixture was stirred at 80° C. for 12 hours. The reaction solution was diluted with water (10 ml) and then extracted with ethyl acetate (10 ml×3). The combined organic phases were washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by preparative HPLC (column: Xtimate C18 150 mm×25 mm×5 µm; mobile phase: water (containing 0.225% formic acid)-acetonitrile; % acetonitrile content: 50%-70%, 7 min) to give the compound 9. MS m/s (ESI): 500.2 [M+H1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.68-7.59 (m, 1H), 7.55 (s, 1H), 7.12-6.95 (m, 2H), 6.51 (s, 1H), 4.16 (t, J=7.2 Hz, 2H), 3.77-3.66 (m, 2H), 3.64-3.51 (m, 2H), 3, 09 (t, J=7.4 Hz, 2H), 2.50-2.48 (m, 2H), 2.06 (d, J=13.6 Hz, 2H), 1.71 (t, J =9.6 Hz, 2H), 1.44 (s, 3H).

Example 10

Synthesis path:

Stage 1

Compound 10-1 (59.12 mg, 401.90 µmol, 1.5 eq) and triethylamine (81.34 mg, 803.79 µmol, 111.88 µl, 3 eq) were dissolved in dichloromethane (5 ml) and then compound 2-3 (0.1 g, 267.93 µmol, 1 eq.) dissolved in dichloromethane (5 ml) was added at 0°C. The reaction system was stirred at 25°C for 1 h. By LCMS and HPLC, it was seen that the compound 2-3 was completely consumed and compound 10 was obtained. The reaction was stopped with water (10 ml), and then the reaction solution was extracted with dichloromethane ( 10 ml ×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Xtimate C18 150 mm×25 mm×5 µm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 42% - 62% , 10.5 min) to give compound 10. MS(ESI) m/s: 484.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.03 (s, 1H), 8.42 (s, 1H), 7.64-7.60 (m, 2H), 4.30 (t , J=7.2 Hz, 2H), 3.63-3.55 (m, 4H), 3.08 (t, J=7.6 Hz, 2H), 2.47-2.43 (m, 2H), 2.07 (d, J=13.2 Hz, 2H), 1.59-1.52 (m, 2H), 1.40 (s, 3H).

Example 11

Synthesis path:

Stage 1

Compound 11-1 (10 g, 69.36 mmol, 9.26 ml, 1 eq.) was dissolved in tetrahydrofuran (100 ml) and then lithium diisopropylamide (2 M, 52.02 ml, 1.5 eq.) was added. at -78°C. After stirring for 0.5 h, chloromethyl ether (8.38 g, 104.05 mmol, 7.90 ml, 1.5 eq.) was added at -78°C. The reaction system was stirred at 25° C. for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that compound 11-1 was completely consumed and new spots were obtained. The reaction solution was poured into 50 ml of a saturated ammonium chloride solution, and extracted with ethyl acetate (50 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 11-2.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.82 (td, J=4.0, 11.8 Hz, 2H), 3.76 (s, 3H), 3.52-3.46 (m , 2H), 3.40 (s, 2H), 3.30 (s, 3H), 2.09-2.05 (m, 2H), 1.62-1.54 (m, 2H).

Stage 2

Compound 11-2 (12 g, 63.76 mmol, 1 eq) was dissolved in a mixture of methanol (100 ml) and water (50 ml) and then sodium hydroxide (5.10 g, 127.51 mmol, 2 eq) was added .). The reaction system was stirred at 40° C. for 16 hours. The reaction solution was extracted with ethyl acetate (50 ml×2). The aqueous phase was adjusted to pH = 1-3 with 1 mol/l hydrochloric acid and extracted with ethyl acetate (50 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 11-3.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ=3.80 (td, J=4.0, 11.6 Hz, 2H), 3.58-3.51 (m, 2H), 3.43 (s, 2H), 3.31 (s, 3H), 2.04-1.99 (m, 2H), 1.62-1.54 (m, 2H).

Stage 3

Compound 11-3 (8.5 g, 48.80 mmol, 1 eq.), triethylamine (7.41 g, 73.19 mmol, 10.19 ml, 1.5 eq.) and benzyl alcohol (10.55 g, 97.59 mmol, 10.15 ml, 2 eq.) was dissolved in toluene (100 ml) and then diphenylphosphoryl azide (16.11 g, 58.56 mmol, 12.69 ml, 1.2 eq.) was added. at 25°C under nitrogen atmosphere. The reaction system was stirred at 110° C. for 5 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that new spots were obtained. The reaction solution was poured into 100 ml of a saturated ammonium chloride solution, and then extracted with ethyl acetate (80 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 100:0 to 10:1, v/v). The purified product was concentrated under reduced pressure to give compound 11-4.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.34-7.29 (m, 5H), 3.74-3.49 (m, 4H), 3.36 (s, 2H), 3.33 (s, 3H), 2.18 (s, 2H), 2.04-1.96 (m, 2H), 1.74-1.66 (m, 2H).

Stage 4

Compound 11-4 (14 g, 50.12 mmol, 1 eq.) in a dry 250 ml hydrogenation flask was dissolved in methanol (200 ml) followed by the addition of wet carbon-supported palladium catalyst (3 g, purity: 10% ). The reaction system was stirred at 25° C. for 16 hours under hydrogen atmosphere (50 psi). According to the results of TLC (simple petroleum ether: ethyl acetate = 5:1) it was seen that the reaction was completed. The reaction solution was filtered and concentrated. The crude product was homogenized with methyl tert-butyl ether (30 ml) and filtered. The filter residue was concentrated under reduced pressure to give compound 11-5.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 3.84-3.81 (m, 2H), 3.68-3.62 (m, 4H), 3.45 (s, 3H), 1 .93-1.88(m, 2H), 1.84-1.80(m, 2H).

Stage 5

Compound 4-9 (0.2 g, 736.23 µmol, 1 eq) was dissolved in dichloromethane (10 ml) and then oxalyl chloride (186.89 mg, 1.47 mmol, 128.89 µl, 2 eq) was added. ) and N,N-dimethylformamide (5.38 mg, 73.62 µmol, 5.66 µl, 0.1 eq.) at 0°C. The reaction system was stirred for 0.5 h at 25°C under nitrogen atmosphere. According to the results of TLC (simple petroleum ether: ethyl acetate = 1:1) it was seen that the compound 4-9 was completely consumed and new spots were obtained. The reaction solution was concentrated under reduced pressure to obtain compound 11-7.

Stage 6

Compound 11-5 (150.16 mg, 826.58 µmol, 1.20 eq, HCl) and triethylamine (209.29 mg, 2.07 mmol, 287.88 µl, 3 eq) were dissolved in dichloromethane (5 ml), and then a solution of compound 11-7 (0.2 g, 689.42 μmol, 1 eq.) in dichloromethane (5 ml) was added at 0°C under nitrogen atmosphere. The reaction system was stirred at 25° C. for 1 hour. LCMS results confirmed that compound 11-7 was completely consumed and compound 11-8 was obtained. The reaction was stopped with 15 ml of water, and then the reaction solution was extracted with dichloromethane (15 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 11-8.

MS(ESI) m/s: 399.1 [M+H] ⁺ .

Stage 7

Compound 11-8 (0.4 g, 1.00 mmol, 1 eq) was dissolved in a mixture of tetrahydrofuran (8 ml) and water (4 ml) and then lithium hydroxide monohydrate (126.26 mg, 3.01 mmol) was added , 3 equiv.). The reaction system was stirred at 25° C. for 12 hours. LCMS results confirmed that compound 11-8 was completely consumed and compound 11-9 was obtained. The reaction solution was adjusted to pH = 1-3 with 1 M dilute hydrochloric acid and extracted with ethyl acetate (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 11-9. MS(ESI) m/s: 385.0 [M+H] ⁺ .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 4.36 (t, J=7.2 Hz, 2H), 3.77-3.72 (m, 4H), 3.64 (s, 2H ), 3.37 (s, 3H), 3.15 (t, J=7.6 Hz, 2H), 2.54-2.50 (m, 2H), 2.19 (d, J=12, 8 Hz, 2H), 1.84-1.77 (m, 2H).

Stage 8

Compound 11-9 (0.2 g, 519.74 µmol, 1 eq.), triethylamine (210.37 mg, 2.08 mmol, 289.37 µl, 4 eq.) and O-(7-azabenzotriazole-) hexafluorophosphate 1-yl)-N,N,N',N'-tetramethyluronium (592.86 mg, 1.56 mmol, 3 eq.) was dissolved in N,N-dimethylformamide (3 ml). After stirring at 25° C. for 0.5 h, compound 1-9 (134.20 mg, 1.04 mmol, 2 eq.) was added. The reaction system was stirred at 55° C. for 3 hours. The results of LCMS and HPLC confirmed that the reaction was complete. 2 drops of water was added to the reaction solution to stop the reaction, and then filtered to obtain a filtrate. The filtrate was purified by preparative HPLC (neutral system; column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 30% - 60%, 11 min) to give compound 12. MS(ESI) m/s: 496.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.95 (s, 1H), 8.42 (s, 1H), 7.87-7.81 (m, 1H), 7.43-7 .39 (m, 2H), 4.29 (t, J=7.2 Hz, 2H), 3.67-3.55 (m, 6H), 3.28 (s, 3H), 3.08 ( t, J=7.6 Hz, 2H), 2.43 (s, 2H), 2.07 (d, J=13.4 Hz, 2H), 1.68-1.60 (m, 2H).

Example 12

Synthesis path:

Stage 1

Titanium tetraisopropanolate (3.41 g, 11.99 mmol, 3.54 ml, 1.2 eq.) in a dry 40 ml flask was dissolved in ammonium/methanol solution (7 M, 5.71 ml, 4 eq.), and then compound 12-1 (1 g, 9.99 mmol, 917.43 μl, 1 eq.) was added dropwise under nitrogen atmosphere at 30°C. After stirring for 2 h, the mixture was cooled to -5°C, and then compound 12-2 (1.04 g, 10.49 mmol, 1.31 ml, 1.05 eq.) was added dropwise at this temperature. After stirring for 2 hours, the resulting mixture was heated to 30° C. and stirred for 12 hours. TLC (petroleum ether:ethyl acetate = 1:1) showed that the reaction was complete. The reaction was stopped with water (1 ml), and then ethanol (20 ml) was added to the reaction solution, stirred for 30 minutes, and filtered. The original solution was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 10:1 to 1:1, v/v) to give compound 12-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.02-3.95 (m, 2H), 3.68-3.62 (m, 2H), 2.01-1.96 (m, 2H) , 1.87 (s, 2H), 1.78-1.74 (m, 2H).

Stage 2

Compound 12-3 (97.85 mg, 775.60 µmol, 1.5 eq.) in a dry 40 ml flask was dissolved in dichloromethane (10 ml) and triethylamine solution (156.97 mg, 1.55 mmol) was added dropwise , 215.91 μl, 3 eq.) and compound 11-7 (150 mg, 517.06 μmol, 1 eq.) in dichloromethane (5 ml) under nitrogen atmosphere at 0°C. The reaction system was stirred at 30°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was diluted with dichloromethane (50 ml) and washed with dilute hydrochloric acid (0.5 mol/l) (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 12-4. MS(ESI) m/s: 380.1 [M+H] ⁺ .

Stage 3

Compound 12-4 (200 mg, 526.60 µmol, 1 eq.) in a dry 50 ml single neck flask was dissolved in a mixture of tetrahydrofuran (3 ml), methanol (3 ml) and water (3 ml), and then added lithium hydroxide monohydrate (44.19 mg, 1.05 mmol, 2 eq.). The reaction solution was stirred at 30°C for 16 hours. According to the results of LCMS, it was seen that the reaction was completed. Tetrahydrofuran and methanol were concentrated under reduced pressure and diluted with 20 ml of water. The aqueous phase was washed with ethyl acetate (5 ml×2), adjusted to pH = 1 with 0.5 M dilute hydrochloric acid and extracted with ethyl acetate (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 12-5. MS(ESI) m/s: 366.1 [M+H] ⁺ .

Stage 4

Compound 12-5 (130 mg, 355.42 μmol, 1 eq.) in a dry 50 ml single neck flask was dissolved in N,N-dimethylformamide (5 ml). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (270.28 mg, 710.83 µmol, 2 eq.) and triethylamine were added under nitrogen atmosphere at 30°C. (107.89 mg, 1.07 mmol, 148.41 µl, 3 eq.). After stirring for 0.5 h, compound 1-9 (68.83 mg, 533.13 µmol, 1.5 eq.) was added. After the reaction, the mixture was heated to 60° C. and stirred for 15.5 hours. It was seen from the results of LCMS and HPLC that the reaction was complete. Water (1 ml) was added to the reaction solution, which was then concentrated. The crude product was purified by preparative HPLC (neutral system, column: Waters Xbridge 150 x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 30% - 50%, 12 min) to give compound 12. MS(ESI) m/s: 477.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.96 (s, 1H), 9.58 (s, 1H), 7.85-7.80 (m, 1H), 7.42-7 .38 (m, 2H), 4.29 (t, J=7.2 Hz, 2H), 3.86-3.82 (m, 2H), 3.57 (t, J=10.0 Hz, 2H), 3.09 (t, J=7.6 Hz, 2H), 2.46-2.44 (m, 2H), 2.30-2.27 (m, 2H), 1.95-1 .90 (m, 2H).

Example 13

Synthesis path:

Stage 1

Compound 13-1 (1 g, 4.40 mmol, 1 eq.) in a single neck flask was dissolved in tetrahydrofuran (20 ml) and sodium hydride (615.93 mg, purity: 60%, 3.5 eq. ) at 0°C under nitrogen atmosphere. After stirring for 0.5 h, compound 13-2 (2.33 g, 9.24 mmol, 2.1 eq.) was added and the reaction system was stirred for 30 min at 30°C. By TLC (petroleum ether : ethyl acetate = 10:1) it was seen that the reaction was complete. The reaction system was poured into dilute hydrochloric acid at a concentration of 0.5 mol/l (100 ml). The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 50:1 to 20:1) to obtain compound 13-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.55 (s, 1H), 4.43 (s, 1H), 3.32-3.26 (m, 1H), 2.41-2.38 (m, 1H), 2.30-2.28 (m, 1H), 2.15-2.14 (m, 1H), 2.13-2.04 (m, 1H), 2.03-2 .01 (m, 1H), 1.54-1.49 (m, 2H), 1.46 (s, 9H), 1.43 (s, 9H), 1.33 (s, 3H).

Stage 2

Wet carbon-supported palladium catalyst (200 mg, content: 10%) in a hydrogenation flask was dissolved in tetrahydrofuran (40 ml) and compound 13-3 (1.35 g, 4.15 mmol, 1 eq.) was added. The reaction system was stirred at 25° C. for 2 h under hydrogen atmosphere (15 psi). By TLC (petroleum ether : ethyl acetate = 10:1) it was seen that the reaction was complete. The reaction solution was filtered and concentrated to give compound 13-4.

Stage 3

Compound 13-4 (1.3 g, 3.97 mmol, 1 eq.) in a dry one-necked flask was dissolved in ethyl acetate (30 ml) and hydrochloric acid/ethyl acetate (4 mol/l, 10 ml, 10.08 equiv.). The reaction system was stirred at 30° C. for 16 hours. The reaction solution was immediately concentrated to give compound 13-5.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 1.85-1.83 (m, 4H), 1.77-1.76 (m, 2H), 1.63-1.60 (m, 3H), 1.45 (s, 9H), 1.35-1.31 (m, 5H).

Stage 4

Compound 13-5 (250 mg, 861.77 µmol, 1 eq.) in a single neck dry flask was dissolved in dichloromethane (10 ml) and triethylamine (261.61 mg, 2.59 mmol, 359.85 µl, 3 equiv.). A solution of compound 11-7 (293.88 mg, 1.29 mmol, 1.5 eq.) in dichloromethane (10 ml) was added dropwise to the resulting mixture under nitrogen atmosphere at 0°C. The reaction system was stirred at 30°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was poured into water (50 ml). Then the aqueous phase was extracted with dichloromethane (20 ml × 3), and the organic phase was washed with 0.5 mol/l dilute hydrochloric acid (20 ml × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 13- 6. MS(ESI) m/s: 425.2 [M+H-(tert-Bu)] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.99 (s, 1H), 4.32 (t, J=7.6 Hz, 2H), 3.84 (s, 3H), 3.14 ( t, J=7.6 Hz, 2H), 2.52-2.48 (m, 2H), 2.31-2.28 (m, 2H), 2.14-2.12 (m, 2H) , 1.68-1.65 (m, 2H), 1.45-1.42 (m, 2H), 1.39-1.36 (m, 12H), 1.24-1.22 (m, 2H), 1.18-1.14 (m, 2H).

Stage 5

Compound 13-6 (90 mg, 187.12 µmol, 1 eq.) was dissolved in a mixture of tetrahydrofuran (3 ml), methanol (3 ml) and water (3 ml) in a flask and lithium hydroxide monohydrate (23.55 mg, 561.35 µmol, 3 eq.). The reaction system was stirred at 30° C. for 16 hours. According to the results of LCMS, it was seen that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol, and diluted with 20 ml of water. The aqueous phase was then washed with ethyl acetate (5 ml × 2), adjusted to pH = 1 with 0.5 mol/l dilute hydrochloric acid and extracted with ethyl acetate (5 ml × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure conditions. The crude product was purified by preparative TLC (dichloromethane:methanol = 10:1, v/v) to give compound 13-7. MS(ESI) m/s: 411.1 [M+H-(tert-Bu)] ⁺ .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 4.38-4.31 (m, 2H), 3.16-3.12 (m, 2H), 2.55-2.48 (m, 2H), 2.32-2.30(m, 2H), 2.14-2.11(m, 2H), 1.75-1.70(m, 1H), 1.65-1.55( m, 2H), 1.44 (s, 9H), 1.35-1.31 (m, 4H), 1.22 (s, 3H).

Stage 6

Compound 13-7 (70 mg, 149.91 µmol, 1 eq.) in a dry flask was dissolved in N,N-dimethylformamide (4 ml) and hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N,N was added, N',N'-tetramethyluronium (114.00 mg, 299.82 µmol, 2 eq.) and triethylamine (45.51 mg, 449.72 µmol, 62.60 µl, 3 eq.) under nitrogen atmosphere at 30 °C After stirring for 30 min, compound 1-9 (29.03 mg, 224.86 µmol, 1.5 eq) was added and the reaction system was heated to 60° C. and stirred for 15.5 h. that the reaction is complete. The reaction solution was poured into 0.2 mol/L dilute hydrochloric acid (50 ml) and then extracted with ethyl acetate (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 13-8. MS(ESI) m/s: 522.1 [M+H-(tert-Bu)] ⁺ .

Stage 7

Compound 13-8 (50 mg, 86.50 µmol, 1 eq.) in a single neck dry flask was dissolved in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (2 ml) and the reaction system was stirred at 25°C for 1 h The results of LCMS and HPLC showed that the reaction was complete. The reaction solution was immediately concentrated. The crude product was purified by preparative HPLC (neutral system, column: Waters Xbridge 150 x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 20% - 40%, 13 min) to give compound 12. MS(ESI) m/s: 522.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.93 (s, 1H), 8.10 (s, 1H), 7.88-7.83 (m, 1H), 7.44-7 .42 (m, 2H), 4.29 (t, J=6.8 Hz, 2H), 3.09 (t, J=8.0 Hz, 2H), 2.47-2.45 (m, 2H), 2.24-2.22(m, 2H), 2.09-2.07(m, 2H), 1.65-1.60(m, 1H), 1.54-1.51( m, 2H), 1.35 (s, 3H), 1.24-1.23 (m, 4H).

Example 14

Synthesis path:

Stage 1

Compound 14-1 (124.74 mg, 1.10 mmol, 2 eq.) and triethylamine (167.43 mg, 1.65 mmol, 230.30 μl, 3 eq.) were dissolved in dichloromethane (5 ml) and then a solution of compound 11-7 (0.16 g, 551.54 μmol, 1 eq.) in dichloromethane (5 ml) was added at 0° C. under nitrogen atmosphere. The reaction system was stirred at 25° C. for 16 hours. According to the results of LCMS, it was seen that compound 11-7 was completely consumed and compound 14-2 was obtained. The reaction was stopped with 20 ml of water, and then the reaction solution was extracted with dichloromethane (15 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 14-2. MS(ESI) m/s: 367.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.53 (d, J=9.6 Hz, 1H), 4.38-4.25 (m, 2H), 3.85 (s, 3H), 3.15-3.10 (m, 2H), 2.55-2.48 (m, 2H), 1.45-1.42 (m, 4H).

Stage 2

Compound 14-2 (0.19 g, 518.11 µmol, 1 eq.) was dissolved in a mixture of methanol (5 ml), tetrahydrofuran (5 ml) and water (5 ml), and then lithium hydroxide monohydrate (65.22 mg, 1.55 mmol, 3 eq.). The reaction system was stirred at 25°C for 2 hours. According to the results of TLC (dichloromethane : methanol = 20:1) it was seen that the compound 14-2 was completely consumed and new spots were obtained. The reaction solution was adjusted to pH = 1-3 with 1 M hydrochloric acid and extracted with ethyl acetate (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 14-3.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 4.76-4.69 (m, 1H), 4.36 (t, J=7.2 Hz, 2H), 3.15 (t, J =7.6 Hz, 2H), 2.56-2.49 (m, 2H), 1.40 (d, J=7.0 Hz, 3H).

Stage 3

Compound 14-3 (0.1 g, 283.53 µmol, 1 eq) was dissolved in dichloromethane (5 ml) and then oxalyl chloride (71.98 mg, 567.07 µmol, 49.64 µl, 2 eq) was added. ) and N,N-dimethylformamide (2.07 mg, 28.35 µmol, 2.18 µl, 0.1 eq.) at 0°C under nitrogen atmosphere. The reaction system was stirred at 25° C. for 0.5 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that compound 14-3 was completely consumed and new spots were obtained. The reaction solution was immediately concentrated under reduced pressure to obtain compound 14-4.

Stage 4

Compound 14-5 (69.28 mg, 538.88 µmol, 2 eq) and triethylamine (81.79 mg, 808.32 µmol, 112.51 µl, 3 eq) were dissolved in dichloromethane (5 ml) and then a solution of compound 14-4 (0.1 g, 269.44 μmol, 1 eq.) in dichloromethane (5 ml) was added at 0° C. under nitrogen atmosphere. The reaction system was heated to 25°C and stirred for 1 h. The results of LCMS and HPLC confirmed that compound 14-4 was completely consumed and compound 14 was obtained. The reaction solution was poured into 20 ml of water to stop the reaction and was extracted with dichloromethane (15 ml × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral; column: Waters Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 37% - 57%, 10.5 min) to give compound 14. MS(ESI) m/s: 463.0 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.37 (s, 1H), 9.45 (s, 1H), 8.25 (d, J=6.0 Hz, 1H), 7, 79 (d, J=1.6 Hz, 1H), 7.57 (dd, J=2.0, 6.0 Hz, 1H), 4.72-4.67 (m, 1H), 4.30 (t, J=7.2 Hz, 2H), 3.13-3.10 (m, 2H), 2.47-2.43 (m, 2H), 1.31 (d, J=6.8 Hz, 3H).

Example 15

Synthesis path:

Stage 1

Compound 15-1 (1.5 g, 7.07 mmol, 1 eq.), triethylamine (1.07 g, 10.60 mmol, 1.48 ml, 1.5 eq.) was added to toluene (15 ml) and benzyl alcohol (1.53 g, 14.13 mmol, 1.47 ml, 2 eq.) followed by the addition of diphenylphosphoryl azide (2.33 g, 8.48 mmol, 1.84 ml, 1.2 eq.) . The reaction system was stirred at 110° C. for 16 hours. LCMS results confirmed that compound 15-1 was completely consumed and compound 15-2 was obtained; the results of TLC (petroleum ether:ethyl acetate = 5:1) showed that new spots were obtained. The reaction solution was poured into a saturated ammonium chloride solution (30 ml) to stop the reaction, and extracted with ethyl acetate (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 100:1 to 10:1, v/v) to give compound 15-2. MS(ESI) m/s: 318.1 [M+H] ⁺ .

Stage 2

Wet carbon-supported palladium catalyst (1 g, purity: 10%) was dissolved in methanol (20 ml) and then compound 15-2 (2 g, 6.30 mmol, 1 eq.) was added. The reaction system was stirred at 25° C. for 16 hours under hydrogen atmosphere (50 psi). According to the results of TLC (simple petroleum ether: ethyl acetate = 5:1) it was seen that the compound 15-2 was completely consumed and new spots were obtained. After that, the reaction solution was filtered, hydrochloric acid in methanol (4 mol/l, 50 ml) was added. The resulting mixture was stirred for 0.5 h and concentrated under reduced pressure to give compound 15-3.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 3.65 (s, 3H), 1.99-1.81 (m, 12H).

Stage 3

Compound 1-3 (15 g, 90.81 mmol, 1 eq.) and compound 1-9 (17.59 g, 136.21 mmol, 1.5 eq.) in a dry flask were dissolved in toluene (450 ml) and lithium hexamethyldisilazide (1 mol/l, 181.61 ml, 2 eq.) was added slowly at 0°C. The reaction system was stirred at 25° C. for 16 hours. According to the results of TLC (petroleum ether : ethyl acetate = 3:1), it was observed that the compound 1-3 was completely consumed. The reaction solution was poured into a saturated ammonium chloride solution (200 ml) and extracted with ethyl acetate (200 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 5:1 to 1:1, v/v) to give compound 15-4.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.70-7.66 (m, 2H), 7.13-7.11 (m, 1H), 7.02-7.00 (m, 1H) , 6.54 (d, J=2.8Hz, 1H), 6.48 (d, J=2.8Hz, 1H), 3.93 (t, J=7.6Hz, 2H), 3 .09 (t, J=7.2 Hz, 2H), 2.56-2.48 (m, 2H).

Stage 4

Compound 15-4 (12 g, 45.76 mmol, 1 eq.) was dissolved in dichloromethane (20 ml) and then methyl oxalyl chloride (11.21 g, 91.51 mmol, 8.43 ml, 2 eq.) was added. The reaction in the reaction system was carried out at 25° C. for 16 hours. According to the results of LCMS, it was observed that compound 15-4 was completely consumed and compound 15-5 was obtained. The reaction solution was poured into saturated sodium bicarbonate solution (200 ml) and extracted with ethyl acetate (200 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 5:1 to 1:1, v/v) to give compound 15-5. MS(ESI) m/s: 349.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.74-7.69 (m, 3H), 7.16-7.09 (m, 2H), 4.39 (t, J=7.6 Hz , 2H), 3.93 (s, 3H), 3.21 (t, J=7.6 Hz, 2H), 2.65-2.55 (m, 2H).

Stage 5

Compound 15-5 (5.37 g, 15.42 mmol, 1 eq.) was dissolved in acetic acid (110 ml) and then N-chlorosuccinimide (3.29 g, 24.67 mmol, 1.6 eq. ). The reaction in the reaction system was carried out at 40° C. for 16 hours. According to the results of LCMS, it was observed that compound 15-6 was obtained. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×3). The organic phase was washed with saturated sodium bicarbonate (1000 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 3:1 to 1:5, v/v) to give compound 15-6. MS(ESI) m/s: 383.0 [M+H] ⁺ .

Stage 6

Compound 15-6 (6.6 g, 17.24 mmol, 1 eq) was dissolved in a mixture of tetrahydrofuran (40 ml), ethanol (40 ml) and water (40 ml) and lithium hydroxide monohydrate (2.17 g, 51.73 mmol, 3 eq.). The reaction system was stirred at 40°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was concentrated under reduced pressure to remove the solvent, then diluted with water (100 ml) and washed with ethyl acetate (30 ml×2). The aqueous phase was adjusted to pH = 1 with 0.5 M dilute hydrochloric acid and then immediately filtered. The filter cake was suspended and washed with dichloromethane (50 ml) and filtered. The resulting filter cake was concentrated under reduced pressure to give compound 15-7. MS(ESI) m/s: 369.1 [M+H] ⁺ .

¹ H NMR (400 MHz, MeOH _- d ₄ ) δ = 7.78-7.73 (m, 1H), 7.31-7.25 (m, 1H), 7.24-7.19 (m, 1H), 4.40-4.39(m, 2H), 3.19-3.13(m, 2H), 2.63-2.54(m, 2H).

Stage 7

Compound 15-7 (1.1 g, 2.98 mmol, 1 eq.) was dissolved in dichloromethane (20 ml) and oxalyl chloride (757.34 mg, 5.97 mmol, 522.30 μl, 2 eq.) was added dropwise. ) and N,N-dimethylformamide (21.80 mg, 298.33 µmol, 22.95 µl, 0.1 eq.) under nitrogen atmosphere at 0°C. The reaction system was stirred at 25°C for 0.5 h. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was immediately concentrated under reduced pressure to obtain compound 15-8.

Stage 8

Compound 15-3 (170.24 mg, 774.86 µmol, 1.5 eq, HCl) and triethylamine (156.82 mg, 1.55 mmol, 215.70 µl, 3 eq) were dissolved in dichloromethane (10 ml), and then a solution of compound 15-8 (0.2 g, 516.58 μmol, 1 eq.) in dichloromethane (10 ml) was added at 0°C under nitrogen atmosphere. The reaction system was stirred at 30° C. for 16 hours. LCMS results confirmed that compound 15-8 was completely consumed and compound 15-9 was obtained. The reaction solution was diluted with 1 M dilute hydrochloric acid (20 ml) and extracted with dichloromethane (20 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 15-9. MS(ESI) m/s: 534.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.48 (s, 1H), 7.76-7.71 (m, 1H), 7.47-7.40 (m, 1H), 7.15 -7.11(m, 2H), 4.32(t,J=7.6Hz, 2H), 3.67(s, 3H), 3.26(t,J=8.0Hz, 2H) , 2.56-2.48 (m, 2H), 2.07-1.97 (m, 12H).

Stage 9

Compound 15-9 (0.3 g, 561.85 µmol, 1 eq.) was dissolved in a mixture of water (3 ml) and dimethyl sulfoxide (6 ml), and then lithium hydroxide monohydrate (70.73 mg, 1.69 mmol , 3 equiv.). The reaction system was stirred at 30° C. for 2 hours. The results of LCMS and HPLC confirmed that the reaction was complete. The reaction solution was filtered, and the filtrate was collected. The filtrate was purified by preparative HPLC (neutral, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 5% - 50%, 20 min) c obtaining compound 15. MS(ESI) m/s: 518.2 [MH] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.92 (s, 1H), 8.35 (s, 1H), 7.87-7.82 (m, 1H), 7.43-7 .39 (m, 2H), 4.26 (t, J=7.0 Hz, 2H), 3.07 (t, J=7.4 Hz, 2H), 2.45-2.42 (m, 2H), 1.92-1.75 (m, 12H).

Example 16

Synthesis path:

Stage 1

Compound 16-1 (1 g, 11.22 mmol, 1.01 ml, 1 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.42 g, 22.45 mmol, 3 38 ml, 2 eq.) was added to anhydrous dichloromethane (10 ml) and then compound 16-2 (1.73 g, 13.47 mmol, 1.2 eq.) was added to the reaction system and stirred at 45°C within 12 hours. According to the results of TLC (simple petroleum ether : ethyl acetate = 5:1) it was observed that the compound 16-1 was completely consumed. The reaction solution was poured into a saturated ammonium chloride solution (20 ml) and extracted with dichloromethane (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 100:1 to 5:1, v/v) to give compound 16-3.

Stage 2

Skeletal nickel hydrogenation catalyst (266.67 mg, 3.11 mmol, 1.69 eq.) was added to the hydrogenation flask and rinsed with ethanol (10 mL×2). Ethanol (5 ml) and compound 16-3 (0.4 g, 1.84 mmol, 1 eq.) were added. The reaction system was stirred at 25° C. for 4 h under hydrogen atmosphere (50 psi). According to the results of TLC (simple petroleum ether: ethyl acetate = 5:1) it was seen that the compound 16-3 was completely consumed and new spots were obtained. The reaction solution was immediately filtered, and the filtrate was concentrated under reduced pressure to obtain compound 16-4.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 2.21(t, J=8.0 Hz, 2H), 1.49 (t, J=8.0 Hz, 2H), 1.39 ( s, 9H), 0.96 (s, 6H).

Stage 3

Compound 16-4 (0.32 g, 1.71 mmol, 1.24 eq.) was added to dichloromethane (10 ml) and then triethylamine (697.62 mg, 6.89 mmol, 959.59 µl, 5 eq.). Then the reaction system was cooled to 0°C. Compound 11-7 (0.4 g, 1.38 mmol, 1 eq.) was dissolved in anhydrous dichloromethane (10 ml) and the resulting solution was added dropwise to the reaction system. The reaction system was stirred at 20°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was washed with saturated ammonium chloride (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 16-5. MS(ESI) m/s: 385.1 [M+H-(tert-Bu)] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.29 (s, 1H), 4.26 (t, J=7.6 Hz, 2H), 3.74 (s, 3H), 3, 05 (t, J=7.6Hz, 2H), 2.46-2.40(m, 2H), 2.25-2.21(m, 2H), 1.93-1.88(m, 2H), 1.39(s, 9H), 1.28(s, 6H).

Stage 4

Compound 16-5 (0.1 g, 226.80 µmol, 1 eq.) was added to a flask with tetrahydrofuran (3 ml), methanol (3 ml) and water (3 ml), and then lithium hydroxide monohydrate was added to the reaction system (47.58 mg, 1.13 mmol, 5 eq.) and stirred at 25° C. for 12 hours. Compound 16-5 was completely consumed by LCMS. Water (20 ml) was added to the reaction solution, adjusted to pH=3 with 1 M hydrochloric acid, and extracted with ethyl acetate (10 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (neutral, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 15% - 45%, 10.5 min) to give compound 16-6. MS(ESI) m/s: 371.1 [M+H-(tert-Bu)] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.50 (s, 1H), 8.26 (s, 1H), 4.25 (t, J=6.8 Hz, 2H), 3, 09 (t, J=6.8 Hz, 2H), 2.43-2.41 (m, 2H), 2.26-2.22 (m, 2H), 1.93-1.89 (m, 2H), 1.40 (s, 9H), 1.29 (s, 6H).

Stage 5

Compound 16-6 (20 mg, 46.85 µmol, 1 eq.) was added to anhydrous dichloromethane (2 ml). The reaction system was cooled to 0°C, oxalyl chloride (11.89 mg, 93.70 µmol, 8.20 µl, 2 eq.) and N,N-dimethylmethanamide (3.42 mg, 46.85 µmol, 3, 60 µl, 1 eq) and stirred at 0°C for 10 min. A drop of the reaction solution was taken and 1 ml of methanol was added thereto to quench the reaction. From the results of LCMS, it was observed that the compound 16-6 was completely consumed and new spots were obtained. The reaction solution was immediately concentrated under reduced pressure to obtain compound 16-7.

Stage 6

Compound 1-9 (18.14 mg, 140.52 µmol, 3 eq.) and triethylamine (23.70 mg, 234.21 µmol, 32.60 µl, 5 eq.) were added to anhydrous dichloromethane (5 ml) and cooled the reaction system to 0°C. Compound 16-7 (20.86 mg, 46.84 μmol, 1 eq.) was dissolved in anhydrous dichloromethane (5 ml) and the resulting solution was added dropwise to the reaction system. The reaction in the reaction system was carried out at 0°C for 1 h. According to the results of LCMS, it was observed that the compound 16-7 was completely consumed. The reaction solution was poured into a saturated ammonium chloride solution (10 ml) and extracted with dichloromethane (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 16-8, which was used directly in the next step.

MS(ESI) m/s: 482.1 [M+H-(tert-Bu)] ⁺ .

Stage 7

Compound 16-8 (25.2 mg, 46.84 µmol, 1 eq.) was added to anhydrous dichloromethane (2 ml). Triethylamine (267.04 mg, 2.34 mmol, 173.41 µl, 50 eq.) was then added to the reaction system and stirred at 25° C. for 0.5 h. was consumed and compound 16 was obtained. The reaction solution was washed with water (20 ml×2), and the resulting organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (neutral, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 15% - 35%, 20 min) to give compound 16.

MS(ESI) m/s: 482.0 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ = 9.97 (s, 1H), 8.49 (s, 1H), 7.57 (d, J=11.6 Hz, 1H), 7, 43 (s, 2H), 4.28-4.26 (m, 2H), 3.07 (m, 2H), 2.25 (m, 4H), 1.94-1.92 (m, 2H) .1.38 (s, 6H).

Example 17

Synthesis path:

Stage 1

Compound 13-6 was separated using SFC (column: DAICELCHIRALCELOJ (250 mm x 30 mm, 10 μm); mobile phase: Neu-ETOH; % B: 30% - 30%, 9 min). Compound 17-1 (column retention time for SFC: 1.16 min) and compound 18-1 (column retention time for SFC: 1.7 min) were obtained. SFC analysis conditions: Column: Daicel OJ-3 chiral column with the following specification: 0.46 cm ID × 5 cm; mobile phase: A: carbon dioxide, B: ethanol for chromatography (containing 0.05% isopropylamine); % B: 5% - 40%; flow rate: 4 ml/min; 4 min; system back pressure: 100 bar.

Compound 17-1: ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.00 (s, 1H), 4.32 (t, J=7.2 Hz, 2H), 3.84 (s, 3H) , 3.14 (t, J=7.8 Hz, 2H), 2.52-2.48 (m, 2H), 2.31-2.28 (d, J=12.8 Hz, 2H), 2.14-2.12 (d, J=7.2 Hz, 2H), 1.76-1.74 (m, 1H), 1.74-1.67 (m, 2H), 1.48 ( s, 3H), 1.44 (s, 9H), 1.42-1.38 (m, 2H), 1.35-1.18 (m, 2H).

Compound 18-1: ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.08 (s, 1H), 4.31 (t, J=7.4 Hz, 2H), 3.83 (s, 3H) , 3.12 (t, J=7.6 Hz, 2H), 2.51-2.47 (m, 2H), 2.17-2.15 (m, 2H), 2.14-2.00 (m, 2H), 1.83-1.70 (m, 3H), 1.48 (s, 3H), 1.47-1.45 (m, 10H), 1.45-1.26 (m , 3H).

Stage 2

Compound 17-1 (360.00 mg, 748.47 µmol, 1 eq.) in a single neck flask was dissolved in a mixture of tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml) and lithium hydroxide monohydrate ( 157.03 mg, 3.74 mmol, 5 eq.). The reaction system was stirred at 30° C. for 16 hours. According to the results of LCMS, it was seen that the reaction was complete. The reaction solution was adjusted to pH = 1 with 0.5 M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 17-2.

MS(ESI) m/s: 411.1 [M+H-(tert-Bu)] ⁺ .

Stage 3

Compound 17-2 (330.00 mg, 706.71 µmol, 1 eq.) in a dry flask was dissolved in N,N-dimethylformamide (15 ml) and triethylamine (214.54 mg, 2.12 mmol, 295.10 µl, 3 eq.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (537.42 mg, 1.41 mmol, 2 eq.) and compound 1- 9 (182.48 mg, 1.41 mmol, 2 eq). The reaction system was stirred at 60°C for 16 h under nitrogen atmosphere. The results of LCMS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (50 ml) and then washed with 0.5 M dilute hydrochloric acid (10 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 10:1 to 1:1, v/v) to give compound 17-3. MS(ESI) m/s: 578.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.48 (d, 7.6 Hz, 1H), 7.77-7.72 (m, 1H), 7.16-7.09 (m, 2H ), 6.20 (s, 1H), 4.33 (t, J=7.6 Hz, 2H), 3.26 (t, J=7.6 Hz, 2H), 2.56-2.49 (m, 2H), 2.32-2.30 (m, 2H), 1.78-1.67 (m, 5H), 1.48 (s, 3H), 1.45 (s, 9H), 1.41-1.38(m, 2H), 1.37-1.17(m, 2H).

Stage 4

Compound 17-3 (280 mg, 484.39 µmol, 1 eq.) in a single-necked dry flask was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (4.62 g, 40.52 mmol, 3 ml, 83, 65 eq.). The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS and HPLC, it was seen that the reaction was completed. The reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (neutral system, column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 16 % - 46%, 10.5 min) to give compound 17 (column: Daicel AS-3 chiral column with the following specification: 0.46 cm ID × 10 cm; mobile phase: A: carbon dioxide, B: ethanol for chromatography (containing 0.05% isopropylamine); % B: 5% - 40%; flow rate: 4 ml/min; 5 min; system back pressure: 100 bar) and the SFC column retention time was 2.18 min. MS (ESI) m/s: 522.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.91 (s, 1H), 8.08 (s, 1H), 7.87-7.82 (m, 1H), 7.43-7 .39 (m, 2H), 4.29 (t, J=7.2 Hz, 2H), 3.08 (t, J=7.4 Hz, 2H), 2.46-2.45 (m, 2H), 2.23 (d, J=10.4 Hz, 2H), 2.07 (d, J=6.8 Hz, 2H), 1.63 (s, 1H), 1.50 (d, J=7.6 Hz, 2H), 1.34 (s, 3H), 1.29-1.20 (m, 4H).

Example 18

Synthesis path:

Stage 1

Compound 18-1 (550.00 mg, 1.14 mmol, 1 eq.) in a single neck flask was dissolved in a mixture of tetrahydrofuran (10 ml), water (10 ml) and methanol (10 ml) and lithium hydroxide monohydrate ( 239.91 mg, 5.72 mmol, 5 eq.). The reaction system was stirred at 30° C. for 16 hours. According to the results of LCMS, it was seen that the reaction was complete. The reaction solution was adjusted to pH = 1 with dilute hydrochloric acid at a concentration of 0.5 mol/l. The aqueous phase was extracted with ethyl acetate (20 ml×3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 18-2.

MS(ESI) m/s: 467.1 [M+H] ⁺ .

Stage 2

Compound 18-2 was dissolved in N,N-dimethylformamide (15 ml) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (879.42 mg, 2.31 mmol, 2 eq.) and triethylamine (351.06 mg, 3.47 mmol, 482.89 µl, 3 eq.) at 30°C under nitrogen atmosphere. After stirring for 30 min, compound 1-9 (298.61 mg, 2.31 mmol, 2 eq.) was added and the reaction system was heated to 60° C. and stirred for 15.5 h. the reaction has ended. The reaction solution was poured into 0.2 mol/L dilute hydrochloric acid (50 ml) and then extracted with ethyl acetate (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 10:1 to 1:1, v/v) to give compound 18-3. MS(ESI) m/s: 578.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.48 (s, 1H), 7.76-7.71 (m, 1H), 7.27-7.11 (m, 2H), 6.25 (s, 1H), 4.32-4.30 (m, 2H), 3.25 (t, J=7.6 Hz, 2H), 2.55-2.50 (m, 2H), 2, 18-2.15 (m, 3H), 2.01-1.92 (m, 2H), 1.84-1.81 (m, 2H), 1.72-1.71 (m, 2H), 1.50 (s, 3H), 1.46 (s, 9H), 1.28-1.25 (m, 2H).

Stage 3

Compound 18-3 was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (4.62 g, 40.52 mmol, 3.00 ml, 78.07 eq.) was added. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS and HPLC, it was seen that the reaction was completed. The reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (neutral system, column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 16 % - 46%, 10.5 min) to give compound 18 (column: Daicel AS-3 chiral column with the following specification: 0.46 cm ID × 10 cm; mobile phase: A: carbon dioxide, B: ethanol for chromatography (containing 0.05% isopropylamine); % B: 5% - 40%; flow rate: 4 ml/min; 5 min; system back pressure: 100 bar) and the retention time in the SFC column was 2.40 min. MS (ESI) m/s: 522.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.90 (s, 1H), 8.29 (s, 1H), 7.87-7.81 (m, 1H), 7.45-7 .38 (m, 2H), 4.28 (t, J=7.2 Hz, 2H), 3.08 (t, J=7.6 Hz, 2H), 2.48-2.44 (m, 2H), 2.15 (d, J=6.8 Hz, 2H), 1.85 (d, J=12.8 Hz, 2H), 1.76-1.61 (m, 5H), 1, 37 (s, 3H), 1.18-1.15 (m, 2H).

Example 19

Synthesis path:

Stage 1

Compound 19-1 (65 g, 416.19 mmol, 1 eq.) and compound 19-2 (32.29 g, 520.24 mmol, 29.09 ml, 1.25 eq.) were dissolved in toluene (1 L ) and compound (7.17 g, 41.62 mmol, 0.1 eq.) was added. The reaction system was heated to 130° C. and stirred for 48 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that the reaction was complete. The reaction solution was immediately concentrated, and the crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate=20:1 to 5:1, v/v) to obtain compound 19-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.95 (s, 4H), 3.68 (s, 3H), 2.37-2.35 (m, 1H), 1.93-1.91 (m, 2H), 1.82-1.76 (m, 4H), 1.58-1.54 (m, 2H).

Stage 2

Diisopropylethylamine (47.00 g, 464.46 mmol, 65.64 ml, 1.5 equiv.) was dissolved in tetrahydrofuran (800 ml) and n-butyllithium (2.5 M, 185.79 ml, 1, 5 equiv.) at -78°C under nitrogen atmosphere. After stirring for 30 minutes, a solution of compound 19-3 (62 g, 309.64 mmol, 1 eq.) in tetrahydrofuran (200 ml) was added dropwise. After stirring for another 30 minutes, iodomethane (65.93 g, 464.46 mmol, 28.91 ml, 1.5 eq.) was added dropwise. Finally, the reaction system was heated to 25° C. and stirred for 16 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The reaction solution was poured into 0.5 M dilute hydrochloric acid (500 ml). The aqueous phase was extracted with ethyl acetate (100 ml×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 10:1, v/v) to give compound 19-4.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.93 (s, 4H), 3.66 (s, 3H), 2.14-2.10 (m, 2H), 1.64-1.60 (m, 4H), 1.59-1.50 (m, 2H), 1.18 (s, 3H).

Stage 3

Compound 19-4 (70 g, 326.71 mmol, 1 eq.) was dissolved in a mixture of tetrahydrofuran (150 ml), methanol (150 ml) and water (150 ml) and potassium hydroxide (91.66 g, 1.63 mol, 5 eq.). The reaction system was stirred at 25° C. for 16 hours. According to the results of LCMS, it was seen that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent and diluted with water (100 ml). The aqueous phase was washed with ethyl acetate (20 ml × 2), adjusted to pH = 4 with 0.5 M dilute hydrochloric acid and extracted with ethyl acetate (50 ml × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced conditions. pressure to obtain compound 19-5.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.92 (s, 4H), 2.13-2.08 (m, 2H), 1.67-1.64 (m, 4H), 1.55 -1.50 (m, 2H), 1.23 (s, 3H).

Stage 4

Compound 19-5 (54 g, 269.69 mmol, 1 eq.) was dissolved in toluene (500 ml) and triethylamine (81.87 g, 809.07 mmol, 112.61 ml, 3 eq.), diphenylphosphoryl azide ( 89.06 g, 323.63 mmol, 70.13 ml, 1.2 eq.) and benzyl alcohol (35.00 g, 323.63 mmol, 33.65 ml, 1.2 eq.). The reaction system was stirred at 100°C for 16 h under nitrogen atmosphere. According to the results of TLC (simple petroleum ether: ethyl acetate = 5:1) it was seen that the reaction was completed. The reaction solution was poured into water (500 ml). The aqueous phase was extracted with ethyl acetate (100 ml×2) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 5:1, v/v) to give compound 19-6.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.37-7.27 (m, 5H), 5.05 (s, 1H), 4.69 (s, 2H), 3.95 (s, 4H ), 2.04 (s, 2H), 1.68-1.59 (m, 6H), 1.40-1.37 (m, 3H).

Stage 5

Compound 19-6 (80 g, 261.98 mmol, 1 eq) was dissolved in tetrahydrofuran (1 L) and hydrochloric acid (2 M, 1 L, 7.63 eq) was added. The reaction system was stirred at 50° C. for 16 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 25:1 to 5:1, v/v) to give compound 19-7.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.40-7.29 (m, 5H), 5.09 (s, 2H), 4.87 (s, 1H), 2.45-2.38 (m, 4H), 2.31-2.27 (m, 2H), 1.85-1.82 (m, 2H), 146 (s, 3H).

Stage 6

Compound 19-8 (13.16 g, 38.27 mmol, 2 eq., HCl) was dissolved in tetrahydrofuran (100 ml) and potassium tert-butoxide (4.29 g, 38.27 mmol, 2 eq.) was added at -10°C under nitrogen atmosphere. After the reaction system was stirred at -10°C for 1 h, a solution of compound 19-7 (5 g, 19.13 mmol, 1 eq.) in tetrahydrofuran (100 ml) was added dropwise to the above reaction solution, and the reaction solution was stirred at 25°C for 2 hours. According to the results of TLC (simple petroleum ether: ethyl acetate = 3:1) it was seen that the reaction was completed. The reaction solution was diluted with ethyl acetate (500 ml) and then filtered. The original solution was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 30:1 to 10:1, v/v) to give compound 19-9.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.37-7.27 (m, 5H), 5.78 (s, 1H), 5.07 (s, 2H), 4.67 (s, 1H ), 4.55 (s, 3H), 2.45-2.40 (m, 1H), 2.04-1.93 (m, 5H), 1.47-1.44 (m, 2H), 1.36(s, 3H).

Stage 7

Compound 19-9 (4 g, 13.82 mmol, 1 eq.) was dissolved in tetrahydrofuran (6.5 ml) and hydrochloric acid (6 M, 3.23 ml, 1.4 eq.) was added dropwise at 0° C. The reaction system was stirred at 0° C. for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The reaction solution was diluted with water (10 ml). The aqueous phase was extracted with ethyl acetate (5 ml×3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 19-10.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.65 (d, J=17.2 Hz, 2H), 7.37-7.27 (m, 5H), 5.06 (s, 2H), 4.61 (d, J= 56.4 Hz, 1H), 2.33-2.21 (m, 2H), 1.87-1.81 (m, 3H), 1.80-1.68 ( m, 2H), 1.37(s, 3H).

Stage 8

Compound 19-10 (1.8 g, 6.54 mmol, 1 eq.) was dissolved in a mixture of tert-butanol (27 ml) and isoamylene (2.58 g, 36.74 mmol, 3.89 ml, 5.62 eq.) and slowly add a solution of sodium dihydrogen phosphate (831.41 mg, 6.93 mmol, 1.06 eq.) and a solution of sodium chlorite (709.48 mg, 7.84 mmol, 1.2 eq.) in water ( 36 ml) at 0°C. The reaction system was stirred at 0°C for 10 min. According to the results of TLC (simple petroleum ether: ethyl acetate = 3:1) it was seen that the reaction was completed. The reaction solution was diluted with water (20 ml). The aqueous phase was extracted with ethyl acetate (5 ml×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 10:1 to 3:1, v/v) to give compound 19-11.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.37-7.27 (m, 5H), 5.06 (s, 2H), 4.65 (d, J= 4.0 Hz, 1H), 2.44-2.30(m, 1H), 2.20-2.17(m, 1H), 1.88-1.66(m, 6H), 1.36-1.31(m, 3H ).

Stage 9

Compound 19-11 (1.7 g, 5.84 mmol, 1 eq.) was dissolved in dichloromethane (15 ml) and oxalyl chloride (1.48 g, 11.67 mmol, 1.02 ml, 2 eq.) was added dropwise. ) and N,N-dimethylformamide (42.65 mg, 583.51 µmol, 44.89 µl, 0.1 eq.) at 0° C. under nitrogen atmosphere. The reaction system was stirred at 25° C. for 1 hour and then concentrated under reduced pressure. The crude product was dissolved in dichloromethane (5 ml) and the resulting solution was slowly added dropwise to a solution of tert-butanol (4.32 g, 58.35 mmol, 5.58 ml, 10 eq.) in dichloromethane (10 ml). The reaction system was stirred at 50° C. for 16 hours. According to the results of LCMS, it was seen that the reaction was complete. The reaction solution was immediately concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 30:1 to 10:1, v/v) to give compound 19-12.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.37-7.27 (m, 5H), 5.05 (s, 2H), 4.64 (d, J= 14.8 Hz, 1H), 2.27-2.14 (m, 2H), 1.82-1.64 (m, 6H), 1.44 (d, J= 3.2 Hz, 9H), 1.36-1.31 ( m, 3H).

Stage 10

Wet carbon-supported palladium catalyst (200 mg, content: 10%), methanol (20 ml) and compound 19-12 (1 g, 2.88 mmol, 1 eq) were added to the hydrogenation flask. After 3 purges with hydrogen, the reaction system was stirred for 16 h at 25° C. under hydrogen atmosphere (50 psi). The reaction solution was filtered and concentrated under reduced pressure to obtain compound 19-13.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 2.18-2.15 (m, 2H), 1.79-1.55 (m, 4H), 1.45 (d, J=2, 4, Hz, 9H), 1.43-1.37 (m, 2H), 1.12 (s, 3H).

Stage 11

Compound 19-13 (294.13 mg, 1.38 mmol, 1 eq.) was dissolved in dichloromethane (20 ml) and triethylamine (418.57 mg, 4.14 mmol, 575.76 μl, 3 eq.) was added. A solution of compound 11-7 (400 mg, 1.38 mmol, 1 eq.) in dichloromethane (10 ml) was added dropwise under nitrogen atmosphere at 0°C. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was poured into dilute hydrochloric acid (0.5 mol/l, 50 ml) and extracted with dichloromethane (20 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 19-14.

MS (ESI) m/z: 467.2 [M+H] ⁺

Stage 12

Compound 19-14 (700 mg, 1.50 mmol, 1 eq.) was dissolved in a mixture of tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml) and lithium hydroxide monohydrate (188.70 mg, 4.5 ml) was added. 50 mmol, 3 eq.). The reaction system was stirred at 25° C. for 16 hours. According to the results of LCMS, it was seen that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent. The aqueous phase was adjusted to pH=1 with 0.5 mol/L dilute hydrochloric acid and extracted with ethyl acetate (20 mL×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 19 -15. MS (ESI) m/z: 453.1 [M+H] ⁺ .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 4.39-4.33 (m, 2H), 3.31-3.11 (m, 2H), 2.53-2.49 (m, 2H), 2.38-2.35 (m, 2H), 1.88-1.70 (m, 6H), 1.46-1.29 (m, 13H).

Stage 13

Compound 19-15 (470 mg, 1.04 mmol, 1 eq.) was dissolved in dichloromethane (20 ml) and oxalyl chloride (263.43 mg, 2.08 mmol, 181.68 μl, 2 eq.) was added dropwise and N,N-dimethylformamide (7.58 mg, 103.77 µmol, 7.98 µl, 0.1 eq.) under nitrogen atmosphere at 0°C. The reaction system was stirred at 25°C for 30 min. Took 1 ml of the reaction solution and added methanol to stop the reaction, and the results of LCMS detection showed that the reaction was completed. The reaction solution was immediately concentrated under reduced pressure to obtain compound 19-16.

Stage 14

Compound 1-9 (273.90 mg, 2.12 mmol, 2 eq.) was dissolved in dichloromethane (20 ml) and triethylamine (322.01 mg, 3.18 mmol, 442.92 μl, 3 eq.) was added. A solution of compound 19-16 (500 mg, 1.06 mmol, 1 eq.) in dichloromethane (10 ml) was added dropwise under nitrogen atmosphere at 0°C. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was poured into dilute hydrochloric acid (0.5 mol/l, 50 ml). The aqueous phase was extracted with ethyl acetate (20 ml×2) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate=1:1, v/v) to give compound 19-17 (Rf=0.35) and compound 20-1 (Rf=0.32).

Compound 19-17: MS (ESI) m/z: 508.1 [M+H-(tert-Bu)] ⁺ .

Compound 20-1：MS (ESI) m/z: 508.1 [M+H-(tert-Bu)] ⁺ .

Stage 15

Compound 19-17 (90 mg, 159.57 µmol, 1 eq) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (363.88 mg, 3.19 mmol, 236.29 µl, 20 eq) was added. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS and HPLC, it was seen that the reaction was completed. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (neutral system, column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate )-acetonitrile, % B (acetonitrile): 23% - 43%, 10.5 min) to give compound 19 (column: Daicel AS-3 chiral column with the following specification: 0.46 cm ID × 10 cm; movable phase: A: carbon dioxide, B: ethanol for chromatography (containing 0.05% isopropylamine); % B: 5% - 40%; flow rate: 4 ml/min; 5 min; system back pressure: 100 bar), and time the column retention for SFC was 2.44 min. MS (ESI) m/z: 508.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.96 (s, 1H), 8.15 (s, 1H), 7.87-7.82 (m, 1H), 7.43-7 .36 (m, 2H), 4.29 (t, J=7.0 Hz, 2H), 3.08(t, J=7.6 Hz, 2H), 2.50-2.46 (m, 2H), 2.22 (d, J=12.8 Hz, 2H), 2.11 (s, 1H), 1.63-1.58 (m, 4H), 1.34 (s, 3H), 1.29-1.23 (m, 2H).

Example 20

Synthesis path:

Compound 20-1 (140 mg, 248.22 µmol, 1 eq) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (566.04 mg, 4.96 mmol, 367.56 µl, 20 eq) was added. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS and HPLC, it was seen that the reaction was completed. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (neutral system, column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate )-acetonitrile, % B (acetonitrile): 18% - 38%, 10.5 min) to give compound 20 (column: Daicel AS-3 chiral column with the following specification: 0.46 cm ID x 10 cm; movable phase: A: carbon dioxide, B: ethanol for chromatography (containing 0.05% isopropylamine); % B: 5% - 40%; flow rate: 4 ml/min; 5 min; system back pressure: 100 bar), and time the SFC column retention was 2.20 min. MS (ESI) m/z: 508.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.95 (s, 1H), 8.30 (s, 1H), 7.87-7.82 (m, 1H), 7.45-7 .39 (m, 2H), 4.28 (t, J=7.2 Hz, 2H), 3.08 (t, J=7.6 Hz, 2H), 2.50-2.46 (m, 2H), 2.24 (s, 1H), 1.83-1.74 (m, 6H), 1.59-1.55 (m, 2H), 1.36 (s, 3H).

Example 21

Synthesis path:

Stage 1

Compound 13-2 (3.63 g, 14.38 mmol, 2.2 eq.) was dissolved in tetrahydrofuran (20 ml) and sodium hydride (784.48 mg, 19.61 mmol, purity: 60%, 3 equiv.) at 0°C under nitrogen atmosphere. The reaction solution was stirred for 30 min, and then a solution of compound 19-10 (1.8 g, 6.54 mmol, 1 eq.) in THF (20 ml) was slowly added dropwise. The reaction system was heated to 25° C. and stirred for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The reaction solution was poured into 0.5 mol/l dilute hydrochloric acid (10 ml). The aqueous phase was extracted with ethyl acetate (20 ml×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 10:1, v/v) to obtain compound 21-1.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.37-7.33 (m, 5H), 6.83-6.77 (m, 1H), 5.75-5.69 (m, 1H) , 5.06 (s, 2H), 4.71-4.53 (m, 2H), 2.21-2.16 (m, 2H), 1.87-1.82 (m, 1H), 1 .76-1.71(m, 2H), 1.63(s, 2H), 1.49(s, 9H), 1.38-1.32(m, 4H).

Stage 2

The carbon-supported palladium catalyst (200 mg, content: 10%) in a hydrogenation flask was dissolved in methanol (30 ml) and compound 21-1 (2 g, 5.35 mmol, 1 eq) was added. After 3 purges with hydrogen, the reaction system was stirred for 16 h at 25° C. under hydrogen atmosphere (50 psi). According to the results of TLC (simple petroleum ether: ethyl acetate = 3:1) it was seen that the reaction was completed. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 21-2.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 2.27-2.22 (m, 2H), 1.70-1.50 (m, 6H), 1.44 (s, 9H), 1 .39-1.36(m, 2H), 1.24-1.18(m, 2H), 1.13-1.11(m, 4H).

Stage 3

Compound 21-2 (332.81 mg, 1.38 mmol, 1 eq.) was dissolved in dichloromethane (20 ml) and triethylamine (418.57 mg, 4.14 mmol, 575.76 μl, 3 eq.) was added. A solution of compound 11-7 (400 mg, 1.38 mmol, 1 eq.) in dichloromethane (10 ml) was added dropwise under nitrogen atmosphere at 0°C. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was poured into 0.5 mol/l dilute hydrochloric acid (50 ml). The aqueous phase was extracted with dichloromethane (20 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 21-3.

MS(ESI) m/s: 439.2 [M+H-(tert-Bu)] ⁺ .

Stage 4

Compound 21-3 (700 mg, 1.41 mmol, 1 eq.) was dissolved in a mixture of tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml) and lithium hydroxide monohydrate (178.01 mg, 4.5 ml) was added. 24 mmol, 3 eq.). The reaction system was stirred at 25° C. for 16 hours. According to the results of LCMS, it was seen that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent. The aqueous phase was adjusted to pH=1 with 0.5 mol/L dilute hydrochloric acid and extracted with ethyl acetate (20 mL×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 21 -4.

MS(ESI) m/s: 425.1 [M+H-(tert-Bu)] ⁺ .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ 4.39-4.33 (m, 2H), 3.17-3.11 (m, 2H), 2.53-2.51 (m, 2H ), 2.32-2.23 (m, 3H), 2.03-2.00 (m, 1H), 1.81-1.55 (m, 2H), 1.58-1.52 (m , 6H), 1.44 (s, 9H), 1.30-1.27 (m, 4H).

Stage 5

Compound 21-4 (570 mg, 1.19 mmol, 1 eq.) was dissolved in dichloromethane (30 ml) and oxalyl chloride (300.84 mg, 2.37 mmol, 207.48 μl, 2 eq.) was added dropwise and N,N-dimethylformamide (8.66 mg, 118.51 µmol, 9.12 µl, 0.1 eq) under nitrogen at 0°C. The reaction system was stirred at 25°C for 30 min. Two drops of the reaction solution were taken and methanol was added to them to stop the reaction, and it was seen from the results of LCMS that the reaction was completed. The reaction solution was immediately concentrated under reduced pressure to obtain compound 21-5.

Stage 6

Compound 1-9 (310.21 mg, 2.40 mmol, 2 eq.) was dissolved in dichloromethane (20 ml) and triethylamine (364.70 mg, 3.60 mmol, 501.65 μl, 3 eq.) was added. A solution of compound 21-5 (600 mg, 1.20 mmol, 1 eq.) in dichloromethane (10 ml) was added dropwise under nitrogen atmosphere at 0°C. The reaction system was stirred at 25° C. for 1 hour. TLC (petroleum ether:ethyl acetate = 1:1) and LCMS showed that the reaction was complete. The reaction solution was poured into dilute hydrochloric acid (0.5 mol/l, 50 ml). The aqueous phase was extracted with ethyl acetate (20 ml×2) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate=1:1, v/v) to give compound 21-6 (Rf=0.35) and compound 22-1 (Rf=0.32).

Compound 21-6: MS(ESI) m/s: 536.2 [M+H-(t-Bu)] ⁺ .

Compound 21-6: MS(ESI) m/s: 536.2 [M+H-(t-Bu)] ⁺ .

Stage 7

Compound 21-6 (70 mg, 118.23 μmol, 1 eq.) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (269.61 mg, 2.36 mmol, 175.07 μl, 20 eq.) was added. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS and HPLC, it was seen that the reaction was completed. The reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (neutral system, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 10% - 50%, 20 min ) to obtain compound 21 (column: Daicel OJ-3 chiral column with the following specification: 0.46 cm ID × 5 cm; mobile phase: A: carbon dioxide, B: chromatography ethanol (containing 0.05% isopropylamine); % B: 5% - 40%; flow rate: 4 ml/min; 3 min; system back pressure: 100 bar) and the retention time in the SFC column was 1.27 min. MS (ESI) m/s: 536.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.93 (s, 1H), 8.09 (s, 1H), 7.88-7.83 (m, 1H), 7.46-7 .40 (m, 2H), 4.31-4.28 (m, 2H), 3.11-3.07 (m, 2H), 2.47-2.43 (m, 2H), 2.23 -2.20 (m, 4H), 1.50-1.41 (m, 4H), 1.34 (s, 3H), 1.24-1.19 (m, 5H).

Example 22

Synthesis path:

Compound 22-1 (80 mg, 135.12 µmol, 1 eq) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (308.12 mg, 2.70 mmol, 200.08 µl, 20 eq) was added. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS and HPLC, it was seen that the reaction was completed. The reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (neutral system, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 10% - 50%, 20 min ) to obtain compound 22 (column: Daicel OJ-3 chiral column with the following specification: 0.46 cm ID × 5 cm; mobile phase: A: carbon dioxide, B: chromatography ethanol (containing 0.05% isopropylamine); % B: 5% - 40%; flow rate: 4 ml/min; 3 min; system back pressure: 100 bar) and the retention time in the SFC column was 1.39 min. MS (ESI) m/s: 536.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.92 (s, 1H), 8.29 (s, 1H), 7.87-7.82 (m, 1H), 7.43-7 .39 (m, 2H), 4.29-4.25 (m, 2H), 3.09-3.04 (m, 2H), 2.47-2.44 (m, 2H), 2.19 -2.15 (m, 2H), 1.86-1.83 (m, 2H), 1.69-1.59 (m, 4H), 1.45-1.43 (m, 2H), 1 .36 (s, 3H), 1.17 (s, 1H), 1.09-1.06 (m, 2H).

Example 23

Synthesis path:

Stage 1

Compound 23-1 (5 g, 35.16 mmol, 1 eq.) was dissolved in carbon tetrachloride (50 ml) and then N-bromosuccinimide (7.51 g, 42.20 mmol, 1.2 eq.) and azobisisobutyronitrile were added (1.73 g, 10.55 mmol, 0.3 eq.). The reaction solution was heated to 90° C. and stirred for 12 hours. According to the results of TLC (petroleum ether:ethyl acetate = 5:1), it was seen that a small amount of compound 23-1 remained and new spots were obtained. The reaction solution was cooled to room temperature, water (50 ml) was added and stirred, and then left to stand until the separation of the organic phase. The separated organic phase was washed with saturated aqueous sodium chloride solution (50 ml×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using a COMBI-FLASH chromatography system (petroleum ether:ethyl acetate = 100:1 to 15:1, v/v) to give compound 23-2.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.95-6.88 (m, 1H), 5.99 (dd, J=1.2, 1.2 Hz, 1H), 4.02 (t , J=3.8 Hz, 2H), 1.52 (s, 9H).

Stage 2

Compound 23-2 (1.60 g, 17.91 mmol, 1.61 ml, 1.1 eq) was dissolved in methanol (50 ml) and tetrakis(triphenylphosphine)palladium (940.79 mg, 814.14 µmol) was added , 0.05 eq.), sodium methoxide (967.63 mg, 17.91 mmol, 1.1 eq.) and compound 16-1 (3.6 g, 16.28 mmol, 1 eq.) at 26° C under nitrogen atmosphere. The reaction mixture was heated to 60° C. and stirred for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that compound 23-2 was completely consumed and new spots were obtained. The reaction solution was poured into water (100 ml) and then extracted with ethyl acetate (50 ml×2). The organic phase was washed with saturated aqueous sodium chloride solution (100 ml×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using a COMBI-FLASH chromatography system (petroleum ether:ethyl acetate = 100:1 to 10:1, v/v) to give compound 23-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.71-6.63 (m, 1H), 5.86-5.82 (m, 1H), 2.78 (dd, J=1.2, 1.2 Hz, 2H), 1.61(s, 6H), 1.48(s, 9H).

Stage 3

Compound 23-3 (200 mg, 872.33 µmol, 1 eq.) and ethanol (10 ml) were added to a dry hydrogenation flask, skeletal nickel hydrogenation catalyst (200 mg, 2.33 mmol, 2.68 eq.) was added to nitrogen atmosphere and purged with hydrogen. The reaction system was stirred for 12 hours at 50° C. under hydrogen atmosphere (50 psi). From the results of TLC (petroleum ether:ethyl acetate = 5:1) it was seen that the conversion of the starting materials was completed and new spots were obtained. The reaction solution was filtered through Celite and then washed with ethanol (20 ml). The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 23-4.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 2.22 (t, J=7.4 Hz, 2H), 1.55-1.52 (m, 2H), 1.31 (s, 9H), 1.30-1.28 (m, 2H), 1.03 (s, 6H).

Stage 4

Compound 23-4 (150 mg, 745.61 µmol, 7.21e-1 eq.) was dissolved in dichloromethane (5 ml) at 26°C and sodium bicarbonate (434.37 mg, 5.17 mmol, 201.10 µl, 5 eq.). A mixture of compound 11-7 (300 mg, 1.03 mmol, 1 eq.) and dichloromethane (5 ml) was added slowly with stirring, dropwise, and then the reaction system was stirred at 26°C for 0.5 h. By LCMS results it was seen that compound 23-5 was obtained. Water (10 ml) was added to the reaction solution with stirring and left to settle to separate liquids to obtain organic phases. The separated aqueous phase was extracted with dichloromethane (10 ml×1), and the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using a COMBI-FLASH chromatography system (petroleum ether:ethyl acetate = 50:1 to 2:1, v/v) to give compound 23-5. MS (ESI) m/z: 477.1 [M+Na] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.11 (s, 1H), 4.24 (t, J=7.4 Hz, 2H), 3.76 (s, 3H), 3.05 ( t, J=7.6 Hz, 2H), 2.43-2.40 (m, 2H), 2.17 (t, J=7.0 Hz, 2H), 1.70-1.69 (m , 2H), 1.57-1.55 (m, 2H), 1.37 (s, 9H), 1.36 (s, 6H).

Stage 5

Compound 23-5 (480 mg, 1.06 mmol, 1 eq.) was dissolved in a mixture of tetrahydrofuran (5 ml), methanol (5 ml) and water (5 ml) and lithium hydroxide monohydrate (221.37 mg, 5.0 ml) was added. 28 mmol, 5 eq.). The reaction mixture was stirred at 50°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. A 2.0 mol/L potassium hydrogen sulfate aqueous solution was added to the reaction solution until pH=5, and the mixture was extracted with ethyl acetate (10 ml×2). The organic phases were combined, washed with saturated sodium chloride solution (10 ml×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 23-6. MS (ESI) m/z: 463.3 [M+Na] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.19 (t, J=7.0 Hz, 2H), 3.22 (s, 1H), 3.01 (t, J=7.6 Hz, 2H), 2.38-2.36(m, 2H), 2.18-2.09(m, 2H), 1.63-1.60(m, 2H), 1.51-1.49( m, 2H), 1.30 (d, J=6.4 Hz, 15H).

Stage 6

Compound 23-6 (100 mg, 226.80 µmol, 1 eq) was dissolved in dichloromethane (5 ml) and oxalyl chloride (57.57 mg, 453.60 µmol, 39.71 µl, 2 eq) and N, N-dimethylformamide (1.66 mg, 22.68 µmol, 1.75 µl, 0.1 eq.) at 0°C. After completion of the addition, the reaction system was heated to 26°C and stirred for 0.5 h. To stop the reaction, a small amount of the reaction solution was added in 1 ml of methanol. The results of TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material was completely consumed and new spots formed. The reaction solution was immediately concentrated under reduced pressure to obtain compound 23-7.

Stage 7

Compound 1-9 (56.21 mg, 435.39 µmol, 2 eq.) was dissolved in dichloromethane (5 ml) and sodium bicarbonate (91.44 mg, 1.09 mmol, 42.33 µl, 5 eq.) was added. . A mixture of compound 23-7 (100 mg, 217.69 µmol, 1 eq.) and dichloromethane (5 ml) was added dropwise at 26°C. After completion of the addition, the reaction system was stirred at 26°C for 0.5 h. According to the results of LCMS, it was seen that the reaction was completed. Water (10 ml) was added to the reaction solution with stirring and allowed to stand to separate liquids to obtain a dichloromethane phase. The aqueous phase was extracted with dichloromethane (10 ml×1), and the organic phases were combined, washed with saturated aqueous sodium chloride solution (10 ml×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 23-8. MS (ESI) m/z: 574.4 [M+Na] ⁺ .

Stage 8

Compound 23-8 (150 mg, 271.73 µmol, 1 eq) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (309.84 mg, 2.72 mmol, 201.19 µl, 10 eq) was added at 26 °C After completion of the addition, the reaction system was stirred at 26°C for 0.5 h. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was immediately concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Xtimate C18 150 mm×25 mm×5 μm; mobile phase: water (containing 0.225% formic acid)-acetonitrile; % content of acetonitrile: 47 % - 77%, 7 min) to give compound 23. MS (ESI) m/z: 518.3 [M+Na] ⁺ .

¹ H NMR (DMSO-d ₆ ) δ = 12.04 (br s, 1H), 9.93 (s, 1H), 8.30 (s, 1H), 7.87-7.82 (m, 1H ), 7.43-7.40 (m, 2H), 4.28 (t, J=7.2 Hz, 2H), 3.08 (t, J=7.6 Hz, 2H), 2.47 -2.45 (m, 2H), 2.19 (t, J=7.2 Hz, 2H), 1.68 (t, J=8.2 Hz, 2H), 1.56-1.52 ( m, 2H), 1.32 (s, 6H).

Example 24

Synthesis path:

Stage 1

Compound 13-2 (25 g, 99.11 mmol, 1 eq.) was dissolved in tetrahydrofuran (100 ml) and then sodium hydride (5.95 g, 148.67 mmol, purity: 60%, 1.5 equiv.). The reaction in the reaction system was carried out at 0°C for 1 h, and then compound 24-1 (22.23 g, 198.22 mmol, 2 eq.) was added thereto and the reaction was carried out at 25°C for 1 h. According to the results of LCMS, it was seen that compound 24-1 was completely consumed and compound 24-2 was obtained. The reaction solution was poured into 500 ml of a saturated ammonium chloride solution, and extracted with ethyl acetate (500 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 20:1 to 5:1, v/v) to give compound 24-2.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.77 (s, 1H), 3.17 (t, J=7.2 Hz, 2H), 2.63 (t, J=6.4 Hz, 2H), 2.52-2.47 (m, 4H), 1.49 (s, 9H).

Stage 2

Compound 24-2 (6 g, 28.53 mmol, 1 eq.) was dissolved in ethanol (20 ml) and then a wet carbon-supported palladium catalyst (0.2 g, 28.53 mmol, content: 10%, 1 equivalent). The reaction in the reaction system was carried out at 25°C for 1 h under hydrogen atmosphere (15 psi). According to the results of TLC (simple petroleum ether : ethyl acetate = 3:1) it was seen that the compound 24-2 was completely consumed. The reaction solution was immediately filtered to obtain a crude product. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 10:1 to 3:1, v/v) to give compound 24-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.45 (s, 1H), 2.40-2.37 (m, 4H), 2.23 (s, 3H), 2.07-2.06 (m, 3H), 1.47 (s, 9H).

Stage 3

Titanium tetraisopropoxide (4.50 g, 15.83 mmol, 4.67 ml, 1.2 eq.) was dissolved in ammonium/methanol solution (7 M, 7.54 ml, 4 eq.) and then compound 24- 3 (2.8 g, 13.19 mmol, 1 eq.). The reaction in the reaction system was carried out at 25°C for 2 h, and then cooled to -5°C, compound 24-4 (1.37 g, 13.85 mmol, 1.73 ml, 1.05 eq.) and then reacted at 25° C. for 14 hours. According to the results of HPLC, it was seen that the compound 24-3 was completely consumed. Water (5 ml) was added to the reaction solution, stirred for 0.5 h, and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 3:1 to 1:1, v/v) to give compound 24-5.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 2.19-2.06 (m, 2H), 2.06-2.03 (m, 2H), 1.86-1.82 (m, 5H) , 1.60-1.53(m, 2H), 1.52(s, 9H), 1.45-1.38(m, 2H).

Stage 4

Compound 24-5 (1.23 g, 5.17 mmol, 1.5 eq.) and triethylamine (1.05 g, 10.34 mmol, 1.44 ml, 3 eq.) were dissolved in dichloromethane (5 ml) and then a solution of compound 11-7 (1 g, 3.45 mmol, 1 eq.) in dichloromethane (5 ml) was added at 0° C. under nitrogen atmosphere. The reaction system was heated to 30° C. and stirred for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) showed that compound 11-7 was completely consumed and new spots were obtained. The results of LCMS confirmed the receipt of compound 24-6. The reaction was stopped with water (30 ml), and then the reaction solution was extracted with dichloromethane (30 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 100:1 to 2:1, v/v) to give compound 24-6. MS(ESI) m/s: 436.0 [M+H-(tert-Bu)] ⁺ .

Stage 5

Compound 24-6 (1 g, 2.03 mmol, 1 eq.) was dissolved in a mixture of tetrahydrofuran (10 ml) and water (5 ml), and then lithium hydroxide monohydrate (255.87 mg, 6.10 mmol, 3 equiv.). The reaction system was stirred at 30° C. for 16 hours. According to the results of LCMS, it was seen that compound 24-6 was completely consumed and compound 24-7 was obtained. The reaction solution was adjusted to pH = 3-5 with 1.0 mol/l dilute hydrochloric acid and extracted with ethyl acetate (30 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 24-7. MS(ESI) m/s: 476.1 [MH] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.43 (br s, 1H), 9.40 (s, 1H), 4.27 (t, J=7.2 Hz, 2H), 3 .06 (t, J=7.5 Hz, 2H), 2.45-2.40 (m, 4H), 2.15 (d, J=6.4 Hz, 2H), 1.91 (s, 1H), 1.79 (d, J=12.8 Hz, 2H), 1.64-1.58 (m, 2H), 1.41 (s, 9H), 1.31-1.23 (m , 2H).

Stage 6

Compound 24-7 (0.4 g, 836.93 µmol, 1 eq.), triethylamine (127.03 mg, 1.26 mmol, 174.74 µl, 1.5 eq.) and O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (381.87 mg, 1.00 mmol, 1.2 eq.) was dissolved in N,N-dimethylformamide (5 ml). The reaction system was stirred at 25° C. for 0.5 h, and then compound 1-9 (324.16 mg, 2.51 mmol, 3 eq.) was added thereto. The reaction system was heated to 60° C. and stirred for 5 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that compound 24-7 was completely consumed and new spots were obtained; the results of LCMS showed that compound 24-8 was obtained. The reaction was stopped with water (30 ml), and then the reaction solution was extracted with ethyl acetate (20 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 100:1 to 2:1, v/v) to give compound 24-8. MS(ESI) m/s: 587.1 [MH] ^- .

Stage 7

Compound 24-8 (0.3 g, 509.31 μmol, 1 eq.) was dissolved in dichloromethane (5 ml) and then trifluoroacetic acid (5 ml) was added. The reaction system was stirred at 30°C for 1 hour. According to the results of LCMS and HPLC, it was seen that the reaction was completed. Water (0.1 ml) was added to the reaction solution to stop the reaction, and then filtered. The filtrate was purified by preparative HPLC (neutral, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 10% - 50%, 20 min) c obtaining compound 24. MS(ESI) m/s: 531.1 [MH] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.96 (s, 1H), 9.45 (br s, 1H), 7.86-7.81 (m, 1H), 7.45- 7.39 (m, 2H), 4.30 (t, J=7.2 Hz, 2H), 3.09 (t, J=7.6 Hz, 2H), 2.53-2.52 (m , 2H), 2.46-2.41 (m, 2H), 2.15 (d, J=6.8 Hz, 2H), 1.83 (d, J=12.8 Hz, 2H), 1 .75 (br s, 1H), 1.65-1.59 (m, 2H), 1.29-1.20 (m, 2H).

Example 25

Synthesis path:

Stage 1

Compound 18-2 (500 mg, 1.07 mmol, 1 eq.) was dissolved in dichloromethane (20 ml) and oxalyl chloride (271.83 mg, 2.14 mmol, 187.47 μl, 2 eq. ) and N,N-dimethylformamide (7.83 mg, 107.08 µmol, 8.24 µl, 0.1 eq.) under nitrogen atmosphere at 0°C. The reaction system was stirred at 25° C. for 1 hour. Two drops of the reaction solution were taken and methanol was added thereto to stop the reaction, and the reaction was seen to be completed by LCMS. The reaction solution was concentrated under reduced pressure to obtain compound 25-1.

Stage 2

Compound 25-1 was dissolved in dichloromethane (15 ml) and TEA (312.70 mg, 3.09 mmol, 430.12 μl, 3 eq.) was added. A solution of compound 25-2 (500.00 mg, 1.03 mmol, 1 eq.) in dichloromethane (5 ml) was added dropwise under nitrogen atmosphere at 0°C. The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was poured into 0.5 mol/l dilute hydrochloric acid (50 ml). The aqueous phase was extracted with dichloromethane (20 ml×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 10:1 to 4:1, v/v) to give compound 25-3. MS(ESI) m/s: 540.1 [M+H-(tert-Bu)] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.47 (s, 1H), 7.38-7.34 (m, 2H), 6.23 (s, 1H), 4.35-4.31 (m, 2H), 3.28-3.23 (m, 2H), 2.52-2.49 (m, 2H), 2.18-2.14 (m, 2H), 2.05-2 .00 (m, 2H), 1.93-1.81(m, 3H), 1.80-1.71 (m, 2H), 1.55 (s, 3H), 1.50-1.45 (m, 9H), 1.32-1.26 (m, 2H).

Stage 3

Compound 25-3 (100.00 mg, 167.78 µmol, 1 eq) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (382.59 mg, 3.36 mmol, 248.44 µl, 20 eq) was added) . The reaction system was stirred at 25°C for 1 hour. According to the results of LCMS and HPLC, it was seen that the reaction was completed. The reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (neutral system, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 10% - 50%, 20 min ) to give compound 25. MS(ESI) m/s: 540.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.99 (s, 1H), 8.29 (s, 1H), 7.65-7.57 (m, 2H), 4.30-4 .26 (m, 2H), 3.09-3.05 (m, 2H), 2.47-2.43 (m, 2H), 2.16-2.12 (m, 2H), 1.85 -1.80(m, 2H), 1.75-1.61(m, 5H), 1.35(s, 3H), 1.21-1.16(m, 2H).

Example 26

Synthesis path:

Stage 1

Compound 24-7 (0.3 g, 627.70 µmol, 1 eq) was dissolved in dichloromethane (5 ml) and then oxalyl chloride (159.34 mg, 1.26 mmol, 109.89 µl, 2 eq) was added. ) and N,N-dimethylformamide (4.59 mg, 62.77 µmol, 4.83 µl, 0.1 eq.) at 0° C. under nitrogen atmosphere. The reaction system was heated to 30° C. and stirred for 0.5 h. The LCMS results confirmed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain compound 26-1, which was used directly in the next step.

Stage 2

Compound 25-2 (133.35 mg, 906.56 µmol, 1.5 eq) and triethylamine (183.47 mg, 1.81 mmol, 252.36 µl, 3 eq) were dissolved in dichloromethane (5 ml) and then a solution of compound 26-1 (0.3 g, 604.37 μmol, 1 eq.) in dichloromethane (5 ml) was added at 0° C. under nitrogen atmosphere. The reaction system was heated to 30°C and stirred for 1 h. The results of LCMS and HPLC confirmed that the reaction was complete. The reaction solution was poured into water (20 ml) and extracted with dichloromethane (15 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (HCl system, column: Xtimate C18 100 mm×30 mm×5 µm; mobile phase: water (containing 0.05% hydrochloric acid)-acetonitrile; % content of acetonitrile: 50% - 75%, 10 min) to give compound 26-2. MS(ESI) m/s: 605.1 [MH] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.07 (s, 1H), 9.46 (s, 1H), 7.64-7.59 (m, 2H), 4.30 (t , J=7.2 Hz, 2H), 3.09 (t, J=7.4 Hz, 2H), 2.53-2.51 (m, 2H), 2.47-2.44 (m, 1H), 2.42-2.41 (m, 2H), 2.15 (d, J=6.8 Hz, 2H), 1.80 (d, J=12.8 Hz, 2H), 1, 65-1.56 (m, 2H), 1.41 (s, 9H), 1.32-1.23 (m, 2H).

Stage 3

Compound 26-2 (15 mg, 24.71 μmol, 1 eq.) was dissolved in dichloromethane (2 ml) and then trifluoroacetic acid (2 ml) was added. The reaction system was stirred at 30°C for 0.5 h. The results of LCMS and HPLC confirmed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (neutral, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 10 mM ammonium bicarbonate)-acetonitrile; % acetonitrile content: 5% - 50%, 20 min) c obtaining compound 26. MS(ESI) m/s: 549.1 [MH] ^- .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.06 (s, 1H), 9.46 (s, 1H), 7.64-7.60 (m, 2H), 4.30 (t , J=7.2 Hz, 2H), 3.09 (t, J=7.8 Hz, 2H), 2.52-2.51 (m, 2H), 2.45-2.41 (m, 2H), 2.17 (d, J=6.8 Hz, 2H), 1.83 (d, J=13.6 Hz, 2H), 1.75 (br s, 1H), 1.65-1 .59 (m, 2H), 1.30-1.24 (m, 2H).

Example 27

Synthesis path:

Stage 1

Compound 13-1 (20 g, 224.48 mmol, 20.16 ml, 1 eq.) was dissolved in dichloromethane (100 ml) and then compound 27-1 (23.19 g, 269.38 mmol, 24, 26 ml, 1.2 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (68.35 g, 448.97 mmol, 67.67 ml, 2 eq.). The reaction system was stirred at 45° C. for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that compound 27-2 was obtained. The reaction solution was poured into a saturated ammonium chloride solution (100 ml) and extracted with dichloromethane (100 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate = 20:1 to 5:1, v/v) to obtain compound 27-2.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.69 (s, 3H), 2.35-2.32 (m, 2H), 2.29-2.26 (m, 2H), 1.60 (s, 6H).

Stage 2

Under nitrogen atmosphere, compound 27-2 (18 g, 102.75 mmol, 1 eq.) in a dry flask was dissolved in tetrahydrofuran (1 L) and lithium aluminum hydride (2.14 g, 56.51 mmol, 0.55 equiv.) at 0°C. The reaction system was slowly heated to 25° C. and stirred for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. A saturated solution of Rochelle's salt (9 ml) was slowly added dropwise to the reaction solution while stirring, and then filtered. The filtrate was immediately concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate = 4:1, v/v) to give compound 27-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.68-3.63 (m, 2H), 2.04-1.97 (m, 2H), 1.59 (s, 6H), 1.55 -1.51 (m, 2H).

Stage 3

Compound 27-3 (2 g, 13.59 mmol, 1 eq.) in a dry flask was dissolved in dichloromethane (50 ml) and pyridinium chlorochromate (4.39 g, 20.38 mmol, 1.5 eq.) was added at 0 °C under nitrogen conditions. The reaction system was stirred at 25° C. for 1 hour. TLC (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The reaction was stopped with water (20 ml), and then the reaction solution was extracted with dichloromethane (10 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate=30:1 to 10:1) to obtain compound 27-4.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.78 (s, 1H), 2.52-2.49 (m, 2H), 2.25-2.23 (m, 2H), 1.60 (s, 6H).

Stage 4

Compound 13-2 (2.68 g, 10.61 mmol, 2.2 eq.) in a dry flask was dissolved in tetrahydrofuran (15 ml) and sodium hydride (578.69 mg, 14.47 mmol, purity: 60) was added %, 3 equiv.) at 0°C under nitrogen atmosphere. After stirring for 30 min, a solution of compound 27-4 (700 mg, 4.82 mmol, 1 eq) in tetrahydrofuran (5 ml) was added and the reaction system was stirred at 25° C. for 16 h. ether : ethyl acetate = 5:1) it was seen that the reaction was completed. The reaction solution was poured into dilute hydrochloric acid (0.5 mol/l, 20 ml). The aqueous phase was extracted with ethyl acetate (20 ml×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate = 30:1 to 10:1, v/v) to give compound 27-5.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.83-6.76 (m, 1H), 5.77 (d, J=15.6 Hz, 1H), 2.16-2.06 (m , 2H), 2.05-2.04 (m, 2H), 1.60 (s, 6H), 1.48 (s, 9H).

Stage 5

Under low argon flow conditions, carbon-supported palladium catalyst (150 mg, purity: 10%) was added to the hydrogenation flask, methanol (20 ml) was slowly added along the side of the flask, and then compound 27-5 (800 mg, 3.29 mmol, 1 eq.). After 3 purges with hydrogen, the reaction system was stirred at 20° C. for 2 h under hydrogen atmosphere (50 psi). According to the results of TLC (simple petroleum ether: ethyl acetate = 5:1) it was seen that the reaction was completed. The reaction solution was immediately filtered and concentrated under reduced pressure to obtain compound 27-6.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 2.22 (t, J=7.6 Hz, 2H), 1.60-1.57 (m, 2H), 1.44 (s, 9H), 1.37-1.28 (m, 4H), 1.10 (s, 6H).

Stage 6

Compound 1-3 (20 g, 121.07 mmol, 1 eq.) and compound 25-2 (26.71 g, 181.61 mmol, 1.5 eq.) were dissolved in toluene (300 ml) and then added to them lithium hexamethyldisilazide (1 mol/l, 242.15 ml, 2 equiv.) at 0°C under nitrogen atmosphere. The reaction system was heated to 25° C. and stirred for 16 h. TLC results confirmed that compound 1-3 was completely consumed and new spots were obtained. The LCMS results confirmed that compound 1-3 was completely consumed and compound 27-7 was obtained. The reaction solution was poured into a saturated ammonium chloride solution (500 ml) to stop the reaction, and extracted with ethyl acetate (200 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate = 100:1 to 1:1.5, v/v) to give compound 27-7. MS(ESI) m/s: 281.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.44 (s, 1H), 7.37-7.28 (m, 2H), 6.61 (d, J=2.8 Hz, 1H), 6.45 (d, J=3.2 Hz, 1H), 3.99 (t, J=2.8 Hz, 2H), 3.13 (t, J=3.2 Hz, 2H), 2, 62-2.55 (m, 2H).

Stage 7

Compound 27-7 (31 g, 110.62 mmol, 1 eq.) was dissolved in dichloromethane (300 ml) and then methyl oxalyl chloride (27.10 g, 221.23 mmol, 20.38 ml, 2 eq.) was added at 0°C under nitrogen conditions. The reaction system was stirred at 25° C. for 1.5 hours. TLC results (petroleum ether:ethyl acetate = 3:1) confirmed that the reaction was complete. The reaction solution was poured into ice water (300 ml) to stop the reaction, and then extracted with ethyl acetate (100 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate = 100:1 to 2.5:1, v/v) to give compound 27-8. MS(ESI) m/s: 367.1 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.92 (s, 1H), 7.80 (s, 1H), 7.43-7.32 (m, 2H), 4.37 (t, J =7.4 Hz, 2H), 3.91 (s, 3H), 3.19 (t, J=7.6 Hz, 2H), 2.65-2.57 (m, 2H).

Stage 8

Compound 27-8 (11 g, 21.02 mmol, 1 eq) was dissolved in acetic acid (110 ml) and then N-chlorosuccinimide (4.21 g, 31.53 mmol, 1.5 eq) was added. The reaction system was stirred at 40° C. for 16 hours. TLC showed that the compound was completely consumed. The reaction solution was poured into water (100 ml) to stop the reaction, and extracted with ethyl acetate (50 ml×3). The organic phase was washed successively with saturated sodium bicarbonate solution (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate = 100:1 to 4:1, v/v) to obtain compound 27-9. MS(ESI) m/s: 401.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.29 (s, 1H), 7.36-7.30 (m, 2H), 4.40 (t, J=7.4 Hz, 2H), 3.98 (s, 3H), 3.26 (t, J=7.6 Hz, 2H), 2.61-2.51 (m, 2H).

Stage 9

Compound 27-9 (8 g, 19.96 mmol, 1 eq.) was dissolved in a mixture of tetrahydrofuran (100 ml) and water (100 ml) and then lithium hydroxide monohydrate (2.51 g, 59.89 mmol, 3 equiv.). The reaction system was stirred at 25° C. for 16 hours. LCMS results confirmed that the compound had been completely consumed. The reaction solution was poured into water (50 ml), extracted with ethyl acetate (50 ml×2), adjusted to pH=2 with 1.0 mol/L hydrochloric acid, and then extracted with ethyl acetate (50 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 27-10. MS(ESI) m/s: 387.1 [M+H] ⁺ .

¹ H NMR (400 MHz, MeOH-d ₄ ) δ = 7.63-7.41 (m, 2H), 4.38 (t, J=7.6 Hz, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.62-2.50 (m, 2H).

Stage 10

Compound 27-10 (150 mg, 387.89 µmol, 1 eq.) in a dry flask was dissolved in dichloromethane (10 ml) and oxalyl chloride (98.47 mg, 775.78 µmol, 67.91 µl, 2 eq. .) and N,N-dimethylformamide (2.84 mg, 38.79 µmol, 2.98 µl, 0.1 eq) under nitrogen at 0°C. The reaction system was stirred at 20°C for 1 hour. Two drops of the reaction solution were taken and methanol was added to them to stop the reaction, and then detection was performed. According to the results of TLC (simple petroleum ether : ethyl acetate = 3:1) it was seen that the conversion of the source materials was completed. The reaction solution was immediately concentrated under reduced pressure to obtain compound 27-11.

Stage 11

Compound 27-6 (87.69 mg, 407.25 µmol, 1.1 eq.) in a dry flask was dissolved in dichloromethane (5 ml) and triethylamine (112.39 mg, 1.11 mmol, 154.59 µl, 3 eq.). A solution of compound 27-11 (150 mg, 370.23 μmol, 1 eq.) in dichloromethane (5 ml) was added at 0° C. under nitrogen atmosphere. The reaction system was stirred at 20°C for 2 hours. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was poured into dilute hydrochloric acid (0.5 mol/l, 20 ml). The aqueous phase was extracted with dichloromethane (10 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 27-12. MS(ESI) m/s: 528.2 [M+H-(tert-Bu)] ⁺ .

Stage 12

Compound 27-12 (150 mg, 256.84 µmol, 1 eq.) in a dry flask was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (585.69 mg, 5.14 mmol, 380.32 µl, 20 eq. ). The reaction system was stirred at 20°C for 1 h. According to the results of LCMS and HPLC, it was seen that the reaction was completed. The reaction solution was immediately concentrated. The crude product was purified by preparative HPLC (neutral system, column: Xtimate C18 150 mm × 25 mm × 5 μm; mobile phase: water (containing 0.04% ammonium hydrochloride + 10 mM ammonium bicarbonate)-acetonitrile; % content of acetonitrile: 28 % - 58%, 10.5 min) to give compound 27. MS(ESI) m/s: 528.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.02 (s, 1H), 8.25 (s, 1H), 7.64-7.60 (m, 2H), 4.28 (t , J=6.8 Hz, 2H), 3.08 (t, J=7.2 Hz, 2H), 2.50-2.46 (m, 2H), 2.20 (t, J=7, 2 Hz, 2H), 1.68-1.64 (m, 2H), 1.50-1.46 (m, 2H), 1.35-1.28 (m, 8H).

Example 28

Synthesis path:

Stage 1

Compound 28-1 (500 mg, 2.67 mmol, 1 eq.) and S-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (1.40 g, 3.47 mmol, 1.3 eq.) were added to dichloromethane (10 ml). The resulting mixture was cooled to -25°C and 1,8-diazabicyclo[5.4.0]undec-7-ene (813.28 mg, 5.34 mmol, 805.23 µl, 2.0 eq. ). The reaction system was stirred at -25° C. for 1.5 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that the compound 28-1 was completely consumed and new spots were obtained. Water (10 ml) was added to the reaction solution with stirring and allowed to stand to separate liquids to obtain a dichloromethane phase. Saturated aqueous sodium chloride solution (10 ml×1) was added to the dichloromethane phase, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using a COMBI-FLASH chromatography system (gradient elution: petroleum ether:ethyl acetate = 50:1 to 5:1, v/v) to give compound 28-2.

¹ H NMR (400 MHz, CHCl ₃ ) δ = 3.99-3.92 (m, 4H), 2.82-2.77 (m, 2H), 2.22-2.17 (m, 2H) , 1.83-1.79(m, 2H), 1.61-1.55(m, 2H).

Stage 2

Compound 28-2 (500 mg, 1.96 mmol, 1 eq.) was dissolved in dichloromethane (30 ml) and sulfuric acid (3 ml) was added at 0°C. The reaction system was heated to 26° C. and stirred for 5 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that compound 28-2 was completely consumed and new spots were obtained. The reaction solution was poured into ice water (30 ml), and a saturated aqueous sodium carbonate solution was added slowly until pH=7. Then, the resulting mixture was extracted with dichloromethane (20 ml×3). The organic phases were combined, washed with saturated aqueous sodium chloride solution (50 ml×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using a COMBI-FLASH chromatography system (petroleum ether:ethyl acetate = 50:1 to 3:1, v/v) to give compound 28-3.

¹ H NMR (400 MHz, CHCl ₃ ) δ = 3.12-3.09 (m, 2H), 2.56-2.48 (m, 2H), 2.45-2.39 (m, 4H) .

Stage 3

Compound 28-3 (270 mg, 1.28 mmol, 1 eq) was dissolved in dichloromethane (5 ml) and methyl(triphenylphosphoranylidene)acetate (427.56 mg, 1.28 mmol, 1 eq) was added at 26°C under nitrogen atmosphere. The reaction system was heated to 50° C. and stirred for 6 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that compound 28-3 was completely consumed and new spots were obtained. The reaction solution was cooled to room temperature, water (10 ml) was added thereto, and then extracted with dichloromethane (10 ml×2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10 ml×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using a COMBI-FLASH chromatography system (petroleum ether:ethyl acetate = 50:1 to 5:1) to give compound 28-4.

¹ H NMR (400 MHz, CHCl ₃ ) δ = 5.76 (s, 1H), 4.01-3.98 (m, 1H), 3.71 (s, 3H), 2.97-2.92 (m, 2H), 2.43-2.37 (m, 1H), 2.32-2.31 (m, 1H), 2.02-1.96 (m, 3H).

Stage 4

Compound 28-4 (250 mg, 935.63 µmol, 1 eq.) and methanol (10 ml) were added to a dry hydrogenation flask and carbon-supported palladium catalyst (20 mg, 935.63 µmol, purity: 5%, 1 equiv.) in a hydrogen atmosphere. The reaction system was stirred at 60° C. for 16 h under hydrogen atmosphere (50 psi). The results of LCMS showed that compound 28-4 was completely consumed. The reaction solution was filtered through Celite to remove the carbon-supported palladium catalyst, and the filtrate was concentrated under reduced pressure to obtain compound 28-5. MS (ESI) m/z: 239.7 [M+H] ⁺ .

Stage 5

Compound 28-5 (67.90 mg, 283.84 µmol, 1 eq) and sodium bicarbonate (143.07 mg, 1.70 mmol, 66.24 µl, 6 eq) were added to dichloromethane (2 ml) and a mixture of compound 27-11 (115 mg, 283.84 µmol, 1 eq.) and dichloromethane (2 ml) was slowly added thereto at 0°C. The reaction system was heated to 26°C and stirred for 0.5 h. According to the results of TLC (simple petroleum ether : ethyl acetate = 2:1) it was seen that the compound 27-11 was completely consumed. Water (10 ml) was added to the reaction solution, followed by extraction with dichloromethane (5 ml×2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (10 ml×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated using a COMBI-FLASH chromatography system (gradient elution: petroleum ether:ethyl acetate = 50:1 to 3:1, v/v) to give compound 28-6. MS (ESI) m/z: 608.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CHCl ₃ ) δ = 8.47 (s, 1H), 7.34 (dd, J=9.0, 6.4 Hz, 2H), 6.22-6.16 (m , 1H), 4.33 (t, J=7.2 Hz, 2H), 3.70-3.69 (m, 3H), 3.27 (t, J=7.6 Hz, 2H), 2 .62-2.52 (m, 3H), 2.41 (d, J=7.2 Hz, 1H), 2.40-2.26 (m, 2H), 2.04-1.96 (m , 1H), 1.86-1.75 (m, 3H), 1.28-1.24 (m, 3H).

Stage 6

Compound 28-6 (60.00 mg, 98.70 µmol, 1 eq.) was dissolved in a mixture of tetrahydrofuran (1 ml), methanol (1 ml) and water (1 ml) and lithium hydroxide monohydrate (24.85 mg, 592.18 µmol, 6 eq.) at 40°C. The reaction system was stirred at 40° C. for 0.5 h. According to the results of LCMS, it was seen that compound 28-6 was completely consumed. A 2 mol/L aqueous potassium hydrogen sulfate solution was added to the reaction solution until pH=4, followed by extraction with dichloromethane (10 mL×2). The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (formic acid system, column: Waters Xbridge 150 mm x 18 mm x 5 µm; mobile phase: water (containing 0.225% formic acid)-acetonitrile; % acetonitrile content: 55% - 85%, 7 min) to give compound 28. MS (ESI) m/z: 594.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.12 (s, 1H), 10.07 (d, J=8.2Hz, 1H), 8.70 (d, J=16.2Hz , 1H), 7.63 (dd, J=10.2, 6.2Hz, 2H), 4.31 (t, J=7.2Hz, 2H), 3.10 (t, J=7 .6Hz, 2H), 2.49-2.43 (m, 3H), 2.35-2.25 (m, 2H), 2.16-2.07 (m, 2H), 1.78-1 .65 (m, 3H), 1.59-1.42 (m, 2H), 1.28-1.17 (m, 1H).

Examples 29 and 30

Synthesis path:

Compound 28 (15 mg, 25.26 μmol, 1 eq.) was separated by SFC (column: Phenomenex-Amylose-1 (250 mm × 30 m, 5 μm); mobile phase: 0.1% NH ₃ H ₂ O EtOH; % B: 35% - 35%, min) to give compound 29 (column retention time for SFC: 1.763 min) and compound 30 (column retention time for SFC: 2.086 min). SFC analysis conditions: column: Agilent 1260 chiral column with DAD detector with the following specification: AD-3 50×3 mm ID, 3 µm; mobile phase: A: carbon dioxide, B: ethanol (containing 0.05% diethanolamine); gradient: B, changing from 5% to 40% in 2.5 minutes, held at 40% for 0.35 minutes, and then allowed to change smoothly for 1.65 minutes; flow rate: 2.5 ml/min; column temperature: 40°C.

Compound 29: ¹ H NMR (DMSO-d ₆ ) δ = 10.14 (br s, 1 H), 8.65 (br s, 1 H), 7.68-7.62 (m, 2 H), 4.35-4.33(m, 2H), 3.13-3.09(m, 2H), 2.37-2.31(m, 2H), 2.09-2.03( m, 2 H), 1.70-1.62 (m, 3 H), 1.59-1.48 (m, 2 H), 1.27-1.21 (m, 4 H).

Compound 30: ¹ H NMR (DMSO-d ₆ ) δ = 10.09 (s, 1 H), 8.70 (s, 1 H), 7.64 (dd, J=10.2, 6.27 Hz , 2 H), 4.31 (t, J=7.2 Hz, 2 H), 3.10 (t, J=7.2 Hz, 2 H), 2.34-2.25 (m, 4 H), 2.14-2.09 (m, 1 H), 1.75-1.32 (m, 4 H), 1.46 (br s, 2 H), 1.24 (s, 2 H ).

Example 31

Synthesis path:

Stage 1

Compound 31-1 (22.94 g, 266.43 mmol, 23.99 ml, 2 eq.), Compound 31-2 (10 g, 133.22 mmol, 9.52 ml, 1 eq.) and 1, 8-diazabicyclo[5.4.0]undec-7-ene (42.59 g, 279.75 mmol, 42.17 ml, 2.1 eq.) in a dry flask was dissolved in dichloromethane (200 ml) and the reaction system was stirred at 40°C for 3 hours. According to the results of LCMS, it was seen that the reaction was completed. The reaction solution was poured into water (500 ml) to separate liquids. The aqueous phase was extracted with dichloromethane (100 ml×2) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, petroleum ether:ethyl acetate = 3:1, v/v) to give compound 31-3.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.62 (s, 6H), 2.32-2.27 (m, 6H), 2.22-2.20 (m, 2H), 1.51 (s, 3H).

Stage 2

Compound 31-3 (10 g, 40.45 mmol, 1 eq.) in a dry flask was dissolved in tetrahydrofuran (100 ml) and sodium methoxide (5 M, 9.71 ml, 1.2 eq.) was added. The reaction system was stirred at 15° C. for 16 hours. According to the results of LCMS, it was seen that compound 31-4 was obtained. The reaction solution was slowly poured into 1 mol/l dilute hydrochloric acid (100 ml) to separate liquids. The aqueous phase was washed with half-saturated brine (50 ml×3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 31-4. MS (ESI) m/z: 216.1 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ = 12.12 (s, 1H), 4.11 (s, 3H), 3.36-3.24 (m, 1H), 2.54-2.45 (m, 2H), 2.40-2.35 (m, 2H), 2.19-1.54 (m, 1H), 1.26 (s, 3H).

Stage 3

Compound 31-4 (4 g, 18.59 mmol, 1 eq.) was dissolved in a mixture of 2-methyltetrahydrofuran (20 ml) and water (20 ml) in a flask and potassium hydroxide (3.13 g, 55.76 mmol, 3 eq.). The reaction system was stirred at 85° C. for 16 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The reaction solution was left to stratify. The aqueous phase was extracted with ethyl acetate (10 ml×6) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate = 20:1 to 3:1, v/v) to give compound 31-5.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 2.89-2.78 (m, 2H), 2.50-2.41 (m, 2H), 2.39-2.27 (m, 2 H ), 2.06-1.82 (m, 2H), 1.56 (s, 3H).

Stage 4

Compound 31-5 (11.4 g, 72.53 mmol, 1 eq.) in a dry flask was dissolved in toluene (100 ml) and compound 31-6 (26.68 g, 79.79 mmol, 1.1 eq. .). The reaction system was stirred at 110°C for 16 h under nitrogen atmosphere. The results of LCMS showed that the reaction was complete. The reaction solution was poured into 0.5 mol/l dilute hydrochloric acid (50 ml). The aqueous phase was extracted with ethyl acetate (10 ml×3) and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, pore size 100-200 mesh, gradient elution: petroleum ether:ethyl acetate = 100:0 to 10:1, v/v) to give compound 31-7.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.70 (s, 1H), 3.68 (s, 3H), 3.51-3.48 (s, 1H), 2.68-2.63 (m, 2H), 2.35-2.04 (m, 3H), 1.77-1.60 (m, 2H), 1.59 (s, 3H).

Stage 5

The backbone nickel hydrogenation catalyst (7.00 g, 119.26 mmol, 3.63 eq.) was dissolved in methanol (60 ml) and then compound 31-7 (7 g, 32.83 mmol, 1 eq.) was added. The reaction system was stirred at 30° C. for 16 h under hydrogen atmosphere (30 psi). According to the results of TLC (dichloromethane : methanol = 10:1) it was seen that the compound 31-7 was completely consumed. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 31-8.

¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 3.65 (s, 3H), 2.29-2.22 (m, 2H), 1.73-1.67 (m, 2H), 1 .56-1.51 (m, 4H), 1.39-1.38 (m, 1H), 1.35 (s, 3H), 1.19-1.14 (m, 2H).

Stage 6

Compound 27-10 (0.5 g, 1.29 mmol, 1 eq.) was dissolved in N,N-dimethylformamide (10 mL) and then benzotriazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate (1.08 g, 2.07 mmol) was added. , 1.6 eq.), 1-hydroxybenzotriazole (297.00 mg, 2.20 mmol, 1.7 eq.) and N,N-diisopropylethylamine (668.41 mg, 5.17 mmol, 900.82 µl, 4 eq.). The resulting mixture was stirred at 20° C. for 0.5 h and then compound 31-8 (287.44 mg, 1.55 mmol, 1.2 eq.) was added thereto. The reaction system was stirred at 40° C. for 15.5 hours. The results of LCMS and HPLC confirmed that the reaction was complete. The reaction solution was poured into water (50 ml) to stop the reaction, and then filtered. The filtrate was extracted with ethyl acetate (20 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (gradient elution: petroleum ether:ethyl acetate = 100:1 to 3:1, v/v). The crude product was then separated with SFC (retention time = 2.35 min) (column: DAICEL CHIRALPAKIC (250 mm × 30 mm, 5 μm); mobile phase: Neu-MeOH; % B: 40% - 40%, 10 min ) to give compound 31-9. MS (ESI) m/z: 554.2 [M+H] ⁺ .

Stage 7

Compound 31-9 (0.1 g, 180.52 µmol, 1 eq) was purified by preparative HPLC (neutral system, column: Xtimate C18 150 mm x 25 mm x 5 µm; mobile phase: water (containing 10 mM bicarbonate ammonium)-acetonitrile, % acetonitrile: 50%-80%, 10.5 min) to give compound 31. MS (ESI) m/z: 554.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.01 (s, 1H), 8.30 (s, 1H), 7.66-7.58 (m, 2H), 4.28 (t , J=7.6 Hz, 2H), 3.58 (s, 3H), 3.08 (t, J=7.6 Hz, 2H), 2.49-2.43 (m, 2H), 2 .26 (d, J=7.0 Hz, 2H), 1.88-1.56 (m, 7H), 1.36 (s, 3H), 1.24-1.11 (m, 2H).

Experimental Example 1: qPCR test in in vitro test for HBV

1. Purpose of the experiment:

Assess the inhibitory effect of the compound on HBV by detecting the content of HBV DNA in HepG2.2.15 cells in a real-time qPCR test with the EC ₅₀ of the compound as an indicator.

2. Materials used during the experiment:

2.1. Cell line: HepG2.2.15 cells

HepG2.2.15 cell culture medium (DMEM/F12, Invitrogen-11330057; 10% serum, Invitrogen-10099141; 100 units/ml penicillin and 10 µg/ml streptomycin, Invitrogen-15140122; 1% essential amino acids, Invitrogen-11140076; 2 mM L-glutamine, Invitrogen-25030081; 300 μg/ml geneticin, Invitrogen-10131027)

2.2. Reagents:

Pancreatin (Invitrogen-25300062)

DPBS (Hyclone-SH30028.01B)

DMSO (Sigma-D2650-100ML)

High Efficiency DNA Purification Kit (QIAamp 96 DNA Blood Kit, Qiagen-51162)

Faststart Universal Probe Reagent (FastStart Universal Probe Master, Roche-04914058001)

2.3. Consumables and devices:

96-well cell culture plate (Corning-3599)

CO ₂ thermostat (HERA-CELL-240)

Optical seal film (ABI-4311971)

96-well quantitative PCR plate (Applied Biosystems-4306737)

Fluorescent Quantitative PCR Instrument (Applied Biosystems-7500 Real Time PCR System)

3. Stages of the experiment and methods:

3.1. HepG2.2.15 cells (4×10 ⁴ cells/well) were inoculated into a 96-well plate and cultured overnight at 37° C. under 5% CO ₂ .

в качестве контроля 0% ингибирования использовали 1% DMSO.3.2. On day 2, the compound was diluted in a 3-fold gradient to give a total of 8 dilution gradients. Compound at various concentrations was added to the wells of the culture plate in duplicate. The final concentration of DMSO in the culture medium was 1%. 1 μM GLS4 was used as a control for 100% inhibition (the structure of GLS4 disclosed in WO2008154817A1 is as follows:

1% DMSO was used as a control for 0% inhibition.

3.3. On day 5, the culture medium was replaced with fresh culture medium containing the compound.

3.4. On the 8th day, the culture medium in the culture wells was collected and the high performance DNA purification kit (Qiagen-51162) was used for DNA extraction. See the product instructions for use for specific steps.

The preparation of the reaction solution for PCR is shown in Table 1.

Table 1. Preparation of the reaction solution for PCR

Name Volume required per well (µl) Volume Required for 80 Wells (µl) Reagent with universal probe for quantitative faststart 12.5 1000 Forward primer (10 µmol) 1 80 Reverse primer (10 µmol) 1 80 Probe (10 µmol) 0.5 40

Forward primer sequence: GTGTCTGCGGCGTTTTATCA

Reverse primer sequence: GACAAACGGGCAACATACCTT

Probe sequence: 5' + FAM + CCTCTKCATCCTGCTGCTATGCCTCATC + TAMRA - 3'

3.6. To each well of a 96-well PCR plate was added 15 μl of the reaction mixture, followed by 10 μl of DNA sample or HBV DNA standard.

3.7. PCR reaction conditions: heating to 95°C for 10 minutes, breaking at 95°C for 15 seconds and elongation at 60°C for 1 minute, 40 cycles in total.

3.8. Data analysis:

3.8.1. Calculation of percent inhibition: % ing. = [1 - (DNA copy number in sample - DNA copy number in 1 μM GLS4)/(DNA copy number in DMSO control - DNA copy number in 1 μM GLS4)]×100.

3.8.2. EC ₅₀ Calculation: The half-maximal inhibitory concentration (EC ₅₀ ) of the compound for HBV was calculated using GraphPad Prism software.

3.8.3. The experimental results are shown in Table 2.

Table 2. Results for EC ₅₀ according to qPCR test

Sample
(title connection) Half maximum inhibitory concentration
(EC ₅₀ ) HBV 1 35 nM 2 3 nM 3 5 nM 4 580 nM 5 7 nM 6 110 nM 7 30 nM 8 9 nM 9 41 nM 10 2 nM eleven 4 nM 12 5 nM 13 19 nM 14 70 nM 15 37 nM 16 41 nM 17 7 nM 18 11 nM 19 20 nM 20 11 nM 21 3 nM 22 14 nM 23 27 nM 24 299 nM 25-3 4 nM 25 4 nM 26 174 nM 27 12 nM 28 2 nM 29 3 nM thirty 1 nM 31 5 nM

Experimental Example 2: hERG potassium channel inhibition test

1. The purpose of the experiment:

Assess the effect of a compound disclosed herein on the hERG potassium channel using an automatic clamp method.

2. Method of conducting the experiment

2.1. Cell culture

The cells used in the experiment stably expressing the hERG potassium channel were CHO-hERE from Aviva Biosciences. CHO-hERG was cultured at 37°C in 5% CO ₂ atmosphere. CHO hERG culture medium is shown in Table 3.

Table 3. CHO hERG culture medium

Reagent Provider Volume (ml) Culture medium F12 Invitrogen 500 Fetal bovine serum Invitrogen 50 G418/geneticin Invitrogen 1 Hygromycin B Invitrogen 1

2.2. Cell pretreatment

The CHO-hERG cells used in this experiment were cultured for at least two days, and the cell density reached 75% or more. Before the experiment, the cells were cleaved with TrypLE, and then the collected cells were resuspended in extracellular fluid.

2.3. Preparation of intracellular and extracellular fluid

The extracellular fluid had to be prepared once a month. The intracellular fluid had to be frozen in aliquots at -20°C. The compositions of the intracellular and extracellular fluid are shown in Table 4.

Table 4. Compositions of intracellular and extracellular fluid

Compound Extracellular fluid (mM) Intracellular fluid (mM) NaCl 145 - KCl 4 120 KOH - 31.25 _CaCl2 2 5.374 MgCl ₂ 1 1.75 Glucose 10 - _Na2ATP - 4 HEPES 10 10 EGTA - 10 pH The pH was adjusted to 7.4 with sodium hydroxide The pH was adjusted to 7.4 with potassium hydroxide Osmotic pressure 295 mOsm 285 mOsm

2.4. Getting a connection

The test compound and its positive control, called amitriptyline, were dissolved in DMSO to form a stock solution at a defined concentration. The stock solution was then diluted to various gradients and finally added to the extracellular fluid in a certain ratio necessary to dilute to test concentration. Before the start of the experiment, the presence of sediment was checked with the naked eye. Finally, the concentration of DMSO in the solution to be tested and the positive control called amitriptyline should not exceed 0.3%.

2.5. Voltage stimulation scheme

At an initial potential of -80 mV, stimulation with a voltage of -50 mV was applied for 80 ms to record the value of the residual current of the cell; then, the hERG channel was opened by depolarization to +20 mV for 4800 ms, the hERG trace current was excited by repolarization to -50 mV for 5000 ms, and data was recorded; and finally, the voltage was restored to the original potential of -80 mV and maintained for 3100 ms. The voltage stimulation described above was repeated every 15,000 ms.

2.6. Capturing data during potential clamping in whole cells using QPatch ^HTX technology

The hERG experiment with QPatch ^HTX was performed at room temperature. Whole cell application scheme, voltage stimulation scheme, and compound detection scheme were created using QPatch Assay Software 5.2 (Sophion Bioscience).

First, 30 repeated predetermined voltage stimulations were performed, as a result of which this region on the current spectrum was taken as the base region for subsequent analysis. Then, 5 μl of extracellular fluid was added and voltage stimulation was repeated three times. Sequentially, in a volume of 5 μl, each compound was added at an effective concentration, and the voltage stimulation was repeated three times. Cells were incubated for at least 5 minutes with compound at each concentration tested. Throughout the process of recording the results, all indicators had to meet the standard of acceptability for data analysis. If there was no compliance with the requirements of the standard, the cell was not included in the range of analysis, and the connection had to be tested again. The aforementioned result logging process was performed automatically by the Qpatch analysis software. Compound concentrations tested were 0.24 μM, 1.20 μM, 6.00 μM, and 30.00 μM, and each concentration was duplicated for at least two cells.

2.7. Data analysis

In each complete current data recording, the percentage inhibition of each compound at the effective concentration can be calculated from the percentage of peak current in the negative control. The dose-response curve was obtained by approximation using the standard Hill equation, and the equation itself is as follows:

I _(C) = I _b + (I _fr - I _b ) × c ⁿ /(IC ₅₀ ⁿ + c ⁿ )

C means test compound concentration, n means slope, I means current

Curve fitting and calculation of the degree of inhibition were performed entirely using Qpatch analytical software. If the degree of inhibition exceeded 50% at the lowest concentration, or the degree of inhibition did not reach 50% at the highest concentration, the corresponding IC ₅₀ of the compound was below the lowest concentration or greater than the highest concentration.

2.8. Test results

Table 5 shows the IC ₅₀ hERG values for the compounds of the examples.

Table 5. IC values ₅₀ hERG for compounds from examples

Sample IC ₅₀ hERG (µM) Compound 18 >40 Compound 25 >40

Experimental Example 3: Cytochrome P450 Isozyme Inhibition Experiment

Purpose of the experiment: to determine the inhibitory effect of the test compound on the activity of microsomal isozymes of human liver cytochrome P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).

Experimental procedure: first, the test compound (10 mM) was diluted in a gradient to prepare working solutions (100x final concentration) with the following concentrations: 5, 1.5, 0.5, 0.15, 0.05, 0.015 and 0.005 mM, and simultaneously prepared working solutions of positive inhibitors of P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and mixtures of their specific substrates (5 in 1); human liver microsomes frozen in a refrigerator at -80°C were thawed on ice, and after thawing, human liver microsomes were diluted in PB to prepare a working solution with a specific concentration (0.253 mg/ml); 20 μl of the substrate mixture (20 μl of PB was added to the control well) and 158 μl of the working solution of human liver microsomes were added to the reaction plate, which was then placed on ice for use; then, 2 µl of test compound at each concentration (N=1) and specific inhibitor (N=2) was added to the appropriate well, and the group without inhibitor (test compound or positive inhibitor) was added with the appropriate organic solvent as a control (test compound control). was 1:1 DMSO:MeOH, the positive control was 1:9 DMSO:MeOH); after pre-incubation in a water bath at 37°C for 10 minutes, 20 µl of dihydrolipoamide dehydrogenase (NADPH) solution was added to the reaction plate and incubated in a water bath at 37°C for 10 min, 400 µl of cold acetonitrile solution (internal) was added to stop the reaction the standard was 200 ng/ml tolbutamide and labetalol) and the reaction plate was placed on a shaker and shaken for 10 minutes; after centrifugation at 4000 rpm for 20 minutes, 200 µl of the supernatant was collected and added to 100 µl of water to dilute the sample, and finally the plate was sealed, mixed by shaking, shaken evenly, and detected by LC/MS/ MS. The experimental results are shown in Table 6.

Table 6. Results of the inhibitory effect of the test compound on the activity of cytochrome P450 isozymes of human liver microsomes

Compound IC ₅₀ (µM) CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4-M Compound 2 >50 >50 >50 >50 >50 Compound 17 >50 >50 >50 >50 >50 Compound 18 >50 >50 >50 >50 >50 Compound 25 >50 >50 >50 >50 >50

Experimental Example 4: Cytotoxicity Experiment

1. The compound was diluted with DMSO (dimethyl sulfoxide) in a 3-fold gradient to give 9 concentrations and added to a 96-well plate in duplicate. The compound concentration was 200 times the final test concentration.

2. Cells were washed once with PBS (phosphate buffered saline), added with 0.25% trypsin and digested for about 2-5 minutes in a 5% CO ₂ incubator at 37°C. Digestion was then stopped with cell culture medium, and the cells were separated into single cells by pipetting with a pipette.

3. Cell density was counted with a cell counter and adjusted to the desired density with medium.

4. Cells were added to a 96-well plate in which the compound was added. The final concentration of DMSO in each well was 0.5%. Wells containing 0.5% DMSO were used as non-toxic negative controls and wells containing cell culture medium were used as controls with 100% cytotoxicity. The cell plate was then incubated for 3 days in a cell incubator in 5% CO ₂ at 37°C.

5. The chemiluminescence signal (RLU) of each well in the cell culture plate was detected using the CellTiter-Glo Cell Viability Detection Kit using an Envision multifunctional microplate reader according to the instructions supplied with the kit.

6. To calculate cell viability in each well (% cell viability), the raw data (RLU) was substituted into the following formula:

Cell viability, % =

_Sample RLU : signal value from the sample well; Mean RLU _{of cell control} : mean signal from cell control well; _{Media Control} Mean RLU: The average of the signal from the media control well.

7. Using the GraphPad Prism software, cell viability data were non-linearly extrapolated to fit a dose-response curve and a 50% cytotoxic concentration (CC ₅₀ ) value was obtained for the compound. The results are shown in Table 7.

Table 7. Results of the 50% Cytotoxic Concentration (CC ₅₀ )

Compound CC ₅₀ (µM) Compound 18 >50 Compound 25 >50

Experimental Example 5: In Vitro Microsomal Stability Experiment

Metabolic stability of the compound in human and CD-1 mouse liver microsomes

Purpose of the experiment: to evaluate the metabolic stability of the compound in human and CD-1 mouse liver microsomes.

Procedures carried out during the experiment: first, the test compound (10 mm) was subjected to a two-step dilution, while the compound was diluted to an intermediate concentration of 100 μm with 100% methanol, and the working solution was diluted to 10 μm with potassium phosphate buffer; prepared eight 96-well incubation plates, which were respectively assigned the names "T0", "T5", "T10", "T20", "T30", "T60", "blank" and "NCF60"; the reaction times corresponding to the first 6 incubation plates were 0, 5, 10, 20, 30 and 60 minutes, respectively; in the case of a blank plate, neither test compound nor control compound was added, and in the case of the NCF60 plate, potassium phosphate buffer was used with a 60 minute incubation instead of the NADPH regeneration system solution; T0, T5, T10, T20, T30, T60 and NCF60 plates were inoculated with 10 µl of working solution with test compound and 80 µl of working solution with microsomes (liver microsome protein concentration was 0.625 mg/ml), while only working solution was added to the blank plate. the microsome solution and then all incubation plates were placed in a 37° C. water bath to pre-incubate for about 10 minutes; after pre-incubation, to start the reaction, 10 μl of the working solution of the NADPH regeneration system was added to each well with a sample of all plates, except for the NCF60 plate and the T0 plate, and 10 μl of potassium phosphate buffer was added to each well of the NCF60 plate; thus, in samples with test compound or control compound, the final concentrations of compound, testosterone, diclofenac and propafenone in the reaction mixture were 1 μM, the concentration of liver microsomes was 0.5 mg/ml, and the final concentrations of DMSO and acetonitrile in the reaction system were respectively 0 .01% (v/v) and 0.99% (v/v); after incubation for the appropriate time (e.g., 5, 10, 20, 30, and 60 minutes) to stop the reaction, 300 µl of stop solution (an acetonitrile solution containing 100 ng/ml tolbutamide and 100 ng/ml labetalol) was added to each sample well ); 300 µl of stop solution and then 10 µl of NADPH working solution were added to the plate T0, all plates with samples were mixed by shaking and centrifuged in a centrifuge (3220 × g) for 20 minutes, and then 100 µl of the supernatant was taken from each well and diluted with 300 µl of pure water for analysis in the liquid chromatography - tandem mass spectrometry system.

The experimental results are shown in Table 8.

Table 8. Metabolic stability results of compound test in human and CD-1 mouse liver microsomes

Compound View T _1/2 (min) CL _{female (micro)} CL _{internal (liver)} (µl/min/mg) (ml/min/kg) 17 CD-1 mice >145 <9.6 <38.0 Human >145 <9.6 <8.6 18 CD-1 mice >145 <9.6 <38.0 Human >145 <9.6 <8.6 25 CD-1 mice >145 <9.6 <38.0 Human >145 <9.6 <8.6

.

Metabolic stability of the compound in liver microsomes of SD rats, beagle dogs and cynomolgus monkeys

Purpose of the experiment: to evaluate the metabolic stability of test compounds 18 and 25 in liver microsomes of rats, beagle dogs and cynomolgus monkeys.

Procedures carried out during the experiment: first, the test compound (10 mm) was subjected to a two-step dilution, while the compound was diluted to an intermediate concentration of 100 μm with 100% methanol, and the working solution was diluted to 10 μm with potassium phosphate buffer; prepared eight 96-well incubation plates, which were respectively assigned the names "T0", "T5", "T10", "T20", "T30", "T60", "blank" and "NCF60"; the reaction times corresponding to the first 6 incubation plates were 0, 5, 10, 20, 30 and 60 minutes, respectively; in the case of a blank plate, neither test compound nor control compound was added, and in the case of the NCF60 plate, potassium phosphate buffer was used with a 60 minute incubation instead of the NADPH regeneration system solution; T0, T5, T10, T20, T30, T60 and NCF60 plates were inoculated with 10 µl of working solution with test compound and 80 µl of working solution with microsomes (liver microsome protein concentration was 0.625 mg/ml), while only working solution was added to the blank plate. the microsome solution and then all incubation plates were placed in a 37° C. water bath to pre-incubate for about 10 minutes; after pre-incubation, to start the reaction, 10 μl of the working solution of the NADPH regeneration system was added to each well with a sample of all plates, except for the NCF60 plate and the T0 plate, and 10 μl of potassium phosphate buffer was added to each well of the NCF60 plate; thus, in samples with test compound or control compound, the final concentrations of compound, testosterone, diclofenac and propafenone in the reaction mixture were 1 μM, the concentration of liver microsomes was 0.5 mg/ml, and the final concentrations of DMSO and acetonitrile in the reaction system were respectively 0 .01% (v/v) and 0.99% (v/v); after incubation for the appropriate time (e.g., 5, 10, 20, 30, and 60 minutes) to stop the reaction, 300 µl of stop solution (an acetonitrile solution containing 100 ng/ml tolbutamide and 100 ng/ml labetalol) was added to each sample well ); 300 µl of stop solution and then 10 µl of NADPH working solution were added to the plate T0, all plates with samples were mixed by shaking and centrifuged in a centrifuge (3220 × g) for 20 minutes, and then 100 µl of the supernatant was taken from each well and diluted with 300 µl of pure water for analysis in the liquid chromatography - tandem mass spectrometry system.

The experimental results are shown in Table 9.

Table 9 Metabolic Stability Results of Test Compound in Liver Microsomes of SD Rats, Beagle Dogs and Javanese Macaques

Compound View T _1/2 (min) CL _{female (micro)} CL _{internal (liver)} (µl/min/mg protein) (ml/min/kg) 18 sd rats >145 <9.6 <17.3 18 Beagle dogs >145 <9.6 <13.8 18 Javanese macaques >145 <9.6 <13.0 25 sd rats >145 <9.6 <17.3 25 Beagle dogs >145 <9.6 <13.8 25 Javanese macaques >145 <9.6 <13.0

Experimental Example 6: Pharmacokinetic Study

Pharmacokinetic study of the test compound in Balb/c mice by oral administration and intravenous injection:

The test compound was mixed with a solution containing dimethyl sulfoxide (10%), polyethylene glycol 400 (60%) and water (30%), and this mixture was vortexed and sonicated until a 0.2 mg/ml clear solution was obtained, which was filtered through a filter Millipore for later use. Female Balb/c mice aged 7-10 weeks were injected intravenously with a solution of the candidate compound at a dose of 1 mg/kg.

The test compound was mixed with an aqueous solution containing 10% polyoxyethylene stearate, and this mixture was vortexed and sonicated to obtain a 0.3 mg/ml clear solution for later use. Female Balb/c mice aged 7-10 weeks were orally administered a solution of the candidate compound at a dose of 3 mg/kg.

Whole blood was collected and blood plasma was obtained. Drug concentration was analyzed by LC-MS/MS and pharmacokinetic parameters were calculated using Phoenix WinNonlin software. The results are shown in table 10.

Table 10. Pharmacokinetic Study Results of Test Compound

Dose Pharmacokinetic parameters Compound 18 Compound 25 IV (1 mg/kg) T _1/2 half-life (h) 2.8 1.95 Clearance CL (ml/min/kg) 50.1 20 Apparent volume of distribution Vd _ss (l/kg) 8.8 3.1 Area under the plasma concentration-time curve AUC _0-24h (nM.h) 617 1488 Oral (3 mg/kg) Peak time T _max (h) 0.5 0.5 Peak concentration C _max (nM) 1460 1480 Area under the plasma concentration-time curve AUC (nM.h) 5018 2274 Bioavailability F (%) 271% 51%

Experimental Example 7: Mice Liver-Blood Ratio Experiment

Liver to Blood Ratio Experiment in Balb/c Mice Orally Administered with Test Compound.

Compound 18 was mixed with an aqueous solution containing 10% polyethylene glycol-15 hydroxystearate, and this mixture was vortexed and sonicated to obtain a 0.3 mg/ml homogeneous suspension for later use. Female Balb/c mice aged 7-10 weeks were orally administered a solution of the candidate compound at a dose of 3 mg/kg.

At a certain point in time, whole blood was collected and blood plasma was obtained. Liver tissue was collected at the appropriate time to prepare a tissue homogenate. Drug concentration was analyzed by LC-MS/MS and pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

Compound 25 was mixed with an aqueous solution containing 10% polyethylene glycol-15 hydroxystearate, and this mixture was vortexed and sonicated to obtain a 0.3 mg/ml clear solution for later use. Female Balb/c mice aged 7-10 weeks were orally administered a solution of the candidate compound at a dose of 3 mg/kg.

At a certain point in time, whole blood was collected and blood plasma was obtained. Liver tissue was collected at the appropriate time to prepare a tissue homogenate. Drug concentration was analyzed by LC-MS/MS and pharmacokinetic parameters were calculated using Phoenix WinNonlin software. The results are shown in Table 11.

Table 11 Liver to Blood Ratio of Test Compound

Compound 18 25 Matrix blood plasma Liver blood plasma Liver AUC _{0-last time point} (nM.h) or (nmol/kg.h) 3694 75412 3476 86036 AUC Ratio (L/P)
Liver/plasma concentration ratio -- 20.4 -- 24.7

Experimental Example 8: In Vivo Efficacy Experiment

Model HDI/HBV

The purpose of the experiment: to evaluate the effectiveness of the compound against hepatitis B virus in mice using the HDI/HBV mouse model.

Compound Preparation: The solvent was an aqueous solution containing 10% polyethylene glycol-15 hydroxystearate; a certain amount of test compounds 18 and 25 were separately dissolved in an aqueous solution containing 10% polyethylene glycol-15 hydroxystearate, and the resulting mixtures were vortexed and sonicated until homogeneous suspensions were obtained. Suspensions were stored at 4°C for later use.

High-pressure injection of a solution of HBV DNA in plasmid through the tail vein of mice: the day of injection of the plasmid was on the 0th day, the day after the injection was the 1st day, and so on. On day 0, all mice were injected with saline containing 10 μg of plasmid DNA through their tail veins at a dose of 8% of body weight, this injection was made in 5 seconds.

Method of administration: intragastric administration was performed to all mice twice a day (interval 8/16 h) on the 1-6th day and once on the 7th day. All mice were sacrificed in the afternoon on the 7th day. The body weight of the mice, which was monitored every day, remained unchanged throughout the experiment.

Sample collection: blood was collected from the submandibular vein 4 hours after the first injection in the morning on the 1st, 3rd and 5th days. All blood samples were collected in tubes with anticoagulant K ₂ -EDTA and centrifuged for 10 minutes at 4°C, 7000g, obtaining approximately 40 μl of blood plasma. Four hours after administration, on the morning of day 7, all mice were sacrificed with CO ₂ . Blood was taken from the heart, and the method of obtaining plasma was the same as above. Two liver tissues were taken, 70-100 mg each, and subjected to rapid freezing with liquid nitrogen. After taking all the samples, they were stored in a refrigerator at -80°C to determine the content of HBV DNA.

Sample Analysis: All plasma and liver samples were detected for HBV DNA by quantitative PCR.

Experimental Results: The experimental results are shown in Table 12, Figure 1 and Figure 2.

Table 12

Compounds tested Dose Decrease in HBV DNA Plasma (5th day)
Δ Log10 copies/µl Liver (7th day)
Δ Log10 copies/100 ng 18 30 mg/kg 2.84 1.99 25 30 mg/kg 3.57 2.36 25 10 mg/kg 2.0 0.94

Claims (40)

1. The compound represented by formula (II) or a pharmaceutically acceptable salt thereof:

Where m is 1; L selected from

T ₁ is selected from the group consisting of N and C (R ₄₃ ); R ₂ is H; R ₃ is selected from the group consisting of Cl, F, Br, I and C _1-6 -alkyl, and C _1-6 -alkyl has 1, 2 or 3 substituents R _c ; each of R ₄₁ and R ₄₅ is independently selected from the group consisting of H; each of R ₄₂ , R ₄₃ and R ₄₄ is independently selected from the group consisting of H, Cl, F, Br, I, CN and C _1-3 -alkyl, and C _1-3 -alkyl optionally has 1, 2 or 3 substituent R _d ; R ₅ is selected from the group consisting of R ₅₁ , C _3-8 cycloalkyl and 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of - NH-, -O- and N, and C _3-8 -cycloalkyl and 5-6-membered heterocycloalkyl optionally have 1, 2 or 3 substituents R ₁ ; R ₅₁ is selected from the group consisting of C _1-7 -alkyl and C _1-3 -heteroalkyl, and C _1-3 -heteroalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of -NH-, -O- and N, with C _1-7 -alkyl and C _1-3 -heteroalkyl optionally having 1, 2 or 3 substituents R _e ; each R ₁ is independently selected from the group consisting of H, Cl, F, Br, I, OH, CN, COOH, C _1-3 -alkyl, -COO-C _1-4 -alkyl and -C _1-3 -alkyl -COO-C _1-4 -alkyl, wherein C _1-3 -alkyl, -COO-C _1-4 -alkyl and -C _1-3 -alkyl-COO-C _1-4 -alkyl optionally have 1, 2 or 3 substituents R _a ; each R _a is independently selected from the group consisting of Cl, F, Br, I, CN, COOH, C _1-3 alkyl and C _1-3 alkoxy, with C _1-3 optionally having 1, 2 or 3 R substituents ; each R _c is independently selected from the group consisting of Cl, F, Br and I; each R _d is independently selected from the group consisting of Cl, F, Br and I; each Re _is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH; each R is independently selected from the group consisting of Cl, F, Br, I, OH, NH ₂ , CN and COOH. 2. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R _a is selected from the group consisting of Cl, F, Br, I, CN, COOH, and -OCH ₃ . 3. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R _c is selected from the group consisting of Cl, F and Br. 4. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein each R ₁ is independently selected from the group consisting of H, Cl, F, OH, CN, COOH, C _1-3 -alkyl, -COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _1-3 -alkyl, and C _1-3 -alkyl, -COO-C _1-3 -alkyl and -C _1-3 -alkyl-COO-C _{1 -3} -alkyl optionally have 1, 2 or 3 substituents R _a . 5. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein each R ₁ is independently selected from the group consisting of H, Cl, F, OH, CN, COOH, CH ₃ , Et,

where CH ₃ , Et,

optionally have 1, 2 or 3 R _a substituents. 6. A compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein each R ₁ is independently selected from the group consisting of H, Cl, F, OH, CN, COOH, CH ₃ , CF ₃ , Et, -CH ₂ -COOH, -CH ₂ -OCH ₃ , -(CH ₂ ) ₂ -COOH,

7. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₃ is selected from the group consisting of Cl, F and C _1-3 alkyl, wherein C _1-3 alkyl optionally has 1, 2 or 3 R _c substituents. 8. A compound or pharmaceutically acceptable salt thereof according to claim 7, wherein R ₃ is selected from the group consisting of Cl, F, CH ₃ , CF ₃ and Et. 9. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₄₂ , R ₄₃ and R ₄₄ are each independently selected from the group consisting of H, Cl, F and CN. 10. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₅₁ is selected from the group consisting of methyl, ethyl, propyl, isopropyl,

moreover, methyl, ethyl, propyl, isopropyl,

And

optionally have 1, 2 or 3 R _e substituents. 11. A compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein R ₅₁ is selected from the group consisting of

And

12. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ₅ is selected from the group consisting of R ₅₁ , cyclohexyl, tetrahydropyranyl, piperidinyl and bicyclo[2.2.2]octyl, wherein cyclohexyl, tetrahydropyranyl, piperidinyl and bicyclo[2.2. 2]octyl optionally have 1, 2 or 3 R ₁ substituents. 13. The compound or pharmaceutically acceptable salt thereof according to claim 12, where R ₅ is selected from the group consisting of R ₅₁ ,

14. The compound or pharmaceutically acceptable salt thereof according to claim 13, where R ₅ is selected from the group consisting of

15. The compound or its pharmaceutically acceptable salt according to claim 1, where the structural unit

selected from the group consisting of

16. A compound represented by the following formulas, its stereoisomer or a pharmaceutically acceptable salt thereof:

17. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 16, selected from the group consisting of

18. Pharmaceutical composition for the treatment or prevention of diseases associated with HBV infection, containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-17. 19. A pharmaceutical composition for the treatment or prevention of diseases associated with HBV infection, according to claim 18, further containing a pharmaceutically acceptable carrier. 20. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-17 as a nucleoprotein inhibitor for the treatment or prevention of diseases associated with HBV infection.

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