CN116199703A - Fused tetracyclic heterocyclic compound, preparation method thereof and application thereof in medicine - Google Patents

Abstract

The present disclosure relates to fused tetracyclic heterocyclic compounds, their preparation methods and their applications in medicine. Specifically, the present disclosure relates to a fused tetracyclic heterocyclic compound represented by general formula (IM), its preparation method and pharmaceutical composition containing the compound and its use as a therapeutic agent, especially as a KRAS G12C inhibitor The use of the agent and the use in the preparation of a medicament for treating and/or preventing tumors.

Description

Condensed tetracyclic heterocyclic compound, preparation method thereof and application thereof in medicine

Technical Field

The present disclosure belongs to the field of medicine, and relates to a fused tetracyclic heterocyclic compound, a preparation method thereof, and its application in medicine. Specifically, the present disclosure relates to a fused tetracyclic heterocyclic compound represented by the general formula (IM), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, in particular, its use as a KRAS G12C inhibitor and its use in the preparation of a drug for treating and/or preventing tumors.

Background Art

The RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the small GTPase superfamily and is widely expressed in various eukaryotic organisms. There are three RAS genes (HRAS, KRAS and NARS) in the human body, which can be expressed as four highly related RAS small GTPases (HRAS, KRAS4A, KARS4B and NRAS). It acts as a binary switch regulated by GDP-GTP. Usually they have two forms of expression: GDP (guanosine diphosphate) binding in the inactive state and GTP (guanosine triphosphate) binding in the activated state. RAS proteins regulate multiple downstream pathways including RAF-MEK-ERK, PI3K/Akt/mTOR by switching between two active states, thereby affecting cell growth, proliferation and differentiation (Nat Rev Cancer, 2007, 7, 295-308). The mutation rate of RAS gene is high in pancreatic cancer, colorectal cancer, non-small cell lung cancer and other tumors. The activated mutant RAS protein promotes abnormal signal transduction, leading to the occurrence and development of cancer and resistance to targeted drugs. Among them, KRAS mutation is the gene with the highest mutation rate among human oncogenes, accounting for 20-30% of all tumors.

In recent years, molecular biology has made significant progress in the study of KRAS protein mutations and signaling pathways, but the development of related targeted drugs is still full of challenges. In the development of chemical drugs, since the affinity between KRAS and GTP is very high, reaching 60pM, and the intracellular GTP concentration is at the mM level, this type of directly competing molecule has extremely high requirements for compound affinity, and there has been no successful case so far. In the development of biological drugs, antibody drugs penetrate the cell membrane to target KRAS protein, and the drug delivery efficiency is relatively low. Therefore, many researchers have tried to find another way, hoping to inhibit the activity of kinases such as RAF, MEK and ERK in the downstream signaling pathway of KRAS to achieve the purpose of inhibiting the KRAS pathway. This type of compound has a certain therapeutic effect, but because the downstream inhibitors cannot completely block the KRAS signal, and the target-related toxic side effects are very large, these compounds have poor efficacy on KRAS mutant tumors. Therefore, the development of KRAS inhibitors with new mechanisms of action has great clinical application value.

KRAS mutations are mainly point mutations, including mutations at amino acids 12, 13, and 61. The most common mutation is the glycine at position 12 to cysteine (G12C), which is more common in lung cancer, especially non-small cell lung cancer (14%). It is also expressed in some colorectal cancer (4%) and pancreatic cancer (2%) patients. In the American cancer population, the incidence of this gene mutation is even greater than the sum of ALK, RET, and TRK gene mutations.

Faced with the difficulty of druggability of KRAS protein, Professor Kevan M. Shokat of the University of California, San Francisco, took the lead in verifying that certain special compounds can bind to KRAS G12C mutant protein through covalent bonds. Through further research, it was found that these covalent compounds can bind to the cysteine at position 12 of KRAS mutant protein and occupy a hydrophobic allosteric regulatory pocket in the switch-II region. The bound KRAS G12C mutant will be irreversibly locked in an inactive state, thereby blocking the signaling pathways and cancer cell viability that depend on the protein (Nature 2013, 503, 548-551). KRASG12C small molecule inhibitor ARS-1620 can effectively inhibit tumor growth in a variety of KRAS G12C mutant tumor models, and even completely regress the tumor. Since KRAS G12C is a mutant protein in tumor cells, and wild-type KRAS does not have this mutation site, it provides a perfect tumor-selective target (Cell, 2018, 572, 578-589).

KRAS G12C has attracted many well-known new drug research and development companies at home and abroad to participate. Although Amgen's fastest-progressing small molecule KRAS G12C inhibitor Sotorasib (AMG510) was approved for marketing by the FDA on May 28, 2021 for patients with non-small cell lung cancer who have received at least one systemic treatment and carry KRAS G12C mutations, Eli Lilly's new generation of KRAS G12C inhibitor LY3537982 has attracted more attention. Eli Lilly reported the preclinical data of LY3537982 at the annual meeting of the American Association for Cancer Research (AACR) in April 2021. The data showed that LY3537982 inhibited cell activity more than 10 times that of Sotorasib and entered Phase I clinical trials in July 2021. It can be seen that highly selective, safe and effective KRASG12C inhibitors are still needed clinically.

Patent applications for KRAS G12C inhibitors that have been disclosed include WO2014152588A1, WO2015054572A1, WO2016164675A1, WO2017087528A1, WO2017201161A1, WO2018119183A2, WO2018206539A1, WO2018217651A1, WO2019099524A1, WO2019215203A1, WO2020081282A1, WO2020178282A1, WO2021118877A1, and the like.

Summary of the invention

The object of the present disclosure is to provide a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof:

in:

X is a nitrogen atom or CR ⁰⁰ ;

Y is a nitrogen atom or CR ³ ;

R ⁰ is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, -OR ^7a , -NR ^8a R ^8b , -S(O) _p1 R ^9a , -C(O)R ^10a , wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of a cyano group, -NR ^x R ^y , -OR ^z , -C(O)NR ^s R ^t , -S(O) _p2 R ^v and R ^c ;

W is CR ^5a or a nitrogen atom;

^R1 is selected from cyano,

Each R ² is the same or different and is independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkoxy group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are independently optionally substituted with one or more substituents selected from a halogen, a cyano group, an amino group and a hydroxyl group;

R ⁰⁰ , R ³ and R ⁴ are the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, -NR ^8c R ^8d , -C(O)R ^10b , -(CR ^a R ^b ) _r -OR ^7b , -S(O) _p3 R ^9b , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, a haloalkyl group, a cyano group, -NR ^p R ^q , -OR ^u , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

R ⁵ , R ^5a and each R ⁶ are the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, -NR ^8e R ^8f , -C(O)NR ^8g R ^8h , -C(O)R ^10c , -C(O)OR ^7c , -OC(O)R ^10d , -OR ^7d , -S(O) _p4 R ^9c , -S(O) _p5 NR ⁸ⁱ R ^8j , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, a haloalkyl group, a cyano group, -NR ^w1 R ^w2 , -OR ^r , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, -NR ^15a R ^15b , -OR ¹⁶ , a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an oxo group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, -NR ^m R ⁿ , a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

^Ra and ^Rb are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkenyl group, an alkynyl group, a hydroxyl group and a cyano group;

^R7a , ^R7b , ^R7c , ^R7d , ^R16 , ^Ru , ^Rr and ^Rz are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, ^-NRkRl , ^hydroxyl and ^Rd ;

R ^c and R ^d are the same or different and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, -C(O)R ^10e , alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

^R8a , ^R8b , ^R8c , ^R8d , ^R8e , ^R8f , ^R8g , ^R8h , ^{R8i, R8j , R15a} , ^R15b , Rx, ^Ry , ^Rs , ^Rt , Rp, ^Rq , ^Rm , ^Rn , ^Rk , ^{R1, Rw1 and Rw2} are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl ^group , ^a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from halogen, oxo, hydroxyl, cyano, alkyl, alkoxy, haloalkyl and haloalkoxy;

or R ^8a and R ^8b together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8c and R ^8d together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8e and R ^8f together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8g and R ^8h together with the nitrogen atom to which they are connected form a heterocyclic group, or R ⁸ⁱ and R ^8j together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^15a and R ^15b together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^x and R ^y together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^s and R ^t together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^p and R ^q together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^m and R ⁿ together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^k and R ^l together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^w1 and R ^w2 together with the nitrogen atom to which it is connected forms a heterocyclic group, wherein the heterocyclic groups are the same or different and are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^9a , R ^9b , R ^9c and R ^v are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an oxo group, a hydroxyl group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group;

R ^10a , R ^10b , R ^10c , R ^10d and R ^10e are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an oxo group, a hydroxyl group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group;

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

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

q is 0, 1, 2, or 3;

p1 is 0, 1, or 2;

p2 is 0, 1, or 2;

p3 is 0, 1, or 2;

p4 is 0, 1 or 2; and

p5 is 0, 1, or 2.

In some embodiments of the present disclosure, in the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, Y is CR ³ , and R ³ is as defined in the general formula (IM).

In some embodiments of the present disclosure, in the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, Y is a nitrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

in:

X is a nitrogen atom or CR ⁰⁰ ;

R ⁰ is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, -OR ^7a , -NR ^8a R ^8b , -S(O) _p1 R ^9a , -C(O)R ^10a , wherein the alkyl group is optionally substituted by one or more substituents selected from the group consisting of a cyano group, -NR ^x R ^y , -OR ^z , -C(O)NR ^s R ^t , -S(O) _p2 R ^v and R ^c ;

W is CR ^5a or a nitrogen atom;

^R1 is selected from cyano,

Each R ² is the same or different and is independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkoxy group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are independently optionally substituted with one or more substituents selected from a halogen, a cyano group, an amino group and a hydroxyl group;

R ⁰⁰ , R ³ and R ⁴ are the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, -NR ^8c R ^8d , -C(O)R ^10b , -(CR ^a R ^b ) _r -OR ^7b , -S(O) _p3 R ^9b , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, a haloalkyl group, a cyano group, -NR ^p R ^q , -OR ^u , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

^R5 , ^R5a and each ^R6 are the same or different and ^are each independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, ^-NR8eR8f , -C(O) ^NR8gR8h , -C(O) ^R10c , -C(O) ^OR7c , -OC(O ^{) R10d} , ^-OR7d , -S(O) _p4R9c , -S(O) ^p5NR8iR8j _, a ^{cycloalkyl group} , a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, a haloalkyl group, a cyano ^group , ^-NRw1Rw2 , ^-ORr , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, -NR ^15a R ^15b , -OR ¹⁶ , a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an oxo group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, -NR ^m R ⁿ , a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

^Ra and ^Rb are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkenyl group, an alkynyl group, a hydroxyl group and a cyano group;

^R7a , ^R7b , ^R7c , ^R7d , ^R16 , ^Ru , ^Rr and ^Rz are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, ^-NRkRl , ^hydroxyl and ^Rd ;

R ^c and R ^d are the same or different and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, -C(O)R ^10e , alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

^R8a , ^R8b , ^R8c , ^R8d , ^R8e , ^R8f , ^R8g , ^R8h , ^{R8i, R8j , R15a} , ^R15b , Rx, ^Ry , ^Rs , ^Rt , Rp, ^Rq , ^Rm , ^Rn , ^Rk , ^{R1, Rw1 and Rw2} are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl ^group , ^a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from halogen, oxo, hydroxyl, cyano, alkyl, alkoxy, haloalkyl and haloalkoxy;

or R ^8a and R ^8b together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8c and R ^8d together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8e and R ^8f together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8g and R ^8h together with the nitrogen atom to which they are connected form a heterocyclic group, or R ⁸ⁱ and R ^8j together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^15a and R ^15b together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^x and R ^y together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^s and R ^t together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^p and R ^q together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^m and R ⁿ together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^k and R ^l together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^w1 and R ^w2 together with the nitrogen atom to which it is connected forms a heterocyclic group, wherein the heterocyclic groups are the same or different and are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^9a , R ^9b , R ^9c and R ^v are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen group, an oxo group, a hydroxyl group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group;

R ^10a , R ^10b , R ^10c , R ^10d and R ^10e are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an oxo group, a hydroxyl group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group;

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

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

q is 0, 1, 2, or 3;

p1 is 0, 1, or 2;

p2 is 0, 1, or 2;

p3 is 0, 1, or 2;

p4 is 0, 1 or 2; and

p5 is 0, 1, or 2.

In some embodiments of the present disclosure, the compound represented by the general formula (IM), the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1-A) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1-B) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), the general formula (I), the general formula (I-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-2-A) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), the general formula (I), the general formula (I-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-2-B) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compounds represented by general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B) or pharmaceutically acceptable salts thereof, wherein each R ² is the same or different and is independently selected from hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl and amino, wherein the C _1-6 alkyl is optionally substituted by one or more substituents selected from halogen and cyano; preferably, R ² is a hydrogen atom.

In some embodiments of the present disclosure, the compounds represented by general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B) or their pharmaceutically acceptable salts, wherein s is 0, 1 or 2; preferably, s is 0.

R¹¹、R¹²和R¹³如通式(I)中所定义。In some embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B) or a pharmaceutically acceptable salt thereof, wherein R ¹ is

R ¹¹ , R ¹² and R ¹³ are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), the general formula (I), the general formula (I-1), the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I), general formula (I-2), general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-1-A), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1-A) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-1-B), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1-B) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I), general formula (I-2), general formula (I-2-A), general formula (II), general formula (II-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-2-A) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IM), general formula (I), general formula (I-2), general formula (I-2-B), general formula (II), general formula (II-2) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-2-B) or a pharmaceutically acceptable salt thereof:

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (I).

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or their pharmaceutically acceptable salts, wherein X is a nitrogen atom.

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein R ⁰ is a hydrogen atom or -OR ^7a , wherein R ^7a is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted by R ^d ; R ^d is a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally selected from halogen, oxo, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C R ⁰ is a hydrogen atom or -OR ^7a , wherein R ^7a is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted by R ^d ; R ^d is a 5- to 8 _- membered heterocyclic group, wherein the 5- to 8-membered heterocyclic group is optionally substituted by one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; most preferably, R ⁰ is -OR ^7a , wherein R ^7a is a methyl group, wherein the methyl group is substituted by R ^d ; R ^d is a 5- to 8-membered heterocyclic group, wherein the 5- to 8-membered heterocyclic group is optionally substituted by one or more substituents selected from halogen and C _1-6 alkyl.

优选地，R⁰为

更优选地，R⁰为

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or their pharmaceutically acceptable salts, wherein R ⁰ is selected from hydrogen atom,

Preferably, R ⁰ is

More preferably, R ⁰ is

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or their pharmaceutically acceptable salts, wherein R ³ is a halogen; preferably, R ³ is a chlorine atom.

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or their pharmaceutically acceptable salts, wherein ^R4 is a hydrogen atom or a halogen; preferably, ^R4 is a hydrogen atom or a fluorine atom.

In some embodiments of the present disclosure, the compounds represented by general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein R ⁵ is -NR ^8e R ^8f , wherein R ^8e and R ^8f are the same or different and are each independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ⁵ is -NH ₂ .

In some embodiments of the present disclosure, the compounds represented by general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein W is CR ^5a or a nitrogen atom, and R ^5a is cyano; more preferably, W is CR ^5a , and R ^5a is cyano.

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein W is CR ^5a and R ^5a is as defined in the general formula (I); preferably, W is CR ^5a and R ^5a is selected from a hydrogen atom, a halogen, a cyano group and a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compounds represented by general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein each R ⁶ is the same or different and is independently a hydrogen atom or a halogen; preferably, each R ⁶ is the same or different and is independently a hydrogen atom or a fluorine atom.

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), and general formula (II-2-B) or their pharmaceutically acceptable salts, wherein each R ⁶ is the same or different and is independently a halogen; preferably a fluorine atom.

In some embodiments of the present disclosure, the compounds represented by general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein R ¹¹ is selected from a hydrogen atom, a halogen and a C _1-6 alkyl; preferably, R ¹¹ is a hydrogen atom or a fluorine atom; more preferably, R ¹¹ is a hydrogen atom.

In some embodiments of the present disclosure, the compounds represented by general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein R ¹² and R ¹³ are the same or different and are each independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group, wherein the alkyl group is optionally substituted by -NR ^m R ⁿ , wherein R ^m and R ⁿ are both hydrogen atoms; preferably, R ¹² and R ¹³ are both hydrogen atoms.

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or their pharmaceutically acceptable salts, wherein q is 1 or 2; preferably, q is 1.

In some embodiments of the present disclosure, the compounds represented by general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein R ⁶ is halogen and q is 1 or 2; preferably, R ⁶ is halogen and q is 1.

R³为卤素；R⁴为氢原子或卤素；R⁵为-NR^8eR^8f，其中R^8e和R^8f相同或不同，且各自独立地为氢原子或C_1-6烷基；R⁶为卤素，且q为1或2；R¹¹选自氢原子、卤素和C_1-6烷基；R¹²和R¹³相同或不同，且各自独立地选自氢原子、卤素和C_1-6烷基，其中所述的烷基任选被-NR^mRⁿ取代，其中R^m和Rⁿ均为氢原子；s为0。In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B) or pharmaceutically acceptable salts thereof, wherein X is a nitrogen atom; W is ^CR5a , and ^R5a is a cyano group; ^R0 is a hydrogen atom or ^-OR7a , wherein ^R7a is a _C1-6 alkyl group, wherein the _C1-6 alkyl group is optionally substituted by ^Rd ; ^Rd is a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally substituted by one or more substituents selected from halogen, oxo, hydroxyl, cyano, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl and _C1-6 haloalkoxy; ^R1 is

R ³ is halogen; R ⁴ is a hydrogen atom or a halogen; R ⁵ is -NR ^8e R ^8f , wherein R ^8e and R ^8f are the same or different and are each independently a hydrogen atom or a C _1-6 alkyl group; R ⁶ is halogen, and q is 1 or 2; R ¹¹ is selected from a hydrogen atom, a halogen and a C _1-6 alkyl group; R ¹² and R ¹³ are the same or different and are each independently selected from a hydrogen atom, a halogen and a C _1-6 alkyl group, wherein the alkyl group is optionally substituted by -NR ^m R ⁿ , wherein R ^m and R ⁿ are both hydrogen atoms; s is 0.

In some embodiments of the present disclosure, the compounds represented by the general formula (IM), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein X is a nitrogen atom; W is CR ^5a , and R ^5a is a cyano group; R ⁰ is a hydrogen atom or -OR ^7a , wherein R ^7a is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted by R ^d ; R ^d is a 5- to 8-membered heterocyclic group, wherein the 5- to 8-membered heterocyclic group is optionally substituted by one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; R ³ is halogen; R ⁴ is a hydrogen atom or halogen; R ⁵ is -NH ₂ ; R ⁶ is a halogen, and q is 1; R ¹¹ is a hydrogen atom; R ¹² and R ¹³ are both hydrogen atoms.

Table A Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a compound represented by the general formula (IMa) or a salt thereof:

in:

X, Y, W, R ⁰ , R ² , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in Formula (IM).

Another aspect of the present disclosure relates to a compound represented by general formula (Ia) or a salt thereof:

in:

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I).

Another aspect of the present disclosure relates to a compound represented by general formula (I-1a) or a salt thereof:

in:

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a compound represented by general formula (I-2a) or a salt thereof:

in:

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in the general formula (I-2).

The compounds represented by the general formula (IMa), general formula (Ia), general formula (I-1a), and general formula (I-2a) of the present disclosure or their salts, wherein the salt is preferably bis(2,2,2-trifluoroacetate).

Table B Typical intermediate compounds disclosed herein include but are not limited to:

Another aspect of the present disclosure relates to a compound represented by the general formula (IMaa) or a salt thereof:

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

X, Y, W, R ⁰ , R ² , R ⁴ , R ⁶ , s and q are as defined in the general formula (IMa).

Another aspect of the present disclosure relates to a compound represented by general formula (Iaa) or a salt thereof:

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (Ia).

Another aspect of the present disclosure relates to a compound represented by general formula (I-1aa) or a salt thereof:

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (I-1a).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-2aa) or a salt thereof:

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (I-2a).

Table C Typical intermediate compounds disclosed herein include, but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (IMa) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) reacts with the compound represented by the general formula (X) or a salt thereof to obtain the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

^R1 is

X, Y, W, R ⁰ , R ² , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in Formula (IM).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (Ia) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) reacts with the compound represented by the general formula (X) or a salt thereof to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (I-1a) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) reacts with the compound represented by the general formula (X) or a salt thereof to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-2) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (I-2a) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) reacts with the compound represented by the general formula (X) or a salt thereof to obtain the compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (Ia) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) reacts with the compound represented by the general formula (XI) or a salt thereof to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (I-1a) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) reacts with the compound represented by the general formula (XI) or a salt thereof to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (I-2a) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) reacts with the compound represented by the general formula (XI) or a salt thereof to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1-A) and general formula (I-1-B) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof is resolved to obtain the compound represented by the general formula (I-1-A) and the general formula (I-1-B) or a pharmaceutically acceptable salt thereof;

in:

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-2-A) and general formula (I-2-B) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof is resolved to obtain the compound represented by the general formula (I-2-A) and the general formula (I-2-B) or a pharmaceutically acceptable salt thereof;

in:

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1-A) and general formula (II-1-B) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof is resolved to obtain the compound represented by the general formula (II-1-A) and the general formula (II-1-B) or a pharmaceutically acceptable salt thereof;

in:

^R1 is

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2-A) and general formula (II-2-B) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof is resolved to obtain the compound represented by the general formula (II-2-A) and the general formula (II-2-B) or a pharmaceutically acceptable salt thereof;

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ and q are as defined in the general formula (II-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IMa) or a salt thereof, comprising:

The compound represented by the general formula (IMaa) or its salt is subjected to the removal of R ^L1 and R ^L2 to obtain the compound represented by the general formula (IMa) or its salt;

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

R ⁵ is -NH ₂ ;

X, Y, W, R ⁰ , R ² , R ⁴ , R ⁶ , s and q are as defined in the general formula (IMa).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (Ia) or a salt thereof, comprising:

The compound represented by the general formula (Iaa) or its salt is subjected to the step of removing R ^L1 and R ^L2 to obtain the compound represented by the general formula (Ia) or its salt;

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

R ⁵ is -NH ₂ ;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (Ia).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1a) or a salt thereof, comprising:

The compound represented by the general formula (I-1aa) or its salt is subjected to the removal of R ^L1 and R ^L2 to obtain the compound represented by the general formula (I-1a) or its salt;

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

R ⁵ is -NH ₂ ;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (I-1a).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-2a) or a salt thereof, comprising:

The compound represented by the general formula (I-2aa) or its salt is subjected to the removal of R ^L1 and R ^L2 to obtain the compound represented by the general formula (I-2a) or its salt;

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

R ⁵ is -NH ₂ ;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (I-2a).

Another aspect of the present disclosure relates to a pharmaceutical composition, which contains compounds of the present disclosure as shown in general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) and Table A, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to the use of compounds shown in formula (IM), formula (I), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B) and Table A or their pharmaceutically acceptable salts or pharmaceutical compositions containing the same in the preparation of drugs for inhibiting KRAS G12C.

The present disclosure further relates to the use of compounds shown in Formula (IM), Formula (I), Formula (I-1), Formula (I-2), Formula (I-1-A), Formula (I-1-B), Formula (I-2-A), Formula (I-2-B), Formula (II), Formula (II-1), Formula (II-2), Formula (II-1-A), Formula (II-1-B), Formula (II-2-A), Formula (II-2-B) and Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same in the preparation of medicaments for treating and/or preventing diseases or conditions mediated by KRAS G12C.

The present disclosure further relates to the use of compounds shown in general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) and Table A or their pharmaceutically acceptable salts or pharmaceutical compositions containing the same in the preparation of drugs for treating and/or preventing tumors.

The present disclosure also relates to a method for inhibiting KRAS G12C, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The present disclosure also relates to a method for treating and/or preventing tumors, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound or a pharmaceutically acceptable salt thereof as shown in the general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicine.

The present disclosure further relates to compounds shown in formula (IM), formula (I), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions containing the same, which are used as KRAS G12C inhibitors. The present disclosure further relates to compounds shown in general formula (IM), general formula (I), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions containing the same, which are used for treating and/or preventing tumors. In the present disclosure, the tumor as described above is preferably cancer; further preferably, the cancer is selected from lung cancer (such as non-small cell lung cancer and small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer (also known as esophageal cancer), endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer (such as colon cancer and rectal cancer), liver cancer, breast cancer, prostate cancer, thyroid cancer, gastric cancer, urothelial cancer, testicular cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, head and neck cancer, kidney cancer, nasopharyngeal cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma (such as astrocytoma and glioblastoma), brain tumor and myeloma; more preferably, the cancer is selected from lung cancer (such as non-small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer and colorectal cancer.

In the present disclosure, the disease or condition mediated by KRAS G12C as described above is preferably a tumor; preferably, the tumor is cancer; more preferably, the cancer is selected from lung cancer (such as non-small cell lung cancer and small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer (also known as esophageal cancer), endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer (such as colon cancer and rectal cancer), liver cancer, breast cancer, prostate cancer, thyroid cancer, gastric cancer, urothelial carcinoma, testicular cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, head and neck cancer, kidney cancer, nasopharyngeal carcinoma, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma (such as astrocytoma and glioblastoma), brain tumor and myeloma; most preferably, the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer and colorectal cancer.

As a general guide, the active compounds of the present disclosure are preferably in a unit dosage form, or in a form that a patient can self-administer in a single dose. The unit dosage form of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit dosages can be 0.1 to 1000 mg.

The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient can be in a form suitable for oral administration, such as tablets, lozenges, pastilles, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets can be uncoated or can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a long period of time.

Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared with suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

Terminology

Unless stated otherwise, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., _C1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., _C1-12 alkyl), and more preferably an alkyl group having 1 to 6 carbon atoms (i.e., _C1-6 alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 _alkenyl ). The alkenyl group preferably has an alkenyl group of 2 to 6 carbon atoms (i.e., _C2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., _C2-12 alkynyl). The alkynyl group preferably has an alkynyl group of 2 to 6 carbon atoms (i.e., _C2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl).

Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic system in which one carbon atom (called spiro atom) is shared between the rings, and the rings may contain one or more double bonds, or the rings may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but not including -O-O-, -O-S- or -S-S-), provided that at least one all-carbon ring is contained and the connection point is on the all-carbon ring, and it has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 7-yuan/5-yuan or 7-yuan/6-yuan monospirocycloalkyl. Non-limiting examples include:

其连接点可在任意位置；

Its connection point can be at any position;

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其连接点可在任意位置；

等。The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

Its connection point can be at any position;

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The term "bridged cycloalkyl" refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

其连接点可在任意位置。

Its connection point can be at any position.

The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S- or -S-S-), and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group), for example a 5- to 8-membered heterocyclic group; more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group); most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered spiro heterocyclic radical), and more preferably has a spiro heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered spiro heterocyclic radical). The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), preferably a monospiro heterocyclic radical or a bispiro heterocyclic radical, more preferably a 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 7-yuan/5-yuan or 7-yuan/6-yuan monospiro heterocyclic radical. Non-limiting examples include:

等。

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The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S- or -S-S-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic group preferably has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and more preferably has a fused heterocyclic group of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan bicyclic fused heterocyclic groups. Non-limiting examples include:

等。

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The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S-, or -S-S-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

等。

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The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthryl, etc. The polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or the naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, and non-limiting examples include:

等。

wait.

The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but does not include -O-O-, -O-S- or -S-S-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5- to 10-membered heteroaryl group), more preferably a monocyclic heteroaryl group having 5 or 6 ring atoms (i.e. a 5- or 6-membered monocyclic heteroaryl group) or a bicyclic heteroaryl group having 8 to 10 ring atoms (i.e. an 8- to 10-membered bicyclic heteroaryl group), most preferably a 5- or 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring, or an 8- to 10-membered bicyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring.

等)、吡嗪基、哒嗪基等。The monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g.

etc.), pyrazinyl, pyridazinyl, etc.

The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

等。

wait.

The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule are reacted. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

The term "hydroxy protecting group" refers to a group that is introduced on a hydroxy group and is easily removed, and is used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to -OH.

The term "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=0".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereomers is usually completed by chromatography.

表示未指定构型，即如果化学结构中存在手性异构体，键

可以为

或

或者同时包含

和

两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。In the chemical structures of the compounds disclosed herein, the bond

Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond

Can be

or

or include both

and

For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

Compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., exists in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. A lactam-lactim equilibrium example is between A and B as shown below:

For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

等。The compounds of the present disclosure may contain atropisomers. The term "atropisomer" is a conformational stereoisomer produced due to hindered or greatly slowed rotation around a single bond in a molecule (this is due to steric interactions with other parts of the molecule and the result of asymmetry of the substituents at both ends of the single bond), and its interconversion is slow enough to allow separation and separation under predetermined conditions. For example, some of the compounds of the present disclosure may exist in the form of a mixture of atropisomers (such as an equal proportion mixture, a mixture enriched in one atropisomer, etc.) or a purified atropisomer. Non-limiting examples include:

wait.

Compounds of the present disclosure include all suitable isotopic derivatives of their compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but different atomic masses. Examples of isotopes that can be introduced into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium, D), ³ H (tritium, T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, 33 S, ³⁴ S, ³⁵ S ^{, 36} S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I, etc., preferably deuterium.

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

When a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium (ie, at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015%. Examples of compounds having a greater than natural abundance of deuterium may be at least 1000 times more abundant in deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times more abundant in deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times more abundant in deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times more abundant in deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times more abundant in deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times more abundant in deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 65.6% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60 ... deuterium is incorporated at least 5000 times more abundant in deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times more abundant in deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times more abundant in deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times more abundant in deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times more abundant in deuterium (i.e., at least 97% deuterium incorporation), at least 6600 times more abundant in deuterium (i.e., at least 99% deuterium incorporation), at least 6633.3 times more abundant in deuterium (i.e., at least 99.5% deuterium incorporation), or more.

"Optionally" or "optionally" means that the event or environment described later can but does not necessarily occur, and includes two situations in which the event or environment occurs or does not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes the situation in which alkyl is substituted with halogen or cyano and the situation in which alkyl is not substituted with halogen and cyano.

"Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without undue effort (by experiment or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as on the specific active substance, and the appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

Synthesis method of the disclosed compound

In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

Solution 1

The present invention discloses a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (IMa) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) and the compound represented by the general formula (X) or a salt thereof react under alkaline conditions to obtain the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

^R1 is

X, Y, W, R ⁰ , R ² , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in Formula (IM).

Solution 2

The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (Ia) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) and the compound represented by the general formula (X) or a salt thereof react under alkaline conditions to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I).

Option 3

The present invention discloses a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (I-1a) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) and the compound represented by the general formula (X) or a salt thereof react under alkaline conditions to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I-1).

Option 4

The present invention discloses a method for preparing a compound represented by general formula (I-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (I-2a) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) and the compound represented by the general formula (X) or a salt thereof react under alkaline conditions to obtain the compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I-2).

Option 5

The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (Ia) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) and the compound represented by the general formula (XI) or a salt thereof react under alkaline conditions to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II).

Option 6

The present invention discloses a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (I-1a) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) and the compound represented by the general formula (XI) or a salt thereof react under alkaline conditions to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II-1).

Option 7

The present invention discloses a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (I-2a) or a salt thereof (preferably di(2,2,2-trifluoroacetate)) and the compound represented by the general formula (XI) or a salt thereof react under alkaline conditions to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof;

in:

L is a halogen; preferably, L is a chlorine atom;

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II-2).

Option 8

The present invention discloses a method for preparing a compound represented by general formula (I-1-A) and general formula (I-1-B) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof is separated by high performance liquid preparative chromatography to obtain the compound represented by the general formula (I-1-A) and the general formula (I-1-B) or a pharmaceutically acceptable salt thereof;

in:

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I-1).

Option 9

The present invention discloses a method for preparing a compound represented by general formula (I-2-A) and general formula (I-2-B) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof is separated by high performance liquid preparative chromatography to obtain the compound represented by the general formula (I-2-A) and the general formula (I-2-B) or a pharmaceutically acceptable salt thereof;

in:

^R1 is

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in the general formula (I-2).

Plan 10

The present invention discloses a method for preparing a compound represented by general formula (II-1-A) and general formula (II-1-B) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof is separated by high performance liquid preparative chromatography to obtain the compound represented by the general formula (II-1-A) and the general formula (II-1-B) or a pharmaceutically acceptable salt thereof;

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II-1).

Plan 11

The present invention discloses a method for preparing a compound represented by general formula (II-2-A) and general formula (II-2-B) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof is separated by high performance liquid preparative chromatography to obtain the compound represented by the general formula (II-2-A) and the general formula (II-2-B) or a pharmaceutically acceptable salt thereof;

in:

X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in the general formula (II-2).

Plan 12

The present invention discloses a method for preparing a compound represented by general formula (IMa) or a salt thereof, which comprises the following steps:

The compound represented by the general formula (IMaa) or a salt thereof is subjected to acidic conditions to remove R ^L1 and R ^L2 to obtain the compound represented by the general formula (IMa) or a salt thereof;

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

R ⁵ is -NH ₂ ;

X, Y, W, R ⁰ , R ² , R ⁴ , R ⁶ , s and q are as defined in the general formula (IMa).

Plan 13

The present invention discloses a method for preparing a compound represented by general formula (Ia) or a salt thereof, which comprises the following steps:

The compound represented by the general formula (Iaa) or a salt thereof is subjected to acidic conditions to remove R ^L1 and R ^L2 to obtain the compound represented by the general formula (Ia) or a salt thereof;

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

R ⁵ is -NH ₂ ;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (Ia).

Scheme 14

The present invention discloses a method for preparing a compound represented by general formula (I-1a) or a salt thereof, which comprises the following steps:

The compound represented by the general formula (I-1aa) or a salt thereof is subjected to acidic conditions to remove R ^L1 and R ^L2 to obtain the compound represented by the general formula (I-1a) or a salt thereof;

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

R ⁵ is -NH ₂ ;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (I-1a).

Plan 15

The present invention discloses a method for preparing a compound represented by general formula (I-2a) or a salt thereof, which comprises the following steps:

The compound represented by the general formula (I-2aa) or a salt thereof is subjected to acidic conditions to remove R ^L1 and R ^L2 to obtain the compound represented by the general formula (I-2a) or a salt thereof;

in:

^RL1 and ^RL2 are the same or different and are each independently an amino protecting group; preferably, ^RL1 and ^RL2 are both tert-butyloxycarbonyl;

R ⁵ is -NH ₂ ;

X, W, R ⁰ , R ² , R ³ , R ⁴ , R ⁶ , s and q are as defined in the general formula (I-2a).

In the above synthesis scheme, the base providing alkaline conditions includes organic bases and inorganic bases, and the organic base includes but is not limited to triethylamine, N,N-diisopropylethylamine, n-butyl lithium, lithium diisopropylamide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, anhydrous potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide, preferably anhydrous potassium carbonate.

In the above synthesis scheme, the acid providing acidic conditions includes organic acids and inorganic acids. The organic acids include but are not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOTf, preferably trifluoroacetic acid; the inorganic acids include but are not limited to hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

The above synthesis scheme is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof.

DETAILED DESCRIPTION

The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

MS was measured using Agilent 1200/1290DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector/waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

The average kinase inhibition rate and _IC50 value were determined using NovoStar microplate reader (BMG, Germany).

The known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals and other companies.

Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

Unless otherwise specified in the examples, the solution refers to an aqueous solution.

Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Embodiment 1-p1, 1-p2

4-((5S,8aR)-10-acryloyl-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 1-p1

4-((5R,8aR)-10-acryloyl-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 1-p2

first step

(R)-tert-Butyl 3-(((tert-Butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 1b

Dissolve (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate 1a (8.8 g, 36.3 mmol, Shanghai Bidex), tert-butyldimethylsilyl chloride (16 g, 106.15 mmol), and 4-dimethylaminopyridine (4 g, 32.47 mmol) in 200 mL of dichloromethane, add triethylamine (15 g, 148.23 mmol, 21.4286 mL), stir and react for 16 hours, concentrate the reaction solution under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the title compound 1b (8 g, yield: 61.7%).

MS m/z(ESI):331.1[M+1].

Step 2

2-Amino-4-bromo-3,6-difluorobenzoic acid methyl ester 1d

2-Amino-4-bromo-3,6-difluorobenzoic acid 1c (9 g, 35.71 mmol, prepared by the method disclosed on page 110 of the specification of patent application "WO2018206539A1") was dissolved in dichloromethane (100 mL) and methanol (10 mL), and 35.71 mL of 2M trimethylsilyldiazomethane in n-hexane solution was added dropwise under an ice bath. After the addition was completed, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system B to obtain the title compound 1d (6.8 g, yield: 71.5%).

MS m/z(ESI):265.9[M+1].

Step 3

Methyl 4-bromo-3,6-difluoro-2-(3-(2,2,2-trichloroacetyl)ureido)benzoate 1e

Compound 1d (2 g, 7.51 mmol) was dissolved in tetrahydrofuran (30 mL), trichloroacetyl isocyanate (1.42 g, 7.5373 mmol, Jiangsu Aikon) was added in batches, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1e (3.4 g, yield: 99%), which was used in the next step without purification.

MS m/z(ESI):452.9[M+1].

Step 4

7-Bromo-5,8-difluoroquinazoline-2,4-diol 1f

The crude compound 1e (3.4 g, 7.48 mmol) was dissolved in 30 mL of 7 M ammonia methanol solution, stirred for reaction for 2 hours, concentrated under reduced pressure to remove most of the solvent, and then slurried with 20 mL of methyl tert-butyl ether. The mixture was filtered and the filter cake was washed with methyl tert-butyl ether. After drying, the crude title compound 1f (2 g, yield: 96.4%) was obtained and used in the next step without purification.

MS m/z(ESI):276.9[M+1].

Step 5

7-Bromo-2,4-dichloro-5,8-difluoroquinazoline 1g

Compound 1f (500 mg, 1.80 mmol) was dissolved in phosphorus oxychloride (5 mL) and stirred at 100°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1g (500 mg, yield: 88.2%), which was used in the next step without purification.

MS m/z(ESI):312.9[M+1].

Step 6

(R)-tert-Butyl 4-(7-bromo-2-chloro-5,8-difluoroquinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 1h

Compound 1g (250 mg, 796.39 μmol) and triethylamine (241 mg, 2.38 mmol) were dissolved in 10 mL of dichloromethane, 1b (276 mg, 836 μmol) was added at 0°C, the mixture was naturally returned to room temperature and stirred for 3 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system B to obtain the crude title compound 1h (200 mg, yield: 41.3%).

MS m/z(ESI):607.2[M+1].

Step 7

(R)-tert-Butyl 4-(7-bromo-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 1i

Compound 1h (209 mg, 344.2 μmol) was added with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (71.2 mg, 1.36 mmol, Yao Ming) and dissolved in 1,4-dioxane (5 mL). Under nitrogen protection, 2M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (260 μL) was added under ice bath and the reaction was naturally restored to room temperature for 2 hours. A small amount of saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the residue was concentrated under reduced pressure and purified with eluent system A to obtain the crude title compound 1i (220 mg, yield: 88%).

MS m/z(ESI):730.1[M+1].

Step 8

(R)-tert-Butyl 5-bromo-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazoline-10(8H)-carboxylate 1j

Compound 1i (220 mg, 301 μmol) was dissolved in tetrahydrofuran (3 mL), 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (1 mL) was added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system A to give the title compound 1j (220 mg, yield: 72%).

MS m/z(ESI):596.2[M+1].

Step 9

(R)-5-Bromo-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazoline-10(8H)-carboxylic acid tert-butyl ester 1k

Compound 1j (130.21 mg, 218.31 μmol) was dissolved in N,N-dimethylformamide (25 mL), and N-chlorosuccinimide (64 mg, 480 μmol) was added. The mixture was reacted at 70°C for 2 hours. Saturated aqueous sodium thiosulfate solution was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 1k (70 mg, yield: 72%).

MS m/z(ESI):630.1[M+1].

Step 10

(8aR)-5-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazoline-10(8H)-carboxylic acid tert-butyl ester

Compound 1k (70 mg, 111 μmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborohexan-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate (67.2 mg, 166.4 μmol, prepared by the method disclosed in Preparation Example 15 on page 50 of the specification of patent application "WO2021118877A1") were dissolved in 3 mL of toluene, and bis(diphenylphosphinophenyl ether)palladium (II) dichloride (12 mg, 16.6 μmol, Shanghai Titan) and cesium carbonate (72.3 mg, 222 μmol) were added. The mixture was replaced with nitrogen, and the reaction was stirred at 105°C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1l (50 mg, yield: 96.7%).

MS m/z(ESI):842.2[M+1].

Step 11

2-Amino-4-((8aR)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetate) 1m

Compound 11 (90 mg, 106.8 μmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added at 0°C, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 1m (90 mg), which was used directly in the next step without purification.

MS m/z(ESI):642.2[M+1].

Step 12

4-((5S,8aR)-10-acryloyl-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 1-p1

4-((5R,8aR)-10-acryloyl-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 1-p2

Compound 1m (90 mg, 0.075 mmol) was suspended in 2 mL of ethyl acetate, 1 mL of tetrahydrofuran and 2 mL of water, and anhydrous potassium carbonate (58 mg, 423.2 μmol) was added. Acryloyl chloride (19 mg, 211.6 μmol) was added under ice bath. After reacting for 5 minutes, the mixture was extracted with ethyl acetate (5 mL×2). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound, i.e., 4-((8aR)-10-acryloyl-6-chloro-4-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 1 (70 mg) was purified by HPLC preparative chromatography (Waters-2545, column: YMCTriart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL/min) to give the title compound (5 mg, 5 mg, yield: 6.7%, 6.7%).

Single configuration compound (short retention time) (5 mg, yield: 6.7%)

MS m/z(ESI):696.2[M+1].

BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。HPLC analysis: retention time 1.36 minutes, purity: 94% (chromatographic column: ACQUITY

BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

¹ H NMR (500MHz, CD3OD): δ7.21(dd,1H),7.12-7.01(m,1H),6.86(dd,9.6Hz,1H),6.31(dt,1H),5.84(d,1H) ,5.46-5.30(m,1H),5.01(s,1H),4.72-4.50(m,3H),4.37(d,2H),4.29-4.06(m,2H),3.62(dt,1H),3.42 (s,5H),3.15(s,1H),2.51-2.17(m,3H),2.08(d,2H),2.02-1.92(m,1H).

Single configuration compound (longer retention time) (5 mg, yield: 6.7%)

MS m/z(ESI):696.2[M+1].

BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。LCMS analysis: retention time 1.39 minutes, purity: 96% (chromatographic column: ACQUITY

BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

1H NMR (500MHz, CD3OD): δ7.21(dd,1H),7.05(t,1H),6.86(t,1H),6.31(dd,1H),5.84(d,1H),5.41-5.26(m ,1H),5.04(d,1H),4.70-4.47(m,3H),4.38-4.06(m,4H),3.64-3.52(m,1H),3.41(dd,1H),3.27(d,4H ),3.10-3.01(m,1H),2.41-2.13(m,3H),2.02(dq,2H),1.93(d,1H).

Embodiment 2-p1, 2-p2

4-((5S,8aR)-10-acryloyl-6-chloro-4-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 2-p1

4-((5R,8aR)-10-acryloyl-6-chloro-4-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 2-p2

Using the synthetic routes in Examples 1-p1 and 1-p2, the raw material in the seventh step ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol was replaced with (S)-(1-methylpyrrolidin-2-yl)methanol to obtain the title compound (5 mg, 5 mg, yield: 9.2%, 9.2%).

Single configuration compound (short retention time) (5 mg, yield: 9.2%)

MS m/z(ESI):652.1[M+1].

BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。HPLC analysis: retention time 1.746 minutes, purity: 94% (chromatographic column: ACQUITY

BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

¹ H NMR (500MHz, CD3OD): δ7.21(dd,1H),7.07-7.05(m,1H),6.87(dd,1H),6.30(dt,1H),5.84(d,1H),5.05- 4.95(m,2H),4.66-4.56(m,3H),4.54-4.47(m,2H),3.60-3.56(m,5H),3.46-3.42(m,4H),2.85-2.75(m,1H ),2.58(s,1H),2.35-2.30(m,1H),2.17-2.13(m,1H),1.87-1.70(m,1H).

Single configuration compound (longer retention time) (5 mg, yield: 9.2%)

MS m/z(ESI):652.1[M+1].

BEH,C18,1.7μm,2.1*50mm；流动相：水(10mM碳酸氢铵)，乙腈，梯度配比：乙腈10％-95％)。LCMS analysis: retention time 1.768 minutes, purity: 96% (chromatographic column: ACQUITY

BEH, C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

¹ H NMR (500MHz, CD3OD): δ7.22(dd,1H),7.07-7.03(m,1H),6.83-6.80(m,1H),6.30(dt,1H),5.84(d,1H), 5.05-4.95(m,2H),4.68-4.56(m,3H),4.54-4.45(m,2H),3.60-3.35(m,5H),3.46-3.40(m,4H),2.85-2.75(m ,1H),2.58(s,1H),2.35-2.3(m,1H),2.17-2.13(m,1H),1.89-1.80(m,1H).

Example 3

4-((8aS)-10-acryloyl-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

Using the synthetic routes in Examples 1-p1 and 1-p2, the first step raw material compound 1a was replaced with (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (Shanghai Bidex) to obtain the title compound 3 (15 mg, yield: 9.8%).

MS m/z(ESI):696.1[M+1].

1H NMR (500MHz, CD3OD): δ7.21(dt,1H),7.05(dd,1H),6.92-6.80(m,1H),6.31(dd,1H),5.89-5.80(m,1H),5.34 (d,1H),5.01(dd,1H),4.70-4.47(m,3H),4.41-4.17(m,3H),4.12(s,1H),3.59(t,1H),3.25(d,5H ),3.07(d,1H),2.46-2.12(m,3H),2.05(d,2H),1.93(s,1H).

Embodiment 4-p1, 4-p2

4-((5S,8aS)-10-Acryloyl-6-chloro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 4-p1

4-((5R,8aS)-10-acryloyl-6-chloro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 4-p2

first step

(8aS)-tert-butyl 5-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thien-4-yl)-6-chloro-4-fluoro-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazoline-10(8H)-carboxylate 4b

Compound 4a (200 mg, 438 μmol) and tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (140 mg, 439 μmol) were dissolved in 3 mL of toluene, and bis(diphenylphosphinophenyl ether)palladium(II) dichloride (47 mg, 65.6 μmol) and cesium carbonate (357 mg, 1.09 mol) were added. The mixture was replaced with nitrogen and stirred at 105°C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 4b (85 mg, yield: 29%).

MS m/z(ESI):685.2[M+1].

Step 2

2-Amino-4-((8aS)-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2-trifluoroacetate)4c

Compound 4b (80 mg, 119.9 μmol) was dissolved in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid was added at 0°C, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 4c (85 mg), which was used directly in the next step without purification.

MS m/z(ESI):485.2[M+1].

Step 3

4-((5S,8aS)-10-Acryloyl-6-chloro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 4-p1

4-((5R,8aS)-10-acryloyl-6-chloro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 4-p2

Compound 4c (85 mg, 119.9 μmol) was suspended in 2 mL of ethyl acetate, 1 mL of tetrahydrofuran and 2 mL of water, and anhydrous potassium carbonate (65 mg, 470 μmol) was added. Acryloyl chloride (11 mg, 121.5 μmol) was added under ice bath. After reacting for 5 minutes, the mixture was extracted with ethyl acetate (5 mL×2). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 4, i.e., 4-((8aS)-(10-acryloyl-6-chloro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazaheptanyl[5,6,7-de]quinazolin-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 4 (60 mg), which was purified by preparative HPLC (Waters-2545, column: YMC Triart-ExrsC18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30mL/min) was used to purify the title compound (16mg, 10mg, yield: 26%, 16%).

Single configuration compound (short retention time) (16 mg, yield: 26%)

MS m/z(ESI):521.1[M+1].

Preparative HPLC analysis: retention time 17.3 minutes, purity: 99% (Waters-2545, chromatographic column: YMCTriart-Exrs, Prep 30*150mm, 5μm; C18, mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30mL/min).

¹ H NMR (500MHz, CD3OD): δ8.56(s,1H),7.44(s,1H),7.20(dd,1H),7.02-7.00(m,1H),6.86-6.80(m,1H), 6.33(d,1H),5.84(d,1H),5.08-5.01(m,2H),4.72-4.60(m,2H),4.26-4.16(m,2H),3.62-3.56(m,1H), 3.31-3.23(m,2H).

Single configuration compound (longer retention time) (10 mg, yield: 16%)

MS m/z(ESI):521.1[M+1].

Preparative HPLC analysis: retention time 18.2 minutes, purity: 99% (Waters-2545, chromatographic column: YMCTriart-Exrs, Prep 30*150mm, 5μm; C18, mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-50%, flow rate: 30mL/min).

¹ H NMR (500MHz, CD3OD): δ8.56(s,1H),7.44(s,1H),7.20(dd,1H),7.02-7.00(m,1H),6.89-6.86(m,1H), 6.33(d,1H),5.82(d,1H),5.06-5.01(m,2H),4.70-4.64(m,2H),4.26-4.16(m,2H),3.64-3.56(m,1H), 3.30-3.25(m,2H).

Embodiment 5-p1, 5-p2

2-Amino-4-((5S,8aR)-6-chloro-4-fluoro-10-(2-fluoroacryloyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 5-p1

2-Amino-4-((5R,8aR)-6-chloro-4-fluoro-10-(2-fluoroacryloyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepano[5,6,7-de]quinazolin-5-yl)-7-fluorobenzo[b]thiophene 3-carbonitrile 5-p2

Compound 1m (135 mg, 155.7 μmol) was suspended in 2 mL of ethyl acetate, 1 mL of tetrahydrofuran and 2 mL of water, and anhydrous potassium carbonate (107.6 mg, 778.7 μmol) was added. 2-Fluoroacryloyl chloride (70.1 mg, 778.7 μmol, prepared by the known method "Tetrahedron, 2016, 72 (32), 4845-4853") was added under ice bath. After reacting for 5 minutes, the mixture was extracted with ethyl acetate (5 mL×2). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 5 (110 mg), which was purified by high performance liquid preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: water (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL/min) was purified to obtain the title compound (8mg, 14mg, yield: 7.1%, 12.5%).

Single configuration compound (short retention time) (8 mg, yield: 7.1%)

MS m/z(ESI):714.2[M+1].

C18,2.7μm，3.0*30mm；流动相：水(5mM醋酸铵)，乙腈，梯度配比：乙腈10％-95％)。HPLC analysis: retention time 1.882 minutes, purity: 96% (chromatographic column:

C18, 2.7 μm, 3.0*30 mm; mobile phase: water (5 mM ammonium acetate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

¹ H NMR (500MHz, CD ₃ OD): δ7.22(dd,1H),7.19-7.16(m,1H),5.39-5.31(m,3H),5.08-5.068(d,1H),4.65-4.55 (m,3H),4.23-4.16(m,5H),3.47-3.41(m,2H),3.30-3.21(m,3H),3.04-3.00(m,1H),2.27-1.98(m,6H) .

Single configuration compound (longer retention time) (14 mg, yield: 12.5%)

MS m/z(ESI):714.2[M+1].

C18,2.7μm，3.0*30mm；流动相：水(5mM醋酸铵)，乙腈，梯度配比：乙腈10％-95％)。HPLC analysis: retention time 1.829 minutes, purity: 90% (chromatographic column:

C18, 2.7 μm, 3.0*30 mm; mobile phase: water (5 mM ammonium acetate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

¹ H NMR (500MHz, CD ₃ OD): δ7.23(dd,1H),7.18-7.16(m,1H),5.39-5.33(m,3H),5.08-5.04(d,1H),4.65-4.55 (m,3H),4.27-4.20(m,5H),3.51-3.41(m,2H),3.30-3.23(m,3H),3.06-3.00(m,1H),2.23-1.98(m,6H) .

Example 6

4-((R)-10-Acryloyl-4-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,10,12a-pentaazabenzo[4,5]heptylcyclo[1,2,3-de]naphth-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile 6

first step

2,6-Dichloro-3-fluoropyridin-4-amine 6b

4-Amino-2,6-dichloropyridine 6a (5 g, 30.6 mmol, Shanghai Bidex) was dissolved in 20 mL of N,N-dimethylformamide and 20 mL of acetonitrile, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (13 g, 36.8 mmol) was added, and the mixture was reacted at 80°C for 0.5 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6b (2.2 g, yield: 39.6%).

MS m/z(ESI):180.9[M+1].

Step 2

4-((tert-Butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester 6c

Compound 6b (1.8 g, 9.94 mmol) was dissolved in tetrahydrofuran (50 mL), and 20 mL of 2M sodium bistrimethylsilylamide tetrahydrofuran solution was added under ice bath. After stirring for 0.5 hour, di-tert-butyl dicarbonate (6.5 g, 29.7 mmol) was added and stirred for 14 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system B to obtain the title compound 6c (1 g, yield: 26.3%), which was used directly in the next step without purification.

MS m/z(ESI):381.1[M+1].

Step 3

4-Amino-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester 6d

Compound 6c (1 g, 2.62 mmol) was dissolved in ethyl acetate (8 mL), and 3 mL of 4 M hydrochloric acid-dioxane solution was added. The reaction was stirred for 2 hours, and the pH was adjusted to neutral with 4 M sodium hydroxide aqueous solution under ice bath. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system B to give the crude title compound 6d (500 mg, yield: 67.8%).

MS m/z(ESI):281.1[M+1].

Step 4

2,6-Dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate tert-butyl ester 6e

The crude compound 6d (500 mg, 1.77 mmol) was dissolved in tetrahydrofuran (10 mL), trichloroacetyl isocyanate (670 mg, 3.55 mmol) was added, and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 6e (835 mg, yield: 99.7%), which was used directly in the next step without purification.

MS m/z(ESI):467.9[M+1].

Step 5

5,7-Dichloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol 6f

The crude compound 6e (835 mg, 1.77 mmol) was dissolved in 7M ammonia methanol solution (10 mL), stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. Methyl tert-butyl ether (10 mL) was added to the residue, stirred for 0.5 hour, and then filtered. The filter cake was dried to obtain the crude title compound 6f (400 mg, yield: 89.9%), which was used directly in the next step without purification.

MS m/z(ESI):249.9[M+1].

Step 6

2,4,5,7-Tetrachloro-8-fluoro-pyrido[4,3-d]pyrimidine 6g

The crude compound 6f (300 mg, 1.19 mmol) was dissolved in phosphorus oxychloride (6 mL), N,N-diisopropylethylamine (800 mg, 6.19 mmol) was added, and the mixture was stirred at 110°C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude title compound 6g (344 mg, yield: 97.7%), which was used directly in the next step without purification. MS m/z (ESI): 285.8 [M+1].

Step 7

(R)-tert-Butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2,7-dichloro-5,8-difluoropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylate 6h

Compound 6g (1.1 g, 3.83 mmol) and N,N-diisopropylethylamine (1.5 g, 11.6 mmol) were dissolved in 50 mL of dichloromethane, 1b (1.3 g, 3.83 mmol) was added at 0°C, and the mixture was naturally stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system B to obtain the crude title compound 6h (1.1 g, yield: 44.8%).

MS m/z(ESI):564.2[M+1].

Subsequently, the synthetic routes in Examples 1-p1 and 1-p2 were adopted, the raw material compound 1h in the seventh step was replaced by compound 6h, and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol was replaced by (S)-(1-methylpyrrolidin-2-yl)methanol to obtain the title compound 6 (5 mg, yield: 22.8%).

MS m/z(ESI):619.2[M+1].

¹ H NMR (500MHz, CD ₃ OD): δ7.41(dd,1H),7.08-7.04(m,1H),6.87-6.83(m,1H),7.33(d,1H),5.86(d,1H ),4.69-4.64(m,4H),4.63-4.58(m,1H),4.38-4.23(m,1H),3.65-3.43(m,2H),3.28-3.26(m,1H),2.82(s ,3H),2.27-1.96(m,4H),1.35-1.21(m,3H),1.05-0.91(m,2H).

Biological evaluation

The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not intended to limit the scope of the present disclosure.

Test Example 1: Biological Evaluation of H358 Proliferation Experiment

The following method was used to determine the inhibitory activity of the disclosed compounds on H358 cell proliferation. The experimental method is briefly described as follows:

Luminescent CellViability Assay)(Promega，G7573)，室温放置10分钟后，使用多功能微孔板酶标仪(PerkinElmer，

2105)读取发光信号值，用Graphpad Prism软件计算化合物抑制活性的IC₅₀值。H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 medium (Hyclone, SH30809.01) (i.e., complete medium) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded in a 96-well plate at a density of 1200 cells/well using complete medium, with 100 μL of cell suspension per well, and cultured overnight in a 37°C, 5% CO ₂ cell culture incubator. On the second day, 10 μL of the compound to be tested prepared in complete medium was added to each well. The final concentration of the compound was 9 concentration points of 5-fold gradient dilution starting from 10 μM. A blank control containing 0.5% DMSO was set, and the well plate was placed in a 37°C, 5% CO ₂ cell culture incubator for 120 hours. On the seventh day, the 96-well cell culture plate was removed, and 50 μL of luminescent cell activity detection reagent (CellTiter-

Luminescent Cell Viability Assay (Promega, G7573) was placed at room temperature for 10 minutes and then analyzed using a multi-function microplate reader (PerkinElmer,

2105) to read the luminescent signal value, and use Graphpad Prism software to calculate the _IC50 value of the inhibitory activity of the compound.

Table 1 Inhibitory activity of the disclosed compounds on H358 cell proliferation

Compound No. IC ₅₀ (nM) The compound with the shorter retention time in 1-p1 and 1-p2 2.06 The compound with the shorter retention time in 2-p1 and 2-p2 2.07 3 1.41 The compound with the shorter retention time in 5-p1 and 5-p2 0.64

Conclusion: The disclosed compounds have an inhibitory effect on the proliferation of H358 cells.

Test Example 2: Biological evaluation of ERK phosphorylation inhibition experiment in H358 cells

The following method was used to determine the inhibitory effect of the disclosed compounds on ERK phosphorylation in H358 cells. The experimental method is briefly described as follows:

H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH30809.01) medium (i.e., complete medium) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded in a 96-well plate at a density of 25,000 cells/well using complete medium, with 190 μL of cell suspension per well, and cultured overnight in a 37°C, 5% CO ₂ cell culture incubator. On the second day, 10 μL of the compound to be tested prepared in a gradient dilution of complete medium was added to each well, and the final concentration of the compound was 9 concentration points of 6-fold gradient dilution starting from 10 μM, and a blank control containing 0.5% DMSO was set, and the well plate was placed in a 37°C, 5% CO ₂ cell culture incubator for 3 hours. After 3 hours, the 96-well cell culture plate was removed, the medium was aspirated, and 200 μL PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well to wash once. The PBS was aspirated, and 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking agent (Cisbio, 64KB1AAC) was added to each well. The well plate was placed on a shaker for lysis at room temperature for 30 minutes. After lysis, pipette and mix well, and transfer 16 μL of lysate to each well to two HTRF 96-well detection plates (Cisbio, 66PL96100), and then 4 μL of premixed phospho-ERK1/2 antibody solution (Cisbio, 64AERPEG) or 4 μL of premixed total-ERK1/2 antibody solution (Cisbio, 64NRKPEG) was added to the two plates. The microplate was sealed with a sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark. On the third day, a PHERAstar multifunctional microplate reader (BMG Labtech, PHERAstar FS) was used to read the fluorescence values at 337 nm excitation and 665 nm and 620 nm emission wavelengths, and Graphpad Prism software was used to calculate the _IC50 value of the compound inhibitory activity based on the compound concentration and the ratio of pERK/total ERK.

Table 2 Inhibitory effect of the disclosed compounds on ERK phosphorylation in H358 cells

Conclusion: The disclosed compounds have an inhibitory effect on ERK phosphorylation in H358 cells.

Test Example 3: Biological Evaluation of MIA PaCa-2 Cell Proliferation Experiment

The following method was used to determine the inhibitory activity of the disclosed compounds on the proliferation of MIA PaCa-2 cells. The experimental method is briefly described as follows:

Luminescent Cell Viability Assay)(Promega，G7573)，室温放置10分钟后，使用多功能微孔板酶标仪(PerkinElmer，EnVision2015)读取发光信号值。用Graphpad Prism软件计算化合物抑制活性的IC₅₀值。MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in DMEM/HIGH GLUCOSE (GE, SH30243.01) medium (i.e., complete medium) containing 10% fetal bovine serum (Corning, 35-076-CV) and 2.5% horse serum (Biyuntian Biotechnology, C0262). On the first day of the experiment, MIA PaCa-2 cells were seeded in a 96-well plate at a density of 500 cells/well using complete medium, 90 μL of cell suspension per well, and cultured overnight in a 37°C, 5% CO ₂ cell culture incubator. On the second day, 10 μL of the compound to be tested prepared in complete medium was added to each well, and the final concentration of the compound was 9 concentration points of 5-fold gradient dilution starting from 10 μM, and a blank control containing 0.5% DMSO was set, and the well plate was placed in a 37°C, 5% CO ₂ cell culture incubator for 72 hours. On the fifth day, the 96-well cell culture plate was taken out and 50 μL of luminescent cell activity detection reagent (CellTiter-

Luminescent Cell Viability Assay (Promega, G7573), after standing at room temperature for 10 minutes, the luminescent signal value was read using a multifunctional microplate reader (PerkinElmer, EnVision 2015). The IC ₅₀ value of the inhibitory activity of the compound was calculated using Graphpad Prism software.

Table 3 Inhibitory activity of the disclosed compounds on MIA PaCa-2 cell proliferation

Compound No. IC ₅₀ (nM) The compound with the shorter retention time in 1-p1 and 1-p2 0.54 The compound with the shorter retention time in 2-p1 and 2-p2 0.71 3 0.55 The compound with the shorter retention time in 5-p1 and 5-p2 0.48

Conclusion: The disclosed compounds have an inhibitory effect on the proliferation of MIA PaCa-2 cells.

Claims (10)

1. A compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof:

in: X is a nitrogen atom or CR ⁰⁰ ; Y is a nitrogen atom or CR ³ ; R ⁰ is selected from the group consisting of hydrogen, alkyl, halogenated alkyl, -OR ^7a , -NR ^8a R ^8b , -S(O) _p1 R ^9a , -C(O)R ^10a , wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of cyano, -NR ^x R ^y , -OR ^z , -C(O)NR ^s R ^t , -S(O) _p2 R ^v and R ^c ; W is CR ^5a or a nitrogen atom; ^R1 is selected from cyano,

Each R ² is the same or different and is independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkoxy group, a hydroxyl group and an amino group, wherein the alkyl group and the alkoxy group are independently optionally substituted with one or more substituents selected from a halogen, a cyano group, an amino group and a hydroxyl group; R ⁰⁰ , R ³ and R ⁴ are the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, -NR ^8c R ^8d , -C(O)R ^10b , -(CR ^a R ^b ) _r -OR ^7b , -S(O) _p3 R ^9b , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, a haloalkyl group, a cyano group, -NR ^p R ^q , -OR ^u , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R ⁵ , R ^5a and each R ⁶ are the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, -NR ^8e R ^8f , -C(O)NR ^8g R ^8h , -C(O)R ^10c , -C(O)OR ^7c , -OC(O)R ^10d , -OR ^7d , -S(O) _p4 R ^9c , -S(O) _p5 NR ⁸ⁱ R ^8j , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, a haloalkyl group, a cyano group, -NR ^w1 R ^w2 , -OR ^r , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, -NR ^15a R ^15b , -OR ¹⁶ , a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an oxo group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, -NR ^m R ⁿ , a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; ^Ra and ^Rb are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkenyl group, an alkynyl group, a hydroxyl group and a cyano group; ^R7a , ^R7b , ^R7c , ^R7d , ^R16 , ^Ru , ^Rr and ^Rz are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from halogen, an alkyl group, an alkenyl group, an alkynyl group, an oxo group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, ^-NRkRl , a ^hydroxyl group and ^Rd ; R ^c and R ^d are the same or different and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, -C(O)R ^10e , alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; ^R8a , ^R8b , ^R8c , ^R8d , ^R8e , ^R8f , ^R8g , ^R8h , ^{R8i, R8j , R15a} , ^R15b , Rx, ^Ry , ^Rs , ^Rt , Rp, ^Rq , ^Rm , ^Rn , ^Rk , ^{R1, Rw1 and Rw2} are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl ^group , ^a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from halogen, oxo, hydroxyl, cyano, alkyl, alkoxy, haloalkyl and haloalkoxy; or R ^8a and R ^8b together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8c and R ^8d together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8e and R ^8f together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^8g and R ^8h together with the nitrogen atom to which they are connected form a heterocyclic group, or R ⁸ⁱ and R ^8j together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^15a and R ^15b together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^x and R ^y together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^s and R ^t together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^p and R ^q together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^m and R ⁿ together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^k and R ^l together with the nitrogen atom to which they are connected form a heterocyclic group, or R ^w1 and R ^w2 together with the nitrogen atom to which it is attached forms a heterocyclic group, wherein the heterocyclic groups are the same or different and are each independently optionally substituted by one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R ^9a , R ^9b , R ^9c and R ^v are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen group, an oxo group, a hydroxyl group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group; R ^10a , R ^10b , R ^10c , R ^10d and R ^10e are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an oxo group, a hydroxyl group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group and a haloalkoxy group; r is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, or 3; p1 is 0, 1, or 2; p2 is 0, 1, or 2; p3 is 0, 1, or 2; p4 is 0, 1 or 2; and p5 is 0, 1, or 2. 2. The compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II), the general formula (II-1) or the general formula (II-2) or a pharmaceutically acceptable salt thereof:

in: X, W, R ⁰ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ and q are as defined in claim 1 . 3. A compound according to the general formula (IM) of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom; and/or R ⁰ is a hydrogen atom or -OR ^7a , wherein R ^7a is a C _1-6 alkyl group, wherein the C _1-6 alkyl group is optionally substituted by R ^d ; R ^d is a 3 to 8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic group is optionally substituted by one or more substituents selected from halogen, oxo, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy. 4. The compound represented by the general formula (IM) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R ³ is a halogen; and/or R ⁴ is a hydrogen atom or a halogen; and/or R ⁵ is -NH ₂ ; and/or W is CR ^5a and R ^5a is a cyano group; and/or each R ⁶ is the same or different and is independently a hydrogen atom or a halogen. 5. A compound represented by the general formula (IM) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

6. A compound represented by the general formula (IMa) or a salt thereof:

in: X, Y, W, R ⁰ , R ² , R ⁴ , R ⁵ , R ⁶ , s and q are as defined in claim 1 . 7. The compound or salt thereof according to claim 6, which is selected from the following compounds:

8. A method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, comprising:

The compound represented by the general formula (IMa) or a salt thereof (preferably bis(2,2,2-trifluoroacetate)) reacts with the compound represented by the general formula (X) or a salt thereof to obtain the compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof; in: L is a halogen; preferably, L is a chlorine atom; ^R1 is

X, Y, W, R ⁰ , R ² , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹³ , s and q are as defined in claim 1 . 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. 10. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and/or preventing a tumor; preferably, the tumor is cancer; further preferably, the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, liver cancer, breast cancer, prostate cancer, thyroid cancer, gastric cancer, urothelial cancer, testicular cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, head and neck cancer, kidney cancer, nasopharyngeal carcinoma, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, brain tumor and myeloma; more preferably, the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer and colorectal cancer.