CN118176198A

CN118176198A - Nitrogen-containing tetracyclic compound, preparation method thereof and application thereof in medicine

Info

Publication number: CN118176198A
Application number: CN202280073106.7A
Authority: CN
Inventors: 李心; 沈峰; 董怀德; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-11-01
Filing date: 2022-11-01
Publication date: 2024-06-11
Also published as: WO2023072297A1; TW202325298A

Abstract

The present disclosure relates to nitrogen-containing tetracyclic compounds, methods for their preparation and their use in medicine. Specifically, the disclosure relates to a nitrogenous tetracyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, particularly application of the compound as a KRAS G12C inhibitor and application of the compound in preparation of medicines for treating and/or preventing tumors.

Description

Nitrogen-containing tetracyclic compound, preparation method thereof and application thereof in medicine

Technical Field

The present disclosure belongs to the field of medicine, and relates to a nitrogenous tetracyclic compound, a preparation method thereof and application thereof in medicine. Specifically, the disclosure relates to a nitrogenous tetracyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, particularly application of the compound as a KRAS G12C inhibitor and application of the compound in preparation of medicines for treating and/or preventing tumors.

Background

The RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the small GTPase superfamily and is widely expressed in various eukaryotes. There are three RAS genes (HRAS, KRAS and NARS) in humans that can be expressed as four highly related RAS small gtpases (HRAS, KRAS4A, KARS B and NRAS). It acts as a binary switch for GDP-GTP regulation. They generally take two forms: a GDP (guanosine diphosphate) bound form in the inactive state and a GTP (guanosine triphosphate) bound form in the active state. RAS proteins regulate a number of 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 RAS gene has higher mutation rate in various tumors such as pancreatic cancer, colorectal cancer, non-small cell lung cancer and the like, and activated mutant RAS protein can promote abnormal signal transduction, so that the occurrence and development of cancer and drug resistance to targeted drugs are caused. Wherein the KRAS mutation is the highest mutation rate gene in human oncogenes, accounting for 20-30% of all tumors.

For mutant forms of KRAS proteins and signal pathway studies, significant advances in molecular biology have been made in recent years, however, the development of related targeted drugs remains a challenge. In chemical development, since the affinity of KRAS and GTP is very high, reaching 60pM, and the intracellular GTP concentration is at the level of mM, such directly competing molecules have extremely high affinity requirements for compounds, and so far there has been no successful case. In terms of development of biological drugs, antibody drugs penetrate cell membrane targeting KRAS proteins, and drug delivery efficiency is low. Therefore, many researchers have tried to develop a new way to inhibit the activities of RAF, MEK, ERK and other kinases in the KRAS downstream signal channel, so as to achieve the purpose of inhibiting the KRAS channel. The compounds have certain curative effects, but the downstream inhibitors can not completely block KRAS signals, and the target related toxic and side effects are large, so that the compounds have poor medicinal effects on KRAS mutant tumors. Therefore, the KRAS inhibitor for developing a new action mechanism has great clinical application value.

KRAS mutations are predominantly point mutations, including mutations at amino acids 12, 13 and 61. Of these, the mutation of glycine to cysteine (G12C) at position 12 is most common, and the mutation is expressed in a large proportion (14%) in lung cancer, especially non-small cell lung cancer, and in some patients with colorectal cancer (4%), pancreatic cancer (2%). In the U.S. cancer population, the incidence of this gene mutation is even greater than ALK, RET, TRK gene mutations in total.

Faced with the difficulty of KRAS protein drug formulation, the Instructions rate of Kevan M. Shoka, san Francisco, california university, previously demonstrated that certain specific compounds bind KRAS G12C muteins via covalent bonds. Through further studies, these covalent compounds were found to bind to cysteine at position 12 of KRAS muteins and occupy a hydrophobic allosteric regulatory pocket in the molecular switch-II region (switch-II regions), and the bound KRAS G12C mutations could be irreversibly locked in an inactivated state, blocking the protein-dependent signaling pathway and cancer cell viability (Nature 2013,503,548-551). The KRAS G12C small molecule inhibitor ARS-1620 can effectively inhibit tumor growth and even completely regress tumors on various KRAS G12C mutant tumor models. Since KRAS G12C is a mutein in tumor cells, whereas wild-type KRAS does not have this mutation site, a perfect tumor-selective target (Cell, 2018,572,578-589) is provided.

KRAS G12C has attracted a number of well-known new drug development enterprises at home and abroad to participate in. While the fastest growing, advanced small molecule KRAS G12C inhibitor Sotorasib (AMG 510) has been approved by the FDA for marketing at 28, 5, 2021, for non-small cell lung cancer patients who have received at least one systemic treatment and carry KRAS G12C mutations, the new generation of KRAS G12C inhibitor LY3537982 from the present is of greater interest. Preclinical data of LY3537982 was reported by american cancer institute (AACR) year 4 at 2021, which showed that LY3537982 was more than 10-fold more inhibited than Sotorasib in cellular activity and entered clinical stage 7 at 2021. It can be seen that there remains a need for highly selective, safe and effective KRAS G12C inhibitors in the clinic.

Patent applications for which KRAS G12C inhibitors have been disclosed include WO2014152588A1、WO2015054572A1、WO2016164675A1、WO2017087528A1、WO2017201161A1、WO2018119183A2、WO2018206539A1、WO2018217651A1、WO2019099524A1、WO2019215203A1、WO2020081282A1、WO2020178282A1、WO2021118877A1 et al.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

x is selected from CR ^aR ^b、NR ^s and an oxygen atom;

Y is selected from (CR ^cR ^d) _r、NR ^t-CR ^eR ^f、CR ^eR ^f-NR ^t、O-CR ^eR ^f and CR ^eR ^f -O;

Z ¹ and Z ² are the same or different and are each independently CR ^u or a nitrogen atom;

ring a is aryl or heteroaryl;

R ^a、R ^b、R ^c、R ^d、R ^e and R ^f are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, hydroxy, and cyano;

R ^s and R ^t are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, and an alkynyl group;

R ¹ is selected from cyano, cyano,

Each R ² is the same or different and is each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, hydroxy, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, and hydroxy;

R ³、R ⁴、R ⁵ and R ^u are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, -NR ^7aR ^7b、-C(O)R ⁸、-OR ⁸、-S(O) _pR ⁸, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano, -NR ^7cR ^7d、-OR ^8a, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Each R ⁶ is the same or different and is each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl 、-NR ^9aR ^9b、-C(O)NR ^9aR ^9b、-C(O)R ¹⁰、-C(O)OR ¹⁰、-OC(O)R ¹⁰、-OR ¹⁰、-S(O) _pR ¹⁰、-S(O) _pNR ^9aR ^9b、 cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano, -NR ^9cR ^9d、-OR ^10a, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ¹¹、R ¹²、R ¹³ and R ¹⁴ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, -NR ^15aR ^15b、-OR ¹⁶, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ^15cR ^15d, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁸、R ^8a、R ¹⁰、R ^10a and R ¹⁶ are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ^17aR ^17b, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^7a、R ^7b、R ^7c、R ^7d、R ^9a、R ^9b、R ^9c、R ^9d、R ^15a、R ^15b、R ^15c、R ^15d、R ^17a And R ^17b are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, and haloalkoxy;

Or R ^7a and R ^7b together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^7c and R ^7d together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ^9a and R ^9b together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^9c and R ^9d together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ^15a and R ^15b together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^15c and R ^15d together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ^17a and R ^17b together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

r is 1 or 2;

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

t is 0, 1,2, 3, 4 or 5; and is also provided with

P is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is (CR ^cR ^d) _r, wherein R ^c and R ^d are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, and C _1-6 haloalkyl, R is 1 or 2, preferably Y is CH ₂ or CH ₂-CH ₂.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ² is the same or different and is each independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, and amino, wherein the C _1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen and cyano; preferably, R ² is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein s is 0,1 or 2; preferably s is 0.

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

wherein:

m is 0 or 1;

The rings A, Z ¹、Z ²、R ¹、R ³、R ⁴、R ⁵、R ⁶ and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; preferably, ring a is a 5 to 10 membered heteroaryl; more preferably, ring a is an 8-to 10-membered bicyclic heteroaryl group containing 1,2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring; more preferably, ring a is benzothienyl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, whereinIs thatW is CR ⁶ or N, t is 0,1, 2,3, or 4, and R ⁶ is defined as in formula (I); preferably, the method comprises the steps of,Is thatW is C (CN) or N, t is 0, 1, 2 or 3, and R ⁶ is as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein R ¹ isWherein R ¹¹、R ¹²、R ¹³ and R ¹⁴ are as defined in formula (I); preferably, R ¹ isWherein R ¹¹、R ¹² and R ¹³ are as defined in formula (I).

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

wherein:

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹² and R ¹³ are as defined in formula (I).

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

wherein:

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

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

wherein:

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

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

wherein:

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

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

wherein:

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

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

wherein:

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

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

wherein:

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein Z ¹ and Z ² are the same or different and are each independently CR ^u or a nitrogen atom, wherein R ^u is selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl; preferably, Z ¹ and Z ² are both nitrogen atoms.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein R ³、R ⁴ and R ⁵ are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl, and C _1-6 haloalkyl; preferably, R ³、R ⁴ and R ⁵ are the same or different and are each independently a hydrogen atom or a halogen.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom or halogen; preferably, R ³ is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom or halogen; preferably, R ⁴ is halogen; more preferably, R ⁴ is F.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom or halogen; preferably, R ⁵ is halogen; more preferably, R ⁵ is Cl.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein each R ⁶ is the same or different and is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, -NH ₂、 C _1-6 alkyl, and C _1-6 haloalkyl; preferably, each R ⁶ is the same or different and is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, and —nh ₂.

In some embodiments of the present disclosure, the compound of formula (III), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein each R ⁶ is the same or different and is each independently selected from the group consisting of a hydrogen atom, halogen, cyano, -NH ₂、C _1-6 alkyl, and C _1-6 haloalkyl; preferably, each R ⁶ is the same or different and is each independently a hydrogen atom or halogen; more preferably, each R ⁶ is the same or different and is each independently a hydrogen atom or fluorine; most preferably, R ⁶ is fluoro.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; preferably, R ¹¹ is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein R ¹² is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; preferably, R ¹² is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; preferably, R ¹³ is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; preferably, R ¹⁴ is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein t is 0, 1, 2, or 3; preferably, t is 3.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein t is 0, or each R ⁶ is the same or different and is each independently selected from halogen, cyano, -NH ₂、C _1-6 alkyl, and C _1-6 haloalkyl, and t is 1,2, or 3.

In some embodiments of the present disclosure, the compound of formula (III), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1; preferably, t is 1.

In some embodiments of the present disclosure, the compound of formula (III), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein t is 0, or R ⁶ is halogen, and t is 1; preferably, R ⁶ is fluoro and t is 1.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom; y is CH ₂ or CH ₂-CH ₂;Z ¹ and Z ² are nitrogen atoms; ring a is a 5 to 10 membered heteroaryl; r ¹ isR ³、R ⁴ and R ⁵ are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; s is 0; t is 0, or each R ⁶ is the same or different and is each independently selected from halogen, cyano, -NH ₂、C _1-6 alkyl, and C _1-6 haloalkyl, and t is 1,2, or 3; r ¹¹ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; r ¹² is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; r ¹³ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; and R ¹⁴ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is an 8-to 10-membered bicyclic heteroaryl group containing 1,2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur in the ring; m is 0 or 1; z ¹ and Z ² are nitrogen atoms; r ¹ isR ³、R ⁴ and R ⁵ are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; t is 0, or each R ⁶ is the same or different and is each independently selected from halogen, cyano, -NH ₂、C _1-6 alkyl, and C _1-6 haloalkyl, and t is 1,2, or 3; r ¹¹ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; r ¹² is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group; and R ¹³ is selected from the group consisting of a hydrogen atom, a halogen, and a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound of formula (III), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B), or a pharmaceutically acceptable salt thereof, wherein W is C (CN) or N; m is 0 or 1; z ¹ and Z ² are nitrogen atoms; r ³、R ⁴ and R ⁵ are the same or different and are each independently a hydrogen atom or a halogen; r ¹¹ is a hydrogen atom; r ¹² is a hydrogen atom; r ¹³ is a hydrogen atom; r ⁶ is halogen and t is 1.

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 (Ia):

wherein:

The rings A, X, Y, Z ¹、Z ²、R ²、R ³、R ⁴、R ⁵、R ⁶, s and t are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIa):

wherein:

The rings A, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by general formula (IIIa):

wherein:

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in formula (III).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-1 a):

wherein:

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (III-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-2 a):

wherein:

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (III-2).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-1-Aa):

wherein:

w, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (III-1-A).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-1-Ba):

wherein:

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (III-1-B).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-2-Aa):

wherein:

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (III-2-A).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-2-Ba):

wherein:

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (III-2-B).

The compounds represented by the general formula (Ia), the general formula (IIa), the general formula (IIIa), the general formula (III-1 a), the general formula (III-2 a), the general formula (III-1-Aa), the general formula (III-1-Ba), the general formula (III-2-Aa) and the general formula (III-2-Ba) or salts thereof are disclosed, wherein the salts are preferably di-2, 2-trifluoroacetate.

Table B typical intermediate 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 (Iaa):

wherein:

R ^W2 is an amino protecting group; preferably, R ^W2 is t-butoxycarbonyl;

the rings A, X, Y, Z ¹、Z ²、R ²、R ³、R ⁴、R ⁵、R ⁶, s and t are as defined in formula (Ia).

Another aspect of the present disclosure relates to a compound represented by the general formula (IIaa):

wherein:

R ^W2 is an amino protecting group; preferably, R ^W2 is t-butoxycarbonyl;

The rings A, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (IIa).

Another aspect of the present disclosure relates to a compound represented by general formula (IIIaa):

wherein:

R ^W1 and R ^W2 are the same or different and are each independently an amino protecting group; preferably, R ^W1 and R ^W2 are both t-butoxycarbonyl;

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in formula (IIIa).

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

wherein:

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (III-1 a).

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

wherein:

W, Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶, m and t are as defined in the general formula (III-2 a).

Table C typical intermediate compounds of the present disclosure include, but are not limited to:

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:

Reacting a compound of formula (Ia) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (X) or a salt thereof to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

R ¹ is

The rings A、X、Y、Z ¹、Z ²、R ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹²、R ¹³、R ¹⁴、s and t are as defined in formula (I).

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:

reacting a compound of formula (IIa) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (X) or a salt thereof to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

R ¹ is

M is 0 or 1;

The rings A、Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹²、R ¹³、R ¹⁴ and t are as defined in formula (II).

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

Reacting a compound of formula (IIIa) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (XI) or a salt thereof to give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹² and R ¹³ are as defined in formula (III).

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

reacting a compound of formula (III-1 a) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (XI) or a salt thereof to give a compound of formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹² and R ¹³ are as defined in the general formula (III-1).

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

Reacting a compound of formula (III-2 a) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (XI) or a salt thereof to give a compound of formula (III-2) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹² and R ¹³ are as defined in the general formula (III-2).

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

resolving the compound of the general formula (III-1) or pharmaceutically acceptable salt thereof to obtain the compound of the general formula (III-1-A) and the general formula (III-1-B) or pharmaceutically acceptable salt thereof;

wherein:

W、Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹²、R ¹³、m And t is as defined in formula (III-1).

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

Resolving the compound of the general formula (III-2) or pharmaceutically acceptable salt thereof to obtain the compound of the general formula (III-2-A) and the compound of the general formula (III-2-B) or pharmaceutically acceptable salt thereof;

wherein:

W、Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹²、R ¹³、m And t is as defined in formula (III-2).

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

Removing R ^W2 from the compound of formula (Iaa) or a salt thereof to obtain a compound of formula (Ia) or a pharmaceutically acceptable salt thereof;

wherein:

R ^W2 is an amino protecting group; preferably, R ^W2 is t-butoxycarbonyl;

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

Removing R ^W2 from the compound of formula (IIaa) or a salt thereof to obtain a compound of formula (IIa) or a pharmaceutically acceptable salt thereof;

wherein:

R ^W2 is an amino protecting group; preferably, R ^W2 is t-butoxycarbonyl;

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

Removing R ^W1 and R ^W2 from the compound of formula (IIIaa) or a salt thereof to obtain a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof;

wherein:

R ^W1 and R ^W2 are both amino protecting groups; preferably, R ^W1 and R ^W2 are both t-butoxycarbonyl;

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

removing R ^W1 and R ^W2 from the compound of formula (III-1 aa) or a salt thereof to obtain a compound of formula (III-1 a) or a pharmaceutically acceptable salt thereof;

wherein:

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

Removing R ^W1 and R ^W2 from the compound of formula (III-2 aa) or a salt thereof to obtain a compound of formula (III-2 a) or a pharmaceutically acceptable salt thereof;

wherein:

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-a), formula (III-1-B), formula (III-2-a), formula (III-2-B), and table a, or a pharmaceutically acceptable salt thereof, in accordance with the present disclosure, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-a), formula (III-1-B), formula (III-2-a), formula (III-2-B) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for inhibiting KRAS G12C.

The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-a), formula (III-1-B), formula (III-2-a), formula (III-2-B) and table a or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for the treatment and/or prevention of a disease or disorder mediated by KRAS G12C.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B) and formula (III-2-B) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment and/or prevention of a tumor.

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

The disclosure further relates to a compound of formula (I), formula (II), formula (III-1), formula (III-2), formula (III-1-A), formula (III-1-B), formula (III-2-A), formula (III-2-B) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to compounds of general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as KRAS G12C inhibitors.

The present disclosure further relates to compounds of general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (III-1-a), general formula (III-1-B), general formula (III-2-a), general formula (III-2-B) and table a or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of a disease or disorder mediated by KRAS G12C.

The present disclosure further relates to compounds of general formula (I), general formula (II), general formula (III-1), general formula (III-2), general formula (III-1-A), general formula (III-1-B), general formula (III-2-A), general formula (III-2-B) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of tumors.

The disease or disorder mediated by KRAS G12C as described above in the present disclosure is preferably a tumor.

The tumor as described above in the present disclosure is a cancer; the cancer is preferably selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer (e.g., 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, renal cancer, nasopharyngeal carcinoma, bone cancer, lymphoma, melanoma, sarcoma, peripheral nerve epithelial tumor, glioma (e.g., astrocytoma and glioblastoma), brain tumor, and myeloma; more preferably from lung cancer (such as non-small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

The active compounds may be formulated in a form suitable for administration by any suitable route, preferably in unit dosage form, or in a form whereby the patient may self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation.

As a general guideline, suitable unit doses may be from 0.1 to 1000mg.

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

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations 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 oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant 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 preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which injectable solution or microemulsion may be injected into the blood stream of a patient by topical bolus injection. Or preferably the solution and microemulsion are administered in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the DELTEC CADD-PLUS. TM.5400 type.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure 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 amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health 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 optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, 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., a C _1-20 alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., a C _1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., a C _1-6 alkyl group). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, 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 alkyl is defined as above having 2 to 12 (e.g., 2, 3,4, 5, 6, 7, 8,9, 10, 11, or 12) carbon atoms (i.e., C _2-12 alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., a C _2-6 alkenyl group). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is defined as above having 2 to 12 (e.g., 2, 3,4, 5, 6, 7, 8,9, 10, 11, or 12) carbon atoms (i.e., a C _2-12 alkynyl group). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., a C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, alkoxy groups, halogen, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, full-carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic (i.e., polycyclic cycloalkyl) system 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 group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8 membered cycloalkyl group), and most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6 membered cycloalkyl group).

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

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

The term "spirocycloalkyl" refers to a polycyclic ring system having one or more carbon atoms (referred to as spiro atoms) shared between the rings, which may contain one or more double bonds within the ring, or which may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., to form a nitroxide; the sulfur may optionally be oxo, i.e., to form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-S-), provided that at least one full carbocyclic ring is contained and the point of attachment is on the full carbocyclic ring, 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., 5 to 20 membered spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spirocycloalkyl group), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spirocycloalkyl group). The spirocycloalkyl group includes a mono-spirocycloalkyl group and a multi-spirocycloalkyl group (e.g., a double spirocycloalkyl group, etc.), preferably a mono-spirocycloalkyl group or a double spirocycloalkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered single spirocycloalkyl group. Non-limiting examples include:

The connection point can be at any position; further comprises: Etc.

The term "fused ring alkyl" refers to a polycyclic ring system having two adjacent carbon atoms shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused to one or more of a heterocyclyl, aryl, or heteroaryl group, wherein the point of attachment is on the monocyclic cycloalkyl group, which may contain one or more double bonds within the ring, and 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., 5 to 20 membered fused ring alkyl groups). The condensed ring alkyl group is preferably a condensed ring alkyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered condensed ring alkyl group), more preferably a condensed ring alkyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered condensed ring alkyl group). The condensed ring alkyl group includes a bicyclic condensed ring alkyl group and a polycyclic condensed ring alkyl group (e.g., a tricyclic condensed ring alkyl group, a tetracyclic condensed ring alkyl group, etc.), preferably a bicyclic condensed ring alkyl group or a tricyclic condensed ring alkyl group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, or 7-membered/6-membered bicyclic condensed ring alkyl group. Non-limiting examples include:

The connection point can be at any position; further comprises:

Etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system having two carbon atoms in common between the rings that are not directly attached, which may contain one or more double bonds within the ring, and which has from 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., a 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10 membered bridged cycloalkyl group). The bridged cycloalkyl group includes a bicyclic bridged cycloalkyl group and a polycyclic bridged cycloalkyl group (e.g., a tricyclic bridged cycloalkyl group, a tetracyclic bridged cycloalkyl group, etc.), preferably a bicyclic bridged cycloalkyl group or a tricyclic bridged cycloalkyl group. Non-limiting examples include:

the connection point can be at any position.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they 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, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1,2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., forming a nitroxide; the sulfur may optionally be oxo, i.e., forming a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-), and having from 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 heterocyclyl) within the ring. The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3 to 12 membered heterocyclic group); further preferred are heterocyclyl groups having 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl groups); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3 to 6 membered heterocyclic group); most preferred are heterocyclyl groups having 5 or 6 ring atoms (i.e., 5 or 6 membered heterocyclyl groups).

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

The polycyclic heterocyclic group includes spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system having one or more double bonds shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2,3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-) with the proviso that at least one monocyclic heterocyclic ring is contained and the point of attachment is on the monocyclic heterocyclic ring, 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., 5 to 20 membered spiroheterocyclic groups). The spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14 membered spiroheterocyclyl group), more preferably a spiroheterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10 membered spiroheterocyclyl group). The spiroheterocyclyl group includes a mono-spiroheterocyclyl group and a multi-spiroheterocyclyl group (e.g., a double-spiroheterocyclyl group, etc.), preferably a mono-or double-spiroheterocyclyl group, more preferably a 3/4-, 3/5-, 3/6-, 4/4-, 4/5-, 4/6-, 5/3-, 5/4-, 5/5-, 5/6-, 5/7-, 6/3-, 6/4-, 6/5-, 6/6-, 6/7-, 7/5-or 7-membered mono-spiroheterocyclyl group. Non-limiting examples include:

Etc.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system having two adjacent atoms shared between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1,2,3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (which may optionally be oxidized, i.e., form nitrogen oxides; which may optionally be oxo, i.e., form sulfoxides or sulfones, but excluding-O-, -O-S-or-S-), which is a monocyclic heterocyclic group fused to one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused to one or more of cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on a monocyclic heterocyclic group 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 heterocyclic groups). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), more preferably a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes a bicyclic and polycyclic fused heterocyclic group (e.g., a tricyclic fused heterocyclic group, a tetracyclic fused heterocyclic group, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic fused heterocyclic group. Non-limiting examples include:

Etc.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system having two atoms not directly connected between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatom (S) selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-or-S-), 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., 5 to 20 membered bridged heterocyclyl). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10 membered bridged heterocyclic group). The number of constituent rings may be classified into a bicyclic bridged heterocyclic group and a polycyclic bridged heterocyclic group (e.g., a tricyclic bridged heterocyclic group, a tetracyclic bridged heterocyclic group, etc.), with a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group being preferred. Non-limiting examples include:

Etc.

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

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having from 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14 membered aryl) having a conjugated pi electron system. The aryl group is preferably an aryl group having 6 to 10 ring atoms (i.e., a 6 to 10 membered aryl group). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of such polycyclic aryl groups include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes a phenyl group fused to one or more of a heterocyclic group or a cyclic alkyl group, or a naphthyl group fused to one or more of a heterocyclic group or a cycloalkyl group, wherein the point of attachment is on the phenyl or naphthyl group, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

Etc.

Aryl groups may be substituted or unsubstituted, and when substituted, they 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, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a monocyclic heteroaryl ring having a conjugated pi electron system (i.e., a monocyclic heteroaryl group) or a polycyclic heteroaryl ring system (i.e., a polycyclic heteroaryl group) containing at least one (e.g., 1, 2, 3, or 4) heteroatom (S) selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized, i.e., form a nitrogen oxide; the sulfur may optionally be oxo, i.e., form a sulfoxide or sulfone, but excluding-O-, -O-S-, or-S-) within the ring having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a5 to 14 membered heteroaryl group). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a5 to 10 membered heteroaryl group), more preferably a monocyclic heteroaryl group having 5 or 6 ring atoms (i.e., a5 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 a5 or 6 membered monocyclic heteroaryl group having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring or an 8 to 10 membered bicyclic heteroaryl group having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring.

Non-limiting examples of such monocyclic heteroaryl groups include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridones (e.g.)Etc.), pyrazinyl, pyridazinyl, etc.

Non-limiting examples of such polycyclic heteroaryl groups include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl group also includes a monocyclic heteroaryl group fused to one or more of a cycloalkyl or heterocyclic group, where the point of attachment is on the monocyclic heteroaryl ring, and in such a case the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

Etc.

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they 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, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyloxycarbonyl (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, and the like.

The term "hydroxy protecting group" refers to an easily removable group introduced on a hydroxy group for blocking or protecting the hydroxy group to react on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

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 aryl-O-, wherein 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-, wherein 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 the alkoxy group 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 hydroxyl 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 "mercapto" refers to-SH.

The term "amino" refers to-NH ₂.

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂.

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

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 compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement 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, conformational isomers and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric atoms. All such stereoisomers, and mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr at the same time containTwo configurations. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named.

The 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 readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any proportions. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactams, and the like. Examples of lactam-lactam balances are between a and B as shown below:

as reference to pyrazolyl, it is understood to include mixtures of either or both tautomers of either of the following structures:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure may comprise atropisomers. The term "atropisomer" is a conformational stereoisomer that results from a blocked or greatly slowed rotation about a single bond in a molecule (as a result of steric interactions with other parts of the molecule and the substituents being asymmetric at both ends of the single bond), whose interconversion is slow enough to allow separation and isolation under predetermined conditions. For example, certain compounds of the present disclosure may exist as a mixture of atropisomers (e.g., an equal proportion of a mixture, a mixture enriched for one atropisomer, etc.) or as a purified one atropisomer. Non-limiting examples include: Etc.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as ² H (deuterium, D), ³ H (tritium ,T)、 ¹¹C、 ¹³C、 ¹⁴C、 ¹⁵N、 ¹⁷O、 ¹⁸O、 ³²p、 ³³p、 ³³S、 ³⁴S、 ³⁵S、 ³⁶S、 ¹⁸F、 ³⁶Cl、 ⁸²Br、 ¹²³I、 ¹²⁴I、 ¹²⁵I、 ¹²⁹I and ¹³¹ I, respectively, and the like, with deuterium being preferred.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

When a position is specifically designated as deuterium D, that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%), i.e. at least 15% deuterium incorporation. The natural abundance of the compounds in the examples may be at least 1000 times greater than the abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times greater than the abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times greater than the abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times greater than the abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times greater than the abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times greater than the abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times greater than the abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times greater than the abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times greater than the abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times greater than the abundance of deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times greater than the abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times greater than the abundance of deuterium (i.e., at least 6600 times greater than the abundance of deuterium (i.99% of deuterium incorporation), or at least 6600 times greater than the abundance of deuterium (i.5% of deuterium incorporation).

"Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that it includes instances where the event or circumstance occurs or does not. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"Substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., alkenes).

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

"Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. May be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate groups with an appropriate 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 and organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent 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 will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and the appropriate therapeutically effective amount in an individual case can be determined by one of skill in the art based on routine experimentation.

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

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by ±10%, and sometimes more preferably within ±5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

Scheme one

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

reacting a compound of formula (Ia) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (X) or a salt thereof under basic conditions to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

R ¹ is

Scheme II

A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

Reacting a compound of formula (IIa) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (X) or a salt thereof under basic conditions to obtain a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

R ¹ is

M is 0 or 1;

Scheme III

A process for the preparation of a compound of formula (III) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

Reacting a compound of formula (IIIa) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (XI) or a salt thereof under basic conditions to give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

Scheme IV

A process for the preparation of a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

Reacting a compound of formula (III-1 a) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (XI) or a salt thereof under basic conditions to give a compound of formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

Scheme five

A process for the preparation of a compound of formula (III-2) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

Reacting a compound of formula (III-2 a) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (XI) or a salt thereof under basic conditions to give a compound of formula (III-2) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

Scheme six

The preparation method of the compound shown in the general formula (III-1-A) and the general formula (III-1-B) or pharmaceutically acceptable salt thereof comprises the following steps:

resolving the compound of the general formula (III-1) or the pharmaceutically acceptable salt thereof by high performance liquid chromatography to obtain the compound of the general formula (III-1-A) and the compound of the general formula (III-1-B) or the pharmaceutically acceptable salt thereof;

wherein:

Scheme seven

The preparation method of the compound shown in the general formula (III-2-A) and the general formula (III-2-B) or pharmaceutically acceptable salt thereof comprises the following steps:

Resolving the compound of the general formula (III-2) or the pharmaceutically acceptable salt thereof by high performance liquid chromatography to obtain the compound of the general formula (III-2-A) and the compound of the general formula (III-2-B) or the pharmaceutically acceptable salt thereof;

wherein:

Scheme eight

A process for the preparation of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

(a) Carrying out Suzuki coupling reaction on a compound shown in a general formula (Iaaa) or salt thereof and a compound shown in a general formula (Iaab) or salt thereof to obtain the compound shown in the general formula (Iaa) or pharmaceutically acceptable salt thereof;

(b) Removing R ^W2 from a compound of formula (Iaa) or a salt thereof under acidic conditions to obtain a compound of formula (Ia) or a pharmaceutically acceptable salt thereof;

wherein:

R ^L is halogen; preferably, R ^L is Br;

R ^W2 is an amino protecting group; preferably, R ^W2 is t-butoxycarbonyl;

r ^X is selected from R is a hydrogen atom or a C _1-6 alkyl group;

Scheme nine

A process for the preparation of a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

(a) Carrying out Suzuki coupling reaction on the compound shown in the general formula (IIaaa) or salt thereof and the compound shown in the general formula (Iaab) or salt thereof to obtain a compound shown in the general formula (IIaa) or pharmaceutically acceptable salt thereof;

(b) Removing R ^W2 from a compound of formula (IIaa) or a salt thereof under acidic conditions to provide a compound of formula (IIa) or a pharmaceutically acceptable salt thereof;

wherein:

R ^L is halogen; preferably, R ^L is Br;

R ^W2 is an amino protecting group; preferably, R ^W2 is t-butoxycarbonyl;

r ^X is selected from R is a hydrogen atom or a C _1-6 alkyl group;

Scheme ten

A process for the preparation of a compound of formula (IIIa) of the disclosure or a pharmaceutically acceptable salt thereof, comprising the steps of:

(a) Carrying out Suzuki coupling reaction on the compound shown in the general formula (IIIaaa) or salt thereof and the compound shown in the general formula (IIIaab) or salt thereof to obtain a compound shown in the general formula (IIIaa) or pharmaceutically acceptable salt thereof;

(b) Removing R ^W1 and R ^W2 from a compound of formula (IIIaa) or a salt thereof under acidic conditions to provide a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof;

wherein:

R ^L is halogen; preferably, R ^L is Br;

r ^X is selected from R is a hydrogen atom or a C _1-6 alkyl group;

Scheme eleven

A process for the preparation of a compound of formula (III-1 a) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

(a) Carrying out Suzuki coupling reaction on the compound shown in the general formula (III-1 aaa) or salt thereof and the compound shown in the general formula (IIIaab) or salt thereof to obtain the compound shown in the general formula (III-1 aa) or pharmaceutically acceptable salt thereof;

(b) Removing R ^W1 and R ^W2 from a compound of formula (III-1 aa) or a salt thereof under acidic conditions to obtain a compound of formula (III-1 a) or a pharmaceutically acceptable salt thereof;

wherein:

R ^L is halogen; preferably, R ^L is Br;

r ^X is selected from R is a hydrogen atom or a C _1-6 alkyl group;

Scheme twelve

A process for the preparation of a compound of formula (III-2 a) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

(a) Carrying out Suzuki coupling reaction on the compound shown in the general formula (III-2 aaa) or salt thereof and the compound shown in the general formula (IIIaab) or salt thereof to obtain the compound shown in the general formula (III-2 aa) or pharmaceutically acceptable salt thereof;

(b) Removing R ^W1 and R ^W2 from a compound of formula (III-2 aa) or a salt thereof under acidic conditions to obtain a compound of formula (III-2 a) or a pharmaceutically acceptable salt thereof;

wherein:

R ^L is halogen; preferably, R ^L is Br;

r ^X is selected from R is a hydrogen atom or a C _1-6 alkyl group;

In the above synthesis scheme, the Suzuki coupling reaction is preferably carried out in the presence of a base, such as cesium carbonate, and a metal catalyst, such as bis (diphenylphosphinophenylether) palladium (II) dichloride.

In the above synthetic schemes, the base providing basic conditions includes organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium t-butoxide and potassium t-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 synthetic schemes, the acid providing acidic conditions include organic acids including, but 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, 1, 4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

The above synthetic schemes are preferably carried out in solvents including, but 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-dimethylformamide, N-dimethylacetamide, and mixtures thereof.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 ^-6 (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated chloroform (CDCl ₃), deuterated methanol (CD ₃ OD) and Tetramethylsilane (TMS) as internal standard.

MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC-MS (manufacturer: agilent, MS model: 6110/6120 Quadrupole MS).

Waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

High Performance Liquid Chromatography (HPLC) analysis used AGILENT HPLC DAD, AGILENT HPLC VWD, and WATERS HPLC E2695-2489 high performance liquid chromatographs.

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

The high performance liquid phase was prepared by using Waters 2545-2767, waters 2767-SQ Detecor2, shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

Chiral preparation was 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 a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

The average inhibition rate of kinase and IC ₅₀ were measured by NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, ALDRICH CHEMICAL Company, shao Yuan chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses Parr 3916EKX type hydrogenometer and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: the volume ratio of the petroleum ether to the ethyl acetate is adjusted according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

4- ((5 Ar,9 s) -4-propenoyl-8-chloro-10-fluoro-4, 5a, 6-tetrahydro-3H-7-oxa-1, 2a1, 4-tetraazadibenzo [ cd, H ] azulen-9-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 1-p1

4- ((5 Ar,9 r) -4-propenoyl-8-chloro-10-fluoro-4, 5a, 6-tetrahydro-3H-7-oxa-1, 2a1, 4-tetraazadibenzo [ cd, H ] azulen-9-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 1-p2

First step

4-Bromo-3-chloro-2, 5-difluorobenzoyl hydrazine 1b

Methyl 4-bromo-3-chloro-2, 5-difluorobenzoate (1.0 g,3.50 mmol) was dissolved in ethanol (30 mL), hydrazine hydrate (410 mg,6.96mmol,85% purity) was added and the reaction stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1b (800 mg, yield: 79.9%).

MS m/z(ESI):284.9[M+1]。

Second step

(R) -3- (((tert-Butyldimethylsilyl) oxy) methyl) -5-oxopiperazine-1-carboxylic acid tert-butyl ester 1d

The compound (R) -3- (hydroxymethyl) -5-oxopiperazine-1-carboxylic acid tert-butyl ester 1c (5.3 g,23mmol, prepared by the well-known method "Organic Letters,2004, vol.6, no.22, p.4069-4072 and Supporting Information" thereof) was dissolved in N, N-dimethylformamide (30 mL), imidazole (3.4 g,49.94 mmol) and tert-butyldimethylchlorosilane (2.3 g,27.92 mmol) were added in sequence and stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1d (6.0 g, yield: 75.6%).

MS m/z(ESI):345.2[M+1]。

Third step

(R) -3- (((tert-Butyldimethylsilyl) oxy) methyl) -5-thiopiperazine-1-carboxylic acid tert-butyl ester 1e

Compound 1d (2.0 g,5.80 mmol) was dissolved in tetrahydrofuran (30 mL) and Lawson reagent (1.8 g,4.4503 mmol) was added. The reaction was carried out at 80℃for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1e (1.0 g, yield: 47.7%).

MS m/z(ESI):361.2[M+1]。

Fourth step

(R) -3- (4-bromo-3-chloro-2, 5-difluorophenyl) -5- (((tert-butyldimethylsilyl) oxy) methyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 1f

Compound 1e (500 mg,1.38 mmol) and compound 1b (375 mg,1.31 mmol) were dissolved in xylene (4 mL) and heated to 120deg.C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1f (250 mg, yield: 30.3%).

MS m/z(ESI):593.2[M+1]。

Fifth step

(R) -9-bromo-8-chloro-10-fluoro-5 a, 6-dihydro-3H-7-oxa-1, 2a1, 4-tetraazadibenzo [ cd, H ] azulene-4 (5H) -carboxylic acid tert-butyl ester 1g

Compound 1f (100 mg, 168.36. Mu. Mol) was dissolved in tetrahydrofuran (2 mL), a 1M tetrahydrofuran solution of tetrabutylammonium fluoride (841.80. Mu.L) was added, the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1g (70 mg, yield: 90.4%).

MS m/z(ESI):459.2[M+1]。

Sixth step

(5 AR) -9- (2- ((tert-Butoxycarbonyl) amino) -3-cyano-7-fluorobenzo [ b ] thiophen-4-yl) -8-chloro-10-fluoro-5 a, 6-dihydro-3H-7-oxa-1, 2a ¹, 4-tetraazadibenzo [ cd, H ] azulene-4 (5H) -carboxylic acid tert-butyl ester 1H

Compound 1g (35 mg, 76.13. Mu. Mol) of tert-butyl 3-cyano-4- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) -7-fluorobenzo [ b ] thiophen-2-yl) carbamate (70 mg, 121.2. Mu. Mol, prepared as described in preparation 15 on page 50 of the patent application "WO2021118877A 1") was dissolved in 2mL of toluene, bis (diphenylphosphinophenyl ether) palladium (II) dichloride (20 mg, 13.9. Mu. Mol, shanghai tai) was added, cesium carbonate (65 mg, 199.7. Mu. Mol) was replaced with nitrogen, the reaction mixture was stirred at 105℃for 6 hours, 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 1h (45 mg, yield: 88%).

MS m/z(ESI):671.2[M+1]。

Seventh step

2-Amino-4- ((5 aR) -8-chloro-10-fluoro-4, 5a, 6-tetrahydro-3H-7-oxa-1, 2a ¹, 4-tetraazadibenzo [ cd, H ] azulen-9-yl) -7-fluorobenzo [ b ] thiophene-3-carbonitrile di-2, 2-trifluoroacetate 1i

Compound 1h (45 mg, 67.05. Mu. Mol) was dissolved in 1mL of methylene chloride, 1mL of trifluoroacetic acid was added at 0℃and the reaction was stirred for 2 hours, and the reaction mixture was concentrated under reduced pressure to give the crude title compound 1i (40 mg), which was used in the next reaction without purification.

MS m/z(ESI):471.1[M+1]。

Eighth step

4- ((5 AR) -4-propenoyl-8-chloro-10-fluoro-4, 5a, 6-tetrahydro-3H-7-oxa-1, 2a ¹, 4-tetraazadibenzo [ cd, H ] azulene-9-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 1

4- ((5 Ar,9 s) -4-propenoyl-8-chloro-10-fluoro-4, 5a, 6-tetrahydro-3H-7-oxa-1, 2a ¹, 4-tetraazadibenzo [ cd, H ] azulen-9-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 1-p1

4- ((5 Ar,9 r) -4-propenoyl-8-chloro-10-fluoro-4, 5a, 6-tetrahydro-3H-7-oxa-1, 2a ¹, 4-tetraazadibenzo [ cd, H ] azulen-9-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 1-p2

Compound 1i (40 mg, 57.2. Mu. Mol) was suspended in 2mL of ethyl acetate, 1mL of tetrahydrofuran and 2mL of water, anhydrous potassium carbonate (52 mg,0.37 mmol) was added, acryloyl chloride (5 mg, 55.24. Mu. Mol) was added under ice-bath, after 5 minutes of reaction, extracted with ethyl acetate (5 mL. Times.2), the organic phases were combined, concentrated under reduced pressure to give the crude title compound 1 (30 mg), purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title compound (2 mg, yield: 6.6%, 6.6%). Single configuration compound (shorter retention time) (2 mg, yield: 6.6%)

MS m/z(ESI):525.2[M+1]。

HPLC analysis: retention time 1.16 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹H NMR(500MHz,CD3OD):δ8.19(d,1H),7.19(dd,1H),7.04(dd,1H),6.94(s,1H),6.38(dd,1H),5.91(d,1H),4.97-4.94(M,2H),4.24(dd,1H),3.36(s,2H),2.21(t,1H),2.05(q,1H).

Single configuration compound (longer retention time) (2 mg, yield: 6.6%)

MS m/z(ESI):525.2[M+1]。

LCMS analysis, retention time 1.18 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹H NMR(500MHz,CD3OD):δ8.21(d,1H),7.19(dd,1H),7.03(t,1H),6.93(d,1H),6.38(dd,1H),5.91(d,1H),4.99-4.93(m,2H),4.23(dd,1H),3.35(s,2H),2.21(t,1H),2.05(q,1H).

Example 2

4- ((3 AS, 8S) -2-propenoyl-7-chloro-9-fluoro-1, 2,3a, 4, 5-hexahydro-6-oxa-2, 3a ¹, 11, 12-tetraazabenzo [7,8] octabicyclo [1,2,3-cd ] inden-8-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 2-p1

4- ((3 AS, 8R) -2-propenoyl-7-chloro-9-fluoro-1, 2,3a, 4, 5-hexahydro-6-oxa-2, 3a ¹, 11, 12-tetraazabenzo [7,8] octabicyclo [1,2,3-cd ] inden-8-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 2-p2

First step

(S) - (2- ((benzyloxy) carbonyl) amino) -4- (((tert-butyldimethylsilyl) oxy) butyl) glycine methyl ester 2b

Benzyl (S) - (4- ((tert-butyldimethylsilyloxy) -1-oxobutan-2-yl) carbamate 2a (2.2 g,6.25mmol, prepared using well-known methods "ANGEWANDTE CHEMIE-International Edition,2004, vol.43, no.29, p.3818-3822 and Supporting Information") and ethyl 2-aminoacetate hydrochloride (1.7 g,12.1mmol, shanghai Pichia) were dissolved in methanol (15 mL), glacial acetic acid (750 mg,12.5 mmol), sodium cyanoborohydride (600 mg,10.03 mmol) were added in succession and the reaction stirred for 14 h. The reaction solution was neutralized with potassium carbonate, then filtered, and the filtrate was concentrated under reduced pressure, water was added, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and 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 2b (0.9 g, yield: 33.9%).

MS m/z(ESI):425.2[M+1]。

Second step

(S) -6- (2- ((tert-butyldimethylsilyl) oxy) ethyl) piperazin-2-one 2c

Methyl (S) - (2- ((benzyloxy) carbonyl) amino) -4- (((tert-butyldimethylsilyl) oxy) butyl) glycinate 2b (1.8 g,4.10 mmol) was dissolved in ethanol (20 mL), palladium on carbon catalyst (10%) (440 mg,4.13 mmol) was added, hydrogen was replaced, and the reaction was stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 2c (1 g), which was used in the next reaction without purification.

MS m/z(ESI):259.2[M+1]。

Third step

(S) -3- (2- ((tert-Butyldimethylsilyl) oxy) ethyl) -5-oxopiperazine-1-carboxylic acid tert-butyl ester 2d

Compound 2c (1.0 g,3.8695 mmol) was dissolved in dichloromethane (10 mL), di-tert-butyl dicarbonate (1.01 g,4.64 mmol) was added and the reaction was reacted for 14 hours, the reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 2d (1.1 g, yield: 79.28%).

MS m/z(ESI):359.2[M+1]。

Fourth step

(S) -3- (2- ((tert-Butyldimethylsilyl) oxy) ethyl) -5-thiopiperazine-1-carboxylic acid tert-butyl ester 2e

Compound 2d (100 mg, 278.9. Mu. Mol) was dissolved in tetrahydrofuran (5 mL) and L.sub.Hemsl (135 mg, 333.3. Mu. Mol) was added. The reaction was heated to 80℃under reflux for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 2e (40 mg, yield: 47.7%).

MS m/z(ESI):375.2[M+1]。

Fifth step

(S) -3- (4-bromo-3-chloro-2, 5-difluorophenyl) -5- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 2f

Compound 2e (250 mg, 667.3. Mu. Mol) and compound 1b (215 mg, 753.1. Mu. Mol) were dissolved in xylene (2 mL) and reacted at 120℃for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 2f (170 mg, yield: 41.8%).

MS m/z(ESI):607.2[M+1]。

Sixth step

(S) -8-bromo-7-chloro-9-fluoro-3, 3a,4, 5-tetrahydro-6-oxa-2, 3a ¹, 11, 12-tetraazabenzo [7,8] octabicyclo [1,2,3-cd ] indene-2 (1H) -carboxylic acid tert-butyl ester 2g

Compound 2f (170 mg, 279.6. Mu. Mol) was dissolved in tetrahydrofuran (5 mL), a 1M tetrahydrofuran solution of tetrabutylammonium fluoride (1.4 mL) was added, the reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 2g (124 mg, yield: 93.6%).

MS m/z(ESI):473.2[M+1]。

Seventh step

(3 AS) -8- (2- ((tert-Butoxycarbonyl) amino) -3-cyano-7-fluorobenzo [ b ] thiophen-4-yl) -7-chloro-9-fluoro-3, 3a,4, 5-tetrahydro-6-oxa-2, 3a ¹, 11, 12-tetraazabenzo [7,8] octabicyclo [1,2,3-cd ] indene-2 (1H) -carboxylic acid tert-butyl ester

Butyl ester 2h

2G (140 mg, 295.5. Mu. Mol) of compound (3-cyano-4- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) -7-fluorobenzo [ b ] thiophen-2-yl) carbamic acid tert-butyl ester (60 mg, 148.4. Mu. Mol) was dissolved in 2mL of toluene, bis (diphenylphosphinophenyl ether) palladium (II) dichloride (20 mg, 13.9. Mu. Mol), cesium carbonate (100 mg, 306.9. Mu. Mol) was added, nitrogen was substituted, the reaction was stirred at 105℃for 6 hours, the reaction solution was cooled to room temperature and then filtered, and 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 2h (56 mg, yield: 55%).

MS m/z(ESI):685.2[M+1]。

Eighth step

2-Amino-4- ((3 aS) -7-chloro-9-fluoro-1, 2,3a, 4, 5-hexahydro-6-oxa-2, 3a ¹, 11, 12-tetraazabenzo [7,8] octabicyclo [1,2,3-cd ] inden-8-yl) -7-fluorobenzo [ b ] thiophene-3-carbonitrile di-2, 2-trifluoroacetate 2i

Compound 2h (56 mg, 81.7. Mu. Mol) was dissolved in 1mL of methylene chloride, 1mL of trifluoroacetic acid was added at 0℃and the reaction was stirred for 2 hours, and the reaction mixture was concentrated under reduced pressure to give the crude title compound 2i (58 mg), which was used in the next reaction without purification.

MS m/z(ESI):485.1[M+1]。

Ninth step

4- ((3 AS) -2-propenoyl-7-chloro-9-fluoro-1, 2,3a, 4, 5-hexahydro-6-oxa-2, 3a ¹, 11, 12-tetraazabenzo [7,8] octabicyclo [1,2,3-cd ] inden-8-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 2

Compound 2i (58 mg, 81.3. Mu. Mol) was suspended in 2mL of ethyl acetate, 1mL of tetrahydrofuran and 2mL of water, anhydrous potassium carbonate (56 mg,0.45 mmol) was added, acryloyl chloride (15 mg, 165.7. Mu. Mol) was added under ice-bath, ethyl acetate (5 mL. Times.2) was used for extraction after 5 minutes, the organic phases were combined, concentrated under reduced pressure to give crude title compound 2 (40 mg), purified by high performance liquid preparative chromatography (Waters-2545, column: sharpSil-T C, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title compound (2 mg,0.7mg, yield: 4.5%, 1.9%).

Single configuration compound (shorter retention time) (2 mg, yield: 4.5%)

MS m/z(ESI):539.2[M+1]。

HPLC analysis: retention time 1.12 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹H NMR(500MHz,CD3OD):δ7.58(s,1H),7.19(dd,1H),7.05(dd,1H),6.92(dd,1H),6.40(d,1H),5.92(s,1H),5.54-5.42(m,1H),4.28(t,2H),3.94(d,1H),3.69-3.57(m,1H),2.34(s,1H),2.21(t,1H),2.12-2.00(m,2H).

Single configuration compound (longer retention time) (0.7 mg, yield: 1.9%)

MS m/z(ESI):539.2[M+1]。

LCMS analysis, retention time 1.13 min, purity: 99% (chromatographic column: ACQUITY)C18,1.7 μm,2.1 x 50mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹H NMR(500MHz,CD3OD):δ7.46(d,1H),7.26(dd,1H),7.06(dd,1H),6.99-6.87(m,1H),6.39(d,1H),5.91(s,1H),5.44-5.33(m,1H),4.724.49(m,2H),4.44-4.31(m,2H),3.773.69(m,1H),2.29(dd,1H),2.112.05(m,2H).

Example 3

4- ((3 AR) -2-propenoyl-7-chloro-9-fluoro-1, 2,3a, 4, 5-hexahydro-6-oxa-2, 3a ¹, 11, 12-tetraazabenzo [7,8] octabicyclo [1,2,3-cd ] inden-8-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 3

First step

((Benzyloxy) carbonyl) -D-homoserine methyl ester 3b

The compound N-benzyloxycarbonyl-D-homoserine 3a (20 g,78.9mmol, shanghai) was dissolved in a mixed solvent of methanol (60 mL) and N-hexane (150 mL), a 2.0M solution of trimethylsilyl diazomethane in N-hexane (79 mL) was added, the reaction was stirred for 6 hours, and the reaction solution was concentrated under reduced pressure to give the crude title compound 3b (21 g), which was used in the next reaction without purification.

MS m/z(ESI):568.2[M+1]。

Second step

N- ((benzyloxy) carbonyl) -O- (tert-butyldimethylsilyl) -D-homoserine methyl ester 3c

The crude compound 3b (21 g,78.5 mmol) was dissolved in N, N-dimethylformamide (30 mL), imidazole (53.48 g,785.5 mmol), t-butyldimethylchlorosilane (59.2 g,392.8 mmol) were added sequentially, the reaction was stirred for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 3c (11.3 g, yield: 37.6%).

Third step

(R) - (4- ((tert-Butyldimethylsilanyloxy) -1-oxobutan-2-yl) carbamic acid benzyl ester 3d

Compound 3c (6 g,15.7 mmol) was dissolved in anhydrous tetrahydrofuran (120 mL), and a 1M solution of diisobutylaluminum hydride in n-hexane (66 mL) was added thereto at-78℃under nitrogen protection, and the temperature was maintained for reaction for 6 hours. The reaction solution was poured into 300mL of 1M glacial hydrochloric acid, stirred for 10 minutes, extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to give crude compound 3d (5.5 g), which was used in the next reaction without purification.

MS m/z(ESI):352.2[M+1]。

Fourth step

(R) - (2- (((benzyloxy) carbonyl) amino) -4- ((tert-butyldimethylsilyl) oxy) butyl) glycine methyl ester 3e

The crude compound 3d (5.50 g,15.64 mmol), ethyl 2-aminoacetate hydrochloride (4.36 g,31.29mmol, shanghai Bifide) was dissolved in methanol (100 mL), glacial acetic acid (1.87 g,31.29 mmol), sodium cyanoborohydride (1.49 g,25.03 mmol) was added in sequence and the reaction stirred for 14 h. The reaction solution was neutralized with potassium carbonate, then filtered, and the filtrate was concentrated under reduced pressure, water was added, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and 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 3e (2.5 g, yield: 36.4%).

MS m/z(ESI):425.2[M+1]。

Fifth step

Using the synthetic route in example 2, the second starting material 2b was replaced with compound 3e to give the title compound 3 (3 mg, yield: 5.3%).

MS m/z(ESI):539.2[M+1]。

1H NMR(500MHz,CD3OD):δ7.58(s,1H),7.19(dd,1H),7.04(d,1H),6.93(dd,1H),6.40(d,1H),5.92(s,1H),5.48(s,1H),4.28-4.25(m,2H),3.90-3.83(m,1H),3.58-3.50(m,1H),2.33-2.25(m,1H),2.21(dd,1H),2.12-2.05(m,2H).

Biological evaluation

The present disclosure is explained in further detail below in connection with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1: biological evaluation of H358 proliferation experiment

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on H358 cell proliferation, and the experimental methods are briefly described below:

H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 medium (Hyclone, SH 30809.01) (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 96-well plates at a density of 1200 cells/well, 100 μl of cell suspension per well, and incubated overnight at 37 ℃ in a 5% co ₂ cell incubator. The next day, 10 μl of the test compound was added per well in a 5-fold gradient from 10 μΜ at 9 concentration points, with a blank control containing 0.5% dmso, and the well plate was incubated in a 5% co ₂ cell incubator at 37 ℃ for 120 hours. On the seventh day, the 96-well cell culture plate is taken out, and 50 mu L of luminous cell activity detection reagent is added into each well Luminescent Cell Viability Assay) (Promega, G7573), after 10 minutes at room temperature, a multifunctional microplate reader (PerkinElmer,2105 Luminescence signal values were read and IC ₅₀ values for compound inhibitory activity were calculated using GRAPHPAD PRISM software.

TABLE 1 inhibitory Activity of the compounds of the present disclosure against H358 cell proliferation

Numbering of compounds	IC ₅₀(nM)
Compounds corresponding to shorter retention times in 2-p1 and 2-p2	14.01

Conclusion: the compounds of the present disclosure have an inhibitory effect on H358 cell proliferation.

Test example 2: biological evaluation of ERK phosphorylation inhibition experiment of H358 cells

The following methods were used to determine the inhibition of ERK phosphorylation of H358 cells by the compounds of the present disclosure. The experimental procedure is briefly described as follows:

H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH 30809.01) 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 at a density of 25,000 cells per well in 96-well plates, 190 μl of cell suspension per well, placed at 37 ℃, and cultured overnight in a 5% co ₂ cell incubator. The next day, 10 μl of the test compound was added per well in a gradient diluted with complete medium, the final concentration of the compound was 9 concentration points at 6-fold gradient dilution starting from 10 μΜ, a blank containing 0.5% dmso was set, the well plate was placed in a 37 ℃ cell incubator with 5% co ₂ and incubated for 3 hours. After 3 hours, the 96-well cell culture plate was removed, the medium was aspirated, and 200. Mu.L of PBS (Shanghai Source culture Biotech Co., ltd., B320) was added to each well and washed once. The PBS was blotted off, 50. Mu.L of blocking reagent-containing (Cisbio, 64KB1 AAC) lysis buffer (Cisbio, 64KL1 FDF) was added to each well, and the well plate was placed on a shaker and lysed by shaking at room temperature for 30 minutes. After lysis, 16. Mu.L of lysate was transferred to each well separately to two HTRF 96-well assay plates (Cisbio, 66PL 96100) after which 4. Mu.L of pre-mixed phospho-ERK1/2 antibody solution (Cisbio, 64 AERPEG) or 4. Mu.L of pre-mixed total-ERK1/2 antibody solution (Cisbio, 64 NRKPEG) were added to each plate. The microplate was sealed with a sealing plate membrane, centrifuged in a microplate centrifuge for 1 min, and incubated overnight at room temperature in the absence of light. On the third day, the fluorescence values of the 337nm wavelength excitation, 665nm and 620nm wavelength emission were read using a PHERASTAR multifunctional microplate reader (BMG Labtech, PHERASTAR FS) and the IC ₅₀ value for the compound inhibitory activity was calculated by GRAPHPAD PRISM software from the ratio of compound concentration and pERK/total ERK.

TABLE 2 inhibition of ERK phosphorylation of H358 cells by the compounds of the present disclosure

Numbering of compounds	IC ₅₀(nM)
Compounds corresponding to shorter retention times in 1-p1 and 1-p2	14.09
Compounds corresponding to longer retention times in 1-p1 and 1-p2	2.32
Compounds corresponding to shorter retention times in 2-p1 and 2-p2	0.25
Compounds corresponding to longer retention times in 2-p1 and 2-p2	3.43

Conclusion: the compounds of the present disclosure have an inhibitory effect on ERK phosphorylation in H358 cells.

Test example 3: biological evaluation of MIA PaCa-2 cell proliferation experiments

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on MIA PaCa-2 cell proliferation. The experimental procedure is briefly described as follows:

MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in DMEM/HIGH GLUCOSE (GE, SH 30243.01) medium (i.e., complete medium) containing 10% fetal bovine serum (Corning, 35-076-CV) and 2.5% horse serum (Biyun biotechnology, C0262). On the first day of the experiment, MIA PaCa-2 cells were seeded in 96-well plates at a density of 500 cells/well using complete medium, 90 μl of cell suspension per well, and incubated overnight at 37 ℃ in a 5% co ₂ cell incubator. The next day, 10 μl of the test compound was added per well in a 5-fold gradient from 10 μΜ at 9 concentration points, a blank containing 0.5% dmso was placed, and the well plate was incubated in a 5% co ₂ cell incubator at 37 ℃ for 72 hours. On the fifth day, the 96-well cell culture plate is taken out, and 50 mu L of luminous cell activity detection reagent is added into each well Luminescent Cell Viability Assay) (Promega, G7573), the luminescence signal value was read using a multifunctional microplate reader (PERKINELMER, ENVISION 2015) after 10 minutes of standing at room temperature. IC ₅₀ values for compound inhibitory activity were calculated using GRAPHPAD PRISM software.

TABLE 3 inhibitory Activity of the compounds of the present disclosure on MIA PaCa-2 cell proliferation

Numbering of compounds	IC ₅₀(nM)
Compounds corresponding to shorter retention times in 2-p1 and 2-p2	1.81

Conclusion: the compounds of the present disclosure have an inhibitory effect on MIA PaCa-2 cell proliferation.

Claims

A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

x is selected from CR ^aR ^b、NR ^s and an oxygen atom;

Y is selected from (CR ^cR ^d) _r、NR ^t-CR ^eR ^f、CR ^eR ^f-NR ^t、O-CR ^eR ^f and CR ^eR ^f -O;

Z ¹ and Z ² are the same or different and are each independently CR ^u or a nitrogen atom;

ring a is aryl or heteroaryl;

R ^a、R ^b、R ^c、R ^d、R ^e and R ^f are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, hydroxy, and cyano;

R ^s and R ^t are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, and an alkynyl group;

R ¹ is selected from cyano, cyano,

Each R ² is the same or different and is each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, hydroxy, and amino, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, and hydroxy;

R ³、R ⁴、R ⁵ and R ^u are the same or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, -NR ^7aR ^7b、-C(O)R ⁸、-OR ⁸、-S(O) _pR ⁸, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano, -NR ^7cR ^7d、-OR ^8a, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Each R ⁶ is the same or different and is each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl 、-NR ^9aR ^9b、-C(O)NR ^9aR ^9b、-C(O)R ¹⁰、-C(O)OR ¹⁰、-OC(O)R ¹⁰、-OR ¹⁰、-S(O) _pR ¹⁰、-S(O) _pNR ^9aR ^9b、 cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl, cyano, -NR ^9cR ^9d、-OR ^10a, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ¹¹、R ¹²、R ¹³ and R ¹⁴ are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, -NR ^15aR ^15b、-OR ¹⁶, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ^15cR ^15d, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁸、R ^8a、R ¹⁰、R ^10a and R ¹⁶ are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ^17aR ^17b, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^7a、R ^7b、R ^7c、R ^7d、R ^9a、R ^9b、R ^9c、R ^9d、R ^15a、R ^15b、R ^15c、R ^15d、R ^17a And R ^17b are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, and haloalkoxy;

Or R ^7a and R ^7b together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^7c and R ^7d together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ^9a and R ^9b together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^9c and R ^9d together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ^15a and R ^15b together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ^15c and R ^15d together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ^17a and R ^17b together with the attached nitrogen atom form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

r is 1 or 2;

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

t is 0, 1,2, 3, 4 or 5; and is also provided with

P is 0, 1 or 2.
A compound of the general formula (I) according to claim 1, wherein X is an oxygen atom, or a pharmaceutically acceptable salt thereof.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 wherein Y is CH ₂ or CH ₂-CH ₂.
A compound of general formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein s is 0.
A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound of general formula (II):

wherein:

m is 0 or 1;

The loops A, Z ¹、Z ²、R ¹、R ³、R ⁴、R ⁵、R ⁶ and t are as defined in claim 1.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring a is an 8-to 10-membered bicyclic heteroaryl group containing 1, 2 or3 heteroatoms selected from nitrogen, oxygen and sulfur in the ring.
A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6 wherein R ¹ isWherein R ¹¹、R ¹² and R ¹³ are as defined in claim 1.
A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is a compound of general formula (III):

wherein:

W is C (CN) or N;

t is 0, 1,2 or 3;

m is 0 or 1;

Z ¹、Z ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹² and R ¹³ are as defined in claim 1.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein Z ¹ and Z ² are both nitrogen atoms.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ³、R ⁴ and R ⁵ are the same or different and are each independently selected from a hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each R ⁶ is the same or different and is each independently selected from a hydrogen atom, halogen, cyano, -NH ₂、C _1-6 alkyl and C _1-6 haloalkyl.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ¹¹ is a hydrogen atom.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ¹² is a hydrogen atom.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R ¹³ is a hydrogen atom.
A compound of general formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
A compound represented by the general formula (Ia):

wherein:

The rings A, X, Y, Z ¹、Z ²、R ²、R ³、R ⁴、R ⁵、R ⁶, s and t are as defined in claim 1.
A compound or salt thereof selected from the following compounds:
a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:

Reacting a compound of formula (Ia) or a salt thereof (preferably di-2, 2-trifluoroacetate salt) with a compound of formula (X) or a salt thereof to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

L is halogen; preferably, L is Cl;

R ¹ is

The loops A、X、Y、Z ¹、Z ²、R ²、R ³、R ⁴、R ⁵、R ⁶、R ¹¹、R ¹²、R ¹³、R ¹⁴、s and t are as defined in claim 1.
A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for inhibiting KRAS G12C.
Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for the treatment and/or prophylaxis of tumors; preferably, the tumor is cancer; the cancer is preferably selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, liver cancer, breast cancer, prostate cancer, thyroid cancer, gastric cancer, urothelial cancer, testicular cancer, leukemia, skin cancer, squamous cell cancer, basal cell cancer, bladder cancer, head and neck cancer, renal cancer, nasopharyngeal cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral nerve epithelial tumor, glioma, brain tumor and myeloma; more preferably selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.