CN116199703A

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

Info

Publication number: CN116199703A
Application number: CN202211532552.8A
Authority: CN
Inventors: 李心; 杨芳; 冯斌强; 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: 2021-12-01
Filing date: 2022-12-01
Publication date: 2023-06-02

Abstract

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

Description

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

Technical Field

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

Background

The RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the superfamily of small gtpases 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 multiple downstream pathways including RAF-MEK-ERK, PI3K/Akt/mTOR by switching between two active states, thereby affecting cell growth, proliferation and differentiation (Nat Rev Cancer,2007,7,295-308). The 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 the sum of ALK, RET, TRK gene mutations.

Faced with the difficulty of KRAS protein drug formulation, the university of California san Diego Kevan M.Shoka professor was first validated 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 is provided (Cell, 2018,572,578-589).

KRAS G12C has attracted a number of well-known new drug development enterprises at home and abroad to participate in. While the fastest growing, small molecule KRAS G12C inhibitor motorasib (AMG 510) has been approved by the FDA for use in non-small cell lung cancer patients who have received at least one systemic treatment and carry KRAS G12C mutations at day 28 of 2021, the new generation of KRAS G12C inhibitor LY3537982 from the present is of greater interest. Preclinical data of LY3537982 was reported by american cancer society (AACR) year 4 at 2021, which showed that LY3537982 inhibited more than 10-fold more cellular activity than sotorastib, 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 KRAS G12C inhibitors that have been published include WO2014152588A1, WO2015054572A1, WO2016164675A1, WO2017087528A1, WO2017201161A1, WO2018119183A2, WO2018206539A1, WO2018217651A1, WO2019099524A1, WO2019215203A1, WO2020081282A1, WO2020178282A1, WO2021118877A1, and the like.

Disclosure of Invention

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

wherein:

x is a nitrogen atom or CR ⁰⁰ ；

Y is a nitrogen atom or CR ³ ；

R ⁰ Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, -OR ^7a 、-NR ^8a R ^8b 、-S(O) _p1 R ^9a 、-C(O)R ^10a Wherein saidOptionally selected from cyano, -NR ^x R ^y 、-OR ^z 、-C(O)NR ^s R ^t 、-S(O) _p2 R ^v And R is ^c Is substituted by one or more substituents;

w is CR ^5a Or a nitrogen atom;

R ¹ selected from cyano group,

Each R is ² The alkyl and the alkoxy are each independently optionally substituted with one or more substituents selected from halogen, cyano, amino and hydroxy;

R ⁰⁰ 、R ³ and R is ⁴ Identical or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, -NR ^8c R ^8d 、-C(O)R ^10b 、-(CR ^a R ^b ) _r -OR ^7b 、-S(O) _p3 R ^9b Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, haloalkyl, cyano, -NR ^p R ^q 、-OR ^u One or more substituents of cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

R ⁵ 、R ^5a and each R ⁶ Identical or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, -NR ^8e R ^8f 、-C(O)NR ^8g R ^8h 、-C(O)R ^10c 、-C(O)OR ^7c 、-OC(O)R ^10d 、-OR ^7d 、-S(O) _p4 R ^9c 、-S(O) _p5 NR ⁸ⁱ R ^8j Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, haloalkyl, cyano, -NR ^w1 R ^w2 、-OR ^r One or more substituents of cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

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

R ^a and R is ^b 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 ^7a 、R ^7b 、R ^7c 、R ^7d 、R ¹⁶ 、R ^u 、R ^r And R is ^z And 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 a moiety selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ^k R ^l Hydroxy and R ^d Is substituted by one or more substituents;

R ^c and R is ^d And are the same or different and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a moiety selected from halogen, oxo, hydroxy, cyano, -C (O) R ^10e Substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

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

R ^9a 、R ^9b 、R ^9c and R is ^v The alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, and haloalkoxy;

R ^10a 、R ^10b 、R ^10c 、R ^10d And R is ^10e The alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, and haloalkoxy;

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

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

q is 0, 1, 2 or 3;

p1 is 0, 1 or 2;

p2 is 0, 1 or 2;

p3 is 0, 1 or 2;

p4 is 0, 1 or 2; and is also provided with

p5 is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (IM) or a pharmaceutically acceptable salt thereof, wherein Y is CR ³ ，R ³ As defined in formula (IM).

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

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

wherein:

x is a nitrogen atom or CR ⁰⁰ ；

R ⁰ Selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, -OR ^7a 、-NR ^8a R ^8b 、-S(O) _p1 R ^9a 、-C(O)R ^10a Wherein said alkyl is optionally selected from cyano, -NR ^x R ^y 、-OR ^z 、-C(O)NR ^s R ^t 、-S(O) _p2 R ^v And R is ^c Is substituted by one or more substituents;

w is CR ^5a Or a nitrogen atom;

R ¹ selected from cyano group,

R ^c and R is ^d Identical or different and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, where the radicals mentionedCycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a member selected from the group consisting of halogen, oxo, hydroxy, cyano, -C (O) R ^10e Substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R is ^8a And R is ^8b Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^8c And R is ^8d Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^8e And R is ^8f Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^8g And R is ^8h Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ⁸ⁱ And R is ^8j Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^15a And R is ^15b Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^x And R is ^y Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^s And R is ^t Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^p And R is ^q Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^m And R is ⁿ Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^k And R is ^l Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^w1 And R is ^w2 In combination with the nitrogen atom to which it is attachedA heterocyclyl group wherein the heterocyclyl groups are the same or different and each is independently 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 0, 1, 2, 3, 4, 5 or 6;

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

q is 0, 1, 2 or 3;

p1 is 0, 1 or 2;

p2 is 0, 1 or 2;

p3 is 0, 1 or 2;

p4 is 0, 1 or 2; and is also provided with

p5 is 0, 1 or 2.

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

wherein:

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

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

wherein:

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

Wherein:

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

wherein:

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

wherein:

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

wherein:

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), or a pharmaceutically acceptable salt thereof, wherein each R ² Identical or different and are each independently selected from hydrogen, halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, hydroxy and amino, wherein said C _1-6 Alkyl is optionally substituted with one or more substituents selected from halogen and cyano; preferably, R ² Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), 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 (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), or a pharmaceutically acceptable salt thereof, wherein R ¹ Is that

R ¹¹ 、R ¹² And R is ¹³ As defined in formula (I).

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

wherein:

X、W、R ⁰ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹¹ 、R ¹² 、R ¹³ and q is as defined in formula (I).

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

Wherein:

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

wherein:

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

wherein:

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

wherein:

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

Wherein:

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

wherein:

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom.

In some embodiments of the present disclosure, the compounds of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B)Or a pharmaceutically acceptable salt thereof, wherein R ⁰ Is a hydrogen atom OR-OR ^7a Wherein R is ^7a Is C _1-6 Alkyl, wherein said C _1-6 Alkyl is optionally substituted with R ^d Substitution; r is R ^d Is a 3-to 8-membered heterocyclic group, wherein the 3-to 8-membered heterocyclic group is optionally substituted with a member selected from the group consisting of halogen, oxo, hydroxy, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; preferably, R ⁰ Is a hydrogen atom OR-OR ^7a Wherein R is ^7a Is C _1-6 Alkyl, wherein said C _1-6 Alkyl is optionally substituted with R ^d Substitution; r is R ^d Is a 5-to 8-membered heterocyclic group, wherein the 5-to 8-membered heterocyclic group is optionally selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; most preferably, R ⁰ is-OR ^7a Wherein R is ^7a Is methyl, wherein the methyl is R ^d Substitution; r is R ^d Is a 5-to 8-membered heterocyclic group, wherein said 5-to 8-membered heterocyclic group is optionally selected from halogen and C _1-6 One or more substituents in the alkyl group.

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein R ⁰ Selected from the group consisting of hydrogen atoms,

Preferably, R ⁰ Is->

More preferably, R ⁰ Is->

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

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

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is-NR ^8e R ^8f Wherein R is ^8e And R is ^8f Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ⁵ is-NH ₂ 。

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein W is CR ^5a Or a nitrogen atom, and R ^5a Is cyano; more preferably, W is CR ^5a And R is ^5a Is cyano.

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein W is CR ^5a ，R ^5a As defined in formula (I); preferably, W is CR ^5a ，R ^5a Selected from hydrogen atom, halogen, cyano and C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein each R ⁶ The same or different, and are each independently a hydrogen atom or a halogen; preferably, each R ⁶ The same or different and are each independently a hydrogen atom or a fluorine atom.

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein each R ⁶ The same or different, and each independently is halogen; fluorine atoms are preferred.

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; preferably, R ¹¹ Is a hydrogen atom or a fluorine atom; more preferably, R ¹¹ Is a hydrogen atom.

In some embodiments of the present disclosure, whatThe compound shown in the general formula (IM), the general formula (I-1), the general formula (I-2), the general formula (I-1-A), the general formula (I-1-B), the general formula (I-2-A), the general formula (I-2-B), the general formula (II-1), the general formula (II-2), the general formula (II-1-A), the general formula (II-1-B), the general formula (II-2-A) and the general formula (II-2-B) or pharmaceutically acceptable salts thereof, wherein R ¹² And R is ¹³ Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 Alkyl, wherein said alkyl is optionally substituted with-NR ^m R ⁿ Substitution, wherein R ^m And R is ⁿ All are hydrogen atoms; preferably, R ¹² And R is ¹³ Are all hydrogen atoms.

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

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein R ⁶ Halogen, and q is 1 or 2; preferably, R ⁶ Halogen, and q is 1.

In some embodiments of the present disclosure, the compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-A), formula (I-1-B), formula (I-2-A), formula (I-2-B), or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom; w is CR ^5a And R is ^5a Is cyano; r is R ⁰ Is a hydrogen atom OR-OR ^7a Wherein R is ^7a Is C _1-6 Alkyl, wherein said C _1-6 Alkyl is optionally substituted with R ^d Substitution; r is R ^d Is a 3-to 8-membered heterocyclic group, wherein the 3-to 8-membered heterocyclic group is optionally substituted with a member selected from the group consisting of halogen, oxo, hydroxy, cyano, C _1-6 Alkyl, C _1-6 Alkoxy group,C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; r is R ¹ Is that

R ³ Is halogen; r is R ⁴ Is a hydrogen atom or a halogen; r is R ⁵ is-NR ^8e R ^8f Wherein R is ^8e And R is ^8f Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group; r is R ⁶ Halogen, and q is 1 or 2; r is R ¹¹ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; r is R ¹² And R is ¹³ Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 Alkyl, wherein said alkyl is optionally substituted with-NR ^m R ⁿ Substitution, wherein R ^m And R is ⁿ All are hydrogen atoms; s is 0.

In some embodiments of the present disclosure, the compound of formula (IM), formula (II-1), formula (II-2), formula (II-1-A), formula (II-1-B), formula (II-2-A), formula (II-2-B), or a pharmaceutically acceptable salt thereof, wherein X is a nitrogen atom; w is CR ^5a And R is ^5a Is cyano; r is R ⁰ Is a hydrogen atom OR-OR ^7a Wherein R is ^7a Is C _1-6 Alkyl, wherein said C _1-6 Alkyl is optionally substituted with R ^d Substitution; r is R ^d Is a 5-to 8-membered heterocyclic group, wherein the 5-to 8-membered heterocyclic group is optionally selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group; r is R ³ Is halogen; r is R ⁴ Is a hydrogen atom or a halogen; r is R ⁵ is-NH ₂ ；R ⁶ Halogen, and q is 1; r is R ¹¹ Is a hydrogen atom; r is R ¹² And R is ¹³ Are all hydrogen atoms.

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

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

wherein:

X、Y、W、R ⁰ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ s and q are as defined in the general formula (IM).

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

wherein:

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

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

wherein:

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

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

wherein:

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

The compound shown as the general formula (IMa), the general formula (Ia), the general formula (I-1 a) and the general formula (I-2 a) or salts thereof, wherein the salts are preferably bis (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 (imoa):

wherein:

R ^L1 and R is ^L2 Identical or different and are each independently an amino protecting group; preferably, R ^L1 And R is ^L2 All are t-butoxycarbonyl groups;

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

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

wherein:

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

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

wherein:

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

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

wherein:

X、W、R ⁰ 、R ² 、R ³ 、R ⁴ 、R ⁶ s and q are as defined in the general formula (I-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 (IM) or a pharmaceutically acceptable salt thereof, comprising:

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

wherein:

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

R ¹ is that

X、Y、W、R ⁰ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹¹ 、R ¹² 、R ¹³ S and q are as defined in the general formula (IM).

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

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

wherein:

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

R ¹ is that

X、W、R ⁰ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹¹ 、R ¹² 、R ¹³ S and q are as defined in formula (I).

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

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

wherein:

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

R ¹ is that

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

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

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

wherein:

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

R ¹ is that

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

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

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

wherein:

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

X、W、R ⁰ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹¹ 、R ¹² 、R ¹³ and q is as defined in formula (II).

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

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

Wherein:

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

X、W、R ⁰ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹¹ 、R ¹² 、R ¹³ and q is as defined in formula (II-1).

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

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

wherein:

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

X、W、R ⁰ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹¹ 、R ¹² 、R ¹³ and q is as defined in formula (II-2).

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

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

wherein:

R ¹ is that

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

resolving the compound shown in the general formula (I-2) or pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (I-2-A) and the general formula (I-2-B) or pharmaceutically acceptable salt thereof;

Wherein:

R ¹ is that

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

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

wherein:

R ¹ is that

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

resolving the compound shown in the general formula (II-2) or pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (II-2-A) and the general formula (II-2-B) or pharmaceutically acceptable salt thereof;

wherein:

X、W、R ⁰ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ and q is as defined in formula (II-2).

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

removing R from a compound represented by the general formula (IMaa) or a salt thereof ^L1 And R is ^L2 Obtaining a compound represented by the general formula (IMa) or a salt thereof;

wherein:

R ⁵ is-NH ₂ ；

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

removing R from a compound represented by the general formula (Iaa) ^L1 And R is ^L2 Obtaining a compound represented by the general formula (Ia) or a salt thereof;

wherein:

R ⁵ is-NH ₂ ；

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

removing R from a compound represented by the general formula (I-1 aa) or a salt thereof ^L1 And R is ^L2 Obtaining a compound represented by the general formula (I-1 a) or a salt thereof;

wherein:

R ⁵ is-NH ₂ ；

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

removing R from a compound represented by the general formula (I-2 aa) or a salt thereof ^L1 And R is ^L2 Obtaining a compound represented by the general formula (I-2 a) or a salt thereof;

wherein:

R ⁵ is-NH ₂ ；

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

The present disclosure further relates to the use of a compound of general formula (IM), general formula (I-1), general formula (I-2), general formula (I-1-a), general formula (I-1-B), general formula (I-2-a), general formula (I-2-B), general formula (II-1), general formula (II-2), general formula (II-1-a), general formula (II-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 (IM), formula (I-1), formula (I-2), formula (I-1-a), formula (I-1-B), formula (I-2-a), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-a), formula (II-1-B), formula (II-2-a), formula (II-2-B) and table a, or 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 present disclosure further relates to the use of a compound of general formula (IM), general formula (I-1), general formula (I-2), general formula (I-1-a), general formula (I-1-B), general formula (I-2-a), general formula (I-2-B), general formula (II-1), general formula (II-2), general formula (II-1-a), general formula (II-1-B), general formula (II-2-a), general formula (II-2-B) and table a or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same 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 (IM), formula (I-1), formula (I-2), formula (I-1-a), formula (I-1-B), formula (I-2-a), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-a), formula (II-1-B), formula (II-2-a), formula (II-2-B), and table a or 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 effective amount of a compound of formula (IM), formula (I-1), formula (I-2), formula (I-1-a), formula (I-1-B), formula (I-2-a), formula (I-2-B), formula (II-1), formula (II-2), formula (II-1-a), formula (II-1-B), formula (II-2-a), formula (II-2-B), and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

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

The present disclosure further relates to compounds of general formula (IM), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-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 (IM), general formula (I-1), general formula (I-2), general formula (I-1-A), general formula (I-1-B), general formula (I-2-A), general formula (I-2-B), general formula (II-1), general formula (II-2), general formula (II-1-A), general formula (II-1-B), general formula (II-2-A), general formula (II-2-B) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of tumors. The tumor as described above in the present disclosure is preferably a cancer; further preferably, the cancer is selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer (also known as esophageal cancer), endometrial cancer, ovarian cancer, 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 cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral nerve epithelial tumor, glioma (e.g., astrocytoma and glioblastoma), brain tumor and myeloma; more preferably, the cancer is selected from lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

The disease or disorder mediated by KRAS G12C as described above in the present disclosure is preferably a tumor; preferably, the tumor is cancer; more preferably, the cancer is selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), pancreatic cancer, cervical cancer, esophageal cancer (also known as esophageal cancer), endometrial cancer, ovarian cancer, 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 cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral nerve epithelial tumor, glioma (e.g., astrocytoma and glioblastoma), brain tumor, and myeloma; most preferably, the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

As a general guideline, the active compounds of the present disclosure are preferably administered in unit doses, or in a manner that the patient can 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. Suitable unit doses may be in the range 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. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

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., C _1-20 Alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C _1-12 Alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). 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, 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 having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined 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., C _2-6 Alkenyl). 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 the group consisting 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 groupsIs described herein).

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where alkyl is as defined 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 Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C _2-6 Alkynyl). 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;

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 heterocyclyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic cycloalkyl group, which may contain within the ringHas one or more double bonds 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 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;

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), such as 5 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 cycloalkyl 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., a 5 to 14 membered heteroaryl group). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10 membered heteroaryl group), more preferably a monocyclic heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6 membered monocyclic heteroaryl group) or a bicyclic heteroaryl group having 8 to 10 ring atoms (i.e., an 8 to 10 membered bicyclic heteroaryl group), most preferably a 5 or 6 membered monocyclic heteroaryl group 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 a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is performed by conventional methods well 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 bond

Indicating the unspecified configuration, i.e.the bond +.>

Can be +.>

Or->

Or at the same time contain->

And->

Two 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, and iodine, and the like, e.g., respectivelyIs that ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ i, etc., deuterium is 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 by 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 (IM) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

reacting a compound represented by the general formula (IMa) or a salt thereof (preferably, bis (2, 2-trifluoroacetate)) with a compound represented by the general formula (X) or a salt thereof under basic conditions to obtain a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof;

wherein:

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

R ¹ is that

Scheme II

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 represented by the general formula (Ia) or a salt thereof (preferably, bis (2, 2-trifluoroacetate)) with a compound represented by the general formula (X) or a salt thereof under basic conditions to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

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

R ¹ is that

Scheme III

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

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

wherein:

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

R ¹ is that

Scheme IV

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

reacting a compound represented by the general formula (I-2 a) or a salt thereof (preferably, bis (2, 2-trifluoroacetate)) with a compound represented by the general formula (X) or a salt thereof under alkaline conditions to obtain a compound represented by the general formula (I-2) or a pharmaceutically acceptable salt thereof;

wherein:

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

R ¹ Is that

Scheme five

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 represented by the general formula (Ia) or a salt thereof (preferably, bis (2, 2-trifluoroacetate)) with a compound represented by the general formula (XI) or a salt thereof under basic conditions to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

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

Scheme six

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

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

wherein:

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

Scheme seven

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

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

Wherein:

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

Scheme eight

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

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

wherein:

R ¹ is that

Scheme nine

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

resolving the compound shown in the general formula (I-2) or the pharmaceutically acceptable salt thereof by high performance liquid chromatography to obtain the compound shown in the general formula (I-2-A) and the general formula (I-2-B) or the pharmaceutically acceptable salt thereof;

wherein:

R ¹ is that

Scheme ten

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

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

Wherein:

Scheme eleven

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

resolving the compound shown in the general formula (II-2) or the pharmaceutically acceptable salt thereof by high performance liquid chromatography to obtain the compound shown in the general formula (II-2-A) and the general formula (II-2-B) or the pharmaceutically acceptable salt thereof;

wherein:

Scheme twelve

A method for producing a compound represented by the general formula (mia) or a salt thereof of the present disclosure, comprising the steps of:

removing R from a compound represented by the general formula (IMaa) or a salt thereof under acidic conditions ^L1 And R is ^L2 Obtaining a compound represented by the general formula (IMa) or a salt thereof;

wherein:

R ⁵ is-NH ₂ ；

Scheme thirteen

The preparation method of the compound shown in the general formula (Ia) or salt thereof comprises the following steps:

removing R from a compound represented by the general formula (Iaa) or a salt thereof under acidic conditions ^L1 And R is ^L2 Obtaining a compound represented by the general formula (Ia) or a salt thereof;

wherein:

R ⁵ is-NH ₂ ；

Scheme fourteen

The preparation method of the compound shown in the general formula (I-1 a) or the salt thereof comprises the following steps:

the compound shown in the general formula (I-1 aa) or salt thereof is subjected to R removal under acidic conditions ^L1 And R is ^L2 Obtaining a compound represented by the general formula (I-1 a) or a salt thereof;

wherein:

R ⁵ is-NH ₂ ；

Scheme fifteen

The preparation method of the compound shown in the general formula (I-2 a) or the salt thereof comprises the following steps:

the compound shown in the general formula (I-2 aa) or salt thereof is subjected to R removal under acidic conditions ^L1 And R is ^L2 Obtaining a compound represented by the general formula (I-2 a) or a salt thereof;

wherein:

R ⁵ is-NH ₂ ；

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 tert-butoxide or potassium tert-butoxide; the inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, anhydrous potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide, preferably anhydrous potassium carbonate.

In the above 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, and inorganic acids 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). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q actual (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

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

The high performance liquid phase was prepared by using a Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne 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.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a 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, shaog 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 a Parr 3916 model EKX hydrogenometer and a 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: dichloromethane/methanol system, B: in the n-hexane/ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for regulation.

Examples 1 to p1,1 to p2

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

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

First step

(R) -3- (((tert-Butyldimethylsilyl) oxy) methyl) piperazine-1-carboxylic acid tert-butyl ester 1b

Tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate 1a (8.8 g,36.3mmol, shanghai Bifide), tert-butyldimethylsilyl chloride (16 g,106.15 mmol), 4-dimethylaminopyridine (4 g,32.47 mmol) were dissolved in 200mL dichloromethane and triethylamine (15 g, 148.23mmol,21.4286 mL) was added and the reaction stirred for 16 h, concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1B (8 g, yield: 61.7%).

MS m/z(ESI):331.1[M+1]。

Second step

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

2-amino-4-bromo-3, 6-difluorobenzoic acid 1c (9 g,35.71mmol, prepared as disclosed on page 110 of the specification in patent application "WO2018206539A 1") was dissolved in dichloromethane (100 mL) and methanol (10 mL), 35.71mL of a 2M n-hexane solution of trimethylsilyl diazomethane was added dropwise under ice bath, stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system B to give the title compound 1d (6.8 g, yield: 71.5%).

MS m/z(ESI):265.9[M+1]。

Third step

4-bromo-3, 6-difluoro-2- (3- (2, 2-trichloroacetyl) ureido) benzoic acid methyl ester 1e

Compound 1d (2 g,7.51 mmol) was dissolved in solvent tetrahydrofuran (30 mL), trichloroacetyl isocyanate (1.42 g,7.5373mmol, jiangsu Aikang) was added in portions and reacted for 2 hours with stirring, and the reaction solution was concentrated under reduced pressure to give crude title compound 1e (3.4 g, yield: 99%) which was used in the next reaction without purification.

MS m/z(ESI):452.9[M+1]。

Fourth step

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

The crude compound 1e (3.4 g,7.48 mmol) was dissolved in 307 mL of 7M methanolic ammonia, stirred for 2 hours, concentrated under reduced pressure to remove most of the solvent, then added with 20mL of methyl tert-butyl ether for beating, filtered, the filter cake was washed with methyl tert-butyl ether, dried to obtain the crude title compound 1f (2 g, yield: 96.4%) which was used in the next reaction without purification.

MS m/z(ESI):276.9[M+1]。

Fifth step

1g of 7-bromo-2, 4-dichloro-5, 8-difluoroquinazoline

Compound 1f (500 mg,1.80 mmol) was dissolved in solvent phosphorus oxychloride (5 mL), and reacted at 100℃for 3 hours with stirring, and the reaction solution was concentrated under reduced pressure to give 1g (500 mg, yield: 88.2%) of the crude title compound, which was used in the next reaction without purification.

MS m/z(ESI):312.9[M+1]。

Sixth step

(R) -4- (7-bromo-2-chloro-5, 8-difluoroquinazolin-4-yl) -3- (((tert-butyldimethylsilyl) oxy) methyl) piperazine-1-carboxylic acid tert-butyl ester for 1h

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

MS m/z(ESI):607.2[M+1]。

Seventh step

(R) -4- (7-bromo-5, 8-difluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3- (((tert-butyldimethylsilyloxy) methyl) piperazine-1-carboxylic acid tert-butyl ester 1i

Compound 1H (209 mg, 344.2. Mu. Mol) was dissolved in ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (71.2 mg,1.36mmol, pharmaceutical composition) and dissolved in 1, 4-dioxane (5 mL), 2M sodium bis (trimethylsilyl) amide in tetrahydrofuran (260. Mu.L) was added under nitrogen blanket, the reaction was allowed to proceed to room temperature naturally for 2 hours, the reaction mixture was quenched with a small amount of saturated ammonium chloride solution and the residue was concentrated under reduced pressure to give the crude title compound 1i (220 mg, yield: 88%) as eluent system A.

MS m/z(ESI):730.1[M+1]。

Eighth step

(R) -5-bromo-4-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8a,9,11, 12-tetrahydropyrazino [2',1':3,4] [1,4] oxazaheptano [5,6,7-de ] quinazolin-10 (8H) -carboxylic acid tert-butyl ester 1j

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

MS m/z(ESI):596.2[M+1]。

Ninth step

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

Compound 1j (130.21 mg, 218.31. Mu. Mol) was dissolved in N, N-dimethylformamide (25 mL), N-chlorosuccinimide (64 mg, 480. Mu. Mol) was added, reacted for 2 hours at 70℃and quenched by adding a saturated aqueous sodium thiosulfate solution to the reaction solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1k (70 mg, yield: 72%).

MS m/z(ESI):630.1[M+1]。

Tenth step

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

Compound 1k (70 mg, 111. Mu. Mol), (3-cyano-4- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) -7-fluorobenzo [ b ] thiophen-2-yl) carbamic acid tert-butyl ester (67.2 mg, 166.4. Mu. Mol, prepared by the method disclosed in preparation example 15 on page 50 of the specification in patent application "WO2021118877A 1"), bis (diphenylphosphinophenyl ether) palladium (II) dichloride (12 mg, 16.6. Mu. Mol, shanghai-Tai-Teng) was added, cesium carbonate (72.3 mg, 222. Mu. Mol) was replaced with nitrogen, the reaction mixture was stirred at 105℃for 6 hours, filtered after cooling to room temperature, 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 1l (50 mg, yield: 96.7%).

MS m/z(ESI):842.2[M+1]。

Eleventh step

2-amino-4- ((8 aR) -6-chloro-4-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8,8a,9,10,11, 12-hexahydropyrazino [2',1':3,4] [1,4] oxazaheptano [5,6,7-de ] quinazolin-5-yl) -7-fluorobenzo [ b ] thiophene-3-carbonitrile bis (2, 2-trifluoroacetate) 1m

Compound 1l (90 mg, 106.8. Mu. Mol) was dissolved in 2mL 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 1m (90 mg), which was used in the next reaction without purification.

MS m/z(ESI):642.2[M+1]。

Twelfth step

The compound 1m (90 mg,0.075 mmol) was suspended in 2mL of ethyl acetate, 1mL of tetrahydrofuran and 2mL of water, anhydrous potassium carbonate (58 mg, 423.2. Mu. Mol) was added while ice-bath, acryloyl chloride (19 mg, 211.6. Mu. Mol) was added, after 5 min of reaction, extracted with ethyl acetate (5 mL. Times.2), the organic phases were combined and concentrated under reduced pressure to give the crude title compound, 4- ((8 aR) -10-propenoyl-6-chloro-4-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8,8a,9,10,11, 12-hexahydropyrazino [2',1':3,4] [1,4] oxaazepino [5,6,7-de ] quinazolin-5-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 1 (70 mg), purified by high performance liquid chromatography (Waters-45:45 mL: 5mL, 5 mL: 35 mg), and a flow rate gradient of acetonitrile (30:25 mL: 30.25 mg, 30% of the aqueous phase).

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

MS m/z(ESI):696.2[M+1]。

HPLC analysis: retention time 1.36 min, purity: 94% (column: ACQUITY)

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

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

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

MS m/z(ESI):696.2[M+1]。

LCMS analysis, retention time 1.39 min, purity: 96% (chromatographic column: ACQUITY)

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

Examples 2-p1,2-p2

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

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

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

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

MS m/z(ESI):652.1[M+1]。

HPLC analysis: retention time 1.746 min, purity: 94% (column: ACQUITY)

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

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

MS m/z(ESI):652.1[M+1]。

LCMS analysis, retention time 1.768 min, purity: 96% (chromatographic column: ACQUITY)

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

Example 3

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

Using the synthetic routes in examples 1-p1 and 1-p2, the first starting compound 1a was replaced with tert-butyl (S) -3- (hydroxymethyl) piperazine-1-carboxylate (Shanghai Bide) to give the title compound 3 (15 mg, yield: 9.8%).

MS m/z(ESI):696.1[M+1]。

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

Examples 4-p1,4-p2

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

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

First step

(8 aS) -5- (2- ((tert-Butoxycarbonyl) amino) -3-cyano-7-fluorobenzo [ b ] thiophen-4-yl) -6-chloro-4-fluoro-8 a,9,11, 12-tetrahydropyrazino [2',1':3,4] [1,4] oxazaheptano [5,6,7-de ] quinazolin-10 (8H) -carboxylic acid tert-butyl 4b

Compound 4a (200 mg, 438. Mu. Mol), (3-cyano-4- (5, 5-dimethyl-1, 3, 2-dioxaborolan-2-yl) -7-fluorobenzo [ b ] thiophen-2-yl) carbamic acid tert-butyl ester (140 mg, 439. Mu. Mol) was dissolved in 3mL of toluene, bis (diphenylphosphinophenyl ether) palladium (II) dichloride (47 mg, 65.6. Mu. Mol), cesium carbonate (317 mg,1.09 mol) was added, nitrogen was substituted, the reaction was stirred for 6 hours at 105℃and cooled to room temperature, the filtrate was filtered, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 4b (85 mg, yield: 29%).

MS m/z(ESI):685.2[M+1]。

Second step

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

Compound 4b (80 mg, 119.9. Mu. Mol) was dissolved in 2mL of methylene chloride, 1mL of trifluoroacetic acid was added at 0℃and the reaction was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to give the crude title compound 4c (85 mg), which was used in the next reaction without purification.

MS m/z(ESI):485.2[M+1]。

Third step

Compound 4c (85 mg, 119.9. Mu. Mol) was suspended in 2mL of ethyl acetate, 1mL of tetrahydrofuran and 2mL of water, anhydrous potassium carbonate (65 mg, 470. Mu. Mol) was added while ice-bath, acryloyl chloride (11 mg, 121.5. Mu. Mol) was added, after 5 minutes of reaction, extracted with ethyl acetate (5 mL. Times.2), the organic phases were combined and concentrated under reduced pressure to give the crude title compound 4, 4- ((8 aS) - (10-propenoyl-6-chloro-8, 8a,9,10,11, 12-hexahydropyrazino [2',1':3,4] [1,4] oxaazepino [5,6,7-de ] quinazolin-5-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile 4 (60 mg), which was purified by high performance liquid phase preparative chromatography (Waters-2545, column YMC-ExC 18, 30 mm,5 μm; mobile phase: aqueous phase: 10mmol/L and acetonitrile (26 mg, 16%) at a flow rate of 26% to 16% acetonitrile, a gradient, 50% of the title compound was obtained.

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

MS m/z(ESI):521.1[M+1]。

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

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

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

MS m/z(ESI):521.1[M+1]。

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

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

Examples 5-p1,5-p2

2-amino-4- ((5 s,8 ar) -6-chloro-4-fluoro-10- (2-fluoroacryloyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8,8a,9,10,11, 12-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [5,6,7-de ] quinazolin-5-yl) -7-fluorobenzo [ b ] thiophene-3-carbonitrile 5-p1

2-amino-4- ((5 r,8 ar) -6-chloro-4-fluoro-10- (2-fluoroacryloyl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8,8a,9,10,11, 12-hexahydropyrazino [2',1':3,4] [1,4] oxazepino [5,6,7-de ] quinazolin-5-yl) -7-fluorobenzo [ b ] thiophene 3-carbonitrile 5-p2

Compound 1m (135 mg, 155.7. Mu. Mol) was suspended in 2mL of ethyl acetate, 1mL of tetrahydrofuran and 2mL of water, anhydrous potassium carbonate (107.6 mg, 778.7. Mu. Mol), 2-fluoropropoyl chloride (70.1 mg, 778.7. Mu. Mol, prepared by the well-known method "Tetrahedron,2016,72 (32), 4845-4853"), after 5 minutes of reaction, extracted with ethyl acetate (5 mL. Times.2), the organic phases were combined and concentrated under reduced pressure to give crude title compound 5 (110 mg), purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L) and acetonitrile, gradient: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title compound (8 mg,14mg, 7.1%, 12.5%).

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

MS m/z(ESI):714.2[M+1]。

HPLC analysis: retention time 1.882 min, purity: 96% (column:

c18,2.7 μm,3.0 x 30mm; mobile phase: water (5 mM ammonium acetate), acetonitrile, gradient ratio: acetonitrile 10% -95%).

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

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

MS m/z(ESI):714.2[M+1]。

HPLC analysis: retention time 1.829 min, purity: 90% (column:

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

Example 6

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

First step

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

4-amino-2, 6-dichloropyridine 6a (5 g,30.6mmol, shanghai Bifide) was dissolved in 20mL of N, N-dimethylformamide and 20mL of acetonitrile, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (13 g,36.8 mmol) was added, the reaction was reacted at 80℃for 0.5 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 6B (2.2 g, yield: 39.6%).

MS m/z(ESI):180.9[M+1]。

Second step

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

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

MS m/z(ESI):381.1[M+1]。

Third step

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

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

MS m/z(ESI):281.1[M+1]。

Fourth step

2, 6-dichloro-5-fluoro-4- (3- (2, 2-trichloroacetyl) ureido) nicotinic acid tert-butyl ester 6e

The crude compound 6d (500 mg,1.77 mmol) was dissolved in tetrahydrofuran (10 mL), trichloroacetyl isocyanate (640 mg,3.55 mmol) was added, the reaction was stirred for 30 minutes, and the reaction solution was concentrated under reduced pressure to give the crude title compound 6e (835 mg, yield: 99.7%) which was used in the next reaction without purification.

MS m/z(ESI):467.9[M+1]。

Fifth step

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

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

MS m/z(ESI):249.9[M+1]。

Sixth step

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

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

Seventh step

(R) -3- (((tert-Butyldimethylsilyl) oxy) methyl) -4- (2, 7-dichloro-5, 8-difluoropyrido [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester for 6h

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

MS m/z(ESI):564.2[M+1]。

The synthetic route in examples 1-p1 and 1-p2 was followed, substituting compound 6 for compound 1H and substituting (2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol for (S) - (1-methylpyrrolidin-2-yl) methanol for the seventh starting compound 1H gave the title compound 6 (5 mg, yield: 22.8%).

MS m/z(ESI):619.2[M+1]。

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

Biological evaluation

The present disclosure is 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 using complete medium, 100. Mu.L of cell suspension per well, placed at 37℃and 5% CO ₂ The cell culture incubator was incubated overnight. The next day, 10. Mu.L of a test compound in a gradient dilution prepared with complete medium was added to each well, the final concentration of the compound was 9 concentration points at 5-fold gradient dilution starting from 10. Mu.M, a blank containing 0.5% DMSO was set, the well plate was placed at 37℃and 5% CO was added ₂ Is cultured in a cell culture incubator for 120 hours. On day seven, the 96-well cell culture plate was removed, and 50. Mu.L of luminescent cell activity detection reagent (CellTiter-

Luminescent Cell Viability Assay) (Promega, G7573), after 10 minutes at room temperature, using a multifunctional microplate reader (Perkinelmer, & gt >

2105 Reading the luminescence signal value and calculating the IC of the inhibitory activity of the compound by using Graphpad Prism software ₅₀ Values.

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 1-p1 and 1-p2	2.06
Compounds corresponding to shorter retention times in 2-p1 and 2-p2	2.07
		3	1.41
Compounds corresponding to shorter retention times in 5-p1 and 5-p2	0.64

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/well in 96-well plates using complete medium, 190. Mu.L of cell suspension per well, placed at 37℃and 5% CO ₂ The cell culture incubator was incubated overnight. The next day, 10. Mu.L of a test compound in a gradient dilution prepared with complete medium was added to each well, the final concentration of the compound was 9 concentration points at which a 6-fold gradient dilution was performed starting from 10. Mu.M, a blank containing 0.5% DMSO was set, and the well plate was placed at 37℃and 5% CO ₂ Is 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, the mixture was blown with a pipette and 16. Mu.L of lysate was transferred to each well separately into two HTRF 96-well assay plates (Cisbio, 66PL 96100), after whichBoth plates were added with 4. Mu.L of premixed phospho-ERK 1/2 antibody solution (Cisbio, 64 AERPEG) or 4. Mu.L of premixed total-ERK 1/2 antibody solution (Cisbio, 64 NRKPEG), respectively. 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, fluorescence values of 337nm wavelength excitation, 665nm and 620nm wavelength emission were read using a PHERAstar multifunctional enzyme-labeled instrument (BMG Labtech, PHERAstar FS), and IC for compound inhibitory activity was calculated using Graphpad Prism software from the ratio of compound concentration and pERK/total ERK ₅₀ Values.

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

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. Mu.L of cell suspension per well, placed at 37℃and 5% CO ₂ The cell culture incubator was incubated overnight. The next day, 10. Mu.L of a test compound in a gradient dilution prepared with complete medium was added to each well, the final concentration of the compound was 9 concentration points at 5-fold gradient dilution from 10. Mu.M, a blank containing 0.5% DMSO was set, and the well plate was placed at 37℃and 5% CO ₂ Is cultured in a cell culture incubator for 72 hours. Fifth dayThe 96-well cell culture plate was removed, and 50. Mu.L of a luminescent cell activity detection reagent (CellTiter-

Luminescent Cell Viability Assay) (Promega, G7573), after 10 minutes at room temperature, the luminescence signal values were read using a multifunctional microplate reader (PerkinElmer, enVision 2015). IC for calculating Compound inhibitory Activity Using Graphpad Prism software ₅₀ Values.

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 1-p1 and 1-p2	0.54
Compounds corresponding to shorter retention times in 2-p1 and 2-p2	0.71
		3	0.55
Compounds corresponding to shorter retention times in 5-p1 and 5-p2	0.48

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

Claims

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

wherein:

x is a nitrogen atom or CR ⁰⁰ ；

Y is a nitrogen atom or CR ³ ；

w is CR ^5a Or a nitrogen atom;

R ¹ selected from cyano group,

R ⁰⁰ 、R ³ and R is ⁴ Identical or different and are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, -NR ^8c R ^8d 、-C(O)R ^10b 、-(CR ^a R ^b ) _r -OR ^7b 、-S(O) _p3 R ^9b Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, alkyl, haloalkyl, cyano, -NR ^p R ^q 、-OR ^u One or more of cycloalkyl, heterocyclyl, aryl and heteroarylSubstituted by substituents;

R ^7a 、R ^7b 、R ^7c 、R ^7d 、R ¹⁶ 、R ^u 、R ^r And R is ^z And 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 a member selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, oxo, alkoxy, haloalkyl, halogenSubstituted alkoxy, cyano, -NR ^k R ^l Hydroxy and R ^d Is substituted by one or more substituents;

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

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

q is 0, 1, 2 or 3;

p1 is 0, 1 or 2;

p2 is 0, 1 or 2;

p3 is 0, 1 or 2;

p4 is 0, 1 or 2; and is also provided with

p5 is 0, 1 or 2.

2. The compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (II), the general formula (II-1) or the general formula (II-2):

wherein:

X、W、R ⁰ 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹¹ 、R ¹² 、R ¹³ and q is as defined in claim 1.

3. A compound of the general formula (IM) according to claim 1 or 2, wherein X is a nitrogen atom; and/or R ⁰ Is a hydrogen atom OR-OR ^7a Wherein R is ^7a Is C _1-6 Alkyl, wherein said C _1-6 Alkyl is optionally substituted with R ^d Substitution; r is R ^d Is a 3-to 8-membered heterocyclic group, wherein the 3-to 8-membered heterocyclic group is optionally substituted with a member selected from the group consisting of halogen, oxo, hydroxy, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group.

4. A compound of the general formula (IM) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ³ Is halogen; and/or R ⁴ Is a hydrogen atom or a halogen; and/or R ⁵ is-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the And/or W is CR ^5a And R is ^5a Is cyano; and/or each R ⁶ The same or different, and are each independently a hydrogen atom or a halogen.

5. A compound of general formula (IM) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

6. a compound represented by the general formula (mia):

wherein:

X、Y、W、R ⁰ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ s and q are as defined in claim 1.

7. The compound of claim 6, or a salt thereof, selected from the following compounds:

8. a process for preparing a compound of the general formula (IM) or a pharmaceutically acceptable salt thereof, which comprises:

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

wherein:

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

R ¹ is that

X、Y、W、R ⁰ 、R ² 、R ⁴ 、R ⁵ 、R ⁶ 、R ¹¹ 、R ¹² 、R ¹³ S and q are as defined in claim 1.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for the treatment and/or prophylaxis of tumors; preferably, the tumor is cancer; further preferred, the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, colorectal cancer, liver cancer, breast cancer, prostate cancer, thyroid cancer, gastric cancer, urothelial cancer, testicular cancer, leukemia, skin cancer, squamous cell 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, the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.