CN117486901A

CN117486901A - Fused piperidine compounds, preparation method thereof and application thereof in medicine

Info

Publication number: CN117486901A
Application number: CN202310957212.8A
Authority: CN
Inventors: 李心; 沈峰; 蔡国栋; 贺峰
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: 2022-08-01
Filing date: 2023-08-01
Publication date: 2024-02-02

Abstract

The present disclosure relates to fused piperidines, methods for their preparation and their use in medicine. Specifically, the disclosure relates to a fused piperidine compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, in particular to application of the compound in preparation of medicines for inhibiting pan-KRAS. Wherein each group in the general formula (I) is defined in the specification.

Description

Fused piperidine compounds, preparation method thereof and application thereof in medicine

Technical Field

The present disclosure relates to a fused piperidine compound, a preparation method thereof and application thereof in medicine, and belongs to the field of medicine. In particular, the disclosure relates to fused piperidine compounds represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application thereof in preparing medicines for inhibiting pan-KRAS.

Background

The KRAS protein encoded by the KARS gene is a small GTPase (small GTPase) belonging to the RAS superfamily of proteins. In cells, KRAS proteins transition between an inactive and an active state, when KRAS binds Guanosine Diphosphate (GDP), in an inactive state, and when Guanosine Triphosphate (GTP) binds, in an active state, causing activation of downstream signaling pathways. KRAS can be activated by tyrosine kinases such as upstream growth factors (e.g., EGFR), and the downstream pathways activated by KRAS are commonly known as RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways that regulate cell proliferation and growth.

KRAS is one of the most common oncogenes in solid tumors, with about 17% of tumors having KRAS mutations, including 90% pancreatic cancer, 50% colon cancer, 25% lung adenocarcinoma, and the like. There is also a proportion of other cancer types such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, breast cancer, etc. The sites where the most frequent gene mutation occurs are codons 12, 13 and 61, with mutations at codon 12 being the most common. KRAS mutations will lock the RAS in a GTP-bound activated state, activating downstream pathways. In addition, KRAS amplification/overexpression or upstream activation also occurs in tumors, which can cause continued activation of RAS downstream pathways, resulting in tumorigenesis.

The KRAS protein surface lacks a small molecule binding site in the traditional sense, has ultrahigh affinity with guanylic acid and is extremely difficult to inhibit, and is long considered as a non-patent drug target. But based on the importance and prevalence of abnormal activation of KRAS in cancer progression, KRAS has been and remains a very interesting target for drug development. Currently, only inhibitors against KRAS G12C and G12D are available in bulk or in clinical stages, and therefore there remains a need to develop pan KRAS inhibitors for the treatment of various KRAS mutant tumors or KRAS dependent tumors.

Related patent applications which have been published so far are WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2022132200A1, WO2022188729A1, WO2022194245A1, WO2022199587A1, WO2021000885A1 and the like.

Disclosure of Invention

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

wherein:

G ⁰ selected from O, S, S (O), S (O) ₂ 、CR ^G0a R ^G0b And NR ^G0c ；

G ¹ Selected from CR ^G1a R ^G1b 、CR ^G1a R ^G1b CR ^G1c R ^G1d C=o and C (O) CR ^G1a R ^G1b ；

Q is N or CR ^2a ；

Ring a is aryl or heteroaryl;

ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

l is selected from single bond, O and NR ^e ；

R ^G0a 、R ^G0b 、R ^G1a 、R ^G1b 、R ^G1c And R is ^G1d The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyHydroxyalkyl, cycloalkyl and heterocyclyl; alternatively, R ^G1a 、R ^G1b Forms a cycloalkyl group together with the attached carbon atom; alternatively, R ^G1c 、R ^G1d Forms a cycloalkyl group together with the attached carbon atom;

R ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g and R is ^1h Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _u -NR ^f R ^g Hydroxyl and hydroxyalkyl groups;

R ^2a and R is ^4a Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _v -NR ^h R ⁱ Hydroxyl, hydroxyalkyl, and cycloalkyl;

each R is ³ And R is ⁶ Identical or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _w -NR ^j R ^k 、-(CH ₂ ) _w1 -(O) _z1 -C(O)NR ^j1 R ^k1 、-(CH ₂ ) _w2 -(O) _z2 -C(O)OR ^j2 Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^5a and R is ^5b The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxy, and hydroxyalkyl; or alternatively

R ^5a 、R ^5b Forms, together with the carbon atom to which they are attached, a cycloalkyl or heterocyclyl group, each of which is independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl;

R ^G0c 、R ^e 、R ^f 、R ^g 、R ^h 、R ⁱ 、R ^j 、R ^k 、R ^j1 、R ^k1 and R is ^j2 The same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

u, v, w, w1 and w2 are the same or different and are each independently selected from 0, 1, 2 and 3;

z1 is 0 or 1;

z2 is 0 or 1;

r is 0, 1, 2 or 3;

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

t is 0, 1, 2, 3, 4 or 5.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein q is 3.

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

wherein the method comprises the steps of

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

ring a, ring B, G ⁰ 、G ¹ 、Q、L、R ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g 、R ^1h 、R ³ 、R ^4a 、R ^5a 、R ^5b 、R ⁶ R and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof, wherein G ⁰ Selected from O, CR ^G0a R ^G0b And NR ^G0c ，R ^G0a And R is ^G0b Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 Haloalkyl, R ^G0c Is a hydrogen atomOr C _1-6 An alkyl group; preferably G ⁰ Selected from O, CH ₂ And NH; further preferably G ⁰ Is O.

In some embodiments of the present disclosure, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof, wherein G ¹ Is CR (CR) ^G1a R ^G1b 、CR ^G1a R ^G1b CR ^G1c R ^G1d Or c=o, R ^G1a 、R ^G1b 、R ^G1c And R is ^G1d Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably G ¹ Is CH ₂ Or c=o; further preferably G ¹ Is CH ₂ 。

In some embodiments of the present disclosure, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof, wherein-G ⁰ -G ¹ -selected from-O-CH ₂ -、-NH-C(O)-、-NH-CH ₂ -、-CH ₂ -CH ₂ -and-O-CH ₂ -CH ₂ -; preferably-O-CH ₂ -or-NH-C (O) -; further preferably-O-CH ₂ -。

In some embodiments of the present disclosure, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof, wherein R ^1c Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R ^1c Selected from hydrogen atoms, halogen, C _1-6 Alkyl and hydroxy; more preferably, R ^1c Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof, wherein R ^1d Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R ^1d Selected from hydrogen atoms, halogen, C _1-6 Alkyl and hydroxy; more preferably, R ^1d Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof, wherein R ^1g Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R ^1g Selected from hydrogen atoms, halogen, C _1-6 Alkyl and hydroxy; more preferably, R ^1g Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof, wherein R ^1h Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R ^1h Selected from hydrogen atoms, halogen, C _1-6 Alkyl and hydroxy; more preferably, R ^1h Is a hydrogen atom.

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

wherein a is 0, 1, 2, 3 or 4;

ring a, ring B, Q, L, R ^1a 、R ^1b 、R ^1e 、R ^1f 、R ³ 、R ^4a 、R ^5a 、R ^5b 、R ⁶ R and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I') or (II) or a pharmaceutically acceptable salt thereof, wherein a is 2.

In some embodiments of the present disclosure, the compound of formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; preferably, ring a is phenyl or naphthyl; further preferred is a naphthyl group.

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

Wherein the method comprises the steps of

R ^3a And R is ^3b The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl;

ring B, Q, L, R ^1a 、R ^1b 、R ^1e 、R ^1f 、R ^4a 、R ^5a 、R ^5b 、R ⁶ R and t are as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II) or (III) or a pharmaceutically acceptable salt thereof is a compound of formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein Q is N or CH; preferably N.

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3-to 14-membered heterocyclyl; preferably, ring B is a 3 to 8 membered heterocyclyl; more preferably, ring B is Or morpholinyl.

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, whereinIs->R ⁶ As defined in formula (I); preferably +.>More preferably +.>

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, whereinis-CH ₂ -or->

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^4a Selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably a hydrogen atom or halogen; further preferred is a hydrogen atom or F; more preferably F.

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

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein L is selected from CH ₂ NH and O; preferably O.

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R ^1a 、R ^1b 、R ^1e 、R ^1f Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and hydroxy; preferably a hydrogen atom, methyl group and hydroxyl group; in some embodiments, R ^1a 、R ^1b 、R ^1e 、R ^1f At least 1 of them is a hydroxyl group, the remainder are hydrogen atoms or C _1-6 An alkyl group; in some embodiments, R ^1a 、R ^1b 、R ^1e 、R ^1f Only 1 of them being hydroxyl groups and the remainder being hydrogen atoms or C _1-6 An alkyl group.

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^1a Is C _1-6 Alkyl, R ^1b Is hydroxy, and R ^1e And R is ^1f All are hydrogen atoms; preferably, R ^1a Is methyl, R ^1b Is hydroxy, and R ^1e And R is ^1f Are all hydrogen atoms.

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^1e Is C _1-6 Alkyl, R ^1f Is hydroxy, and R ^1a And R is ^1b All are hydrogen atoms; preferably, R ^1e Is methyl, R ^1f Is hydroxy, and R ^1a And R is ^1b Are all hydrogen atoms.

In some embodiments of the present disclosure, the general formula (I), (I') or (II)) A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each R ³ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _w -NR ^j R ^k Hydroxy and C _1-6 Hydroxyalkyl group, R ^j And R is ^k Identical or different and are each independently a hydrogen atom or C _1-6 Alkyl, w is 0 or 1; preferably, each R ³ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, hydroxy, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; further preferably, each R ³ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, hydroxy and cyclopropyl; still more preferably, each R ³ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and hydroxy; still further preferably, each R ³ Identical or different and are each independently selected from halogen and C _1-6 An alkyl group; most preferably, each R ³ Identical or different and each independently F or ethyl; .

In some embodiments of the present disclosure, the compound of formula (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^3a Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, R ^3a Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; further preferably, R ^3a Is halogen; more preferably, R ^3a F.

In some embodiments of the present disclosure, the compound of formula (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^3b Selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl and 3 to 8 memberedCycloalkyl; preferably, R ^3b Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; further preferably, R ^3b Is C _1-6 An alkyl group; more preferably, R ^3b Is ethyl.

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R ^5a And R is ^5b Is a hydrogen atom, or R ^5a 、R ^5b Together with the attached carbon atom, form a 3-to 6-membered cycloalkyl group; preferably, R ^5a And R is ^5b Is a hydrogen atom, or R ^5a 、R ^5b Together with the same carbon atom to which it is attached, form a cyclopropyl group.

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein each R ⁶ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _w -NR ^j R ^k Hydroxy and C _1-6 Hydroxyalkyl group, R ^j And R is ^k Identical or different and are each independently a hydrogen atom or C _1-6 Alkyl, w is 0 or 1; preferably, each R ⁶ Identical or different and are each independently selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; further preferred is halogen; more preferably F.

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1; more preferably 1.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is naphthyl; each R is ³ Identical or different and are each independently selected from halogen and C _1-6 An alkyl group; a is 2; q is N; r is R ^4a Is halogen; l is O; r is R ^1a 、R ^1b 、R ^1e 、R ^1f At least 1 of them is hydroxyl and the rest are hydrogen atomsSon or C _1-6 An alkyl group; r is R ^5a And R is ^5b Is a hydrogen atom, or R ^5a 、R ^5b Together with the attached carbon atom, form a 3-to 6-membered cycloalkyl group; r is 1 or 3; ring B is a 3 to 8 membered heterocyclyl; r is R ⁶ Is halogen; and t is 0 or 1.

In some embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is naphthyl; each R is ³ Identical or different and are each independently selected from halogen and C _1-6 An alkyl group; a is 2; q is N; r is R ^4a Is halogen; l is O; r is R ^1a 、R ^1b 、R ^1e 、R ^1f Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and hydroxy; r is R ^5a And R is ^5b Is a hydrogen atom, or R ^5a 、R ^5b Together with the attached carbon atom, form a 3-to 6-membered cycloalkyl group; r is 1 or 3; ring B is a 3 to 8 membered heterocyclyl; r is R ⁶ Is halogen; and t is 0 or 1.

In some embodiments of the present disclosure, the compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein Q is N; r is R ^3a Is halogen; r is R ^3b Is C _1-6 An alkyl group; r is R ^4a Is halogen; l is O; r is R ^1a 、R ^1b 、R ^1e 、R ^1f Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and hydroxy;is thatR ⁶ Is halogen; and t is 0 or 1.

In some embodiments of the present disclosure, the compound of formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein Q is N; r is R ^3a Is halogen; r is R ^3b Is C _1-6 An alkyl group; r is R ^4a Is halogen; l is O; r is R ^1a 、R ^1b 、R ^1e 、R ^1f Only 1 of them being hydroxyl groups and the remainder being hydrogen atoms or C _1-6 An alkyl group;is->R ⁶ Is halogen; and t is 0 or 1.

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

another aspect of the present disclosure relates to a compound represented by the general formula (I' a) or a salt thereof,

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

G ⁰ 、G ¹ ring a, ring B, Q, L, R ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g 、R ^1h 、R ³ 、R ^4a 、R ^5a 、R ^5b 、R ⁶ And a, r and t are as defined in formula (I').

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

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

ring a, ring B, Q, L, R ^1a 、R ^1b 、R ^1e 、R ^1f 、R ³ 、R ^4a 、R ^5a 、R ^5b 、R ⁶ And a, r and t are as defined in formula (II).

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

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

ring B, Q, L, R ^1a 、R ^1b 、R ^1e 、R ^1f 、R ^3a 、R ^3b 、R ^4a 、R ^5a 、R ^5b 、R ⁶ R and t are as defined in formula (III).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-1A) or (III-2A) or a salt thereof,

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

ring B, Q, L, R ^1a 、R ^1b 、R ^1e 、R ^1f 、R ^3a 、R ^3b 、R ^4a 、R ^5a 、R ^5b 、R ⁶ R and t are as defined in formula (III-1).

In some embodiments of the present disclosure, the general formula (I), (I'),A compound represented by (II), (III-1), (III-2), (III-1A) or (III-2A) or a pharmaceutically acceptable salt thereof, whereinIs-> R ^1a And R is ^1b Different from each other and each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _u -NR ^f R ^g Hydroxyl and hydroxyalkyl radicals, R ^f 、R ^g And u is as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I), (I'), (II), (III-1), (III-2), (III-1A) or (III-2A) or a pharmaceutically acceptable salt thereof, wherein Is-> R ^1e And R is ^1f Different from each other and each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _u -NR ^f R ^g Hydroxyl and hydroxyalkyl radicals, R ^f 、R ^g And u is as defined in formula (I).

Table B 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 the general formula (I'), or a pharmaceutically acceptable salt thereof, comprising:

deprotection of a compound of formula (I 'A) or a salt thereof to give a compound of formula (I') or a pharmaceutically acceptable salt thereof;

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

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, the method comprising:

deprotection of a compound of formula (IIA) or a salt thereof to give a compound of formula (II) or a pharmaceutically acceptable salt thereof;

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III):

Deprotection of a compound of formula (IIIA) or a salt thereof to give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

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

deprotection of a compound of formula (III-1A) or a salt thereof to give a compound of formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

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

deprotection of a compound of formula (III-2A) or a salt thereof to give a compound of formula (III-2) or a pharmaceutically acceptable salt thereof;

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

ring B, Q, L, R ^1a 、R ^1b 、R ^1e 、R ^1f 、R ^3a 、R ^3b 、R ^4a 、R ^5a 、R ^5b 、R ⁶ R and t are as defined in formula (III-2).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), (I'), (II), (III-1), (III-2) or shown in table a of the present disclosure, 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 shown in general formula (I), (I'), (II), (III-1), (III-2) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting KRAS wild-type and/or KRAS mutant activity; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations; more preferably in the manufacture of a medicament for inhibiting KRAS G12D.

The present disclosure further relates to the use of a compound shown in general formula (I), (I'), (II), (III-1), (III-2) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder mediated by KRAS wild type and/or KRAS mutant form; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations; more preferably in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition mediated by KRAS G12D.

The present disclosure further relates to the use of a compound shown in general formula (I), (I'), (II), (III-1), (III-2) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gall bladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferred are those selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

The present disclosure further relates to a method of inhibiting KRAS wild-type and/or KRAS mutant activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I'), (II), (III-1), (III-2) or shown in table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations; more preferred is a method of inhibiting KRAS G12D.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder mediated by KRAS wild-type and/or KRAS mutant comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I'), (II), (III-1), (III-2) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations; more preferred are methods of treating and/or preventing a disease or disorder mediated by KRAS G12D.

The present disclosure further relates to a method of treating and/or preventing cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I'), (II), (III-1), (III-2) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gall bladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferred are those selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

The present disclosure further relates to a compound of formula (I), (I'), (II), (III-1), (III-2) or 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 a compound of formula (I), (I'), (II), (III-1), (III-2) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting KRAS wild-type and/or KRAS mutant activity; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations; more preferably for inhibiting KRAS G12D activity.

The present disclosure further relates to a compound of formula (I), (I'), (II), (III-1), (III-2) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of a disease or disorder mediated by KRAS wild type and/or KRAS mutant form; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations; more preferably for the treatment and/or prophylaxis of a disease or condition mediated by KRAS G12D.

The present disclosure further relates to a compound of formula (I), (I'), (II), (III-1), (III-2) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of cancer; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gall bladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferred are those selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

The diseases or conditions described in the present disclosure are diseases or conditions treated and/or prevented by inhibiting KRAS wild-type and/or KRAS mutant activity; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations; more preferably a disease or disorder treated and/or prevented by inhibiting KRAS G12D.

Preferably, the disease or disorder mediated by KRAS wild type and/or KRAS mutants described in the present disclosure is cancer, preferably selected from one or more of the KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13D and Q61H mutations; more preferably, the KRAS G12D-mediated disease or disorder described in the present disclosure is cancer; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gall bladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferred are those selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

Colorectal cancer described in the present disclosure is preferably colon cancer or rectal cancer.

Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue carcinoma is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyoma, leiomyosarcoma, dedifferentiated liposarcoma, polymorphous liposarcoma, malignant fibrous histiocytoma, round cell sarcoma and synovial sarcoma; lymphomas are selected from hodgkin's disease and non-hodgkin's lymphomas (e.g., mantle cell lymphomas, diffuse large B-cell lymphomas, follicular central lymphomas, marginal zone B-cell lymphomas, lymphoplasmacytic lymphomas, and peripheral T-cell lymphomas); the liver cancer is preferably hepatocellular carcinoma; lung cancer (also known as bronchogenic carcinoma) is selected from the group consisting of non-small cell lung cancer (NSCLC), small Cell Lung Cancer (SCLC) and squamous cell carcinoma; the kidney cancer is selected from the group consisting of renal cell carcinoma, clear cell, and renal eosinophil tumor; leukemia is selected from Chronic Lymphocytic Leukemia (CLL), chronic myelogenous leukemia, acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic Myelogenous Leukemia (CML), and Acute Myelogenous Leukemia (AML); the skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; the myeloma is preferably multiple myeloma.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches or syrups.

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.

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 oil, or in a 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, or 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 is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass 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 suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. 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.

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

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 particular compound employed, the severity of the disease, 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, 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 aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group having from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms _1-12 Alkyl), more preferably alkyl 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-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 A group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2-diethylpentyl group, n-decyl group, 3-diethylhexyl group, 2-diethylhexyl group, and various branched isomers thereof, and the like. 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, preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C _2-12 Alkenyl), more preferably alkenyl 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, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., C _2-12 Alkynyl), more preferably alkynyl 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, the substituents are preferably selected from one or more of alkoxy, halogen, 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 or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14 membered cycloalkyl), preferably comprising 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl), more preferably comprising 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered, monocyclic, polycyclic group sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl group is classified into a single spirocycloalkyl group or a multiple spirocycloalkyl group (e.g., a double spirocycloalkyl group) according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 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/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the connection point can be at any position; />

Etc.

The term "fused ring alkyl" refers to 5 to 20 membered, all carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a double-ring or multi-ring condensed ring alkyl group (e.g., tricyclic, tetra-ring), preferably a double-ring or tricyclic, 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/6-membered double-ring alkyl group. Non-limiting examples of fused ring alkyl groups include:

The connection point can be at any position;

etc.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Cycloalkyl groups which may be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridge are preferred, bicyclic, tricyclic or tetracyclic, more preferred bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

the connection point can be at any position.

The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples includeEtc.; preferably->

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3 to 20 membered heterocyclyl) wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but excluding the ring portions of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. Preferably containing from 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms (i.e., 3 to 14 membered heterocyclyl), of which 1 to 4 (e.g., 1,2,3, and 4) are heteroatoms; more preferably from 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8 membered heterocyclyl) or from 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14), wherein 1-3 is a heteroatom (e.g., 1,2, and 3); more preferably 3 to 8 ring atoms, of which 1-3 (e.g., 1,2, and 3) are heteroatoms; most preferably contain 5 or 6 ring atoms (i.e., 5-or 6-membered heterocyclyl) of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered spiroheterocyclyl). The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, and are preferably single spiroheterocyclyl groups and double spiroheterocyclyl groups. More preferably 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/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), and the remaining ring atoms are carbon. Preferably 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered fused heterocyclyl). The number of constituent rings may be classified into a bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic group, preferably a bicyclic or tricyclic, 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 of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (i.e., 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (e.g., 7, 8, 9 or 10 membered) (i.e., 7 to 10 membered bridged heterocyclyl). Heterocyclic groups which may be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridge according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

the heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

etc.

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

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (fused polycyclic being a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 8 to 10 membered (e.g., 8, 9, or 10 membered), and even more preferably 5 or 6 membered (i.e., 5 or 6 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Etc.

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any useful point of attachment, preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include (trimethylsilyl) ethoxymethyl (SEM), tetrahydropyranyl, t-butoxycarbonyl (Boc), acetyl, benzyl, allyl, p-toluenesulfonyl (Ts), p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro; the amino protecting group is preferably Boc.

The term "hydroxy protecting group" refers to a hydroxy derivative that is typically used to block or protect a hydroxy group while the reaction proceeds on other functional groups of the compound. As an example, preferably, the hydroxyl protecting group is, for example: triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like; the hydroxyl protecting group is preferably MOM.

The term "alkynyl protecting group" refers to an easily removable group introduced on an alkynyl group in order to keep the active hydrogen in the acetylene or terminal alkyne unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like; the alkynyl protecting group is preferably TIPS.

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.

MOM refers to methoxymethyl.

Boc means t-butoxycarbonyl.

TIPS refers to triisopropylsilyl groups.

TBS means t-butyldimethylsilyl.

The compounds of the present disclosure may comprise rotamers and conformationally constrained states of all manner thereof. Also included are atropisomers, the term "atropisomers" being stereoisomers resulting from the blocked rotation about a single bond, wherein the energy difference due to steric strain or other contributors is profiled to a sufficiently high rotational barrier to allow separation of individual conformational isomers. 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.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of keto-enol equilibrium are shown below:

All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

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. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named. 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 derivatization with a 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 known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time contain->And->Two configurations.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, e.g., respectively 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.

"optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may be, but need not be, present, and the description includes alkyl groups substituted with halogen or cyanoSubstituted cases and cases where the alkyl group is not substituted with halogen and cyano.

"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 (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or pharmaceutically acceptable salts or prodrugs 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. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

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

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

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

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

Methods of synthesizing compounds of the present disclosure

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

scheme one

The present disclosure provides a process for preparing a compound represented by the general formula (I'), or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (I 'A) or a salt thereof under acidic conditions to give a compound of formula (I') or a pharmaceutically acceptable salt thereof;

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

Scheme II

The present disclosure provides a process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (IIA) or a salt thereof under acidic conditions to give a compound of formula (II) or a pharmaceutically acceptable salt thereof;

Wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

Scheme III

The present disclosure provides a process for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (IIIA) or a salt thereof under acidic conditions to give a compound of formula (III) or a pharmaceutically acceptable salt thereof;

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

Scheme IV

The present disclosure provides a process for preparing a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (III-1A) or a salt thereof under acidic conditions to give a compound of formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

Scheme five

The present disclosure provides a process for preparing a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof, which comprises:

deprotection of a compound of formula (III-2A) or a salt thereof under acidic conditions to give a compound of formula (III-2) or a pharmaceutically acceptable salt thereof;

Wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

Reagents providing acidic conditions in the above synthetic schemes 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; the inorganic acids include, but are not limited to, hydrogen chloride, dioxane hydrochloride solution, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; preferably a dioxane solution of hydrochloric acid.

In the above synthesis scheme, when R ³ When the terminal alkyne is contained, the terminal alkyne can be protected by TIPS, and the reagent for removing the TIPS is preferably tetrabutylammonium fluoride in tetrahydrofuran or cesium fluoride.

The reaction of the above steps is preferably carried out in solvents including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, 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 determined 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 (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

Thermo Ultimate 3000-Q exact (manufacturer: thermo, MS model: thermo Qexact)

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

The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemical, 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: the volume ratio of the n-hexane to the ethyl acetate is adjusted according to the polarity of the compound, and can be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like.

Where the compounds in the examples contain two or more chiral centers, the relative stereochemistry of these compounds is identified by NMR studies and/or X-ray diffraction. In these cases, the prefix "rel" is used, followed by the identification of these compounds using R/S nomenclature, where R/S provides only relative stereochemical information (e.g., trans or cis), and does not represent absolute stereochemistry. For example, the number of the cells to be processed,representation->1:1 mixtures of (c), i.e. racemates.

Example 1

rel- (5 ar,6 s) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-6-ol (mixture of trans isomers) 1-p1

Or (b)

rel- (5 ar,6 r) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-6-ol (mixture of cis isomers) 1-p2

First step

2- (((tert-Butyldimethylsilyl) oxy) methyl) pyridin-3-ol 1b

Compound 2- (hydroxymethyl) pyridine-3-phenolhydrochloride 1a (10 g,61.8 mmol) was dissolved in N, N-Dimethylformamide (DMF) (300 mL), imidazole (13 g,190.9 mmol) was added, t-butyldimethylchlorosilane (7.6 g,92.3 mmol) was replaced with nitrogen, the reaction was reacted at 60℃for 24 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 1B (5.0 g, yield: 33.7%);

MS m/z(ESI):240.2[M+1]。

second step

2- (((tert-Butyldimethylsilyl) oxy) methyl) piperidin-3-ol (mixture of isomers) 1c

Compound 1b (5 g,20.9 mmol) was dissolved in ethanol (50 mL) and water (25 mL), platinum dioxide (950 mg,4.18mmol, shanghai shao) was added, the reaction was heated at 50℃for 48 hours under a 2MPa hydrogen atmosphere, the reaction solution was allowed to room temperature, filtered, washed with ethanol, and the filtrate was concentrated under reduced pressure to give the crude title compound 1c (mixture of non-corresponding isomers) (5.1 g), which was used directly in the next reaction without purification.

MS m/z(ESI):246.2[M+1]。

Third step

Benzyl 2- (((tert-butyldimethylsilyloxy) methyl) -3-hydroxypiperidine-1-carboxylate (mixture of isomers) 1d

Crude compound 1c (5.1 g,20.7 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL), sodium carbonate (560 mg,5.28 mmol) was added, benzyl chloroformate (3.55 g,20.8mmol, shanghai taitant) was added under ice-water bath, the reaction was stirred at room temperature naturally for 1 hour, water was added to the reaction solution, extraction was performed with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1d (mixture of diastereomers) (1.3 g, yield: 16.5%).

MS m/z(ESI):380.2[M+1]。

Fourth step

(±) -2- (((tert-butyldimethylsilyl) oxy) methyl-3-oxopiperidine-1-carboxylic acid benzyl ester 1e

Oxalyl chloride (610 mg,4.8mmol, 410. Mu.L) was added to dichloromethane (10 mL) under nitrogen protection, dimethyl sulfoxide (750 mg,9.6mmol, 682. Mu.L) was added dropwise at-78℃and after 30 minutes of reaction at the maintained temperature, compound 1d (1.3 g,3.42 mmol) was added, reaction was carried out at-78℃for 30 minutes, triethylamine (1.4 g,13.8 mmol) was added, reaction was resumed at room temperature for 30 minutes, water quenching was added, dichloromethane (10 mL. Times.3) was used, the organic phases were combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and concentrated under reduced pressure to give the crude title compound 1e (1.2 g) which was used directly in the next reaction without purification.

MS m/z(ESI):378.2[M+1]。

Fifth step (. + -.) -rel- (2R, 3S) -2- (((tert-butyldimethylsilyl) oxy) methyl) -3-hydroxy-3-methylpiperidine-1-carboxylic acid benzyl ester

(mixture of trans isomers)

1f-1

Or (. + -.) -rel- (2R, 3R) -2- (((tert-butyldimethylsilyl) oxy) methyl) -3-hydroxy-3-methylpiperidine-1-carboxylic acid benzyl ester

(mixture of cis-isomers) 1f-2

The crude compound 1e (1.3 g,3.44 mmol) was dissolved in tetrahydrofuran (20 mL), a 2.5M solution of methyl magnesium bromide in tetrahydrofuran (2 mL) was added under ice bath, after keeping the temperature for 1 hour, quenched by adding saturated aqueous ammonium chloride, and quenched with ethyl acetate (15 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give the crude title compound 1f-1 or 1f-2 (1.1 g), which was used in the next reaction without purification.

MS m/z(ESI):394.2[M+1]。

Sixth step (. + -.) -rel- (2R, 3S) -2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methylpiperidin-3-ol (mixture of trans isomers) 1g-1

Or (. + -.) -rel- (2R, 3R) -2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methylpiperidin-3-ol (mixture of cis isomers) 1g-2

The crude compound 1f-1 or 1f-2 (1.0 g, 762.2. Mu. Mol) was dissolved in methanol (20 mL), 10% palladium on carbon catalyst (wet) (1.0 g) was added, and the mixture was stirred at 40℃under hydrogen atmosphere for 12 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1g-1 or 1g-2 (700 mg), and the product was directly used for the next reaction without purification.

MS m/z(ESI):260.2[M+1]。

Seventh step

4- ((tert-Butoxycarbonyl) amino) -2, 6-dichloro-5-fluoropropionic acid tert-butyl ester 1i

The crude compound 2, 6-dichloro-3-fluoropyridin-4-amine (1.8 g,9.94mmol, prepared as disclosed in Preparation 14 (a) on page 46 of the specification in patent application "WO2016191524A 1") was dissolved in tetrahydrofuran (50 mL), 2M solution of sodium bis-trimethylsilyl amide in tetrahydrofuran (20 mL) was added under ice bath, stirred for 0.5 hour, di-tert-butyl dicarbonate (6.5 g,29.7 mmol) was added, stirred for 14 hours, quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure after removal of the desiccant by filtration, and the residue was purified with eluent system B to give the title compound 1i (1 g, yield: 26.3%).

MS m/z(ESI):381.1[M+1]。

Eighth step

4-amino-2, 6-dichloro-5-fluoronicotinic acid tert-butyl ester 1j

Compound 1i (1 g,2.62 mmol) was dissolved in ethyl acetate (8 mL), 4M dioxane hydrochloride solution (3 mL) 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 extraction (15 mL. Times.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 A to give the title compound 1j (500 mg, yield: 67.8%). MS m/z (ESI): 281.1[ M+1].

Ninth step

2, 6-dichloro-5-fluoro-4- (3- (2, 2-trichloroacetyl) ureido) nicotinic acid tert-butyl ester 1k

Compound 1j (500 mg,1.77 mmol) was dissolved in tetrahydrofuran (10 mL), trichloroacetyl isocyanate (640 mg,3.55mmol, shanghai Honghai) was added, the reaction was stirred for 30 min, and the reaction solution was concentrated under reduced pressure to give the crude title compound 1k (835 mg), which was used in the next reaction without purification.

MS m/z(ESI):467.9[M+1]。

Tenth step

5, 7-dichloro-8-fluoro-pyrido [4,3-d ] pyrimidine-2, 4-diol 1l

The crude compound 1k (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 1l (400 mg, yield: 89.9%) which was used directly in the next reaction without purification.

MS m/z(ESI):249.9[M+1]。

Eleventh step

2,4,5, 7-tetrachloro-8-fluoro-pyrido [4,3-d ] pyrimidine 1m

1l (875 mg,3.5 mmol) of the crude compound was dissolved in phosphorus oxychloride (25 mL), N-diisopropylethylamine (2.3 g,17.5 mmol) was added, the reaction was stirred at 110℃for 1 hour, the reaction solution was cooled to room temperature and then concentrated under reduced pressure to give the crude title compound 1m (1.14 g), and the product was used in the next step without purification.

MS m/z(ESI):285.8[M+1]。

Twelfth step (±) -rel- (2 r,3 s) -2- (((tert-butyldimethylsilyloxy) methyl) -3-methyl-1- (2, 5, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (mixture of trans isomers) 1n-1

Or (. + -.) -rel- (2R, 3R) -2- (((tert-butyldimethylsilyl) oxy) methyl) -3-methyl-1- (2, 5, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (mixture of cis-isomers) 1n-2

The crude compound 1m (1.14 g,3.97 mmol) was dissolved in dichloromethane (50 mL), -N, N-diisopropylethylamine (2.58 g,20 mmol), compound 1g-1 or 1g-2 (745 mg,2.87 mmol), was added at 78deg.C, the reaction was allowed to spontaneously recover to room temperature, stirring was carried out for 14 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system A to give the title compound 1N-1 or 1N-2 (936 mg, yield: 45.9%).

MS m/z(ESI):509.2[M+1]。

Thirteenth step

rel- (2R, 3S) -2- (((tert-butyldimethylsilyloxy) methyl) -1- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperidin-3-ol (mixture of trans isomers) 1o-1

Or (b)

rel- (2R, 3R) -2- (((tert-butyldimethylsilyl) oxy) methyl) -1- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperidin-3-ol (mixture of cis isomers) 1o-2

Compound 1N-1 or 1N-2 (100 mg, 196. Mu. Mol) was dissolved in 1, 4-dioxane (2 mL), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (60 mg,3.77mmol, pharmaceutical), molecular 4A sieve (100 mg, 190.23. Mu. Mol), N, N-diisopropylethylamine (122 mg, 945.7. Mu. Mol), reacted overnight at 110℃and then filtered after cooling to room temperature, and the filtrate was concentrated under reduced pressure to give crude title compound 1o-1 or 1o-2 (130 mg) which was used directly in the next step without purification.

MS m/z(ESI):632.2[M+1]。

Fourteenth step

rel- (5 ar,6 s) -2-chloro-1-fluoro-11- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalene-6-ol (mixture of trans isomers) 1p-1

Or (b)

rel- (5 ar,6 r) -2-chloro-1-fluoro-11- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalene-6-ol (mixture of cis isomers) 1p-2

The crude compound 1o-1 or 1o-2 (130 mg, 207. Mu. Mol) was dissolved in tetrahydrofuran (2 mL), a 1M tetrahydrofuran solution of tetrabutylammonium fluoride (1 mL) was added, the reaction was allowed to react at 60℃for 14 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified with eluent system A to give the title compound 1p-1 or 1p-2 (71 mg, yield: 71.0%).

MS m/z(ESI):482.2[M+1]。

Fifteenth step

rel- (5 ar,6 s) -2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-11- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-6-ol (mixture of trans isomers) 1q-1

Or (b)

rel- (5 ar,6 r) -2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-11- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-6-ol (mixture of cis isomers) 1q-2

Compound 1p-1 or 1p-2 (71 mg, 147. Mu. Mol), 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (80 mg, 222. Mu. Mol, prepared by the method disclosed by Intermediate 18 at page 104 of the specification in patent application "WO 2021/04671"), was dissolved in 1.4-dioxabicyclo (2 mL) and water (0.4 mL), and triphenylphosphine palladium (34 mg, 29. Mu. Mol, shanghai-Tai) and cesium carbonate (144 mg, 442. Mu. Mol) were added and reacted at 100℃under nitrogen atmosphere for 14 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dissolved with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1q-1 or 1q-2 (100 mg), which was used in the next step without purification.

MS m/z(ESI):680.2[M+1]。

Sixteenth step

Or (b)

The crude compound 1q-1 or 1q-2 (100 mg, 147. Mu. Mol) was dissolved in ethyl acetate (2 mL), a solution of 4M hydrochloric acid in 1, 4-dioxane (0.5 mL) was added under ice-water bath, the reaction was carried out for 1 hour at a maintained temperature, and then concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: sharpsil-T C, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile in a gradient ratio: acetonitrile 35% -45%, flow rate: 30 mL/min) to give the title compound 1-p1 or 1-p2 (5 mg, yield: 5.3%).

MS m/z(ESI):636.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.65(t,1H),7.30-7.16(m,2H),7.05(dd,1H),5.46(dd,1H),5.37(t,1H),4.60-4.48(m,1H),4.36-4.21(m,2H),3.86(d,1H),3.16-2.98(m,2H),2.57(d,1H),2.43-2.33(m,1H),2.33-2.19(m,2H),2.12(dd,2H),2.01(h,2H),1.93-1.87(m,1H),1.83(d,1H),1.68(d,3H),1.05(q,6H),0.97-0.79(m,3H)。

Examples 1-p1-1,1-p1-2 or 1-p2-1,1-p2-2

(5 aR, 6S) -2- (8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-6-ol 1-p1-1

(5 aS, 6R) -2- (8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-6-ol 1-p1-2

(5 aR, 6R) -2- (8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-6-ol 1-p2-1

(5 aS, 6S) -2- (8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -6-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-6-ol 1-p2-2

The mixture of isomers 1-p1 or 1-p2 (10 mg, 15.7. Mu. Mol) was resolved by chiral column (Gilson 281, column CHIRALPAK OD-H, 20X 250mm,10 μm; mobile phase A: n-hexane; mobile phase B: ethanol (0.5% NH 3), gradient ratio: A: B:70:30, flow rate: 20 mL/min) to give the title compound 3mg, yield: 30%,30% and retention times of 6.2min and 15.1min, respectively.

Single configuration compounds (shorter retention time): 6.2min, (3 mg, yield: 30%).

MS m/z(ESI):636.2[M+1]。

HPLC analysis: purity: 95% (chromatographic 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,CD ₃ OD): delta 7.65 (dt, 1H), 7.30-7.19 (m, 2H), 7.04 (dd, 1H), 5.50-5.40 (m, 1H), 5.26 (t, 1H), 4.52 (ddd, 2H), 4.37-4.29 (m, 1H), 4.22 (d, 1H), 3.90-3.81 (m, 1H), 3.26-3.16 (m, 2H), 3.11 (tdd, 1H), 3.02 (td, 1H), 2.61-2.50 (m, 1H), 2.36 (dd, 1H), 2.27 (ddd, 1H), 2.22-2.18 (m, 1H), 2.17-2.07 (m, 2H), 2.01 (dp, 3H), 1.93-1.76 (m, 3H), 1.73-1.66 (m, 1H), 1.61 (d, 1.44 (d, 3H), 0.80 (d, 3.80H). Single configuration compounds (longer retention time): 15.1min, (3 mg, yield: 30%).

MS m/z(ESI):636.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.61(dt,1H),7.26-7.15(m,2H),7.00(dd,1H),5.46-5.36(m,1H),5.22(t,1H),4.48(ddd,2H),4.33-4.25(m,1H),4.18(d,1H),3.86-3.77(m,1H),3.22-3.12(m,2H),3.07(tdd,1H),2.98(td,1H),2.57-2.46(m,1H),2.32(dd,1H),2.23(ddd,1H),2.18-2.14(m,1H),2.13-2.03(m,2H),1.97(dp,3H),1.89-1.72(m,3H),1.69-1.62(m,1H),1.57(t,1H),1.40(d,2H),0.91-0.76(m,3H)。

Example 2

(±) -rel- (5 ar,6 s) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-6-methyl-11- ((1- (morpholinomethyl) cyclopropyl) methoxy) -5,5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalene

-6-phenol (mixture of trans isomers) 2-p1

Or (±) -rel- (5 ar,6 r) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-6-methyl-11- ((1- (morpholinomethyl) cyclopropyl) methoxy) -5,5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalene

-6-phenol (mixture of cis-isomers) 2-p2

First step

4- ((1- (((tert-butyldimethylsilyl) oxy) methyl) cyclopropyl) methyl) morpholine 2b

The compound (1- (((tert-butyldimethylsilyloxy) methyl) cyclopropyl) methyl methanesulfonate 2a (3.4 g,11.5mmol, prepared as disclosed in Example 34, page 94 of the specification in patent application "WO2010039079A 1"), morphine (2 g,23 mmol) dissolved in acetonitrile (50 mL), anhydrous potassium carbonate (4.7 g,34.6 mmol) and sodium iodide (1.7 g,11.5 mmol) were added and reacted at 80℃for 1 hour, the reaction cooled to room temperature, filtered, the filtrate concentrated under reduced pressure and the residue purified by silica gel column chromatography with eluent system A to give the title compound 2b (2.5 g, yield: 75.8%).

MS m/z(ESI):286.2[M+1]。

Second step

(1- (morpholinomethyl) cyclopropyl) methoxide 2c

Compound 2b (0.5 g,1.75 mmol) was dissolved in 1, 4-dioxane (2 mL) of 4M hydrochloric acid and reacted for 2 hours with stirring, the reaction solution was concentrated under reduced pressure, the residue was slurried with ethyl acetate, filtered, and the filter cake was dried to give the crude title compound 2c (150 mg), the product was used in the next step without purification.

MS m/z(ESI):172.2[M+1]。

The third step (. + -.) -rel- (5 aR, 6S) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-6-methyl-11- ((1- (morpholinomethyl) cyclopropyl) methoxy) -5,5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalene

-6-phenol (mixture of trans isomers) 2-p1

-6-phenol (mixture of cis-isomers) 2-p2

Using the synthetic route in example 1, the thirteenth starting compound ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol was replaced with compound 2c to give the title compound 2-p1 or 2-p2 (2 mg, yield: 3%).

MS m/z(ESI):648.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.66(s,1H),7.35-7.13(m,2H),7.06(d,1H),5.54-5.28(m,2H),4.49(td,3H),3.87(d,1H),3.66(s,2H),3.37(t,5H),3.16(d,1H),2.69-2.33(m,4H),2.22(d,3H),1.97-1.59(m,4H),1.39(dd,4H),0.88(dq,2H),0.74(s,1H),0.51(s,1H)。

Example 3

rel- (5 aS, 8R) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-8-ol (mixture of trans isomers) 3-p1

rel- (5 aS, 8S) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-8-ol (mixture of cis isomers) 3-p2

First step

6- (hydroxymethyl) pyridin-3-ol 3b

Methyl 5-hydroxy-2-picolinate 3a (5.0 g,32.65mmol, shanghai) was dissolved in tetrahydrofuran (100 mL), 1M lithium aluminum hydride in tetrahydrofuran (65.3 mL) was added, the reaction was refluxed for 2 hours, the reaction solution was cooled to room temperature, quenched by addition of sodium sulfate decahydrate under ice-water bath, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified with eluent system B to give the title compound 3B (1.0 g, yield: 24.4%).

MS m/z(ESI):126.2[M+1]。

Second step

6- (((tert-butyldimethylsilyl) oxy) methyl) pyridin-3-ol 3c

Compound 3B (1.0 g,8 mmol) was dissolved in N, N-dimethylformamide (50 mL), t-butyldimethylchlorosilane (987 mg,12 mmol), imidazole (1.6 g,23.5 mmol) was added, the reaction was allowed to react at 65℃for 24 hours under nitrogen protection, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified with eluent system B to give the title compound 3c (0.9 g, yield: 47%).

MS m/z(ESI):240.2[M+1]。

Third step

6- (((tert-butyldimethylsilyloxy) methyl) piperidin-3-ol (mixture of non-enantiomers) 3d

Compound 3c (0.9 g,3.76 mmol) was dissolved in ethanol (40 mL) and water (20 mL), platinum dioxide (170 mg, 748.6. Mu. Mol) was added, and the mixture was reacted under a hydrogen atmosphere of 2MPa at 50℃for 48 hours, the reaction solution was cooled to room temperature, filtered, washed with ethanol, and the filtrate was concentrated under reduced pressure to give the crude title compound 3d (mixture of non-enantiomer) (920 mg), which was used in the next reaction without purification.

MS m/z(ESI):246.2[M+1]。

Fourth step

2- (((tert-butyldimethylsilyloxy) methyl-5-hydroxypiperidine-1-carboxylic acid benzyl ester (mixture of diastereomers) 3e

The crude title compound 3d (920 mg,3.75 mmol) was dissolved in tetrahydrofuran (15 mL) and water (15 mL), sodium carbonate (560 mg,5.28 mmol) was added, benzyl chloroformate (640 mg,3.75 mmol) was added under ice-water bath, the reaction was stirred at room temperature for 1 hour naturally, water was added to the reaction solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, 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 title compound 3e (mixture of diastereomers) (280 mg, yield: 19.6%).

MS m/z(ESI):380.2[M+1]。

Fifth step

(±) -2- (((tert-butyldimethylsilyl) oxy) methyl) -5-oxopiperidine-1-carboxylic acid benzyl ester 3f

Oxalyl chloride (131 mg,1.03mmol, 88. Mu.L) was added to dichloromethane under nitrogen protection, dimethyl sulfoxide (161 mg,2.06mmol, 146.36. Mu.L) was added dropwise at-78℃and after stirring for 30 min, compound 3e (280 mg, 737.68. Mu. Mol) was added, triethylamine (300 mg,2.96mmol, 414. Mu.L) was added after reaction at-78℃for 30 min, the reaction was resumed for 30 min, water quenching was added, extraction was performed with dichloromethane (10 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the filtrate was concentrated under reduced pressure after removal of the drying agent by filtration to give the crude title compound 3f (300 mg) which was used directly in the next reaction without purification.

MS m/z(ESI):378.2[M+1]。

Sixth step (. + -.) -rel- (2S, 5R) -2- (((tert-butyldimethylsilyl) oxy) methyl) -5-hydroxy-5-methylpiperidine-1-carboxylic acid benzyl ester

(mixture of trans isomers) 3g-1

And

(±) -rel- (2 s,5 s) -2- (((tert-butyldimethylsilyl) oxy) methyl) -5-hydroxy-5-methylpiperidine-1-carboxylic acid benzyl ester

(mixture of cis-isomers) 3g-2

The crude compound 3f (300 mg, 794.6. Mu. Mol) was dissolved in tetrahydrofuran (5 mL), a 2.5M solution of methyl magnesium bromide in tetrahydrofuran (355. Mu.L) was added under ice-water bath, the reaction was carried out for 1 hour at a maintained temperature, then saturated aqueous ammonium chloride solution was added for quenching, extraction was carried out with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the filtrate after removal of the drying agent by filtration was concentrated under reduced pressure to give the crude title compounds 3g-1 and 3g-2 (300 mg, retention time: short: retention time. Apprxeq.7:3), and the product was used for the next reaction without purification.

MS m/z(ESI):394.2[M+1]。

HPLC analysis method: the retention times were 2.75min and 2.83min, respectively, (column chromatography: ACQUITY)BEH, C18,1.7 μm,2.1 x 50mm; mobile phase: water (1%formic acid), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

Seventh step (. + -.) -rel- (2S, 5R) -6- (((tert-butyldimethylsilyl) oxy) methyl) -3-methylpiperidin-3-ol (mixture of trans isomers) 3h-1

And (. + -.) -rel- (2S, 5S) -6- (((tert-butyldimethylsilyl) oxy) methyl) -3-methylpiperidin-3-ol (mixture of cis isomers) 3h-2

A mixture (0.3 g, 762.2. Mu. Mol) of the crude compound 3g-1 and 3g-2 was dissolved in methanol (10 mL), a 10% palladium-carbon catalyst (wet) (240 mg) was added, the reaction was carried out at 40℃for 1 hour under a hydrogen atmosphere, the reaction solution was cooled to room temperature, then filtration was carried out, and the filtrate was concentrated under reduced pressure to obtain a mixture (167 mg) of the crude title compounds 3h-1 and 3h-2, which was directly used for the next reaction without purification.

MS m/z(ESI):260.2[M+1]。

Eighth step (±) -rel- (3 r,6 s) -6- (((tert-butyldimethylsilyloxy) methyl) -3-methyl-1- (2, 5, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (mixture of trans isomers) 3i-1

And (. + -.) -rel- (3S, 6S) -6- (((tert-butyldimethylsilyloxy) methyl) -3-methyl-1- (2, 5, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) piperidin-3-ol (mixture of cis isomers) 3i-2

A mixture of crude compounds 3h-1 and 3h-2 was dissolved in dichloromethane (5 mL), -N, N-diisopropylethylamine (317 mg,2.6 mmol), compound 1m (135 mg, 520.3. Mu. Mol), was added at 78deg.C, the reaction was naturally resumed at room temperature for 14 hours, concentrated under reduced pressure, and the residue was purified with eluent system A to give a mixture of the title compounds 3i-1 and 3i-2 (97 mg, yield: 36.3%).

MS m/z(ESI):509.2[M+1]。

Ninth step

rel- (3R, 6S) -6- (((tert-butyldimethylsilyl) oxy) methyl) -1- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperidin-3-ol (mixture of trans isomers) 3j-1

And

mixtures of rel- (3 s,6 s) -6- (((tert-butyldimethylsilyl) oxy) methyl) -1- (5, 7-dichloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperidin-3-ol (mixture of cis isomers) 3j-2

A mixture (97 mg, 190.23. Mu. Mol) of the compounds 3i-1 and 3i-2 was dissolved in 1, 4-dioxane (2 mL), ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (60 mg,3.77 mmol), 4A molecular sieves (100 mg), N, N-diisopropylethylamine (122 mg, 945.7. Mu. Mol) were added, the reaction mixture was reacted at 110℃for 14 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a mixture (126 mg) of the crude title compounds 3j-1 and 3j-2, which was used in the next step without purification.

MS m/z(ESI):632.2[M+1]。

Tenth step

rel- (5 aS, 8R) -2-chloro-1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalene-8-ol (mixture of trans isomers) 3k-1

And

mixtures of rel- (5 aS, 8S) -2-chloro-1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalene-8-ol (mixture of cis isomers) 3k-2

A mixture of crude compounds 3j-1 and 3j-2 (126 mg, 199. Mu. Mol) was dissolved in tetrahydrofuran (2 mL), 1M tetrabutylammonium fluoride in tetrahydrofuran (1 mL) was added, the reaction solution was reacted at 60℃for 14 hours, cooled to room temperature, concentrated under reduced pressure, and the residue was purified with eluent system A to give a mixture of the title compounds 3k-1 and 3k-2 (83 mg, yield: 83%).

MS m/z(ESI):482.2[M+1]。

Eleventh step

rel- (5 aS, 8R) -2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-8-ol (mixture of trans isomers) 3l-1

And

mixtures of rel- (5 aS, 8S) -2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-8-ol (mixture of cis isomers) 3l-2

A mixture of compounds 3k-1 and 3k-2 (83 mg, 172.22. Mu. Mol), 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (93 mg, 258.1. Mu. Mol) was dissolved in 1.4-dioxan (2 mL) and water (0.4 mL), tetrakis triphenylphosphine palladium (40 mg, 34.6. Mu. Mol), cesium carbonate (170 mg, 521.7. Mu. Mol) was added, the reaction mixture was cooled to room temperature under nitrogen at 100℃and concentrated under reduced pressure, dissolved with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give a mixture of the crude title compounds 3l-1 and 3l-2 (120 mg), the product was directly used for the next reaction without purification.

MS m/z(ESI):680.2[M+1]。

Twelfth step

A mixture of 3L-1 and 3L-2 (120 mg, 176. Mu. Mol) of crude compound was dissolved in ethyl acetate (2 mL), a 1, 4-dioxane solution (0.5 mL) of 4M hydrochloric acid was added under ice-water bath, after maintaining the temperature for 1 hour, the mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: sharpsil-T C, 30X 150mm,5 μm; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38% -45%, flow rate: 30 mL/min) to give the title compound (2 mg,10mg, yield: 1.7%, 8.9%).

3-p1 or 3-p2 (shorter retention time) (2 mg, yield: 1.7%)

MS m/z(ESI):636.2[M+1]。

HPLC analysis: retention time 1.688 min, purity: 99% (chromatographic column: HALO)C18,2.7 μm,3.0 x 30mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%). ¹ H NMR(500MHz,CD ₃ OD):δ7.67(dd,1H),7.30(d,1H),7.25(td,1H),7.08(dd,1H),5.41-5.26(m,2H),4.62-4.56(m,2H),4.37-4.23(m,2H),4.00(s,1H),3.26(t,2H),3.22-3.18(m,1H),3.13-3.01(m,2H),2.51(ddd,2H),2.41-2.34(m,1H),2.33-2.26(m,1H),2.25-2.18(m,1H),2.15(d,1H),2.02(td,2H),1.99-1.90(m,3H),1.68(p,1H),1.48-1.41(m,1H),1.25(d,1H),1.21(d,1H),0.95-0.84(m,3H)。

3-p1 or 3-p2 (longer retention time) (10 mg, yield: 8.9%)

MS m/z(ESI):636.2[M+1]。

HPLC analysis: retention time 1.734 min, purity: 99% (chromatographic column: HALO) C18,2.7 μm,3.0 x 30mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%). ¹ H NMR(500MHz,CD ₃ OD):δ7.67(ddd,1H),7.29(dd,1H),7.25(td,1H),7.06(dd,1H),5.42-5.25(m,2H),4.66-4.53(m,2H),4.41-4.20(m,2H),3.91(t,1H),3.31-3.22(m,2H),3.20-3.10(m,1H),3.05(d,1H),2.64-2.42(m,2H),2.41-2.16(m,4H),2.03(s,2H),1.98-1.84(m,2H),1.83-1.76(m,1H),1.67(td,1H),1.51-1.40(m,1H),1.33(s,3H),0.89(dtd,3H)。

Examples 3-p1-1,3-p1-2 or 3-p2-1,3-p2-2

(5 aS, 8R) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-8-ol 3-p1-1

(5 aR, 8S) -2- (8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-8-ol 3-p1-2

(5 aS, 8S) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-8-ol 3-p2-1

(5 aR, 8R) -2- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-11- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-3, 9a,10, 12-tetraazabenzo [4,5] heptano [1,2,3-de ] naphthalen-8-ol 3-p2-2

The mixture of isomers (10 mg, 15.7. Mu. Mol) corresponding to the longer retention times in compounds 3-p1 and 3-p2 was resolved by chiral column (Gilson 281, column: IC,20 x 250mm,10 μm; mobile phase a: n-hexane, mobile phase B: ethanol (0.5% NH 3), gradient ratio: a is as follows: 70:30, flow rate: 20 mL/min) to give the title compound 3mg, yield: 30%,30% and retention times of 7.3min and 14.6min, respectively. Single configuration compounds (shorter retention time): 7.3min, (3 mg, yield: 30%).

MS m/z(ESI):636.2[M+1]。

HPLC analysis: purity: 95% (column chromatography: HALO)C18,2.7 μm,3.0 x 30mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(500MHz,CD ₃ OD):δ7.67(ddd,1H),7.30(d,1H),7.26(td,1H),7.06(dd,1H),5.44-5.31(m,3H),4.65-4.53(m,4H),4.43(d,1H),4.28(d,1H),3.92(t,1H),3.15(d,2H),2.46(dt,2H),2.36-2.23(m,3H),2.21(t,1H),2.07(s,2H),1.95(s,2H),1.93-1.86(m,1H),1.80(d,1H),1.33(s,3H),0.94-0.85(m,3H)。

Single configuration compounds (longer retention time): 14.6min, (3 mg, yield: 30%).

MS m/z(ESI):636.2[M+1]。

HPLC analysis: purity: 94.5% (column: HALO)C18,2.7 μm,3.0 x 30mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient proportioning: acetonitrile 10% -95%).

¹ H NMR(500MHz,CD ₃ OD):δ7.60(ddd,1H),7.22(d,1H),7.18(td,1H),6.99(dd,1H),5.37-5.24(m,3H),4.58-4.46(m,4H),4.36(d,1H),4.21(d,1H),3.84(t,1H),3.08(d,2H),2.39(dt,2H),2.29-2.16(m,3H),2.14(t,1H),1.99(s,2H),1.88(s,2H),1.86-1.79(m,1H),1.73(d,1H),1.26(s,3H),0.87-0.78(m,3H)。

Biological evaluation

Test example 1: biological evaluation of AGS cell ERK phosphorylation inhibition assay (HTRF method)

AGS cells were cultured in complete medium of RPMI1640 (Hyclone, SH 30809.01) containing 10% foetal calf serum. On the first day of the experiment, AGS cells were seeded in 96-well plates at 40000 cells per well 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 μl of gradient diluted test compound, compound in complete medium, was added to each well The final concentration of (2) was 9 concentration points from 10. Mu.M at 5-fold gradient dilution, a blank containing 0.5% DMSO was set, the well plate was placed at 37℃and 5% CO was used ₂ Is incubated for 1 hour. After the incubation was completed, 96-well cell culture plates were removed, the medium was aspirated, and 200. Mu.L of PBS (Shanghai Source culture Biotechnology Co., ltd., B320) was added to each well and washed once. The PBS was pipetted off, 50. Mu.L of blocking reagent-containing lysis buffer (lysbuffer) (Cisbio, 64KL1 FDF) was added to each well, and the well plate was lysed by shaking at room temperature on a shaker for 40 minutes. After lysis, 16. Mu.L of lysate was transferred to each well of two HTRF 96-well assay plates (Cisbio, 66PL 96100) and then 4. Mu.L of either premixed phosphorylated ERK1/2 antibody solution (Cisbio, 64 AERPEG) or 4. Mu.L of premixed total ERK1/2 antibody solution (Cisbio, 64 NRKPEG) was added to each well. The microplate was sealed with a sealing plate membrane, centrifuged in a microplate centrifuge for 1 min, and incubated overnight at room temperature in the absence of light. On the third day, the fluorescence values emitted at 337nm wavelength excitation, 665nm and 620nm wavelength were read using a multifunctional microplate reader (PerkinElmer, enVision).

Calculating the ratio of 665nm and 620nm fluorescence signals of the phosphorylated ERK1/2 and the total ERK1/2 at each concentration of the compound, and calculating the IC of the inhibitory activity of the compound according to the ratio of the phosphorylated ERK1/2 corrected by the ratio of the compound concentration to the total ERK1/2 by using Graphpad Prism software ₅₀ Values, results are presented in table 1 below.

TABLE 1 data on ERK phosphorylation inhibition Activity of AGS cells

Conclusion: the compound disclosed by the disclosure has a better inhibition effect on the ERK phosphorylation of AGS cells.

Test example 2: biological evaluation of 3D proliferation inhibition experiment of GP2D cells

On the first day of the experiment, GP2d cells, which grew well and reached 70% -80% confluence, were digested, resuspended in DMEM/high sugar medium (Hyclone, SH 30243.01) containing 10% FBS and the cell density was adjusted to the desired. Low suction in U shapemu.L of cell suspension was added to each well of a 96-well plate (Corning, CLS7007-24 EA) at a cell density of 1000 cells/well. After centrifugation of the cell plates at 2500 rpm for 5 minutes, they were subjected to 37℃and 5% CO ₂ Culturing overnight in an incubator. The next day, 20mM test compound in DMSO was diluted with DMSO to a first concentration of 0.2mM, then diluted with a 5-fold gradient for a total of 9 concentration points, and control wells were DMSO. The gradient diluted compounds were then further diluted 20-fold with medium. The final concentration of the test compound after dilution by adding 10. Mu.L of culture medium to each well of the cell plate was 9 concentration points at 1. Mu.M, 5-fold gradient dilution. Cell wells containing 0.5% DMSO were set as vehicle control wells, and wells with medium and 0.5% DMSO alone were blank control wells. Compound concentrations and control wells were each provided with multiple wells, with final DMSO concentration per well of 0.5%. After centrifugation of the cell plates at 2500 rpm for 3 min, they were subjected to 37℃and 5% CO ₂ Culturing in an incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed, and 50. Mu.L of the luminescent cell activity detection reagent CellTiter-3DCell Viability Assay (Promega, G9683), shaking at room temperature for 25 min in the absence of light, and transferring 100 μL to white opaque OPTIPLate per well after up-and-down pipetting with a pipettor ^TM -96 well plates (PerkinElmer, 6005290) and luminescence signal values were read using a multi-function microplate reader (PerkinElmer, enVision 2105).

The inhibition was calculated using the following formula: inhibition ratio = (luminescence value _{Vehicle control well} -luminescence value _{Test compounds} ) (luminescence value) _{Vehicle control well} -luminescence value _{Blank control wells} ) X 100%. Plotting the concentration of each compound against the corresponding inhibition rate using GraphPad Prism software and calculating the IC of the compound ₅₀ Values. The results are shown in Table 2 below.

TABLE 2 3D proliferation inhibition Activity data for GP2D cells

Conclusion: the compound disclosed by the disclosure has a better inhibition effect on 3D proliferation of GP2D cells.

Test example 3: inhibition of SW620 cell 3D proliferation by compounds of the present disclosure

On the first day of the experiment, SW620 cells, which grew well and reached 70% -80% confluence, were digested, resuspended in leibeovitz's L-15 (Gibco, 11415064) medium containing 10% FBS, and the cell density was adjusted to the desired one. 90. Mu.L of cell suspension was added per well in U-shaped low adsorption 96 well plates (Corning, CLS7007-24 EA) at a cell density of 1000 cells/well. Centrifuging the cell plate at 2500 rpm for 5 min, and standing at 37deg.C without CO ₂ Culturing overnight in an incubator. The next day, 20mM test compound in DMSO was diluted with DMSO to a first concentration of 2mM, then diluted with a 5-fold gradient for a total of 9 concentration points, and control wells were DMSO. The gradient diluted compounds were then further diluted 20-fold with medium. The final concentration of the test compound after dilution by adding 10. Mu.L of culture medium to each well of the cell plate was 9 concentration points of 10. Mu.M, 5-fold gradient dilution. Cell wells containing 0.5% DMSO were set as vehicle control wells, and wells with medium and 0.5% DMSO alone were blank control wells. Compound concentrations and control wells were each provided with multiple wells, with final DMSO concentration per well of 0.5%. Centrifuging the cell plate at 2500 rpm for 3 min, and standing at 37deg.C without CO ₂ Culturing in an incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed, and 50. Mu.L of the luminescent cell activity detection reagent CellTiter-3DCell Viability Assay (Promega, G9683), shaking at room temperature for 25 min in the absence of light, and transferring 100 μL to white opaque OPTIPLate per well after up-and-down pipetting with a pipettor ^TM -96 well plates (PerkinElmer, 6005290) and luminescence signal values were read using a multi-function microplate reader (PerkinElmer, enVision 2105).

The inhibition was calculated using the following formula: inhibition ratio = (luminescence value _{Vehicle control well} -luminescence value _{Test compounds} ) (luminescence value) _{Vehicle control well} -luminescence value _{Blank control wells} ) X 100%. According to the GraphPad Prism softwareCompound concentrations were plotted against the corresponding inhibition ratios and IC of the compounds was calculated ₅₀ The values are shown in Table 3.

Data on 3D proliferation inhibitory Activity of Compounds of Table 3 on SW620 cells

Conclusion: the compound disclosed by the disclosure has a better inhibition effect on SW620 cell 3D proliferation.

Test example 4: biological evaluation of MIAPaCa-2 cell 3D proliferation assay

On the first day of the experiment, MIA PaCa-2 cells, which grew well and reached 70% -80% confluence, were digested, resuspended in DMEM/HIGH GLUCOSE (GE, SH 30243.01) medium containing 10% FBS and 2.5% horse serum, and the cell density was adjusted to the desired. 90. Mu.L of cell suspension was added per well in U-shaped low adsorption 96 well plates (Corning, CLS7007-24 EA) at a cell density of 1000 cells/well. After centrifugation of the cell plates at 2500 rpm for 5 minutes, they were subjected to 37℃and 5% CO ₂ Culturing overnight in an incubator. The next day, 20mM test compound in DMSO was diluted with DMSO to a first concentration of 2mM, then diluted with a 5-fold gradient for a total of 9 concentration points, and control wells were DMSO. The gradient diluted compounds were then further diluted 20-fold with medium. The final concentration of the test compound after dilution by adding 10. Mu.L of culture medium to each well of the cell plate was 9 concentration points of 10. Mu.M, 5-fold gradient dilution. Cell wells containing 0.5% DMSO were set as vehicle control wells, and wells with medium and 0.5% DMSO alone were blank control wells. Compound concentrations and control wells were each provided with multiple wells, with final DMSO concentration per well of 0.5%. After centrifugation of the cell plates at 2500 rpm for 3 min, they were subjected to 37℃and 5% CO ₂ Culturing in an incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed, and 50. Mu.L of the luminescent cell activity detection reagent CellTiter-3D Cell Viability Assay (Promega, G9683), shaking at room temperature for 25 min in the absence of light, and transferring 100 μL to white opaque OPTIPLate per well after up-and-down pipetting with a pipettor ^TM -96 well plates (PerkinElmer, 6005290) and luminescence signal values were read using a multi-function microplate reader (PerkinElmer, enVision 2105).

The inhibition was calculated using the following formula: inhibition ratio = (luminescence value _{Vehicle control well} -luminescence value _{Test compounds} ) (luminescence value) _{Vehicle control well} -luminescence value _{Blank control wells} ) X 100%. Plotting the concentration of each compound against the corresponding inhibition rate using GraphPad Prism software and calculating the IC of the compound ₅₀ Values. The results are shown in Table 4 below.

TABLE 4 inhibitory Activity of the compounds of the present disclosure on 3D proliferation of MIA PaCa-2 cells

Conclusion: the compounds of the present disclosure have an inhibitory effect on MIA PaCa-2 cell 3D proliferation.

Test example 5: biological evaluation of MKN1 cell 3D proliferation inhibition experiment

On the first day of the experiment, MKN1 cells, which grew well and reached 70% -80% confluence, were digested, resuspended in RPMI 1640 (Hyclone, SH 30809.01) medium containing 10% FBS, and the cell density was adjusted to the desired. 90. Mu.L of cell suspension was added per well in U-shaped low adsorption 96 well plates (Corning, CLS7007-24 EA) at a cell density of 1000 cells/well. After centrifugation of the cell plates at 2500 rpm for 5 minutes, they were subjected to 37℃and 5% CO ₂ Culturing in an incubator for 24 hours. The next day, 20mM test compound in DMSO was diluted with DMSO to a first concentration of 2mM, then diluted with a 5-fold gradient for a total of 9 concentration points, and control wells were DMSO. The gradient diluted compounds were then further diluted 20-fold with medium. The final concentration of the test compound after dilution by adding 10. Mu.L of culture medium to each well of the cell plate was 9 concentration points of 10. Mu.M, 5-fold gradient dilution. The arrangement comprisesCell wells with 0.5% DMSO were vehicle control wells, and wells with medium and 0.5% DMSO alone were blank control wells. Compound concentrations and control wells were each provided with multiple wells, with final DMSO concentration per well of 0.5%. After centrifugation of the cell plates at 2500 rpm for 3 min, they were subjected to 37℃and 5% CO ₂ Culturing in an incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed, and 50. Mu.L of the luminescent cell activity detection reagent CellTiter-3DCell Viability Assay (Promega, G9683), shaking at room temperature for 25 min in the absence of light, and transferring 100 μL to white opaque OPTIPLate per well after up-and-down pipetting with a pipettor ^TM -96 well plates (PerkinElmer, 6005290) and luminescence signal values were read using a multi-function microplate reader (PerkinElmer, enVision 2105).

The inhibition was calculated using the following formula: inhibition ratio = (luminescence value _{Vehicle control well} -luminescence value _{Test compounds} ) (luminescence value) _{Vehicle control well} -luminescence value _{Blank control wells} ) X 100%. Plotting the concentration of each compound against the corresponding inhibition rate using GraphPad Prism software and calculating the IC of the compound ₅₀ Values. The results are shown in Table 5 below.

TABLE 5 inhibitory Activity of the compounds of the present disclosure on MKN1 cell 3D proliferation

Conclusion: the compounds of the present disclosure have an inhibitory effect on MKN1 cell 3D proliferation.

Claims

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

wherein:

G ⁰ selected from O, S, S (O), S (O) ₂ 、CR ^G0a R ^G0b And NR ^G0c ；

Q is N or CR ^2a ；

Ring a is aryl or heteroaryl;

ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

l is selected from single bond, O and NR ^e ；

R ^G0a 、R ^G0b 、R ^G1a 、R ^G1b 、R ^G1c And R is ^G1d The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, and heterocyclyl; alternatively, R ^G1a 、R ^G1b Forms a cycloalkyl group together with the attached carbon atom; alternatively, R ^G1c 、R ^G1d Forms a cycloalkyl group together with the attached carbon atom;

z1 is 0 or 1;

z2 is 0 or 1;

r is 0, 1, 2 or 3;

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

t is 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein G ¹ Is CH ₂ 。

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G ⁰ Is O.

4. A compound according to any one of claims 1 to 3, which is a compound represented by the general formula (II):

wherein a is 0, 1, 2, 3 or 4;

ring a, ring B, Q, L, R ^1a 、R ^1b 、R ^1e 、R ^1f 、R ³ 、R ^4a 、R ^5a 、R ^5b 、R ⁶ R and t are as defined in claim 1.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Q is N.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring a is naphthyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3-to 8-membered heterocyclyl; preferably, ring B isOr morpholinyl.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ^4a Is a hydrogen atom or a halogen.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein r is 1 or 3.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein L is O.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R ^1a 、R ^1b 、R ^1e 、R ^1f Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and hydroxy.

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein each R ³ Identical or different and are each independently selected from halogen, C _1-6 Alkyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, hydroxy, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl.

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ^5a And R is ^5b Is a hydrogen atom; or R is ^5a 、R ^5b Together with the attached carbon atoms, form a 3-to 6-membered cycloalkyl group.

14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each R ⁶ The same or different, and are each independently halogen.

15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is a compound of:

16. a compound represented by the general formula (I' a):

Wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

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

G ⁰ 、G ¹ ring a, ring B, Q, L, R ^1a 、R ^1b 、R ^1c 、R ^1d 、R ^1e 、R ^1f 、R ^1g 、R ^1h 、R ³ 、R ^4a 、R ^5a 、R ^5b 、R ⁶ R and t are as defined in claim 1.

17. The compound of claim 16, or a salt thereof, which is a compound of:

18. a process for preparing a compound of formula (I') or a pharmaceutically acceptable salt thereof, which comprises:

wherein,

R ^y is a hydroxyl protecting group; preferably MOM;

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

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for inhibiting KRAS wild-type and/or KRAS mutant activity; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations.

21. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition mediated by KRAS wild-type and/or KRAS mutant; the KRAS mutant is preferably selected from one or more of KRAS G12A, G C, G12D, G12V, G12R, G12S, G D and Q61H mutations.

22. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for the treatment and/or prophylaxis of cancer, preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gall bladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibromas, gliomas, neuroblastomas and glioblastomas; more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.