CN115385937A

CN115385937A - Pyrimido-cycloalkyl compounds, preparation method and medical application thereof

Info

Publication number: CN115385937A
Application number: CN202210570041.9A
Authority: CN
Inventors: 李心; 黄崧; 董怀德; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-05-25
Filing date: 2022-05-24
Publication date: 2022-11-25

Abstract

The disclosure relates to pyrimido-cycloalkyl compounds, methods for their preparation and their use in medicine. Specifically, the disclosure relates to a pyrimido cycloalkyl compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound as a therapeutic agent, especially an application of the compound in preparing a drug for inhibiting KRAS G12D. Wherein each group in the general formula (I) is defined in the specification.

Description

Pyrimido-cycloalkyl compounds, preparation method thereof and application thereof in medicines

Technical Field

The disclosure belongs to the field of medicines, and relates to a pyrimido-cycloalkyl compound, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to pyrimido cycloalkyl compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds in preparation of drugs for inhibiting KRAS G12D.

Background

RAS is one of the most mutation-frequent oncogenes in tumors, and about 30% of human malignancies are associated with mutations in the RAS gene. The RAS family includes KRAS, NRAS and HRAS, with KRAS mutations being most common, accounting for approximately 85%. KRAS mutations are common in solid tumors, with high frequency mutations in all three human fatal cancers, lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). In KRAS gene mutation, 97% of amino acid residues 12 or 13 are mutated, and G12D is an important mutation. Data analysis on the European and American population shows that: in pancreatic, colorectal and non-small cell lung cancers, G12D mutations account for 36%, 12% and 4% of patients, respectively.

After KRAS is activated, it regulates the functions of cell proliferation, survival, migration and metabolism through a plurality of downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM 1-RAc. After mutation of KRAS gene, the protein is continuously activated, resulting in continuous activation of downstream signaling pathways to promote tumorigenesis.

KRAS protein is considered as an unpageable drug target for a long time because of the surface lack of conventional small molecule binding sites and the ultrahigh affinity with guanylic acid, so that the KRAS protein is extremely difficult to inhibit. But based on the importance and prevalence of abnormal KRAS activation in cancer progression, KRAS has been and remains a very interesting target for drug development. At present, in addition to the KRAS G12C inhibitor, there is still a lack of KRAS inhibitors effective against other mutations, so that most KRAS mutated patients remain drug-free. G12D, as a mutant widely expressed in various tumors, has important clinical significance in developing an inhibitor against the same.

Related patent applications which have been disclosed so far are WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2019155399A1 and the like.

Disclosure of Invention

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

wherein:

G ² is NR ^d ；

Ring a is aryl or heteroaryl;

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

l is selected from the group consisting of a single bond, O and NR ^e ；

R ¹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _u -NR ^f R ^g Hydroxyl and hydroxyalkyl;

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

R ² 、R ^2c To the carbon atom to which it is attached, or R ^2a 、R ^2b To the carbon atom to which it is attached, or R ^4a 、R ^4b Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group;

R ³ and R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _w -NR ^j R ^k Nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ are the same or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl group, haloalkyl group, cyano group, hydroxy group and hydroxyalkyl group;

R ^d 、R ^e 、R ^f 、R ^g 、R ^h 、R ⁱ 、R ^j and R ^k Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

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

m is 0, 1 or 2;

n is 0 or 1;

r is 0, 1 or 2;

p is 0, 1,2,3, 4 or 5;

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

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

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

wherein

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

G ² ring A, ring B, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, r and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or (I-1), or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably, ring a is phenyl or naphthyl; further preferred is naphthyl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein ring B is a 7-to 10-membered fused heterocyclic group, R ⁶ Can be substituted at any position on the ring B; preferably, ring B is

R ⁶ Can be substituted at any position on the ring B; it is further preferred that the first and second liquid crystal compositions,

is composed of

R ⁶ As defined in formula (I); more preferably still, the first and second liquid crystal compositions are,

is composed of

R ⁶ Is halogen; most preferably, ,

is composed of

R ⁶ Is halogen (preferably F).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or (I-1) or a pharmaceutically acceptable salt thereofA salt wherein ring a is phenyl or naphthyl; and/or ring B is

R ⁶ Can be substituted at any position of the ring B.

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

wherein

G ² Ring A, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, q, r and t are as defined in formula (I).

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

wherein

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

G ² ring A, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, r and t are as defined in formula (I).

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

Is composed of

R ³ The definition is as defined in formula (I); preferably, R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, hydroxy, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; more preferably, R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, hydroxy and cyclopropyl; further preferably, R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, ethyl, hydroxy and cyclopropyl; most preferably, R ³ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an ethyl group and a hydroxyl group.

In some embodiments of the present disclosure, the compound of formula (I), (I-1), (II), or (II-1), or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl and R is ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, hydroxy, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, ring A is phenyl and R is ³ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group and a 3 to 8 membered cycloalkyl group; more preferably, ring A is phenyl and R ³ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group and a cyclopropyl group.

In some preferred embodiments of the present disclosure, the compound of formula (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; preferably, ring a is phenyl or naphthyl; further preferred is naphthyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ^d Is a hydrogen atom or C _1-6 An alkyl group; preferably, R ^d Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein n is 0.

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

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ² And R ^2c Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 Haloalkyl, or R ² 、R ^2c Together with the carbon atom to which they are attached form a 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl group; preferably, R ² And R ^2c Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; more preferably, R ² And R ^2c Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ^2a And R ^2b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 Haloalkyl, or R ^2a 、R ^2b Together with the carbon atom to which they are attached form a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group; preferably, R ^2a And R ^2b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; more preferably, R ^2a And R ^2b Are the same or different and are each independently a hydrogen atom or a methyl group; most preferably, R ^2a Is a hydrogen atom, R ^2b Is a methyl group.

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

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ^2b Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ^2b Is C _1-6 An alkyl group;more preferably methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ^4a And R ^4b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 Haloalkyl, or R ^4a 、R ^4b Together with the carbon atom to which they are attached form a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group; preferably, R ^4a And R ^4b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ^2a And R ^2b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 Haloalkyl, or R ^2a 、R ^2b Together with the carbon atom to which they are attached form a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group; and/or R ^4a And R ^4b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 Haloalkyl, or R ^4a 、R ^4b Together with the carbon atom to which they are attached form a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group; preferably, R ^2a And R ^2b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; and/or R ^4a And R ^4b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein G ² Is NH.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein L is O.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ^e To hydrogen atomsSeed or C _1-6 An alkyl group; preferably, R ^e Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, cyano, amino, - (CH) ₂ ) _u -NR ^f R ^g Hydroxy and C _1-6 Hydroxyalkyl radical, R ^f And R ^g Are the same or different and are each independently a hydrogen atom or C _1-6 Alkyl, u is 0 or 1; preferably, R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; further preferably, R ¹ Is a hydrogen atom.

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

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I-1) or (II-1) orA pharmaceutically acceptable salt thereof, wherein R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _w -NR ^j R ^k And C _1-6 Hydroxyalkyl radical, R ^j And R ^k Are the same or different and are each independently a hydrogen atom or C _1-6 Alkyl, w is 0 or 1; preferably, R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl; more preferably, R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl and cyclopropyl; most preferably, R ³ Are the same or different and are each independently selected from the group consisting of hydrogen atoms, halogens, ethyl groups, and cyclopropyl groups.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein R ⁵ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R ⁵ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl, hydroxy and C _1-6 A hydroxyalkyl group; further preferably, R ⁵ Is a hydrogen atom.

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

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1, preferably 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1, preferably 1.

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

In some preferred embodiments of the present disclosure, the compound of formula (I-1) or (II-1), or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein t is 1 or2, preferably 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein v is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (II) or (II-1), or a pharmaceutically acceptable salt thereof, wherein w is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein G ² Is NH; ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl; l is O; p is 1; r ¹ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is ² 、R ^2c 、R ^2a 、R ^2b 、R ^4a And R ^4b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; or R ² 、R ^2c To the carbon atom to which it is attached, or R ^2a 、R ^2b To the carbon atom to which it is attached, or R ^4a 、R ^4b Together with the carbon atom to which they are attached form a 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl group; q is 1 or 2; r ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, hydroxy and cyclopropyl; r is 0 or 1; r ⁵ Selected from hydrogen atoms, C _1-6 Alkyl, hydroxy and C _1-6 A hydroxyalkyl group; t is 1; r ⁶ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; m is 1; and n is 0.

In some embodiments of the disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein G ² Is NH; ring a is phenyl or naphthyl; l is O; p is 1; r ¹ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is ² 、R ^2c 、R ^2a 、R ^2b 、R ^4a And R ^4b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; q is 1 or 2; r is ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, hydroxy and cyclopropyl; r is 0 or 1; r is ⁵ Selected from hydrogen atoms, C _1-6 Alkyl, hydroxy and C _1-6 A hydroxyalkyl group; t is 1; r ⁶ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; m is 1; and n is 0.

In some embodiments of the disclosure, the compound of formula (II-1) or a pharmaceutically acceptable salt thereof, wherein G ² Is NH; ring a is phenyl or naphthyl; l is O; p is 1; r ¹ Selected from hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; r is ² 、R ^2c 、R ^2a 、R ^2b 、R ^4a And R ^4b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; q is 0, 1 or 2; r is ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl and cyclopropyl; r is 0 or 1; r ⁵ Selected from hydrogen atom, C _1-6 Alkyl, hydroxy and C _1-6 A hydroxyalkyl group; t is 1; r ⁶ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group; m is 1; and n is 0.

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

another aspect of the disclosure relates to a compound of formula (IA) or a salt thereof,

wherein,

r is an amino protecting group; preferably Boc;

ring A, ring B, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, q, r and t are as defined in formula (I).

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

wherein,

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

R ⁰ is a hydrogen atom or a hydroxyl protecting group; the hydroxyl protecting group is preferably MOM;

r is an amino protecting group; preferably Boc;

ring A, ring B, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, r and t are as defined in the general formula (I-1).

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

wherein,

r is an amino protecting group; preferably Boc;

ring A, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, q, r and t are as defined in formula (II).

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

wherein,

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

r is an amino protecting group; preferably Boc;

rings A, L、R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, r and t are as defined in the general formula (II-1).

In some preferred embodiments of the present disclosure, the compound of formula (I-1A) or (II-1A), or a pharmaceutically acceptable salt thereof, wherein R ⁰ Is MOM or Bn.

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

another aspect of the present disclosure relates to a method of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising:

carrying out deprotection reaction on the compound of the general formula (IA) or salt thereof to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof; optionally, when R ³ And/or R ⁶ When the group contains a protecting group, the deprotection reaction may further comprise removing R before, simultaneously with or after the deprotection reaction ³ And/or R ⁶ A step of protecting groups on the group; preferably, the protecting group is a hydroxyl protecting group MOM;

wherein,

r is an amino protecting group; preferably Boc;

G ² is NH;

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

when R is ⁰ When the hydrogen atom is a hydrogen atom, removing the amino protecting group R from the compound of the general formula (I-1A) or a salt thereof to obtain a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof;

when R is ⁰ When the protecting group is a hydroxyl group, the protecting group R is removed from the compound of the formula (I-1A) or a salt thereof ⁰ And an amino protecting group R to give a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof;

wherein,

r is an amino protecting group; preferably Boc;

G ² is NH;

ring A, ring B, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, q, r and t are as defined in the general formula (I-1).

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

subjecting the compound of formula (IIA) or a salt thereof to a deprotection reaction to give a compound of formula (II) or a salt thereofA pharmaceutically acceptable salt; optionally, when R ³ And/or R ⁶ When the group contains a protecting group, the deprotection reaction may further comprise removing R before, simultaneously with or after the deprotection reaction ³ And/or R ⁶ A step of protecting groups on the group; preferably, the protecting group is a hydroxyl protecting group MOM;

wherein R is an amino protecting group; preferably Boc;

G ² is NH;

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

when R is ⁰ When the hydrogen atom is a hydrogen atom, removing the amino protecting group R from the compound of the general formula (II-1A) or a salt thereof to obtain a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof;

when R is ⁰ In the case of a hydroxyl-protecting group, the compound of the formula (II-1A) or a salt thereof is freed from the hydroxyl-protecting group R ⁰ And an amino protecting group R to give a compound of formula (II-1) or a pharmaceutically acceptable salt thereof;

wherein,

r is an amino protecting group; preferably Boc;

G ² is NH;

ring A, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, q, r and t are as defined in the general formula (II-1).

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

The disclosure further relates to the use of a compound of general formula (I), (I-1), (II-1), or shown in table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting KRAS G12D.

The present disclosure further relates to the use of a compound of general formula (I), (I-1), (II-1), or shown in table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of a disease or disorder, which is cancer; the disease or condition is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal 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 tumors, 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 preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

The present disclosure further relates to a method of inhibiting KRAS G12D comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (II-1), or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (II-1), or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or disorder is cancer; the disease or condition is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal 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 tumors, 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 is a cancer selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

The present disclosure further relates to a compound of general formula (I), (I-1), (II-1) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure further relates to a compound of general formula (I), (I-1), (II-1) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting KRAS G12D.

The present disclosure further relates to a compound of general formula (I), (I-1), (II-1) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or disorder, wherein said disease or disorder is cancer; the disease or condition is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal 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 tumors, 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 is a cancer selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

The diseases or disorders described in this disclosure are diseases or disorders that are treated and/or prevented by inhibiting KRAS G12D.

The colorectal cancer according to the present disclosure is preferably a colon cancer or a rectal cancer.

Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; the soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyoma, leiomyosarcoma, dedifferentiated liposarcoma, polymorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; the lymphoma is selected from hodgkin's disease and non-hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B cell lymphoma, follicular center lymphoma, marginal zone B cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T cell lymphoma); the liver cancer is preferably hepatocellular carcinoma; lung cancer (also known as bronchogenic lung cancer) is selected from non-small cell lung cancer (NSCLC), small Cell Lung Cancer (SCLC) and squamous cell carcinoma; kidney cancer selected from renal cell carcinoma, clear cell and nephroeosinophilic tumor; the 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 may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, 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), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

As a general guide, the active compound is preferably administered in a unit dose, or in a manner such that the patient can self-administer the compound in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder, or liquid. Suitable unit doses may be from 0.1 to 1000mg.

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

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, 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 oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the 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 a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed 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 the oil phase, the injection or microemulsion being injectable in the bloodstream of the patient by local bolus injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the model Deltec CADD-PLUS. TM. 5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into 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 therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of the drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or 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 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group having 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 an alkyl group having 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl). <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- ,2,2- , </xnotran> And various branched chain isomers thereof, and the like. The alkyl group may be substituted or unsubstituted and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from the group consisting of a D atom, a halogen, an alkoxy group,One or more of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon radical, which is the residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and which is a straight or branched chain radical containing from 1 to 20 carbon atoms, preferably having from 1 to 12 (e.g., 1,2,3, 4,5, 6,7,8, 9, 10, 11, and 12) carbon atoms (i.e., C) _1-12 Alkylene), more preferably alkylene having 1 to 6 carbon atoms (i.e., C) _1-6 Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ -), 1-ethylene (-CH (CH) ₃ ) -), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) -), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) -), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ -) 1, 4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. The alkylene group may be substituted or unsubstituted and when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl (i.e., C) groups having 2 to 12 (e.g., 2,3, 4,5, 6,7,8, 9, 10, 11, and 12) carbon atoms are preferred _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. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxyOne or more of aryl, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl (i.e., C) groups having 2 to 12 (e.g., 2,3, 4,5, 6,7,8, 9, 10, 11, and 12) carbon atoms are preferred _2-12 Alkynyl), more preferably an alkynyl group containing 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, and the cycloalkyl ring contains 3 to 20 carbon atoms (i.e., 3 to 20-membered cycloalkyl groups), preferably 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 groups), further preferably 3 to 8 (e.g., 3, 4,5, 6,7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl groups), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl groups). 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 polycyclic group (i.e., a 5 to 20 membered spirocycloalkyl group) having a single ring with one carbon atom (referred to as a spiro atom) in common between the rings, which may contain one or more double bonds. Preferably 6 to 14 membered (i.e. 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (e.g. 7,8, 9 or 10 membered) (i.e. 7 to 10 membered spirocycloalkyl). Spirocycloalkyl groups are classified into mono-spirocycloalkyl groups and multi-spirocycloalkyl groups (e.g., bis-spirocycloalkyl groups, etc.), preferably mono-spirocycloalkyl groups and bis-spirocycloalkyl groups, according to the number of spiro atoms shared between rings. 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 spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring alkyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered fused ring alkyl) all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings can contain one or more double bonds. Preferably 6 to 14 (i.e. 6 to 14 fused cycloalkyl) members, more preferably 7 to 10 (e.g. 7,8, 9 or 10) (i.e. 7 to 10 fused cycloalkyl) members. They can be divided into bicyclic and polycyclic (e.g., tricyclic, tetracyclic, etc.) fused cycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, 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/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 bicyclic fused cycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered bridged cycloalkyl), all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14 (i.e. 6 to 14 bridged cycloalkyl), more preferably 7 to 10 (e.g. 7,8, 9 or 10) (i.e. 7 to 10 bridged cycloalkyl). They may be classified into bicyclic and polycyclic (e.g., tricyclic, tetracyclic, etc.) bridged cycloalkyl groups according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

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

Etc.; preferably, it is

Cycloalkyl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available 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. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from the group consisting of D atoms, 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 mono-or polycyclic cyclic substituent comprising from 3 to 20 (e.g., 3, 4,5, 6,7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3-to 20-membered heterocyclyl group) wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), but does not include a ring moiety of-O-, -O-S-, or-S-, with the remaining ring atoms being carbon. Preferably 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 groups) 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) or from 6 to 14 ring atoms (e.g., 6,7,8, 9, 10, 11, 12, 13 and 14), of which 1-3 are heteroatoms (e.g., 1,2 and 3); more preferably 3 to 8 ring atoms (i.e. 3 to 8 membered heterocyclyl), of which 1-3 (e.g. 1,2 and 3) are heteroatoms; most preferably, it contains 5 or 6 ring atoms (i.e., a 5 or 6 membered heterocyclyl group), of which 1-3 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 (i.e., a 5 to 20 membered spiroheterocyclyl group) in which one atom (referred to as a spiro atom) is shared between single rings, 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 a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14 (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 (e.g. 7,8, 9 or 10) membered (i.e. 7 to 10 membered spiroheterocyclyl). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group and a poly-spiro heterocyclic group (e.g., a double-spiro heterocyclic group, etc.) according to the number of spiro atoms shared between rings, and the mono-spiro heterocyclic group and the double-spiro heterocyclic group are preferable. 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/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered spiroheterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered fused heterocyclyl) 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 the rings may contain one or more double bonds in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 (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 (e.g., 7,8, 9 or 10) membered (i.e., 7 to 10 membered fused heterocyclyl). They can be divided into bicyclic and polycyclic (e.g., tricyclic, tetracyclic, etc.) fused heterocyclic groups according to the number of constituting rings, and are preferably bicyclic or tricyclic, 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/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 bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered bridged heterocyclyl) polycyclic heterocyclic group in which any two rings share two atoms not directly attached, 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., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 (e.g. 6,7,8, 9, 10, 11, 12, 13 and 14) membered (i.e. 6 to 14 bridged heterocyclyl), more preferably 7 to 10 (e.g. 7,8, 9 or 10) membered (i.e. 7 to 10 bridged heterocyclyl). They may be divided into bicyclic and polycyclic (e.g., tricyclic, tetracyclic, etc.) bridged heterocyclic groups depending on the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

and so on.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available 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 "aryl" refers to a 6 to 14 membered, all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group (i.e., a 6 to 14 membered aryl group) having a conjugated pi-electron system, preferably a 6 to 10 membered (i.e., 6 to 10 membered aryl group), such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, 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, may be substituted at any available point of attachment, with 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 "heteroaryl" refers to a heteroaromatic system (i.e., 5-to 14-membered heteroaryl) 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. The heteroaryl group is preferably a 5-to 10-membered (e.g., 5,6,7,8, 9 or 10-membered) (i.e., 5-to 10-membered heteroaryl), further preferably 8-to 10-membered (e.g., 8, 9 or 10-membered), more preferably 5-or 6-membered (i.e., 5-or 6-membered heteroaryl), for example, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with 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 above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived by removal of one hydrogen atom from the parent ring atom, or those derived by removal of two hydrogen atoms from the parent ring atom or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the reaction is carried out elsewhere in the molecule. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl (Boc), acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro. Preferably, the amino protecting group is Boc.

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

The term "cycloalkyloxy" refers to cycloalkyl-O-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 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 "ammoniaThe radical "means-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means "= 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.

Bn means benzyl.

MOM refers to methoxymethyl.

Boc means t-butyloxycarbonyl.

TIPS refers to triisopropylsilyl groups.

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 present 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 interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. An example of a keto-enol equilibrium is between A and B as shown below.

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

The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in a molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then diastereoisomeric resolution is performed by a conventional method known in the art to obtain a pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds described in this disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be made of

Or

Or at the same time contain

And

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

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. Term "Isotopic derivatives "refer to compounds in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, 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., preferably deuterium.

Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs 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, where replacement by deuterium may be partial or complete, partial replacement by deuterium meaning replacement of at least one hydrogen by at least one deuterium.

When a position is specifically designated as deuterium, D, the position is understood to be deuterium with an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds of examples may have a natural abundance of deuterium greater than at least 1000 times the abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times the abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times the abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times the abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times the abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times the abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times the abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times the abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times the abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times the abundance of deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times the abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times the abundance of deuterium (i.e., at least 97% deuterium incorporation), at least 99.e., at least 99.99% deuterium incorporation of deuterium, or more than 99.99.99.99.3.99% deuterium incorporation of deuterium.

"optionally" or "optionally" means that the subsequently described event or circumstance can, 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, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen or cyano.

"substituted" means that one or more, preferably 1 to 6, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.

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

"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group 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 acids as well as organic acids.

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

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 effective for the intended use.

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

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

Synthesis of the Compounds of the disclosure

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

scheme one

The invention discloses a method for preparing a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

carrying out deprotection reaction on the compound of the general formula (IA) or salt thereof under acidic condition to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof; optionally, when R ³ And/or R ⁶ When a protecting group is present on the group, before, simultaneously with or after the deprotection reactionAlso includes removing R under acidic or basic conditions ³ And/or R ⁶ A step of protecting groups on the group; preferably, the protecting group is a hydroxyl protecting group MOM;

wherein R is an amino protecting group; preferably Boc;

G ² is NH;

Scheme two

A process for producing a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof, which comprises:

when R is ⁰ When the hydrogen atom is adopted, the amino protecting group R of the compound of the general formula (I-1A) or the salt thereof is removed under the acidic condition to obtain the compound of the general formula (I-1) or the pharmaceutically acceptable salt thereof;

when R is ⁰ In the case of a hydroxyl-protecting group, the compound of the formula (I-1A) or a salt thereof is freed from the hydroxyl-protecting group R under acidic conditions ⁰ And an amino protecting group R to give a compound of the general formula (I-1) or a pharmaceutically acceptable salt thereof;

wherein,

r is an amino protecting group; preferably Boc;

G ² is NH;

Scheme three

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

carrying out deprotection reaction on the compound of the general formula (IIA) or salt thereof under an acidic condition to obtain a compound of a general formula (II) or pharmaceutically acceptable salt thereof; optionally, when R ³ And/or R ⁶ When a protecting group is present on the group, the deprotection reaction may further comprise removing R under acidic or basic conditions before, simultaneously with or after the deprotection reaction ³ And/or R ⁶ A step of protecting groups on the group; preferably, the protecting group is a hydroxyl protecting group MOM;

wherein R is an amino protecting group; preferably Boc;

G ² is NH;

Scheme four

A process for producing a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, which comprises:

when R is ⁰ When the hydrogen atom is a hydrogen atom, removing the amino protecting group R from the compound of the general formula (II-1A) or a salt thereof under acidic conditions to obtain a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof;

when R is ⁰ When the protecting group is a hydroxyl group, the compound of the formula (II-1A) or a salt thereof is subjected to removal of the protecting group R under acidic conditions ⁰ And an amino protecting group R to give a compound of the general formula (II-1) or a pharmaceutically acceptable salt thereof;

wherein,

r is an amino protecting group; preferably Boc;

G ² is NH;

Reagents that provide 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 acid includes but is not limited to hydrogen chloride, hydrochloric acid dioxane solution, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably dioxane hydrochloride solution.

The reagents in the above synthesis schemes that provide basic conditions include organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride or 1, 8-diazabicycloundec-7-ene, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide.

The reaction of the above step is preferably carried out in a solvent including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

Detailed Description

The following examples are presented to further illustrate the present disclosure, but are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds being determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) at 10 ^-6 The units in (ppm) are given. NMR was measured using Bruker AVANCE-400 NMR spectrometer or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

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

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

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

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, agilent HPLC 1200VWD and Waters HPLC e2695-2489 liquid chromatographs.

Chiral HPLC analytical determination Agilent 1260DAD HPLC was used.

High Performance liquid preparation preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281.

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

The CombiFlash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plate adopts a cigarette platform 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.

Silica gel column chromatography generally uses 200-300 mesh silica gel from Futai Huanghai silica gel as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenator.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds, and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: the volume ratio of the n-hexane/ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

4- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Oct-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methyl-5, 6,7, 8-tetrahydroquinazolin-7-yl) naphthalen-2-ol (diastereomer mixture) 1

First step of

3- (3- (benzyloxy) naphthalen-1-yl) -4-methylcyclohex-1-one (mixture of diastereomers) 1c

The compounds 2- (3- (benzyloxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan 1a (1g, 2.77mmol), (±) -4-methylcyclo-2-en-1-one 1b (310mg, 2.81mmol, shanghai shao), potassium trimethylsilanolate (713mg, 5.55mol, shanghai shao), chlororhodium (I) dimer (100mg, 202.8 μmol, shanghai Biao) were dissolved in 10ml of a mixed solution of 1, 4-dioxane and water (V: V = 5). The reaction was carried out at 80 ℃ for 14 hours under a nitrogen atmosphere, the reaction mixture was cooled to room temperature, diluted with 30mL of water, extracted 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 1c (800 mg, yield: 83.6%). MS m/z (ESI) 345.2[ m +1].

Second step of

4- (3- (benzyloxy) naphthalen-1-yl) -5-methyl-2-oxocyclohexane-1-carboxylic acid ethyl ester (mixture of diastereomers) 1d

Compound 1c (0.8g, 2.32mmol), diethyl carbonate (2.4g, 20.31mmol, guo Yao) were dissolved in tetrahydrofuran (20 mL), sodium hydride (279mg, 6.97mmol,60% pure) was added, the mixture was heated to 70 ℃ for reaction at 2 hours, the reaction liquid was cooled to room temperature, a saturated aqueous ammonium chloride solution (20 mL) was added, extraction was conducted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1d (420 mg, yield: 43.4%). MS m/z (ESI) 417.2[ 2 ] M +1].

The third step

7- (3- (benzyloxy) naphthalen-1-yl) -6-methyl-5, 6,7, 8-tetrahydroquinazoline-2, 4 (1H, 3H) -dione (mixture of diastereomers) 1e

Compound 1d (420mg, 1.01mmol), urea (150mg, 2.49mmol), sodium methoxide (120mg, 2.22mmol) were dissolved in methanol (30 mL), and the reaction was refluxed for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1e (390 mg, yield: 93.7%). MS m/z (ESI) 413.2[ 2 ], M +1].

The fourth step

7- (3- (benzyloxy) naphthalen-1-yl) -2, 4-dichloro-6-methyl-5, 6,7, 8-tetrahydroquinazoline (mixture of diastereomers) 1f

Compound 1e (390mg, 945.50. Mu. Mol) was dissolved in phosphorus oxychloride (10 mL), reacted at 100 ℃ for 6 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give the title compound 1f (220 mg, yield: 51.7%).

MS m/z(ESI):448.9[M+1]。

The fifth step

(1R, 5S) -3- (7- (3- (benzyloxy) naphthalen-1-yl) -2-chloro-6-methyl-5, 6,7, 8-tetrahydroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (mixture of diastereomers) 1g

Compound 1f (100mg, 222.53. Mu. Mol), (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-8-carboxylic acid tert-butyl ester (50mg, 235.5291. Mu. Mol, jiangsu Aikang) and N, N-diisopropylethylamine (58mg, 448.76. Mu. Mol) were dissolved in N, N-dimethylformamide (5 mL) and reacted at 80 ℃ for 2 hours, the reaction solution was cooled to room temperature, diluted with 20mL of water, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure after removing the drying agent by filtration, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1g (110 mg, yield: 79%).

MS m/z(ESI):624.9[M+1]。

The sixth step

(1R, 5S) -3- (7- (3- (benzyloxy) naphthalen-1-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methyl-5, 6,7, 8-tetrahydroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (mixture of diastereomers) 1i

1g (110mg, 175.9. Mu. Mol) of the compound was dissolved in 1, 4-dioxane (5 mL), and sodium hydride (25mg, 625.0. Mu. Mol,60% purity) was added thereto, followed by stirring for 5 minutes, followed by addition of ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol for 1H (110mg, 175.94. Mu. Mol, hydrabamine) and reaction at 90 ℃ for 6 hours. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride (20 mL) was added, extraction was performed with ethyl acetate (20 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 1i (85 mg, yield: 64.5%)

MS m/z(ESI):748.2[M+1]。

Seventh step

(1R, 5S) -3- (2- (((2R, 7aS) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -7- (3-hydroxynaphthalen-1-yl) -6-methyl-5, 6,7, 8-tetrahydroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (mixture of diastereomers) 1j

Compound 1i (85mg, 113.6. Mu. Mol) was dissolved in 10mL of methanol, 10% palladium on carbon catalyst (wet) (50 mg) was added, hydrogen gas was substituted three times, the reaction mixture was stirred for 6 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated to give the title compound 1j (65 mg, yield: 86.9%) which was used in the next reaction without purification. MS m/z (ESI) 658.2[ 2 ], M +1].

The eighth step

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methyl-5, 6,7, 8-tetrahydroquinazolin-7-yl) naphthalen-2-ol (mixture of diastereomers) 1

Compound 1j (65mg, 98.8. Mu. Mol) was dissolved in 4mL of 4M dioxane hydrochloride solution, reacted with stirring for 2 hours, and the reaction mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium hydrogencarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -45%, flow rate: 30 mL/min) to give the title compound 1 (13 mg, yield: 23.5%). MS m/z (ESI) 558.2[ deg. ] M +1].

¹ H NMR(500MHz,MeOD):δ8.11-8.09(d,1H),7.69-7.68(d,1H),7.40-7.37(m,1H),7.32-7.29(m,1H),7.04-7.02(m,2H),5.37-5.35(m,1H),5.24(m,1H),4.27-4.24(m,1H),4.19-4.15(m,1H),4.10-4.05(m,1H),3.74-3.71(d,2H),3.63-3.62(m,2H),3.47-3.42(m,1H),3.26-3.18(m,3H),3.17-3.12(m,1H),3.08-2.99(m,2H),2.86(m,1H),2.75-2.71(m,1H),2.63-2.58(m,1H),2.33-2.18(m,5H),2.15-2.09(m,2H),2.02-1.79(m,3H),0.95-0.93(d,3H)。

Example 2

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methyl-5, 6,7, 8-tetrahydroquinazolin-7-yl) -5-fluoronaphthalen-2-ol (mixture of diastereomers) 2

Example 3

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydroquinazolin-7-yl) -5-ethylnaphthalen-2-ol (mixture of diastereomers) 3

Example 4

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydroquinazolin-7-yl) -5-fluoronaphthalene-2-ol (mixture of diastereomers) 4

First step of

(±) -3- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) cyclohex-1-one 4c

The compound 2- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan 4a (1g, 2.77mmol, prepared by the method disclosed in patent application "WO2021/041671" on page 522 of Example 282), cyclohex-2-en-1-one 4b (310mg, 2.81mmol, shanghai Yanhou), potassium phosphate (713mg, 5.55mol), (1,5-cyclooctadiene) chlororhodium (I) dimer (100mg, 202.8. Mu. Mol, obtained from Shanghai) was dissolved in 1 mL of a mixed solution of 1,4-dioxane and water (V: V = 5). The reaction was carried out at 80 ℃ for 14 hours under a nitrogen atmosphere, the reaction mixture was cooled to room temperature, diluted with 30mL of water, extracted 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 4c (800 mg, yield: 83.6%).

MS m/z(ESI):303.2[M+1]。

Second step of

(±) -4- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2-oxocyclohexane-1-carboxylic acid ethyl ester 4d

Compound 4c (0.8g, 2.32mmol) was dissolved in tetrahydrofuran (10 mL), after stirring at-78 ℃ for 2 minutes, a 1M solution of lithium bistrimethylsilyl amide in tetrahydrofuran (7 mL) was added, the reaction was stirred at the temperature for 1 hour, ethyl cyanoformate (2.4 g,20.31mmol, shaokao) was added, the reaction was stirred at the temperature for further 0.5 hour, the reaction solution was quenched by addition of water, extracted with ethyl acetate (20 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 4d (420 mg, yield: 43.4%).

MS m/z(ESI):375.2[M+1]。

The third step

(±) -7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydroquinazolin-4-ol 4e

Compound 4d (120mg, 320.5 μmol), S-methylisothiourea hemisulfate (270mg, 969.9 μmol, shanghai shao distal), sodium methoxide (105mg, 1.9mol) were dissolved in 5mL of a mixed solution of ethanol and water (V: V = 5. The reaction was allowed to react at 50 ℃ for 3 hours, the reaction mixture was cooled to room temperature, diluted with 10mL of water, extracted 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 4e (30 mg, yield: 23%). MS m/z (ESI) 401.2[ 2 ], M +1].

The fourth step

(±) -7- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydroquinazolin-4-yl trifluoromethanesulfonate 4f

Compound 4e (100mg, 250.9. Mu. Mol) was dissolved in 5mL of dichloromethane, N-diisopropylethylamine (100mg, 773.7. Mu. Mol), trifluoromethanesulfonic anhydride (85mg, 310.2. Mu. Mol) were added, the reaction was reacted at 0 ℃ for 2 hours, the reaction solution was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 4f (100 mg, yield: 75%).

MS m/z(ESI):533.2[M+1]。

The fifth step

(1R, 5S) -3- (7- (8-fluoro-3- (methoxymethyloxy) naphthalen-1-yl) -2- (methylthio) -5,6,7, 8-tetrahydroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4g

Compound 4f (40mg, 75.3. Mu. Mol), (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (20mg, 94.2. Mu. Mol, jiangsu Aikang) and N, N-diisopropylethylamine (60mg, 464.2. Mu. Mol) were dissolved in N, N-dimethylformamide (5 mL), reacted at 0 ℃ for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give 4g of the title compound (30 mg, yield: 67%).

MS m/z(ESI):595.2[M+1]。

The sixth step

(1R, 5S) -3- (7- (8-fluoro-3- (methoxymethyloxy) naphthalen-1-yl) -2- (methylsulfinyl) -5,6,7, 8-tetrahydroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 4h

Compound 4g (36mg, 60.5. Mu. Mol) was dissolved in ethyl acetate (5 mL), m-chloroperoxybenzoic acid (12mg, 69.5. Mu. Mol) was added, the reaction was stirred for 14 hours, the reaction solution was quenched with saturated aqueous sodium thiosulfate, washed with saturated aqueous sodium bicarbonate, and concentrated under reduced pressure by the organic phase to give the crude title compound 4h (36 mg, yield: 97%, the product was used in the next reaction without purification.

MS m/z(ESI):611.2[M+1]。

Step seven

(1R, 5S) -3- (7- (8-fluoro-3- (methoxymethyloxy) naphthalen-1-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methyloxy) -5,6,7, 8-tetrahydroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (diastereomer mixture) 4i

The crude compound 4H (37mg, 60.5. Mu. Mol), ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol 1H (20mg, 125.6. Mu. Mol, phenicol) was dissolved in toluene (3 mL), sodium tert-butoxide (14mg, 145.6. Mu. Mol) was added under ice bath, after stirring for 30 minutes while maintaining the temperature, saturated aqueous ammonium chloride solution was added and quenched, extracted with ethyl acetate (20 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 4i (20 mg, yield: 46%), which was used in the next step without purification.

MS m/z(ESI):706.2[M+1]。

The eighth step

Crude compound 4i (20mg, 28.3. Mu. Mol) was dissolved in 3mL of 4M dioxane hydrochloride solution, stirred and reacted for 1 hour, and the reaction solution was concentrated under reduced pressure and then purified by high performance liquid chromatography (Waters-2545, column: sharpSil-T C18, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium hydrogencarbonate) and acetonitrile, gradient ratio: acetonitrile 30% -45%, flow rate: 30 mL/min) to give title compound 4 (9 mg, yield: 56.5%). MS m/z (ESI) 562.2[ m +1].

¹ H NMR(500MHz,CD ₃ OD):δ7.50-7.49(d,1H),7.35-7.31(m,1H),7.09-7.06(d,2H),7.00-6.96(q,1H),5.35-5.24(d,2H),4.21-4.04(m,4H),3.72-3.69(m,1H),3.58-3.57(m,2H),3.39-3.37(m,2H),3.26-3.18(m,3H),3.06-2.98(m,2H),2.88-2.83(m,1H),2.77-2.72(m,1H),2.67-2.64(m,1H),2.32-2.18(m,3H),2.15-2.04(m,2H),1.99-1.94(m,2H),1.91-1.79(m,4H)。

Example 5

3- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydroquinazolin-7-yl) -5-chloro-4-cyclopropylphenol (mixture of diastereomers) 5

Using the synthetic route described in Example 4, the starting compound 4a from the first step was replaced with the compound 2- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan (prepared by the method disclosed in Example 283 on page 526 of the specification in patent application "WO 2021/041671") to give the title compound 5 (100 mg, yield: 30%).

MS m/z(ESI):568.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ6.70(d,1H),6.63(d,1H),5.37(s,1H),5.26(s,1H),4.61(s,2H),4.27(d,1H),4.18(dd,1H),4.09(dd,1H),3.97-3.90(m,1H),3.81-3.70(m,3H),3.48(d,2H),3.32-3.21(m,3H),3.11-3.03(m,2H),2.99(dd,1H),2.80(d,1H),2.75-2.62(m,2H),2.32(dd,1H),2.28-2.16(m,3H),2.15-2.09(m,1H),2.07-1.84(m,8H)。

Example 6

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydroquinazolin-7-yl) -5, 6-difluoronaphthalene-2-ol (mixture of diastereomers) 6

Using the synthetic route described in Example 4, the starting compound 4a from the first step was replaced with the compound 2- (7, 8-difluoro-3- (methoxymethyloxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (prepared by the method disclosed in Example 246, page 437 of the specification, of patent application "WO 2021/041671") to give the title compound 6 (100 mg, yield: 30%)

MS m/z(ESI):580.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ7.49(ddd,1H),7.33(td,1H),7.12(d,1H),7.04(t,1H),5.40-5.28(m,1H),4.27-4.12(m,2H),4.08(dt,2H),3.73(d,1H),3.66(s,2H),3.45-3.38(m,1H),3.25-3.18(m,3H),3.07(d,1H),3.01(td,1H),2.91-2.81(m,1H),2.77(dd,1H),2.65(d,1H),2.32-2.25(m,1H),2.20(ddt,2H),2.10(d,2H),2.00(dq,3H),1.89(d,5H)。

Example 7

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -5,6,7, 8-tetrahydroquinazolin-7-yl) naphthalen-2-ol (mixture of diastereomers) 7

Using the synthetic route in example 1, the starting material compound 1b was replaced with compound 4b in the first step to give the title compound 7 (13 mg, yield: 25.6%).

MS m/z(ESI):544.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.08-8.06(d,1H),7.69-7.68(d,1H),7.41-7.38(t,1H),7.35-7.31(t,1H),7.03-7.01(m,2H),5.37-5.25(m,2H),4.21-4.08(m,3H),3.93(m,1H),3.75-3.61(m,3H),3.47-3.40(m,1H),3.25-3.13(m,3H),3.09-3.03(m,2H),2.91-2.81(m,2H),2.67-2.63(m,1H),2.30-1.88(m,10H),1.36-1.31(m,2H)。

Biological evaluation

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

1. Purpose of testing

This experiment was performed by examining the inhibitory effect of compounds on cell ERK phosphorylation, based on IC ₅₀ The size of the compound disclosed in the disclosure is evaluated on the inhibition effect of the KRAS target.

2. Experimental methods

AGS cells (nanjing kebai, CBP 60476) were cultured in RPMI1640 (Hyclone, SH 30809.01) complete medium containing 10% fetal bovine serum. The first day of the experiment, AGS cells were seeded in 96-well plates at a density of 40000 cells/well using complete medium, 190. Mu.L of cell suspension per well, placed at 37 ℃,5% ₂ The cell culture box was cultured overnight.

The following day, 10. Mu.L of test compound diluted in a gradient prepared with complete medium was added to each well, the final concentration of the compound was 9 concentration points at which 5-fold gradient dilution was performed from 10. Mu.M, a blank containing 0.5% DMSO was set, the well plate was placed at 37 ℃,5% CO ₂ The cell culture chamber of (1) was incubated for 1 hour. After completion of incubation, the 96-well cell culture plate was removed, the medium was aspirated off, and 200. Mu.L of PBS (Shanghai culture Biotech Co., ltd., B320) was added to each well and washed once. Suck off PBS, 50. Mu.L of lysis buffer (lysis buffer, cisbio,64KL1 FDF) containing blocking reagent (blocking reagent, cisbio,64KB1 AAC) was added to each well, and the well plate was placed on a shaker and lysed for 40 minutes at room temperature with shaking. After lysis, the cells were pipetted and mixed, 16. Mu.L of lysate was transferred to two HTRF 96-well assay plates (Cisbio, 66PL 96100) per well, and then 4. Mu.L of 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 plate. The plate was sealed with a sealing membrane, centrifuged for 1 min in a microplate centrifuge and incubated overnight at room temperature in the dark.

On the third day, the fluorescence values of the 337nm wavelength excitation, 665nm and 620nm wavelength emission were read using an ENVISION multifunctional microplate reader (PerkinElmer, ENVISION).

3. Data analysis

IC of inhibitory Activity of Compounds was calculated using Graphpad Prism software based on Compound concentration and ratio of phosphorylated ERK/Total ERK ₅₀ See table 1 below for values, results.

TABLE 1 cellular ERK phosphorylation inhibitory Activity data

Example numbering	AGS/IC ₅₀ (nM)
		1	17.2
4	8.6
		5	26.4
6	7.2
		7	14.7

And (4) conclusion: the compound disclosed by the invention has a good inhibition effect on AGS cell ERK phosphorylation.

Test example 2: SPR method for detecting affinity of disclosed compound and KRAS protein subtype G12D or WT

Biotinylated Avi-KRAS-WT or Avi-KRAS-G12D was first treated with MgCl containing 100mM ₂ Diluted to 20. Mu.g/mL in 1 XHBS-P + (Cat. # BR 1006-71) buffer, and then flowed through SA (Cat. # BR 1005-31) biosensing chip channel 2 for 420s, to achieve a coupling level of approximately 5000-7000 RU. Then samples of the small molecular compound are sequentially injected from low to high for 120s, and then are dissociated for 720s. The test employs a single cycle kinetic mode. The Biacore 8K instrument detects the reaction signal in real time to obtain a binding dissociation curve. After the test is finished, data analysis is carried out by Biacore 8K evaluation software, data fitting is carried out by adopting a model of 1.

TABLE 2 affinity data of the compounds for KRAS protein subtypes G12D or WT

And (4) conclusion: the compounds of the present disclosure have better affinity with KRAS protein subtype G12D or WT.

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

1. Purpose of testing

The inhibition effect of the disclosed compound on the KRAS target spot is evaluated by testing the 3D proliferation inhibition effect of the disclosed compound on GP2D cells.

2. Experimental methods

GP2d cells (CBP 60010, nanjing Kebai) were cultured in complete medium, DMEM/high sugar medium (Hyclone, SH 30243.01) containing 10% fetal bovine serum (Corning, 35-076-CV)And (5) nourishing. On the first day of the experiment, GP2d cells were seeded at a density of 1000 cells/well on a 96-well low adsorption plate (Corning, CLS7007-24 EA) using complete medium, 90. Mu.L of cell suspension was centrifuged at 2000rpm for 5 minutes at room temperature and then placed at 37 ℃ for 5% CO ₂ The cell culture box was cultured overnight.

The following day, 10 μ L of test compound diluted in a gradient of complete medium was added to each well, and the final concentration of compound in GP2d cells was 9 concentration points diluted in a 3-fold gradient starting from 1 μ M, setting a blank containing 0.5% DMSO. The well plate was left at 37 ℃ 5% CO ₂ The cell culture chamber of (2) was cultured for 120 hours. The seventh day, the 96 well cell culture plate was removed and 50. Mu.L of CellTiter-

After shaking the 3D reagent (Promega, G9682) at room temperature for 25 minutes, the mixture was aspirated and 50 μ L was transferred to a white opaque 96-well plate (PE, 6005290), and the luminescence signal value was read using a multi-functional microplate reader (PerkinElmer, ENVISION).

3. Data analysis

IC of compound inhibitory activity was calculated using Graphpad Prism software ₅₀ See table 3 below for values, results.

TABLE 3 data on cell 3D proliferation inhibitory Activity

Example numbering	GP2d/IC ₅₀ (nM)
		6	28.2
7	67.0

And (4) conclusion: the compound disclosed by the invention has a better inhibiting effect on the 3D proliferation of GP2D cells.

Claims

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

wherein:

G ² is NR ^d ；

Ring a is aryl or heteroaryl;

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

l is selected from the group consisting of a single bond, O and NR ^e ；

Each R is ¹ Are the same 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;

each R is ³ And R ⁶ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _w -NR ^j R ^k Nitro, hydroxy, hydroxyalkylCycloalkyl, heterocyclyl, aryl and heteroaryl;

m is 0, 1 or 2;

n is 0 or 1;

r is 0, 1 or 2;

p is 0, 1,2,3, 4 or 5;

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

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

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

wherein:

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

G ² ring A, ring B, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, r and t are as defined in claim 1.

3. The compound according to claim 1 or2, or a pharmaceutically acceptable salt thereof, wherein ring a is phenyl or naphthyl; and/or ring B is

R ⁶ Can be substituted at any position of the ring B.

4. The compound according to claim 1, which is a compound represented by the general formula (II):

wherein, G ² Ring A, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, q, r and t are as defined in claim 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein n is 0.

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

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ^2a And R ^2b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; and/or R ^4a And R ^4b Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein G is ² Is NH.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L is O.

10. According to any one of claims 1 to 9The compound or a pharmaceutically acceptable salt thereof, wherein R ¹ Is a hydrogen atom.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R ² And R ^2c Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R ³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, hydroxyl and cyclopropyl.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is a hydrogen atom.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Are 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, selected from the following compounds:

16. a compound represented by the general formula (I-1A):

wherein:

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

R ⁰ is a hydrogen atom or a hydroxyl protecting group;

r is an amino protecting group; preferably Boc;

ring A, ring B, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, r and t are as defined in claim 2.

17. A compound having the structure:

18. a process for producing a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof according to claim 2, which comprises:

R ⁰ is a hydrogen atom or a hydroxyl protecting group; the hydroxyl protecting group is preferablyIs MOM;

wherein,

r is an amino protecting group; preferably Boc;

G ² is NH;

ring A, ring B, L, R ¹ 、R ² 、R ^2c 、R ^2a 、R ^2b 、R ³ 、R ^4a 、R ^4b 、R ⁵ 、R ⁶ M, n, p, q, r and t are as defined in claim 2.

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 G12D.

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 which is cancer.

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 prevention of a disease or condition selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, cancer of the throat, oral cancer, salivary gland cancer, esophageal cancer, gastric 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, neurofibroma, glioma, neuroblastoma, and glioblastoma; preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.