CN115385938A

CN115385938A - Benzopyrimidine compounds, preparation method thereof and application thereof in medicines

Info

Publication number: CN115385938A
Application number: CN202210570116.3A
Authority: CN
Inventors: 李心; 钟家鑫; 曾长根; 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 a benzo pyrimidine compound, a preparation method thereof and application thereof in medicine. In particular to a benzo pyrimidine compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, especially application of the compound in preparation of a medicine for inhibiting KRAS G12D. Wherein each group in the general formula (I) is defined in the specification.

Description

Phenylpyrimidine compounds, preparation method thereof and application thereof in medicines

Technical Field

The disclosure belongs to the field of medicines, and relates to a benzo pyrimidine compound, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to a benzo pyrimidine compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application thereof in preparing a medicament for inhibiting KRAS G12D.

Background

RAS is one of the most mutation-rate 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 (17%), colorectal (33%), and pancreatic (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, the KRAS regulates and controls multiple functions such as cell proliferation, survival, migration and metabolism through a plurality of downstream signal pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM 1-RAc. After KRAS gene mutation, 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. However, based on the importance and prevalence of abnormal activation of KRAS in cancer progression, KRAS has been and remains a very interesting target for drug development. 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 patents which have been disclosed so far are WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2021000885A1 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 ；

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;

R ² 、R ^2a and R ^4a 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 ) _v -NR ^h R ⁱ Hydroxyl, hydroxyalkyl and cycloalkyl groups;

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

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.

In some preferred embodiments of the present disclosure, the compound of formula (I), 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; more preferably, ring a is naphthyl.

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

Is composed of

R ³ Is as defined in formula (I); preferably, each 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; further preferably, each 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 and cyclopropyl; even more preferablyEach of 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 hydroxy; most preferably, each R ³ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, F, ethyl, ethynyl, and hydroxyl.

Is composed of

Wherein:

R ^3a and R ^3b 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, R ^3a And R ^3b 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 hydroxy; more preferably, R ^3a And R ^3b Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl and hydroxyl; further preferably, R ^3a Selected from halogen, C _1-6 Alkyl and C _2-6 Alkynyl radical, R ^3b Is a hydroxyl group; most preferably, R ^3a Selected from F, ethyl and ethynyl, R ^3b Is a hydroxyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 7-to 10-membered fused heterocyclyl and R is 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); preferably, the first and second liquid crystal display panels are,

is composed of

R ⁶ Is halogen; most preferably, the first and second substrates are,

is composed of

R ⁶ Is F.

In some preferred embodiments of the present disclosure, the compound of formula (I) 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.

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

wherein

G ² 、L、R ¹ 、R ² 、R ^2a 、R ³ 、R ^4a 、R ⁵ 、R ⁶ N, p, q, 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 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 represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein n is 0.

In some preferred embodiments of the present disclosure, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ² 、R ^2a And R ^4a 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; preferably, R ² 、R ^2a And R ^4a Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ² 、R ^2a And R ^4a Are the same or different and are each independently selected from the group consisting of a hydrogen atom, F and a methyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ² 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 ^2a Is a hydrogen atom or C _1-6 Alkyl, wherein said alkyl is preferably methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R ^4a Is a hydrogen atom or a halogen, wherein the halogen is preferably fluorine.

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

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

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

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or (II)A compound or a pharmaceutically acceptable salt thereof, wherein each 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, each 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 each 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 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, each 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; even more preferably, each 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 hydroxyl; even more preferably, each R ³ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl and hydroxy; most preferably, each R ³ Identical or different and are each independently selected from the group consisting of F, ethyl, ethynyl and hydroxyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein each 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, 3-to 8-membered cycloalkyl and-O-C _1-6 alkyl-O-C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I) or (II) 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) or (II) or a pharmaceutically acceptable salt thereof, wherein each R is 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, each 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; further preferably, R ⁶ Is halogen; most preferably, R ⁶ Is F.

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

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

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

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

In some preferred embodiments of the present disclosure, the compound represented by formula (I) or (II) 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) or (II) 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) or (II) 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

Is composed of

Wherein:

R ^3a and R ^3b 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, R ^3a And R ^3b 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 hydroxy; more preferably, R ^3a And R ^3b Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl and hydroxyl; further preferably, R ^3a Selected from halogen, C _1-6 Alkyl and C _2-6 Alkynyl, R ^3b Is a hydroxyl group; most preferably, R ^3a Selected from F, ethyl and ethynyl, R ^3b Is a hydroxyl group.

Is composed of

R ⁶ As defined in formula (II); preferably, the first and second electrodes are formed of a metal,

is composed of

R ⁶ Selected from halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group; more preferably still, the first and second liquid crystal compositions are,

is composed of

R ⁶ Is halogen; most preferably, the first and second substrates are,

is composed of

R ⁶ Is F.

In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein G ² Is NH; l is O; n is 0; 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 ^2a And R ^4a 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 2 or 3; 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; 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 is ⁶ Selected from hydrogen atoms, halogens, C _1-6 Alkyl and C _1-6 A haloalkyl group.

Is composed of

R ^3a Selected from halogen, C _1-6 Alkyl and C _2-6 Alkynyl radical, R ^3b Is a hydroxyl group; g ² Is NH; l is O; n is 0; p is 0; r ² Is a hydrogen atom; r is ^2a Is a hydrogen atom or C _1-6 An alkyl group; r is ^4a Is a hydrogen atom or a halogen; r is 1; r is ⁵ Is a hydrogen atom;

is composed of

R ⁶ Is a halogen.

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 the content of the first and second substances,

r is an amino protecting group; preferably Boc;

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

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

wherein the content of the first and second substances,

r is an amino protecting group; preferably Boc;

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

In some preferred embodiments of the present disclosure, the general formula (IA)) Or (IIA) or a salt thereof, wherein each 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, 3-to 8-membered cycloalkyl and-O-C _1-6 alkyl-O-C _1-6 An alkyl group; preferably, each 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-O-C _1-6 alkyl-O-C _1-6 An alkyl group; more preferably, each R ³ Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, hydroxy and-O-C _1-6 alkyl-O-C _1-6 An alkyl group; most preferably, each R ³ Identical or different and each is independently selected from the group consisting of F, ethyl, ethynyl, hydroxyl, and-OMOM.

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

Is composed of

Wherein:

R ^3a and R ^3b 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, 3-to 8-membered cycloalkyl and-O-C _1-6 alkyl-O-C _1-6 An alkyl group; preferably, R ^3a And R ^3b 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-O-C _1-6 alkyl-O-C _1-6 An alkyl group; more preferably, R ^3a And R ^3b Are the same or different and are each independently selected from halogen, C _1-6 Alkyl radical, C _2-6 Alkynyl, hydroxy and-O-C _1-6 alkyl-O-C _1-6 An alkyl group; further preferably, R ^3a Selected from halogen, C _1-6 Alkyl and C _2-6 Alkynyl radical, R ^3b Is hydroxy or-O-C _1-6 alkyl-O-C _1-6 An alkyl group; most preferably, R ^3a Selected from F, ethyl and ethynyl, R ^3b Is hydroxyl or-OMOM.

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

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

a compound represented by the general formula (IA)Subjecting the compound or salt thereof to deprotection reaction to obtain a compound shown as a 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 the content of the first and second substances,

r is an amino protecting group; preferably Boc;

G ² is NH;

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

carrying out deprotection reaction on the compound shown in the general formula (IIA) or salt thereof to obtain a compound shown in a general formula (II) 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;

In some preferred embodiments of the present disclosure, a method of preparing a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, when R is ³ And/or R ⁶ Is an-O-alkyl group,simultaneous deprotection of R in the deprotection reaction ³ And/or R ⁶ To a-alkyl-O-alkyl group on to R ³ And/or R ⁶ A compound of formula (I) or (II) being-OH or a pharmaceutically acceptable salt thereof.

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

The present disclosure further relates to the use of a compound of general formula (I), (II) 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), (II) 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), (II) 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), (II), 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 preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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

The present disclosure further relates to a compound of general formula (I), (II) 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), (II) 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 preferably 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 described in the present disclosure is preferably colon cancer or rectal cancer.

Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; 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, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose 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 coloring agent 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 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 suspensions 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.

The compounds of the present disclosure can be administered by the addition of water to prepare water-suspended dispersible powders and granules. 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 a drug administered depends on a variety of factors, including, but not limited to: 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, 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 containing 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. Alkyl groups may be substituted or unsubstituted and, when substituted,which may be substituted at any available point of attachment, the substituents preferably being one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl radicals (i.e. C) containing from 2 to 12, for example 2,3, 4,5, 6, 7, 8, 9, 10, 11 and 12, carbon atoms are preferred _2-12 Alkenyl), more preferably an alkenyl group containing 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl (i.e., C) groups containing 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 having 2 to 6 carbon atoms (i.e., C) _2-6 Alkynyl). Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 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), preferably 3 to 8 (e.g., 3, 4,5, 6, 7 and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), 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 spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds (i.e., a 5 to 20 membered spirocycloalkyl). 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 a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, according to the number of spiro atoms shared between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring alkyl" refers to a 5 to 20 membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, and in which one or more of the rings may contain one or more double bonds (i.e., a 5 to 20 membered fused ring alkyl). Preferably 6 to 14 (i.e. 6 to 14 fused ring alkyl) members, more preferably 7 to 10 (e.g. 7, 8, 9 or 10) members (i.e. 7 to 10 fused ring alkyl). Bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls are classified 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/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 20 member bridged cycloalkyl). 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, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

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

Etc.; preference is given to

Cycloalkyl 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 "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 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon (i.e., a 3-to 20-membered heterocyclyl). Preferably 3 to 14 (e.g., 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms (i.e., 3 to 14 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4,5, 6, 7, and 8), wherein 1-3 are heteroatoms (e.g., 1,2, and 3) (i.e., 3-to 8-membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 (e.g., 1,2 and 3) are heteroatoms (i.e., 3-to 6-membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e. a 5 or 6 membered heterocyclyl group). 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 sharing one atom (referred to as a spiro atom) 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., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. Which may contain one or more double bonds (i.e., 5 to 20 membered spiroheterocyclyl). Preferably 6 to 14 (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14) and more preferably 7 to 10 (e.g. 7, 8, 9 or 10) (i.e. 6 to 14 spiro heterocyclyl). The spiro heterocyclic group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group according to the number of spiro atoms shared between rings, and preferably the single spiro heterocyclic group and the double spiro heterocyclic group. More preferred is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings 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 (i.e., a 5 to 20 membered fused heterocyclyl). 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 may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting 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/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-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 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., form a sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., a 5 to 20 membered bridged heterocyclyl). 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 classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to 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 heterocyclyl groups (including mono-, spiro-, fused and bridged heterocyclyl groups) as described above fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

and the like.

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 that shares an adjacent pair 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., a 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 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 (i.e., a 5-to 14-membered heteroaryl). Heteroaryl is preferably 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) (i.e., 8 to 10 membered heteroaryl), more preferably 5 or 6 membered (i.e., 5 or 6 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring that is attached to 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 removing one hydrogen atom from the parent ring atom, or those derived by removing two hydrogen atoms from the parent ring atom or from two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

The term "amino protecting group" is a group that is easily removed and is introduced so that the amino group remains 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 agent is Boc.

The term "hydroxy groupBy "protecting group" is meant a derivative of a hydroxyl group that is typically used to block or protect the hydroxyl group while the reaction is carried out on other functional groups of the compound. By way of example, the hydroxyl protecting group may preferably be (C) _1-10 Alkyl or aryl) ₃ Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl and the like; may be C _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy-substituted C _1-6 Alkyl or phenyl substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy-substituted C _1-4 Alkyl groups, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), etc.; may be (C) _1-10 Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C) _1-6 Alkyl or 6 to 10 membered aryl) sulfonyl; may also be (C) _1-6 Alkoxy or 6 to 10 membered aryloxy) carbonyl; preferably, the hydroxyl protecting group is MOM.

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 "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group 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 "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 "amino" refers to the group-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.

Bn is 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 referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. 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 nomenclature of the compounds does not exclude any tautomers.

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 that

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. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but 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 and the like, 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 of deuterium may be partial or complete, and replacement of partial deuterium means replacement of at least one hydrogen by at least one deuterium.

When a position is specifically designated as deuterium D, that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. at least 15% deuterium incorporation). The compounds of the examples can have deuterium at a natural abundance that is greater than deuterium by at least 1000 times the abundance (i.e., at least 15% deuterium incorporation), deuterium at least 2000 times the abundance (i.e., toDeuterium doping of at least 30%), deuterium at least 3000 times abundance (i.e. deuterium doping of at least 45%), deuterium at least 3340 times abundance (i.e. deuterium doping of at least 50.1%), deuterium at least 3500 times abundance (i.e. deuterium doping of at least 52.5%), deuterium at least 4000 times abundance (i.e. deuterium doping of at least 60%), deuterium at least 4500 times abundance (i.e. deuterium doping of at least 67.5%), deuterium at least 5000 times abundance (i.e. deuterium doping of at least 75%), deuterium at least 5500 times abundance (i.e. deuterium doping of at least 82.5%), deuterium at least 6000 times abundance (i.e. deuterium doping of at least 90%), deuterium at least 6333.3 times abundance (i.e. deuterium doping of at least 95%), deuterium at least 6466.7 times abundance (i.e. deuterium doping of at least 97%), deuterium at least 6600 times abundance (i.e. deuterium doping of at least 99%), at least 3.3.3 times abundance (i.e. deuterium doping of at least 99.5%) or more abundance. "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 "optionally halogen-or cyano-substituted C _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.

"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 "optionally halogen-or cyano-substituted C _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 and 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 determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/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 being used in the body of a mammal, and has due biological activity. Salts may 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 preparation method of a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

carrying out deprotection reaction on a compound shown as a general formula (IA) or salt thereof under an acidic condition to obtain a compound shown as a 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, 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 two

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

carrying out deprotection reaction on a compound shown as a general formula (IIA) or a salt thereof under an acidic condition to obtain a compound shown as a general formula (II) or a 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;

In the above synthetic schemes, the process for preparing a compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof, when R ³ And/or R ⁶ is-O-alkyl, with simultaneous removal of R in a deprotection reaction ³ And/or R ⁶ to-alkyl-O-alkyl on to R ³ And/or R ⁶ A compound represented by the general formula (I) or (II) which is-OH, or a pharmaceutically acceptable salt thereof.

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 acids include, but are not limited to, hydrogen chloride, hydrochloric acid dioxane solution, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; preferably, the agent providing acidic conditions is a dioxane hydrochloride solution.

The reagents that provide basic conditions in the above synthetic schemes include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium t-butoxide, potassium t-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solutions of tetrabutylammonium fluoride or 1, 8-diazabicycloundecen-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 present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) 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 assay using Agilent 1260 DAD HPLC.

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.

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

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by 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 of the Litsea crassirhizomes 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 invention may be synthesized by 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, shao Yuan Chemical technology (Accela ChemBio Inc), darri Chemicals, and the like.

In the examples, the reaction can be carried out in 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 clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenator.

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

A CEM Discover-S908860 type microwave reactor was used for the microwave reaction.

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: in a dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can also 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) quinazolin-7-yl) -5-fluoronaphthalen-2-ol 1

First step of

(1R, 5S) -3- (7-bromo-2-chloroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 1b

The compound 7-bromo-2,4-dichloroquinazoline 1a (400mg, 1.43mol, prepared by the method disclosed in Example 1 on page 21 of the specification of the patent application "US2013/0012489 A1"), triethylamine (290mg, 2.86mmol) was dissolved in 10mL of dichloromethane, tert-butyl (361mg, 1.58mmol, jiangsu aikang) 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (361mg, 1.58mmol) was added at-40 ℃, the reaction solution was concentrated under reduced pressure after keeping the temperature for reaction for 2 hours, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1B (630 mg, yield: 96.4%).

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

Second step of

(1R, 5S) -3- (7-bromo-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 1d

Compound 1b (300mg, 661.1. Mu. Mol) was dissolved in 1, 4-dioxane (4 mL), ((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol 1c (120mg, 753.7. Mu. Mol, pharmamine), 0.33mL of a 2M solution of sodium bistrimethylsilyl amide tetrahydrofuran, N, N-diisopropylethylamine (256mg, 1.98mmol), 4A molecular sieve (300 mg), stirred at 90 ℃ for 14 hours, the reaction was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 1d (250 mg, yield: 65.6%). MS m/z (ESI) 575.8[ m +1]

The third step

(1R, 5S) -3- (7- (8-fluoro-3- (methoxymethyloxy) naphthalen-1-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 1f

Compound 1d (100mg, 173.4 μmol), compound 2- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborocyclopentane 1e (80mg, 240.8 μmol, prepared using the method disclosed by Example 282 on page 522 of the specification in patent application "WO 2021/041671"), tetrakis (triphenylphosphine) palladium (20mg, 17.3 μmol, adamas), anhydrous cesium carbonate (113mg, 346.8 μmol) were dissolved in a mixed solution of 3ml of 1, 4-dioxane and water (V: V = 5) and reacted at 100 ℃ for 5 hours under a nitrogen atmosphere, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound 1f (121 mg, yield: 99.3%) as eluent system a.

MS m/z(ESI):702.2[M+1]

The fourth step

Compound 1f (121mg, 172.4. Mu. Mol) was dissolved in acetonitrile (4 mL), 4mL of 4M dioxane hydrochloride was added, the reaction mixture was reacted at room temperature 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 bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38% -45%, flow rate: 30 mL/min) to give the title compound 1 (41 mg, yield: 42.6%).

MS m/z(ESI):558.2[M+1]

¹ H NMR(500MHz,CD ₃ OD):δ7.95(d,1H),7.58-7.53(m,2H),7.36(td,1H),7.31(dt,1H),7.23(t,1H),6.99(d,1H),6.88(dd,1H),5.40-5.22(m,1H),4.51(s,2H),4.32-4.17(m,2H),3.62(d,4H),3.26-3.20(m,2H),3.03(td,1H),2.41-2.12(m,3H),2.01(dt,3H),1.89(d,5H).

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) quinazolin-7-yl) -5-ethylnaphthalene-2-ol

Using the synthetic route described in example 1, the starting material compound 1e in the third step was replaced with the compound 2- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolan (prepared by the method disclosed in Intermediate 21 on page 111 of the specification in patent application "WO 2021/041671") to obtain the title compound 2 (9.3 mg, yield: 19.1%).

MS m/z(ESI):568.2[M+1]

¹ H NMR(500MHz,CD ₃ OD):δ7.96(d,1H),7.61-7.53(m,2H),7.33(d,1H),7.31-7.25(m,1H),7.18(d,1H),7.12(d,1H),6.89(d,1H),5.32(dd,1H),4.50(dt,2H),4.34-4.15(m,2H),3.75-3.52(m,4H),3.29-3.22(m,2H),3.03(td,1H),2.36(q,2H),2.33-2.10(m,3H),2.08-1.95(m,3H),1.89(s,5H),0.82(td,3H).

Example 3

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethylnaphthalen-2-ol 3

First step of

7-bromo-8-fluoroquinazoline-2, 4 (1H, 3H) -dione 3b

The compound 2-amino-4-bromo-3-fluorobenzoic acid 3a (2g, 8.54mmol, obtained after Shanghai, N.H.) and urea (2.57g, 42.7 mmol) were mixed, heated to 200 ℃ for reaction for 3 hours, cooled to room temperature and triturated the solid to give the crude title compound 3b (2.2 g, yield: 99.3%) which was used in the next step without purification.

MS m/z(ESI):258.9[M+1]

Second step of

7-bromo-2, 4-dichloro-8-fluoroquinazoline 3c

The crude product 3b (2.2 g, 8.49mmol) was dissolved in phosphorus oxychloride (15 mL), N-diisopropylethylamine (3.3 g,25.5 mmol) was added, the reaction mixture was stirred at 100 ℃ for 14 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude title compound 3c (2.5 g, yield: 99.3%) which was used in the next step without purification. MS m/z (ESI) 294.9[ 2] M +1]

The third step

(1R, 5S) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3d

Compound 3c (500mg, 1.69mol), triethylamine (350mg, 3.45mmol) were dissolved in 10mL of dichloromethane, tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (370mg, 1.74mmol) was added at-40 ℃, the reaction mixture was stirred for 2 hours while maintaining the temperature, and after the reaction was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3d (730 mg, yield: 91.5%).

MS m/z(ESI):471.2[M+1]

The fourth step

(1R, 5S) -3- (7-bromo-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3e

Compound 3d (300mg, 635.92. Mu. Mol), compound 1c (203mg, 1.27mmol) were dissolved in N, N-dimethylformamide (2.5 mL), tetrahydrofuran (2.5 mL), cesium carbonate (622mg, 1.90mmol), 1, 4-diazidobicyclo [2.2.2] octane (20mg, 178.29. Mu. Mol) were added, the reaction was stirred under a nitrogen atmosphere for 14 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 3e (350 mg, yield: 92.5%).

MS m/z(ESI):594.2[M+1]

The fifth step

(1R, 5S) -3- (7- (8-ethyl-3- (methoxymethyloxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3f

Compound 3e (39mg, 65.6 μmol), compound 2- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (29.1mg, 85.2 μmol), tetrakis (triphenylphosphine) palladium (15.1mg, 13.1 μmol, adamas), cesium carbonate (64.1mg, 196.8 μmol) were dissolved in a mixed solution of 3ml1, 4-dioxane and water (V: V = 5). The reaction was carried out at 100 ℃ for 14 hours under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 3f (30 mg, yield: 62.7%).

MS m/z(ESI):730.2[M+1]

The sixth step

Compound 3f (30mg, 41.1. Mu. Mol) was dissolved in 10mL of 4M dioxane hydrochloride solution and reacted at room temperature for 0.5 hour, and the reaction mixture was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: sharpSil-TC18, 30X 150mm, 5. Mu.m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38% -45%, flow rate: 30 mL/min) to give the title compound 3 (5 mg, yield: 20.8%).

MS m/z(ESI):586.2[M+1]

¹ H NMR(500MHz,CD ₃ OD):δ7.83(d,1H),7.63(d,1H),7.35(t,1H),7.28-7.24(m,2H),7.15(d,1H),6.93(d,1H),4.33(s,1H),4.27-4.25(m,1H),3.69(s,2H),3.63(dd,3H),3.27(d,2H),3.10-3.03(m,2H),2.42(tt,3H),2.35-2.16(m,4H),2.04(p,3H),1.91(d,4H),0.87(td,3H).

Example 4

4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-7-yl) -5-fluoronaphthalen-2-ol 4

Using the synthetic route in example 3, the starting material compound 2- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan in the fifth step was replaced with compound 1e to obtain the title compound 4 (23.1 mg, yield: 40.1%).

MS m/z(ESI):576.2[M+1]

¹ H NMR(500MHz,CD ₃ OD):δ7.81(d,1H),7.56(d,1H),7.36(td,1H),7.32-7.22(m,2H),7.01(d,1H),6.88(dd,1H),5.36(dt,1H),4.55(td,,2H),4.45-4.27(m,2H),3.78(s,2H),3.66(dt,2H),3.45-3.37(m,2H),3.12(td,1H),2.49-2.27(m,2H),2.28-2.01(m,4H),1.93(d,5H).

Example 5

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) quinazolin-7-yl) -5-ethynylnaphthalen-2-ol 5

First step of

(1R, 5S) -3- (7- (8-ethynyl-3- (methoxymethyloxy) naphthalen-1-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 5b

Compound 1d (100mg,173.4 μmol), compound triisopropyl ((6- (methoxymethoxy) -8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane 5a (120mg,242.6 μmol, prepared using the method disclosed in patent application "WO2021/041 A1" at page 103 intermedate 17), tetrakis (triphenylphosphine) palladium (30mg, 25.9 μmol, adamas), cesium carbonate anhydrous (113mg, 346.8 μmol) were dissolved in a mixed solution of 3ml1,4-dioxane and water (V: V = 5). The reaction was carried out at 100 ℃ for 5 hours under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure, 10mL of methylene chloride was added, the mixture was washed with water and a saturated sodium chloride solution in this order, the organic phase was dried over anhydrous sodium sulfate, dried by filtration to remove the drying agent and concentrated under reduced pressure to give the crude title compound 5b (122 mg, yield: 99.3%), which was used in the next reaction without purification. MS m/z (ESI): 708.2[ 2], [ M +1]

Second step of

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) quinazolin-7-yl) -5-ethynylnaphthalene-2-ol 5

The crude compound 5b (100mg, 141.2. Mu. Mol) was dissolved in ethyl acetate (3 mL), 4M hydrochloric acid/dioxane solution (0.5 mL) was added, the reaction mixture was reacted at room temperature for 1 hour, the reaction mixture 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 38% -45%, flow rate: 30 mL/min) to obtain the title compound 5 (0.88 mg, yield: 1.1%).

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

1H NMR(500MHz,CD ₃ OD):δ8.05(d,1H),8.02(d,1H),7.76(dd,1H),7.73(dd,2H),7.62(d,1H),7.57-7.52(m,1H),7.21(d,1H),5.41(s,1H),4.60(s,2H),4.36-4.21(m,2H),3.75-3.61(m,5H),3.27(d,2H),3.07(d,1H),2.44-2.24(m,3H),2.21(t,3H),2.05(d,5H).

Example 6

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

First step of

(1R, 5S) -3- (7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 6b

The compound 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline 6a (1g, 2.39mol, prepared by the method disclosed in Example 59a on page 318 of the specification of patent application "WO2020097537 A2"), N-diisopropylethylamine (1g, 7.73mmol) was dissolved in 20mL of dichloromethane, tert-butyl (1r, 5s) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (1g, 4.78mmol) was added at-40 ℃, the reaction mixture was concentrated under reduced pressure after stirring for 2 hours with maintaining the temperature, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 6B (1 g, yield: 69.9%).

MS m/z(ESI):596.9[M+1]

Second step of

(1R, 5S) -3- (7-bromo-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-iodoquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 6c

Compound 6b (200mg, 334.6. Mu. Mol), compound 1c (159mg, 993.7 mmol) were dissolved in N, N-dimethylformamide (2.5 mL), tetrahydrofuran (2.5 mL), cesium carbonate (327mg, 1mmol), 1, 4-diazabicyclo [2.2.2] octane (10mg, 89.1. Mu. Mol), and the reaction mixture was stirred under nitrogen for 14 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 6c (200 mg, yield: 82.9%).

MS m/z(ESI):720.2[M+1]

The third step

(1R, 5S) -3- (7-bromo-8-fluoro-2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methylquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 6d

Compound 6c (100mg, 138.81 μmol), methylboronic acid (9mg, 150.35 μmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (11mg, 13.48 μmol), potassium phosphate (88mg, 414.57 μmol), was dissolved in a mixed solution of 3ml of 1, 4-dioxane and water (V: V = 5). The reaction mixture was concentrated under reduced pressure under a nitrogen atmosphere at 90 ℃ for 14 hours, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 6d (60 mg, yield: 71.0%).

MS m/z(ESI):608.2[M+1]

The fourth step

(1R, 5S) -3- (8-fluoro-7- (8-fluoro-3- (methoxymethyloxy) naphthalen-1-yl) -2- (((2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) -6-methyl-quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 6e

Compound 6d (60mg, 98.6 μmol), compound 1e (49mg, 147.5 μmol), tetrakis (triphenylphosphine) palladium (17mg, 14.7 μmol, adamas), cesium carbonate (64mg, 196.4 μmol) were dissolved in 3ml of a mixed solution of 1, 4-dioxane and water (V: V = 5). Reacting at 95 ℃ for 4 hours under nitrogen atmosphere, concentrating the reaction solution under reduced pressure, adding 10mL of dichloromethane, washing with water and saturated sodium chloride solution in sequence, drying with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a crude title compound 6e (70 mg, yield: 96.7%), wherein the product is directly used for the next reaction without purification.

MS m/z(ESI):734.2[M+1]

The fifth step

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

The crude compound 6e (70mg, 95.3. Mu. Mol) was dissolved in ethyl acetate (2 mL), 4M dioxane hydrochloride solution (1 mL) was added, the reaction mixture was reacted at room temperature for 1 hour, and the reaction mixture 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 38% -45%, flow rate: 30 mL/min) to obtain the title compound 6 (15 mg, yield: 26.6%).

MS m/z(ESI):590.2[M+1]

1H NMR(500MHz,CD ₃ OD):δ7.63(s,1H),7.57(d,1H),7.35(td,1H),7.27(t,1H),6.92(d,1H),6.86(dd,1H),4.65-4.45(m,3H),4.31(dd,1H),4.24(d,1H),3.71-3.56(m,4H),3.42(d,1H),3.27-3.15(m,1H),3.10-2.99(m,1H),2.43-2.14(m,3H),2.10(s,3H),1.96(dq,8H).

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 compounds of the disclosure were evaluated for their inhibitory effect on KRAS targets.

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 incubated overnight.

The following day, 10. Mu.L of test compound diluted in a gradient prepared from complete medium was added to each well, the final concentration of compound was 9 concentration points diluted in a 5-fold gradient starting from 10. Mu.M, a blank containing 0.5% DMSO was set, the well plate was placed at 37 ℃ and 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. PBS was aspirated, 50. Mu.L of lysis buffer (lysis buffer, cisbio,64KL1 FDF) containing blocking solution (blocking reagent, cisbio,64KB1 AAC) was added to each well, and the well plates were 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-ERK 1/2 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, fluorescence values of 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 phosphorylated ERK/Total ERK ratio ₅₀ See table 1 below for values, results.

TABLE 1 cellular ERK phosphorylation inhibitory Activity data

Example numbering	AGS/IC ₅₀ (nM)
		1	21.7
2	8.9
		3	2.6
4	9.4
		6	13.5

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 incubated with a medium containing 100mM MgCl ₂ The 1 XHBS-P + (Cat. # BR 1006-71) buffer solution is diluted to 20 mu g/mL, then flows through SA ((Cat. # BR 1005-31) biosensing chip channel 2 for 420s to obtain a coupling level of about 5000-7000RU, samples of the small molecular compound are sequentially injected from low to high for 120s, and then are dissociated for 720s, a single-cycle kinetic mode is adopted in the test, a Biacore 8K instrument detects reaction signals in real time to obtain a binding dissociation curve, a Biacore 8K evaluation software is used for data analysis after the test is finished, and a model 1 is adopted for data fitting and affinity data are obtained.

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 to 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 method

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). 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 incubated overnight.

The following day, 10. Mu.L of a gradient diluted in complete medium was added to each well

The final concentration of test compound, GP2d cells, was 9 concentration points with 3-fold gradient dilution from 1 μ M, setting a blank containing 0.5% DMSO. The well plate was placed at 37 ℃ 5% ₂ The cell culture chamber of (2) was cultured for 120 hours. On the seventh day, 96 well cell culture plates were removed and 50. Mu.L of each well was added

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)
		3	5.3
4	13.2

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

Test example 4: pharmacokinetic evaluation

1. C57 mouse assay

1. Abstract

The drug concentration in plasma of C57 mice at various times after intravenous injection (i.v.) of the compound of example 3 was determined by LC/MS method using C57 mice as test animals. The pharmacokinetic behavior of the compounds of the disclosure was studied in C57 mice and evaluated for their pharmacokinetic profile.

2. Test protocol

2.1 test drugs

The compound of example 3.

2.2 test animals

9C 57 mice, female, were provided by Wintorlawa laboratory animals, inc. The administration is intravenous.

2.3 pharmaceutical formulation

An amount of the compound of example 3 is weighed out separately, and added with 5% DMSO +5% Tween 80+90% physiological saline to prepare a colorless clear solution of 0.1 mg/mL.

2.4 administration

The dose was 1.0mg/kg and the volume was 0.1mL/10g.

3. Operation of

0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours before and 5 minutes after administration, blood is collected from the orbit by 0.1mL, placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000rpm for 1 minute (4 ℃), plasma is separated within 1 hour, and the sample is stored at-80 ℃. Blood sampling to centrifugation process was performed under ice bath conditions. Food was consumed 2 hours after dosing.

Determination of the content of the test compound in the plasma of C57 mice after administration of the drugs at different concentrations: 25 μ L of C57 mouse plasma samples were taken at various time points post-dose, 50 μ L of camptothecin (100 ng/mL) was added to each sample, and the protein was precipitated with 200 μ L of acetonitrile, vortex mixed for 5 minutes, and centrifuged at 4000rpm for 10 minutes. mu.L of the supernatant was diluted with 200. Mu.L of water and 0.1. Mu.L of the diluted supernatant was injected for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

TABLE 4 pharmacokinetic parameters of Compounds of the disclosure

And (4) conclusion: the compound disclosed by the invention has good pharmacokinetic properties in a C57 mouse body, is high in exposure amount, large in steady-state distribution volume, easy to distribute in tissues and has pharmacokinetic advantages.

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;

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

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;

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

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

2. The method of claim 1A compound 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.

3. The compound according to claim 1 or2, which is a compound represented by the general formula (II):

wherein G is ² 、L、R ¹ 、R ² 、R ^2a 、R ³ 、R ^4a 、R ⁵ 、R ⁶ N, p, q, r and t are as defined in claim 1.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein n is 0.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ² 、R ^2a And R ^4a 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.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein G is ² Is NH.

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

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen atom, halogen、C _1-6 Alkyl and C _1-6 A haloalkyl group.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein q is 2 or 3.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein each 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.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein 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; preferably, R ⁵ Is a hydrogen atom.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein each 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.

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, which is a compound of:

14. a compound represented by the general formula (IA):

wherein:

r is an amino protecting group; preferably Boc;

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

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, having the structure:

16. a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises:

subjecting a compound represented by the general formula (IA) or a salt thereof to deprotection reaction to obtain a compound represented by the general formula (I)Or a 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;

wherein, the first and the second end of the pipe are connected with each other,

r is an amino protecting group; preferably Boc;

G ² is NH;

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

18. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for inhibiting KRAS G12D.

19. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition which is cancer.

20. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, 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, laryngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small bowel 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.