CN115701429B - 4- (1H-indol-1-yl) pyrimidine-2-amino derivative, and preparation method and application thereof - Google Patents

4- (1H-indol-1-yl) pyrimidine-2-amino derivative, and preparation method and application thereof Download PDF

Info

Publication number
CN115701429B
CN115701429B CN202210868336.4A CN202210868336A CN115701429B CN 115701429 B CN115701429 B CN 115701429B CN 202210868336 A CN202210868336 A CN 202210868336A CN 115701429 B CN115701429 B CN 115701429B
Authority
CN
China
Prior art keywords
alkyl
substituted
deuterium
cycloalkyl
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202210868336.4A
Other languages
Chinese (zh)
Other versions
CN115701429A (en
Inventor
杨飞
邓海兵
喻红平
陈椎
徐耀昌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbisko Therapeutics Co Ltd
Original Assignee
Abbisko Therapeutics Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbisko Therapeutics Co Ltd filed Critical Abbisko Therapeutics Co Ltd
Publication of CN115701429A publication Critical patent/CN115701429A/en
Application granted granted Critical
Publication of CN115701429B publication Critical patent/CN115701429B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention relates to a 4- (1H-indol-1-yl) pyrimidine-2-amino derivative, a preparation method and application thereof. In particular, the present invention relates to 4- (1H-indol-1-yl) pyrimidin-2-amino derivatives having the structure of formula (I), to processes for their preparation, to pharmaceutical compositions containing them and to their use as EGFR inhibitors and to their use in the manufacture of a medicament for the treatment and/or prophylaxis of cancer, tumour or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations, in particular in the treatment and/or prophylaxis of hyperproliferative diseases and diseases of induced cell death disorders. Wherein each substituent of formula (I) is as defined in the specification.

Description

4- (1H-indol-1-yl) pyrimidine-2-amino derivative, and preparation method and application thereof
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a 4- (1H-indole-1-yl) pyrimidine-2-amino derivative, and a preparation method and application thereof.
Background
Lung cancer is a leading cause of cancer death worldwide, with 85% of non-small cell lung cancers (NSCLC). Multi-target therapies directed against Epidermal Growth Factor Receptor (EGFR) mutations, anaplastic Lymphoma Kinase (ALK) translocations, ROS1 proto-oncogene receptor tyrosine kinase (ROS 1) rearrangements and B-raf proto-oncogenes, serine/threonine kinase (BRAF) have been successfully developed and clinically validated. Inhibitors against EGFR can significantly increase the progression free survival of adenocarcinomas in NSCLC, while acquired drug resistant mutations can be targeted by third generation EGFR inhibitors.
Although classical EGFR activating mutations (exons 19 and 21) and resistant mutations (T790M) can be inhibited by existing drugs, insertion mutations of Exon 20 (Exon 20) also result in structural activation of EGFR signaling and are not sensitive to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and involve the insertion or repetition of 1-7 amino acids between amino acids 762-774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all EGFR mutations. These mutations are mutually exclusive with other known oncogene-driven mutations and are enriched in adenocarcinomas of females, non-smokers, asian populations, and non-small cell lung cancer patients. In addition to NSCLC, EGFR exon 20 insertion mutations are also found in a rare head and neck cancer, nasal squamous cell carcinoma (SNSCC). In addition, a structurally similar exon 20 insertion mutation was also found in HER2, another member of the EGFR family.
Several retrospective analytical studies have shown that currently available generation 1, 2 and 3 EGFR inhibitors have limited efficacy for exon 20 insertion mutations, except for the a763-Y764insFQEA mutation. Irreversible inhibitor wave Ji Tini (Poziotinib) and EGFR/MET bispecific antibody amivanthaab are in clinical trials. Several small molecule inhibitors, including TAK-788 and TAS-6417, have shown clinically significant efficacy in EGFR exon 20 non-small cell lung cancer patients. However, adverse reactions in clinical use are unavoidable due to their limited selectivity for the wild type EGFR and may lead to dose-limiting toxicity. Meanwhile, it is clinically shown that the existing compounds may have an insufficient exposure. Thus, there is an urgent need for small molecule inhibitors with higher exposure and/or high selectivity for EGFR exon 20 insertion mutations for these patients.
Disclosure of Invention
The invention aims to provide 4- (1H-indol-1-yl) pyrimidine-2-amino derivatives, and a preparation method and application thereof, and the series of compounds have strong inhibition effect on EGFR exon 20 insertion, deletion or other mutation cytologic activity, have high selectivity on EGFR wild type, can be widely applied to the preparation of medicaments for treating and/or preventing cancers, tumors or metastatic diseases at least partially related to EGFR exon 20 insertion, deletion or other mutation, particularly medicaments for treating hyperproliferative diseases and diseases inducing cell death disorder, so that the novel EGFR inhibitor is hopeful to be developed.
The present invention provides in a first aspect a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein X is CH or N; y is a bond, O, S, N (R) 10 ) Or C (R) 11 R 12 )；
With the proviso that when X is CH, o is 2 and p is 2, Y is not N (R 10 ) Alternatively, when X is CH, o is 1 and p is 1, and Y is C (R 11 R 12 ) When R is 11 And R is 12 Together with the carbon atom to which it is directly attached, does not form a 4 membered heterocyclic group;
each R 1 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Alternatively, when m is equal to or greater than 2, two adjacent R 1 Together with the carbon atom to which it is directly attached form a C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said groups optionally being further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
R 2 and R is 3 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, -S (O) r R 13 and-C (O) R 15 Alternatively, R 2 And R is 3 Together with the nitrogen atom to which it is directly attached, form a 3-to 12-membered heterocyclic group, which is optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano、C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
R 4 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 ；
R 5 Selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, said groups optionally being further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
each R 6 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Alternatively, when n.gtoreq.2, two R 6 Together with the moieties directly linked thereto form C (O), C 3-12 Cycloalkyl or 3-12 membered heterocyclyl;
R 7 、R 8 and R is 9 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C (O) OR 14 、-C(O)R 15 、-C(O)NR 16 R 17 and-C 0-4 alkyl-NR 16 R 17 Is substituted by a substituent of (2);
R 10 selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, -C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 and-C 0-4 alkyl-C (O) NR 16 R 17 ；
R 11 And R is 12 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Alternatively, R 11 And R is 12 Together with the carbon atom to which it is directly attached form a C (O), C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said groups optionally being further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
each R 13 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl and-NR 16 R 17 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
each R 14 Each independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-to 10-membered heteroaryl, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, =o, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
each R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxyGroup and-NR 16 R 17 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
each R 16 And R is 17 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkoxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, di C 1-10 Alkylamino and C 1-10 Alkanoyl, said radicals optionally being further substituted with one or more radicals selected from deuterium, halogen, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, mono-C 1-10 Alkylamino, di C 1-10 Alkylamino and C 1-10 Substituted alkanoyl;
alternatively, R 16 And R is 17 Together with the nitrogen atom to which it is directly attached, form a 4-10 membered heterocyclic group, said group optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxyRadical, C 6-10 Aryl, C 6-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, mono-C 1-10 Alkylamino, di C 1-10 Alkylamino and C 1-10 Substituted alkanoyl;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5 or 6;
o is 1, 2 or 3;
p is 1, 2 or 3;
each r is independently 0, 1 or 2.
As a preferred embodiment, each R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 1 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 、-C 0-4 alkyl-O-C (O) R 15 、-C 0-4 alkyl-NR 16 R 17 、-C 0-4 alkyl-C (=nr 16 )R 15 、-C 0-4 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-4 alkyl-C (O) NR 16 R 17 and-C 0-4 alkyl-N (R) 16 )-C(O)R 15 Alternatively, when m is equal to or greater than 2, two adjacent R 1 Together with the carbon atom to which it is directly attached form a C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 、-C 0-4 alkyl-O-C (O) R 15 、-C 0-4 alkyl-NR 16 R 17 、-C 0-4 alkyl-C (=nr 16 )R 15 、-C 0-4 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-4 alkyl-C (O) NR 16 R 17 and-C 0-4 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
R 2 and R is 3 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -S (O) r R 13 and-C (O) R 15 Alternatively, R 2 And R is 3 Together with the nitrogen atom to which it is directly attached, form a 3-6 membered heterocyclic group, said group optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
R 4 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 、-C 0-4 alkyl-O-C (O) R 15 、-C 0-4 alkyl-NR 16 R 17 、-C 0-4 alkyl-C (=nr 16 )R 15 、-C 0-4 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-4 alkyl-C (O) NR 16 R 17 and-C 0-4 alkyl-N (R) 16 )-C(O)R 15 ；
R 5 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, said groups optionally being further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 、-C 0-4 alkyl-O-C (O) R 15 、-C 0-4 alkyl-NR 16 R 17 、-C 0-4 alkyl-C (=nr 16 )R 15 、-C 0-4 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-4 alkyl-C (O) NR 16 R 17 and-C 0-4 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
each R 6 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 、-C 0-4 alkyl-O-C (O) R 15 、-C 0-4 alkyl-NR 16 R 17 、-C 0-4 alkyl-C (=nr 16 )R 15 、-C 0-4 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-4 alkyl-C (O) NR 16 R 17 and-C 0-4 alkyl-N (R) 16 )-C(O)R 15 Alternatively, when n.gtoreq.2, two R 6 Together with the moieties directly linked thereto form C (O), C 3-6 Cycloalkyl or 3-6 membered heterocyclyl;
R 7 、R 8 and R is 9 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C (O) OR 14 、-C(O)R 15 、-C(O)NR 16 R 17 and-C 0-4 alkyl-NR 16 R 17 Is substituted by a substituent of (2);
R 10 selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 and-C 0-4 alkyl-C (O) NR 16 R 17 ；
R 11 And R is 12 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 、-C 0-4 alkyl-O-C (O) R 15 、-C 0-4 alkyl-NR 16 R 17 、-C 0-4 alkyl-C (=nr 16 )R 15 、-C 0-4 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-4 alkyl-C (O) NR 16 R 17 and-C 0-4 alkyl-N (R) 16 )-C(O)R 15 Alternatively, R 11 And R is 12 Together with the carbon atom to which it is directly attached form a C (O), C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-O-R 14 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 、-C 0-4 alkyl-O-C (O) R 15 、-C 0-4 alkyl-NR 16 R 17 、-C 0-4 alkyl-C (=nr 16 )R 15 、-C 0-4 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-4 alkyl-C (O) NR 16 R 17 and-C 0-4 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
wherein R is 13 、R 14 、R 15 、R 16 、R 17 M, n and r are as described for the compounds of formula (I).
In a preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is a compound of formula (ii):
wherein X is CH or N; y is a bond, O, S, N (R) 10 ) Or C (R) 11 R 12 )；
With the proviso that when X is CH, o is 2 and p is 2, Y is not N (R 10 ) Alternatively, when X is CH, o is 1 and p is 1, and Y is C (R 11 R 12 ) When R is 11 And R is 12 Together with the carbon atom to which it is directly attached, does not form a 4 membered heterocyclic group;
each R 1 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Alternatively, when m is equal to or greater than 2, two adjacent R 1 Together with the carbon atom to which it is directly attached form a C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
R 2 and R is 3 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -S (O) r R 13 and-C (O) R 15 Alternatively, R 2 And R is 3 Together with the nitrogen atom to which it is directly attached, form a 3-6 membered heterocyclic group, which optionally furtherIs/are selected from deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
R 4 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 ；
R 5 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, said groups optionally being further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Is substituted by (2)Substitution;
each R 6 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Alternatively, when n.gtoreq.2, two R 6 Together with the moieties directly linked thereto form C (O), C 3-6 Cycloalkyl or 3-6 membered heterocyclyl;
R 7 and R is 8 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 16 R 17 Is substituted by a substituent of (2);
R 10 selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -C 0-4 alkyl-S (O) r R 13 、-C 0-4 alkyl-C (O) OR 14 、-C 0-4 alkyl-C (O) R 15 and-C 0-4 alkyl-C (O) NR 16 R 17 ；
R 11 And R is 12 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Alternatively, R 11 And R is 12 Together with the carbon atom to which it is directly attached form a C (O), C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
wherein R is 13 、R 14 、R 15 、R 16 、R 17 M, n, o, p and r are as described for the compounds of formula (I).
As a preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is a compound of formula (iii):
wherein X is CH or N; y is a bond, O, S, N (R) 10 ) Or C (R) 11 R 12 )；
With the proviso that when X is CH, o 1 When 1, Y is not N (R 10 )；
R 1a 、R 1b 、R 1c And R is 1d Each independently selected from hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl and C 3-6 Cycloalkyl radicals, such as those mentioned aboveThe radicals optionally being further substituted by one or more radicals selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
R 2 and R is 3 Each independently selected from hydrogen, deuterium and C 1-4 Alkyl, or R 2 And R is 3 Together with the nitrogen atom to which it is directly attached, form a 3-6 membered heterocyclic group, said group optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
R 5 selected from hydrogen, deuterium and C 1-4 Alkyl, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
R 10 selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -S (O) r R 13 、-C(O)OR 14 、-C(O)R 15 and-C (O) NR 16 R 17 ；
R 11 And R is 12 Each independently selected from hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -O-R 14 and-NR 16 R 17 Alternatively, R 11 And R is 12 Together with the carbon atom to which it is directly attached form a C (O), C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -SF 5 、-S(O) r R 13 、-O-R 14 、-C(O)OR 14 、-C(O)R 15 、-O-C(O)R 15 、-NR 16 R 17 、-C(＝NR 16 )R 15 、-N(R 16 )-C(＝NR 17 )R 15 、-C(O)NR 16 R 17 and-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2);
o 1 0 or 1;
wherein R is 13 、R 14 、R 15 、R 16 、R 17 And r is as described for the compounds of formula (I).
As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, X is CH; y is a bond, O, S or C (R) 11 R 12 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein,R 11 and R is 12 As described for the compounds of formula (III).
As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, X is N; y is a bond, O, S, N (R) 10 ) Or C (R) 11 R 12 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 10 、R 11 And R is 12 As described for the compounds of formula (III).
As a further preferred embodiment, R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 1a 、R 1b 、R 1c And R is 1d Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 Alkyl and C 3-6 Cycloalkyl groups.
As a further preferred embodiment, R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 2 And R is 3 Each independently selected from hydrogen, deuterium, methyl, ethyl and isopropyl, or R 2 And R is 3 Together with the nitrogen atom to which it is directly attached, form a 4-5 membered heterocyclic group, which is optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, bromine, hydroxy, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl and-NR 16 R 17 Is substituted by a substituent of (2); wherein R is 16 And R is 17 As described for the compounds of formula (III).
As a further preferred embodiment, R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 5 Selected from hydrogen, deuterium, methyl and ethyl, optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, bromine, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and substituents of 3-6 membered heterocyclyl.
As a further preferred embodiment, R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 10 Selected from hydrogen, deuterium, hydroxy, methyl, ethyl, halo substituted C 1-2 Alkyl, deuterium substituted C 1-2 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -S (O) r R 13 、-C(O)OR 14 、-C(O)R 15 and-C (O) NR 16 R 17 ；
Wherein R is 13 、R 14 、R 15 、R 16 、R 17 And r is as described for the compounds of formula (III).
As a further preferred embodiment, R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 11 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl or methoxy;
R 12 selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -O-R 14 and-NR 16 R 17 The above groups are optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, bromine, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and = O;
alternatively, R 11 And R is 12 Together with the carbon atom to which it is directly attached form a C (O), C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally being further substituted by one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and = O;
wherein R is 14 、R 16 And R is 17 As described for the compounds of formula (III).
As a preferred embodiment, each R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 13 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl and-NR 16 R 17 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
each R 14 Each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, =o, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
each R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 16 R 17 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 16 R 17 Is substituted by a substituent of (2);
each R 16 And R is 17 Each independently selected from hydrogen, deuterium,Hydroxy, C 1-4 Alkoxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, di C 1-4 Alkylamino and C 1-4 Alkanoyl, said radicals optionally being further substituted with one or more radicals selected from deuterium, halogen, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 Alkylamino, di C 1-4 Alkylamino and C 1-4 Substituted alkanoyl;
alternatively, R 16 And R is 17 Together with the nitrogen atom to which it is directly attached, form a 4-6 membered heterocyclic group, said group optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C 6-8 Aryl, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 Alkylamino, di C 1-4 Alkylamino and C 1-4 The substituent of the alkanoyl group is substituted.
As a most preferred embodiment, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, includes, but is not limited to, the following:
/>
/>
in a second aspect the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
therein, X, Y, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 M, n, o and p are as described for the compounds of formula (I).
In a third aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also relates to the use of the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of cancer, tumor or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations.
The invention also relates to the use of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prophylaxis and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders.
The invention also relates to the use of the aforementioned compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prophylaxis and/or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynaecological tumors, urological tumor, skin tumor, sarcoma, nasal cavity sinus inverted papilloma or nasal cavity sinus squamous cell carcinoma associated with nasal cavity sinus inverted papilloma at least in part with EGFR exon 20 insertion, deletion or other mutation.
The invention also relates to the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, for use as a medicament.
The invention also relates to the use of the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, for the treatment and/or prevention of cancer, tumour or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations.
The invention also relates to the use of the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders.
The invention also relates to the use of the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, for the treatment and/or prophylaxis of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynaecological tumors, urological tumors, skin tumors, sarcomas, nasal sinus inverted papillomas or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papillomas, which are at least partially related to EGFR exon 20 insertions, deletions or other mutations.
The present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease associated at least in part with an insertion, deletion or other mutation of exon 20 of EGFR, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders, which comprises administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for the treatment and/or prophylaxis of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynaecological tumor, urological tumor, skin tumor, sarcoma, nasal sinus inverted papilloma or nasal sinus inverted papilloma-related nasal sinus squamous cell carcinoma, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
Detailed Description
The inventor of the application researches widely and intensively, and develops a 4- (1H-indol-1-yl) pyrimidine-2-amino derivative with the structure shown in the following formula (I) for the first time, and the series of compounds can be widely applied to the preparation of medicines for treating and/or preventing cancers, tumors or metastatic diseases at least partially related to EGFR exon 20 insertion, deletion or other mutations, particularly medicines for treating hyperproliferative diseases and diseases inducing cell death disorder, and are expected to be developed into a new generation EGFR inhibitor. On this basis, the present invention has been completed.
Detailed description: unless stated to the contrary or otherwise specified, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to straight or branched chain saturated aliphatic hydrocarbon groups, preferably straight and branched chain alkyl groups including 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited to methyl, ethylN-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched isomers thereof, and the like. "C 1-10 Alkyl "refers to straight chain alkyl and branched alkyl groups comprising 1 to 10 carbon atoms," C 1-4 Alkyl "refers to straight chain alkyl groups and branched alkyl groups containing 1 to 4 carbon atoms," C 0-8 Alkyl "refers to straight chain alkyl and branched alkyl groups comprising from 0 to 8 carbon atoms," C 0-4 Alkyl "refers to straight chain alkyl groups and branched alkyl groups comprising from 0 to 4 carbon atoms.
The alkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
"cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, and cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably cycloalkyl comprising 3 to 12 or 3 to 8 or 3 to 6 carbon atoms, e.g., "C 3-12 Cycloalkyl "refers to cycloalkyl groups comprising 3 to 12 carbon atoms," C 3-6 Cycloalkyl "refers to cycloalkyl groups comprising 3 to 6 carbon atoms, wherein:
monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to a polycyclic group having one carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as single-, double-, or multiple-spirocycloalkyl groups according to the number of common spiro atoms between rings, and include, but are not limited to:
"fused ring alkyl" refers to an all-carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system. The number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups including, but not limited to:
"bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms that are not directly attached, and which may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated pi-electron system. Bridged cycloalkyl groups, which may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic depending on the number of constituent rings, include, but are not limited to:
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
"heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi electron system, and the heterocyclyl has one or more (preferably 1, 2, 3 or 4) ring atoms selected from nitrogen, oxygen, S (O) (=nh) or S (O) r (wherein r is an integer of 0, 1, 2), but excluding the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms are carbon, preferably a heterocyclic group comprising 3 to 12 or 3 to 8 or 3 to 6 or 5 to 6 ring atoms, e.g., "3-4 membered heterocyclic group" means a ring group comprising 3 to 4 ring atoms, "3-6 membered heterocyclic group" means a ring group comprising 3 to 6 ring atoms, "3-12 membered heterocyclic group" means a ring group comprising 3 to 12 ring atoms, "4-10 membered heterocyclic group" means a ring group comprising 4 to 10 ring atoms.
Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S (O) (=nh) or S (O) r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings has a fully conjugated pi-electron system. The spiroheterocyclyl groups are classified as single spiroheterocyclyl groups, double spiroheterocyclyl groups or multiple spiroheterocyclyl groups according to the number of common spiro atoms between rings. Spiroheterocyclyl groups include, but are not limited to:
"fused heterocyclyl" refers to each ring in a system and the other rings in the systemA polycyclic heterocyclic group sharing an adjacent pair of atoms, one or more (preferably 1, 2, 3 or 4) of which may contain one or more (preferably 1, 2 or 3) double bonds, but none of which has a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S (O) (=nh) or S (O) r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, they may be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclylalkyl groups, including but not limited to:
"bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more (preferably 1, 2 or 3) double bonds, but none of which has a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S (O) (=nh) or S (O) r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, bridged heterocyclyl groups that may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic include, but are not limited to:
the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, including but not limited to:
the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group,C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
"aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic (i.e., ring bearing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group containing 6 to 10 or 6 to 8 or 6 carbons, e.g., "C 6-10 Aryl "refers to an all-carbon aryl group containing 6-10 carbons," C 6-8 Aryl "refers to all-carbon aryl groups containing 6 to 8 carbons including, but not limited to, phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:
"aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 memberedHeterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
"heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S (O) r (where r is an integer of 0, 1, 2), preferably a heteroaromatic system containing 5 to 10 or 5 to 8 or 5 to 6 ring atoms, e.g., "5 to 8 membered heteroaryl" refers to a heteroaromatic system containing 5 to 8 ring atoms, "5 to 10 membered heteroaryl" refers to a heteroaromatic system containing 5 to 10 ring atoms including, but not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, including but not limited to:
"heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroarylRadical, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched alkenyl group containing 2 to 10 or 2 to 4 carbons, e.g., "C 2-10 Alkenyl "refers to straight or branched alkenyl groups containing 2 to 10 carbons," C 2-4 Alkenyl "refers to straight or branched alkenyl groups containing 2 to 4 carbons. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.
"alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Substituted by substituents.
"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched alkynyl group containing 2 to 10 or 2 to 4 carbons, e.g., "C 2-10 Alkynyl "refers to straight or branched chain alkynyl groups containing 2 to 10 carbons," C 2-4 Alkynyl "refers to straight or branched chain alkynyl groups containing 2 to 4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.
"Alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
"alkoxy" refers to an-O-alkyl group, where alkyl is as defined above, e.g., "C 1-10 Alkoxy "refers to an alkyloxy group containing 1 to 10 carbons," C 1-4 Alkoxy "refers to an alkyl oxy group containing 1 to 4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
"alkoxy" may be optionally substituted orUnsubstituted, when substituted, a substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
"Cycloalkoxy" means-O-cycloalkyl, wherein cycloalkyl is as defined above, e.g., "C 3-12 Cycloalkoxy "refers to a cycloalkyloxy group of 3 to 12 carbons," C 3-8 Cycloalkoxy "refers to a cycloalkyloxy group having 3-8 carbons including, but not limited to, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"Cycloalkoxy" groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
"Heteroepoxy" refers to an-O-heterocyclic group wherein the heterocyclic group is defined as above, and heterocyclyloxy includes, but is not limited to, azetidinyloxy, oxetyloxy, azetidinyloxy, nitrogen, oxetyloxy, and the like.
"Heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 13 、-C 0-8 alkyl-O-R 14 、-C 0-8 alkyl-C (O) OR 14 、-C 0-8 alkyl-C (O) R 15 、-C 0-8 alkyl-O-C (O) R 15 、-C 0-8 alkyl-NR 16 R 17 、-C 0-8 alkyl-C (=nr 16 )R 15 、-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 、-C 0-8 alkyl-C (O) NR 16 R 17 and-C 0-8 alkyl-N (R) 16 )-C(O)R 15 Is substituted by a substituent of (2).
“C 1-10 Alkanoyl "means C 1-10 The monovalent radicals remaining after removal of the hydroxyl groups from the alkyl acid are also generally denoted as "C 0-9 alkyl-C (O) - ", e.g.," C 1 alkyl-C (O) - "refers to acetyl; "C 2 Alkyl-)C (O) - "refers to propionyl; "C 3 alkyl-C (O) - "refers to butyryl or isobutyryl.
“-C 0-8 alkyl-S (O) r R 13 "finger-S (O) r R 13 Wherein the sulfur atom is attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-O-R 14 "means-O-R 14 Wherein the oxygen atom is attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-C (O) OR 14 "means-C (O) OR 14 Wherein the carbonyl group is attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-C (O) R 15 "means-C (O) R 15 Wherein the carbonyl group is attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-O-C (O) R 15 "means-O-C (O) R 15 Wherein the oxygen atom is attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-NR 16 R 17 "refer to-NR 16 R 17 Wherein nitrogen atoms are attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-C (=nr 16 )R 15 "refer to-C (=NR) 16 )R 15 Wherein carbon atoms are attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-N (R) 16 )-C(＝NR 17 )R 15 "means-N (R) 16 )-C(＝NR 17 )R 15 Wherein nitrogen atoms are attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-C (O) NR 16 R 17 "means-C (O) NR 16 R 17 Wherein the carbonyl group is attached to C 0-8 On alkyl radicals, C 0-8 Alkyl groupIs defined as above.
“-C 0-8 alkyl-N (R) 16 )-C(O)R 15 "means-N (R) 16 )-C(O)R 15 Wherein nitrogen atoms are attached to C 0-8 On alkyl radicals, C 0-8 The definition of alkyl is as described above.
"halogen substituted C 1-10 Alkyl "refers to a 1-10 carbon alkyl group with hydrogen on the alkyl optionally substituted with fluorine, chlorine, bromine, iodine atoms, including but not limited to difluoromethyl (-CHF) 2 ) Dichloromethyl (-CHCl) 2 ) Dibromomethyl (-CHBr) 2 ) Trifluoromethyl (-CF) 3 ) Trichloromethyl (-CCl) 3 ) Tribromomethyl (-CBr) 3 ) Etc.
"halogen substituted C 1-10 Alkoxy "refers to a 1-10 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
"deuterium substituted C 1-10 Alkyl "refers to 1-10 carbon alkyl groups where the hydrogen on the alkyl is optionally substituted with deuterium atoms. Including but not limited to a deuteromethyl group (-CH) 2 D) Di-deuteromethyl (-CHD) 2 ) Trideuteromethyl (-CD) 3 ) Etc.
"deuterium substituted C 1-10 Alkoxy "refers to a 1-10 carbon alkyl group with hydrogen on the alkyl group optionally substituted with deuterium atoms. Including but not limited to mono-deuteromethoxy, di-deuteromethoxy, tri-deuteromethoxy, and the like.
"halogen" means fluorine, chlorine, bromine or iodine. "EtOAc" refers to ethyl acetate. "PE" refers to petroleum ether. "DMF" refers to dimethylformamide. "DIPEA" refers to N, N-diisopropylethylamine. "BINAP" refers to 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine. "THF" refers to tetrahydrofuran. "TFAA" refers to trifluoroacetic anhydride.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not, i.e., instances where it is substituted or unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more "hydrogen atoms" in the group are substituted independently of each other with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, in line with the theory of chemical valence, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., olefins).
"stereoisomers", which are named stereisomer, refer to isomers produced by the different spatial arrangements of atoms in the molecule, and can be classified into cis-trans isomers, enantiomers, and enantiomers. Stereoisomers due to rotation of a single bond are known as conformational isomers (conformational stereo-isomers), sometimes also known as rotamers. Stereoisomers due to bond length, bond angle, double bonds in the molecule, rings, etc. are called configurational isomers (configuration stereo-isomers), which are classified into two types. Wherein isomers due to the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely become geometric isomers (also known as cis-trans isomers), fall into the Z, E configuration. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the compounds of the present invention are understood to comprise E and/or Z forms if they contain double bonds, unless otherwise indicated. Stereoisomers with different optical properties due to the lack of anti-axisymmetry in the molecule are called optical isomers (optical isomers) and are classified as R, S configurations. "stereoisomers" as used herein, unless otherwise indicated, are understood to include one or more of the enantiomers, configurational isomers and conformational isomers described above.
By "pharmaceutically acceptable salts" is meant in the present invention pharmaceutically acceptable acid or base addition salts, including inorganic and organic acid salts, which salts can be prepared by methods known in the art.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using a Bruker AVANCE-400/500 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (MeOH-d) 4 ) And deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
The LC-MS measurement was performed by using an Agilent 6120 mass spectrometer. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being dry solvent and the reaction temperature being in degrees celsius (°c) without specific description.
1. Preparation of intermediates
Intermediate I-1: preparation of 4-fluoro-5-nitro-2- (2, 2-trifluoroethoxy) aniline
The first step: synthesis of 4-fluoro-1-nitro-2- (2, 2-trifluoroethoxy) benzene
2, 4-difluoro-1-nitrobenzene (5 g,31.43 mmol) was dissolved in THF (50 mL) and Cs was added 2 CO 3 (10.24 g,31.43 mmol) and CF 3 CH 2 OH (2.26 mL,31.43 mmol), and stirred overnight at room temperature. After the completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, 4-fluoro-1-nitro-2- (2, 2-trifluoroethoxy) benzene (6.5 g, yield: 86.4%) was obtained. MS m/z (ESI) 240.0[ M+H ] ] + 。
And a second step of: synthesis of 4-fluoro-2- (2, 2-trifluoroethoxy) aniline
4-fluoro-1-nitro-2- (2, 2-trifluoroethoxy) benzene (7.5 g,31.37 mmol) was dissolved in MeOH (60 mL) and water (15 mL) and NH was added 4 Cl (16.78 g,313.65 mmol) and Fe powder (17.52 g,313.65 mmol) and the reaction was stirred at 85℃for 2 hours. After the reaction, the mixture was filtered, and the filtrate was concentrated. The crude product was separated by column chromatography to give 4-fluoro-2- (2, 2-trifluoroethoxy) aniline (5.5 g, yield: 83.8%). MS m/z (ESI) 210.0[ M+H ]] + 。
And a third step of: synthesis of 4-fluoro-5-nitro-2- (2, 2-trifluoroethoxy) aniline
4-fluoro-2- (2, 2-trifluoroethoxy) aniline (3 g,14.34 mmol) was dissolved in concentrated sulfuric acid (10 mL), and KNO was added in portions 3 (1.74 g,17.21 mmol) and stirred at 0deg.C for 1 hour. After the completion of the reaction, the reaction mixture was poured into ice water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave 4-fluoro-5-nitro-2- (2, 2-trifluoroethoxy) aniline (3.5 g, yield: 86.3%). MS m/z (ESI) 255.0[ M+H ]] + 。
Intermediate I-2: preparation of 2-ethoxy-4-fluoro-5-nitroaniline
The first step: synthesis of 2-ethoxy-4-fluoro-1-nitrobenzene
5-fluoro-2-nitrophenol (5.0 g,31.83 mmol) was dissolved in DMF (150 mL) followed by K 2 CO 3 (13.2 g,95.48 mmol) and iodoethane (5.1 mL,63.65 mmol) were stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, 2-ethoxy-4-fluoro-1-nitrobenzene (4.6 g, yield: 78.1%) was obtained. MS m/z (ESI): 186.0[ M+H ]] + 。
And a second step of: synthesis of 2-ethoxy-4-fluoroaniline
2-ethoxy-4-fluoro-1-nitrobenzene (4.5 g,24.31 mmol) was dissolved in methanol (60 mL) and water (15 mL) followed by NH addition 4 Cl (13.0 g,243.05 mmol) and Fe powder (13.57 g,243.05 mmol), heated at 85℃and stirred for 2 hours. After the reaction, the mixture was filtered, and the filtrate was concentrated to give 2-ethoxy-4-fluoroaniline (3.5 g, yield: 92.8%) by column chromatography of the crude product. M is MS m/z(ESI):156.0[M+H] + 。
And a third step of: synthesis of 2-ethoxy-4-fluoro-5-nitroaniline
2-ethoxy-4-fluoroaniline (3.5 g,22.56 mmol) was dissolved in concentrated sulfuric acid (10 mL) and KNO was added in portions 3 (2.74 g,27.07 mmol) and stirred at 0deg.C for 1 hour. After the reaction, the reaction mixture was poured into ice water, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave 2-ethoxy-4-fluoro-5-nitroaniline (2.0 g, yield: 42.0%). MS m/z (ESI) 201.0[ M+H ] ] + 。
Intermediate I-3 is prepared by selecting corresponding starting materials with reference to a preparation method of intermediate I-2.
Intermediate I-4: preparation of 2- (difluoromethoxy) -4-fluoro-5-nitroaniline
The first step: synthesis of 2- (difluoromethoxy) -4-fluoro-1-nitrobenzene
5-fluoro-2-nitrophenol (10.0 g,63.65 mmol) was dissolved in DMF (100 mL) followed by Na addition 2 CO 3 (20.24 g,190.96 mmol), heated to 90℃and added in portions with stirring ClCF 2 CO 2 Na (33.97 g,222.79 mmol) was reacted for 3 hours at 90 ℃. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phase was washed with saturated brine and with anhydrous sodium sulfateAnd (5) drying. Filtration, concentration and column chromatography of the crude product gave 2- (difluoromethoxy) -4-fluoro-1-nitrobenzene (10.1 g, yield: 74.7%).
1 H NMR(400MHz,CDCl 3 )δ8.03(dd,J＝9.1,5.6Hz,1H),7.14(ddt,J＝8.6,2.2,1.0Hz,1H),7.09(ddd,J＝9.0,7.1,2.6Hz,1H),6.64(t,J＝72.3Hz,1H)。
And a second step of: synthesis of 2- (difluoromethoxy) -4-fluoroaniline
2- (difluoromethoxy) -4-fluoro-1-nitrobenzene (10.1 g,47.55 mmol) was dissolved in ethanol (80 mL), then Pd/C (1.0 g, 10%) was added, the reaction was performed three times with hydrogen evolution at room temperature overnight, and the temperature was raised to 40℃for 3 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to give 2- (difluoromethoxy) -4-fluoroaniline (8.0 g, yield: 85.2%). MS m/z (ESI): 178.1[ M+H ] ] + 。
And a third step of: synthesis of 2- (difluoromethoxy) -4-fluoro-5-nitroaniline
2- (difluoromethoxy) -4-fluoroaniline (8.0 g,40.51 mmol) was dissolved in concentrated sulfuric acid (40 mL) and KNO was added in portions at 0deg.C 3 (4.51 g,44.56 mmol) and stirring at 0deg.C was continued for 0.5 hours after the addition, and then the reaction was allowed to proceed to room temperature for 2 hours. After the reaction, the mixture was poured into ice water, the pH was adjusted to 8 with an aqueous 8N NaOH solution, extraction was performed three times with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography gave 2- (difluoromethoxy) -4-fluoro-5-nitroaniline (4.73 g, yield: 45.4%).
Intermediate II-1: preparation of N- (2-methoxy-6-morpholino-5-nitropyridin-3-yl) acetamide
The first step: synthesis of 6-chloro-2-methoxypyridin-3-amine
6-chloro-2-methoxy-3-nitropyridine (10 g,53.03 mmol), NH 4 Cl (14.2 g,0.27 mol), fe powder (14.8 g,0.27 mol) were placed in EtOH (90 mL) and water (30 mL), and the mixture was stirred at 80℃for 1.5 h under nitrogen. The reaction was cooled to room temperature, filtered, and the filtrate was diluted with water and extracted with ethyl acetate. The organic phase was washed successively with saturated NaHCO 3 The aqueous solution and brine were washed and dried over anhydrous sodium sulfate. Filtration, concentration and column chromatography gave 6-chloro-2-methoxypyridin-3-amine (6.21 g, yield: 73.8%). MS m/z (ESI): 159.1[ M+H ] ] + 。
And a second step of: synthesis of N- (6-chloro-2-methoxypyridin-3-yl) acetamide
6-chloro-2-methoxypyridin-3-amine (6.21 g,39.16 mmol) was added to CH 2 Cl 2 To (100 mL) was added DIPEA (7.59 g,58.74 mmol) and acetyl chloride (3.69 g,46.99 mmol) in sequence with cooling in an ice-water bath and stirring was continued for 1.5 hours at 0deg.C. CH for reaction solution 2 Cl 2 Diluted, then washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. Filtration, concentration and crude column chromatography gave N- (6-chloro-2-methoxypyridin-3-yl) acetamide (7.02 g, yield: 89.4%). MS m/z (ESI) 201.1[ M+H ]] + 。
And a third step of: synthesis of N- (6-chloro-2-methoxy-5-nitropyridin-3-yl) acetamide
N- (6-chloro-2-methoxypyrazole)To TFAA (100 mL) was added pyridin-3-yl) acetamide (7.02 g,35.14 mmol), and concentrated nitric acid (3.64 g,38.65 mmol) was added with cooling in an ice-water bath and stirring was continued at 0deg.C for 1.5 hours under nitrogen. The reaction solution was added dropwise to ice water to precipitate a solid. The solid was filtered, washed with water and dried to give N- (6-chloro-2-methoxy-5-nitropyridin-3-yl) acetamide (7.60 g, yield: 88.1%). MS m/z (ESI): 246.1[ M+H ]] + 。
Fourth step: synthesis of N- (2-methoxy-6-morpholino-5-nitropyridin-3-yl) acetamide
N- (6-chloro-2-methoxy-5-nitropyridin-3-yl) acetamide (500 mg,2.04 mmol), DIPEA (789.4 mg,6.11 mmol) and morphine (354.7 mg,4.07 mmol) were placed in acetonitrile (20 mL) and heated at 80℃under nitrogen for 1.5 h. The reaction was cooled to room temperature and concentrated. The crude product was isolated by column chromatography to give N- (2-methoxy-6-morpholino-5-nitropyridin-3-yl) acetamide (600 mg, yield: 99.5%). MS m/z (ESI): 297.1[ M+H ] ] + 。
Intermediate II-2: preparation of N- (6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
The first step: synthesis of 6-bromo-3-nitro-2- (2, 2-trifluoroethoxy) pyridine
2, 2-trifluoroethanol (3.73 g,37.25 mmol) was placed in THF (200 mL), 60% NaH (1.56 g,39.02 mmol) was added under ice-water bath, the mixture was stirred at 0℃for 30 minutes, then 2, 6-dibromo-3-nitropyridine (10.0 g,35.47 mmol) was added and stirring was continued at 0℃for 1 hour. The reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate, followed bySequentially with saturated NaHCO 3 The aqueous solution and brine were washed and dried over anhydrous sodium sulfate. Filtration and concentration gave 6-bromo-3-nitro-2- (2, 2-trifluoroethoxy) pyridine (9.5 g, yield: 84.8%). MS m/z (ESI) 302.0[ M+H ]] + 。
And a second step of: synthesis of 6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-amine
6-bromo-3-nitro-2- (2, 2-trifluoroethoxy) pyridine (9.5 g,31.56 mmol), NH 4 Cl (16.88 g,0.32 mol) and Fe powder (8.8 g,0.16 mol) were placed in ethanol (60 mL) and water (60 mL), and the mixture was stirred at 80℃for 1.5 hours under nitrogen blanket. The reaction was cooled to room temperature, filtered, the filtrate diluted with water and extracted with ethyl acetate, followed by sequential extraction with saturated NaHCO 3 The aqueous solution and brine were washed and dried over anhydrous sodium sulfate. Filtration and concentration gave 6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-amine (8.25 g, yield: 96.5%). MS m/z (ESI): 272.0[ M+H ]] + 。
And a third step of: synthesis of N- (6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-amine (8.25 g,30.44 mmol) was placed in acetic anhydride (50 mL) and stirred at room temperature under nitrogen for 1 hour. The reaction solution was diluted with ethyl acetate, which was then washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. Filtration, concentration and crude column chromatography gave N- (6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (8.3 g, yield: 87.1%). MS m/z (ESI) 314.0[ M+H ]] + 。
Fourth step: synthesis of N- (6-bromo-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
N- (6-bromo-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (8.3 g,26.5 mmol) was placed in TFAA (100 mL), concentrated nitric acid (7.48 g,79.53 mmol) was added under ice-water bath cooling and the mixture was stirred at 0deg.C for 1 hour under nitrogen blanket. The reaction was completed, the reaction solution was added dropwise to ice water, and a solid was precipitated, and the solid was filtered, washed with water and dried to give N- (6-bromo-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (9.2 g, yield: 96.9%). MS m/z (ESI): 359.0[ M+H ] ] + 。
Fifth step: synthesis of N- (6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
N- (6-bromo-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (500 mg,1.40 mmol), DIPEA (541.4 mg,4.19 mmol) and morphine (243.3 mg,2.80 mmol) were placed in acetonitrile (20 mL) and the mixture stirred at 80℃for 1.5 h under nitrogen. The reaction solution was cooled to room temperature, concentrated, and the crude product was separated by column chromatography to give N- (6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (500 mg, yield: 98.3%). MS m/z (ESI): 365.1[ M+H ]] + 。
The intermediates II-3 to II-12 are prepared by selecting the corresponding starting materials with reference to the preparation method of the intermediate II-1 or II-2.
/>
2. Preparation of specific examples
Example 1: preparation of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide
The first step: synthesis of 1- (2-chloropyrimidin-4-yl) -6-fluoro-1H-indole-3-carbaldehyde
6-fluoro-1H-indole-3-carbaldehyde (3.0 g,18.39 mmol), 2, 4-dichloropyrimidine (4.11 g,27.58 mmol) and K 2 CO 3 (5.08 g,36.78 mmol) was placed in acetonitrile (100 mL) and stirred at room temperature under nitrogen overnight. The reaction solution was filtered, and the filtrate was concentrated, and the obtained crude product was separated by column chromatography to give 1- (2-chloropyrimidin-4-yl) -6-fluoro-1H-indole-3-carbaldehyde (1.73 g, yield: 34.1%). MS m/z (ESI): 276.1[ M+H ] ] + 。
And a second step of: synthesis of 6-fluoro-1- (2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde
1- (2-Chloropyrimidin-4-yl) -6-fluoro-1H-indole-3-carbaldehyde (400 mg,1.45 mmol), 4-fluoro-2-methoxy-5-nitroaniline (405 mg,2.18 mmol), cs 2 CO 3 (1418mg，4.35mmol)、Pd(OAc) 2 (65 mg,0.29 mmol) and BINAP (180 mg,0.29 mmol) were placed in 1, 4-dioxane (20 mL) and stirred at 90℃for 1 hour under nitrogen. The reaction solution was diluted with water and with CH 2 Cl 2 The extract was then carried out, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentrating. The crude product was separated by column chromatography to give 6-fluoro-1- (2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (342 mg, yield: 51.5%). MS m/z (ESI): 426.0[ M+H ]] + 。
And a third step of: synthesis of 6-fluoro-1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde
6-fluoro-1- (2- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (267 mg,0.38 mmol) and DIPEA (146 mg,1.13 mmol) were placed in 1, 4-dioxane (3 mL), morpholine (98 mg,1.13 mmol) was added and stirred overnight at 110 ℃. CH for reaction solution 2 Cl 2 Dilute and sequentially use saturated NH 4 The organic phase was dried over anhydrous sodium sulfate. Filtration, concentration and direct separation using a preparative column afforded 6-fluoro-1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (230 mg, yield: 76.9%). MS m/z (ESI): 493.2[ M+H ] ] + 。
Fourth step: synthesis of 4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine
6-fluoro-1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (200 mg,0.41 mmol) and dimethylamine hydrochloride (165 mg,2.03 mmol) were placed in CH 2 Cl 2 To a mixed solution of MeOH (10 mL, 1:1), naBH was then added 3 CN (127 mg,2.03 mmol), was stirred at 50℃for 5 hours. CH for reaction solution 2 Cl 2 Dilute and sequentially use saturated NH 4 The organic phase was dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate, and directly using the filtrate for the next reaction. MS m/z (ESI): 522.2[ M+H ]] + 。
Fifth step: n (N) 1 Synthesis of- (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholino-benzene-1, 3-diamine
4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine (0.41 mmol) was placed in a methanol/water (8 mL, 4:1) mixture and Fe powder (181 mg,3.25 mmol) and NH were added 4 Cl (325 mg,6.09 mmol). The mixture was stirred at 80℃for 3 hours under nitrogen. CH for reaction solution 2 Cl 2 Dilute and use saturated NaHCO in turn 3 The mixture was washed with water and brine, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate, and directly using the filtrate for the next reaction. MS m/z (ESI): 492.2[ M+H ] ] + 。
Sixth step: synthesis of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide
N 1 - (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholino-benzene-1, 3-diamine (0.41 mmol) and NaHCO 3 (170 mg,2.03 mmol) was placed in a mixture of THF (8 mL) and water (2 mL), and acryloyl chloride (55 mg,0.61 mmol) was added under ice-water cooling, followed by stirring for 15 min, and then ammonia (5 mL) was added and stirring was continued for 5 min. The reaction was extracted twice with EtOAc, the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate followed by column chromatography on silica gel afforded crude product, which was then isolated by column chromatography to afford N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide (55.5 mg, yield: 25%). MS m/z (ESI) 546.2[ M+H ]] + 。
1 H NMR(400MHz,CDCl 3 )δ9.41(s,1H),8.57(s,1H),8.45(d,J＝5.6Hz,1H),8.11-7.93(m,2H),7.65(dd,J＝8.6,5.6Hz,1H),7.55(s,1H),6.97(td,J＝8.9,2.4Hz,1H),6.85(d,J＝5.7Hz,1H),6.80(s,1H),6.38(dd,J＝17.0,1.7Hz,1H),6.29(dd,J＝16.9,9.8Hz,1H),5.76(d,J＝9.9Hz,1H),3.91(s,3H),3.89(d,J＝4.9Hz,4H),3.72(s,2H),2.91(t,J＝4.6Hz,4H),2.35(s,6H)。
Example 2: preparation of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2-morpholino-4- (2, 2-trifluoroethoxy) phenyl) acrylamide
The first step: synthesis of 4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) aniline
4-fluoro-5-nitro-2- (2, 2-trifluoroethoxy) aniline (1.5 g,5.90 mmol) was dissolved in acetonitrile (20 mL) and then K was added 2 CO 3 (1.63 g,11.81 mmol) and morpholine (0.78 mL,8.85 mmol) were stirred at 80℃for 2 hours. After the completion of the reaction, the filtrate was filtered, concentrated and separated by column chromatography to give 4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) aniline (1.5 g, yield: 63.3%). MS m/z (ESI) 322[ M+H ]] + 。
And a second step of: synthesis of 6-fluoro-1- (2- ((4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) phenyl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde
1- (2-Chloropyrimidin-4-yl) -6-fluoro-1H-indole-3-carbaldehyde (200 mg,0.73 mmol) was dissolved in 1, 4-dioxane (15 mL), then 4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) aniline (256 mg,0.80 mmol), cs were added 2 CO 3 (473 mg,1.45 mmol), BINAP (316 mg,0.51 mmol) and Pd (OAc) 2 (81 mg,0.36 mmol) under nitrogen, stirring for 2 hours at 90 ℃. Concentrating after the reaction is finished, and separating the crude product by column chromatography to obtain 6-fluoro-1- (2- ((4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) phenyl) amino) pyrimidine-4-yl) -1H-indole-3-carbaldehyde (240 m)g, yield: 59%). MS m/z (ESI): 561.2[ M+H ]] + 。
And a third step of: synthesis of 4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) phenyl) pyrimidin-2-amine
6-fluoro-1- (2- ((4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) phenyl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (230 mg,0.41 mmol) dissolved in CH 2 Cl 2 To a mixture of (10 mL) and MeOH (10 mL) was then added dimethylamine hydrochloride (167 mg,2.05 mmol) and NaBH 3 CN (103 mg,1.64 mmol), was stirred overnight at 45 ℃. After the reaction, the mixture was concentrated, and the crude product was separated by column chromatography to give 4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) phenyl) pyrimidin-2-amine (170 mg, yield: 70%). MS m/z (ESI): 590.2[ M+H ]] + 。
Fourth step: n (N) 1 Synthesis of- (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -4-morpholino-6- (2, 2-trifluoroethoxy) benzene-1, 3-diamine
4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (4-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) phenyl) pyrimidin-2-amine (150 mg,0.25 mmol) was dissolved in MeOH (10 mL) and water (2.5 mL) then NH was added 4 Cl (136 mg,2.54 mmol) and Fe powder (142 mg,2.54 mmol) were stirred at 85℃for 2 hours. After the reaction, the mixture was filtered, and the filtrate was concentrated. Separating the crude product by column chromatography to obtain N 1 - (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -4-morpholino-6- (2, 2-trifluoroethoxy) benzene-1, 3-diamine (130 mg, yield: 77.6%). MS m/z (ESI): 560.2[ M+H ]] + 。
Fifth step: synthesis of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2-morpholino-4- (2, 2-trifluoroethoxy) phenyl) acrylamide
N 1 - (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -4-morpholino-6- (2, 2-trifluoroethoxy) benzene-1, 3-diamine (130 mg,0.23 mmol) in THF (4 mL) and saturated NaHCO 3 To the aqueous solution (1 mL) was then added dropwise acryloyl chloride (0.04 mL,0.47 mmol), and the mixture was stirred at room temperature for 10 minutes. Adding CH after the reaction is finished 2 Cl 2 The organic phase was extracted, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate followed by column chromatography separation gives crude product, which is then further prepared by column separation to give N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2-morpholino-4- (2, 2-trifluoroethoxy) phenyl) acrylamide (24 mg, yield: 16%). MS m/z (ESI): 614.3[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ9.10(s,1H),8.84(s,1H),8.36(d,J＝5.7Hz,1H),8.22(s,1H),8.13(s,1H),8.02(s,1H),7.66(dd,J＝8.6,5.8Hz,1H),7.13-7.07(m,2H),7.01(td,J＝9.0,2.5Hz,1H),6.67(dd,J＝17.1,10.2Hz,1H),6.20(dd,J＝17.0,1.8Hz,1H),5.73(d,J＝9.8Hz,1H),4.68(q,J＝8.9Hz,2H),3.83(t,J＝4.4Hz,4H),3.54(s,2H),2.88(t,J＝4.3Hz,4H),2.17(s,6H)。
19 F NMR(400MHz,DMSO-d 6 )δ-72.79,-117.75。
Examples 3 to 22 and 39 can be prepared by selecting the corresponding starting materials with reference to the whole or part of the synthesis method of examples 1 or 2:
/>
/>
/>
/>
example 23: preparation of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -6-methoxy-2-morpholinopyridin-3-yl) acrylamide
The first step: synthesis of 6-fluoro-1- (2- ((2-methoxy-6-morpholino-5-nitropyridin-3-yl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde
1- (2-Chloropyrimidin-4-yl) -6-fluoro-1H-indole-3-carbaldehyde (150 mg,0.46 mmol) and N- (2-methoxy-6-morpholino-5-nitropyridin-3-yl) acetamide (137 mg,0.46 mmol), cs 2 CO 3 (452mg，1.39mmol)、Pd(OAc) 2 (21 mg,0.09 mmol) and BINAP (58 mg,0.09 mmol) were placed in 1, 4-dioxane (10 mL) and stirred at 105℃for 1 hour under nitrogen. The reaction was cooled to room temperature and MeOH (5 mL) and K were then added 2 CO 3 (500 mg) and stirred at 60℃for 20 minutes, and the reaction solution was cooled to room temperature. Filtration, concentration of the filtrate, and separation by column chromatography gave 6-fluoro-1- (2- ((2-methoxy-6-morpholino-5-nitropyridin-3-yl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (125 mg, yield: 57.8%). MS m/z (ESI): 494.2[ M+H ]] + 。
And a second step of: synthesis of 4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (2-methoxy-6-morpholino-5-nitropyridin-3-yl) pyrimidin-2-amine
6-fluoro-1- (2- ((2-methoxy-6-morpholino-5-nitropyridin-3-yl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (125 mg,0.263 mmol) and dimethylamine hydrochloride (107 mg,1.317 mmol) were placed in CH 2 Cl 2 To a mixture of MeOH (10 mL, 1:1), stirred at room temperature for 10 min, then NaBH was added 3 CN (66 mg,1.05 mmol), and the mixture was stirred overnight at 45 ℃. The reaction solution was cooled to room temperature and concentrated. The crude product was isolated by column chromatography to give 4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (2-methoxy-6-morpholino-5-nitropyridin-3-yl) pyrimidin-2-amine (95 mg, yield: 69.1%). MS m/z (ESI): 523.2[ M+H ] ] + 。
And a third step of: n (N) 3 Synthesis of- (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -2-methoxy-6-morpholinopyridine-3, 5-diamine
4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (2-methoxy-6-morpholino-5-nitropyridin-3-yl) pyrimidin-2-amine (95 mg,0.18 mmol) was placed in MeOH (10 mL) followed by the addition of Fe powder (101 mg,1.82 mmol) and saturated NH 4 Aqueous Cl (3 mL). Stirring is carried out at 80℃for 1 hour under nitrogen. The reaction solution was cooled to room temperature, filtered, and the filtrate was treated with CH 2 Cl 2 Diluted and then sequentially treated with saturated NaHCO 3 The aqueous solution and brine were washed and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and separation by column chromatography gave N3- (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -2-methoxy-6-morpholinopyridine-3, 5-diamine (45 mg, yield: 50.2%). MS m/z (ESI): 493.2[ M+H ]] + 。
Fourth step: synthesis of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -6-methoxy-2-morpholinopyridin-3-yl) acrylamide
N 3 - (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -2-methoxy-6-morpholinopyridine-3, 5-diamine (45 mg,0.09 mmol) placed in CH 2 Cl 2 (3 mL) of Et was added successively with cooling in an ice-water bath 3 N (18.5 mg,0.18 mmol) and acryloyl chloride (9.1 mg,0.10 mmol) were stirred at 0deg.C for 30 min. Adding ammonia water for quenching, CH 2 Cl 2 Extraction was performed twice. The organic phase was washed successively with saturated NaHCO 3 The aqueous solution and brine were washed and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and separated by reverse phase column chromatography to give N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -6-methoxy-2-morpholinopyridin-3-yl) acrylamide (21.2 mg, yield: 42.5%). MS m/z (ESI): 547.2[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ9.32(s,1H),8.89(s,1H),8.36(d,J＝5.7Hz,1H),8.23(s,1H),8.13(s,1H),8.01(s,1H),7.69-7.65(dd,J＝8.5,5.8Hz,1H),7.12-7.10(d,J＝5.8Hz,1H),7.07-7.01(m,1H),6.64-6.57(dd,J＝17.0,10.2Hz,1H),6.23-6.18(dd,J＝17.0,2.1Hz,1H),5.73-5.70(dd,J＝10.1,2.1Hz,1H),3.86(s,3H),3.80-3.76(m,4H),3.54(s,2H),3.21-3.16(m,4H),2.18(s,6H)。
19 F NMR(400MHz,DMSO-d 6 )δ–117.55。
Example 24: preparation of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2-morpholino-6- (2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide
The first step: synthesis of 6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-amine
N- (6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (500 mg,1.40 mmol) was placed in MeOH (20 mL), concentrated hydrochloric acid (0.52 mL,6.18 mmol) was added and stirred overnight at 60℃under nitrogen. The reaction solution was cooled to room temperature, concentrated, and then saturated NaHCO was added 3 Adjusting pH of the aqueous solution to 8-9, and adding CH 2 Cl 2 And (5) extracting. The organic phase was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and separation by column chromatography gave 6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-amine (105 mg, yield: 24.3%). MS m/z (ESI) 323.1[ M+H ] ] + 。
And a second step of: synthesis of 6-fluoro-1- (2- ((6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde
1- (2-Chloropyrimidin-4-yl) -6-fluoro-1H-indole-3-carbaldehyde (75 mg,0.27 mmol) and 6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-amine (105 mg,0.33 mmol), cs 2 CO 3 (266mg，0.82mmol)、Pd(OAc) 2 (12.2 mg,0.05 mmol) and BINAP (33.9 mg,0.05 mmol) were placed in 1, 4-dioxane (10 mL) and stirred at 105℃for 1 hour under nitrogen. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and separated by column chromatography to give 6-fluoro-1- (2- ((6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (133 mg, yield: 87.1%). MS m/z (ESI): 562.1[ M+H ]] + 。
And a third step of: synthesis of 4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) pyrimidin-2-amine
6-fluoro-1- (2- ((6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) amino) pyrimidin-4-yl) -1H-indole-3-carbaldehyde (133 mg,0.24 mmol) and dimethylamine hydrochloride (96.6 mg,1.18 mmol) were placed in CH 2 Cl 2 To a mixture of MeOH (15 mL, 1:1), stirred at room temperature for 10 min, then NaBH was added 3 CN (59.5 mg,0.95 mmol) was stirred overnight at 45 ℃. The reaction solution was cooled to room temperature and concentrated. The crude product was isolated by column chromatography to give 4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) pyrimidin-2-amine (120 mg, yield: 85.6%). MS m/z (ESI): 591.2[ M+H ]] + 。
Fourth step: n (N) 3 Synthesis of- (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -6-morpholino-2- (2, 2-trifluoroethoxy) pyridine-3, 5-diamine
4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (6-morpholino-5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) pyrimidin-2-amine (120 mg,0.20 mmol) was placed in methanol (10 mL) followed by Fe powder (114 mg,2.03 mmol) and saturated NH 4 Aqueous Cl (3 mL). The mixture was stirred at 80℃for 1 hour under nitrogen. The reaction solution was cooled to room temperature, filtered, and the filtrate was treated with CH 2 Cl 2 Diluted and then sequentially treated with saturated NaHCO 3 The aqueous solution and brine were washed and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate, and separating by column chromatography to obtain N 3 - (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -6-morpholino-2- (2, 2-trifluoroethoxy) pyridine-3, 5-diamine (41 mg, yield: 35.9%). MS m/z (ESI): 561.1[ M+H ] ] + 。
Fifth step: synthesis of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2-morpholino-6- (2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide
N 3 - (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -6-morpholino-2- (2, 2-trifluoroethoxy) pyridine-3, 5-diamine (41 mg,0.07 mmol) placed in CH 2 Cl 2 (3 mL) of Et was added successively with cooling in an ice-water bath 3 N (14.8 mg,0.15 mmol) and acryloyl chloride (7.9 mg,0.09 mmol) were stirred at 0deg.C for 30 min. Adding ammonia water for quenching, CH 2 Cl 2 Extraction was performed 2 times. The organic phases were combined, followed by saturated NaHCO 3 The aqueous solution and brine were washed and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate followed by reverse phase column chromatography gave N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2-morpholino-6- (2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide (10.5 mg, yield: 23.4%). MS m/z (ESI): 615.2[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ9.41(s,1H),9.00(s,1H),8.35(d,J＝5.7Hz,1H),8.11(s,2H),8.01(s,1H),7.69-7.65(dd,J＝8.7,5.8Hz,1H),7.12(d,J＝5.7Hz,1H),7.05-7.00m,1H),6.65-6.58(dd,J＝17.0,10.2Hz,1H),6.24-6.19(dd,J＝17.0,2.0Hz,1H),5.75-5.71(dd,J＝10.1,2.0Hz,1H),4.95-4.88(m,2H),3.80-3.77(m,4H),3.54(s,2H),3.21-3.17(m,4H),2.18(s,6H)。
19 F NMR(400MHz,DMSO-d 6 )δ-72.12,-117.55。
Example 25: preparation of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-morpholinopiperidin-1-yl) -6- (2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide
The first step: synthesis of N- (4- (6-fluoro-3-formyl-1H-indol-1-yl) pyrimidin-2-yl) -N- (6- (4-morpholinopiperidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide
1- (2-Chloropyrimidin-4-yl) -6-fluoro-1H-indole-3-carbaldehyde (200 mg,0.73 mmol) and N- (6- (4-morpholinopiperidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (325 mg,0.73 mmol) were placed in 1, 4-dioxane (10 mL) and Pd (OAc) was added 2 (32.6 mg,0.15 mmol), BINAP (90.4 mg,0.15 mmol) and Cs 2 CO 3 (709 mg,2.18 mmol). The reaction was carried out at 100℃for 1 hour under nitrogen protection. After the completion of the reaction, the crude product was concentrated directly, and the crude product was separated by column chromatography to give N- (4- (6-fluoro-3-formyl-1H-indol-1-yl) pyrimidin-2-yl) -N- (6- (4-morpholinopiperidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) acetamide (300 mg, yield: 35%). MS m/z (ESI): 687.2[ M+H ]] + 。
And a second step of: synthesis of 4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (6- (4-morpholinopiperidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) pyrimidin-2-amine
The crude product was dissolved in THF (5 mL) and Me was added at room temperature 2 NH HCl/THF solution (5.0 mL,10mmol, 2.0M) was stirred at room temperature for half an hour until the acetyl removal was complete. Then NaBH is added 3 CN (79 mg,1.26 mmol) and stirring was continued at room temperature for half an hour until the reaction was complete. Adding methanol (2 mL) for quenching reaction, directly concentrating the reaction solution, and separating the crude product by column chromatography [ CH ] 2 Cl 2 /MeOH：9/1]4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (6- (4-morpholinopiperidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) pyrimidin-2-amine (170 mg, yield: 91%). MS m/z (ESI): 674.2[ M+H ]] + 。
And a third step of:N 3 synthesis of- (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -6- (4-morpholinopiperidin-1-yl) -2- (2, 2-trifluoroethoxy) pyridine-3, 5-diamine
4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) -N- (6- (4-morpholinopiperidin-1-yl) -5-nitro-2- (2, 2-trifluoroethoxy) pyridin-3-yl) pyrimidin-2-amine (170 mg,0.24 mmol) was dissolved in MeOH (30 mL), pd/C (50 mg, 10%) was added and stirred at room temperature under normal pressure hydrogen overnight. After the reaction is finished, the reaction solution is filtered through diatomite, and the filtrate is concentrated to obtain N 3 - (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -6- (4-morpholinopiperidin-1-yl) -2- (2, 2-trifluoroethoxy) pyridine-3, 5-diamine (150 mg, yield: 92%). MS m/z (ESI): 644.3[ M+H ]] + 。
Fourth step: synthesis of N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-morpholinopiperidin-1-yl) -6- (2, 2-trifluoroethoxy) pyridin-3-yl) acrylamide
N 3 - (4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) -6- (4-morpholinopiperidin-1-yl) -2- (2, 2-trifluoroethoxy) pyridine-3, 5-diamine (150 mg,0.22 mmol) dissolved in CH 2 Cl 2 (10 mL) of Et 3 N (44 mg,0.44 mmol). Acryloyl chloride (23 mg,0.26 mmol) was slowly added with cooling in an ice-water bath and reacted at 0deg.C for 30 min. After the reaction is completed, ammonia water is added for quenching, and saturated NaHCO is added 3 The aqueous solution was stirred at room temperature for 10 minutes. CH for mixed solution 2 Cl 2 And (5) extracting. The organic phases were combined and concentrated. The crude product was isolated by preparative chromatography to give N- (5- ((4- (3- ((dimethylamino) methyl) -6-fluoro-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-morpholinopiperidin-1-yl) -6- (2, 2-trifluoroethoxy)Base) pyridin-3-yl) acrylamide (30 mg, yield: 19%). MS m/z (ESI): 698.4[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ9.29(s,1H),8.96(s,1H),8.35(d,J＝5.7Hz,1H),8.22-8.05(m,2H),8.00(s,1H),7.67(dd,J＝8.6,5.8Hz,1H),7.11(d,J＝5.8Hz,1H),7.02(td,J＝9.0,2.5Hz,1H),6.63(dd,J＝17.0,10.3Hz,1H),6.22(dd,J＝17.0,2.1Hz,1H),5.77-5.69(m,1H),4.91(q,J＝9.1Hz,2H),3.66-3.56(m,6H),3.54(s,2H),2.78(t,J＝12.2Hz,2H),2.58-2.51(m,4H),2.37-2.27(m,1H),2.18(s,6H),1.91-1.80(m,2H),1.71-1.58(m,2H)。
Examples 26 to 38 can be prepared by selecting the corresponding starting materials with reference to the whole or part of the synthesis method of examples 23, 24 or 25:
/>
/>
/>
the nuclear magnetic data of the compound prepared in the above example are as follows:
/>
/>
/>
biological test evaluation
(cell proliferation assay)
Reagent and consumable
Fetal bovine serum FBS (GBICO, cat#10099-141);
luminescence cell viability assay kit (Promega, cat#g7572);
Black transparent flat bottom 96-well plateCat#3603)。
(II) instruments
SpectraMax multi-label microplate detector MD,2104-0010A;
a carbon dioxide incubator, thermo Scientific 3100 series;
biosafety cabinet, thermo Scientific,1300 series type A2;
inverted microscope, olympus, CKX41SF;
siemens refrigerator KK25E76TI.
(III) cell lines and culture conditions
/>
(IV) Experimental procedure
1. Cell culture and seeding:
(1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability was above 90%.
(2) Adjusting the cell concentration to achieve a desired final density; mu.L of the cell suspension was added to a 96-well plate.
(3) Cells were plated in 96-well plates at 37 ℃,5% co 2 And incubated overnight at 95% humidity.
2. T0 reference data:
(1) mu.L of PBS was added to each well of the T0 plate containing the cells.
(2) The CTG reagent was thawed and the cell plates equilibrated to room temperature for 30 minutes.
(3) An equal volume of CTG solution was added to each well.
(4) Shake on an orbital shaker for 5 minutes to lyse cells.
(5) The cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal.
(6) The T0 fluorescent signal value is read.
3. Dilution and addition of Compounds
(1) According to the compound information table, corresponding volumes of DMSO were added to the corresponding compound powders to prepare 10mM stock solutions.
(2) A 1000-fold, 3.16-fold diluted compound solution was prepared.
(3) The 1000 Xdiluted compound solution was diluted 100-fold with PBS to prepare a 10-fold compound solution at a maximum concentration of 10. Mu.M, 9 concentrations, 3.16-fold dilution, and 10. Mu.L of the drug solution was added to each well seeded with 96-well plates to seed cells. Three duplicate wells were set for each compound concentration, with a final DMSO concentration of 0.1%.
(4) The cells were placed in 96-well plates containing the drug at 37℃and 5% CO 2 And 95% humidity, and further culturing for 72 hours, and then performing CTG analysis.
4. Fluorescent signal reading
(1) The CTG reagent was thawed and the cell plates equilibrated to room temperature for 30 minutes.
(2) An equal volume of CTG solution was added to each well.
(3) Shake on an orbital shaker for 5 minutes to lyse cells.
(4) The cell plates were left at room temperature for 20 minutes to stabilize the fluorescent signal.
(5) The fluorescence value is read.
5. Data processing
Data were analyzed using GraphPad Prism 7.0 software and data were fitted using nonlinear S-curve regression to obtain dose-response curves, from which IC was calculated 50 Values (units: nM), specific experimental results are shown in Table 1:
cell viability (%) = (Lum test drug-Lum broth control)/(Lum cell control-Lum broth control) ×100%.
Table 1: biological test results
From the biological activity data of the compounds of the specific examples, the series of compounds of the invention have strong inhibition effect on EGFR exon 20 insertion, deletion or other mutation at the cellular level, the selectivity to EGFR WT reaches more than 30 times, partial compounds of the examples even obtain more than 100 times of selectivity, and the high-selectivity compounds obtained by the invention have wider development prospect.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be understood that various changes and modifications may be made by those skilled in the art after reading the foregoing disclosure of the invention, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (9)

1. A compound of formula (iii), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein X is CH or N; y is a bond, O, S, N (R) 10 ) Or C (R) 11 R 12 )；
With the proviso that when X is CH, o 1 When 1, Y is not N (R 10 )；
R 1a 、R 1b 、R 1c And R is 1d Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 2 and R is 3 Each independently selected from methyl or ethyl, or R 2 And R is 3 Together with the nitrogen atom to which it is directly attached, form a 4-5 membered heterocyclic group, said group optionally being substituted with one or more groups selected from deuterium, fluorine, chlorine, bromine, hydroxy, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Substituted by alkyl;
R 5 selected from hydrogen, deuterium, methyl and ethyl, optionally substituted with one or more groups selected from deuterium, fluorine, chlorine, bromine, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl substituents are substituted;
R 10 selected from hydrogen, deuterium, hydroxy, methyl, ethyl, halo substituted C 1-2 Alkyl, deuterium substituted C 1-2 Alkyl, 3-6 membered heterocyclyl;
R 11 selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, hydroxyl or methoxy;
R 12 selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, optionally substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycleA group and = O;
alternatively, R 11 And R is 12 Together with the carbon atom to which it is directly attached form a C (O), C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and = O;
o 1 1.
2. The compound of formula (iii), stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein X is CH; y is a bond, O, S or C (R) 11 R 12 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 11 And R is 12 As defined in claim 1.
3. The compound of formula (iii), stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein X is N; y is a bond, O, S, N (R) 10 ) Or C (R) 11 R 12 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 10 、R 11 And R is 12 As defined in claim 1.
4. The compound of formula (iii), stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
5. a process for the preparation of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1, comprising the steps of:
Therein, X, Y, R 1a 、R 1b 、R 1c 、R 1d 、R 2 、R 3 、R 5 And o1 is as defined in claim 1.
6. A pharmaceutical composition comprising a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
7. Use of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer, tumour or metastatic disease associated at least in part with an insertion, deletion or other mutation of EGFR exon 20.
8. Use of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4 for the manufacture of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders.
9. Use of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for the manufacture of a medicament for the prevention and/or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, urological tumor, skin tumor, sarcoma, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma at least in part with EGFR exon 20 insertion, deletion or other mutation.
CN202210868336.4A 2021-08-02 2022-07-22 4- (1H-indol-1-yl) pyrimidine-2-amino derivative, and preparation method and application thereof Active CN115701429B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110879962 2021-08-02
CN2021108799629 2021-08-02

Publications (2)

Publication Number Publication Date
CN115701429A CN115701429A (en) 2023-02-10
CN115701429B true CN115701429B (en) 2024-03-12

Family

ID=85142365

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210868336.4A Active CN115701429B (en) 2021-08-02 2022-07-22 4- (1H-indol-1-yl) pyrimidine-2-amino derivative, and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN115701429B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106117185A (en) * 2015-08-31 2016-11-16 广州科擎新药开发有限公司 2,4 2 nitrogen-containing group substituted pyrimidines compounds and its preparation method and application
CN106660993A (en) * 2014-06-12 2017-05-10 上海复尚慧创医药研究有限公司 Certain protein kinase inhibitors
CN106928150A (en) * 2015-12-31 2017-07-07 恩瑞生物医药科技（上海）有限公司 Acrylamide anil and its application pharmaceutically
CN107406442A (en) * 2014-12-23 2017-11-28 达纳－法伯癌症研究所公司 New pyrimidine and sanatory method as EGFR inhibitor
CN109328059A (en) * 2016-01-07 2019-02-12 Cs制药技术有限公司 The selective depressant of the important mutant of clinic of EGFR tyrosine kinase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106660993A (en) * 2014-06-12 2017-05-10 上海复尚慧创医药研究有限公司 Certain protein kinase inhibitors
CN107406442A (en) * 2014-12-23 2017-11-28 达纳－法伯癌症研究所公司 New pyrimidine and sanatory method as EGFR inhibitor
CN106117185A (en) * 2015-08-31 2016-11-16 广州科擎新药开发有限公司 2,4 2 nitrogen-containing group substituted pyrimidines compounds and its preparation method and application
CN106928150A (en) * 2015-12-31 2017-07-07 恩瑞生物医药科技（上海）有限公司 Acrylamide anil and its application pharmaceutically
CN109328059A (en) * 2016-01-07 2019-02-12 Cs制药技术有限公司 The selective depressant of the important mutant of clinic of EGFR tyrosine kinase

Also Published As

Publication number Publication date
CN115701429A (en) 2023-02-10

Similar Documents

Publication Publication Date Title
CN110117273B (en) 2H-indazole derivatives as Cyclin Dependent Kinase (CDK) inhibitors and their medical use
JP6431593B6 (en) Pyridinylaminopyrimidine derivative, method for producing the same, and use thereof
EP3746072B1 (en) 2h-indazole derivatives as cdk4 and cdk6 inhibitors and therapeutic uses thereof
CN110546145B (en) Azaaryl derivative, preparation method and pharmaceutical application thereof
JP2021501215A (en) Amino-substituted nitrogen-containing condensed ring compound, its preparation method and use
CN111868058B (en) FGFR inhibitor, preparation method and pharmaceutical application thereof
JP2023145547A (en) Cd73 inhibitor, preparation method therefor and application thereof
CN110691775B (en) Aldehyde pyridine derivative with FGFR4 inhibitory activity, and preparation method and application thereof
CN115803326B (en) EGFR inhibitor, preparation method thereof and application thereof in pharmacy
CN115701429B (en) 4- (1H-indol-1-yl) pyrimidine-2-amino derivative, and preparation method and application thereof
CN116096372A (en) EGFR inhibitor, preparation method and pharmaceutical application thereof
CN115836064A (en) Triazine derivative with EGFR (epidermal growth factor receptor) inhibitory activity and preparation method and application thereof
CN115836070A (en) Fused ring compound as EGFR inhibitor and preparation method and application thereof
CN116528859A (en) Crystal form containing free alkali of di-fused ring derivative inhibitor and preparation method and application thereof
CN115803325B (en) EGFR inhibitor and preparation method and application thereof
WO2022042612A1 (en) Dihydropyrrolo[2,3-d]pyridazin-7-one derivative, preparation method therefor, and application thereof
CN113861195B (en) Multi-condensed-ring EGFR inhibitor as well as preparation method and application thereof
JP7449028B2 (en) EGFR inhibitor and its manufacturing method and application
CN116670126A (en) Azaheteroaryl derivatives with EGFR inhibiting activity, preparation method and application thereof
CN113527215B (en) Quinazoline compound, preparation method and application thereof
TWI820414B (en) Quinazoline compounds, preparation method and use thereof
CN116981662A (en) Pyrimidine-4, 6-diamine derivative, preparation method and pharmaceutical application thereof
CN117430600A (en) Selective EGFR inhibitor, preparation method and pharmaceutical application thereof
CN117440945A (en) Pyrimidine or pyridine derivative, preparation method thereof and application thereof in pharmacy
CN116171155A (en) Pyrido [2,3-d ] pyrimidine-2 (1H) -ketone derivative, preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant