CN115803326B - EGFR inhibitor, preparation method thereof and application thereof in pharmacy - Google Patents

EGFR inhibitor, preparation method thereof and application thereof in pharmacy Download PDF

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CN115803326B
CN115803326B CN202180049014.0A CN202180049014A CN115803326B CN 115803326 B CN115803326 B CN 115803326B CN 202180049014 A CN202180049014 A CN 202180049014A CN 115803326 B CN115803326 B CN 115803326B
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deuterium
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CN115803326A (en
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邓海兵
杨飞
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

To an EGFR inhibitor having the structure of formula (I), a process for its preparation, pharmaceutical compositions containing it, its use as an EGFR inhibitor and its use in the treatment and/or prophylaxis of cancer, tumors or metastatic diseases associated at least in part with EGFR exon 20 insertion or deletion mutations, particularly in the treatment of hyperproliferative disorders and diseases in which cell death is induced. Wherein each substituent of formula (I) is as defined in the specification.

Description

EGFR inhibitor, preparation method thereof and application thereof in pharmacy
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to an EGFR inhibitor, a preparation method thereof and application thereof in pharmacy.
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 developed and clinically validated. EGFR inhibition can significantly increase the progression free survival of adenocarcinoma NSCLC, which is then targeted by third generation inhibitors after acquired drug resistance mutations.
Although classical EGFR activating mutations (exons 19 and 21) and drug resistant mutations (T790M) were successfully inhibited, in-frame insertion of exon 20 also resulted in structural activation of EGFR signaling and was associated with de novo resistance to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and include 1-7 amino acids inserted or repeated in-frame between 762-774 amino acids 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 is also found in HER2, another member of the Receptor Tyrosine Kinase (RTK) EGFR family.
Multiple retrospective analysis showed that currently available generation 1, 2 and 3 EGFR inhibitors had limited efficacy for exon 20 insertion mutations, except for the a763-Y764insFQEA mutation. Irreversible inhibitors Poziotinib and EGFR/MET bispecific antibody amivantmaab 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, but due to limited selectivity for EGFR WT (wild type), their adverse effects are unavoidable and may lead to dose-limiting toxicity. Thus, for these patients, there is an urgent need for highly selective small molecule inhibitors of EGFR exon 20 insertion mutation.
Disclosure of Invention
The invention aims to provide an EGFR inhibitor, a preparation method and application thereof in pharmacy. The series of compounds have strong inhibition effect on EGFR exon 20 insertion, deletion or other mutant cytologic activities and high selectivity on EGFR wild type, can be widely applied to preparing 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, and are expected to develop a new generation EGFR inhibitor.
The first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein X is 1 And X 2 Each independently is CR 7 Or N; y is CR 8 Or N; z is NR 9 Or O;
ring a is a 3-12 membered nitrogen containing heterocyclyl, preferably selected from the group consisting of:
each R 1 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, and C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 2-10 OlefinsRadical, 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 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 and-C 0-8 alkyl-N (R) 13 )-C(O)R 12 ；
Each R 2 Independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, and 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 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 and-C 0-8 alkyl-N (R) 13 )-C(O)R 12 Alternatively, when n is not less than 2, two adjacent R 2 Together with the directly connected parts thereof form a C 4-8 Cycloalkyl or 5-8 membered heterocyclyl;
R 3 and R is 4 Each independently selected from hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, halogen substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
R 5 selected from hydrogen, deuterium, halogen, cyano, 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 11 、-C(O)R 12 、-C(O)-NR 13 R 14 and-C 0-4 alkyl-NR 13 R 14 ；
R 7 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 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 and-C 0-8 alkyl-N (R) 13 )-C(O)R 12 ；
R 6 And R is 8 Each independently selected from hydrogen, deuterium, halogen, cyano, and C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) rR 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (=nr 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 The above groups are independently optionally 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) rR 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 and-C 0-8 alkyl-N (R) 13 )-C(O)R 12 With the proviso that when ring A is substituted with substituentsWhen R is 8 Not unsubstituted or halogen-substituted C 1-4 An alkoxy group;
R 9 selected from hydrogen, deuterium, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclyl;
Each R 10 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 13 R 14 The above groups are independently 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 heteroarylOxy and-NR 13 R 14 Is substituted by a substituent of (2);
each R 11 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 5-10 membered heteroaryl, the above groups being independently 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 13 R 14 Is substituted by a substituent of (2);
each R 12 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 heteroaryloxy and-NR 13 R 14 The above groups are independently 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 13 R 14 Is substituted by a substituent of (2);
each R 13 And R is 14 Each independently selected from hydrogen, deuterium, hydroxy, 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-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C 1-10 Alkanoyl, said radicals being independently optionally further substituted with one or more members selected from deuterium, halogenPlain, hydroxy, = O, 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 13 And R is 14 Together with the nitrogen atom to which it is directly attached, form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, 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;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4; and is also provided with
Each r is independently 0, 1 or 2.
In a preferred embodiment, in the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, R 1 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 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (=nr 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 ；
R 2 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 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (=nr 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 Alternatively, when n is not less than 2, two adjacent R 2 Together with the directly connected parts thereof form a C 4-8 Cycloalkyl or 5-8 membered heterocyclyl;
R 3 and R is 4 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
R 5 selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 13 R 14 ；
R 6 And R is 8 Each independently selected from hydrogen, deuteriumHalogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O)rR 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 The above groups are independently 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 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) rR 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (=nr 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 With the proviso that when ring A is substituted with substituentsWhen R is 8 Not unsubstituted or halogen-substituted C 1-4 An alkoxy group;
R 7 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)rR 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
R 9 Selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl;
wherein X is 1 、X 2 Y, Z, ring A, m, n, R 10 、R 11 、R 12 、R 13 、R 14 And r is as described for the compounds of formula (I).
In a preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (II a) as follows:
wherein Z is NR 9 Or O;
ring a is a 3-12 membered nitrogen containing heterocyclyl, preferably selected from the group consisting of:
R 1a 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 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
R 1b 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 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
R 2 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 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
R 3 Selected from hydrogen, deuterium, halogen and C 1-4 An alkyl group;
R 5 selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 13 R 14 ；
R 8 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterogeniesCyclic group, -O-R 11 、-O-C(O)R 12 、-NR 13 R 14 、-N(R 13 )-C(＝NR 14 )R 12 and-N (R) 13 )-C(O)R 12 The above groups are independently 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 3-8 Cycloalkyl, 3-8 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 10 、-C 0-4 alkyl-O-R 11 、-C 0-4 alkyl-C (O) OR 11 、-C 0-4 alkyl-C (O) R 12 、-C 0-4 alkyl-O-C (O) R 12 、-C 0-4 alkyl-NR 13 R 14 、-C 0-4 alkyl-C (=nr 13 )R 12 、-C 0-4 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-4 alkyl-C (O) NR 13 R 14 and-C 0-4 alkyl-N (R) 13 )-C(O)R 12 With the proviso that when ring A is substituted with substituentsWhen R is 8 Not unsubstituted or halogen-substituted C 1-4 An alkoxy group;
R 9 selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
wherein R is 10 、R 11 、R 12 、R 13 、R 14 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, Z is NH or O;
R 1a selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, tridentate methyl and dideuteromethyl;
R 1b selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, tridentate methyl and dideuteromethyl;
R 2 selected from hydrogen, deuterium, fluorine, chlorine, bromine and cyano;
R 3 selected from hydrogen, deuterium and fluorine;
R 5 selected from hydrogen, deuterium and methyl.
As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring a is selected from the group consisting of:
as a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 8 Selected from C 3-6 Cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-6 Cycloalkyl C 1-4 Alkoxy and 3-6 membered heterocycloalkyl C 1-4 Alkoxy, said groups being independently 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 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 Is substituted by a substituent of (2); wherein R is 10 、R 11 、R 12 、R 13 、R 14 And r is as described for the compounds of formula (I).
As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 8 Selected from the group consisting of Said-> Each independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, methoxy, cyano and nitro.
As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 8 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-2 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and-NR 13 R 14 The above groups are independently 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)rR 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 With the proviso that when ring A is substituted with substituentsWhen R is 8 Not unsubstituted or halogen-substituted C 1-2 An alkoxy group; wherein R is 10 、R 11 、R 12 、R 13 、R 14 And rAs described for the compounds of formula (I).
As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 8 Selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, difluoromethyl, trifluoromethyl, ethynyl, methoxy, ethoxy, monofluoromethoxy, methoxyethoxy, trifluoroethoxy, cyclopropyl, morpholinyl, 3-chloro-propylamino, trifluoroethylamino, 2-methoxyethylamino, said->Each independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, methoxy, cyano and nitro, provided that when ring A is +.>When R is 8 Not methoxy, ethoxy, monofluoromethoxy or trifluoroethoxy.
In a preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (II b) as follows:
Wherein Z is NR 9 Or O;
ring a is a 3-12 membered nitrogen containing heterocyclyl, preferably selected from the group consisting of:
R 1a 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 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
R 1 b is 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)rR 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
R 2 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 10 、-O-R 11 、-C(O)OR 11 、-C(O)R 12 、-O-C(O)R 12 、-NR 13 R 14 、-C(＝NR 13 )R 12 、-N(R 13 )-C(＝NR 14 )R 12 、-C(O)NR 13 R 14 and-N (R) 13 )-C(O)R 12 ；
R 3 Selected from hydrogen, deuterium, halogen and C 1-4 An alkyl group;
R 5 selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl and-C 0-4 alkyl-NR 13 R 14 ；
R 9 Selected from hydrogen, deuterium, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group;
wherein R is 10 、R 11 、R 12 、R 13 、R 14 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, Z is O;
R 1a Selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, tridentate methyl and dideuteromethyl;
R 1b selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, tridentate methyl and dideuteromethyl;
R 2 selected from hydrogen, deuterium, fluorine, chlorine, bromine and cyano;
R 3 selected from hydrogen, deuterium and fluorine;
R 5 selected from hydrogen, deuterium and methyl.
As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring a is selected from the group consisting of:
preferably, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each R 10 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 13 R 14 The above groups are independently 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 13 R 14 Is substituted by a substituent of (2);
each R 11 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, the above groups being independently 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 13 R 14 Is substituted by a substituent of (2);
each R 12 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 group, 5 - 8-membered heteroaryl, 5-8-membered heteroaryloxy and-NR 13 R 14 The above groups are independently 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 13 R 14 Is substituted by a substituent of (2);
each R 13 And R is 14 Each independently selected from hydrogen, deuterium, hydroxy, 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 and C 1-4 Alkanoyl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, 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 13 And R is 14 Together with the nitrogen atom to which it is directly attached, form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl, said 4-8 membered heterocyclyl or 5-8 membered heteroaryl optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, 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:
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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:
wherein X is halogen, preferably selected from fluorine, chlorine and bromine; ring A, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 、X 2 Y, Z, m and n are as defined 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 compound of the formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and/or treating 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 cavity sinus inverted papilloma or nasal cavity sinus squamous cell carcinoma related to nasal cavity sinus inverted papilloma.
The invention also relates to the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts 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, after extensive and intensive research, develops an EGFR inhibitor with a structure shown as a formula (I) for the first time, and the series of compounds can be widely applied to preparing medicines for treating and/or preventing cancers, tumors or metastatic diseases at least partially related to EGFR exon 20 insertion, deletion or other mutation, particularly medicines for treating hyperproliferative diseases and diseases inducing cell death disorder, and is hopeful to develop 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 from 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited toMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 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) rR 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 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 4-8 Cycloalkyl "refers to cycloalkyl groups comprising 4 to 8 carbon atoms," C 3-8 Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 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:
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"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-S (O) r R 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 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, one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclyl being selected from nitrogen, oxygen or S (O) r (wherein r is a heteroatom of integers 0, 1, 2), but excluding the ring moieties of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferred heterocyclic groups include 3 to 12 or 3 to 8 or 3 to 6 ring atoms, e.g. "3- 6 The "membered heterocyclic group" means a heterocyclic group containing 3 to 6 ring atoms, "3-8 membered heterocyclic group" means a heterocyclic group containing 3 to 8 ring atoms, "4-8 membered heterocyclic group" means a heterocyclic group containing 4 to 8 ring atoms, "4-10 membered heterocyclic group" means a heterocyclic group containing 4 to 10 ring atoms, "5-8 membered heterocyclic group" means a heterocyclic group containing 5 to 8 ring atoms, "3-12 membered heterocyclic group" means a heterocyclic group containing 3 to 12 ring atoms.
Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (referred to as the spiro atom) in common between monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is an integer 0, 1, 2) heteroatoms, 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" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more (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 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 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, 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-S (O) r R 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 Substituted.
"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 carbons, e.g., "C 6-10 Aryl "refers to all-carbon aryl groups containing 6 to 10 carbons including, but not limited to, phenyl and naphthyl," C 6-8 Aryl "refers to an all-carbon aryl group containing 6-8 carbons. 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, azideNitrogen radicals, 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-S (O) rR 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 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 substitution 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) rR 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 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) rR 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 Is substituted by a substituent of (2).
"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) rR 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 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 alkyloxy group containing 1 to 4 carbons," C 1-2 Alkoxy group"refers to an alkyl oxy group having 1-2 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
"alkoxy" 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) rR 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 Is substituted by a substituent of (2).
"Cycloalkoxy" or "cycloalkyloxy" 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 3-6 Cycloalkoxy "refers to a cycloalkyloxy group having 3-6 carbons including, but not limited to, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"Cycloalkoxy" or "cycloalkyloxy" 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 group5-to 10-membered heteroaryl, =o, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) rR 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 Is substituted by a substituent of (2).
"Heterocyclyloxy" or "heterocyclyloxy" refers to an-O-heterocyclyl group wherein heterocyclyl is defined as above, including but not limited to azetidinyloxy, oxetyloxy, azetidinyloxy, nitrogen, oxetyloxy, and the like.
"Heterocyclyloxy" or "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 10 、-C 0-8 alkyl-O-R 11 、-C 0-8 alkyl-C (O) OR 11 、-C 0-8 alkyl-C (O) R 12 、-C 0-8 alkyl-O-C (O) R 12 、-C 0-8 alkyl-NR 13 R 14 、-C 0-8 alkyl-C (=nr 13 )R 12 、-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 、-C 0-8 alkyl-C (O) NR 13 R 14 or-C 0-8 alkyl-N (R) 13 )-C(O)R 12 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 10 "means-S (O) rR 10 Wherein the sulfur atom is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-O-R 11 "means-O-R 11 Wherein the oxygen atom is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-C (O) OR 11 "means-C (O) OR 11 Wherein the carbonyl group is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-C (O) R 12 "means-C (O) R 12 Wherein the carbonyl group is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-O-C (O) R 12 "means-O-C (O) R 12 Wherein the oxygen atom is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-NR 13 R 14 "refer to-NR 13 R 14 Wherein nitrogen atoms are attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-C (=nr 13 )R 12 "refer to-C (=NR) 13 )R 12 Wherein nitrogen atoms are attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-N (R) 13 )-C(＝NR 14 )R 12 "means-N (R) 13 )-C(＝NR 14 )R 12 Wherein nitrogen atoms are attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-C (O) NR 13 R 14 "means-C (O) NR 13 R 14 Wherein the carbonyl group is attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
“-C 0-8 alkyl-N (R) 13 )-C(O)R 12 "means-N (R) 13 )-C(O)R 12 Wherein nitrogen atoms are attached to C 0-8 On alkyl groups, where C 0-8 The definition of alkyl is as described above.
"halogen substituted C 1-10 Alkyl "refers to 1-10 carbon alkyl groups optionally substituted with fluorine, chlorine, bromine, iodine atoms for hydrogen on the alkyl group, including, but not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
"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 mono-, di-, tri-deuteromethyl, and the like.
"halogen" means fluorine, chlorine, bromine or iodine.
"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 stereoisomers with different optical properties due to the lack of trans-axisymmetry in the molecule are called optical isomers (optical isomers) and are classified into 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 addition salts, including inorganic acid salts and organic acid salts, which salts may 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 Bruker AVANCE-400/500 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) 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 1: preparation of 2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) aniline
The first step: synthesis of tert-butyl-3-hydroxy-1H-pyrazole-1-carboxylic acid ester
1H-pyrazol-3-ol (25.0 g,0.30 mol) and triethylamine (75 mL,0.39 mol) were dissolved in DCM (250 mL), and di-tert-butyl dicarbonate (53.7 mL,0.33 mol) was added, and the reaction was stirred at room temperature for 5 hours. Concentrated under reduced pressure and dried to give tert-butyl-3-hydroxy-1H-pyrazole-1-carboxylate (54.8 g, yield: 100%). MS m/z (ESI): 185[ M+H ] ] + 。
And a second step of: synthesis of tert-butyl-3- (3-fluoro-4-nitrophenoxy) -1H-pyrazole-1-carboxylate
tert-butyl-3-hydroxy-1H-pyrazole-1-carboxylate (8.30 g,45.1 mmol) and 2, 4-difluoro-1-nitrobenzene (7.53 g,47.4 mmol) were dissolved in N, N-dimethylformamide (100 mL), potassium carbonate (12.45 g,90.2 mmol) was added at room temperature, the reaction stirred at room temperature for 24 hours, diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine solution and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and separation by column chromatography gave a crude product, which was recrystallized from ethyl acetate/petroleum ether (50 mL/500 mL) to give tert-butyl-3- (3-fluoro-4-nitrophenoxy) -1H-pyrazole-1-carboxylate (3.20 g, yield: 22%). MS m/z (ESI): 268[ M-56+H ]] + 。
And a third step of: synthesis of tert-butyl-3- (4-amino-3-fluorophenoxy) -1H-pyrazole-1-carboxylate
Tert-butyl-3- (3-fluoro-4-nitrophenoxy) -1H-pyrazole-1-carboxylate (3.00 g,9.28 mmol) was dissolved in methanol/dichloromethane (50 mL/50 mL), palladium on carbon (10%, 300 mg) was added, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. Suction filtration, concentration of the filtrate, and separation of the residue by column chromatography to give tert-butyl-3- (4-amino-3-fluorophenoxy) -1H-pyrazole-1-carboxylic acid ester (2.20 g, yield) The rate is as follows: 81%). MS m/z (ESI): 294[ M+H ]] + 。
Fourth step: synthesis of tert-butyl-3- (4- (((benzyloxy) carbonyl) amino) -3-fluorophenoxy) -1H-pyrazole-1-carboxylic acid ester
Tert-butyl-3- (4-amino-3-fluorophenoxy) -1H-pyrazole-1-carboxylate (2.20 g,7.5 mmol) and benzyl chloroformate (1.92 g,11.3 mmol) were dissolved in tetrahydrofuran (50 mL), potassium carbonate (2.07 g,15.0 mmol) was added at room temperature and the mixture stirred at 60℃for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was concentrated and separated by column chromatography to give tert-butyl-3- (4- (((benzyloxy) carbonyl) amino) -3-fluorophenoxy) -1H-pyrazole-1-carboxylate (2.4 g, yield: 75%). MS m/z (ESI): 428[ M+H ]] + 。
Fifth step: synthesis of benzyl (4- (((1H-pyrazol-3-yl) oxy) -2-fluorophenyl) carbamate
Tert-butyl-3- (4- (((benzyloxy) carbonyl) amino) -3-fluorophenoxy) -1H-pyrazole-1-carboxylic acid ester (2.40 g,5.6 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added at room temperature and the mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride (150 mL), neutralized with a saturated aqueous sodium hydrogencarbonate solution (100 mL), separated, washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give benzyl (4- (((1H-pyrazol-3-yl) oxy) -2-fluorophenyl) carbamate (1.80 g, yield: 98%). MS m/z (ESI): 328[ M+H) ] + 。
Sixth step: synthesis of benzyl (2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenylcarbamate
Benzyl (4- (((1H-pyrazol-3-yl) oxy) -2-fluorophenyl) carbamate (1.80 g,5.50 mmol) and 2-methyl-3-fluoro-5-bromopyridine were placed in dry toluene (60 mL), trans-N, N' -dimethyl-1, 2-cyclohexanediamine (312 mg,2.2 mmol), cuprous iodide (210 mg,1.1 mmol) and potassium carbonate (1.52 g,11.0 mmol) were added, and the mixture was stirred at 120℃for 20 hours the reaction mixture was concentrated directly, and the residue was separated by column chromatography to give benzyl (2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenylcarbamate (355 mg, yield: 36%). MS m/z (ESI): 437 M+H] + 。
Seventh step: synthesis of 2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) aniline
Benzyl (2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenylcarbamate (850 mg,1.95 mmol) was dissolved in methanol/dichloromethane (20 mL/20 mL), palladium hydroxide (10%, 85 mg) was added, the reaction solution was stirred at room temperature under a hydrogen atmosphere for 4 hours, suction filtration was carried out, and the filtrate was concentrated to give 2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) aniline (588 mg, yield: 100%). MS m/z (ESI): 303[ M+H) ] + 。
Intermediate 2 can be prepared by selecting the corresponding starting materials with reference to the full or partial synthesis of intermediate 1:
intermediate 3: preparation of 1- (3- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) azetidin-1-yl) prop-2-en-1-one
The first step: synthesis of tert-butyl-3- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) azetidine-1-carboxylate
4-chloro-7-methoxyquinazolin-6-ol (700 mg,3.33 mmol), tert-butyl-3-hydroxyazetidine-1-carboxylic acid ester (865 mg,5.0 mmol) and triphenylphosphine (1.32 g,5.0 mmol) were placed in dry dichloromethane (20 mL), diisopropyl azodicarboxylate (1.01 g,5.0 mmol) was added with ice cooling, and the reaction stirred at room temperature overnight. The reaction solution was directly concentrated, and the residue was separated by column chromatography to give crude t-butyl-3- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) azetidine-1-carboxylate (2.2 g) which was directly used in the next reaction. MS m/z (ESI): 366[ M+H ]] + 。
And a second step of: synthesis of 6- (azetidin-3-yloxy) -4-chloro-7-methoxyquinazoline hydrochloride
Crude tert-butyl-3- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) azetidine-1-carboxylate (2.2 g) was placed in hydrogen chloride/1, 4-dioxane solution (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Tetrahydrofuran (10 mL) was added to the reaction mixture, and after filtration of the resulting white solid, the cake was dried to give 6- (azetidin-3-yloxy) -4-chloro-7-methoxyquinazoline hydrochloride (300 mg) which was used directly in the next reaction. MS m/z (ESI): 266[ M+H ] ] + 。
And a third step of: synthesis of 1- (3- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) azetidin-1-yl) prop-2-en-1-one
6- (azetidin-3-yloxy) -4-chloro-7-methoxyquinazoline hydrochloride (300 mg,1.0 mmol) and triethylamine (404 mg,44.0 mmol) were placed in dichloromethane (40 mL) and propylene was added under ice-bath coolingAlkene-acyl chloride (136 mg,1.5 mmol), the reaction was stirred for 1 hour with ice bath cooling. The reaction solution was concentrated directly, and the residue was separated by column chromatography to give 1- (3- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) azetidin-1-yl) prop-2-en-1-one (57 mg, yield: 18%). MS m/z (ESI): 320[ M+H ]] + 。
Intermediates 4-6 can be prepared by selecting the corresponding starting materials with reference to the overall or partial synthetic method of intermediate 3:
intermediate 7: preparation of 1- (4- ((4-chloro-7-cyclopropoxy quinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
The first step: synthesis of 5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-fluoro-2-nitrobenzoic acid
To a solution of 4, 5-difluoro-2-nitrobenzoic acid (20.0 g,98.5 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (39.64 g,196.9 mmol) in N, N-dimethylformamide (100 mL) was added sodium hydride (60% in oil, 7.88g,196.9 mmol) in portions under ice-bath cooling, and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for 19 hours. Ice water was added to the reaction solution to quench, 1mol/L hydrochloric acid was used to adjust the pH to about 2-3, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Suction filtration and concentration of the filtrate under reduced pressure gave a crude product of 5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-fluoro-2-nitrobenzoic acid (50 g crude). Will be thick The product was used directly in the next reaction. MS m/z (ESI): 329[ M-56+H ]] + 。
And a second step of: synthesis of tert-butyl 4- (2-fluoro-5- (methyl (methoxycarbonyl)) -4-nitrophenoxy) piperidine-1-carboxylate
To a solution of 5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-fluoro-2-nitrobenzoic acid (50 g crude, 98.5 mmol) in N, N-dimethylformamide (200 mL) was added methyl iodide (12.3 mL,197.7 mmol) and potassium carbonate (27.33 g,197.7 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was concentrated under reduced pressure, and the residue was separated by column chromatography to give tert-butyl 4- (2-fluoro-5- (methylester (methoxycarbonyl)) -4-nitrophenoxy) piperidine-1-carboxylate (39.0 g, yield: 99%). MS m/z (ESI): 343[ M-56+H] + 。
And a third step of: synthesis of 5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-cyclopropoxy-2-nitrobenzoic acid
To a solution of tert-butyl 4- (2-fluoro-5- (methoxycarbonyl) -4-nitrophenoxy) piperidine-1-carboxylate (10.0 g,25.1 mmol) and cyclopropane (2.92 g,50.2 mmol) in N, N-dimethylformamide (100 mL) was added sodium hydride (60%, in oil, 2.01g,50.2 mmol) in portions and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for 3 hours. Ice water was added to the reaction solution to quench, and the pH was adjusted to about 2-3 with 1mol/L hydrochloric acid and stirred for 30 minutes, and the precipitate was suction-filtered, washed with water and dried to give a crude product of 5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-cyclopropoxy-2-nitrobenzoic acid (10.8 g, purity: 69%, yield: 70.3%). The crude product was used directly in the next reaction without further purification. MS m/z (ESI): 367[ M-56+H ] ] + 。
Fourth step: synthesis of 2-amino-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-cyclopropoxy benzoic acid
To a solution of 5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-cyclopropoxy-2-nitrobenzoic acid (10.8 g crude, 69% purity, 17.6 mmol) in methanol (100 mL) and dichloromethane (100 mL) was added 10% wet palladium on carbon (540 mg) and the reaction mixture was stirred at room temperature under hydrogen atmosphere overnight. The reaction solution was filtered off with suction, washed with methanol, and the filtrate was concentrated by rotary evaporation under reduced pressure to give 2-amino-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-cyclopropoxybenzoic acid (9.5 g). The crude product was used directly in the next reaction. MS m/z (ESI): 393[ M+H ]] + 。
Fifth step: synthesis of tert-butyl 4- ((7-cyclopropoxy-4-hydroxyquinazolin-6-yl) oxy) piperidine-1-carboxylate
To a solution of 2-amino-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4-cyclopropoxy benzoic acid (7.7 g crude, 70% purity, 13.7 mmol) in ethylene glycol monomethyl ether (100 mL) was added formamidine acetate (5.72 g,54.9 mmol) and the reaction mixture was stirred at 130℃for 1 hour. The reaction solution was cooled to room temperature, water (300 mL) was added and the mixture was stirred at room temperature for 1 hour, and the precipitate was filtered off with suction, washed with water and dried to give a crude product (6.5 g crude) of tert-butyl 4- ((7-cyclopropoxy-4-hydroxyquinazolin-6-yl) oxy) piperidine-1-carboxylate. The crude product was used directly in the next reaction. MS m/z (ESI): 402[ M+H ] ] + 。
Sixth step: synthesis of tert-butyl 4- ((4-chloro-7-cyclopropyloxy quinazolin-6-yl) oxy) piperidine-1-carboxylate
To a solution of tert-butyl 4- ((7-cyclopropoxy-4-hydroxyquinazolin-6-yl) oxy) piperidine-1-carboxylate (2.3 g,5.16 mmol) in dichloroethane (50 mL) was added N, N-diisopropylethylamine (5.11 mL,30.94 mmol) and phosphorus oxychloride (1.92 mL,20.62 mmol) and the reaction mixture was stirred at 80℃for 3 hours. The reaction solution was cooled to room temperature, poured into ice water, basified with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic phase was concentrated by rotary evaporation and the residue was separated by column chromatography [ developing solvent: petroleum ether/ethyl acetate=0-20%]Tert-butyl 4- ((4-chloro-7-cyclopropyloxy quinazolin-6-yl) oxy) piperidine-1-carboxylate (1.60 g, yield: 74%) was obtained. MS m/z (ESI): 420[ M+H ]] + 。
Seventh step: synthesis of 4-chloro-7-cyclopropyloxy-6- (piperidin-4-yloxy) quinazoline hydrochloride
To a solution of tert-butyl 4- ((4-chloro-7-cyclopropyloxy quinazolin-6-yl) oxy) piperidine-1-carboxylate (1.60 g,3.81 mmol) in 1, 4-dioxane (10 mL) was added hydrogen chloride/1, 4-dioxane solution (20 mL,80mmol,4 mol/L), and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated by rotary evaporation under reduced pressure to give 4-chloro-7-cyclopropyloxy-6- (piperidin-4-yloxy) quinazoline hydrochloride (1.35 g). The crude product was used directly in the next reaction. MS m/z (ESI): 320[ M+H ] ] + 。
Eighth step: synthesis of 1- (4- ((4-chloro-7-cyclopropoxy quinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
To a solution of 4-chloro-7-cyclopropoxy-6- (piperidin-4-yloxy) quinazoline hydrochloride (1.35 g crude, purity: 75%,2.84 mmol) in tetrahydrofuran (30 mL) were added water (15 mL) and sodium bicarbonate (119 g,14.2 mmol), and the reaction mixture was cooled to 0℃and acryloyl chloride (3836 mg,4.26 mmol) was added dropwise. The reaction solution was stirred at 0℃for 30 minutes. The reaction mixture was diluted with ethyl acetate and saturated brine, the mixture was separated, and the organic phase was concentrated by rotary evaporation under reduced pressure, and the residue was separated by column chromatography to give 1- (4- ((4-chloro-7-cyclopropyloxy quinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one (980 mg, yield: 89.5%). MS m/z (ESI): 374[ M+H ]] + 。
Intermediates 8-37 can be prepared by selecting the corresponding starting materials with reference to the overall or partial synthetic method of intermediate 7:
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intermediate 38: preparation of tert-butyl 4- ((4-chloro-7-methylquinazolin-6-yl) oxy) piperidine-1-carboxylate
The first step: synthesis of 4-bromo-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -2-nitrobenzoic acid
Tert-butyl 4-hydroxypiperidine-1-carboxylate (6.63 g,33 mmol) was placed in dry N, N-dimethylformamide (100 mL), sodium hydrogen (1.32 g,33 mmol) was added with ice-bath cooling and stirred for 30 min, then 4-bromo-5-fluoro-2-nitrobenzoic acid (4.35 g,16.48 mmol) was added and the reaction stirred at room temperature overnight. Quenching the reaction liquid with water, extracting with dichloromethane, regulating pH of water phase with dilute hydrochloric acid to about 2, extracting with ethyl acetate, and concentrating the organic phase 4-bromo-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -2-nitrobenzoic acid (7.3 g) was obtained and the crude product was used directly in the next reaction. MS m/z (ESI): 345/347[ M-100+H] + 。
And a second step of: synthesis of 2-amino-4-bromo-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) benzoic acid
4-bromo-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -2-nitrobenzoic acid (4.45 g,10.00 mmol) was placed in water (100 mL) and methanol (100 mL), ammonium chloride (6.41 g,119.9 mmol) and iron powder (4.47 g,79.95 mmol) were added and the reaction was heated to 60℃and stirred for 18 hours. The reaction solution was filtered, and the filtrate was concentrated to give 2-amino-4-bromo-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) benzoic acid (5.2 g) which was directly used in the next reaction. MS m/z (ESI): 416/418[ M+H ]] + 。
And a third step of: synthesis of tert-butyl 4- ((7-bromo-4-oxo-3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate
2-amino-4-bromo-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) benzoic acid (5.2 g,12.52 mmol) was placed in ethylene glycol monomethyl ether (30 mL), and cimetidine acetate (5.21 g,50.09 mmol) was added and the reaction solution was heated to 100℃and stirred for 1 hour. The reaction mixture was dried, water was added to precipitate a solid, the solid was filtered, and the cake was dried to give tert-butyl 4- ((7-bromo-4-oxo-3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate (4.2 g, yield 79%). MS m/z (ESI): 424/426[ M+H ] ] + 。
Fourth step: synthesis of tert-butyl 4- ((7-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate
Tert-butyl 4- ((7-bromo-4-oxo-3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate (212 mg,0.50 mmol), tetramethylstannane (0.14 mL,1.00 mmol), tris (2-methylphenyl) phosphorus (15.2 mg,0.05 mmol), tris ((1E, 4E) -1, 5-diphenylpenta-1, 4-dien-3-one) dipalladium (22.88 mg,0.03 mmol) were placed in N, N-dimethylformamide (5 mL), and the reaction mixture was heated to 90℃under nitrogen and stirred for 2 hours. The reaction solution was concentrated and then separated by column chromatography to give tert-butyl 4- ((7-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate (180 mg). MS m/z (ESI): 360[ M+H ]] + 。
Fifth step: synthesis of tert-butyl 4- ((4-chloro-7-methylquinazolin-6-yl) oxy) piperidine-1-carboxylate
Tert-butyl 4- ((7-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate (180 mg,0.50 mmol) was placed in dichloroethane (10 mL), diisopropylethylamine (0.50 mL,3.01 mmol) and phosphorus oxychloride (0.19 mL,2.00 mmol) were added and the reaction heated to 80℃and stirred for 18 hours. The reaction solution was concentrated and then separated by column chromatography to give tert-butyl 4- ((4-chloro-7-methylquinazolin-6-yl) oxy) piperidine-1-carboxylate (90 mg, yield 50%). MS m/z (ESI): 379[ M+H ] ] + 。
Intermediates 39-41 can be prepared by selecting the corresponding starting materials in whole or in part by reference to intermediate 38:
intermediate 42: preparation of tert-butyl 4- ((4-chloro-7- (trifluoromethyl) quinazolin-6-yl) oxy) piperidine-1-carboxylate
The first step: synthesis of methyl 5-fluoro-2-nitro-4- (trifluoromethyl) benzoate
Methyl 4-bromo-5-fluoro-2-nitrophenyl ester (1.2 g,4.32 mmol) was placed in dry N, N-dimethylformamide (2 mL), cuprous iodide (740 mg,3.89 mmol) was added, and methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (4.94 mL,38.83 mmol) was stirred overnight at 90 ℃. The filtrate was filtered, concentrated, and the residue was subjected to column chromatography to give methyl 5-fluoro-2-nitro-4- (trifluoromethyl) benzoate (900 mg, yield: 16%).
And a second step of: synthesis of tert-butyl 4- (5- (methyl (methoxycarbonyl)) -4-nitro-2- (trifluoromethyl) phenoxy) piperidine-1-carboxylate
Tert-butyl 4-hydroxypiperidine-1-carboxylate (1.36 g,6.74 mmol) was placed in dry N, N-dimethylformamide (10 mL), sodium hydrogen (279 mg,6.74 mmol) was added with ice-bath cooling and stirred for one hour, then methyl 5-fluoro-2-nitro-4- (trifluoromethyl) benzoate (900 mg,0.67 mmol) was added and the reaction solution was stirred overnight at room temperature to give tert-butyl 4- (5- (methylcarbo-yl (methoxycarbonyl)) -4-nitro-2- (trifluoromethyl) phenoxy) piperidine-1-carboxylate. The reaction solution was directly used for the next reaction. MS m/z (ESI): 393[ M-56+H ] ] + 。
And a third step of: synthesis of 5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -2-nitro-4- (trifluoromethyl) benzoic acid
To a reaction solution (1.51 g,3.37 mmol) of tert-butyl 4- (5- (methylcarbomethoxy) phenoxy) -4-nitro-2- (trifluoromethyl) piperidine-1-carboxylate was added water (1) in this order00 mL), sodium hydroxide (673.5 mg,16.84 mmol), stirring at room temperature for three hours, dichloromethane extraction of the reaction solution, adjustment of the pH of the aqueous phase to approximately 2 with dilute hydrochloric acid, ethyl acetate extraction, and direct concentration of the organic phase to give 5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -2-nitro-4- (trifluoromethyl) benzoic acid (1.46 g) which was used directly in the next reaction. MS m/z (ESI): 379[ M-56+H] + 。
Fourth step: synthesis of 2-amino-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4- (trifluoromethyl) benzoic acid
5- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) oxy) -2-nitro-4- (trifluoromethyl) benzoic acid (1.46 g,3.37 mmol) was placed in methanol (50 mL), ammonium chloride (1.44 g,26.94 mmol) and iron powder (940.51 mg, 16.84mmol) were added and the reaction heated to 60℃and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to give 2-amino-5- ((1- (tert-butoxycarbonyl) piperidin-4-yl) oxy) -4- (trifluoromethyl) benzoic acid (1.36 g). The crude product was used directly in the next reaction. MS m/z (ESI): 349[ M-56+H ] + 。
Fifth step: synthesis of tert-butyl 4- ((4-oxo-7- (trifluoromethyl) -3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate
Tert-butyl 4- ((4-oxo-7- (trifluoromethyl) -3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate (1.36 g, 3.365 mmol) was placed in ethylene glycol monomethyl ether (30 mL), and cimetidine acetate (1.40 g,13.47 mmol) was added, and the reaction solution was heated to 90℃and stirred for 18 hours. The reaction solution was dried by spinning, and separated by column chromatography to give tert-butyl 4- ((4-oxo-7- (trifluoromethyl) -3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate (350 mg crude product, purity: 16%, yield: 4.02%). MS m/z (ESI): 414[ M+H ]] + 。
Sixth step: synthesis of tert-butyl 4- ((4-chloro-7- (trifluoromethyl) quinazolin-6-yl) oxy) piperidine-1-carboxylate
Tert-butyl 4- ((4-oxo-7- (trifluoromethyl) -3, 4-dihydroquinazolin-6-yl) oxy) piperidine-1-carboxylate (50 mg,0.12 mmol) was placed in dichloroethane (5 mL), diisopropylethylamine (0.12 mL,0.73 mmol) and phosphorus oxychloride (0.05 mL,0.48 mmol) were added and the reaction was heated to stir for 18 hours. The reaction solution was concentrated and then separated by column chromatography to give tert-butyl 4- ((4-chloro-7-methylquinazolin-6-yl) oxy) piperidine-1-carboxylate (20 mg, yield: 38%). MS m/z (ESI): 432.3[ M+H ] ] + 。
Intermediate 43: preparation of tert-butyl-4- ((4-chloroquinazolin-6-yl) oxy) piperidine-1-carboxylate
The first step: synthesis of quinazoline-4, 6-diols
2-amino-5-hydroxybenzoic acid (15 g,98 mmol) was dissolved in formamide (150 mL), stirred at 200℃for 1 hour, cooled to room temperature, water (50 mL) was added, filtered, the filter cake was washed with water several times, finally with methyl t-butyl ether for 1 time, and dried to give quinazoline-4, 6-diol (12 g, yield: 75%). MS m/z (ESI): 163[ M+H ]] + 。
And a second step of: synthesis of 4-hydroxyquinazolin-6-yl acetate
Quinazoline-4, 6-diol (2 g,12.33 mmol) was dissolved in acetic anhydride (15 mL)Pyridine (3 mL) was added, stirred at 100℃for 5 hours, the reaction mixture was concentrated, a proper amount of water was added to precipitate a solid, and the solid was filtered and dried to give 4-hydroxyquinazolin-6-yl acetate (1.3 g, yield: 51%). MS m/z (ESI): 205[ M+H ]] + 。
And a third step of: synthesis of 4-chloroquinazolin-6-yl acetate
4-Hydroxyquinazolin-6-yl acetate (800 mg,3.92 mmol) was dissolved in thionyl chloride (10 mL), DMF (1 mL) was added dropwise, stirring was carried out overnight at 85℃and after concentrating, a suitable amount of ethyl acetate was added, saturated sodium bicarbonate solution was added under ice bath, ethyl acetate was separated, brine was washed, dried over anhydrous sodium sulfate, filtered and concentrated, and column chromatography was carried out to give 4-chloroquinazolin-6-yl acetate (700 mg, yield: 80%). MS m/z (ESI): 223[ M+H ] ] + 。
Fourth step: synthesis of 4-chloroquinazolin-6-ol
4-chloroquinazolin-6-yl acetate (700 mg,3.144 mmol) was dissolved in methanol (5 mL), 7N methanolic ammonia solution (15 mL) was added, stirring was performed at room temperature for 3 hours, methyl tert-butyl ether was added, precipitate was separated out, filtration was performed, and the filter cake was washed with an appropriate amount of methyl tert-butyl ether, and after drying, 4-chloroquinazolin-6-ol was obtained (600 mg, yield: 95%). MS m/z (ESI): 179[ M+H ]] + 。
Fifth step: synthesis of tert-butyl-4- ((4-chloroquinazolin-6-yl) oxy) piperidine-1-carboxylate
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4-chloroquinazolin-6-ol (600 mg,3.32 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g,4.98 mmol), triphenylphosphine (1.3 g,4.98 mmol), diisopropyl azodicarboxylate (1 g)4.98 mmol) was dissolved in dry dichloromethane (20 mL), stirred overnight at room temperature under nitrogen, concentrated on silica gel and column chromatographed to give tert-butyl-4- ((4-chloroquinazolin-6-yl) oxy) piperidine-1-carboxylate (800 mg, yield: 66%). MS m/z (ESI): 364[ M+H ]] + 。
Intermediates 44-53 can be prepared by selecting the corresponding starting materials with reference to the overall or partial synthetic method of intermediate 43:
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2. preparation of specific examples
Example 1: preparation of 1- (4- ((4- ((2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) amino) quinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
The first step: synthesis of tert-butyl-4- ((4- ((2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) amino) quinazolin-6-yl) oxy) piperidine-1-carboxylate
Tert-butyl-4- ((4-chloroquinazolin-6-yl) oxy) piperidine-1-carboxylate (50 mg,0.137 mmol), 2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) aniline (30 mg,0.106 mmol) was dissolved in isopropanol (10 mL), stirred overnight at 80 ℃, and column chromatography after concentration afforded tert-butyl-4- ((4- ((2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) amino) quinazolin-6-yl) oxy) piperidine-1-carboxylate (50 mg, yield: 77%). MS m/z (ESI): 612[ M+H ]] + 。
And a second step of: synthesis of N- (2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) -6- (piperidin-4-oxy) quinazolin-4-amine
Tert-butyl-4- ((4- ((2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) amino) quinazolin-6-yl) oxy) piperidine-1-carboxylate (50 mg,0.0818 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 1 hour, concentrated and dried to give the crude N- (2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) -6- (piperidin-4-oxy) quinazolin-4-amine trifluoroacetate (100 mg, yield: 100%) which was used directly in the next reaction. MS m/z (ESI): 512[ M+H ] ] + 。
And a third step of: synthesis of 1- (4- ((4- ((2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) amino) quinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
N- (2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) -6- (piperidin-4-yloxy) quinazolin-4-amine trifluoroacetate (100 mg,0.0818 mmol) was dissolved in tetrahydrofuran (4 mL) and saturated aqueous sodium bicarbonate (1 mL), after being placed under ice bath, allylic chloride (11 mg,0.121 mmol) was added, and after stirring for 10 minutes, the reaction was completed and the direct reverse phase column was isolated to give 1- (4- ((4- ((2-fluoro-4- ((1- (6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) amino) quinazolin-6-yl) piperidin-1-yl) prop-2-en-1-one (24 mg, yield: 52%). MS m/z (ESI): 566[ M+H ]] + 。
1 H NMR(400MHz，MeOH-d 4 )δ8.73(d，J＝2.6Hz，1H)，8.34(s，1H)，8.19(d，J＝2.6Hz，1H)，7.97(dd，J＝8.5，2.7Hz，1H)，7.80(d，J＝2.5Hz，1H)，7.69(d，J＝9.1Hz，1H)，7.58-7.51(m，1H)，7.51-7.44(m，1H)，7.32(d，J＝8.5Hz，1H)，7.15-7.01(m，2H)，6.78-6.66(m，1H)，6.19-6.08(m，2H)，5.66(dd，J＝10.5，2.0Hz，1H)，4.83-4.76(m，1H)，3.96-3.80(m，2H)，3.63-3.50(m，2H)，2.48(s，3H)，2.11-1.97(m，2H)，1.87-1.69(m，2H)。
Examples 2 to 10, 30 to 34 can be prepared by selecting the corresponding starting materials with reference to the whole or part of the synthesis method of example 1:
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example 11: preparation of 1- (3- ((4- ((2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) azetidin-1-yl) prop-2-en-1-one
1- (3- ((4-chloro-7-methoxyquinazolin-6-yl) oxy) azetidin-1-yl) prop-2-en-1-one (28 mg,0.087 mmol) and 2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) aniline (26 mg,0.087 mmol) were placed in isopropanol (3 mL), trifluoroacetic acid (1 drop) was added, and the reaction solution was stirred at 50℃for 3 hours. The reaction solution was directly concentrated, and the residue was separated by reverse phase column chromatography to give 1- (3- ((4- ((2-fluoro-4- ((1- (5-fluoro-6-methylpyridin-3-yl) -1H-pyrazol-3-yl) oxy) phenyl) amino) -7-methoxyquinazolin-6-yl) oxy) azetidin-1-yl) prop-2-en-1-one (23 mg, yield: 45%). MS m/z (ESI): 586[ M+H ] ] + 。
1 H NMR(400MHz，DMSO-d 6 )δ9.46(s，1H)，8.81(d，J＝2.0Hz，1H)，8.62(d，J＝2.6Hz，1H)，8.36(s，1H)，8.10(d，J＝10.7Hz，1H)，7.58-7.48(m，2H)，7.32-7.22(m，2H)，7.13(dd，J＝8.7，2.6Hz，1H)，6.44-6.32(m，2H)，6.14(dd，J＝17.0，2.1Hz，1H)，5.70(dd，J＝10.1，2.1Hz，1H)，5.22-5.17(m，1H)，4.80(t，J＝8.2Hz，1H)，4.57(dd，J＝11.0，6.6Hz，1H)，4.29(d，J＝10.0Hz，1H)，3.98-3.94(m，4H)，2.48(d，J＝2.5Hz，3H)。
Examples 12 to 24, 26 to 29 and 35 to 54 can be prepared by selecting the corresponding raw materials with reference to the whole or part of the synthesis method of example 11:
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the nuclear magnetic data of the compounds prepared in the above examples are as follows:
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biological test evaluation
1. 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 hole plate Cat#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
No. Cell lines Cell culture medium Cell density
1 A431 DMEM+15％FBS 5000
2 Ba/F3 EGFR-D770-N771ins_SVD RPMI1640+10％FBS 3000
3 Ba/F3 EGFR-V769_D770insASV RPMI1640+10％FBS 3000
(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 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) The cells were lysed by shaking for 5 minutes on an orbital shaker.
(5) The cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal.
(6) The value of the T0 luminescence signal 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. Luminescent 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) The cells were lysed by shaking for 5 minutes on an orbital shaker.
(4) The cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal.
(5) The luminescence 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
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From the biological activity data of the compounds of the specific examples, the compounds of the invention have strong inhibition effect on EGFR exon 20 insertion mutation at the cellular level and strong selectivity on EGFR WT. The selectivity of the activity of some compounds in Ba/F3 EGFR-V769_d770insASV cells against EGFR WT (wild type) cells for inhibition of proliferation is improved by more than 50% compared to positive compounds, e.g. examples 1, 11, 12, 13 and 48, especially examples 1 and 12 by more than 60 fold; most surprising is that the compound of example 12 has a high selectivity of proliferation inhibiting activity in Ba/F3 EGFR-D770-N771ins_svd cells relative to EGFR WT (wild type) cells in addition to a high selectivity of proliferation inhibiting activity in Ba/F3 EGFR-V769-D770 insASV cells, up to 75-fold.
2. Mouse pharmacokinetic experiments
1. Test drug
The compounds used in this test are derived from the compounds of the specific examples of the present invention.
2. Test animals
ICR mice male n=3 original source: shanghai Sipuler-BiKai laboratory animal Co., ltd.
3. Pharmaceutical formulation and administration
The compound is weighed and respectively dissolved in the menstruum of 0.5 percent SDS+0.5 percent CMCNa, and the mixture is evenly shaken and sonicated to prepare colorless clear solution. 3 mice were orally administered after one night of fasting. The administration dose is 10mg/kg. The administration was by single oral administration (PO) to ICR mice, respectively.
4. Sample collection:
about 90. Mu.L/time point was bled via the orbit, heparin sodium was anticoagulated, placed on ice after collection, and the plasma was centrifuged within 1 hour (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ℃). The time point of blood collection was 0,0.25,0.5,1,2,4,6,8 and 24 hours. The sample was stored in a refrigerator at minus 20 ℃. After euthanasia of the mice, 3-5 μl of cerebrospinal fluid (CSF) dry ice was taken for storage. And taking 0.1-0.2g of brain tissue after heart perfusion, and preserving with dry ice, wherein the collection time points are 1h,4h and 24h.
40. Mu.L of plasma sample, 160. Mu.L of ice-cold acetonitrile containing an internal standard, 2) brain tissue 1:5 by weight was homogenized by adding physiological saline, whereas 40. Mu.L of brain homogenate was homogenized by adding 160. Mu.L of ice-cold acetonitrile containing an internal standard; 3) The cerebrospinal fluid was diluted to 40. Mu.L and 160. Mu.L of ice-cold acetonitrile containing an internal standard was added. Vortex for 3 min, centrifuge for 5 min at 11000 rpm. 100. Mu.L of the supernatant was added to 100. Mu.L of water, and 5. Mu.L of the mixture was sampled to LC/MS/MS for analysis.
3. Plasma and brain protein binding Rate experiment
1. Test procedure
1.1A 50mM sodium phosphate buffer solution, pH7.4 was prepared.
With sodium dihydrogen phosphate (NaH) 2 PO 4 ) Disodium hydrogen phosphate (Na 2 HPO 4 ) Preparing 50mM sodium phosphate buffer solution with NaOH or H 3 PO4 was adjusted to pH 7.4+/-0.1.
1.2 test compound and control were dissolved in DMSO to prepare 10mM stock solutions.
1.3 preparation of dosing solution:
10mM test compound and positive compound were gradually diluted to a final concentration of 20 Xsolution (20. Mu.M):
500 μm solution: mu.L of 10mM stock solution was added to 190. Mu.L of DMSO;
20. Mu.M solution: mu.L of 500. Mu.M solution was added to 192. Mu.L of 50mM sodium phosphate buffer solution. The final concentration of DMSO was set to 4%.
1.4 Preparation of 1. Mu.M test compound and positive compound dosing matrix:
mu.L of 20. Mu.M matrix was added to 380. Mu.L of plasma or brain to prepare the final drug administration matrix.
1.5 collecting 0 hour samples: 25 μl of the compound-containing matrix was added to a blank 96-well collection plate and stored at-20deg.C.
1.6 preparation of Balanced dialysis device
100. Mu.L of buffer was added to the receiving side of the equilibrated plate.
100. Mu.L of the dosing matrix containing the test compound or positive compound (see step 1.4) was then added to the dosing side of the equilibrated plate.
The prepared equilibrium dialysis plate was placed in a shaking table at 37℃and shaken at 60 rpm for 5 hours.
1.7 at the end of incubation (5 hours), sample preparation:
1.7.1 preparation of Receiver side (Receiver) samples:
25. Mu.L of the sample on the receiving side was removed and placed in a 96-well sample collection plate, and the same volume of matrix (blank plasma) was added for mixing.
200 μl of ACN with internal standard was added and the sample vortexed for 10 minutes and then centrifuged at 5594×g for 15 minutes.
1.7.2 preparation of dosing side (Donor) samples:
1. Mu.M test compound and 1. Mu.M positive compound administration side sample: 25. Mu.L of the drug administration side sample was taken and mixed with 25. Mu.L of a blank buffer solution.
200. Mu.L of ACN containing an internal standard was added and shaken at 600 revolutions per minute for 10 minutes, followed by centrifugation at 5594 Xg for 15 minutes on a centrifuge (Thermo, multifure. Times.3R).
1.7.3 preparation of 0 hour samples:
the 0 hour sample was re-melted at 37℃and the same administration side sample was prepared.
1.7.4 after centrifugation of all samples, the prepared samples were sent to LC-MS/MS analysis.
1.8 plasma or brain protein binding rate was calculated by the following formula:
binding ratio% = ([ administration side ]] 5h - [ receiving side ]] 5h ) Side of administration] 5h ×100％
Fu% = 100% -binding rate, fu is unbound fraction.
4. Blood brain barrier penetration analysis in mice
Kp, uu brain was calculated by AUC or concentration in brain or plasma and Fu measured by the above method. Kp, uu brain refers to the relationship between brain and unbound drug concentration in blood, used to assess the ability of a drug to penetrate the blood brain barrier. The Kpu, uu brain after administration was calculated by the following formula:
kp, uu brain= [ AUC (brain)/AUC (plasma) ]× [ Fu (brain)/Fu (plasma) ]. Or alternatively
Kp, uu brain= [ drug concentration (brain)/drug concentration (plasma) ]× [ Fu (brain)/Fu (plasma).
Table 2: kp, uu brain data for exemplary compounds
Kp, uu brain (1 h administration) Kp, uu brain (4 h administration)
Example 12 0.10 0.06
Positive compounds 0.01 ＜0.01
From the above data, it was found that the positive compound was a compound which did not substantially enter the brain, and the compound of example 12 of the present invention had a certain brain-entering effect. From the brain entry test data, the compound of the example 12 of the present invention has higher Kp and uu brain than the positive compound, and the test proves that the compound of the example 12 of the present invention has more excellent brain barrier penetration characteristics.
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 (iia), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein Z is O;
ring a is selected from the following groups:
R 1a selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, tridentate methyl and dideuteromethyl;
R 1b selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, cyclopropyl, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, tridentate methyl and dideuteromethyl;
R 2 selected from hydrogen, deuterium, fluorine, chlorine, bromine and cyano;
R 3 selected from hydrogen, deuterium and fluorine;
R 5 selected from hydrogen, deuterium, and methyl;
R 8 selected from C 3-6 A cycloalkoxy group and a 3-6 membered heterocycloalkoxy group, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl and deuterium substituted C 1-4 The substituent of the alkyl group is substituted.
2. The compound of formula (IIa), stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R 8 Selected from the group consisting ofSaid->Each independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl and cyano.
3. A compound of formula (iia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 or 2, selected from the group consisting of:
4. A compound of formula (iia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1
The preparation method of the salt is characterized by comprising the following steps:
or alternatively, the first and second heat exchangers may be,
wherein X is selected from fluorine, chlorine and bromine; ring A, R 1a 、R 1b 、R 2 、R 3 、R 5 、R 8 And Z is as defined in claim 1.
5. A pharmaceutical composition comprising a compound of formula (iia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-3 and a pharmaceutically acceptable carrier.
6. Use of a compound of formula (iia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer, tumors or metastatic disease associated at least in part with an insertion or deletion mutation of exon 20 of EGFR.
7. Use of a compound of formula (iia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 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.
8. Use of a compound of formula (iia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for the preparation of a medicament for the prophylaxis and/or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck 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 at least in part with an EGFR insertion or deletion mutation.
9. Use of a compound of formula (iia), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 8 for the manufacture of a medicament for the prevention and/or treatment of breast cancer which is at least partly associated with an EGFR exon 20 insertion or deletion mutation.
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