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CN116096372B - EGFR inhibitor, preparation method and pharmaceutical application thereof - Google Patents

EGFR inhibitor, preparation method and pharmaceutical application thereof Download PDF

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Publication number
CN116096372B
CN116096372B CN202180047548.XA CN202180047548A CN116096372B CN 116096372 B CN116096372 B CN 116096372B CN 202180047548 A CN202180047548 A CN 202180047548A CN 116096372 B CN116096372 B CN 116096372B
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alkyl
deuterium
substituted
cycloalkyl
hydroxy
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CN116096372A (en
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张鸣鸣
赵保卫
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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Abstract

Relates to an EGFR inhibitor, a preparation method and pharmaceutical application thereof. In particular to an EGFR inhibitor with a structure shown in a formula (I), a preparation method thereof, a pharmaceutical composition containing the EGFR inhibitor, and application of the EGFR inhibitor as the EGFR inhibitor and application of the EGFR inhibitor in 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, in particular to preparation of medicaments for treating and/or preventing hyperproliferative diseases and diseases inducing cell death disorder. Wherein each substituent of formula (I) is as defined in the specification.

Description

EGFR inhibitor, preparation method and pharmaceutical application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to an EGFR inhibitor, a preparation method 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 successfully developed and clinically validated. Inhibitors against EGFR can significantly increase the progression free survival of adenocarcinomas in NSCLC, while acquired drug resistant mutations can be targeted by third generation EGFR inhibitors.
Although classical EGFR activating mutations (exons 19 and 21) and resistant mutations (T790M) can be inhibited by existing drugs, insertion mutations of Exon 20 (Exon 20) also result in structural activation of EGFR signaling and are not sensitive to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and involve the insertion or repetition of 1-7 amino acids between amino acids 762-774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all EGFR mutations. These mutations are mutually exclusive with other known oncogene-driven mutations and are enriched in adenocarcinomas of females, non-smokers, asian populations, and non-small cell lung cancer patients. In addition to NSCLC, EGFR exon 20 insertion mutations are also found in a rare head and neck cancer, nasal squamous cell carcinoma (SNSCC). In addition, a structurally similar exon 20 insertion mutation was also found in HER2, another member of the EGFR family.
Several retrospective analytical studies have shown that currently available generation 1,2 and 3 EGFR inhibitors have limited efficacy for exon 20 insertion mutations, except for the a763-Y764insFQEA mutation. Irreversible inhibitor waves Ji Tini (Poziotinib) and EGFR/MET bispecific antibody Amivantamab 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. Adverse reactions in clinical use are unavoidable due to their limited selectivity for EGFR wild type and may lead to dose-limiting toxicity. Meanwhile, it is clinically shown that the existing compounds may have an insufficient exposure. Thus, there is an urgent need for small molecule inhibitors with higher exposure and/or high selectivity for EGFR exon 20 insertion mutations for these patients.
Disclosure of Invention
The invention aims to provide an EGFR inhibitor, a preparation method and pharmaceutical application thereof, and the series of compounds have strong inhibition effect on EGFR exon 20 insertion, deletion or other mutation cytologic activity and high selectivity on EGFR wild type, can be widely applied to the preparation of medicaments for treating and/or preventing cancers, tumors or metastatic diseases at least partially related to EGFR exon 20 insertion, deletion or other mutation, particularly medicaments for treating hyperproliferative diseases and diseases inducing cell death disorder, and are expected to develop a new generation EGFR inhibitor.
The present invention provides in a first aspect a compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof:
wherein,
X is CH or N;
Y 1、Y2、Y3 and Y 4 are each independently CR 1 or N;
R 1 is selected from the group consisting of hydrogen, deuterium, hydroxy, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, hydroxy 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 、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9, and-N (R 8)-C(O)R7;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9, and-N (R 8)-C(O)R7, which are independently optionally further substituted with one or more substituents 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、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9, and-N (R 8)-C(O)R7);
R 4a and R 4b are each independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, -C (O) OR 6、-C(O)R7, and-C (O) NR 8R9;
Each R 5 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and-NR 8R9, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 8R9;
Each R 6 is independently selected from the group consisting of 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, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 8R9;
Each R 7 is selected from the group consisting of 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 heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl oxy, and-NR 8R9, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl oxy, and-NR 8R9;
Each R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C 6-10 aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, Dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, Substituents for 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1-10 alkanoyl;
Or R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl, said 4-10 membered heterocyclyl or 4-10 membered heteroaryl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1-10 alkanoyl;
n is 0,1, 2, 3 or 4; and is also provided with
Each r is independently 0,1 or 2.
As a preferred embodiment, in the compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo 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 、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (R 8)-C(O)R7;
Wherein R 5、R6、R7、R8、R9 and R are as described for the compounds of formula (I).
In a preferred embodiment, in the compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 1 is selected from hydrogen, deuterium, hydroxy, halogen, cyano, C 1-4 alkyl, halo substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl 、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-C(O)NR8R9 and-N (R 8)-C(O)R7;
Wherein R 5、R6、R7、R8、R9 and R are as described for the compounds of formula (I).
In a preferred embodiment, in the compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, each R 5 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and-NR 8R9, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-10 aryloxy, 5-8 membered heteroaryloxy and-NR 8R9;
each R 6 is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR 8R9;
each R 7 is selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl oxy, and-NR 8R9, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl oxy, and-NR 8R9;
Each R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, 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, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, Dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C 1-4 alkyl, Halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 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 alkanoyl;
Or R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, said 4-8 membered heterocyclic group optionally being further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered hetero epoxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered hetero aryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl.
As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II):
wherein,
X is CH or N;
Y 1、Y2、Y3 and Y 4 are each independently CR 1 or N;
R 1 is selected from hydrogen, deuterium, hydroxy, halogen, cyano, C 1-4 alkyl, halo substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl 、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-C(O)NR8R9, and-N (R 8)-C(O)R7;
Each R 3 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo 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 、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9, and-N (R 8)-C(O)R7;
R 4a and R 4b are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and-C (O) R 7;
Each R 5 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, and-NR 8R9, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR 8R9;
each R 6 is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR 8R9;
each R 7 is selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl oxy, and-NR 8R9, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl oxy, and-NR 8R9;
Each R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, 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, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, Dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C 1-4 alkyl, Halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 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 alkanoyl;
Or R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl, said 4-8 membered heterocyclyl optionally being further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, 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 alkanoyl;
n is 0,1, 2, 3 or 4; and is also provided with
Each r is independently 0,1 or 2.
As a still further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (III):
wherein,
X is CH or N;
y 2 and Y 4 are each independently CR 1 or N;
Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl 、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-NR8R9、-P(O)R8R9, and-C (=nr 8)R7;
r 4a and R 4b are each independently selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, and-C (O) R 7;
Wherein R 5、R6、R7、R8、R9 and R are as described for the compounds of formula (I).
As a still further preferred embodiment, in the compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, R 4a and R 4b are each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2、-CF3、-CHD2、-CD3 and-C (O) R 7; wherein R 7 is as described for the compound of formula (I);
preferably, R 4a is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2、-CF3、-CHD2, and-CD 3;R4b is selected from hydrogen, deuterium, and-C (O) R 7; wherein R 7 is as described for the compound of formula (I).
As a still further preferred embodiment, in the compound of formula (I), a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, each R 1 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, cyclopropyl, cyclobutyl, oxetanyl, C 1-4 alkyl, halo substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl 、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-NR8R9、-P(O)R8R9, and-C (=nr 8)R7;
Wherein R 5、R6、R7、R8、R9 and R are as described for the compounds of formula (I).
In a preferred embodiment, in the compound of formula (I), a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof, each R 5 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and-NR 8R9, which are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, and C 1-4 alkoxy;
Each R 6 is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, hydroxy, oxo, cyano, C 1-4 alkyl, and C 1-4 alkoxy;
Each R 7 is selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, phenyl and-NR 8R9, which are independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, hydroxy, cyano, C 1-4 alkyl and C 1-4 alkoxy;
Each R 8 and R 9 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl;
Or R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, said 4-8 membered heterocyclic group optionally being further substituted with one or more substituents selected from deuterium, fluoro, chloro, hydroxy, C 1-4 alkyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, phenyl, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl.
As a most preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof, includes, but is not limited to, the following compounds:
In a second aspect the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
Wherein X, Y 1、Y2、Y3、Y4、R2、R3、R4a、R4b and n are as described for the compounds of formula (I).
In a third aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer, a prodrug 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, a prodrug or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of cancers, tumors or metastatic diseases which are at least partially associated with EGFR exon 20 insertions, deletions or other mutations.
The invention also relates to the use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof for the preparation of a medicament 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 compound of the formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof for preparing medicaments 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 inverted papilloma related nasal cavity sinus squamous cell carcinoma.
The invention also relates to the use of the compounds of formula (I), stereoisomers, prodrugs 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, prodrugs 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, prodrugs 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 tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynaecological tumor, urological tumor, skin tumor, sarcoma, nasal sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma at least in part with EGFR exon 20 insertion, deletion or other mutation.
The 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, prodrug or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for preventing and/or treating 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, a prodrug 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 at least in part associated with EGFR exon 20 insertion, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof.
Detailed Description
The inventor of the present application has studied extensively and intensively, developed an EGFR inhibitor having the structure of the following formula (I) for the first time, and the series of compounds of the present application can be widely used for preparing medicines for treating and/or preventing cancers, tumors or metastatic diseases at least partially associated with EGFR exon 20 insertion, deletion or other mutations, in particular medicines for treating hyperproliferative diseases and diseases inducing cell death disorder, and are expected to be developed into a new generation EGFR inhibitor. On this basis, the present application 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 comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like. "C 1-10 alkyl" refers to straight chain and branched alkyl groups comprising from 1 to 10 carbon atoms, and "C 1-4 alkyl" refers to straight chain and branched alkyl groups comprising from 1 to 4 carbon atoms.
The alkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1,2,3 or 4) selected independently 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、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by the substituent of R 8)-C(O)R7).
"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which refers to a cyclic hydrocarbon that 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 classified as monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 to 6 carbon atoms, e.g., "C 3-12 cycloalkyl" refers to cycloalkyl including 3 to 12 carbon atoms, "C 3-8 cycloalkyl" refers to cycloalkyl including 3 to 8 carbon atoms, "C 3-6 cycloalkyl" refers to cycloalkyl including 3 to 6 carbon atoms, wherein:
Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to a polycyclic group having one carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more (preferably 1,2 or 3) double bonds, but no ring has a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as single-, double-, or multiple-spirocycloalkyl groups according to the number of common spiro atoms between rings, and include, but are not limited to:
"fused ring alkyl" refers to an all-carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system. The number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups including, but not limited to:
"bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms that are not directly attached, and which may contain one or more (preferably 1,2, or 3) double bonds, but no ring has a fully conjugated pi-electron system. Bridged cycloalkyl groups, which may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic depending on the number of constituent rings, include, but are not limited to:
The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by substituents of R 8)-C(O)R7).
"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means that the cyclic hydrocarbon may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a fully conjugated pi electron system, and one or more (preferably 1,2, 3 or 4) ring atoms of the heterocyclic group are selected from nitrogen, oxygen or S (O) r (where r is an integer 0,1, 2) heteroatoms, but does not include the ring portion of-O-, -O-S-or-S-and the remaining ring atoms are carbon, preferably a heterocyclic group comprising 3 to 12 or 3 to 8 or 3 to 6 ring atoms, e.g. "3-6 membered heterocyclic group" means a ring group comprising 3 to 6 ring atoms, "4-8 membered heterocyclic group" means a ring group comprising 4 to 8 ring atoms, "3-8 membered heterocyclic group" means a ring group comprising 3 to 8 ring atoms, "4-10 membered heterocyclic group" means a ring comprising 4 to 10 ring atoms "comprising 3 to 12 ring atoms".
Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (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 a heteroatom of S (O) r (wherein r is an integer 0,1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1,2 or 3), but none of the rings has a fully conjugated pi-electron system. The spiroheterocyclyl groups are classified as single spiroheterocyclyl groups, double spiroheterocyclyl groups or multiple spiroheterocyclyl groups according to the number of common spiro atoms between rings. Spiroheterocyclyl groups include, but are not limited to:
"fused heterocyclyl" 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, wherein 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 integer 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" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly attached, which may contain one or more (preferably 1,2, or 3) double bonds, but none of which have a fully conjugated pi-electron system, wherein one or more (preferably 1,2,3, or 4) ring atoms are selected from nitrogen, oxygen, or a heteroatom of S (O) r (where r is an integer of 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 substituent is preferably one or more (preferably 1,2,3 or 4) selected independently 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 heterocyclic, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by the substituent of R 8)-C(O)R7).
"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 with adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group containing 6-10 or 6-8 carbons, e.g., "C 6-10 aryl" refers to an all-carbon aryl group containing 6-10 carbons, and "C 6-8 aryl" refers to an all-carbon aryl group containing 6-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:
The "aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by substituents of R 8)-C(O)R7).
"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 6 membered heteroaryl refers to a heteroaromatic system containing 5 to 6 ring atoms, 5 to 8 membered heteroaryl refers to a heteroaromatic system containing 5 to 8 ring atoms, 5 to 10 membered heteroaryl refers to a heteroaromatic system containing 5 to 10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, including but not limited to:
"heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by the substituents of R 8)-C(O)R7).
"Alkenyl" refers to 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 a straight or branched alkenyl group containing 2 to 10 carbons, and C 2-4 alkenyl refers to a straight or branched alkenyl group 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 substituent is preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by the substituent of R 8)-C(O)R7).
"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 a straight or branched alkynyl group containing 2 to 10 carbons, and C 2-4 alkynyl refers to a straight or branched alkynyl group containing 2 to 4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.
"Alkynyl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1,2,3 or 4) 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、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by the substituent of R 8)-C(O)R7).
"Alkoxy" refers to an-O-alkyl group wherein alkyl is as defined above, e.g., "C 1-10 alkoxy" refers to an alkyl oxy group containing 1-10 carbons and "C 1-4 alkoxy" refers to an alkyl oxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
"Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by the substituent of R 8)-C(O)R7).
"Cycloalkoxy" refers to-O-cycloalkyl wherein cycloalkyl is as defined above, e.g., "C 3-12 Cycloalkoxy" refers to cycloalkyloxy of 3-12 carbons, and "C 3-8 Cycloalkoxy" refers to cycloalkyloxy of 3-8 carbons, including but not limited to cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"Cycloalkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by the substituent of R 8)-C(O)R7).
"Heteroepoxy" refers to an-O-heterocyclic group wherein the heterocyclic group is defined as above, and heterocyclyloxy includes, but is not limited to, azetidinyloxy, oxetyloxy, azetidinyloxy, nitrogen, oxetyloxy, and the like.
"Heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-O-C(O)R7、-NR8R9、-P(O)R8R9、-C(＝NR8)R7、-N(R8)-C(＝NR9)R7、-C(O)NR8R9 and-N (substituted by the substituents of R 8)-C(O)R7).
"C 1-10 alkanoyl" refers to a monovalent radical remaining after removal of the hydroxyl group of a C 1-10 alkyl acid, also commonly referred to 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.
"Halo-substituted C 1-10 alkyl" refers to a 1-10 carbon alkyl group on the alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms, including, but not limited to, difluoromethyl (-CHF 2), dichloromethyl (-CHCl 2), dibromomethyl (-CHBr 2), trifluoromethyl (-CF 3), trichloromethyl (-CCl 3), tribromomethyl (-CBr 3), and the like.
"Halo-substituted C 1-10 alkoxy" refers to a 1-10 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with a fluorine, chlorine, bromine, or iodine atom. 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 group is optionally substituted with a deuterium atom. Including, but not limited to, mono-deuteromethyl (-CH 2 D), di-deuteromethyl (-CHD 2), tri-deuteromethyl (-CD 3), and the like.
"Deuterium substituted C 1-10 alkoxy" refers to a 1-10 carbon alkyl group where the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to mono-deuteromethoxy, di-deuteromethoxy, tri-deuteromethoxy, 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).
"Stereoisomer" is named stereoisomer, and refers to an isomer produced by the different spatial arrangements of atoms in a molecule, and can be classified into cis-trans isomers and enantiomers, and also into enantiomers and diastereomers. Stereoisomers due to rotation of single bonds are known as conformational isomers (conformational stereo-isomers), sometimes also known as rotamers (rotamer). 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 the isomer due to the inability of the double bond or single bond of the ring-forming carbon atom to rotate freely becomes the geometric isomer (geometric isomer), also known as cis-trans isomer (cis-trans isomer), and is classified into two configurations of Z, E. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the compounds of the present invention are understood to comprise E and/or Z forms if they contain double bonds, unless otherwise indicated. Stereoisomers with different optical properties due to the lack of anti-axisymmetry in the molecule are called optical isomers (optical isomers) and are classified 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, preferably in the S configuration.
By "pharmaceutically acceptable salts" is meant in the present invention pharmaceutically acceptable acid or base addition salts, including inorganic and organic acid salts, which salts can be prepared by methods known in the art.
"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using a Bruker AVANCE-400/500 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3) as solvents and Tetramethylsilane (TMS) as internal standard.
The LC-MS measurement was performed by using an Agilent 6120 mass spectrometer. HPLC was performed using Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (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 specific examples
Example 1a and example 1b: preparation of (S) -N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide and (R) -N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide
The first step: synthesis of 2- (2-bromophenyl) oxaprozin
O-bromobenzaldehyde (55.5 g,0.3 mol), trimethylsulfonium iodide (71 g,0.34 mol) was dissolved in DMF (200 mL), potassium hydroxide (33.6 g,0.6 mol) was added and the reaction was stirred at room temperature for 1 hour, LCMS showed complete reaction, the reaction solution was extracted by delamination with saturated aqueous NaHCO 3 (500 mL), ethyl acetate (500 mL), and the organic phase dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give crude 2- (2-bromophenyl) oxaprozin (60 g, 96% yield) which was used in the next reaction without further purification.
And a second step of: synthesis of tert-butyl (1- (2-bromophenyl) -2-hydroxyethyl) carbamate
2- (2-Bromophenyl) oxaprozin (60 g,0.3 mol) was dissolved in acetonitrile (500 mL), and concentrated sulfuric acid (59 g,0.6 mol) was slowly added dropwise. The reaction was stirred at room temperature for 8 hours, water (300 mL) was added and the reaction was stirred at 50 ℃ for 16 hours, LCMS showed complete reaction. Ethyl acetate (200 mL) was added to the reaction solution, water (200 mL) was separated, the organic phase was discarded, and the pH of the aqueous phase was adjusted to 9-10 with 6M NaOH. To the aqueous solution was added Boc 2 O (122 g,0.56 mol) and the reaction was stirred at room temperature for 2 hours, the resulting mixture was filtered, the filter cake was washed with water (100 mL), methyl tert-butyl ether (3 x 20 mL), and the filter cake was collected and dried to give tert-butyl (1- (2-bromophenyl) -2-hydroxyethyl) carbamate (25.5 g, 29% yield). ESI-MS:260[ M-56] +.
And a third step of: synthesis of tert-butyl (1- (2-bromophenyl) -2- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate
4-Chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (5.0 g,17.8 mmol), tert-butyl (1- (2-bromophenyl) -2-hydroxyethyl) carbamate (4.7 g,14.9 mmol), triphenylphosphine (7.8 g,29.8 mmol) were dissolved in anhydrous tetrahydrofuran (200 mL), the reaction stirred under nitrogen for 10min, DEAD (5.2 g,29.8 mmol) was added, the reaction stirred at 24℃for 16H under nitrogen, LCMS showed complete reaction, and the reaction mixture was concentrated to give crude tert-butyl (1- (2-bromophenyl) -2- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate (9.0 g, 99% yield). ESI-MS:577[ M+H ] +. The reaction was used directly in the next reaction.
Fourth step: synthesis of tert-butyl (1- (2-bromophenyl) -2- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate
Tert-butyl (1- (2-bromophenyl) -2- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate (9.0 g,17.8 mmol) was dissolved in tetrahydrofuran (200 mL) and water (50 mL), and concentrated aqueous ammonia (50 mL) was added. The reaction was stirred at 100 ℃ for 16 hours with sealed tube, LCMS showed complete reaction, the resulting mixture was filtered, the filter cake was washed with methyl tert-butyl ether (2 x 30 ml) and the filter cake was collected to give tert-butyl (1- (2-bromophenyl) -2- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate (6.45 g, 65% yield). ESI-MS:558[ M+H ] +.
Fifth step: synthesis of tert-butyl (1- (2-bromophenyl) -2- (4-amino-5- (quinolin-3) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate
Tert-butyl (1- (2-bromophenyl) -2- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate (4.3 g,7.7 mmol), quinoline-3-boronic acid (2.0 g,11.56 mmol), pd (dppf) Cl 2 (281mg, 0.38 mmol), sodium carbonate (2.5 g,23.12 mmol) were dissolved in dioxane (200 mL) and water (20 mL), the reaction was stirred at 60℃for 2 hours under nitrogen, LCMS showed completion of the reaction, the reaction solution was concentrated to about (150 mL) after adding water (100 mL), the resulting mixture was filtered, the filter cake was washed with ethyl acetate (2X 20 mL) and the filter cake was collected to give tert-butyl (1- (2-bromophenyl) -2- (4-amino-5- (quinolin-3) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate (3.91 g, 90% yield). ESI-MS:559[ M+H ] +.
Sixth step: synthesis of tert-butyl (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) carbamate
Tert-butyl (1- (2-bromophenyl) -2- (4-amino-5- (quinolin-3) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethyl) carbamate (2.1 g,3.76 mmol), pd 2(dba)3 (340 mg,0.37 mmol), tricyclohexylphosphine (208 mg,0.74 mmol), sodium hydroxide (750 mg,18.8 mmol) were dissolved in dioxane (100 mL) and water (20 mL), the reaction was stirred at 110℃for 16H under nitrogen, LCMS showed complete reaction, the reaction concentrated to dryness, the residue was extracted in layers with saturated aqueous NaHCO 3 (100 mL) and dichloromethane (100 mL), the organic phase was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was separated by flash column chromatography on silica gel (0-40% EA: PE with 20% EtOH in the EA phase) to give tert-butyl (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) carbamate (1.42 g, 79% yield). ESI-MS:479[ M+H ] +.
Seventh step: 12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4': synthesis of 4, 5-pyrrolo [2,1-a ] isoquinoline-5, 11-diamine
Tert-butyl (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) carbamate (1.42 g,2.97 mmol) was dissolved in 4M hydrogen chloride dioxane solution (30 mL), the reaction was stirred for 1 hour at 24 ℃, LCMS showed complete reaction, the reaction was concentrated to dryness, and the residue was washed with methyl tert-butyl ether (3 x 30 mL) to give 12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinoline-5, 11-diamine (1.01 g, 90% yield). ESI-MS:379[ M+H ] +.
Eighth step: synthesis of N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide
12- (Quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinoline-5, 11-diamine (600 mg,1.59 mmol), triethylamine (1 mL) dissolved in dichloromethane (10 mL), slowly dropwise add acryloyl chloride (171 mg,1.9 mmol) at 0deg.C, stir at 0-24deg.C for 1H, LCMS showed complete reaction, quench the reaction with saturated aqueous NaHCO 3 (10 mL), concentrate the reaction to dryness, and isolate the residue by flash reverse phase silica gel chromatography column [ 0-40% MeCN: H 2 O ] to give N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide (203 mg, 28% yield). ESI-MS:433[ M+H ] +.
Ninth step: synthesis of (S) -N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide and (R) -N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide
N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide (203 mg,0.20 mmol) was isolated by chiral resolution:
(1a) (S) -N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide (28.2 mg, resolution recovery 14%).
1H NMR(400MHz,Methanol-d4)δ8.89(d,J＝2.2Hz,1H),8.49(d,J＝2.5Hz,1H),8.06(dd,J＝5.6,2.3Hz,2H),7.95(d,J＝8.2Hz,1H),7.79(ddd,J＝8.5,6.9,1.5Hz,1H),7.63(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.18(t,J＝7.5Hz,1H),6.94(tt,J＝7.8,1.8Hz,1H),6.88-6.79(m,1H),6.26-6.10(m,2H),5.58(dd,J＝9.5,2.6Hz,1H),5.43(t,J＝4.2Hz,1H),4.45(s,2H),4.18(d,J＝12.9Hz,1H).ESI-MS：433[M+H]+.
(1B) (R) -N- (11-amino-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) acrylamide (14.3 mg, resolution recovery 7%).
1H NMR(400MHz,Methanol-d4)δ8.90(d,J＝2.2Hz,1H),8.50(d,J＝2.4Hz,1H),8.12-8.02(m,2H),7.96(d,J＝8.0Hz,1H),7.79(ddd,J＝8.5,6.8,1.4Hz,1H),7.63(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.18(t,J＝7.6Hz,1H),6.95(t,J＝7.7Hz,1H),6.85(d,J＝7.9Hz,1H),6.32-6.09(m,2H),5.58(dd,J＝9.5,2.6Hz,1H),5.44(t,J＝4.2Hz,1H),4.45(s,2H),4.19(d,J＝13.2Hz,1H).ESI-MS：433[M+H]+.
Examples 2a to 38b can be prepared by selecting the corresponding starting materials with reference to the whole or part of the synthesis methods of examples 1, 1a, 1 b:
Example 39: preparation of N- (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) -N-methacrylamide
The first step: synthesis of 2-bromo-1- (2-bromo-4-fluorophenyl) ethan-1-one
1- (2-Bromo-4-fluorophenyl) ethan-1-one (6.2 g,28.4 mmol) was dissolved in acetic acid (20 mL) and tribromopyridine (9.3 g,29.1 mmol) was added. The reaction was stirred at 70℃for 2 hours. Water (60 mL) was added to the reaction and extracted with methyl tert-butyl ether (30 mL. Times.2). The organic phases were combined and washed with saturated aqueous sodium bicarbonate (30 ml x 3). The organic phase is dried and concentrated to obtain a crude product of 2-bromo-1- (2-bromo-4-fluorophenyl) ethane-1-ketone, which is directly used for the next reaction.
And a second step of: synthesis of 1- (2-bromo-4-fluorophenyl) -2- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethan-1-one
Crude 2-bromo-1- (2-bromo-4-fluorophenyl) ethan-1-one was dissolved in acetonitrile (40 mL), and 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (7.9 g,28.4 mmol) and potassium carbonate (3.9 g,28.3 mmol) were added. The reaction solution was reacted at 60℃for 1 hour. Water (100 mL) was added and extracted with ethyl acetate (40 mL. Times.3). The organic phases were combined and concentrated to give crude 1- (2-bromo-4-fluorophenyl) -2- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethan-1-one which was used directly in the next reaction. ESI-MS 493.9[ M+H ] +.
And a third step of: synthesis of 2- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethan-1-one
Crude 1- (2-bromo-4-fluorophenyl) -2- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) ethan-1-one was dissolved in tetrahydrofuran (50 mL), aqueous ammonia (20 mL) was added, and the mixture was reacted in a sealed tank at 100℃for 16 hours. To the reaction solution was added water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated and separated using a normal phase column [ methanol: dichloromethane=0% -10% ] to give 2- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethan-1-one (2.2 g, total three step yield: 16%). ESI-MS:475.0[ M+H ] +.
Fourth step: synthesis of 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethan-1-one
2- (4-Amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethan-1-one (2.2 g,4.7 mmol) was dissolved in a mixed solvent of dioxane (30 mL) and water (6 mL), and quinoline-3-ylboronic acid (1.2 g,6.8 mmol), potassium carbonate (2.1 g,14.9 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.22 g,0.27 mmol) were added. The reaction solution was reacted under nitrogen protection at 60℃for 18 hours. To the reaction was added water (100 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated and separated using a normal phase column [ methanol: dichloromethane=0% -5% ] to give crude 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethan-1-one (0.63 g). ESI-MS:476.0[ M+H ] +.
Fifth step: synthesis of 7- (2- (2-bromo-4-fluorophenyl) -2- (methylimino) ethyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Crude 2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethan-1-one (0.63 g,1.3 mmol) was dissolved in dichloromethane (30 mL), and titanium tetraisopropoxide (3.7 g,12.9 mmol), methylamine hydrochloride (0.97 g,14.3 mmol) and triethylamine (3 mL,40.6 mmol) were added. The reaction mixture was reacted at 50℃for 1 hour. Water (100 mL) was added to the reaction solution, the filtrate was filtered, the filtrate was recovered, and the separated organic phase was concentrated to give crude 7- (2- (2-bromo-4-fluorophenyl) -2- (methylimino) ethyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (0.78 g) which was directly used in the next reaction. ESI-MS:489.0[ M+H ] +.
Sixth step: synthesis of 7- (2- (2-bromo-4-fluorophenyl) -2- (methylamino) ethyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Crude 7- (2- (2-bromo-4-fluorophenyl) -2- (methylimino) ethyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (0.78 g) was dissolved in a mixed solvent of N, N-dimethylformamide (12 mL) and acetic acid (3 mL), and sodium cyanoborohydride (0.64 g,10.2 mmol) was added. The reaction solution was reacted at room temperature for 30 minutes. Water (80 mL) was added to the reaction mixture, and the pH of the reaction mixture was adjusted to 9 or higher using sodium hydroxide, followed by separation to obtain a solution containing 7- (2- (2-bromo-4-fluorophenyl) -2- (methylamino) ethyl) -5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine, which was used directly in the next reaction. ESI-MS:491.0[ M+H ] +.
Seventh step: synthesis of methyl tert-butyl (2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethylcarbamate
To the reaction solution of the previous step were added dichloromethane (10 mL) and di-tert-butyl dicarbonate (4 mL,19.3 mmol). The reaction solution was stirred at room temperature for 16 hours. To the reaction solution was added water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the concentrated organic phase was separated using a normal phase column to give crude methyl tert-butyl (2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethylcarbamate (0.26 g). ESI-MS:591.2[ m+h ] +.
Eighth step: synthesis of tert-butyl (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimidine [5',4':4,5] pyrrolo [2,1-a ] isoquinoline-5-carbamic acid (methyl) ester
Crude tert-butyl (2- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -1- (2-bromo-4-fluorophenyl) ethylcarbamate (0.26 g,0.4 mmol) was dissolved in a mixed solvent of dioxane (8 mL) and water (1 mL), palladium acetate (0.03 g,0.1 mmol), tricyclohexylphosphine (0.07 g,0.26 mM) and sodium hydroxide (0.05 g,1.3 mmol) were added to the reaction mixture, which was reacted under nitrogen protection at 100℃for 3.5 hours, water (20 mL) was added thereto, and ethyl acetate (20 mL) was used for extraction, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to give crude tert-butyl (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimidine [5',4, 5] pyrrolo [2,1-a ] isoquinolin-5-yl ] carbamate (MS-511) which was directly used for the subsequent reaction of [2,1-a ] methyl carbamate (MS-511).
Ninth step: 2-fluoro-N 5 -methyl-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4': synthesis of 4, 5-pyrrolo [2,1-a ] isoquinoline-5, 11-diamine
Tert-butyl (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimidine [5',4': crude 4, 5-pyrrolo [2,1-a ] isoquinoline-5-carbamate was dissolved in dioxane (20 mL), and a solution of 4M hydrogen chloride in dioxane (20 mL) was added to the reaction, and the reaction was stirred at room temperature for 2 hours. 4,5] pyrrolo [2,1-a ] isoquinoline-5, 11-diamine (8.4 mg, total six step reaction yield: 4%). ESI-MS:411.0[ M+H ] +.
Tenth step: synthesis of N- (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) -N-methacrylamide
2-Fluoro-N 5 -methyl-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinoline-5, 11-diamine (8.4 mg,0.02 mmol) was dissolved in dichloromethane (5 mL), and N, N-diisopropylethylamine (0.5 mL,3.0 mM) and acryloyl chloride (2.9 mg,0.03 mmol) were added. The reaction solution was reacted at room temperature for 1 hour. The reaction mixture was concentrated and separated by high performance liquid chromatography to give N- (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) -N-methacrylamide (1.7 mg, 19%). ESI-MS:465.2[ M+H ] +.
1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.62(s,1H),8.48(s,1H),8.20(d,J＝8.5Hz,1H),8.12(d,J＝8.1Hz,1H),7.92(t,J＝7.7Hz,1H),7.75(t,J＝7.5Hz,1H),7.38(s,1H),7.20(dd,J＝9.9,7.4Hz,1H),6.86(s,1H),6.50(dd,J＝10.3,2.5Hz,1H),6.25(d,J＝16.7Hz,1H),6.09(s,1H),5.80(d,J＝10.5Hz,1H),4.60(s,2H),2.83(s,3H).
Chiral resolution of N- (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) -N-methacrylamide affords (S) -N- (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) -N-methacrylamide (39 a) and (R) -N- (11-amino-2-fluoro-12- (quinolin-3-yl) -5, 6-dihydropyrimido [5',4':4,5] pyrrolo [2,1-a ] isoquinolin-5-yl) -N-methacrylamide (39 b).
Examples 40a to 45b can be prepared by selecting the corresponding starting materials with reference to examples 39, 39a, 39b, all or part of the synthetic methods:
the nuclear magnetic data of the compound prepared in the above example are as follows:
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-D770ins_ASV 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 desired final density; mu.L of the cell suspension was added to a 96-well plate.
(3) Cells were incubated overnight in 96-well plates at 37 ℃,5% co 2 and 95% humidity.
2. T0 reference data:
(1) mu.L of PBS was added to each well of the T0 plate containing the cells.
(2) The CTG reagent was thawed and the cell plates equilibrated to room temperature for 30 minutes.
(3) An equal volume of CTG solution was added to each well.
(4) Shake on an orbital shaker for 5 minutes to lyse cells.
(5) The cell plates were left at room temperature for 20 minutes to stabilize the luminescence signal.
(6) The T0 fluorescent signal value is read.
3. Dilution and addition of Compounds
(1) According to the compound information table, corresponding volumes of DMSO were added to the corresponding compound powders to prepare 10mM stock solutions.
(2) A 1000-fold, 3.16-fold diluted compound solution was prepared.
(3) The 1000 Xdiluted compound solution was diluted 100-fold with PBS to prepare a 10-fold compound solution at a maximum concentration of 10. Mu.M, 9 concentrations, 3.16-fold dilution, and 10. Mu.L of the drug solution was added to each well seeded with 96-well plates to seed cells. Three duplicate wells were set for each compound concentration, with a final DMSO concentration of 0.1%.
(4) Cells were placed in 96-well plates with drug at 37 ℃,5% co 2 and 95% humidity, and cultured for a further 72 hours before CTG analysis.
4. Fluorescent signal reading
(1) The CTG reagent was thawed and the cell plates equilibrated to room temperature for 30 minutes.
(2) An equal volume of CTG solution was added to each well.
(3) Shake on an orbital shaker for 5 minutes to lyse cells.
(4) The cell plates were left at room temperature for 20 minutes to stabilize the fluorescent signal.
(5) The fluorescence value is read.
5. Data processing
The data were analyzed using GRAPHPAD PRISM 7.0.0 software and fitted using non-linear S-curve regression to obtain the dose-response curve, from which IC 50 values (units: nM) were calculated, for specific experimental results, see Table 1:
Cell viability (%) = (Lum test drug-Lum broth control)/(Lum cell control-Lum broth control) ×100%.
Table 1: biological test results
From the biological activity data of the compounds of the specific examples, the compounds of the invention have strong inhibition effect on EGFR exon 20 insertion, deletion or other mutation at the cellular level and have certain selectivity on EGFR WT.
All documents mentioned in this disclosure are incorporated by reference in this disclosure 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 application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (7)

1. A compound of formula (iii), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Wherein X is N;
y 2 and Y 4 are each independently CR 1 or N;
Each R 1 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, cyclopropyl, cyclobutyl, oxetanyl, C 1-4 alkyl, halo substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl 、-S(O)rR5、-O-R6、-C(O)OR6、-C(O)R7、-NR8R9、-P(O)R8R9 and-C (=nr 8)R7;
R 4a is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2、-CF3、-CHD2, and-CD 3;
R 4b is selected from hydrogen, deuterium, and-C (O) R 7;
Each R 5 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and-NR 8R9, said groups being independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, and C 1-4 alkoxy;
Each R 6 is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, hydroxy, oxo, cyano, C 1-4 alkyl, and C 1-4 alkoxy;
Each R 7 is selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, phenyl and-NR 8R9, which are independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, hydroxy, cyano, C 1-4 alkyl and C 1-4 alkoxy;
Each R 8 and R 9 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl;
Or R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl, said 4-8 membered heterocyclyl being optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, hydroxy, C 1-4 alkyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, phenyl, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl; and is also provided with
Each r is independently 0,1 or 2.
2. The compound of formula (iii), stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
3. a process for the preparation of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1, comprising the steps of:
wherein X, Y 2、Y4、R1、R4a and R 4b are as defined in claim 1.
4. A pharmaceutical composition comprising a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-2 and a pharmaceutically acceptable carrier.
5. Use of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer, tumour or metastatic disease associated at least in part with an insertion, deletion or other mutation of EGFR exon 20.
6. Use of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 for the manufacture of a medicament for the prevention and/or treatment of lung cancer, pancreatic 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 papilloma or nasal sinus squamous cell carcinoma associated with nasal sinus inverted papilloma associated with EGFR exon 20 insertions, or other mutations.
7. The use according to claim 6, wherein the lung cancer is non-small cell lung cancer; the gastrointestinal tumor is colon cancer or gastric cancer; the tumor of the head and neck is head and neck cancer; the breast and other gynecological tumors are breast cancer, ovarian cancer or uterine cancer.
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