CN116262741A - Compounds as EGFR inhibitors - Google Patents

Compounds as EGFR inhibitors Download PDF

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CN116262741A
CN116262741A CN202211610689.0A CN202211610689A CN116262741A CN 116262741 A CN116262741 A CN 116262741A CN 202211610689 A CN202211610689 A CN 202211610689A CN 116262741 A CN116262741 A CN 116262741A
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cycloalkyl
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王建设
张汉承
蔡聪聪
贾薇
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Hangzhou Amethyst Pharmaceutical Technology Co ltd
Hangzhou Innogate Pharma Co Ltd
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Hangzhou Innogate Pharma Co Ltd
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    • C07—ORGANIC CHEMISTRY
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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
    • C07D401/14—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 three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

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Abstract

The invention provides a compound serving as a mutant EGFR inhibitor, in particular to a compound with a structure shown in a formula (I) or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate thereof. The saidThe compounds of (2) can be used for treating or preventing diseases or disorders associated with the activity or expression level of mutant EGFR.

Description

Compounds as EGFR inhibitors
Technical Field
The present invention relates to the field of pharmaceutical chemistry; in particular, the invention relates to a novel compound, a synthesis method thereof and application of the novel compound serving as a mutant EGFR inhibitor in preparation of medicines for treating various diseases related to tumors and the like.
Background
EGFR (Epidermal Growth Factor Receptor) is an important member of the HER/ErbB family and is a receptor tyrosine kinase. It is widely distributed on the cell membrane of various tissues of human body, and its structure is divided into extracellular region, transmembrane region and intracellular kinase domain. By binding the ligand EGF, EGFR can form dimers on the cell membrane, including homodimers formed between EGFR and heterodimers with other receptor tyrosine kinases of the family, erbB2, erbB3 or erbB 4. The formation of dimers causes phosphorylation of intracellular tyrosine at critical sites, activating a range of downstream signaling pathways within the cell, such as MAPK pathways and PI3K pathways. These critical signaling pathways play an important role in the processes of cell proliferation, survival, and anti-apoptosis. When abnormal activation of EGFR signaling pathway occurs, such as over-expression of ligand and receptor, amplification, deletion and mutation of EGFR gene, etc., it can promote transformation of cells to cancer direction, and promote proliferation, invasion, migration and angiogenesis of tumor cells, etc. Mutations and deletions of the EGFR gene occur frequently in non-small cell lung cancer, mainly at exons 18-21. Mutations at the L858R site, with deletion of exon 19 and exon 21, are the most common type of EGFR mutation, accounting for 90% of all mutation types. The population is a population of non-smoking female lung adenocarcinoma patients of asian origin.
EGFR inhibitors currently on the market have three generations in common, with gefitinib being a representative inhibitor of the first generation
Figure BDA0003999457530000011
Erlotinib>
Figure BDA0003999457530000012
And icotinib (kemelna), a representative inhibitor of the second generation is afatinib (afatinib), and a representative inhibitor of the third generation is aortitinib (AZD 9291). Ornitinib (AZD 9291) is an oral small molecule third generation EGFR inhibitor, is a first lung cancer drug aiming at EGFR T790M mutation, can target EGFR gene mutation (including 18, 19 and 21 mutation) and EGFR inhibitor acquired drug resistance (T790M) of non-small cell lung cancer, and the advent of the AZT inhibitor brings good survival benefit to more lung cancer patients. AZD9291 can obviously prolong the survival time by about one year. However, after that, resistance developed very rapidly, typically within 9-13 months, mainly due to mutation at the C797 position of exon 20 of EGFR, i.e., EGFR del19/L858R T790M C797S mutation, also known as EGFR "triple mutation", was not controlled by EGFR inhibitors of the first, second or third generation.
Since no approved EGFR kinase inhibitors are currently available for the "triple mutation" type, it is critical to develop kinase inhibitors against the EGFR del19/L858R T790M C797S mutation. Meanwhile, as the compound has lower inhibition activity on wild EGFR, the side effects of the wild EGFR inhibitor, such as diarrhea, rash and the like, can be reduced, and the compound is more suitable for treating tumors.
Disclosure of Invention
The object of the present invention is to provide a novel class of mutant EGFR inhibitors.
In a first aspect of the present invention, there is provided a compound having the structure shown in formula (I) below, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof:
Figure BDA0003999457530000021
in formula (I):
R 1 a group selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Haloalkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl, C 3-6 Cycloalkyl C 2-4 Alkynyl, 3-to 6-membered heterocyclyl C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl-D-, or 3-to 6-membered heterocyclyl-D-; the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl, -C (O) R a Or = M; m is selected from O or CR b R c The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is b And R is c Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; r is R a Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, or C 3-6 Cycloalkyl; d is selected from the group consisting of a bond, -O-, -S-, or-N k -；
R 2 Selected from the group consisting of C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 9-membered heterocyclyl, 3-6 membered cycloalkyl-O-, 3-to 9-membered heterocyclyl-O-; the C is 2-4 Alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, R f -S(O) 2 -(CR d R e ) p -、R f -S(O)-(CR d R e ) p -、R f -P(O)(R g )-(CR d R e ) p -、R a C(O)-(CR d R e ) p -, or = CR h R i The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is d And R is e Each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, or C 1-4 Haloalkoxy groups; r is R f Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; r is R g Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, NR k R k 、C 3-6 Cycloalkyl, 3-6 membered cycloalkyl-O-, or 3-to 6-membered heterocyclyl; or R is f And R is g And together with the phosphorus atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; r is R h Selected from hydrogen, fluorine, or C 1-4 An alkyl group; r is R i Selected from R f -S(O) 2 -(CR d R e ) P -or R f -P(O)(R g )-(CR d R e ) P -; r is a number of k Each independently selected from hydrogen or C 1-4 An alkyl group; p is selected from 0, 1, 2, or 3;
R 3 a group selected from the group consisting of: c (C) 3-8 Cycloalkyl or 3-to 12-membered heterocyclyl; the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR j 、SR j 、NR k R k 、R j O-C 1-4 Alkyl, R k R k N-C 1-4 Alkyl, R j O-C 1-4 alkyl-O-, R k R k N-C 1-4 alkyl-O-, R j O-C 1-4 alkyl-NR k -、R k R k N-C 1-4 alkyl-NR k -; wherein R is j Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, or 3-to 6-membered heterocyclyl; each R is k Is defined as above;
X 1 、X 2 、X 3 and X 4 Each independently selected from N or CR m The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is m Selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, C 1-4 Haloalkoxy, CN, NR k R k Or C 3-6 Cycloalkyl; each R is k Is defined as above;
wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl groups is optionally and each independently substituted with 1 to 3 substituents selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, aryl, heteroaryl, CN, NO 2 、OR j 、SR j 、NR k R k 、C(O)R n 、C(O)OR j 、C(O)NR k R k 、NR k C(O)R n 、NR k S(O) 2 R n Or S (O) 2 R n Provided that the chemical structure formed is stable and meaningful; wherein R is j And R is k Is defined as above; r is R n Selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, aryl, or heteroaryl.
Unless otherwise specified, the above aryl groups are aromatic groups having 6 to 12 carbon atoms; heteroaryl is a 5-to 15-membered (preferably 5-to 12-membered) heteroaryl group; the heterocyclic group may be a monocyclic or polycyclic heterocyclic group (including spiro, fused and bridged rings); the cyclic structure is a saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic group.
In another preferred embodiment, in formula (I):
R 1 a group selected from the group consisting of:
Figure BDA0003999457530000031
Figure BDA0003999457530000032
R 1 a site of attachment to the other moiety of the compound of formula (I);
R 2 a group selected from the group consisting of:
Figure BDA0003999457530000033
Figure BDA0003999457530000034
R 2 a site of attachment to the other moiety of the compound of formula (I);
". Times." represents chiral centers;
R 3 a group selected from the group consisting of:
Figure BDA0003999457530000041
“---”R 3 a site of attachment to the other moiety of the compound of formula (I);
". Times." represents chiral centers;
fragments
Figure BDA0003999457530000042
A group selected from the group consisting of:
Figure BDA0003999457530000043
Figure BDA0003999457530000046
representing and R 1 A site of ligation; />
Figure BDA0003999457530000044
Representing and R 2 A site of ligation; />
Figure BDA0003999457530000047
Representation ofAnd R is R 3 The site of ligation.
In another preferred embodiment, formula (I) is formula (II):
Figure BDA0003999457530000045
R p selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; k is selected from 0, 1, 2, or 3;
m and n are each independently selected from 1, 2, or 3;
the remaining groups are as defined above.
In another preferred embodiment, formula (I) is formula (III):
Figure BDA0003999457530000051
R p selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; k is selected from 0, 1, 2, or 3;
m and n are each independently selected from 1, 2, or 3;
the remaining groups are as defined above.
In another preferred embodiment, formula (I) is formula (IVa) or formula (IVb):
Figure BDA0003999457530000052
R p selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, or 3-to 6-membered heterocyclyl; k is selected from 0, 1, 2, or 3;
R q Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, or 3-to 6-membered heterocyclyl;
m and n are each independently selected from 1, 2, or 3;
the remaining groups are as defined above.
In another preferred embodiment, formula (I) is formula (Va) or formula (Vb):
Figure BDA0003999457530000053
R p selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, or 3-to 6-membered heterocyclyl; k is selected from 0, 1, 2, or 3;
d is selected from the group consisting of a bond, -O-, -S-, or-N k -；R k Is as defined above;
ring A is selected from C 3-6 Cycloalkyl or 3-to 6-membered heterocyclyl;
R t selected from hydrogen, halogen, C 1-4 Alkyl, or-C (O) R a The method comprises the steps of carrying out a first treatment on the surface of the Or two R t Attached to the same carbon atom on ring a and taken together with that carbon atom form c=m; m is selected from O or CR b R c The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is b And R is c Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; r is R a Is as defined above;
m and n are each independently selected from 1, 2, or 3;
f is selected from 0, 1, 2, or 3;
the remaining groups are as defined above.
In another preferred embodiment, formula (I) is formula (VI):
Figure BDA0003999457530000061
each R is p Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; or two R p Together with the carbon atoms to which they are attached, form an optionally substituted 3-to 6-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S;
R f Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl;
R 1 and R is 3 Is as defined above.
In another preferred embodiment, each R p Each independently selected from methyl; or two R p Together with the carbon atoms to which they are attached, form a 3-membered cyclic structure;
R f selected from methyl;
R 1 a group selected from the group consisting of:
Figure BDA0003999457530000062
Figure BDA0003999457530000063
R 1 a site of attachment to the other moiety of the compound of formula (VI);
R 3 a group selected from the group consisting of:
Figure BDA0003999457530000064
Figure BDA0003999457530000066
R 3 a site of attachment to the other moiety of the compound of formula (VI);
"×" indicates chiral centers.
In another preferred embodiment, formula (I) is formula (VII):
Figure BDA0003999457530000065
each R is p Each independently selected from hydrogen, C 1-4 An alkyl group; or two R p Together with the carbon atoms to which they are attached, form a 3-membered cyclic structure;
R d and R is e Each independently selected from hydrogen, C 1-4 An alkyl group; p is selected from 1 or 2;
R f selected from C 1-4 Alkyl, C 3-6 NaphtheneA group, 3-to 6-membered heterocyclyl;
R g selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered cycloalkyl-O-, or 3-to 6-membered heterocyclyl;
R 1 and R is 3 Is as defined above.
In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:
Figure BDA0003999457530000071
Figure BDA0003999457530000081
Figure BDA0003999457530000091
"x" means chiral centers, which may be in the R configuration or the S configuration, or a mixture of R and S.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the first aspect of the invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, and a pharmaceutically acceptable carrier.
In a third aspect of the invention, there is provided the use of a compound according to the first aspect of the invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, for the manufacture of a pharmaceutical composition for the treatment of a disease, disorder or condition associated with mutant EGFR activity or expression level.
In another preferred embodiment, the disease, disorder or condition is selected from the group consisting of: non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, renal cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, and other solid tumors and hematological tumors.
Detailed Description
The inventor has studied intensively for a long time, and has unexpectedly found a mutant EGFR inhibitor with novel structure, and a preparation method and application thereof. The compounds of the present invention may be used in the treatment of various diseases associated with the activity of the mutant EGFR. Based on the above findings, the inventors have completed the present invention.
Terminology
Unless specifically stated otherwise, references herein to "or" have the same meaning as "and/or" refer to "or" and ".
Unless otherwise specified, each chiral carbon atom (chiral center) of all compounds of the invention may optionally be in the R configuration or S configuration, or a mixture of R and S configurations.
As used herein, the term "alkyl" alone or as part of another substituent refers to a straight chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched groups. Having a limit of the number of carbon atoms before the alkyl group (e.g. C 1-10 ) When used, the term alkyl is defined as having 1 to 10 carbon atoms. For example, C 1-8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
As used herein, the term "alkenyl" alone or as part of another substituent refers to a straight or branched chain carbon chain group having at least one carbon-carbon double bond. Alkenyl groups may be substituted or unsubstituted. Having a limit on the number of carbon atoms before the alkenyl group (e.g. C 2-8 ) When used, means that the alkenyl group contains 2 to 8 carbon atoms. For example, C 2-8 Alkenyl refers to alkenyl groups containing 2 to 8 carbon atoms and includes ethenyl, propenyl, 1, 2-butenyl, 2, 3-butenyl, butadienyl, or the like.
As used herein, the term, alone or as part of another substituent"alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be straight or branched, or a combination thereof. Having a definition of the number of carbon atoms before alkynyl (e.g. C 2-8 Alkynyl) means that the alkynyl contains 2 to 8 carbon atoms. For example, the term "C 2-8 Alkynyl "refers to straight or branched chain alkynyl groups having 2 to 8 carbon atoms and includes ethynyl, propynyl, isopropoxynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or the like.
As used herein, the term "cycloalkyl" alone or as part of another substituent refers to a group having a saturated or partially saturated unit ring, bicyclic or polycyclic (fused, bridged or spiro) ring system. When a cycloalkyl group has a defined number of carbon atoms (e.g. C 3-10 ) When referring to cycloalkyl groups, said cycloalkyl groups contain 3 to 10 carbon atoms. In some preferred embodiments, the term "C 3-8 Cycloalkyl "refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "spirocycloalkyl" refers to a bicyclic or polycyclic group having a single carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. "fused ring alkyl" refers to an all-carbon bi-or multi-cyclic group in which 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 double bonds, but none of the rings has a fully conjugated pi-electron system. "bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. The atoms contained in the cycloalkyl are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited to the cycloalkyl groups described below.
Figure BDA0003999457530000101
/>
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted. The following are examples of aryl groups, and the present invention is not limited to the following aryl groups.
Figure BDA0003999457530000111
"heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one or more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a polycyclic group containing a heterocyclic group (containing one or more heteroatoms selected from nitrogen, oxygen and sulfur) fused to an aryl group, with the attachment site located on the aryl group. Heteroaryl groups may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the heteroaryl groups described below.
Figure BDA0003999457530000112
"heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Polycyclic heterocyclyl refers to heterocyclyl groups including spiro, fused and bridged rings. "Spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (referred to as the spiro atom) with the other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon. "fused ring heterocyclyl" refers to 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 of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system, and in which one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon. "bridged heterocyclic group" refers to a polycyclic heterocyclic group wherein any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system, and wherein one or more of the ring atoms are selected from nitrogen, oxygen, or sulfur and the remaining ring atoms are carbon. If both saturated and aromatic rings are present in the heterocyclyl (e.g., the saturated and aromatic rings are fused together), the point of attachment to the parent must be at the saturated ring. And (3) injection: when the point of attachment to the parent is on an aromatic ring, it is referred to as heteroaryl, and not as heterocyclyl. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
Figure BDA0003999457530000121
As used herein, the term "halogen" refers to F, cl, br, and I, alone or as part of other substituents.
As used herein, the term "substituted" (with or without "optionally" modification) means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, i.e., two rings have one common carbon atom. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such as (but not limited to): c (C) 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxy, carboxyl (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl, C 2-10 Ester groups, amino groups.
For convenience and in accordance with conventional understanding, the terms "optionally substituted" or "optionally substituted" are used only to refer to sites that can be substituted with substituents, and do not include those that are not chemically realizable.
As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with tissue of a subject (e.g., a human) without undue adverse side effects. In some embodiments, pharmaceutically acceptable salts of certain compounds of the invention include salts of the compounds of the invention having an acidic group (e.g., potassium, sodium, magnesium, calcium) or salts of the compounds of the invention having a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).
The application is as follows:
the present invention provides the use of a class of compounds of formula (I), or deuterated derivatives thereof, salts, isomers (enantiomers or diastereomers, if present), hydrates, pharmaceutically acceptable carriers or excipients thereof, for inhibiting mutant EGFR.
The compounds of the invention are useful as a mutant EGFR inhibitor.
The invention is a single inhibitor of mutant EGFR, and achieves the aim of preventing, relieving or curing diseases by regulating the activity of the mutant EGFR. Diseases referred to include, but are not limited to: non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, renal cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, and other solid tumors and hematological tumors.
The compounds of the present invention and deuterated derivatives thereof, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates and/or compositions thereof, may be formulated with pharmaceutically acceptable excipients or carriers and the resulting compositions may be administered to mammals, such as men, women and animals, in vivo for the treatment of conditions, symptoms and diseases. The composition may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, and sterile injectable solutions. Sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin (augmentation), glycine, disintegrants (e.g., starch, croscarmellose sodium, complex silicates, and polymeric polyethylene glycols), granulating binders (e.g., polyvinylpyrrolidone, sucrose, gelatin, and acacia), and lubricants (e.g., magnesium stearate, glycerol, and talc). In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders. The amount of the compound or pharmaceutical composition of the present invention administered to a patient is not fixed and is typically administered in a pharmaceutically effective amount. Meanwhile, the amount of the compound actually administered may be decided by a physician according to the actual circumstances, including the condition to be treated, the administration route selected, the actual compound administered, the individual condition of the patient, etc. The dosage of the compounds of the invention will depend on the particular use being treated, the mode of administration, the condition of the patient, and the judgment of the physician. The proportion or concentration of the compounds of the invention in the pharmaceutical composition depends on a variety of factors including the dosage, physicochemical properties, route of administration, etc.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions.
Pharmaceutical compositions and methods of administration
Because the compounds of the present invention have excellent inhibitory activity against mutant EGFR, the compounds of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present invention as a main active ingredient are useful for treating, preventing and alleviating diseases associated with the activity or expression level of mutant EGFR.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 5-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.
Figure BDA0003999457530000131
Figure BDA0003999457530000132
) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 5 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The main advantages of the invention include:
1. there is provided a compound of formula I.
2. Provides a mutant EGFR inhibitor with novel structure, and preparation and application thereof, wherein the inhibitor can inhibit the activity of mutant EGFR at very low concentration.
3. A pharmaceutical composition for treating diseases associated with mutant EGFR activity is provided.
4. Provided is a mutant EGFR inhibitor which is orally absorbed well.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Some representative compounds of the present invention may be prepared by the following synthetic methods, in which the reagents and conditions for each step may be selected from those conventionally used in the art for such preparation methods, and the above selections may be made by one skilled in the art based on the knowledge of the art after the structure of the compounds of the present invention is disclosed.
Examples:
some of the compounds of the present invention can be prepared by the following method.
Abbreviations (abbreviations)
Ac=acetyl group
Bn=benzyl group
Boc=t-butoxycarbonyl group
t-BuOK = potassium tert-butoxide
m-cpba=3-chloroperoxybenzoic acid
C-phos=2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl
DAST = diethylaminosulfur trifluoride
Dcm=dichloromethane
Ddq=2, 3-dichloro-5, 6-dicyanobenzoquinone
Dipea=n, N-diisopropylethylamine
DIBAL-H = diisobutylaluminum hydride
DMA = N, N-dimethylacetamide
Dmf=n, N-dimethylformamide
DMSO = dimethyl sulfoxide
EtOAc = ethyl acetate
HATU = urea N, N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate
HMPA = hexamethylphosphoric triamide
Lihmds=lithium bis trimethylsilylamide
Me=methyl group
Ms=methanesulfonyl group
Nmp=n-methylpyrrolidone
NIS = N-iodosuccinimide
Oxone=potassium monopersulfate
Pd(dppf)Cl 2 = [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (II)
Pd 2 (dba) 3 =tris (dibenzylideneacetone) dipalladium
Ph=phenyl
i-prah=isopropanol
Tbaf=tetra-n-butylammonium fluoride
TIPS = triisopropyl silicon group
Tea=triethylamine
TFA = trifluoroacetic acid
THF = tetrahydrofuran
Xantphos Pd G3 = [ (4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene) -2- (2 '-amino-1, 1' -biphenyl) ] methane sulfonic acid palladium
Example 1: preparation of Compound 1
Figure BDA0003999457530000161
Compound 1a (see WO2021133809A1,3.5g,16.1 mmol) was dissolved in a mixed solvent of tetrahydrofuran (35 mL), methanol (35 mL) and water (35 mL), and potassium monopersulfate (Oxone, 29.7g,48.3 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. The reaction was quenched with water (50 mL), the mixture was extracted with ethyl acetate (3X 50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure after filtration to give compound 1b (2.1 g, yield 52.3%) as a pale yellow solid. MS m/z 250.1[ M+H ] ] + 。
Compound 1b (2 g,8.02 mmol) was dissolved in 1, 4-dioxane solution of hydrogen chloride (4M, 20 mL). The reaction solution was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give compound 1c (1.4 g, yield 94%) as a pale yellow solid. MS (MS)m/z 150.1[M+H] + 。
Compound 1c (1G, 6 mmol), cesium carbonate (1.9G, 6 mmol) and Xantphos Pd G3 (190 mg,0.2 mmol) were added sequentially under nitrogen by dissolving compound 8-bromo-3-chloroisoquinoline compound 1o (500 mg,2 mmol) in anhydrous 1, 4-dioxane (6 mL). The reaction mixture was heated to 95℃and reacted for 16 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted three times with ethyl acetate (3×15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 1d (230 mg, yield 37%) as a white solid. MS m/z,311.03[ M+H ]] + ； 1 H NMR(500MHz,CDCl 3 )δ9.09(s,1H),7.60(s,1H),7.52(t,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H),6.47(d,J＝7.6Hz,1H),4.51(t,J＝7.6Hz,2H),4.14-4.04(m,2H),3.53-3.38(m,3H),2.98(s,1H)。
Compound 1d (230 mg,0.74 mmol) was dissolved in acetic acid (8 mL) and N-iodosuccinimide (166.5 mg,0.74 mmol) was added. The reaction mixture was stirred at 25℃for 1 hour. The reaction was quenched with water (15 mL), the mixture was extracted with dichloromethane (3X 20 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 1e (250 mg, yield 77%) as a yellow solid. MS m/z 436.83[ M+H ] ] + ； 1 H NMR(500MHz,CDCl 3 )δ8.96(s,1H),7.99(d,J＝8.2Hz,1H),7.84(s,1H),6.27(d,J＝8.3Hz,1H),4.56-4.46(m,2H),4.11(m,2H),3.51-3.41(m,3H),2.99(s,3H)。
Compound 1e (150 mg,0.34 mmol) was dissolved in 1, 4-dioxane (5 mL) and water (1.2 mL), and the compounds isopropenylboronic acid pinacol ester compound 1p (64 mg,0.38 mmol), potassium carbonate (57 mg,0.41 mmol) and Pd (dppf) Cl were added sequentially 2 (28 mg,0.034 mmol). The reaction mixture was warmed to 80 ℃ and stirred for 3 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (3X 15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filteredThe filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound 1f (95 mg, yield 79.6%) as a white solid. MS m/z 351.33[ M+H ]] + ； 1 H NMR(500MHz,CDCl 3 )δ9.09(s,1H),7.85(s,1H),7.38(d,J＝7.9Hz,1H),6.48(d,J＝7.9Hz,1H),5.41(s,1H),5.00(s,1H),4.49(t,J＝7.6Hz,2H),4.07(dd,J＝7.6,5.1Hz,2H),3.50-3.43(m,3H),3.00(s,3H),2.13(s,3H)。
Compound 1f (65 mg,0.185 mmol) was dissolved in ethyl acetate (20 mL) under hydrogen atmosphere, and platinum dioxide (30 mg,0.132 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 1g (60 mg, yield 92%) of a yellow solid compound. MS m/z 353.11[ M+H ]] + ； 1 H NMR(500MHz,CDCl 3 )δ9.11(s,1H),7.84(s,1H),7.48-7.45(m,1H),6.53(d,J＝8.0Hz,1H),4.45(t,J＝7.5Hz,2H),4.02(dd,J＝7.6,5.3Hz,2H),3.48-3.38(m,4H),2.98(s,3H),1.34(d,J＝7.0Hz,6H)。
Compound 1h (3 g,11.48mmol, see Synlett,2009,12,1933-1936) was dissolved in N, N-dimethylformamide (30 mL), sodium hydride (918 mg,60%,22.96 mmol) was added at 0deg.C, and stirred at room temperature for 30 min. Benzyl bromide (2.1 mL,17.22 mmol) was added dropwise at 0deg.C, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give compound 1i (3.15 g, yield 89.8%) as a white solid. MS m/z 351.3[ M+H ] ] + ； 1 H NMR(500MHz,CDCl 3 )δ7.42-7.22(m,5H),4.79(t,J＝11.1Hz,1H),4.57-4.22(m,2H),4.09-3.84(m,1H),3.44(d,J＝24.5Hz,1H),3.20(s,3H),3.13(s,3H),3.00(dd,J＝39.8,14.0Hz,1H),2.89-2.70(m,1H),1.95-1.81(m,1H),1.80-1.72(m,1H),1.44(m,9H).
Compound 1i (2.5 g,7.12 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (12 mL) and water (12 mL), and the reaction mixture was stirred at 60℃for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure and then redispersed in tetrahydrofuran (5 mL), ph=8 was adjusted with saturated aqueous sodium bicarbonate solution, addInto di-tert-butyl dicarbonate (Boc) 2 O,3.1g,14.23 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate (3×30 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=4:1) to give a colorless transparent liquid compound 1j (1.75 g, yield 80.5%). MS m/z 306.4[ M+H ]] + ； 1 H NMR(500MHz,CDCl 3 )δ7.41-7.28(m,5H),4.79(d,J＝11.8Hz,1H),4.57(d,J＝11.6Hz,1H),4.35-3.98(m,2H),3.94-3.77(m,1H),3.40-3.22(m,2H),2.63-2.51(m,1H),2.48-2.37(m,1H),1.46(s,9H)。
Compound 1j (1.08 g,3.54 mmol) and difluoromethyl (2-pyridyl) sulfone (546.5 mg,2.83 mmol) were dissolved in anhydrous N, N-dimethylformamide (15 mL). Hexamethylphosphonic triamide (1.5 mL) and lithium bis trimethylsilylamide (5.6 mL,5.6 mmol) were added at-60℃under nitrogen. The reaction solution was stirred at-60℃for 1 hour, then slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1) to give compound 1k (590 mg, yield 49.1%) as a pale yellow liquid. MS m/z 340.3[ M+H ] ] + 。 1 H NMR(500MHz,CDCl 3 )δ7.29-7.16(m,5H),4.49-3.98(m,5H),2.86-2.62(m,2H),2.30-2.09(m,2H),1.34(s,9H)。
Compound 1k (400 mg,1.19 mmol) was dissolved in anhydrous dichloromethane (10 mL) and 2, 3-dichloro-5, 6-dicyanobenzoquinone (535 mg,2.36 mmol) was added. The reaction mixture was stirred at room temperature for 2 days. The reaction was quenched by addition of saturated aqueous sodium bicarbonate, the mixture was extracted with ethyl acetate (3×150 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:2) to give 1l (60 mg, yield 20.4%) of a yellow liquid compound. MS m/z 250.3[ M+H ]] + 。 1 H NMR(500MHz,CDCl 3 )δ4.56(s,1H),4.38-4.15(m,2H),3.00-2.68(m,2H),2.41-2.33(m,1H),2.24(d,J＝14.2Hz,1H),1.90(bs,1H),1.47(s,9H)。
Compound 1l (60 mg,0.24 mmol) was dissolved in 1, 4-dioxane (4M, 2 mL) of hydrogen chloride and the reaction mixture was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 1m (43 mg, yield 96.2%). MS m/z 150.2[ M+H ]] + 。
Compound 1m (43 mg,0.23 mmol) and 2-chloro-4 aminopyrimidine (30 mg,0.23 mmol) were dissolved in isopropanol (2 mL), triethylamine (70.3 mg,0.69 mmol) was added and the reaction mixture was stirred at 100℃for 6 hours. The reaction was quenched with water (10 mL), the compound was extracted with ethyl acetate (3X 15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane: meoh=20:1) to give compound 1n as a yellow solid (40 mg, yield 71.3%). MS m/z 243.2[ M+H ] ] + 。
1g (40 mg,0.113 mmol) of compound and 1n (33 mg,0.136 mmol) of compound were dissolved in anhydrous 1, 4-dioxane (2 mL) under nitrogen atmosphere, and Pd was added in sequence 2 (dba) 3 (10.4 mg,0.01 mmol), C-Phos (9.9 mg,0.022 mmol) and cesium carbonate (73.9 mg,0.226 mmol). The reaction mixture was stirred at 100℃for 16 hours. The reaction solution was cooled to room temperature, quenched with water (5 mL), the mixture was extracted with ethyl acetate (3X 15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by preparative chromatography on silica gel plate (dichloromethane: meoh=15:1) to give compound 1 (3.02 mg, yield 4.8%) as a pale yellow solid. MS m/z 559.2[ M+H ]] + 。 1 H NMR(500MHz,CDCl 3 )δ9.06(s,1H),8.51(s,1H),8.05(d,J＝5.7Hz,1H),7.49-7.38(m,2H),6.43(d,J＝7.9Hz,1H),6.26(d,J＝5.7Hz,1H),5.08(d,J＝14.1Hz,1H),4.98(d,J＝13.0Hz,1H),4.71(s,1H),4.46(t,J＝7.5Hz,2H),4.03(t,J＝6.6Hz,2H),3.58(q,J＝6.8Hz,1H),3.52-3.37(m,3H),3.15(dd,J＝14.1,2.0Hz,1H),3.04(td,J＝12.8,3.5Hz,1H),2.99(s,3H),2.51(bs,1H),2.40-2.32(m,1H),2.08-1.96(m,1H),1.37(m,6H)。
Example 2: preparation of Compound 2
Figure BDA0003999457530000191
The compound 8-bromo-3-chloroisoquinoline (compound 1o,500mg,2 mmol) was dissolved in anhydrous 1, 4-dioxane (5 mL) under nitrogen, and the compounds thiomorpholine-1, 1-dioxide (307 mg,2.27 mmol), cesium carbonate (1.1G, 3.4 mmol) and XantPhos Pd G3 (190 mg,0.2 mmol) were added sequentially. The reaction mixture was heated to 95℃and reacted for 16 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (10 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 2a (155 mg, yield 26.1%) as a white solid. MS m/z 296.98[ M+H ] ] + 。
Compound 2a (155 mg,0.52 mmol) was dissolved in acetic acid (5 mL) and N-iodosuccinimide (118 mg,0.52 mmol) was added. The reaction mixture was stirred at 25℃for 1 hour. The reaction was quenched with water (8 mL), the mixture was extracted with dichloromethane (8 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 2b (190 mg, yield 86.1%) as a yellow solid. MS m/z 422.9[ M+H ]] +
Compound 2b (150 mg,0.35 mmol) was dissolved in 1, 4-dioxane (5 mL) and water (1.2 mL), and the compound isopropenylboronic acid pinacol ester (compound 1p,66mg,0.39 mmol), potassium carbonate (60 mg,0.42 mmol) and Pd (dppf) Cl were added sequentially 2 (29 mg,0.035 mmol). The reaction mixture was warmed to 80 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature, quenched with water (8 mL), the mixture was extracted with ethyl acetate (8 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 2c (80 mg, yield 68%) as a white solid. MS m/z 337.04[ M+H ] ] + 。
Compound 2c (40 mg,0.118 mmol) was dissolved under hydrogen atmosphereTo ethyl acetate (30 mL) was added platinum dioxide (20 mg,0.088 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Compound 2d (27 mg, 67.7% yield) was obtained as a yellow solid. MS m/z 339.09[ M+H ]] + 。
Compound 2d (3.3 mg,0.0097 mmol) was dissolved in 1, 4-dioxane (0.3 mL) under nitrogen, and compound 2e (see WO2021133809A1,2mg,0.00885 mmol), cesium carbonate (5.77 mg,0.0177 mmol), C-Phos (0.4 mg,0.000885 mmol) and Pd were added sequentially 2 (dba) 3 (0.8 mg,0.000885 mmol) and the reaction mixture was stirred at 100deg.C for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel thin layer chromatography (dichloromethane: methanol=20:1) to give compound 2 (1.3 mg, yield 25.3%) as a white solid. MS (ES) + ,m/z):529.27[M+H] + 。 1 H NMR(500MHz,CDCl 3 )δ9.29(s,1H),8.64(s,1H),8.09(d,J＝5.6Hz,1H),7.53-7.45(m,2H),7.06(d,J＝7.8Hz,1H),6.20(d,J＝5.6Hz,1H),4.59(m,1H),4.50-4.41(m,1H),3.73(d,J＝16.0Hz,1H),3.66-3.60(m,5H),3.59-3.50(m,2H),3.34(s,4H),2.04-1.97(m,1H),1.97-1.89(m,2H),1.51(d,J＝21.8Hz,3H),1.38(d,J＝6.8Hz,6H)。
Example 3: preparation of Compound 3
Figure BDA0003999457530000201
The compound 8-bromo-3-chloroisoquinoline (compound 1o, 284 mg,2 mmol), tetramethylsulfonyl piperidine (319 mg,2.2 mmol), cesium carbonate (1303 mg,4 mmol) and Xantphos Pd G3 (189 mg,0.2 mmol) was added to 1, 4-dioxane (5 mL) under nitrogen. The reaction mixture was stirred at 100℃for 6 hours. The reaction was cooled to room temperature, and quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (5 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 3a (420 mg, yield 61.4%) as a yellow solid. MS m/z 325.0[ M+H ] ] + 。
Compound 3a (400 mg,1.23 mmol) was dissolved in dichloromethane (20 mL) and acetic acid (2 mL) and N-iodosuccinimide (270 mg,1.23 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. Dichloromethane (20 mL) was added to dilute the reaction solution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 3b (350 mg, yield 63.2%) as a yellow solid. MS m/z 450.8[ M+H ]] + 。
Under nitrogen, compound 3b (200 mg, 0.447 mmol), pinacol isopropenylborate (Compound 1p,78mg,0.467 mmol), potassium carbonate (80 mg,0.577 mmol) and Pd (dppf) Cl 2 (42 mg,0.058 mmol) was added to 1, 4-dioxane (8 mL) and water (2 mL) and the reaction mixture was stirred at 80deg.C for 4 hours. The reaction was cooled to room temperature, and quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (10 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 3c (100 mg, yield 61.7%) as a yellow solid. MS M/z 365 [ M+H ] ] + 。
Compound 3c (30 mg,0.082 mmol) was dissolved in ethyl acetate (20 mL) under hydrogen atmosphere, and platinum dioxide (15 mg) was added. The reaction mixture was stirred at 25℃for 2 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give compound 3d (25 mg, yield 83.3%) as a yellow solid. MS m/z 367.0[ M+H ]] + 。
Compound 3d (3.6 mg,0.0097 mmol), compound 2e (2 mg,0.0088 mmol), cesium carbonate (5.8 mg,0.0177 mmol), C-Phos (0.4 mg,0.0009 mmol) and tris (dibenzylideneacetone) dipalladium (0.8 mg,0.0009 mmol) were added to 1, 4-dioxane (0.4 mL) under nitrogen, and the reaction mixture was warmed to 100deg.C and stirred for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained crude product was purified by preparative thin layer chromatography plate (dichloromethane: methanol=20:1) to give compound 3 (1.7 mg, yield 31.1%) as a yellow solid. MS m/z 557.2[ M+H ]] + 。 1 H NMR(500MHz,CDCl 3 )δ9.28(s,1H),8.60(s,1H),8.08(d,J＝5.6Hz,1H),7.54(s,1H),7.45(d,J＝7.8Hz,1H),6.95(d,J＝7.8Hz,1H),6.20(d,J＝5.6Hz,1H),4.59(dd,J＝13.5,8.4Hz,1H),4.52-4.41(m,1H),3.77-3.69(m,1H),3.66-3.51(m,5H),3.06-3.01(m,1H),2.94(s,3H),2.87(t,J＝11.6Hz,2H),2.38-2.29(m,2H),2.25-2.16(m,2H),2.01-2.00(m,1H),1.98-1.90(m,2H),1.50(d,J＝21.8Hz,3H),1.37(d,J＝6.8Hz,6H)。
Example 4: preparation of Compound 4
Figure BDA0003999457530000211
The compound 1- (diphenylmethyl) -2, 2-dimethylazetidin-3-ol (920 mg,3.44 mmol) was dissolved in dichloromethane (10 mL) under nitrogen. Triethylamine (1042 mg,10.32 mmol) and methanesulfonyl chloride (591 mg,5.16 mmol) were added at 0deg.C. The reaction mixture was naturally warmed to room temperature and stirred for 3 hours. The reaction was quenched with water (5 mL) and the mixture extracted with dichloromethane (10 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 4a (1.1 g, 92.4%), which was used directly in the next reaction. MS m/z 346.1[ M+H ] ] +
Methyl methanesulfonylacetate (680 mg,4.47 mmol) was dissolved in N, N-dimethylformamide (20 mL) under nitrogen, sodium hydride (60%, 206mg,5.16 mmol) was added at 0deg.C and stirred for 15 minutes. Then, a solution of compound 4a (1.1 g,3.44 mmol) in N, N-dimethylformamide was added thereto, and the reaction mixture was stirred at 80℃for 16 hours. The reaction was quenched with water (10 mL) and the mixture was extracted with ethyl acetate (3X 20 mL). The combined organic phases were washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give compound 4b (830 mg, yield 63.2%) as a yellow solid. MS m/z 402.2[ M+H ]] + 。
Lithium chloride (704 mg,16.53 mmol) was added to a solution of compound 4b (830 mg,2.07 mmol) in N, N-dimethylacetamide (8 mL) at room temperature and the reaction mixture was stirred at 150℃for 4 hours. Cold waterThe reaction was quenched with water (10 mL), the mixture was extracted with ethyl acetate (20 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to give compound 4c (230 mg, yield 32.3%) as a yellow solid. MS m/z 344.1[ M+H ] ] + 。
Compound 4c (180 mg,0.524 mmol) was dissolved in methanol (30 mL) under hydrogen atmosphere, and trifluoroacetic acid (1 mL) and 10% palladium on charcoal hydroxide (50 mg) were added. The reaction mixture was stirred at 25℃for 4 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol=10:1) to give compound 4d (60 mg, yield 64.6%) as a colorless oil. MS m/z 178.1[ M+H ]] + 。
Under nitrogen, compound 4d (60 mg,0.34 mmol), 8-bromo-3-chloroisoquinoline (Compound 1o,75mg,0.31 mmol), cesium carbonate (202 mg,0.62 mmol), xantphos Pd G3 (17 mg,0.018 mmol) and Pd 2 (dba) 3 (0.8 mg,0.0009 mmol) was added to 1, 4-dioxane (2 mL). The reaction mixture was warmed to 100 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 4e (40 mg, yield 38.5%) as a yellow solid. MS M/z339.1[ M+H ]] + 。
Compound 4e (40 mg,0.118 mmol) was dissolved in dichloromethane (2 mL) and acetic acid (0.2 mL) and N-iodosuccinimide (26.5 mg,0.118 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. The crude product obtained was concentrated under reduced pressure and purified by thin layer chromatography (petroleum ether: ethyl acetate=1:1) to give compound 4f (50 mg, yield 91.3%) as a yellow solid. MS m/z 464.9[ M+H ] ] + 。
Under nitrogen, compound 4f (35 mg,0.075 mmol), pinacol isopropenylborate (Compound 1p,13.3mg,0.079 mmol), potassium carbonate (13 mg,0.097 mmol) and Pd (dppf) Cl 2 (8 mg,0.01 mmol) was added to 1, 4-dioxane (2 mL) and water (0.5 mL), and the reaction mixture was stirred at 80deg.C for 2 h. The reaction was cooled to room temperature, and quenched by the addition of water (2 mL). The mixture was extracted with ethyl acetate (5 mL. Times.3)The combined organic phases were taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 4g (25 mg, yield 86.4%) of a yellow solid compound. MS m/z 378.9[ M+H ]] + 。
4g (25 mg,0.065 mmol) of the compound was dissolved in ethyl acetate (10 mL) under a hydrogen atmosphere, and platinum dioxide (10 mg) was added. The reaction mixture was stirred at 25℃for 2 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the compound as a yellow solid for 4h (25 mg, yield 99.5%). MS m/z 381.0[ M+H ]] + 。
Under nitrogen, compound 4h (4.6 mg,0.012 mmol), compound 2e (2.5 mg, 0.0111 mmol), cesium carbonate (7 mg,0.022 mmol), C-Phos (0.5 mg,0.0011 mmol) and Pd were reacted under nitrogen 2 (dba) 3 (1 mg,0.0011 mmol) was added to 1, 4-dioxane (0.5 mL). The reaction mixture was heated to 100℃and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained crude product was purified by preparative thin layer chromatography plate (dichloromethane: methanol=15:1) to give compound 4 (2.7 mg, yield 31.1%) as a yellow solid. MS m/z 571.1[ M+H ] ] + 。 1 H NMR(500MHz,CDCl 3 )δ9.37(s,1H),8.54(s,1H),8.07(d,J＝5.6Hz,1H),7.45(d,J＝7.9Hz,1H),7.37(s,1H),6.85(d,J＝8.0Hz,1H),6.16(d,J＝5.3Hz,1H),4.63-4.55(m,1H),4.51-4.43(m,1H),4.05(td,J＝7.7,2.0Hz,1H),3.90(t,J＝7.5Hz,1H),3.78-3.70(m,1H),3.62-3.51(m,3H),3.36-3.24(m,2H),3.14-3.06(m,1H),3.00(s,3H),2.02-1.98(m,1H),1.97-1.91(m,2H),1.51(d,J＝21.8Hz,3H),1.40-1.34(m,6H),1.25(s,3H),1.05(d,J＝3.4Hz,3H)。
EXAMPLE 5 preparation of Compound 5
Figure BDA0003999457530000231
Dimethyl phosphine oxide (316 mg,4.0 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) under nitrogen. A solution of sodium bistrimethylsilyl amide (2.2 mL,4.38 mmol) was added dropwise under ice cooling, and the reaction mixture was stirred at room temperature for 20 minutes. Dropwise adding compound 3-under ice bathA solution of iodomethyl) azetidine-1-carboxylic acid tert-butyl ester (1 g,3.37 mmol) in tetrahydrofuran (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL), the mixture was extracted with dichloromethane (10 mL. Times.3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 5a (700 mg, yield 84%) as a colorless liquid. MS m/z 248.11[ M+H ]] + 。
Compound 5a (100 mg,0.4 mmol) was dissolved in a 1, 4-dioxane solution (4M, 5 mL) of hydrogen chloride and the reaction mixture was stirred at 25℃for 1 hour. The reaction solution was concentrated under reduced pressure to give crude compound 5b (70 mg, yield 95%). MS m/z 184.01[ M+H ]] +
The compound 8-bromo-3-chloroisoquinoline (370 mg,1.53 mmol) was dissolved in anhydrous 1, 4-dioxane (10 mL) under nitrogen, and compound 5b (420 mg,2.29 mmol), cesium carbonate (960 mg,2.95 mmol) and Xantphos Pd G3 (138 mg,0.15 mmol) were added sequentially. The reaction mixture was heated to 95℃and reacted for 16 hours. The reaction was cooled to room temperature, and quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (10 ml×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol=12:1) to give compound 5c (350 mg, yield 74%) as a yellow solid. MS m/z 309.14[ M+H ] ] + 。
Compound 5c (50 mg,0.162 mmol) was dissolved in acetic acid (3 mL) and N-iodosuccinimide (37 mg,0.162 mmol) was added. The reaction mixture was stirred at 25℃for 1 hour. The reaction was quenched with water (8 mL), the mixture was extracted with dichloromethane (8 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound 5d (50 mg, yield 71%) as a yellow solid. MS m/z 434.88[ M+H ]] +
Compound 5d (250 mg,0.575 mmol) was dissolved in 1, 4-dioxane (7 mL) and water (1.75 mL), and the compounds isopropenylboronic acid pinacol ester (107 mg,0.633 mmol), potassium carbonate (96 mg,0.69 mmol) and Pd (dppf) Cl were added sequentially 2 (47mg，0.0575mmol). The reaction mixture was warmed to 80 ℃ and stirred for 3 hours. Cooled to room temperature, quenched with water (8 mL) and the mixture extracted with ethyl acetate (8 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol=15:1) to give compound 5e (70 mg, yield 35%) as a yellow solid. MS m/z 349.14[ M+H ]] + 。
Compound 5e (45 mg,0.129 mmol) was dissolved in ethyl acetate (30 mL) under hydrogen atmosphere, and platinum dioxide (20 mg,0.088 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 5f (40 mg, yield 88.6%) as a yellow solid. MS m/z 351.11[ M+H ] ] + 。
Compound 5f (4.26 mg,0.012 mmol) was dissolved in 1, 4-dioxane (0.3 mL) under nitrogen, and compound 2e (2.5 mg, 0.0111 mmol), cesium carbonate (7.16 mg,0.022 mmol), C-Phos (0.5 mg,0.0011 mmol) and Pd were added sequentially 2 (dba) 3 (1 mg,0.0011 mmol). The reaction mixture was stirred at 100℃for 6 hours. Cooled to room temperature, quenched with water (8 mL) and the mixture extracted with ethyl acetate (8 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by thin layer chromatography on silica gel (dichloromethane: methanol=10:1) to give compound 5 (3 mg, yield 46%) as a yellow solid. MS m/z 541.24[ M+H ]] + 。 1 H NMR(500MHz,CDCl 3 )δ9.07(s,1H),8.52(s,1H),8.06(d,J＝5.6Hz,1H),7.46(s,1H),7.39(d,J＝8.0Hz,1H),6.39(d,J＝8.0Hz,1H),6.19(d,J＝5.5Hz,1H),4.60(dd,J＝13.5,8.7Hz,1H),4.49-4.40(m,3H),3.95-3.89(m,2H),3.76-3.67(m,1H),3.59-3.48(m,3H),3.31-3.20(m,1H),2.20-2.14(m,2H),1.97-1.89(m,2H),1.55(s,3H),1.53(s,3H),1.50(d,J＝21.9Hz,3H),1.34(t,J＝5.3Hz,6H)。
Example 6: preparation of Compound 6
Figure BDA0003999457530000241
Compound 6a (2.4 g,9.47 mmol) was dissolved in dichloromethane (50 mL), triethylamine (2.88 g,28.42 mmol) and methanesulfonyl chloride (1.63 g,14.21 mmol) were added at 0deg.C and stirred at 0deg.C for 4 hours. Dichloromethane (50 mL) was added to dilute the reaction, and the mixture was washed three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure to give compound 6b (3 g, yield 95.5%) as a pale yellow oil. MS m/z 332.1[ M+H ]] + 。
Compound 6b (3 g,9.05 mmol) and methyl methanesulfonylacetate (1.79 g,11.77 mmol) were dissolved in N, N-dimethylformamide (30 mL) and sodium hydride (60%, 552mg,3.58 mmol) was added at 0deg.C. Stirring was carried out at 80℃for 16 hours under nitrogen atmosphere. The reaction was quenched by addition of saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate (3×80 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:2) to give compound 6c (2.5 g, yield 71.3%) as a pale yellow solid. MS m/z 388.2[ M+H ] ] + 。
Compound 6c (2.5 g,6.45 mmol) was dissolved in N, N-dimethylacetamide (15 mL), lithium chloride (1.37 g,32.26 mmol) was added and the reaction mixture stirred at 150℃for 8 hours. After the reaction mixture was cooled, ethyl acetate (50 mL) was added to dilute the reaction solution, and the mixture was washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 6d (860 mg, yield 40.4%) as a pale yellow solid. MS m/z 330.1[ M+H ]] + 。
Compound 6d (860 mg,2.61 mmol) was dissolved in methanol (25 mL) and trifluoroacetic acid (0.1 mL) under nitrogen atmosphere, palladium on charcoal (10%, 86 mg) was added to replace the nitrogen in the bottle with hydrogen. The reaction mixture was stirred at room temperature for 4 hours. Diatomite and methanol were added thereto for filtration, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid compound 6e (400 mg, yield 93.8%). MS m/z 164.1[ M+H ]] + 。
Compound 6f (8-bromo-3-chloroisoquinoline, 500mg,2.06 mmol) and compound 6e (400 mg,2.45 mmol) were dissolved in anhydrous 1, 4-dioxane (10 mL) under nitrogenXantphos Pd G3 (195.3 mg,0.206 mmol) and cesium carbonate (1.34G, 4.12 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 16 hours. The reaction solution was cooled to room temperature, quenched with water (20 mL), the mixture was extracted with ethyl acetate (3X 30 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 6g (250 mg, yield 37.3%) of a pale yellow solid compound. MS m/z 325.3[ M+H ] ] + 。
6g (230 mg,0.71 mmol) of the compound was dissolved in acetic acid (5 mL) and methylene chloride (1 mL), N-iodosuccinimide (159.3 mg,0.71 mmol) was added at 0℃and stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give a pale yellow solid compound for 6h (270 mg, yield 77.8%). MS m/z 451.3[ M+H ]] + 。
Under nitrogen, 6h (50 mg,0.11 mmol) of the compound and triisopropylsilylacetylene (40.5 mg,0.22 mmol) were dissolved in anhydrous N, N-dimethylformamide (2 mL) and triethylamine (1 mL), and cuprous iodide (3.2 mg,0.017 mmol) and Pd (PPh) were added in this order 3 ) 2 Cl 2 (3.9 mg,0.005 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL), the mixture was extracted with ethyl acetate (3X 15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was isolated and purified by preparative thin layer silica gel plate (petroleum ether: ethyl acetate=1:1) to give compound 6i (50 mg, yield 89.2%) as a pale yellow solid. MS m/z 505.3[ M+H ] ] + 。
Compound 6i (18 mg,0.036 mmol) and compound 2e (7.6 mg,0.037 mmol) were dissolved in anhydrous 1, 4-dioxane (1 mL) under nitrogen atmosphere, and Pd was added sequentially 2 (dba) 3 (3.3 mg,0.0036 mmol), C-Phos (3.1 mg,0.0071 mmol) and cesium carbonate (34.8 mg,0.107 mmol). The reaction mixture was stirred at 100℃for 6 hours. The reaction mixture was cooled to room temperature, quenched with water (5 mL), and the mixture was quenched with acetic acidEthyl ester (3×15 mL) was extracted, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by preparative thin layer chromatography on silica gel plate (dichloromethane: methanol=15:1) to give compound 6j (12 mg, yield 48.4%) as a pale yellow solid. MS m/z 695.4[ M+H ]] + 。
Compound 6j (12 mg,0.017 mmol) was dissolved in tetrahydrofuran (1 mL), tetrabutylammonium fluoride in tetrahydrofuran (1N, 0.021mL,0.021 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Concentrating under reduced pressure to obtain crude product. The crude product was purified by reverse phase column chromatography (C18 column, mobile phase H) 2 O(0.1％NH 3. H 2 Mecn=1:1) to give compound 6 (5 mg, yield 53.7%) as a yellow solid. MS m/z 539.1[ M+H ]] + 。 1 H NMR(500MHz,CDCl 3 )δ9.02(s,1H),8.58(s,1H),8.09(d,J＝5.6Hz,1H),7.69(d,J＝8.0Hz,1H),7.33(s,1H),6.38(d,J＝8.1Hz,1H),6.22(d,J＝5.6Hz,1H),4.77(t,J＝7.9Hz,1H),4.61(dd,J＝13.8,8.5Hz,1H),4.47(s,1H),4.40-4.33(m,1H),3.88-3.81(m,1H),3.74-3.64(m,1H),3.60-3.47(m,2H),3.45-3.32(m,3H),3.12-3.03(m,1H),2.98(s,3H),2.02-1.96(m,1H),1.95-1.84(m,2H),1.55(d,J＝6.1Hz,3H),1.50(d,J＝21.9Hz,3H)。
Example 7: preparation of Compound 7
Figure BDA0003999457530000261
Under nitrogen, 6-h (50 mg,0.11 mmol) and 4, 5-tetramethyl-2- (oxetan-3-yl) -1,3, 2-dioxaborolan (81.7 mg,0.44 mmol) were dissolved in 1, 4-dioxane/water (2 mL/0.4 mL) and [1,1' -bis (diphenylphosphino) ferrocene was added sequentially ]Palladium dichloride (8.1 mg,0.01 mmol) and cesium carbonate (72.3 mg,0.22 mmol). The reaction mixture was stirred at 100℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (10 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified by preparative chromatography on silica gel plates (petroleum ether: ethyl acetate=1:3). ObtainingCompound 7-a (5.8 mg, yield 13.7%) is a pale yellow solid. MS m/z 381.2[ M+H ]] + 。
Compounds 7-a (5.8 mg,0.015 mmol) and 2-e (3.1 mg,0.013 mmol) were dissolved in anhydrous 1, 4-dioxane (1 mL) under nitrogen, and tris (dibenzylideneacetone) dipalladium (1.1 mg,0.0012 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (1.1 mg,0.0025 mmol) and cesium carbonate (8.1 mg,0.025 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 6h. After LCMS monitoring the reaction, the reaction was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by preparative chromatography on silica gel plate (DCM: meoh=12:1). Compound 7 (1.25 mg, yield 48.4%) was obtained as a pale yellow solid. MS m/z 571.7[ M+H ] ] + 。
Example 8: preparation of Compound 8
Figure BDA0003999457530000262
Compound 6-h (19 mg,0.042 mmol) was dissolved in DMF/TEA (1 mL/0.5 mL) under nitrogen, and a solution of propyne in DMF (1M, 126uL,0.126 mmol), ditolylphosphine palladium dichloride (1.6 mg,0.002 mmol) and cuprous iodide (1.2 mg, 0.006mmol) were added sequentially. The reaction mixture was stirred at 35℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (10 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified by preparative chromatography on silica gel plates (petroleum ether: ethyl acetate=1:2). Compound 8-a (9 mg, yield 58.8%) was obtained as a pale yellow solid. LCMS (ES) + ,m/z):363.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.07(s,1H),8.07(s,1H),7.61(d,J＝8.0Hz,1H),6.51(d,J＝8.0Hz,1H),4.73(t,J＝7.9Hz,1H),4.35(m,1H),3.80(t,J＝7.1Hz,1H),3.46–3.26(m,2H),3.06(m,1H),2.97(s,3H),2.19(s,3H),1.53(d,J＝6.1Hz,3H)。
Compounds 8-a (4.5 mg,0.012 mmol) and 2-e (3 mg,0.012 mmol) were reacted under nitrogen) Dissolved in anhydrous 1, 4-dioxane (1 mL), tris (dibenzylideneacetone) dipalladium (1.1 mg,0.0012 mmol), 2-dicyclohexylphosphine-2 ', 6' -bis (N, N-dimethylamino) -1,1' -biphenyl (1.1 mg,0.0025 mmol), cesium carbonate (8.1 mg,0.025 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by preparative chromatography on silica gel plate (DCM: meoh=15:1). Compound 8 (3.53 mg, yield 51.5%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):553.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.03(s,1H),8.29(s,1H),8.10(d,J＝5.6Hz,1H),7.58(d,J＝8.0Hz,1H),7.40(s,1H),6.46(d,J＝5.7Hz,1H),6.39(d,J＝8.0Hz,1H),4.74(t,J＝7.8Hz,1H),4.68(dd,J＝13.7,9.0Hz,1H),4.52(d,J＝13.3Hz,1H),4.33(m,1H),3.79(t,J＝7.2Hz,1H),3.68-3.64(m,1H),3.48-3.33(m,4H),3.10-3.02(m,1H),2.97(s,3H),2.18(s,3H),2.04-1.99(m,1H),1.93-1.85(m,2H),1.53(d,J＝6.1Hz,3H),1.48(d,J＝21.8Hz,3H)。
Example 9: preparation of Compound 9
Figure BDA0003999457530000271
Compound 9-a (940 mg,4 mmol) was dissolved in dichloromethane (30 mL) under nitrogen, and triethylamine (1200 mg,12 mmol) and methanesulfonyl chloride (686 mg,6 mmol) were added at 0deg.C. The reaction mixture was naturally warmed to room temperature and stirred for 3 hours. The reaction was quenched with water (5 mL), the mixture was extracted with dichloromethane (3X 10 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give compound 9-b (1.25 g, 99.9%) which was used directly in the next reaction.
Compound 9-b (1.25 g,4 mmol) was dissolved in DMF (25 mL) under nitrogen, sodium methyl mercaptide (95%, 365mg,5.2 mmol) was added in portions and the reaction stirred at room temperature for 16h. The reaction was quenched with water (10 mL), the mixture extracted with ethyl acetate (3X 20 mL), and the organics combinedThe phases were washed with saturated brine (3×10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (35% ethyl acetate) to give compound 9-c (920 mg, yield 77.7%) as a yellow oil. MS m/z 266.1[ M+H ]] + 。
Metropropolyoxybenzoic acid (85%, 1690mg,8.3 mmol) was added to a dichloromethane solution (30 mL) of compound 9-c (920 mg,3.47 mmol) at room temperature, and the reaction mixture was stirred at 25℃for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (85% ethyl acetate) to give 9-d (800 mg, yield 77.5%) as a colourless oil. MS m/z 298.1[ M+H ] ] + 。
Compound 9-d (800 mg,2.69 mmol) was dissolved in methanol (50 mL) under a hydrogen atmosphere, and 10% palladium hydroxide on charcoal (100 mg) was added. The reaction mixture was stirred at 25℃for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give 9-e (380 mg, yield 86.6%) as a colorless oily compound. MS m/z 164.1[ M+H ]] + 。
Compound 9-e (196 mg,1.2 mmol) 8-bromo-3-chloroisoquinoline (242.5 mg,1 mmol), cesium carbonate (652 mg,2 mmol), xantphos Pd G3 (57 mg,0.06 mmol) was added to 1, 4-dioxane (8 mL) under nitrogen. The reaction mixture was warmed to 100 ℃ and stirred for 16 hours. The reaction was cooled to room temperature, quenched with water (2 mL), and the mixture was extracted with ethyl acetate (3X 20 mL). The combined organic phases were washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (85% ethyl acetate) to give compound 9-f (130 mg, 40.1% yield) as a yellow solid. MS m/z 325.1[ M+H ]] + 。
Compound 9-f (130 mg,0.4 mmol) was dissolved in dichloromethane (5 mL), and acetic acid (0.5 mL) and N-iodosuccinimide (90 mg,0.4 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. The crude product obtained was concentrated under reduced pressure and purified by flash chromatography (85% ethyl acetate) to give 9-g (150 mg, yield 83.2%) of compound as a yellow solid. MS m/z 451[ M+H ] ] + 。
Compound 9-g (40 mg,0.08 under nitrogen atmosphere9 mmol), pinacol isopropenylborate (18 mg,0.11 mmol), sodium carbonate (14 mg,0.134 mmol) and tetrakis (triphenylphosphine) palladium (10 mg,0.009 mmol) were added to 1, 4-dioxane (3 mL) and water (0.75 mL) and the reaction mixture stirred at 60℃for 16 h. The reaction was cooled to room temperature, and quenched by the addition of water (2 mL). The mixture was extracted with ethyl acetate (3×10 ml), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by flash chromatography (85% ethyl acetate) to give compound 9-h (20 mg, yield 61.7%) as a yellow solid. MS M/z365.1[ M+H ]] + 。
Compound 9-h (20 mg,0.055 mmol) was dissolved in ethyl acetate (10 mL) under hydrogen atmosphere, and platinum dioxide (10 mg) was added. The reaction mixture was stirred at 25℃for 2 hours. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give compound 9-i (20 mg, yield 99.4%) as a yellow solid. MS m/z 367.1[ M+H ]] + 。
Compound 9-i (4.8 mg,0.0132 mmol), compound 2-e (2.5 mg,0.01 mmol), cesium carbonate (7 mg,0.022 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (0.5 mg,0.0011 mmol) and tris (dibenzylideneacetone) dipalladium (1 mg,0.0011 mmol) were added to 1, 4-dioxane (0.5 mL) under nitrogen. The reaction mixture was heated to 100℃and stirred for 6 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained crude product was purified by preparative thin layer chromatography plate (dichloromethane: methanol=15:1) to give compound 9 (2 mg, yield 32.7%) as a yellow solid. MS m/z 557.4[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 )δ9.28(s,1H),8.53(s,1H),8.07(d,J＝5.6Hz,1H),7.47(s,1H),7.41(d,J＝8.0Hz,1H),6.81(d,J＝8.0Hz,1H),6.20(d,J＝5.6Hz,1H),4.60(dd,J＝13.7,8.5Hz,1H),4.53-4.43(m,1H),3.78-3.68(m,1H),3.67-3.42(m,7H),3.41-3.34(m,1H),3.28(d,J＝6.9Hz,2H),3.07-2.99(m,1H),2.98(s,3H),2.49-2.38(m,1H),1.98-1.90(m,3H),1.51(d,J＝21.8Hz,3H),1.38-1.35(m,6H)。
Example 10: preparation of Compound 10
Figure BDA0003999457530000291
Under nitrogen, compound 6-h (10 mg,0.022 mmol) and cyclopropylacetylene (4.4 mg,0.066 mmol) were dissolved in N, N-dimethylformamide/triethylamine (1 mL/0.5 mL), and ditolylphosphine palladium dichloride (0.8 mg,0.001 mmol) and cuprous iodide (0.6 mg, 0.003mmol) were added sequentially. The reaction mixture was stirred at 40℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (10 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified by preparative chromatography on silica gel plates (petroleum ether: ethyl acetate=1:2). Compound 10-a (3.3 mg, yield 38.2%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):389.2[M+H] + 。
Under nitrogen, compound 10-a (3.3 mg,0.0085 mmol) and 2-e (2 mg,0.0085 mmol) were dissolved in anhydrous 1, 4-dioxane (0.5 mL), and tris (dibenzylideneacetone) dipalladium (0.78 mg,0.00085 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (0.74 mg,0.0017 mmol) and cesium carbonate (5.5 mg,0.017 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by preparative chromatography on silica gel plate (DCM: meoh=15:1). Compound 10 (2.00 mg, yield 40.7%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):579.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.02(s,1H),8.20(s,1H),8.12(d,J＝5.7Hz,1H),7.55(d,J＝8.0Hz,1H),7.40(s,1H),6.53(d,J＝5.7Hz,1H),6.37(d,J＝8.0Hz,1H),4.77-4.65(m,2H),4.55(d,J＝13.7Hz,1H),4.32(q,J＝6.2Hz,1H),3.78(t,J＝7.1Hz,1H),3.67-3.61(m,1H),3.46-3.35(m,4H),3.09-3.00(m,1H),2.97(s,3H),2.04-2.00m,1H),1.94-1.88(m,2H),1.53(d,J＝6.2Hz,3H),1.48(d,J＝21.8Hz,3H),0.95-0.92(m,2H),0.88-0.86(m,3H)。
Example 11: preparation of Compound 11
Figure BDA0003999457530000292
Compound 4-h (3 mg,0.00787 mmol) and compound 11-a (2 mg, 0.00786 mmol, see WO2021133809A 1) were dissolved in anhydrous 1, 4-dioxane (0.3 mL) under nitrogen, and tris (dibenzylideneacetone) dipalladium (0.72 mg,0.000787 mmol), 2-dicyclohexylphosphine were added sequentially
2', 6' -bis (N, N-dimethylamino) -1,1' -biphenyl (0.34 mg,0.000787 mmol) and cesium carbonate (5.2 mg,0.01574 mmol). The reaction mixture was stirred at 100℃for 16 hours. The reaction solution was cooled to room temperature, quenched with water (5 mL), the mixture was extracted with ethyl acetate (3X 10 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by preparative chromatography on silica gel plate (dichloromethane: meoh=20:1) to give compound 11 (3.2 mg, 71.3% yield) as a pale yellow solid. MS m/z 571.4[ M+H ]] + 。 1 H NMR(500MHz,CDCl 3 )δ9.37(s,1H),8.59(s,1H),8.07(d,J＝5.6Hz,1H),7.45(d,J＝7.9Hz,1H),7.43(s,1H),6.85(d,J＝7.9Hz,1H),6.15(d,J＝5.6Hz,1H),4.68(d,J＝12.9Hz,1H),4.52(dd,J＝47.6,41.7Hz,1H),4.38-4.31(m,1H),4.05(t,J＝7.7Hz,1H),3.89(dd,J＝13.5,5.9Hz,1H),3.74-3.67(m,1H),3.63-3.55(m,2H),3.37-3.23(m,2H),3.15-3.06(m,1H),3.00(s,3H),2.03(d,J＝12.9Hz,2H),1.95-1.90(m,1H),1.58(s,3H),1.38(s,6H),1.25(s,3H),1.06(s,3H)。
Example 12: preparation of Compound 12
Figure BDA0003999457530000301
The compound 4-methyl-4-hydroxypiperidine (115 mg,1 mmol) was dissolved in isopropanol (3 mL) under nitrogen. Triethylamine (150 mg,1.5 mmol) and 4-amino-2-chloropyrimidine (130 mg,1 mmol) were added. The reaction mixture was stirred at 100℃for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol=20:1) to give compound 12-a (150 mg, 72.1%). MS M/z209.2[ M+H ] ] + 。
Compound 12-a (2.3 mg,0.01 mmol), compound 4-h (3.8 mg,0.01 mmol), cesium carbonate (6.5 mg,0.02 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (0.5 mg,0.001 mmol) and tris (dibenzylideneacetone) dipalladium (0.9 mg,0.001 mmol) were added to 1, 4-dioxane (0.5 mL) under nitrogen. The reaction mixture was warmed to 100 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained crude product was purified by preparative thin layer chromatography plate (dichloromethane: methanol=15:1) to give compound 12 (2 mg, yield 36.2%) as a yellow solid. MS m/z 553.3[ M+H ]] + 。 1 H NMR(500MHz,CDCl 3 )δ9.37(s,1H),8.66(s,1H),8.06(d,J＝5.6Hz,1H),7.44(d,J＝7.9Hz,1H),7.42-7.32(m,1H),6.84(d,J＝8.0Hz,1H),6.07(d,J＝5.6Hz,1H),4.44-4.37(m,2H),4.05(t,J＝7.7Hz,1H),3.90(t,J＝7.5Hz,1H),3.63-3.53(m,3H),3.36-3.24(m,2H),3.13-3.05(m,1H),3.01(s,3H),1.75-1.67(m,4H),1.57(s,3H),1.39-1.32(m,9H),1.05(s,3H)。
Example 13: preparation of Compound 13
Figure BDA0003999457530000302
Under nitrogen, compounds 4-h (2.5 mg,0.0066 mmol) and 13-a (see WO2021133809A1,2mg,0.0096 mmol) were dissolved in anhydrous 1, 4-dioxane (0.5 mL), tris (dibenzylideneacetone) dipalladium (0.60 mg,0.00066 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (0.57 mg,0.00131 mmol), cesium carbonate (4.2 mg,0.013 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by preparative chromatography on silica gel plate (DCM: meoh=18:1). Compound 13 (1.50 mg, yield 41.3%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):553.3[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.02(s,1H),8.20(s,1H),8.12(d,J＝5.7Hz,1H),7.55(d,J＝8.0Hz,1H),7.40(s,1H),6.53(d,J＝5.7Hz,1H),6.37(d,J＝8.0Hz,1H),4.77-4.65(m,2H),4.55(d,J＝13.7Hz,1H),4.32(q,J＝6.2Hz,1H),3.78(t,J＝7.1Hz,1H),3,67-3,61(m,1H),3.46-3.35(m,4H),3.09-3.00(m,1H),2.97(s,3H),2.04-2.00(m,1H),1.94-1.88(m,2H),1.53(d,J＝6.2Hz,3H),1.48(d,J＝21.8Hz,3H),0.95-0.92(m,2H),0.88-0.86(m,3H)。
Example 14: preparation of Compound 14
Figure BDA0003999457530000311
Under nitrogen, compound 4-h (10 mg,0.026 mmol) and 14-a (see WO2021133809A1,7mg,0.029 mmol) were dissolved in anhydrous 1, 4-dioxane (1 mL) and tris (dibenzylideneacetone) dipalladium (2.40 mg,0.0026 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (2.30 mg,0.0052 mmol) and cesium carbonate (17.1 mg,0.052 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by preparative chromatography on silica gel plate (DCM: meoh=15:1). Compound 14 (6.74 mg, yield 44.0%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):583.4[M+H] + : 1 H NMR(500MHz,CDCl 3 )δ9.36(s,1H),8.64(s,1H),8.07(d,J＝5.6Hz,1H),7.49(s,1H),7.45(d,J＝7.9Hz,1H),6.84(d,J＝8.0Hz,1H),6.11(d,J＝5.7Hz,1H),4.52-4.40(m,2H),4.04(t,J＝7.7Hz,1H),3.90(t,J＝7.5Hz,1H),3.80-3.76(m,2H),3.68-3.63(m,3H),3.57(m,1H),3.50-3.42(m,2H),3.36-3.23(m,2H),3.14-3.06(m,1H),3.01(s,3H),2.04-2.01(m,2H),1.70-1.66(m,3H),1.37(dd,J＝9.5,6.8Hz,6H),1.25(s,3H),1.05(s,3H)。
Example 15: preparation of Compound 15
Figure BDA0003999457530000312
Under nitrogen, compound 4-f (75 mg,0.161 mmol) and cyclopropylboronic acid (15.2 mg,0.177 mmol) were dissolvedPalladium acetate (27.2 mg,0.121 mmol), tricyclohexylphosphine (67.9 mg,0.242 mmol) and potassium phosphate (102.8 mg, 0.284 mmol) were added sequentially to ethylene glycol dimethyl ether (2 mL). The reaction mixture was stirred at 90℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (10 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by preparative chromatography on silica gel plates (petroleum ether: ethyl acetate=1:4) to give a crude product of preliminary purification. The crude product was isolated and purified by C18 reverse phase chromatography (A: water (0.05% formic acid), B: acetonitrile; 25% B to 80% B,12 minutes). Compound 15-a (13.7 mg, yield 22.4%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):379.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.40(s,1H),8.11(s,1H),7.36(d,J＝7.8Hz,1H),6.86(d,J＝7.9Hz,1H),4.08(t,J＝7.8Hz,1H),3.90(t,J＝7.5Hz,1H),3.36-3.22(m,2H),3.14-3.07(m,1H),3.00(s,3H),2.14-2.06(m,1H),1.58(s,3H),1.13-0.98(m,5H),0.70(t,J＝4.8Hz,2H)。
Compounds 15-a (6 mg,0.016 mmol) and 2-e (3.94 mg,0.0174 mmol) were dissolved in anhydrous 1, 4-dioxane (1 mL) under nitrogen, and tris (dibenzylideneacetone) dipalladium (1.5 mg,0.0016 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (1.4 mg,0.0032 mmol) and cesium carbonate (10.3 mg,0.032 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by preparative chromatography on silica gel plate (DCM: meoh=20:1). Compound 15 (6.5 mg, yield 72.1%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):569.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.34(s,1H),8.60(s,1H),8.08(d,J＝5.7Hz,1H),7.46(s,1H),7.27(d,J＝7.8Hz,1H),6.75(d,J＝7.8Hz,1H),6.27(d,J＝5.7Hz,1H),4.63-4.52(m,1H),4.49-4.37(m,1H),4.06(t,J＝7.7Hz,1H),3.89(t,J＝7.5Hz,1H),3.7-3.65(m,1H),3.60-3.47(m,2H),3.37-3.23(m,2H),3.14-3.06(m,1H),3.00(s,3H),2.20-2.14(m,1H),2.05-1.99(m,1H),1.90-1.85(m,2H),1.58(s,3H),1.47(d,J＝21.8Hz,3H),1.07(s,3H),1.04-1.01(m,2H),0.74-0.70(m,2H)。
Example 16: preparation of Compound 16
Figure BDA0003999457530000321
Compounds 4-f (30 mg,0.064 mmol) and silacyclobutane (11 mg,0.193 mmol) were dissolved in toluene (1.5 mL) under nitrogen, and palladium acetate (1.45 mg,0.0065 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (8.0 mg,0.0128 mmol) and cesium carbonate (42 mg,0.129 mmol) were added sequentially. The reaction mixture was stirred at 90℃for 24h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (10 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified by preparative chromatography on silica gel plates (petroleum ether: ethyl acetate=1:20). Compound 16-a (16 mg, yield 62.9%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):394.2[M+H] + 。
Compounds 16-a (6 mg,0.015 mmol) and 2-e (3.8 mg,0.0168 mmol) were dissolved in anhydrous 1, 4-dioxane (1 mL) under nitrogen, and tris (dibenzylideneacetone) dipalladium (1.4 mg,0.0015 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (1.3 mg, 0.003mmol) and cesium carbonate (9.9 mg,0.03 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by preparative chromatography on silica gel plate (DCM: meoh=15:1). Compound 16 (8 mg, yield 89.9%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):584.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.38(s,1H),8.21(s,1H),8.06(d,J＝5.7Hz,1H),7.56(s,1H),6.88(d,J＝8.1Hz,1H),6.68(d,J＝8.1Hz,1H),6.27(d,J＝5.7Hz,1H),4.78(dd,J＝14.1,8.9Hz,1H),4.62(dd,J＝13.3,4.9Hz,1H),4.08-3.94(m,5H),3.82(t,J＝7.7Hz,1H),3.68(ddd,J＝19.8,9.5,4.5Hz,1H),3.37-3.29(m,3H),3.25(dd,J＝14.1,4.8Hz,1H),3.07-3.02(m,1H),2.99(s,3H),2.36(p,J＝7.2Hz,2H),2.00-1.98(m,1H),1.95-1.88(m,2H),1.55(dd,J＝21.8,3.9Hz,3H),1.49(d,J＝3.4Hz,3H),1.00(d,J＝3.6Hz,3H)。
Example 17: preparation of Compound 17
Figure BDA0003999457530000331
Under nitrogen, compound 4-h (12 mg,0.031 mmol) and 17-a (see WO2021133809A1,7.8mg,0.034 mmol) were dissolved in anhydrous 1, 4-dioxane (1 mL), and tris (dibenzylideneacetone) dipalladium (2.88 mg,0.0031 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (2.74 mg,0.0063 mmol) and cesium carbonate (20.5 mg,0.063 mmol) were added sequentially. The reaction mixture was stirred at 100℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by preparative chromatography on silica gel plate (DCM: meoh=15:1). Compound 17 (6.70 mg, yield 37.3%) was obtained as a pale yellow solid. LC-MS (ES) + ,m/z):571.1[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.37(s,1H),8.58(s,1H),8.06(d,J＝5.6Hz,1H),7.44(d,J＝7.9Hz,1H),7.40(s,1H),6.84(d,J＝7.9Hz,1H),6.15(d,J＝5.7Hz,1H),4.91-4.76(m,1H),4.61-4.56(m,1H),4.35-4.25(m,1H),4.05(t,J＝7.7Hz,1H),3.90(t,J＝7.5Hz,1H),3.86-3.75(m,1H),3.66-3.57(m,3H),3.52(s,3H),3.36-3.24(m,2H),3.13-3.06(m,1H),3.00(s,3H),3.06-3.01(m,1H),1.88-1.82(m,1H),1.57(s,3H),1.37(ddd,J＝10.2,6.8,3.0Hz,6H),1.06(s,3H)。
Example 18: process for the preparation of compound 18
Figure BDA0003999457530000341
Compound 18-a (15 g,115.26 mmol) was dissolved in dichloromethane (150 mL) and imidazole (23.5 g,345.78 mmol), triisopropylchloride was addedSilane (26.7 g,138.31 mmol). Stirred at room temperature for 3 hours. The reaction mixture was extracted with water (100 mL) and dichloromethane (3X 100 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=40:1) to give 18-b (31 g, yield 93.9%) as a colorless oily compound. MS (ES) + ,m/z):287.3[M+H] + 。
Compound 18-b (31 g,108.2 mmol) was dissolved in methanol (150 mL), and xylylenediamine (29.7 g,162.3 mmol) was added thereto, and the reaction mixture was heated to 70℃and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=50:1) to give compound 18-c (40.8 g, yield 80.3%) as a yellow oil. MS (ES) + ,m/z):470.3[M+H] + 。
Compound 18-c (30 g,63.67 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen, a solution of t-butylmagnesium chloride (192 mL,192 mmol) in tetrahydrofuran was added at 0deg.C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution, filtered and washed with ethyl acetate, the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate after filtration was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=15:1) to give compound 18-d (10 g, yield 37%) as a white solid. MS (ES) + ,m/z):344.1.[M+H] + 。
Compound 18-d (9.5 g,22.42 mmol) was dissolved in tetrahydrofuran (80 mL) under nitrogen, and a solution of triisopropyloxymethyl titanium and ethylmagnesium bromide (56 mL,56 mmol) in tetrahydrofuran was added. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with water at 0 ℃, filtered and washed with dichloromethane, the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give compound 18-e (3.1 g, yield 32.8%) as a yellow oil. MS (ES) + ,m/z):436.3[M+H] + 。
Compound 18-e (3.1 g,7.11 mmol) was dissolved in tetrahydrofuran (12 mL) and tetrabutylammonium fluoride (TBAF, 10.7mL,10.7 mmol) was added to the solutionThe furan solution and the reaction solution were stirred at room temperature for 2 hours. Water quenching, ethyl acetate extraction (3X 20 mL), washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give compound 18-f (1.13 g, yield 57%) as a yellow oil. MS (ES) + ,m/z):280[M+H] + 。
Compound 18-f (800 mg,2.86 mmol) was dissolved in dichloromethane, triethylamine (866 mg,8.58 mmol) and methanesulfonyl chloride (490 mg,4.29 mmol) were added at 0℃and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give 18-g of crude product, which was dissolved in DMF (10 mL), sodium iodide (1.28 g,8.58 mmol) and sodium methane sulfinate (1.03 g,8.58 mmol) were added and the reaction was stirred for 5 hours at 80 ℃. The reaction mixture was cooled to room temperature, water (10 mL) was added, extraction was performed with ethyl acetate (3X 30 mL), the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give compound 18-h (370 mg, yield 37.9%) as a yellow solid. MS (ES) + ,m/z):342.1[M+H] + 。
Compound 18-h (370 mg,1.08 mmol) was dissolved in methanol (20 mL), and 20% palladium on carbon hydroxide (80 mg) and trifluoroacetic acid (1 mL) were added thereto, followed by stirring at room temperature under a hydrogen atmosphere for 16h. Filtering, concentrating the filtrate to obtain crude compound. The crude product was purified by silica gel column chromatography (dichloromethane: methanol=15:1) to give 18-i (80 mg, yield 42.3%) as a yellow oil.
Compound 18-i (40 mg,0.228 mmol) was dissolved in dioxane (1 mL), and compound 8-bromo-3-chloroisoquinoline (55 mg,0.228 mmol), cesium carbonate (185 mg,0.57 mmol) and Xantphos Pd G3 (21.6 mg,0.228 mmol) were added and stirred under nitrogen at 80℃for 16h. Quenching with water, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 18-j (20 mg, yield 26%) as a yellow solid. MS (ES) + ,m/z):337.1[M+H] + 。
Compound 18-j (20 mg,0.059 mmol) was dissolved in dichloromethane (2 mL) and acetic acid (0.2 mL) and N-iodosuccinimide (12 mg,0.053 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes. Adding 1N sodium hydroxide aqueous solution for quenching, extracting with dichloromethane, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give compound 18-k (19 mg, yield 70.3%) as a yellow solid. MS (ES) + ,m/z):462.9[M+H] + 。
Under nitrogen, compound 18-k (19 mg,0.04 mmol), pinacol isopropenylborate (10.4 mg,0.06 mmol), potassium carbonate (7.2 mg,0.052 mmol) and [1,1' -bis (diphenylphosphino) ferrocene were reacted in a nitrogen atmosphere]Palladium dichloride (3.2 mg,0.04 mmol) was added to 1, 4-dioxane (2 mL) and water (0.5 mL), and the reaction mixture was stirred at 80℃for 2 hours. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (2 mL) was added, ethyl acetate (3×5 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 18-l (10 mg, yield 64.5%) as a yellow solid. MS (ES) + ,m/z):377.1[M+H] + 。
Under hydrogen atmosphere, 18-l (10 mg,0.026 mmol) was dissolved in ethyl acetate (10 mL) and PtO was added 2 (10 mg). The reaction mixture was stirred at 25℃for 2 hours. The filtrate was concentrated under reduced pressure after filtration through celite was added to give compound 18-m (10 mg, yield 99%) as a yellow solid. MS (ES) + ,m/z):379.1[M+H] + 。
Compound 18-m (4 mg,0.01 mmol), compound 2-e (2.3 mg,0.01 mmol), cesium carbonate (6.5 mg,0.02 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (0.9 mg,0.002 mmol), tris (dibenzylideneacetone) dipalladium (0.9 mg,0.001 mmol) were added to 1, 4-dioxane (0.5 mL) under nitrogen, and the reaction mixture was warmed to 100℃and stirred for 2 hours. LCMS monitored the reaction was complete, cooled to room temperature, and the reaction was directly purified by Prep-TLC (dichloromethane: methanol=15:1). Yellow solid compound 18 (2.6 mg, yield 45.6%) was obtained. LCMS ES + ,m/z):569.3[M+H] + 。
Example 19: process for the preparation of compound 19
Figure BDA0003999457530000361
Compound 18-m (4 mg,0.01 mmol), compound 17-a (2.3 mg,0.01 mmol), cesium carbonate (6.5 mg,0.02 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (0.9 mg,0.002 mmol), tris (dibenzylideneacetone) dipalladium (0.9 mg,0.001 mmol) were added to 1, 4-dioxane (0.5 mL) under nitrogen, and the reaction mixture was warmed to 100℃and stirred for 2 hours. LCMS monitored the reaction was complete, cooled to room temperature, and the reaction was directly purified by Prep-TLC (dichloromethane: methanol=15:1). Compound 19 (1.1 mg, yield 19.4%) is obtained as a yellow solid. LCMS (ES) + ,m/z):569.3[M+H] + 。
Example 20: preparation of Compound 20
Figure BDA0003999457530000362
Under nitrogen, compounds 15-a (6 mg,0.016 mmol) and 17-a (see WO2021133809A1,3.94mg,0.0174 mmol) were dissolved in anhydrous 1, 4-dioxane (1 mL), and tris (dibenzylideneacetone) dipalladium (2.0 mg,0.0032 mmol), 2-dicyclohexylphosphine-2 '6' -bis (N, N-dimethylamino) -1,1' -biphenyl (2.8 mg,0.0064 mmol) and cesium carbonate (10.3 mg,0.032 mmol) were added sequentially. The reaction mixture was stirred at 105℃for 16h. After completion of LCMS monitoring, the reaction mixture was cooled to room temperature, water (5 mL) was added, ethyl acetate (3×15 mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified by preparative chromatography on silica gel plate (DCM: meoh=20:1) to give compound 20 (6.5 mg, yield 72.1%) as a pale yellow solid. LC-MS (ES) + ,m/z):569.2[M+H] + ； 1 H NMR(500MHz,CDCl 3 )δ9.34(s,1H),8.63(s,1H),8.08(d,J＝5.7Hz,1H),7.43(s,1H),7.27(d,J＝8.0Hz,1H),6.75(d,J＝7.9Hz,1H),6.25(d,J＝5.7Hz,1H),4.85-4.69(m,1H),4.55-4.45(m,1H),4.27-4.16(m,1H),4.06(t,J＝7.8Hz,1H),3.89(t,J＝7.5Hz,1H),3.67-3.45(m,3H),3.49(s,3H),3.34-3.23(m,2H),3.12-3.06(m,1H),3.00(s,3H),2.21-2.16(m,1H),2.02-1.98(m,1H),1.81-1.77(m,1H),1.58(s,3H),1.06(s,3H),0.90-0.87(m,2H),0.75-0.68(m,2H)。
EXAMPLE 21 EGFR (T790M/L858R/C797S) enzyme Activity test
Method A Compounds were tested for EGFR T790M/L858R/C797S kinase inhibitory activity using the method of Lantha screen assay. Compounds were dissolved in 100% DMSO and prepared as 10mM stock solution to prepare 1 XKinase buffer (50mM HEPES,pH 7.5,0.0015% Brij-35). The test compounds were diluted in a gradient and 100nL of the compound was transferred to the reaction plate. A2-fold final concentration of Kinase solution was prepared using a 1 XKinase buffer. Adding 5 mu L of kinase solution to each of the compound well and the positive control well; mu.L of 1 XKinase buffer was added to the negative control wells. The reaction plate is vibrated and mixed uniformly. A mixed solution of ATP and Fluorescein-polygT was prepared at a final concentration of 2-fold using a 1 XKinase buffer. mu.L of the substrate mixture was added to initiate the reaction. After shaking and mixing, incubation was carried out at room temperature for 30 minutes. A2-fold final concentration of detection solution (final concentration of 2nM antibody, 10mM EDTA) was prepared. The kinase reaction was stopped by adding 10. Mu.L of the detection solution, centrifuged briefly with a centrifuge, mixed by shaking, incubated for 60 minutes, and fluorescence was read by Envision at excitation wavelength of 340nM and emission wavelengths of 520nM and 495nM. Data were collected and fluorescence values were calculated at 520nM/495 nM. The inhibition Ratio was calculated using the formula Percent inhibition = (max-sample Ratio)/(max-min) 100. Wherein min: negative control Kong Junzhi, representing conversion reading without enzyme wells; max: positive control Kong Junzhi, represents a conversion reading for DMSO inhibition wells. The IC50 values of each compound for enzyme activity were obtained by fitting a curve using XLFIT exceladd-in version 5.4.0.8. The formula is as follows: y=bottom+ (Top-Bottom)/(1+ (IC 50/X)/(HillSlope). Compound IC 50 The values are shown in Table 1.
Method B methods of using HTRF compounds were tested for EGFR T790M/L858R/C797S kinase inhibitory activity. Preparing a 1x kinase reaction buffer; 2.5-fold kinase and substrate buffer were prepared: wherein the working concentration of the kinase solution is 0.002 ng/. Mu.L; substrate(s)The ATP working concentration of the mixture solution was 0.5. Mu.M and the final concentration of the submount TK was 1. Mu.M. The test compound was diluted 50-fold with DMSO, diluted 4-fold in a 96-well dilution plate, 1. Mu.L of the compound was added to 39. Mu.L of kinase reaction buffer, and shaken on a microplate shaker for 20min. Transfer 2. Mu.L of 2.5 Xkinase to 384 reaction plates, add 1. Mu.L of test compound to 384 reaction plates, centrifuge at 1000rpm, incubate at 25℃for 10min. Transfer 2. Mu.L of the 2.5 Xsubstrate mixture to 384 reaction plates, centrifuge at 1000rpm, incubate at 25℃for 40min. A2 XSa-XL 665/TK-anti-Cryptate cocktail was formulated with HTRF detection buffer. mu.L of Sa-XL 665/TK-anti-Cryptate was added to each well, centrifuged at 1000rpm for 60 seconds and incubated at 25℃for 1 hour. Fluorescence signals of 620nM (Cryptate) and 665nM (XL 665) were read with a BMG microplate reader. The inhibition was calculated as compound inhibition (% inh) =100% - (compound-positive control)/(negative control-positive control) ×100%. The IC50 (median inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula: data analysis was performed using Graphpad 7.0 software. Y=bottom+ (Top-Bottom)/(1+10+ (log ic 50-X) Hill Slope)). Log of compound concentration, Y inhibition (% inhibition). Compound IC 50 The values are shown in Table 1.
Inhibitory Activity of the Compounds of Table 1 against EGFR (T790M/L858R/C797S) enzymes
Figure BDA0003999457530000371
EXAMPLE 22 pharmacokinetic Studies in rats
Instrument: the XEVO TQ-S LC/MS from Waters, all measured data were collected and processed by Masslynx V4.1 software and data calculated and processed using Microsoft Excel. And calculating pharmacokinetic parameters by using WinNonLin 8.0 software and adopting a statistical moment method. Mainly comprises kinetic parameters T max 、T 1/2 、C max 、AUC 0-24h Etc. Chromatographic column: ACQUITY UPLC BEH C18 (2.1 mm. Times.50 mm,1.7 μm); column temperature 40 ℃; mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, the flow rate is 0.350 ml/min, gradient elution is adopted, and the elution gradient is 0.50min:10% b;1.50min:90% b;2.50min:90% B;2.51min:10% b;3.50min: stop. Sample injection amount: 1 mul.
Animals: SD male rats 3, with body weight range of 200-220g, were fed to laboratory animal center laboratory for 2 days after purchase, fasted for 12 hours before and 4 hours after administration, and were free to drink water during the test. Blood samples were taken at defined time points after the rats were perfused.
A solvent: 0.4% ethanol+ 0.4%Tween 80+99.2% (0.5% methylcellulose M450). Preparation of a gastric administration solution: precisely weighing the compound, adding into solvent, and performing ultrasonic treatment at normal temperature for 5 min to completely dissolve the medicine to obtain 0.3 mg/ml liquid medicine.
Drug sample: multiple structurally similar samples (molecular weights differing by more than 2 units) are typically taken, accurately weighed, and administered together (case PK). This allows simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single administration was also used to study the pharmacokinetics of drug samples in rats.
Blood was taken from the orbit at 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours after intragastric administration, respectively. Plasma samples were taken at 50. Mu.L, 200. Mu.L of acetonitrile (containing internal standard verapamil 2 ng/mL) was added, and after vortexing for 3min, centrifuged at 20000rcf at 4℃for 10min, and the supernatant was taken for LC-MS/MS analysis.
Accurately weighing the compound to prepare different concentrations, quantitatively analyzing on a mass spectrum to establish a standard curve, and then testing the concentration of the compound in the plasma to obtain the concentration of the compound at different time points. All measured data are collected and processed by related software, and pharmacokinetic parameter calculation is carried out by adopting a statistical moment method (mainly comprising a kinetic parameter T max 、T 1/2 、C max 、AUC 0-24h Etc.). Kinetic parameters of a portion of representative compounds are shown in table 2.
TABLE 2 pharmacokinetic parameters in rats
Figure BDA0003999457530000381
Figure BDA0003999457530000382
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (13)

1. A compound of the structure shown in formula (I) or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof:
Figure FDA0003999457520000011
in formula (I):
R 1 a group selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Haloalkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl, C 3-6 Cycloalkyl C 2-4 Alkynyl, 3-to 6-membered heterocyclyl C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl-D-, or 3-to 6-membered heterocyclyl-D-; the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl, -C (O) R a Or = M; m is selected from O or CR b R c The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is b And R is c Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; r is R a Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, or C 3-6 Cycloalkyl; d is selected from the group consisting of a bond, -O-, -S-, or-N k -；
R 2 Selected from the group consisting of C 2-4 Alkynyl, C 3-6 NaphtheneA group, a 3-to 9-membered heterocyclyl, a 3-6-membered cycloalkyl-O-, a 3-to 9-membered heterocyclyl-O-; the C is 2-4 Alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, R f -S(O) 2 -(CR d R e ) p -、R f -S(O)-(CR d R e ) p -、R f -P(O)(R g )-(CR d R e ) p -、R a C(O)-(CR d R e ) p -, or = CR h R i The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is d And R is e Each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, or C 1-4 Haloalkoxy groups; r is R f Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; r is R g Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, NR k R k 、C 3-6 Cycloalkyl, 3-6 membered cycloalkyl-O-, or 3-to 6-membered heterocyclyl; or R is f And R is g And together with the phosphorus atom to which they are attached form an optionally substituted 4-to 8-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S; r is R h Selected from hydrogen, fluorine, or C 1-4 An alkyl group; r is R i Selected from R f -S(O) 2 -(CR d R e ) P -or R f -P(O)(R g )-(CR d R e ) P -; r is a number of k Each independently selected from hydrogen or C 1-4 An alkyl group; p is selected from 0, 1, 2, or 3;
R 3 selected from the group consisting of C 3-8 Cycloalkyl or 3-to 12-membered heterocyclyl; the cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from the group consisting of: hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, CN, OR j 、SR j 、NR k R k 、R j O-C 1-4 Alkyl, R k R k N-C 1-4 Alkyl, R j O-C 1-4 alkyl-O-, R k R k N-C 1-4 alkyl-O-, R j O-C 1-4 alkyl-NR k -、R k R k N-C 1-4 alkyl-NR k -; wherein R is j Selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, or 3-to 6-membered heterocyclyl; each R is k Is defined as above;
X 1 、X 2 、X 3 and X 4 Each independently selected from N or CR m The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is m Selected from hydrogen, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, hydroxy, C 1-4 Haloalkoxy, CN, NR k R k Or C 3-6 Cycloalkyl; each R is k Is defined as above;
wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl groups is optionally and each independently substituted with 1 to 3 substituents selected from the group consisting of: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, aryl, heteroaryl, CN, NO 2 、OR j 、SR j 、NR k R k 、C(O)R n 、C(O)OR j 、C(O)NR k R k 、NR k C(O)R n 、NR k S(O) 2 R n Or S (O) 2 R n Provided that the chemical structure formed is stable and meaningful; wherein R is j And R is k Is defined as above; r is R n Selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, aryl, or heteroaryl.
Unless otherwise specified, the above aryl groups are aromatic groups having 6 to 12 carbon atoms; heteroaryl is a 5-to 15-membered (preferably 5-to 12-membered) heteroaryl group; the heterocyclic group may be a monocyclic or polycyclic heterocyclic group (including spiro, fused and bridged rings); the cyclic structure is a saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic group.
2. The compound of claim 1, wherein in formula (I):
R 1 A group selected from the group consisting of:
Figure FDA0003999457520000021
Figure FDA0003999457520000022
R 1 a site of attachment to the other moiety of the compound of formula (I);
R 2 a group selected from the group consisting of:
Figure FDA0003999457520000023
Figure FDA0003999457520000024
R 2 a site of attachment to the other moiety of the compound of formula (I);
". Times." represents chiral centers;
R 3 a group selected from the group consisting of:
Figure FDA0003999457520000031
Figure FDA0003999457520000032
R 3 a site of attachment to the other moiety of the compound of formula (I);
". Times." represents chiral centers;
fragments
Figure FDA0003999457520000033
A group selected from the group consisting of:
Figure FDA0003999457520000034
Figure FDA0003999457520000035
representing and R 1 A site of ligation; />
Figure FDA0003999457520000036
Representing and R 2 A site of ligation; />
Figure FDA0003999457520000037
Representing and R 3 The site of ligation.
3. The compound of any one of claims 1-2, wherein formula (I) is formula (II):
Figure FDA0003999457520000038
R p selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; k is selected from 0, 1, 2, or 3;
m and n are each independently selected from 1, 2, or 3;
the remaining groups are as defined in claims 1-2.
4. The compound of any one of claims 1-2, wherein formula (I) is formula (III):
Figure FDA0003999457520000041
R p selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; k is selected from 0, 1, 2, or 3;
m and n are each independently selected from 1, 2, or 3;
the remaining groups are as defined in claims 1-2.
5. The compound of any one of claims 1-2, wherein formula (I) is formula (IVa) or formula (IVb):
Figure FDA0003999457520000042
R p Selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, or 3-to 6-membered heterocyclyl; k is selected from 0, 1, 2, or 3;
R q selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, or 3-to 6-membered heterocyclyl;
m and n are each independently selected from 1, 2, or 3;
the remaining groups are as defined in claims 1-2.
6. A compound according to any one of claims 1 to 2, wherein formula (I) is formula (Va) or formula (Vb):
Figure FDA0003999457520000043
R p selected from hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, or 3-to 6-membered heterocyclyl; k is selected from 0, 1, 2, or 3;
d is selected from the group consisting of a bond, -O-, -S-, or-N k -；R k Is defined as in claim 1;
ring A is selected from C 3-6 Cycloalkyl or 3-to 6-membered heterocyclyl;
R t selected from hydrogen, halogen, C 1-4 Alkyl, or-C (O) R a The method comprises the steps of carrying out a first treatment on the surface of the Or two R t Attached to the same carbon atom on ring a and taken together with that carbon atom form c=m; m is selected from O or CR b R c The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is b And R is c Each independently selected from hydrogen, fluorine, or C 1-4 An alkyl group; r is R a Is defined as in claim 1;
m and n are each independently selected from 1, 2, or 3;
f is selected from 0, 1, 2, or 3;
the remaining groups are as defined in claims 1-2.
7. The compound of claim 1, wherein formula (I) is formula (VI):
Figure FDA0003999457520000051
Each R is p Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl; or two R p Together with the carbon atoms to which they are attached, form an optionally substituted 3-to 6-membered cyclic structure which may additionally contain 0-1 heteroatoms optionally selected from N, O, S;
R f selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl;
R 1 and R is 3 Is defined as set forth in claim 2.
8. The compound of claim 7, wherein:
each R is p Each independently selected from methyl; or two R p Together with the carbon atoms to which they are attached, form a 3-membered cyclic structure;
R f selected from methyl;
R 1 a group selected from the group consisting of:
Figure FDA0003999457520000052
Figure FDA0003999457520000053
R 1 a site of attachment to the other moiety of the compound of formula (VI);
R 3 a group selected from the group consisting of:
Figure FDA0003999457520000054
Figure FDA0003999457520000055
R 3 a site of attachment to the other moiety of the compound of formula (VI);
"×" indicates chiral centers.
9. The compound of claim 1, wherein formula (I) is formula (VII):
Figure FDA0003999457520000056
each R is p Each independently selected from hydrogen, C 1-4 An alkyl group; or two R p Together with the carbon atoms to which they are attached, form a 3-membered cyclic structure;
R d and R is e Each independently selected from hydrogen, C 1-4 An alkyl group; p is selected from 1 or 2;
R f selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl;
R g selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered cycloalkyl-O-, or 3-to 6-membered heterocyclyl;
R 1 and R is 3 Is defined asThe method of claim 8.
10. The compound of claim 1, wherein the compound of formula (I) is selected from the group consisting of:
Figure FDA0003999457520000061
Figure FDA0003999457520000071
Figure FDA0003999457520000081
"x" means chiral centers, which may be in the R configuration or the S configuration, or a mixture of R and S.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, and a pharmaceutically acceptable carrier.
12. Use of a compound according to any one of claims 1 to 10, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate thereof, for the preparation of a pharmaceutical composition for the treatment of a disease, disorder or condition associated with mutant EGFR activity or expression level.
13. The use according to claim 12, wherein the disease, disorder or condition is selected from the group consisting of: non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous carcinoma, cervical cancer, esophageal cancer, renal cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, and other solid tumors and hematological tumors.
CN202211610689.0A 2021-12-14 2022-12-14 Compounds as EGFR inhibitors Pending CN116262741A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023241618A1 (en) * 2022-06-14 2023-12-21 南京明德新药研发有限公司 Aminopyrimidine compounds and use thereof
WO2024008048A1 (en) * 2022-07-04 2024-01-11 杭州德睿智药科技有限公司 Novel pyrimidine or triazine-substituted pyridoheterocyclic compound

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023241618A1 (en) * 2022-06-14 2023-12-21 南京明德新药研发有限公司 Aminopyrimidine compounds and use thereof
WO2024008048A1 (en) * 2022-07-04 2024-01-11 杭州德睿智药科技有限公司 Novel pyrimidine or triazine-substituted pyridoheterocyclic compound

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