CN108727382B - Heterocyclic compounds as BTK inhibitors and uses thereof - Google Patents

Heterocyclic compounds as BTK inhibitors and uses thereof Download PDF

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CN108727382B
CN108727382B CN201710258020.2A CN201710258020A CN108727382B CN 108727382 B CN108727382 B CN 108727382B CN 201710258020 A CN201710258020 A CN 201710258020A CN 108727382 B CN108727382 B CN 108727382B
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phenyl
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btk
alkyl
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CN108727382A (en
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李洪林
丁健
徐玉芳
谢华
赵振江
陈海洋
刁妍妍
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention relates to heterocyclic compounds as BTK inhibitors and uses thereof. Specifically, the invention relates to a compound shown in formula I with BTK inhibitory activity, a pharmaceutical composition containing the compound shown in formula I and application of the compound in preparing a drug for treating or preventing BTK related diseases or inhibiting BTK:

Description

Heterocyclic compounds as BTK inhibitors and uses thereof
Technical Field
The present invention relates to the field of medicinal chemistry; in particular, the invention relates to compounds having BTK inhibitory activity and uses thereof.
Background
Immune cells can be generally divided into two categories, T cells and B cells, wherein the main role of B cells is to secrete various antibodies to help the body resist the invasion of various adversaries. Bruton's Tyrosine Kinase (BTK) is expressed predominantly in B cells, and is distributed in the lymphatic, hematopoietic, and blood systems. In recent years, researches on B cells, particularly B cell non-Hodgkin lymphoma and rheumatoid arthritis show that BTK is often abnormally expressed. BTK is a key kinase in the B cell antigen receptor (BCR) signaling pathway, can regulate the maturation and differentiation of normal B cells, and is also closely associated with various diseases of B cell lymphoid tissue disorders.
BTK is a member of the Tec family of non-receptor protein tyrosine kinases. The Tec family is the second 2 large family of human non-receptor kinases to the Src family, the major members of which include BTK, BMX (etk), ITK, Tec, and txk (rlk). BTK was identified in 1993 as a defective protein in human X-linked agammaglobulinemia (XLA). This protein is expressed in ALL stages of B cell development (except for terminally differentiated plasma cells), Btk is an essential gene for cell differentiation and proliferation during the transition from pre-B lymphocytes to late B cells, and is expressed in B cell lymphomas, Acute Lymphoblastic Leukemia (ALL), and plasmacytomas. In addition, there is a small amount of expression in bone marrow cells and erythroid progenitor cells.
The BTK structure comprises 5 major domains, respectively the PH domain (Pleckstrin homology), the TH domain (Tec homology), the SH3 domain (Src homology 3), the SH2 domain (Src homology 2) and the SH1 domain (Src homology 1). Wherein the PH domain contains the transcription factor BAP-135/TFII-I and the binding site of the active down-regulation factor PIN1, IBTK, and is also responsible for mediating the effects of BTK with the 2 nd messenger phosphatidylinositol triphosphate (PIP 3). The TH domain is contiguous with the PH domain and is composed of 80 amino acid residues, including the BTK motif (Zn cofactor binding site), the PKC- β binding site, and the conserved region of the proline-rich motif. The SH1 domain contains an activation loop, an ATP binding site, a catalyst, and an allosteric inhibitory fragment. Activation (phosphorylation) of BTK initially occurs in the activation loop in the SH1 domain, with further activation occurring in SH2 and SH3 domains that contain a major autophosphorylation site. These SH domains also include Nuclear Localization Signals (NLS) required for nuclear cytoplasmic shuttling by BTK and multiple receptors downstream of Nuclear Export Sequences (NES) BTK, including growth factors, B cell antigens, chemokines, and non-specific immune receptors. Thus, BTK activation can trigger a variety of cellular processes, such as cell proliferation, survival, differentiation, angiogenesis, cytokine synthesis, and antigen presentation.
The BTK activation process is complex, and an important step in this process is the migration of BTK to the cell membrane. Some receptors on the cell membrane are activated by stimulation with the corresponding ligands, the activated receptors recruit and phosphorylate the intracellular signal transduction kinase PI3K, and the phosphorylated PI3K in turn converts PIP2 on the membrane into the 2 nd messenger PIP 3. PIP3 binds to PH domain of BTK, BTK is then recruited to cell membrane, Tyr-551 residue is phosphorylated by Syk and Lyn kinase, then self-phosphorylation reaction is carried out at Tyr-223 residue, so that the activated BTK with physiological activity can be combined with adaptor BLNK/SLP65 through SH2 domain, the generated compound then activates phospholipase C-gamma 2 (PLC-gamma 2), further the cascade reaction is initiated, and finally the intracellular continuous calcium ion influx is caused, and downstream signal paths such as MEK/ERK, p38MAPK and NK/SAPK paths are indirectly activated. Mutations of the BTK gain-of-function type have also been confirmed in colorectal cancer, Acute Lymphoblastic Leukemia (ALL), and Chronic Myelogenous Leukemia (CML). Therefore, aberrant activation of BTK-dependent pathways has been shown to be closely associated with the development of multiple tumors.
BTK small molecule inhibitors have good prospects for treating hematological malignancies and autoimmune disorders. Ibrutinib (ibrutinib) is currently the most attractive BTK targeted inhibitor, has significant therapeutic effects on a variety of B cell tumors as well as autoimmune diseases in preclinical and clinical studies, and has been approved by the FDA in the united states for marketing for the treatment of Mantle Cell Lymphoma (MCL) and CLL. Several other compounds, such as CC-292 and ONO-4059, have also entered clinical or late clinical studies.
Figure BDA0001273961530000021
There remains a need in the art to develop highly active, specific BTK inhibitors.
Disclosure of Invention
The invention aims to provide a BTK inhibitor with high activity and strong specificity and application thereof in preparing a medicament for treating BTK mediated diseases.
In a first aspect, the present invention provides the use of a compound of formula I or a salt thereof in the manufacture of a BTK inhibitor or in the manufacture of a medicament for the treatment or prevention of a BTK-mediated disease:
Figure BDA0001273961530000031
in the formula (I), the compound is shown in the specification,
r is hydrogen, C1-C3Lower alkyl, C1-C3Lower alkoxy, halogen (e.g., F, Cl, Br), amino, substituted amino;
b is selected from the following group: optionally substituted (C3-C8) cycloalkyl, (C3-C8) heterocyclyl, (C6-C10) aryl, or (C5-C10) arylheterocyclyl;
R2each independently selected from the group consisting of:
Figure BDA0001273961530000032
Figure BDA0001273961530000041
when Z is1When is-C (O) -, Z2Is composed of
Figure BDA0001273961530000051
Or when Z is1Is composed of
Figure BDA0001273961530000052
When Z is2is-C (O) -;
R3selected from the group consisting of: hydrogen, optionally substituted C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally substituted C3-C8Cycloalkyl, optionally substituted C1-C10Alkoxy, optionally substituted aryl, optionally substituted benzyl, optionally substituted heterocyclyl, optionally substituted arylheterocyclyl, -O- (CH)n-O-C1-C3An alkyl group;
n is an integer from 1 to 3, preferably 1.
In a specific embodiment, B is selected from:
Figure BDA0001273961530000053
in a specific embodiment, the compound is represented by formula I-1 below:
Figure BDA0001273961530000054
In the formula, A is benzene ring, five-membered or six-membered heterocycle, C3-C8Cycloalkyl or R';
when A is R', R1Is absent, R' is selected from C1-C6Alkyl radical, C1-C6Haloalkyl or (C)6-C10) An arylformyl group;
R1each independently selected from hydrogen, halogen, C1-C3Alkoxy radical, C1-C3Alkyl radical, C1-C4Alkylamido, substituted piperazinyl, substituted homopiperazinyl,Substituted morpholinyl, substituted thiomorpholinyl, 4-N-methylpiperazinyl, 4-N-acetylpiperazinyl, 4-N, N-dimethylpiperidinyl, substituted piperidinyl, -NRaRbWherein R isaAnd RbCan be independently selected from alkyl and nitrogen-containing alkyl;
m is any integer of 0 to 7, preferably 1 to 7;
B、R2、Z1and Z2As defined above.
In a specific embodiment, the compound is represented by formula II-1 or II-2 below:
Figure BDA0001273961530000061
in the formula, B, R1、R2、R3As defined above;
m is an integer of 0 to 5, preferably 1 to 5.
In a specific embodiment, the compound is represented by the following formula III-1 or III-2:
Figure BDA0001273961530000062
in the formula (I), the compound is shown in the specification,
R2is selected from
Figure BDA0001273961530000063
R3Is selected from H; c1-C6Alkyl, preferably methyl or isopropyl; phenyl substituted C1-C6An alkyl group; optionally substituted phenoxyphenyl; or optionally substituted benzyl;
R4、R5、R6、R7and R8Independently selected from the group consisting of:
Figure BDA0001273961530000064
in a specific embodiment, the compound of formula (I),
R2is selected from
Figure BDA0001273961530000065
R3Is selected from H or C1-C6Alkyl (preferably methyl or propyl or isopropyl);
R4Is H, C1-C3Alkoxy (preferably methoxy);
R5is H, C1-C3Alkyl (preferably methyl) or C1-C3Alkoxy (preferably methoxy);
R6is H, or
Figure BDA0001273961530000071
R7And R8Is H.
In a second aspect, the present invention provides the use of a specific compound selected from the group consisting of:
Figure BDA0001273961530000072
Figure BDA0001273961530000081
Figure BDA0001273961530000091
Figure BDA0001273961530000101
Figure BDA0001273961530000111
in a specific embodiment, the BTK-mediated disease is cancer or an autoimmune disease.
In particular embodiments, the cancer comprises a hematologic malignancy or a solid tumor, such as: acute Lymphocytic Leukemia (ALL), Chronic Myeloid Leukemia (CML), Mantle Cell Lymphoma (MCL), large intestine cancer; the autoimmune disease includes rheumatoid arthritis, resistance to organ transplant rejection, resistance to psoriasis or lupus erythematosus.
In a third aspect, the present invention provides a method of treating or preventing a BTK-mediated disease, comprising administering to a subject in need thereof a compound according to the first or second aspect of the present invention or a pharmaceutical composition comprising said compound.
In a fourth aspect, the present invention provides a compound of formula I:
Figure BDA0001273961530000121
in the formula (I), the compound is shown in the specification,
R、B、R2、Z1and Z2As is defined above in the foregoing description,
wherein the content of the first and second substances,
r is hydrogen, C 1-C3Lower alkyl, C1-C3Lower alkoxy, halogen (e.g. F, Cl, Br), amino or NRcRdAnd R isc、RdIs independently selected from H, C1-C6Alkyl radical, C1-C6Haloalkyl or (C)6-C10) An arylformyl group;
and/or
R3Selected from the group consisting of: hydrogen, (C)3-C6) Cycloalkyl group, (C)1-C8) Heterocyclic group, (C)1-C8) Alkoxy, -O- (CH)n-O-C1-C3Alkyl, benzyl, (C)6-C10) Aryl or (C)5-C10) Aromatic heterocyclic groups, wherein said aryl and aromatic heterocyclic groups may optionally be substituted with one to five groupsAnd (3) substitution: halogen, nitro, cyano, hydroxy, amino, (C)1-C8) Alkyl, (C)1-C8) Alkoxy group, (C)3-C6) Cycloalkyl group, (C)6-C10) Aryloxy group, (C)5-C10) Heterocyclyl, -O- (CH)n-O-C1-C3Alkyl radical, C3-C6Cycloalkyl oxy, C3-C6Heterocycloalkyloxy, amido, optionally substituted carbamoyl, n is an integer from 1 to 3, preferably 1;
and/or
R2Selected from the group consisting of:
Figure BDA0001273961530000122
Figure BDA0001273961530000131
in a preferred embodiment of the present invention,
r is hydrogen, C1-C3Lower alkyl, C1-C3Lower alkoxy, halogen (e.g. F, Cl, Br), amino or NRcRdAnd R isc、RdIndependently selected from H, C1-C6Alkyl radical, C1-C6Haloalkyl or (C)6-C10) An arylformyl group;
R3selected from the group consisting of: hydrogen, (C)3-C6) Cycloalkyl group, (C)1-C8) Heterocyclic group, (C)1-C8) Alkoxy, -O- (CH)n-O-C1-C3Alkyl, benzyl, (C)6-C10) Aryl or (C)5-C10) An aromatic heterocyclic group, wherein said aryl and aromatic heterocyclic groups may be optionally substituted with one to five of the following groups: halogen, nitro, cyano, hydroxy, amino, (C) 1-C8) Alkyl, (C)1-C8) Alkoxy group, (C)3-C6) Cycloalkyl group, (C)6-C10) Aryloxy groupBase, (C)5-C10) Heterocyclyl, -O- (CH)n-O-C1-C3Alkyl radical, C3-C6Cycloalkyl oxy, C3-C6Heterocycloalkyloxy, amido, optionally substituted carbamoyl, n is an integer from 1 to 3, preferably 1;
or
R is hydrogen, C1-C3Lower alkyl, C1-C3Lower alkoxy, halogen (e.g. F, Cl, Br), amino or NRcRdAnd R isc、RdIndependently selected from H, C1-C6Alkyl radical, C1-C6Haloalkyl or (C)6-C10) An arylformyl group;
R2selected from the group consisting of:
Figure BDA0001273961530000141
Figure BDA0001273961530000151
or alternatively
R3Selected from the group consisting of: hydrogen, (C)3-C6) Cycloalkyl group, (C)1-C8) Heterocyclic group, (C)1-C8) Alkoxy, -O- (CH)n-O-C1-C3Alkyl, benzyl, (C)6-C10) Aryl or (C)5-C10) An aromatic heterocyclic group, wherein said aryl and aromatic heterocyclic groups may be optionally substituted with one to five of the following groups: halogen, nitro, cyano, hydroxy, amino, (C)1-C8) Alkyl, (C)1-C8) Alkoxy group, (C)3-C6) Cycloalkyl group, (C)6-C10) Aryloxy group, (C)5-C10) Heterocyclyl, -O- (CH)n-O-C1-C3Alkyl radical, C3-C6Cycloalkyl oxy, C3-C6Heterocycloalkyloxy, amido, optionally substituted aminomethylAcyl, n is an integer from 1 to 3, preferably 1;
R2selected from the group consisting of:
Figure BDA0001273961530000161
Figure BDA0001273961530000171
in a specific embodiment, the compound is of formula I-1:
Figure BDA0001273961530000181
in the formula, A is R';
R1is absent;
r' is C1-C6Alkyl radical, C1-C6Haloalkyl, or (C6-C10) arylformyl;
B、R2、Z1And Z2As defined above.
In a particular embodiment, R' is C1-C3Alkyl radical, C1-C3A haloalkyl group.
In a specific embodiment, R3Selected from the group consisting of:
Figure BDA0001273961530000182
in a specific embodiment, R3Comprises the following steps:
Figure BDA0001273961530000183
it is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors have conducted extensive and intensive studies and unexpectedly found a group of compounds having novel structures, which are capable of inhibiting BTK with high activity and high selectivity, and IC of BTK inhibitory activity of some of the compounds50Values reached the nM range. The present invention has been completed based on this finding.
The present inventors synthesized a series of candidate compounds having BTK inhibitory activity. By carrying out structure optimization design on the obtained candidate compounds, a batch of novel pyrimidopyrimidine heterocyclic compounds with potential BTK inhibitory activity are discovered. The obtained compounds were subjected to activity evaluation at molecular level, and various compounds were evaluated for BTK inhibitory activity IC50Values reached the nM range.
Definition of terms
The groups to which the present invention relates have meanings conventionally understood in the art. Some of the groups referred to herein are defined as follows:
as used herein, "alkyl" refers to a saturated, branched or straight-chain alkyl group having a carbon chain length of 1 to 10 carbon atoms, with preferred alkyl groups including those varying in length from 2 to 8, 1 to 6, 1 to 4, 3 to 8, 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl and the like. The alkyl group may be substituted with 1 or more substituents, for example, with halogen or haloalkyl. For example, the alkyl group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group. The alkyl groups described herein may also be substituted with aryl groups, thereby forming, for example, benzyl groups.
Similarly, "cycloalkyl" herein refers to a substituted or unsubstituted saturated cyclic alkyl group having a carbon chain length of 3 to 10, preferably 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Herein, "alkoxy" refers to an oxy group substituted with an alkyl group. Preferred alkoxy groups are alkoxy groups of 1 to 6 carbon atoms in length, more preferably 1 to 4 carbon atoms in length, and even more preferably 1 to 3 carbon atoms in length. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, and the like. Alkoxy groups may be substituted with 1 or more substituents, for example with halogen or haloalkyl. For example, the alkoxy group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.
As used herein, "alkenyl" generally refers to a monovalent hydrocarbon group having at least one double bond, generally containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, and may be straight or branched. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
As used herein, "alkynyl" generally refers to a monovalent hydrocarbon group having at least one triple bond, generally containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more generally 2 to 4 carbon atoms, and may be straight or branched. Examples of alkenyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, hexynyl, and the like.
Herein, "halogen" means fluorine, chlorine, bromine or iodine.
As used herein, "aryl" means a monocyclic, bicyclic or tricyclic aromatic group having 6 to 14 carbon atoms, and includes phenyl, naphthyl, phenanthryl, anthryl, indenyl, fluorenyl, tetralinyl, indanyl and the like. Aryl groups may be optionally substituted with 1-5 (e.g., 1, 2, 3, 4, or 5) substituents selected from: halogen, C1-4Aldehyde group, C1-6Alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxy, C 1-4Alkoxy, ethoxycarbonyl, N (CH)3) And C1-4Acyl, etc., heterocyclic or heteroaryl, etc.
As used herein, "heterocyclyl" includes, but is not limited to, 5-or 6-membered heterocyclic groups containing 1-3 heteroatoms selected from O, S or N, including, but not limited to, furyl, thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl, and the like.
As used herein, "arylheterocyclyl" means a ring system containing 5 to 14 ring atoms and having 6, 10, or 14 electrons in common in the ring system. And the ring atoms contained are carbon atoms and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. Useful aryl heterocyclic groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl and the like.
The aryl heterocyclic group may be optionally substituted with 1 to 5 (e.g., 1, 2, 3, 4, or 5) substituents selected from the group consisting of: halogen, C1-4Aldehyde group, C1-6Straight or branched chain alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxy, C 1-4Alkoxy, ethoxycarbonyl, N (CH)3) And C1-4An acyl group.
As used herein, "acyloxy" refers to a group of the formula "-O-C (O) -R", wherein R may be selected from alkyl, alkenyl (e.g., C1-6 or C1-3 alkenyl), and alkynyl. Said R may be optionally substituted.
As used herein, "amido" refers to a group of the formula "-R '-NH-C (O) -R", wherein R' may be selected from hydrogen or alkyl, R may be selected from alkyl, alkenyl (e.g., C1-6 or C1-3 alkenyl), alkynyl, or NRcRdSubstituted alkyl, by NRcRdSubstituted alkenyl and NRcRdSubstituted alkynyl, alkyl substituted by halogen, alkenyl substituted by cyano, wherein RcAnd RdCan be selected from alkyl and alkenyl groups.
As used herein, "arylformyl" refers to aryl, e.g., (C)6-C10) Aryl is a group formed with a formyl group and attached to the main structure of the compound through the formyl group.
Herein, "optionally substituted" means that the substituent group it modifies may be optionally substituted with 1 to 5 (e.g., 1, 2, 3, 4, or 5) substituents selected from: halogen, C1-4Aldehyde group、C1-6Straight or branched chain alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g. trifluoromethyl), halogen-substituted alkoxy (e.g. trifluoromethoxy), carboxy, C 1-4Alkoxy, ethoxycarbonyl, N (CH)3) And C1-4An acyl group.
Compounds of the invention and uses thereof
For the purpose of the present invention, the present invention provides a compound represented by the following formula I or a salt thereof, thereby enabling the preparation of a BTK inhibitor or the preparation of a medicament for treating or preventing BTK-mediated diseases:
Figure BDA0001273961530000211
in the formula (I), the compound is shown in the specification,
r is hydrogen, C1-C3Lower alkyl, C1-C3Lower alkoxy, halogen (e.g., F, Cl, Br), amino, substituted amino;
b is selected from the following group: optionally substituted (C3-C8) cycloalkyl, (C3-C8) heterocyclyl, (C6-C10) aryl, or (C5-C10) arylheterocyclyl;
R2each independently selected from the group consisting of:
Figure BDA0001273961530000212
Figure BDA0001273961530000221
when Z is1When is-C (O) -, Z2Is composed of
Figure BDA0001273961530000231
Or when Z is1Is composed of
Figure BDA0001273961530000232
When Z is2is-C (O) -;
R3is selected from the followingGroup (2): hydrogen, optionally substituted C1-C10Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, optionally substituted C3-C8Cycloalkyl, optionally substituted C1-C10Alkoxy, optionally substituted aryl, optionally substituted benzyl, optionally substituted heterocyclyl, optionally substituted arylheterocyclyl, -O- (CH)n-O-C1-C3An alkyl group;
n is an integer from 1 to 3, preferably 1.
In particular embodiments, B may be selected from:
Figure BDA0001273961530000233
further, the compound of the present invention may be represented by the following formula I-1:
Figure BDA0001273961530000234
in the formula, A is benzene ring, five-membered or six-membered heterocycle, C3-C8Cycloalkyl or R';
When A is R', R1Is absent, R' is selected from C1-C6Alkyl radical, C1-C6Haloalkyl or (C)6-C10) An arylformyl group;
R1each independently selected from hydrogen, halogen, C1-C3Alkoxy radical, C1-C3Alkyl radical, C1-C4Alkylamido, substituted piperazinyl, substituted homopiperazinyl, substituted morpholinyl, substituted thiomorpholinyl, 4-N-methylpiperazinyl, 4-N-acetylpiperazinyl, 4-N, N-dimethylpiperidinyl, substituted piperidinyl, -NRaRbWherein R isaAnd RbCan be independently selected from alkyl and nitrogen-containing alkyl;
m is any integer of 0 to 7, preferably 1 to 7;
B、R2、Z1and Z2As hereinbefore describedAnd (4) limiting.
Still further, the compound of the present invention may be represented by the following formula II-1 or II-2:
Figure BDA0001273961530000241
in the formula, B, R1、R2、R3As defined above;
m is an integer from 0 to 5, preferably from 1 to 5.
Still further, the compound of the present invention may be represented by the following formula III-1 or III-2:
Figure BDA0001273961530000242
in the formula (I), the compound is shown in the specification,
R2is selected from
Figure BDA0001273961530000243
R3Is selected from H; c1-C6Alkyl, preferably methyl or isopropyl; phenyl-substituted C1-C6An alkyl group; optionally substituted phenoxyphenyl; or optionally substituted benzyl;
R4、R5、R6、R7and R8Independently selected from the group consisting of:
Figure BDA0001273961530000244
alternatively, the first and second electrodes may be,
R2is selected from
Figure BDA0001273961530000245
R3Is selected from H or C1-C6Alkyl (preferably methyl or propyl or isopropyl);
R4is H, C1-C3Alkoxy (preferably methyl)Oxy);
R5is H, C1-C3Alkyl (preferably methyl) or C 1-C3Alkoxy (preferably methoxy);
R6is H, or
Figure BDA0001273961530000251
R7And R8Is H.
In a specific embodiment, the present invention provides the use of a compound selected from the group consisting of:
Figure BDA0001273961530000252
Figure BDA0001273961530000261
Figure BDA0001273961530000271
Figure BDA0001273961530000281
Figure BDA0001273961530000291
Figure BDA0001273961530000301
Figure BDA0001273961530000311
Figure BDA0001273961530000321
Figure BDA0001273961530000331
the above table shows the structure of the compounds of the invention and their BTK inhibitory activity, wherein:
IC of Compounds whose Activity is designated "A50≤10nM；
IC of Compounds Activity designated "B50Is 10<IC50≤100nM；
IC of Compounds whose Activity is designated "C50Is 100<IC50≤1000nM；
IC of Compounds whose Activity is designated "D50Is 1000nM<IC50。
On the basis that the compound can have BTK inhibition activity, the invention provides a pharmaceutical composition for inhibiting BTK, which comprises a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Examples of pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, inorganic and organic acid salts, such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate salts; and inorganic and organic base salts formed with bases such as sodium hydroxy, TRIS (hydroxymethyl) aminomethane (TRIS, tromethamine) and N-methylglucamine.
Although the requirements vary from person to person, the skilled person can determine the optimal dosage of each active ingredient in the pharmaceutical composition of the invention. Typically, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered orally to a mammal daily in an amount of from about 0.0025 to 50 mg/kg body weight. But preferably about 0.01 to 10 mg per kg is administered orally. For example, a unit oral dosage may include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of a compound of the present invention. A unit dose may be administered one or more times daily in one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently from about 0.25 to 10 mg, of a compound of the invention or a solvate thereof.
The pharmaceutical compositions of the present invention may be formulated in a form suitable for a variety of routes of administration, including but not limited to, for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical administration for the treatment of tumors and other diseases. The amount administered is an amount effective to ameliorate or eliminate one or more symptoms. For the treatment of a particular disease, an effective amount is an amount sufficient to ameliorate or in some way reduce the symptoms associated with the disease. Such amounts may be administered as a single dose or may be administered according to an effective treatment regimen. The amount administered may be sufficient to cure the disease, but is generally administered to ameliorate the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms. The dosage of the drug will be determined by the age, health and weight of the patient, the kind of concurrent treatment, the frequency of the treatment, and the desired therapeutic benefit.
The pharmaceutical preparation of the present invention can be administered to any mammals as long as they can obtain the therapeutic effects of the compound of the present invention. Of these mammals, the most important is the human being.
The compounds of the present invention or pharmaceutical compositions thereof are useful in the treatment of various BTK mediated diseases. Herein, the BTK-mediated disease is cancer or an autoimmune disease; wherein the cancer comprises a hematologic malignancy or a solid tumor, such as: acute Lymphocytic Leukemia (ALL), Chronic Myeloid Leukemia (CML), Mantle Cell Lymphoma (MCL), large intestine cancer; the autoimmune disease includes rheumatoid arthritis, resistance to organ transplant rejection, resistance to psoriasis or lupus erythematosus.
The pharmaceutical preparations of the present invention can be manufactured in a known manner. For example, by conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. In the manufacture of oral formulations, solid excipients and active compounds may be combined, optionally grinding the mixture. If desired or necessary after addition of suitable amounts of auxiliaries, the granulate mixture is processed to give tablets or dragee cores.
Suitable adjuvants are, in particular, fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone. If desired, disintegrating agents such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added. Adjuvants are, in particular, flow regulators and lubricants, for example silica, talc, stearates, such as calcium magnesium stearate, stearic acid or polyethylene glycol. If desired, a suitable coating resistant to gastric juices can be provided to the tablet core. For this purpose, concentrated saccharide solutions can be used. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. For the preparation of coatings resistant to gastric juices, suitable cellulose solutions can be used, for example cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate. Dyes or pigments may be added to the coating of the tablet or lozenge core. For example, for identifying or for characterizing combinations of active ingredient doses.
Based on the above compounds and pharmaceutical compositions, the present invention further provides a method for treating or preventing BTK-mediated diseases, which comprises administering to a subject in need thereof a compound or pharmaceutical composition of the present invention. The method of administration includes, but is not limited to, various methods of administration known in the art, and may be determined based on the actual condition of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal, or topical routes of administration.
In a particular embodiment, the present invention provides a compound of formula I or a salt thereof, having a novel structure:
Figure BDA0001273961530000351
in the formula (I), the compound is shown in the specification,
R、B、R2、Z1and Z2As defined above, the above-mentioned,
wherein the content of the first and second substances,
r is hydrogen, C1-C3Lower alkyl, C1-C3Lower alkoxy, halogen (e.g. F, Cl, Br), amino or NRcRdAnd R isc、RdIndependently selected from H, C1-C6Alkyl radical, C1-C6Haloalkyl or (C)6-C10) An arylformyl group;
and/or
R3Selected from the group consisting of: hydrogen, (C)3-C6) Cycloalkyl group, (C)1-C8) Heterocyclic group, (C)1-C8) Alkoxy, -O- (CH)n-O-C1-C3Alkyl, benzyl, (C)6-C10) Aryl or (C)5-C10) An aromatic heterocyclic group, wherein said aryl and aromatic heterocyclic groups may be optionally substituted with one to five of the following groups: halogen, nitro, cyano, hydroxy, amino, (C) 1-C8) Alkyl, (C)1-C8) Alkoxy group, (C)3-C6) Cycloalkyl group, (C)6-C10) Aryloxy group, (C)5-C10) Heterocyclyl, -O- (CH)n-O-C1-C3Alkyl radical, C3-C6Cycloalkyl oxy, C3-C6Heterocycloalkyloxy, amido, optionally substituted carbamoyl, n is an integer from 1 to 3, preferably 1;
and/or
R2Selected from the group consisting of:
Figure BDA0001273961530000352
Figure BDA0001273961530000361
in a preferred embodiment, R, R is as described above2And R3Can be combined at will. For example, the following combinations are possible:
r is hydrogen, C1-C3Lower alkyl, C1-C3Lower alkoxy, halogen (e.g. F, Cl, Br), amino or NRcRdAnd R isc、RdIndependently selected from H, C1-C6Alkyl radical, C1-C6Haloalkyl or (C)6-C10) An arylformyl group;
R3selected from the group consisting of: hydrogen, (C)3-C6) Cycloalkyl, (C)1-C8) Heterocyclic group, (C)1-C8) Alkoxy, -O- (CH)n-O-C1-C3Alkyl, benzyl, (C)6-C10) Aryl or (C)5-C10) An aromatic heterocyclic group, wherein said aryl and aromatic heterocyclic groups may be optionally substituted with one to five of the following groups: halogen, nitro, cyano, hydroxy, amino, (C)1-C8) Alkyl, (C)1-C8) Alkoxy group, (C)3-C6) Cycloalkyl group, (C)6-C10) Aryloxy group, (C)5-C10) Heterocyclyl, -O- (CH)n-O-C1-C3Alkyl radical, C3-C6Cycloalkyloxy radical, C3-C6Heterocycloalkyloxy, amido, optionally substituted carbamoyl, n is an integer from 1 to 3, preferably 1;
or
R is hydrogen, C1-C3Lower alkyl, C1-C3Lower alkoxy, halogen (e.g. F, Cl, Br), amino or NR cRdAnd R isc、RdIndependently selected from H, C1-C6Alkyl radical, C1-C6Haloalkyl or (C)6-C10) An arylformyl group;
R2selected from the group consisting of:
Figure BDA0001273961530000371
Figure BDA0001273961530000381
or
R3Selected from the group consisting of: hydrogen, (C)3-C6) Cycloalkyl group, (C)1-C8) Heterocyclic group, (C)1-C8) Alkoxy, -O- (CH)n-O-C1-C3Alkyl, benzyl, (C)6-C10) Aryl or (C)5-C10) An aromatic heterocyclic group, wherein said aryl and aromatic heterocyclic groups may be optionally substituted with one to five of the following groups: halogen, nitro, cyano, hydroxy, amino, (C)1-C8) Alkyl, (C)1-C8) Alkoxy group, (C)3-C6) Cycloalkyl group, (C)6-C10) Aryloxy group, (C)5-C10) Heterocyclyl, -O- (CH)n-O-C1-C3Alkyl radical, C3-C6Cycloalkyl oxy, C3-C6Heterocycloalkyloxy, amido, optionally substituted carbamoyl, n is an integer from 1 to 3, preferably 1;
R2selected from the group consisting of:
Figure BDA0001273961530000391
Figure BDA0001273961530000401
in a specific embodiment, the structurally novel compounds of the present invention are represented by formula I-1:
Figure BDA0001273961530000411
in the formula, A is R'; r1Is absent; r' is C1-C6Alkyl radical, C1-C6Haloalkyl, or (C6-C10) arylformyl; B. r2、Z1And Z2As defined above.
Further, R' may be C1-C3Alkyl radical, C1-C3A haloalkyl group.
In a preferred embodiment, R3May be selected from the group consisting of:
Figure BDA0001273961530000412
more preferably
Figure BDA0001273961530000413
In a particular embodiment, the substituents in the general formula of the present invention are each the corresponding groups in any of the specific compounds disclosed herein.
The invention has the advantages that:
1. the compound of the present invention has excellent inhibitory activity against BTK;
2. the compound of the invention has high selectivity to BTK; and
3. the compound lays a foundation for developing a medicament capable of inhibiting BTK with high activity and high selectivity, has great industrialization and commercialization prospects and market values, and has remarkable economic benefit.
The technical solution of the present invention will be further described with reference to the following specific embodiments, but the following embodiments are not intended to limit the present invention, and all of the various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Materials and methods
Method for detecting BTK inhibitory activity
1.1 expression of BTK recombinant protein
1) Construction of PfastBac1-BTK vector
Carrying out PCR amplification on a BTK target fragment (M1-S695), carrying out double enzyme digestion on a PCR product and a vector PfastBac1 by using BamHI and XhoI, connecting enzyme digestion products, transforming to DH5 alpha competent cells, selecting a single clone, and finally obtaining a recombinant plasmid pFastBac1-BTK with a correct sequence through sequencing verification.
2) Acquisition of baculovirus
Transposing the constructed plasmid to DH10Bac competent cells for blue-white screening, selecting a monoclonal with successful transposition, extracting bacmid after shaking bacteria, and identifying the bacmid through bacteria liquid PCR. The correct bacmid was identified for transfection into Sf9 cells, resulting in P1, P2 and higher titers of P3 virus strains, respectively.
3) BTK protein expression and identification
Sf9 cells were cultured to logarithmic phase (about 2X 10)6One cell/mL), the P3 strain having a high titer was added to a culture medium containing Sf9 cells grown in log phase, cultured at 27 ℃ for 3 days, centrifuged at 500 × g for 5min, the supernatant was discarded, harvested, and stored at-80 ℃. Protein expression was then detected by immunoblotting (Western Blot).
1.2 purification of BTK recombinant proteins
The bacterial pellet expressed by the P3 strain was collected by centrifugation at 1790rpm at room temperature. The lysate used to dissolve the cells was 250mM NaCl, 0.25% NP-40,50mM CHES (pH 9.0). The cells were disrupted by a high-pressure cell disrupter, and then centrifuged at 12000rpm at 4 ℃ for 45min to collect the supernatant. And (3) adding the supernatant into a Ni-NTA chromatographic column, eluting the target protein by using an imidazole concentration gradient method, and collecting the eluted protein solution. And concentrating the eluent containing the target protein, and changing the eluent to the lowest imidazole concentration. The solution was dialyzed against TEV enzyme at 4 ℃ for 16h, and the solution was re-run through a Ni-NTA column, and the His-Tag-free flow-through was collected in a buffer of 200mM NaCl,20mM CHES (pH 9.0), 1mM TCEP. Finally, the purified protein was separated by HiTrap Superdex75 molecular sieves using 100mM NaCl,10mM Tris-HCl pH 8.5, 1mM TCEP as equilibration buffer.
1.3 molecular level screening of BTK inhibitors
The BTK inhibitor molecular level screening experiment adopts ThermoFisher company
Figure BDA0001273961530000432
Assay Kit (PV 3190). The experimental method comprises the following steps: diluting a compound to be detected in a concentration gradient manner, adding 2.5 mu L of Test Compounds into a 384-hole plate, adding 5 mu L of BTK Kinase/Peptide Substrate Mixture and 2.5 mu L of ATP Solution into each group of three parallel controls, oscillating for 30s, uniformly mixing, and incubating for 1h at room temperature; adding 5 μ L of Development Solution, shaking for 30s, mixing, and incubating at room temperature for 1 h; then 5 mul of Stop Reagent is added, the mixture is oscillated for 30s and mixed evenly, a fluorescence signal is detected by using an enzyme-labeling instrument, the excitation wavelength is 400nm, and the emission wavelength is 445nm and 520nm respectively. The inhibition of the compounds at 7 concentration gradients was determined and the IC of each compound was calculated by Origin 8.0 fitting of the curve50The value is obtained.
The synthesis process of the pyrimido [4,5-d ] pyrimidine-2, 4(1H,3H) -diketone compound is as follows:
Figure BDA0001273961530000431
reagents and conditions: (a) DIPEA, CH3CN,reflux；(b)ArNH2,CH3CN,reflux；(c)NaOH,THF,reflux；(d)R3NH2,HATU,DIPEA,DMF；(e)NaH,CDI,THF,reflux；(f)trifluoroacetic acide,CH2Cl2,0℃ to r.t；(g)acyl chloride,Et3N,CH2Cl2,0℃ to r.t
In the above preparation process, R3、R4、R5Reference is made to the corresponding group definitions above. The corresponding compounds can be prepared by those skilled in the art according to the actual preparation needs by using various starting compounds conventionally obtained in the field as raw materials.
Example 1
The specific synthesis method of the steps a-g is as follows:
synthesis of ethyl 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2-chloropyrimidine-5-carboxylate
Figure BDA0001273961530000441
2, 4-dichloro-5-nitropyrimidine (2.210g,10mmol) and DIPEA (1.290g,10mmol) were weighed into a 50mL single-neck flask, and dissolved in 15mL of acetonitrile. Tert-butyl (3-aminophenyl) carbamate (2.080g,10mmol) was dissolved in 10mL of acetonitrile, added dropwise to the reaction mixture, and refluxed for 2 h. TLC tracking till the raw material conversion, cooling to room temperature, suction filtering, washing with acetonitrile, and drying the filter cake to obtain 3.371g of ethyl 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2-chloropyrimidine-5-carboxylate with 86% yield.1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.50(s,1H),8.80(s,1H),7.70(s,1H),7.35(d,J＝8.0Hz,1H),7.29(t,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),4.38(q,J＝7.2Hz,2H),1.49(s,9H),1.36(t,J＝7.2Hz,3H).LC-MS:m/z:393.1(M+H)+.
Synthesis of ethyl 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenylamino) pyrimidine-5-carboxylate
Figure BDA0001273961530000442
Ethyl 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2-chloropyrimidine-5-carboxylate (1.960g,5mmol), aniline (0.558g,6mmol) were weighed into a 100mL single-neck flask, dissolved in 40mL acetonitrile, and refluxed for 3h at elevated temperature. TLC tracks the conversion of the starting material, cools to room temperature, suction filters, washes with water, and dries the filter cake to give 1.930g of ethyl 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenylamino) pyrimidine-5-carboxylate in 86% yield. 1H NMR(400MHz,CDCl3)δ10.46(s,1H),8.76(s,1H),7.57(d,J＝8.0Hz,2H),7.36(t,J＝7.6Hz,3H),7.23(d,J＝8.0Hz,1H),7.16(t,J＝7.2Hz,1H),7.04(d,J＝7.6Hz,1H),6.36(s,1H),4.37(q,J＝7.2Hz,2H),1.54(s,9H),1.41(t,J＝7.2Hz,3H).LC-MS:m/z:450.4(M+H)+.
Synthesis of 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenylamino) pyrimidine-5-carboxylic acid
Figure BDA0001273961530000443
Ethyl 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenylamino) pyrimidine-5-carboxylate (1.796g,4mmol) was weighed into a 100mL single-neck flask, dissolved in 30mL tetrahydrofuran, and 10mL of 1M NaOH solution was added dropwise, warmed to 50 ℃ and stirred for 3 h. TLC tracking till the raw material is converted, cooling to room temperature, adding dilute hydrochloric acid to adjust the pH to acidity, performing suction filtration, washing with water, and drying a filter cake to obtain 1.499g of 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenylamino) pyrimidine-5-carboxylic acid with the yield of 89%.1H NMR(400MHz,DMSO-d6) δ 10.44(s,1H),9.82(s,1H),9.36(s,1H),8.70(s,1H),7.69(d, J ═ 8.0Hz,2H),7.63(s,1H),7.43(s,1H),7.26-7.21(m,4H),6.98(t, J ═ 6.8Hz,1H),1.47(s,9H), hrms (esi): calculated value C22H24N5O4(M+H)+422.1828, Experimental value 422.1823.
Synthesis of tert-butyl 3- (5- (methylcarbamoyl-2- (phenylamino) pyrimidin-4-amino) phenyl) carbamate
Figure BDA0001273961530000451
In a 50mL flask, 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -2- (phenylamino) pyrimidine-5-carboxylic acid (1.263g,3mmol), DIPEA (0.774g,6mmol) were weighed and dissolved in 10mL anhydrous DMF. HATU (1.368g,3.6mmol) was added to the reaction mixture in portions and stirred at room temperature for 1 hour. Methylamine hydrochloride (0.396g,6mmol) was added and stirred at room temperature overnight. TLC tracks the conversion of the starting material, ice water is added, suction filtration and washing with water are carried out to obtain 0.612g of tert-butyl 3- (5- (methylcarbamoyl-2- (phenylamino) pyrimidin-4-amino) phenyl) carbamate with a yield of 47%. 1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),9.59(s,1H),9.31(s,1H),8.64(s,1H),8.50(d,J＝4.8Hz,1H),7.68(d,J＝7.8Hz,2H),7.62(s,1H),7.49(br,1H),7.23(t,J＝7.8Hz,2H),7.19(d,J＝8.0Hz,1H),7.15(d,J＝8.0Hz,1H),6.96(t,J＝7.2Hz,1H),2.79(d,J＝4.4Hz,3H),1.47(s,9H).LC-MS:m/z:435.2(M+H)+.
(3- (3-methyl-2, 4-dioxo-7- (phenylamino) -3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H) -yl) phenyl) carbamic acid tert-butyl ester
Figure BDA0001273961530000452
Tert-butyl 3- (5- (methylcarbamoyl-2- (phenylamino) pyrimidin-4-ylamino) phenyl) carbamate (0.434g,1mmol), K were weighed2CO3(0.276g,2mmol) was dissolved in a 25mL flask in 5mL of anhydrous tetrahydrofuran, and the mixture was refluxed overnight. TLC followed the conversion of the starting material, cooled to room temperature, added ice water, extracted with EA, collected the organic layer, rotary evaporated to remove the solvent and the crude product was chromatographed on silica gel (EA/PE 2:1, v/v) to give 193mg, 42% yield.1H NMR(400MHz,DMSO-d6) δ 9.62(s,1H),8.92(s,1H),7.66(s,1H),7.52(d, J ═ 8.0Hz,1H),7.45(t, J ═ 8.0Hz,1H),7.36-7.32(m,2H),7.02(d, J ═ 8.0Hz,3H),6.90(d, J ═ 7.6Hz,1H),3.29(s,3H),1.45(s,9H), hrms (esi): calculated value C, H24H25N6O4(M+H)+461.1937, Experimental value 461.1939.
Synthesis of 1- (3-aminophenyl) -3-methyl-7- (phenylamino) pyrimido [4,5-d ] pyrimidine-2, 4(1H, 3H) -dione
Figure BDA0001273961530000461
Weighing (3- (3-methyl-2, 4-dioxo-7- (phenylamino) -3, 4-dihydropyrimido [4,5-d ]]Pyrimidin-1 (2H) -yl) phenyl) carbamic acid tert-butyl ester (0.193g,0.42mmol) in a 50mL flask was dissolved by adding 5mL of dichloromethane, and 1mL of trifluoroacetic acid was slowly added dropwise and stirred at room temperature overnight. TLC followed conversion of starting material and saturated NaHCO was added 3Neutralizing the solution, extracting with dichloromethane, collecting organic layer, rotary evaporating to remove solvent to obtain 1- (3-aminophenyl) -3-methyl-7- (phenylamino) pyrimido [4,5-d]Pyrimidine-2, 4(1H, 3H) -dione 0.136g, yield 90%, product nonePurified and directly used for the next reaction.
Synthesis of N- (3- (3-methyl-2, 4-dioxo-7- (phenylamino) -3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H) -yl) phenyl) acrylamide (No. 1)
Figure BDA0001273961530000462
Weighing 1- (3-aminophenyl) -3-methyl-7- (phenylamino) pyrimido [4,5-d]Pyrimidine-2, 4(1H, 3H) -dione (0.136g,0.38mmol), DIPEA (0.097g,0.76mmol) and a 25mL flask were dissolved by adding 3mL of dichloromethane, and stirred for 15 minutes under ice bath. Further, acryloyl chloride (0.041g,0.46mmol) was dissolved in 1mL of dichloromethane, and added dropwise to the above reaction solution, followed by stirring overnight at room temperature. TLC tracks the conversion of the starting material, spin-dries, and the crude product is chromatographed over silica gel (EA/PE 1.5:1, v/v) to give N- (3- (3-methyl-2, 4-dioxo-7- (phenylamino) -3, 4-dihydropyrimido [4,5-d ]]Pyrimidin-1 (2H) -yl) phenyl) acrylamide 83mg, 53% yield.1H NMR(400MHz,DMSO-d6) δ 10.38(s,1H),8.93(s,1H),7.82(d, J ═ 3.2Hz,1H),7.80(s,1H),7.53(t, J ═ 8.0Hz,1H),7.33-7.29(m,2H),7.15(d, J ═ 7.8Hz,1H),7.02-6.96(m,2H),6.89(t, J ═ 6.0Hz,1H),6.44(dd, J ═ 17.2Hz, J ═ 10.4Hz,1H),6.26(dd, J ═ 17.2Hz, J ═ 1.6Hz,1H),5.76(dd, J ═ 10.4Hz, J ═ 2.0, 1H),3.30(s,3H), calculated values of (hrc: (dd, J ═ 10.4Hz, J ═ 2.0, 1H),3.30 (ms, 3H), 3.30: (C), (d, 1H), and (H) are included in the formula 22H19N6O3(M+H)+415.1519, experimental value 415.1512.
The following compounds were synthesized according to the methods described above in steps a-g:
n- (3- (7- ((2-methoxyphenyl) amino) -3-methyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 2)
Figure BDA0001273961530000471
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.89(s,1H),8.68(s,1H),7.80(s,1H),7.76(d,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.12(d,J＝7.6Hz,1H) 6.95(d, J ═ 7.6Hz,2H),6.44(dd, J ═ 16.8Hz, J ═ 10.0Hz,1H),6.25(dd, J ═ 17.2Hz, J ═ 2.0Hz,1H),5.76(dd, J ═ 10.4Hz, J ═ 2.0Hz,1H),3.78(s,3H),3.29(s,3H), hrms esi (calculated value C), C (calculated value C) and C (calculated value g), C (calculated value g, J) (C (calculated value g), C (J) (1, 3H), and H) (calculated value g (C) and C (calculated value g) are calculated values of C (C, d) and H)23H21N6O4[M+H]+445.1624, Experimental value 445.1631.
N- (3- (7- ((4-methoxyphenyl) amino) -3-methyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 3)
Figure BDA0001273961530000472
1H NMR(400MHz,DMSO-d6) δ 10.37(s,1H),10.23(s,1H),8.88(s,1H),7.82(d, J ═ 8.0Hz,1H),7.79(s,1H),7.53(t, J ═ 8.0Hz,1H),7.22(d, J ═ 7.6Hz,2H),7.12(d, J ═ 8.0Hz,1H),6.56(d, J ═ 7.6Hz,2H),6.44(dd, J ═ 16.8Hz, J ═ 10.0Hz,1H),6.24(dd, J ═ 16.8Hz, J ═ 1.6Hz,1H),5.76(dd, J ═ 10.0Hz, J ═ 1.6, 1H),3.65(s,3H),3.29 (ms), 29 (C, C), (calculated values of (d, J ═ 10.0Hz, J ═ 1.6Hz,1H),3.65 (ms, 3H), and 29H)23H21N6O4[M+H]+445.1624, Experimental value 445.1627.
N- (3- (7- ((2-methoxy-4-morpholinophenyl) amino) -3-methyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO. 4)
Figure BDA0001273961530000473
1H NMR(400MHz，DMSO-d6) δ 10.36(s, 1H), 8.80(s, 1H), 8.44(s, 1H), 8.03(s, 1H)7.85(d, J ═ 8.0Hz,1H),7.69(t, J ═ 2.0Hz,1H),7.52(t, J ═ 8.4Hz,1H),7.31(d, J ═ 8.8Hz,1H),7.09(d, J ═ 7.6Hz,1H),6.57(d, J ═ 2.0Hz,1H),6.45(dd, J ═ 16.8Hz, J ═ 10.0Hz,1H),6.26(dd, J ═ 17.2Hz, J ═ 2.0Hz,1H),5.77 (esi, J ═ 10.4, J ═ 2, 3.7H), 3.7 (3.7H ),3.7 (H, 3.7H), 3.7 (H), 3.7H), 3.7 (H, 3.7H, 3H), 3.7, 3H),3, m) calculated values of values 27H28N7O5[M+H]+528.1995, Experimental value 528.1993.
N- (3- (7- ((2-methoxy-4-thiomorpholinophenyl) amino) -3-methyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 5)
Figure BDA0001273961530000481
H NMR(400MHz,DMSO-d6) δ 10.35(s,1H),8.84(s,1H),8.60(s,1H),8.85(s,1H),7.70(s,1H),7.48(t, J ═ 8.0Hz,1H),7.17(d, J ═ 8.4Hz,1H),7.09(d, J ═ 7.6Hz,1H),6.44(dd, J ═ 17.2Hz, J ═ 10.0Hz,1H),6.27(dd, J ═ 16.8Hz, J ═ 2.0Hz,1H),5.97(s,1H),5.77(dd, J ═ 10.0Hz, J ═ 1.6Hz,1H),3.75(s,3H),3.42-3.39(m,4H),3.28(s, 3.63, 2H), 3.63-2 (ms, 4H), 18 (ms, 18, 4.6H), calculated values (hrc, 1H), 3.8 (d, 1H), 3.8H, 1H), 1H, and m, 3.627H28N7O4S[M+H]+546.1923, Experimental value 546.1924.
N- (3- (7- ((4- (4-acetyl-3-) -2-methoxyphenyl) amino) -3-methyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (sequence No. 6)
Figure BDA0001273961530000482
1H NMR(400MHz，DMSO-d6) δ 10.34(s, 1H), 8.83(s, 1H), 8.59(s, 1H), 7.86(s, 1H), 7.69(s,1H),7.48(t, J ═ 8.4Hz,1H),7.17(d, J ═ 8.8Hz,1H),7.09(d, J ═ 8.0Hz,1H),6.55(s,1H),6.44(dd, J ═ 17.2Hz, J ═ 10.4Hz,1H),6.26(dd, J ═ 17.2Hz, J ═ 1.6Hz,1H),5.99(s,1H),5.76(dd, J ═ 10.0Hz, J ═ 1.2Hz,1H),3.76(s,3H),3.58-3.54 (s, 4H), 3.05 (s,3H),3.05 (m), 3.05 (H), 3.05-1H), 3.05 (H), 3.2H), C, 1H), and calculated values (d, 1H) of (d)29H31N8O5[M+H]+571.2417, Experimental value 571.2417.
N- (3- (7- ((4- (4- (dimethylamino) piperidine) -2-methoxyphenyl) amino) -3-methyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 7)
Figure BDA0001273961530000483
1H NMR(400MHz,DMSO-d6) δ 10.36(s,1H),8.83(s,1H),8.54(s,1H),7.88-7.86(m,1H),7.70(s,1H),7.47(t, J ═ 8.0Hz,1H),7.16(d, J ═ 8.4Hz,1H),7.08(d, J ═ 8.0Hz,1H),6.50-6.43(m,2H),6.26(dd, J ═ 16.8Hz, J ═ 1.6Hz,1H),5.98(s,1H),5.76(dd, J ═ 10.0Hz, J ═ 1.2Hz,1H),3.75(s,3H),3.59-3.58(m,2H),3.28(s,3H),2.60-2.55(m,2H), 2H (m,1H), 2H, 1H), calculated values (m,2H), 2H, 1H, 18H, 1H, 18H, 1H, 2H, 1H, 18H, m,1H, 2H, 1H, 2H, 1H, 2H, m,1H, 2H, m,2H, 1H, m,2H, m,2H, 1H, m,2H, C, 1H, 2H, 1H, 2H, and m,1H, 2H, 18, 1H, 2H, 1H, 18, 1H, 18, 2H, 18, 1H, 18, 1H, 18, 2H, 18, 2H, 18, 2H, 2, 1H, 2, 18, 2H, 2, 18, 2, 18, 2H, and so on the like30H35N8O4[M+H]+571.2781, Experimental value 571.2780.
N- (3- (7- ((4- (4- (dimethylamino) piperidine) -2-methoxyphenyl) amino) -3-ethyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 8)
Figure BDA0001273961530000491
1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),10.56(s,1H),8.84(s,1H),8.62(s,1H),7.92-7.90(m,1H),7.71(s,1H),7.48(t,J＝8.0Hz,1H),7.17(d,J＝6.8Hz,1H),7.10(d,J＝7.2Hz,1H),6.55-6.49(m,2H),6.28(dd,J＝16.8Hz,J＝1.6Hz,1H),6.00(s,1H),5.78(dd,J＝11.2Hz,J＝1.2Hz,1H),3.94(q,J＝6.4Hz,2H),3.76(s,3H),3.72-3.68(m,2H),2.73(s,6H),2.60(t,J＝8.0Hz,1H),2.63-2.58(m,2H),2.09(d,J＝11.2Hz,2H),1.72-1.68(m,2H),1.18(t,J＝6.4Hz,3H).HRMS(ESI)(m/z):(M+H)+calcd forC31H37N8O4585.2938,found,585.2928.
N- (3- (7- ((4- (4- (dimethylamino) piperidine) -2-methoxyphenyl) amino) -3-propyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 9)
Figure BDA0001273961530000492
1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.84(s,1H),8.63(s,1H),7.92(s,1H),7.69(s,1H),7.49(t,J＝8.0Hz,1H),7.19(d,J＝6.8Hz,1H),7.10(d,J＝7.8Hz,1H),6.54-6.48(m,2H),6.28(dd,J＝16.8Hz,J＝1.2Hz,1H),6.00(s,1H),5.78(dd,J＝10.4Hz,J＝1.6Hz,1H),3.86(t,J＝6.8Hz,2H),3.76(s,3H),3.72-3.69(m,2H),3.26-3.21(m,1H),2.72(s,6H),2.62-2.57(m,2H),2.07(d,J＝11.2Hz,2H),1.70-1.67(m,2H),1.65-1.60(m,2H),0.90(t,J＝7.2Hz,3H).HRMS(ESI)(m/z):(M+H)+calcd for C32H39N8O4 599.3094,found,599.3099.
N- (3- (7- ((4- (4- (dimethylamino) piperidine) -2-methoxyphenyl) amino) -3-isopropyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 10)
Figure BDA0001273961530000493
H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.83(s,1H),8.60(s,1H),7.91(s,1H),7.69(s,1H),7.48(t,J＝8.0Hz,1H),7.19(d,J＝5.6Hz,1H),7.10(d,J＝7.6Hz,1H),6.55-6.48(m,2H),6.28(dd,J＝17.2Hz,J＝1.6Hz,1H),6.00(s,1H),5.78(dd,J＝10.0Hz,J＝1.6Hz,1H),5.17-5.10(m,1H),3.76(s,3H),3.72-3.68(m,2H),3.26-3.20(m,1H),2.72(s,6H),2.63-2.59(m,2H),2.07(d,J＝10.8Hz,2H),1.70-1.67(m,2H),1.44(d,J＝6.8Hz,6H).HRMS(ESI)(m/z):(M+H)+calcd forC32H39N8O4599.3094,found,599.3079.
N- (3- (3-benzyl-7- ((4- (4- (dimethylamino) piperidine) -2-methoxyphenyl) amino) -2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 11)
Figure BDA0001273961530000501
1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.87(s,1H),8.69(s,1H),7.91(s,1H),7.69(s,1H),7.48(t,J＝8.0Hz,1H),7.38(d,J＝7.2Hz,2H),7.33(t,J＝7.2Hz,2H),7.26(t,J＝7.2Hz,1H),7.19(d,J＝8.0Hz,1H),7.11(d,J＝6.8Hz,1H),6.54-6.47(m,2H),6.27(dd,J＝16.8Hz,J＝1.6Hz,1H),6.01-5.99(m,1H),5.77(dd,J＝10.0Hz,J＝1.6Hz,1H),5.10(s,2H),3.76(s,3H),3.72-3.69(m,2H),3.27-3.21(m,1H),2.73(s,6H),2.62-2.57(m,2H),2.08(d,J＝11.2Hz,2H),1.71-1.68(m,2H).HRMS(ESI)(m/z):(M+H)+calcd forC36H39N8O4647.3094,found,647.3088.
N- (3- (7- ((4- (4- (dimethylamino) piperidine) -2-methoxyphenyl) amino) -2, 4-dioxo-3-phenylethyl-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 12)
Figure BDA0001273961530000502
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.85(s,1H),8.67(s,1H),7.91(s,1H),7.72(s,1H),7.49(t,J＝8.0Hz,1H),7.32(t,J＝7.6Hz,2H),7.26-7.23(m,3H),7.19(d,J＝12.8Hz,1H),7.07(d,J＝6.8Hz,1H),6.56-6.49(m,2H),6.28(dd,J＝17.2Hz,J＝1.6Hz,1H),6.01-5.99(m,1H),5.78(dd,J＝10.4Hz,J＝1.6Hz,1H),4.10-4.08(m,2H),3.77(s,3H),3.72-3.69(m,2H),3.24-3.19(m,1H),2.90(t,J＝7.6Hz,2H),2.71(s,6H),2.62-2.57(m,2H),2.07(d,J＝11.2Hz,2H),1.70-1.68(m,2H).HRMS(ESI)(m/z):(M+H)+calcd forC37H41N8O4661.3251,found,661.3251.
N- (3- (7- ((4- (4- (dimethylamino) piperidine) -2-methoxyphenyl) amino) -2, 4-dioxo-3- (3-phenylpropyl) -3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (number 13)
Figure BDA0001273961530000511
1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.81(s,1H),8.60(s,1H),7.92(s,1H),7.78(s,1H),7.48(t,J＝8.0Hz,1H),7.28-7.19(m,5H),7.14(t,J＝7.2Hz,1H),7.07(d,J＝7.2Hz,1H),6.61-6.52(m,2H),6.29(dd,J＝17.2Hz,J＝1.6Hz,1H),6.02(s,1H),5.78(dd,J＝10.0Hz,J＝1.6Hz,1H),3.94(t,J＝7.2Hz,2H),3.76(s,3H),3.22-3.17(m,1H),2.69(s,6H),2.68-2.63(m,4H),2.08(d,J＝10.4Hz,2H),1.94(t,J＝6.8Hz,2H).HRMS(ESI)(m/z):(M+H)+calcd forC38H43N8O4675.3407,found,675.3403.
N- (3- (3-isopropyl-7- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (number 14)
Figure BDA0001273961530000512
1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.83(s,1H),8.63(s,1H),7.85(d,J＝7.2Hz,1H),7.73(s,1H),7.47(t,J＝8.0Hz,1H),7.20(d,J＝8.4Hz,1H),7.09(d,J＝7.6Hz,1H),6.56-6.51(m,2H),6.27(dd,J＝17.2Hz,J＝1.6Hz,1H),6.03-6.01(m,1H),5.77(dd,J＝10.4Hz,J＝1.2Hz,1H),5.17-5.10(m,1H),3.76(s,3H),3.29(t,J＝4.0Hz,4H),3.20(t,J＝4.0Hz,4H),2.75(s,3H),1.44(d,J＝6.4Hz,6H).HRMS(ESI)(m/z):(M+H)+calcd forC30H35N8O4571.2781,found,571.2775.
N- (3- (3-isopropyl-7- ((3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO. 15)
Figure BDA0001273961530000513
1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),10.18(s,1H),8.88(s,1H),7.89(s,1H),7.72(s,1H),7.50(t,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),6.91(s,1H),6.49(dd,J＝16.8Hz,J＝10.0Hz,1H),6.43-6.41(m,1H),6.27(dd,J＝16.8Hz,J＝1.6Hz,1H),5.77(dd,J＝10.0Hz,J＝1.6Hz,1H),5.18-5.11(m,1H),3.56(s,3H),3.04-3.01(m,8H),2.63(s,3H),1.44(d,J＝6.8Hz,6H).HRMS(ESI)(m/z):(M+H)+calcd forC30H35N8O4571.2781,found,571.2773.
N- (3- (3-isopropyl-7- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO. 16)
Figure BDA0001273961530000521
1H NMR(400MHz，DMSO-d6)δ10.54(s，1H)，10.22(s，1H)，8.88(s，1H)，7.90(d，J＝
7.2Hz,1H),7.74(s,1H),7.51(t,J＝8.0Hz,1H),7.18(s,1H),7.13(d,J＝8.0Hz,1H),7.08(d,J＝6.4Hz,1H),6.69(d,J＝7.6Hz,1H),6.50(dd,J＝17.2Hz,J＝10.4Hz,1H),6.26(dd,J＝17.2Hz,J＝1.6Hz,1H),5.76(dd,J＝10.4Hz,J＝1.6Hz,1H),5.18-5.11(m,1H),3.12(t,J＝4.0Hz,4H),2.92(t,J＝4.0Hz,4H),2.70(s,3H),1.97(s,3H),1.44(d,J＝7.2Hz,6H).HRMS(ESI)(m/z):(M+H)+calcd forC30H35N8O3555.2832,found,555.2831.
N- (3- (7- ((4- (4- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -3-isopropyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO. 17)
Figure BDA0001273961530000522
1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.45(s,1H),7.95(s,1H),7.83(s,1H),7.68(d,J＝8.0Hz,1H),7.46(t,J＝8.0Hz,1H),7.35(d,J＝8.8Hz,1H),7.04(d,J＝7.6Hz,1H),6.38(dd,J＝16.8Hz,J＝1.6Hz,1H),6.27-6.17(m,2H),5.83(dd,J＝9.6Hz,J＝1.6Hz,1H),5.69(d,J＝10.4Hz,1H),5.36-5.29(m,1H),3.81(s,3H),3.39(t,J＝7.6Hz,2H),2.88(s,3H),2.45(t,J＝7.6Hz,2H),2.32(s,6H),1.55(d,J＝6.8Hz,6H).HRMS(ESI)(m/z):(M+H)+calcd forC30H37N8O4573.2938,found,573.2932.
N- (3- (7- ((4- (2- (dimethylamino) ethoxy) -2-methoxyphenyl) amino) -3-isopropyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 18)
Figure BDA0001273961530000523
H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.84(s,1H),8.64(s,1H),7.80(d,J＝7.2Hz,1H),7.71(s,1H),7.48(t,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),7.10(d,J＝6.0Hz,1H),6.52-6.42(m,2H),6.29(dd,J＝17.2Hz,J＝10.4Hz,1H),5.99-5.78(m,1H),5.75(dd,J＝10.4Hz,J＝1.6Hz,1H),5.15-5.11(m,1H),3.95(t,J＝4.0Hz,4H),3.75(s,3H),2.61(t,J＝4.0Hz,4H),2.22(s,6H),1.44(d,J＝6.8Hz,6H).HRMS(ESI)(m/z):(M+H)+calcd forC29H34N7O5560.2621,found,560.2627.
N- (3- (3-isopropyl-7- ((2-methylamino-4- (4- (4-methylpiperazin-1 yl) piperidin-1-yl) phenyl) amino) -2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 19)
Figure BDA0001273961530000531
1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.82(s,1H),8.57(s,1H),7.91(s,1H),7.70(s,1H),7.47(t,J＝8.0Hz,1H),7.18(d,J＝6.8Hz,1H),7.09(d,J＝7.6Hz,1H),6.56-6.49(m,2H),6.27(dd,J＝16.8Hz,J＝1.6Hz,1H),5.99-5.97(m,1H),5.77(dd,J＝10.0Hz,J＝1.6Hz,1H),5.17-5.10(m,1H),3.76(s,3H),3.64-3.61(m,2H),2.96-2.75(m,6H),2.60-2.56(m,6H),1.87-1.85(m,1H),1.54-1.50(m,2H),1.44(d,J＝6.8Hz,6H).HRMS(ESI)(m/z):(M+H)+calcd forC35H44N9O4654.3516,found,654.3519.
N- (3- (7- ((4- (4-acetylpiperazinyl) -2-methoxyphenyl) amino) -3-ethyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 20)
Figure BDA0001273961530000532
1H NMR(400MHz，DMSO-d6) δ 1038(s, 1H), 885(s, 1H), 864(s, 1H), 788(d, J ═ 40Hz,1H),7.69(s,1H),7.49(t, J ═ 8.0Hz,1H),7.18(d, J ═ 8.4Hz,1H),7.12(d, J ═ 7.6Hz,1H),6.55(s,1H),6.46(dd, J ═ 17.2Hz, J ═ 10.0Hz,1H),6.27(dd, J ═ 16.8Hz, J ═ 1.6Hz,1H),6.00-5.97(m,1H),5.78(dd, J ═ 10.0Hz, J ═ 2.0Hz,1H),3.94(q, J ═ 4, 3.7 (m, 3H), 3.7 (m,1H),3.7 (H, 3.06H), 3.7 (H, 3.7H), 3.06) (hrd, 3.7H, 3.06, 3.7H), 3.7 (H), 3.06, 3.7 (H), 3.7 (H, 3.7 (H), 3.7, 18H), 3, 18H), 3.7 (H), 3, 18H), 3.7, 18, 3, 18, 3,4, 3,4, 3,4, 3,4, 3,4, 3,4, 18, 4, 3,4, 18, 4, 18, 4, 1H), and the calculated values of (H), and the like30H33N8O5[M+H]+585.2574, Experimental value 585.2572.
N- (3- (7- ((4- (4-acetylpiperazinyl) -2-methoxyphenyl) amino) -3-isopropyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H)) phenyl) acrylamide (SEQ ID NO: 21)
Figure BDA0001273961530000541
H NMR(400MHz,DMSO-d6) δ 10.37(s,1H),8.83(s,1H),8.61(s,1H),7.86(d, J ═ 8.0Hz,1H),7.67(s,1H),7.48(t, J ═ 8.0Hz,1H),7.17(d, J ═ 7.6Hz,1H),7.10(d, J ═ 7.6Hz,1H),6.55(s,1H),6.45(dd, J ═ 16.8Hz, J ═ 10.0Hz,1H),6.27(dd, J ═ 16.8Hz, J ═ 1.6Hz,1H),6.00-5.97(m,1H),5.78(dd, J ═ 10.0Hz, J ═ 2.0, 1H, 5.11.5 (s, 3.7H), 3.7 (H), 4.7 (H), 3.7 (H), 4(d, 4 (H), 3.6H), 4.6H), 4(d, 4 (H), 3H), 4(d, 4 (H), 4 (H), 4 (H) and so as calculated values of d, 1H), 4 (H) are included in (H), 1H) and so as well as to 7(d, 1H) as shown in (1H) as well as shown in (1H) and the formula (1H) as shown in (1H) are included in each of which are included in each of the formula (1H) and the formula (1H) as shown in (1H) and the formula (1 31H35N8O5[M+H]+599.2730, Experimental value 599.2731.
N- (3- (7- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -3-benzyl-2, 4-dioxo-3, 4-dihydropyrimido [4,5-d ] pyrimidin-1 (2H) -yl) phenyl) acrylamide (No. 22)
Figure BDA0001273961530000542
1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.87(s,1H),8.69(s,1H),7.87(d,J＝5.6Hz,1H),7.68(s,1H) 7.48(t, J ═ 8.0Hz,1H),7.38(d, J ═ 6.8Hz,2H),7.33(t, J ═ 7.2Hz,2H),7.26(t, J ═ 7.2Hz,1H),7.17(d, J ═ 8.0Hz,1H),7.12(d, J ═ 7.8Hz,1H),6.55(s,1H),6.44(dd, J ═ 16.8Hz, J ═ 10.0Hz,1H),6.26(dd, J ═ 17.2Hz, J ═ 2.0Hz,1H),5.98(s,1H),5.77(dd, J ═ 10.0, J ═ 1.6, 1H),5.09(s,2H),3.76(s, 3.05H), 3.05 (m-3H), 3.05-2H), 3.05 (m, 3H), 3.8H, 1H,3, 5.8, 3, 5, 3, 5, m, 5, 1, 5, m, 5, 1, 5, 1, 5, 1, m, and so as calculated values of (d) are included in, 1H) of (d) are calculated values of (d) of (m) are calculated values of (m) respectively35H35N8O5[M+H]+647.2730, experimental value 647.2735.
The specific synthesis method of compound 23 is as follows:
Figure BDA0001273961530000543
reagents and conditions: (a) - (e) as hereinbefore described; (f) n, N, N' -trimethylethylenediamine, K2CO3,DMSO；(n)Zn,NH4Cl,CH3OH; (o) acyl chloride, Et3N,CH2Cl20 ℃ to room temperature.
Synthesis of 7- ((4- ((2- (dimethylamino) ethyl) (methyl) amino-2-methoxy-5-nitrophenyl) amino) -3-methyl-1-phenylpyrimidino [4,5-d ] pyrimidine-2, 4(1H,3H) -dione
Figure BDA0001273961530000551
Weighing 7- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) -3-methyl-1-phenylpyrimidino [4, 5-d)]Pyrimidine-2, 4(1H,3H) -dione (438mg,1mmol), K2CO3(207mg,1.5mmol) and N, N, N' -trimethylethylenediamine (153mg,1.5mmol) in a 10mL single-neck flask were dissolved in 4mL of DMSO, warmed to 90 ℃ and stirred for 4 hours. TLC tracking until the raw material is converted, cooling to room temperature, adding ice water, extracting with ethyl acetate, collecting organic phase, spin-drying, and separating the crude product by silica gel column chromatography (DCM/CH) 3OH ═ 20:1, v/v), to give 7- ((4- ((2- (dimethylamino) ethyl) (methyl) amino-2-methoxy-5-nitrophenyl) amino) -3-methyl-1-phenylpyrimidino [4, 5-d)]358mg of pyrimidine-2, 4(1H,3H) -dione, yield 69%.1H NMR(400MHz,CDCl3)δ8.97(s,1H),7.88(s,1H),7.63(s,1H),7.46-7.43(m,3H),7.19-7.16(m,2H),6.52(s,1H),3.83(s,3H),3.39(s,3H),3.08(t,J＝6.4Hz,2H),2.71(s,3H),2.41(t,J＝6.8Hz,2H),2.17(s,6H).LC-MS:m/z:521.3(M+H)+.
Synthesis of 7- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -3-methyl-1-phenylpyrimidino [4,5-d ] pyrimidine-2, 4(1H,3H) -dione
Figure BDA0001273961530000552
Weighing 7- ((4- ((2- (dimethylamino) ethyl) (methyl) amino-2-methoxy-5-nitrophenyl) amino) -3-methyl-1-phenylpyrimidino [4, 5-d)]Pyrimidine-2, 4(1H,3H) -dione (312mg,0.6mmol) was dissolved in a 50mL single-neck flask by adding 8mL of methanol, 1mL of a saturated ammonium chloride solution was added dropwise, and zinc powder (390mg,6mmol) was added thereto and stirred at room temperature overnight. TLC tracking to raw material conversion, filtering to remove zinc powder, spin-drying the filtrate, and separating the crude product by silica gel column chromatography (DCM/CH)3OH 15:1, v/v) to give 7- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -3-methyl-1-phenylpyrimidino [4,5-d]Pyrimidine-2, 4(1H,3H) -dione 180mg, yield 61%.
1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.11(s,1H),7.60(t,J＝7.6Hz,2H),7.52(t,J＝7.2Hz,1H),7.33(d,J＝7.6Hz,2H),6.89(s,1H),6.51(s,1H),3.70(s,3H),3.40(s,3H),2.81(t,J＝6.4Hz,2H),2.52(s,3H),2.29(t,J＝6.8Hz,2H),2.19(s,6H).LC-MS:m/z:491.3(M+H)+.
Synthesis of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6-methyl-5, 7-dioxo-8-phenyl-5, 6,7, 8-tetrahydropyrimido [4,5-d ] pyrimidin-2-yl) amino) phenyl) acrylamide (SEQ ID NO. 23)
Figure BDA0001273961530000561
Weighing 7- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -3-methyl-1-phenylpyrimidino[4,5-d]Pyrimidine-2, 4(1H,3H) -dione (147mg,0.3mmol) and DIPEA (77mg,0.6mmol) were dissolved in a 25mL flask by adding 3mL of dichloromethane, and stirred for 15 minutes in ice bath. Further, acryloyl chloride (33mg,0.36mmol) was dissolved in 1mL of methylene chloride, and the resulting solution was added dropwise thereto, followed by stirring at room temperature overnight. TLC tracking the conversion of the starting material, spin-drying, and separating the crude product by silica gel column chromatography (DCM/CH)3OH 15:1, v/v) to yield N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((6-methyl-5, 7-dioxo-8-phenyl-5, 6,7, 8-tetrahydropyrimidino [4, 5-d)]Pyrimidin-2-yl) amino) phenyl) acrylamide 80mg, 49% yield.
1H NMR(400MHz,CDCl3) δ 9.36(s,1H),9.08(s,1H),7.88(s,1H),7.50-7.46(m,5H),6.58(dd, J ═ 17.2Hz, J ═ 10.0Hz,1H),6.48(dd, J ═ 17.2Hz, J ═ 1.6Hz,1H),5.83(dd, J ═ 10.0Hz, J ═ 2.0Hz,1H),3.83(s,3H),3.48(s,3H),3.23(t, J ═ 6.0Hz,2H),3.06(t, J ═ 6.4Hz,2H),2.77(s,6H),2.68(s,3H), hrms (esi), calculated value C28H33N8O4(M+H)+545.2625, experimental value 545.2630.
The synthesis of the 5, 8-dihydropteridine-6, 7-diketone compound of the invention is as follows:
Figure BDA0001273961530000562
reagents and conditions: (a) (Boc) 2O,Et3N,CH3OH, room temperature, 24 h; (b)2, 4-dichloro-5-nitropyrimidine, Na2CO3DMF, 70 ℃ below zero, 1 h; (c) arylamine, DIPEA, THF, room temperature, overnight; (d) h2Pd/C, MeOH, room temperature, 10 h; (e) refluxing diethyl oxalate, triethylamine and EtOH for 30 h; (f) alkyl halides, Cs2CO3DMF, room temperature, overnight; (g) trifluoroacetic acid, CH2Cl2Room temperature, 5 h; (h) acryloyl chloride, Et3N,CH2Cl2From 0 ℃ to room temperature overnight.
Example 2
Synthesis of tert-butyl (3-aminophenyl) carbamate
Figure BDA0001273961530000571
1, 3-phenylenediamine (10.800g,100mmol) and triethylamine (10.100g,100mmol) were weighed into a 250mL single-neck flask, dissolved in 100mL of methanol, and stirred for 15 minutes under ice bath conditions. Another Boc-anhydride (21.800g,100mmol) was dissolved in 40mL of methanol, and the solution was added dropwise to the reaction solution, followed by stirring at room temperature for 24 hours. TLC followed the conversion of starting material, removed solvent by rotary evaporation and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate 4:1, v/v) to give (3-aminophenyl) carbamic acid tert-butyl ester as a white solid 13.312g with 64% yield.1H NMR(400MHz,CDCl3)δ7.03(t,J＝8.0Hz,1H),6.96(s,1H),6.55(dd,J＝8.0Hz,J＝1.2Hz,1H),6.43(s,1H),6.36(dd,J＝8.0Hz,J＝1.6Hz,1H),3.54(s,2H),1.51(s,9H).LC-MS:m/z:209.1(M+H)+.
Synthesis of tert-butyl (3- (2-chloro-5-nitropyrimidin-4-amino) phenyl) carbamate
Figure BDA0001273961530000572
2, 4-dichloro-5-nitropyrimidine (1.940g, 10mmol) and N, N-diisopropylethylamine (2.580g, 20mmol) were weighed into a 100mL round-bottomed flask, dissolved in 30mL DMF, and stirred for 10 minutes under ice-bath conditions. Tert-butyl (3-aminophenyl) carbamate (2.080g, 10.0mmol) was dissolved in 20mL of DMF, and was slowly added dropwise to the reaction mixture, followed by stirring at room temperature for 2 hours. TLC tracks the complete conversion of the raw material, ice water is added into the reaction solution, solid is separated out, and the solution is filtered, washed and dried. Crude product is CH 2Cl2Recrystallization gave (3- (2-chloro-5-nitropyrimidine-4-amino) phenyl) carbamic acid tert-butyl ester as an orange solid, 2.950g, 81% yield.
1H NMR(400MHz,CDCl3)δ10.19(s,1H),9.20(s,1H),7.84(s,1H),7.36(d,J＝5.2Hz,2H),7.21-7.18(m,1H),6.63(s,1H),1.56(s,9H).LC-MS:m/z:366.1(M+H)+.
Synthesis of tert-butyl (3- ((2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -5-nitropyrimidin-4-yl) amino) phenyl) carbamate
Figure BDA0001273961530000581
Tert-butyl (3- (2-chloro-5-nitropyrimidin-4-amino) phenyl) carbamate (2.920g, 8mmol) and N, N-diisopropylethylamine (2.064g, 16mmol) were weighed into a 100mL three-necked flask, and dissolved in 30mL of tetrahydrofuran. Dissolving 2-methoxy-4- (4-methylpiperazino) aniline (1.768g, 8mmol) in 15mL tetrahydrofuran, slowly dripping into the reaction solution under the protection of argon, and heating and refluxing overnight after dripping. TLC tracks the conversion of raw materials, rotary evaporation removes part of solvent, solid is separated out, suction filtration, tetrahydrofuran washing and drying. Crude product is CH2Cl2Recrystallization gave 3.340g of tert-butyl (3- ((2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -5-nitropyrimidin-4-yl) amino) phenyl) carbamate as a reddish brown solid in 76% yield.
1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.42(s,1H),9.19(s,1H),9.03(s,1H),7.54(s,1H),7.39(d,J＝8.4Hz,1H),7.22(t,J＝8.8Hz,2H),7.09(t,J＝8.0Hz,1H),6.61(d,J＝1.6Hz,1H),6.34(d,J＝8.8Hz,1H),3.76(s,3H),3.15(t,J＝4.4Hz,4H),2.47(t,J＝4.4Hz,4H),2.24(s,3H),1.47(s,9H).LC-MS:m/z:551.4(M+H)+.
Synthesis of tert-butyl (3- ((5-amino-2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) pyrimidin-4-yl) amino) phenyl) carbamate
Figure BDA0001273961530000582
Tert-butyl (3- ((2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -5-nitropyrimidin-4-yl) amino) phenyl) carbamate (3.300g, 6mmol) and palladium-carbon catalyst (0.318g, 0.3mmol, 10% Pd) are weighed and dissolved in a 250mL thick-walled pressure-resistant bottle, 80mL of methanol is added, hydrogen is introduced, and the reaction is carried out at room temperature for 6 hours. TLC tracks the conversion of raw materials, suction filtration is carried out, filtrate is dried in a rotating mode, and the crude product is recrystallized by ethanol to obtain 2.775g of (3- ((5-amino-2- ((2-methoxy-4- (4-methylpiperazinyl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) carbamic acid tert-butyl ester white solid with the yield of 89%.
1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.17(s,1H),7.99(d,J＝8.8Hz,1H),7.96(s,1H),7.59(s,1H),7.32(d,J＝8.0Hz,1H),7.16(t,J＝8.0Hz,1H),7.06(d,J＝8.0Hz,1H),6.98(s,1H),6.60(d,J＝2.4Hz,1H),6.38(dd,J＝8.8Hz,J＝2.4Hz,1H),4.39(s,2H),3.82(s,3H),3.07(t,J＝4.4Hz,4H),2.48(t,J＝4.4Hz,4H),2.25(s,3H),1.48(s,9H).LC-MS:m/z:521.3(M+H)+.
Synthesis of tert-butyl (3- (2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8 (5H)) phenyl) carbamate
Figure BDA0001273961530000591
Tert-butyl (3- ((5-amino-2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) pyrimidin-4-yl) amino) phenyl) carbamate (2.600g, 5mmol) and triethylamine (1.010g, 10mmol) were weighed into a 100mL flask and dissolved in 40mL of ethanol. Diethyl oxalate (2.190g, 15mmol) was added to the reaction mixture, and the mixture was refluxed at elevated temperature for 48 hours. TLC tracks the conversion of the raw material, and then the raw material is filtered, and the filter cake is washed by ethanol and dried. To obtain 2.155g of tert-butyl (3- (2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8 (5H)) phenyl) carbamate as a yellow solid with a yield of 75%.
1H NMR(400MHz,DMSO-d6) δ 9.64(s,1H),8.14(s,1H),7.59(s,1H),7.57(s,1H),7.55(d, J ═ 8.0Hz,1H),7.43(t, J ═ 8.0Hz,1H),7.26(d, J ═ 8.8Hz,1H),6.95(d, J ═ 7.6Hz,1H),6.53(d, J ═ 2.4Hz,1H),6.06(d, J ═ 8.0Hz,1H),3.77(s,3H),3.03(t, J ═ 4.4Hz,4H),2.44(t, J ═ 4.4Hz,4H),2.22(s,3H),1.45(s, 9H): C)29H35N8O5(M+H)+575.2730, experimental value 575.2725.
Synthesis of N- (3- (2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8- (5H)) phenyl) acrylamide (SEQ ID NO. 24)
Figure BDA0001273961530000592
Tert-butyl (3- (2- ((2-methoxy-4- (4-methylpiperazinyl) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8 (5H)) phenyl) carbamate (0.861g, 1.5mmol) was weighed into a 50mL round-bottomed flask, dissolved by adding 10mL dichloromethane, and slowly added dropwise to 2mL trifluoroacetic acid and stirred at room temperature overnight. TLC to follow the conversion of the starting material, saturated NaHCO was added3The solution was neutralized to alkalinity, extracted with dichloromethane, the organic layer was collected and the solvent was removed by rotary evaporation to yield 491mg of 8- (3-aminophenyl) -2- ((2-methoxy-4- (4-methylpiperazinyl) phenyl) amino) -5, 8-dihydropteridine-6, 7-dione, in 69% yield and the product was used in the next step without purification.
Weighing 8- (3-aminophenyl) -2- ((2-methoxy-4- (4-methylpiperazinyl) phenyl) amino) -5, 8-dihydropteridine-6, 7-dione (0.474g, 1mmol), Et3N (0.152g, 1.5mmol) was dissolved in a 25mL flask by adding 10mL of dichloromethane, and stirred for 10 minutes under ice bath conditions. Another acryloyl chloride (105. mu.L, 1.3mmol) was dissolved in 2mL of dichloromethane, slowly added to the above reaction solution, and stirred overnight at room temperature after dropwise addition. TLC tracing conversion of raw material, adding ice water, extracting with dichloromethane, collecting organic layer, rotary evaporating to remove solvent, and separating and purifying crude product by silica gel column chromatography (DCM/CH) 3OH 15:1, v/v). 124mg of N- (3- (2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8- (5H)) phenyl) acrylamide is obtained with a yield of 23%.
1H NMR(400MHz,DMSO-d6) δ 10.69(s,1H),8.22(s,1H),7.51(d, J ═ 8.0Hz,1H),7.76(s,1H),7.64(s,1H),7.52(t, J ═ 8.0Hz,1H),7.28(d, J ═ 8.8Hz,1H),7.08(d, J ═ 8.0Hz,1H),6.59-6.52(m,2H),6.26(dd, J ═ 16.8Hz, J ═ 1.2Hz,1H),6.07(d, J ═ 8.4Hz,1 ddh), 5.77(d, J ═ 10.0Hz, J ═ 1.2Hz,1H),3.78(s,3H),3.31(t, J ═ 4.4H), 3.4 (t, 4H), 3.74 (s, 4H), 3.4H, 4 (m, 4H), calculated values (hrc, 3.74, 3.8 Hz,1H), 3.8H, 3.4H, m, 3.74, C, 1H, and d, d31H39N8O5(M+H)+529.2312, Experimental value 529.2312.
Synthesis of tert-butyl (3- (5-ethyl-2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8 (5H)) phenyl) carbamate
Figure BDA0001273961530000601
Tert-butyl (3- (2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8 (5H)) phenyl) carbamate (0.861g, 1.5mmol), Cs were weighed2CO3(0.587g, 1.8mmol) was dissolved in 25mL flask by the addition of 10mL of DMF, iodoethane (180. mu.L, 2.25mmol) was added dropwise, and the mixture was stirred overnight at room temperature after dropwise addition. TLC tracing conversion of the starting material, adding water, extracting with dichloromethane, collecting the organic layer, rotary evaporating to remove the solvent, and separating and purifying the crude product by silica gel column chromatography (DCM/CH) 3OH ═ 20:1, v/v). To obtain 414mg of tert-butyl (3- (5-ethyl-2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8 (5H)) phenyl) carbamate with the yield of 46%.
1H NMR(400MHz,CDCl3) δ 8.59(s,1H),7.69(s,1H),7.58(s,1H),7.54(d, J ═ 8.0Hz,1H),7.50(t, J ═ 8.0Hz,1H),7.44(s,1H),6.99(d, J ═ 7.2Hz,1H),6.72(s,1H),6.45(d, J ═ 2.4Hz,1H),6.17(d, J ═ 6.8Hz,1H),4.55(q, J ═ 7.2Hz,2H),3.83(s,3H),3.14(t, J ═ 4.4Hz,4H),2.62(t, J ═ 4.4Hz,4H),2.38(s,3H),1.51(t, J ═ 6.8, 3H), ms (s,1H), 9.48H), calculated values (hrc: (C), (H), (esi, 1H), (s,1H), and (s,3H), and (esi) of these values31H39N8O5(M+H)+603.3043, experimental value 603.3043.
Synthesis of N- (3- (5-ethyl-2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8- (5H)) phenyl) acrylamide (sequence number 26)
Figure BDA0001273961530000602
Tert-butyl (3- (5-ethyl-2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8 (5H)) phenyl) carbamate (0.400g, 0.66mmol) was weighed into a 50mL round-bottomed flask, 10mL dichloromethane was addedThe alkane was dissolved, and 2mL of trifluoroacetic acid was added dropwise slowly and stirred at room temperature overnight. TLC followed conversion of starting material and saturated NaHCO was added3Neutralizing the solution to be alkaline, extracting by dichloromethane, collecting an organic layer, removing the solvent by rotary evaporation, recrystallizing the crude product by dichloromethane to obtain 185mg of 8- (3-aminophenyl) -5-ethyl-2- ((2-methoxy-4- (4-methylpiperazinyl) phenyl) amino) -5, 8-dihydropteridine-6, 7-diketone, wherein the yield is 55 percent, and the product is directly used for the next reaction.
Weighing 8- (3-aminophenyl) -5-ethyl-2- ((2-methoxy-4- (4-methylpiperazinyl) phenyl) amino) -5, 8-dihydropteridine-6, 7-dione (0.180g, 0.36mmol), Et3N (0.055g, 0.54mmol) was dissolved in 10mL of dichloromethane in a 25mL flask and stirred for 10 minutes in ice bath. Further, acryloyl chloride (38. mu.L, 0.47mmol) was dissolved in 1mL of methylene chloride, and the resulting solution was slowly added thereto, followed by dropwise addition at room temperature and stirring overnight. TLC tracing conversion of raw material, adding ice water, extracting with dichloromethane, collecting organic layer, rotary evaporating to remove solvent, and separating and purifying crude product by silica gel column chromatography (DCM/CH)3OH 15:1, v/v). 98mg of N- (3- (5-ethyl-2- ((2-methoxy-4- (4-methylpiperazino) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridine-8- (5H)) phenyl) acrylamide is obtained with a yield of 49%.
1H NMR(400MHz,DMSO-d6) δ 10.42(s,1H),8.57(s,1H),7.92(s,1H),7.89(s,1H),7.70(s,1H),7.53(t, J ═ 8.0Hz,1H),7.32(d, J ═ 8.8Hz,1H),7.10(d, J ═ 7.6Hz,1H),6.53(d, J ═ 2.4Hz,1H),6.45(dd, J ═ 17.2Hz, J ═ 10.4Hz,1H),6.26(dd, J ═ 16.8Hz, J ═ 1.6Hz,1H),6.06-6.04(m,1H),5.77(dd, J ═ 10.0Hz, J ═ 1.6, 1H, 4.42(q, 3.3.3H), 3.7.7H, 3.7 (t, 3.3H), 3.7.3H, 3H, 3.7H, 3H, 3, 3.7H, 3H, 4H, 3H, 4H, 3H, 4H, 1H, 4H, 3H, 4H, 1H, 4H, 1H, and calculated values of (dd, 4H, 1H, 4H, 1H, 4H, 1H, 4H, 1H 29H33N8O4(M+H)+557.2625, Experimental value 557.2615.
The following compounds are synthesized according to the method of the steps:
n- (3- (2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-methyl-6, 7-dioxo-6, 7-dihydropteridin-8- (5H) -yl) phenyl) acrylamide (SEQ ID NO. 25)
Figure BDA0001273961530000611
1H NMR(400MHz,DMSO-d6) δ 10.46(s,1H),8.48(s,1H),7.92(d, J ═ 8.0Hz,1H),7.69(s,1H),7.66(s,1H),7.53(t, J ═ 8.0Hz,1H),7.22(d, J ═ 8.8Hz,1H),7.07(d, J ═ 8.0Hz,1H),6.53(d, J ═ 1.6Hz,1H),6.46(dd, J ═ 16.8Hz, J ═ 10.0Hz,1H),6.26(dd, J ═ 17.2Hz, J ═ 1.6Hz,1H),6.02(d, J ═ 8.4Hz,1H),5.77 (esi, J ═ 10.0, J ═ 1.2Hz, 1.6Hz, 3.53H), 3.3.3.3H, 3.3.3H, 3.3H), 3.3.3.3H, 3.7 (H), 3.7 (m ═ 3.7H), 3.7 (m ═ 3.7 (H), 3.7 (m) and 3.7 (m) are calculated values28H31N8O4(M+H)+543.2468, Experimental value 543.2470.
N- (3- (2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6, 7-dioxo-5-propyl-6, 7-dihydropteridin-8- (5H) -yl) phenyl) acrylamide (SEQ ID NO. 27)
Figure BDA0001273961530000621
1H NMR(400MHz,DMSO-d6) δ 10.70(s,1H),8.58(s,1H),7.97(s,1H),7.91(d, J ═ 8.0Hz,1H),7.77(s,1H),7.53(t, J ═ 8.0Hz,1H),7.35(d, J ═ 8.8Hz,1H),7.11(d, J ═ 8.0Hz,1H),6.59-6.52(m,2H),6.26(dd, J ═ 16.8Hz, J ═ 1.2Hz,1H),6.11-6.09(m,1H),5.77(dd, J ═ 10.0Hz, J ═ 1.6Hz,1H),4.32(t, J ═ 6.8, 2H),3.78(s,3H), 3.29 (s, 3.31H), 3.7 (t, 3.85H), 3.7.7 (m ═ 3, 3.7, 3H), 3.7 (m ═ 3.7, 3H), 3.7 (m ═ 3, 3.8H), 3.7, 3, 7, 3, 7, 3, 7, 3, 7, 3, 1, 3, 7, 1H),3, 7, 1H, 1, 7, 1, 7, 8, 1H, 1, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H 30H35N8O4(M+H)+571.2781, Experimental value 571.2780.
N- (3- (5-isopropyl-2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridin-8- (5H) -yl) phenyl) acrylamide (SEQ ID NO: 28)
Figure BDA0001273961530000622
1H NMR(400MHz,DMSO-d6)δ10.63(s,1H) 8.57(s,1H),7.96(s,1H),7.90(d, J ═ 8.4Hz,1H),7.75(s,1H),7.53(t, J ═ 8.0Hz,1H),7.36(d, J ═ 8.8Hz,1H),7.11(d, J ═ 7.6Hz,1H),6.60(d, J ═ 2.0Hz,1H),6.54(dd, J ═ 16.8Hz, J ═ 10.0Hz,1H),6.27(dd, J ═ 16.8Hz, J ═ 1.6Hz,1H),6.12-6.10(m,1H),5.77(dd, J ═ 10.0Hz, J ═ 1.6, 1H),5.38 (s, 3.3H), 3.79 (m, 3.79 (H), 3.3.3H, 3H), 3.79 (d, 3.3H), 3.3H, 3H, 3.79 (H), 3.3.3H), 3.79 (d, 3H), 3.3H, 3H, 79, 3H, 330H35N8O4(M+H)+571.2781, experimental value 571.2780.
N- (3- (2- ((3-methyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-isopropyl-6, 7-dioxo-6, 7-dihydropteridin-8- (5H) -yl) phenyl) acrylamide (SEQ ID NO: 29)
Figure BDA0001273961530000623
1H NMR(400MHz,DMSO-d6) δ 10.54(s,1H),9.61(s,1H),8.61(s,1H),7.91(d, J ═ 8.0Hz,1H),7.76(s,1H),7.55(t, J ═ 8.0Hz,1H),7.20(s,1H),7.13(d, J ═ 8.0Hz,1H),6.69(d, J ═ 8Hz,1H),6.50(dd, J ═ 17.2Hz, J ═ 10.4Hz,1H),6.26(dd, J ═ 17.2Hz, J ═ 2.0Hz,1H),5.76 (esi, J ═ 10.0Hz, J ═ 1.6Hz,1H),5.37-5.31(m,1H),2.94-2.91 (s, 2H), 2.82 (s, 2H), 5.85 (m, 3.85H), 5.6H, 3H, 18H, m: (s, 3.85H), m: (s, 3.6H), 3.6H, 1H, 15H, 1H, 15H, 1H, 15H, 1H, 15H, 1 30H35N8O3(M+H)+555.2832, Experimental value 555.2833.
N- (3- (2- ((3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5-isopropyl-6, 7-dioxo-6, 7-dihydropteridin-8- (5H) -yl) phenyl) acrylamide (SEQ ID NO: 30)
Figure BDA0001273961530000631
1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),9.57(s,1H),8.62(s,1H),7.90(d,J＝8.4Hz,1H),7.75(s,1H),7.54(t,J＝8.0Hz,1H),7.12(d,J＝7.6Hz,1H),7.04-6.99(m,2H),6.55-6.49(m,2H),6.27(dd,J＝17.2Hz,J＝2.0Hz,1H),5.77(dd,J＝10.0Hz,J＝1.6Hz,1H),5.37-5.31(m,1H),3.57(s,3H),3.19-3.07(m,8H),2.74(s,3H),1.40(d, J ═ 6.0Hz,6H), hrms (esi): calculated value C30H35N8O4(M+H)+571.2781, Experimental value 571.2782.
N- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -5-isopropyl-6, 7-dioxo-6, 7-dihydropteridin-8- (5H) -yl) phenyl) acrylamide (SEQ ID NO: 31)
Figure BDA0001273961530000632
1H NMR(400MHz,CDCl3) δ 8.69(s,1H),8.57(s,1H),7.75(s,1H),7.71(d, J ═ 8.0Hz,1H),7.61(s,1H),7.44(t, J ═ 8.0Hz,1H),6.98(d, J ═ 8.0Hz,1H),6.35(dd, J ═ 16.4Hz, J ═ 0.8Hz,1H),6.26-6.19(m,2H),5.92-5.90(m,1H),5.64(dd, J ═ 10.0Hz, J ═ 1.2Hz,1H),5.49-5.43(m,1H),3.80(s,3H),3.40(t, J ═ 7.6Hz,2H),2.87(s,3H),2.50(t, 6H), 6.6 (s,6H), 6H (s,6H), 6H), hrc: (C, 48H), 6.6H, 6H, and hrc (d, 6H), and 5.6H) are calculated values (d, 6.6.6.6H), and C (d, 6.6H), and C30H37N8O4(M+H)+573.2938, Experimental value 573.2939.
N- (3- (2- ((4- (2- (dimethylamino) ethoxy) -2-methoxyphenyl) amino) -5-isopropyl-6, 7-dioxo-6, 7-dihydropteridin-8- (5H) -yl) phenyl) acrylamide (SEQ ID NO: 32)
Figure BDA0001273961530000633
1H NMR(400MHz,DMSO-d6) δ 10.64(s,1H),8.57(s,1H),8.01(s,1H),7.87(d, J ═ 8.4Hz,1H),7.78(s,1H),7.53(t, J ═ 8.0Hz,1H),7.39(d, J ═ 7.2Hz,1H),7.11(d, J ═ 8.0Hz,1H),6.60(d, J ═ 2.4Hz,1H),6.54(dd, J ═ 17.2Hz, J ═ 10.4Hz,1H),6.26(dd, J ═ 17.2Hz, J ═ 2.0Hz,1H),6.16-6.14(m,1H),5.76 (esi, J ═ 10.0, J ═ 1H, 6.5, 5.5 (5, 5.5, 3, H) H, 3, and so on the like 29H34N7O5(M+H)+560.2621, Experimental value 560.2625.
N- (3- (5-isopropyl-2- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -6, 7-dioxo-6, 7-dihydropteridin-8 (5H) -yl) phenyl) acrylamide (sequence number 33)
Figure BDA0001273961530000641
1H NMR(400MHz,DMSO-d6) δ 10.58(s,1H),8.56(s,1H),7.94(d, J ═ 8.0Hz,1H),7.91(s,1H),7.72(s,1H),7.53(t, J ═ 8.0Hz,1H),7.32(d, J ═ 8.8Hz,1H),7.11(d, J ═ 8.4Hz,1H),6.55-6.48(m,2H),6.27(dd, J ═ 17.2Hz, J ═ 2.0Hz,1H),6.08-6.06(m,1H),5.78(dd, J ═ 10.0Hz, J ═ 1.6Hz,1H),5.36-5.30(m,1H),3.77(s,3H),3.62-3.60(m,2H), 3.81H), 6.81-6.81 (m,2H), 6H, 1.81(m, 1H), 6H, 1.7 (m,1H), 1.81-6H, 1.27 (m,2H),6.27 (m,1H), 6.7 (m,1H), 6.1H), 6H), 1H), 1.7 (m,1H), 1.6H), 6H) HRMS (ESI) calculated value C35H44N9O4(M+H)+654.3516, experimental value 654.3512.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (4)

1. Use of a compound of formula I or a salt thereof in the manufacture of a BTK inhibitor or of a medicament for the treatment or prevention of a BTK-mediated disease, which is a cancer or an autoimmune disease, wherein the cancer is acute lymphocytic leukemia, chronic myelogenous leukemia, mantle cell lymphoma or large bowel cancer, and the autoimmune disease is rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis or lupus erythematosus:
Figure FDA0003686463610000011
The compound of formula I is represented by the following formula III-1 or III-2:
Figure FDA0003686463610000012
in the formulae III-1 and III-2,
R2is that
Figure FDA0003686463610000013
R3Is selected from C1-C6An alkyl group;
R4selected from:
Figure FDA0003686463610000014
R5selected from:
Figure FDA0003686463610000015
R6selected from the group consisting of:
Figure FDA0003686463610000016
R7is that
Figure FDA0003686463610000017
R8Is that
Figure FDA0003686463610000018
2. The use according to claim 1, wherein, in the formula,
R6is H or
Figure FDA0003686463610000021
3. The use according to claim 2, wherein, in the formula,
R3selected from methyl or propyl or isopropyl;
R4is a methoxy group;
R5is methyl or methoxy.
4. Use of a compound selected from the group consisting of a BTK inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a BTK-mediated disease, which is a cancer or an autoimmune disease, wherein the cancer is acute lymphocytic leukemia, chronic myelogenous leukemia, mantle cell lymphoma or large intestine cancer, and the autoimmune disease is rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis or lupus erythematosus:
Figure FDA0003686463610000022
Figure FDA0003686463610000031
Figure FDA0003686463610000041
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CA3129665A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015006492A1 (en) * 2013-07-09 2015-01-15 Dana-Farber Cancer Institute, Inc. Kinase inhibitors for the treatment of disease
CN105061438A (en) * 2010-06-23 2015-11-18 韩美科学株式会社 Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity
CN105377835A (en) * 2013-07-11 2016-03-02 贝达药业股份有限公司 Protein tyrosine kinase modulators and methods of use
CN105732637A (en) * 2014-12-30 2016-07-06 广东东阳光药业有限公司 Hetero-aromatic compounds and applications thereof in pharmacy
WO2016124160A1 (en) * 2015-02-06 2016-08-11 华东理工大学 Pyrimidopyrimidinedione derivatives as egfr inhibitors and application thereof
CN106892922A (en) * 2015-12-18 2017-06-27 华东理工大学 As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105061438A (en) * 2010-06-23 2015-11-18 韩美科学株式会社 Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity
WO2015006492A1 (en) * 2013-07-09 2015-01-15 Dana-Farber Cancer Institute, Inc. Kinase inhibitors for the treatment of disease
CN105377835A (en) * 2013-07-11 2016-03-02 贝达药业股份有限公司 Protein tyrosine kinase modulators and methods of use
CN105732637A (en) * 2014-12-30 2016-07-06 广东东阳光药业有限公司 Hetero-aromatic compounds and applications thereof in pharmacy
WO2016124160A1 (en) * 2015-02-06 2016-08-11 华东理工大学 Pyrimidopyrimidinedione derivatives as egfr inhibitors and application thereof
CN106892922A (en) * 2015-12-18 2017-06-27 华东理工大学 As the 5,8- dihydropteridine -6,7- derovatives of EGFR inhibitor and its application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation;Yongjia Hao et al.;《J. Med. Chem. 》;20160711;摘要，第7115页 *
Yongjia Hao et al..Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation.《J. Med. Chem. 》.2016, *

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