CN106660993B - Kinase inhibitor - Google Patents

Kinase inhibitor Download PDF

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CN106660993B
CN106660993B CN201580031253.8A CN201580031253A CN106660993B CN 106660993 B CN106660993 B CN 106660993B CN 201580031253 A CN201580031253 A CN 201580031253A CN 106660993 B CN106660993 B CN 106660993B
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methyl
amino
ethyl
methoxy
pyrimidin
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CN106660993A (en
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李同双
赵兴东
田强
张卫鹏
刘洪彬
王宪龙
谭浩瀚
谭锐
刘启洪
姜立花
刘研新
令狐莉
林敏�
孙婧
王为波
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Shanghai Allist Medicine Polytron Technologies Inc
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Shanghai Fochon Pharmaceutical Co Ltd
Fochon Pharmaceuticals Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention relates to a class of mutated EGFR selective inhibitors, pharmaceutical compositions and methods of use.

Description

Kinase inhibitor
Technical Field
The present invention relates to a novel class of aminopyrimidine ring derivatives and pharmaceutically acceptable salts thereof which selectively inhibit the activity of mutant Epidermal Growth Factor (EGFR) kinase and are useful as medicaments for the treatment of proliferative diseases, such as cancer, in mammals, especially humans. The invention also relates to a use of said compounds in the treatment of cancer, and to pharmaceutical preparations containing said compounds.
Background
Protein tyrosine kinases catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue on a protein substrate. Protein tyrosine kinases can be classified as either receptor (e.g., EGFR, HER-2, VEGFR, FGFR) or non-receptor (e.g., Src, Jak, Abl). Receptor tyrosine kinases function to activate secondary signaling factors through phosphorylation, which leads signals from outside the cell to inside the cell. A variety of cellular processes are initiated by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival.
Inappropriate or uncontrolled activation of tyrosine kinase activity, such as overexpression or mutation of the kinase, has been shown to result in uncontrolled cell growth. There is a lot of evidence that EGFR is involved in the development of human tumors, more than 60% of all solid tumors expressing at least one EGFR or its ligand. Overexpression of EGFR is common in breast, lung, head and neck, and bladder cancers.
The first generation of reversible, ATP-competitive EGFR kinase inhibitors, such as gefitinib and erlotinib, are effective clinical treatments for non-small cell lung cancer carrying mutations in the EGFR kinase domain activity (Nature,2009,462, 1070-107). Although first generation EGFR inhibitors show encouraging clinical efficacy, over time almost all patients develop resistance to these inhibitors, e.g., the gatekeeper mutation T790M, with about half of the resistant mutations of gefitinib and erlotinib developing the T790M mutation. (proc.natl.acad.sci.u.s.a.2008,105,2070-2075) furthermore, the T790M mutation was also inherently present and the T790M mutation may have an independent oncogenic effect.
Currently developed drugs, including second generation covalent inhibitors such as afatinib, neratinib, canertinib, and dacatinib, are effective against T790M resistance mutations, but exhibit dose-dependent toxicity such as diarrhea and rash due to simultaneous inhibition of wild-type EGFR.
Thus, there remains a pressing need for selective inhibitors of mutant EGFR kinases. Although mutant EGFR selective inhibitors have been reported in the literature, e.g., WO 2013014448 and WO 2012061299, there is still a strong need for novel EGFR mutant selective inhibitors that have advantages in at least one of therapeutic efficacy, stability, selectivity, safety, pharmacodynamic and pharmacokinetic profile in the treatment of aberrantly proliferating diseases. The invention relates to a novel EGFR mutation selective inhibitor.
Disclosure of Invention
The invention relates to novel aminopyrimidine ring derivatives, pharmaceutical compositions thereof, and their use as medicaments.
In one aspect, the present invention provides at least one compound of formula (I):
Figure BDA0001177209820000021
and/or at least one pharmaceutically acceptable salt thereof,
wherein:
q is selected from aryl and heteroaryl;
x is selected from N and C;
y is selected from N and C;
R1selected from: hydrogen, C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl and heterocyclyl-C1-4Alkyl, wherein each alkyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6aSubstituted with the substituent(s);
R1’selected from hydrogen and halogen;
R2and R3Are respectively selected from: hydrogen, halogen, hydroxy, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6aWherein each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6bSubstituted with the substituent(s); or R2And R3Together with the carbon atom to which they are attached form a group containing0.1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be unsubstituted or substituted by 1 or 2 heteroatoms selected from R6aSubstituted with the substituent(s);
each R4Independently selected from: hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, -OR8、-NR7S(O)rR8、-NO2-halogen, -S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8and-CR7(N-OR8) (ii) a Wherein each C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl and C3-10Cycloalkyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R6aSubstituted with the substituent(s);
each R5Independently selected from: hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, -OR8、-NR7S(O)rR8、-NO2Halogen, -S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8and-CR7(N-OR8) Wherein each C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl and heterocyclyl are unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R6aSubstituted with the substituent(s); each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6bSubstituted with the substituent(s);
each R6aIndependently selected from: c1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, -OR8、-NR7S(O)rR8、-NO2Halogen, -S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8and-CR7(N-OR8)；
Each R6bIndependently selected from: r6aAryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4An alkyl group;
each R7And each R8Independently selected from: hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, cycloalkyl-C1-4Alkyl, heterocyclic radical C1-4Alkyl, aryl, heteroaryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4An alkyl group; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6aWherein each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6bSubstituted with the substituent(s); or R7And R8Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be unsubstituted or substituted with 1 or 2 heteroatoms selected from R6bSubstituted with the substituent(s);
each R9And each R10Independently selected from: hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, cycloalkyl-C1-4Alkyl, heterocyclic radicalHeterocyclic radical-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4An alkyl group; or R9And R10Together with the carbon atom or atoms to which they are attached form a 3-7 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be unsubstituted or substituted by 1 or 2 heteroatoms selected from R6aSubstituted with the substituent(s);
m is independently selected from 0, 1, 2and 3;
n is independently selected from 0, 1, 2and 3;
each r is independently selected from 1 and 2;
each t is independently selected from 1, 2and 3.
In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
In another aspect, the present invention provides a method for modulating mutant EGFR, the method comprising administering to a system or subject in need thereof a therapeutically effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt or pharmaceutical composition, thereby modulating mutant EGFR.
In another aspect, the invention also provides a method of treating, ameliorating or preventing a disorder responsive to inhibition of mutated EGFR comprising administering to a system or subject in need thereof an effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt or pharmaceutical composition, or in combination with another therapeutic agent, for treating the above disorder.
In another aspect, the invention provides the use of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt for the manufacture of a medicament for the treatment of a mutated EGFR-mediated disorder. The compounds can be used alone or in combination with another therapeutic agent to treat a mutant EGFR-mediated disorder, wherein the disorder is an autoimmune disease, a transplant disease, an infectious disease, or a cell proliferation disorder.
Furthermore, the present invention provides a method of treating a cell proliferative disorder, the method comprising administering to a system or subject in need thereof an effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt or pharmaceutical composition, or in combination with another therapeutic agent, to treat the above disorder.
Alternatively, the present invention provides the use of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt for the manufacture of a medicament for the treatment of a cell proliferative disorder. In particular embodiments, the compounds can be used alone or in combination with another therapeutic agent to treat a cell proliferative disorder, wherein the disorder includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of the breast, kidney, prostate, colorectal, thyroid, ovary, pancreas, neuron, lung, uterus, or gastrointestinal tract.
In the above methods of using the compounds of the present invention, at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt may be used in a system consisting of cells or tissues, or in a mammalian, such as human or animal, subject.
Detailed Description
The terms used herein are defined as follows:
"alkyl" refers to branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Unless otherwise indicated, "alkyl" means C1-C6An alkyl group. For example, "C1-C6C in alkyl1-C6"refers to a linear or branched arrangement of groups having 1,2,3,4, 5 or 6 carbon atoms. For example, "C1-C8Alkyl groups "include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.
"cycloalkyl" refers to a saturated aliphatic cyclic hydrocarbon group having a specified number of carbon atoms. "cycloalkyl" means C, unless otherwise indicated3-C10A cycloalkyl group. For example, "cycloalkyl" includes, but is not limited to, cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, and cyclohexyl.
"alkenyl" means a straight nonaromatic chain containing from 2 to 10 carbon atoms and at least one carbon-carbon double bondA chain, branched or cyclic hydrocarbon group. In some embodiments, 1 carbon-carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C2－6Alkenyl "means alkenyl containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain a double bond, and substituted alkenyl groups, if indicated, may be substituted.
"alkynyl" refers to a straight, branched or cyclic hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, there may be 3 carbon-carbon triple bonds. Thus, "C2-6Alkynyl "refers to alkynyl groups containing 2-6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight, branched or cyclic portion of the alkynyl group may contain a triple bond, and a substituted alkynyl group, if indicated, may be substituted.
"aryl" includes: 5-and 6-membered aromatic carbocyclic rings, such as phenyl; bicyclic rings having at least one aromatic carbon ring, such as naphthyl, indane and 1,2,3, 4-tetrahydroquinoline, and tricyclic rings having at least one aromatic carbon ring, such as fluorene. Aryl substituents are considered to be linked through an aromatic ring if they are bicyclic or tricyclic and at least one of the rings is non-aromatic.
For example, aryl includes 5-and 6-membered aromatic carbocyclic rings fused to a 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, provided that the site of attachment is an aromatic carbocyclic ring. Divalent radicals, which are formed from substituted benzene derivatives and have free valence electrons on the ring atoms, are named substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose name ends with "-yl", which are obtained by removing one more hydrogen atom from a carbon atom containing the valence electron of the radical, are named after the name of the monovalent radical plus "-idene", for example, naphthyl, which has two attachment sites, is called naphthylene. The definition of aryl, however, does not include, nor overlap with, heteroaryl, and is defined individually as follows. Thus, if one or more aromatic carbocyclic rings are fused to an aromatic ring of a heterocyclic ring, the ring system formed should be considered heteroaryl rather than aryl as defined herein.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"heteroaryl" means
A 5-to 8-membered aromatic monocyclic ring, which contains 1 to 4, and in certain embodiments 1 to 3, heteroatoms selected from N, O and S, the remainder being carbon atoms;
an 8-to 12-membered bicyclic ring containing 1 to 4, and in certain embodiments 1 to 3, heteroatoms selected from N, O and S, the remainder being carbon atoms, and wherein at least one heteroatom is present in the aromatic ring; and
11-to 14-membered tricyclic rings. The ring contains from 1 to 4, and in certain embodiments from 1 to 3, heteroatoms selected from N, O and S, the remainder being carbon atoms, and at least one of the heteroatoms is present in the aromatic ring.
When the total number of S and O in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O in the heteroaryl is no greater than 2. In some embodiments, the total number of S and O in the heteroaryl is no greater than 1.
Examples of heteroaryl groups include, but are not limited to (the numbering of the attachment site is preferred, as in position 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 1-pyrazolyl, 2, 3-pyrazolyl, 2, 4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazo, tetrazolyl, thienyl, benzothienyl, furyl, benzofuranyl, benzimidazolinyl, dihydroindolyl, pyrazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7, 8-tetrahydroisoquinolinyl.
Further, heteroaryl groups include, but are not limited to, pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinolyl, and isoquinolyl groups. As defined below for heterocyclic groups, "heteroaryl" includes N-oxide derivatives of nitrogen-containing heteroaryl groups.
The nomenclature of monovalent heteroaryl radicals ends with the "radical", which derives a divalent radical derived by removing a further hydrogen atom from the carbon atom containing the valence electron, by adding "idene" to the name of the monovalent radical, for example: the pyridyl group having two attachment sites is called a pyridylidene. The definition of heteroaryl does not include, nor overlap with, aryl as defined above.
If the heteroaryl substituent is a bicyclo or tricyclic ring, and at least one of the rings is non-aromatic or contains no heteroatoms, it is generally considered to be linked via an aromatic ring or a heteroatom-containing ring, respectively.
"heterocycle" (and derivatives thereof such as "heterocyclic" or "heterocyclyl") refers broadly to a single cyclic aliphatic hydrocarbon, typically having from 3 to 12 ring atoms, containing at least 2 carbon atoms, and further containing from 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and also to combinations comprising at least one of the foregoing heteroatoms. Alternatively, the heterocyclic ring as defined above may be a polycyclic ring system (e.g. bicyclic) wherein two or more rings are connected by fusion or bridging, wherein at least one ring contains one or more heteroatoms independently selected from oxygen, sulphur, nitrogen. "heterocycle" also refers to a 5-to 7-membered heterocyclic ring fused to 5-and 6-membered aromatic carbocyclic rings containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, provided that the site of attachment is on the heterocyclic ring. Heterocycles may be saturated or contain one to more double bonds (i.e., partially unsaturated). The heterocyclic ring may be substituted with oxo (oxo). Either the carbon atom or the heteroatom of the heterocycle may be the attachment site, provided that a stable structure is formed. When a substituent is present on the heterocycle, the substituent may be attached to any heteroatom or carbon atom on the heterocycle, provided that a stable chemical structure is formed. The heterocyclic and heteroaryl definitions described herein do not overlap.
Suitable heterocycles include, for example (attachment site is preferably 1) 1-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinonyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl and 2, 5-piperazinyl. Also included are 2-morpholino and 3-morpholino (oxygen atom position numbering is preferably 1). Substituted heterocycles also include ring systems substituted with one or more oxo groups, such as piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl. The bis-heterocyclic compounds include, for example:
Figure BDA0001177209820000071
Figure BDA0001177209820000081
as used herein, "aralkyl" refers to an aryl-substituted alkyl group. Exemplary aralkyl groups include benzyl, phenethyl, naphthylmethyl, and the like. In some embodiments, aralkyl groups contain 7 to 20 or 7 to 11 carbon atoms. When using "aryl radicals C1-4Alkyl "in which" C1-4"refers to the number of carbon atoms in the alkyl portion rather than the aryl portion. Likewise, when "aryl C" is used1-10Alkyl "in which" C1-10"refers to the number of carbon atoms in the alkyl portion rather than the aryl portion.
As used herein, "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group. When using "heterocyclyl C1-6Alkyl "in which" C1-6"refers to the number of carbon atoms in the alkyl moiety rather than in the heterocyclyl moiety.
As used herein, "cycloalkylalkyl" refers to cycloalkyl-substituted alkyl groups. When using "C3-10Cycloalkylalkyl "in which" C3-10"refers to the number of carbon atoms in the cycloalkyl moiety rather than the alkyl moiety. When using "C3-7Cycloalkylalkyl "in which" C3-7"refers to the number of carbon atoms in the cycloalkyl moiety rather than the alkyl moiety. When using "C3-8Cycloalkylalkyl "in which" C3-8"refers to the number of carbon atoms in the cycloalkyl moiety rather than the alkyl moiety. When using "cycloalkyl radicals C1-10Alkyl "in which" C1-10"refers to the number of carbon atoms in the alkyl moiety rather than the cycloalkyl moiety.
As used herein, "heteroarylalkyl" refers to a heteroaryl-substituted alkyl group. When using "heteroaryl C1-4Alkyl "in which" C1-4"refers to a cycloalkyl moiety rather than a heteroarylThe number of carbon atoms of the radical moiety. Likewise, when "heteroaryl C" is used1-10Alkyl "in which" C1-10"refers to the number of carbon atoms in the alkyl moiety rather than in the heteroaryl moiety.
To avoid ambiguity, for example: when alkyl, cycloalkyl, heterocyclylalkyl, aryl and/or heteroaryl substitutions are mentioned, it is meant that each of these groups is substituted individually or that these groups are mixed. That is: if R is1Is aralkyl, the aryl moiety may be unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R6bMay also be unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R6aA substituent of (1).
"pharmaceutically acceptable salt" refers to salts with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. The salt of an inorganic base may be selected, for example, from: aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, manganous, potassium, sodium and zinc salts. Further, the salt of a pharmaceutically acceptable inorganic base may be selected from ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may be present in the solid salt, as well as in the form of hydrates. The pharmaceutically acceptable salts of organic non-toxic bases may be selected, for example, from: primary, secondary and tertiary amine salts, the substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.
When the compound referred to in this patent is a base, it is necessary to prepare a salt thereof with at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids. For example, selected from the group consisting of acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In some embodiments, these acids may be selected, for example: citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids.
"protecting group" (Pg) refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. For example, "amino protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality on a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a class of hydroxy substituents that are effective in blocking or protecting the hydroxy function. Suitable protecting groups include, but are not limited to, acetyl and silyl groups. "carboxy protecting group" refers to a class of carboxy substituents that function effectively to block or protect a carboxy group. Common carboxyl protecting groups include, but are not limited to, -CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylthio) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description and instructions for the use of protecting Groups, see T.W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991。
By "administering" or "administration" of at least one compound and/or at least one pharmaceutically acceptable salt thereof is meant providing a compound of the invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.
An "effective amount" is an amount of a compound of interest, or a pharmaceutically acceptable salt thereof, that is capable of eliciting a biological or medical response in a tissue, system, animal or human that is observable by a researcher, veterinarian, clinician or other clinician.
The "composition" includes: the invention may take the form of a kit, article of manufacture, or any combination thereof. The pharmaceutical composition comprises: products comprising the active ingredient and an inert ingredient as a carrier, as well as products produced by any two or more of the ingredients, directly or indirectly, by combination, complexation or aggregation, or by dissociation of one or more of the ingredients, or by other types of reactions or interactions of one or more of the ingredients.
By "pharmaceutically acceptable" is meant compatible with the other ingredients of the formulation and not unacceptably toxic to the user.
1. The present invention provides at least one compound of formula (I):
Figure BDA0001177209820000101
and/or at least one pharmaceutically acceptable salt thereof,
wherein:
q is selected from aryl and heteroaryl;
x is selected from N and C;
y is selected from N and C;
R1selected from: hydrogen, C1-10Alkyl radical, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl and heterocyclyl-C1-4Alkyl, wherein each alkyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6aSubstituted with the substituent(s);
R1’selected from hydrogen and halogen;
R2and R3Are respectively selected from: hydrogen, halogen, hydroxy, CN, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected fromR6aWherein each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6bSubstituted with the substituent(s); or R2And R3Together with the carbon atom to which they are attached form a 5-6 membered ring containing 0, 1,2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be unsubstituted or substituted with 1 or 2 heteroatoms selected from R6aSubstituted with the substituent(s);
each R4Independently selected from: hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, -OR8、-NR7S(O)rR8、-NO2-halogen, -S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8and-CR7(N-OR8) (ii) a Wherein each C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl and C3-10Cycloalkyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R6aSubstituted with the substituent(s);
each R5Independently selected from: hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl radical, C3-10cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4Alkyl, -OR8、-NR7S(O)rR8、-NO2Halogen, -S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8and-CR7(N-OR8) Wherein each C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl and heterocyclyl are unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R6aSubstituted with the substituent(s); each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6bSubstituted with the substituent(s);
each R6aIndependently selected from: c1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-10Cycloalkyl, -OR8、-NR7S(O)rR8、-NO2Halogen, -S (O)rR7、-SR8、-S(O)2OR7、-OS(O)2R8、-S(O)rNR7R8、-NR7R8、-(CR9R10)tOR8、-(CR9R10)tNR7R8、-(CR9R10)tSR8、-(CR9R10)tS(O)rR8、-(CR9R10)tCO2R8、-(CR9R10)tCONR7R8、-(CR9R10)tNR7CO2R8、-(CR9R10)tOCONR7R8、-(CR9R10)tNR7CONR7R8、-(CR9R10)tNR7SO2NR7R8、-O(CR9R10)tNR7R8、-C(O)R7、-C(O)(CR9R10)tOR8、-C(O)(CR9R10)tNR7R8、-C(O)(CR9R10)tSR8、-C(O)(CR9R10)tS(O)rR8、-CO2R8、-CO2(CR9R10)tCONR7R8、-OC(O)R7、-CN、-C(O)NR7R8、-NR7C(O)R8、-OC(O)NR7R8、-NR7C(O)OR8、-NR7C(O)NR7R8and-CR7(N-OR8)；
Each R6bIndependently selected from: r6aAryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4An alkyl group;
each R7And each R8Independently selected from: hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, cycloalkyl-C1-4Alkyl, heterocyclic radical C1-4Alkyl, aryl, heteroaryl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4An alkyl group; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6aWherein each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from R6bSubstituted with the substituent(s); or R7And R8Together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and N, which ring may be unsubstituted or substituted with 1 or 2 heteroatoms selected from R6bSubstituted with the substituent(s);
each R9And each R10Independently selected from: hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, cycloalkyl-C1-4Alkyl, heterocyclyl-C1-4Alkyl, aryl-C1-4Alkyl, heteroaryl and heteroaryl-C1-4An alkyl group; or R9And R10Together with the carbon atom or atoms to which they are attached form a 3-7 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be substituted with 1-2 heteroatoms selected from R6aSubstituted with the substituent(s);
m is independently selected from 0, 1, 2and 3;
n is independently selected from 0, 1, 2and 3;
each r is independently selected from 1 and 2;
each t is independently selected from 1, 2and 3.
2.1, and/or at least one pharmaceutically acceptable salt thereof, wherein X is selected from N and C and Y is selected from C.
At least one compound of any one of claims 1-2, and/or at least one pharmaceutically acceptable salt thereof, wherein X is selected from N and Y is selected from C.
4.1-2, and/or at least one pharmaceutically acceptable salt thereof, wherein X and Y are both C, and,
n is 2and one R5Is (3R) -3- (dimethylamino) pyrrol-1-yl, (3S) -3- (dimethylamino) pyrrol-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl]- (methyl) amino, [2- (methylamino) ethyl](methyl) amino, 5-methyl-2, 5-diazaspiro [3.4 ]]Sunflower-2-yl, (3aR,6aR) -5-methylhexa-hydro-pyrrole [3,4-b]Pyrrol-1 (2H) -yl, 1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl, 4-methylpiperazin-1-yl, 4- [2- (dimethylamino) -2-oxyethyl]Piperazin-1-yl, methyl [2- (4-methylpiperazin-1-yl) ethyl]Amino, methyl [2- (morpholin-4-yl) ethyl]Amino, 1-amino-1, 2,3, 6-tetrahydropyridin-4-yl or 4- [ (2S) -2-aminopropionyl]Piperazin-1-yl, another R5Is a methoxy group or a methyl group,
R1、R1’and R2Is hydrogen, and R3When hydrogen, fluorine, chlorine, methyl or cyano,
q is not 4,5,6, 7-tetrahydropyrrolo [1,5-a ] pyridin-3-yl, pyrazolo [1,5-a ] pyridin-3-yl or 1H-indol-3-yl. .
At least one compound of any one of claims 1 to 4, and/or at least one pharmaceutically acceptable salt thereof, wherein the general formula is
Figure BDA0001177209820000131
6.1-5, and/or at least one pharmaceutically acceptable salt thereof, wherein R1’Selected from hydrogen.
7.1-5, and/or at least one pharmaceutically acceptable salt thereof, wherein R1’Selected from fluorine.
8.1-7, and/or at least one pharmaceutically acceptable salt thereof, wherein R1Selected from hydrogen.
9.1-8, and/or at least one pharmaceutically acceptable salt thereof, wherein R2Selected from hydrogen.
10.1-9, and/or at least one pharmaceutically acceptable salt thereof, wherein R3Selected from hydrogen, halogen and C1-10An alkyl group.
11.10, and/or at least one pharmaceutically acceptable salt thereof, wherein R3Selected from hydrogen.
At least one compound of any one of claims 1-11, and/or at least one pharmaceutically acceptable salt thereof, wherein Q is selected from heteroaryl.
13.12, and/or at least one pharmaceutically acceptable salt thereof, wherein Q is selected from
Figure BDA0001177209820000132
14.1 to 13And/or at least one pharmaceutically acceptable salt thereof, wherein R is4Selected from hydrogen, C1-10Alkyl, halogen and cyano, wherein C1-10Alkyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R6aIs substituted with the substituent(s).
15.14, and/or at least one pharmaceutically acceptable salt thereof, wherein R4Selected from the group consisting of hydrogen, methyl, halogen and cyano, wherein methyl is unsubstituted or substituted with at least one group independently selected from R6aIs preferably R6aIs fluorine.
16.1-15, and/or at least one pharmaceutically acceptable salt thereof, wherein R5Independently selected from OR8Heterocyclic group, NR7R8Wherein heterocyclyl is unsubstituted or substituted by at least one, such as 1,2,3 or 4, independently selected from R6aIs substituted with the substituent(s).
17.16, and/or at least one pharmaceutically acceptable salt thereof, wherein R5Independently selected from methoxy, ethoxy, isopropoxy, piperazin-1-yl, 4-methylpiperazin-1-yl, methyl (2- (methylamino) ethyl) amino, (2- (dimethylamino) ethyl) (methyl) amino, (2- (ethyl) (methyl) amino) ethyl) (methyl) amino and (methyl (2- (N-methylacetamido) ethyl) amino).
18. At least one compound is selected from:
n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (6-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (6-methoxy-2- (methyl (2- (N-methylacetamido) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-ethoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (6-isopropoxy-2- (methyl (2- (N-methylacetamido) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-isopropoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide,
N- (6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperidin-1-yl) pyridin-3-yl) acrylamide,
N- (6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperidin-1-yl) pyridin-3-yl) acrylamide,
N- (6-ethoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperidin-1-yl) pyridin-3-yl) acrylamide,
N- (6-isopropoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperidin-1-yl) pyridin-3-yl) acrylamide,
N- (6-isopropoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperidin-1-yl) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (6-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (5-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (4-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((5-fluoro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((5-methyl-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -5-methoxy-6- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-2-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) -2-fluoroacrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylindazin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methylindazin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (5- ((4- (1-cyanoindolizin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (5- ((4- (1-cyanoindolizin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-3-yl) pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide,
N- (5- ((4- (1-chloroindolizin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (5- ((4- (1-chloroindolizin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylindazin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methylindazin-1-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (5- ((4- (3-cyanoindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (5- ((4- (3-cyanoindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-1-yl) pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-1-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide,
N- (5- ((4- (3-chloroindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (5- ((4- (3-chloroindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (6-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) pyridin-3-yl) acrylamide,
N- (4-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acrylamide,
N- (5- ((4- (3-cyano-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (5- ((4- (3-cyano-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,
N- (5- ((4- (1-chloroimidazo [1,5-a ] pyrid-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (5- ((4- (1-chloroimidazo [1,5-a ] pyrid-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1- (trifluoromethyl) imidazo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1- (trifluoromethyl) imidazo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylimidazol [1,5-a ] pyrid-in-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1- (methylimidazol [1,5-a ] pyrid-in-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylimidazol [1,5-a ] pyrid-in-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide,
N- (5- ((4- (1, 2-dihydropyrrolo [3,2,1-hi ] indol-5-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,
N- (5- ((4- (1, 2-dihydropyrrolo [3,2,1-hi ] indol-5-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methyl-1H-indazol-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methyl-1H-indazol-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylimidazol [1,5-a ] pyrid-in-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylimidazo [1,5-a ] pyrid-in-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide,
and pharmaceutically acceptable salts thereof.
In another aspect, the invention provides a pharmaceutical combination comprising at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof, wherein the route of administration of the combination includes oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal administration, via inhalation, vaginal, intraocular, by topical administration (e.g., through a catheter or stent), subcutaneous, intraadipose, intraarticular, or intrathecal.
In another aspect, the invention provides a kit comprising at least one compound of any one of the above 1-18 and pharmaceutically acceptable salts thereof; and instructions including one or more of the following: instructions for what disease the composition applies to, composition storage information, dosage information, and how to use the composition. In a particular variation, the kit comprises the compound in a multiple dose form.
In another aspect, the present invention provides a preparation comprising at least one compound of any one of the above 1-18 and pharmaceutically acceptable salts thereof; and a packaging material. In one variation, the packaging material comprises a container. In one particular variation, the container includes a label that identifies one or more of the following: instructions for what disease the compound applies to, stored information, dosage information, and/or how to use the composition. In another variation, the article of manufacture comprises the compound in a multiple dose form.
In another aspect, the invention provides a method of treatment comprising administering to a subject at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof.
In another aspect, the present invention provides a method of inhibiting mutant EGFR by the action of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof with mutant EGFR.
In another aspect, the invention provides a method of inhibiting mutant EGFR, comprising causing at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof to be present in a body, to inhibit the activity of mutant EGFR in the body.
In another aspect, the invention provides a method of treating a disease state for which mutated EGFR activity contributes to the pathology and/or symptomology of the disease, the method comprising causing a therapeutically effective amount of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof to be present in a subject to ameliorate the disease state.
In variations of each of the above methods, the disease state is selected from: cancerous proliferative diseases (e.g., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, colon, epidermis, esophagus, testicular, gynecological, or thyroid cancer); non-cancerous proliferative diseases (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and Benign Prostatic Hypertrophy (BPH)); pancreatitis; kidney disease; pain; preventing blast implantation; treating diseases associated with angiogenesis or vasculogenesis (e.g., tumor angiogenesis, acute and chronic infectious diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid cancer); asthma; neutrophil chemotaxis (e.g., reperfusion injury from myocardial infarction and stroke and inflammatory arthritis); septic shock; t cell-mediated diseases where immunosuppression is valuable (e.g., prevention of organ transplant rejection, graft versus host disease, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibiting keratinocytes responsive to the growth factor mixture; chronic Obstructive Pulmonary Disease (COPD) and other diseases.
In another aspect, the invention provides a method of treating a disease state for which a mutation in the EGFR gene contributes to the pathology and/or symptomology of the disease, such as melanoma, lung cancer, colon cancer and other types of tumors.
In another aspect, the present invention relates to the use of at least one compound of any one of 1 to 18 and pharmaceutically acceptable salts thereof as a medicament. In another aspect, the invention relates to the use of any one of the compounds of at least one of 1-18 and pharmaceutically acceptable salts thereof for the manufacture of a medicament for inhibiting mutant EGFR.
In another aspect, the invention relates to the manufacture of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof as a medicament for treating pathological and/or symptomatic disease states resulting from mutated EGFR activity.
Administration and pharmaceutical compositions
Generally, the compounds of the present invention will be administered in a therapeutically effective amount via any of the usual and acceptable means known in the art, alone or in combination with one or more therapeutic agents. The therapeutically effective amount may vary widely depending on the severity of the disease, age and relative health of the subject, the potency of the compound used and other general skills known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the required dosage will vary depending upon the mode of administration, the particular condition being treated and the desired effect.
In general, satisfactory results are achieved at daily dosages of from 0.001 to 100mg/kg body weight, in particular from about 0.03 to 2.5mg/kg body weight. Daily doses for larger mammals, such as humans, may be administered in a convenient form, for example in divided doses up to four times a day or in sustained release form, from about 0.5mg to about 2000mg, or more specifically, from 0.5mg to 1000 mg. Suitable unit dosage forms for oral administration contain from about 1 to 50mg of the active ingredient.
The compounds of the invention may be administered in the form of pharmaceutical compositions, by any conventional route; e.g., enterally, e.g., orally, e.g., in the form of tablets or capsules, parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., in the form of a lotion, gel, ointment, or cream, or in the form of a nasal or suppository.
Pharmaceutical compositions comprising a compound of the invention in free base or pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in conventional manner by means of mixing, granulating, coating, dissolving or lyophilizing processes. For example, pharmaceutical compositions comprising a compound of the invention in combination with at least one pharmaceutically acceptable carrier or diluent may be formulated in conventional manner by admixture with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of active substance.
In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution. In the case of lyophilized compositions comprising the active ingredient alone or in admixture with a carrier such as mannitol, the dispersion or suspension may be replenished prior to use. The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain viscosity increasing agents including, but not limited to, sodium carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizing agents such as tween 80 (polyoxyethylene (20) sorbitan monooleate).
Suspensions may contain vegetable oils, synthetic or semi-synthetic oils, as the oily component in the oil, commonly used for injection purposes. Examples include liquid fatty acid esters containing as the acid component a long chain fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, if desired, with antioxidants such as vitamin E, 3-carotene or 3, 5-di-tert-butylhydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di-or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof, ethylene glycol and glycerol.
Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, isopropyl myristate, isopropyl palmitate, isopropyl myristate,
Figure BDA0001177209820000211
m2375 (polyoxyethylene glycerol),
Figure BDA0001177209820000212
M1944CS (unsaturated polyglycolyzed glycerides and mixtures containing glycerides and polyglycolyzed esters of almond oil by alcoholysis), LABRASOLTM(saturated polyglycolized glycerides prepared by alcoholysis of TCM and containing glycerides and polyethylene glycol esters; both available from GaKefosse, France), and/or
Figure BDA0001177209820000213
812 (triglycerides of saturated fatty acids with chain lengths of C8 to C12 from H ü ls AG, germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.
Pharmaceutical compositions for oral administration may be obtained, for example, by mixing the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules by adding further excipients, in the form of tablets or tablet cores.
Suitable carriers include, but are not limited to, fillers, for example sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, for example starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
The tablet cores may be provided with a suitable, optionally enteric, coating by using, inter alia, a concentrated sugar solution, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or a coating solution of a suitable organic solvent or solvent mixture, or, for enteric coatings, the preparation of suitable cellulose preparations, such as solutions of acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of the active ingredient.
Pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft, sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may contain the active ingredients in the form of granules, for example in admixture with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oils or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and detergents, for example of the fatty acid ester type of polyoxyethylene sorbitol, are added.
Pharmaceutical compositions suitable for rectal administration, for example suppositories, comprise a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
Pharmaceutical compositions suitable for parenteral administration may comprise the active ingredient in water-soluble form, for example as a water-soluble salt or as an aqueous injection suspension comprising a viscosity-increasing substance, for example sodium carboxymethylcellulose, an aqueous solution of sorbitol and/or dextran, if desired, and a stabilizer. The active ingredient, optionally together with excipients, may also be in a lyophilized form and may be prepared as a solution by addition of a suitable solvent prior to parenteral administration. The solutions used, for example for parenteral administration, can also be used as infusion solutions. Injectable preparations are generally prepared under sterile conditions, and filled, for example, in ampoules or vials, and in sealed containers.
The compounds of the invention may be administered as the sole active ingredient or with other drugs useful in immunomodulating therapy or useful against neoplastic diseases. For example, the compounds of the present invention may be used in combination with a pharmaceutical composition effective for each of the above-mentioned diseases, for example, the compounds of the present invention may be used in combination with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatin, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituximab, doxorubicin, gefitinib or imatinib; or also with cyclosporins, rapamycin, ascomycins or their immunosuppressive analogues, e.g. cyclosporins a, cyclosporins G, FK-506, sirolimus and everolimus, glucocorticoids such as: prednisone, cyclophosphamide, azathioprine, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid, phenolate and 15-deoxyspergualin, immunosuppressive monoclonal antibodies, such as monoclonal antibody leukocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or their ligands, or other immunomodulatory compounds, such as CTLA41 g.
The invention also provides a pharmaceutical combination, e.g. a kit, comprising a) a compound as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-drug. The kit may contain instructions for its use.
Examples
There are various methods for synthesizing the compound or at least one pharmaceutically acceptable salt thereof, and representative methods are exemplified in this example. It is to be noted, however, that at least one compound of formula I or at least one pharmaceutically acceptable salt thereof may also be obtained synthetically by other synthetic routes.
In certain compounds of formula (I), the linkage between an atom and another atom may result in the presence of a particular stereoisomer (e.g., a chiral center). The synthesis of at least one compound of formula (I) or at least one pharmaceutically acceptable salt thereof may result in a mixture of different isomers (enantiomers, diastereomers). Unless a particular configuration is specified, all recited compounds include different stereoisomers that may exist.
At least one compound of formula (I) may also be prepared as a pharmaceutically acceptable acid addition salt, for example, by reacting the free base form of the compound of the invention with a pharmaceutically acceptable inorganic or organic acid. Or reacting at least one compound of formula (I) in free acid form with a pharmaceutically acceptable inorganic or organic base to form a pharmaceutically acceptable base addition salt. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compounds of formula (I) are described in the definitions section of this application. In addition, salt forms of the compounds of formula (I) can also be prepared by using salts of the starting materials or intermediates.
The free acid or base of the compound of formula (I) may be prepared from the corresponding base addition salt or acid addition salt thereof. The acid addition salt forms of the compounds of formula (I) may be converted to the corresponding free base, for example by treatment with a suitable base such as ammonium hydroxide solution, sodium hydroxide and the like. The base addition salt forms of the compounds of formula (I) may be converted to the corresponding free acids, for example by treatment with a suitable acid such as hydrochloric acid and the like.
The N-oxide of at least one compound of formula (I) or at least one pharmaceutically acceptable salt thereof may be prepared by methods known in the art. For example, the N-oxide may be obtained by reacting a non-oxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, peroxymaleic acid, peroxybenzoic acid, peroxyacetic acid, m-chloroperoxybenzoic acid, and the like) in an inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at a temperature near 0 ℃. Alternatively, the N-oxides of the compounds of formula (I) may also be prepared from the N-oxides of the starting materials.
The non-oxidized compound of formula I can be prepared by reacting N-oxide thereof with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide and the like) in a corresponding inert organic solvent (such as acetonitrile, ethanol, hydrated dioxane and the like) at 0-80 ℃.
Protected derivatives of compounds of formula I may be prepared by methods well known to those skilled in the art. For a detailed technical description of the addition and removal of protecting groups see: greene, Protecting Groups in organic Synthesis,3rd edition, John Wiley & Sons, Inc.1999.
The labels and common sense, charts and examples used in these reactions are consistent with the current scientific literature, e.g., the journal of the American chemical Association or the journal of biochemistry. Unless otherwise indicated, standard single or three letter abbreviations generally refer to L-amino acid residues. All starting materials used were purchased from commercial suppliers and used without further purification unless otherwise indicated. For example, the following abbreviations are used in the examples and throughout the specification: g (g), mg (mg), L (L), mL (mL), μ L (μ L), psi (pounds per square inch), M (mol), mM (mmol), i.v. (i.v.), Hz (Hz), MHz (megahertz), mol (mol), mmol (mmol), RT (ambient temperature), min (min), h (h), mp (melting point), TLC (thin layer chromatography), Rr (retention time), RP (reversed phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DME (1, 2-dimethyl ether), DCM (dichloromethane), DCE (dichloroethane), DMF (N, N-dimethylformamide), DMPU (N, N-dimethylpropylurea), CDI (1, 1-carbonyldiimidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et2O (diethyl ether), EDCI (1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (t-butyloxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMSE (2- (trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilane), TBS (t-butyldimethylsilyl), DMAP (dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (t-butyl), HPLC (high performance liquid chromatography), BOP (bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride), AF (tetrabutylammonium fluoride), TBmC (m-chloroperbenzoic acid).
Ether or Et2O is diethyl ether; brine is then a saturated aqueous NaCl solution. Unless otherwise indicated, all temperatures refer to degrees Celsius (degrees Celsius) and all reactions are carried out in an inert atmosphere at room temperature.
1H NMR spectrumRecorded using a Bruker Avance 400 NMR spectrometer. Chemical shifts are expressed in ppm. The coupling constants are all in hertz (Hz). Apparent diversity is described in the split mode and is assigned as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (generalized peak)
Low resolution Mass Spectrometry (MS) and compound purity data were from a Waters ZQ mass spectrometry single-pole system equipped with an electrospray ion detector (ESI), ultraviolet detectors (220 and 254nm) and Evaporative Light Scattering Detector (ELSD). Thin layer chromatography was performed using 0.25mm E.Merck silica gel plate (60F-254), 5% phosphomolybdic acid in ethanol, ninhydrin or p-phenylene oxide solution and observing under ultraviolet lamp. The flash column chromatography used was silica gel (230- "400 mesh, Merck).
Synthetic route
At least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof may be synthesized by various methods, some exemplary methods are provided below and in the examples. Other synthetic methods can be readily suggested by those skilled in the art based on the information disclosed herein.
It may be necessary to protect reactive groups in the reactions described below in order to prevent these reactive groups from participating in other undesired reactions: such as hydroxyl, amino, imino, mercapto or carboxyl groups, which are contained in the final product. Commonly used protecting Groups are referred to T.W.Greene and P.G.M.Wuts in "Protective Groups in organic Chemistry" John Wiley and Sons, 1991.
The synthetic routes for all compounds of the invention are illustrated by the following routes and examples. The starting materials used are commercially available or may be prepared according to established procedures or by methods exemplified herein.
The intermediates listed in the following figures were either obtained from the literature or synthesized according to established analogous synthetic methods.
The compounds of formula I of the present invention may be prepared by the route shown in figure 1. The intermediate of formula III is coupled with amino aromatic hydrocarbon of formula IV through Buchwald ammoniation reaction or other ammoniation conditions provided by literature to obtain intermediate VII or VI, the nitro group of intermediate VII is reduced by iron powder/ammonium chloride in single solvent or mixed solvent such as ethanol-water to obtain amine VIII, and the intermediate VIII can also be obtained by removing the protecting group on the amino group of intermediate VI. Intermediate VI can be obtained by coupling intermediate III with amino-arene V. The amine VIII is condensed with an acid IX or an acid chloride X to give the compound I. The compounds I can also be obtained by reacting the amines VIII first with the acid chlorides XI and then in aqueous solution of a base such as sodium hydroxide, the elimination reaction takes place.
Figure BDA0001177209820000261
An alternative synthetic route to the key intermediate amine VIII is shown in FIG. 2. Amine XIII is coupled with halogenated XIV or XV under similar conditions as shown in FIG. 1 or converted to amine VIII from the literature known nitro compound VII or intermediate VI under conditions as shown in FIG. 1.
Figure BDA0001177209820000271
As shown in fig. 3, in some cases, the compound of formula I is obtained by coupling intermediate III with intermediate VIa under the conditions shown in fig. 1 or fig. 2.
Figure BDA0001177209820000281
The preparation method of VIaa is shown in FIG. 4. The intermediate VIaa is obtained by taking commercially provided dichloropyrimidine as a starting material and sequentially carrying out chlorine regioselective substitution reaction, bromination, amination, deprotection, acetylation and reduction reaction.
Figure BDA0001177209820000282
As an illustration of the preparation of intermediate XIV, the synthetic method of XIVa is shown in fig. 5. Commercially available dichloropyrimidine reacted with an amine followed by a sodium alkyl alkoxide and subsequent halogenation gave the intermediate XIVa.
Figure BDA0001177209820000283
In some cases, the order of carrying out the reactions shown in the above schemes may be adjusted to ensure that the reactions proceed or to avoid side reactions. The following examples are for a full understanding of the present invention and are not to be construed as limiting the invention in any way.
Example 1
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- (4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (1)
6-chloro-2-methoxy-3-nitropyridine (1a)
To a solution of 2, 6-dichloro-3-nitropyridine (5.79g, 30.0mmol) in dry tetrahydrofuran (30mL) was added methanol (1.15mL, 28.5mmol) at 0 ℃ followed by 4 portions of sodium hydride (60%, 1.20g, 30.0 mmol). After stirring at 0 ℃ for 1h, the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50mL) and extracted with ethyl acetate (2X 30mL). The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness and the residue was recrystallized from n-hexane to give 6-chloro-2-methoxy-3-nitropyridine (1a) as a pale yellow solid (4.04g, 71%).
1 1 2 2N- (6-methoxy-5-nitropyridin-2-yl) -N, N, N-trimethylethane-1, 2-diamine (1b)
6-chloro-2-methoxy-3-nitropyridine (1a) (3.77g, 20.0mmol) and N1,N1,N2Heating and refluxing a solution of (2.24g, 22.0mmol) of trimethylethane-1, 2-diamine in ethanol (45mL) for 3h, evaporating off the solvent under reduced pressure, and purifying the residue by column chromatography on silica gel using dichloromethane/methanol/aqueous ammonia (92:6:2) as eluent to give N1- (6-methoxy-5-nitropyridin-2-yl) -N1,N2,N2-trimethylethane-1, 2-diamine (1b) (2.40g, 47%). MS-ESI (M/z) 255[ M +1 ]]+。
1 1 2 2N- (3-bromo-6-methoxy-5-nitropyridin-2-yl) -N, N, N-trimethylethane-1, 2-diamine (1c)
In N1- (6-methoxy-5-nitropyridin-2-yl) -N1,N2,N2A suspension of (1.33g, 5.24mmol) of (1b) trimethylethane-1, 2-diamine in acetonitrile (30mL) was added N-bromosuccinimide (1.40g,7.82mmol) at 0 deg.C and stirred at 0 deg.C for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel eluting with dichloromethane/methanol/aqueous ammonia (92:6:2) to give N as a yellow solid1- (3-bromo-6-methoxy-5-nitropyridin-2-yl) -N1,N2,N2-trimethylethane-1, 2-diamine (1c) (1.47g, 84%). MS-ESI (M/z):333and 335[1:1, M +1 ]]+。
2 3 2N- (2- (dimethylamino) ethyl) -N- (diphenylmethylene) -6-methoxy-N-methyl-5-nitropyridine-2, 3- Diamine (1d)
Will N1- (3-bromo-6-methoxy-5-nitropyridin-2-yl) -N1,N2,N2-trimethylethane-1, 2-diamine (1c) (666mg,2.00mmol), Pd2(dba)3A mixture of (55mg,0.060mmol), (+/-) -BINAP (75mg,0.120mmol), benzophenone imine (471mg,2.60mmol) and sodium tert-butoxide (250mg,2.60mmol) in toluene (8mL) was heated to 110 ℃ under nitrogen for 2h and then cooled to room temperature. The solid was removed by filtration through celite and washed with ethyl acetate. The filtrate was distilled under reduced pressure to remove the solvent and the residue was purified by silica gel column chromatography (eluent 20-40% ethyl acetate/N-hexane) to give N2- (2- (dimethylamino) ethyl) -N3- (diphenylmethanone) -6-methoxy-N2Methyl-5-nitropyridine-2, 3-diamine (1d) as a yellow solid (227mg, 26%). MS-ESI (M/z):434[ M +1 [)]+。
2 2N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-5-nitropyridine-2, 3-diamine (1e)
At room temperature under N2- (2- (dimethylamino) ethyl) -N3- (diphenylmethanone) -6-methoxy-N2Methyl-5-nitropyridine-2, 3-diamine (1d) (194mg,0.45mmol) in methanol (5mL) concentrated hydrochloric acid (1mL) was added and the mixture was stirred at room temperature for 1h, then diluted with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 ×) and the extractsAfter washing with water and brine, the mixture was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent 3-10% methanol/dichloromethane) to give N2- (2- (dimethylamino) ethyl) -6-methoxy-N2Methyl-5-nitropyridine-2, 3-diamine (1e) as a yellow solid (12.4mg, 10%). MS-ESI (M/z) 270[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5-nitropyridin-3-yl) acrylamide (1f)
At 0 ℃ to N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-5-nitropyridine-2, 3-diamine (1e) (12.4mg,0.046mmol) in tetrahydrofuran-water (10:1,1mL) mixture was added 3-chloropropionyl chloride (14mg,0.11mmol), stirred at 0 ℃ for 0.5h, sodium hydroxide (20mg,0.50mmol) was added, the mixture was heated to 60 ℃ for reaction for 3h, cooled to room temperature, diluted with water, extracted with ethyl acetate (2 ×), the extract solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent 5% methanol/dichloromethane) to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5-nitropyridin-3-yl) acrylamide (1f) (6.7mg, 45%). MS-ESI (M/z):324.2[ M +1 ] (M + 1) ]) (6.7mg, 45%). The]+。
N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (1g)
A mixture of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5-nitropyridin-3-yl) acrylamide (1f) (6.7mg,0.021mmol), iron powder (7.0mg,0.12mmol) and ammonium chloride (1.1mg,0.021mmol) in ethanol-water (3:1,2mL) was heated under reflux for 6h, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography over silica gel with dichloromethane/methanol/aqueous ammonia (92:6:2) as eluent to give N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (1g) (3.6mg, 59%). MS-ESI (M/z):294[ M +1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- (4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (1)
Reacting N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-Methoxypyridin-3-yl) acrylamide (1g) (3.6mg,0.012mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1H) (6.0mg,0.025mmol) (prepared according to document WO 2013/14448) and p-toluenesulfonic acid monohydrate (4.7mg,0.025mmol) in 2-pentanol (0.5mL) mixture heated to 105 ℃ for 2H, the solvent evaporated under reduced pressure, the residue purified by silica gel column chromatography with dichloromethane/methanol (95:5) as eluent to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (1), (1) 5.0mg, 82%). MS-ESI (M/z) 500[ M +1 ]]+。
Example 2
N- (6-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (2)
Tert-butyl 2- ((6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2b)
A solution of 1a (4.00g,21.3mmol) and tert-butylmethyl (2- (methylamino) ethyl) carbamate (2a,4.38g,22.3mmol) (prepared according to the literature, j.med. chem.,1992,35,565) in ethanol (47mL) was heated under reflux for 3h, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography with 15-30% ethyl acetate/n-hexane as eluent to give tert-butyl 2- ((6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2b) (4.65g, 63%) as a yellow solid. MS-ESI (M/z):341[ M +1 [)]+。
Tert-butyl 2- ((3-bromo-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamic acid Ester (2c)
To a suspension of tert-butyl 2- ((6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2b) (4.32g,12.7mmol) in acetonitrile was added N-bromosuccinimide (3.40g,19.1mmol) at 0 deg.C, the mixture was stirred for 1h at 0 deg.C, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel with 20-30% ethyl acetate/N-hexane as eluent to give tert-butyl 2- ((3-bromo-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2c) as a yellow solid (5.00g,9 g)3%). MS-ESI (M/z):419and 421[1:1, M +1 and M +3 ]]+。
Tert-butyl 2- ((3- (diphenylmethylene) -6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) Yl) carbamic acid ester (2d)
2- ((3-bromo-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2c) (2.095g,5.00mmol), Pd2(dba)3A mixture of (137mg,0.150mmol), (+/-) -BINAP (187mg,0.300mmol), benzophenone imine (1.177g,6.50mmol) and sodium tert-butoxide (624mg,6.50mmol) in toluene (20mL) was heated to 110 ℃ under nitrogen for 3h, cooled to room temperature, filtered off the solid over celite, washed with ethyl acetate, evaporated to dryness under reduced pressure and the residue was purified by column chromatography over silica gel with 20-40% ethyl acetate/n-hexane as eluent to give tert-butyl 2- ((3- (benzhydrylidene) -6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2d) as a light yellow solid (600mg, 23%). MS-ESI (M/z):520[ M +1 ]]+。
Tert-butyl 2- ((3-amino-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamic Acid ester (2e)
Hydrochloric acid (1N,0.5mL) was added to a solution of tert-butyl 2- ((3- (diphenylmethylene) -6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2d) (580mg,1.12mmol) in ethanol (20mL) at room temperature, heated to 50 ℃ to react for 7 h. the mixture was diluted with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 ×), the extracts were washed with water and brine, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, eluent 20-40% ethyl acetate/N-hexane to give tert-butyl 2- ((3-amino-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2e) as an orange solid (280mg, 68%). MS-ESI (M/z):356[ M +1 ]/[ M ]/(-) 356]+。
Tert-butyl 2- ((3-acrylamido-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) Carbamate (2f)
To tert-butyl 2- ((3-amino-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) at 0 deg.C) 3-Chloropropioyl chloride (120mg,0.946mmol) was added to a solution of carbamate (2e) (280mg,0.789mmol) in tetrahydrofuran-water (10:1,5.5mL), stirred at 0 ℃ for 0.5h, sodium hydroxide NaOH (126mg,3.76mmol) was added, the mixture was heated to 65 ℃ to react for 1h and then cooled to room temperature, the mixture was diluted with water, ethyl acetate was extracted (2 ×), the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography with 30-50% ethyl acetate/n-hexane as eluent to give tert-butyl 2- ((3-acrylamido-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2f) (185mg, 57%). MS-ESI (M/z):410.3[ M +1 ] (M + 1)]+。
Tert-butyl 2- ((3-acrylamido-5-amino-6-methoxypyridin-2-yl) (methyl) amino) ethyl (methyl) Carbamate (2g)
Tert-butyl 2- ((3-acrylamido-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2f) (185mg,0.452mmol), iron powder (152mg,2.71mmol), ammonium chloride (24.2mg,0.452mmol) in ethanol-water (3:1,15mL) was heated at reflux for 1 h. The solid was removed by filtration through celite and washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with water and brine, and the solvent was evaporated to dryness under reduced pressure to give crude tert-butyl 2- ((3-acrylamido-5-amino-6-methoxypyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2g) (149mg, 87%) as a brown oil. MS-ESI (M/z) 380[ M +1 ]]+。
N- (6-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (2)
A mixture of tert-butyl 2- ((3-acrylamido-5-amino-6-methoxypyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2g) (94.0mg,0.248mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1H,72.5mg,0.298mmol) and p-toluenesulfonic acid monohydrate (56.6mg,0.298mmol) in 2-pentanol (1.5mL) was heated to 105 ℃ for 2H. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol/ammonia (92:7:1) to give N- (6-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (2) ((1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino)100.0mg,83％)。MS-ESI(m/z):487.4[M+1]+。
Example 3
N- (2- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-) Indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (3)
Adding acetaldehyde (40% in water, 9.0mg,0.082mmol) and sodium triacetoxyborohydride (8.7mg,0.041mmol) to a solution of N- (6-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (2) (15.4mg,0.0317mmol) in 1, 2-dichloroethane (1mL) at room temperature, stirring the mixture at room temperature for 1H, diluting with saturated aqueous sodium bicarbonate (5mL), extracting with dichloromethane (2 × 5mL), drying the extract with sodium sulfate, evaporating the solvent to dryness, purifying the residue by silica gel column chromatography with an eluent of dichloromethane/methanol/ammonia (95:4:1) to obtain N- (2- ((2- (ethyl (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-3-yl) acrylamide (77 mg, 12M) as a brown solid (5M), and stirring at room temperature]+。
Example 4
N- (6-methoxy-2- (methyl (2- (N-methylacetamido) ethyl) amino) -5- (4- (1-methyl-1H-indole) Indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (4)
To a solution of N- (6-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (2) (28.3mg,0.058mmol) in dichloromethane (1mL) was added DIPEA (15.2. mu.L, 0.087mmol), cooled to 0 ℃, and a solution of acetic anhydride (0.20mL in dichloromethane (5.9 mg) was added dropwise the mixture stirred at room temperature for 1H, diluted with saturated aqueous sodium bicarbonate (5mL), dichloromethane extracted (2 × 5mL), the extracts were dried over sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography with an eluent of 2-3% methanol/dichloromethane to give N- (6-methoxy-2- (methyl (2- (N-methylacetamido) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (4),as a yellow solid (15.1mg, 49%). MS-ESI (M/z) 528.4[ M +1 ]]+。
Example 5
N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidine Pyridin-2-yl) amino) pyridin-3-yl) acrylamide (5)
6-chloro-2-ethoxy-3-nitropyridine (5a)
Preparation of 6-chloro-2-ethoxy-3-nitropyridine (5a) methanol was replaced by ethanol according to the synthesis of 1 a. MS-ESI (M/z) 203[ M +1 ]]+。
N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidine Pyridin-2-yl) amino) pyridin-3-yl) acrylamide (5)
Preparation of the title compound N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (5) (36.1mg) 6-chloro-2-methoxy-3-nitropyridine (1a) was replaced with 6-chloro-2-ethoxy-3-nitropyridine (5a) according to the synthesis of example 2. MS-ESI (M/z):501[ M +1 ]]+。
Example 6
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-ethoxy-5- ((4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (6)
To a solution of N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (5) (10.1mg,0.020mmol) in 1, 2-dichloroethane (0.6mL) was added acetaldehyde (37% in water, 17mg) and sodium triacetoxyborohydride (6.4mg,0.030mmol) at room temperature, and after stirring the mixture at room temperature for 1H, saturated aqueous sodium bicarbonate (2mL) was added for dilution, dichloromethane was extracted (2 × 2mL), the extract was dried over sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography with an eluent of 5-10% dichloromethane/methanol to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-ethoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (6) as gray colorSolid (8.5mg, 82%). MS-ESI (M/z) 515[ M +1 ]]+。
Example 7
N- (6-isopropoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (7)
6-chloro-2-isopropoxy-3-nitropyridine (7a)
Preparation of 6-chloro-2-isopropoxy-3-nitropyridine (7a) methanol was replaced by isopropanol according to the synthesis of 1 a. MS-ESI (M/z):217[ M +1]+。
N- (6-isopropoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (7)
Preparation of the title compound 7(36.1mg) 6-chloro-2-methoxy-3-nitropyridine (1a) was replaced with 6-chloro-2-isopropoxy-3-nitropyridine (7a) according to the synthesis of example 2. MS-ESI (M/z) 515[ M +1 ]]+。
Example 8
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-isopropoxy-5- (4- (1-methyl-1H-indole-) 3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (8)
Preparation of the title compound 8(6.3mg, 75%) N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (5) was replaced with N- (6-isopropoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (7) according to the synthesis of example 6. MS-ESI (M/z):529[ M +1]+。
Example 9
N- (6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) Pyridin-3-yl) acrylamide (9)
Preparation of the title compound 9(25mg) tert-butyl (2- (methylamino) ethyl) carbamate (2a) was replaced with tert-butylpiperazine-1-carbamate according to the synthesis method of example 2. MS (Mass Spectrometry)-ESI(m/z):485[M+1]+。
Example 10
N- (6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazine- 1-yl) pyridin-3-yl) acrylamide (10)
Preparation of title compound 10(5.2mg) N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (5) was replaced with N- (6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide (9) according to the synthesis of example 6. MS-ESI (M/z):499[ M +1 ]]+。
Example 11
N- (6-ethoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) Pyridin-3-yl) acrylamide (11)
Preparation of title compound 11(55mg) according to the synthetic method of example 2, methyl (2- (methylamino) ethyl) carbamate (2a) was replaced with tert-butylpiperazine-1-carboxylate and 6-chloro-2-methoxy-3-nitropyridine (1a) was replaced with 6-chloro-2-ethoxy-3-nitropyridine (5a), respectively. MS-ESI (M/z):499[ M +1 ]]+。
Example 12
N- (6-ethoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazine- 1-yl) pyridin-3-yl) acrylamide (12)
Preparation of title compound 12(7.2mg) N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (5) was replaced with N- (6-ethoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide (11) according to the synthesis of example 6. MS-ESI (M/z) 513[ M +1 ]]+。
Example 13
N- (6-isopropoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1- Yl) pyridin-3-yl) acrylamide (13)
Title compound 13(75mg) was prepared according to the synthesis method of example 2 substituting tert-butylmethyl (2- (methylamino) ethyl) carbamate (2a) for tert-butylpiperazine-1-carbamate and 6-chloro-2-methoxy-3-nitropyridine (1a) for 6-chloro-2-isopropoxy-3-nitropyridine (7a), respectively. MS-ESI (M/z) 513[ M +1 ]]+。
Example 14
N- (6-isopropoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiper Oxazin-1-yl) pyridin-3-yl) acrylamide (14)
Preparation of title compound 14(7.4mg) N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (5) was replaced with N- (6-isopropoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide (13) according to the synthesis of example 6. MS-ESI (M/z):527[ M +1 [)]+。
Example 15
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (7-fluoro-1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide (15)
1 1 2 2N- (6-chloro-3-nitropyridin-2-yl) -N, N, N-trimethylethane-1, 2-diamine (15a)
To a solution of 2, 6-chloro-3-nitropyridine (19.3g,100.0mmol) and triethylamine (20.2g,200.0mmol) in dry dichloromethane (200mL) at 0 deg.C was slowly added N dropwise1,N1,N2-a solution of trimethylethane-1, 2-diamine (10.2g,100.0mmol) in dry dichloromethane (20mL) over 0.5h, the reaction mixture stirred at 0 ℃ for 1.5h the mixture was diluted with water (200mL), dichloromethane extracted (100mL × 3). the organic layers were combined, washed with brine (200mL), dried over sodium sulfate, filtered to remove solids, the filtrate was concentrated to give N1- (6-chloro-3-nitropyridin-2-yl) -N1,N2,N2Trimethylethane-1, 2-diamine (15a) as a yellow oil (23.8g, 91%). MS-ESI (M/z):259[ M +1]+。
1 1 2 2N- (6-methoxy-3-nitropyridin-2-yl) -N, N, N-trimethylethane-1, 2-diamine (15b)
At 0-5 ℃ to N1- (6-chloro-3-nitropyridin-2-yl) -N1,N2,N2-trimethylethane-1, 2-diamine (15a) (23.8g,91.9mmol) in methanol (200mL) sodium methoxide (10.8g,183.8mmol) was added and the mixture heated under reflux for 2h, cooled to room temperature, evaporated to dryness in methanol, diluted with water (200mL), extracted with dichloromethane (200mL × 2) combined organic layers, washed with water (200mL × 2) and brine (200mL), dried over sodium sulfate, filtered off the solid, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:1) as eluent to give N1- (6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Trimethylethane-1, 2-diamine (15b) as a yellow oil (18.0g, 77%). MS-ESI (M/z) 255[ M +1 ]]+。
1 1 2 2N- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N, N, N-trimethylethane-1, 2-diamine (15c)
At 0-5 ℃ to N1- (6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2-trimethylethane-1, 2-diamine (15b) (11.0g,43.1mmol) in 3 portions in glacial acetic acid (120mL) solution N-iodosuccinimide (11.6g,51.8mmol) was added and the mixture was stirred at room temperature for 4.5h1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Trimethylethane-1, 2-diamine (15c) as a yellow oil (14.0g, 88%). MS-ESI (M/z):381[ M +1 ]]+。
1 1 2 2N- (5- ((diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N, N, N-trimethylethan Alkane-1, 2-diamine (15d)
Under inert nitrogen, adding N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2A mixture of-trimethylethane-1, 2-diamine (15c) (10.0g,26.2mmol), tris (dibenzylideneacetone) dipalladium (0) (1.2g,1.3mmol), (+/-) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (1.6g,2.6mmol), benzophenone imine (7.1g,39.4mmol) and sodium tert-butoxide (3.8g,39.4mmol) in toluene (150mL) was heated to 110 ℃ for 16 h. Cooling to room temperature, filtering with diatomaceous earth, removing solid, washing with ethyl acetate, evaporating solvent under reduced pressure, purifying the residue by silica gel column chromatography, eluting with ethyl acetate to obtain N1- (5- ((diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Trimethylethane-1, 2-diamine (15d) as red oil (2.2g, 19%). MS-ESI (M/z):434[ M +1 [)]+。
2 2N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-3-nitropyridine-2, 5-diamine (15e)
At room temperature, to N1- (5- ((diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2-trimethylethane-1, 2-diamine (15d) (2.2g,5.1mmol) in tetrahydrofuran (150mL) 0.5N hydrochloric acid (24mL) was added and stirred at room temperature for 1.5 h-tetrahydrofuran was evaporated to dryness under reduced pressure and potassium carbonate adjusted to pH 9-10. the resulting mixture was extracted with dichloromethane (30mL × 4), the organic layers were combined, washed with brine (200mL), dried over sodium sulfate, the solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography using dichloromethane/methanol (20: 1-10: 1) as eluent to give N2- (2- (dimethylamino) ethyl) -6-methoxy-N2Methyl-3-nitropyridine-2, 5-diamine (15e) as a red oil (0.7g, 51%). MS-ESI (M/z) 270[ M +1 ]]+。
7-fluoro-1-methyl-1H-indole (15f)
To a solution of 7-fluoro-1H-indole (1.0g,7.4mmol) in N, N-dimethylformamide (10mL) was added sodium hydride (60% in mineral oil, 0.44g,11.1mmol) at 0-5 deg.C, the resulting suspension was stirred at room temperature for 20 minutes, iodomethane (0.7mL,11.1mmol) was added at room temperature and stirred at room temperature for 1H. Reaction ofQuenched with water (40mL), the mixture extracted with ethyl acetate (30mL × 3), the organic layers combined, washed with water (30mL × 3) and brine (30mL), dried over sodium sulfate, the solid filtered off, the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:20) to give 7-fluoro-1-methyl-1H-indole (15f) as a pale yellow liquid (1.0g, 91%). MS-ESI (M/z):150[ M +1 ]/(15 f)]+。
3- (2-Chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g)
A solution of 7-fluoro-1-methyl-1H-indole (15f) (0.60g,4.0mmol), 2, 4-dichloropyrimidine (0.60g,4.0mmol), anhydrous iron (III) chloride (0.65g,4.0mmol) in 1, 2-ethylene glycol dimethyl ether (12mL) was stirred at 60 ℃ for 7H, the reaction was quenched with water (40mL), the resulting mixture was extracted with ethyl acetate (30mL × 3), the organic layers were combined, water (30mL × 3) and brine (30mL) were washed, sodium sulfate was dried, the solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1: 5-1: 2) as eluent to give 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) as a brown solid (0.50g, 48%). MS-ESI [ M + 1/z ]: 262[ M + 1/z ] (262]+。
2 5N- (2- (dimethylamino) ethyl) -N- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methyl 2oxy-N-methyl-3-nitropyridine-2, 5-diamine (15h)
3- (2-Chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) (30.0mg,0.11mmol), N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-3-nitropyridine-2, 5-diamine (15e) (31.0mg,0.11mmol), cesium carbonate (112.0mg,0.33mmol), tris (dibenzylideneacetone) dipalladium (0) (21.0mg,0.022mmol), (+/-) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (29.0mg,0.044mmol) in dioxane (3mL) mixture was stirred at 100 ℃ for 7h, cooled to room temperature, the reaction was quenched with water (40mL), the resulting mixture was extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with water (30mL × 3) and brine (30mL), dried over sodium sulfate, the solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluent dichloromethane/methanol/ammonia (100:5:0.5), N was obtained2- (2- (dimethylamino) ethyl) -N5- (4- (7-fluoro)-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N2Methyl-3-nitropyridine-2, 5-diamine (15h) as a yellow solid (34.0mg, 60%). MS-ESI (M/z):495[ M +1 [)]+。
2 5N- (2- (dimethylamino) ethyl) -N- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methyl 2oxy-N-methylpyridine-2, 3, 5-triamine (15i)
Will N2- (2- (dimethylamino) ethyl) -N5- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N2A mixture of methyl-3-nitropyridine-2, 5-diamine (15h) (34.0mg,0.07mmol), iron powder (41.0mg,0.73mmol), ammonium chloride (13.0mg,0.24mmol) in ethanol (12mL) and water (3mL) was stirred at 80 ℃ for 1.5h, the solid was filtered off, the ethanol was washed (5mL × 3), the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the eluent was dichloromethane/methanol/ammonia (100:5: 0.5-100: 10:0.5) to give N2- (2- (dimethylamino) ethyl) -N5- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N2-methyl-N22,3, 5-Triamine (15i) as a yellow oil (28.0mg, 88%). MS-ESI (M/z):465[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (7-fluoro-1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide (15)
At 0 ℃ to N2- (2- (dimethylamino) ethyl) -N5- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N2-methyl-N2Adding acryloyl chloride (5.5mg,0.06mmol) to a solution of (15i) methylpyridine-2, 3, 5-triamine (28.0mg,0.06mmol) in anhydrous dichloromethane (1mL), stirring at 0 ℃ for 1H, quenching the reaction with saturated aqueous sodium bicarbonate solution (20mL), extracting the resulting mixture with dichloromethane (20mL × 3), combining the organic layers, washing with water (20mL × 3) and brine (20mL), drying with sodium sulfate, filtering off the solids, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography with dichloromethane/methanol/ammonia water (100:5:0.5 to 100:10:0.5) as eluent to obtain N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (7-fluoro-1-methyl-1H-indole)Indol-3-yl) pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide (15) as a yellow solid (20.0mg, 65%). MS-ESI (M/z):519[ M +1 ]]+。
Example 16
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (6-fluoro-1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide (16)
Preparation of the title compound 16(20.0mg) 7-fluoro-1H-indole was replaced with 6-fluoro-1H-indole according to the synthesis of example 15. MS-ESI (M/z):519[ M +1 ]]+。
Example 17
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (5-fluoro-1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide (17)
Preparation of the title compound 17(25.0mg) 7-fluoro-1H-indole was replaced with 5-fluoro-1H-indole according to the synthesis of example 15. MS-ESI (M/z):519[ M +1 ]]+。
Example 18
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (4-fluoro-1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide (18)
Preparation of the title compound 18(23.0mg) according to the synthesis of example 15, 7-fluoro-1H-indole was replaced with 4-fluoro-1H-indole. MS-ESI (M/z):519[ M +1 ]]+。
Example 19
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((5-fluoro-4- (1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide (19)
3- (2-chloro-5-fluoropyrimidin-4-yl) -1-methyl-1H-indole (19a)
A solution of 1-methyl-1H-indole (0.50g,3.8mmol), 2, 4-dichloro-5-fluoropyrimidine (0.64g,3.8mmol) and anhydrous iron (III) chloride (0.62g,3.8mmol) in 1, 2-ethanediol dimethyl ether (7.0mL) was stirred at 60 ℃ for 7H. The reaction was quenched with water (40mL) and the resulting mixture was extracted with ethyl acetate(30mL × 3) was taken, the organic layers combined, washed with water (30mL × 3) and brine (30mL), dried over sodium sulfate, the solid filtered off, the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography using ethyl acetate/petroleum ether (1:5 to 1:2) as eluent to give 3- (2-chloro-5-fluoropyrimidin-4-yl) -1-methyl-1H-indole (19a) as a brown solid (0.54g, 54%). MS-ESI (M/z):262[ M + 1: (M/z):262[ M + 1%]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((5-fluoro-4- (1-methyl-1H-indol-3-yl) Pyrimidin-2-yl) amino) -6-methoxypyridin-3-yl) acrylamide (19)
Preparation of the title compound 19(23.0mg) 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) was replaced with 3- (2-chloro-5-fluoropyrimidin-4-yl) -1-methyl-1H-indole (19a) according to the synthesis of example 15. MS-ESI (M/z):519[ M +1 ]]+。
Example 20
N- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl Yl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (20)
3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indole (20a)
1-methyl-1H-indole (0.50g,3.8mmol), 2,4, 5-trichloropyrimidine (0.64g,3.8mmol), anhydrous iron (III) chloride (0.62g,3.8mmol) in 1, 2-ethylene glycol dimethyl ether (7.0mL) solution was stirred at 60 ℃ for 7H, the reaction was quenched with water (40mL), the resulting mixture was extracted with ethyl acetate (30mL × 3), the organic layers were combined, washed with water (30mL × 3) and brine (30mL), dried over sodium sulfate, the solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1: 5-1: 2) as eluent to give 3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indole (20a) as a brown solid (0.56g, 53%), MS-ESI (M/z):278[ M + 1:2 ] (M + 1:2)]+。
N- (5- ((5-chloro-4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl Yl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (20)
Preparation of the title compound 20(20.0mg) according to the synthetic method of example 15, 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) instead of 3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indole (20 a). MS-ESI (M/z):535[ M +1 ]]+。
Example 21
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((5-methyl-4- (1-methyl-1H-) Indol-3-ylPyrimidine as one kind of foodPyridin-2-yl) amino) pyridin-3-yl) acrylamide (21)
3- (2-chloro-5-methylpyrimidin-4-yl) -1-methyl-1H-indole (21a)
1-methyl-1H-indole (0.50g,3.8mmol), 2, 4-dichloro-5-methylpyrimidine (0.64g,3.8mmol), anhydrous iron (III) chloride (0.62g,3.8mmol) in 1, 2-ethylene glycol dimethyl ether (7.0mL) solution was stirred at 60 ℃ for 7H, the reaction was quenched with water (40mL), the resulting mixture was extracted with ethyl acetate (30mL × 3), the organic layers were combined, water (30mL × 3) and brine (30mL) were washed, sodium sulfate was dried, the solid was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1: 5-1: 2) as eluent to give 3- (2-chloro-5-methylpyrimidin-4-yl) -1-methyl-1H-indole (21a) as a brown solid (0.50g, 47%). MS-ESI (M +1 z):258[ M + 1%]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((5-methyl-4- (1-methyl-1H-) Indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (21)
Preparation of the title compound 21(26.0mg) 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) was replaced with 21a according to the synthesis of example 15. MS-ESI (M/z) 515[ M +1 ]]+。
Example 22
N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -5-methoxy-6- ((4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) pyridin-2-yl) acrylamide (22)
5-bromo-3-methoxy-2-nitropyridine (22a)
Preparation of 5-bromo-3-methoxy-2-nitropyridine (22a) the synthesis described in US2006/84665 was followed.
Tert-butyl (2- ((5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamic acid ester (22b)
A mixture of 5-bromo-3-methoxy-2-nitropyridine (22a) (2.8g,12.02mmol), tert-butylmethyl (2- (methylamino) ethyl) carbamate (2.67g,13.22mmol), palladium acetate (0.27g,1.20mmol), Xantphos (0.69g,1.20mmol) and cesium carbonate (11.7g,35.91mmol) in toluene (56mL) was stirred at 100 ℃ for 2.5h under nitrogen, the mixture was cooled to room temperature, water (200mL) was added and quenched, ethyl acetate was extracted (3 × 50mL), the extract was washed with brine, dried, concentrated, and purified by chromatography on a silica gel column with 50% ethyl acetate/n-hexane eluent to give tert-butyl (2- ((5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22b) as a yellow solid (3.0g, 73%), MS-ESI (M/z) 341[ M + 1.1.341 ]. The mixture was cooled to room temperature]+。
Tert-butyl (2- ((2-bromo-5-methoxy-6-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamic acid methyl ester Acid ester (22c)
To a mixture of tert-butyl (2- ((5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22b) (1.70g,5.00mmol) in glacial acetic acid (30mL) at 0 deg.C was added a solution of bromine (0.88g,5.50mmol) in glacial acetic acid (5mL), the mixture was stirred at 0 deg.C for 0.5h, stirred at room temperature, diluted with water (150mL), extracted with ethyl acetate (3 ×), the extracts were washed with saturated aqueous sodium bicarbonate and brine, sodium sulfate was dried, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography with eluent of 20-40% ethyl acetate/n-hexane to give tert-butyl (2- ((2-bromo-5-methoxy-6-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (22c) as a yellow solid (1.53g, 73%), MS-ESI (M/z):419.2and 421.2[1:1, M + 3and M + 3%]+。
Tert-butyl (2- ((2- ((diphenylmethylene) amino) -5-methoxy-6-nitropyridin-3-yl) (methyl) amino) Ethyl (methyl) carbamate (22d)
Tert-butyl (2- ((2-bromo-5-methoxy-6-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (22c) (419mg,1.00mmol), Pd2(dba)3(27.5mg,0.030mmol), (+/-) -BINAP (37.4mg,0.060mmol), benzophenone imine (199mg,1.10mmol) and sodium tert-butoxide (192mg,2.0 mmol)0mmol) of a mixture in toluene (5mL), heated to 80 ℃ under nitrogen for 4h, cooled to room temperature, the solvent evaporated under reduced pressure, tetrahydrofuran (14mL) and 0.5N hydrochloric acid (14mL) were added successively, the mixture was stirred at room temperature for 1.5h, diluted with sodium bicarbonate (50mL), ethyl acetate extracted (2 ×), the extracts washed with brine, dried over magnesium sulfate, the solvent evaporated under reduced pressure, the residue was purified by column chromatography on silica gel with 20-50% ethyl acetate/N-hexane as eluent to give tert-butyl (2- ((2- ((diphenylmethylene) amino) -5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22d) as a yellow solid (76mg, 21%). MS-ESI (M/z):356.2[ M +1 ]/, (M + 1) ethyl (methyl) carbamate]+。
Tert-butyl (2- ((2-acrylamido-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) Yl) carbamic acid ester (22e)
To a mixture of tert-butyl (2- ((2- ((diphenylmethylene) amino) -5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22d) (75mg,0.211mmol) in acetonitrile (3mL) at 0 ℃ was added 3-chloropropionyl chloride (53.6mg,0.422mmol), DMAP (51.5mg,0.422mmol) and DIPEA (81.7mg,0.633mmol) the mixture was stirred at 0 ℃ for 2.5h, sodium hydroxide (10N,0.8mL) was added and the mixture was stirred at room temperature for 1.5h, diluted with water, ethyl acetate extracted (2 ×) and the solvent was evaporated to dryness under reduced pressure, the residue was purified by silica gel column chromatography with an eluent of 5% methanol/dichloromethane to give tert-butyl (2- ((2-acrylamido-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (22e) (28.5mg, 33%) MS-ESI (M) M + 2M: (1.410): 1.5: (M): 1.5%) of ethyl (2-ethyl) carbamate (22e) (28.5]+。
Tert-butyl (2- ((2-acrylamido-6-amino-5-methoxypyridin-3-yl) (methyl) amino) ethyl (methyl) Carbamate (22f)
Heating and refluxing a mixture of tert-butyl (2- ((2-acrylamido-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22e) (28.5mg,0.070mmol), iron powder (19.5mg,0.348mmol) and ammonium chloride (3.7mg,0.070mmol) in ethanol-water (3:1,15mL) for 2h, evaporating the solvent under reduced pressure, purifying the residue by silica gel column chromatography with an eluent of 92:6:2 dichloromethane-methanol-ammonia to give tert-butyl (2- ((2-acrylamido-6-amino-5-methyl) esterOxopyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22f) (9.0mg, 34%). MS-ESI (M/z) 380.2[ M +1 ]]+。
Tert-butyl (2- ((2-acrylamido-5-methoxy-6- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-) Yl) amino) pyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22g)
Tert-butyl (2- ((2-acrylamido-6-amino-5-methoxypyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22f) (8.6mg,0.023mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1H,6.6mg,0.027mmol), Pd2(dba)3A mixture of (3.4mg,0.0036mmol), BINAP (2.2mg,0.0036mmol) and cesium carbonate (11mg,0.034mmol) in dioxane (0.5mL) was heated to 100 deg.C for 2.5 h. Diluting with water, and extracting with dichloromethane. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with 95:5 dichloromethane-methanol to give tert-butyl (2- ((2-acrylamido-5-methoxy-6- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22g) (3.3mg, 25%). MS-ESI (M/z):586.3[ M +1 ] M]+。
N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -5-methoxy-6- ((4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) pyridin-2-yl) acrylamide (22)
To a solution of tert-butyl (2- ((2-acrylamido-5-methoxy-6- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22g) (3.3mg) in dichloromethane (0.5mL) at room temperature was added trifluoroacetic acid (0.5mL) the mixture was stirred at room temperature for 40 minutes the solvent was evaporated, NaBH (OAc) was added3(3.5mg), 1, 2-dichloroethane (0.3mL) and formaldehyde (37% water, 15 mg). The mixture was stirred at room temperature for 1h, diluted with sodium bicarbonate and extracted with dichloromethane. The crude product was purified by column chromatography on silica gel eluting with 95:4:1 dichloromethane-methanol-ammonia to give N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -5-methoxy-6- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-2-yl) acrylamide (22) (2.5mg, 89%). MS-ESP 501.4[ M +1 ]]+。
Example 23
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (23)
2 2 5N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (1-methyl-1H-indol-3-yl) pyrimidine Pyridin-2-yl) -3-nitropyridine-2, 5-diamine (23a)
Preparation of the title compound 23a the synthesis of example 2 was followed, adding N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (2g) by N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-3-nitropyridine-2, 5-diamine (15 e). MS-ESI (M/z) 477[ M +1 ]]+。
2 2 5N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (1-methyl-1H-indol-3-yl) pyrimidine Pyridin-2-yl) pyridine-2, 3, 5-triamine (23b)
Preparation of the title Compound 23b according to the procedure for the synthesis of 15i, N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15h) by N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (23 a). MS-ESI (M/z):447[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (23)
Will N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5(4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) (20mg,0.045mmol), HOBT (18mg,0.135mmol), EDCI (26mg,0.135), triethylamine (14mg,0.135mmol) in DMF (2mL) was stirred at 35 ℃ for 3H, the reaction was cooled to room temperature, water (5mL) was added and quenched, the mixture was adjusted to pH 9-10 with sodium carbonate, and ethyl acetate (8mL × 3-3)). The organic layers were combined, washed with brine (20mL) and dried over sodium sulfate. The solid was removed by filtration, the filtrate was concentrated under low pressure and the residue was purified by column chromatography over silica gel with dichloromethane/methanol (10:1) as eluent to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (23). MS-ESI (M/z):518[ M +1 [)]+。
Example 24
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) phenyl) -2-fluoroacrylamide (24)
1 1N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-2-nitrobenzene-1, 4-diamine (24a)
4-fluoro-2-methoxy-5-nitroaniline (3.0g,16.0mmol) (prepared according to document WO 2013/14448), N1,N1,N2A mixture of-trimethylethane-1, 2-diamine (2.0g,19.7mmol) and DIPEA (2.7g,20.8mmol) DMA was stirred at 80 ℃ for 5h, cooled to room temperature, DMA evaporated, diluted with water (50mL), dichloromethane extracted (50mL × 3) & combined organic layers, washed with water (100mL) and brine (100mL), dried over sodium sulfate, filtered to remove solids, the filtrate concentrated at low pressure, the residue purified by silica gel column chromatography with dichloromethane/methanol (20: 1-10: 1) eluent to give N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitrobenzene-1, 4-diamine (24 a). MS-ESI (M/z):269[ M + 1%]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indole-3-) Yl) pyrimidin-2-yl) amino) phenyl) -2-fluoroacrylamide (24)
Preparation of the title compound 24 according to the synthesis of example 23, N2- (2- (methoxy) ethyl) -6-methoxy-N2Replacement of-methyl-3-nitropyridine-2, 5-diamine (15e) by N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitrobenzene-1, 4-diamine (24 a). MS-ESI (M/z):517[ M + 1%]+。
Example 25
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylindozin-3-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (25)
1- (2-ethoxy-2-oxyethyl) -2-ethylpyridine-1-bromide (25a)
To a mixture of 2-ethylpyridine (10g,0.09mol) in ethanol (200mL) was added ethyl 2-bromoacetate (23g,0.14mmol), heated under reflux for 16h, then cooled to room temperature and concentrated under reduced pressure to give crude 1- (2-ethoxy-2-oxyethyl) -2-ethylpyridine-1-carbonyl bromide (25a) which was used in the next reaction without further purification. MS-ESI (M/z):194[ M [)]+。
Ethyl 1-methylindoxazine-3-carboxylate (25b)
To an ethanol solution (100mL) of 1- (2-ethoxy-2-oxyethyl) -2-ethylpyridine-1-bromide (25a) (10g,0.036mol) and potassium carbonate (15g,0.10mol) was added (E) -ethyl 2-cyano-3-ethoxyacrylate (25g,0.14 mol). The mixture was heated under reflux for 15h, then cooled to room temperature, concentrated under reduced pressure, the residue was extracted with ethyl acetate (50mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with n-hexane/ethyl acetate (50: 1-20: 1) as eluent to give ethyl 1-methylindoxazine-3-carboxylate (25 b). MS-ESI (M/z):275[ M + 1M + 3-carboxylate (25 b): 275]+。
N-methoxy-N, 1-dimethylindolizine-3-amide (25c)
To a solution of ethyl 1-methylindoxazine-3-carboxylate (25b) (3.0g,0.014mol) and N, O-dimethylhydroxylamine hydrochloride (3.6g,0.037mol) in tetrahydrofuran (50mL) at 0 deg.C was added isopropylmagnesium chloride (2M in Et2O,35mL,0.07mol), stirring the mixture for 1h, adding water for quenching, extracting with ethyl acetate (50mL × 3), combining organic layers, washing with brine, drying with sodium sulfate, filtering, concentrating under reduced pressure, purifying the residue by silica gel column chromatography, wherein an eluent is N-hexane/ethyl acetate (20: 1-10: 1) to obtain N-methoxy-N, 1-dimethylindolizine-3-amide (25c), MS-ESI (M/z):219[ M + 1: (M + 1): 219]+。
1- (1-methylindozin-3-yl) ethanone (25d)
To N-methoxy-N, 1-dimethylindolizine-3-amide (25c) (2.6 g) at 0 deg.C0.012mol) in tetrahydrofuran (50mL), stirred for 1h, quenched with water, extracted with ethyl acetate (50mL × 3), combined organic layers, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1- (1-methylindozin-3-yl) ethanone (25d) which is used in the next step without further purification, MS-ESI (M/z):174[ M +1]+。
(E) -1- (1-methylindozin-3-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (25e)
Adding pyrrolidine (10mL,0.12mol) to a DMF-DMA (25mL) solution of 1- (1-methylindozin-3-yl) ethanone (25d) (2.0g,0.012mol) at 25 ℃, stirring at 90 ℃ for 1h, extracting with ethyl acetate (50mL × 3) and washing the organic layer with brine, drying with sodium sulfate, filtering, concentrating under reduced pressure, purifying the residue by silica gel column chromatography, wherein the eluent is n-hexane/ethyl acetate (10: 1-2: 1) to obtain (E) -1- (1-methylindozin-3-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (25E) and MS-ESI (M/z):255[ M + 1: (M + 1): 255: (M + 1): 1)]+。
4- (1-Methylidazin-3-yl) pyrimidin-2-amine (25f)
To a solution of (E) -1- (1-methylindozin-3-yl) -3- (pyrrolidin-1-yl) propan-2-en-1-one (25E) (1.0g,0.0039mol) and potassium carbonate (2.7g,0.012mol) in isopropanol (10mL) at 25 deg.C was added guanidine hydrochloride (1.1g,0.19 mol). The mixture was stirred at 130 deg.C for 16h, then cooled to room temperature, ethyl acetate extracted (50mL × 3). The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography with dichloromethane/methanol (30:1) as eluent to give 4- (1-methylindozin-3-yl) pyrimidin-2-amine (25 f). MS-ESI (M/z):225[ M + 1: (M/z):225]+。
2 2 5N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (1-methylindazin-3-yl) pyrimidine-2- Yl) -3-Nitropyridine-2, 5-diamine (25g)
To 4- (1-methylindozin-3-yl) pyrimidin-2-amine (25f) (150mg,0.67mmol), N at 25 deg.C1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2-trimethylethane-1, 2-diamine (15c) (382mg,0.33mmol and cesium carbonate (0.87g,2.67mmol) in tolueneTo a solution of Xantphos (193mg,0.33mmol) in 1, 4-dioxane (2.5mL) was added palladium acetate (75mg,0.33 mmol). After stirring the mixture at 110 ℃ for 3h, it was cooled to room temperature and extracted with ethyl acetate (50 mL. times.3). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purifying the residue by silica gel column chromatography with dichloromethane/methanol (40: 1-20: 1) as eluent to obtain N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (1-methylindozin-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (25 g). MS-ESI (M/z) 477[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylindozin-3-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (25)
Preparation of the title compound 25 the synthesis of example 15 was followed, adding N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (1-methylindozin-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (25 g). MS-ESI (M/z):501[ M +1 ]]+。
Example 26
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methylindozin-3-yl) Pyrimidin-2-yl) amino) phenyl) acrylamide (26)
1 1 2 2N- (4-iodo-5-methoxy-2-nitrophenyl) -N, N, N-trimethylethane-1, 2-diamine (26a)
At 0 ℃ to N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitrobenzene-1, 4-diamine (24a) (3.2g,11.9mmol) in 1N sulfuric acid (50mL) was added sodium nitrite (1.28g,17.9mmol) and the mixture was stirred at 0 ℃ for 15 min, then potassium iodide (4.0g,23.8mmol) was added and the mixture was stirred at 90 ℃ for 1h, cooled to room temperature, adjusted to pH 9-10 with sodium carbonate the resulting mixture was extracted with ethyl acetate (20mL × 3), the organic layers combined, washed with brine (20mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, the residuePurifying by silica gel column chromatography eluting with dichloromethane/methanol (20:1) to obtain N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (26 a). MS-ESI (M/z) 380[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methylindozin-3-yl) Pyrimidin-2-yl) amino) phenyl) acrylamide (26)
Preparation of the title compound 26 the synthesis of example 25 was followed, adding N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (26 a). MS-ESI (M/z) 500[ M +1 ]]+。
Example 27
N- (5- ((4- (1-cyanoindolizin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -6-methoxypyridin-3-yl acrylamide (27)
1- (2-ethoxy-2-oxyethyl) pyridine-1-bromide (27a)
To a mixture of pyridine (10g,0.09mol) in ethanol (200mL) was added ethyl 2-bromoacetate (23g,0.14mmol), heated at reflux for 16h, then cooled to room temperature and concentrated under low pressure to give crude 1- (2-ethoxy-2-oxyethyl) pyridine-1-bromide (27a) which was used in the next reaction without further purification. MS-ESI (M/z):167[ M ]]+。
Ethyl 1-cyanoindolizine-3-carboxylic acid ester (27b)
To an ethanol solution (250mL) of 1- (2-ethoxy-2-oxyethyl) pyridine-1-bromide (27a) (10g,0.04mol) and triethylamine (29mL,0.2mol) was added (E) -3-methacrylonitrile (10g,0.12 mol). the mixture was heated under reflux for 15h, then cooled to room temperature, concentrated under reduced pressure, the residue was extracted with ethyl acetate (50mL × 3). the combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, purified by column chromatography on silica gel with an eluent of n-hexane/ethyl acetate (50:1 to 20:1) to give ethyl 1-cyanoindolizine-3-carboxylate (27 b).MS-ESI(m/z):215[M+1]+。
N- (5- ((4- (1-cyanoindolizin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -6-methoxypyridin-3-yl acrylamide (27)
Preparation of the title compound 27 according to the synthesis method of example 25, ethyl 1-methylindolizine-3-carboxylate (25b) was replaced with ethyl 1-cyanoindolizine-3-carboxylate (27 b). MS-ESI (M/z):501[ M +1 ]]+。
Example 28
N- (5- ((4- (1-cyanoindolizin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -4-methoxyphenyl) acrylamide (28)
Preparation of the title compound 28 according to the procedure for the synthesis of example 27, N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (26 a). MS-ESI (M/z) 511[ M +1 ]]+。
Example 29
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-3-yl) pyrimidin-2-yl) amino) - 6-methoxypyridin-3-yl) acrylamide (29)
Preparation of the title compound 29 according to the procedure for the synthesis of example 25, 2-ethylpyridine was replaced with 2-methylpyridine. MS-ESI (M/z):487[ M +1 ]]+。
Example 30
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-3-yl) pyrimidin-2-yl) amino) - 4-methoxyphenyl) acrylamide (30)
Preparation of the title compound 30 according to the synthesis of example 29, N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-Trim chlorideEthane-1, 2-diamine (26 a). MS-ESI (M/z):486[ M +1 [)]+。
Example 31
N- (5- ((4- (1-Chloroindazin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino 6-methoxypyridin-3-yl acrylamide (31)
Ethyl indolizine-3-carboxylic acid ester (31a)
Preparation of the title compound, ethyl indolizine-3-carboxylate (31a) 2-ethylpyridine was replaced with 2-methylpyridine according to the synthetic procedure for compound 25 b. MS-ESI (M/z) 190[ M +1 ]]+。
Ethyl 1-chloridazine-3-carboxylate (31b)
Adding N-chlorosuccinimide (0.3g,2.2mmol) to a solution of ethyl indolizine-3-carboxylate (31a) (0.4g,2.2mmol) in DMF (5mL) at 0 deg.C, stirring the mixture at 25 deg.C for 1h, extracting with ethyl acetate (50mL × 3), washing the combined organic layers with brine, drying over sodium sulfate, concentrating under reduced pressure, purifying by column chromatography on silica gel to give ethyl 1-chloroindolizine-3-carboxylate (31b), MS-ESI (M/z):224[ M +1 ]: 224[ M +1]+。
N- (5- ((4- (1-Chloroindazin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino 6-methoxypyridin-3-yl) acrylamide(31)
Preparation of the title compound 31 according to the synthesis method of example 25, ethyl 1-methylindolizine-3-carboxylate (25b) was replaced with ethyl 1-chloroindolizine-3-carboxylate (31 b). MS-ESI (M/z):521[ M +1 ]]+。
Example 32
N- (5- ((4- (1-Chloroindazin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino Yl) -4-methoxyphenyl) acrylamide (32)
Preparation of the title compound 32 the synthesis of example 31 was followed, adding N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (26 a). MS-ESI (M/z):520[ M +1 ]]+。
Example 33
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylindozin-1-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (33)
3-methylindolizine-1-carbonitrile (33a)
A mixture of 2-bromopropanal (7.26g,53.4mmol) and 2-pyridineacetonitrile (6.3g,53.4mmol) in tetrahydrofuran (70mL) was heated at 70 ℃ for 24 h. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and hydrochloric acid (20mL,2M), and the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (10:1 to 5:1) as eluent to give 3-methylindoxazine-1-carbonitrile (33 a). MS-ESI (M/z) 157[ M +1 ]]+。
1- (3-methylindozin-1-yl) ethane-1-imine (33b)
To a solution of 3-methylindoxazine-1-carbonitrile (33a) (1.6g,10.3mmol) in tetrahydrofuran was added 3M methylmagnesium bromide (18mL) in an ice-water bath, and the mixture was stirred at room temperature for 15 h. The mixture was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1- (3-methylindozin-1-yl) ethane-1-imine (33 b). MS-ESI (M/z):173[ M +1 ]]+。
1- (3-Methylidazin-1-yl) ethan-1-one (33c)
To a solution of 1- (3-methylindazin-1-yl) ethane-1-imine (33b) (1.0g,5.8mmol) in tetrahydrofuran was added 6N sulfuric acid (60mL) at room temperature, heated to 55 ℃ for 24h, and cooled to room temperature. The reaction mixture was diluted with water and dichloromethane, the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 1- (3-methylindozin-1-yl) ethan-1-one (33 c). MS-ESI (M/z):174[ M +1]+。
1- (3-methylindozin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33d)
To 1- (3-methylindozin-1-yl) ethane at 25 DEG C-1-ketone (33c) (110mg,0.7mmol) in DMF was added DMF-DMA (170mg,1.4mmol) and pyrrolidine (50mg,0.7 mmol). The mixture was stirred for 1.5h at 90 ℃. After cooling to room temperature, extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give crude 1- (3-methylindozin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33 d). MS-ESI (M/z) 255[ M +1 ]]+。
4- (3-Methylidazin-1-yl) pyrimidin-2-amine (33e)
To a solution of 1- (3-methylindozin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33d) (300mg,1.2mmol) in isopropanol was added guanidine hydrochloride (337mg,3.5mmol) and potassium carbonate (662mg,4.8 mmol). The mixture was stirred in a sealed tube at 120 ℃ for 20 h. Cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4- (3-methylindazin-1-yl) pyrimidin-2-amine (33 e). MS-ESI (M/z) 225[ M +1 ]]+。
2 2 5N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (3-methylindazin-3-yl) pyrimidine-2- Yl) -3-nitropyridine-2, 5-diamine (33f)
A mixture of 4- (3-methylindozin-1-yl) pyrimidin-2-amine (33e) (30.0mg,0.13mmol), 25c (76.0mg,0.20mmol), palladium acetate (15.0mg,0.07mmol), Xantphos (38.0mg,0.07mmol) and cesium carbonate (170mg,0.52mmol) in toluene (1mL) and dioxane (0.5mL) was heated to 110 ℃ under nitrogen for 3 h. Cooling to room temperature, adding water for dilution, and extracting with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 9% methanol in dichloromethane to give N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (3-methylindozin-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (33 f). MS-ESI (M/z) 477[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylindozin-1-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (33)
Preparation of the title compound 33 according to the synthesis of example 15, N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (3-methylindozin-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (33 f). MS-ESI (M/z):501[ M +1 ]]+.
Example 34
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methylindozin-1-yl) Pyrimidin-2-yl) amino) phenyl) acrylamide (34)
Preparation of the title compound 34 the synthesis of example 33 was followed, N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (26 a). MS-ESI (M/z) 500[ M +1 ]]+。
Example 35
N- (5- ((4- (3-Cyanoindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -6-methoxypyridin-3-yl acrylamide (35)
1-Acetylindolizine-3-carbonitrile (35a)
A mixture of 1- (cyanomethyl) pyridine-1-bromide (10g,50.3mmol), 4-methoxybut-3-en-2-one (5.1g,50.3mmol) and triethylamine (10g,100.6mmol) in ethanol (100mL) was heated at 80 ℃ for 7 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with dichloromethane and water, the organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The residue was stirred in isopropanol for 0.5h, filtered and dried to give 1-acetylindolizine-3-carbonitrile (35a) as a yellow solid. MS-ESI (M/z) 185[ M +1 ]]+。
1- (3- (pyrrolidin-1-yl) acryloyl) indolizine-3-carbonitrile (35b)
To a solution of 1- (3-methylindozin-1-yl) ethan-1-one (33c) (110mg,0.7mmol) in DMF was added DMF-DMA (170mg,1.4mmol) and pyrrolidine (50mg,0.7 mmol). The mixture was stirred for 1.5h at 90 ℃. After cooling to room temperature, extraction was carried out with ethyl acetate. Is provided withThe organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude 1- (3-methylindazin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33 d). To a solution of 1-acetylindolizine-3-carbonitrile (35a) (400mg,2.17mmol) in DMF was added DMF-DMA (516mg,4.34mmol) and pyrrolidine (308mg,4.34 mmol). The mixture was stirred for 1.5h at 90 ℃. After cooling to room temperature, extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude 1- (3- (pyrrolidin-1-yl) acryloyl) indolizine-3-carbonitrile (35 b). MS-ESI (M/z) 266[ M +1 ]]+。
1- (2-Aminopyrimidin-4-yl) indolizine-3-carbonitrile (35c)
To a solution of 1- (3- (pyrrolidin-1-yl) acryloyl) indolizine-3-carbonitrile (35b) (637mg,2.4mmol) in 1-butanol was added guanidine hydrochloride (690mg,7.2mmol) and potassium carbonate (1.3g,9.6 mmol). The mixture was stirred for 20h at 115 ℃. After cooling to room temperature, water was added for dilution, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude 1- (2-aminopyridin-4-yl) indolizine-3-carbonitrile (35 c). MS-ESI (M/z) 236[ M +1 ]]+。
N- (5- ((4- (3-Cyanoindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -6-methoxypyridin-3-yl acrylamide (35)
Preparation of the title compound 35 according to the procedure for the synthesis of example 33, 4- (3-methylindozin-1-yl) pyrimidin-2-amine (33e) was replaced with 1- (2-aminopyridin-4-yl) indolizine-3-carbonitrile (35 c). MS-ESI (M/z):512[ M +1 [)]+。
Example 36
N- (5- ((4- (3-Cyanoindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -4-methoxyphenyl) acrylamide (36)
Preparation of the title compound 36 the synthesis of example 35 was followed, adding N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (26 a). MS-ESI (M/z) 511[ M +1 ]]+。
Example 37
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-1-yl) pyrimidin-2-yl) amino) - 6-methoxypyridin-3-yl) acrylamide (37)
1- (2-ethoxy-2-oxyethyl) pyridine-1-bromide (37a)
To a mixture of pyridine (10g,0.09mol) in ethanol (200mL) was added ethyl 2-bromoacetate (23g,0.14mmol), heated at reflux for 16h, then cooled to room temperature to give crude 1- (2-ethoxy-2-oxyethyl) pyridine-1-bromide (27a) which was used in the next reaction without further purification. MS-ESI (M/z):167[ M ]]+. A solution of pyridine (2.00g,25.30mmol) and ethyl 2-bromoacetate (6.3g,38.00mmol) in ethanol (20mL) was heated at 70 ℃ for 1h under nitrogen. Concentrated under reduced pressure, the residue was filtered through celite and washed with petroleum ether to give 6.9 g of 1- (2-ethoxy-2-oxyethyl) pyridine-1-carbonyl bromide (37 a). MS-ESI (M/z) 167[ M +1 ]]+。
Ethyl 1-acetylindolizine-3-carboxylate (37b)
Adding (E) -3-methacrylonitrile (10g,0.12mol) to an ethanol solution (250mL) of 1- (2-ethoxy-2-oxyethyl) pyridine-1-bromide (27a) (10g,0.04mol) and triethylamine (29mL,0.2mol), heating under reflux for 15h, concentrating under reduced pressure, collecting the residue (50mL ×) and the combined organic layer, washing with brine, drying with sodium sulfate, filtering, concentrating under reduced pressure, purifying the residue by silica gel column chromatography using n-hexane/ethyl acetate (50: 1-20: 1) as eluent to obtain ethyl 1-cyanoindolizine-3-carboxylate, adding triethylamine (4.50g,44.60mmol) to an ethanol solution (65mL) of 1- (2-ethoxy-2-oxyethyl) pyridine-1-bromide (37a) (5.50g,15.10mmol) and 4-methoxybut-3-en-2 one (2.3g,22.3mmol) at 20 ℃ and extracting the residue by column chromatography using ethyl acetate (50mL) as eluent to obtain ethyl 1- (2-ethoxy-2-oxyethyl) pyridine-1-bromide (37a mixture, heating under reflux for 80 ℃ and concentrating under reduced pressure to obtain ethyl acetate-3-ethyl acetate-1-2-ethyl acetate (35M) as eluent, concentrating under reduced pressure to obtain a purified silica gel column chromatography (65mL) of 4.50g, 30M) and extracting the]+。
1- (indolizin-1-yl) ethan-1-one (37c)
To a solution of ethyl 1-acetylindolizine-3-carboxylate (37b) (2.60g,11.3mmol) in methanol (30mL) at 20 deg.C) 10% sodium hydroxide (2.0g,50.6M mol) was added, the mixture was heated at 65 ℃ for 1h, concentrated under reduced pressure to remove the solvent, polyphosphoric acid (10.0g) and methanol (40mL) were added, the mixture was heated at 65 ℃ for 40 min, cooled to room temperature, diluted with water, extracted with dichloromethane (3 × 50mL), the extract was washed with sodium bicarbonate and brine, dried over sodium sulfate and concentrated to give 1- (indolizin-1-yl) ethan-1-one (37c) (1.23g), MS-ESI (M/z):160[ M + 1-yl) ethan-1-one (37c) (1.23g)]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-1-yl) pyrimidin-2-yl) amino) - 6-methoxypyridin-3-yl) acrylamide (37)
Preparation of the title compound 37 following the procedure for the synthesis of example 35, 1-acetylindolizine-3-carbonitrile (35a) was replaced with 1- (indolizin-1-yl) ethan-1-one (37 c). MS-ESI (M/z):487[ M +1 ]]+。
Example 38
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indolizin-1-yl) pyrimidin-2-yl) amino) - 4-methoxyphenyl) acrylamide (38)
Preparation of the title compound 38 the procedure for the synthesis of example 37 was followed, mixing N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (26 a). MS-ESI (M/z):486[ M +1 [)]+。
Example 39
N- (5- ((4- (3-Chloroindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino 6-methoxypyridin-3-yl acrylamide (39)
1- (3-Chlorindolizin-1-yl) ethan-1-one (39a)
Stirring a mixture of 1- (indolizin-1-yl) ethane-1-one (37c) and cuprous chloride (962mg,5.7mmol) in acetonitrile (6mL) at room temperature for 4h, adding water (10mL) for dilution, extracting with dichloromethane (3 × 10mL), drying extract liquid sodium sulfate, concentrating under reduced pressure, purifying residue by silica gel column chromatography, and eluting with petroleum ether/ethyl acetate (8: 1-6: 1) to obtain 1- (3-chloroindolizin-1-yl) ethyl acetateAlk-1-one (39 a). MS-ESI (M/z):194[ M +1 ]]+。
N- (5- ((4- (3-Chloroindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino 6-methoxypyridin-3-yl acrylamide (39)
Preparation of the title compound 39 following the procedure for the synthesis of example 35, 1-acetylindolizine-3-carbonitrile (35a) was replaced with 1- (3-chloroindolizin-1-yl) ethan-1-one (39 a). MS-ESI (M/z):521[ M +1 ]]+。
Example 40
N- (5- ((4- (3-Chloroindolizin-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino Yl) -4-methoxyphenyl) acrylamide (40)
Preparation of the title compound 40 according to the procedure for the synthesis of example 39, N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (26 a). MS-ESI (M/z):520[ M +1 ]]+。
EXAMPLE 41
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methyl-1H-indole-1-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (41)
1- (2-Chloropyrimidin-4-yl) -3-methyl-1H-indole (41a)
To a solution of 2, 4-dichloropyrimidine (2.89g,20.0mmol) and 3-methyl-1H-indole (1.31g,10.0mmol) in DMA (50mL) at room temperature were added HOBT (306mg,2.0mmol) and potassium carbonate (1.93g,14.0mmol), the mixture was stirred at 70 ℃ for 24H, diluted with water (50mL), extracted with ethyl acetate (2X 30mL), the extract washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (10: 1-5: 1) to give 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indole (41a) as a yellow solid (1g, 40%).
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methyl-1H-indole-1-) Yl) pyrimidin-2-yl) aminoYl) pyridin-3-yl) acrylamide (41)
Preparation of the title compound 41(17.3mg) 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1H) was replaced with 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indole (41a) as in 1. MS-ESI (M/z):501[ M +1 ]]+。
Example 42
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-1H-indole-1-) Yl) pyrimidin-2-yl) amino) phenyl) acrylamide (42)
N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (3-methyl-1H-indol-1-yl) pyrimidin-2-amine (42a)
A mixture of 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indole (41a) (278mg,1.14mmol), 4-fluoro-2-methoxy-5-nitroaniline (213mg,1.14mmol) (prepared according to document WO 2013/14448), and p-toluenesulfonic acid monohydrate (260mg,1.37mmol) in 2-pentanol (4mL) was heated at 105 ℃ for 2H, filtered, and concentrated under reduced pressure to give N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (3-methyl-1H-indol-1-yl) pyrimidin-2-amine (42a) (320mg, 72%). MS-ESI (M/z):394[ M +1 [)]+。
1 1 4N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-N- (4- (3-methyl-1H-indol-1-yl) pyrimidine Pyridin-2-yl) -2-nitrophenyl-1, 4-diamine (42b)
Mixing N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (3-methyl-1H-indol-1-yl) pyrimidin-2-amine (42a) (160mg,0.407mmol), N1,N1,N2A mixture of trimethylethane-1, 2-diamine (0.064mL,0.489mmol) and DIPEA (0.088mL,0.529mmol) in DMA was heated at 85 ℃ for 3 h. Concentrating under reduced pressure, purifying the residue by silica gel column chromatography eluting with dichloromethane/methanol/ammonia (92:6:2) to obtain N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine (42b) (139mg, 73%).
MS-ESI(m/z):476[M+1]+。
1 1 4N- (2- (dimethylamino) ethyl) -5-methoxy-N-methyl-N- (4- (3-methyl-1H-indol-1-yl)) Pyrimidine as one kind of food Pyridin-2-yl) -2-nitrophenyl-1, 4-diamine (42c)
Will N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42b) (139mg,0.293mmol), iron powder (98mg,1.76mmol) and ammonium chloride (22.0mg,0.293mmol) in ethanol-water (3:1,15mL) mixture was heated at reflux for 1H. The pad was filtered through celite, washed with ethyl acetate, the washings diluted with ethyl acetate, washed with water and brine. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane/methanol/ammonia (92:6:2) to give N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrophenyl-1, 4-diamine (42c) (120mg, 92%). MS-ESI (M/z):446[ M +1 ]]+。
3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-1H-indole) Indol-1-yl) pyrimidin-2-yl) amino) phenyl) propionamide (42d)
At 0 ℃ to N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42c) (120mg,0.27mmol) in tetrahydrofuran-water (10:1,3mL) was added 3-chloropropionyl chloride (0.031mL,0.32mmol), stirred at 0 ℃ for 2H, added ammonia (0.5mL), diluted with water and extracted with ethyl acetate. The solvent was evaporated to dryness and the residue was purified by silica gel column chromatography eluting with 2-5% methanol/dichloromethane to give 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) phenyl) propionamide (42d) (100mg, 69%). MS-ESI (M/z):536[ M +1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-1H-indole-1-) Yl) pyrimidin-2-yl) amino) phenyl) acrylamide (42)
To a solution of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) phenyl) propanamide (42d) (100mg,0.187mmol) in tetrahydrofuran-water (10:1,2mL) at room temperature was addedSodium hydroxide (60mg,1.5mmol) was added, stirred for 2h, diluted with water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with 1-2% methanol/dichloromethane to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (42) (60mg, 65%). MS-ESI (M/z) 500[ M +1 ]]+。
Example 43
N- (6-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazine- 1-yl) pyridin-3-yl) acrylamide (43)
N- (4-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) Phenyl) acrylamide (43a)
Preparation of the title compound 43a (10mg) according to the synthetic method of example 41, N1,N1,N2-trimethylethane-1, 2-diamine with tert-butylpiperazine-1-carboxylate. MS-ESI (M/z) 485[ M +1 ]]+。
N- (6-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazine- 1-yl) pyridin-3-yl) acrylamide (43)
Preparation of title compound 43(4.9mg) N- (6-ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (5) was replaced with N- (4-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) phenyl) acrylamide (43a) according to the synthesis of example 6. MS-ESI (M/z):499[ M +1 ]]+。
Example 44
N- (4-methoxy-5- ((4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazine- 1-yl) phenyl) acrylamide (44)
Preparation of the title compound 44 the procedure was followed for the synthesis of example 42, coupling N1,N1,N2-trimethylethane-1, 2-diamine is replaced by 1-methylpiperazine. MS-ESI (M/z) 498[ M +1 ]]+。
Example 45
N- (5- ((4- (3-cyano-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -6-methoxypyridin-3-yl acrylamide (45)
1- (2-Chloropyrimidin-4-yl) -1H-indole-3-carbonitrile (45b)
Preparation of the title compound, 1- (2-chloropyrimidin-4-yl) -1H-indole-3-carbonitrile (45b) (220mg) according to the synthetic method of 41a, 3-methyl-1H-indole was replaced with 1H-indole-3-carbonitrile (45a) (preparation of this reagent according to the reference: JOC 1958,23, 1178). MS-ESI (M/z) 255[ M +1 ]]+。
N- (5- ((4- (3-cyano-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -6-methoxypyridin-3-yl acrylamide (45)
Preparation of the title compound 45(7.0mg) according to the synthesis of example 15, 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) was replaced with 1- (2-chloropyrimidin-4-yl) -1H-indole-3-carbonitrile (45 b). MS-ESI (M/z):512[ M +1 [)]+。
Example 46
N- (5- ((4- (3-cyano-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) -4-methoxyphenyl acrylamide (46)
Preparation of the title compound 46(5mg) according to the synthetic method of example 45, N2- (2- (dimethylamino) ethyl) -6-methoxy-N2Replacement of-methyl-3-nitropyridine-2, 5-diamine (15e) by N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitropyridine-1, 4-diamine (24 a). MS-ESI (M/z) 511[ M +1 ]]+。
Example 47
N- (5- ((4- (1-chloroimidazole [1,5-a ]))]And pyridine-3-yl pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) Ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (47)
2- (methylthio) -N- (pyridin-2-yl) pyrimidine-4-amide (47a)
Pyridin-2-ylmethylamine (900mg,8.3mmol),2- (methylthio) pyrimidinePyridine-4-carboxylic acid (1g,5.9mmol) (prepared according to document WO 2006/117368), HOBT (2.4g,17.7mmol), EDCI (3.4g,17.7mmol), triethylamine (1.78g,17.7mmol) in DMF (10mL) mixture was stirred at room temperature for 2 h. the reaction was cooled to room temperature, quenched with water (10mL), adjusted to pH 9-10 with sodium carbonate, extracted with ethyl acetate (15mL × 3), combined organic layers, washed with brine (20mL), dried with sodium sulfate, filtered to remove solids, the filtrate was concentrated, the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate (2: 1-1: 1) as eluent to give 2- (methylthio) -N- (pyridin-2-yl) pyrimidine-4-amide (47 a). MS-ESI (M/z):247[ M + 1: (M + 1: 1): 247]+。
3- (2- (methylthio) pyrimidin-4-yl) imidazole [1,5-a]Pyridine (47b)
A solution of 2- (methylthio) -N- (pyridin-2-yl) pyrimidine-4-amide (47a) (370mg,1.5mmol) in acetonitrile (2mL) was added phosphorus oxychloride (2.5mL), the mixture was stirred at 85 ℃ for 20h, cooled to room temperature, quenched with water (10mL), adjusted to pH 8-9 with sodium hydroxide, extracted with dichloromethane (8mL × 3), the organic layers were combined, washed with brine (20mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a ] as a crude product]And pyridine (47 b). MS-ESI (M/z):243[ M +1 [)]+。
1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a]Pyridine (47c)
To 3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a ] at room temperature]Pyridine (200mg,0.83mmol) in DMF (2mL) was added N-chlorosuccinimide (144mg,1.08mmol), stirred at room temperature for 2h, quenched (5mL) with water, the resulting mixture was extracted with dichloromethane (5mL × 2), the organic layers were combined, washed with brine (10mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a ] imidazole]And pyridine (47 c). MS-ESI (M/z):277[ M +1 ]]+。
4- (1-chloroimidazole [1,5-a ]]And pyridin-3-yl) pyrimidin-2-ol (47d)
To 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a]To a solution of the pyridine (47c) (150mg,0.54mmol) in NMP (5mL) was added 10% sodium hydroxide (2mL), stirred at 100 ℃ for 24h, the reaction cooled to room temperature, adjusted to pH 5-6 with 2N hydrochloric acid, the resulting mixture extracted with dichloromethane (10mL × 3), the organic layers combined, washed with brine (20mL), sulfurDrying sodium salt, and concentrating to obtain crude product 4- (1-chloroimidazole [1,5-a ]]And pyridin-3-yl) pyrimidin-2-ol (47 d). MS-ESI (M/z):247[ M + 1[ ]]+。
A-chloro-3- (2-chloropyrimidin-4-yl) imidazo [1,5-a]Pyridine (47e)
4- (1-chloroimidazole [1,5-a ]]Pyrophosphorus oxychloride (1mL) was added to a solution of (47d) (140mg,0.57mmol) in acetonitrile (1mL), the mixture was stirred at 80 ℃ for 1.5h, cooled to room temperature, quenched with water (5mL), adjusted to pH 8-9 with sodium hydroxide, extracted with dichloromethane (8mL × 3), the organic layers were combined, washed with brine (20mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 1-chloro-3- (2-chloropyrimidin-4-yl) imidazole [1,5-a ] 1,5-a]And pyridine (47 e). MS-ESI (M/z):265[ M +1 [)]+。
1 4N- (4- (1-chloroimidazole [1,5-a ]]Pyridin-3-yl) pyrimidin-2-yl-N- (2- (dimethylamino) ethyl) -2- 4methoxy-N-methyl-5-nitrobenzene-1, 4-diamine (47f)
1-chloro-3- (2-chloropyrimidin-4-yl) imidazole [1,5-a ] is reacted with a catalyst]Pyridine (47e) (54mg,0.20mmol), N2- (2- (dimethylamino) ethyl) -6-methoxy-N2A mixture of methyl-3-nitropyridine-2, 5-diamine (15e) (61mg,0.22mmol) and methanesulfonic acid (27mg,0.24mmol) in isopropanol (2.5mL) was stirred at 90 ℃ for 3h, cooled to room temperature, quenched with water (10mL), adjusted to pH 8-9 with sodium carbonate, extracted with ethyl acetate (30mL × 3), the organic layers combined, washed with water (30mL) and brine (30mL), dried over sodium sulfate, filtered to remove solids, the filtrate concentrated, and the residue purified by silica gel column chromatography with dichloromethane/methanol as eluent (10:1) to give N1- (4- (1-chloroimidazo [1,5-a ]]And pyridin-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-diamine (47 f). MS-ESI (M/z) 498[ M +1 ]]+。
N- (5- ((4- (1-chloroimidazole [1,5-a ]))]And pyridine-3-yl pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) Ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (47)
Preparation of the title compound (47) according to the synthesis of example 15, N2- (2- (dimethylamino) ethyl) -N5- (4- (7-fluoro-1-methyl-1H-indole)-3-yl) pyrimidin-2-yl) -6-methoxy-N2Replacement of-methyl-3-nitropyridine-2, 5-diamine (15h) by N1- (4- (1-chloroimidazo [1,5-a ]]And pyridin-3-yl) pyrimidin-2-yl) -N4- (2- (dimethylamino) ethyl) -2-methoxy-N4-methyl-5-nitrobenzene-1, 4-diamine (47 f). MS-ESI (M/z):468[ M +1 [)]+。
Example 48
N- (5- ((4- (1-chloroimidazole [1,5-a ]))]And pyridine-3-yl pyrimidine-2-yl) amino) -2- ((2- (dimethylamino) Ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (48)
Preparation of the title compound 48 according to the procedure for the synthesis of example 47, N2- (2- (dimethylamino) ethyl) -6-methoxy-N2Replacement of-methyl-3-nitropyridine-2, 5-diamine (15e) by N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitropyridine-1, 4-diamine (24 a). MS-ESI (M/z):521[ M +1 ]]+。
Example 49
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1- (trifluoromethyl) imidazole) [1,5-a]And pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (49)
1-iodo-3- (2- (methylthio) pyrimidin-4-yl) imidazole [1,5-a]Pyridine (49a)
To 3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a ] at room temperature]And pyridine (47b) (300mg,1.24mmol) in DMF (5mL) was added N-iodosuccinimide (362mg,1.61mmol), the mixture stirred at room temperature for 2h reaction quenched with water (5mL), the resulting mixture extracted with dichloromethane (8mL × 2) the combined organic layers washed with brine (10mL), dried over sodium sulfate and concentrated under reduced pressure to give 1-iodo-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a ] imidazole [1,5-a ]]And pyridine (49 a). MS-ESI (M/z):369[ M +1 ]]+。
3- (2- (methylthio) pyrimidin-4-yl) -1- (trifluoromethyl) imidazole [1,5-a]Pyridine (49b)
1-iodo-3- (2- (methylmercapto) pyrimidine-4-yl) imidazole [1,5-a]Bipyridine (49a) (200mg,0.54mmol), (trifluoromethyl) trimethylsilane (153mg,1.08mmol), phenanthroline (194mg,1.08mmol), tris (hydroxymethyl) phosphonium chlorideA mixture of methyl borate (112mg,1.08mmol), potassium fluoride (63mg,1.08mmol) and copper (I) iodide (154mg,0.81mmol) in dimethylsulfoxide (5mL) was stirred overnight at 60 deg.C, the reaction was cooled to room temperature, quenched with water (10mL), extracted with ethyl acetate (10mL × 3), the organic layers were combined, washed with water (20mL) and brine (20mL), dried over sodium sulfate, filtered to remove the solids, the filtrate was concentrated, the residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:2) as eluent to give 3- (2- (methylthio) pyrimidin-4-yl) -1- (trifluoromethyl) imidazo [1,5-a ] 1,5-a]And pyridine (49 b). MS-ESI (M/z):311[ M +1 [)]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1- (trifluoromethyl) imidazole) [1,5-a]And pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (49)
Preparation of the title compound 49 according to the procedure for the synthesis of example 47, 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a]Replacement of the pyridopyridine (47c) with 3- (2- (methylthio) pyrimidin-4-yl) -1- (trifluoromethyl) imidazole [1,5-a ]]And pyridine (49 b). MS-ESI (M/z):556[ M +1 [)]+。
Example 50
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1- (trifluoromethyl) imidazole) [1,5-a]And pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (50)
Preparation of the title compound 50 according to the procedure for the synthesis of example 47, N2- (2- (dimethylamino) ethyl) -6-methoxy-N2Replacement of-methyl-3-nitropyridine-2, 5-diamine (15e) by N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitropyridine-1, 4-diamine (24 a). MS-ESI (M/z) 555[ M +1 ]]+。
Example 51
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylimidazol [1, 5-a)] And pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (51)
1-methyl-3- (2- (methylmercapto) pyrimidin-4-yl) imidazole [1,5-a]Pyridine (51a)
Preparation of the title compound 51a47b, pyridine-2-ylmethylamine was replaced with 1- (pyridin-2-yl) ethan-1-amine. MS-ESI (M/z):257[ M +1 ]]+。
3- (2-Chloropyrimidin-4-yl) -1-methylimidazol [1,5-a]Pyridine (51b)
Preparation of the title Compound 51b according to the procedure for the synthesis of 47e, 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazole [1,5-a]Replacement of the pyridopyridine (47c) with 1-methyl-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a]And pyridine (51 a). MS-ESI (M/z):245[ M +1 [)]+。
2 2 5N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (1-methylimidazol [1, 5-a)]Pyridine- 3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (51c)
Preparation of the title compound (51c) according to the procedure for the synthesis of 15i, 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) was replaced with 3- (2-chloropyrimidin-4-yl) -1-methylimidazol [1, 5-a)]And pyridine (51 b). MS-ESI (M/z):448[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylimidazol [1, 5-a)] And pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (51)
Preparation of the title compound 51 the synthesis of example 15 was followed, adding N2- (2- (dimethylamino) ethyl) -N5- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N2-methyl-N2Replacement of-methylpyridine-2, 3, 5-triamine (15i) by N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (1-methylimidazole [1,5-a ]]And-pyridin-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (51 c). MS-ESI (M/z):502[ M +1 [)]+。
Example 52
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1- (methylimidazole [1, 5-) a]And pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (52)
Preparation of the title compound 52 according to the synthesis of example 51, N2- (2- (dimethylamino) ethyl) -6-methoxy-N2Replacement of-methyl-3-nitropyridine-2, 5-diamine (15e) by N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-2-nitropyridine-1, 4-diamine (24 a). MS-ESI (M/z):501[ M +1 ]]+.
Example 53
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylimidazol [1, 5-a)] And pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (53)
Preparation of the title compound (53) according to the synthesis of example 23, N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5Replacement of (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b)
N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (1-methylimidazole [1,5-a ]]And-pyridin-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (51 c). MS-ESI (M/z):520[ M +1 ]]+。
Example 54
N- (5- ((4- (1, 2-dihydropyrrole [3,2, 1-hi)]Indol-5-yl pyrimidin-2-yl) amino) -2- ((2- (dimethylin) Amino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (54)
2- (2-Nitrophenyl) ethanol (54a)
A mixture of 1-methyl-2-nitrobenzene (48g,0.35mol), formaldehyde (10.4g,0.35mol), 20% sodium hydroxide (3.6mL) and dimethyl sulfoxide was heated at 50 ℃ for 2h, then the mixture was cooled to room temperature, diluted with water (200mL), and extracted with ethyl acetate (300 mL. times.3). The combined organic layers were washed with water (200 mL. times.2) and brine (200mL), dried over sodium sulfate, filtered to remove solids, the filtrate was concentrated, and the residue was purified by column chromatography over silica gel using ethyl acetate/petroleum ether (1:1) as eluent to give 2- (2-nitrophenyl) ethanol (54a) as a brown oil (14.4g, 25%).
Tert-butyldimethyl (2-nitrophenylethoxy) silane (54b)
To a solution of 2- (2-nitrophenyl) ethanol (54a) (1.7g,0.01mol) in dry dichloromethane (15ml) were added imidazole (0.88g,0.013mol) and tert-butyldimethylchlorosilane (2.1g,0.014mol), and the mixture was stirred at room temperature for 2 h. The mixture was then filtered, diluted with dichloromethane (30mL), washed with 1N hydrochloric acid (30mL), water and aqueous sodium bicarbonate, the organic layers combined, dried over sodium sulfate, the solid removed by filtration, and the filtrate concentrated to give tert-butyldimethyl (2-nitrophenylethoxy) silane (54b) as a brown oil (2.8g, 97%).
7- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indole (54c)
To a solution of tert-butyldimethyl (2-nitrophenylethoxy) silane (54b) (4.5g,16mmol) in dry tetrahydrofuran (50ml) was added vinyl magnesium bromide (56ml,56mmol) dropwise at-70 ℃ under nitrogen. The mixture was slowly warmed to room temperature, poured into aqueous ammonium chloride, and extracted with ethyl acetate (50 mL). The combined organic layers were dried over sodium sulfate, filtered to remove solids, the filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:100) to give 7- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indole (54c) as a yellow oil (2.6g, 59%). MS-ESI (M/z):276[ M +1 [)]+。
2- (3- (2-Chloropyrimidin-4-yl) -1H-indol-7-yl) ethanol (54d)
Preparation of the title compound 54d (0.33g, 30%, brown solid) 7-fluoro-1-methyl-1H-indole (15f) was replaced with 7- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indole (54c) according to 15g of the synthesis. MS-ESI (M/z):274[ M +1 ]]+。
7- (2-chloroethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (54e)
A suspension of 2- (3- (2-chloropyrimidin-4-yl) -1H-indol-7-yl) ethanol (54d) (50mg,0.18mmol) in dry CAN (5mL) was added dropwise sulfinyl chloride (0.44mg,0.36mmol) at 0 ℃ the resulting mixture stirred at room temperature overnight, cooled to room temperature, extracted with aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (20mL), the organic layers combined, washed with water (20mL × 2) and brine (200mL), dried over anhydrous sodium sulfate, filtered to remove solids, the filtrate concentrated, the residue purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:3) as eluent to give 7- (2-chloroethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (54e) as a brown solid (0.30g, 50%). MS-ESI (M/z):292[ M + 1: (M + 1: -3) ]]+。
5- (2-Chloropyrimidin-4-yl) -1, 2-dihydropyrrolo [3,2,1-hi]Indole (54f)
To a solution of 7- (2-chloroethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (54e) (33mg,0.11mmol) in DMF (3mL) at room temperature was added cesium carbonate (78mg,0.22mmol), heated at 60 ℃ for 10H the mixture was cooled to room temperature, quenched with water (20mL), extracted with ethyl acetate (20mL), the organic layers combined, washed with water (20mL × 2) and brine (200mL), dried over anhydrous sodium sulfate, filtered to remove solids, and the filtrate was concentrated to give 5- (2-chloropyrimidin-4-yl) -1, 2-dihydropyrrole [3,2,1-hi ] at room temperature]Indole (54f) as a brown solid (0.30g, 100%). MS-ESI (M/z) 256[ M +1 ]]+。
N- (5- ((4- (1, 2-dihydropyrrole [3,2, 1-hi)]Indol-5-yl pyrimidin-2-yl) amino) -2- ((2- (dimethylin) Amino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (54)
Preparation of the title compound 54(5.0mg) according to the procedure for the synthesis of 15, 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) was replaced with 5- (2-chloropyrimidin-4-yl) -1, 2-dihydropyrrolo [3,2,1-hi]Indole (54 f). MS-ESI (M/z) 513[ M +1 ]]+。
Example 55
N- (5- ((4- (1, 2-dihydropyrrole [3,2, 1-hi)]Indol-5-yl pyrimidin-2-yl) amino) -2- ((2- (dimethylin) Amino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (55)
Preparation of the title compound (55) according to the synthesis of example 54, N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2Replacement of-trimethylethane-1, 2-diamine (15c) by N1- (4-iodo-5-methoxy-2-nitrophenyl) -N1,N2,N2-trimethylethane-1, 2-diamine (24 a). MS-ESI (M/z):512[ M +1 [)]+。
Example 56
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methyl-1H-indazol-1-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (56)
3-methyl-1H-indazole (56a)
To a solution of 1- (2-fluorophenyl) ethanone (20g,0.14mol) in ethane-1, 2-diol (70mL) at room temperature was added hydrazine hydrate (4.7mL,0.15mol), held at this temperature for 2H, then heated to 150 ℃ overnight the mixture was cooled to room temperature, quenched with water (200mL), dichloromethane extracted (200mL), the organic layers combined, washed with water (200mL × 2) and brine (200mL), dried over anhydrous sodium sulfate, filtered to remove solids, the filtrate was concentrated, and the residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20) as eluent to give 3-methyl-1H-indazole (56a) as a brown solid (7g, 37%). MS-ESI (M/z):133[ M + 1H-indazole (56 a): M + 1%]+。
1- (2-Chloropyrimidin-4-yl) -3-methyl-1H-indazole (56b)
To a solution of 3-methyl-1H-indazole (56a) (1.1g,8.3mmol) in dry DMF at 0 deg.C was added sodium hydride and the temperature was maintained for 2H, then 2, 4-dichloropyrimidine (1.24g,8.3mmol) was added and the resulting mixture stirred at room temperature overnight, quenched by addition of aqueous ammonium chloride (20mL), extracted with ethyl acetate (50mL), the organic layers combined, washed with water (50mL × 2) and brine (50mL), dried over anhydrous sodium sulfate, filtered to remove solids, the filtrate concentrated, and the residue purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20) as eluent to give 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indazole (56b) as a white solid (0.85g, 43%). MS-ESI (M/z):245[ M + 1-indazole (M + 1: 20): 245[ M +1]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methyl-1H-indazol-1-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (56)
Preparation of title compound 56(8.0mg) according to the procedure for the synthesis of example 15, 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) was replaced with 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indazole (56 b). MS-ESI (M/z):502[ M +1 [)]+。
Example 57
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methyl-1H-indazol-1-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (57)
Preparation of the title compound 57(5.0mg) according to the synthetic method of example 23, 3- (2-chloropyrimidine)-4-yl) -1-methyl-1H-indole (1H) was replaced with 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indazole (56 b). MS-ESI (M/z):520[ M +1 ]]+。
Example 58
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indazol-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (58)
1- (1-methyl-1H-indazol-3-yl) ethanone (58a)
The title compound 58a was prepared according to the literature: heterocylic chem.,2013,50: E221.
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indazol-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (58)
Preparation of the title compound 58 following the synthesis of example 25, 1- (1-methylindozin-3-yl) ethanone (25d) was replaced with 1- (1-methyl-1H-indazol-3-yl) ethanone (58 a). MS-ESI (M/z):502[ M +1 [)]+。
Example 59
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indazol-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (59)
2 2N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N5- (4- (1-methyl-1H-indazol-3-yl) pyrimidine Pyridin-2-yl) -3-nitropyridine-2, 5-diamine (59a)
Preparation of compound 59a 1- (1-methyl-indolizin-3-yl) ethanone (25d) was replaced with 1- (1-methyl-1H-indazol-3-yl) ethanone (58a) according to the synthesis of example 25. MS-ESI (M/z):448[ M +1 ]]+。
2 2N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N5- (4- (1-methyl-1H-indazol-3-yl) pyrimidine Pyridin-2-yl) pyridine-2, 3, 5-triamine (59b)
Preparation of the title compound 59b according to the synthesis of 15i, N1- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N1,N2,N2-trimethylethane-1, 2-diamine(15h) By substitution into N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (59 a). MS-ESI (M/z):447[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indazol-3-) Yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (59)
Preparation of the title compound (59) according to the synthesis of example 23, N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5Replacement of- (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) by N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (59 b). MS-ESI (M/z):520[ M +1 ]]+。
Example 60
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylimidazol [1, 5-a)] And pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (60)
1- (3-methylimidazol [1,5-a ]]And pyridin-1-yl) ethan-1-one (60a)
The title compound 60a was prepared according to the literature synthesis: journal of Chemical society, 1955,2834.
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylimidazol [1, 5-a)] And pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (60)
Preparation of the title compound 60 according to the procedure for the synthesis of example 25, 1- (1-methylindozin-3-yl) ethanone (25d) was replaced with 1- (3-methylimidazol [1,5-a ]]And-pyridin-1-yl) ethan-1-one (60 a). MS-ESI (M/z):502[ M +1 [)]+。
Example 61
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylimidazol [1, 5-a)] And pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (61)
2 2 5N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (3-methylimidazol [1, 5-a)]Pyridine- 1-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (61a)
Preparation of the title compound 61a 1- (1-methylindozin-3-yl) ethanone (25d) was replaced with 1- (3-methylimidazol [1,5-a ] according to the synthesis method of example 25]And-pyridin-1-yl) ethan-1-one (60 a). MS-ESI (M/z):448[ M +1 ]]+。
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylimidazol [1, 5-a)] And pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (61)
Preparation of the title compound 61 the synthesis of example 23 was followed, adding N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5Replacement of- (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) by N2- (2- (dimethylamino) ethyl) -6-methoxy-N2-methyl-N5- (4- (3-methylimidazol [1,5-a ]]And-pyridin-1-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine. MS-ESI (M/z):520[ M +1 ]]+。
Cell proliferation assay
The inhibition of L858R/T790M EGFR by compounds was tested by determining their inhibition of H1975 cell proliferation. In this experiment, the inhibition of L858R/T790M EGFR by compounds was determined by examining the inhibition of H1975 cell proliferation by compounds. H1975 cells were cultured in RPMI-1640 medium containing 40-80% fetal bovine serum. H1975 cells in logarithmic growth phase are inoculated into 96-well culture plates at a density of 3000/well and at 37 ℃ with 5% CO2Incubate overnight. The compounds were added to 96-well plates at different concentrations (final concentrations 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5nM) at 37 ℃ in 5% CO2Incubate for 72 hours. The medium was discarded, and 20. mu.l MTS/100. mu.l medium was added to each well. After 1.5h incubation, the reaction was stopped by adding 25. mu.l of 10% SDS per well. The absorbance at 490nm and 650nm was measured with a microplate reader. IC calculation Using GraphPad prism5.050。
The inhibition of wild-type EGFR by compounds was examined by measuring the inhibition of a431 cell proliferation by compounds. In this experiment, the inhibitory effect of a compound on wild-type EGFR was determined by examining the inhibitory effect of a compound on a431 cell proliferation. A431 cells were cultured in RPMI-1640 medium containing 40-80% fetal bovine serum. H1975 cells in logarithmic growth phase are inoculated into 96-well culture plates at a density of 3000/well and at 37 ℃ with 5% CO2Incubate overnight. The compounds were added to 96-well plates at different concentrations (final concentrations 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5nM) at 37 ℃ in 5% CO2Incubate for 72 hours. The medium was discarded, and 20. mu.l MTS/100. mu.l medium was added to each well. After 1.5h incubation, the reaction was stopped by adding 25. mu.l of 10% SDS per well. The absorbance at 490nm and 650nm was measured with a microplate reader. IC calculation Using GraphPad Prism5.050。
Selected compounds prepared as described above were tested according to the biological methods described herein. The results are shown in Table 1. TABLE 1
Examples H1975IC50(nM) A431IC50(nM)
1 112 >1000
15 156 /
16 193 >1000
17 128 1213
18 183 /
19 76 /
20 48 /
21 69 /
23 184 /
24 219 /
25 219 >1000
27 324 >1000
32 190 >1000
36 244 1193
38 183 /
41 350 /
50 476 /
51 348 /
53 452 /
54 481 /

Claims (9)

1. A compound and/or a pharmaceutically acceptable salt thereof, wherein the structural formula of the compound is:
Figure FDA0002520164330000011
wherein:
q is
Figure FDA0002520164330000012
X is N and Y is C;
R1is hydrogen;
R1’is hydrogen;
R2is hydrogen;
R3is hydrogen;
R4is selected from C1-10An alkyl group; wherein C is1-10Alkyl is unsubstituted or substituted with at least one substituent independently selected from halogen;
each R5Independently selected from: -OR8、-NR7R8；
Each R7And each R8Independently selected from: c1-10An alkyl group; wherein each alkyl is unsubstituted or substituted with at least one group independently selected from C1-10Alkyl, halogen, -N (C)1-10Alkyl) (C1-10Alkyl) and-CN;
m is 1;
n is 2.
2. The compound of claim 1 and/or a pharmaceutically acceptable salt thereof, wherein each R is7And each R8Independently selected from: c1-10An alkyl group; wherein each alkyl group is unsubstituted or substituted by 1,2,3 or 4 groups independently selected from C1-10Alkyl, halogen, -N (C)1-10Alkyl) (C1-10Alkyl) and-CN.
3. The compound of claim 1 and/or a pharmaceutically acceptable salt thereof, wherein R4Is methyl, wherein methyl is unsubstituted or substituted with 1,2 or 3 fluoro.
4. A compound of claim 1 or 3, and/or a pharmaceutically acceptable salt thereof, wherein R5Independently selected from methoxy, ethoxy, isopropoxy, methyl (2- (methylamino) ethane)The group) amino, (2- (dimethylamino) ethyl) (methyl) amino, and (2- (ethyl) (methyl) amino) ethyl) (methyl) amino.
5. A compound, or a pharmaceutically acceptable salt thereof, which compound is:
n- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide.
6. A pharmaceutical composition comprising a compound of any one of claims 1-5 and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
7. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 6, in the manufacture of a medicament for modulating mutated EGFR.
8. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 6, in the manufacture of a medicament for treating, ameliorating, or preventing a symptom responsive to inhibition of mutated EGFR, and optionally in combination with another therapeutic agent.
9. Use of a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 6, in the manufacture of a medicament for the treatment of a cell proliferative disorder, optionally in combination with another therapeutic agent.
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