CN111875585B

CN111875585B - Kinase inhibitors

Info

Publication number: CN111875585B
Application number: CN202010883613.XA
Authority: CN
Inventors: 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
Original assignee: Shanghai Allist Medicine Polytron Technologies Inc
Current assignee: Shanghai Allist Medicine Polytron Technologies Inc
Priority date: 2014-06-12
Filing date: 2015-06-12
Publication date: 2023-06-23
Anticipated expiration: 2035-06-12
Also published as: CN111892579B; CN106660993B; CN106660993A; WO2015188777A1; CN111892579A; CN111875585A

Abstract

The invention relates to a mutant EGFR selective inhibitor, a pharmaceutical composition and a using method thereof.

Description

Kinase inhibitors

The present application is a divisional application of chinese patent application No. 201580031253.8, entitled "class of kinase inhibitors", filed on 6 th month 12 of 2015.

Technical Field

The present invention relates to a novel class of aminopyrimidine ring derivatives and pharmaceutically acceptable salts thereof, which selectively inhibit mutated Epidermal Growth Factor (EGFR) kinase activity, and as a medicament for the treatment of proliferative diseases, such as cancer, in mammals, particularly humans. The invention also relates to a co-use of said compounds in the treatment of cancer, and to pharmaceutical formulations containing said compounds.

Background

Protein tyrosine kinases catalyze the transfer of phosphate groups from ATP or GTP to tyrosine residues of a protein substrate. Protein tyrosine kinases can be classified as receptors (e.g., EGFR, HER-2, VEGFR, FGFR) or non-receptors (e.g., src, jak, abl). The receptor tyrosine kinase acts to activate secondary signaling factors via phosphorylation, which conduct 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 kinases, has been demonstrated to result in uncontrolled cell growth. There is a great deal of evidence that EGFR is involved in the development of human tumors, more than 60% of which express at least one EGFR or ligand thereof in all solid tumors. 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 therapies for the clinical treatment of non-small cell lung cancer carrying mutations in the EGFR kinase region activity (Nature, 2009,462,1070-107). Although the first generation EGFR inhibitors showed encouraging clinical efficacy, almost all patients developed resistance to these inhibitors over time, e.g., approximately half of the goalkeeper mutations T790M, gefitinib and erlotinib had the T790M mutation. (Proc. Natl. Acad. Sci. U.S. A.2008,105,2070-2075) furthermore, the T790M mutation is also naturally occurring, and the T790M mutation may have independent carcinogenesis.

The drugs currently developed, including second generation covalent inhibitors such as afatinib, lenatinib, canetinib and dacatinib, are effective against the T790M resistant mutation but exhibit dose dependent toxicity such as diarrhea and rash due to simultaneous inhibition of wild-type EGFR.

Thus, a need remains for mutant EGFR kinase selective inhibitors. Although mutant EGFR selective inhibitors have been reported in the literature, such as WO 2013014448 and WO 2012061299, there remains a strong need for novel EGFR selective inhibitors that have at least one of therapeutic, stability, selectivity, safety, pharmacodynamic and pharmacokinetic profile advantage in treating abnormal proliferative diseases. The present invention relates to a novel class of EGFR mutation-selective inhibitors.

Disclosure of Invention

The invention relates to novel aminopyrimidine ring derivatives and pharmaceutical compositions thereof, and application thereof as medicines.

In one aspect, the present invention provides at least one compound of formula (I):

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;

R ¹ selected from: hydrogen, C _1-10 Alkyl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-C _1-4 Alkyl, heterocyclyl and heterocyclyl-C _1-4 Alkyl, wherein each alkyl, cycloalkyl and heterocyclyl is unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, independently selected from R ^6a Is substituted by a substituent of (a);

R ^1’ selected from hydrogen and halogen;

R ² and R is ³ Respectively selected from: hydrogen, halogen, hydroxy, CN, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-C _1-4 Alkyl, heterocyclyl-C _1-4 Alkyl, aryl-C _1-4 Alkyl, heteroaryl and heteroaryl-C _1-4 Alkyl, 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 R ^6a Wherein each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, independently selected from R ^6b Is substituted by a substituent of (a); or R is ² And R is ³ Together with the carbon atoms 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 atoms selected from R ^6a Is substituted by a substituent of (a);

each R ⁴ Independently selected from: hydrogen, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl, -OR ⁸ 、-NR ⁷ S(O) _r R ⁸ 、-NO ₂ Halogen, -S (O) _r R ⁷ 、-SR ⁸ 、-S(O) ₂ OR ⁷ 、-OS(O) ₂ R ⁸ 、-S(O) _r NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-O(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-C(O)R ⁷ 、-CO ₂ R ⁸ 、-CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ 、-OC(O)R ⁷ 、-CN、-C(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)R ⁸ 、-OC(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)OR ⁸ 、-NR ⁷ C(O)NR ⁷ R ⁸ and-CR ⁷ (N-OR ⁸ ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein each C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl and C _3-10 Cycloalkyl is unsubstituted or substituted by at least one, e.g. 1, 2, 3 or 4, independently selected from R ^6a Is substituted by a substituent of (a);

each R ⁵ Independently selected from: hydrogen, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-C _1-4 Alkyl, heterocyclyl-C _1-4 Alkyl, aryl-C _1-4 Alkyl, heteroaryl and heteroaryl-C _1-4 Alkyl, -OR ⁸ 、-NR ⁷ S(O) _r R ⁸ 、-NO ₂ Halogen, -S (O) _r R ⁷ 、-SR ⁸ 、-S(O) ₂ OR ⁷ 、-OS(O) ₂ R ⁸ 、-S(O) _r NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-O(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-C(O)R ⁷ 、-CO ₂ R ⁸ 、-CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ 、-OC(O)R ⁷ 、-CN、-C(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)R ⁸ 、-OC(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)OR ⁸ 、-NR ⁷ C(O)NR ⁷ R ⁸ and-CR ⁷ (N-OR ⁸ ) Wherein each C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl and heterocyclyl groups are unsubstituted or at least substitutedOne, e.g. 1, 2, 3 or 4, is independently selected from R ^6a Is substituted by a substituent of (a); each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, independently selected from R ^6b Is substituted by a substituent of (a);

each R ^6a Independently selected from: c (C) _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl, -OR ⁸ 、-NR ⁷ S(O) _r R ⁸ 、-NO ₂ Halogen, -S (O) _r R ⁷ 、-SR ⁸ 、-S(O) ₂ OR ⁷ 、-OS(O) ₂ R ⁸ 、-S(O) _r NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t OR ⁸ 、-(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t SR ⁸ 、-(CR ⁹ R ¹⁰ ) _t S(O) _r R ⁸ 、-(CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ 、-

O(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-C(O)R ⁷ 、-C(O)(CR ⁹ R ¹⁰ ) _t OR ⁸ 、-C(O)(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-C(O)(CR ⁹ R ¹⁰ ) _t SR ⁸ 、-C(O)(CR ⁹ R ¹⁰ ) _t S(O) _r R ⁸ 、-CO ₂ R ⁸ 、-CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ 、-OC(O)R ⁷ 、-CN、-C(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)R ⁸ 、-OC(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)OR ⁸ 、-NR ⁷ C(O)NR ⁷ R ⁸ and-CR ⁷ (N-OR ⁸ )；

Each R ^6b Independently selected from: r is R ^6a Aryl, aryl-C _1-4 Alkyl, heteroaryl and heteroaryl-C _1-4 An alkyl group;

each R ⁷ And each R ⁸ Independently selected from: hydrogen, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, cycloalkyl-C _1-4 Alkyl, heterocyclyl C _1-4 Alkyl, aryl, heteroaryl, aryl-C _1-4 Alkyl, heteroaryl and heteroaryl-C _1-4 An 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 R ^6a Wherein each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, independently selected from R ^6b Is substituted by a substituent of (a); or R is ⁷ And R is ⁸ Together 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 R ^6b Is substituted by a substituent of (a);

each R ⁹ And each R ¹⁰ Independently selected from: hydrogen, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, cycloalkyl-C _1-4 Alkyl, heterocyclyl-C _1-4 Alkyl, aryl-C _1-4 Alkyl, heteroaryl and heteroaryl-C _1-4 An alkyl group; or R is ⁹ And R is ¹⁰ Together 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 with 1 or 2 atoms selected from R ^6a Is substituted by a substituent of (a);

m is independently selected from 0, 1, 2 and 3;

n is independently selected from 0, 1, 2 and 3;

each r is independently selected from 1 and 2;

each t is independently selected from 1, 2 and 3.

In another aspect, the 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 invention provides methods for modulating mutant EGFR comprising administering to a system or individual 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 individual 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 may be used alone or in combination with another therapeutic agent to treat a mutated 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 comprising administering to a system or individual 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-mentioned 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 may 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 breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumors.

In the above-described 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, e.g., 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 a specified number of carbon atoms. Unless otherwise noted, "alkyl" refers to C ₁ -C ₆ An alkyl group. For example, "C ₁ -C ₆ "C in" alkyl ₁ -C ₆ "refers to a group having a linear or branched arrangement of 1, 2, 3, 4, 5 or 6 carbon atoms. For example, "C ₁ -C ₈ Alkyl "includes, but is 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. Unless otherwise noted, "cycloalkyl" refers to C ₃ -C ₁₀ Cycloalkyl groups. For example, "cycloalkyl" includes, but is not limited to, cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, and cyclohexyl.

"alkenyl" refers to a non-aromatic straight, branched or cyclic hydrocarbon radical containing 2 to 10 carbon atoms and having at least one carbon-carbon double bond. In some embodiments, there are 1 carbon-carbon double bond, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C _2－6 Alkenyl "refers to alkenyl groups 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 if indicated, substituted alkenyl groups indicate that they may be substituted.

"alkynyl" means having 2 to 10 carbon atoms and at least oneA straight, branched or cyclic hydrocarbon group having a carbon-carbon triple bond. In some embodiments, 3 carbon-carbon triple bonds may be present. Thus, "C _2-6 Alkynyl "refers to alkynyl groups containing 2 to 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 if indicated, substituted alkynyl groups may be substituted.

"aryl" includes: 5-and 6-membered aromatic carbocycles 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. If the aryl substituents are bi-or tri-cyclic and at least one of the rings is non-aromatic, it is considered to be linked through an aromatic ring.

For example, aryl groups include 5-and 6-membered aromatic carbocycles fused to a 5-7 membered heterocycle containing one or more heteroatoms selected from N, O and S, provided that the attachment site is an aromatic carbocycle. Divalent radicals formed from substituted benzene derivatives and having free valence electrons at the ring atoms are designated as substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals, whose name ends with a "-group", which are obtained by removing a further hydrogen atom from a carbon atom containing a free valence electron, are named after the monovalent radical name plus a "-subunit (-idene)", for example, a naphthalene group having two linking sites is known as a naphthylene group. However, the definition of aryl does not include, nor overlap with, heteroaryl, as defined solely below. Thus, if one or more aromatic carbocycles are fused to a heterocyclic aromatic 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 containing 1 to 4, in some 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, in some 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 ring. The ring contains 1 to 4, in some 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.

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 (numbering of the attachment site is preferential, designated 1-position) 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, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furanyl, benzofuranyl, benzimidazolinyl, indolinyl, 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, quinolone and isoquinolyl groups. As defined below for heterocyclyl, "heteroaryl" includes N-oxide derivatives of nitrogen-containing heteroaryl.

The name of a monovalent heteroaryl radical is terminated by a "radical" from which a divalent radical is derived, obtained by removing a further hydrogen atom from a carbon atom containing a free valence electron, the name of the divalent radical being given by adding a "sub (-idene)" to the name of the monovalent radical, for example: pyridyl groups having two attachment sites are known as pyridine subunits. Heteroaryl is defined as not including nor overlapping aryl groups as defined above.

Heteroaryl substituents are generally considered to be attached through an aromatic or heteroatom-containing ring if they are bicyclic or tricyclic and wherein at least one ring is non-aromatic or contains no heteroatoms, respectively.

"heterocycle" (and derivatives thereof as "heterocyclic" or "heterocyclyl") refers generally to a single cyclic aliphatic hydrocarbon, typically having 3 to 12 ring atoms, at least 2 carbon atoms, and further having 1-3 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 ring) in which two or more rings are attached through a fused or bridged ring in which at least one ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen. "heterocycle" also refers to a 5-to 7-membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen and sulfur fused to a 5-and 6-membered aromatic carbocyclic ring, provided that the attachment site is on the heterocycle. The heterocyclic ring may be saturated or contain one to more double bonds (i.e., partially unsaturated). The heterocycle may be substituted with oxo (oxo). The carbon or heteroatom of the heterocycle may be the attachment site, provided that a stable structure is formed. When a substituent is present on a heterocycle, the substituent may be attached to any heteroatom or carbon atom of the heterocycle provided that a stable chemical structure is formed. The heterocyclic ring and heteroaryl groups as described herein are defined as non-overlapping.

Suitable heterocycles include, for example (with the attachment sites being prioritized 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 number preferably 1). The 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 bisheterocyclic compounds include, for example:

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 C _1-4 Alkyl "in which" C _1-4 "refers to the number of carbon atoms in the alkyl moiety but not the aryl moiety. Similarly, when "aryl C" is used _1-10 Alkyl "in which" C _1-10 "refers to the number of carbon atoms in the alkyl moiety but not the aryl moiety.

As used herein, "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group. When "heterocyclyl C" is used _1-6 Alkyl "in which" C _1-6 "refers to the number of carbon atoms in the alkyl moiety but not the heterocyclyl moiety.

"cycloalkylalkyl" as used herein refers to cycloalkyl-substituted alkyl. When using "C _3-10 Cycloalkyl alkyl ", wherein" C _3-10 "refers to the number of carbon atoms in the cycloalkyl moiety but not the alkyl moiety. When using "C _3-7 Cycloalkyl alkyl ", wherein" C _3-7 "refers to the number of carbon atoms in the cycloalkyl moiety but not the alkyl moiety. When using "C _3-8 Cycloalkyl alkyl ", wherein" C _3-8 "refers to the number of carbon atoms in the cycloalkyl moiety but not the alkyl moiety. When "cycloalkyl C" is used _1-10 Alkyl "in which" C _1-10 "refers to the number of carbon atoms in the alkyl moiety, but not the cycloalkyl moiety.

"heteroarylalkyl" as used herein refers to heteroaryl substituted alkyl. When "heteroaryl C" is used _1-4 Alkyl "in which" C _1-4 "refers to the number of carbon atoms in the cycloalkyl moiety but not the heteroaryl moiety. Similarly, when "heteroaryl C" is used _1-10 Alkyl "in which" C _1-10 "refers to the number of carbon atoms in the alkyl moiety but not the heteroaryl moiety.

To avoid ambiguity, for example: when referring to alkyl, cycloalkyl, heterocyclylalkyl, aryl, and/or heteroaryl substitution thereof, it is meant that each of these groups is substituted individually or that a mixture of these groups is substituted. That is: if R is ¹ Is an aralkyl group, the aryl moiety may be unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, independently selected from R ^6b The alkyl moiety may also be unsubstituted or substituted with at least one substituent, such as 1, 2, 3 or 4, independently selectedFrom R ^6a Is a substituent of (a).

"pharmaceutically acceptable salts" refers to salts with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of inorganic bases may be selected, for example, from: aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, divalent manganese, potassium, sodium, zinc salts. Further, the pharmaceutically acceptable salt of an inorganic base may be selected from the group consisting of ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may be present in the solid salt, and also the form of hydrates may be present. The pharmaceutically acceptable salts of organic non-toxic bases may be selected from, for example: primary, secondary and tertiary amine salts, substituted amines include 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, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.

When the compounds referred to in this patent are bases, salts thereof are prepared with at least one pharmaceutically acceptable non-toxic acid selected from the group consisting of inorganic and organic acids. For example selected from 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 acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid.

"protecting group" (Pg) refers to a class of substituents that are used to react with other functional groups on a compound to block or protect a particular functional group. For example, "amino protecting group" refers to a substituent attached to an amino group that blocks or protects an amino function on a compound. Suitable amino protecting groups includeAcetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a class of hydroxy substituents that effectively block or protect the function of a hydroxy group. Suitable protecting groups include, but are not limited to, acetyl and silyl. "carboxy protecting group" refers to a class of carboxy substituents that effectively block or protect a carboxy group. Commonly used carboxyl protecting groups include, but are not limited to, -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrothiophenyl) ethyl, 2- (diphenylphosphine) -ethyl, nitroethyl, and the like. General description and instructions for protecting groups, see T.W. Greene, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991。

By "administering" or "administering" 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 an individual in need of treatment.

An "effective amount" refers to that 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: products comprising specific amounts of specific ingredients, and any combination of direct or indirect specific amounts of such specific ingredients. The pharmaceutical composition comprises: products comprising an active ingredient and an inert ingredient as a carrier, as well as any two or more ingredients, directly or indirectly, products made by combining, compounding, or aggregation, or products produced by decomposition of one or more ingredients, or products produced by other types of reactions or interactions of one or more ingredients.

By "pharmaceutically acceptable" is meant compatible with the other ingredients of the formulation and not unacceptably toxic to the wearer.

1. The present invention provides at least one compound of formula (I):

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;

R ^1’ selected from hydrogen and halogen;

each R ⁵ Independently selected from: hydrogen, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-C _1-4 Alkyl, heterocyclyl-C _1-4 Alkyl, aryl-C _1-4 Alkyl, heteroaryl and heteroaryl-C _1-4 Alkyl, -OR ⁸ 、-NR ⁷ S(O) _r R ⁸ 、-NO ₂ Halogen, -S (O) _r R ⁷ 、-SR ⁸ 、-S(O) ₂ OR ⁷ 、-OS(O) ₂ R ⁸ 、-S(O) _r NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-O(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-C(O)R ⁷ 、-CO ₂ R ⁸ 、-CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ 、-OC(O)R ⁷ 、-CN、-C(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)R ⁸ 、-OC(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)OR ⁸ 、-NR ⁷ C(O)NR ⁷ R ⁸ and-CR ⁷ (N-OR ⁸ ) Each of which isC (C) _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl and heterocyclyl are unsubstituted or substituted with at least one, e.g., 1, 2, 3 or 4, independently selected from R ^6a Is substituted by a substituent of (a); each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, independently selected from R ^6b Is substituted by a substituent of (a);

each R ^6a Independently selected from: c (C) _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-10 Cycloalkyl, -OR ⁸ 、-NR ⁷ S(O) _r R ⁸ 、-NO ₂ Halogen, -S (O) _r R ⁷ 、-SR ⁸ 、-S(O) ₂ OR ⁷ 、-OS(O) ₂ R ⁸ 、-S(O) _r NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t OR ⁸ 、-(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t SR ⁸ 、-(CR ⁹ R ¹⁰ ) _t S(O) _r R ⁸ 、-(CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ 、-(CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ 、-O(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-C(O)R ⁷ 、-C(O)(CR ⁹ R ¹⁰ ) _t OR ⁸ 、-C(O)(CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ 、-C(O)(CR ⁹ R ¹⁰ ) _t SR ⁸ 、-C(O)(CR ⁹ R ¹⁰ ) _t S(O) _r R ⁸ 、-CO ₂ R ⁸ 、-CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ 、-OC(O)R ⁷ 、-CN、-C(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)R ⁸ 、-OC(O)NR ⁷ R ⁸ 、-NR ⁷ C(O)OR ⁸ 、-NR ⁷ C(O)NR ⁷ R ⁸ and-CR ⁷ (N-OR ⁸ )；

each R ⁷ And each R ⁸ Independently selected from: hydrogen, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, cycloalkyl-C _1-4 Alkyl, heterocyclyl C _1-4 Alkyl, aryl, heteroaryl, aryl-C _1-4 Alkyl, heteroaryl and heteroaryl-C _1-4 An 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 R ^6a Wherein each aryl and heteroaryl is unsubstituted or substituted with at least one, such as 1, 2, 3 or 4, independently selected from R ^6b Is substituted by a substituent of (a); or R is ⁷ And R is ⁸ Together 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 R ^6b Is substituted by a substituent of (a);

each R ⁹ And each R ¹⁰ Independently selected from: hydrogen, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, cycloalkyl-C _1-4 Alkyl, heterocyclyl-C _1-4 Alkyl, aryl-C _1-4 Alkyl, heteroaryl and heteroaryl-C _1-4 An alkyl group; or R is ⁹ And R is ¹⁰ Together 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 R ^6a Is substituted by a substituent of (a);

m is independently selected from 0, 1,2 and 3;

n is independently selected from 0, 1,2 and 3;

each r is independently selected from 1 and 2;

each t is independently selected from 1,2 and 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 according to 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.

At least one compound according to any one of claims 1 to 2, and/or at least one pharmaceutically acceptable salt thereof, wherein X and Y are both C, and,

n=2, one R ⁵ Is (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, (3 aR,6 aR) -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-oxoethyl ]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 R ⁵ Is a methoxy group or a methyl group,

R ¹ 、R ^1’ and R is ² Is hydrogen, and R ³ In the case of hydrogen, fluorine, chlorine, methyl or cyano,

q is not 4,5,6, 7-tetrahydropyrrole [1,5-a ] pyridin-3-yl, pyrazolo [1,5-a ] pyridin-3-yl or 1H-indol-3-yl.

5.1-4, and/or at least one pharmaceutically acceptable salt thereof, wherein the formula is

At least one compound according to any one of claims 6.1-5, and +.Or at least one pharmaceutically acceptable salt thereof, wherein R ^1’ Selected from hydrogen.

At least one compound according to any one of claims 1 to 5, and/or at least one pharmaceutically acceptable salt thereof, wherein R ^1’ Selected from fluorine.

At least one compound according to any one of claims 1 to 7, and/or at least one pharmaceutically acceptable salt thereof, wherein R ¹ Selected from hydrogen.

At least one compound according to any one of claims 1 to 8, and/or at least one pharmaceutically acceptable salt thereof, wherein R ² Selected from hydrogen.

At least one compound according to any one of claims 1 to 9, and/or at least one pharmaceutically acceptable salt thereof, wherein R ³ Selected from hydrogen, halogen and C _1-10 An alkyl group.

11.10, and/or at least one pharmaceutically acceptable salt thereof, wherein R ³ Selected 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 the group consisting of

14.1-13, and/or at least one pharmaceutically acceptable salt thereof, wherein R ⁴ Selected from hydrogen, C _1-10 Alkyl, halogen and cyano, wherein C _1-10 Alkyl is unsubstituted or substituted with at least one, e.g. 1, 2, 3 or 4, independently selected from R ^6a Is substituted by a substituent of (a).

15.14, and/or at least one pharmaceutically acceptable salt thereof, wherein R ⁴ Selected from hydrogen, methyl, halogen and cyano, wherein methyl is unsubstituted or is independently selected from at least one R ^6a Is substituted by substituents of (C), preferably R ^6a Is fluorine.

At least one compound according to any one of claims 1 to 15, and/or at least one pharmaceutically acceptable salt thereof, wherein R ⁵ Independently selected from OR ⁸ Heterocyclyl, NR ⁷ R ⁸ Wherein the heterocyclic groups are unsubstituted or substituted with at least one, e.g. 1, 2, 3 or 4, independently selected from R ^6a Is substituted by a substituent of (a).

17.16, and/or at least one pharmaceutically acceptable salt thereof, wherein R ⁵ Independently 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-methylacetylamino) 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-methylacetylamino) 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-methylindolin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methylindolin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,

N- (5- ((4- (1-cyanoindol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,

N- (5- ((4- (1-cyanoindol-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- (indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide,

N- (5- ((4- (1-chloroindol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,

N- (5- ((4- (1-chloroindol-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-methylindolin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methylindolin-1-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,

N- (5- ((4- (3-cyanoindol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,

N- (5- ((4- (3-cyanoindol-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- (indol-1-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide,

N- (5- ((4- (3-chloroindol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,

N- (5- ((4- (3-chloroindol-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 ] pyridin-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 ] pyridin-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-methylimidazole [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- (methylimidazole [1,5-a ] naphthyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methylimidazole [1,5-a ] pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide,

N- (5- ((4- (1, 2-dihydropyrrol [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-dihydropyrrol [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-methylimidazole [1,5-a ] pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (3-methylimidazole [1,5-a ] pyridin-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 composition comprises oral, parenteral, intraperitoneal, intravenous, arterial injection, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposomal, via inhalation, vaginal, intraocular, by topical administration (e.g., via a catheter or stent), subcutaneous, intrafat, intra-articular, or intrathecal.

In another aspect, the invention provides a kit comprising at least one of the compounds of 1-18 above and pharmaceutically acceptable salts thereof; instructions comprising one or more of the following: instructions for what disease the composition is used for, information on the composition storage, dosage information, and how to use the composition. In a particular variation, the kit comprises multiple dosage forms of the compound.

In another aspect, the invention provides an article of manufacture comprising at least one of the compounds of 1-18 above, and pharmaceutically acceptable salts thereof; and (3) packaging materials. In one variation, the packaging material comprises a container. In a particular variation, the container includes a label that identifies one or more of the following: instructions for what diseases the compound is used in, stored information, dosage information and/or how to use the composition. In another variation, the article of manufacture comprises the compound in multi-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 invention provides a method of inhibiting mutant EGFR by reacting 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 the step of causing at least one compound of any one of 1-18, and pharmaceutically acceptable salts thereof, to be present in a subject to inhibit mutant EGFR activity in the subject.

In another aspect, the invention provides a method of treating a disease state in 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 occur in a subject, ameliorating the disease state.

In a variation of each of the above methods, the disease state is selected from the group consisting of: cancerous proliferative diseases (e.g. brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, colon, epidermis, esophagus, testis, gynaecology or thyroid cancer); noncancerous proliferative disorders such as benign skin hyperplasia (e.g., psoriasis), restenosis, and Benign Prostatic Hypertrophy (BPH); pancreatitis; kidney disease; pain; preventing embryo cell 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, hemangiomas, glioma, melanoma, kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer and epidermoid carcinoma); asthma; neutrophil chemotaxis (e.g., reperfusion injury and inflammatory arthritis of myocardial infarction and stroke); infectious shock; diseases of T cell reception where immunosuppression is valuable (e.g., preventing organ transplant rejection, graft versus host disease, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis); atherosclerosis; inhibiting keratinocytes that react to the mixture of growth factors; chronic Obstructive Pulmonary Disease (COPD) and other diseases.

In another aspect, the invention provides a method of treating a disease state in which mutations in the EGFR gene cause pathology and/or symptomatology of the disease, such as melanoma, lung cancer, colon cancer and other types of tumors.

In a further aspect, the invention relates to the use of at least one compound according to any one of 1-18, and pharmaceutically acceptable salts thereof, as a medicament. In another aspect, the invention relates to the use of at least one compound of any one of 1-18, and pharmaceutically acceptable salts thereof, as an EGFR agent for inhibiting mutations.

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 a disease state of a pathology and/or symptomatology caused by mutated EGFR activity.

Administration and pharmaceutical compositions

In general, the compounds of the present invention will be administered in a therapeutically effective amount via any common and acceptable means known in the art, alone or in combination with one or more therapeutic agents. The therapeutically effective amount can vary widely depending on the disease severity, 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 on the mode of administration, the particular condition to be treated and the effect desired.

Generally, satisfactory results are achieved at daily doses of 0.001 to 100mg/kg body weight, specifically from about 0.03 to 2.5mg/kg body weight. The daily dosage of a larger mammal, such as a human, may be from about 0.5mg to about 2000mg, or more specifically, from 0.5mg to 1000mg, administered in a convenient form, e.g., in divided doses up to four times daily or in sustained release form. Suitable unit dosage forms for oral administration contain from about 1 to 50mg of the active ingredient.

The compounds of the present invention may be administered in the form of a pharmaceutical composition by any conventional route; for example enterally, for example orally, for example in the form of tablets or capsules, parenterally, for example in the form of injectable solutions or suspensions; or topically, for example in the form of lotions, gels, ointments or creams, or in the form of a nose or suppository.

Pharmaceutical compositions containing a compound according to the invention in free base or pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by 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 prepared in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. The unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of the active substance.

In one embodiment, the pharmaceutical composition is a solution of the active ingredient, comprising 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 supplemented prior to use. The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, dissolution promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbiocides such as sorbic acid or benzoic acid. The solution or suspension may also contain a viscosity enhancing agent including, but not limited to, sodium carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or a solubilizing agent such as tween 80 (polyoxyethylene (20) sorbitan monooleate).

Suspensions may contain vegetable oils as oily components in the oil, synthetic or semisynthetic oils, commonly used for injection purposes. Examples include liquid fatty acid esters containing long chain fatty acids having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms, as the acid component. 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, arachic acid, behenic acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brasileic acid and linoleic acid, and may contain antioxidants, such as vitamin E, 3-carotene or 3, 5-di-tert-butylhydroxytoluene, if desired. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or multivalent, 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,

M2375 (polyoxyethylene glycerol), ->

M1944CS (unsaturated polyethylene glycol glyceride and glyceride-containing polyethylene glycol ester of oleum Armeniacae amarum by alcoholysis), LABRASOL ^TM (saturated polyglycolized glycerides and containing glycerides and polyglycol esters prepared by alcoholysis of TCM; both available from GaKefosse, france), and/or

812 (saturated fatty acid triglyceride with chain length of C8-C12 of Huls AG of Germany), vegetable oil such as oleum gossypii, oleum Armeniacae amarum, oleum Olivarum, oleum riciniSesame oil, soybean oil or peanut oil.

Pharmaceutical compositions for oral administration may be in the form of tablets or cores, for example, by mixing the active ingredient with one or more solid carriers, granulating the resulting mixture, if desired, and processing the mixture or granules by adding additional excipients.

Suitable carriers include, but are not limited to, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the abovementioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow regulators 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, in particular, concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions of suitable organic solvents or solvent mixtures, or, for enteric coatings, the preparation of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate solutions. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.

Pharmaceutical compositions for oral administration may also include hard gelatin capsules, including gelatin or soft, sealed capsules comprising gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers such as cornstarch, 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, may also be added.

Pharmaceutical compositions suitable for rectal administration, such as 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 water-soluble salts or aqueous injection suspensions comprising viscosity-increasing substances, for example sodium carboxymethylcellulose, aqueous sorbitol solutions and/or dextran, and if desired stabilizers. The active ingredient, optionally together with excipients, may also be in a lyophilized form and may be prepared in solution by the addition of a suitable solvent prior to parenteral administration. The solutions used, for example for parenteral administration, may also be used as infusion solutions. Preparation of injectable formulations is typically carried out under sterile conditions, filling into, for example, ampoules or vials, and sealing containers.

The compounds of the invention may be administered as the sole active ingredient or with other drugs useful in immunomodulating therapy or for anti-neoplastic disease. For example, the compounds of the present invention may be used with pharmaceutical compositions effective against the various diseases described above, e.g., cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatin, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituximab, doxorubicin, gefitinib, or imatinib; or also with cyclosporin, rapamycin, ascomycin or immunosuppressive analogues thereof, e.g. cyclosporin a, cyclosporin G, FK-506, sirolimus and everolimus, glucocorticoids such as: prednisone, cyclophosphamide, azathioprine, methotrexate, gold salts, sulfasalazine, antimalarial, butralia, leflunomide, mizoribine, mycophenolic acid ester and 15-deoxyspergualin, immunosuppressive monoclonal antibodies, such as monoclonal antibody leukocyte receptors, e.g., 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, e.g., CTLA41g.

The invention also provides a pharmaceutical combination, e.g. a kit, comprising a) a compound disclosed herein, which may be 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. However, it is noted that at least one compound of formula I or at least one pharmaceutically acceptable salt thereof may also be obtained by synthesis via other synthetic routes.

In certain compounds of formula (I), the linkage between an atom and other atoms may result in the presence of a particular stereoisomer (e.g., 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 specifically indicated to be of a particular configuration, the listed compounds all include the different stereoisomers that may be present.

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 the form of the free acid with a pharmaceutically acceptable inorganic or organic base to form a pharmaceutically acceptable base addition salt. Suitable inorganic and organic acids and bases for the preparation of pharmaceutically acceptable salts of the compounds of formula (I) are described in the definitions section of this application. Furthermore, the salt forms of the compounds of formula (I) may also be prepared by using salts of the starting materials or intermediates.

The free acid or free base of the compound of formula (I) may be prepared by its corresponding base addition salt or acid addition salt. The acid addition salt form of the compound of formula (I) may be converted to the corresponding free base, for example by treatment with a suitable base (e.g. ammonium hydroxide solution, sodium hydroxide, etc.). 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 or the like.

At least one N-oxide of a 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., trifluoroacetic acid, peroxymaleic acid, peroxybenzoic acid, peroxyacetic acid, and m-chloroperoxybenzoic acid, etc.) in an inert organic solvent (e.g., halogenated hydrocarbon such as methylene chloride) at a temperature of approximately 0 ℃. Alternatively, the N-oxide of the compound of formula (I) may also be prepared by the N-oxide of the starting material.

The non-oxidized form of the compound of formula I can be prepared by reacting its N-oxide with a reducing agent (e.g., sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide, etc.) at 0-80℃in a corresponding inert organic solvent (e.g., acetonitrile, ethanol, dioxane hydrate, etc.).

The protected derivatives of the 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 signs and common sense used in these reactions, schemes and tables and examples are consistent with current scientific literature, such as journal of the american chemical society or journal of biochemistry. Unless otherwise indicated, standard single or three letter abbreviations generally refer to L-form amino acid residues. Unless otherwise indicated, all starting materials used were purchased from commercial suppliers and were used without further purification. For example, the following abbreviations are used in the examples and throughout the specification: g (gram), mg (milligrams), L (liter), mL (milliliter), μL (microliter), psi (pounds per square inch), M (moles), mM (milli)Molar), i.v. (intravenous), hz (hertz), MHz (megahertz), mol (moles), mmol (millimoles), RT (ambient temperature), min (minutes), h (hours), mp (melting point), TLC (thin layer chromatography), rr (retention time), RP (reverse 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), et ₂ O (diethyl ether), EDCI (1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (t-butoxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), ac (acetyl), atm (atmospheric pressure), TMSE (2- (trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilane), TBS (t-butyldisilyl), DMAP (dimethylaminopyridine), me (methyl), OMe (methoxy), et (ethyl), tBu (t-butyl), HPLC (high performance liquid chromatography), BOP (bis (2-oxo-3-oxazolidinyl) phosphinic chloride), TBAF (tetrabutylammonium fluoride), mCPBA (m-chloroperoxybenzoic acid).

Ethers or Et ₂ O refers to diethyl ether; brine refers to saturated aqueous NaCl solution. Unless otherwise indicated, all temperatures are temperatures in degrees celsius and all reactions are carried out in an inert atmosphere at room temperature.

¹ The H NMR spectrum was recorded using a Bruker Avance 400 nuclear magnetic resonance spectrometer. Chemical shifts are expressed in ppm. The coupling constant is in hertz (Hz). Apparent diversity is described in split mode and is defined as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (flood peak)

Low resolution Mass Spectrometry (MS) and compound purity data were from a single pole system of Waters ZQ liquid chromatography equipped with electrospray ion detector (ESI), ultraviolet detector (220 and 254 nm) and Evaporative Light Scattering Detector (ELSD). The thin layer chromatography was carried out using a 0.25mm E.Merck silica gel plate (60F-254), 5% phosphomolybdic acid ethanol solution, ninhydrin or p-phenylene oxide solution and observed under an ultraviolet lamp. Flash column chromatography using 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 different methods, some exemplary methods being provided below and in the examples. Other synthetic methods can be readily suggested by those skilled in the art based on the disclosure of the present invention.

It may be necessary to protect reactive groups from other undesirable reactions that may be involved in such reactions as described below: such as hydroxyl, amino, imino, mercapto or carboxyl groups, which are included in the final product. A common protecting group can be found in 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 originate from commercial products or can be prepared according to existing processes or the processes exemplified herein.

The intermediates listed in the schemes below are either obtained from the literature or synthesized according to existing analogous synthetic methods.

The compounds of formula I of the present invention can be prepared by the route shown in scheme 1. Coupling the intermediate of formula III with an aminoaromatic hydrocarbon of formula IV by Buchwald ammonification or other ammonification conditions provided in the literature to give intermediate VII or VI, reducing the nitro group of intermediate VII with iron powder/ammonium chloride in a single solvent or a mixed solvent such as ethanol-water to give amine VIII, which may 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. Condensation of amine VIII with acid IX or acid chloride X gives compound I. The compounds I can also be obtained by a two-stage reaction, in which the amine VIII is first reacted with the acid chloride XI and then the elimination reaction takes place in an aqueous base such as sodium hydroxide.

Scheme 1

An alternative synthetic route for key intermediate amine VIII is shown in scheme 2. Amine XIII is coupled with halogenated XIV or XV under similar conditions as shown in scheme 1, or nitro compound VII or intermediate VI known from the literature is converted to amine VIII under the conditions shown in scheme 1.

Scheme 2

As shown in scheme 3, in some cases, compounds of formula I are obtained by coupling intermediate III with intermediate VIa under the conditions shown in scheme 1 or scheme 2.

Scheme 3

The preparation of VIaa is shown in scheme 4. The intermediate VIaa is obtained by using commercially available dichloropyrimidine as a starting material and sequentially performing regioselective substitution reaction, bromination, amination, deprotection, acetylation and reduction reaction of chlorine.

Scheme 4

As an illustration of the preparation of intermediate XIV, the synthesis of XIVa is shown in scheme 5. Commercial dichloropyrimidine is reacted with an amine followed by sodium alkyl alkoxide followed by halogenation to afford intermediate XIVa.

Scheme 5

In some cases, the order of reaction implementation shown in the above schemes may be adjusted to ensure that the reaction proceeds or that side reactions are avoided. The following examples are provided for a full understanding of the 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-indol-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 (5.79 g,30.0 mmol) in dry tetrahydrofuran (30 mL) was added methanol (1.15 mL,28.5 mmol) at 0deg.C followed by 4 portions of sodium hydride (60%, 1.20g,30.0 mmol). After stirring at 0℃for 1h, stirring at room temperature for 1h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2X 30 mL). 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 (1 a) as a pale yellow solid (4.04 g, 71%).

N ¹ - (6-methoxy-5-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine(1b)

6-chloro-2-methoxy-3-nitropyridine (1 a) (3.77 g,20.0 mmol) and N ¹ ,N ¹ ,N ² A solution of trimethylethane-1, 2-diamine (2.24 g,22.0 mmol) in ethanol (45 mL) was heated under reflux for 3h, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel with dichloromethane/methanol/ammonia (92:6:2) as eluent to give N ¹ - (6-methoxy-5-nitropyridin-2-yl) -N ¹ ,N ² ,N ² Trimethylethane-1, 2-diamine (1 b) (2.40 g, 47%). MS-ESI (m/z): 255[ M+1 ] ] ⁺ 。

N ¹ - (3-bromo-6-methoxy-5-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine(1c)

In N ¹ - (6-methoxy-5-nitropyridin-2-yl) -N ¹ ,N ² ,N ² A suspension of trimethylethane-1, 2-diamine (1 b) (1.33 g,5.24 mmol) in acetonitrile (30 mL) was added N-bromosuccinimide (1.40 g,7.82 mmol) at 0deg.C and stirred for 1h at 0deg.C. Reduction ofThe solvent was evaporated to dryness under pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol/aqueous ammonia (92:6:2) to give N as a yellow solid ¹ - (3-bromo-6-methoxy-5-nitropyridin-2-yl) -N ¹ ,N ² ,N ² Trimethylethane-1, 2-diamine (1 c) (1.47 g, 84%). MS-ESI (m/z): 333and 335[1:1,M+1] ⁺ 。

² ³ ² N- (2- (dimethylamino) ethyl) -N- (dibenzenyl) -6-methoxy-N-methyl-5-nitropyridine-2, 3- Diamine (1 d)

Will N ¹ - (3-bromo-6-methoxy-5-nitropyridin-2-yl) -N ¹ ,N ² ,N ² Trimethylethane-1, 2-diamine (1 c) (666 mg,2.00 mmol), pd ₂ (dba) ₃ A mixture of (55 mg,0.060 mmol), (+/-) -BINAP (75 mg,0.120 mmol), benzophenone imine (471 mg,2.60 mmol) and sodium tert-butoxide (250 mg,2.60 mmol) in toluene (8 mL) 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 off 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 N ² - (2- (dimethylamino) ethyl) -N ³ - (dibenzenyl) -6-methoxy-N ² -methyl-5-nitropyridine-2, 3-diamine (1 d) was a yellow solid (227 mg, 26%). MS-ESI (m/z): 434[ M+1 ]] ⁺ 。

² ² N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-5-nitropyridine-2, 3-diamine (1 e)

At room temperature under N ² - (2- (dimethylamino) ethyl) -N ³ - (dibenzenyl) -6-methoxy-N ² A solution of methyl-5-nitropyridine-2, 3-diamine (1 d) (194 mg,0.45 mmol) in methanol (5 mL) was added to concentrated hydrochloric acid (1 mL). After stirring the mixture at room temperature for 1h, it was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×). The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. Evaporating the solvent under reduced pressure, and purifying the residue by silica gel column chromatography (eluent of 3-10% methanol/dichloromethane) to obtain N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-5-nitropyridine-2, 3-diamine (1 e) was a yellow solid (12.4 mg, 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 N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² A mixture of methyl-5-nitropyridine-2, 3-diamine (1 e) (12.4 mg,0.046 mmol) in tetrahydrofuran-water (10:1, 1 mL) was added 3-chloropropionyl chloride (14 mg,0.11 mmol), stirred at 0deg.C for 0.5h, sodium hydroxide (20 mg,0.50 mmol) was added, the mixture was heated to 60deg.C for 3h, cooled to room temperature, diluted with water, extracted with ethyl acetate (2X), and the extract solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent 5% methanol/dichloromethane) to give N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5-nitropyridin-3-yl) acrylamide (1 f) (6.7 mg, 45%). MS-ESI (m/z): 324.2[ M+1 ] ] ⁺ 。

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 (1 f) (6.7 mg,0.021 mmol), iron powder (7.0 mg,0.12 mmol) and ammonium chloride (1.1 mg,0.021 mmol) in ethanol-water (3:1, 2 mL) was heated to reflux for 6h, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with dichloromethane/methanol/ammonia (92:6:2) to give N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (1 g) (3.6 mg, 59%). MS-ESI (m/z) 294[ M+1 ]] ⁺ 。

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- (4- (1-methyl-1H-indol-3-) Base) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (1)

N- (5-amino-2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (1 g) (3.6 mg,0.012 mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole(1h) A mixture of (6.0 mg,0.025 mmol) (prepared according to WO 2013/14448) and p-toluenesulfonic acid monohydrate (4.7 mg,0.025 mmol) in 2-pentanol (0.5 mL) was heated to 105℃and the solvent evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluting with methylene chloride/methanol (95:5) 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) (5.0 mg, 82%). MS-ESI (m/z): 500[ M+1 ] ] ⁺ 。

Example 2

N- (6-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1-methyl-1H-indol-3-)) Base) 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 (4.00 g,21.3 mmol) and tert-butylmethyl (2- (methylamino) ethyl) carbamate (2 a,4.38g,22.3 mmol) (prepared according to literature, J.Med. Chem.,1992,35,565) in ethanol (47 mL) was heated to reflux for 3h, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 15-30% ethyl acetate/n-hexane to give tert-butyl 2- ((6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 b) (4.65 g, 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 Esters (2 c)

To a suspension of tert-butyl 2- ((6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 b) (4.32 g,12.7 mmol) in acetonitrile at 0deg.C was added N-bromosuccinimide (3.40 g,19.1 mmol), the mixture was stirred at 0deg.C for 1h, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent 20-30% ethyl acetate/N-hexane to give tert-butyl 2- ((3-bromo-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) amino) Formate (2 c) as a yellow solid (5.00 g, 93%). MS-ESI (M/z): 419and 421[1:1,M+1 and M+3] ⁺ 。

Tert-butyl 2- ((3- (benzhydryl) -6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) Radical) carbamate (2 d)

2- ((3-bromo-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 c) (2.095 g,5.00 mmol), pd ₂ (dba) ₃ (137 mg,0.150 mmol), (+/-) -BINAP (187 mg,0.300 mmol), benzophenone imine (1.177 g,6.50 mmol) and sodium tert-butoxide (624 mg,6.50 mmol) in toluene (20 mL), heating to 110℃under nitrogen for 3h, cooling to room temperature, pad celite filtration of the solid, washing with ethyl acetate, evaporating the solvent under reduced pressure, purifying the residue by silica gel column chromatography with eluent 20-40% ethyl acetate/n-hexane to give tert-butyl 2- ((3- (benzhydryl) -6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 d) as a pale yellow solid (600 mg, 23%). MS-ESI (m/z): 520[ M+1 ]] ⁺ 。

Tert-butyl 2- ((3-amino-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) aminomethyl Acid esters (2 e)

To a solution of tert-butyl 2- ((3- (benzhydryl) -6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 d) (580 mg,1.12 mmol) in ethanol (20 mL) was added hydrochloric acid (1 n,0.5 mL) at room temperature and heated to 50 ℃ for reaction for 7h. The mixture was diluted with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×), the extract was washed with water and brine, dried over magnesium sulfate, the solvent evaporated under reduced pressure and the residue purified by column chromatography on silica gel with 20-40% ethyl acetate/n-hexane as eluent to give tert-butyl 2- ((3-amino-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 e) as an orange solid (280 mg, 68%). MS-ESI (m/z): 356[ M+1 ] ] ⁺ 。

Tert-butyl 2- ((3-acrylamido-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) Carbamic acid ester [ ]2f)

To a solution of tert-butyl 2- ((3-amino-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 e) (280 mg,0.789 mmol) in tetrahydrofuran-water (10:1, 5.5 ml) was added 3-chloropropionyl chloride (120 mg,0.946 mmol), stirred at 0℃for 0.5h, sodium hydroxide NaOH (126 mg,3.76 mmol) was added and the mixture was heated to 65℃for 1h and cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate (2×). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel 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 (2 f) (185 mg, 57%). MS-ESI (m/z): 410.3[ M+1 ]] ⁺ 。

Tert-butyl 2- ((3-acrylamido-5-amino-6-methoxypyridin-2-yl) (methyl) amino) ethyl (methyl) Carbamates (2 g)

Tert-butyl 2- ((3-acrylamido-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 f) (185 mg,0.452 mmol), iron powder (152 mg,2.71 mmol), ammonium chloride (24.2 mg,0.452 mmol) in ethanol-water (3:1, 15 mL) were heated to reflux for 1h. 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 under reduced pressure to give crude tert-butyl 2- ((3-acrylamido-5-amino-6-methoxypyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2 g) (149 mg, 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 (2 g) (94.0 mg,0.248 mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1H, 72.5mg,0.298 mmol) and p-toluenesulfonic acid monohydrate (56.6 mg,0.298 mmol) in 2-pentanol (1.5 mL) was heated to 105℃for 2H. Reduced pressure evaporating to drynessThe residue was purified by column chromatography on silica gel eluting with methylene chloride/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) (100.0 mg, 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)

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) (15.4 mg,0.0317 mmol) in 1, 2-dichloroethane (1 mL) was added acetaldehyde (40% water, 9.0mg,0.082 mmol) and sodium triacetoxyborohydride (8.7 mg,0.041 mmol), the mixture was stirred at room temperature for 1H, then diluted with saturated aqueous sodium bicarbonate (5 mL), the dichloromethane extract (2X 5 mL) was dried over sodium sulfate, the solvent evaporated under reduced pressure, and the residue was purified by silica gel column chromatography with dichloromethane/methanol/ammonia (95:4:1) to give 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 as a brown solid (12.77 g). MS-ESI (m/z): 515[ M+1 ] ] ⁺ 。

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) (28.3 mg,0.058 mmol) in dichloromethane (1 mL) was added DIPEA (15.2L, 0.087 mmol), cooled to 0deg.C and acetic anhydride (0.20 mL dichloromethane containing 5.9 mg) was added dropwise. The mixture was stirred at room temperature for 1h and saturatedAnd aqueous sodium bicarbonate (5 mL), dichloromethane extraction (2X 5 mL), drying of the extract over sodium sulfate, evaporation of the solvent under reduced pressure, purification of the residue by silica gel column chromatography eluting with 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 (15.1 mg, 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) azoi-m Pyridin-2-yl) amino) pyridin-3-yl acrylamide (5)

6-chloro-2-ethoxy-3-nitropyridine (5 a)

Preparation of 6-chloro-2-ethoxy-3-nitropyridine (5 a) methanol was replaced with ethanol according to the synthetic method of 1 a. MS-ESI (m/z): 203[ M+1 ]] ⁺ 。

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) (36.1 mg) was prepared according to the synthesis method of example 2 substituting 6-chloro-2-methoxy-3-nitropyridine (1 a) with 6-chloro-2-ethoxy-3-nitropyridine (5 a). MS-ESI (m/z): 501[ M+1 ]] ⁺ 。

Example 6

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-ethoxy-5- ((4- (1-methyl-1H-indol-3-) Base) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (6)

To 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) (10.1) at room temperatureTo a solution of 0.020 mmol) in 1, 2-dichloroethane (0.6 mL) was added acetaldehyde (37% in water, 17 mg) and sodium triacetoxyborohydride (6.4 mg,0.030 mmol), the mixture was stirred at room temperature for 1H, diluted with saturated aqueous sodium bicarbonate (2 mL), dichloromethane extracted (2X 2 mL), the extract was dried over sodium sulfate, the solvent evaporated under reduced pressure, the residue was purified by column chromatography on silica gel with eluent 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 a grey solid (8.5 mg, 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 (7 a)

Preparation of 6-chloro-2-isopropoxy-3-nitropyridine (7 a) methanol was replaced with isopropanol according to the synthetic method of 1 a. MS-ESI (m/z): 217[ M+1 ]] ⁺ 。

Preparation of the title compound 7 (36.1 mg) 6-chloro-2-methoxy-3-nitropyridine (1 a) was replaced by 6-chloro-2-isopropoxy-3-nitropyridine (7 a) according to the synthetic method 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 title compound 8 (6.3 mg, 75%) N- (6-ethoxy-2- (methyl) according to the synthesis method of example 6(2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (5) is 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). 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 (25 mg) tert-butyl (2- (methylamino) ethyl) carbamate (2 a) was replaced by tert-butylpiperazine-1-carbamate according to the synthesis method of example 2. MS-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 the title compound 10 (5.2 mg) according to the method of example 6N- (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). 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 the title compound 11 (55 mg) according to the synthesis method of example 2, methyl (2- (methylamino) ethyl) carbamate (2 a) was replaced with tert-butylpiperazine-1-carboxylate and 6-chloro-2-methoxy-3-nitropyridine (1 a) was replaced with 6-chloro-2-ethoxy-3-nitropyridine (5 a), 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 the title compound 12 (7.2 mg) according to the method of synthesis of example 6N- (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). 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- Base) pyridin-3-yl acrylamide (13)

The title compound 13 (75 mg) was prepared according to the synthetic method of example 2 substituting tert-butylmethyl (2- (methylamino) ethyl) carbamate (2 a) with tert-butylpiperazine-1-carbamate and 6-chloro-2-methoxy-3-nitropyridine (1 a) with 6-chloro-2-isopropoxy-3-nitropyridine (7 a), 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-methylpiperazine) Oxazin-1-yl) pyridin-3-yl acrylamide (14)

Preparation of the title compound 14 (7.4 mg) 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 synthetic method 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 ² N- (6-chloro-3-nitropyridin-2-yl) -N, N, N-trimethylethane-1, 2-diamine (15 a)

N was slowly added dropwise to a solution of 2, 6-chloro-3-nitropyridine (19.3 g,100.0 mmol) and triethylamine (20.2 g,200.0 mmol) in dry dichloromethane (200 mL) at 0deg.C ¹ ,N ¹ ,N ² A solution of trimethylethane-1, 2-diamine (10.2 g,100.0 mmol) in dry dichloromethane (20 ml) was added over 0.5h and the reaction mixture was stirred at 0deg.C for 1.5h. The mixture was diluted with water (200 mL) and extracted with dichloromethane (100 mL. Times.3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered to remove solids, and the filtrate concentrated to give N ¹ - (6-chloro-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² Trimethylethane-1, 2-diamine (15 a) as a yellow oil (23.8 g, 91%). MS-ESI (m/z): 259[ M+1 ]] ⁺ 。

¹ ¹ ² ² N- (6-methoxy-3-nitropyridin-2-yl) -N, N, N-trimethylethane-1, 2-diamine (15 b)

At 0-5 deg.C, to N ¹ - (6-chloro-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² To a solution of trimethylethane-1, 2-diamine (15 a) (23.8 g,91.9 mmol) in methanol (200 mL) was added sodium methoxide (10.8 g,183.8 mmol), and the mixture was heated to reflux for 2h, cooled to room temperature, evaporated to dryness, diluted with water (200 mL), and extracted with dichloromethane (200 mL. Times.2). The organic layers were combined, washed with water (200 mL. Times.2) and brine (200 mL), and dried over sodium sulfate. Filtering off solids, concentrating the filtrate under reduced pressure, purifying the crude product by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as eluent to obtain N ¹ - (6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² Trimethylethane-1, 2-diamine (15 b) as a yellow oil (18.0 g, 77%). MS-ESI (m/z): 255[ M+1 ]] ⁺ 。

¹ ¹ ² ² N- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N, N, N-trimethylethane-1, 2-diamine (15 c)

At 0-5 deg.C, to N ¹ - (6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² To a solution of trimethylethane-1, 2-diamine (15 b) (11.0 g,43.1 mmol) in glacial acetic acid (120 mL) was added N-iodosuccinimide (11.6 g,51.8 mmol) in 3 portions, and the mixture was stirred at room temperature for 4.5h. The solvent was evaporated under reduced pressure, diluted with water (300 mL), extracted with ethyl acetate (200 mL. Times.3), the organic layers were combined, washed with water (200 mL. Times.2) and brine (200 mL), and dried over sodium sulfate. Filtering off solids, concentrating the filtrate under reduced pressure, purifying the crude product by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as eluent to obtain N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² Trimethylethane-1, 2-diamine (15 c) as a yellow oil (14.0 g, 88%). MS-ESI (m/z): 381[ M+1 ]] ⁺ 。

¹ ¹ ² ² N- (5- ((diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N, N, N-trimethylethan Alkyl-1, 2-diamine (15 d)

Under inert nitrogen, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² A mixture of trimethylethane-1, 2-diamine (15 c) (10.0 g,26.2 mmol), tris (dibenzylideneacetone) dipalladium (0) (1.2 g,1.3 mmol), (+/-) -2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl (1.6 g,2.6 mmol), benzophenone imine (7.1 g,39.4 mmol) and sodium t-butoxide (3.8 g,39.4 mmol) in toluene (150 mL) was heated to 110℃and reacted for 16h. Cooling to room temperature, filtering with celite to remove solid, washing with ethyl acetate, evaporating the solvent under reduced pressure, purifying the residue by silica gel column chromatography, eluting with ethyl acetate to obtain N ¹ - (5- ((diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² Trimethylethane-1, 2-diamine (15 d) as a red oil (2.2 g, 19%). MS-ESI (m/z): 434[ M+1 ]] ⁺ 。

² N-(2-( ² Dimethylamino) ethyl) -6-methoxy-N-methyl-3-nitropyridine-2, 5-diamine (15 e)

At room temperature, N is ¹ - (5- ((diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² A solution of trimethylethane-1, 2-diamine (15 d) (2.2 g,5.1 mmol) in tetrahydrofuran (150 mL) was added to 0.5N hydrochloric acid (24 mL), and the mixture was stirred at room temperature for 1.5h. Evaporating tetrahydrofuran under reduced pressure, and regulating pH value to 9-10 with potassium carbonate. The resulting mixture was extracted with dichloromethane (30 ml×4), the organic layers were combined, washed with brine (200 mL) and dried over sodium sulfate. Filtering out solid, concentrating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography, eluting with dichloromethane/methanol (20:1-10:1) to obtain N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 e) as a red oil (0.7 g, 51%). MS-ESI (m/z): 270[ M+1 ]] ⁺ 。

7-fluoro-1-methyl-1H-indole (15 f)

To a solution of 7-fluoro-1H-indole (1.0 g,7.4 mmol) in N, N-dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 0.44g,11.1 mmol) and the resulting suspension was stirred at room temperature for 20 min, methyl iodide (0.7 mL,11.1 mmol) was added at room temperature and stirred at room temperature for 1H. The reaction was quenched with water (40 mL), the mixture extracted with ethyl acetate (30 mL. Times.3), the organic layers combined, washed with water (30 mL. Times.3) and brine (30 mL) and dried over sodium sulfate. The solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:20) to give 7-fluoro-1-methyl-1H-indole (15 f) as a pale yellow liquid (1.0 g, 91%). MS-ESI (m/z): 150[ M+1 ] ] ⁺ 。

3- (2-Chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g)

A solution of 7-fluoro-1-methyl-1H-indole (15 f) (0.60 g,4.0 mmol), 2, 4-dichloropyrimidine (0.60 g,4.0 mmol), anhydrous ferric (III) chloride (0.65 g,4.0 mmol) in 1, 2-ethylene glycol dimethyl ether (12 mL) was stirred at 60℃for 7H. The reaction was quenched with water (40 mL) and the resulting mixture was extracted with ethyl acetate (30 mL. Times.3), the organic layers were combined, and water (30 mLX 3) and brine (30 mL), dried over sodium sulfate. The solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:5-1:2) to give 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) as a brown solid (0.50 g, 48%). MS-ESI (m/z): 262[ M+1 ]] ⁺ 。

² N-(2-(Dimethylamino group ⁵ ) Ethyl) -N- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methyl ² oxy-N-methyl-3-nitropyridine-2, 5-diamine (15 h)

3- (2-Chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) (30.0 mg,0.11 mmol), N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² A mixture of methyl-3-nitropyridine-2, 5-diamine (15 e) (31.0 mg,0.11 mmol), cesium carbonate (112.0 mg,0.33 mmol), tris (dibenzylideneacetone) dipalladium (0) (21.0 mg,0.022 mmol), (+/-) -2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl (29.0 mg,0.044 mmol) and dioxane (3 mL) was stirred at 100℃for 7h and cooled to room temperature. The reaction was quenched with water (40 mL), the resulting mixture was extracted with ethyl acetate (30 mL. Times.3), the organic layers were combined, washed with water (30 mL. Times.3) and brine (30 mL) and dried over sodium sulfate. The solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol/aqueous ammonia (100:5:0.5) to give N ² - (2- (dimethylamino) ethyl) -N ⁵ - (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 h) as a yellow solid (34.0 mg, 60%). MS-ESI (m/z): 495[ M+1 ]] ⁺ 。

² ⁵ N- (2- (dimethylamino) ethyl) -N- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methyl ² oxy-N-methylpyridine-2, 3, 5-triamine (15 i)

Will N ² - (2- (dimethylamino) ethyl) -N ⁵ - (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N ² A mixture of methyl-3-nitropyridine-2, 5-diamine (15 h) (34.0 mg,0.07 mmol), iron powder (41.0 mg,0.73 mmol), ammonium chloride (13.0 mg,0.24 mmol) in ethanol (12 mL) and water (3 mL) was stirred at 80 ℃Mix for 1.5h. The solid was filtered off, washed with ethanol (5 mL. Times.3), and the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with dichloromethane/methanol/ammonia water (100:5:0.5-100:10:0.5) to obtain N ² - (2- (dimethylamino) ethyl) -N ⁵ - (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N ² -methyl-N ² Picoline-2, 3, 5-triamine (15 i) as a yellow oil (28.0 mg, 88%). MS-ESI (m/z): 465[ M+1 ]] ⁺ 。

At 0 ℃ to N ² - (2- (dimethylamino) ethyl) -N ⁵ - (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N ² -methyl-N ² To a solution of picoline-2, 3, 5-triamine (15 i) (28.0 mg,0.06 mmol) in dry dichloromethane (1 mL) was added acryloyl chloride (5.5 mg,0.06 mmol) and stirred at 0deg.C for 1h. The reaction was quenched with saturated aqueous sodium bicarbonate (20 mL) and the resulting mixture was extracted with dichloromethane (20 mL. Times.3). The organic layers were combined, washed with water (20 mL. Times.3) and brine (20 mL), and dried over sodium sulfate. The solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography over silica gel eluting with methylene chloride/methanol/aqueous ammonia (100:5:0.5-100:10:0.5) to give 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) as a yellow solid (20.0 mg, 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 (20.0 mg) according to the method for the synthesis of example 15 substituting 7-fluoro-1H-indole with 6-fluoro-1H-indole. 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 (25.0 mg) according to the method for the synthesis of example 15 substituting 7-fluoro-1H-indole with 5-fluoro-1H-indole. 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 (23.0 mg) according to the method for the synthesis of example 15 substituting 7-fluoro-1H-indole 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 (19 a)

A solution of 1-methyl-1H-indole (0.50 g,3.8 mmol), 2, 4-dichloro-5-fluoropyrimidine (0.64 g,3.8 mmol) and anhydrous ferric (III) chloride (0.62 g,3.8 mmol) in 1, 2-ethyleneglycol dimethyl ether (7.0 mL) was stirred at 60℃for 7H. The reaction was quenched with water (40 mL), the resulting mixture was extracted with ethyl acetate (30 mL. Times.3), the organic layers were combined, washed with water (30 mL. Times.3) and brine (30 mL) and dried over sodium sulfate. The solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:5-1:2) to give 3- (2-chloro-5-fluoropyrimidin-4-yl) -1-methyl-1H-indole (19 a) as a brown solid (0.54 g, 54%). MS-ESI (m/z): 262[ M+1 ] ] ⁺ 。

N- (2- ((2- (dimethylamino) ethyl)Yl) (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 (23.0 mg) following the synthesis method of example 15 3- (2-chloro-pyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) was replaced with 3- (2-chloro-5-fluoropyrimidin-4-yl) -1-methyl-1H-indole (19 a). 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) Base) (methyl) amino) -6-methoxypyridin-3-yl acrylamide (20)

3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indole (20 a)

A solution of 1-methyl-1H-indole (0.50 g,3.8 mmol), 2,4, 5-trichloropyrimidine (0.64 g,3.8 mmol) and anhydrous ferric (III) chloride (0.62 g,3.8 mmol) in 1, 2-ethyleneglycol dimethyl ether (7.0 mL) was stirred at 60℃for 7H. The reaction was quenched with water (40 mL), the resulting mixture was extracted with ethyl acetate (30 mL. Times.3), the organic layers were combined, washed with water (30 mL. Times.3) and brine (30 mL) and dried over sodium sulfate. The solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:5-1:2) to give 3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indole (20 a) as a brown solid (0.56 g, 53%). MS-ESI (m/z): 278[ M+1 ] ] ⁺ 。

Preparation of the title compound 20 (20.0 mg) following the synthesis method of example 15 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) was replaced with 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) o-f-1) Indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl acrylamide (21)

3- (2-chloro-5-methylpyrimidin-4-yl) -1-methyl-1H-indole (21 a)

A solution of 1-methyl-1H-indole (0.50 g,3.8 mmol), 2, 4-dichloro-5-methylpyrimidine (0.64 g,3.8 mmol) and 1, 2-ethylene glycol dimethyl ether (7.0 mL) of anhydrous ferric (III) chloride (0.62 g,3.8 mmol) was stirred at 60℃for 7H. The reaction was quenched with water (40 mL), the resulting mixture was extracted with ethyl acetate (30 mL. Times.3), the organic layers were combined, washed with water (30 mL. Times.3) and brine (30 mL) and dried over sodium sulfate. The solid was filtered off, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:5-1:2) to give 3- (2-chloro-5-methylpyrimidin-4-yl) -1-methyl-1H-indole (21 a) as a brown solid (0.50 g, 47%). MS-ESI (m/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 (26.0 mg) following the synthesis method of example 15 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) was replaced with 21a. MS-ESI (m/z): 515[ M+1 ]] ⁺ 。

Example 22

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)

5-bromo-3-methoxy-2-nitropyridine(22a)

Preparation of 5-bromo-3-methoxy-2-nitropyridine (22 a) is according to the synthetic method described in US 2006/84665.

Tert-butyl (2- ((5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate(22b)

5-bromo-3-methoxy-2-nitropyridine (22 a) (2.8 g,12.02 mmol), tert-butylmethyl (2- (methylamino) ethyl) carbamate (2) was reacted under nitrogen.67g,13.22 mmol), palladium acetate (0.27 g,1.20 mmol), xantphos (0.69 g,1.20 mmol) and cesium carbonate (11.7 g,35.91 mmol) in toluene (56 mL) were stirred at 100deg.C for 2.5h. The mixture was cooled to room temperature, quenched with water (200 mL) and extracted with ethyl acetate (3X 50 mL). The extract was washed with brine, dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel eluting with 50% ethyl acetate/n-hexane to give tert-butyl (2- ((5-methoxy-6-nitropyridin-3-yl) (meth) amino) ethyl) (meth) carbamate (22 b) as a yellow solid (3.0 g, 73%). MS-ESI (m/z): 341[ M+1 ] ] ⁺ 。

Tert-butyl (2- ((2-bromo-5-methoxy-6-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate(22c)

To a mixture of tert-butyl (2- ((5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22 b) (1.70 g,5.00 mmol) in glacial acetic acid (30 mL) was added a solution of bromine (0.88 g,5.50 mmol) in glacial acetic acid (5 mL) at 0deg.C. The mixture was stirred at 0deg.C for 0.5h, at room temperature, diluted with water (150 mL) and extracted with ethyl acetate (3X). The extract was washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel with 20-40% ethyl acetate/n-hexane as eluent to give tert-butyl (2- ((2-bromo-5-methoxy-6-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (22 c) as a yellow solid (1.53 g, 73%). MS-ESI (M/z): 419.2and 421.2[1:1,M+1 and M+3] ⁺ 。

Tert-butyl (2- ((2- ((benzhydryl) 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 (22 c) (319 mg,1.00 mmol), pd ₂ (dba) ₃ (27.5 mg,0.030 mmol), (+/-) -BINAP (37.4 mg,0.060 mmol), benzophenone imine (199mg, 1.10 mmol) and sodium tert-butoxide (192 mg,2.00 mmol) in toluene (5 mL) were reacted under nitrogen with heating at 80℃for 4h. Cool to room temperature and evaporate the solvent under reduced pressure. Tetrahydrofuran (14 mL) and 0.5N hydrochloric acid (14 mL) were added successively, and the mixture was stirred at room temperature for 1.5h, diluted with sodium bicarbonate (50 mL) Ethyl acetate extraction (2×). The extract was washed with brine, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and 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- ((benzhydryl) amino) -5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22 d) as a yellow solid (76 mg, 21%). MS-ESI (m/z): 356.2[ M+1)] ⁺ 。

Tert-butyl (2- ((2-acrylamido-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate(22e)

To tert-butyl (2- ((2- ((benzhydryl) amino) -5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22 d) at 0 ℃C)To a mixture of (75 mg,0.211 mmol) acetonitrile (3 mL) was added 3-chloropropionyl chloride (53.6 mg, 0.428 mmol), DMAP (51.5 mg,0.422 mmol) and DIPEA (81.7 mg,0.633 mmol). The mixture was stirred at 0deg.C for 2.5h and sodium hydroxide (10N, 0.8 mL) was added. The mixture was stirred at room temperature for 1.5h, diluted with water and extracted with ethyl acetate (2×). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel with 5% methanol in dichloromethane as eluent to give tert-butyl (2- ((2-acrylamido-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22 e) (28.5 mg, 33%). MS-ESI (m/z): 410.2[ M+1) ] ⁺ 。

Tert-butyl (2- ((2-acrylamido-6-amino-5-methoxypyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate(22f)

A mixture of tert-butyl (2- ((2-acrylamido-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22 e) (28.5 mg,0.070 mmol), iron powder (19.5 mg,0.348 mmol) and ammonium chloride (3.7 mg,0.070 mmol) in ethanol-water (3:1, 15 mL) was heated to reflux for 2h, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel with 92:6:2 dichloromethane-methanol-ammonia as eluent to give tert-butyl (2- ((2-acrylamido-6-amino-5-methoxypyridin-3-yl) (methyl) amino) ethyl (methyl) carbamate (22 f) (9.0 mg, 34%). MS-ESI (m/z): 380.2[ M+1] +.

Tert-butyl (2- ((2-acrylamido-5-methoxy-6- ((4- (1-methyl-1H-indol-3-yl)) azoi-ne)Pyridin-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 (22 f) (8.6 mg,0.023 mmol), 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1H, 6.6mg,0.027 mmol), pd ₂ (dba) ₃ (3.4 mg,0.0036 mmol), BINAP (2.2 mg,0.0036 mmol) and cesium carbonate (11 mg,0.034 mmol) were heated to 100deg.C for 2.5h. Diluting with water, extracting with dichloromethane. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 95:5 methylene chloride-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 (22 g) (3.3 mg, 25%) MS-ESI (m/z): 586.3[ M+1] ] ⁺ 。

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 (22 g) (3.3 mg) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature the mixture was stirred at room temperature for 40 min, the solvent was evaporated to dryness, and NaBH (OAc) was added ₃ (3.5 mg), 1, 2-dichloroethane (0.3 mL) 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 methylene chloride-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) (2.5 mg, 89%). MS-ESP 501.4[ M+1 ]] ⁺ 。

Example 23

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)

N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (23 a)

Preparation of the title compound 23a according to the synthetic method of example 2, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (2 g) replaced with N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 e). MS-ESI (m/z): 477[ M+1 ]] ⁺ 。

N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridin-2, 3, 5-triamine(23b)

Preparation of title compound 23b according to the synthetic method of 15i, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 h) substitution to N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (23 a). MS-ESI (m/z): 447[ M+1 ]] ⁺ 。

Will N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ A mixture of (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23 b) (20 mg,0.045 mmol), HOBT (18 mg,0.135 mmol), EDCI (26 mg,0.135 mmol) and triethylamine (14 mg,0.135 mmol) in DMF (2 ml) was stirred at 35℃for 3H. The reaction was cooled to room temperature and quenched by the addition of water (5 mL). The pH of the mixture was adjusted to 9-10 with sodium carbonate and ethyl acetate (8 mL. Times.3). The organic layers were combined, washed with brine (20 mL) and dried over sodium sulfate. The solid was removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (10:1) 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-indol-3-yl) pyrimidin-2-yl) amino) phenyl) -2-fluoroacrylamide(24)

N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -methyl-2-nitrobenzene-1, 4-diamine(24a)

4-fluoro-2-methoxy-5-nitroaniline (3.0 g,16.0 mmol) (prepared according to WO 2013/14448), N ¹ ,N ¹ ,N ² A DMA mixture of trimethylethane-1, 2-diamine (2.0 g,19.7 mmol) and DIPEA (2.7 g,20.8 mmol) was stirred at 80℃for 5h and cooled to room temperature. The DMA was evaporated to dryness, diluted with water (50 mL), extracted with dichloromethane (50 mL. Times.3). The organic layers were combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered to remove solids, the filtrate concentrated at low pressure, and the residue purified by column chromatography on silica gel eluting with methylene chloride/methanol (20:1-10:1) to give N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -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-indol-3-yl) pyrimidin-2-yl) amino) phenyl) -2-fluoroacrylamide (24)

Preparation of the title compound 24 according to the synthetic method of example 23, N ² - (2- (methoxy) ethyl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 e) substitution with N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -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-methylindolin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide(25)

1- (2-ethoxy-2-oxoethyl) -2-ethylpyridine-1-yl bromide(25a)

To ethanol (200 mL) of 2-ethylpyridine (10 g,0.09 mol)) To the mixture was added ethyl 2-bromoacetate (23 g,0.14 mmol), heated under reflux for 16h, then cooled to room temperature and concentrated at low pressure to give crude 1- (2-ethoxy-2-oxoethyl) -2-ethylpyridine-1-yl bromide (25 a) which was used in the next reaction without further purification. MS-ESI (m/z): 194[ M] ⁺ 。

Ethyl 1-methylindolazine-3-carboxylate(25b)

To an ethanol solution (100 mL) of 1- (2-ethoxy-2-oxoethyl) -2-ethylpyridine-1-yl bromide (25 a) (10 g,0.036 mol) and potassium carbonate (15 g,0.10 mol) was added (E) -ethyl 2-cyano-3-ethoxyacrylate (25 g,0.14 mol). The mixture was heated under reflux for 15h, then cooled to room temperature, concentrated under reduced pressure, and the residue extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (50:1-20:1) to give ethyl 1-methylindoline-3-carboxylate (25 b). MS-ESI (m/z): 275[ M+1 ] ] ⁺ 。

N-methoxy-N, 1-dimethylindolizine-3-amide(25c)

To a solution of ethyl 1-methylindoline-3-carboxylate (25 b) (3.0 g,0.014 mol) and N, O-dimethylhydroxylamine hydrochloride (3.6 g,0.037 mol) in tetrahydrofuran (50 mL) at 0deg.C was added magnesium isopropylchloride (2M in Et ₂ O,35mL,0.07 mol). After stirring the mixture for 1h, it was quenched with water and extracted with ethyl acetate (50 mL. Times.3). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by silica gel column chromatography with N-hexane/ethyl acetate (20:1-10:1) as eluent to give N-methoxy-N, 1-dimethylindolizine-3-amide (25 c). MS-ESI (m/z): 219[ M+1 ]] ⁺ 。

1- (1-methylindolin-3-yl) ethanone(25d)

To a solution of N-methoxy-N, 1-dimethylindolizine-3-amide (25 c) (2.6 g,0.012 mol) in tetrahydrofuran (50 mL) was added methyl magnesium bromide (3M diethyl ether, 8.0mL,0.024 mol) at 0deg.C. After stirring the mixture for 1h, it was quenched with water and extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 1- (1-methylindolin-3-yl) ethanone (25 d) which was used for the next reaction without further purification. MS-ESI (m/z)):174[M+1] ⁺ 。

(E) -1- (1-methylindolin-3-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one(25e)

Pyrrolidine (10 mL,0.12 mol) was added to a solution of 1- (1-methylindolin-3-yl) ethanone (25 d) (2.0 g,0.012 mol) in DMF-DMA (25 mL) at 25 ℃. After stirring the mixture at 90℃for 1h, it was 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. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (10:1-2:1) to give (E) -1- (1-methylindolin-3-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (25E). MS-ESI (m/z): 255[ M+1 ] ] ⁺ 。

4- (1-methylindolin-3-yl) pyrimidin-2-amine (25 f)

Guanidine hydrochloride (1.1 g,0.19 mol) was added to a solution of (E) -1- (1-methylindolin-3-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (25E) (1.0 g,0.0039 mol) and potassium carbonate (2.7 g,0.012 mol) in isopropanol (10 mL) at 25 ℃. After stirring the mixture at 130℃for 16h, 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. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (30:1) to give 4- (1-methylindolin-3-yl) pyrimidin-2-amine (25 f). MS-ESI (m/z): 225[ M+1 ]] ⁺ 。

² ² ⁵ N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (1-methylindolin-3-yl) pyrimidine-2-) Phenyl) -3-nitropyridine-2, 5-diamine (25 g)

To 4- (1-methylindolin-3-yl) pyrimidin-2-amine (25 f) (150 mg,0.67 mmol), N at 25 ℃ ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² To a solution of trimethylethane-1, 2-diamine (15 c) (382 mg,0.33 mmol) and cesium carbonate (0.87 g,2.67 mmol) in toluene (5 mL) and 1, 4-dioxane (2.5 mL) was added Xantphos (193 mg,0.33 mmol) palladium acetate (75 mg,0.33 mmol), the mixture was stirred at 110℃for 3 hours, cooled to room temperature, extracted with ethyl acetate (50 mL. X3). The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography Purifying by using methylene dichloride/methanol (40:1-20:1) as eluent to obtain N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methylindolin-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-methylindolin-3-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (25)

Preparation of title compound 25 according to the synthesis method of example 15, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methylindolin-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-methylindolin-3-yl) Pyrimidin-2-yl) amino) phenyl) acrylamide (26)

¹ ¹ ² ² N- (4-iodo-5-methoxy-2-nitrophenyl) -N, N, N-trimethylethane-1, 2-diamine (26 a)

At 0 ℃ to N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ To a solution of methyl-2-nitrobenzene-1, 4-diamine (24 a) (3.2 g,11.9 mmol) in 1N sulfuric acid (50 mL) was added sodium nitrite (1.28 g,17.9 mmol). The mixture was stirred at 0deg.C for 15 min, then potassium iodide (4.0 g,23.8 mmol) was added. The mixture was stirred for 1h at 90℃and cooled to room temperature, and the pH was adjusted to 9-10 with sodium carbonate. The resulting mixture was extracted with ethyl acetate (20 mL. Times.3), the organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (20:1) to give N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (26 a). MS-ESI (m/z): 380[ M+1 ]] ⁺ 。

Preparation of the title compound 26 according to the synthesis method of example 25, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (26 a). MS-ESI (m/z): 500[ M+1 ]] ⁺ 。

Example 27

N- (5- ((4- (1-cyanoindol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -6-methoxypyridin-3-yl acrylamide (27)

1- (2-ethoxy-2-oxoethyl) pyridine-1-yl bromide (27 a)

To a mixture of pyridine (10 g,0.09 mol) in ethanol (200 mL) was added ethyl 2-bromoacetate (23 g,0.14 mmol), heated to reflux for 16h, then cooled to room temperature, and concentrated at low pressure to give crude 1- (2-ethoxy-2-oxoethyl) pyridine-1-bromide (27 a) 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 a solution of 1- (2-ethoxy-2-oxoethyl) pyridine-1-bromide (27 a) (10 g,0.04 mol) and triethylamine (29 mL,0.2 mol) in ethanol (250 mL) was added (E) -3-methacrylonitrile (10 g,0.12 mol). The mixture was heated under reflux for 15h, then cooled to room temperature, concentrated under reduced pressure, and the residue extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (50:1-20:1) to give ethyl 1-cyanoindolizine-3-carboxylate (27 b). MS-ESI (m/z): 215[ M+1 ] ] ⁺ 。

N- (5- ((4- (1-cyanoindol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide(27)

Preparation of the title compound 27 following the synthetic method of example 25 ethyl 1-methylindolazine-3-carboxylate (25 b) was replaced with ethyl 1-cyanoindolizine-3-carboxylate (27 b). MS-ESI (m/z): 501[ M+1 ]] ⁺ 。

Example 28

N- (5- ((4- (1-cyanoindol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide(28)

Preparation of title compound 28 according to the synthesis method for example 27, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -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 the 2-ethylpyridine was replaced with 2-methylpyridine according to the synthetic method of example 25. MS-ESI (m/z): 487[ M+1 ]] ⁺ 。

Example 30

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indol-3-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (30)

Preparation of the title compound 30 according to the synthesis method of example 29, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (26 a). MS-ESI (m/z): 486[ M+1 ]] ⁺ 。

Example 31

N- (5- ((4- (1-chloroindol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide(31)

Ethylinazine-3-carboxylic acid esters(31a)

Preparation of the title compound ethylindolizine-3-carboxylate (31 a) 2-ethylpyridine was replaced with 2-methylpyridine according to the synthetic method of compound 25 b. MS-ESI (m/z): 190[ M+1 ]] ⁺ 。

Ethyl 1-chloroindolizine-3-carboxylate(31b)

N-chlorosuccinimide (0.3 g,2.2 mmol) was added to a solution of ethylindolizine-3-carboxylate (31 a) (0.4 g,2.2 mmol) in DMF (5 mL) at 0deg.C, the mixture was stirred for 1h at 25deg.C, ethyl acetate extracted (50 mL. Times.3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (50:1) to give ethyl 1-chloroindolizine-3-carboxylate (31 b). MS-ESI (m/z): 224[ M+1 ]] ⁺ 。

N- (5- ((4- (1-chloroindol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (31)

Preparation of the title compound 31 following the synthetic method of example 25 ethyl 1-methylindolazine-3-carboxylate (25 b) was replaced with ethyl 1-chloroindolizine-3-carboxylate (31 b). MS-ESI (m/z): 521[ M+1 ]] ⁺ 。

Example 32

N- (5- ((4- (1-chloroindol-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) ammonia Phenyl) -4-methoxyphenyl acrylamide (32)

Preparation of title compound 32 according to the synthesis method of example 31, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -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-methylindolin-1-yl) Pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (33)

3-methylindolazine-1-carbonitrile (33 a)

A mixture of 2-bromopropionaldehyde (7.26 g,53.4 mmol) and 2-pyridine acetonitrile (6.3 g,53.4 mmol) in tetrahydrofuran (70 mL) was heated at 70deg.C for 24h. The mixture was concentrated under reduced pressure, the residue diluted with ethyl acetate and hydrochloric acid (20 ml,2 m), 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 column chromatography on silica gel eluting with petroleum ether/ethyl acetate (10:1-5:1) to give 3-methylindoline-1-carbonitrile (33 a). MS-ESI (m/z): 157[ M+1 ] ] ⁺ 。

1- (3-methylindolin-1-yl) ethane-1-imine (33 b)

To a solution of 3-methylindolazine-1-carbonitrile (33 a) (1.6 g,10.3 mmol) in tetrahydrofuran was added 3M methyl magnesium bromide (18 mL) in an ice-water bath and stirred at room temperature for 15h. 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-methylindolin-1-yl) ethane-1-imine (33 b). MS-ESI (m/z): 173[ M+1 ]] ⁺ 。

1- (3-methylindolin-1-yl) ethan-1-one (33 c)

To a solution of 1- (3-methylindolin-1-yl) ethane-1-imine (33 b) (1.0 g,5.8 mmol) in tetrahydrofuran was added 6N sulfuric acid (60 mL) at room temperature, and the mixture was heated to 55℃for 24 hours 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-methylindolin-1-yl) ethan-1-one (33 c). MS-ESI (m/z): 174[ M+1 ]] ⁺ 。

1- (3-methylindolin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33 d)

To a solution of 1- (3-methylindolin-1-yl) ethan-1-one (33 c) (110 mg,0.7 mmol) in DMF was added DMF-DMA (170 mg,1.4 mmol) and pyrrolidine (50 mg,0.7 mmol) at 25 ℃. The mixture was stirred at 90℃for 1.5 h. After cooling to room temperature, ethyl acetate extraction was performed. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give crude 1- (3-methylindolin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33 d). MS-ESI (m/z): 255[ M+1 ] ] ⁺ 。

4- (3-methylindolin-1-yl) pyrimidin-2-amine (33 e)

To a solution of 1- (3-methylindolin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33 d) (300 mg,1.2 mmol) in isopropanol was added guanidine hydrochloride (337 mg,3.5 mmol) and potassium carbonate (662 mg,4.8 mmol). The mixture was stirred in a closed tube at 120℃for 20h. 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-methylindolin-1-yl) pyrimidin-2-amine (33 e). MS-ESI (m/z): 225[ M+1 ]] ⁺ 。

² ² ⁵ N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (3-methylindolin-3-yl) pyrimidine-2- 3-nitropyridine-2, 5-diamine (33 f)

A mixture of 4- (3-methylindolin-1-yl) pyrimidin-2-amine (33 e) (30.0 mg,0.13 mmol), 25c (76.0 mg,0.20 mmol), palladium acetate (15.0 mg,0.07 mmol), xanthos (38.0 mg,0.07 mmol) and cesium carbonate (170 mg,0.52 mmol) in toluene (1 mL) and dioxane (0.5 mL) was heated to 110℃under nitrogen to react for 3h. Cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purifying the residue by silica gel column chromatography with 9% methanol/dichloromethane as eluent to obtain N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (3-methylindolin-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-methylindolin-1-yl) Pyrimidin-2-yl) amino) pyridin-3-yl)Acrylamide (33)

Preparation of title compound 33 according to the synthesis method of example 15, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (3-methylindolin-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-methylindolin-1-yl) Pyrimidin-2-yl) amino) phenyl) acrylamide (34)

Preparation of title compound 34 according to the synthesis method for example 33, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (26 a). MS-ESI (m/z): 500[ M+1 ]] ⁺ 。

Example 35

N- (5- ((4- (3-cyanoindol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -6-methoxypyridin-3-yl acrylamides(35)

1-Acetylindolizine-3-carbonitrile (35 a)

A mixture of 1- (cyanomethyl) pyridin-1-yl bromide (10 g,50.3 mmol), 4-methoxybut-3-en-2-one (5.1 g,50.3 mmol) and triethylamine (10 g,100.6 mmol) in ethanol (100 mL) was heated at 80deg.C for 7h. 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 as a yellow solid (35 a). MS-ESI (m/z): 185[ M+1 ]] ⁺ 。

1- (3- (pyrrolidin-1-yl) acryloyl) indolizine-3-carbonitrile (35 b)

To a solution of 1- (3-methylindolin-1-yl) ethan-1-one (33 c) (110 mg,0.7 mmol) in DMF was added DMF-DMA (170 mg,1.4 mmol) and pyrrolidine (50 mg,0.7 mmol). The mixture was stirred at 90℃for 1.5 h. After cooling to room temperature, ethyl acetate extraction was performed. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give crude 1- (3-methylindolin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33 d). To a solution of 1-acetylindolizine-3-carbonitrile (35 a) (400 mg,2.17 mmol) in DMF was added DMF-DMA (516 mg,4.34 mmol) and pyrrolidine (308 mg,4.34 mmol). The mixture was stirred at 90℃for 1.5 h. After cooling to room temperature, ethyl acetate extraction was performed. 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-Aminonaphthyridin-4-yl) indolizine-3-carbonitrile (35 c)

To a solution of 1- (3- (pyrrolidin-1-yl) acryloyl) indolizine-3-carbonitrile (35 b) (637 mg,2.4 mmol) in 1-butanol was added guanidine hydrochloride (69mg, 7.2 mmol) and potassium carbonate (1.3 g,9.6 mmol). The mixture was stirred at 115℃for 20 h. After cooling to room temperature, water was added to dilute the mixture, and ethyl acetate was used for extraction. 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 ]] ⁺ 。

Preparation of the title compound 35 following the synthetic method of example 33 4- (3-methylindolin-1-yl) pyrimidin-2-amine (33 e) was replaced with 1- (2-aminopiperidin-4-yl) indolizine-3-carbonitrile (35 c). MS-ESI (m/z): 512[ M+1 ]] ⁺ 。

Example 36

N- (5- ((4- (3-cyanoindol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) Amino) -4-methoxyphenyl) acrylamide(36)

Preparation of the title compound 36 according to the synthetic method of example 35, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (26 a). MS-ESI (m/z): 511[ M+1 ]] ⁺ 。

Example 37

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (indol-1-yl) pyrimidin-2-yl) amino) 6-methoxypyridin-3-yl) acrylamide (37)

1- (2-ethoxy-2-oxoethyl) pyridine-1-yl bromide (37 a)

To a mixture of pyridine (10 g,0.09 mol) in ethanol (200 mL) was added ethyl 2-bromoacetate (23 g,0.14 mmol), heated to reflux for 16h, and then cooled to room temperature to give crude 1- (2-ethoxy-2-oxoethyl) pyridine-1-bromide (27 a) which was used in the next reaction without further purification. MS-ESI (m/z): 167[ M] ⁺ . A solution of pyridine (2.00 g,25.30 mmol) and ethyl 2-bromoacetate (6.3 g,38.00 mmol) in ethanol (20 mL) was heated at 70deg.C under nitrogen for 1h. 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-oxoethyl) pyridine-1-yl bromide (37 a). MS-ESI (m/z): 167[ M+1 ]] ⁺ 。

Ethyl 1-acetylindolizine-3-carboxylate(37b)

To an ethanol solution (250 mL) of 1- (2-ethoxy-2-oxoethyl) pyridine-1-bromide (27 a) (10 g,0.04 mol) and triethylamine (29 mL,0.2 mol) was added (E) -3-methacrylonitrile (10 g,0.12 mol). The mixture was heated under reflux for 15h, concentrated under reduced pressure, and the residue (50 mL. Times.3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, and the eluent is n-hexane/ethyl acetate (50:1-20:1) to obtain ethyl 1-cyanoindolizine-3-carboxylate. To 1- (2-ethoxy-2-oxoethyl) pyridine-1-bromide (37 a) (5.50 g,15.10 mmol) and 4-methoxybut-3-en-2-one at 20deg.C A solution of 2.3g,22.3 mmol) in ethanol (65 mL) was added triethylamine (4.50 g,44.60 mmol). The mixture was heated at 80℃overnight, then cooled to room temperature, diluted with water and extracted with ethyl acetate (3X 50 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 1-acetylindolizine-3-carboxylate (37 b) (2.65 g). MS-ESI (m/z): 232[ M+1 ]] ⁺ 。

1- (indol-1-yl) ethan-1-one(37c)

To a methanol solution (30 mL) of ethyl 1-acetylindolizine-3-carboxylate (37 b) (2.60 g,11.3 mmol) was added 10% sodium hydroxide (2.0 g,50.6 mmol) at 20deg.C. The mixture was heated at 65℃for 1h, concentrated under reduced pressure to remove the solvent, polyphosphoric acid (10.0 g) and methanol (40 ml) were added, and the mixture was heated at 65℃for 40 minutes. Cooled to room temperature, diluted with water, extracted with dichloromethane (3X 50 mL) and washed with sodium bicarbonate and brine, dried over sodium sulfate and concentrated to give 1- (indol-1-yl) ethan-1-one (37 c) (1.23 g). MS-ESI (m/z): 160[ M+1 ]] ⁺ 。

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 synthetic method of example 35 1-acetylindolizine-3-carbonitrile (35 a) 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- (indol-1-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide(38)

Preparation of the title compound 38 according to the synthesis method of example 37, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (26 a). MS-ESI (m/z): 486[ M+1 ]] ⁺ 。

Example 39

N- (5- ((4- (3-chloroindol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (39)

1- (3-chloroindol-1-yl) ethan-1-one(39a)

A mixture of 1- (indol-1-yl) ethan-1-one (37 c), cuprous chloride (962 mg,5.7 mmol) and acetonitrile (6 mL) was stirred at room temperature for 4h, diluted with water (10 mL) and extracted with dichloromethane (3X 10 mL). The extract was 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 (8:1-6:1) to give 1- (3-chloroindolizin-1-yl) ethan-1-one (39 a). MS-ESI (m/z): 194[ M+1 ]] ⁺ 。

Preparation of the title compound 39 following the synthetic method of example 35 1-acetylindolizine-3-carbonitrile (35 a) 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-chloroindol-1-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (40)

Preparation of the title compound 40 according to the synthesis method for example 39, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -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-indol-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 (2.89 g,20.0 mmol) and 3-methyl-1H-indole (1.31 g,10.0 mmol) in DMA (50 mL) was added HOBT (306 mg,2.0 mmol) and potassium carbonate (1.93 g,14.0 mmol), and the mixture was stirred at 70℃for 24H, diluted with water (50 mL), extracted with ethyl acetate (2X 30 mL.) the extract 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 petroleum ether/ethyl acetate (10:1-5:1) to give 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indole (41 a) as a yellow solid (1 g, 40%).

The title compound 41 (17.3 mg) was prepared in the same manner as 1 substituting 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1H) with 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indole (41 a). MS-ESI (m/z): 501[ M+1 ]] ⁺ 。

Example 42

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-1H-indol-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 (41 a) (218 mg,1.14 mmol), 4-fluoro-2-methoxy-5-nitroaniline (213 mg,1.14 mmol) (prepared according to WO 2013/14448) and p-toluenesulfonic acid monohydrate (260 mg,1.37 mmol) in 2-pentanol (4 mL) was heated to 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 (42 a) (320 mg, 72%). MS-ESI (m/z): 394[ M+1 ]] ⁺ 。

N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -methyl-N ⁴ - (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42b)

N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (3-methyl-1H-indol-1-yl) pyrimidin-2-amine (42 a) (160 mg,0.407 mmol), N ¹ ,N ¹ ,N ² A DMA mixture of trimethylethane-1, 2-diamine (0.064 mL,0.489 mmol) and DIPEA (0.088 mL,0.529 mmol) was heated at 85℃for 3h. Concentrating under reduced pressure, purifying the residue by silica gel column chromatography, eluting with dichloromethane/methanol/ammonia (92:6:2) to obtain N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -methyl-N ⁴ - (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42 b) (139 mg, 73%). MS-ESI (m/z): 476[ M+1 ]] ⁺ 。

N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -methyl-N ⁴ - (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine(42c)

Will N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -methyl-N ⁴ A mixture of- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42 b) (139 mg,0.293 mmol), iron powder (98 mg,1.76 mmol) and ammonium chloride (22.0 mg,0.293 mmol) in ethanol-water (3:1, 15 mL) was heated at reflux for 1H. Pad celite was filtered, washed with ethyl acetate, the washes were diluted with ethyl acetate, water and brine. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol/ammonia (92:6:2) to give N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -methyl-N ⁴ - (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42 c) (120 mg, 92%). MS-ESI (m/z): 446[ M+1 ]] ⁺ 。

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)

At 0 ℃ to N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -methyl-N ⁴ A mixture of (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42 c) (120 mg,0.27 mmol) in tetrahydrofuran-water (10:1, 3 mL) was added 3-chloropropionyl chloride (0.031 mL,0.32 mmol), stirred at 0deg.C for 2H, aqueous ammonia (0.5 mL) was added, diluted with water, and extracted with ethyl acetate. The solvent was evaporated and the residue was purified by column chromatography on silica gel eluting with 2-5% methanol in 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) propanamide (42 d) (100 mg, 69%). MS-ESI (m/z): 536[ M+1 ]] ⁺ 。

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyPhenyl-5- ((4- (3-methyl-1H-indol-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) propionamide (42 d) (100 mg,0.187 mmol) in tetrahydrofuran-water (10:1, 2 mL) was added sodium hydroxide (60 mg,1.5 mmol), stirred for 2H, diluted with water and extracted with ethyl acetate at room temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 1-2% methanol in 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) (60 mg, 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-methylpiperazin-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 (10 mg) N was synthesized according to the procedure for the synthesis of example 41 ¹ ,N ¹ ,N ² -trimethylethane-1, 2-diamine is replaced by tert-butylpiperazine-1-carboxylate. MS-ESI (m/z): 485[ M+1 ]] ⁺ 。

Preparation of the title compound 43 (4.9 mg) 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 (43 a) according to the synthetic procedure 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-methylpiperazin-1-yl) phenyl) propanEnamides(44)

Preparation of title compound 44 according to the synthetic method of example 42, N ¹ ,N ¹ ,N ² -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) (methyl) 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 (45 b) (220 mg) 3-methyl-1H-indole was replaced with 1H-indole-3-carbonitrile (45 a) according to the synthetic procedure of 41a (preparation of this reagent according to literature: JOC 1958,23,1178). MS-ESI (m/z): 255[ M+1 ]] ⁺ 。

Preparation of the title compound 45 (7.0 mg) following the synthesis method of example 15 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) 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) (methyl) amino) -4-methoxyphenyl) acrylamide(46)

Preparation of the title compound 46 (5 mg) N was synthesized according to the procedure for the synthesis of example 45 ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 e) substitution with N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -methyl-2-nitropyridine-1, 4-diamine (24 a). MS-ESI (m/z): 511[ M+1 ]] ⁺ 。

Example 47

N- (5- ((4- (1-chloroimidazo [1, 5-a))]Pyridin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) amino) Ethyl) (methyl) amino) -6-methoxypyridin-3-yl acrylamide (47)

2- (Methylmercapto) -N- (pyridin-2-yl) pyrimidine-4-amide (47 a)

A mixture of pyridin-2-ylmethylamine (900 mg,8.3 mmol), 2- (methylthio) pyrimidine-4-carboxylic acid (1 g,5.9 mmol) (prepared according to WO 2006/117368), HOBT (2.4 g,17.7 mmol), EDCI (3.4 g,17.7 mmol), triethylamine (1.78 g,17.7 mmol) in DMF (10 ml) was stirred at room temperature for 2h. The reaction was cooled to room temperature, quenched with water (10 mL), adjusted to pH 9-10 with sodium carbonate, and extracted with ethyl acetate (15 mL. Times.3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered to remove solids, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (2:1-1:1) as eluent to give 2- (methylsulfanyl) -N- (pyridin-2-yl) pyrimidine-4-amide (47 a). MS-ESI (m/z): 247[ M+1 ]] ⁺ 。

3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a]And pyridine (47 b)

A solution of 2- (methylsulfanyl) -N- (pyridin-2-yl) pyrimidine-4-amide (47 a) (370 mg,1.5 mmol) in acetonitrile (2 mL) was added to phosphorus oxychloride (2.5 mL) and the mixture stirred at 85℃for 20h. Cool to room temperature and quench with water (10 mL). The pH was adjusted to 8-9 with sodium hydroxide and extracted with methylene chloride (8 mL. Times.3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a]And pyridine (47 b). MS-ESI (m/z): 243[ M+1 ]] ⁺ 。

1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazole [1,5-a]And pyridine (47 c)

At room temperature, 3- (2- (methylthio) pyrimidin-4-yl) imidazole [1,5-a]A solution of pyridine (200 mg,0.83 mmol) in DMF (2 mL) was added N-chlorosuccinimide (144 mg,1.08 mmol), stirred at room temperature for 2h, quenched with water (5 mL). The resulting mixture was extracted with dichloromethane (5 mL. Times.2), the organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude 1-chloro-3- (2- (methylsulfanyl) pyrimidin-4-yl) imidazo [1,5-a]And pyridine (47 c). MS-ESI (m/z): 277[ M+1 ]] ⁺ 。

4- (1-chloroimidazo [1, 5-a)]Pyridin-3-yl) pyrimidin-2-ol (47 d)

To 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazole [1,5-a]To a solution of pyridine (47 c) (150 mg,0.54 mmol) in NMP (5 mL) was added 10% sodium hydroxide (2 mL) and the mixture was stirred at 100deg.C for 24h. The reaction was cooled to room temperature and the pH was adjusted to 5-6 with 2N hydrochloric acid. The resulting mixture was extracted with dichloromethane (10 mL. Times.3), the organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, and concentrated to give crude 4- (1-chloroimidazo [1, 5-a) ]And pyridin-3-yl) pyrimidin-2-ol (47 d). MS-ESI (m/z): 247[ M+1 ]] ⁺ 。

1-chloro-3- (2-chloropyrimidin-4-yl) imidazole [1,5-a]And pyridine (47 e)

4- (1-chloroimidazo [1, 5-a)]And pyridin-3-yl) pyrimidin-2-ol (47 d) (140 mg,0.57 mmol) in acetonitrile (1 mL) was added phosphorus oxychloride (1 mL) and the mixture stirred at 80℃for 1.5h, cooled to room temperature and quenched with water (5 mL). The pH was adjusted to 8-9 with sodium hydroxide and extracted with methylene chloride (8 mL. Times.3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude 1-chloro-3- (2-chloropyrimidin-4-yl) imidazo [1,5-a]And pyridine (47 e). MS-ESI (m/z): 265[ M+1 ]] ⁺ 。

¹ ⁴ N- (4- (1-chloroimidazo [1,5-a ])]Pyridin-3-yl) pyrimidin-2-yl-N- (2- (dimethylamino) ethyl) -2-) ⁴ methoxy-N-methyl-5-nitrobenzene-1, 4-diamine (47 f)

1-chloro-3- (2-chloropyrimidin-4-yl) imidazo [1,5-a]And pyridine (47 e) (54 mg,0.20 mmol), N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² A mixture of methyl-3-nitropyridine-2, 5-diamine (15 e) (61 mg,0.22 mmol) and isopropanol (2.5 mL) of methanesulfonic acid (27 mg,0.24 mmol) was stirred at 90℃for 3h, the reaction cooled to room temperature, quenched with water (10 mL), pH adjusted to 8-9 with sodium carbonate, and extracted with ethyl acetate (30 mL. Times.3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered to remove solids, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (10:1) to give N ¹ - (4- (1-chloroimidazo [1, 5-a)]Pyridin-3-yl) pyrimidin-2-yl) -N ⁴ - (2- (dimethylamino) ethyl) -2-methoxy-N ⁴ -methyl-5-nitrobenzene-1, 4-diamine (47 f). MS-ESI (m/z): 498[ M+1 ]] ⁺ 。

Preparation of the title compound (47) according to the synthesis method of example 15, N ² - (2- (dimethylamino) ethyl) -N ⁵ - (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 h) substitution to N ¹ - (4- (1-chloroimidazo [1, 5-a)]Pyridin-3-yl) pyrimidin-2-yl) -N ⁴ - (2- (dimethylamino) ethyl) -2-methoxy-N ⁴ -methyl-5-nitrobenzene-1, 4-diamine (47 f). MS-ESI (m/z): 468[ M+1 ]] ⁺ 。

Example 48

N- (5- ((4- (1-chloroimidazo [1, 5-a))]Pyridin-3-yl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) amino) Ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (48)

Preparation of title compound 48 according to the method for the synthesis of example 47, N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 e) substitution with N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -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]And pyridine (49 a)

At room temperature, 3- (2- (methylthio) pyrimidin-4-yl) imidazole [1,5-a]A solution of naphthyridine (47 b) (300 mg,1.24 mmol) in DMF (5 mL) was added N-iodosuccinimide(362 mg,1.61 mmol) and the mixture was stirred at room temperature for 2h. The reaction was quenched with water (5 mL) and the resulting mixture was extracted with dichloromethane (8 mL. Times.2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 1-iodo-3- (2- (methylsulfanyl) pyrimidin-4-yl) imidazole [1, 5-a)]And pyridine (49 a). MS-ESI (m/z): 369[ M+1 ]] ⁺ 。

3- (2- (Methylmercapto) pyrimidin-4-yl) -1- (trifluoromethyl) imidazole [1,5-a]And pyridine (49 b)

1-iodo-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a]And a mixture of pyridine (49 a) (200 mg,0.54 mmol), (trifluoromethyl) trimethylsilane (153 mg,1.08 mmol), phenanthroline (194 mg,1.08 mmol), trimethylborate (112 mg,1.08 mmol), potassium fluoride (63 mg,1.08 mmol) and copper (I) iodide (154 mg,0.81 mmol) in dimethyl sulfoxide (5 mL) was stirred overnight at 60 ℃. The reaction was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (10 mL. Times.3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, the solids removed by filtration, the filtrate concentrated, and the residue purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:2) to give 3- (2- (methylsulfanyl) pyrimidin-4-yl) -1- (trifluoromethyl) imidazole [1,5-a ]And pyridine (49 b). MS-ESI (m/z): 311[ M+1 ]] ⁺ 。

Preparation of the title compound 49 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a ] according to the synthetic method of example 47]And pyridine (47 c) is replaced by 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)

TitledPreparation of Compound 50N was synthesized according to the procedure of example 47 ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 e) substitution with N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -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-methylimidazole [1, 5-a)] And pyridin-3-yl) pyrimidin-2-yl amino) pyridin-3-yl acrylamide (51)

1-methyl-3- (2- (methylthio) pyrimidin-4-yl) imidazole [1,5-a ]And pyridine (51 a)

Preparation of the title compound 51a according to the synthetic method of 47b, pyridin-2-ylmethylamine was replaced with 1- (pyridin-2-yl) ethane-1-amine. MS-ESI (m/z): 257[ M+1 ]] ⁺ 。

3- (2-Chloropyrimidin-4-yl) -1-methylimidazole [1,5-a ]]And pyridine (51 b)

Preparation of the title compound 51b 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1,5-a ] according to the synthetic method of 47e]And pyridine (47 c) is replaced by 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 ⁵ N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (1-methylimidazole [1, 5-a)]And pyridine- 3-yl) pyrimidin-2-yl-pyridin-2, 3, 5-triamine (51 c)

Preparation of the title compound (51 c) according to the synthetic method of 15i, 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) was replaced with 3- (2-chloropyrimidin-4-yl) -1-methylimidazole [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-methylimidazole [1, 5-a)]Pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide(51)

Preparation of the title compound 51 according to the synthetic method of example 15, N ² - (2- (dimethylamino) ethyl) -N ⁵ - (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N ² -methyl-N ² -substitution of picoline-2, 3, 5-triamine (15 i) with N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methylimidazole [1, 5-a)]And pyridin-3-yl) pyrimidin-2-yl) pyridin-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 synthetic method of example 51, N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-3-nitropyridine-2, 5-diamine (15 e) substitution with N ¹ - (2- (dimethylamino) ethyl) -5-methoxy-N ¹ -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-methylimidazole [1, 5-a)]Pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide(53)

Preparation of the title compound (53) according to the synthetic method of example 23, N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridin-2, 3, 5-triamine (23 b) is replaced with N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methylimidazole [1, 5-a)]And pyridin-3-yl) pyrimidin-2-yl) pyridin-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- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide(54)

2- (2-Nitro)Phenyl) ethanol(54a)

A mixture of 1-methyl-2-nitrobenzene (48 g,0.35 mol), formaldehyde (10.4 g,0.35 mol), 20% sodium hydroxide (3.6 mL) and dimethyl sulfoxide was heated at 50℃for 2h, then the mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (300 mL. Times.3). The combined organic layers were washed with water (200 mL. Times.2) and brine (200 mL), dried over sodium sulfate, filtered to remove the solids, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 2- (2-nitrophenyl) ethanol (54 a) as a brown oil (14.4 g, 25%).

Tert-butyldimethyl (2-nitrophenylethoxy) silane(54b)

To a solution of 2- (2-nitrophenyl) ethanol (54 a) (1.7 g,0.01 mol) in dry dichloromethane (15 ml) was added imidazole (0.88 g,0.013 mol) and t-butyldimethylchlorosilane (2.1 g,0.014 mol) and stirred at room temperature for 2h. The mixture was then filtered, diluted with dichloromethane (30 mL), washed with 1N hydrochloric acid (30 mL), water and aqueous sodium bicarbonate, the combined organic layers dried over sodium sulfate, the solid removed by filtration and the filtrate concentrated to give tert-butyldimethyl (2-nitrophenoxy) silane (54 b) as a brown oil (2.8 g, 97%).

7- (2- ((tert-butyldimethylsilyloxy) ethyl) -1H-indole(54c)

To a solution of tert-butyldimethyl (2-nitrophenoxyethoxy) silane (54 b) (4.5 g,16 mmol) in dry tetrahydrofuran (50 ml) was added dropwise vinylmagnesium bromide (56 ml,56 mmol) at-70℃under nitrogen. The mixture was slowly warmed to room temperature, and the mixture was poured into aqueous ammonium chloride solution and extracted with ethyl acetate (50 mL). The combined organic layers were dried over sodium sulfate, the solids removed by filtration, the filtrate concentrated and the residue purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:100) to give 7- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indole (54 c) as a yellow oil (2.6 g, 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 (0.33 g,30%, brown solid) according to the method of synthesis of 15g 7-fluoro-1-methyl-1H-indole (15 f) was replaced with 7- (2- ((t-butyl)Dimethylsilyl) oxy) ethyl) -1H-indole (54 c). 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 (54 d) (50 mg,0.18 mmol) in dry CAN (5 ml) was added dropwise to thionyl chloride (0.44 mg,0.36 mmol) at 0deg.C. The resulting mixture was stirred overnight at room temperature, cooled to room temperature, extracted with aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with water (20 mL. Times.2) and brine (200 mL), dried over anhydrous sodium sulfate, filtered to remove the solids, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:3) to give 7- (2-chloroethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (54 e) as a brown solid (0.30 g, 50%). MS-ESI (m/z): 292[ M+1 ] ] ⁺ 。

5- (2-Chloropyrimidin-4-yl) -1, 2-dihydropyrrole [3,2,1-hi ] indole (54 f)

To a solution of 7- (2-chloroethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (54 e) (33 mg,0.11 mmol) in DMF (3 ml) was added cesium carbonate (78 mg,0.22 mmol) at room temperature and heated at 60℃for 10H. The mixture was cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with water (20 mL. Times.2) and brine (200 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, and the filtrate was concentrated to give 5- (2-chloropyrimidin-4-yl) -1, 2-dihydropyrrole [3,2, 1-hi)]Indole (54 f) was a brown solid (0.30 g, 100%). MS-ESI (m/z) 256[ M+1 ]] ⁺ 。

Preparation of the title compound 54 (5.0 mg) according to the synthetic method of 15 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) was replaced with 5- (2-chloropyrimidin-4-yl) -1, 2-dihydropyrrole [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- (dimethylamino) ethyl) (methyl) amino) -4-methylOxyphenyl) acrylamides(55)

Preparation of the title compound (55) according to the synthesis method of example 54, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 c) replaced with N ¹ - (4-iodo-5-methoxy-2-nitrophenyl) -N ¹ ,N ² ,N ² -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 (56 a)

To a solution of 1- (2-fluorophenyl) ethanone (20 g,0.14 mol) in ethane-1, 2-diol (70 ml) was added hydrazine hydrate (4.7 ml,0.15 mol) at room temperature, which was maintained at this temperature for 2h, and then heated to 150℃overnight. The mixture was cooled to room temperature, quenched with water (200 mL) and extracted with dichloromethane (200 mL). The combined organic layers were washed with water (200 mL. Times.2) and brine (200 mL), dried over anhydrous sodium sulfate, filtered to remove the solids, the filtrate concentrated, and the residue purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:20) to give 3-methyl-1H-indazole (56 a) as a brown solid (7 g, 37%). MS-ESI (m/z): 133[ M+1 ]] ⁺ 。

1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indazoles(56b)

Sodium hydride was added to a solution of 3-methyl-1H-indazole (56 a) (1.1 g,8.3 mmol) in dry DMF at 0deg.C, the temperature was maintained for 2H, then 2, 4-dichloropyrimidine (1.24 g,8.3 mmol) was added and the resulting mixture was stirred overnight at room temperature. Aqueous ammonium chloride (20 mL) was added thereto to quench, followed by extraction with ethyl acetate (50 mL). The combined organic layers were washed with water (50 mL. Times.2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the solids, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:20) to give 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indazole (56 b) as a white solid (0.85 g, 43%). MS-ESI (m/z): 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 the title compound 56 (8.0 mg) following the synthesis method of example 15 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15 g) 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) pyridine-3-yl) -2-fluoroacrylamide (57)

Preparation of the title compound 57 (5.0 mg) following the synthesis method of example 23 3- (2-chloropyrimidin-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-indazole-3-) Base) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (58)

1- (1-methyl-1H-indazol-3-yl) ethanone (58 a)

The preparation of the title compound 58a is described in literature: heterochemistry chem.2013, 50:E221.

Preparation of the title compound 58 1- (1-methylindolin-3-yl) ethanone (25 d) was replaced with 1- (1-methyl-1H-indazol-3-yl) ethanone (58 a) according to the synthetic method of example 25. MS-ESI (m/z): 502[ M+1 ]] ⁺ 。

Example 59

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ((4- (1-methyl-1H-indazole-3-) Base) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (59)

² ² N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N5- (4- (1-methyl-1H-indazol-3-yl) azoi-m Pyridin-2-yl) -3-nitropyridine-2, 5-diamine (59 a)

Preparation of Compound 59a 1- (1-methylindolin-3-yl) ethanone (25 d) was replaced with 1- (1-methyl-1H-indazol-3-yl) ethanone (58 a) according to the synthetic method of example 25. MS-ESI (m/z): 448[ M+1 ]] ⁺ 。

² ² N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N5- (4- (1-methyl-1H-indazol-3-yl) azoi-m Pyridin-2-yl) pyridin-2, 3, 5-triamine (59 b)

Preparation of the title compound 59b according to the synthetic method of 15i, N ¹ - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N ¹ ,N ² ,N ² -trimethylethane-1, 2-diamine (15 h) substitution to N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (59 a). MS-ESI (m/z): 447[ M+1 ] ] ⁺ 。

Preparation of the title compound (59) according to the synthesis method of example 23, N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) pyridin-2, 3, 5-triamine (23 b) substitution to N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (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-methylimidazole [1, 5-a)] And pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl acrylamide (60)

1- (3-methylimidazole [1, 5-a)]Pyridino-1-yl) ethan-1-one (60 a)

Preparation of the title compound 60a was according to literature synthetic methods: journal of Chemical society, 1955,2834.

Preparation of the title compound 60 1- (1-methylindolin-3-yl) ethanone (25 d) was replaced by 1- (3-methylimidazole [1, 5-a) according to the synthetic method of example 25 ]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-methylimidazole [1, 5-a)] Pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (61)

² ² ⁵ N- (2- (dimethylamino) ethyl) -6-methoxy-N-methyl-N- (4- (3-methylimidazole [1, 5-a)]And pyridine- 1-yl) pyrimidin-2-yl) pyridin-2, 3, 5-triamine (61 a)

Preparation of the title compound 61a 1- (1-methylindolin-3-yl) ethanone (25 d) was replaced by 1- (3-methylimidazole [1, 5-a) according to the synthetic method of example 25]And pyridin-1-yl) ethan-1-one (60 a). MS-ESI (m/z): 448[ M+1 ]] ⁺ 。

Preparation of the title compound 61 according to the synthesis method for example 23, N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) pyridin-2, 3, 5-triamine (23 b) substitution to N ² - (2- (dimethylamino) ethyl) -6-methoxy-N ² -methyl-N ⁵ - (4- (3-methylimidazole [1, 5-a)]And pyridin-1-yl) pyrimidin-2-yl) pyridin-2, 3, 5-triamine. MS-ESI (m/z): 520[ M+1 ] ] ⁺ 。

Cell proliferation assay

Inhibition of L858R/T790M EGFR by compounds was tested by measuring the inhibition of H1975 cell proliferation by the compounds. In this experiment, the inhibition of L858R/T790M EGFR by compounds was determined by examining the inhibition of H1975 cell proliferation by the compounds. H1975 cells were cultured in RPMI-1640 medium containing 40-80% fetal bovine serum. H1975 cells in logarithmic growth phase were inoculated into 96-well culture plates at a density of 3000/well, 37℃and 5% CO ₂ Incubate overnight. Various concentrations (final concentrations 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM) of compound were added to 96-well plates at 37℃with 5% CO ₂ Incubate for 72 hours. The medium was discarded and 20. Mu.l MTS/100. Mu.l medium per 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. Calculation of IC with GraphPad Prism 5.0 ₅₀ 。

Inhibition of wild-type EGFR by compounds was tested by measuring inhibition of a431 cell proliferation by the compounds. In this experiment, inhibition of wild-type EGFR by compounds was determined by examining the inhibition of a431 cell proliferation by compounds. A431 cells were cultured in RPMI-1640 medium containing 40-80% fetal bovine serum. H1975 cells in logarithmic growth phase were inoculated into 96-well culture plates at a density of 3000/well, 37℃and 5% CO ₂ Incubate overnight. Various concentrations (final concentrations 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM) of compound were added to 96-well plates at 37℃with 5% CO ₂ Incubate for 72 hours. The medium was discarded and 20. Mu.l MTS/100. Mu.l medium per well. After 1.5h incubation, the reaction was stopped by adding 25. Mu.l of 10% SDS per well. Measurement of 490nm and 65 nm with an ELISA readerAbsorption at 0 nm. Calculation of IC with GraphPad Prism 5.0 ₅₀ 。

The 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	H1975 IC ₅₀ (nM)	A431 IC ₅₀ (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

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structural formula:

wherein:

q is

X is N;

y is C;

R ¹ is hydrogen;

R ^1’ is hydrogen;

R ² is hydrogen;

R ³ is hydrogen;

each R ⁴ Independently selected from: c (C) _1-10 Alkyl and fluoro; wherein each C _1-10 Alkyl radicals being unsubstituted orSubstituted with at least one substituent independently selected from halogen;

each R ⁵ Independently selected from: -OR ⁸ and-NR ⁷ R ⁸ ；

Each R ⁷ And each R ⁸ Independently selected from: c (C) _1-10 An alkyl group; wherein each alkyl is unsubstituted or substituted with at least one member independently selected from C _1-10 Alkyl, halogen, -N (C) _1-10 Alkyl) (C) _1-10 Alkyl) and-CN;

m is 2;

n is 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one refers to 1, 2, 3, or 4.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ⁴ Independently selected from: methyl and fluoro, wherein methyl is unsubstituted or substituted with 1, 2 or 3 fluoro.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein each R ⁴ Independently selected from: methyl and fluoro, wherein methyl is unsubstituted.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein n = 2, one R ⁵ Selected from-OR ⁸ Another R ⁵ Selected from-NR ⁷ R ⁸ 。

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein each R ⁵ Independently selected from methoxy, ethoxy, isopropoxy, methyl (2- (methylamino) ethyl) amino, (2- (dimethylamino) ethyl) (methyl) amino and (2- (ethyl (methyl) amino) ethyl) (methyl) amino.

7. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable thereofA salt of C _1-10 The alkyl groups are independently selected from methyl and ethyl.

8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein halogen is fluoro.

10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

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 and

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.

11. A pharmaceutical composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

12. Use of a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for modulating mutated EGFR.

13. Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 11, in the manufacture of a medicament for treating, ameliorating or preventing a symptom responsive to inhibition of mutated EGFR, wherein the compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition is optionally in combination with another therapeutic agent.

14. A method of manufacturing a medicament for treating a symptom responsive to inhibition of mutated EGFR, comprising the medicament comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 11.

15. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the treatment of abnormal cell proliferation, wherein the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, is optionally combined with another therapeutic agent.

16. A method of manufacturing a medicament for the treatment of abnormal cell proliferation comprising the medicament comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11.