WO2015188777A1

WO2015188777A1 - Certain protein kinase inhibitors

Info

Publication number: WO2015188777A1
Application number: PCT/CN2015/081332
Authority: WO
Inventors: Tongshuang Li; Xingdong ZHAO; Qiang Tian; Weipeng Zhang; Hongbin Liu; Xianlong WANG; Haohan TAN; Rui Tan; Qihong Liu; Lihua Jiang; Yanxin Liu; Li LINGHU; Min Lin; Jing Sun; Weibo Wang
Original assignee: Shanghai Fochon Pharmaceutical Co Ltd
Priority date: 2014-06-12
Filing date: 2015-06-12
Publication date: 2015-12-17
Also published as: CN111892579A; CN111875585A; CN111892579B; CN111875585B; CN106660993A; CN106660993B

Abstract

Provided are certain EGFR mutant selective inhibitors, pharmaceutical compositions thereof, and methods of use therefor.

Description

CERTAIN PROTEIN KINASE INHIBITORS

FIELD OF THE INVENTION

This invention relates to novel amino pyrimidine ring derivatives and the pharmaceutically acceptable salts thereof. The compounds of the present invention are mutant-selective epidermal growth factor receptor (EGFR) kinase inhibitors. The compounds of this invention are useful for the treatment of hyper-proliferative diseases such as cancer, in mammals and especially in humans. This invention also relates to the use of the compounds in the treatment of cancer and the pharmaceutical preparations containing them.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue located on a protein substrate. Protein tyrosine kinase can be broadly classified as receptor (e.g. EGFR, HER-2, VEGFR, FGFR) or non-receptor (e.g. Src, Jak, Abl) . Receptor tyrosine kinases act to transmit signals from the outside of a cell to the inside by activating secondary messaging effectors via a phosphorylation event. A variety of cellular processes are promoted by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival.

Inappropriate or uncontrolled activation of tyrosine kinase activity, for example over-expression or mutation of this kinase, has been shown to result in uncontrolled cell growth. There is strong precedent for involvement of the EGFR in human cancer because over 60％of all solid tumors overexpress at least one of these proteins or their ligands. Overexpression of EGFR is commonly found in breast, lung, head and neck, bladder tumors.

The first-generation reversible, ATP-competitive EGFR kinase inhibitors, gefitinib and erlotinib, are effective clinical therapies for non-small cell lung cancers that harbor activating mutations in the EGFR kinase domain. (Nature, 2009, 462, 1070-1074) Although first-generation EGFR inhibitors showed encouraging clinical responses, almost all patients developed resistance to these inhibitors over time, such as by mutation of gatekeeper residue T790M, which accounts for about half of all resistance to gefitinib and erlotinib (Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 2070-2075) . Moreover, T790M may also be pre-existing； there may be an independent, oncogenic role for the T790M mutation.

Current drugs in development, including second-generation covalent inhibitors, such as afatinib, neratinib, canertinib and dacomitinib, are effective against the resistance mutation but exhibit dose-limiting toxicities such as diarrhea and skin rash due to concurrent inhibition of WT EGFR.

Therefore, there remains a need to provide mutant-selective EGFR kinase inhibitors useful as therapeutic agents. Although mutant-selective EGFR inhibitors were disclosed in the arts, e.g., WO 2013014448 and WO 2012061299, there is still a need for new mutant-selective EGFR inhibitors that have at least one advantageous property selected from potency, stability, selectivity, toxicity and pharmacodynamics properties as an alternative for the treatment of hyper-proliferative diseases. In this regard, a novel class of mutant-selective EGFR inhibitors is provided herein.

DISCLOSURE OF THE INVENTION

Disclosed herein are certain novel amino pyrimidine ring derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals.

In one aspect, disclosed herein is 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；

R¹ is selected from hydrogen, C_1-10alkyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, and heterocyclyl-C_1-4alkyl, wherein alkyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6a；

R^1’ is selected from hydrogen and halogen；

R² and R³ are independently selected from hydrogen, halogen, hydroxyl, CN, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R^6a, and each aryl and heteroaryl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6b； or R² and R³ 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, and optionally substituted with 1or 2 R^6a groups；

each R⁴ is independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, -OR⁸, -NR⁷S (O) _rR⁸, -NO₂, -halogen, -S (O) _rR⁷, -SR⁸, -S (O) ₂OR⁷, -OS (O) ₂R⁸, -S (O) _rNR⁷R⁸, -NR⁷R⁸, -O (CR⁹R¹⁰) _tNR⁷R⁸, -C (O) R⁷, -CO₂R⁸, -CO₂ (CR⁹R¹⁰) _tCONR⁷R⁸, -OC (O) R⁷, -CN, -C (O) NR⁷R⁸, -NR⁷C (O) R⁸, -OC (O) NR⁷R⁸, -NR⁷C (O) OR⁸, -NR⁷C (O) NR⁷R⁸, and -CR⁷ (N-OR⁸) , wherein C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, and C_3-10cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6a；

each R⁵ is independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, -OR⁸, -NR⁷S (O) _rR⁸, -NO₂, halogen, -S (O) _rR⁷, -SR⁸, -S (O) ₂OR⁷, -OS (O) ₂R⁸, -S (O) _rNR⁷R⁸, -NR⁷R⁸, -O (CR⁹R¹⁰) _tNR⁷R⁸, -C (O) R⁷, -CO₂R⁸, -CO₂ (CR⁹R¹⁰) _tCONR⁷R⁸, -OC (O) R⁷, -CN, -C (O) NR⁷R⁸, -NR⁷C (O) R⁸, -OC (O) NR⁷R⁸, -NR⁷C (O) OR⁸, -NR⁷C (O) NR⁷R⁸, and -CR⁷ (N-OR⁸) , wherein C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R^6a, and each aryl and heteroaryl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6b；

each R^6a is independently selected from C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, -OR⁸, -NR⁷S (O) _rR⁸, -NO₂, halogen, -S (O) _rR⁷, -SR⁸, -S (O) ₂OR⁷, -OS (O) ₂R⁸, -S (O) _rNR⁷R⁸, -NR⁷R⁸, - (CR⁹R¹⁰) _tOR⁸, - (CR⁹R¹⁰) _tNR⁷R⁸, - (CR⁹R¹⁰) _tSR⁸, - (CR⁹R¹⁰) _tS (O) _rR⁸, - (CR⁹R¹⁰) _tCO₂R⁸, - (CR⁹R¹⁰) _tCONR⁷R⁸, - (CR⁹R¹⁰) _tNR⁷CO₂R⁸, - (CR⁹R¹⁰) _tOCONR⁷R⁸, - (CR⁹R¹⁰) _tNR⁷CONR⁷R⁸, - (CR⁹R¹⁰) _tNR⁷SO₂NR⁷R⁸, -O (CR⁹R¹⁰) _tNR⁷R⁸, -C (O) R⁷, -C (O) (CR⁹R¹⁰) _tOR⁸, -C (O) (CR⁹R¹⁰) _tNR⁷R⁸, -C (O) (CR⁹R¹⁰) _tSR⁸, -C (O) (CR⁹R¹⁰) _tS (O) _rR⁸, -CO₂R⁸, -CO₂ (CR⁹R¹⁰) _tCONR⁷R⁸, -OC (O) R⁷, -CN, -C (O) NR⁷R⁸, -NR⁷C (O) R⁸, -OC (O) NR⁷R⁸, -NR⁷C (O) OR⁸, -NR⁷C (O) NR⁷R⁸, and -CR⁷ (N-OR⁸) ；

each R^6b is independently selected from R^6a, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4 alkyl；

each R⁷ and each R⁸ are independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, cycloalkyl, cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R^6a, and aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R^6b； or R⁷ and R⁸ together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1or 2 R^6b groups；

each R⁹ and each R¹⁰ are independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, cycloalkyl, cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl； or R⁹ and R¹⁰ together with the carbon atom (s) to which they are attached form a ring of 3 to 7 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1or 2 R^6a groups；

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 yet another aspect, disclosed herein are the pharmaceutical compositions comprising at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

In yet another aspect, disclosed herein are the methods for modulating mutant EGFR, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, thereby modulating said mutant EGFR.

In yet another aspect, disclosed herein are the methods to treat, ameliorate or prevent a condition which responds to inhibition of mutant EGFR comprising administering to a system or subject in need of such treatment an effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.

In yet another aspect, disclosed herein are the uses of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by mutant EGFR. The compounds of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by mutant EGFR, wherein said condition is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.

Furthermore, disclosed herein are the methods for treating a cell proliferative disorder, comprising administering to a system or subject in need of such treatment an effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.

Alternatively, disclosed herein are the uses of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cell-proliferative disorder. In particular examples, the compounds of the disclosure may be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.

In the above methods for using the compounds of the disclosure, at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to a mammalian subject such as a human or animal subject.

As used herein the following definitions are applicable.

The term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Unless otherwise specified, “alkyl” refers to C_l-C₁₀alkyl. For example, C_1-6, as in "C_l-6alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement. For example, "C_l-8alkyl" includes but is not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, and octyl.

The term "cycloalkyl" means a saturated aliphatic cyclic hydrocarbon group having the specified number of carbon atoms. Unless otherwise specified, “cycloalkyl” refers to C_3-l0cycloalkyl. For example, "cycloalkyl" includes but is not limited to cyclopropyl, methyl-cyclopropyl, 2, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, and cyclohexyl.

The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. In some embodiments, one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C_2-6alkenyl" means an alkenyl radical having from 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 double bonds and may be substituted if a substituted alkenyl group is indicated.

The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present. Thus, "C_2-6alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups include but are not limited to ethynyl, propynyl, butynyl, and 3-methylbutynyl. The straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.

The term "aryl" encompasses 5-and 6-membered carbocyclic aromatic rings, for example, benzene； bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline； and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene. In cases where the aryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

For example, aryl includes 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.

The term "halogen" (or "halo" ) refers to fluorine, chlorine, bromine and iodine.

The term “heteroaryl” refers to

5-to 8-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon；

8-to 12-membered bicyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring； and

11-to 14-membered tricyclic rings containing one or more, for example, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1) , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 1-pyrazolyl, 2, 3-pyrazolyl, 2, 4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.

Further heteroaryl groups include but are not limited to pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl. As with the definition of heterocycle below, "heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.

Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not encompass or overlap with aryl as defined above.

In cases where the heteroaryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.

The term "heterocycle" (and variations thereof such as "heterocyclic" , or "heterocyclyl" ) broadly refers to a single aliphatic ring, usually with 3 to 12 ring atoms, containing at least 2 carbon atoms in addition to one or more, preferably one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms. Alternatively , a heterocycle as defined above may be multicyclic ring system (e.g. bicyclic) in which two or more rings may be fused or bridged together, wherein at least one such ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen. “Heterocycle” also refers to 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S fused with 5-and 6-membered carbocyclic aromatic ring, provided that the point of attachment is at the heterocyclic ring. The rings may be saturated or have one or more double bonds (i.e. partially unsaturated) . The heterocycle can be substituted by oxo. The point of the attachment may be carbon or heteroatom in the heterocyclic ring, provided that attachment results in the creation of a stable structure. When the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. Heterocycle does not overlap with heteroaryl.

Suitable heterocycles include, for example (as numbered from the linkage position assigned priority 1) , 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, and 2, 5-piperazinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1) . Substituted heterocycle also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl. Bicyclic heterocycles include, for example:

As used herein, “arylalkyl” refers to an alkyl moiety substituted by an aryl group. Example arylalkyl groups include benzyl, phenethyl, and naphthylmethyl groups. In some embodiments, arylalkyl groups have from 7 to 20 or 7 to 11 carbon atoms. When used in the phrase "arylC_l-4alkyl” , the term "C_1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety. Likewise, when used in the phrase "arylC_1-10alkyl” , the term "C_1-10” refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.

As used herein, “heterocyclylalkyl” refers to alkyl substituted by heterocyclyl. When used in the phrase "heterocyclyl-C_1-6alkyl” , the term "C_1-6” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.

As used herein, "cycloalkylalkyl" refers to alkyl substituted by cycloalkyl. When used in the phrase "C_3-10cycloalkylalkyl” , the term "C_3-10” refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety. When used in the phrase "C_3-7cycloalkylalkyl” , the term "C_3-7” refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety. When used in the phrase "C_3-8cycloalkylalkyl” , the term "C_3-8” refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety. When used in the phrase "cycloalkyl-C_l-10alkyl” , the term "C_1-10” refers to the alkyl portion of the moiety and does not describe the number of atoms in the cycloalkyl portion of the moiety.

As used herein, "heteroarylalkyl" refers to alkyl substituted by heteroaryl. When used in the phrase "heteroaryl-C_l-4alkyl” , the term "C_1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety. Likewise, when used in the phrase "heteroaryl-C_l-10 alkyl” , the term "C_1-10” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.

For avoidance of doubt, reference, for example, to substitution of alkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers to substitution of each of those groups individually as well as to substitutions of combinations of those groups. That is, if R¹ is arylalkyl, the aryl portion may be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6b and the alkyl portion may also be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituens, independently selected from R^6a.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases may be selected, for example, from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Further, for example, the pharmaceutically acceptable salts derived from inorganic bases may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in one or more crystal structures, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases may be selected, for example, from salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, and tripropylamine, tromethamine.

When the compound disclosed herein is basic, salts may be prepared using at least one pharmaceutically acceptable non-toxic acid, selected from inorganic and organic acids. Such acid may be selected, for example, from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids. In some embodiments, such acid may be selected, for example, from citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.

The term "protecting group" or "Pg" refers to a substituent that can be commonly employed to block or protect a certain functionality while reacting other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include but are not limited to acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC) , benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc) . Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include but are not limited to acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include --CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991.

The terms "administration of" and or "administering" at least one compound and/or at least one pharmaceutically acceptable salt should be understood to mean providing at least one compound and/or at least one pharmaceutically acceptable salt thereof to the individual in recognized need of treatment.

The term "effective amount" means the amount of the at least one compound and/or at least one pharmaceutically acceptable salt that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s) , and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

The term "pharmaceutically acceptable" it is meant compatible with the other ingredients of the formulation and not unacceptably deleterious to the recipient thereof.

1. Disclosed herein is 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’is selected from hydrogen and halogen；

each R^6b is independently selected from R^6a, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl；

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. At least one compound of 1 and/or at least one pharmaceutically acceptable salt thereof, wherein X is selected from N and C, and Y is C.

3. At least one compound of any one of 1-2 and/or at least one pharmaceutically acceptable salt thereof, wherein X is N, and Y is C.

4. At least one compound of any one of 1-2 and/or at least one pharmaceutically acceptable salt thereof, wherein: when both X and Y are C, and

n ＝ 2, one R⁵ is (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl] - (methyl) amino, [2- (methylamino) ethyl] (methyl) amino, 5-methyl-2, 5-diazaspiro [3.4] oct-2-yl, (3aR, 6aR) -5-methylhexa-hydro-pyrrolo [3, 4-b] pyrrol-1 (2H) -yl, 1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl, 4-methylpiperizin-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-aminopropanoyl] piperazin-1-yl, the other R⁵ is methoxy or methyl,

R¹, R^1’a nd R² are hydrogen, and R³ is H, F, Cl, CH₃ or CN,

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

5. At least one compound of any one of 1 to 4 and/or at least one pharmaceutically acceptable salt thereof, wherein the formula is

6. At least one compound of any one of 1 to 5 and/or at least one pharmaceutically acceptable salt thereof, wherein R^1’ is hydrogen.

7. At least one compound of any one of 1 to 5 and/or at least one pharmaceutically acceptable salt thereof, wherein R^1’ is selected from halogen, preferably R^1’ is fluorine.

8. At least one compound of any one of 1 to 7 and/or at least one pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen.

9. At least one compound of any one of 1 to 8 and/or at least one pharmaceutically acceptable salt thereof, wherein R² is hydrogen.

10. At least one compound of any one of 1 to 9 and/or at least one pharmaceutically acceptable salt thereof, wherein R³ is selected from hydrogen, halogen, and C_1-10 alkyl.

11. At least one compound of 10 and/or at least one pharmaceutically acceptable salt thereof, wherein R³ is hydrogen.

12. At least one compound of any one of 1 to11 and/or at least one pharmaceutically acceptable salt thereof, wherein Q is selected from heteroaryl.

13. At least one compound of 12 and/or at least one pharmaceutically acceptable salt thereof, wherein Q is selected from

14. At least one compound of any one of 1 to 13 and/or at least one pharmaceutically acceptable salt thereof, wherein R⁴ is selected from hydrogen, C_1-10 alkyl, halogen and CN, wherein C_1-10 alkyl are unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6a.

15. At least one compound of 14 and/or at least one pharmaceutically acceptable salt thereof, wherein R⁴ is selected from hydrogen, methyl, halogen and CN, wherein methyl are unsubstituted or substituted with at least one substituent independently selected from R^6a, preferably R^6a is fluorine.

16. At least one compound of any one of 1 to 15 and/or at least one pharmaceutically acceptable salt thereof, wherein R⁵ is independently selected from OR⁸, heterocyclyl, NR⁷R⁸, wherein heterocyclyl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6a.

17. At least one compound of 16 and/or at least one pharmaceutically acceptable salt thereof, wherein R⁵ is 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, selected from

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

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

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

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

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

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

N- (6-isopropoxy-2- (methyl (2- (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-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-methylpiperazin-1 -yl) pyridin-3-yl) acrylamide,

N- (6-ethoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin -3-yl) acrylamide,

N- (6-ethoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) pyridin-3-yl) acrylamide,

N- (6-isopropoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide,

N- (6-isopropoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-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-methylindolizin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,

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

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

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

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

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

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

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

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (3-methylindolizin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,

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

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

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

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

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -5- ( (4- (indolizin-1-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide,

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

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

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

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

N- (6-methoxy-5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1 -yl) pyridin-3-yl) acrylamide,

N- (4-methoxy-5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1 -yl) phenyl) acrylamide,

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

N- (5- ( (4- (3-cyano-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (methyl ) amino) -4-methoxyphenyl) acrylamide,

N- (5- ( (4- (1-chloroimidazo [1, 5-a] 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-methylimidazo [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-methylimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,

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

N- (5- ( (4- (1, 2-dihydropyrrolo [3, 2, 1-hi] indol-5-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,

N- (5- ( (4- (1, 2-dihydropyrrolo [3, 2, 1-hi] indol-5-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,

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

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

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

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

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

and pharmaceutically acceptable salts thereof.

In another of its aspects, there is provided a pharmaceutical composition comprising at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent) , subcutaneously, intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof, and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the composition is to be administered, storage information for the composition, dosing information and instructions regarding how to administer the composition. In one particular variation, the kit comprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article of manufacture comprising at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof, and packaging materials. In one variation, the packaging material comprises a container for housing the compound. In one particular variation, the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound. In another variation, the article of manufacture comprises the compound in a multiple dose form.

In a further of its aspects, there is provided a therapeutic method comprising administering to a subject at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof.

In another of its aspects, there is provided a method of inhibiting a mutant EGFR kinase comprising contacting the mutant EGFR with at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof.

In yet another of its aspects, there is provided a method of inhibiting a mutant EGFR comprising causing at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof to be present in a subject in order to inhibit the mutant EGFR in vivo.

In another of its aspects, there is provided a method of treating a disease state for which a mutant EGFR possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising causing at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof to be present in a subject in a therapeutically effective amount for the disease state.

In one variation of each of the above methods the disease state is selected from the group consisting of cancerous hyperproliferative disorders (e.g., brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, epidermoid, esophageal, testicular, gynecological or thyroid cancer) ； non-cancerous hyperproliferative disorders (e.g., benign hyperplasia of the skin (e.g., psoriasis) , restenosis, and benign prostatic hypertrophy (BPH) ) ； pancreatitis； kidney disease； pain； preventing blastocyte implantation； treating diseases related to vasculogenesis or angiogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, exzema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer) ； asthma； neutrophil chemotaxis (e.g., reperfusion injury in myocardial infarction and stroke and inflammatory arthritis) ； septic shock； T-cell mediated diseases where immune suppression would be of value (e.g., the prevention of organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis) ； atherosclerosis； inhibition of keratinocyte responses to growth factor cocktails； chronic obstructive pulmonary disease (COPD) and other diseases.

In another of its aspects, there is provided a method of treating a disease state for which a mutation in the mutant EGFR gene contributes to the pathology and/or symptomology of the disease state including, for example, melanomas, lung cancer, colon cancer and other tumor types.

In still another of its aspects, the present invention relates to the use of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof as a medicament. In yet another of its aspects, the present invention relates to the use of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for inhibiting a mutant EGFR.

In a further of its aspects, the present invention relates to the use of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease state for which a mutant EGFR possesses activity that contributes to the pathology and/or symptomology of the disease state.

Administration and Pharmaceutical Compositions

In general, compounds of the disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors known to those of ordinary skill in the art. For example, for the treatment of neoplastic diseases and immune system disorders, the required dosage will also vary depending on the mode of administration, the particular condition to be treated and the effect desired.

In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.001 to about 100 mg/kg per body weight, or particularly, from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e. g. humans, may be in the range from about 0.5 mg to about 2000 mg, or more particularly, from about 0.5 mg to about 1000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.

Compounds of the disclosure may be administered as pharmaceutical compositions by any conventional route； for example, enterally, e.g., orally, e.g., in the form of tablets or capsules； parenterally, e.g., in the form of injectable solutions or suspensions； or topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.

Pharmaceutical compositions comprising a compound of the present disclosure in free form or in a pharmaceutically acceptable salt form in association 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 disclosure in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance.

In one embodiment, the pharmaceutical compositions are solutions of the active ingredient, including suspensions or dispersions, such as isotonic aqueous solutions. In the case of lyophilized compositions comprising the active ingredient alone or together with a carrier such as mannitol, dispersions or suspensions can be made up before use. The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include but are not limited to antioxidants such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid. The solutions or suspensions may further comprise viscosity-increasing agents, including but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or solubilizers, e.g. Tween 80 (polyoxyethylene (20) sorbitan mono-oleate) .

Suspensions in oil may comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. Examples include liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include but are not limited to lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, and if desired, may contain antioxidants, for example vitamin E, 3-carotene or 3, 5-di-tert-butyl-hydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, for example a mono-, di-or trivalent, alcohol. Suitable alcohol components include but are not limited to methanol, ethanol, propanol, butanol or pentanol or isomers thereof； glycol and glycerol.

Other suitable fatty acid esters include but are not limited ethyl-oleate, isopropyl myristate, isopropyl palmitate,

M 2375, (polyoxyethylene glycerol) ,

M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and comprising glycerides and polyethylene glycol ester) , LABRASOL^TM (saturated polyglycolized glycerides prepared by alcoholysis of TCM and comprising glycerides and polyethylene glycol ester； all available from GaKefosse, France) , and/or

812 (triglyceride of saturated fatty acids of chain length C8 to C12 from Hüls AG, Germany) , and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or groundnut oil.

Pharmaceutical compositions for oral administration may be obtained, for example, by combining the active ingredient with one or more solid carriers, and if desired, granulating a resulting mixture, and processing the mixture or granules by the inclusion of additional excipients, to form tablets or tablet cores.

Suitable carriers include but are not limited to fillers, such as sugars, for example lactose, saccharose, 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, disintegrators, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow conditioners 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.

Tablet cores may be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.

Pharmaceutical compositions for oral administration may also include hard capsules comprising 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 corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.

Pharmaceutical compositions suitable for rectal administration are, for example, suppositories comprising 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 aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers. The active ingredient, optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions. The manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.

The compounds of the disclosure may be administered as the sole active ingredient, or together with other drugs useful against neoplastic diseases or useful in immunomodulating regimens. For example, the compounds of the disclosure may be used in accordance with the disclosure in combination with pharmaceutical compositions effective in various diseases as described above, e.g. with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicine, gefitinib, or imatinib； or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil, 15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g. monoclonal antibodies to 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 disclosure also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the disclosure as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.

EXAMPLES

Various methods may be developed for synthesizing the at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof. Representative methods for synthesizing the at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that the at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that others may devise.

It will be readily recognized that certain compounds of formula (I) have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers) . It is recognized that synthesis of the at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers) . Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.

The at least one compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) can be prepared by, for example, reacting the free acid form of the at least one compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like) . A compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc) .

The N-oxides of the at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80 ℃.Alternatively, the N-oxides of the compounds of formula (I) can be prepared from the N-oxideof an appropriate starting material.

Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80 ℃.

Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, Inc. 1999.

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification: g (grams) ； mg (milligrams) ； L (liters) ； mL (milliliters) ； μL (microliters) ； psi (pounds per square inch) ； M (molar) ； mM (millimolar) ； i.v. (intravenous) ； Hz (Hertz) ； MHz (megahertz) ； mol (moles) ； mmol (millimoles) ； RT (room temperature) ； min (minutes) ； h (hours) ； mp (melting point) ； TLC (thin layer chromatography) ； Rt (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-dimethoxyethane) ； DCM (dichloromethane) ； DCE (dichloroethane) ； DMF (N, N-dimethylformamide) ； DMPU (N, N'-dimethylpropyleneurea) ； CDI (1, 1-carbonyldiimidazole) ； IBCF (isobutyl chloroformate) ； HOAc (acetic acid) ； HOSu (N-hydroxysuccinimide) ； HOBT (1-hydroxybenzotriazole) ； Et₂O (diethyl ether) ； EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) ； BOC (tert-butyloxycarbonyl) ； FMOC (9-fluorenylmethoxycarbonyl) ； DCC (dicyclohexylcarbodiimide) ； CBZ (benzyloxycarbonyl) ； Ac (acetyl) ； atm (atmosphere) ； TMSE (2- (trimethylsilyl) ethyl) ； TMS (trimethylsilyl) ； TIPS (triisopropylsilyl) ； TBS (t-butyldimethylsilyl) ； DMAP (4-dimethylaminopyridine) ； Me (methyl) ； OMe (methoxy) ； Et (ethyl) ； tBu (tert-butyl) ； HPLC (high pressure liquid chomatography) ； BOP (bis (2-oxo-3-oxazolidinyl) phosphinic chloride) ； TBAF (tetra-n-butylammonium fluoride) ； m-CPBA (meta-chloroperbenzoic acid) .

References to ether or Et₂O are to diethyl ether； brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ℃ (degrees Centigrade) . All reactions were conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm) . Coupling constants are in units of hertz (Hz) . Splitting patterns describe apparent multiplicities and are designated as s (singlet) , d (doublet) , t (triplet) , q (quartet) , m (multiplet) , and br (broad) .

Low-resolution mass spectra (MS) and compound purity data were acquired on a Shimadzu LC/MS single quadrapole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm) , and evaporative light scattering detector (ELSD) . Thin-layer chromatography was performed on 0.25 mm E. Merck silica gel plates (60F-254) , visualized with UV light, 5％ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck) .

Synthetic Schemes

At least one compound of formula I and/or at least one pharmaceutically acceptable salt thereof may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. Other reaction schemes could be readily devised by those skilled in the art in view of the present disclosure.

In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

Synthetic methods for preparing the compounds of the present disclosure are illustrated in the following Schemes and Examples. Starting materials are commercially available or may be made according to procedures known in the art or as illustrated herein.

The intermediates shown in the following schemes are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art.

The compound of formula I of the present disclosure can be prepared as shown in Scheme 1. Coupling of intermediates such as those of formula III with amino-arene such as IV using such coupling conditions as Buchwald amination reaction or amination conditions known in the literature provides the intermediate VII or VI. Reduction of the nitro group in intermediate VII using conditions such as Fe/NH₄Cl in a solvent or mixture of solvents such as EtOH and H₂O provides amine VIII. Alternatively intermediate VIII can be prepared by cleavage of the protecting group on the amine of intermediate VI. intermediate VI can be obtained by the coupling between intermediate III and amino-arene V. Coupling of amine VIII with acid IX or acyl chloride X provides compound I. Compound of formula I can also be synthesized via a two-step sequence by reacting amine VIII with acyl chloride XI followed by elimination reaction in the presence of a base such as NaOH in a solvent such as H₂O.

An alternative approach to the key intermediate amine VIII is shown in Scheme 2. Coupling of amine XIII with halide XIV or XV under similar conditions as described in Scheme 1 or known in the literature provides nitro VII or intermediate VI, which can be further converted to amine VIII under conditions as described in Scheme 1.

In some cases, compound of formula I can be prepared by coupling of intermediate III with intermediate VIa under the conditions as described in Scheme 1 or Scheme 2 as shown in Scheme 3.

One preparation of VIaa is illustrated in Scheme 4. Starting from the commercially available dichloropyridine 1, intermediate VIaa can be prepared via a sequence of region-selective displacement of chloride, bromination, amination, deprotection, acylation and reduction.

As an illustration of the preparation of intermediate XIV, an approach to XIVa is described in Scheme 5. Sequential reaction of commercial available dichloropyridine with amine and sodium alkoxide followed by halogenation provides intermediate XIVa.

In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not 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 THF (30 mL) at 0℃ was added methanol (1.15 mL, 28.5 mmol) followed NaH (60％, 1.20 g, 30.0 mmol) in 4 portions. The mixture was stirred at 0℃ for 1 h and then at r.t. for 1 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 30 mL) . The extracts were washed with brine and dried over MgSO₄. Solvent was evaporated, and the residue was crystallized from hexanes to give 6-Chloro-2-methoxy-3-nitropyridine (1a) as pale yellow solid (4.04 g, 71％) .

N¹- (6-Methoxy-5-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (1b)

The solution of 6-Chloro-2-methoxy-3-nitropyridine (1a) (3.77 g, 20.0 mmol) and N¹, N¹, N²-trimethylethane-1, 2-diamine (2.24 g, 22.0 mmol) in ethanol (45 mL) was heated at reflux for 3 h. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/methanol/ammonia (92:6:2) to provide N¹- (6-Methoxy-5-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (1b) (2.40 g, 47％) . MS-ESI (m/z) : 255 [M + 1] ⁺.

N¹- (3-Bromo-6-methoxy-5-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (1c)

To a suspension of N¹- (6-Methoxy-5-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (1b) (1.33 g, 5.24 mmol) in acetonitrile (30 mL) at 0℃ was added NBS (1.40 g, 7.82 mmol) . The mixture was stirred at 0℃ for 1 h. Solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with DCM/methanol/ammonia (92:6:2) to give N¹- (3-Bromo-6-methoxy-5-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (1c) as yellow solid (1.47 g, 84％) . MS-ESI (m/z) : 333 and 335 [1:1, M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -N³- (diphenylmethylene) -6-methoxy-N²-methyl-5-nitropyri dine-2, 3-diamine (1d)

The mixture of N¹- (3-Bromo-6-methoxy-5-nitropyridin-2-yl) -N¹, N², N²-trimethylethane -1, 2-diamine (1c) (666 mg, 2.00 mmol) , Pd₂ (dba) ₃ (55 mg, 0.060 mmol) , (+/-) -BINAP (75 mg, 0.120 mmol) , benzophenone imine (471 mg, 2.60 mmol) , and t-BuONa (250 mg, 2.60 mmol) in toluene (8 mL) was heated under nitrogen at 110C for 2 h, and cooled to room temperature. The solid was removed by filtration through celite and washed with ethyl acetate. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20-40％ethyl acetate in hexanes to give N²- (2- (dimethylamino) ethyl) -N³-(diphenylmethylene) -6-methoxy-N²-methyl-5-nitropyridine-2, 3-diamine (1d) as pale yellow solid (227 mg, 26％) . MS-ESI (m/z) : 434 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-5-nitropyridine-2, 3-diamine (1e)

To a solution of N²- (2- (dimethylamino) ethyl) -N³- (diphenylmethylene) -6-methoxy-N²-methyl-5-nitropyridine-2, 3-diamine (1d) (194 mg, 0.45 mmol) in methanol (5 mL) at r.t. was added concentrated hydroloric acid (1 mL) . The mixture was stirred at room temperature for 1 h. The mixture was diluted with NaHCO₃ (aq. ) and extracted with ethyl acetate (3 ×) . The extracts were washed with water and brine, and dried over MgSO₄. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 3-10％methanol in DCM to give N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-5-nitropyridine -2, 3-diamine (1e) as 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) acrylam ide (1f)

To a mixture of N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-5-nitropyridine -2, 3-diamine (1e) (12.4 mg, 0.046 mmol) in THF-H₂O (10:1, 1 mL) at 0℃ was added 3-chloropropanoyl chloride (14 mg, 0.11 mmol) . The mixture was stirred at 0℃ for 0.5 h. NaOH (20 mg, 0.50 mmol) was added. The mixture was heated at 60 ℃ for 3 h and cooled to r.t.. The mixture was diluted with water and extracted with ethyl acetate (2 ×) . Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 5％methanol in DCM to give N- (2- ( (2- (Dimethylamino) ethyl) (methyl) amino) -6-methoxy-5-nitropyridin-3-yl) acrylamide (1f) (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) acryla mide (1g)

The mixture of N- (2- ( (2- (Dimethylamino) ethyl) (methyl) amino) -6-methoxy-5-nitropyridin-3-yl) acrylamide (1f) (6.7 mg, 0.021 mmol) , Fe (7.0 mg, 0.12 mmol) , and NH₄Cl (1.1 mg, 0.021 mmol) in ethanol-H₂O (3:1, 2 mL) was heated at reflux for 6 h. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/methanol/ammonia (92:6:2) to give N- (5-Amino-2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (1g) (3.6 mg, 59％) . MS-ESI (m/z) : 294 [M + 1] ⁺.

The mixture of N- (5-Amino-2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (1g) (3.6 mg, 0.012 mmol) , 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1h) (6.0 mg, 0.025 mmol) (prepared by following the literature, WO2013/14448) , and p-TsOH·H₂O (4.7 mg, 0.025 mmol) in 2-pentanol (0.5 mL) was heated at 105℃ for 2 h. Solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/methanol (95:5) to give 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) (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-yl) p yrimidin-2-yl) amino) pyridin-3-yl) acrylamide (2)

tert-Butyl 2- ( (6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2b)

The solution of 1a (4.00 g, 21.3 mmol) and tert-butyl methyl (2- (methylamino) ethyl) carbamate (2a, 4.38 g, 22.3 mmol) (prepared by following the literature, J. Med. Chem., 1992, 35, 565) in ethanol (47 mL) was heated at reflux for 3 h. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 15-30％ethyl acetate in hexanes to give tert-Butyl 2- ( (6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2b) (4.65 g, 63％) as yellow solid. MS-ESI (m/z) : 341 [M + 1] ⁺.

tert-Butyl 2- ( (3-bromo-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2c)

To a suspension of tert-Butyl 2- ( (6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2b) (4.32 g, 12.7 mmol) in acetonitrile (50 mL) at 0C was added NBS (3.40 g, 19.1 mmol) . The mixture was stirred at 0℃ for 1 h. Solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20-30％ethyl acetate hexanes to give tert-Butyl 2- ( (3-bromo-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2c) as yellow solid (5.00 g, 93％) . MS-ESI (m/z) : 419 and 421 [1:1, M +1] ⁺.

tert-Butyl 2- ( (3- (diphenylmethyleneamino) -6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2d)

The mixture of tert-Butyl 2- ( (3-bromo-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2c) (2.095 g, 5.00 mmol) , Pd₂ (dba) ₃ (137 mg, 0.150 mmol) , (+/-) -BINAP (187 mg, 0.300 mmol) , benzophenone imine (1.177 g, 6.50 mmol) , and t-BuONa (624 mg, 6.50 mmol) in toluene (20 mL) was heated under nitrogen at 110C for 3 h, and cooled to room temperature. The solid was removed by filtration through celite and washed with ethyl acetate. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20-40％ethyl acetate in hexanes to give tert-Butyl 2- ( (3- (diphenylmethyleneamino) -6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2d) as 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) carbamate (2e)

To a solution of tert-Butyl 2- ( (3- (diphenylmethyleneamino) -6-methoxy-5-nitropyridin -2-yl) (methyl) amino) ethyl (methyl) carbamate (2d) (580 mg, 1.12 mmol) in ethanol (20 mL) at r.t. was added hydroloric acid (1 N, 0.5 mL) . The mixture was heated at 50C for 7 h. The mixture was diluted with NaHCO₃ (aq. ) and extracted with ethyl acetate (3 ×) . The extracts were washed with water and brine, and dried over MgSO₄. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20-40％ethyl acetate in hexanes to give tert-Butyl 2- ( (3-amino-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2e) as 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) carbamate (2f)

To a mixture of tert-Butyl 2- ( (3-amino-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2e) (280 mg, 0.789 mmol) in THF-H₂O (10:1, 5.5 mL) at 0℃ was added 3-chloropropanoyl chloride (120 mg, 0.946 mmol) . The mixture was stirred at 0℃ for 0.5 h. NaOH (126 mg, 3.76 mmol) was added. The mixture was heated at 65℃ for 1 h and cooled to r.t.. The mixture was diluted with water and extracted with ethyl acetate (2 ×) . Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 30-50％ethyl acetate in hexanes to give tert-Butyl 2- ( (3-acrylamido-6-methoxy-5-nitropyridin -2-yl) (methyl) amino) ethyl (methyl) carbamate (2f) (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) carbamate (2g)

The mixture of tert-Butyl 2- ( (3-acrylamido-6-methoxy-5-nitropyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2f) (185 mg, 0.452 mmol) , iron powder (152 mg, 2.71 mmol) , and NH₄Cl (24.2 mg, 0.452 mmol) in ethanol-H₂O (3:1, 15 mL) was heated at reflux for 1 h. The solid was removed by filtration through celite and washed with ethyl acetate. The filtrates were diluted with ethyl acetate and washed with water and brine. Solvents were evaporated under reduced pressure to give crude tert-Butyl 2- ( (3-acrylamido-5-amino-6-methoxypyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2g) (149 mg, 87％) as brown oil. MS-ESI (m/z) : 380 [M + 1] ⁺.

The mixture of tert-Butyl 2- ( (3-acrylamido-5-amino-6-methoxypyridin-2-yl) (methyl) amino) ethyl (methyl) carbamate (2g) (94.0 mg, 0.248 mmol) , 3- (2-chloropyrimidin-4-yl) -1 -methyl-1H-indole (1h, 72.5 mg, 0.298 mmol) , and p-TsOH·H₂O (56.6 mg, 0.298 mmol) in 2-pentanol (1.5 mL) was heated at 105C for 2 h. Solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/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-ind ol-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) at room temperature was added acetaldehyde (40％in water, 9.0 mg, 0.082 mmol) followed by NaBH (OAc) ₃ (8.7 mg, 0.041 mmol) . The mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO₃ (5 mL) and extracted with DCM (2 × 5 mL) . The extracts were dried over Na₂SO₄. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/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 (3) as brown solid (12.5 mg, 77％) . MS-ESI (m/z) : 515 [M + 1] ⁺.

Example 4

N- (6-Methoxy-2- (methyl (2- (N-methylacetamido) ethyl) amino) -5- (4- (1-methyl-1H-indol- 3-yl) pyrimidin-2-ylamino) 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-ylamino) pyridin-3-yl) acrylamide (2) (28.3 mg, 0.058 mmol) in DCM (1 mL) was added DIPEA (15.2 μL, 0.087 mmol) , and cooled to 0℃. A solution of Ac₂O (5.9 mg in 0.20 mL DCM) was added dropwise. The mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCO₃ (5 mL) and extracted with DCM (2 × 5 mL) . The extracts were dried over Na₂SO₄. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 2-3％methanol in DCM to give N- (6-Methoxy-2- (methyl (2- (N-methylacetamido) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (4) as 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) pyr imidin-2-ylamino) pyridin-3-yl) acrylamide (5)

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

6-chloro-2-ethoxy-3-nitropyridine (5a) was prepared according to the synthetic method of 1a by replacing methanol with ethanol. 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-ylamino) pyridin-3-yl) acrylamide (5) (36.1 mg) was prepared according to the synthetic method of Example 2 by replacing 6-Chloro-2-methoxy-3-nitropyridine (1a) with 6-chloro-2-ethoxy-3-nitropyridine (5a) . 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-yl ) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (6)

To a solution of N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) (10.1 mg, 0.020 mmol) in 1, 2-dichloroethane (0.6 mL) at room temperature was added formaldehyde (37％in water, 17 mg) followed by NaBH (OAc) ₃ (6.4 mg, 0.030 mmol) . The mixture was stirred at room temperature for 1 h.The mixture was diluted with saturated aqueous NaHCO₃ (2 mL) and extracted with DCM (2 × 2 mL) . The extracts were dried over Na₂SO₄. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 5-10％methanol in DCM 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 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-ylamino) pyridin-3-yl) acrylamide (7)

6-chloro-2-isopropoxy-3-nitropyridine (7a)

The title compound 6-chloro-2-isopropoxy-3-nitropyridine (7a) was prepared according to the synthetic method of 1a by replacing methanol with isopropanol. MS-ESI (m/z) : 217 [M + 1] ⁺.

The title compound 7 (36.1 mg) was prepared according to the synthetic method of Example 2 by replacing 6-Chloro-2-methoxy-3-nitropyridine (1a) with 6-chloro-2-isopropoxy-3-nitropyridine (7a) . MS-ESI (m/z) : 515 [M + 1] ⁺.

Example 8

N- (2- ( (2- (Dimethylamino) ethyl) (methyl) amino) -6-isopropoxy-5- (4- (1-methyl-1H-indol- 3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (8)

The title compound 8 (6.3 mg, 75％) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) with N- (6-Isopropoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acr ylamide (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) p yridin-3-yl) acrylamide (9)

The title compound 9 (25 mg) was prepared according to the synthetic method of Example 2 by replacing tert-butyl methyl (2- (methylamino) ethyl) carbamate (2a) with tert-butyl piperazine-1-carboxylate. 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-methylpiperaz in-1-yl) pyridin-3-yl) acrylamide (10)

The title compound 10 (5.2 mg) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) 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) py ridin-3-yl) acrylamide (11)

The title compound 11 (55 mg) was prepared according to the synthetic method of Example 2 by replacing methyl (2- (methylamino) ethyl) carbamate (2a) with tert-butyl piperazine-1-carboxylate and replacing 6-Chloro-2-methoxy-3-nitropyridine (1a) with 6-chloro-2-ethoxy-3-nitropyridine (5a) respectively. MS-ESI (m/z) : 499 [M + 1] ⁺.

Example 12

N- (6-ethoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazi n-1-yl) pyridin-3-yl) acrylamide (12)

The title compound 12 (7.2 mg) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) 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-y l) pyridin-3-yl) acrylamide (13)

The title compound 13 (75 mg) was prepared according to the synthetic method of Example 2 by replacing tert-butyl methyl (2- (methylamino) ethyl) carbamate (2a) with tert-butyl piperazine-1-carboxylate and replacing 6-Chloro-2-methoxy-3-nitropyridine (1a) with 6-chloro-2-isopropoxy-3-nitropyridine (7a) respectively. MS-ESI (m/z) : 513 [M + 1] ⁺.

Example 14

N- (6-isopropoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpipe razin-1-yl) pyridin-3-yl) acrylamide (14)

The title compound 14 (7.4 mg) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) 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) . 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)

N¹- (6-chloro-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15a)

To a solution of 2, 6-dichloro-3-nitropyridine (19.3 g, 100.0 mmol) and triethylamine (20.2 g, 200.0 mmol) in dry dichloromethane (200 mL) was added a solution of N¹, N¹, N²-trimethylethane-1, 2-diamine (10.2 g, 100.0 mmol) in dry dichloromethane (20 ml) dropwise at 0℃for over 0.5 h . Then the reaction mixture was stirred for 1.5 h at 0℃. The mixture was diluted with water (200 mL) and extracted with dichloromethane (100 mL × 3) . The organic layers were combined, washed with brine (200 mL) , and dried over Na₂SO₄. The solids were filtered and the filtrate was concentrated in vacuum to give N¹- (6-chloro-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15a) as yellow oil (23.8 g, 91％) . MS-ESI (m/z) : 259 [M + 1] ⁺.

N¹- (6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15b)

To a solution of N¹- (6-chloro-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15a) (23.8 g, 91.9 mmol) in methanol (200 mL) was added sodium methoxide (10.8 g, 183.8 mmol) at 0-5℃. The mixture was heated to reflux for 2 h. Then the mixture was cooled to r.t. and methanol was evaporated, diluted with water (200 mL) and extracted with dichloromethane (200 mL × 2) . The organic layers were combined and washed with water (200 mL × 2) and brine (200 mL) , and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give N¹- (6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15b) as yellow oil (18.0 g, 77％) . MS-ESI (m/z) : 255 [M + 1] ⁺.

N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c)

To a solution of N¹- (6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15b) (11.0 g, 43.1 mmol) in glacial acetic acid (120 mL) was added N-iodosuccinimide (11.6 g, 51.8 mmol) for 3 batches at 0-5℃, and the mixture was stirred at room temperature for 4.5 h. Then solvent was evaporated under reduced pressure, diluted with water (300 mL) and extracted with ethyl acetate (200 mL × 3) . The organic layers were combined, washed with water (200 mL × 2) and brine (200 mL) , and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) as yellow solid (14.0 g, 88％) . MS-ESI (m/z) : 381 [M + 1] ⁺.

N¹- (5- ( (diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylet hane-1, 2-diamine (15d)

A mixture of N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane -1, 2-diamine (15c) (10.0 g, 26.2 mmol) , tris (dibenzylideneacetone) dipalladium (0) (1.2 g, 1.3 mmol) , (+/-) -2, 2'-bis (diphenylphosphino) -1, 1'-binaphthyl (1.6 g, 2.6 mmol) , benzophenone imine (7.1 g, 39.4 mmol) , and sodium tert-butoxide (3.8 g, 39.4 mmol) in toluene (150 mL) was stirred at 110℃under an inert atmosphere of nitrogen for 16 h. The resulting mixture was cooled to room temperature, the solids were removed by filtration through celite and washed with ethyl acetate. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give N¹- (5- ( (diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15d) as red oil (2.2 g, 19％) . MS-ESI (m/z) : 434 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e)

To a solution of N¹- (5- ( (diphenylmethylene) amino) -6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15d) (2.2 g, 5.1 mmol) in tetrahydrofuran (150 mL) was added 0.5 N hydrochloric acid (24 mL) at room temperature. The resulting solution was stirred at room temperature for 1.5 h. Tetrahydrofuran was evaporated under reduced pressure. The pH value of the mixture was adjusted to 9-10 with potassium carbonate. The resulting mixture was extracted with dichloromethane (30 mL × 4) . The organic layers were combined, washed with brine (20 mL) , and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20:1～10:1) to give N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) as red oil (0.7 g, 51％) . MS-ESI (m/z) : 270 [M + 1] ⁺.

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

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％dispersion in mineral oil, 0.44g, 11.1 mmol) at 0-5℃. The resulting suspension was stirred at room temperature for 20 min. Iodomethane (0.7 mL, 11.1 mmol) was added at room temperature. Then the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by water (40 mL) , and the mixture was extracted with ethyl acetate (30 mL × 3) . The organic layers were combined, washed with water (30 mL × 3) and brine (30 mL) , and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. 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 (15f) as light yellow liquid (1.0 g, 91％) . MS-ESI (m/z) : 150 [M + 1] ⁺.

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

A solution of 7-fluoro-1-methyl-1H-indole (15f) (0.60 g, 4.0 mmol) , 2, 4-dichloropyrimidine (0.60 g, 4.0 mmol) , anhydrous Iron (III) chloride (0.65 g, 4.0 mmol) in 1, 2-dimethoxyethane (12 mL) was stirred at 60℃ for 7 h. The reaction was quenched by water (40 mL) , the resulting mixture was extracted with ethyl acetate (30 mL × 3) , the organic layers were combined and washed with water (30 mL × 3) and brine (30 mL) , dried over anhydrous sodium sulfate. The solids were filtered out and the filtrate was concentrated in vacuum. 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 (15g) as brown solid (0.50 g, 48％) . MS-ESI (m/z) : 262 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -N⁵- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6 -methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15h)

A mixture of 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) (30.0 mg, 0.11 mmol) , N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) (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 (diphenylphosphino) -1, 1'-binaphthyl (29.0 mg, 0.044 mmol) in dioxane (3 mL) was stirred at 100℃ for 7 h, and cooled to r.t.. The reaction was quenched by water (30 mL) , the resulting mixture was extracted with ethyl acetate (30 mL × 3) , the organic layers were combined and washed with water (30 mL × 3) and brine (30 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol/aqueous ammonia (100:5:0.5) to give N²- (2- (dimethylamino) ethyl) -N⁵- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15h) as yellow solid (34.0 mg, 60％) . MS-ESI (m/z) : 495 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -N⁵- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6 -methoxy-N²-methylpyridine-2, 3, 5-triamine (15i)

A mixture of N²- (2- (dimethylamino) ethyl) -N⁵- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15h) (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℃ for 1.5 h. The solids were filtered out, washed with ethanol (5 mL × 3) , and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol/aqueous ammonia (100:5:0.5～100:10:0.5) to give N²- (2- (dimethylamino) ethyl) -N⁵- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N²-methylpyridine-2, 3, 5-triamine (15i) as yellow oil (28.0 mg, 88％) . MS-ESI (m/z) : 465 [M + 1] ⁺.

To a solution of N²- (2- (dimethylamino) ethyl) -N⁵- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N²-methylpyridine-2, 3, 5-triamine (15i) (28.0 mg, 0.06 mmol) in anhydrous dichloromethane (1 mL) was added acryloyl chloride (5.5 mg, 0.06 mmol) at 0℃. The resulting solution was stirred at 0℃ for 1 h. The reaction was quenched by saturated aqueous sodium bicarbonate (20 mL) , and the resulting mixture was extracted with dichloromethane (20 mL × 3) . The organic layers were combined, washed with water (20 mL × 3) and brine (20 mL) , and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane/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 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)

The title compound 16 (20.0 mg) was prepared according to the synthetic method of Example 15 by replacing 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)

The title compound 17 (25.0 mg) was prepared according to the synthetic method of Example 15 by replacing 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)

The title compound 18 (23.0 mg) was prepared according to the synthetic method of Example 15 by replacing 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 (19a)

A solution of 1-methyl-1H-indole (0.50 g, 3.8 mmol) , 2, 4-dichloro-5-fluoropyrimidine (0.64 g, 3.8 mmol) , anhydrous Iron (III) chloride (0.62 g, 3.8 mmol) in 1, 2-dimethoxyethane (7.0 mL) was stirred at 60℃ for 7 h. The reaction was quenched by water (40 mL) , and the resulting mixture was extracted with ethyl acetate (30 mL × 3) . The organic layers were combined, washed with water (30 mL × 3) and brine (30 mL) , and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. 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 (19a) as brown solid (0.54 g, 54％) . MS-ESI (m/z) : 262 [M + 1] ⁺.

The title compound 19 (23.0 mg) was prepared according to the synthetic method of Example 15 by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) with 3- (2-chloro-5-fluoropyrimidin-4-yl) -1-methyl-1H-indole (19a) . 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- (dimethylamin o) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (20)

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

A solution of 1-methyl-1H-indole (0.50 g, 3.8 mmol) , 2, 4, 5-trichloropyrimidine (0.70 g, 3.8 mmol) , anhydrous Iron (III) chloride (0.62 g, 3.8 mmol) in 1, 2-dimethoxyethane (7.0 mL) was stirred at 60℃ for 7 h. The reaction was quenched by water (40 mL) , and the resulting mixture was extracted with ethyl acetate (30 mL × 3) . The organic layers were combined, washed with water (30 mL × 3) and brine (30 mL) , and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. 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 (20a) as brown solid (0.56 g, 53％) . MS-ESI (m/z) : 278 [M + 1] ⁺.

The title compound 20 (20.0 mg) was prepared according to the synthetic method of Example 15 by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) with 3- (2, 5-dichloropyrimidin-4-yl) -1-methyl-1H-indole (20a) . MS-ESI (m/z) : 535 [M + 1] ⁺.

Example 21

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (5-methyl-4- (1-methyl-1H -indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (21)

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

A solution of 1-methyl-1H-indole (0.50 g, 3.8 mmol) , 2, 4-dichloro-5-methylpyrimidine (0.62 g, 3.8 mmol) , anhydrous Iron (III) chloride (0.62 g, 3.8 mmol) in 1, 2-dimethoxyethane (7.0 mL) was stirred at 60℃ for 7 h. The reaction was quenched by water (40 mL) , the resulting mixture was extracted with ethyl acetate (30 mL × 3) , the organic layers were combined and washed with water (30 mL × 3) and brine (30 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. 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 (21a) as brown solid (0.50 g, 47％) . MS-ESI (m/z) : 258 [M + 1] ⁺.

The title compound 21 (26.0 mg) was prepared according to the synthetic method of Example 15 by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) 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)

5-bromo-3-methoxy-2-nitropyridine (22a) was prepared according to the synthetic method described in US2006/84665.

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

A mixture of 5-bromo-3-methoxy-2-nitropyridine (22a) (2.8 g, 12.02 mmol) , tert-butyl methyl (2- (methylamino) ethyl) carbamate (2.67 g, 13.22 mmol) , Pd (OAc) ₂ (0.27 g, 1.20 mmol) , Xantphos (0.69 g, 1.20 mmol) and Cs₂CO₃ (11.7 g, 35.91 mmol) in toluene (56 mL) was stirred at 100℃ under nitrogen for 2.5 h. The mixture was cooled to r.t., quenched with water (200 mL) and extracted with EA (3×50 mL) . The extracts were washed with brine, dried over Na₂SO₄, concentrated and purified by column chromatography on silica gel eluting with 50％ethyl acetate in hexanes to give tert-butyl (2- ( (5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22b) as yellow solid (3.0 g, 73％) . MS-ESI (m/z) : 341 [M + 1] ⁺.

tert-Butyl (2- ( (2-bromo-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22c)

To a solution of tert-butyl (2- ( (5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22b) (1.70 g, 5.00 mmol) in acetic acid (30 mL) at 0℃ was added a solution of Br₂ (0.88 g, 5.50 mmol) in acetic acid (5 mL) . The mixture was stirred at 0℃ for 0.5 h and then at room temperature for 1 h. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 ×) . The extracts were washed with saturated aqueous NaHCO₃ and brine and dried over Na₂SO₄. Solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20-40％ethyl acetate in hexanes to give tert-Butyl (2- ( (2-bromo-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22c) as yellow solid (1.53 g, 73％) . MS-ESI (m/z) : 419.2 and 421.2 [1:1, M + 1] ⁺.

tert-Butyl (2- ( (2- ( (diphenylmethylene) amino) -5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22d)

The mixture of tert-Butyl (2- ( (2-bromo-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22c) (419 mg, 1.00 mmol) , Pd₂ (dba) ₃ (27.5 mg, 0.030 mmol) , (+/-) -BINAP (37.4 mg, 0.060 mmol) , benzophenone imine (199 mg, 1.10 mmol) , and t-BuONa (192 mg, 2.00 mmol) in toluene (5 mL) was heated under nitrogen at 80C for 4 h. The mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. THF (14 mL) and 0.5 N HCl (14 mL) were added successively. The mixture was stirred at r.t. for 1.5 h. The mixture was diluted with NaHCO₃ (50 mL) , extracted with ethyl acetate (2×) . The extracts were washed with brine and dried over Na₂SO₄. Solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 30-50％ethyl acetate in hexanes to give tert-Butyl (2- ( (2- ( (diphenylmethylene) amino) -5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22d) as 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 a mixture of tert-Butyl (2- ( (2- ( (diphenylmethylene) amino) -5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22d) (75 mg, 0.211 mmol) in acetonitrile (3 mL) at 0℃ was added 3-chloropropanoyl chloride (53.6 mg, 0.422 mmol) followed by DMAP (51.5 mg, 0.422 mmol) and DIPEA (81.7 mg, 0.633 mmol) . The mixture was stirred at 0℃ for 2.5 h. NaOH (10 N, 0.8 mL) was added. The mixture was stirred at r.t. for 1.5 h. The mixture was diluted with water and extracted with ethyl acetate (2 ×) . Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 5％methanol in DCM to give tert-Butyl (2- ( (2-acrylamido-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22e) (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)

The mixture of tert-Butyl (2- ( (2-acrylamido-5-methoxy-6-nitropyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22e) (28.5 mg, 0.070 mmol) , Fe (19.5 mg, 0.348 mmol) , and NH₄Cl (3.7 mg, 0.070 mmol) in ethanol-H₂O (3:1, 1.5 mL) was heated at reflux for 2 h. Solvents were evaporated under reduced pressure. The residue was purified by silica gel column eluting with 92:6:2 DCM-methanol-ammonia to give tert-Butyl (2- ( (2-acrylamido-6-amino-5-methoxypyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22f) (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) pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22g)

The mixture of tert-Butyl (2- ( (2-acrylamido-6-amino-5-methoxypyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22f) (8.6 mg, 0.023 mmol) , 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1h, 6.6 mg, 0.027 mmol) , Pd₂ (dba) ₃ (3.4 mg, 0.0036 mmol) , BINAP (2.2 mg, 0.0036 mmol) , and Cs₂CO₃ (11 mg, 0.034 mmol) in dioxane (0.5 mL) was heated at 100℃ for 2.5 h. The mixture was diluted with water and extracted with dichloromethane. Solvent was evaporated under reduced pressure. The residue was purified by silica gel column eluting with 95:5 DCM-methanol to give tert-Butyl (2- ( (2-acrylamido-5-methoxy-6- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) ethyl) (methyl) carbamate (22g) (3.3 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 (22g) (3.3 mg) in DCM (0.5 mL) at r.t. was added TFA (0.5 mL) . The mixture was stirred at r.t. for 40 min. Solvents were evaporated. To this was added NaBH (OAc) ₃ (3.5 mg) , 1, 2-dichloroethane (0.3 mL) and CH₂O (37％aqueous, 15 mg) . The mixture was stirred at r.t. for 1 h. The mixture was diluted with NaHCO₃, extracted with DCM. The crude product was purified by silica gel column, eluted with 95:4:1 DCM-MeOH-NH₄OH 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)

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indol-3-yl) pyri midin-2-yl) -3-nitropyridine-2, 5-diamine (23a)

The title compound 23a was prepared according to the synthetic method of Example 2 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (2g) with N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) . MS-ESI (m/z) : 477 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indol-3-yl) pyri midin-2-yl) pyridine-2, 3, 5-triamine (23b)

The title compound 23b was prepared according to the synthetic method of 15i by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15h) with N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -3-nitropy9ridine-2, 5-diamine (23a) . MS-ESI (m/z) : 447 [M + 1] ⁺.

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (1-methylimidazo [1, 5- a] pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (23)

A mixture of N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) (20 mg, 0.045 mmol) , HOBT (18 mg, 0.135 mmol) , EDCI (26 mg, 0.135) , TEA (14 mg, 0.135 mmol) , in DMF (2 ml) was stirred at 35℃for 3 h. The reaction was cooled to room temperature and quenched by water (5 mL) . The mixture was adjusted to pH 9～10 using sodium carbonate. The resulting mixture was extracted with EA (8 mL × 3) . The organic layers were combined and washed with brine (20 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (10:1) as the eluant to give N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (1-methylimidazo [1, 5-a] pyridin-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)

N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (24a)

A mixture of 4-fluoro-2-methoxy-5-nitroaniline (3 g, 16.0 mmol) (prepared by following the literature WO2013/14448) , N¹, N¹, N²-trimethylethane-1, 2-diamine (2 g, 19.7 mmol) and DIPEA (2.7 g, 20.8 mmol) in DMA was stirred at 80 ℃ for 5 h and then cooled to r.t.. DMA was evaporated, and the mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3) . The organic layers were combined and washed with water (100 mL ) and brine (100 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20:1～10:1) to give N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (24a) . MS-ESI (m/z) : 269 [M + 1] ⁺.

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ( (4- (1-methylimidazo [1, 5- a] pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -2-fluoroacrylamide (24)

The title compound 24 was prepared according to the synthetic method of Example 23 by replacing N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) with N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (24a) . MS-ESI (m/z) : 517 [M + 1] ⁺.

Example 25

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (1-methylindolizin-3-yl ) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (25)

1- (2-ethoxy-2-oxoethyl) -2-ethylpyridin-1-ium bromide (25a)

To a mixture of 2-ethylpyridine (10 g, 0.09 mol) in EtOH (200 mL) was added ethyl 2-bromoacetate (23 g, 0.14 mmol) . The mixture was heated to reflux for 16 h, then cooled to ambient temperature, and concentrated in vacuum. The crude product 1- (2-ethoxy-2-oxoethyl) -2-ethylpyridin-1-ium bromide (25a) was used for next step without further purification. MS-ESI (m/z) : 194 [M] ⁺.

ethyl 1-methylindolizine-3-carboxylate (25b)

To a solution of 1- (2-ethoxy-2-oxoethyl) -2-ethylpyridin-1-ium bromide (25a) (10 g, 0.036 mol) and K₂CO₃ (15 g, 0.10 mol) in EtOH (100 mL) was added (E) -ethyl 2-cyano-3-ethoxyacrylate (25 g, 0.14 mol) . The mixture was heated to reflux for 15 h, then cooled to ambient temperature, and concentrated in vacuum. The residue was extracted with EtOAc (50 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash column chromatography eluting with hexane/ethyl acetate (50:1～20:1) to give ethyl 1-methylindolizine-3-carboxylate (25b) . MS-ESI (m/z) : 275 [M + 1] ⁺.

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

To a solution of ethyl 1-methylindolizine-3-carboxylate (25b) (3.0 g, 0.014 mol) and N, O-Dimethylhydroxylamine hydrochloride (3.6 g, 0.037 mol) in THF (50 mL) was added i-PrMgCl (2 M in Et₂O, 35 mL , 0.07 mol) at 0℃. The mixture was stirred for 1 h then quenched with H₂O. The mixture was extracted with EtOAc (50 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash column chromatography eluting with hexane/ethyl acetate (20:1～10:1) to give N-methoxy-N, 1-dimethylindolizine-3-carboxamide (25c) . MS-ESI (m/z) : 219 [M + 1] ⁺.

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

To a solution of N-methoxy-N, 1-dimethylindolizine-3-carboxamide (25c) (2.6 g, 0.012 mol) in THF (50 mL) was added MeMgBr (3 M in Et₂O, 8.0 mL , 0.024 mol) at 0℃. The mixture was stirred for 1 h, then quenched with H₂O and extracted with EtOAc (50 mL × 3) . The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuum. This crude product 1- (1-methylindolizin-3-yl) ethanone (25d) was used for next step without further purification. MS-ESI (m/z) : 174 [M + 1] ⁺.

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

To a solution of 1- (1-methylindolizin-3-yl) ethanone (25d) (2.0 g, 0.012 mol) in DMF-DMA (25 mL) was added pyrrolidine (10 mL, 0.12 mol) at 25℃. The mixture was stirred for 1 h at 90℃, and then extracted with EtOAc (50 mL × 3) . The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10:1～2:1) to give (E) -1- (1-methylindolizin-3-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (25e) . MS-ESI (m/z) : 255 [M + 1] ⁺.

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

To a solution of (E) -1- (1-methylindolizin-3-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (25e) (1.0 g, 0.0039 mol) and K₂CO₃ (2.7 g, 0.012 mol) in i-PrOH (10 mL) was added guanidine hydrochloride (1.1 g , 0.19 mol) at 25℃. The mixture was stirred for 16 h at 130℃, then cooled to ambient temperature, extracted with EtOAc (50 mL x 3) . The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash column chromatography eluting with DCM/MeOH (30:1) to give 4- (1-methylindolizin-3-yl) pyrimidin-2-amine (25f) . MS-ESI (m/z) : 225 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methylindolizin-3-yl) pyrim idin-2-yl) -3-nitropyridine-2, 5-diamine (25g)

To a solution of 4- (1-methylindolizin-3-yl) pyrimidin-2-amine (25f) (150 mg, 0.67 mmol) , N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) (382 mg, 0.33 mmol) , and Cs₂CO₃ (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) and Pd (OAc) ₂ (75 mg, 0.33 mmol) at 25℃. The mixture was stirred for 3 h at 110℃, then cooled to ambient temperature, and extracted with EtOAc (50 mL × 3) . The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by flash column chromatography eluting with DCM/MeOH (40:1～20:1) to give N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methylindolizin-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (25g) . MS-ESI (m/z) : 477 [M + 1] ⁺.

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- (4- (1-methylindolizin-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (25)

The title compound 25 was prepared according to the synthetic method of Example 15 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15h) with N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methylindolizin-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (25g) . MS-ESI (m/z) : 501 [M + 1] ⁺.

Example 26

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ( (4- (1-methylindolizin-3-yl ) pyrimidin-2-yl) amino) phenyl) acrylamide (26)

N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a)

To a solution of N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (24a) (3.2 g, 11.9 mmol) in 1 N H₂SO₄ (50 mL) was added NaNO₂ (1.28 g, 17.9 mmol) at 0℃. The mixture was stirred at 0℃ for 15 min, then KI (4.0 g, 23.8 mmol) was added. The mixture was stirred at 90℃ for 1 h. The reaction was cooled to room temperature. The mixture was adjusted to pH 9～10 using sodium carbonate. The resulting mixture was extracted with EA (20 mL × 3) . The organic layers were combined, washed with brine (20 mL) , and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20:1) to give N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . MS-ESI (m/z) : 380 [M + 1] ⁺.

The title compound 26 was prepared according to the synthetic method of Example 25 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) with N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . MS-ESI (m/z) : 500 [M + 1] ⁺.

Example 27

N- (5- ( (4- (1-cyanoindolizin-3-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (me thyl) amino) -6-methoxypyridin-3-yl) acrylamide (27)

1- (2-ethoxy-2-oxoethyl) pyridin-1-ium bromide (27a)

To a mixture of pyridine (10 g, 0.09 mol) in EtOH (200 mL) was added ethyl 2-bromoacetate (23 g, 0.14 mmol) . The mixture was heated to reflux for 16 h, then cooled to ambient temperature, and concentrated in vacuum. The crude product 1- (2-ethoxy-2-oxoethyl) pyridin-1-ium bromide (27a) was used for next step without further purification. MS-ESI (m/z) : 167 [M] ⁺.

ethyl 1-cyanoindolizine-3-carboxylate (27b)

To a solution of 1- (2-ethoxy-2-oxoethyl) pyridin-1-ium bromide (27a) (10 g, 0.04 mol) and TEA (29 mL, 0.2 mol) in EtOH (250 mL) was added (E) -3-methoxyacrylonitrile (10 g, 0.12 mol) . The mixture was heated to reflux for 15 h, then cooled to ambient temperature, and concentrated in vacuum. The residue was extracted with EtOAc (50 mL x 3) . The organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuum. The residue was purified by flash column chromatography eluting with hexane/ethyl acetate (50:1～20:1) to give ethyl 1-cyanoindolizine-3-carboxylate (27b) . MS-ESI (m/z) : 215 [M + 1] ⁺.

The title compound 27 was prepared according to the synthetic method of Example 25 by replacing ethyl 1-methylindolizine-3-carboxylate (25b) with ethyl 1-cyanoindolizine-3-carboxylate (27b) . MS-ESI (m/z) : 501 [M + 1] ⁺.

Example 28

N- (5- ( (4- (1-cyanoindolizin-3-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (me thyl) amino) -4-methoxyphenyl) acrylamide (28)

The title compound 28 was prepared according to the synthetic method of Example 27 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) with N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . MS-ESI (m/z) : 511 [M + 1] ⁺.

Example 29

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -5- ( (4- (indolizin-3-yl) pyrimidin-2-yl) ami no) -6-methoxypyridin-3-yl) acrylamide (29)

The title compound 29 was prepared according to the synthetic method of Example 25 by replacing 2-ethylpyridine with 2-methylpyridine. MS-ESI (m/z) : 487 [M + 1] ⁺.

Example 30

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -5- ( (4- (indolizin-3-yl) pyrimidin-2-yl) ami no) -4-methoxyphenyl) acrylamide (30)

The title compound 30 was prepared according to the synthetic method of Example 29 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) with N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . MS-ESI (m/z) : 486 [M + 1] ⁺.

Example 31

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

ethylindolizine-3-carboxylate (31a)

The title compound ethyl indolizine-3-carboxylate (31a) was prepared according to the synthetic method of compound 25b by replacing 2-ethylpyridine with 2-methylpyridine. MS-ESI (m/z) : 190 [M + 1] ⁺.

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

To a solution of ethyl indolizine-3-carboxylate (31a) (0.42 g, 2.2 mmol) in DMF (5 mL) was added NCS (0.3 g, 2.2 mmol) at 0℃. The mixture was stirred at 25℃ for 1 h, and extracted with EtOAc (50 mL × 3) . The organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuum. The residue was purified by flash column chromatography eluting with hexane/ethyl acetate (50:1) to give ethyl 1-chloroindolizine-3-carboxylate (31b) . MS-ESI (m/z) : 224 [M + 1] ⁺.

The title compound 31 was prepared according to the synthetic method of Example 25 by replacing compound ethyl 1-methylindolizine-3-carboxylate (25b) with ethyl 1-chloroindolizine-3-carboxylate (31b) . MS-ESI (m/z) : 521 [M + 1] ⁺.

Example 32

N- (5- ( (4- (1-chloroindolizin-3-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (m ethyl) amino) -4-methoxyphenyl) acrylamide (32)

The title compound 32 was prepared according to the synthetic method of Example 31 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) with N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . MS-ESI (m/z) : 520 [M + 1] ⁺.

Example 33

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (3-methylindolizin-1-yl ) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (33)

3-methylindolizine-1-carbonitrile (33a)

A mixture of 2-bromopropanal (7.26 g, 53.4 mmol) and 2-pyridylacetonitrile (6.3 g, 53.4 mmol) in THF (70 mL) was heated to 70℃ for 24 h. The mixture was concentrated in vacuum. The residue was diluted with EtOAc and hydrochloride acid (20 mL, 2 M) . The organic layer was washed with sat. aq. NaHCO3 solution, brine, dried over Na₂SO₄, and concentrated in vacuum. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (10:1～5:1) to give 3-methylindolizine-1-carbonitrile (33a) . MS-ESI (m/z) : 157 [M + 1] ⁺.

1- (3-methylindolizin-1-yl) ethan-1-imine (33b)

To a solution of 3-methylindolizine-1-carbonitrile (33a) (1.6 g, 10.3 mmol) in THF was added 3 M CH₃MgBr (18 mL) at ice-water bath, and the reaction mixture was stirred at ambient temperature for 15 h. The mixture was quenched with sat. aq. NH₄Cl solution, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuum to give 1- (3-methylindolizin-1-yl) ethan-1-imine (33b) . MS-ESI (m/z) : 173 [M + 1] ⁺.

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

To a solution of 1- (3-methylindolizin-1-yl) ethan-1-imine (33b) (1.0 g, 5.8 mmol) in THF was added dropwise 6 N H₂SO₄ (60 mL) at ambient temperature, heated to 55℃ for 24 h, then cooled to ambient temperature. The reaction mixture was diluted with water and DCM. The organic layer was separated, washed with sat. aq. NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated in vacuum. The residue was purified by flash column chromatography to give 1- (3-methylindolizin-1-yl) ethan-1-one (33c) . MS-ESI (m/z) : 174 [M + 1] ⁺.

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

To a solution of 1- (3-methylindolizin-1-yl) ethan-1-one (33c) (110mg, 0.7mmol) in DMF was added DMF-DMA (170mg, 1.4 mmol) and pyrrolidine (50mg, 0.7mmol) . The mixture was heated to 90℃ for 1.5 h. After cooled to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give crude product 1- (3-methylindolizin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33d) . MS-ESI (m/z) : 255 [M + 1] ⁺.

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

To a solution of 1- (3-methylindolizin-1-yl) -3- (pyrrolidin-1-yl) prop-2-en-1-one (33d) (300 mg, 1.2 mmol) in propanol was added guanidine hydrochloride (337 mg, 3.5 mmol) and K₂CO₃ (662 mg, 4.8 mmol) . The mixture was heated to 120℃ for 20 h in a sealed tube. After cooled to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give crude product 4- (3-methylindolizin-1-yl) pyrimidin-2-amine (33e) . MS-ESI (m/z) : 225 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (3-methylindolizin-1-yl) pyrim idin-2-yl) -3-nitropyridine-2, 5-diamine (33f)

A mixture of 4- (3-methylindolizin-1-yl) pyrimidin-2-amine (33e) (30.0 mg, 0.13 mmol) , 25c (76.0 mg, 0.20 mmol) , Pd (OAc) ₂ (15.0 mg, 0.07 mmol) , Xantphos (38.0 mg, 0.07 mmol) , and Cs2CO3 (170 mg, 0.52 mmol) in toluene (1mL) and dioxane (0.5 mL) was heated under nitrogen at 110 ℃ for 3 h. After cooled to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography on silica gel eluting with 9％methanol in dichloromethane to give N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (3-methylindolizin-1-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (33f) . MS-ESI (m/z) : 477 [M + 1] ⁺.

The title compound 33 was prepared according to the synthetic method of Example 15 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15h) with compound N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (3-methylindolizin-1-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (33f) . MS-ESI (m/z) : 501 [M + 1] ⁺.

Example 34

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ( (4- (3-methylindolizin-1-yl ) pyrimidin-2-yl) amino) phenyl) acrylamide (34)

The title compound 34 was prepared according to the synthetic method of Example 33 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) with N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . MS-ESI (m/z) : 500 [M + 1] ⁺.

Example 35

N- (5- ( (4- (3-cyanoindolizin-1-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (me thyl) amino) -6-methoxypyridin-3-yl) acrylamide (35)

1-acetylindolizine-3-carbonitrile (35a)

A mixture of 1- (cyanomethyl) pyridin-1-ium 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 EtOH (100 mL) was heated to 80℃ for 7 h. The reaction mixture was concentrated in vacuum. The residue was diluted with DCM and water. The organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated. The residue was stirred for 0.5 h in iso-propanol. Yellow solid was collected by filtration and dried in vacuum to give 1-acetylindolizine-3-carbonitrile (35a) . MS-ESI (m/z) : 185 [M + 1] ⁺.

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

To a solution of 1-acetylindolizine-3-carbonitrile (35a) (400 mg, 2.17 mmol) in DMF was added DMF-DMA (516 mg, 4.34 mmol) and pyrrolidine (308 mg, 4.34 mmol) . The reaction mixture was heated to 90℃ for 1 h. After cooled to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give the crude product 1- (3- (pyrrolidin-1-yl) acryloyl) indolizine-3-carbonitrile (35b) . MS-ESI (m/z) : 266 [M + 1] ⁺.

1- (2-aminopyrimidin-4-yl) indolizine-3-carbonitrile (35c)

To a solution of 1- (3- (pyrrolidin-1-yl) acryloyl) indolizine-3-carbonitrile (35b) (637 mg, 2.4 mmol) in 1-butanol was added guanidine hydrochloride (690 mg, 7.2 mmol) and K₂CO₃ (1.3 g, 9.6 mmol) . The mixture was heated to 115℃ for 20 h. After cooled to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na₂SO₄ and concentrated to give the crude product 1- (2-aminopyrimidin-4-yl) indolizine-3-carbonitrile (35c) . MS-ESI (m/z) : 236 [M + 1] ⁺.

The title compound 35 was prepared according to the synthetic method of Example 33 by replacing 4- (3-methylindolizin-1-yl) pyrimidin-2-amine (33e) with 1- (2-aminopyrimidin-4-yl) indolizine-3-carbonitrile (35c) . MS-ESI (m/z) : 512 [M + 1] ⁺ .

Example 36

N- (5- ( (4- (3-cyanoindolizin-1-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (me thyl) amino) -4-methoxyphenyl) acrylamide (36)

The title compound 36 was prepared according to the synthetic method of Example 35 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) with N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . MS-ESI (m/z) : 511 [M + 1] ⁺.

Example 37

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -5- ( (4- (indolizin-1-yl) pyrimidin-2-yl) ami no) -6-methoxypyridin-3-yl) acrylamide (37)

1- (2-ethoxy-2-oxoethyl) pyridin-1-ium bromide (37a)

A mixture of pyridine (2.00 g, 25.30 mmol) and ethyl 2-bromoacetate (6.3 g, 38.00 mmol) in EtOH (20 mL) was heated under nitrogen at 70℃ for 1 h. The solvent was evaporated under reduced pressure. The residue was filtered through celite pad and the pad was washed with PE, gave 6.9 g 1- (2-ethoxy-2-oxoethyl) pyridin-1-ium bromide (37a) . MS-ESI (m/z) : 167 [M + 1] ⁺.

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

To a mixture of 1- (2-ethoxy-2-oxoethyl) pyridin-1-ium bromide (37a) (5.50 g, 15.10 mmol) and 4-methoxybut-3-en-2-one (2.3 g, 22.3 mmol) in EtOH (65 mL) at 20℃, was added TEA (4.50 g, 44.60 mmol) . The mixture was heated at 80℃ overnight. The mixture was cooled to room temperature and diluted with water. The solution was extracted with EA (3 × 50mL) . The organic layer was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give ethyl 1-acetylindolizine-3-carboxylate (37b) (2.65 g) . MS-ESI (m/z) : 232 [M + 1] ⁺.

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

To a solution of ethyl 1-acetylindolizine-3-carboxylate (37b) (2.60 g, 11.3 mmol) in MeOH (30 mL) was added 10％NaOH (2.0 g, 50.6m mol) at 20℃. The mixture was heated at 65℃for 1 h. After the solvent was evaporated under reduced pressure, PPA (10.0g) and MeOH (40 ml) was add to the residue and the mixture was heated at 65℃ for 40 min. The mixture was cooled to room temperature and diluted with water. The solution was extracted with DCM (3 × 50mL) . The extracts were washed with NaHCO₃, brine, dried over Na₂SO₄ and concentrated to give 1- (indolizin-1-yl) ethan-1-one (37c) (1.23 g) . MS-ESI (m/z) : 160 [M + 1] ⁺.

N- (5- (4- (indolizin-1-yl) pyrimidin-2-ylamino) -2- (N- (2- (dimethylamino) ethyl) -N-methyla mino) -6-methoxypyridin-3-yl) acrylamide (37)

The title compound 37 was prepared according to the synthetic method of Example 35 by replacing 1-acetylindolizine-3-carbonitrile (35a) with1- (indolizin-1-yl) ethan-1-one (37c) . MS-ESI (m/z) : 487 [M + 1] ⁺.

Example 38

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -5- ( (4- (indolizin-1-yl) pyrimidin-2-yl) ami no) -4-methoxyphenyl) acrylamide (38)

The title compound 38 was prepared according to synthetic the method of Example 37 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) with N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . MS-ESI (m/z) : 486 [M + 1] ⁺.

Example 39

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

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

A mixture of 1- (indolizin-1-yl) ethan-1-one (37c) (600 mg, 3.8 mmol) , CuCl (962 mg, 5.7 mmol) in CH₃CN (6 mL) was stirred at r.t. for 4 h. The mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL) . The extracts were dried over Na₂SO₄. Solvents were evaporated under reduced pressure. The residue was purified through flash column chromatography eluting with PE/EA (8:1～6:1) to give 1- (3-chloroindolizin-1-yl) ethan-1-one (39a) . MS-ESI (m/z) : 194 [M + 1] ⁺.

The title compound 39 was prepared according to the synthetic method of Example 35 by replacing 1-acetylindolizine-3-carbonitrile (35a) with1- (3-chloroindolizin-1-yl) ethan-1-one (39a) . MS-ESI (m/z) : 521 [M + 1] ⁺.

Example 40

N- (5- ( (4- (3-chloroindolizin-1-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (m ethyl) amino) -4-methoxyphenyl) acrylamide (40)

The title compound 40 was prepared according to the synthetic method of Example39by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) withN¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (26a) . 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) at room temperature was added HOBT (306 mg, 2.0 mmol) followed K₂CO₃ (1.93 g, 14.0 mmol) . The mixture was stirred at 70℃ for 24 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 30 mL) . The extracts were washed with brine and dried over Na₂SO₄. Solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (10:1～5:1) to give 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indole (41a) as yellow solid (1 g, 40％) .

The title compound 41 (17.3 mg) was prepared by using the same procedure as described for 1 by replacing 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1h) with 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indole (41a) . 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)

The mixture of 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indole (41a) (278 mg, 1.14 mmol) , 4-fluoro-2-methoxy-5-nitroaniline (213 mg, 1.14 mmol) (prepared by following the literature, WO2013/14448) , and p-TsOH·H₂O (260 mg, 1.37 mmol) in 2-pentanol (4 mL) was heated at 105℃ for 2 h. The mixture was filtrated, and the filtration was evaporated under reduced pressure to give N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (3-methyl-1H-indol-1-yl) pyrimidin-2-amine (42a) (320 mg, 72％) . MS-ESI (m/z) : 394 [M + 1] ⁺.

N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (3-methyl-1H-indol-1-yl) pyri midin-2-yl) -2-nitrobenzene-1, 4-diamine (42b)

The solution of N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (3-methyl-1H-indol-1-yl) pyrimidin-2-amine (42a) (160 mg, 0.407 mmol) , N¹, N¹, N²-trimethylethane-1, 2-diamine (0.064 mL , 0.489 mmol) and DIPEA (0.088 mL, 0.529 mmol) in DMA (1.6 mL) was heated at 85℃ for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with DCM/methanol/ammonia (92:6:2) to provide N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42b) (139 mg, 73％) . MS-ESI (m/z) : 476 [M + 1] ⁺.

N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (3-methyl-1H-indol-1-yl) pyri midin-2-yl) -2-nitrobenzene-1, 4-diamine (42c)

The mixture of N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42b) (139 mg, 0.293 mmol) , iron powder (98 mg, 1.76 mmol) , and NH₄Cl (22.0 mg, 0.293 mmol) in ethanol-H₂O (3:1, 15 mL) was heated at reflux for 1 h. The solid was removed by filtration through celite and washed with ethyl acetate. The filtrates were diluted with ethyl acetate and washed with water and brine. The solvent was evaporated under reduced pressure and the residue was column chromatography on silica gel eluting with DCM-methanol-ammonia (92:6:2) to give N¹- (2- (dimethylamino) ethyl) -5-methoxy -N¹-methyl-N⁴- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42c) (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)

To a mixture of N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-N⁴- (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) -2-nitrobenzene-1, 4-diamine (42c) (120 mg, 0.27 mmol) in THF-H₂O (10:1, 3 mL) at 0℃ was added 3-chloropropanoyl chloride (0.031 mL, 0.32 mmol) . The mixture was stirred at 0℃ for 2 h. Ammonium Hydroxidethe (0.5mL) was added. The mixture was diluted with water and extracted with ethyl acetate. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 2-5％methanol in DCM 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 (42d) (100 mg, 69％) . MS-ESI (m/z) : 536 [M + 1] ⁺.

To a solution of 3-chloro-N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy -5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) phenyl) propanamide (42d) (100 mg, 0.187 mmol) in THF-H₂O (10:1, 2 mL) at room temperature was added NaOH (60 mg, 1.5 mmol) . The mixture was stirred for 2 h. The mixture was diluted with water and extracted with ethyl acetate. Solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 1-2％methanol in DCM to give N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) phenyl) acryl amide (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-methylpiperaz in-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) p henyl) acrylamide (43a)

The title compound 43a (10 mg) was prepared according to the synthetic method of Example 41 by replacing N¹, N¹, N²-trimethylethane-1, 2-diamine with tert-butyl piperazine-1-carboxylate. MS-ESI (m/z) : 485 [M + 1] ⁺.

N- (6-methoxy-5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) pyridin-3-yl) acrylamide (43)

The title compound 43 (4.9 mg) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) with N- (4-methoxy-5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) phenyl) acrylamide (43a) . 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-methylpiperaz in-1-yl) phenyl) acrylamide (44)

The title compound 44 was prepared according to the synthetic method of Example 42 by replacing N¹, N¹, N²-trimethylethane-1, 2-diamine with 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) (m ethyl) amino) -6-methoxypyridin-3-yl) acrylamide (45)

1- (2-chloropyrimidin-4-yl) -1H-indole-3-carbonitrile (45b)

The title compound 1- (2-chloropyrimidin-4-yl) -1H-indole-3-carbonitrile (45b) (220 mg) was prepared according to the synthetic method of 41a by replacing 3-methyl-1H-indole with 1H-indole-3-carbonitrile (45a) (This reagent was prepared according to the synthetic method described in literature: JOC 1958, 23, 1178) . MS-ESI (m/z) : 255 [M + 1] ⁺.

The title compound 45 (7.0 mg) was prepared according to the synthetic method of Example 15 by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) with 1- (2-chloropyrimidin-4-yl) -1H-indole-3-carbonitrile (45b) . 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) (m ethyl) amino) -4-methoxyphenyl) acrylamide (46)

The title compound 46 (5 mg) was prepared according to the synthetic method of Example 45 by replacing N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) with N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (24a) . 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- (dimethyla mino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (47)

2- (methylthio) -N- (pyridin-2-yl) pyrimidine-4-carboxamide (47a)

A mixture of pyridin-2-ylmethanamine (900 mg, 8.3 mmol) , 2- (methylthio) pyrimidine -4-carboxylic acid (1 g, 5.9 mmol) (prepared by following the literature WO2006/117368) , HOBT (2.4 g, 17.7 mmol) , EDCI (3.4 g, 17.7 mmol) , TEA (1.78 g, 17.7 mmol) in DMF (10 ml) was stirred at r.t. for 2 h. The reaction was cooled to room temperature and quenched by water (10 mL) . The mixture was adjusted to pH 9～10 using sodium carbonate. The resulting mixture was extracted with EA (15 mL × 3) . The organic layers were combined and washed with brine (20 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with PE/EA (2:1～1:1) to give 2- (methylthio) -N- (pyridin-2-yl) pyrimidine-4-carboxamide (47a) . MS-ESI (m/z) : 247 [M + 1] ⁺.

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

To a solution of 2- (methylthio) -N- (pyridin-2-yl) pyrimidine-4-carboxamide (47a) (370 mg, 1.5 mmol) in CH₃CN (2 mL) was added POCl₃ (2.5 mL) , the mixture was stirred at 85 ℃ for 20 h. The reaction was cooled to room temperature and quenched by water (10 mL) . The mixture was adjusted to pH 8-9 using NaOH. The resulting mixture was extracted with DCM (8 mL × 3) . The organic layers were combined and washed with brine (20 mL) , dried over Na₂SO₄ and concentrated in vacuum to give crude product 3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (47b) MS-ESI (m/z) : 243 [M + 1] ⁺

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

To a solution of 3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (200 mg, 0.83 mmol) in DMF (2 mL) was add NCS (144 mg, 1.08 mmol) at r.t.. The mixture was stirred at r.t. for 2 h. The reaction was quenched by water (5 mL) . The resulting mixture was extracted with DCM (5 mL × 2) . The organic layers were combined and washed with brine (10 mL) , dried over Na₂SO₄ and concentrated in vacuum to give crude product 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (47c) . MS-ESI (m/z) : 277 [M + 1] ⁺

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

To a solution of 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (47c) (150 mg, 0.54 mmol) in NMP (5mL) was add 10％NaOH (2 mL) . The mixture was stirred at 100 ℃for 24 h. The reaction was cooled to room temperature. The mixture was adjusted to pH 5-6 using 2 N HCl. The resulting mixture was extracted with DCM (10 mL × 3) . The organic layers were combined and washed with brine (20 mL) , dried over Na₂SO₄ and concentrated in vacuum to give crude product 4- (1-chloroimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-ol (47d) . MS-ESI (m/z) : 247 [M + 1] ⁺

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

To a solution of 4- (1-chloroimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-ol (47d) (140 mg, 0.57 mmol) in CH₃CN (1 mL) was added POCl₃ (1 mL) . The mixture was stirred at 80℃ for 1.5 h. The reaction was cooled to room temperature and quenched by water (5 mL) . The mixture was adjusted to pH 8-9 using Na₂CO₃. The resulting mixture was extracted with DCM (8 mL × 3) . The organic layers were combined and washed with brine (20 mL) , dried over Na₂SO₄ and concentrated in vacuum to give crude product 1-chloro-3- (2-chloropyrimidin-4-yl) imidazo [1, 5-a] pyridine (47e) . MS-ESI (m/z) : 265 [M + 1] ⁺

N¹- (4- (1-chloroimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl ) -2-methoxy-N⁴-methyl-5-nitrobenzene-1, 4-diamine (47f)

A mixture of 1-chloro-3- (2-chloropyrimidin-4-yl) imidazo [1, 5-a] pyridine (47e) (54 mg, 0.20 mmol) , N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) (61 mg, 0.22 mmol) and MsOH (27 mg, 0.24 mmol) in PrOH (2.5 mL) was stirred at 90℃ for 3 h. The reaction was cooled to room temperature and quenched by water (10 mL) . The mixture was adjusted to pH 8-9 using Na₂CO₃. The resulting mixture was extracted with ethyl acetate (30 mL ×3) .The organic layers were combined and washed with water (30 mL) and brine (30 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The residue was purified by chromatography on silica gel column eluting with dichloromethane/methanol (10:1) give N¹- (4- (1-chloroimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy -N⁴-methyl-5-nitrobenzene-1, 4-diamine (47f) . MS-ESI (m/z) : 498 [M + 1] ⁺..

N- (5- ( (4- (1-chloroimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethyla mino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (47)

The title compound (47) was prepared according to the synthetic method of Example 15 by replacing N²- (2- (dimethylamino) ethyl) -N⁵- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15h) with N¹- (4- (1-chloroimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) -N⁴- (2- (dimethylamino) ethyl) -2-methoxy -N⁴-methyl-5-nitrobenzene-1, 4-diamine (47f) . 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- (dimethyla mino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (48)

The title compound (48) was prepared according to the synthetic method of Example 47 by replacing N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) with N¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (24a) . MS-ESI (m/z) : 521 [M + 1] ⁺.

Example 49

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (1- (trifluoromethyl) imi dazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (49)

1-iodo-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (49a)

To a solution of 3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (47b) (300 mg, 1.24 mmol) in DMF (5 mL) was add NIS (362 mg, 1.61 mmol) at r.t.. The mixture was stirred at r.t. for 2 h. The reaction was quenched by water (5 mL) . The resulting mixture was extracted with DCM (8 mL × 2) . The organic layers were combined and washed with brine (10 mL) , dried over Na₂SO₄ and concentrated in vacuum to give crude product 1-iodo-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (49a) . MS-ESI (m/z) : 369 [M + 1] ⁺

3- (2- (methylthio) pyrimidin-4-yl) -1- (trifluoromethyl) imidazo [1, 5-a] pyridine (49b)

A mixture of 1-iodo-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (49a) (200 mg, 0.54 mmol) , (Trifluoromethyl) trimethylsilane (153 mg, 1.08 mmol) , Phen (194 mg, 1.08 mmol) , Trimethyl borate (112 mg, 1.08 mmol) , Potassium fluoride (63 mg, 1.08 mmol) and copper (I) iodide (154 mg, 0.81 mmol) in DMSO (5 mL) was stirred at 60℃ overnight. The reaction was cooled to room temperature and quenched by water (10 mL) . The resulting mixture was extracted with ethyl acetate (10 mL × 3) , the organic layers were combined and washed with water (20 mL) and brine (20 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with acetate/petroleum ether (1:2) to give 3- (2- (methylthio) pyrimidin-4-yl) -1- (trifluoromethyl) imidazo [1, 5-a] pyridine (49b) . MS-ESI (m/z) : 311 [M + 1] ⁺..

The title compound 49 was prepared according to the synthetic method of Example 47 by replacing 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (47c) with 3- (2- (methylthio) pyrimidin-4-yl) -1- (trifluoromethyl) imidazo [1, 5-a] pyridine (49b) . MS-ESI (m/z) : 556 [M + 1] ⁺

Example 50

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ( (4- (1- (trifluoromethyl) imi dazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (50)

The title compound 50 was prepared according to the synthetic method of Example 47 by replacing N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) with N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (24a) . MS-ESI (m/z) : 555 [M + 1] ⁺.

Example 51

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (1-methylimidazo [1, 5- a] pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (51)

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

The title compound 51a was prepared according to the synthetic method of 47b by replacing pyridin-2-ylmethanamine with 1- (pyridin-2-yl) ethan-1-amine. MS-ESI (m/z) : 257 [M + 1] ⁺.

3- (2-chloropyrimidin-4-yl) -1-methylimidazo [1, 5-a] pyridine (51b)

The title compound 51b was prepared according to the synthetic method of 47e by replacing 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (47c) with 1-methyl-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (51a) . MS-ESI (m/z) : 245 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methylimidazo [1, 5-a] pyrid in-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (51c)

The title compound (51c) was prepared according to the synthetic method of 15i by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) with 3- (2-chloropyrimidin-4-yl) -1-methylimidazo [1, 5-a] pyridine (51b) . MS-ESI (m/z) : 448 [M + 1] ⁺.

The title compound 51 was prepared according to the synthetic method of Example 15 by replacing N²- (2- (dimethylamino) ethyl) -N⁵- (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N²-methylpyridine-2, 3, 5-triamine (15i) with N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methylimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-tri amine (51c) . MS-ESI (m/z) : 502 [M + 1] ⁺.

Example 52

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ( (4- (1-methylimidazo [1, 5- a] pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (52)

The title compound 52 was prepared according to the synthetic method of Example 51 by replacing N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-3-nitropyridine-2, 5-diamine (15e) with N¹- (2- (dimethylamino) ethyl) -5-methoxy-N¹-methyl-2-nitrobenzene-1, 4-diamine (24a) . MS-ESI (m/z) : 501 [M + 1] ⁺.

Example 53

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (1-methylimidazo [1, 5- a] pyridin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (53)

The title compound (53) was prepared according to the method of Example 23 by replacing N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) with N²- (2- (dimethylamino) ethyl) -6-methoxy -N²-methyl-N⁵- (4- (1-methylimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (51c) . MS-ESI (m/z) : 520 [M + 1] ⁺.

Example 54

N- (5- ( (4- (1, 2-dihydropyrrolo [3, 2, 1-hi] indol-5-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethy lamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide (54)

2- (2-nitrophenyl) ethanol (54a)

A mixture of 1-methyl-2-nitrobenzene (48 g, 0.35 mol) , Formaldehyde (10.4 g, 0.35 mol) , 20％NaOH (3.6 ml) and DMSO was heated at 50℃ for 2 h. Then the mixture was cooled to r.t., diluted with water (200 mL) and extracted with Ethyl acetate (300 mL × 3) . The organic layers were combined and washed with water (200 mL × 2) and brine (200 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:1) to give 2- (2-nitrophenyl) ethanol (54a) as brown oil (14.4 g, 25％) .

tert-butyldimethyl (2-nitrophenethoxy) silane (54b)

To a solution of 2- (2-nitrophenyl) ethanol (54a) (1.7 g, 0.01 mol) in dry DCM (15 ml) was added the imidazole (0.88 g, 0.013 mol) followed by tert-Butyldimethylsilyl chloride (2.1 g, 0.014 mol) at r.t for 2 h. Then the mixture was filtered, diluted with DCM (30 mL) and washed with 1 N HCl (30 mL) , water and aq NaHCO₃. The organic layers were combined and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The crude product was concentrated to give tert-butyldimethyl (2-nitrophenethoxy) silane (54b) as brown oil (2.8 g, 97％)

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

To a solution of tert-butyldimethyl (2-nitrophenethoxy) silane (54b) (4.5 g, 16 mmol) in dry THF (50 ml) was added dropwise the vinylmagnesium bromide (56 ml, 56 mmol) under N₂ at -70℃. The mixture was slowly warm to r.t. The mixture was poured into aq NH₄Cl and extracted with ethyl acetate (50 mL) . The organic layers were combined and dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The crude product was 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 (54c) as 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)

The title compound 54d (0.33 g, 30％, brown solid) was prepared by using the same procedure as described for 15g by replacing 7-fluoro-1-methyl-1H-indole (15f) with 7- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -1H-indole (54c) . MS-ESI (m/z) : 274 [M + 1] ⁺

7- (2-chloroethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (54e)

To the suspension of 2- (3- (2-chloropyrimidin-4-yl) -1H-indol-7-yl) ethanol (54d) (50 mg, 0.18 mmol) in dry CAN (5 ml) was added dropwise thionyl chloride (0.44 mg, 0.36 mmol) at 0℃.And then the resulting mixture was stirred for overnight at r.t. The mixture was cooled to r.t, quenched with aq NaHCO₃ (20 ml) and extracted with ethyl acetate (20 mL) . The organic layers were combined and washed with water (20 mL × 2) and brine (200 mL) , dried over anhydrous sodium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum. The crude product 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 (54e) as brown solid (0.30 g, 50％) . MS-ESI (m/z) : 292 [M + 1] ⁺

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

To a solution of 7- (2-chloroethyl) -3- (2-chloropyrimidin-4-yl) -1H-indole (54e) (33 mg, 0.11 mmol) in DMF (3 ml) was added Cs₂CO₃ (78 mg, 0.22 mmol) at r.t, and then was heated to 60℃ for 10 h. The mixture was cooled to r.t, quenched with water (20 ml) and extracted with ethyl acetate (20 mL) . The organic layers were combined and washed with water (20 mL × 2) and brine (20 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum to give 5- (2-chloropyrimidin-4-yl) -1, 2-dihydropyrrolo [3, 2, 1-hi] indole (54f) as brown solid (0.30 g, 100％) . MS-ESI (m/z) : 256 [M + 1] ⁺

The title compound 54 (5.0 mg) was prepared by using the same procedure as described for 15 by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) with 5- (2-chloropyrimidin-4-yl) -1, 2-dihydropyrrolo [3, 2, 1-hi] indole (54f) . MS-ESI (m/z) : 513 [M + 1] ⁺.

Example 55

N- (5- ( (4- (1, 2-dihydropyrrolo [3, 2, 1-hi] indol-5-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethy lamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (55)

The title compound (55) was prepared according to the synthetic method of Example 54 by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15c) withN¹- (4-iodo-5-methoxy-2-nitrophenyl) -N¹, N², N²-trimethylethane-1, 2-diamine (24a) . MS-ESI (m/z) : 512 [M + 1] ⁺.

Example 56

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (3-methyl-1H-indazol- 1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (56)

3-methyl-1H-indazole (56a)

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

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

To a solution of 3-methyl-1H-indazole (56a) (1.1 g, 8.3 mmol) in dry DMF was added NaH at 0℃ while maintaining this temperature for 2 h, and then was added 2, 4-dichloropyrimidine (1.24 g, 8.3 mmol) at 0℃. The resulting mixture was stirred at r.t for overnight. The mixture was quenched with aq NH₄Cl (20 ml) and extracted with ethyl acetate (50 mL) . The organic layers were combined and washed with water (50 mL × 2) and brine (50 mL) , dried over Na₂SO₄. The solids were filtered out and the filtrate was concentrated in vacuum. The crude product 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 (56b) as white solid (0.85 g, 43％) . MS-ESI (m/z) : 245 [M + 1] ⁺

N- (5- ( (4- (4, 5-dihydropyrrolo [3, 2, 1-hi] indol-1-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethy lamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide (56)

The title compound 56 (8.0 mg) was prepared by using the same procedure as described for 15 by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) with 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indazole (56b) . MS-ESI (m/z) : 502 [M + 1] ⁺.

Example 57

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (3-methyl-1H-indazol- 1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (57)

The title compound 57 (5.0 mg) was prepared according to the synthetic method of Example 23 by replacing 3- (2-chloropyrimidin-4-yl) -1-methyl-1H-indole (1h) with 1- (2-chloropyrimidin-4-yl) -3-methyl-1H-indazole (56b) . MS-ESI (m/z) : 520 [M + 1] ⁺.

Example 58

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (1-methyl-1H-indazol- 3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (58)

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

The title compound 58a was prepared according to the synthetic method described in literature: J. Heterocyclic Chem., 2013, 50: E221.

The title compound 58 was prepared according to the synthetic method of Example 25 by replacing 1- (1-methylindolizin-3-yl) ethanone (25d) with 1- (1-methyl-1H-indazol-3-yl) ethanone (58a) . MS-ESI (m/z) : 502 [M + 1] ⁺.

Example 59

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

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N5- (4- (1-methyl-1H-indazol-3-yl) py rimidin-2-yl) -3-nitropyridine-2, 5-diamine (59a)

The compound 59a was prepared according to the synthetic method of Example 25 by replacing 1- (1-methylindolizin-3-yl) ethanone (25d) with 1- (1-methyl-1H-indazol-3-yl) ethanone (58a) . MS-ESI (m/z) : 448 [M + 1] ⁺.

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indazol-3-yl) py rimidin-2-yl) pyridine-2, 3, 5-triamine (59b)

The title compound 59b was prepared according to the synthetic method of 15i by replacing N¹- (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N¹, N², N²-trimethylethane-1, 2-diamine (15h) with N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (59a) . MS-ESI (m/z) : 447 [M + 1] ⁺.

The title compound (59) was prepared according to the synthetic method of Example 23 by replacing N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) with N²- (2- (dimethylamino) ethyl) -6-methoxy -N²-methyl-N⁵- (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (59b) . MS-ESI (m/z) : 520 [M + 1] ⁺.

Example 60

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (3-methylimidazo [1, 5- a] pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide (60)

1- (3-methylimidazo [1, 5-a] pyridin-1-yl) ethan-1-one (60a)

The title compound 60a was prepared according to the synthetic method described in literature: Journal of Chemical society., 1955, 2834.

The title compound 60 was prepared according to the synthetic method of Example 25 by replacing 1- (1-methylindolizin-3-yl) ethanone (25d) with 1- (3-methylimidazo [1, 5-a] pyridin-1-yl) ethan-1-one (60a) . MS-ESI (m/z) : 502 [M + 1] ⁺.

Example 61

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (3-methylimidazo [1, 5- a] pyridin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) -2-fluoroacrylamide (61)

N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (3-methylimidazo [1, 5-a] pyrid in-1-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (61a)

The compound 61a was prepared according to the synthetic method of Example 25 by replacing 1- (1-methylindolizin-3-yl) ethanone (25d) with 1- (3-methylimidazo [1, 5-a] pyridin-1-yl) ethan-1-one (60a) . MS-ESI (m/z) : 448 [M + 1] ⁺.

The title compound 61 was prepared according to the synthetic method of Example 23 by replacing N²- (2- (dimethylamino) ethyl) -6-methoxy-N²-methyl-N⁵- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) with N²- (2- (dimethylamino) ethyl) -6-methoxy -N²-methyl-N⁵- (4- (3-methylimidazo [1, 5-a] pyridin-1-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (61a) . MS-ESI (m/z) : 520 [M + 1] ⁺.

Cell Proliferation Assays

To investigate whether a compound is able to inhibit the activity of L858R/T790M EGFR in cells, a mechanism-based assay using H1975 cell was developed. In this assay, inhibition of L858R/T790M EGFR was detected by the inhibition of H1975 cells proliferation. H1975 cells were cultured in culture flasks to 40-80％confluence in RPMI-1640 plus 10％fetal bovine serum. Cells were collected and plated onto 96-well plates at desired cell density (3000 cells/well) . Plates were incubated overnight at 37℃, with 5％CO₂ to adhere. Compounds were added to the plates, the final compound concentrations were 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM. Place plates at 37 ℃, with 5％CO₂ for 48 h. After removing the medium, 20 μl MTS /100 μl medium mixture solution were added to each well and incubate the plates for exactly 1.5 hours. Stop the reaction by adding 25 μl 10％SDS per well. Measure absorbance at 490 nm and 650 nm (reference wavelength) . IC₅₀ was calculated using GraphPad Prism 5.0.

To investigate whether a compound is able to inhibit the activity of WT EGFR in cells, a mechanism-based assay using A431 cell was developed. In this assay, inhibition of WT EGFR was detected by the inhibition of A431 cells proliferation. A431 cells were cultured in culture flasks to 40-80％confluence in DMEM plus 10％fetal bovine serum. Cells were collected and plated onto 96-well plates at desired cell density (3000 cells/well) . Plates were incubated overnight at 37℃, with 5％CO₂ to adhere. Compounds were added to the plates, the final compound concentrations were 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM. Place plates at 37 ℃, with 5％CO₂ for 48 h. After removing the medium, 20 μl MTS /100 μl medium mixture solution were added to each well and incubate the plates for exactly 1.5 hours. Stop the reaction by adding 25 μl 10％SDS per well. Measure absorbance at 490 nm and 650 nm (reference wavelength) . IC₅₀ was calculated using GraphPad Prism 5.0.

Select compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in the table 1.

Table 1

Example	H1975 IC₅₀ (nM)	A431 IC₅₀ (nM)
Example	H1975 IC₅₀ (nM)	A431 IC₅₀ (nM)	1	112	>1000
15	156	/	1	112	>1000
15	156	/	16	193	>1000
17	128	1213	16	193	>1000
17	128	1213	18	183	/
19	76	/	18	183	/
19	76	/	20	48	/
21	69	/	20	48	/
21	69	/	23	184	/
24	219	/	23	184	/
24	219	/	25	219	>1000
27	324	>1000	25	219	>1000
27	324	>1000	32	190	>1000
36	244	1193	32	190	>1000
36	244	1193	38	183	/
41	350	/	38	183	/
41	350	/	50	476	/
51	348	/	50	476	/
51	348	/	53	452	/
54	481	/	53	452	/

Claims

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；

R¹ is selected from hydrogen, C_1-10alkyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, and heterocyclyl-C_1-4alkyl, wherein alkyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6a；

R^1’ is selected from hydrogen and halogen；

R² and R³ are independently selected from hydrogen, halogen, hydroxyl, CN, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R^6a, and each aryl and heteroaryl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6b； or R² and R³ 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, and optionally substituted with 1or 2 R^6a groups；

each R⁴ is independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, -OR⁸, -NR⁷S (O) _rR⁸, -NO₂, -halogen, -S (O) _rR⁷, -SR⁸, -S (O) ₂OR⁷, -OS (O) ₂R⁸, -S (O) _rNR⁷R⁸, -NR⁷R⁸, -O (CR⁹R¹⁰) _tNR⁷R⁸, -C (O) R⁷, -CO₂R⁸, -CO₂ (CR⁹R¹⁰) _tCONR⁷R⁸, -OC (O) R⁷, -CN, -C (O) NR⁷R⁸, -NR⁷C (O) R⁸, -OC (O) NR⁷R⁸, -NR⁷C (O) OR⁸, -NR⁷C (O) NR⁷R⁸, and -CR⁷ (N-OR⁸) , wherein C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, and C_3-10cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6a；

each R⁵ is independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, -OR⁸, -NR⁷S (O) _rR⁸, -NO₂, halogen, -S (O) _rR⁷, -SR⁸, -S (O) ₂OR⁷, -OS (O) ₂R⁸, -S (O) _rNR⁷R⁸, -NR⁷R⁸, -O (CR⁹R¹⁰) _tNR⁷R⁸, -C (O) R⁷, -CO₂R⁸, -CO₂ (CR⁹R¹⁰) _tCONR⁷R⁸, -OC (O) R⁷, -CN, -C (O) NR⁷R⁸, -NR⁷C (O) R⁸, -OC (O) NR⁷R⁸, -NR⁷C (O) OR⁸, -NR⁷C (O) NR⁷R⁸, and -CR⁷ (N-OR⁸) , wherein C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R^6a, and each aryl and heteroaryl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6b；

each R^6a is independently selected from C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, -OR⁸, -NR⁷S (O) _rR⁸, -NO₂, halogen, -S (O) _rR⁷, -SR⁸, -S (O) ₂OR⁷, -OS (O) ₂R⁸, -S (O) _rNR⁷R⁸, -NR⁷R⁸, - (CR⁹R¹⁰) _tOR⁸, - (CR⁹R¹⁰) _tNR⁷R⁸, - (CR⁹R¹⁰) _tSR⁸, - (CR⁹R¹⁰) _tS (O) _rR⁸, - (CR⁹R¹⁰) _tCO₂R⁸, - (CR⁹R¹⁰) _tCONR⁷R⁸, - (CR⁹R¹⁰) _tNR⁷CO₂R⁸, - (CR⁹R¹⁰) _tOCONR⁷R⁸, - (CR⁹R¹⁰) _tNR⁷CONR⁷R⁸, - (CR⁹R¹⁰) _tNR⁷SO₂NR⁷R⁸, -O (CR⁹R¹⁰) _tNR⁷R⁸, -C (O) R⁷, -C (O) (CR⁹R¹⁰) _tOR⁸, -C (O) (CR⁹R¹⁰) _tNR⁷R⁸, -C (O) (CR⁹R¹⁰) _tSR⁸, -C (O) (CR⁹R¹⁰) _tS (O) _rR⁸, -CO₂R⁸, -CO₂ (CR⁹R¹⁰) _tCONR⁷R⁸, -OC (O) R⁷, -CN, -C (O) NR⁷R⁸, -NR⁷C (O) R⁸, -OC (O) NR⁷R⁸, -NR⁷C (O) OR⁸, -NR⁷C (O) NR⁷R⁸, and -CR⁷ (N-OR⁸) ；

each R^6b is independently selected from R^6a, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl；

each R⁷ and each R⁸ are independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, cycloalkyl, cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R^6a, and aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R^6b； or R⁷ and R⁸ together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1or 2 R^6b groups；

each R⁹ and each R¹⁰ are independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, cycloalkyl, cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl； or R⁹ and R¹⁰ together with the carbon atom (s) to which they are attached form a ring of 3 to 7 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1or 2 R^6a groups；

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.
At least one compound of claim 1 and/or at least one pharmaceutically acceptable salt thereof, wherein X is selected from N and C, and Y is C.
At least one compound of any one of claims 1 to 2 and/or at least one pharmaceutically acceptable salt thereof, wherein X is N, and Y is C.
At least one compound of any one of claims 1 to 2 and/or at least one pharmaceutically acceptable salt thereof, wherein when both X and Y are C, and,

n ＝ 2, one R⁵ is (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl] - (methyl) amino,

[2- (methylamino) ethyl] (methyl) amino, 5-methyl-2, 5-diazaspiro [3.4] oct-2-yl,

(3aR, 6aR) -5-methylhexa-hydro-pyrrolo [3, 4-b] pyrrol-1 (2H) -yl,

1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl, 4-methylpiperizin-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-aminopropanoyl] piperazin-1-yl, the other R⁵ is methoxy or methyl, and,

R¹, R^1’ and R² are hydrogen, and R³ is H, F, Cl, CH₃ or CN,

Q is not 4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyridine-3-yl, pyrazolo [1, 5-a] pyridin-3-yl or 1H-indol-3-yl.
At least one compound of any one of claims 1 to 4 and/or at least one pharmaceutically acceptable salt thereof, wherein the formula is
At least one compound of any one of claims 1 to 5 and/or at least one pharmaceutically acceptable salt thereof, wherein R^1’ is hydrogen.
At least one compound of any one of claims 1 to 5 and/or at least one pharmaceutically acceptable salt thereof, wherein R^1’ is selected from halogen, preferably R^1’ is fluorine.
At least one compound of any one of claims 1 to 7 and/or at least one pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen.
At least one compound of any one of claims 1 to 8 and/or at least one pharmaceutically acceptable salt thereof, wherein R² is hydrogen.
At least one compound of any one of claims 1 to 9 and/or at least one pharmaceutically acceptable salt thereof, wherein R³ is selected from hydrogen, halogen, and C_1-10 alkyl.
At least one compound of claim 10 and/or at least one pharmaceutically acceptable salt thereof, wherein R³ is hydrogen.
At least one compound of any one of claims 1 to 11 and/or at least one pharmaceutically acceptable salt thereof, wherein Q is selected from heteroaryl.
At least one compound of claim 12 and/or at least one pharmaceutically acceptable salt thereof, wherein Q is selected from
At least one compound of any one of claims 1 to 13 and/or at least one pharmaceutically acceptable salt thereof, wherein R⁴ is selected from hydrogen, C_1-10alkyl, halogen and CN, wherein C_1-10alkyl are unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6a.
At least one compound of claim 14 and/or at least one pharmaceutically acceptable salt thereof, wherein R⁴ is selected from hydrogen, methyl, halogen and CN, wherein methyl are unsubstituted or substituted with at least one substituent independently selected from R^6a, preferably R^6a is fluorine.
At least one compound of any one of claims 1 to 15 and/or at least one pharmaceutically acceptable salt thereof, wherein R⁵ is independently selected from OR⁸, heterocyclyl, NR⁷R⁸, wherein heterocyclyl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^6a.
At least one compound of claim 16 and/or at least one pharmaceutically acceptable salt thereof, wherein R⁵ is 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) .
At least one compound, selected from

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

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

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

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

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

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

N- (6-isopropoxy-2- (methyl (2- (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-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-methylpiperazin-1-yl) pyridin-3-yl) acrylamide,

N- (6-ethoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide,

N- (6-ethoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) pyridin-3-yl) acrylamide,

N- (6-isopropoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide,

N- (6-isopropoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-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-in dol-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-methylindolizin-3-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,

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

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

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

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

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

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

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

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxy-5- ( (4- (3-methylindolizin-1-yl) pyrimidin-2-yl) amino) pyridin-3-yl) acrylamide,

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

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

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

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

N- (2- ( (2- (dimethylamino) ethyl) (methyl) amino) -5- ( (4- (indolizin-1-yl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide,

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

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

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

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

N- (6-methoxy-5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1 -yl) pyridin-3-yl) acrylamide,

N- (4-methoxy-5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1 -yl) phenyl) acrylamide,

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

N- (5- ( (4- (3-cyano-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,

N- (5- ( (4- (1-chloroimidazo [1, 5-a] 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) imidaz o [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) imidaz o [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide,

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

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

N- (5- ( (4- (1, 2-dihydropyrrolo [3, 2, 1-hi] indol-5-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (methyl) amino) -6-methoxypyridin-3-yl) acrylamide,

N- (5- ( (4- (1, 2-dihydropyrrolo [3, 2, 1-hi] indol-5-yl) pyrimidin-2-yl) amino) -2- ( (2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide,

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

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

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

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

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

and pharmaceutically acceptable salts thereof.
A pharmaceutical composition, comprising at least one compound of claims 1 to 18, and/or at least one pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
A method for modulating EGFR mutant, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of claims 1 to 18, and/or at least one pharmaceutically acceptable salt thereof , or at least one pharmaceutical composition thereof.
A method to treat, ameliorate or prevent a condition, which responds to inhibition of EGFR mutant, comprising administering to a subject in need of such treatment an effective amount of at least one compound of claims 1 to 18, and/or at least one pharmaceutically acceptable salt thereof, or of at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
A method for making a medicament for treating a condition, which responds to inhibition of EGFR mutant, comprising including to the medicament at least one compound of claims 1 to 18, and/or at least one pharmaceutically acceptable salt thereof.
A method for treating a cell proliferative disorder, comprising administering to a subject in need of such treatment an effective amount of at least one compound of claims 1 to 18, and/or at least one pharmaceutically acceptable salt thereof or of at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
A method for making a medicament for treating a cell-proliferative disorder, comprising including in the medicament at least one compound of claims 1 to 18, and/or at least one pharmaceutically acceptable salt thereof.