WO2017097113A1 - Aminopyrimidine compounds for inhibiting acitivity of protein tyrosine kinase - Google Patents

Abstract

The present invention relates to aminopyrimidine compounds capable of inhibiting the activity of protein tyrosine kinase, and to preparation and uses thereof. Specifically, disclosed are an aminopyrimidine compound shown in Formula (I), and a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a crystal form, a prodrug, or an isotope-variant medicine composition, comprising the compound. The compound in the present invention can be used for treating and/or preventing protein tyrosine kinase related diseases such as cell proliferative diseases, cancers, and immune diseases.

Description

Aminopyrimidine compound for inhibiting protein tyrosine kinase activity Technical field

The invention belongs to the field of medicine. Specifically, the present invention relates to aminopyrimidine compounds having an inhibitory effect on protein tyrosine kinase activity, pharmaceutical compositions containing the same, and methods for their preparation and use. More particularly, the present invention relates to aminopyrimidines for use in the treatment of diseases associated with dysregulation of metabolic pathways of protein tyrosine kinases such as, but not limited to, EGFR (including HER), ALK, PDGFR, such as tumors and related diseases, and Its pharmaceutical composition and method of use.

Background technique

Protein tyrosine kinase (PTK) is a class of kinases that catalyze the transfer of γ-phosphate on ATP to protein tyrosine residues, which catalyzes the phosphorylation of tyrosine residues in a variety of substrate proteins. It plays an important role in cell growth, proliferation and differentiation. Because protein tyrosine kinases have a profound effect on cells, their activity is highly regulated. Kinases are turned on or off by phosphorylation (sometimes by autophosphorylation), by binding to activators, inhibitory proteins or small molecules, or by controlling their localization in cells. Dysfunctions of kinase activity are currently known to be associated with a variety of diseases caused by genetic abnormalities or environmental factors. Some serious pathological conditions, including cancer and chronic inflammation, are associated with intracellular signal stimulation, and because kinases actively transmit signals, their inhibition provides a powerful pathway to inhibit or control the signal transduction cascade.

Protein tyrosine kinases can be classified into non-receptor type and membrane receptor type depending on whether they are present in the cell membrane receptor. Non-receptor tyrosine kinase (nrRTK) is represented by Src, in addition to Yes, Fyn, Lck, Fgr, Lyn, Fps/Fes and Ab1. Receptor tyrosine kinases (RTKs) can be divided into 9 types according to their structures. Among them, the following four types are commonly used: epidermal growth factor receptor (EGFR) family, insulin receptor family, PDGF. /MCSF/SCF receptor family, and the fibroblast growth factor receptor (FGFR) family.

The epidermal growth factor receptor (human EGFR; ErbB-1; HER1) is a member of the ErbB receptor family, and the ErbB receptor family is the four closely related receptor tyrosine kinase EGFR (ErbB-1), HER2/c - NEU (ErbB-2), a subfamily of HER 3 (ErbB-3) and HER 4 (ErbB-4). EGFR is a cell surface receptor for members of the epidermal growth factor family (EGF family) of the extracellular protein ligand. Mutations that affect EGFR expression or activity may result in cancer. It has been reported that EGFR is in an dysregulated state in most solid tumors such as lung cancer, breast cancer and brain tumors. It is estimated that 30% of epithelial cancers are associated with mutations, amplification or dysregulation of EGFR or family members.

A receptor tyrosine kinase inhibitor (RTKI) is an inhibitor of a receptor tyrosine kinase. The inhibitor is usually a small molecule compound that is reactive (reversible or irreversible) to the receptor tyrosine kinase. Inhibition, blocking the activation of intracellular regions after binding of cell surface receptors to ligands, thereby inhibiting the final biological effects of signal transduction pathways.

In recent years, the field of research on receptor tyrosine kinase inhibitors has attracted much attention. The first generation of receptor tyrosine kinase inhibitors are single-target tyrosine kinase inhibitors, such as gefitinib, erlotinib and the like. Gefitinib is an EGFR tyrosine kinase inhibitor, mainly used for non-small cell lung cancer (NSCLC), and has an efficiency of more than 80% for tyrosine kinase gene coding region mutant tumors. Erlotinib is an EGFR tyrosine kinase inhibitor, and the drug is effective in about 10% of patients with relapsed non-small cell lung cancer.

However, acquired resistance to gefitinib or erlotinib has become a major clinical problem after a period of treatment. Studies have shown that a major cause of drug resistance is due to the T790M mutation, which is the "gatekeeper" of EGFR. Then, developed the T790M Second-generation receptor tyrosine kinase inhibitors, such as afatinib, are irreversible inhibitors of EGFR and show advantages in clinical trials. Although these inhibitors potently inhibit the T790M mutation, they also inhibit wild-type EGFR (WT EGFR), which has serious side effects, which limits clinical applications.

Third-generation and subsequent EGFR inhibitors, including compounds such as AZD9291 and CO-1686, irreversibly inhibit EGFR, and are still more effective in patients with T790M-resistant mutations, but also have an inhibitory effect on wild-type EGFR.

Therefore, it is necessary to further develop new EGFR inhibitors that not only effectively inhibit the T790M mutation, but also have high selectivity for the T790M mutation relative to the wild type.

Summary of the invention

The present invention provides a new class of EGFR inhibitors that have better pharmacodynamic/pharmacokinetic properties and are more selective for the T790M mutation, the L858R mutation, and the L858R/T790M double mutation.

Thus, in one aspect, the invention provides a compound of formula (I):

among them,

R _{1 is} independently selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

R _{2 is} independently selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

Linker L is selected from

1) C, N, O or S atoms, as long as valency allows; wherein C and N may be optionally substituted with R ^a;

2) C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, C _3-10 carbocyclylene, 3 to 10 membered heterocyclylene, C _6-14 aroma Or a C _5-10 heteroarylene; wherein the group is optionally substituted with one or more R ^a ;

3) -C (= O) - , - C (= O) O -, - C (= O) N (R b) -, - N (R b) C (= O) -, - N (R b C(=O)O-, -N(R ^b )C(=O)N(R ^b )-, -N(R ^b )S(=O)-, -N(R ^b )S(=O ₂ -, -OC(=O)-, -OC(=O)N(R ^b )-, -OS(=O)-, -OS(=O) ₂ -, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ O- or -S(=O) ₂ N(R ^b )-;

R ^{a is} selected from H, halogen, -CN, -NO ₂ , oxo, C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy;

R ^b is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

X is selected from C or N atoms as long as the valence bond permits;

Ring A is selected from a C _3-6 carbocyclic group, a 3 to 10 membered heterocyclic group, a C _6-14 aryl group or a C _5-10 heteroaryl group;

R ₃ is selected from ^{_{halogen, -CN, -NO 2, -R c}} , -C (= O) R c, -C (= O) OR c, -C (= O) N (R c) (R c) , -N(R ^c )(R ^c ), -N(R ^c )C(=O)R ^c , -N(R ^c )C(=O)OR ^c , -N(R ^c )C(=O N(R ^c )(R ^c ), -N(R ^c )S(=O)R ^c , -N(R ^c )S(=O)N(R ^c )(R ^c ), -N(R ^c ) S(=O) ₂ R ^c , -N(R ^c )S(=O) ₂ N(R ^c )(R ^c ), -OR ^c , -OC(=O)R ^c , -OC(= O) OR ^c , -OC(=O)N(R ^c )(R ^c ), -S(=O)R ^c , -S(=O)OR ^c , -S(=O)N(R ^c ) (R ^c ), -S(=O) ₂ R ^c , -S(=O) ₂ OR ^c , -S(=O) ₂ N(R ^c )(R ^c ), -SC(=O)R ^c , -SC(=O)OR ^c or -SC(=O)N(R ^c )(R ^c ), as long as chemically permits;

R ^{c is} selected from the group consisting of H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl a 3- to 10-membered heterocyclic group, a C _6-14 aryl group or a C _5-10 heteroaryl group; wherein the C _3-10 carbocyclic group, a 3 to 10 membered heterocyclic group, a C _6-14 aryl group or The C _5-10 heteroaryl group is also optionally substituted by C _1-6 alkyl, C _1-6 haloalkyl or -C(=O)C _1-6 alkyl;

m is 0, 1 or 2;

n is 1, 2 or 3;

p represents a single bond or a double bond, as long as the valence is allowed;

q represents a single bond or a double bond, as long as the valence is allowed;

R ₄ , R ₅ and R _{6 are} independently selected from H, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl;

W is selected from N, O or S atom, where N may optionally be substituted with R ^a;

The premise is that when m is 0, X is a C atom;

Or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In a particular embodiment, a compound of the invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compounds of the invention are provided in a therapeutically effective amount. In a particular embodiment, the compounds of the invention are provided in a prophylactically effective amount.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.

In another aspect, the invention provides a compound, a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a crystal form, a prodrug or an isotopic variant thereof, and other therapeutic agents, and a pharmaceutically acceptable compound, A kit of acceptable carriers, adjuvants or vehicles.

In another aspect, the invention provides a method of treating cancer caused by EGFR (including cancer caused by EGFR mutation, eg, a cancer with a T790M mutation, a L858R mutation, and a L858R/T790M double mutation) in a subject in need thereof A method comprising: administering to a subject an effective amount of a compound of the invention. In a specific embodiment, the EGFR-induced cancer is selected from the group consisting of: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cancer, Gastrointestinal stromal tumors, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, etc. In a specific embodiment, the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the <RTIgt;

definition

Chemical definition

The definitions of specific functional groups and chemical terms are described in more detail below.

When a range of values is recited, each value and sub-range within the range are intended to be included. For example, "C _1-6 alkyl" includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1 -2} , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and C _{5 -6} alkyl.

It will be understood that any of the moieties defined below may be substituted by a number of substituents, as described herein, and the corresponding definitions are within the scope of their inclusion, including such substitutions. Unless otherwise stated, the term "substituted" is as defined below.

"C _1-6 alkyl" refers to a straight or branched saturated hydrocarbon group having from 1 to 6 carbon atoms, also referred to herein as "lower alkyl." In some embodiments, a C _1-4 alkyl group is particularly preferred. Examples of the alkyl group include, but are not limited to, methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), uncle Butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butyl (C ₅ ), tert-amyl (C ₅ ) and n-hexyl (C ₆ ). Unless otherwise stated, each alkyl group is independently optionally substituted, ie, unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl") For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. In some embodiments, the alkyl group is unsubstituted C _1-6 alkyl group (e.g., -CH _3). In some embodiments, the alkyl group is a substituted _C1-6 alkyl group.

"C _2-6 alkenyl" means a straight or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon double bonds (eg, 1, 2 or 3 carbon-carbon double bonds) . One or more carbon-carbon double bonds may be internal (eg, in 2-butenyl) or end (eg, in 1-butenyl). In some embodiments, _C2-4 alkenyl is particularly preferred. Examples of the alkenyl group include, but are not limited to, vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butene A group (C ₄ ), a butadienyl group (C ₄ ), a pentenyl group (C ₅ ), a pentadienyl group (C ₅ ), a hexenyl group (C ₆ ), and the like. Unless otherwise specified, each of the alkenyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl") For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. In some embodiments, an alkenyl group is an unsubstituted C _2-6 alkenyl group. In some embodiments, an alkenyl group is a substituted C _2-6 alkenyl group.

"C _2-6 alkynyl group" refers to one or more carbon having 2 to 6 carbon atoms, - carbon triple bonds (e.g., 1, 2 or 3 carbon - carbon triple bonds), and optionally one or more carbon a linear or branched hydrocarbon group of a carbon double bond (for example, 1, 2 or 3 carbon-carbon double bonds). In some embodiments, a _C2-4 alkynyl group is particularly preferred. In some embodiments, an alkynyl group does not contain any double bonds. The one or more carbon oxime bonds may be internal (eg, in 2-butynyl) or end (eg, in 1-butynyl). Examples of the alkynyl group include, but are not limited to, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2- Butynyl (C ₄ ), pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Unless otherwise stated, each of the alkynyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl") For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. In some embodiments, an alkynyl group is an unsubstituted C _2-6 alkynyl group. In some embodiments, an alkynyl group is a substituted C _2-6 alkynyl group.

As used herein, "alkylene", "alkenylene" and "alkynylene" refer to the divalent groups of the above alkyl, alkenyl and alkynyl groups, respectively. When specific "alkylene", "alkenylene" and "alkynylene" provide the range or number of carbons, it is to be understood that the range or number refers to the range of carbon in the linear divalent carbon chain or number. "Alkylene", "alkenylene" and "alkynylene" may be substituted by one or more substituents as described herein, or may be unsubstituted.

The "C _1-6 alkylene group" means a hydrogen atom which removes a C _1-6 alkyl group to form a divalent alkylene group, and may be a substituted or unsubstituted alkylene group. In some embodiments, C _1-4 alkylene is particularly preferred. Unsubstituted alkylene groups include, but the are not limited to: methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene _{(-CH 2 CH 2 CH 2 -} ), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) ,and many more. Exemplary substituted alkylene groups, for example, the alkylene groups substituted with one or more alkyl groups (methyl groups) include, but are not limited to, substituted methylene groups (-CH(CH ₃ )- , -C(CH ₃ ) ₂ -), substituted ethylene (-CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) _2- ), substituted propylene (-CH(CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH ₂ CH(CH ₃ ) -, -C(CH ₃ ) ₂ CH ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH ₂ C(CH ₃ ) ₂ -), and the like.

The "C _2-6 alkenylene group" means a hydrogen atom which removes a C _2-6 alkenyl group to form a divalent alkenylene group, and may be a substituted or unsubstituted alkenylene group. In some embodiments, _C2-4 alkenylene is particularly preferred. Exemplary unsubstituted alkenyl groups include the alkylene but are not limited to: ethenylene (-CH = CH-) and propenylene _{(e.g., -CH = CHCH 2 -, -} CH 2 -CH = CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted ethylene groups (-C(CH ₃ )=CH- , -CH=C(CH ₃ )-), substituted propenylene (-C(CH ₃ )=CHCH ₂ -, -CH=C(CH ₃ )CH ₂ -, -CH=CHCH(CH ₃ )- , -CH=CHC(CH ₃ ) ₂ -, -CH(CH ₃ )-CH=CH-, -C(CH ₃ ) ₂ -CH=CH-, -CH ₂ -C(CH ₃ )=CH-, -CH ₂ -CH=C(CH ₃ )-), and so on.

The "C _2-6 alkynylene group" means a hydrogen atom which removes a C _2-6 alkynyl group to form a divalent alkynylene group, and may be a substituted or unsubstituted alkynylene group. In some embodiments, a _C2-4 alkynylene group is particularly preferred. Exemplary of the alkylene groups include, but are not limited to alkynyl: ethynylene (-C = C-), a substituted or unsubstituted alkylene group propynyl (-C = CCH ₂ -), and the like.

"C _1-6 alkoxy" refers to the group -OR wherein R is a substituted or unsubstituted C _1-6 alkyl group. In some embodiments, a C _1-4 alkoxy group is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, N-Hexyloxy and 1,2-dimethylbutoxy.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halo group is F, Cl or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

Thus, "C _1-6 haloalkyl" and "C _1-6 haloalkoxy" mean the above-mentioned "C _1-6 alkyl" and "C _1-6 alkoxy" which are bonded to one or more halogen groups. Replaced by the regiment. In some embodiments, a C _1-4 haloalkyl group is particularly preferred, more preferably a C _1-2 haloalkyl group. In some embodiments, a C _1-4 haloalkoxy group is particularly preferred, more preferably a C _1-2 haloalkoxy group. Exemplary haloalkyl groups include, but the are not limited _{to: -CF 3, -CH 2 F,} -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl ₂ , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. Exemplary haloalkoxy groups include, but are not limited to, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , and the like.

"C _3-10 carbocyclyl" refers to a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, a C _3-6 carbocyclyl group is particularly preferred, more preferably a C _5-6 carbocyclic group. Carbocyclyl also includes ring systems wherein the above carbocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to be represented The number of carbons in the carbocyclic system. Exemplary such carbocyclic groups include, but are not limited to, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl ( C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptene (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo [2.2.1] Heptyl (C ₇ ), bicyclo [2.2.2] octyl (C ₈ ), cyclodecyl (C ₉ ), cyclodecenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthyl (C ₁₀ ), spiro[4.5]decyl (C ₁₀ ), and the like. Unless otherwise specified, each of the carbocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclic ring"base"). In some embodiments, the carbocyclic group is an unsubstituted C _3-10 carbocyclic group. In some embodiments, a carbocyclic group is a substituted C _3-10 carbocyclic group.

"3 to 10 membered heterocyclic group" or a group of a 3 to 10 membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring hetero atoms, wherein each hetero atom is independently selected from nitrogen and oxygen. , sulfur, boron, phosphorus and silicon. In the heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. In some embodiments, a 3- to 6-membered heterocyclic group is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclic ring. a group which is a 5 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring hetero atoms. Unless otherwise stated, each of the heterocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heterocyclic") or substituted with one or more substituents ("substituted hetero Ring base"). In some embodiments, the heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In some embodiments, a heterocyclic group is a substituted 3-10 membered heterocyclyl. The heterocyclic group further includes a ring system in which the above heterocyclic ring is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic ring, or wherein the above heterocyclic ring is bonded to one or more aryl groups or A heteroaryl fused ring system wherein the point of attachment is on a heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclic groups containing one hetero atom include, but are not limited to, aziridine, oxacyclopropane, thiorenyl. Exemplary 4-membered heterocyclic groups containing one hetero atom include, but are not limited to, azetidinyl, oxetanyl and thietane. Exemplary 5-membered heterocyclic groups containing one hetero atom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxalanyl, oxasulfuranyl, disulfuranyl, and Azolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolyl, and thiadiazolyl. Exemplary 6-membered heterocyclic groups containing one hetero atom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxoalkyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one hetero atom include, but are not limited to, azepanyl, oxaheptyl, and thiaheptanyl. Exemplary 8-membered heterocyclic groups containing one hetero atom include, but are not limited to, azacyclooctyl, oxacyclooctyl, and thicyclooctyl. Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclyl) fused to a _C6 aryl ring include, but are not limited to, indanyl, isoindoline , dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups fused to a C ₆ aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and many more.

"C _6-14 aryl" refers to 4n + 2 aromatic mono- or polycyclic ring system having 6 to 14 ring carbon atoms and zero heteroatoms (e.g., bicyclic or tricyclic) (e.g., having A group of 6, 10 or 14 π electrons shared in a ring. In some embodiments, an aryl group having six ring carbon atoms ( "C ₆ aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (" _C10 aryl"; for example, naphthyl, eg, 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (" _C14 aryl"; for example, fluorenyl). In some embodiments, a C _6-10 aryl group is particularly preferred, more preferably a C ₆ aryl group. The aryl group also includes a ring system in which the above aryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to be represented. The number of carbon atoms in the aryl ring system. Unless otherwise stated, each of the aryl groups is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl group is an unsubstituted C _6-14 aryl group. In some embodiments, the aryl group is a substituted C _6-14 aryl group.

"C _{5-10heteroaryl} " refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (eg, having a shared arrangement in a ring arrangement) a group of 6 or 10 π electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems wherein the above heteroaryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case a carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, C _5-6 heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n + 2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Unless otherwise stated, each of the heteroaryl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"base"). In some embodiments, the heteroaryl is an unsubstituted 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a substituted 5-10 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .

As used herein, "carbocyclylene", "heterocyclylene", "arylene" and "heteroarylene" refer to the above-mentioned carbocyclic, heterocyclic, aryl and heteroaryl, respectively. A valency group which removes a hydrogen atom from the group at any possible position to obtain a divalent group. "Carbocyclylene", "heterocyclylene", "arylene" and "heteroarylene" may be substituted by one or more substituents as described herein, or unsubstituted. Exemplary unsubstituted "carbocyclylene", "heterocyclylene", "arylene" and "heteroarylene" include, but are not limited to, the following groups:

Wherein Z represents an O, N or S atom.

"Oxo group" means =0.

Other definitions

The term "pharmaceutically acceptable salt" means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino and inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method. Other pharmaceutically acceptable salts include: adipic acid salts, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin ester, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Further pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.

"Subjects" for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "person," "patient," and "subject" are used interchangeably herein.

"Disease," "disorder," and "disorder" are used interchangeably herein.

The term "treatment" as used herein, unless otherwise indicated, includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or condition ("prophylactic treatment").

Generally, an "effective amount" of a compound refers to an amount sufficient to cause a target biological response. As will be understood by one of ordinary skill in the art, an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.

Unless otherwise indicated, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. Delay or minimize. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.

A "prophylactically effective amount" of a compound, as used herein, is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.

"Combination" and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention. For example, a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.

"Cancer-induced cancer" refers to a cancer characterized by an unsuitable high expression of the EGFR gene or a mutation of the EGFR gene that alters the biological activity of the EGFR nucleic acid molecule or polypeptide. Cancers caused by EGFR can occur in any tissue including brain, blood, connective tissue, liver, mouth, muscle, spleen, stomach, testes, and trachea. Cancers caused by EGFR include, but are not limited to, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia , tissue cell lymphoma, nasopharyngeal cancer.

An "EGFR mutation" or "EGFR mutant" includes one or more deletions, substitutions or additions in the amino acid or nucleotide sequence of the EGFR protein or EGFR coding sequence. The EGFR mutation may also include one or more deletions, substitutions or additions, or fragments thereof, so long as the mutant retains or increases tyrosine kinase activity relative to wild-type EGFR. In a particular EGFR mutation, the kinase or phosphorylation activity can be increased or decreased relative to wild-type EGFR (eg, at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70). %, 80%, 90% or even 100%). Exemplary EGFR mutations include, but are not limited to, the T790M mutation, the L858R mutation, and the L858R/T790M double mutation.

detailed description

Compound

Herein, the "compound of the present invention" means a compound of the formula (I) - a compound of the formula (VI) (including a subset of each formula, for example, a compound of the formula (VIf) and a compound of the formula (VIf-1)), a pharmaceutically thereof thereof An acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation.

In one embodiment, the invention relates to a compound of formula (I):

among them,

R _{1 is} independently selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

R _{2 is} independently selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

Linker L is selected from

1) C, N, O or S atoms, as long as valency allows; wherein C and N may be optionally substituted with R ^a;

2) C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, C _3-10 carbocyclylene, 3 to 10 membered heterocyclylene, C _6-14 aroma Or a C _5-10 heteroarylene; wherein the group is optionally substituted with one or more R ^a ;

3) -C(=O)-, -C(=O)O-, -C(=O)N(R ^b )-, -N(R ^b )C(=O)-, -N(R ^b C(=O)O-, -N(R ^b )C(=O)N(R ^b )-, -N(R ^b )S(=O)-, -N(R ^b )S(=O ₂ -, -OC(=O)-, -OC(=O)N(R ^b )-, -OS(=O)-, -OS(=O) ₂ -, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ O- or -S(=O) ₂ N(R ^b )-;

R ^{a is} selected from H, halogen, -CN, -NO ₂ , oxo, C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy;

R ^{b is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

X is selected from C or N atoms as long as the valence bond permits;

Ring A is selected from a C _3-6 carbocyclic group, a 3 to 10 membered heterocyclic group, a C _6-14 aryl group or a C _5-10 heteroaryl group;

R _{3 is} selected from the group consisting of halogen, -CN, -NO ₂ , -R ^c , -C(=O)R ^c , -C(=O)OR ^c , -C(=O)N(R ^c )(R ^c ) , -N(R ^c )(R ^c ), -N(R ^c )C(=O)R ^c , -N(R ^c )C(=O)OR ^c , -N(R ^c )C(=O N(R ^c )(R ^c ), -N(R ^c )S(=O)R ^c , -N(R ^c )S(=O)N(R ^c )(R ^c ), -N(R ^c ) S(=O) ₂ R ^c , -N(R ^c )S(=O) ₂ N(R ^c )(R ^c ), -OR ^c , -OC(=O)R ^c , -OC(= O) OR ^c , -OC(=O)N(R ^c )(R ^c ), -S(=O)R ^c , -S(=O)OR ^c , -S(=O)N(R ^c ) (R ^c ), -S(=O) ₂ R ^c , -S(=O) ₂ OR ^c , -S(=O) ₂ N(R ^c )(R ^c ), -SC(=O)R ^c , -SC(=O)OR ^c or -SC(=O)N(R ^c )(R ^c ), as long as chemically permits;

R ^{c is} selected from the group consisting of H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl a 3- to 10-membered heterocyclic group, a C _6-14 aryl group or a C _5-10 heteroaryl group; wherein the C _3-10 carbocyclic group, a 3 to 10 membered heterocyclic group, a C _6-14 aryl group or The C _5-10 heteroaryl group is also optionally substituted by C _1-6 alkyl, C _1-6 haloalkyl or -C(=O)C _1-6 alkyl;

m is 0, 1 or 2;

n is 1, 2 or 3;

p represents a single bond or a double bond, as long as the valence is allowed;

q represents a single bond or a double bond, as long as the valence is allowed;

R ₄ , R ₅ and R _{6 are} independently selected from H, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl;

W is selected from N, O or S atom, where N may optionally be substituted with R ^a;

The premise is that when m is 0, X is a C atom;

Or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof.

Preferably, in this embodiment, R _{1 is} independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy. More preferably, R _{1 is} independently selected from halogen, C _1-6 alkoxy or C _1-6 haloalkoxy. More preferably, R ₁ is C _1-6 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n Pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy. More preferably, R ₁ is a C _1-4 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and sec-butoxy. More preferably, R ₁ is a halogen such as Cl or Br. More preferably, R ₁ is Cl or methoxy. Most preferably, R ₁ is methoxy.

Preferably, in this embodiment, R _{2 is} independently selected from halogen, C _1-6 alkyl or C _1-6 haloalkyl. More preferably, R ₂ is a C _1-6 haloalkyl group. More preferably, R ₂ is C _1-4 haloalkyl. More preferably, R ₂ is C _1-2 haloalkyl, for example _{-CF 3, -CH 2 F, -CHF} 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, - CH ₂ Cl and -CHCl ₂ . Most preferably, R ₂ is -CF ₃ .

Preferably, in this embodiment, L is selected from: 1) C, N or O atoms; optionally substituted with R ^a; 2) C _1-6 alkylene, C _3-10 alkylene carbocyclic group, 3 To a 10-membered heterocyclylene group, a C _6-14 arylene group or a C _5-10 heteroarylene group, more preferably a C _1-6 alkylene group, a C _3-10 carbocyclic group or a 3 to 10 member a heterocyclylene group, more preferably a 3- to 10-membered heterocyclylene group, more preferably a 3- to 6-membered heterocyclylene group, more preferably a 5- to 6-membered heterocyclylene group; optionally R ^Ra substituted; 3) -C (= O) -, - C (= O) O -, - C (= O) N (R b) -, - N (R b) C (= O) -, - N ( R ^b )S(=O) ₂ -, -OC(=O)-, -OS(=O)-, -OS(=O) ₂ -, -S(=O)- or -S(=O) ₂ -, more preferably, -C(=O)-, -C(=O)O-, -C(=O)N(R ^b )-, -N(R ^b )C(=O)- or -OC(=O)-, more preferably, -C(=O)-, -C(=O)O- or -OC(=O)-, most preferably, -C(=O)-.

Preferably, in this embodiment, R ^a is selected from H, halogen, -CN, oxo, C _1-6 alkyl or C _1-6 haloalkyl. More preferably, R ^a is selected from H, halogen or oxo group. Most preferably, R ^a is H.

Preferably, in this embodiment, R ^{b is} selected from H or C _1-6 alkyl. More preferably, R ^{b is} selected from H or C _1-4 alkyl.

Preferably, in this embodiment, Ring A is selected from a C _3-6 carbocyclic group or a 3 to 10 membered heterocyclic group. More preferably, Ring A is selected from a C _5-6 carbocyclic group or a 3 to 6 membered heterocyclic group. Most preferably, Ring A is a 5- to 6-membered heterocyclic group.

Preferably, in this embodiment, R3 is selected from ^{_{halogen, -CN, -NO 2, -R c}} , -C (= O) R c, -C (= O) OR c, -C (= O) N (R ^c )(R ^c ), -N(R ^c )(R ^c ), -N(R ^c )C(=O)R ^c , -N(R ^c )S(=O)R ^c , -N (R ^c )S(=O) ₂ R ^c , -OR ^c , -OC(=O)R ^c or -S(=O) ₂ R ^c as long as it is chemically acceptable. More preferably, R _{3 is} selected from -R ^c , -C(=O)R ^c , -C(=O)OR ^c , -C(=O)N(R ^c )(R ^c ) or -S(= O) ₂ R ^c as long as the chemical allows.

Preferably, in this embodiment, R ^{c is} selected from the group consisting of H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, 3 to 10 membered heterocyclic. More preferably, R ^{c is} selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, 5- to 6-membered heterocyclic. In a preferred embodiment, the heterocyclic group in R ^c is optionally substituted by C _1-6 alkyl, C _1-6 haloalkyl or -C(=O)C _1-6 alkyl. In a preferred embodiment, the heterocyclic group in R ^c is optionally substituted by -C(=O)C _1-6 alkyl.

Preferably, in this embodiment, m is 0 or 1. In a preferred embodiment, m is zero. In another preferred embodiment, m is one.

Preferably, in this embodiment, n is 1 or 2. More preferably, n is 1.

Preferably, in this embodiment, both p and q represent a single bond. In a preferred embodiment, p represents a single bond and q represents a double bond. In another preferred embodiment, p represents a double bond and q represents a single bond.

Preferably, in this embodiment, R ₄ , R ₅ and R _{6 are} independently selected from the group consisting of H, halogen, -CN, C _1-6 alkyl. More preferably, R ₄ , R ₅ and R ₆ are both H.

Preferably, in this embodiment, W is selected from N or O atoms.

In another embodiment, the invention relates to compounds of formula (IIa)-(IIe):

Wherein Y is selected from C, N, O or S atoms, and R _{1 -} R ₆ , X, W, A, n and q are as defined above.

In another embodiment, the invention relates to compounds of formula (IIIa)-(IIIf):

Wherein Y is selected from C, N, O or S atoms, and R _{1 -} R ₆ , R ^a , X, W, A, n, p and q are as defined above.

In another embodiment, the invention relates to compounds of formula (IVa)-(IVo):

Wherein Y is selected from C, N, O or S atoms, and R _{1 -} R ₆ , R ^a , X, W, A, n, p and q are as defined above.

In another embodiment, the invention relates to a compound of formula (Va)-(Vo):

Wherein Y is selected from C, N, O or S atoms, o is 0, ₁ , 2 or 3, and R _{1 -} R ₆ , R ^a , X, W, A, n and q are as defined above.

In another embodiment, the invention relates to compounds of formula (VIa)-(VIf):

Wherein Y is selected from C, N, O or S atoms, and R _{1 -} R ₆ , W, A, n and q are as defined above.

In a more specific embodiment, the invention relates to a compound of the formula:

Wherein R ₁ is Cl or methoxy, W is -O- or -NH-, and R ₃ and n are as defined above.

The compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included. The isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.

The invention also includes all suitable isotopic variations of the compounds of the invention. An isotopic variation of a compound of the invention is defined as wherein at least one atom is replaced by an atom having the same atomic number but differing in atomic mass from the atomic mass typically found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, respectively. ¹⁸ F, ³¹ P, ³² p, ³⁵ S and ³⁶ Cl. Some isotopic variations of the compounds of the invention, such as those in which a radioisotope such as ³ H or ¹⁴ C is incorporated, are useful in drug and/or substrate tissue distribution studies. Deuterated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with isotopes (e.g., hydrazine, i.e., ² H) can provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. . Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures, for example by illustrative methods or by the preparations described in the Examples below, using appropriate isotopic variations of the appropriate reagents.

The present inventors have unexpectedly discovered that the deuterated diaminopyrimidine compound of the present invention and a pharmaceutically acceptable salt thereof have equivalent or more excellent pharmacokinetics and/or compared to the undeuterated compound. It has pharmacodynamic properties and is therefore suitable as a compound for inhibiting EGFR kinase, and is therefore more suitable for the preparation of a medicament for treating cancer and EGFR kinase-related diseases.

The compound of the present invention or a pharmaceutically acceptable salt thereof may be in an amorphous or crystalline form. Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.

Those skilled in the art will appreciate that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize from the solvent. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the invention.

In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery:solubility limitations overcome by the use of prodrugs", Advanced Drug Deliver yReviews (1996) 19(2) 115-130, each This article is incorporated herein by reference.

A prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of formula (I) in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amine or sulfhydryl group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amine or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, mercapto and amine functional groups of the compounds of formula (I). Further, in the case of a carboxylic acid (-COOH), an ester such as a methyl ester, an ethyl ester or the like can be used. The ester itself may be active and/or may hydrolyze under conditions in humans. Suitable pharmaceutically acceptable body Hydrolyzable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.

Pharmaceutical compositions, formulations and kits

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active component. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active component. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active component.

A pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block polymers, polyethylene glycol and lanolin.

The invention also includes kits (e.g., pharmaceutical packs). Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container). In some embodiments, provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent. In some embodiments, a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.

The following formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention. However, the invention is not limited to the following pharmaceutical compositions.

Exemplary Formulation 1 - Tablet: The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2 - Tablet: The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 3 - Tablet: The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 4-Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 5 - Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 6-Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound) in a tablet press.

Exemplary Formulation 7-Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 8 - Capsules: The compound of the invention in dry powder form can be combined with the starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).

Exemplary Formulation 9-Liquid: The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then It was mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.

Exemplary Formulation 10 - Injection: The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.

Administration

The pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration. Drug, administration by implant or other means of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.

Generally, an effective amount of a compound provided herein is administered. Depending on the circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc., the amount of compound actually administered can be determined by the physician. .

When used to prevent a condition of the invention, the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above. Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.

The pharmaceutical compositions provided herein ("long-term administration") can also be administered chronically. Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.

The pharmaceutical composition of the present invention can be further delivered using various methods of administration. For example, in some embodiments, a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, allowing the concentration of active ingredient in the blood to rise quickly to be effective Level. In other embodiments, the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body. Moreover, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.

Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions. In such compositions, the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration. A carrier or excipient and a processing aid.

For oral doses, a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing modes, each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.

In order to provide a blood level similar to the use of an injectable dose, or a lower blood level than the injectable dose, a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

The injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours. In order to obtain a sufficient level of steady state, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered. For a human patient of 40 to 80 kg, the maximum total dose cannot exceed about 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

The transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.

The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.

The above components of the composition for oral administration, injection or topical administration are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, In Section 8 of Pennsylvania, this document is incorporated by reference.

The compounds of the invention may also be administered in sustained release form or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The invention further relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted. In some embodiments, the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (eg, 10-50% in water).

combination

The compounds of the invention or compositions thereof may be administered in combination with other therapeutic agents to treat the disease. Examples of known therapeutic agents include, but are not limited to, Adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan ( Topotecan), taxol, interferon, platinum derivatives, taxanes (eg, paclitaxel), vinca alkaloids (eg, vinblastine), anthracycline ( Anthracycline) (eg, doxombicin), epipodophyllotoxin (eg, etoposide), cisplatin, mTOR inhibitor (eg, rapamycin), Methotrexate, actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate, chlorobenzene Metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agent (eg chlorambucil) ), 5-fluorouracil, camptothecin, cisplatin, metronidazole (metron) idazole) and Gleevec ^TM. In other embodiments, the compounds of the invention are administered in combination with a biological agent such as Avastin or VECTIBIX.

In some embodiments, a compound of the invention or a composition thereof can be administered in combination with any one or more anti-proliferative or chemotherapeutic agents selected from the group consisting of: abarelix, aldileukin (aldesleukin), alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, day Asparaginase, azacitidine, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, white Busulfan, calbuterone, capecitabine, camptothecin, carboplatin, carmustine, celecoxib, cetuximab Antibiotic (cetuximab), chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, actinomycin D, darbepoetin ( (darbepoetin alfa), daunorubicin, denilukin , dexrazoxane, docetaxel, doxorubicin, doxorubicin hydrochloride, dromostanolone propionate, epirubicin, ebertin alpha Epoetin alfa), erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, fluururidine ), fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, acetic acid ammonia Ruilin (histrelin Acetate), hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alpha- 2a, interferon alpha-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, left-handed Levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, sodium mesaconate (mesna), A Aminopterin, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, Nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, Pegaspargase, pegfilgrastim, pemetrexed diso Ddium), pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, Rasburyase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate (sunitinib maleate), talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa (thiotepa), topotecan, toremifene, tosimmomab, trastuzumab, tretinoin, ATRA, uracil mustard ), valrubicin, vinblastine, vincristine, vinorelbine, zoledronate or zoledronic acid.

Other examples of therapeutic agents to which the compounds of the invention may also be combined include, but are not limited to, therapeutic agents for Alzheimer's Disease, such as donepezil hydrochloride and rivastigmine. ; therapeutic agents for Parkinson's Disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole ( Pramipexole), bromocriptine, pergolide, trihexephendyl, and amantadine; a therapeutic agent for multiple sclerosis (MS), Such as beta interferon, glatiramer acetate and mitoxantrone; therapeutic agents for asthma, such as albuterol and montelukast; therapeutic agents for schizophrenia, such as Zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RA, azathioprine , cyclophosphamide and sulfasalazine (sulfasalazi) Ne); immunomodulators and immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, Cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-par a drug for the treatment of cardiovascular diseases, such as a beta blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, and a statin; a therapeutic agent for liver diseases, Such as corticosteroids, cholestyramine, interferon and antiviral agents; therapeutic agents for blood disorders such as corticosteroids, anti-leukemia agents and growth factors; and therapeutic agents for immunodeficiency disorders, such as gamma spheres protein.

Those other active agents can be administered separately from the compositions containing the compounds of the invention as part of a multiple dosing regimen. Alternatively, those active agents may be part of a single dosage form, mixed with a compound of the invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents can be provided simultaneously, sequentially, or at intervals from one another (usually within 5 hours of each other).

treatment

The invention provides a method for inhibiting a protein tyrosine kinase (such as EGFR kinase) or treating a disease (such as cancer, cell proliferative disease, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease or A method of metabolic disease comprising the steps of administering a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug thereof, to a subject in need of treatment Or an isotope variant, or a pharmaceutical composition of the invention.

The compounds of the invention are useful in the treatment of cancer caused by EGFR. In particular, the compounds are useful for treating cancer caused by EGFR expressing an EGFR mutant and for treating cancer caused by EGFR that is refractory to RTKI therapy (eg, erlotinib or gefitinib).

The compounds of the invention are inhibitors of at least one mutant of EGFR and are therefore suitable for treatment with one or more EGFR mutants (eg, deletion mutations, activating mutations, resistance mutations, or combinations thereof, specific examples include T790M mutations, One or more disorders associated with the activity of the L858R mutation and the L858R/T790M double mutation. Accordingly, in a particular embodiment, the invention provides a method of treating a mutant EGFR mediated disorder comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, to a patient in need thereof a solvate, hydrate, crystal form, prodrug or isotopic variation, or a step of administering a pharmaceutical composition of the invention.

Cancers treatable by the compounds of the invention include, but are not limited to, non-small cell lung cancer (NSCLS), small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, Hyperproliferative diseases such as gastrointestinal stromal tumors, leukemia, histiocytic lymphoma, and nasopharyngeal carcinoma. In addition, the compounds of the invention may also be used to maintain the maintenance of cancer recurrence in patients in need of such treatment.

An effective amount of a compound of the invention will generally be administered in a single or multiple doses at an average daily dose of from 0.01 mg to 50 mg of compound per kilogram of patient body weight, preferably from 0.1 mg to 25 mg of compound per kilogram of patient body weight. In general, the compounds of the invention may be administered to a patient in need of such treatment in a daily dosage range of from about 1 mg to about 3500 mg per patient, preferably from 10 mg to 1000 mg. For example, the daily dose per patient can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000 mg. It can be administered one or more times daily, weekly (or several days apart) or on an intermittent schedule. For example, the compound can be administered one or more times per day on a weekly basis (e.g., every Monday), continually or for several weeks, such as 4-10 weeks. Alternatively, the administration may be continued for several days (e.g., 2-10 days), followed by a few days (e.g., 1-30 days) without administration of the compound, and the cycle may be repeated indefinitely or repeated for a given number of times, such as 4-10 Cycles. For example, the compounds of the invention may be administered daily for 5 days, then intermittently for 9 days, then administered daily for 5 days, then intermittent for 9 days, and so on, optionally repeating the cycle or repeating 4-10 times.

When an RTKI (e.g., erlotinib or gefitinib) is used in combination with a compound of the invention, the individual components of the combination therapy can be administered at their dosage level and regimen for monotherapy. For example, erlotinib has been orally administered at a dose of 150 mg per day for the treatment of NSCLC, and has been orally administered at a dose of 100 mg per day for pancreatic cancer. In another example, gefitinib has been orally administered at a dose of 250 mg per day for the treatment of NSCLC.

Preferably, when RTKI (e.g., erlotinib or gefitinib) is used in combination with a compound of the invention, the dosage level of one or both components is reduced compared to when used alone.

Example

The following examples are provided to provide a person skilled in the art with a complete disclosure and description of how to make, prepare and evaluate the methods and compounds claimed herein, and are intended to be merely illustrative of the invention and not to limit the scope of the invention.

resolve resolution

The compounds of the present invention can be prepared according to conventional methods in the art and using suitable reagents, starting materials, and purification methods known to those skilled in the art.

plan 1

Scheme 1 illustrates the preparation of intermediates. Specifically, the intermediate can be prepared by the following steps: 5-substituted 2,4-dichloropyrimidine (which is commercially available or obtained from known starting materials by reactions well known in the art) and protected The 3-substituted aniline is coupled under typical coupling conditions, the protecting group is removed, and the intermediate is then coupled with a substituted acrylic acid or a derivative thereof (e.g., acryloyl chloride) to provide an intermediate.

Scenario 2

Scheme 2 illustrates several preparations of another intermediate. Specifically, the intermediate can be prepared by subjecting a 2-substituted 4-halonitrobenzene (which is commercially available or obtained from a known raw material by a reaction well known in the art) to a coupling reaction, The reduction reaction is carried out to obtain an intermediate; or the 3-substituted 4-nitrobenzoic acid (ester) is reduced, halogenated, coupled, and reduced to obtain an intermediate.

Option 3

Scheme 3 illustrates the preparation of a compound of formula (I). Specifically, the intermediates which can be prepared by the schemes 1 and 2 are obtained by a coupling reaction.

The preparation of the compound of the formula (I) of the present invention is more specifically described below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.

Usually, in the preparation, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C). The reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.

Example 1

N-(3-((2-(4-(1-acetylpiperidin-4-yl)oxy)-2-methoxyphenyl))amino)-5-(trifluoromethyl)pyrimidine- 4-based, amino, phenyl) propylene Amide

step 1:

4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (4.70 g, 23.3 mmol), 4-fluoro-2-methoxynitrobenzene (2 g, 11.6 mmol), tetrabutylammonium bromide (0.754 g, 2.34) Methyl) and potassium hydroxide aqueous solution were stirred in toluene at 60 ° C overnight. The reaction mixture was returned to room temperature, diluted with water and extracted with ethyl acetate. The collected organic phase was dried and purified by flash chromatography eluting elut elut elut elut elut elut . ¹ H NMR (300 MHz, CDCl ₃ ) (δ/ppm): 8.01 (d, J = 9.6 Hz, 1H), 6.56-6.49 (m, 2H), 4.61-4.57 (m, 1H), 3.96 (s, 3H) , 3.75-3.67 (m, 2H), 3.44 - 3.36 (m, 2H), 2.01-1.94 (m, 2H), 1.84-1.76 (m, 2H), 1.45 (s, 9H). LC-MS (APCI): m / z = 353.2 (M + 1) +, purity: 97.6%.

Step 2:

4-(3-Methoxy-4-nitrophenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.42 mmol) was added to a mixture of ethanol (15 mL) and water (5 mL) In a flask, iron powder (0.48 g, 8.51 mmol) and ammonium chloride (38 mg, 0.71 mmol) were successively added and stirred for 1 h. After evaporation of ethanol under reduced pressure, water was added and extracted with dichloromethane. The product was obtained as a light brown oil (4-(4-amino-3-methoxy-phenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.25 g, yield 56.7%). LC-MS (APCI): m / z = 323.2 (M + 1) +, purity: 90.5%.

Step 3:

Add n-butanol (9 mL) to a 50 mL three-necked flask equipped with magnetic stirring, N ₂ ball, thermometer, and cool in an ice water bath, keep the internal temperature not exceeding 5 ° C, and add tert-butyl 3-aminophenyl)carbamate (0.96). g, 4.6 mmol), 2,4-dichloro-5-trifluoromethylpyrimidine (1.0 g, 4.6 mmol) was added dropwise, then N,N-diisopropylethylamine (0.67 g, 5.5 mmol) The reaction mixture was slowly added dropwise, and the mixture was stirred for 1 hour in an ice water bath. The mixture was stirred at room temperature for 4 hours, and a large amount of white solid was filtered, washed with n-butanol (2 mL), dried, and dried at 50 ° C to give a white solid. The yield was 78.3%. ^{1 H NMR (400MHz, DMSO-} d6) (δ / ppm): 9.53 (s, 1H), 9.46 (s, 1H), 8.57 (s, 1H), 7.58 (s, 1H), 7.28-7.26 (m, 2H), 7.04-7.01 (m, 1H), 1.48 (s, 9H), LC-MS (APCI): m/z = 389.1 (M+1) ⁺ , purity: 97%.

Step 4:

Dichloromethane (15 mL) was added to a 100 mL three-necked flask, and (3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)carbamic acid tert-butyl ester (1.0) was added with stirring. g, 2.57 mmol), cooled in an ice water bath, trifluoroacetic acid (3 mL) was added dropwise, the ice bath was removed, and the reaction was stirred at room temperature for 1 h under N ₂ atmosphere. Dichloromethane (50 mL) was added again, and triethylamine (5.6 mL, 40.4 mmol) was added dropwise to the trifluoroacetic acid. The mixture was cooled to -10 ° C, and acryloyl chloride (0.27 g) was slowly added dropwise under a nitrogen atmosphere. , 3mmol), stir for 5min. Add H ₂ O (100mL) to quench the reaction, the organic layer was separated, washed successively with water (100mL x 2), 0.5M HCl (aq., 15mL), washed with saturated aqueous sodium bicarbonate (15 mL), dried over anhydrous sodium sulfate The mixture was filtered, and the filtrate was evaporated. EtOAcjjjjjjjjj ¹ H NMR (300 MHz, DMSO-d6) δ (ppm): 10.25 (s, 1H), 9.59 (s, 1H), 8.59 (s, 1H), 7.80-1.79 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.50-6.41 (m, 1H), 6.30-6.23 (m, 1H), 5.77 ( Dd, J = 9.3 Hz, 2.1 Hz, 1H). LC-MS (APCI): m/z = 343.1 (M + 1) ⁺ , purity: 98%.

Step 5:

Add N-(3-(2-chloro-5-trifluoromethylpyrimidin-4-ylamino)phenyl)acrylamide (0.21 g, 0.62 mmol) and trifluoroacetic acid (three drops) to 4-(4) -Amino-3-methoxy-phenoxy)piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.62 mmol) in 1,4-dioxane solution was added to 60 ° C and stirred for 3 h. After the temperature of the reaction mixture was cooled to room temperature, 3 ml of triethylamine was added, and the residue was evaporated to dryness, and the crude product was purified by column chromatography (PE: EA = 4:1) to afford white product (240 mg, yield: 61.3%). ^{1 HNMR (300MHz, DMSO-d} 6) (δ / ppm): 10.15 (s, 1H), 8.69 (br s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.75 (br s, 1H), 7.53-7.48 (m, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.16-7.15 (m, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.49-6.40 (m , 1H), 8.29-8.22 (m, 2H), 5.76 (dd, J = 9.9 Hz, 2.4 Hz, 1H), 4.46-4.44 (m, 1H), 3.75 (s, 3H), 3.67-3.62 (m, 3H), 3.30-3.18 (m, 2H), 1.85-1.83 (m, 2H), 1.50-1.45 (m, 2H), 1.41 (s, 9H). LC-MS (APCI): m / z = 629.2 (M + 1) +, purity: 95.6%.

Step 6:

Adding trifluoroacetic acid (2 mL) to 4-(4-(4-(3-acrylamidophenyl)-5-trifluoromethylpyrimidin-2-ylamino)-3-methoxyphenoxy)per A solution of tert-butyl pyridine-1-carboxylate (200 mg) in dichloromethane (15 mL) Spin dry and use directly in the next step.

Step 7:

Add triethylamine (60 mg, 0.6 mmol) to N-(3-(2-(2-methoxy-4-(piperidin-4-yloxy)phenylamino)-5-trifluoromethylpyrimidine 4-ylamino) phenyl) acrylamide (0.1g, 0.19mmol) in dichloromethane (10 mL), cooled to 0 deg.] C, under nitrogen atmosphere was added Ac ₂ O (25mg, 0.25mmol), stirred for 10min After adding water, it is extracted with dichloromethane, dried over anhydrous sodium sulfate and then dried, and then filtered to afford white product N-(3-((4-(1-acetylpiperidin-4-yl)oxy) 2-(2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (60 mg, yield 55%). ^{1 H NMR (300MHz, DMSO-} d 6) (δ / ppm): 10.16 (s, 1H), 8.67 (br s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.75 (br s , 1H), 7.52-7.48 (m, 2H), 7.25 (t, J = 8.4 Hz, 1H), 7.16 (br s, 1H), 8.59 (d, J = 2.7 Hz, 1H), 6.49-6.40 (m , 1H), 6.29-6.22 (m, 2H), 6.76 (dd, J = 9.9 Hz, 2.4 Hz, 1H), 4.51-4.49 (m, 1H), 3.84-3.81 (m, 1H), 3.77 (s, 3H), 3.66-3.63 (m, 1H), 3.30-3.23 (m, 2H), 2.02 (s, 3H), 1.86-1.81 (m, 2H), 1.58-1.55 (m, 2H). LC-MS (APCI): m / z = 571.2 (M + 1) +, purity: 97.5%.

Example 2

N-(3-((2-(4-(1-acetylpiperidin-4-yl)amino)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidine-4- Amino)phenyl)propene Amide

step 1:

The synthesis procedure was the same as in the step 1 of Example 1 to give the product 4-(3-methoxy-4-nitrophenylamino)piperidine-1-carboxylic acid tert-butyl ester (0.96 g, yield: 93.6%). LC-MS (APCI): m / z = 352 (M + 1) +, purity: 95.1%.

Step 2:

The synthesis procedure was the same as in the step 2 of Example 1 to give the crude product of 4-(4-amino-3-methoxyphenylamino)piperidine-1-carboxylic acid tert-butyl ester (0.19 g, yield: 91%). , used directly in the next step.

Step 3:

The synthesis procedure was the same as in Step 3 of Example 1 to give 4-((4-(4-(3-acrylamidophenylamino)-5-trifluoromethylpyrimidin-2-yl)amino-3-methyl as a white solid. Tert-butyl oxyphenyl)amino)piperidine-1-carboxylate (89 mg, yield: 54.6%).

Step 4:

The synthesis procedure was the same as in Step 4 of Example 1 to give the product N-(3-(2-(2-methoxy-4-(piperidin-4-ylamino)phenyl)amino)-5-trifluoromethyl Pyrimidin-2-yl)amino)phenyl)acrylamide was used directly in the next step.

Step 5:

The synthesis procedure was the same as in Step 5 of Example 1, to give the product N-(3-((2-(1-acetylpiperidin-4-yl)amino)-2-methoxyphenyl)amino)- 5-(Trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (48 mg, yield: 60.3%). ^{1 H NMR (300MHz, DMSO-} d 6) (δ / ppm): 10.25 (s, 1H), 8.45 (br s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.65 (br s , 1H), 7.52-7.49 (m, 1H), 7.26-7.22 (m, 3H), 6.54-6.45 (m, 1H), 6.29-6.22 (m, 2H), 6.05-6.90 (m, 1H), 5.77 -5.74(m,1H),5.40-5.37(m,1H),4.22-4.18(m,1H),3.78-3.82(m,1H),3.68(s,3H),3.24-3.15(m,1H) , 2.86-2.79 (m, 1H), 2.00 (s, 3H), 1.93-1.85 (m, 2H), 1.30-1.25 (m, 3H). LC-MS (APCI): m / z = 570.1 (M + 1) +, purity: 95.6%.

Example 3

N-(3-((2-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxyphenyl)amino)-5-( Trifluoromethyl)pyrimidin-4-yl)amino) Phenyl)acrylamide

step 1:

Add PdCl ₂ (dppf) ₂ (422 mg, 0.052 mmol) to 4-bromo-2-methoxynitrobenzene (2.0 g, 8.62 mmol), 4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1,2,5,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester and K ₂ CO ₃ (3.57 g, 19.38 mmol) In a solution of 1,4-dioxane (40 mL), it was heated to 90 ° C under a nitrogen atmosphere and stirred for 14 h. After pouring into water (150 mL), it was extracted with dichloromethane (50 mL×3), and then evaporated to dryness to give a yellow solid product 4-(3-methoxy-4-nitrophenyl)-1,2,5,6 - Tetrahydropyridine-1-carboxylic acid tert-butyl ester (1.6 g, yield: 56%). _{^{1 H NMR (300MHz, CDCl 3}} ) (δ / ppm): 7.87 (d, J = 9Hz, 1H), 7.03-7.00 (m, 2H), 6.19 (s, 1H), 4.13 (t, J = 3Hz, 2H), 3.99 (s, 3H), 3.67 (t, J = 6 Hz, 2H), 1.53 (s, 9H). LC-MS (APCI): m / z = 335.2 (M + 1) +, purity: 94.6%.

Step 2:

The specific procedure was the same as in Step 4 of Example 1, without isolation, to give the product 4-(3-methoxy-4-nitrophenyl)-1,2,3,6-tetrahydropyridine: LC-MS (APCI ): m/z = 235.3 (M + 1) ⁺ , purity: 93.4%.

Step 3:

Add triethylamine (181.4 mg, 1.79 mmol) and acetic anhydride (91.5 mg, 896 μmol) to the reaction mixture of the previous step, stir at room temperature for 30 min, spin dry, and pass the column (DCM:MeOH = 40:1 - 20 :1) Yield of 1-(4-(3-methoxy-4-nitrophenyl)-1,2,5,6-tetrahydropyridin-1-yl)ethanone as a yellow oil (150 mg, yield : 90.9%). ¹ H NMR (300 MHz, CDCl ₃ ) (δ / ppm): 7.89 (d, J = 8.7 Hz, 1H), 7.05-7.00 (m, 2H), 6.25-6.16 (m, 1H), 4.32-4.18 (m, 2H), 4.00 (s, 3H), 3.88-3.69 (m, 2H), 2.64 - 2.62 (m, 2H). LC-MS (APCI): m / z = 277.3 (M + 1) +, purity: 98.9%.

Step 4:

Add 1N aqueous HCl (3 drops) to 1-(4-(3-methoxy-4-nitrophenyl)-1,2,5,6-tetrahydropyridin-1-yl)ethanone (150 mg , 542.9 μmol) and a solution of iron powder (182 mg, 3.26 mmol) in ethanol (10 mL), refluxed at 95 ° C for 2 h, dried over a brown oil, dissolved in dichloromethane, washed with water and brine. The organic phase-dried yellow-black oily product 1-(4-(3-methoxy-4-aminophenyl)-1,2,5,6-tetrahydropyridin-1-yl)ethanone was collected. LC-MS (APCI): m / z = 247.2 (M + 1) +, purity: 94.6%.

Step 5:

Trifluoroacetic acid (three drops) was added to 1-(4-(3-methoxy-4-aminophenyl)-1,2,5,6-tetrahydropyridin-1-yl)ethanone (133 mg, 540 μmol) and N-(3-((2-chloro-5-trifluoromethylpyrimidin-4-yl)amino)phenyl)acrylamide (185 mg, 540 μmol) of 1,4-dioxane (5 mL) After stirring at 60 ° C for 2 h, triethylamine was added dropwise to adjust to neutrality. After dichloromethane extraction, the column was dried (DCM:MeOH = 40:1) to afford white product N-(3- ((2-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl) Pyrimidin-4-yl)amino)phenyl)acrylamide (90 mg, yield: 30.2%). ¹ H NMR (300 MHz, CDCl ₃ ) (δ/ppm): 8.32 (s, 1H), 8.18 (s, 1H), 7.89-7.79 (m, 2H), 7.64-7.51 (m, 2H), 7.38-7.34 ( m, 1H), 7.24-7.20 (m, 1H), 6.90-6.75 (m, 3H), 6.43 (d, J = 7.5 Hz, 1H), 6.22 - 6.15 (m, 1H), 6.01-5.94 (d, J=18 Hz, 1H), 5.75 (d, J=6.3 Hz, 1H), 4.23-4.11 (m, 2H), 3.90 (s, 3H), 3.80 (t, J = 3.2 Hz, 1H), 3.64 (t) , J = 3.2 Hz, 1H), 2.52 (d, J = 13.5 Hz, 2H), 2.17 - 2.14 (m, 3H). LC-MS (APCI): m / z = 553.3 (M + 1) +, purity: 97.8%.

Example 4

N-(3-((2-(4-(1-acetylpiperidin-4-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) Amino)phenyl)acrylamide

step 1:

Pd/C (9 mg) was added to 1-(4-(3-methoxy-4-aminophenyl)-1,2,5,6-tetrahydropyridin-1-yl)ethanone under a hydrogen atmosphere. (90 mg, 365 μmol) in EtOAc (10 mL) EtOAc (EtOAc) Ethyl ketone (90 mg, 99.2%). LC-MS (APCI): m / z = 249.4 (M + 1) +, purity: 95.1%.

Step 2:

The synthesis procedure was the same as in the step 5 of Example 3 to give the white solid product N-(3-((2-((4-(1-acetylpiperidin-4-yl)-2-methoxyphenyl)amino)) 5-(Trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (60 mg, yield: 29.8%). _{^{1 H NMR (300MHz, CDCl 3}} ) (δ / ppm): 8.32 (s, 1H), 8.14 (d, J = 8.4Hz, 1H), 7.89 (m, 1H), 7.76-7.71 (m, 2H), 7.55 (br s, 1H), 7.39-7.28 (m, 2H), 6.91 (s, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 6.50- 6.44 (m, 1H), 6.30-6.21 (dd, J = 16.8 Hz, 10.2 Hz, 1H), 5.80-5.76 (dd, J = 10.2 Hz, 1.5 Hz, 1H), 4.81-4.76 (m, 1H), 3.96-3.87 (m, 4H), 3.21-3.11 (m, 1H), 2.72-2.58 (m, 2H), 2.14 (s, 3H), 1.92-1.83 (m, 2H), 1.66-1.56 (m, 2H) ). LC-MS (APCI): m / z = 555.4 (M + 1) +, purity: 95.5%.

Example 5

N-(3-((2-((2-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-trifluoro Methyl)pyrimidin-4-yl)amino)phenyl) Acrylamide

step 1:

4-Fluoro-2-methoxynitrobenzene (1.0 g, 5.84 mmol), 1-methyl-4-(4-piperidinyl)piperazine (0.9 g, 7.0 mmol), K ₂ CO ₃ ( 2.0 g, 14.6 mmol) were sequentially added to a three-necked flask containing 4 mL of DMF, heated to 80 ° C, and stirred overnight. The reaction mixture was cooled to room temperature, diluted with water and evaporated with ethyl sulfate. 4-yl)-4-methylpiperazine (1.0 g, yield: 51.1%). ¹ H NMR (300 MHz, CDCl ₃ ) (δ / ppm): 8.01 (d, J = 9.3 Hz, 1H), 6.43 (dd, J = 9.6 Hz, 2.7 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 3.98-3.94 (m, 2H), 3.87 (s, 3H), 3.03-2.94 (m, 2H), 2.65-2.62 (m, 4H), 2.54-2.46 (m, 5H), 2.32 (s, 3H), 2.01-1.96 (m, 2H), 1.65-1.60 (m, 2H), LC-MS (APCI): m/z=335.2 (M+1)+; purity: 95.0%.

Step 2:

1-(1-(3-Methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine (0.2 g, 0.59 mmol) was added to ethanol (6 mL) and A three-necked flask of water (2 mL) was added, then iron powder (0.2 g, 3.58 mmol), ammonium chloride (16 mg, 0.29 mmol) was added again, and refluxed for 2 h. After the reaction mixture was cooled to room temperature, ethanol was evaporated. , saturated _{NaHCO 3 (aq., 5mL)} , extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate and rotary evaporation, to give a pale brown oily product of 2-methoxy-4- (4- (4 -Methylpiperazin-1-yl)piperidine-1-aniline (180 mg, yield: 100%). LC-MS (APCI): m/z = 305 (M+1) ⁺ , purity: 90.3%.

Step 3:

The synthesis procedure was the same as in the step 5 of Example 3 to give a white solid product (40 mg, yield: 11.1%). ^{1 H NMR (300MHz, DMSO-} d 6) (δ / ppm): 10.25 (s, 1H), 8.45 (br s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.65 (br s , 1H), 7.52-7.49 (m, 1H), 7.26-7.22 (m, 3H), 6.54-6.45 (m, 1H), 6.29-6.22 (m, 2H), 6.05-6.90 (m, 1H), 5.77 -5.74(m,1H),3.77-3.72(m,2H),2.82-2.61(m,11H),2.48-2.34(m,3H),2.03(s,3H),1.91-1.85(m,2H) , 1.59-1.52 (m, 2H). LC-MS (APCI): m / z = 611.1 (M + 1) +, purity: 94.5%.

Example 6

N-(3-((2-(2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4- Amino)phenyl)acryloyl amine

step 1:

4-Fluoro-2-methoxynitrobenzene (0.5 g, 2.92 mmol), 4-piperidinylmorpholine (0.6 g, 3.5 mmol), K ₂ CO ₃ (0.54 g, 3.8 mmol) A three-necked flask containing 3 mL of DMF was stirred at room temperature overnight under a nitrogen atmosphere. Diluted in cold water (50 mL), filtered and dried to give 4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)morpholine (0.5 g, yield 53%) ). LC-MS (APCI): m / z = 322.2 (M + 1) +, purity: 96.3%.

Step 2:

The synthesis procedure was the same as in the step 2 of Example 5 to give the product as a yellow solid (0.12 g, yield 67%). LC-MS (APCI): m / z = 292.1 (M + 1) +, purity: 98%.

Step 3:

The synthesis procedure was the same as in the step 5 of Example 3 to give a brown solid product (120 mg, yield 67%). _{^{1 H NMR (300MHz, CDCl 3}} ) (δ / ppm): 8.29 (s, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.88 (s, 1H), 7.49-7.53 (m, 2H), 7.33 (t, J = 8.7 Hz, 1H), 7.16-7.19 (br, 1H), 6.87 (s, 1H), 6.48-6.52 (m, 2H), 6.37-6.42 (m, 2H), 6.26 (q, J = 10.2 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 3.86 (s, 3H), 3.77 (s, 4H), 3.64 (d, J = 15.6 Hz, 2H), 2.69 (d, J = 16 Hz, 2H), 2.62 (s, 4H), 2.33 (t, J = 7.8 Hz, 1H), 1.96 (d, J = 6.3 Hz, 4H). LC-MS (APCI): m / z = 598.3 (M + 1) +, purity: 97%.

Example 7

N-(3-((2-(4-(4-acetylpiperazine-1-carbonyl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) Amino)phenyl)acryloyl amine

step 1:

A solution of oxalyl chloride in dichloromethane (2.8 ml, 5.6 mmol) was added dropwise to a solution of 3-methoxy-4-nitrobenzoic acid (1.0 g, 5.1 mmol) in tetrahydrofuran (14 ml) at 0 ° C Add a few drops of DMF. The reaction mixture was stirred at room temperature under nitrogen for 4 h, then cooled to room temperature and then evaporated to dryness. A two-necked flask containing 1-acetylpiperazine (0.85 g, 6.6 mmol) in dichloromethane (15 mL) was cooled to 0 ° C and triethylamine (1 mL, 7.7 mmol) was added to the mixture. The methylene chloride solution obtained in the previous step was slowly added dropwise to the reaction mixture, stirred for 30 min, quenched with water (20 mL), and extracted with dichloromethane (15 mL×2). The product was spin-dried to give the product N-1-(4-(3-methoxy-4-nitrobenzoyl)acetylpiperazine (1.1 g, 70.2% yield). LC-MS (APCI): m /z = 308.1 (M + 1) +, purity: 95.1%.

Step 2:

The synthesis procedure was the same as in the step 2 of Example 1 to give the product as a yellow solid, N-1-(4-(4-amino-3-methoxybenzoyl)acetylpiperazine (0.13 g, yield: 72%). LC-MS (APCI): m/z =278.2 (M+1)+, purity: 98.3%.

Step 3:

The synthesis procedure was the same as in the step 5 of Example 3 to give the brown solid product N-(3-((2-(4-(4-acetylpiperazine-1-carbonyl)-2-methoxyphenyl)amino)- 5-(Trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (110 mg, yield 43%). _{^{1 H NMR (300MHz, CDCl 3}} ) (δ / ppm): 10.23 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.86 (t, J = 8.1 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 1.2 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.65 (d, J = 6 Hz, 1H), 6.43 (dd, J = 17.1 Hz, 9.9 Hz, 1H), 6.34 (dd, J = 17.1 Hz, 1.8 Hz, 1H), 5.76 (s, 1H) , 3.78 (s, 3H), 3.24 (s, 3H), 2.04 (d, J = 6 Hz, 4H), 1.23-1.34 (m, 4H). LC-MS (APCI): m/z = 584.2 (M + 1) +, purity: 97.

Example 8

N-(3-((2-(4-(1-acetylpiperidin-4-methylene)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl Amino)phenyl)acryloyl amine

step 1:

3-methoxy-4-nitrobenzoic acid (0.48 g, 1.66 mmol), methanol (5 mL), and sulfuric acid (3 mL) were sequentially added to a one-neck flask under a nitrogen atmosphere and refluxed for 2 h. Diluted with water (30 mL), EtOAc (3 mL), EtOAc (EtOAc) %). LC-MS (APCI): m / z = 212 (M + 1) +, purity: 95.3%.

Step 2:

Under a nitrogen atmosphere, 3-methoxy-4-nitrobenzoate, 50mL of tetrahydrofuran were added to a single neck flask was cooled to 0 deg.] C, was added LiAlH ₄ (0.16g), stirred for 30min, added decahydrate The mixture was diluted with sodium sulfate and evaporated to dryness crystals crystals crystals LC-MS (APCI): m / z = 184.1 (M + 1) +, purity: 98.1%.

Step 3:

(3-methoxy-4-nitrophenyl)methanol (0.5 g, 2.73 mmol) and dichloromethane (20 mL) were placed in a stirred 25 mL one-neck flask and cooled to 0 ° C under nitrogen atmosphere. Phosphorus tribromide (960 mg, 3.55 mmol) was added slowly and stirred at room temperature for 3 h. Water (30 mL) and dichloromethane (30 mL) were added to the mixture and the mixture was stirred for 5 min, and then extracted with dichloromethane. The organic phase was collected, washed with water, dried over anhydrous sodium sulfate -Bromomethyl-2-methoxynitrobenzene (0.37 g, yield 55%). LC-MS (APCI): m / z = 246.1 (M + 1) +, purity: 94.8%.

Step 4:

4-Bromomethyl-2-methoxynitrobenzene (100 mg, 0.4 mmol) and triethyl phosphite (68 mg, 0.4 mmol) were added to a 100 mL one-necked flask, heated to 160 ° C and at this temperature After stirring for 4 hours, it was cooled to room temperature, and stirred for 1 h in an ice-water bath. The filtrate was filtered and evaporated to dryness to give the product as a yellow oil (yield: 123 mg, LC-MS (APCI): m/z=304 (M+1)+, purity: 96.6%.

Step 5:

NaH (1.52 g, 15 mmol) and MsCl (1.5 g, 13 mmol) were sequentially added to a solution containing diethyl 3-methoxy-4-nitrophenyl phosphate (3 g, 10 mmol) at 0 ° C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h, EtOAc (EtOAc) (EtOAc) saturated NaHCO ₃ solution (20mL) was washed, dried over anhydrous sodium sulfate spin, to give a pale solid product is N-4- (3- methoxy-4-nitrophenyl methylene) piperidine-carboxylate ( 1.5 g, yield 43%). _{^{1 HNMR (300MHz, CDCl 3)}} (δ / ppm): 7.87 (d, J = 8.4Hz, 1H), 6.85-6.88 (m, 2H), 6.37 (s, 1H), 3.97 (s, 3H), 3.55 (t, J = 7.8 Hz, 2H), 3.45 (t, J = 7.8 Hz, 2H), 2.45 (t, J = 7.8 Hz, 2H), 2.15 (t, J = 7.8 Hz, 2H), 1.51 (s) , 9H). LC-MS (APCI): m / z = 349 (M + 1) +, purity: 98.4%.

Step 6:

The synthesis procedure was the same as in the steps 2 and 3 of Example 3 to give N-(4-(3-methoxy-4-nitrobenzylidene)acetylpiperidine as a white solid (0.66 g, yield 79%) LC-MS (APCI): m/z = 291.2 (M + 1) ⁺ , purity: 98.6%.

Step 7:

The N- (4- (3- methoxy-4-amino-benzylidene) acetyl piperidine (0.2g, 0.69mmol), iron powder _{(0.21g, 3.75mmol), NH 4} Cl (33mg, 0.62 The mixture was added to a stirred mixture of ethanol (10 mL) and water (2 mL), and then evaporated to EtOAc. 4- (3-methoxy-4-nitrophenyl methylene) acetyl piperidine (0.13g, yield 73%) LC-MS (APCI ):. m / z = 261.3 (m + 1) + , purity: 93.6%.

Step 8:

The synthesis procedure was the same as in the step 5 of Example 3 to give N-(3-((2-(4-)-acetyl-piperidine-4-methylene)-2-methoxyphenyl)amino -5-(Trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (90 mg, yield 38%). ¹ H NMR (300 MHz, CDCl ₃ ) (δ / ppm): 8.32 (s, 1H), 7.78 (d, J = 5.7 Hz, 1H), 7.36 (q, J = 6.6 Hz, 1H), 6.89-6.92 ( m, 2H), 6.62-6.72 (m, 4H), 6.43-6.49 (m, 2H), 6.34 (m, 2H), 5.79 (d, J = 10.2 Hz, 2H), 3.89 (d, J = 4.8 Hz) , 3H), 3.41-3.69 (m, 4H), 2.53 (q, J = 6.9 Hz, 2H), 2.39 (m, 2H), 2.16 (d, J = 4.5 Hz, 3H). LC-MS (APCI): m / z = 567.3 (M + 1) +, purity: 97.1%.

Example 9

N-(3-((2-(4-(1-acetylpiperidin-4-methyl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl) Amino)phenyl)acrylamide

step 1:

The synthesis procedure was the same as in the step 1 of Example 4 to give 1-(4-(4-amino-3-methoxybenzyl)piperidin-1-yl)ethanone (yield: 90%). LC-MS (APCI): m / z = 263.2 (M + 1) +, purity: 94.6%.

Step 2:

The synthesis procedure was the same as in the step 5 of Example 3 to give the white solid product N-(3-((2-(4-(1-acetylpiperidine-4-methyl)-2-methoxyphenyl)amino)- 5-(Trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide (85 mg, yield 37%). _{^{1 H NMR (300MHz, CDCl 3}} ) (δ / ppm): 8.33 (s, 1H), 8.09 (d, J = 9Hz, 1H), 7.90 (s, 1H), 7.36 (d, J = 18Hz, 2H) , 7.49-7.54 (br, 2H), 7.31-7.39 (m, 2H), 6.91 (s, 2H), 6.64 (s, 1H), 6.57 (d, J = 6.9 Hz, 1H), 6.50 (d, J = 1.5 Hz, 1H), 6.44 (d, J = 1.8 Hz, 1H), 6.21-6.30 (m, 1H), 5.79 (d, J = 10.2 Hz, 2H), 5.79 (dd, J = 9.9 Hz, 1.2 Hz, 1H), 4.59 (d, J = 13.5 Hz, 1H), 3.88 (s, 3H), 3.76-3.80 (m, 2H), 2.94 - 3.03 (m, 2H), 2.43-2.51 (m, 4H) , 2.39 (m, 2H), 2.09 (s, 3H), 2.53 (q, J = 6.9 Hz, 2H), 1.27-1.32 (m, 2H). LC-MS (APCI): m/z = 569.4 (M+1)+, purity: 94.6%.

Example 10

N-(3-((2-(4-(4-acetylpiperazin-1-yl)methyl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl)amino)phenyl)propene Amide

step 1:

The synthesis procedure was the same as in the step 2 of Example 1 to give a yellow solid product (0.12 g, yield 68%). LC-MS (APCI): m / z = 322.2 (M + 1) +, purity: 95.6%.

Step 2:

The synthesis was carried out in the same manner as in Step 3 of Example 1 to give a brown solid product (110 mg, yield 43%), LC-MS (APCI): m/z = 628.3 (M+1) ⁺ , purity: 97.6%.

Step 3:

4-(4-((4-(3-acrylamidophenyl)amino)-5-trifluoromethylpyrimidin-2-yl)amino)-3-methoxyphenyl) - a solution of methyl piperazine-1-carboxylic acid tert-butyl ester in methylene chloride was cooled to 0 ° C, trifluoroacetic acid was added dropwise, stirred at room temperature for 3 h, added dichloromethane, cooled in ice brine, and added triethylamine And slowly adding acetyl chloride dropwise, adding water and quenching, separating the organic phase, washing with water (100 mL x 2), 0.5 M HCl (aq., 15 mL), saturated NaHCO ₃ solution (15 mL), dried over anhydrous sodium sulfate and then dried. The white solid product N-(3-((4-(4-acetylpiperazin-1-yl)methyl)-2-methoxyphenyl)amino)-5-(trifluoro) Methyl)pyrimidin-4-yl)amino)phenyl)acrylamide (85 mg, yield 47%). ¹ H NMR (300 MHz, CDCl ₃ ) (δ / ppm): 8.30 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.91 - 7.96 (m, 3H), 7.43 (d, J = 0.6) Hz, 1H), 7.91-7.96 (m, 3H), 7.30-7.36 (m, 2H), 6.89 (dd, J = 16.5 Hz, 1.5 Hz, 2H), 6.69 (d, J = 6.6 Hz, 1H), 6.21-6.41 (m, 2H), 5.76 (dd, J = 9.9 Hz, 1.5 Hz, 1H), 3.87 (s, 3H), 3.64 (t, J = 4.2 Hz, 2H), 3.45-3.53 (m, 4H) ), 2.43-2.50 (m, 4H), 1.25 (s, 3H). LC-MS (APCI): m / z = 570.1 (M + 1) +, purity: 96.6%.

Biological test

(1) Kinase inhibition

Reagents and consumables:

WT EGFR (Cama, Cat. No. 08-115), EGFR [L858R/T790M] (Cama, Cat. No. 08-510), ATP (Sigma, Cat. No. A7699-1G), DMSO (Sigma, Cat. No. D2650), 96-well Plate (Coming, Cat. No. 3365), 384-well plate (Greiner, Cat. No. 784076), HTRF Kinase TK Kit (Cisbio, Cat. No. 62TK0PEJ), Erlotinib (Selleckchem, Cat. No. S7787), EGFR [d746-750] (Life Technologies, Cat. No. PV6178), 5x Kinase Buffer A (Life Technologies, Cat. No. PV3186), Kinase Tracer 199 (Life Technologies, Cat. No. PV5830),

Eu-anti-GST antibody (Life Technologies, catalog number PV5594).

Specific experimental methods:

Compound formulation: The test compound was dissolved in DMSO to make a 20 mM mother liquor. Then, it was diluted 3 times in a medium gradient of DMSO and diluted 10 times. When dosing, dilute with buffer for 10 times.

EGFR and EGFR [L858R/T790M] Kinase Assay: EGFR or EGFR [L858R/T790M] kinase was mixed with pre-diluted compounds of different concentrations in 5x Kinase Buffer A for 10 minutes at each concentration. The corresponding substrate and ATP were added, and the room temperature was reacted for 20 minutes (in which a negative positive control was set: a negative blank control and a positive erlotinib). After the reaction, the detection reagent (the reagent in the HTRF Kinase TK kit) was added, and after incubation at room temperature for 30 minutes, the enzyme activity in the presence of the compound of the present invention at each concentration was measured by an Evnvision microplate reader, and the compound concentrations of different concentrations were calculated. The inhibitory activity of the enzyme activity was then fitted according to the four-parameter equation, and the inhibitory activity of the enzyme activity under different concentrations of the compound was fitted according to Graphpad 5.0 software, and the IC ₅₀ value was calculated.

The results of the kinase inhibition in the examples are summarized in Table 1 below.

Table 1

(2) Cytotoxicity experiment

The anti-proliferative activity of the compound of the present invention against three tumor cells cultured in vitro was examined by MTS method. The experimental results show that the compound of the present invention has an inhibitory effect on the in vitro proliferation of cancer cells cultured in vitro; wherein the inhibition of proliferation of lung cancer cells in vitro is stronger than that of skin cancer cells in vitro.

Cell line:

Skin cancer cell line A431 (purchased from the American Standard Collection of Biological Products (ATCC)); lung cancer cells NCI-H1975 (purchased from the American Standard Collection of Biological Products (ATCC)) and HCC827 (purchased from the American Standard Collection of Biological Products (ATCC) Both were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U/ml penicillin, and 100 μg/ml streptomycin.

Reagents and consumables:

RPMI-1640 (GIBCO, catalog number A10491-01); fetal bovine serum (GIBCO, catalog number 10099141); 0.25% trypsin-EDTA (GIBCO, catalog number 25200); penicillin-streptomycin, liquid (GIBCO, catalog number 15140-122); DMSO (Sigma, Cat. No. D2650); MTS Test Kit (Promega, Cat. No. G3581), 96-well plate (Coming, Cat. No. 3365).

Specific experimental methods:

Compound preparation: The test compound was dissolved in DMSO to prepare a 20 mM mother liquor and stored at -20 °C. Dilute 3 times with a gradient of DMSO and the like, and dilute 10 times. The drug medium was diluted 4 times with the drug.

MTS cell viability assay: 0.25% trypsin-EDTA digested logarithmic growth phase cells, inoculated with 150 μl in 96-well plates at an optimized density, and added to the medium 4 times after dilution for 4 hours, 50 μl/well (generally 10 Concentrations: 100, 33.3, 11.1, 3.70, 1.23, 0.412, 0.137, 0.0457, 0.0152, 0.00508 μM). A well of the same volume of 0.5% DMSO was added as a control. After the cells were cultured for 72 hours, MTS was assayed for cell viability.

Specific procedure: adherent cells, discard the medium, and add a mixture containing 20 μL of MTS and 100 μl of medium to each well. OD490 was detected after being placed in an incubator for 1-4 hours, with the OD650 value as a reference. Using GraphPad Prism software to make dose-response curves and calculate IC _50.

The results of the inhibition of in vitro proliferation of cancer cells in the examples are summarized in Table 2 below.

Table 2

Claims (23)

1. Compound of formula (I)

   

   among them,

   R _{1 is} independently selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

   R _{2 is} independently selected from H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

   Linker L is selected from

   1) C, N, O or S atoms, as long as valency allows; wherein C and N may be optionally substituted with R ^a;

   2) C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, C _3-10 carbocyclylene, 3 to 10 membered heterocyclylene, C _6-14 aroma Or a C _5-10 heteroarylene; wherein the group is optionally substituted with one or more R ^a ;

   3) -C (= O) - , - C (= O) O -, - C (= O) N (R b) -, - N (R b) C (= O) -, - N (R b C(=O)O-, -N(R ^b )C(=O)N(R ^b )-, -N(R ^b )S(=O)-, -N(R ^b )S(=O ₂ -, -OC(=O)-, -OC(=O)N(R ^b )-, -OS(=O)-, -OS(=O) ₂ -, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ O- or -S(=O) ₂ N(R ^b )-;

   R ^{a is} selected from H, halogen, -CN, -NO ₂ , oxo, C _1-6 alkyl, C _1-6 haloalkyl or C _1-6 alkoxy;

   R ^b is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

   X is selected from C or N atoms as long as the valence bond permits;

   Ring A is selected from a C _3-6 carbocyclic group, a 3 to 10 membered heterocyclic group, a C _6-14 aryl group or a C _5-10 heteroaryl group;

   R ₃ is selected from ^{_{halogen, -CN, -NO 2, -R c}} , -C (= O) R c, -C (= O) OR c, -C (= O) N (R c) (R c) , -N(R ^c )(R ^c ), -N(R ^c )C(=O)R ^c , -N(R ^c )C(=O)OR ^c , -N(R ^c )C(=O N(R ^c )(R ^c ), -N(R ^c )S(=O)R ^c , -N(R ^c )S(=O)N(R ^c )(R ^c ), -N(R ^c ) S(=O) ₂ R ^c , -N(R ^c )S(=O) ₂ N(R ^c )(R ^c ), -OR ^c , -OC(=O)R ^c , -OC(= O) OR ^c , -OC(=O)N(R ^c )(R ^c ), -S(=O)R ^c , -S(=O)OR ^c , -S(=O)N(R ^c ) (R ^c ), -S(=O) ₂ R ^c , -S(=O) ₂ OR ^c , -S(=O) ₂ N(R ^c )(R ^c ), -SC(=O)R ^c , -SC(=O)OR ^c or -SC(=O)N(R ^c )(R ^c ), as long as chemically permits;

   R ^{c is} selected from the group consisting of H, halogen, -CN, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl a 3- to 10-membered heterocyclic group, a C _6-14 aryl group or a C _5-10 heteroaryl group; wherein the C _3-10 carbocyclic group, a 3 to 10 membered heterocyclic group, a C _6-14 aryl group or The C _5-10 heteroaryl group is also optionally substituted by C _1-6 alkyl, C _1-6 haloalkyl or -C(=O)C _1-6 alkyl;

   m is 0, 1 or 2;

   n is 1, 2 or 3;

   p represents a single bond or a double bond, as long as the valence is allowed;

   q represents a single bond or a double bond, as long as the valence is allowed;

   R ₄ , R ₅ and R _{6 are} independently selected from H, halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl;

   W is selected from N, O or S atom, where N may optionally be substituted with R ^a;

   The premise is that when m is 0, X is a C atom;

   Or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof.
2. A compound according to claim 1, wherein R ₁ is halogen, -CN, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, and R ₂ is halogen, -CN, C _1-6 An alkyl group or a C _1-6 haloalkyl group, W is -O- or -NH-, and R ₄ , R ₅ and R ₆ are both H.
3. A compound according to claim 1 or 2, wherein R ₁ is Cl or a methoxy group, R ₂ is CF ₃ , W is -O- or -NH-, and R ₄ , R ₅ and R ₆ are both H.
4. A compound according to any one of claims 1 to 3, wherein L is selected from the group consisting of

   1) C, N or O atoms; optionally substituted with R ^a;

   2) C _1-6 alkylene, C _3-10 carbocyclylene, 3 to 10 membered heterocyclylene, C _6-14 arylene or C _5-10 heteroarylene; preferably, C _{1 -6} alkylene, C _3-10 alkylene group or a carbocyclic 3-10 yuan heterocyclylene; optionally substituted with R ^a;

   3) -C(=O)-, -C(=O)O-, -C(=O)N(R ^b )-, -N(R ^b )C(=O)-, -N(R ^b )S(=O) ₂ -, -OC(=O)-, -OS(=O)-, -OS(=O) ₂ -, -S(=O)- or -S(=O) ₂ - Preferably, -C(=O)-, -C(=O)O-, -C(=O)N(R ^b )-, -N(R ^b )C(=O)- or -OC( =O)-.
5. A compound according to any one of claims 1 to 4, wherein L is selected from the group consisting of

   1) C, N or O atoms; optionally substituted with R ^a;

   2) 3-10 yuan heterocyclylene; preferably 3-6 yuan heterocyclylene; more preferably, 5-6 yuan heterocyclylene; optionally substituted with R ^a;

   3) -C(=O)-, -C(=O)O- or -OC(=O)-; preferably, -C(=O)-.
6. A compound of claim 1 selected from the group consisting of:

   

   Wherein o is 0, ₁ , 2 or 3, and R _{1 -} R ₆ , R ^a , X, W, A, n, p and q are as defined in any one of claims 1-5.
7. A compound of claim 6 which is selected from the group consisting of:

   

   

   Wherein R _{1 -} R ₆ , R ^a , X, W, A, n and q are as defined in any one of claims 1-5.
8. A compound of claim 1 selected from the group consisting of:

   

   Wherein Y is selected from C, N, O or S atoms, o is 0, ₁ , 2 or 3, and R _{1 -} R ₆ , R ^a , X, W, n, p and q are as claimed in any one of claims 1 to 5 Defined by item.
9. A compound of claim 1 selected from the group consisting of:

   

   Wherein Y is selected from C, N, O or S atoms, o is 0, ₁ , 2 or 3, and R _{1 -} R ₆ , R ^a , W, n and q are as defined in any one of claims 1-5.
10. A compound of claim 1 selected from the group consisting of:

    

    Wherein R ₁ is Cl or methoxy, W is -O- or -NH-, and R ₃ and n are as defined in claim 1.
11. A compound according to any one of claims 1 to 10, wherein

    R _{3 is} selected from the group consisting of halogen, -CN, -R ^c , -C(=O)R ^c , -C(=O)OR ^c , -C(=O)N(R ^c )(R ^c ), -N( R ^c )(R ^c ), -S(=O)R ^c or -S(=O) ₂ R ^c as long as it is chemically acceptable;

    R ^{c is} selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, 3 to 10 membered heterocyclic; wherein the 3 to 10 membered heterocyclic group is optionally C _1-6 alkyl, C _{1 -6} haloalkyl or -C(=O)C _1-6 alkyl.
12. The compound of claim 11 wherein

    R _{3 is} selected from -R ^c , -C(=O)R ^c , -C(=O)OR ^c , -C(=O)N(R ^c )(R ^c ) or -S(=O) ₂ R ^c ;

    R ^{c is} selected from H, C _1-6 alkyl, C _1-6 haloalkyl or 5- to 6-membered heterocyclic; wherein the 5- to 6-membered heterocyclic group is optionally -C(=O)C _{1- 6} alkyl substitution.
13. A compound according to claim 12, wherein R _{3 is} selected from the group consisting of H, Me, -C(=O)Me, -C(=O)CF ₃ , -C(=O)OH, -C(=O)N(Me) (Me), -C(=O)N(Et)(Et), -C(=O)OtBu, -S(=O) ₂ Me or 1,4-piperidinylene, wherein the 1,4 - The piperidinylene group is substituted by -C(=O)Me.
14. A compound of claim 1 selected from the group consisting of:

    
15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof, and pharmaceutically acceptable Acceptable excipients.
16. The pharmaceutical composition of claim 15 further comprising an additional therapeutic agent.
17. Kit, which includes

    a first container comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof;

    Optionally, a second container containing other therapeutic agents; and

    Optionally, a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound and/or other therapeutic agent.
18. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof, for use in the treatment of cancer caused by EGFR Use of the drug.
19. A method of treating cancer caused by EGFR in a subject, the method comprising administering to the subject a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, stereoisomerism A pharmaceutically, solvated, hydrated, crystalline, prodrug or isotopic variant, or a pharmaceutical composition according to any one of claims 15-16.
20. The method of claim 18 or the method of claim 19, wherein the cancer caused by the EGFR is selected from the group consisting of: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer , epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma.
21. The use or method of claim 20, wherein the cancer caused by EGFR is a T790M mutation, a L858R mutation, and a L858R/T790M double mutation in non-small cell lung cancer.
22. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof, or any of claims 15-16 A pharmaceutical composition for treating cancer caused by EGFR.
23. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof, or any of claims 15-16 A pharmaceutical composition for treating a T790M mutation, a L858R mutation, and a L858R/T790M double mutation in non-small cell lung cancer.