CN110437163A - Pyrimidines as tyrosine kinase inhibitor - Google Patents

Abstract

This disclosure relates to pyrimidine compound shown in Formulas I, the pharmaceutical composition comprising these one or more compounds and their purposes as tyrosine kinase inhibitor and epidermal growth factor receptor inhibitor.The disclosure additionally provides the method for the treatment of cancer.

Description

Pyrimidines as tyrosine kinase inhibitor

Cross reference to related applications

This application claims the priority for the U.S. Provisional Application 62/666,382 submitted on May 3rd, 2018, this application Full content is incorporated herein by reference.

Technical field

The disclosure belongs to field of medicinal chemistry.Particularly, this disclosure relates to pyrimidine compound, comprising it is one or more these The pharmaceutical composition of compound and their use as tyrosine kinase inhibitor and epidermal growth factor receptor inhibitor On the way.The disclosure additionally provides the method for the treatment of cancer.

Background technique

Tyrosine kinase inhibitor (TKIs) to EGF-R ELISA (EGFR) with specificity is with EGFR Clinical activity is shown in the Patients with Non-small-cell Lung of activated mutant.Referring to Hidaka et al., " Most T790M mutations are present on the same EGFR allege as activating mutations in subjects with non-small cell lung cancer,”Lung Cancer 108:76-82(2017)。

It may be common for the uncommon acquired EGFR medicament-resistant mutation for Buddhist nun difficult to understand；Mutation in EGFR C797S can eliminate Austria The uncommon covalent bond with EGFR for Buddhist nun.Referring to Ou et al. " Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796(G796S/R)together with C797S/R and K792F/H mutations in one EGFR(L858R/T790M)NSCLE subject who progressed on osimertinib,"Lung Cancer108:228-231(2017).C797S mutation will not the significant structure for changing EGFR kinases And function, but the mutation increase it is locally hydrophilic around 797 residues.Referring to Kong et al. " Structural pharmacological studies on EGFR T790M/C797S,”Biochemical and Biophysical Research Communications 488:266-272(2017)。

With EGFR mutation lung cancer can for example to Gefitinib and Tarceva EGFR tyrosine kinase inhibitor It is highly sensitive.Referring to Mitsudomi et al. " Epidermal growth factor receptor in relation to tumor development:EGFR gene and cancer,”FEBS Journal 277:301-308(2010)。

Afatinib has been disclosed as the advanced stage EGFR saltant type Patients with Non-small-cell Lung after first generation TKIs failure Potential treatment drug.Referring to Zhang et al. " The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first- generation tyrosine kinase inhibitors:a systematic review and meta-analysis,” Journal of Thoracic Disease 9(7):1980-1987(2017).Afatinib is wished in structure with Austria for Buddhist nun not Together, their combination is different；Afatinib can even be combined in a manner of unexpected.Referring to Ramalingam et al. “Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non- Small-Cell Lung Cancer,"Journal of Clinical Oncology(2017)；Also referring to Thress et al. “Acquired EGFR C797S mutation mediates resistance to AZD9291in non-small cell lung cancer harboring EGFR T790M,"Nature Medicine 21(6):560-564(2015)；Duong- Ly et al. " Kinase inhibitor profiling reveals unexpected opportunities to inhibit disease-associated mutant kinases,"Cell Rep.14(4):772-781(2016)；Yosaatmadja etc. People " Binding mode of the breakthrough inhibitor AZD9291to epidermal growth factor receptor revealed,”Journal of Structural Biology192:539-544(2015)。

Mutation simulated compound and use in conjunction with the kinase domain of EGFR have specificity to Survivin albumen Small molecule therapy cancer or the method for tumour studied in United States Patent (USP) 8,710,068 and 9,295,676.

Summary of the invention

In certain embodiments, present disclose provides the compound of formula (I),

Or its pharmaceutically acceptable salt, wherein formula (I) compound is as defined herein.

In certain embodiments, present disclose provides the compound of formula (II),

Or its pharmaceutically acceptable salt, wherein formula (II) compound is as defined herein.

In certain embodiments, present disclose provides the pharmaceutical compositions comprising formula (I) or formula (II) compound.At certain In a little embodiments, this disclosure provides the methods for the treatment of cancer comprising applying treatment to subject in need has The compound of effect amount.

It has been found that formula (I) or formula (II) compound is the inhibitor of EGFR kinases.It is not wishing to be bound by theory, predicts this A little compounds inhibit EGFR kinases by the chamber near ATP binding pocket in targeting kinase domain.The inhibitor performance Out for C797S, L858R and T790M mutation and the activity of EGFR sensitizing mutation.The inhibitor can also inhibit potently The activity of HER2.

In view of the benefit of the disclosure, the various embodiments and embodiment of invention disclosed herein theme are general for this field Logical technical staff is possible and will be apparent.In the disclosure, to " some embodiments ", " certain embodiment party The reference of case ", " certain exemplary implementation schemes " and similar phrase indicates that those embodiments are the non-limits of present subject matter Property example processed, and there may be the alternative embodiments being not excluded for.

The article " one " used herein, "one" refers to one or more than one (i.e. at least one) of the article with "the" Grammar object.For example, " element " indicates an element or more than one element.

As used herein, term " about " indicates ± the 10% of described value.It only for example, include the change of " about 30wt.% " The composition for closing object may include the compound of 27wt.% to the compound of 33wt.%.

Word " comprising " by with its open meaning it is consistent in a manner of use, that is, mean that given product or method can be optional Ground also has supplementary features or element other than those of being expressly recited.It should be appreciated that with " comprising " language description Any embodiment, in addition to this it is expected that with term " by ... form " and/or " substantially by ... form " retouch The similar embodiment mode stated, and within the scope of this disclosure.

The compound of the disclosure

In certain embodiments, present disclose provides the compound of formula (I),

Wherein

Q is

R₁It independently is H, the amino that optionally replaces, the C optionally replaced_1-6Alkyl, the C optionally replaced_1-6Alkoxy, optionally Substituted C_2-6Alkenyl, the C optionally replaced_2-6Alkynyl, cyano, halogen, hydroxyl, nitro, optionally replaces the benzyloxy optionally replaced Phenoxy group or mono-, two- or trifluoromethyl；

N is 1,2 or 3；

R₂It is H or C_1-6Alkyl；

R₃It is H or C_1-6Alkyl；

R₄It is H, N (R₆)₂, the optionally C that replaces_1-3Alkyl, the C optionally replaced_1-3Alkoxy, cyano, halogen, hydroxyl, nitre Base, (S) -3- ((tetrahydrofuran -3- base) oxygroup) or mono-, two- or trifluoromethyl；

R₅It is H or C_1-6Alkyl；

R₆It is independently H, C_1-3Alkyl, C_1-6Alkylamine or C_1-6Alkyl hydroxy；

X is C_1-6Alkyl ,-N (R₅)C(O)-、-O-(C_1-6Alkyl)-,-N (R₅)-(C_1-6Alkyl)-,-C (O) N (R₅)-、-C (O)N(R₅)-(C_1-6Alkyl)-,-SO₂N(R₅)-or-N (R₅)SO₂-(C_1-6Alkyl)-；

Y is

R₇It is C_1-6Alkyl, C_1-6Alkyl hydroxy, the C optionally replaced_1-6Alkyl ether, C_1-6Alkyl carboxylic acid, C_1-6Alkyl dicarboxyl Acid, the C optionally replaced_1-6Arrcostab, C_1-6Alkyl carboxylate or ester, the C optionally replaced_1-6Alkyl phosphoric acid or C_1-6Alkylsurfuric acid；

R₈It is C_1-6Alkyl；

R₉It is C_1-6Alkyl carboxylic acid；

U is C or N；

R₁₀It is C_1-6Alkyl carboxylic acid, C_1-6Alkylol, C_1-6Alkyl ether or C_1-6Arrcostab；

R₁₁It is H, C_1-6Alkyl, C_1-6Alkylol, C_1-6Alkyl ether or C_1-6Arrcostab；

W is C, S or O；

R₁₂It is C_1-6Alkyl carboxylic acid or C_1-6Alkyl hydroxy；

R₁₃It is H or C_1-6Alkyl；

R₁₄It is C_1-6Alkyl；

J is O or S；

R₁₅It is the naphthenic base optionally replaced, the Heterocyclylalkyl optionally replaced, the aryl optionally replaced, the heteroaryl optionally replaced Base, C_1-6Cyanoalkyl；With

R₁₆It is the aryl or Heterocyclylalkyl optionally replaced；

Wherein * represents connection site,

Or pharmaceutically acceptable salt.

In certain embodiments, Q can be

In certain embodiments, Q can be

In certain embodiments, Q can be

In certain embodiments, Q can be

In certain embodiments, Q can be

In certain embodiments, Q can be

In certain embodiments, Q can be

In certain embodiments, Q can be

In certain embodiments, R₁It can be cyano or halogen.In certain embodiments, R₁It can be fluorine or chlorine.

In certain embodiments, n can be 1.In certain embodiments, n can be 2.In certain embodiments, N can be 3.

In certain embodiments, R₂It can be H.In certain embodiments, R₂It can be methyl or ethyl.

In certain embodiments, R₃It can be H.In certain embodiments, R₃It can be methyl or ethyl.

In certain embodiments, R₄It can be the C optionally replaced_1-6Alkoxy.In certain embodiments, C_1-6Alcoxyl Base can be by C_1-6Alkyl hydroxy, C_1-3Alkoxy, C_3-6Naphthenic base or the Heterocyclylalkyl optionally replaced replace.In certain embodiment party In case, R₄It can be N (R₆)₂。

In certain embodiments, R₄It can be C_1-3Alkoxy.In certain embodiments, R₄It can be ethyoxyl.

In certain embodiments, X can be C_1-6Alkyl.In certain embodiments, X can be-N (R₅)C(O)-。 In certain embodiments, X can be-O- (C_1-6Alkyl)-.In certain embodiments, X can be N (R₅)-(C_1-6Alkane Base)-.In certain embodiments, X can be-C (O) N (R₅)-.In certain embodiments, X can be-C (O) N (R₅)- (C_1-6Alkyl)-.In certain embodiments, X can be-SO₂N(R₅)-.In certain embodiments, X can be-N (R₅SO₂-(C_1-6Alkyl)-.

In certain embodiments, Y can be

In certain embodiments, Y can be

In certain embodiments, Y can be

In certain embodiments, Y can be

In certain embodiments, Y can be

In certain embodiments, Y can be

In certain embodiments, Y can be

In certain embodiments, R₇It can be C_1-6Alkyl carboxylic acid.In certain embodiments, R₇It can be optional substitution C_1-6Arrcostab.In certain embodiments, R₇It can be C_1-6Alkyl dicarboxylic aid.In certain embodiments, R₇It can be and appoint Choose the C in generation_1-6Alkyl phosphoric acid.

In certain embodiments, R₁₀It can be C_1-6Alkylol.In certain embodiments, R₁₀It can be C_2-4Alkyl Alcohol.In certain embodiments, R₁₀It can be C₃Alkylol.In certain embodiments, R₁₀It can be C₂Or C₄Alkylol.

In certain embodiments, R₁₀It can be C_1-6Alkyl ether.In certain embodiments, R₁₀It can be C₁Alkyl ether, C₂Alkyl ether, C₃Alkyl ether, C₄Alkyl ether, C₅Alkyl ether or C₆Alkyl ether.In certain embodiments, R₁₀Can be- CH₂CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₃、-CH₂OCH₂CH₂CH₃、-CH₂CH₂CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₂CH₃、- CH₂CH₂OCH₂CH₂CH₃Or-CH₂OCH₂CH₂CH₂CH₃。

In certain embodiments, R₁₀It can be C_1-6Arrcostab.In certain embodiments, R₁₀It can be C₁Arrcostab, C₂Arrcostab, C₃Arrcostab, C₄Arrcostab, C₅Arrcostab or C₆Arrcostab.In certain embodiments, R₁₀Can be- CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂OC (=O) CH₃Or-CH₂CH₂CH₂CH₂OC (=O) CH₃。

In certain embodiments, R₁₁It can be C_1-6Alkylol.

In certain embodiments, R₁₁It can be H or C_1-6Alkyl.In certain embodiments, R₁₁Can be H or C_1-3Alkyl.In certain embodiments, R₁₁It can be methyl.

In certain embodiments, W can be C.In certain embodiments, W can be S.In certain embodiments, W can be O.

In certain embodiments, R₁₂It can be C_1-6Alkyl carboxylic acid.In certain embodiments, R₁₂It can be C_1-6Alkane Base alcohol.

In certain embodiments, J can be O.In certain embodiments, wherein J can be S.

In certain embodiments, U can be N.

In certain embodiments, R₁₅It can be the naphthenic base optionally replaced.In certain embodiments, R₁₅It can be The Heterocyclylalkyl optionally replaced.

In certain embodiments, R₁₆It can be the aryl optionally replaced.In certain embodiments, R₁₆It can be and appoint Choose the Heterocyclylalkyl in generation.

In certain embodiments, the compound of the disclosure can have the following structure:

Or its pharmaceutically acceptable salt.

In certain embodiments, the compound of the disclosure can have the following structure:

Or its pharmaceutically acceptable salt.

In certain embodiments, the compound of the disclosure can have the following structure:

Or its pharmaceutically acceptable salt.

In certain embodiments, the compound of the disclosure can have the following structure:

Or its pharmaceutically acceptable salt.

In certain embodiments, the disclosure provides formula (II) compound,

Wherein,

R₁₀It is C_1-6Alkyl carboxylic acid, C_1-6Alkylol, C_1-6Alkyl ether or C_1-6Arrcostab；

R₁₁It is H, C_1-6Alkyl, C_1-6Alkylol, C_1-6Alkyl ether or C_1-6Arrcostab；

R₁₇It is the aryl optionally replaced or the heteroaryl optionally replaced；

R₁₈It is H or C_1-6Alkyl；With

R₁₉It is H, the amine optionally replaced or the diamines optionally replaced

Or its pharmaceutically acceptable salt.

In certain embodiments, R₁₇It can be the bicyclic aryl optionally replaced or the bicyclic heteroaryl optionally replaced.In In certain embodiments, R₁₇It can be the indoles optionally replaced.

In certain embodiments, the compound of the disclosure can have the following structure:

Or its pharmaceutically acceptable salt.

In certain embodiments, the preferred embodiment as formula (I) compound, present disclose provides the chemical combination of formula (III) Object or its pharmaceutically acceptable salt,

Wherein,

R₁Selected from cyano or halogen；

R₄It is the C optionally replaced_1-3Alkoxy or (S) -3- ((tetrahydrofuran -3- base) oxygroup)；

R₁₀It is C_1-6Alkyl carboxylic acid, C_1-6Alkyl ether or C_1-6Arrcostab；

R₁₁It is H or C_1-6Alkyl.

In certain embodiments, R₁It can be fluorine or chlorine.

In certain embodiments, R₄It is the C optionally replaced_1-3Alkoxy；In certain embodiments, R₄It is ethyoxyl.

In certain embodiments, R₁₀It is C_1-6Alkyl ether or C_1-6Arrcostab；In certain embodiments, R₁₀It is C₁Alkane Base ether, C₂Alkyl ether, C₃Alkyl ether, C₄Alkyl ether, C₅Alkyl ether, C₆Alkyl ether, C₁Arrcostab, C₂Arrcostab, C₃Arrcostab, C₄ Arrcostab, C₅Arrcostab or C₆Arrcostab；In certain embodiments, R₁₀It is CH₂CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₃、- CH₂OCH₂CH₂CH₃、-CH₂CH₂CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₂CH₂CH₃、- CH₂OCH₂CH₂CH₂CH₃、-CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂OC (=O) CH₃、 Or-CH₂CH₂CH₂CH₂OC (=O) CH₃。

In certain embodiments, R₁₁It can be H or C_1-3Alkyl；In certain embodiments, R₁₁It can be methyl.

In certain embodiments, the more preferable mode as formula (I) compound, present disclose provides the chemical combination of formula (IV) Object or its pharmaceutically acceptable salt,

Wherein,

R_1aOr R_1bIt is each independently selected from cyano or halogen；

R₄It is the C optionally replaced_1-3Alkoxy or (S) -3- ((tetrahydrofuran -3- base) oxygroup)；

R₁₀It is C_1-6Alkyl carboxylic acid, C_1-6Alkyl ether or C_1-6Arrcostab；

R₁₁It is H or C_1-6Alkyl.

In certain embodiments, R_1aOr R_1bIt is each independently selected from fluorine or chlorine；In certain embodiments, R_1aIt is Fluorine, R_1bIt is chlorine.

In certain embodiments, R₄It is the C optionally replaced_1-3Alkoxy；In certain embodiments, R₄It is ethyoxyl.

In certain embodiments, R₁₀It is C_1-6Alkyl ether or C_1-6Arrcostab；In certain embodiments, R₁₀It is C₁Alkane Base ether, C₂Alkyl ether, C₃Alkyl ether, C₄Alkyl ether, C₅Alkyl ether, C₆Alkyl ether, C₁Arrcostab, C₂Arrcostab, C₃Arrcostab, C₄ Arrcostab, C₅Arrcostab or C₆Arrcostab；In certain embodiments, R₁₀It is CH₂CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₃、- CH₂OCH₂CH₂CH₃、-CH₂CH₂CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₂CH₂CH₃、- CH₂OCH₂CH₂CH₂CH₃、-CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂OC (=O) CH₃、 Or-CH₂CH₂CH₂CH₂OC (=O) CH₃。

In certain embodiments, R₁₁It can be H or C_1-3Alkyl；In certain embodiments, R₁₁It can be methyl.

In certain embodiments, present disclose provides the above compounds for treating cancer.In certain embodiments In, present disclose provides its pharmaceutically acceptable salt of the above compound for treating cancer or its pharmaceutical compositions.At certain In a little embodiments, cancer can be lung cancer, head cancer, neck cancer or cancer of pancreas.

In certain embodiments, present disclose provides its pharmaceutically acceptable salt of above compound or its medicine groups Close purposes of the object in the drug of preparation treating cancer.In certain embodiments, cancer can be lung cancer, head cancer, neck cancer or Cancer of pancreas.

In certain embodiments, present disclose provides its pharmaceutically acceptable salt of above compound or its medicine groups Close purposes of the object in treating cancer.In certain embodiments, cancer can be lung cancer, head cancer, neck cancer or cancer of pancreas.

In certain embodiments, the disclosure provides the method for the treatment of cancer comprising applies to subject in need The disclosure compound or its pharmaceutically acceptable salt of therapeutically effective amount.In certain embodiments, the disclosure provides treatment The method of cancer comprising apply the disclosure compound of therapeutically effective amount to subject in need or its is pharmaceutically acceptable Salt or its pharmaceutical composition.In certain embodiments, cancer can be lung cancer, head cancer, neck cancer or cancer of pancreas.

Preferably, in certain embodiments, the cancer is selected from EGFR saltant type cancer；In certain embodiments, The cancer is selected from the EGFR saltant type that there is L858R, T790M, C797S or d746-750 to choose any one kind of them the above gene mutation Cancer；In certain embodiments, the cancer is selected from the EGFR saltant type cancer with L858R gene mutation；In certain realities It applies in scheme, the cancer is selected from the EGFR saltant type cancer with T790M gene mutation；In certain embodiments, described Cancer is selected from the EGFR saltant type cancer with C797S gene mutation；In certain embodiments, the cancer is selected from and has The EGFR saltant type cancer of d746-750 gene mutation.

It is highly preferred that in certain embodiments, the cancer be selected from C797S, d746-750/T790M/C797S, The EGFR saltant type cancer of L858R, L858R/T790M or L858R/T790M/C797S gene mutation.

In certain embodiments, the disclosure provides pharmaceutical composition, and it includes the disclosure compounds of therapeutically effective amount Or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers.

Detailed description of the invention

Fig. 1 SGI-078 compound nuclear magnetic resonance spectroscopy.

Fig. 2 SGI-078 mass spectrum.

Fig. 3 SGI-105 compound nuclear magnetic resonance spectroscopy.

Fig. 4 SGI-105 mass spectrum.

Fig. 5 SGI-106 compound nuclear magnetic resonance spectroscopy.

Fig. 6 SGI-106 mass spectrum.

Specific embodiment

Definition

As used herein, term " compound of the disclosure " or " compound of the disclosure " refer to disclosed herein appoint What compound or its pharmaceutically acceptable salt, such as the compound or its medicine of formula (I) or formula (II) or formula (III) or formula (IV) Acceptable salt on.

As used herein, term " halogenated " and " halogen " refer to fluorine, chlorine, bromine or iodine.

As used herein, term " C_1-6Alkyl " itself or a part of use as another group refer to 1 to 6 The straight chain and branched non cyclic saturated hydrocarbons of carbon atom.In certain embodiments, alkyl group can be selected from straight chain (C₁-C₆) alkyl Group and branch (C₃-C₆) alkyl group.(C₁-C₆) alkyl group can be methyl, ethyl, propyl, isopropyl, butyl, Zhong Ding Base, tert-butyl, isobutyl group, amyl, 3- amyl, hexyl etc..In certain embodiments, alkyl group can be straight chain (C₂-C₆) Alkyl group and branch (C₃-C₆) alkyl group.(C₂-C₆) alkyl group can be ethyl, propyl, isopropyl, butyl, Zhong Ding Base, tert-butyl, isobutyl group, amyl, 3- amyl, hexyl etc..In certain embodiments, alkyl group can be straight chain (C₁-C₄) Alkyl group and branch (C₃-C₄) alkyl group.(C₁-C₄) alkyl group can be methyl, ethyl, propyl, isopropyl, butyl, Sec-butyl, tert-butyl and isobutyl group.

As used herein, term " C_2-6Alkenyl " itself or a part of use as another group refer to 2 to 6 Carbon atom and straight chain and branched non cyclic hydrocarbon including at least one carbon-to-carbon double bond.Straight chain and branch C_2-6Alkenyl can be ethylene Base, allyl, 1- cyclobutenyl, 2- cyclobutenyl, isobutenyl, 1- pentenyl, 2- pentenyl, 3-methyl-1-butene base etc..At certain In a little embodiments, C_2-6Alkenyl can be C_2-4Alkenyl.C_2-4Alkenyl can be vinyl, acrylic, isopropenyl, cyclobutenyl With secondary cyclobutenyl.

As used herein, term " C_2-6Alkynyl " itself or a part of use as another group refer to 2 to 6 Carbon atom and straight chain and branched non cyclic hydrocarbon including at least one carbon-carbon triple bond.Straight chain and branch C_2-6Alkynyl can be acetylene Base, propinyl, butine -1- base, crotonylene-base, pentyne -1- base, pentyne -2- base, 3- methyl butyne -1- base, pentyne -4- base, Hexin -1- base, hexin -2- base, hexin -5- base etc..C_2-6Alkynyl include acetenyl (i.e. acetenyl), propinyl, 1- butynyl, 2- butynyl, 1- pentynyl, valerylene base, 3- methyl-1-butynyl, 4- pentynyl etc..In certain embodiments, C_2-6Alkynes Base can be C_2-4Alkynyl.C_2-4Alkynyl can be acetenyl, propinyl, butynyl and 2- butynyl.

As used herein, term " C_1-6Alkyl hydroxy " itself or a part as another group can be by one or Any of above C that multiple hydroxyls replace_1-6Alkyl.C_1-6Alkyl hydroxy can be methylol, ethoxy, hydroxypropyl and hydroxyl butyl, Such as methylol, 1- ethoxy, 2- ethoxy, 1,2- dihydroxy ethyl, 2- hydroxypropyl, 3- hydroxypropyl, 3- hydroxyl butyl, 4- hydroxyl fourth Base, 2- hydroxyl -1- methyl-propyl and 1,3- dihydroxy propyl- 2- base.

As used herein, " naphthenic base " group can be selected from containing 1,2 or 3 ring have 3,4,5,6,7,8,9,10,11, Or saturated cyclic (the i.e. C of 12 carbon atoms_3-12Naphthenic base).In certain embodiments, naphthenic base can have one or two A ring.In certain embodiments, naphthenic base can be C_3-8Naphthenic base.In certain embodiments, naphthenic base can be C_3-7 Naphthenic base.In certain embodiments, naphthenic base can be C_3-6Naphthenic base.In certain embodiments, naphthenic base can be ring Propyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, norborny, decahydronaphthalenes and adamantyl.

As used herein, term " heterocycle " or " Heterocyclylalkyl " itself or a part of use as another group refer to 3 It is saturation or unsaturated and non-aromatic to 12 unit monocycle heterocycles.3 circle heterocyclic rings can contain 1 hetero atom；4 yuan miscellaneous Ring can contain 2 hetero atoms；5 circle heterocyclic rings can contain 4 hetero atoms；6 circle heterocyclic rings can contain 4 hetero atoms；7 circle heterocyclic rings can contain 5 hetero atoms.Each hetero atom can be independently selected from nitrogen (can be quaternized), oxygen and sulphur (including sulfoxide and sulfone).(3- It is first to 12-) heterocycle can pass through nitrogen or carbon atom connects.(3- to 12- member) heterocyclic group can be thiazolidinyl, morpholinyl, Pyrrolidone-base, pyrrolidinyl, piperidyl, piperazinyl, 2,3 dihydro furan base, dihydro pyranyl, hydantoins, valerolactam Base, Oxyranyle, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, dihydropyridine base, tetrahydro pyridyl, tetrahydro are phonetic Piperidinyl, tetrahydro-thienyl, tetrahydro thiapyran base etc..

As used herein, term " C_1-6What alkoxy " itself or a part as another group used, which can be, has The linear chain or branched chain non-cyclic hydrocarbon of one or more ethers and 1 to 6 carbon atom.Straight chain and branch C_1-6Alkoxy can be first Oxygroup, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy, methoxy, 2- methoxy ethyl, 5- methoxypentyl, 3- ethoxybutyl, methoxyl group n-propyl etc..

As used herein, term C_n-mAlkyl ether refers to the ether containing n-m carbon, specifically for example, C_1-6Alkyl ether is to contain The ether of 1-6 C；It can also be expressed as R₁₇-O-R₁₈, wherein R₁₇And R₁₈Respectively stand alone as C_1-6Alkyl.

As used herein, term C_n-mArrcostab refers to the ester containing n-m carbon, specifically for example, C_1-6Arrcostab is to contain The ester of 1-6 C；It can also be expressed as R₁₉-COO-R₂₀, wherein R₁₉And R₂₀Respective independent C_1-5Alkyl.

As used herein, term " aryl " can be C_6-14Aryl, such as C_6-10Aryl.C_6-14Aryl can be phenyl, naphthalene Base, phenanthryl, anthryl, indenyl, azulenyl, xenyl, biphenylene and fluorenyl, such as phenyl, naphthalene and xenyl.Certain In embodiment, aryl can be (6 to 12 yuan) aryl.

As used herein, term " heteroaryl " itself or a part of use as another group can be 5 to 12 at The aromatic heterocycle of member, including monocycle and bicyclic system, wherein at least one carbon atom (one or two ring) are independently selected Replace from the hetero atom of nitrogen, oxygen and sulphur or at least two carbon atoms of one or two ring are independently selected from nitrogen, oxygen and sulphur Hetero atom replace.(5- to 12- member) heteroaryl can be pyridyl group, furyl, benzofuranyl, thienyl, benzothiophene Base, quinolyl, isoquinolyl, pyrrole radicals, indyl, oxazolyl, benzoxazolyl, imidazole radicals, benzimidazolyl, thiazolyl, Benzothiazolyl, isoxazolyl, oxadiazoline base, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidine radicals, pyrimidine radicals, pyrazinyl, thiophene Di azoly, triazine radical, thienyl, thiadiazolyl group, quinolyl, phthalazinyl, quinazolyl etc..

As used herein, term " amino " refers to-NH₂。

As used herein, term " hydroxyl " refers to-OH.

As used herein, term " cyano " refers to-CN.

As used herein, term " nitro " refers to-NO₂。

As used herein, term " carboxylic acid " refers to-COOH.

Choose the optional substituent group on the group in generation, unless otherwise indicated, including one or more groups, for example, 1,2 or 3 groups, independently selected from above-mentioned halogen, halogenated (C_1-6) alkyl, aryl, heterocycle, naphthenic base, C_1-6Alkyl, C_2-6Alkenyl, C_2-6 Alkynyl, aryl (C_1-6) alkyl, aryl (C_2-6) alkenyl, aryl (C_2-6) alkynyl, naphthenic base (C_1-6) alkyl, heterocycle (C_1-6) alkyl, Hydroxyl (C_1-6) alkyl, amino (C_1-6) alkyl, carboxyl (C_1-6) alkyl, alkoxy (C_1-6) alkyl, nitro, amino, urea groups, cyanogen Base, alkyl-carbonyl-amino, hydroxyl, sulfydryl, alkyl carbonyl epoxide, aryloxy group (such as phenoxy group and benzyloxy), virtue (C_1-6) alcoxyl Base, formamido, sulfonamido, azido, C_1-6Alkoxy, halogenated (C_1-6) alkoxy, carboxyl, amino carbonyl, (=O) and mercapto Base (C_1-6) alkyl.Preferred optionally substituent group includes halogen, halogenated (C_1-6) alkyl, hydroxyl (C_1-6) alkyl, amino (C_1-6) alkane Base, hydroxyl, nitro, C_1-6Alkyl, C_1-6Alkoxy, halogen (C_1-6) alkoxy and amino.

The compound of the disclosure includes the institute of the compound of disclosed formula (I) or formula (II) or formula (III) or formula (IV) There is salt.The disclosure includes its all nontoxic pharmaceutically acceptable salt of disclosed compound.In certain embodiments, medicine Acceptable addition salt can be inorganic and addition salts and basic salt of organic acid on.In certain embodiments, pharmaceutically Acceptable salt can be metal salt, such as sodium salt, sylvite, cesium salt etc.；Alkaline-earth metal, such as calcium salt, magnesium salts；Organic amine salt is such as Triethylamine salt, pyridiniujm, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexyl amine salt, N, N'- dibenzyl ethylenediamine salt Deng；Inorganic acid salt such as hydrochloride, hydrobromate, phosphate, sulfate etc.；Acylate such as citrate, lactate, tartaric acid Salt, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalates, formates etc.；Sulphur Hydrochlorate such as mesylate, benzene sulfonate, tosilate etc.；And amino-acid salt, such as arginine salt, aspartate, paddy ammonia Hydrochlorate etc..

In certain embodiments, the compound of the disclosure can be containing one or more asymmetric centers, therefore can be with Generate enantiomter, diastereoisomer and other stereoisomeric forms in any ratio, such as epimer.Present disclosure is intended to contain It covers the purposes of all these possible forms and their racemic and splits form and its mixture.In view of present disclosure, Each enantiomer can be separated according to method known to persons of ordinary skill in the art.When compound as described herein contains olefinic When double bond or other geometry asymmetric centers, unless otherwise indicated, they include E and Z geometric isomer.All tautomers It is also included in the disclosure.

As used herein, term " stereoisomer " is the generic term of all isomers of individual molecule, the isomery Body is only different in the orientation of its space atom.It includes enantiomter and the compound with more than one chiral centre Enantiomer, these enantiomers are not mirror-images of each other (diastereomer).

Term " chiral centre " refers to the carbon atom of group connections different from four.

Term " epimer " refers to diastereoisomer, in corresponding molecular entity, has only at two or more There are an opposite configurations in multiple tetrahedron generations center.

Term " Stereocenter " is the atom with group, so that the exchange of any two group generates stereoisomer.

Term " enantiomter " and " enantiomter " refer to the molecule that cannot be superimposed on its mirror image, and therefore, it is It is optically active, wherein enantiomer rotatory polarization optical plane in one direction, and its mirror image compounds is in the opposite direction Rotatory polarization optical plane.

Term " racemic " refers to the mixture of the enantiomer of equal portions, and the mixture is that optics is inactive.

As used herein, term " treatment (treating) ", " treatment (treat) " or " treatment (treatment) " refer to Therapeutic treatment and preventative or preventive measure, wherein purpose is prevention or slows down (mitigation) undesirable physiological status, disease Disease or disease, or obtain beneficial or desired clinical effectiveness.For purposes of the present invention, beneficial or desired clinical effectiveness includes But it is not limited to mitigate symptom；Reduction situation, the degree of conditions or diseases；Situation, the stabilization of conditions or diseases state (are not disliked Change)；Delayed onset slows down situation, the progress of conditions or diseases；Improvement situation, conditions or diseases state；(either with alleviation It is partial or whole), either detectable or undetectable or situation, conditions or diseases enhancing or Improve.Treatment includes causing clinically significant reaction, with or without excessive side effect.Treatment may include patient's The inhibition of the cell Proliferation or tumour growth of disease being treated, the improvement of symptom, extension survival mitigate its bad shadow It rings.In certain embodiments, the compound of the disclosure can be used at least one combination with other therapeutic agents.

As used herein, term " L858R/T790M ", " d746-750/T790M/C797S ", " L858R/T790M/ C797S " is indicated while being had the gene mutation.Such as the EGFR saltant type cancer of L858R/T790M/C797S gene mutation Disease indicates L858R, T790M and C797S treble genes mutation type EGFR saltant type cancer.

Treatment method and pharmaceutical composition

Due to their activity, the compound of the disclosure be can be advantageously used in medicine.As described above, the chemical combination of the disclosure Object can be used for treating the cancer of subject with this need.Term " subject " as used herein, which refers to, can undergo the disclosure Any animal of the beneficial effect of compound.Primary animal is mammal, such as the mankind and companion animals, but the disclosure Content is not limited to this.

In order to detect the expression or activity of EGFR, the tissue obtained from subject (cancerous tissue, vascular wall tissue, skin, mouth Transmucosal etc.) or body fluid (blood, lymph) etc. can be applied to the expression or active test of detection EGFR.These tests are abilities Known to field technique personnel.

When being applied to subject, the compound of the present invention be can be used as comprising pharmaceutically acceptable carrier or excipient Composition component application.The compound of the present invention can be applied by any approach appropriate, as determined by doctor.It gives Prescription method may include intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, Epidural cavity, oral, sublingual, oral cavity, Intracerebral, intravaginal, transdermal, transmucosal, rectum, sucking or part (such as ear, nose, eyes or skin).Distribution can be office Portion or system.In certain embodiments, application can lead to disclosure compound and be discharged into blood flow.

The pharmaceutical composition of the disclosure can take solution, suspension, lotion, tablet, pill, granule, powder, more Grain, the capsule containing liquid, the capsule containing powder, contains granose capsule, lozenge, extended release preparation, bolt at capsule Agent, transdermal patch, transmucosal film, sublingual tablet, aerosol, spray or any other be suitble to the form used.In a reality It applies in scheme, composition is in tablet form.

In one embodiment, composition is in capsule form (see, for example, United States Patent (USP) No.5,698,155).Its His suitable drug excipient example is described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R.Gennaro ed., 19th ed.1995) is introduced as quotation.

The pharmaceutical composition of the disclosure may include proper amount of pharmaceutically acceptable excipient, to provide for tested The form that person properly applies.In certain embodiments, drug excipient can be diluent, suspending agent, solubilizer, bonding Agent, disintegrating agent, preservative, colorant, lubricant etc..Drug excipient can be liquid, such as water or oil, including petroleum, dynamic Those of object, plant or synthesis source, such as peanut oil, soybean oil, mineral oil, sesame oil etc..Drug excipient can be salt Water, gum arabic, gelatin, gelatinized corn starch, talcum, keratin, colloidal silicon dioxide, urea etc..Adjuvant, stabilization can be used Agent, thickener, lubricant and colorant.In certain embodiments, when giving subject, pharmaceutically acceptable excipient It can be sterile.When the intravenously compound of the application disclosure, water can be excipient.Saline solution and glucose are water-soluble Liquid and glycerite also are used as liquid excipient, such as Injectable solution.In certain embodiments, drug excipient It may include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, odium stearate, glycerol list tristearin Acid esters, talcum, sodium chloride, dry skimmed milk, glycerol, propylene glycol, water, ethyl alcohol etc..In certain embodiments, composition can contain A small amount of wetting agent or emulsifier or pH buffer.It can be used for preparing the pharmaceutically acceptable carrier and excipient of peroral dosage form Specific example be described in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association(1986)。

In certain embodiments, the compound of the disclosure can be formulated for oral administration preparation.To oral delivery Disclosure compound for example can be tablet, capsule, soft capsule, caplet, pastille, aqueous or oily solution, suspension, particle, The form of powder, lotion, syrup or elixir.It, can be by this tablet pressure when mixing the compound of the present invention in oral tablet System, tablet crush, enteric coating, sweet tablet, film coating, multiple tabletting or multilayer package.

The oral administration of Compound of the disclosure can contain one or more other adjuvants, such as sweetener, such as fruit Sugar, Aspartame or saccharin；Flavoring agent such as peppermint, wintergreen or cherry；Colorant；With preservative agent and stabilizer, with provide It is stable, pharmaceutically orally available dosage form.The technology and composition for being used to prepare solid oral dosage form are described in Pharmaceutical Dosage Forms:Tablets (Lieberman, Lachman and Schwartz, eds., 2nd Ed.), published by Marcel Dekker, Inc.Prepare tablet (compression and molding), the skill of capsule (hard and soft gelatin) and pill Art and composition be also described in Remington's Pharmaceutical Sciences 1553-1593 (Arthur Osol, ed.,16^thed.,Mack Publishing,Easton,PA1980).Liquid oral dosage form may include aqueous and non-aqueous molten The solution and/or suspension that liquid, lotion, suspension, He Youfei effervescence granular reconstruct, optionally containing one or more suitable Solvent, preservative, emulsifier, suspending agent, diluent, sweetener, colorant, flavoring agent etc..It is used to prepare liquid oral dosage form Technology and composition be described in Pharmaceutical Dosage Forms:Disperse Systems, (Lieberman, Rieger and Banker, eds.) it is published by Marcel Dekker, Inc.

When the compound of the disclosure is configured to for carrying out parenteral administration by injection (for example, continuous infusion or inject) When, preparation can be the form of suspension in oiliness or aqueous carrier, solution or lotion, and such preparation can be into One step includes pharmaceutically required additive, such as one or more stabilizers, suspending agent, dispersing agent etc..Work as parenteral injection When the compound of the disclosure, the form of for example isotonic sterile solution can be.The compound of the disclosure can also be powder shape Formula, for being reconstructed into injectable formulation.

In certain embodiments, the compound of the disclosure can be configured to the pharmaceutical composition for being used to intravenously apply Object.In certain embodiments, such composition includes the aqueous buffer of sterile isotonic.In certain embodiments, composition It may include solubilizer.The compound of the disclosure for intravenously applying may include local anesthetic, such as benzocainum or third Amine cacaine, to mitigate the pain of injection site.In certain embodiments, the ingredient can be individually or to mix Unit dosage form provides, for example, in sealing container such as ampoule or sachet the amount of surfactant as dry jelly Dry powder or without the form of aqueous concentrate.It, can be for example with containing sterile pharmaceutical grade when through the compound of the infusion application disclosure The distribution of the infusion bottle of water or salt water.When through the compound of the injection application disclosure, the aseptic injection that can provide ampoule is used Water or salt water allow to blending constituent before administration.

When giving the compound of the disclosure by sucking, dry aerosol or aqueous or part water can be configured to Property solution.

In another embodiment, the compound of the present invention can deliver in vesica, especially liposome.(referring to Langer, Science249:1527-1533 (1990) and Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer 317-327and 353-365(1989))。

In certain embodiments, the compound of the disclosure can be with local administration.This can be for example, by perioperative Local infusion, local application, such as in conjunction with postoperative wound dressing, by injection, by means of conduit, pass through suppository or filling Intestines, or realized by implantation material, the implantation material is porous, non-porous or gelatinous material, including film, such as elasticity Film or fiber.

In certain embodiments, the compound of the present invention can release immediately form delivering.In other embodiments, The compound of the disclosure can deliver in controlled release system or sustained release system.The pharmaceutical composition of controlled-or sustained-release can With the common objective for improving drug therapy, different from the result realized by its non-control or non-sustained release counterpart.In In certain embodiments, controlled-or sustained-release composition may include minimal amount of disclosure compound, in the shortest time Interior treatment.The advantages of controlled-or sustained-release composition includes extending pharmaceutical activity, reduces dose frequency and increases compliance.Control It releases or sustained-release composition can advantageously time for starting of influence or other feature, such as the blood of disclosure compound Level, and therefore can reduce the generation of adverse side effect.

Controlled-or sustained-release composition can initially release immediately a certain amount of the compounds of this invention, generate institute rapidly The therapeutic effect needed, and the gradually the compounds of this invention with the other amounts of sustained release, to keep treatment effect within the extended time Fruit is horizontal.In order to maintain in vivo the disclosure compound constant level, the compound of the disclosure can be with certain rate It is discharged from preparation, the rate will replace the amount being metabolized and from the disclosure compound drained in vivo.It can be by various The control of conditional stimulus active constituent or sustained release, the including but not limited to variation of pH, the variation of temperature, the concentration of enzyme or can It is acquired, the concentration or availability of water or other physiological conditions or compound.

The controlled release and sustained release method used according to the disclosure can be selected from techniques known in the art.Example includes but unlimited In being described in United States Patent (USP) No.3,845,770；3,916,899；3,536,809；3,598,123；4,008,719；5,674, 533；5,059,595；5,591,767；5,120,548；5,073,543；5,639,476；5,354,556 and 5,733,566, often One introduces as quotation.Such dosage form can be used for providing control or the sustained release of one or more active constituents, for example, making With hydroxypropyl methyl cellulose, other polymers matrix, gel, permeable membrane, osmosis system, multiple coatings, particle, more particles, Liposome, microballoon, or combinations thereof to provide the required release characteristics of different proportion.In view of present disclosure, can easily select Select suitable controlled-or sustained-release prescription known in the art, including those described herein, the compound one with the disclosure It rises and uses.

When with tablet or pill, pharmaceutical composition of the invention can be coated to postpone disintegration in the gastrointestinal tract And absorption, to provide continuous action within the extended period.Around the permoselective membrane of osmotically active driving compound It is applicable to the composition of oral administration.Later in these platforms, the fluid from capsule surroundings environment is by driving compound It absorbs, driving compound is swollen so that medicament or the displacement of medicament composition through hole.With the mark-on curve phase of immediate release formulation Instead, these delivery platforms can provide the delivery characteristics of substantially zero level.Such as glyceryl monostearate or glycerol can also be used The time delay material of stearate.Orally administered composition may include excipient, such as mannitol, lactose, starch, magnesium stearate, saccharin Sodium, cellulose and magnesium carbonate.In certain embodiments, excipient can be pharmaceutical grade.

The amount of the disclosure compound of effective treating cancer can be determined by standard clinical techniques.Furthermore, it is possible to using External and/or in vivoassay assists in optimal dose range.Used exact dose, which might also depend on, to be for example administered The degree of approach and cancer to be treated, and can be determined according to the case where the judgement of practitioner and/or each subject. Used exact dose might also depend on the degree of such as administration route and cancer to be treated, and can be according to working It the judgement of person and/or determines the case where each subject.The variation of dosage can depend on typical factor, such as treated Weight, age, gender and the physical condition (for example, liver and renal function) of person, cancer to be treated, the severity of symptom, with And presence and the used specific compound etc. of spacing of doses, any harmful side effect.

Suitable effective dose can be daily about 0.01mg/kg weight to about 3000mg/kg subject's weight.Certain In embodiment, suitable effective dose can be daily about 0.01mg/kg to about 2500mg/kg subject's weight or daily About 0.01mg/kg is to about 1000mg/kg subject's weight.In certain embodiments, effective dose can be daily about 100mg/kg subject's weight is lower.In certain embodiments, effective dose can be for disclosure compound daily about 0.01mg/kg is to about 100mg/kg subject's weight, in another embodiment, about 0.02mg/kg to about 50mg/kg daily Subject's weight, in another embodiment, about 0.025mg/kg to about 20mg/kg subject's weight daily.Administration can be with It is single dose or divided dose.

According to the present invention, the method for treating the cancer of subject with this need may further include in addition to this public affairs A effective amount of second therapeutic agent also is co-administered to subject except the compound (that is, first therapeutic agent) opened.In view of the disclosure Content and disclosed clinical research, a effective amount of second therapeutic agent can be known or be determined by doctor.In an implementation of the disclosure In scheme, second therapeutic agent can be applied to object with treating cancer.In this embodiment, the compound of the disclosure and Two therapeutic agents can be added or act synergistically with treating cancer.Alternatively, second therapeutic agent can be used for treating the disease for being different from cancer Disease.In certain embodiments, as single group comprising a effective amount of disclosure compound and a effective amount of second therapeutic agent Object is closed, the compound of the disclosure can be administered simultaneously with second therapeutic agent.It in certain embodiments, can be in application effective quantity Second therapeutic agent before or after apply a effective amount of disclosure compound.It in this embodiment, can be in the second treatment Agent applies the compound of the disclosure while playing its therapeutic effect, or plays its treating cancer in the compound of the disclosure Second therapeutic agent is applied while therapeutic effect.

Illustrative anticancer drug includes Tarceva, Gefitinib, Lapatinib, or in United States Patent (USP) 5,747,498； 6,900,221；7,087,613；RE41065 (corresponding Tarceva)；United States Patent (USP) 5,457,105；5,616,582；5,770, 599 ((corresponding Gefitinibs)；United States Patent (USP) 6,391,874；6,713,485；6,727,256；6,828,320；With 7,157, The structured any compound of tool in 466 (corresponding to Lapatinib).When being administered in combination with this anticancer drug, anticancer drug Ratio with disclosure compound can be in the range of about 1:100 to about 100:1.Independent embodiment provides the range can It is about 1:10 to about 10:1, about 1:5 to about 5:1, about 1:2 to about 2:1, or about 1:1.

Second of therapeutic agent can be but not limited to opium excitomotor, nonopioid analgesic, non-steroid anti-inflammatory drug, Antimigraine, Cox-IA inhibitor, 5- lipoxidase inhibitor, antemetic, Beta-3 adrenergic retarding agent, anticonvulsive drug resist Depressant drug, Ca²⁺Channel blocker, anticancer agent treat or prevent the medicament of UI, treat or prevent the medicament of anxiety disorder, treatment or The medicament for preventing memory disorders treats or prevents the medicament of constipation, treats or prevents cough for treating or preventing fat medicament The medicament coughed treats or prevents the medicament of diarrhea, treats or prevents the medicament of hypertension, treats or prevents the medicament of epilepsy, uses In treating or preventing anorexia/cachectic medicament, the medicament of drug abuse is treated or prevented, the medicament of ulcer is treated or prevented, The medicament for treating or preventing IBD, treats or prevents the medicament of IBS, for treating or preventing the medicament of addictive disorders, for controlling The medicament for treating or preventing Parkinson's disease and parkinson's syndrome, for treating or preventing the medicament of apoplexy, for treating or preventing The medicament of epileptic attack, for treating or preventing mental disease, treats or prevents the prosperous court of a feudal ruler for treating or preventing the medicament of pruritus The choreic medicament of Dun Shi, treats or prevents the medicament of ALS, treats or prevents the medicament of cognitive disorder, treats or prevents inclined head The medicament of pain, treatment, prevention or the medicament for inhibiting vomiting are used to treat or pre- for treating or preventing the medicament of dyskinesia The medicament of anti-depression or its any mixture.

Embodiment

Compound, pharmaceutical composition or the more specific content of method described herein refer to following embodiment.Following embodiment It is only used for explaining, and should not be construed as limited to these embodiments.On the contrary, embodiment should be interpreted comprising due to herein It is provided introduction and will become apparent from any content and variation.

Embodiment 1:MTT testing program

Mtt assay can be used to adaptability of the screening compounds as EGFR inhibitor.MTT testing scheme sample is as follows:

50 μ L cells are cultivated in microwell plate, it is ensured that reasonable cell density is to generate stronger control signal.SKBR3, BT474, MDA-MB-231, MDA-MB-453, MDA-MB-468, M1:5000 cells/well, 5%FBS；NE91, NR6 and NR6 spread out Raw cell line: 2500 cells/wells, 5%FBS；H1975:5000 cells/well, 1%FBS.

The 50 μ L culture mediums containing various concentration inhibitor are added.37 DEG C, 5%CO₂It is lower to be incubated for 72 hours.

Former culture medium is replaced with 100 μ L fresh cultures.At 37 DEG C, 5%CO₂It is lower to place 4 hours.

25 μ L MTT (5mg/mL stock solution, final concentration 1mg/mL) are added into each hole.By microtiter plate 37 DEG C be incubated for 2 hours.

100 μ L Extraction buffers (50%DMF/20%SDS of pH4.7) are added into each hole.

It is incubated overnight at 37 DEG C, OD measurement is carried out at 570nm.

MTT measurement scheme is also illustrated in Hansen etc., referring to " Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill,”J.Immunol.Methods119:203-210(1989)。

Embodiment 2:RBC HotSpot kinase assay scheme

RBC HotSpot kinase assays can be carried out to determine kinase activity data.Sample RBC HotSpot kinase assays Scheme is as follows:

Reagent: alkali reaction buffer；20mM Hepes (pH 7.5), 10mM MgCl₂, 1mM EGTA, 0.02% Brij35,0.02mg/ml BSA, 0.1mM Na₃VO₄, 2mM DTT, 1%DMSO.

Add required co-factor respectively into each kinase reaction.

Compound processing: test compound is dissolved in 100%DMSO to certain concentration.Serial dilution can be used Integra ViafloAssist is carried out in DMSO.

Response procedures:

Substrate is prepared in freshly prepd reaction buffer.

Any desired co-factor is added into above-mentioned substrate solution.

Kinases is added in substrate solution and is gently mixed.

Pass through Acoustic technology (Echo550；Nanoliter range) that the compound in 100%DMSO is added to kinases is anti- It answers in mixture, and is incubated at room temperature 20 minutes.

It will³³P-ATP (10 μ Ci/ μ L of specific activity) is added in reaction mixture to start reaction.

At room temperature, it is incubated for 2 hours.

Radioactivity is detected by filter combination method.

Kinase activity data are represented by with carrier (dimethyl sulfoxide) reaction compared to residue kinase activity in test sample Percentage.Prism (GraphPad software) can be used and obtain IC₅₀Value and matched curve.

Anastassiadis etc. discloses another suitable method for measuring determining kinase inhibitor selectivity, “Comprehensive assay of kinase catalytic activity reveals features of kinase Inhibitor selectivity, ", (2011) Nature Biotechnology 29 (11): 1039-1045, by drawing Mode is incorporated herein.

The preparation of embodiment 3:SGI-078

The synthetic route of SGI-078 is as follows.The synthesis can be realized by following steps:

1) preparation of compound 003-2

The 150mL ethanol solution of compound 003-1 (15g, 71.73mmol) is cooled to 0 DEG C, is slowly added ethyl alcohol thereto Sodium (10.74g, 157.81mmol).Then mixture flows back 2 hours (LCMS monitoring reaction).Concentration boils off solvent, uses HCl/water Solution adjusts pH=2~3.Filter solid is crossed, filter cake is collected, vacuum drying obtains compound 003-2 (14g, yield 83%), for Huang Color solid.

2) preparation of compound 003-3

In 250mL round-bottomed flask, DMF (474mg, 6.49mmol) solution of compound 003-2 (14g, 59.52mmol) It is cooled to 0 DEG C, 120mL thionyl chloride is added dropwise thereto.Then mixture is stirred at room temperature 4 hours and (is monitored by LCMS Reaction).Solvent is evaporated, 50mL PE:EA=3:1 is added, and be stirred at room temperature 1 hour.Filter solid is crossed, collection filter cake is simultaneously true Sky is dry, obtains compound 003-3 (11g, yield 72.8%), is yellow solid.

3) preparation of compound 003-4

By chloro- 4- fluoroaniline (6.94g, 47.71mmol) the 100mL isopropyl of compound 003-3 (11g, 43.37mmol) and 3- Alcoholic solution, reflux 1 hour (passing through LCMS and TLC monitoring reaction).Filter solid is crossed, filter cake is collected and is dried in vacuo, chemical combination is obtained Object 003-4 (14g, yield 89%) is yellow solid.

4) preparation of compound 003-5

By compound 003-4 (14g, 38.6mmol), iron powder (12.1g, 216.16mmol), glacial acetic acid (11g, It 184mmol) is added in the solution of 80mL ethyl alcohol and 40mL water, reflux 1.5 hours (being monitored by LCMS and TLC).Solvent is evaporated, Use Na₂CO₃In aqueous solution and solution is to pH=9~10.It is extracted with DCM (80mL × 5), salt water (50mL x1) water, through Na₂SO₄ Dry, vacuum concentration obtains compound 003-5 (10g, yield 77.9%), is faint yellow solid.

5) preparation of compound 078-2

It will be cooled to containing compound 078-1 (1.2g, 7.27mmol), DMF (20mg, 0.27mmol) 25mL DCM solution 0 DEG C, oxalyl chloride (1.2g, 9.45mmol) is added dropwise thereto.Then mixture is stirred at room temperature 1 hour.Reaction is mixed Object vacuum drying, obtains compound 078-2 (1.6g (crude product)), is yellow oil, is used for next step.

6) preparation of compound 078-4

By the 20mL DCM solution containing compound 078-3 (1.0g, 11.22mmol), imidazoles (1.15g, 16.83mmol) It is cooled to 0 DEG C, and tert-butyldimethylsilyl chloride (2.03g, 13.46mmol) slowly is added thereto.It then will mixing Object is stirred at room temperature overnight.Residue is purified by silica gel flash column chromatography (PE/EtOAc=20:1), obtains compound 078-4 (1.2g, 52.6% yield) is yellow oil.

7) preparation of compound 078-5

To the molten of the 15mL DMF containing compound 003-5 (2g, 6.01mmol) and triethylamine (1.52g, 15.03mmol) The solution of compound 078-2 (1.6g (crude product)) 5mL DMF is added dropwise in liquid.Then at room temperature and N by reaction mixture₂It protects Shield is lower to stir 2 hours (monitoring by LCMS).20mL water is added and is extracted with EtOAc (40mL x2), is washed with water (20mL x3), Salt water (20mL x1) washing, through Na₂SO₄It dries and is concentrated in vacuo.Pass through the flash chromatography eluting remnants of silica gel using DCM Object obtains compound 078-5 (2.5g, 86.5%), is yellow oil.

8) preparation of compound 078-6

To the molten of the 15mL THF containing compound 078-5 (1.5g, 3.13mmol) and triethylamine (475mg, 4.7mmol) Compound 078-4 (866mg, 3.76mmol) is added in liquid.Then mixture is stirred at room temperature overnight (being monitored by LCMS).It will Reaction mixture is extracted with EtOAc (20mL x2), is washed with water (10mL x1), salt water (20mL x1) washing, through Na₂SO₄It is dry And be concentrated in vacuo, it obtains compound 078-6 (2g, (crude product)), yellow oil, in next step.

9) preparation of compound SGI-078

20mL methanol solution containing compound 078-6 (2g (crude product)) is cooled to 0 DEG C, and 4N HCl (2mL) is added dropwise. Then mixture is stirred at room temperature 1.5 hours (being monitored by LCMS).Crude mixture is purified by preparative HPLC, is obtained It is faint yellow solid to SGI-078 (gross production rate of 210mg, 11.2%, two step).

Nuclear magnetic resonance spectroscopy is shown:¹H NMR(400MHz,DMSO-d₆):δ10.71(br s,1H),9.94(s,1H) .9.87 (s, 1H), 9.05 (s, 1H), 8.76 (s, 1H), 8.04-8.01 (m, 1H), 7.73-7.70 (m, 1H), 7.50 (t, J= 9.2Hz, 1H), 7.36 (s, 1H), 6.85 (s, 2H), 4.34 (q, J=6.8Hz, 2H), 4.06-3.95 (m 2H), 3.50 (t, J =6.0Hz, 2H), 3.24-3.05 (m, 2H), 2.80 (s, 3H), 1.90-1.76 (m, 2H), 1.48 (t, J=6.8Hz, 3H) (Fig. 1).

Mass spectrum MS (ESI) m/z 488.2 [M+H]⁺(Fig. 2).

The preparation of embodiment 4:SGI-105 and SGI-106

The synthetic route of SGI-105 and SGI-106 is as follows.It can be realized and be synthesized by following steps:

1) preparation of compound 003-2

The 150mL ethanol solution of compound 003-1 (15g, 71.73mmol) is cooled to 0 DEG C, and is slowly added to sodium ethoxide (10.74g, 157.81mmol).Then by mixture 2 hours (being monitored by LCMS) of reflux.It is evaporated and by solution HCl Aqueous solution is neutralized to pH=2~3.Filter solid is crossed, filter cake is collected and is dried in vacuo, compound 003-2 (14g, yield are obtained It 83%), is yellow solid.

2) preparation of compound 003-3

It is in 250mL round-bottomed flask, the DMF (474mg, 6.49mmol) of compound 003-2 (14g, 59.52mmol) is molten Liquid is cooled to 0 DEG C, and 120mL thionyl chloride is added dropwise.Then mixture is stirred at room temperature 4 hours (being monitored by LCMS). It is evaporated and 50mL PE:EA=3:1 is added, and be stirred at room temperature 1 hour.Filter solid is crossed, filter cake is collected and vacuum is dry It is dry, compound 003-3 (11g, yield 72.8%) is obtained, is yellow solid.

3) preparation of compound 003-4

The chloro- 4- fluoroaniline (6.94g, 47.71mmol) of compound 003-3 (11g, 43.37mmol) and 3- is different in 100mL Solution in propyl alcohol flows back 1 hour (being monitored by LCMS and TLC).Filter solid is crossed, filter cake is collected and is dried in vacuo, chemical combination is obtained Object 003-4 (14g, yield 89%) is yellow solid.

4) preparation of compound 003-5

By compound 003-4 (14g, 38.6mmol), iron powder (12.1g, 216.16mmol), glacial acetic acid (11g, It 184mmol) flows back in 80mL ethyl alcohol and 40mL water 1.5 hours (being monitored by LCMS and TLC).It is evaporated and is used solution Na₂CO₃Aqueous solution is neutralized to pH=9~10, and is extracted with DCM (80mL × 5), salt water (50mL x1) washing, through Na₂SO₄It is dry It is dry and be concentrated in vacuo, compound 003-5 (10g, yield 77.9%) is obtained, is faint yellow solid.

5) preparation of compound 078-2

The 25mL DCM solution of compound 078-1 (1.2g, 7.27mmol) and DMF (20mg, 0.27mmol) are cooled to 0 DEG C, and oxalyl chloride (1.2g, 9.45mmol) is added dropwise.Then mixture is stirred at room temperature 1 hour.By reaction mixture vacuum It is dry, compound 078-2 (1.6g (crude product)) is obtained, is yellow oil, is used for next step.

6) preparation of compound 078-5

To the 15mL DMF solution for containing compound 003-5 (2g, 6.01mmol) and triethylamine (1.52g, 15.03mmol) Middle dropwise addition 078-2 (1.6g (crude product)) DMF (5mL) solution.Then by reaction mixture in room temperature and N₂Lower stirring 2 hours.By LCMS monitoring.20mL water is added and is extracted with EtOAc (40mL x2), is washed, is used with water (20mL x3) and salt water (20mL x1) Na ₂SO ₄It dries and is concentrated in vacuo.Residue is used DCM as the eluant, eluent on silica gel, is obtained by flash column chromatography It is yellow oil to compound 078-5 (2.5g, 86.5%).

7) preparation of compound 105-2

It will be molten containing compound 105-1 (1.0g, 11.22mmol) and triethylamine (2.27g, 22.44mmol) 15mL DCM Liquid is cooled to 0 DEG C, and di-tert-butyl dicarbonate (2.94g, 13.46mmol) is added dropwise.Then mixture is stirred at room temperature 1.5 Hour (being monitored by TLC).Reaction mixture is extracted with DCM (15mL x2), with water (10mL x1) and salt water (20mL x1) Washing, uses Na₂SO ₄It dries and is concentrated in vacuo.Residue is purified by silica gel flash column chromatography (PE/EA=2:1), is changed It closes object 105-2 (1.1g, 51.9%), is white oil object.

8) preparation of compound 105-3

By THF (10mL) suspension of sodium hydride (109mg, 7.55mmol), it is cooled to 0 DEG C and compound 105-2 is added dropwise (1.1g, 5.81mmol) 15mL THF solution.Then mixture is stirred 0.5 hour at 0 DEG C.It is slowly added to iodomethane (990mg, 6.97mmol), and mixture is stirred at room temperature 1.5 hours (being monitored by TLC).Reaction mixture is used EtOAc (20mL x2) extraction, is washed with water (10mL x1) and salt water (20mL x1), uses Na₂SO ₄It dries and is concentrated in vacuo. Residue is purified by silica gel flash column chromatography (PE/EA=20:1), obtains 105-3 (700mg, 59.3%), is white oil Object.

9) preparation of compound 105-4

Solution of the compound 105-3 (700mg, 3.44mmol) in 10mL methanol is cooled to 0 DEG C and 4N HCl is added dropwise (2mL).Then mixture is stirred at room temperature 1.5 hours (being monitored by LCMS).Reaction mixture is dried in vacuo, is obtained Compound 105-4 (550mg (crude product)) is white oil object, is used for next step.

10) preparation of compound 105

To the 15mL DMF solution for containing compound 078-5 (1.1g, 2.3mmol) and triethylamine (475mg, 4.6mmol) Middle addition 105-4 (550mg (crude product)).Then mixture is stirred at room temperature overnight and (is checked by LCMS).Pass through preparation Type TLC (DCM/MeOH=20:1) purifies crude mixture, obtains SGI-105 (120mg, 10.3%), is faint yellow solid.

Nuclear magnetic resonance spectroscopy is shown:¹H NMR(400MHz,CD₃OD-d₄):δ8.89(s,1H),8.48(s,1H),8.02 (dd, J=7.2Hz, 2.8Hz, 1H), 7.70-7.64 (m, 1H), 7.25 (t, J=9.2Hz, 1H), 7.21 (s, 1H), 7.07- 6.98 (m, 1H), 6.54 (d, J=15.2Hz, 1H), 4.33 (q, J=6.8Hz, 2H), 3.46 (t, J=6.0Hz, 2H), 3.44- 3.33 (m, 2H), 3.34 (s, 2H), 2.59 (t, J=7.2Hz, 2H), 2.80 (s, 3H), 2.35 (s, 3H), 1.88-1.75 (m, 2H), 1.56 (t, J=6.8Hz, 3H) (Fig. 3).

Mass spectrum MS (ESI) m/z 502.3 [M+H]⁺(Fig. 4).

10) preparation of compound 106-2

Ethyl formate (7.2g, 84mmol) will be added to the 50mL ethanol solution of compound 106-1 (5g, 56mmol).So Afterwards by mixture 18 hours (being monitored by TLC) of reflux.Reaction mixture is dried in vacuo, and passes through the quick column (PE/ of silica gel EtOAc=10:1 it) purifies, obtains compound 106-2 (4.1g, 62.4%), be grease.

11) preparation of compound 106-3

To containing lithium aluminium hydride reduction (2g, 52.5mmol) 30mL THF suspension in be added compound 106-2 (4.1g, 35mmol).Then by mixture 2 hours (being monitored by TLC) of reflux.10mL water is added and filters, collects filtrate and vacuum is dense Contracting, and purified by the quick column of silica gel (PE/EtOAc=10:1), compound 106-3 (2g, 55.6%) is obtained, is grease.

12) preparation of compound 106-4

Compound 106-3 (1.0g, 9.7mmol), triethylamine (1.96g, 19.4mmol) and N, N- dimethyl pyrazole will be contained The 15mL DCM solution of pyridine -4- amine (109mg, 0.97mmol), is cooled to 0 DEG C, and di-tert-butyl dicarbonate is added dropwise (2.54g, 11.64mmol).Then mixture is stirred at room temperature 1.5 hours (being monitored by TLC).Reaction mixture is used DCM (15mL x2) extraction, is washed with water (10mL x1) and salt water (20mL x1), uses Na₂SO ₄It dries and is concentrated in vacuo.It is logical The quick column of silica gel (PE/EtOAc=2:1) purifying residue is crossed, compound 106-4 (1.2g, 60.9%) is obtained, is grease.

13) preparation of compound 106-5

Suspension of the sodium hydride (354mg, 8.85mmol) in 10mL THF is cooled to 0 DEG C, and chemical combination is added dropwise Object 106-4 (1.2g, 5.9mmol) THF (15mL) solution.Then mixture is stirred 0.5 hour at 0 DEG C.It is slowly added to iodine Methane (1.51g, 10.62mmol).Then mixture is stirred at room temperature 1.5 hours (being monitored by TLC).Reaction is mixed Object is extracted with EtOAc (20mL × 2), is washed with water (10mL) and salt water (20mL x1), through Na₂SO₄It dries and is concentrated in vacuo. Residue is purified by silica gel flash column chromatography (PE/EtOAc=20:1), compound 106-5 (600mg, 46.9%) is obtained, is Grease.

14) preparation of compound 106-6

Solution of the compound 106-5 (600mg, 2.76mmol) in 10mL methanol is cooled to 0 DEG C, and 4N is added dropwise HCl(2mL).Then mixture is stirred at room temperature 1.5 hours (being monitored by LCMS).Reaction mixture is dried in vacuo, Compound 106-6 (500mg (crude product)) is obtained, is grease, is reacted for next step.

15) preparation of compound 106

It is molten to the 10mL DMF containing compound 078-5 (500mg, 1.04mmol) and triethylamine (210mg, 2.08mmol) Compound 106-6 (500mg, crude product) is added in liquid.Then mixture is stirred at room temperature overnight and (is monitored by LCMS).It is logical Preparative TLC (DCM/MeOH=20:1) purifying crude mixture is crossed, SGI-106 (23mg, 4.3%) is obtained, is pale yellow colored solid Body.

Nuclear magnetic resonance spectroscopy is shown:¹H NMR(400MHz,CD₃OD-d₄):δ8.90(s,1H),8.47(s,1H),8.01 (dd, J=7.2Hz, 2.8Hz, 1H), 7.69-7.64 (m, 1H), 7.25 (t, J=9.2Hz, 1H), 7.21 (s, 1H), 7.04- 6.99 (m, 1H), 6.68 (d, J=15.6Hz, 1H), 4.33 (q, J=6.8Hz, 2H), 3.69 (d, J=6.8Hz, 2H), 3.45 (t, J=6.0Hz, 2H), 3.44-3.33 (m, 2H), 3.34 (s, 2H), 2.88 (t, J=8.0Hz, 2H), 2.63 (s, 3H), 1.78-1.71 (m, 2H), 1.68-1.61 (m, 2H), 1.56 (t, J=6.8Hz, 3H) (Fig. 5).

Mass spectrum MS (ESI) m/z 516.4 [M+H]⁺(Fig. 6).

Embodiment 5: activity of the different inhibitor to various EGFR mutant

In the presence of 10 μM of ATP, different inhibitor are as shown in table 1 below to the activity of various EGFR mutant.SGI-078 and SGI-105 all show to the very strong activity of EGFR (C797S) and to EGFR (d746-750/T790M/C797S) and The excellent activity of EGFR (L858R/T790M/C797S).Test is as described in Examples 1 and 22.As a result as shown in table 1 below.

Table 1

Embodiment 6: the IC50 of exemplary EGFR kinase inhibitor is measured

The in-vitro multiplication activity of A431 and NCI-1975 cell is detected, to determine EGFR kinase inhibitor IC50, as a result such as Shown in the following table 2.SGI-078 and SGI-105 has weak activity to the A431 cell of expression Wild type EGFR, to expression EGFR (T790M) the NCI-H1975 cell of mutant has preferably activity.SG1-105 is in terms of inhibiting HCI-H1975 cell Proliferation Have than SGI-078 more strongly active.SGI-105 even slightly better than AZD-9291 (181nM vs.260nM).Test such as 1 He of embodiment Described in 2.

Table 2

Embodiment 7: the IC50 of exemplary EGFR kinase inhibitor is measured

Compared with AZD9291 and SGI-101, the oral PK result of study of SGI-105 is as shown in table 3 below.By compound with The single dose mouse of 10mg/kg.Test is as described in Examples 1 and 22.

Table 3

Claims (46)

1. such as formula (I) compound,

Wherein

Q is selected from

R₁It is independently H, optionally substituted amino, the C optionally replaced_1-6Alkyl, the C optionally replaced_1-6Alkoxy optionally takes The C in generation_2-6Alkenyl, optionally substituted C_2-6Alkynyl, the benzyloxy optionally replaced, halogen, hydroxyl, nitro, optionally replace cyano Phenoxy group or mono-, two- or trifluoromethyl；

N is 1,2 or 3；

R₂It is H or C_1-6Alkyl；

R₃It is H or C_1-6Alkyl；

R₄It is H, N (R₆)₂, the optionally C that replaces_1-3Alkyl, the C optionally replaced_1-3Alkoxy, cyano, halogen, hydroxyl, nitro, (S) -3- ((tetrahydrofuran -3- base) oxygroup) or mono-, two- or trifluoromethyl；

R₅It is H or C_1-6Alkyl；

R₆It is independently H, C_1-3Alkyl, C_1-6Alkylamine or C_1-6Alkyl hydroxy；

X is C_1-6Alkyl ,-N (R₅)C(O)-、-O-(C_1-6Alkyl)-,-N (R₅)-(C_1-6Alkyl)-,-C (O) N (R₅)-、-C(O)N (R₅)-(C_1-6Alkyl)-,-SO₂N(R₅)-or-N (R₅)SO₂-(C_1-6Alkyl)-；

Y is

R₇It is C_1-6Alkyl, C_1-6Alkyl hydroxy, the C optionally replaced_1-6Alkyl ether, C_1-6Alkyl carboxylic acid, C_1-6Alkyl dicarboxylic aid, optionally Substituted C_1-6Arrcostab, C_1-6Alkyl carboxylate or ester, the C optionally replaced_1-6Alkyl phosphoric acid or C_1-6Alkylsurfuric acid；

R₈It is C_1-6Alkyl；

R₉It is C_1-6Alkyl carboxylic acid；

U is C or N；

R₁₀It is C_1-6Alkyl carboxylic acid, C_1-6Alkylol, C_1-6Alkyl ether or C_1-6Arrcostab；

R₁₁It is H, C_1-6Alkyl, C_1-6Alkylol, C_1-6Alkyl ether or C_1-6Arrcostab；

W is C, S or O；

R₁₂It is C_1-6Alkyl carboxylic acid or C_1-6Alkyl hydroxy；

R₁₃It is H or C_1-6Alkyl；

R₁₄It is C_1-6Alkyl；

J is O or S；

R₁₅Be the naphthenic base optionally replaced, the Heterocyclylalkyl optionally replaced, the aryl optionally replaced, the heteroaryl optionally replaced, C_1-6Cyanoalkyl；With

R₁₆It is the aryl or Heterocyclylalkyl optionally replaced；

Wherein * represents connection site,

Or its pharmaceutically acceptable salt.

2. compound according to claim 1, wherein Q be can be

3. according to claim 1 or 2 described in any item compounds, R₁It is cyano or halogen.

4. compound according to claim 3, R₁It is fluorine or chlorine.

5. compound according to claim 1-4, n is 2.

6. compound according to claim 1-5, R₄It is the C optionally replaced_1-6Alkoxy.

7. compound according to claim 6, R₄It is C_1-6Alkoxy, the C_1-6Alkoxy is by C_1-6Alkyl hydroxy, C_1-3Alkane Oxygroup, C_3-6Naphthenic base or the Heterocyclylalkyl optionally replaced replace.

8. compound according to claim 7, R₄It is C_1-3Alkoxy.

9. compound according to claim 8, R₄It is ethyoxyl.

10. -9 described in any item compounds according to claim 1, R₁₀It is C_1-6Alkylol.

11. -9 described in any item compounds according to claim 1, R₁₀It is C_1-6Alkyl ether.

12. compound according to claim 11, R₁₀It is C₁Alkyl ether, C₂Alkyl ether, C₃Alkyl ether, C₄Alkyl ether, C₅Alkane Base ether or C₆Alkyl ether.

13. compound according to claim 12, R₁₀It is-CH₂CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₃、- CH₂OCH₂CH₂CH₃、-CH₂CH₂CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₂CH₂CH₃Or- CH₂OCH₂CH₂CH₂CH₃。

14. -9 described in any item compounds according to claim 1, R₁₀It is C_1-6Arrcostab.

15. compound according to claim 14, R₁₀It is C₁Arrcostab, C₂Arrcostab, C₃Arrcostab, C₄Arrcostab, C₅Alkane Base ester or C₆Arrcostab.

16. compound according to claim 15, R₁₀It is-CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂OC (=O) CH₃Or-CH₂CH₂CH₂CH₂OC (=O) CH₃。

17. -16 described in any item compounds according to claim 1, R₁₁It is C_1-6Alkylol.

18. -16 described in any item compounds according to claim 1, R₁₁It is H or C_1-6Alkyl.

19. compound according to claim 18, R₁₁It is H or C_1-3Alkyl.

20. compound according to claim 19, R₁₁It is methyl.

21. compound according to claim 1 or its pharmaceutically acceptable salt are selected from formula (III) compound:

Wherein,

R₁Selected from cyano or halogen；

R₄It is the C optionally replaced_1-3Alkoxy or (S) -3- ((tetrahydrofuran -3- base) oxygroup)；

R₁₀It is C_1-6Alkyl carboxylic acid, C_1-6Alkyl ether or C_1-6Arrcostab；

R₁₁It is H or C_1-6Alkyl.

22. compound according to claim 21, wherein R₁It is fluorine or chlorine.

23. according to the described in any item compounds of claim 21 or 22, wherein R₄It is the C optionally replaced_1-3Alkoxy.

24. compound according to claim 23, wherein R₄It is ethyoxyl.

25. according to the described in any item compounds of claim 21-24, wherein R₁₀It is C_1-6Alkyl ether or C_1-6Arrcostab.

26. compound according to claim 25, wherein R₁₀It is C₁Alkyl ether, C₂Alkyl ether, C₃Alkyl ether, C₄Alkyl ether, C₅Alkyl ether, C₆Alkyl ether, C₁Arrcostab, C₂Arrcostab, C₃Arrcostab, C₄Arrcostab, C₅Arrcostab or C₆Arrcostab.

27. compound according to claim 26, wherein R₁₀It is CH₂CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₃、- CH₂OCH₂CH₂CH₃、-CH₂CH₂CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₂CH₂CH₃、- CH₂OCH₂CH₂CH₂CH₃、-CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂OC (=O) CH₃、 Or-CH₂CH₂CH₂CH₂OC (=O) CH₃。

28. according to the described in any item compounds of claim 21-27, wherein R₁₁It is H or C_1-3Alkyl.

29. compound according to claim 28, wherein R₁₁It is methyl.

30. compound according to claim 1 or its pharmaceutically acceptable salt are selected from formula (IV) compound:

Wherein,

R_1aOr R_1bIt is each independently selected from cyano or halogen；

R₄It is the C optionally replaced_1-3Alkoxy or (S) -3- ((tetrahydrofuran -3- base) oxygroup)；

R₁₀It is C_1-6Alkyl carboxylic acid, C_1-6Alkyl ether or C_1-6Arrcostab；

R₁₁It is H or C_1-6Alkyl.

31. compound according to claim 30, wherein R_1aOr R_1bIt is each independently selected from fluorine or chlorine.

32. compound according to claim 31, wherein R_1aIt is fluorine, R_1bIt is chlorine.

33. according to the described in any item compounds of claim 30-32, wherein R₄It is the C optionally replaced_1-3Alkoxy.

34. compound according to claim 33, wherein R₄It is ethyoxyl.

35. according to the described in any item compounds of claim 30-34, wherein R₁₀It is C_1-6Alkyl ether or C_1-6Arrcostab.

36. compound according to claim 35, wherein R₁₀It is C₁Alkyl ether, C₂Alkyl ether, C₃Alkyl ether, C₄Alkyl ether, C₅Alkyl ether, C₆Alkyl ether, C₁Arrcostab, C₂Arrcostab, C₃Arrcostab, C₄Arrcostab, C₅Arrcostab or C₆Arrcostab.

37. compound according to claim 36, wherein R₁₀It is CH₂CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₃、- CH₂OCH₂CH₂CH₃、-CH₂CH₂CH₂CH₂OCH₃、-CH₂CH₂CH₂OCH₂CH₃、-CH₂CH₂OCH₂CH₂CH₃、- CH₂OCH₂CH₂CH₂CH₃、-CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂C (=O) OCH₂CH₃、-CH₂CH₂CH₂OC (=O) CH₃、 Or-CH₂CH₂CH₂CH₂OC (=O) CH₃。

38. according to the described in any item compounds of claim 30-37, wherein R₁₁It is H or C_1-3Alkyl.

39. the compound according to claim 38, wherein R₁₁It is methyl.

Compound below 40. or its pharmaceutically acceptable salt:

41. a kind of pharmaceutical composition, it includes any one of the claim 1-40 compound or its pharmaceutically acceptable salt.

42. medicine described in any one of the claim 1-40 compound or its pharmaceutically acceptable salt or claim 43 Purposes of the compositions in preparation treating cancer.

43. purposes described in claim 42, wherein cancer is selected from lung cancer, head cancer, neck cancer or cancer of pancreas.

44. the described in any item purposes of claim 42 or 43, wherein cancer be selected from L858R, T790M, C797S or D746-750 chooses any one kind of them the EGFR saltant type cancer of the above gene mutation.

45. purposes described in claim 44, wherein cancer be selected from C797S, d746-750/T790M/C797S, L858R, The EGFR saltant type cancer of L858R/T790M or L858R/T790M/C797S gene mutation.

46. purposes described in claim 45, wherein cancer be selected from C797S, d746-750/T790M/C797S, L858R, The EGFR saltant type lung cancer of L858R/T790M or L858R/T790M/C797S gene mutation.