CN110092759A - The chloro- 2,4- pyrimidine derivatives of 5- as anti-tumor drug - Google Patents
The chloro- 2,4- pyrimidine derivatives of 5- as anti-tumor drug Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention provides the chloro- 2,4- pyrimidine derivatives of 5- as ALK inhibitor.The compound is the officinal salt of compound shown in compound or Formulas I shown in Formulas I, prodrug, hydrate, solvated compounds, metabolite, wherein R1, R2, R3, R4, R5It is defined as in the description.It can be used as ALK inhibitor using the compound and pharmaceutical composition, be used to prepare into the antineoplaston drug for inhibiting anaplastic lymphoma kinase.
Description
Technical field
The invention belongs to biomedicine fields, and specifically the present invention relates to chloro- 2, the 4- pyrimidines of 5- as anti-tumor drug
Derivative.
Background technique
Tyrosine kinase participates in the pathogenesis of most of cancers.However, few tyrosine kinase are proved in lymph
There are specific pathogenic effects in tumor.Anaplastic lymphoma kinase (ALK) is most of primary cutaneous types (ALCL)
Oncogene conversion expression is carried out by different kinds of molecules mechanism.ALK transposition or abnormal expression lead to tumour.ALK gene
Activated mutant or transposition identified in the cancer of several types, including primary cutaneous type, neuroblastoma,
Inflammatory myofibroblastic tumor and non-small cell lung cancer.Some ALK inhibitor clinically have proven to effective to various cancers.Tool
For body, a small number of ALK inhibitor, on medical market with anti-NSCLC (non-small cell lung cancer) and existing drug is such as
Crizotinib Ceritinib and Brigatinib.
Although the compound for largely having inhibitory activity to protein kinase has been studied, and some protein kinases press down
Preparation such as Crizotinib, Ceritinib etc. has listed the treatment for NSCLC, but can generate drug resistance, adverse reaction
Greatly, there are a degree of defects, and in China, there is presently no on ALK inhibitor medicaments with independent intellectual property rights
City, thus, develop safer, the new A LK inhibitor medicaments of efficient treating cancer have huge social value and warp
Ji benefit.
Summary of the invention
The purpose of the present invention is to provide a kind of chloro- 2,4- pyrimidine derivatives of 5- as anti-tumor drug and its applications.
In the first aspect of the present invention, provides one kind such as formula (I) compound represented or its is pharmaceutically acceptable
Salt, prodrug, metabolite, hydrate or solvate:
In formula (I):
X is-(S=O)-or-(O=S=O)-；
Y is N or CH；
R1It is selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C3-8Naphthenic base, substitution
Or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl and substituted or unsubstituted C1-8Alkoxy；
R2It is selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkenyl, replace or not
Substituted C2-8Alkynyl, substituted or unsubstituted C3-8Naphthenic base, substituted or unsubstituted 3- to 8- circle heterocyclic ring base, replace
Or unsubstituted aryl and substituted or unsubstituted heteroaryl；
R3And R6Independently selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl and substituted or unsubstituted C1-8
Alkoxy；
R4And R5Independently selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C1-8Alkoxy,
Substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl；Alternatively, R4And R5The atom one connected with them
It rises and forms 3- to 8- member ring, the 3- to 8- member ring is optionally substituted by one or more substituents, and the substituent group is selected from: halogen
Element, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C1-8Alkoxy, C3-8Naphthenic base, C1-4Alkyl-substituted or unsubstituted 3- to 8-
Circle heterocyclic ring base.
In another preferred example, the above-mentioned alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl are appointed
Selection of land and replaced each independently by the 1-3 substituent group for being each independently selected from the following group: halogen, hydroxyl, C1-4Alkyl, C2-4Alkene
Base, C2-4Alkynyl, C3-8Naphthenic base, 3- to 12- circle heterocyclic ring base, aryl, heteroaryl ,-CN ,-NO2、C1-4Alkoxy；Except non-specifically
Illustrate, above-mentioned aryl is the aryl containing 6-12 carbon atom；Heteroaryl is 5- to 15- unit's heteroaryl.
In another preferred example, R1It is selected from: hydrogen and generation or unsubstituted C1-4Base.
In another preferred example, R2For substituted or unsubstituted C1-4Base.
In another preferred example, R3For substituted or unsubstituted C1-4Alkoxy.
In another preferred example, R6For hydrogen or substituted or unsubstituted C1-4Alkyl.
In another preferred example, X is-(S=O)-and-(O=S=O)-.
In another preferred example, Y N.
In another preferred example, Y CH, and R4And R5Coupled carbon atom is collectively formed optionally containing 0-3
(such as 1,2 or 3) is independently selected from the heteroatomic 3- of N, O or S to 8- member ring (preferably 6 member rings).
In another preferred example, Y N, and R4And R53- is collectively formed to 8- member ring (preferably in coupled N atom
6 member rings), the optionally described 3- to 8- member ring also contains 0-3 (such as 1,2 or 3) and is independently selected from the hetero atom of N, O or S；Appoint
3- described in selection of land is substituted by one or more substituents to 8- member ring, and the substituent group is selected from: halogen, C1-8Alkyl, C3-8Cycloalkanes
Base, C1-4Alkyl-substituted or unsubstituted 3- is to 8- circle heterocyclic ring base.
In another preferred example, it is described when X be-(S=O)-when, the compound be R configuration, S configuration or R, S mixed
Type.
In another preferred example, shown in the structure of the compound such as formula (II):
Wherein, J is N or C；K is N or C；R7It is selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, replace or it is unsubstituted
C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted C1-8It is alkoxy, substituted or unsubstituted
C3-8Naphthenic base, substituted or unsubstituted 3- to 8- circle heterocyclic ring base, substituted or unsubstituted aryl and replace or do not take
The heteroaryl in generation；
X、R1、R2、R3、R6Each as described above.
In another preferred example, J C；And K is N.
In another preferred example, J N；And K is C.
In another preferred example, J N；And K is C；And R7To be substituted or unsubstituted optionally containing 0-3
(such as 1,2 or 3) is independently selected from heteroatomic 3- to the 8- circle heterocyclic ring base of N, O or S.
In another preferred example, R7For C1-4It is alkyl-substituted to contain 2 heteroatomic 3- of N to 8- circle heterocyclic ring base.
In another preferred example, the formula (I) compound has structure selected from the group below:
Wherein * is chiral atom.
The second aspect of the present invention provides the purposes of formula described in first aspect present invention (I) compound, is used for:
(a) drug of preparation treatment disease relevant to anaplastic lymphoma kinase (ALK) activity or expression；And/or
(b) anaplastic lymphoma kinase (ALK) targeted inhibition agent is prepared；And/or
(c) inhibit to external non-therapeutic the activity of anaplastic lymphoma kinase (ALK).
In another preferred example, described " anaplastic lymphoma kinase (ALK) activity or the relevant disease of expression " includes swollen
Tumor.
In another preferred example, the tumour includes being not limited to: lymthoma, lung cancer, bladder cancer, breast cancer, kidney, stomach
Cancer, liver cancer, oophoroma, prostate cancer, cervical carcinoma, intestinal cancer, cell carcinoma, Huppert's disease, cancer of pancreas, leukaemia etc..
In another preferred example, the tumour includes primary cutaneous type, neuroblastoma, inflammatory muscle fibre
Blastoma and non-small cell lung cancer.
The third aspect of the present invention, provides a kind of pharmaceutical composition, and the pharmaceutical composition includes:
(i) compound or its pharmaceutically acceptable salt, prodrug, metabolism described in a effective amount of first aspect present invention
Product, hydrate or solvate；With
(ii) pharmaceutically acceptable carrier.
The fourth aspect of the present invention provides a kind of method for treating tumour, the method includes the steps:
To formula (I) compound as described in the first aspect of the invention or its pharmacy of the objects of needs application therapeutically effective amount
Upper acceptable salt, or the pharmaceutical composition as described in the third aspect of the present invention of the object application therapeutically effective amount to needs.
The fifth aspect of the present invention provides a kind of preparation method of compound as described in the first aspect of the invention, should
Method comprising steps of
(a) in atent solvent, compound A-13 and compound A4 react to obtain compound shown in Formulas I
In another preferred example, the method also includes steps:
(b) in atent solvent, compound A1 and compound A2 react to obtain compound A-13:
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Specific embodiment
For the present inventor by extensive and in-depth research, obtaining one kind has significantly anaplastic lymphoma kinase (ALK)
The compound of inhibiting effect, these compounds can be used for preparing treatment and anaplastic lymphoma kinase (ALK) activity or expression
The pharmaceutical composition of relevant disease.On this basis, the present invention is completed.
Before describing the present invention, it should be understood that the present invention is not limited to the specific method and experiment conditions, because this
Class method and condition can change.It should also be understood that its purpose of the term as used herein is only that description specific embodiment, and
And it is not intended to be restrictive, the scope of the present invention will be limited only by the claims which follow.
Unless otherwise defined, otherwise whole technologies used herein and scientific term all have such as fields of the present invention
The normally understood identical meanings of those of ordinary skill.As used herein, in use, term in mentioning the numerical value specifically enumerated
" about " mean that the value can change not more than 1% from the value enumerated.For example, as used herein, statement " about 100 " includes 99 Hes
101 and between whole values (for example, 99.1,99.2,99.3,99.4 etc.).
Although can be used in implementation or test of the invention and heretofore described similar or of equal value any method
And material, place enumerates preferred method and material herein.
The present invention relates to be related to as the chloro- 2,4- substituted pyrimidines derivative of novel 5- of ALK inhibitor and these chemical combination
Object is preparing the purposes in the drug for treating and preventing cancer.
The purpose of the present invention is to provide the officinal salt of compound shown in logical formula (I) compound represented or Formulas I, hydrations
Object, solvate, metabolite or prodrug:
In formula (I):
X is-(S=O)-or-(O=S=O)-；
Y is N or CH；
R1It is selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C3-8Naphthenic base, substitution
Or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl and substituted or unsubstituted C1-8Alkoxy；
R2It is selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkenyl, replace or not
Substituted C2-8Alkynyl, substituted or unsubstituted C3-8Naphthenic base, substituted or unsubstituted 3- to 8- circle heterocyclic ring base, replace
Or unsubstituted aryl and substituted or unsubstituted heteroaryl；
R3And R6Independently selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl and substituted or unsubstituted C1-8
Alkoxy；
R4And R5Independently selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C1-8Alkoxy,
Substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl；Alternatively, R4And R5The atom one connected with them
It rises and forms 3- to 8- member ring, the 3- to 8- member ring is optionally substituted by one or more substituents, and the substituent group is selected from: halogen
Element, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C1-8Alkoxy, C3-8Naphthenic base, C1-4Alkyl-substituted or unsubstituted 3- to 8-
Circle heterocyclic ring base.
It is preferably carried out in mode at of the invention one, R1And R2It can be independent substituent group, also can connect into one
A ring；R3And R6It can be two same or different substituent groups；R4And R5It can be same or different substituent group, it can
To connect into one five yuan or hexatomic ring.
R1, R2, R3, R4, R5, R6One or more hetero atoms can be contained, such as, but not limited to, F, Cl, N, O, S.
As a result, in the present specification in the whole text in, those skilled in the art can be to R described in compound shown in Formulas I1-R6Base
Group and its substituent group selected, to provide described in the embodiment of the present invention, compound shown in stable Formulas I or its can medicine
With salt, hydrate, solvate, metabolite.
Typical compound of the invention includes, but are not limited to:
Wherein * is chiral atom, including R configuration, S configuration, R, S mixed type compound.
Term
Except illustrate place, "or" referred to herein have meaning identical with "and/or" (refer to "or" and
"and").
In place of illustrating, among all compounds of the invention, each asymmetric carbon atom (chiral centre) can be optional
Ground is the mixture of R configuration or S configuration or R configuration and S configuration.
As used herein, when individually or as other substituent group a part, term " alkyl " refers to 1~8 carbon original
The straight chain (that is, unbranched) or branched alkyl of son, or combinations thereof.The alkyl can be saturation, single insatiable hunger and/or it is more not
Saturation, and may include the atomic group of divalent or multivalence.Before alkyl there is carbon atom number to limit (such as C1-8) when, refer to described
Alkyl contain 1-8 carbon atom, for example, C1-8Alkyl may include the linear or branched alkyl group with 1-8 carbon atom, example
Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl or similar group.
As used herein, when individually or as other substituent group a part, term " alkenyl " refers to linear chain or branched chain, tool
There is the carbochain of at least one carbon-carbon double bond.Alkenyl with a double bond can be represented as-CnH2n-1, the alkene with 2 double bonds
Base can be represented as-CnH2n-3.Before alkenyl there is carbon atom number to limit (such as C2-8) when, refer to that the alkenyl contains 2-8
Carbon atom, for example, the linear chain or branched chain alkenyl with 2-8 carbon atom, such as vinyl, acrylic, 1,2- cyclobutenyl, 2,3-
Cyclobutenyl, butadienyl or similar group.
As used herein, when individually or as other substituent group a part, term " alkynyl " refers to at least one
The aliphatic hydrocarbon of triple carbon-carbon bonds.The alkynyl can be linear chain or branched chain, or combinations thereof.In some embodiments
In, the alkynyl has 2-8 (for example, 2-8,2-6 or 2-4) a carbon atom.Before alkynyl there is carbon atom number to limit (such as
C2-8Alkynyl) when, refer to that the alkynyl contains 2-8 carbon atom, for example, term " C2-8Alkynyl " refers to 2~8 carbon atoms
Linear chain or branched chain alkynyl, for example, acetenyl, propinyl, isopropynyl, butynyl, butynyl, secondary butynyl, tertiary butynyl,
Or similar group.
As used herein, when individually or as other substituent group a part, term " naphthenic base " refer to saturation or
Monocyclic, bicyclic or tricyclic (including and ring, bridged ring or loop coil) ring system of fractional saturation.The naphthenic base can have 3-16
(for example, 3-10 or 5-10) carbon atom.Before some naphthenic base there is carbon atom number to limit (such as C3-10) when, refer to described
Naphthenic base contain 3-10 carbon atom.In some preferred embodiments, term " C3-8Naphthenic base " refers to 3~8 carbon atoms
Saturation or fractional saturation monocycle or bicyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopenta, suberyl or similar group.
As used herein, term " alkoxy " or " alkyl oxy " refer to the alkyl being connected by oxygen atom (for example,-O- alkane
Base), wherein alkyl is as described above.The example of specific alkoxy for example (but being not limited to) methoxyl group, ethyoxyl, propoxyl group,
Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.Alkoxy can be taken by one or more
Replace for base, the substituent group such as halogen, amino, cyano or hydroxyl.Alkoxy can be linear chain or branched chain.Work as alkane
Before oxygroup there is carbon atom number to limit (such as C1-8) when, refer to that the naphthenic base contains 1-8 carbon atom.
As used herein, when individually or as other substituent group a part, term " halogen " refers to F, Cl, Br and I.
As used herein, when individually or as other substituent group a part, term " aryl " refers to monocycle, two rings or condensed ring
Aromatic series carbon hydrogen group.The aryl can be substituted or unsubstituted.Before an aryl there is carbon atom number to limit
(such as C6-12) when, refer to that the aryl contains 6-12 carbon atom.The example of aryl such as (but being not limited to): phenyl, biphenyl
Base, naphthalene or similar group (each carbon atom therein can arbitrarily be replaced).The aryl can be free of or comprising
One or more identical or different (such as 2,3,4) hetero atoms, the hetero atom can be selected from N, O or S.
As used herein, when individually or as other substituent group a part, term " heteroaryl " refers to monocycle, two rings or thick
The aromatic group of ring, the group have specific ring carbons number (for example, C4-10Have 4-10 a at ring carbon original
Son), and including at least one identical or different hetero atom selected from N, O or S.Each ring atom can arbitrarily be replaced.
The heteroaryl can be 5- to 15- member, and the heteroatomic aromatic rings of N, O or S are each independently selected from 1-5
Base.The example of heteroaryl such as (but being not limited to): pyridine, pyrimidine, pyrroles, indazole, indoles, furans, benzofuran, thiophene,
Or similar group.
As used herein, when individually or as other substituent group a part, term " heterocycle " refers to monocycle or condensed ring
Saturation or fractional saturation substituent group, the group have specific ring carbons number (for example, C3-11There is 3-11 cyclization
Carbon atom), and including at least one identical or different hetero atom selected from N, O or S.The heterocycle can be 3- extremely
15- member, the heteroatomic heterocycle of N, O or S are each independently selected from 1-5.The example of heterocycle is for example (but not
It is limited to): Azacyclyl, oxa- ring group, thia ring group, nitrogen oxa- ring group, nitrogen thia ring group, oxygen thia ring group etc., more preferably
For heterocycle appeared in each embodiment of the application.In the present invention, heterocycle can be for monocyclic, bicyclic or tricyclic (including simultaneously
Ring, bridged ring or loop coil).
As used herein, term " arbitrarily " or " optionally " (for example, " arbitrarily being replaced "), refer to that the part is
It is substituted or unsubstituted, and the substitution only occurs and chemically achievable position.For example, H, covalent bond or-C (=O)-base
Group cannot be substituted with a substituent.
As used herein, term " substitution " (when modifying with or without " arbitrarily ") refers to one or more on specific group
A hydrogen atom is replaced specific substituent group.Specific substituent group is the substituent group accordingly described above, or each implementation
Substituent group appeared in example.Unless stated otherwise, some group arbitrarily replaced can be in any substitutive of the group
On site with one be selected from specific group substituent group, the substituent group at various locations on can be it is identical or different.
Cyclic substituents, such as Heterocyclylalkyl can be connected with another ring, such as naphthenic base, so that spiral shell second cycle line is formed, for example,
Two rings have a shared carbon atom.It will be understood by those skilled in the art that the combination of substituent group desired by the present invention is that
Stable a bit or chemically achievable combination.The substituent group such as (but being not limited to): C1-8Alkyl, C2-8Alkenyl, C2-8Alkynes
Base, C3-8Naphthenic base, 3- to 12- circle heterocyclic ring base, aryl, heteroaryl, halogen, hydroxyl, carboxyl (- COOH), cyano, C1-8Aldehyde radical,
C2-10Acyl group, C2-10Ester group, amino.
For convenience and meet conventional understanding, term " any to replace " or " optionally replacing " are only applicable to be substituted
Site replaced base, without including those chemically irrealizable substitutions.
The universal synthesis method of compound
Compound shown in this present invention general formula I can be made by following method, however the condition of this method, such as be reacted
Following explanation is not limited to the time required to object, solvent, alkali, the amount of compound used therefor, reaction temperature, reaction etc..Chemical combination of the present invention
Various synthetic methods describing in the present specification or known in the art can also optionally be combined and easily be made by object
, such combination can be easy to carry out by those skilled in the art in the invention.
In the preparation process in accordance with the present invention, each reaction is usually in atent solvent, and -78 DEG C of reaction temperature~150 DEG C are (preferably
20~120 DEG C) under carry out.Each step reaction time is usually 0.5~48h, preferably 2~12h.
Reaction equation A describes the universal synthesis method of the compounds of this invention:
Reaction equation A:
As used herein, term " pharmaceutically acceptable salt " refers to the compounds of this invention and pharmaceutically acceptable inorganic acid
Salt is formed by with organic acid, wherein preferred inorganic acid includes (but being not limited to): hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, ammonia
Base sulfonic acid and phosphoric acid etc.；Preferred organic acid includes (but being not limited to): citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzene
Sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acids, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, amber
Amber acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid flutter acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, and glutamic acid resists
Bad hematic acid, p-aminobenzene sulfonic acid, Aspirin and isethionic acid etc..As used herein, unless stated otherwise, term
" pharmaceutically acceptable salt ", which refers to, to be suitble to contact with the tissue of object (for example, people), without the side effect of generation immoderation
Salt.In some embodiments, the pharmaceutically acceptable salt of a certain compound of the invention includes this hair with acidic-group
The salt (for example, sylvite, sodium salt, magnesium salts, calcium salt) of bright compound or the salt (example of the compound of the present invention with basic group
Such as, sulfate, hydrochloride, phosphate, nitrate, carbonate).
As used herein, term " pharmaceutically acceptable solvate " refer to the compounds of this invention with it is pharmaceutically acceptable
Solvent forms solvate, wherein the pharmaceutically acceptable solvent includes (but being not limited to): water, ethyl alcohol, methanol, different
Propyl alcohol, tetrahydrofuran, methylene chloride.The hydrate of compound shown in formula I, solvate (such as methylate, dealing with alcohol
Object, DMSO compound) it is also within the scope of the invention.The method of solvation is well known in the art.
As used herein, term " pharmaceutically acceptable stereoisomer " refers to chiral atom involved by the compounds of this invention
It can be R configuration, or S configuration, or combinations thereof.
Pharmaceutical composition and method of administration
Since the compounds of this invention has an excellent inhibitory activity to ALK kinases, the compounds of this invention and its each
Kind crystal form, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and it is main for containing the compounds of this invention
The pharmaceutical composition of active constituent can be used for treating, prevent and alleviate by disease relevant to ALK kinase activity or expression quantity.
The compound of the present invention can be used for treating or the increment of pre- anti-cancer and inhibition cancer cell.
According to the prior art, the compounds of this invention can be used for treating following disease (but being not limited to): various cancers, and column are such as
It is lung cancer, bladder cancer, breast cancer, kidney, gastric cancer, liver cancer, oophoroma, prostate cancer, cervical carcinoma, intestinal cancer, cell carcinoma, multiple
Property myeloma, cancer of pancreas, lymthoma, leukaemia etc..
According to a particular embodiment of the invention, the drug is at least one following: being used as kinase inhibitor, inhibits
ALK kinase activity, treatment or pre- anti-cancer and the increment for inhibiting cancer cell.Specific example according to the present invention, the present invention couple
The compound in vitro surveys the activity (IC50) of the increment activity suppression of Non-small cell lung carcinoma cell strain H2228
Examination, test result show that compound shown in Formulas I of the present invention all has the value-added activity of good inhibition H2228, the present invention
The compound can be used as ALK inhibitor, be used to prepare into the antineoplaston drug for inhibiting anaplastic lymphoma kinase.
Therefore, drug of the present invention can be effective as ALK inhibitor, for treat it is one or more kinds of with
The related tumor disease of ALK activity, especially non-small cell lung cancer.
Pharmaceutical composition of the invention include safe and effective amount within the scope of the compounds of this invention or its be pharmacologically subjected to
Salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " refers to: the amount of compound is enough obviously
Improve the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contains 1-2000mg the compounds of this invention/agent,
More preferably, containing 5-200mg the compounds of this invention/agent.Preferably, described is " one " for a capsule or tablet.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
Propellant be mixed together.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition
(such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament
Amount is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage be also contemplated that administration route, patient health situation etc. because
Element, within the scope of these are all skilled practitioners technical ability.
In the specific embodiment being described below, compound structure is by nuclear magnetic resonance (NMR) and LC-MS color
(LC-MS) is composed to determine.Wherein, NMR is displaced (δ) and is provided with the unit of hundred a ten thousandths (ppm), and the measurement of NMR is to use
Bruker AVANCE-400 nuclear magnetic resonance spectrometer, measurement solvent are deuterated chloroform (CDCl3), deuterated methanol (CD3), OD deuterated dimethyl sulfoxide
(DMSO-d6), inside it is designated as tetramethylsilane (TMS).The measurement Agilent6120 mass spectrograph of LC-MS chromatography LC-MS,
The measurement of HPLC uses model are as follows: Agilent 1260 (Poroshell 4.6 × 50mm of 120EC-C18 chromatographic column)
Microwave reaction uses XH-800A microwave high pressure synthesizer.
The instrument model of mtt assay survey compound of formula I IC50 value: the Flexstation 3 of MD company.
The detection of reaction process in following example uses thin-layered chromatography (TLC), reacts used solvent
System has: n-hexane/ethyl acetate system, methylene chloride/methanol system, and the volume ratio of solvent is different according to the polarity of compound
And it is adjusted.Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, thin-layered chromatography (TLC)
The specification that the silica gel plate used uses is 0.15-0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4-0.5mm.
Column chromatography is generally carrier using Yantai Huanghai Sea silica gel 200-300 mesh silica gel.
The system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound uses include: A: two
Chloromethanes and methanol system, B: n-hexane and ethyl acetate system, the volume ratio of solvent it is different according to the polarity of compound and into
Row is adjusted, and the alkalinity such as a small amount of triethylamine and acetic acid can also be added or acid reagent is adjusted.
Starting material used in following example can be used or be synthesized according to methods known in the art, or
Commercially available from Aladdin Reagent Company, splendid remote chemistry is scientific and technological, reaches the companies such as auspicious chemicals.
Main advantages of the present invention are:
(1) have present invention firstly discloses a new class of pair of anaplastic lymphoma kinase (ALK) and significantly inhibit effect
Compound；
(2) the compound of the present invention has significant ground and its excellent inhibitory activity to ALK, thus can be used for tumour
Treatment.
(3) in series compound of the invention, certain compounds inhibit tumour cell (H2228) value-added activity significant excellent
In positive control (ceritinib), there are the potentiality instead of positive control medicine, therefore development prospect is huge.
Combined with specific embodiments below, the further old present invention in detail.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.The experimental method of detailed conditions is not specified in the following example, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.Following reality
Applying experimental material used in example and reagent can obtain unless otherwise instructed from commercially available channel.
Embodiment 1
The chloro- N2- of 5- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-N4- (3- methyl -2- sulfonyloxy methyl
Base) phenyl) pyrimidine -2,4- diamines.
The first step
1- methyl -2- mesyl -3- nitrobenzene
3- nitro -2- toluene fluoride (5.00g, 32.2mmol) is dissolved in 15g dimethyl sulfoxide, methyl sulfinic acid sodium is added
(4.94g, 48.4mmol) is heated to 85 DEG C, is stirred to react 12 hours.Reaction solution is cooled to room temperature, 50g water, cooling is added
It to 0-10 DEG C, stirs 40 minutes, filtering, vacuum drying obtains title product 1- methyl -2- mesyl -3- nitrobenzene 1b
(5.89g, pale solid), yield 85%.
Second step
2- mesyl -3- methylaniline
1- methyl -2- mesyl -3- nitrobenzene (5.89g, 27.4mmol) is dissolved in 25g dehydrated alcohol, is added
5% palladium carbon (0.6g), hydrogen are replaced three times, under nitrogen atmosphere (0.4MPa), are stirred to react 48 hours.Reaction solution is passed through into diatomite
Filtering, filtrate decompression concentration purify gained residue with silica gel column chromatography (eluent n-hexane/ethyl acetate=5:1), obtain
To title product 2- mesyl -3- methylaniline 1c (4.41g, white solid), yield 87%.
Third step
The chloro- N- of 2,5- bis- ((3- methyl -2- mesyl) benzene) pyrimidine -4- amine
The mixed solvent of DMF/DMSO (50ml/5ml) is cooled to 0 DEG C, is added NaH (1.37g), half an hour is stirred, adds
DMF/DMSO (20ml/2ml) solution for entering 2- mesyl -3- methylaniline (4.41g, 23.8mmol), after dripping off, at 0 DEG C
Half an hour is stirred, DMF/DMSO (15ml/1.5ml) solution of 2,4,5- trichloropyrimidines (8.73g, 47.6mmol) is slowly added dropwise,
After dripping off, it is warming up to room temperature, is stirred 24 hours.300ml water is added, stirs 1 hour, filtering obtains yellow solid, uses silicagel column
Chromatography (eluent, n-hexane/ethyl acetate=5:1) purifies this yellow solid, obtains title product 2, chloro- the N- ((3- of 5- bis-
Methyl -2- mesyl) benzene) pyrimidine -4- amine 1e (4.35g, white solid), yield 55%.
4th step
4- (4- (the chloro- 4- of 5- (3- methyl -2- mesyl) aniline) pyrimidine -2- amino) -5- isopropoxy -2- methylbenzene
Phenylpiperidines -1- carboxylic acid tert-butyl alcohol ether
By 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) piperidines -1- carboxylic acid tert-butyl alcohol ether (2.28g,
6.26mmol), the chloro- N- of 2,5- bis- ((3- methyl -2- mesyl) benzene) pyrimidine -4- amine (2.18g, 6.26mmol), 4,5- is bis-
Diphenylphosphine -9,9- xanthphos (0.376g, 0.626mmol), palladium acetate (73.76mg, 0.313mmol), cesium carbonate
(6.4g, 19.64mmol) and 40ml tetrahydrofuran are added in reaction flask, and 150 DEG C of microwave are reacted 20 minutes.Reaction solution is cooled to
Room temperature, vacuum distillation purify remnants obtained by (eluent, n-hexane/ethyl acetate=5:1) with silica gel column chromatography after being evaporated
Object obtains title product 4- (4- (the chloro- 4- of 5- (3- methyl -2- mesyl) aniline) pyrimidine -2- amino) -5- isopropoxy -
2- aminomethyl phenyl piperidines -1- carboxylic acid tert-butyl alcohol ether 1g (1.78g, white solid), yield 42%.
5th step
The chloro- N2- of 5- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-N4- ((3- methyl -2- mesyl)
Phenyl) pyrimidine -2,4- diamines
By 4- (4- (the chloro- 4- of 5- (3- methyl -2- mesyl) aniline) pyrimidine -2- amino) -5- isopropoxy -2- methyl
Phenylpiperidine -1- carboxylic acid tert-butyl alcohol ether (1.78g, 2.76mmol) is dissolved in 50ml methylene chloride, is added trifluoroacetic acid (20g),
It stirs 1 hour, is concentrated under reduced pressure at room temperature, be added 20ml sodium hydrate aqueous solution (20%), 70ml ethyl acetate, stirring half is small
When, liquid separation, water phase uses 70ml ethyl acetate to extract again, merges organic phase, organic phase washed with water (30ml × 1) and saturation chlorination
Sodium solution (30ml × 2) washing, anhydrous sodium sulfate dries, filters, filtrate decompression concentration, and with n-hexane/ethyl acetate (10/
1) it crystallizes, obtains the chloro- N2- of title product 5- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-N4- ((3- methyl -
2- mesyl) phenyl) pyrimidine -2,4- diamines 1 (1.28g, white solid), yield 85%.
LCMS:544
1H-NMR (400MHz, CDCl3): δ=1.38 (d, J=6.1Hz, 6H), 1.59-1.78 (m, 5H), 2.18 (s,
3H), 2.35 (s, 3H), 2.84 (s, 3H), 2.75-2.82 (m, 3H), 3.20-3.24 (M, 2H), 4.56 (sept, J=
6.1Hz),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01
(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Embodiment 2
The chloro- N2- of 5- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-N4- ((3- methyl -2- mesyl)
Phenyl) pyrimidine -2,4- diamines
The synthetic method of embodiment 2 is referring to embodiment 1.
LC-MS:558
1H-NMR (400MHz, CDCl3): δ=1.24 (m, J=6.5Hz, 3H), 1.38 (d, J=6.1
Hz,6H),1.59-1.78(m,5H),2.18(s,3H),2.35(s,3H),3.45(m,2H),2.75-2.82(m,
3H), 3.20-3.24 (M, 2H), 4.56 (sept, J=6.1Hz), 6.82 (s, 1H), 7.25-7.29 (m, 1H), 7.56 (br, s,
1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,
1H)ppm.
Embodiment 3
The chloro- N2- of (R, S) -5- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-N4- (2- isopropyl Asia sulphur
Acyl group) phenyl) pyrimidine -2,4- diamines.
The first step
The chloro- N- of 2,5- bis- (2- (isopropyl thioether) phenyl) pyrimidine -4- amine
The thio anilinechloride of 2- isopropyl (5g, 24.4mmol) and 2,4,5- trichloropyrimidine (4.48g, 24.4mmol) is molten
In the in the mixed solvent of 50ml toluene and 5ml n-butanol, it is added n,N-diisopropylethylamine (6.3g, 48.8mmol), heats back
Stream reaction 24 hours, is cooled to room temperature, and 20ml water is added, and stirs 10 minutes, stratification obtains organic phase, and organic phase is successively
It being washed with water (20ml × 1) and saturated sodium chloride solution (20ml × 2), anhydrous sodium sulfate dries, filters, filtrate decompression concentration,
And with alcohol crystal, title product 2, the chloro- N- of 5- bis- (2- (isopropyl thioether) phenyl) pyrimidine -4- amine 3b (6.2g, white are obtained
Solid), yield 81%.
Second step
The chloro- N- of (R, S) -2,5- two (2- (isopropylsulfinyl base) phenyl) pyrimidine -4- amine
The chloro- N- of 2,5- bis- (2- (isopropylsulfinyl base) phenyl) pyrimidine -4- amine (6.2g, 20mmol) is dissolved in 100ml bis-
In chloromethanes, it is cooled to 0-5 DEG C, the dichloromethane solution (3.14g85%mCPBA/ of metachloroperbenzoic acid is slowly added dropwise
100ml methylene chloride), drip off within about 1 hour, after dripping off, be warming up to room temperature, stir 5 hours, then be cooled to -5 DEG C -- it 10 DEG C, stirs
It mixes 1 hour, filters, filter off insoluble matter, filtrate decompression concentration, residue adds n-hexane, and ethyl acetate crystallizes (n-hexane/acetic acid
Ethyl ester=5:1), obtain the chloro- N- of title product (R, S) -2,5- bis- (2- (isopropylsulfinyl base) phenyl) pyrimidine -4- amine 3c
(5.2g, white solid), yield 80%.
Third step
(R, S) -4- (4- (the chloro- 4- of 5- (2- isopropylsulfinyl base) aniline) pyrimidine -2- amino) -5- isopropoxy -2- first
Base Phenylpiperidine -1- carboxylic acid tert-butyl alcohol ether
Synthetic method obtains title product (R, S) -4- (4- (chloro- 4- of 5- referring to the synthetic method of the 4th step of embodiment 1
(2- isopropylsulfinyl base) aniline) pyrimidine -2- amino) -5- isopropoxy -2- aminomethyl phenyl piperidines -1- carboxylic acid tert-butyl alcohol ether is (white
Color solid), yield 40%
4th step
The chloro- N2- of (R, S) -5- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-N4- (2- isopropyl Asia sulphur
Acyl group) phenyl) pyrimidine -2,4- diamines.
Synthetic method obtains title product (R, S) -5- chloro- N2- (2- isopropyl referring to the synthetic method of the 5th step of embodiment 1
Oxygroup -5- methyl -4- (piperidin-4-yl) phenyl)-N4- (2- isopropylsulphinyl) phenyl) (white is solid for pyrimidine -2,4- diamines
Body), yield 83%.
LC-MS:542
1H-NMR(400MHz,DMSO-d6): δ=1.18 (d, J=6.8Hz, 6H), 1.24 (d, J=6.1Hz, 6H),
1.46-1.62(m,4H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),
3.45-3.51 (m, 1H), 4.51-4.57 (m, 2H), 6.82 (s, 1H), 7.32-7.36 (t, J=7.6Hz, 1H), 7.51 (s,
1H), 7.59-7.63 (t, J=7.2Hz, 1H), 7.85 (dd, 1H), 8.05 (s, 1H), 8.23 (s, 1H), 8.45-8.47 (m,
1H)ppm.
It is split by chiral preparatory column, the chloro- N2- of available (R) -5- (2- isopropoxy -5- methyl -4- (piperidines -4-
Base) phenyl)-N4- (2- isopropylsulphinyl) phenyl) pyrimidine -2,4- diamines and the chloro- N2- of (S) -5- (2- isopropoxy -5-
Methyl -4- (piperidin-4-yl) phenyl)-N4- (2- isopropylsulphinyl) phenyl) pyrimidine -2,4- diamines.
Embodiment 4
The chloro- N2- of 5- (2- methoxyl group-4- (4- (4- methyl-1-piperazinyl)-1- piperidyl) phenyl)-N4- ((3- methyl-
2- mesyl) phenyl) pyrimidine -2,4- diamines
By the chloro- N- of 2,5- bis- ((3- methyl -2- mesyl) phenyl) pyrimidine -4- amine (1.56g, 4.70mmol) and 2- first
Oxygroup -4- (4- (4- methyl piperazine base) piperidyl) aniline (2g, 6.59mmol) is dissolved in 2-methyl cellosolve (25ml), is added
This mixture is poured into a heavy-walled glass bottle by 2.5M acidic alcohol (5ml), is heated to 120 DEG C, is reacted 6 hours, cooling
It to room temperature, is concentrated under reduced pressure, 50ml water, 50ml ethyl acetate is added into residue, stirring layering is removed ethyl acetate layer, received
Collect water layer, 20% sodium hydrate aqueous solution tune pH value is added dropwise to 12 in water layer.With methylene chloride (50ml × 3) aqueous phase extracted, have
Machine is mutually successively washed with water (30ml × 1) and saturated sodium chloride solution (30ml × 2), and anhydrous sodium sulfate dries, filters, and filtrate subtracts
Pressure concentration, concentrate silica gel column chromatography purify (eluent, methylene chloride/methanol=10:1) gained residue, marked
Inscribe the chloro- N2- of product 5- (2- methoxyl group-4- (4- (4- methyl-1-piperazinyl)-1- piperidyl) phenyl)-N4- ((3- methyl-2-
Mesyl) phenyl) pyrimidine -2,4- diamines 4 (1.41g, pale solid), yield 50%.
LC-MS:600
1H-NMR(400MHz,CD3OD): δ=1.66 (dq, J=3.89,12.09Hz, 2H), 1.97-2.08 (m, 2H),
2.29(s,3H),2.35(s,3H),2.89(s,3H),2.33-2.42(m,1H),2.43-2.62(m,4H),2.62-2.86(m,
6H), 3.69 (d, J=12.30Hz, 2H), 3.84 (s, 3H), 6.65 (d, J=2.51Hz, 1H), 7.25 (ddt, J=1.00,
2.26,7.53Hz, 1H), 7.47-7.54 (m, 1H), 7.60 (m, 1H), 7.66 (d, J=8.78Hz, 1H), 8.02 (s, 1H),
8.33 (dd, J=4.52,8.03Hz, 1H) ppm.
Embodiment 5
The chloro- N2- of (R, S)-5- (2- methoxyl group-4- (4- (4- methyl-1-piperazinyl)-1- piperidyl) phenyl)-N4- ((2-
Isopropylsulfinyl base) phenyl) pyrimidine -2,4- diamines
The synthetic method of embodiment 5 is referring to embodiment 4.
LC-MS:598
1H-NMR(400MHz,CD3OD): δ=1.30 (d, J=7.0Hz, 6H), 1.66 (dq, J=3.89,12.09Hz,
2H),1.97-2.08(m,2H),2.29(s,3H),2.33-2.42(m,1H),2.43-2.62(m,4H),2.62-2.86(m,
6H), 3.18 (m, J=6.7Hz, 1H) 3.69 (d, J=12.30Hz, 2H), 3.84 (s, 3H), 6.45 (dd, J=2.51,
8.78Hz, 1H), 6.65 (d, J=2.51Hz, 1H), 7.25 (ddt, J=1.00,2.26,7.53Hz, 1H), 7.47-7.54 (m,
1H), 7.60 (m, 1H), 7.66 (d, J=8.78Hz, 1H), 8.02 (s, 1H), 8.33 (dd, J=4.52,8.03Hz, 1H) ppm.
It is split by chiral preparatory column, the chloro- N2- of (R)-5- (2- methoxyl group-4- (4- (4- methyl-1-piperazine can be prepared
Piperazine base) -1- piperidyl) phenyl)-N4- ((2- isopropylsulfinyl base) phenyl) pyrimidine -2,4- diamines and the chloro- N2- (2- of (S) -5-
Methoxyl group-4- (4- (4- methyl-1-piperazinyl)-1- piperidyl) phenyl)-N4- ((2- isopropylsulfinyl base) phenyl) pyrimidine-2,
4- diamines.
There is one there is greater activity in R, S counterpart, so the activity of one of homochiral isomers can be bigger.
Test case:
Biological assessment
Test case 1, the compounds of this invention inhibit measurement to the increment of source of people non-small cell lung cancer cell strain H2228.
The cell strain source that this experiment uses: H2228 (Chinese Academy of Sciences's cell bank, article No. SCSP-5001)
In vitro cell experiment as described below can measure increasing of the test-compound to Non-small cell lung carcinoma cell strain
It is worth inhibitory activity, activity can use IC50Value indicates.The general approach of such test is as follows: first (being purchased from cell strain to be measured
Chinese Academy of Sciences's cell bank) it is seeded on 96 well culture plates with 5000 cells of matters cell concentration/ml medium, every hole is inoculated with 80 μ L cells
Suspension, then by cell in 5% carbon dioxide incubator 37 DEG C cultivate, allow they grow to overnight, replace culture medium
It is molten added with a series of concentration gradients (3 μM, 1 μM, 0.3 μM, 0.1 μM, 30nM, 10nM, 3nM, 1nM, 0.3nM) test-compound
Plate is placed back in incubator by the culture medium of liquid, continuous to be incubated for 72 hours, is terminated after being incubated for, is added into cell plates
MTT (storage concentration: 5mg/ml) 10 holes μ L/, are placed in 37 DEG C and 5%CO2 incubator and are incubated for 4h.It inhales and abandons liquid in hole, be added
10min is shaken in 120 hole μ L/ DMSO, and after formazan is completely dissolved, the suction at 570nm wavelength is measured on FlexStation3
Luminosity calculates motility rate.
It calculates Cell growth%Control=ODs/AVER (ODNC) × 100%
Wherein:
ODS: the light absorption value (untested compound) of sample well
ODNC: negative hole light absorption value (cell+culture medium+DMSO)
IC50Value can be by the way that under some column various concentrations, test-compound calculates the inhibition numerical value of cell.
The compounds of this invention bioactivity from the above analysis gained, calculate resulting IC50Value such as table 1:
Table 1: inhibiting rate of the target compound to tumour cell H2228
| Embodiment number | IC50/(nM) |
| 1 | 145.2 |
| 2 | 65.4 |
| 3 (R, S mixed compounds) | 46 |
| 4 | 106.1 |
| 5 (R, S mixed compounds) | 4.58 |
| Positive control (Ceritinib) | 49 |
Conclusion: preferred compound of the present invention has apparent increment inhibitory activity to H2228 cell.Wherein compound 5
It shows significant more preferably inhibitory activity, the activity of compound 5 and has reached 10 times of positive control or more.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. one kind such as formula (I) compound represented or its pharmaceutically acceptable salt, prodrug, metabolite, hydrate or molten
Object is closed in agent:
Wherein, in formula (I):
X is-(S=O)-or-(O=S=O)-；
Y is N or CH；
R1It is selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C3-8Naphthenic base, replace or
Unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl and substituted or unsubstituted C1-8Alkoxy；
R2It is selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8It is alkenyl, substituted or unsubstituted
C2-8Alkynyl, substituted or unsubstituted C3-8Naphthenic base, substituted or unsubstituted 3- to 8- circle heterocyclic ring base, replace or do not take
The aryl in generation and substituted or unsubstituted heteroaryl；
R3And R6Independently selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl and substituted or unsubstituted C1-8Alcoxyl
Base；
R4And R5Independently selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C1-8Alkoxy, substitution
Or unsubstituted aryl and substituted or unsubstituted heteroaryl；Alternatively, R4And R5The atom connected with them shape together
At 3- to 8- member ring, the 3- to 8- member ring is optionally substituted by one or more substituents, and the substituent group is selected from: halogen,
C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl, C1-8Alkoxy, C3-8Naphthenic base, C1-4Alkyl-substituted or unsubstituted 3- is miscellaneous to 8- member
Ring group.
2. compound as described in claim 1, which is characterized in that R1It is selected from: hydrogen and substituted or unsubstituted C1-4Base.
3. compound as described in claim 1, which is characterized in that R2For substituted or unsubstituted C1-4Base.
4. compound as described in claim 1, which is characterized in that R3For substituted or unsubstituted C1-4Alkoxy.
5. compound as described in claim 1, which is characterized in that R6For hydrogen or substituted or unsubstituted C1-4Alkyl.
6. compound as described in claim 1, which is characterized in that X is-(S=O)-and-(O=S=O)-.
7. the purposes of formula (I) compound as described in claim 1, which is characterized in that be used for:
(a) drug of preparation treatment disease relevant to anaplastic lymphoma kinase (ALK) activity or expression；And/or
(b) anaplastic lymphoma kinase (ALK) targeted inhibition agent is prepared；And/or
(c) inhibit to external non-therapeutic the activity of anaplastic lymphoma kinase (ALK).
8. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition includes:
(i) compound or its pharmaceutically acceptable salt described in a effective amount of first aspect present invention, prodrug, metabolite,
Hydrate or solvate；With
(ii) pharmaceutically acceptable carrier.
9. a kind of preparation method of compound as described in claim 1, which is characterized in that the method comprising the steps of:
(a) in atent solvent, compound A-13 and compound A4 react to obtain compound shown in Formulas I:
Wherein, X, Y, R1、R2、R3、R4、R5、R6It is as described in claim 1 respectively.
10. a kind of method for treating tumour, which is characterized in that the method includes the steps:
It is pharmaceutically acceptable to formula as described in claim 1 (I) compound or its of the object application therapeutically effective amount of needs
Salt, or the pharmaceutical composition as claimed in claim 8 to the objects of needs application therapeutically effective amount.
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| CN201810093773.7A CN110092759A (en) | 2018-01-31 | 2018-01-31 | The chloro- 2,4- pyrimidine derivatives of 5- as anti-tumor drug |
| CN201980023403.9A CN112004809A (en) | 2018-01-31 | 2019-01-24 | 5-chloro-2, 4-pyrimidine derivatives as antitumor agents |
| PCT/CN2019/072915 WO2019149128A1 (en) | 2018-01-31 | 2019-01-24 | 5-chloro-2,4-pyrimidine derivative used as anti-tumor drug |
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| CN201980023403.9A Pending CN112004809A (en) | 2018-01-31 | 2019-01-24 | 5-chloro-2, 4-pyrimidine derivatives as antitumor agents |
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| CN113501808A (en) * | 2021-06-04 | 2021-10-15 | 清远中大创新药物研究中心 | Novel pyrimidine derivative of sulfinyl anilino and application of novel pyrimidine derivative in preparation of antitumor drugs |
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| CN1788001A (en) * | 2003-03-14 | 2006-06-14 | 诺瓦提斯公司 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
| CN1832929A (en) * | 2003-08-15 | 2006-09-13 | 诺瓦提斯公司 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| CN106699743A (en) * | 2015-11-05 | 2017-05-24 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
| WO2017158619A1 (en) * | 2016-03-15 | 2017-09-21 | Natco Pharma Limited | A modified process for the preparation of ceritinib and amorphous form of ceritinib |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2671744C (en) * | 2006-12-08 | 2012-08-28 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1788001A (en) * | 2003-03-14 | 2006-06-14 | 诺瓦提斯公司 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
| CN1832929A (en) * | 2003-08-15 | 2006-09-13 | 诺瓦提斯公司 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
| CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
| CN106699743A (en) * | 2015-11-05 | 2017-05-24 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
| WO2017158619A1 (en) * | 2016-03-15 | 2017-09-21 | Natco Pharma Limited | A modified process for the preparation of ceritinib and amorphous form of ceritinib |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113501808A (en) * | 2021-06-04 | 2021-10-15 | 清远中大创新药物研究中心 | Novel pyrimidine derivative of sulfinyl anilino and application of novel pyrimidine derivative in preparation of antitumor drugs |
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| WO2019149128A1 (en) | 2019-08-08 |
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