CN106029646A - Pyrimidine-2,4-diamine derivative and pharmaceutical anticancer composition containing same as active ingredient - Google Patents
Pyrimidine-2,4-diamine derivative and pharmaceutical anticancer composition containing same as active ingredient Download PDFInfo
- Publication number
- CN106029646A CN106029646A CN201580010933.1A CN201580010933A CN106029646A CN 106029646 A CN106029646 A CN 106029646A CN 201580010933 A CN201580010933 A CN 201580010933A CN 106029646 A CN106029646 A CN 106029646A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- pyrimidine
- base
- chloro
- isopropelsulfonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 230000001093 anti-cancer Effects 0.000 title claims description 8
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000006548 oncogenic transformation Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 208000038009 orphan disease Diseases 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000012128 staining reagent Substances 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000003441 suberic acid derivatives Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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 relates to a pyrimidine-2,4-diamine derivative or pharmaceutically acceptable salts thereof, and a pharmaceutical composition for preventing or treating cancer, which contains a pyrimidine-2,4-diamine derivative as an active ingredient. A compound according to the present invention is very effective in suppressing anaplastic lymphoma kinase (ALK) activity, and as a result, can improve the effectiveness of treatment on cancer cells having anaplastic lymphoma kinase (ALK) fusion proteins, such as EML4-ALK and NPM-ALK, and is expected to effectively prevent recurrence of cancer, thus being useful as a composition for preventing or treating cancer.
Description
Technical field
The present invention relates to pyrimidine-2,4-diamine derivative or its pharmaceutically acceptable salt, and containing pyrimidine-2,4-bis-
Amine derivative is used for preventing or treating the pharmaceutical composition of cancer as active component.
Background technology
The normal cell bred from according to certain rule and necessary mode or suppress is different, and cancerous cell ignores these necessary rule
Then with mode infinite multiplication in the tissue, the cell mass that cancer is made up of the undifferentiated cell of this class infinite multiplication, also
It is referred to as tumor.The cancerous cell of unrestricted propagation invades surrounding tissue, even invades other organ, causes serious painful and asks
Topic, even death, therefore, be considered as the disease that can not be cured by cancer.
According to the report of American Cancer Society, the new patient suffering from cancer for 2007 in global range after diagnosing is at least
12000000 people, wherein 7,600,000 people are dead, show every day about 20,000 patient to die from cancer.In Korea S, according to statistics bureau of Korea S
Report, cancer mortality is the first dead reason in 2006.Therefore, in the urgent need to developing the anticancer for the treatment of of cancer excellent effect
Agent, in order to reduce and physical pain painful by the emotion experienced caused by cancer onset and during treatment cancer, simultaneously
Improve the quality of life of patient.
Although all previous effort, but not yet it is expressly understood that normal cell becomes the mechanism of cancerous cell.Cancer is logical
Cross external factor (such as environmental factors, chemicals, radiation and virus) and internal factor (such as inherited genetic factors and immune factor)
Common effect develop.The gene relating to cancer development is oncogene and antioncogene.When two relevant to cancer
When balance between gene is broken by any of the above described internal factor or external factor, just develop into cancer.
Cancer is broadly divided into leukemia and solid carcinoma two class.Cancer almost develops at each body part, causes pulmonary carcinoma, stomach
Cancer, breast carcinoma, oral cancer, hepatocarcinoma, uterus carcinoma, esophageal carcinoma and skin carcinoma etc..Employ some targeting agents (such as imatinib mesylate
(Gleevec) and Trastuzumab (Herceptin)) to treat some cancer, but suppression cell proliferation surgical operation, radiation treat
Method, chemotherapy are main anti-cancer treatments.But, these methods are not targeted therapies, and conventional chemotherapy is
Big problem is the side effect caused by cytotoxicity and drug resistance, even if this is to use after with anticarcinogen success early treatment
The reason that anti-cancer agent therapy is the most failed.In order to overcome chemotherapeutic restriction, the anticancer mechanism of targeting agent is clearly being managed
On the basis of solution, need constantly to develop targeting agent.
In order to develop targeting agent, have been carried out tumor and form the research of involved specific molecular biological factor.Tool
For body, Molecular Biological Factors is used in the prediction of cancer prognosis or is used for chemotherapy or radiotherapeutic decision is made
In.
The most representative medicine of tyrosine kinase receptor (one of Molecular Biological Factors involved by cancer) can be suppressed
Thing is imatinib mesylate.Imatinib mesylate is formed by suppressing the transposition in the Philadelphia chromosome observed in chronic myelocytic leukemia
Bcr-Abl fusion gene shows that antitumaous effect, imatinib mesylate are one of tyrosine kinase inhibitors, and at treatment chronic granulocyte
In leukemia effectively.Other anticarcinogen as tyrosine kinase inhibitor is: gefitinib (gefitinib) and Erlotinib
(erlotinib), it is EGFR (EGF-R ELISA) the tyrosine-kinase enzyme level used in the treatment of nonsmall-cell lung cancer
Agent；And in the treatment of renal cell carcinoma use Sorafenib (sorafenib) and Sutent (sunitinib).But, this
A little medicines show the most hemorrhage, have a heart attack, the side effect of heart failure and liver failure etc..
Recently, anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) is identified in kinds of tumors, and therefore, anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase is
Through being the target of research.
In the cancer development of ALK mediation, it is believed that ALK-NPM (the kernel phosphorus found in primary cutaneous type
Acid albumin) fusion gene is key factor.Once ALK is activated by gene fusion, and the tyrosine kinase being included in ALK starts different
Often effect causes cancer.That is, anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) the induction cell proliferation of abnormal activation, interruption cell wither
Die, to prevent cell death, to reset cytoskeleton, and therefore change cell shape.Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) carcinogenic
Convert by ALK and downstream interaction between molecule complete.Downstream molecules is the thing of signal transduction in mediated cell
Matter.ALK interacts with the tyrosine kinase gene of normal gene or other oncogenic transformation, to activate other approach multiple.
Specifically, the ALK gene in lung carcinoma cell is melted to EML4 (the micro-pipe of echinoderm relevant sample albumen sample 4) gene
Close, to produce active tyrosine kinase EML4-ALK.Now, the cancer induction activity of EML4-ALK depends on enzymatic activity.Mosse
Et al. also report confirm in 491 neuroblastoma samples about 26% ALK gene amplification.It addition, include with
Under many non-hematopoietic cell tumors in be found that ALK gene: large B cell lymphoid tumor, generalized tissue cellular proliferative disorder, inflammatory
Myofibroblastoma, esophageal squamous cell carcinoma, nonsmall-cell lung cancer, rhabdomyosarcoma, myofibroblastoma, breast carcinoma and
K-1735.In inflammatory haematogonium tumor (a kind of orphan disease), it is frequently observed that different types of anaplastic
Lymphom kinase (ALK) fusion protein, shows that this type of fusion protein degree of depth participates in tumor development.
By using the method blocking ALK activated channel, developing the anticarcinogen of a kind of targeting ALK-NPM.The most
Confirmed by suppression ATP competitiveness c-Met/HGFR and ALK by Pfizer (Pfizer), be developed to the suppression of tumorigenesis mutation specific
Gram azoles of one of the small molecule tyrosine kinase inhibitors of agent has in treatment nonsmall-cell lung cancer for Buddhist nun (PF-02341066)
Effect, therefore, gram azoles was approved as new drug in 2011 by FDA for Buddhist nun.
Also demonstrate that NVP-TAE684 and LDK-378 and Japan's Chugai (Chugai) that Novartis (Novartis) develops
Exploitation CH5424802 can not only primary cutaneous type cell line and also can be at Human Neuroblastoma Cell Line
Middle reduction tumor size.
Patent documentation 1～patent document 3 describe that in order to suppress ALK activity, developing the candidate with multiple framework
Therapeutic agent, pyrimidine derivatives can Selective depression ALK, therefore can be developed as anticarcinogen.
Therefore, the present inventor attempts to develop and effectively suppresses anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK, Anaplastic lymphoma
Kinase) compound of activity.As a result, the inventors discovered that pyrimidine-2 being in ad hoc structure, 4-diamine derivative is in suppression
In ALK activity extremely excellent, therefore can be used as cancer prevention agent or cancer therapeutic agent, thus complete the present invention.
Prior art literature
Patent documentation
Patent documentation 1:WO 2009143389 A1
Patent documentation 2:WO 2008051547 A1
Patent documentation 3:WO 2004080980 A1
Summary of the invention
It is an object of the invention to provide pyrimidine-2,4-diamine derivative or its pharmaceutically acceptable salt.
It is a further object of the present invention to provide the method for preparing described pyrimidine-2,4-diamine derivative.
It is yet another object of the invention to provide containing described pyrimidine-2,4-diamine derivative or its pharmaceutically acceptable salt
As active component, for preventing or treat the pharmaceutical composition of cancer.
A further object of the present invention is to provide containing described pyrimidine-2,4-diamine derivative or it is pharmaceutically acceptable
Salt is as active component, for preventing or treating by the disease caused by the overactivity of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK)
Pharmaceutical composition.
It is yet another object of the invention to provide containing described pyrimidine-2,4-diamine derivative or its pharmaceutically acceptable salt
Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) inhibitor as active component.
To achieve these goals, the present invention provides pyrimidine-2 that formula 1 represents, 4-diamine derivative or its pharmaceutically can connect
The salt being subject to.
[formula 1]
In formula 1,
Represent singly-bound or double bond；
WhenWhen being singly-bound,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-10Straight chained alkyl；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-10Straight or branched alkyl；Or-C (=O)
R5, now R5It is-H ,-OH or C1-10Straight or branched alkyl；
WhenWhen being double bond,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-10Straight chain or
Alkyl group；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-10Straight or branched alkyl；Or-C (=O)
R5, now R5It is-H ,-OH or C1-10Straight or branched alkyl.
Present invention also offers for preparing above-mentioned pyrimidine-2, the method for 4-diamine derivative, described method includes following
Following steps shown in reaction equation 1:
Reacted by the compound making compound that formula 2 represents and formula 3 represent, the compound (step that formula 4 represents
1)；And
The compound that the compound represented by the formula 4 making in step 1 preparation and formula 5 are represented reacts, formula 1 expression
Compound (step 2).
[reaction equation 1]
(in reaction equation 1, R1、R2、R3And R4As defined in formula 1).
Present invention also offers the pyrimidine-2,4-diamine derivative represented containing formula 1 or its pharmaceutically acceptable salt is made
For active component, for preventing or treat the pharmaceutical composition of cancer.
Present invention also offers the pyrimidine-2,4-diamine derivative represented containing formula 1 or its pharmaceutically acceptable salt is made
For active component, for preventing or treating by the medicine of the disease caused by the overactivity of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK)
Compositions.
It addition, the invention provides pyrimidine-2 represented containing formula 1,4-diamine derivative or its pharmaceutically acceptable salt
Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) inhibitor as active component.
Beneficial effect
The compound of the present invention is excellent in suppression anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK), therefore, and can by it advantageously
For improving the therapeutic effect to the cancerous cell containing ALK fusion protein (such as EML4-ALK and NPM-ALK), and the present invention
Compound effectively, therefore, can be effectively served as prevention or the pharmaceutical composition for the treatment of cancer in prophylaxis of cancer recurs.
Detailed description of the invention
Hereinafter, the present invention is described in detail.
The invention provides pyrimidine-2,4-diamine derivative or its pharmaceutically acceptable salt that formula 1 represents.
[formula 1]
In formula 1,
Represent singly-bound or double bond；
WhenWhen being singly-bound,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-10Straight chained alkyl；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-10Straight or branched alkyl；Or-C (=O)
R5, now R5It is-H ,-OH or C1-10Straight or branched alkyl；
WhenWhen being double bond,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-10Straight chain or
Alkyl group；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-10Straight or branched alkyl；Or-C (=O)
R5, now R5It is-H ,-OH or C1-10Straight or branched alkyl.
Preferably,
WhenWhen being singly-bound,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-5Straight chained alkyl；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-5Straight or branched alkyl；Or-C (=O) R5,
Now R5It is-OH or C1-5Straight or branched alkyl；
WhenWhen being double bond,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-5Straight or branched
Alkyl；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-5Straight or branched alkyl；Or-C (=O) R5,
Now R5It is-OH or C1-5Straight or branched alkyl.
It is highly preferred that
WhenWhen being singly-bound,
R1It is-Cl or-CF3；
R2It is-H ,-CH3Or-F；
R3It is-CH3Or-CHF2；
R4It is-H ,-CH3、-CH2CH3、-CH2CH2OH ,-C (=O) CH3Or-C (=O) OH；
WhenWhen being double bond,
R1It is-Cl or-CF3；
R2It is-H ,-CH3Or-F；
R3It is-CH3、-CH(CH3)2Or-CHF2；
R4It is-H ,-CH3、-CH2CH3、-CH2CH2OH ,-C (=O) CH3Or-C (=O) OH.
Pyrimidine-2,4-the diamine derivative that formula 1 represents can be enumerated by following compound:
(1) the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-
Base) phenyl) pyrimidine-2,4-diamidogen；
(2) the chloro-N2-of 5-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-
(isopropelsulfonyl) phenyl) pyrimidine-2,4-diamidogen；
(3) the chloro-N2-of 5-(2-(difluoro-methoxy)-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl
Base sulfonvlphenyl) pyrimidine-2,4-diamidogen；
(4) the chloro-N2-of 5-(2-(difluoro-methoxy)-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) benzene
Base) pyrimidine-2,4-diamidogen；
(5) the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(piperidin-4-yl) phenyl) is phonetic
Pyridine-2,4-diamidogen；
(6) N4-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-base) benzene
Base)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen；
(7) N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl
Sulfonyl) phenyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen；
(8) N2-(2-(difluoro-methoxy)-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl sulphur
Acyl group) phenyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen；
(9) N2-(2-(difluoro-methoxy)-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl)-5-
(trifluoromethyl) pyrimidine-2,4-diamidogen；
(10) the chloro-N2-of 5-(5-fluoro-2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl
Base sulfonyl) phenyl) pyrimidine-2,4-diamidogen；
(11) the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-5-methyl-4-(1,2,3,6-tetra-
Pyridinium hydroxide-4-base) phenyl) pyrimidine-2,4-diamidogen；
(12) the chloro-N2-of 5-(5-fluoro-2-methoxyl group-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) benzene
Base) pyrimidine-2,4-diamidogen；
(13) the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-5-methyl-4-(piperidin-4-yl)
Phenyl) pyrimidine-2,4-diamidogen；
(14) (2-is (different for-N4-for the chloro-N2-of 5-(4-(1-ethyl-1,2,3,6-tetrahydropyridine-4-base)-2-methoxyphenyl)
Sulfonyl propyl base) phenyl) pyrimidine-2,4-diamidogen；
(15) the chloro-N2-of 5-(4-(1-hydroxyethyl-1,2,3,6-tetrahydropyridine-4-base)-2-methoxyphenyl)-N4-
(2-(isopropelsulfonyl) phenyl) pyrimidine-2,4-diamidogen；
(16) 1-(4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-first
Phenyl)-5,6-dihydropyridine 1 (2H)-yl) ethyl ketone；
(17) 4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-methoxy
Base phenyl)-5,6-dihydropyridine-1 (2H)-formic acid；And
(18) 4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-methoxy
Base phenyl)-1 (2H)-methyl-5,6-dihydropyridine.
Pyrimidine-2 that formula 1 can be represented, 4-diamine derivative uses as the form of pharmaceutically acceptable salt,
Wherein, described salt is preferably the acid-addition salts that pharmaceutically acceptable free acid is formed.Acid-addition salts as herein described can be by
Following acid obtains: mineral acid, such as hydrochloric acid, nitric acid, phosphoric acid, sulphuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid；Nontoxic
Organic acid, such as aliphatic monocarboxylic acid ester/dicarboxylic ester, the substituted alkanoate of phenyl, hydroxy alkane acid ester, chain docosandioic acid
Ester, aromatic acid and aliphatic/aromatic sulfonic acid；Or organic acid, such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid,
Gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid.By the following salt enumerating pharmaceutical innocuous: sulphuric acid
Salt, pyrosulfate, disulfate, sulphite, bisulfites, nitrate, phosphate, dibasic alkaliine, dihydric phosphate,
Metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, caprate, caprylate, third
Olefin(e) acid salt, formates, isobutyrate, caprate, enanthate, propiolate, oxalates, malonate, succinate, suberic acid
Salt, sebacate, fumarate, maleate, butine-1,4-diacid salt, hexane-1,6-diacid salt, benzoate, chlorobenzene first
Hydrochlorate, ar-Toluic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, right
Phthalate, benzene sulfonate, toluene fulfonate, closilate, xylenesulfonate, phenyl acetate salt, phenylpropionic acid salt,
PB, citrate, lactate, hydroxybutyric acid salt, glycollate, malate, tartrate, mesylate, third
Sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt and mandelate.
The acid-addition salts in the present invention can be prepared by conventional method known to those skilled in the art.Such as, formula 1 is represented
Pyrimidine-2,4-diamine derivative is dissolved in the organic solvent of such as methanol, ethanol, acetone, dichloromethane or acetonitrile, Xiang Qi
Middle addition organic acid or mineral acid, to induce precipitation.Then, precipitate is filtered, be dried to obtain salt.Or, by solvent and
The acid of excess is under reduced pressure distilled, and is dried to obtain salt.Or, precipitation is crystallized in organic solvent, to obtain salt.
The present invention not only includes pyrimidine-2 that formula 1 represents, 4-diamine derivative, also include its pharmaceutically acceptable salt,
Solvate, hydrate or the possible optical isomer being produced from described pyrimidine-2,4-diamine derivative.
Present invention also offers for preparing above-mentioned pyrimidine-2, the method for 4-diamine derivative, described method includes following
Following steps shown in reaction equation 1:
Reacted by the compound making compound that formula 2 represents and formula 3 represent, the compound (step that formula 4 represents
1)；And
The compound that the compound represented by the formula 4 making in step 1 preparation and formula 5 are represented reacts, formula 1 expression
Compound (step 2).
[reaction equation 1]
(in reaction equation 1, R1～R4As defined in the description.)
Hereinafter, step by step the preparation method of the present invention is explained in more detail.
In the preparation process in accordance with the present invention, step 1 is anti-with the compound that formula 3 represents by the compound making formula 2 represent
Should, to obtain the compound that formula 4 represents.
Specifically, in the presence of organic solvent and alkali, by making compound that formula 2 represents via alkylation and formula 3 table
The compound reaction shown, carrys out the compound that formula 4 represents.
Now, organic solvent used herein is selected from by following formed group: oxolane；Dioxane；Ether
Solvent, including ether and 1,2-dimethoxy-ethane；Lower alcohol, including methanol, ethanol, propanol and butanol；Dimethylformamide
(DMF), dimethyl sulfoxide (DMSO),Toluene fulfonate, closilate, dimethylbenzene sulphur
Hydrochlorate, phenyl acetate salt, phenylpropionic acid salt, PB, citrate, lactate, beta-hydroxy-butanoic acid salt, glycollate,
Malate, tartrate, mesylate, propane sulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt and mandelate.
Alkali used herein is selected from by following formed group: organic base, such as pyridine, triethylamine, N, N-bis-is different
Propylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0]-7-endecatylene (DBU)；And inorganic base, such as hydroxide
Sodium, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, described alkali can equivalent or be excessively used.Reaction temperature is 50 DEG C～200
DEG C, mixing time is 0.5 hour～20 hours.
After above-mentioned reaction completes, and then use organic solvent to extract, be subsequently dried, filter, and under reduced pressure
Distillation.It is additionally carried out column chromatography, to obtain the compound that formula 4 represents.
In the preparation process in accordance with the present invention, step 2 is by making compound and formula 5 table that in step 1, the formula 4 of preparation represents
The compound reaction shown, to obtain the compound that formula 1 represents.
Specifically, in the presence of organic solvent and alkali, by making compound that formula 4 represents via alkylation and formula 5 table
The compound reaction shown, carrys out the compound that formula 1 represents.
Now, organic solvent used herein is selected from by following formed group: oxolane；Dioxane；Ether
Solvent, including ether and 1,2-dimethoxy-ethane；Lower alcohol, including methanol, ethanol, propanol and butanol；Dimethylformamide
(DMF), dimethyl sulfoxide (DMSO),Toluene fulfonate, closilate, dimethylbenzene sulphur
Hydrochlorate, phenyl acetate salt, phenylpropionic acid salt, PB, citrate, lactate, beta-hydroxy-butanoic acid salt, glycollate,
Malate, tartrate, mesylate, propane sulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt and mandelate.
Alkali used herein is selected from by following formed group: organic base, such as pyridine, triethylamine, N, N-bis-is different
Propylethylamine (DIPEA) and 1,8-diazabicyclo [5.4.0]-7-endecatylene (DBU)；And inorganic base, such as hydroxide
Sodium, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, described alkali can equivalent or be excessively used.Reaction temperature is 50 DEG C～200
DEG C, mixing time is 0.5 hour～20 hours.
After above-mentioned reaction completes, and then use organic solvent to extract, be subsequently dried, filter, and under reduced pressure
Distillation.It is additionally carried out column chromatography, to obtain the compound that formula 1 represents.
Present invention also offers the pyrimidine-2,4-diamine derivative represented containing formula 1 or its pharmaceutically acceptable salt is made
For active component, for preventing or treat the pharmaceutical composition of cancer.
Present invention also offers the pyrimidine-2,4-diamine derivative represented containing formula 1 or its pharmaceutically acceptable salt is made
For active component, for preventing or treating by the medicine of the disease caused by the overactivity of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK)
Compositions.
It addition, the invention provides pyrimidine-2 represented containing formula 1,4-diamine derivative or its pharmaceutically acceptable salt
Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) inhibitor as active component.
The pharmaceutical composition of the present invention and the feature of inhibitor are, by suppression anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK)
Activation carrys out expression and the growth of anticancer.
ALK is the gene of induction cancer cell multiplication, and described cancer cell multiplication is activated by gene fusion.Now, it is included in
Tyrosine kinase in ALK starts Effects of Anomalous with induction cell proliferation, interruption apoptosis, rearrangement cytoskeleton, change carefully
Born of the same parents' shape also activates other approach, or with other normal or carcinogenic tyrosine kinase interactions.
In order to check pyrimidine-2 that formula 1 represents, the ALK inhibitory activity of 4-diamine derivative, by the change of the present invention
Compound processes with ALK enzyme and multiple cancerous cell, then measures IC50And GI50.As a result, compared to control compound (gram azoles
For Buddhist nun and LDK-378), pyrimidine-2 that formula 1 represents, the inhibitory activity of the most compounds display excellence of 4-diamine derivative
(seeing EXPERIMENTAL EXAMPLE 1～EXPERIMENTAL EXAMPLE 3).
Can be by suppression anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) activity, pyrimidine-2 represented by formula 1,4-diamidogen spreads out
Biology is used for preventing or treating cancer.Such as, can be used for described derivant treating nonsmall-cell lung cancer, neuroblastoma,
Inflammatory haematogonium tumor, rhabdomyosarcoma, myofibroblastoma, breast carcinoma, gastric cancer, pulmonary carcinoma, melanoma, large B cell
Lymphoma, generalized tissue cellular proliferative disorder, inflammatory myofibroblastic tumor, esophageal squamous cell carcinoma, uterus carcinoma and prostate
Cancer.
Can be by the pyrimidine-2,4-diamine derivative represented containing formula 1 or the medicine of its pharmaceutically acceptable salt
Compositions preparation is used for being orally administered to or parenteral gives.
By the following preparation enumerated for being orally administered to: tablet, pill, hard/soft capsule, solution, suspensoid,
Emulsion, syrup, granule, elixir and lozenge etc..In addition to the active component, this type of preparation can include diluent (such as
Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) and lubricant (such as silicon dioxide, Talcum,
Stearic acid and magnesium salt thereof or calcium salt and/or Polyethylene Glycol).It is (such as aluminium-magnesium silicate, gelatinized corn starch, bright that tablet can comprise binding agent
Glue, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone) and if need disintegrating agent (such as form sediment
Powder, agarose, alginic acid or its sodium salt or azeotropic mixture), and/or absorbent, coloring agent, flavoring agent and sweeting agent can additionally contain
Have in this.
Pyrimidine-2,4-diamine derivative containing formula 1 expression can pass through parenteral as the pharmaceutical composition of active component
Giving, described parenteral includes subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
In order to compositions being prepared as the preparation given for parenteral, pyrimidine-2 in water, formula 1 represented, 4-diamidogen
Derivant or its pharmaceutically acceptable salt mix with stabilizer or buffer agent to generate solution or suspension, are then prepared
Become ampulla or bottle agent.Compositions described herein can be carried out sterilizing, said composition additionally contain preservative, stabilizer, can
WP or emulsifying agent, for regulating the salt of osmotic pressure and/or buffer and the useful material of other treatment, and this group
Compound can be prepared by conventional mixing, granulation or coating method.
Can determine the present invention's according to the order of severity of age, body weight, sex, administration way, health status and disease
Pyrimidine-2,4-diamine derivative containing formula 1 expression is as the effective dose of the pharmaceutical composition of active component.This dosage is preferred
For 0.01mg/kg/ days～1000mg/kg/ days, within one day, can give several times via oral route or parenteral route or preferably one
It gives for 1～3 time.
Hereinafter, use and manufacture embodiment and embodiment, to for preparing pyrimidine-2 that formula 1 represents, 4-diamidogen
The method of derivant is described in more detail.Following example are only spreads out to the pyrimidine-2,4-diamidogen represented for formula 1
The embodiment that biological method explains, can not limit the invention to this.Can be by using known in organic synthesis field
Synthesis condition and suitable reagent complete by the preparation method described by following example.
The chloro-N4-of embodiment 1:5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,2,3,6-tetrahydrochysene pyrrole
Pyridine-4-base) phenyl) preparation of pyrimidine-2,4-diamidogen
Step 1:4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-first
Phenyl) preparation of-5,6-dihydropyridine-1 (2H)-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (1.6g, 4.6mmol) is dissolved in 25ml
THF in, be added thereto to 4-(4-amino-3-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (1.4g,
4.6mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene(266mg,
0.46mmol) and Cs2CO3(4.5g, 13.8mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2
(51.6mg, 0.23mmol).After filling nitrogen, reactant mixture is stirred 18 hours at 130 DEG C.After completion of the reaction, tightly
Then by this mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA
4: 1), to obtain target compound (330mg, productivity: 20%).
1H NMR(CDCl3, 300MHz) δ 9.55 (s, 1H), 8.58 (d, J=8.4Hz, 1H), 8.24 (d, J=8.7Hz,
1H), 8.16 (s, 1H), 7.94 (d, J=8.1Hz, 1H), 7.68 (t, J=7.8Hz, 1H), 7.59 (s, 1H), 6.92 (s, 2H),
6.0-5.98 (m, 1H), 4.09 (s, 2H), 3.92 (s, 3H), 3,65-3.63 (m, 2H), 3.29-3.19 (m, 1H), 2.53 (s,
2H), 1.66 (s, 3H), 1.49 (s, 9H), 1.32 (d, J=6.9Hz, 6H).
The chloro-N4-of step 2:5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,2,3,6-tetrahydrochysene pyrrole
Pyridine-4-base) phenyl) pyrimidine-2, the preparation of 4-diamidogen
4-(the 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) that will obtain in step 1
Amino)-3-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate compound (1.13g, 1.84mmol) is dissolved in
In MeOH, it is added thereto to the dioxane being dissolved in 4M HCl of 6ml, is stirred at room temperature 0.5 hour subsequently.In reaction
After completing, and then HCl is removed, use ether decant subsequently.Result, it is thus achieved that the target compound (productivity: 99%) of 300mg.
1H NMR (MeOH, 300MHz) δ 8.28 (s, 1H), 8.22-8.21 (m, 1H), 8.04 (d, J=4.8Hz, 1H),
7.75-7.56 (m, 1H), 7.62-7.58 (m, 1H), 7.51 (d, J=5.1Hz, 1H), 7.20 (s, 1H), 7.01-7.00 (m,
1H), 6.24 (s, 1H), 3.94 (s, 3H), 3.91 (s, 2H), 3.43-3.40 (m, 1H), 2.85 (s, 2H), 1.26 (d, J=
13.2,6Hz).
The chloro-N2-of embodiment 2:5-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-
(2-(isopropelsulfonyl) phenyl) pyrimidine-2, the preparation of 4-diamidogen
(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-5-is different for step 1:4-
Propoxyl group-2-aminomethyl phenyl)-5, the preparation of 6-dihydropyridine-1 (2H)-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (1g, 2.88mmol) is dissolved in 20ml's
In THF, it is added thereto to 4-(4-amino-5-isopropoxy-2-aminomethyl phenyl)-5,6-dihydropyridine-1 tertiary fourth of (2H)-formic acid
Ester (955mg, 2.88mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (167mg,
0.288mmol) and Cs2CO3(2.8g, 8.64mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2
(32mg, 0.144mmol).After filling nitrogen, reactant mixture is stirred 18 hours at 130 DEG C.After completion of the reaction, immediately
This mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA 4:
1), to obtain target compound (642mg, productivity: 34%).
1H NMR(CDCl3, 300MHz) δ 9.49 (s, 1H), 8.57 (d, J=8.4Hz, 1H), 8.16 (s, 1H), 8.04 (s,
1H), 7.94 (dd, J=0.9Hz, 1.2Hz, 1H), 7.66-7.59 (m, 2H), 6.63 (s, 1H), 5.54 (brs, 1H), 4.58-
4.54 (m, 1H), 4.04 (s, 2H) 3.63 (t, J=5.4Hz, 2H), 3.30-3.21 (m, 1H), 2.35-2.33 (m, 2H), 2.09
(s, 3H), 1.50 (s, 9H), 1.38 (d, J=6.0Hz, 6H), 1.33 (d, J=6.9Hz, 6H).
The chloro-N2-of step 2:5-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-
(2-(isopropelsulfonyl) phenyl) pyrimidine-2, the preparation of 4-diamidogen
4-(the 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) that will obtain in step 1
Amino)-5-isopropoxy-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate compound (600mg,
0.91mmol) it is dissolved in MeOH, is added thereto to the dioxane being dissolved in 4M HCl of 5ml, the most at room temperature stirs
Mix 0.5 hour.After completion of the reaction, and then HCl is removed, use ether decant subsequently.Result, it is thus achieved that the target chemical combination of 630mg
Thing (productivity: 99%).
1H NMR(CDCl3, 300MHz) and δ 8.27 (brs, 2H), 8.04 (d, J=7.5Hz, 1H), 7.78-7.73 (m, 1H),
7.60-7.55 (m, 1H), 7.34 (s, 1H), 6.87 (s, 1H), 5.66 (s, 1H), 3.84 (s, 2H), 3.65 (s, 3H), 2.61
(s, 2H), 2.13 (s, 3H), 1.30 (d, J=6Hz, 6H), 1.26 (d, J=6.9Hz, 6H).
The chloro-N2-of embodiment 3:5-(2-(difluoro-methoxy)-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-
(isopropelsulfonyl phenyl) pyrimidine-2, the preparation of 4-diamidogen
Step 1:4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) pyrimidine-2-base) amino)-3-(difluoro first
Epoxide) phenyl)-5, the preparation of 6-dihydropyridine-1 (2H)-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (200mg, 0.58mmol) is dissolved in 5ml
THF in, be added thereto to 4-(4-amino-3-(difluoro-methoxy) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate
(195mg, 0.58mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (33mg,
0.058mmol) and Cs2CO3(550mg, 1.74mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd
(OAc)2.After filling nitrogen, reactant mixture is stirred 18 hours at 130 DEG C.After completion of the reaction, and then by this mixing
Thing EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA 6: 1), to obtain
Target compound (120mg, productivity: 32%).
1H-NMR (300MHz, CDCl3) δ 8.53 (d, J=8.4Hz, 1H), 8.31 (d, J=9.0Hz, 1H), 8.18 (s,
1H), 7.94 (d, J=8.1Hz, 1H) 7.66 (t, J=7.2,1H) 7.33-7.29 (m, 2H), 7.17 (d, J=5.1Hz, 2H),
6.01 (s, 1H), 4.08 (s, 2H) 3.66 (t, J=5.4Hz, 2H), 3.26-3.21 (m, 1H), 2.50 (s, 2H), 1.49 (s,
9H), 1.33 (d, J=6.6,6H).
The chloro-N2-of step 2:5-(2-(difluoro-methoxy)-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-
(isopropelsulfonyl phenyl) pyrimidine-2, the preparation of 4-diamidogen
4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) pyrimidine-2-base) ammonia that will obtain in step 1
Base)-3-(difluoro-methoxy) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (100mg, 0.154mmol) is dissolved in
In MeOH, it is added thereto to the dioxane being dissolved in 4M HCl of 7ml, is stirred at room temperature 1 hour subsequently.Reacting
Cheng Hou, and then removes HCl, uses ether decant subsequently.Result, it is thus achieved that the target compound as the 90mg of yellow solid (produces
Rate: 95%).
1H-NMR (300MHz, MeOD) δ 8.31 (s, 1H), 8.11-8.00 (m, 1H), 8.00 (d, J=10.8Hz, 1H),
7.62-7.55 (m, 4H), 7.38 (s, 1H), 6.24 (d, J=0.9Hz, 1H) 3.9 (s, 2H), 3.50 (s, 2H), 2.82 (s,
2H), 1.23 (d, J=4.2Hz, 6H).
The chloro-N2-of embodiment 4:5-(2-(difluoro-methoxy)-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropyl sulphonyl
Base) phenyl) pyrimidine-2, the preparation of 4-diamidogen
Step 1:4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-(two
Fluorine methoxyl group) phenyl) preparation of piperidines-1-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (87mg, 0.25mmol) is dissolved in 3ml
THF in, be added thereto to 4-(4-amino-3-(difluoro-methoxy) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate
(85mg, 0.25mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (15mg,
0.025mmol) and Cs2CO3(244mg, 0.75mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2
(2.8mg, 0.013mmol).After filling nitrogen, reactant mixture is stirred 18 hours at 130 DEG C.After completion of the reaction, tightly
Then by this mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA
4: 1), to obtain target compound (25mg, productivity: 18%).
1H-NMR (300MHz, CDCl3) δ 9.61 (s, 1H), 8.53 (d；J=8.4Hz, 1H) 8.22 (t, J=8.1Hz,
2H), 7.93 (d, J=7.8,1H), 7.64 (t, J=8.1,1H), 7.28 (d, J=7.5Hz, 2H), 7.01 (d, J=8.7Hz,
2H), 4.28-4.24 (m, 2H), 3.25-3.21 (m, 1H), 2.84 (t, J=12.9Hz, 2H) 2.67 (t, J=12.3Hz, 1H),
2.17 (s, 1H), 1.85 (d, J=12.3Hz, 2H), 1.49 (s, 9H), 1.32 (d, J=6.6Hz, 6H).
The chloro-N2-of step 2:5-(2-(difluoro-methoxy)-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl)
Phenyl) pyrimidine-2, the preparation of 4-diamidogen
4-(the 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) that will obtain in step 1
Amino)-3-(difluoro-methoxy) phenyl) piperidines-1-t-butyl formate compound (23mg, 0.042mmol) is dissolved in MeOH,
It is added thereto to the dioxane being dissolved in 4M HCl of 3ml, is stirred at room temperature 1 hour subsequently.After completion of the reaction, tightly
Then HCl is removed, use ether decant subsequently.Result, it is thus achieved that as the 21mg of yellow solid target compound (productivity:
93%).
1H-NMR (300MHz, MeOD) δ 8.26-8.25 (m, 1H), 8.16-8.14 (m, 1H) 7.95-7.94 (m, 1H)
7.68-7.48 (m, 2H), 7.24-7.07 (m, 1H), 3.64 (s, 1H), 3.57-3.51 (m, 1H), 1.28 (d, J=19.8Hz,
6H).
The chloro-N4-of embodiment 5:5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(piperidin-4-yl) benzene
Base) pyrimidine-2, the preparation of 4-diamidogen
Step 1:4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-first
Phenyl) preparation of piperidines-1-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (274mg, 0.79mmol) is dissolved in
In the THF of 20ml, be added thereto to 4-(4-amino-3-methoxyphenyl) piperidines-1-t-butyl formate (243mg,
0.79mmol).Be added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (46mg, 0.079mmol) and
Cs2CO3(772mg, 2.37mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2(8.86mg,
0.039mmol).After filling nitrogen, reactant mixture is stirred 18 hours at 130 DEG C.After completion of the reaction, and then should
Mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA 4: 1), with
Obtain target compound (180mg, productivity: 37%).
1H-NMR (300MHz, CDCl3) δ 9.54 (s, 1H), 8.59 (d, J=8.4Hz, 1H), 8.17 (d, J=7.5Hz,
2H), 7.93-7.90 (m, 1H), 7.67-7.50 (m, 1H), 7.30 (s, 1H), 7.30-7.28 (d, J=7.8Hz, 1H), 6.75-
6.73 (m, 2H), 4.23 (brs, 2H), 4.15-4.08 (m, 1H), 3.8 (s, 3H), 3.26-3.22 (m, 1H), 2.85-2.76
(m, 2H), 2.66-2.58 (m, 1H), 1.86-1.81 (m, 2H), 1.49 (s, 9H), 1.32 (d, J=6.6Hz, 6H).
The chloro-N4-of step 2:5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(piperidin-4-yl) phenyl)
Pyrimidine-2, the preparation of 4-diamidogen
4-(the 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) that will obtain in step 1
Amino)-3-methoxyphenyl) piperidines-1-t-butyl formate (170mg, 0.28mmol) is dissolved in MeOH, is added thereto to
The dioxane being dissolved in 4M HCl of 3ml, is stirred at room temperature 0.5 hour subsequently.After completion of the reaction, and then will
HCl removes, and uses ether decant subsequently.Result, it is thus achieved that the target compound (productivity: 99%) of 150mg.
1H-NMR (300MHz, MeOD) δ 8.22 (brs, 1H), 8.01 (d, J=5.7Hz, 1H) 7.75-7.73 (m, 1H),
7.59-7.57 (m, 1H), 7.38-7.36 (m, 1H), 7.05 (s, 1H), 6.86-6.83 (m, 1H), 3.89 (s, 3H), 3.55-
3.49 (m, 2H) 3.20-3.16 (m, 2H), 3.01-2.94 (m, 1H), 2.11-1.95 (m, 4H), 1.25 (d, J=5.4Hz,
6H).
Embodiment 6:N4-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-
Base) phenyl)-5-(trifluoromethyl) pyrimidine-2, the preparation of 4-diamidogen
Step 1:4-(4-((4-((2-(isopropelsulfonyl) phenyl) amino)-5-(trifluoromethyl) pyrimidine-2-base) ammonia
Base)-3-methoxyphenyl)-5, the preparation of 6-dihydropyridine-1 (2H)-t-butyl formate
By chloro-for 2-N-(2-(isopropelsulfonyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine (100mg, 0.26mmol)
It is dissolved in the THF of 2ml, is added thereto to 4-(4-amino-3-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-formic acid uncle
Butyl ester (160mg, 0.53mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (15mg,
0.026mmol) and Cs2CO3(275mg, 0.79mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2
(3mg, 0.013mmol).After filling nitrogen, reactant mixture is stirred 2 hours at 150 DEG C.After completion of the reaction, and then
By this mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA 4:
1), to obtain target compound (15mg, productivity: 8.4%).
1H-NMR (300MHz, CDCl3) δ 9.63 (s, 1H), 8.60 (s, 1H), 7.92 (d, J=6Hz, 1H), 7.82 (D, J
=9Hz, 1H), 7.14-7.06 (m, 3H), 6.98-6.88 (m, 1H), 6.19 (s, 1H), 4.17 (s, 1H), 4.07 (brs, 1H),
3.90 (s, 1H), 3.73 (s, 1H), 3.64 (s, 3H), 3.17-3.13 (m, 1H), 2.62 (s, 1H), 2.51-2.49 (m, 1H),
2.2 (s, 1H), 1.49 (s, 9H), 1.27 (d, J=5.7Hz, 6H).
Step 2:N4-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-
Base) phenyl)-5-(trifluoromethyl) pyrimidine-2, the preparation of 4-diamidogen
By the 4-that obtains in step 1, (((4-((2-(isopropelsulfonyl) phenyl) amino)-5-(trifluoromethyl) is phonetic for 4-
Pyridine-2-base) amino)-3-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (14mg, 0.021mmol) dissolves
In MeOH, it is added thereto to the dioxane being dissolved in 4M HCl of 2ml, is stirred at room temperature 0.5 hour subsequently.Instead
After should completing, and then HCl is removed, use ether decant subsequently.Result, it is thus achieved that the target compound (productivity: 99%) of 14mg.
1H-NMR (300MHz, MeOD) δ 8.49-8.47m, 1H), 8.00 (d, J=1.5Hz, 2H), 7.77-7.76 (m,
1H), 7.61-7.58 (m, 3H), 7.13-7.11 (m, 1H), 6.86-6.84 (m, 1H), 6.18 (s, 1H), 3.9 (s, 3H),
3.88-3.86 (m, 2H), 3.50-3.47 (m, 2H), 2.82-2.79 (m, 2H), 1.22 (d, J=3Hz, 6H).
Embodiment 7:N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-
(isopropelsulfonyl) phenyl)-5-(trifluoromethyl) pyrimidine-2, the preparation of 4-diamidogen
(((4-((2-(isopropelsulfonyl) phenyl) amino)-5-(trifluoromethyl) is phonetic for 5-isopropoxy-4-for step 1:4-
Pyridine-2-base) amino)-2-aminomethyl phenyl)-5, the preparation of 6-dihydropyridine-1 (2H)-t-butyl formate
By molten for chloro-for 2-N-(2-(isopropelsulfonyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine (5mg, 0.58mmol)
Solution, in the THF of 2ml, is added thereto to 4-(4-amino-5-isopropoxy-2-aminomethyl phenyl)-5, and 6-dihydropyridine-1 (2H)-
T-butyl formate (139mg, 0.42mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene
(12mg, 0.021mmo1) and Cs2CO3(205mg, 0.63mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd
(OAc)2(3mg, 0.0105mmol).After filling nitrogen, reactant mixture is stirred 2 hours at 150 DEG C.Complete in reaction
After, and then by this mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography
(Hx: EA 4: 1), to obtain target compound (26mg, productivity: 17%).
1H-NMR (300MHz, CDCl3) δ 9.12 (s, 1H), 8.41 (s, 1H), 8.31-8.28 (m, 1H), 7.97 (d, J=
7.8Hz, 2H), 7.82 (s, 1H), 7.64-7.58 (m, 1H), 7.34-7.26 (m, 1H), 6.63 (s, 1H), 5.54-5.53 (m,
1H), 4.59 (t, J=6Hz, 1H), 4.03 (s, 2H), 3.63-3.59 (m, 2H), 3.26-3.21 (m, 1H), 2.32 (s, 2H),
1.97 (s, 3H), 1.50 (s, 9H), 1.38 (d, J=6.3Hz, 6H), 1.31 (d, J=6.9Hz, 6H).
(2-is (different for-N4-for step 2:N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)
Sulfonyl propyl base) phenyl)-5-(trifluoromethyl) pyrimidine-2, the preparation of 4-diamidogen
4-(5-isopropoxy-4-((4-((2-(isopropelsulfonyl) phenyl) the amino)-5-that will obtain in step 1
(trifluoromethyl) pyrimidine-2-base) amino)-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (26mg,
0.038mmol) it is dissolved in MeOH, is added thereto to the dioxane being dissolved in 4M HCl of 3ml, the most at room temperature stirs
Mix 1 hour.After completion of the reaction, and then HCl is removed, use ether decant subsequently.Result, it is thus achieved that the target compound of 25mg
(productivity: 99%).
1H-NMR (300MHz, MeOD) δ 8.54-8.50 (m, 1H), 8.05 (d, J=9Hz, 1H), 7.80-7.75 (m,
1H), 7.637.58 (m, 1H), 7.35 (s, 1H), 6.82 (s, 1H), 5.63 (d, J=1.2Hz, 1H), 4.66-4.62 (m, 1H),
3.83 (s, 2H), 3.74-3.72 (m, 1H), 3.59-3.57 (m, 1H), 2.58 (s, 2H), 2.03-2.01 (s, 3H), 1.32 (d,
J=6Hz, 6H), 1.24 (d, J=6.9Hz, 6H).
Embodiment 8:N2-(2-(difluoro-methoxy)-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl
Base sulfonyl) phenyl)-5-(trifluoromethyl) pyrimidine-2, the preparation of 4-diamidogen
Step 1:4-(3-(difluoro-methoxy)-4-((4-((2-(isopropelsulfonyl) phenyl) amino)-5-(fluoroform
Base) pyrimidine-2-base) amino) phenyl)-5, the preparation of 6-dihydropyridine-1 (2H)-t-butyl formate
By chloro-for 2-N-(2-(isopropelsulfonyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine (35mg, 0.08mmol)
It is dissolved in the THF of 2ml, is added thereto to 4-(4-amino-3-(difluoro-methoxy) phenyl)-5,6-dihydropyridine-1 (2H)-
T-butyl formate (54mg, 0.16mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene
(5mg, 0.008mmol) and Cs2CO3(77mg, 0.24mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd
(OAc)2(1mg, 0.004mmol).After filling nitrogen, reactant mixture is stirred 1 hour at 150 DEG C.After completion of the reaction,
And then by this mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx:
EA 4: 1), to obtain target compound (3.5mg, productivity: 7%).
1H-NMR (300MHz, CDCl3) δ 9.25 (s, 1H), 8.43 (s, 1H), 8.30-8.27 (m, 1H), 8.23-8.20
(m, 1H), 7.97-7.94 (m, 1H), 7.65-7.59 (m, 1H), 7.54 (s, 1H), 7.37-7.32 (m, 1H), 7.16 (s, 1H),
7.11-7.08 (m, 1H), 6.03-6.00 (m, 1H), 4.10 (s, 2H), 3.66-3.63 (m, 2H), 3.25-3.16 (m, 1H),
2.49-2.48 (m, 2H), 2.04 (s, 3H), 1.49 (s, 9H), 1.31 (d, J=6,9Hz, 6H).
Step 2:N2-(2-(difluoro-methoxy)-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl
Sulfonyl) phenyl)-5-(trifluoromethyl) pyrimidine-2, the preparation of 4-diamidogen
4-(3-(difluoro-methoxy)-4-((4-((2-(isopropelsulfonyl) phenyl) ammonia that will obtain in step 1
Base)-5-(trifluoromethyl) pyrimidine-2-base) amino) phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (3.5mg,
3.53mmol) it is dissolved in MeOH, is added thereto to the dioxane being dissolved in 4M HCl of 1ml, the most at room temperature stirs
Mix 0.5 hour.After completion of the reaction, and then HCl is removed, use ether decant subsequently.Result, it is thus achieved that the target compound of 7mg
(productivity: 99%).
1H-NMR (300MHz, MeOD) δ 8.51 (s, 1H), 7.99 (d, J=4.5Hz, 1H), 7.71 (s, 1H), 7.63 (d,
J=4.2Hz, 1H), 7.58-7.55 (m, 1H), 7.33 (s, 1H), 7.20-7.18 (m, 1H), 6.21 (s, 1H), 3.90 (s,
2H), 3.51-3.50 (m, 3H), 2.81 (s, 2H), 1.22 (d, J=3.9Hz, 6H).
Embodiment 9:N2-(2-(difluoro-methoxy)-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) benzene
Base)-5-(trifluoromethyl) pyrimidine-2, the preparation of 4-diamidogen
Step 1:4-(3-(difluoro-methoxy)-4-((4-((2-(isopropelsulfonyl) phenyl) amino)-5-(fluoroform
Base) pyrimidine-2-base) amino) phenyl) preparation of piperidines-1-t-butyl formate
By chloro-for 2-N-(2-(isopropelsulfonyl) phenyl)-5-(trifluoromethyl) pyrimidine-4-amine (60mg, 0.16mmol)
It is dissolved in the THF of 3ml, is added thereto to 4-(4-amino-3-(difluoro-methoxy) phenyl) piperidines-1-t-butyl formate
(110mg, 0.32mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (9mg,
0.32mmol) and Cs2CO3(156mg, 0.48mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2
(2mg, 0.008mmol).After filling nitrogen, reactant mixture is stirred 18 hours at 130 DEG C.After completion of the reaction, immediately
This mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA 4:
1), to obtain target compound (35mg, productivity: 32%).
1H-NMR (300MHz, CDCl3), δ 9.43 (s, 1H), 8.38 (s, 1H), 8.19 (d, J=8.4Hz, 1H), 7.89
(dd, J=7.8Hz, 8.1Hz, 1H), 7.53-7.48 (m, 1H), 7.39 (s, 1H), 7.22 (t, J=7.5Hz, 1H), 7.11-
7.08 (m, 1H), 7.04 (s, 1H), 4.29-4.23 (m, 2H), 3.29-3.20 (m, 1H), 2.86-2.77 (m, 1H), 2.72-
2.63 (m, 1H), 2.17 (s, 1H), 2.04 (s, 1H), 1.87-1.83 (m, 4H), 1.49 (s, 9H), 1.31 (d, J=6.9Hz,
6H).
Step 2:N2-(2-(difluoro-methoxy)-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) benzene
Base)-5-(trifluoromethyl) pyrimidine-2, the preparation of 4-diamidogen
4-(3-(difluoro-methoxy)-4-((4-((2-(isopropelsulfonyl) phenyl) ammonia that will obtain in step 1
Base)-5-(trifluoromethyl) pyrimidine-2-base) amino) phenyl) piperidines-1-t-butyl formate (35mg, 0.051mmol) is dissolved in
In MeOH, it is added thereto to the dioxane being dissolved in 4M HCl of 3ml, is stirred at room temperature 0.5 hour subsequently.In reaction
After completing, and then HCl is removed, use ether decant subsequently.Result, it is thus achieved that the target compound (productivity: 99%) of 29mg.
1H-NMR (300MHz, MeOD), δ 8.50 (s, 1H), 7.90-7.78 (m, 2H), 7.48-4.45 (m, 3H), 7.23-
7.19 (m, 2H), 3.75-3.72 (m, 1H), 3.59-3.53 (m, 2H), 2.14-1.88 (m, 5H), 1.19-1.15 (m, 6H).
The chloro-N2-of embodiment 10:5-(5-fluoro-2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-
(isopropelsulfonyl) phenyl) pyrimidine-2, the preparation of 4-diamidogen
(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-2-is fluoro-for step 1:4-
5-methoxyphenyl)-5, the preparation of 6-dihydropyridine-1 (2H)-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (123mg, 0.35mmol) is dissolved in 4ml
THF in, be added thereto to 4-(4-amino-2-fluoro-5-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate
(115mg, 0.35mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (20mg,
0.033mmol) and Cs2CO3(322mg, 1mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2
(4mg, 0.033mmol).After filling nitrogen, reactant mixture is stirred 8 hours at 130 DEG C.After completion of the reaction, and then
By this mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA 4:
1), to obtain target compound (82mg, productivity: 37%).
1H-NMR (300MHz, CDCl3) δ 9.54 (brs, 1H), 8.52-8.49 (m, 1H), 8.19-8.12 (m, 2H),
7.95-7.92 (m, 1H), 7.74-7.66 (m, 2H), 7.33-7.26 (m, 2H), 6.72-6.69 (m, 1H), 5.92-5.90 (m,
1H) 4.08 (s, 2H), 3.90 (d, J=3.9Hz, 3H), 3.64-3.62 (m, 2H), 3.24-3.22 (m, 1H), 2.52 (brs,
2H), 2.05 (d, J=3.9Hz, 1H), 1.61 (d, 4H), 1.51 (d, J=3.9Hz, 9H), 1.31-1.29 (m, 6H).
(2-is (different for-N4-for the chloro-N2-of step 2:5-(5-fluoro-2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)
Sulfonyl propyl base) phenyl) pyrimidine-2, the preparation of 4-diamidogen
4-(the 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) that will obtain in step 1
Amino)-2-fluoro-5-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (70mg, 0.11mmol) is dissolved in
In MeOH, it is added thereto to the dioxane being dissolved in 4M HCl of 3ml, is stirred at room temperature 0.5 hour subsequently.In reaction
After completing, and then HCl is removed, use ether decant subsequently.Result, it is thus achieved that the target compound (productivity: 99%) of 77mg.
1H NMR (MeOD, 300MHz) δ 8.43 (s, 1H), 8.17-8.11 (m, 2H), 7.917.86 (m, 1H), 7.72-
7.67 (m, 1H), 7.53 (d, J=12.3Hz, 1H), 7.08 (d, J=6.6Hz, 1H), 6.12 (s, 1H), 4.0 (s, 3H), 3.81
(d, J=5.1Hz, 1H), 3.67 (d, J=3.4Hz, 1H), 3.53 (m, 3H), 2.85 (s, 2H), 1.32 (d, J=6.6Hz,
6H).
The chloro-N4-of embodiment 11:5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-5-methyl-4-(1,2,3,
6-tetrahydropyridine-4-base) phenyl) pyrimidine-2, the preparation of 4-diamidogen
Step 1:4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-5-first
Epoxide-2-aminomethyl phenyl)-5, the preparation of 6-dihydropyridine-1 (2H)-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (107mg, 0.31mmol) is dissolved in 4ml
THF in, be added thereto to 4-(4-amino-5-methoxyl group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 tertiary fourth of (2H)-formic acid
Ester (100mg, 0.31mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (18mg,
0.31mmol) and Cs2CO3(303mg, 0.93mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2
(4mg, 0.015mmol).After filling nitrogen, reactant mixture is stirred 18 hours at 130 DEG C.After completion of the reaction, immediately
This mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA 4:
1), to obtain target compound (32mg, productivity: 17%).
1H NMR(CDCl3, 300MHz) δ 9.5 (s, 1H), 8.57 (d, J=8.4Hz, 1H), 8.16 (s, 1H), 7.94 (dd,
J=7.8,8.1Hz, 1H), 7.66-7.60 (m, 1H), 7.51 (s, 1H), 6.61 (s, 1H), 5.55 (s, 1H), 4.04 (d,
2.4Hz, 2H), 3.87 (s, 3H), 3.64 (t, J=5.4Hz), 3.27-3.23 (m, 1H), 2.34 (d, J=0.9Hz), 2.12
(s, 3H), 1.50 (s, 9H), 1.32 (d, J=6.9Hz).
The chloro-N4-of step 2:5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-5-methyl-4-(1,2,3,6-
Tetrahydropyridine-4-base) phenyl) pyrimidine-2, the preparation of 4-diamidogen
4-(the 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) that will obtain in step 1
Amino)-5-methoxyl group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (27mg, 0.04mmol) is dissolved in
In MeOH, it is added thereto to the dioxane being dissolved in 4M HCl of 3ml, is stirred at room temperature 1 hour subsequently.Reacting
Cheng Hou, and then removes HCl, uses ether decant subsequently.Result, it is thus achieved that the target compound (productivity: 99%) of 30mg.
1H NMR (MeOD.300MHz) δ 8.24 (s, 1H), 8.03 (d, J=7.56Hz, 1H), 6.52-6.46 (m, 1H),
6.34 (t, J=7.5Hz, 1H), 7.31 (s, 1H), 6.88 (s, 1H), 5.67 (s, 1H), 3.85 (s, 3H), 3.75-3.71 (m,
1H), 3.59-3.57 (m, 1H), 2.62 (s, 2H), 2.14 (s, 3H), 1.26 (d, J=6.3Hz, 6H).
The chloro-N2-of embodiment 12:5-(5-fluoro-2-methoxyl group-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropyl sulphonyl
Base) phenyl) pyrimidine-2, the preparation of 4-diamidogen
(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-2-is fluoro-for step 1:4-
5-methoxyphenyl) preparation of piperidines-1-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (97mg, 0.28mmol) is dissolved in 5ml
THF in, be added thereto to 4-(4-amino-2-fluoro-5-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-t-butyl formate
(90mg, 0.28mmol).It is added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (17mg,
0.03mmol) and Cs2CO3(275mg, 0.84mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2
(4mg, 0.05mmol).After filling nitrogen, reactant mixture is stirred 18 hours at 120 DEG C.After completion of the reaction, and then
By this mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA4: 1),
To obtain target compound (75.5mg, productivity: 42%).
1H NMR(CDCl3, 300MHz) and δ 9.5 (s, 1H), 8.51 (d, J=8.4Hz, lH), 8.17 (s, 1H), 8.13 (d, J
=12.9Hz, 1H), 7.94 (dd, J=8.1Hz, 8.1Hz), 7.74-7.69 (m, 1H), 7.60 (s, 1H), 6.65 (d, J=
6.6Hz), 4.15-4.08 (m, 1H), 3.87 (s, 3H), 3.24-3.19 (m, 1H), 2.86 (t, J=12.6Hz, 2H), 1.82
(d, J=12.3Hz, 2H), 1.49 (s, 9H), 1.32 (d, J=6.9Hz, 1H).
The chloro-N2-of step 2:5-(5-fluoro-2-methoxyl group-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl)
Phenyl) pyrimidine-2, the preparation of 4-diamidogen
4-(the 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) that will obtain in step 1
Amino)-2-fluoro-5-methoxyphenyl) piperidines-1-t-butyl formate (75mg, 0.048mmol) is dissolved in MeOH, wherein
Add the dioxane being dissolved in 4M HCl of 3ml, be stirred at room temperature 1 hour subsequently.After completion of the reaction, and then will
HCl removes, and uses ether decant subsequently.Result, it is thus achieved that the target compound (productivity: 99%) of 65mg.
1H NMR (MeOD, 300MHz) δ 8.34 (s, 1H), 8.12-8.09 (m, 1H), 8.04-8.02 (d, J=7.8Hz,
1H), 7.82-7.77 (m, 1H), 7.63-7.58 (m, 1H), 7.40 (d, J=11.7Hz, 1H), 6.96 (d, J=6.6Hz, 1H),
3.91 (s, 3H), 3.73 (d, J=5.1Hz, 1H), 3.59 (d, J=4.5Hz, 2H), 3.40-3.36 (m, 1H), 3.18-3.16
(m, 3H), 1.24 (d, J=6.6Hz, 6H).
The chloro-N4-of embodiment 13:5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-5-methyl-4-(piperidines-
4-yl) phenyl) pyrimidine-2, the preparation of 4-diamidogen
Step 1:4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-5-first
Epoxide-2-aminomethyl phenyl) preparation of piperidines-1-t-butyl formate
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (86mg, 0.25mmol) is dissolved in 3ml
THF in, be added thereto to 4-(4-amino-5-methoxyl group-2-aminomethyl phenyl) piperidines-1-t-butyl formate (80mg,
0.25mmol).Be added thereto to 4 in order, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (15mg, 0.025mmol) and
Cs2CO3(244mg, 0.75mmol), is de-gassed by filling nitrogen subsequently.It is added thereto to Pd (OAc)2(3mg,
0.012mmol).After filling nitrogen, reactant mixture is stirred 18 hours at 130 DEG C.After completion of the reaction, and then should
Mixture EA/H2O extracts.By organic layer MgSO4It is dried, filters, then concentrate.Carry out column chromatography (Hx: EA 4: 1), with
Obtain target compound (30mg, productivity: 20%).
1H NMR(CDCl3, 300MHz) δ 9.51 (s, 1H), 8.59 (d, J=8.4Hz, 1H), 8.15 (s, 1H), 8.00 (s,
1H), 7.94 (dd, J=12,8.1Hz, 1H), 7.65-7.59 (m, 1H), 7.47 ((s, 1H), 6.69 (s, 1H), 4.29 (d, J=
20.1Hz, 2H), 3.86 (s, 3H), 3.28-3.23 (m, 1H), 2.86-2.78 (m, 3H), 2.19 (s, 3H), 1.77-1.73 (d,
J=12.6Hz, 2H), 1.49 (s, 9H), 1.32 (d, J=6.9Hz, 6H).
The chloro-N4-of step 2:5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-5-methyl-4-(piperidines-4-
Base) phenyl) pyrimidine-2, the preparation of 4-diamidogen
4-(the 4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) that will obtain in step 1
Amino)-5-methoxyl group-2-aminomethyl phenyl) piperidines-1-t-butyl formate (17mg, 0.026mmol) is dissolved in MeOH, Xiang Qi
The dioxane being dissolved in 4M HCl of middle addition 3ml, is stirred at room temperature 0.5 hour subsequently.After completion of the reaction, immediately
And HCl is removed, use ether decant subsequently.Result, it is thus achieved that the target compound (productivity: 99%) of 15mg.
1H NMR (MeOD, 300MHz) δ 8.27-8.23 (m, 1H), 8.01 (d, J=7.5Hz, 1H), 7.75-7.71 (m,
1H), 7.57-7.52 (m, 1H), 7.31 (s, 1H), 6.9 (s, 1H), 3.88 (s, 3H), 3.73 (d, J=5.1Hz, 1H), 3.65
(s, 2H), 3.57-3.47 (m, 3H), 3.21-3.18 (m, 2H), 2.22 (s, 3H), 1.25 (d, J=5.4Hz, 6H).
The chloro-N2-of embodiment 14:5-(4-(1-ethyl-1,2,3,6-tetrahydropyridine-4-bases)-2-methoxyphenyl)-N4-
(2-(isopropelsulfonyl) phenyl) pyrimidine-2, the preparation of 4-diamidogen
By obtain in embodiment 1 the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,
2,3,6-tetrahydropyridine-4-bases) phenyl) pyrimidine-2,4-diamidogen (50mg, 0.097mmol) is dissolved in the EtOH of 1ml, is stirring
Mix down and be added thereto to DIPEA (0.06ml, 0.375mmol).It is added thereto to iodoethane (0.016ml, 0.15mmol), subsequently
It is stirred at room temperature 18 hours.After completion of the reaction, and then by this mixture MC/H2O extracts.By organic layer MgSO4Dry
Dry, then concentrate.Carry out column chromatography, to obtain target compound (19.3mg).
1H-NMR (300MHz, CDCl3), δ 9.55 (s, 1H), 8.56 (d, J=8.4Hz, 1H), 8.25 (d, J=9Hz,
1H), 8.16 (s, 1H), 7.94 (dd, J=1.5,1.5Hz, 1H), 7.68-7.63 (m, 1H), 7.59 (s, 1H), 7.31-7.28
(m, 1H), 6.91-6.88 (m, 2H), 5.98 (s, 1H), 5.29 (s, 1H), 3.92 (s, 3H), 3.56 (s, 2H), 3.26-3.21
(m, 1H), 3.15-3.11 (m, 2H), 2.99-2.92 (m, 2H), 2.83 (s, 2H), 1.42 (t, J=7.2Hz, 3H), 1.32 (d,
J=6.6Hz, 6H).
The chloro-N2-of embodiment 15:5-(4-(1-hydroxyethyl-1,2,3,6-tetrahydropyridine-4-bases)-2-methoxyphenyl)-
N4-(2-(isopropelsulfonyl) phenyl) pyrimidine-2, the preparation of 4-diamidogen
By obtain in embodiment 1 the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,
2,3,6-tetrahydropyridine-4-bases) phenyl) pyrimidine-2,4-diamidogen (40mg) is dissolved in the DMF of 1ml, adds the most wherein
Enter CS2CO3(65mg, 0.2mmol).It is added thereto to bromoethanol (0.01ml, 0.12mmol), is stirred at room temperature 18 subsequently little
Time.After completion of the reaction, and then by this mixture MC/H2O extracts.By organic layer MgSO4It is dried, then concentrates.Carry out
Column chromatography, to obtain target compound (12mg).
1H-NMR (300MHz, CDCl3), δ 9.55 (s, 1H), 8.58 (d, J=7.8Hz, 1H), 8.25 (d, J=9Hz,
1H), 8.17 (s, 1H), 7.94-7.91 (m, 1H), 7.68-7.63 (m, 1H), 7.60 (s, 1H), 6.93 (s, 2H), 6.01 (s,
1H), 3.92 (s, 3H), 3.83-3.80 (m, 2H), 3.64 (s, 1H), 3.45 (s, 2H), 3.28-3.19 (m, 1H), 3.02-
2.99 (m, 2H), 2.88-2.85 (m, 2H), 2.71-2.70 (m, 2H), 1.32 (d, J=6.9Hz, 6H).
Embodiment 16:1-(4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) ammonia
Base)-3-methoxyphenyl)-5,6-dihydropyridine-1 (2H)-yl) preparation of ethyl ketone
By obtain in embodiment 1 the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,
2,3,6-tetrahydropyridine-4-bases) phenyl) pyrimidine-2,4-diamidogen (50mg, 0.097mmol) is dissolved in the CH of 1ml2Cl2In, stirring
Mix down and be added thereto to Et3N (0.03ml, 0.23mmol).It is added thereto to acetic anhydride (0.02ml, 0.15mmol), exists subsequently
Stir 18 hours under room temperature.After completion of the reaction, and then by this mixture MC/H2O extracts.By organic layer MgSO4Dry
Dry, then concentrate.Carry out column chromatography, to obtain target compound (40mg).
1H-NMR (300MHz, CDCl3), δ 9.57 (s, 1H), 8.58 (d, J=8.1Hz, 1H), 8.23 (dd, J=
2.4.0.9Hz, 1H), 8.16 (s, 1H), 7.94 (dd, J=1.5.1.5Hz, 1H), 7.67-7.62 (m, 2H), 6.92-6.87
(m, 2H), 6.03 (d, 16.5Hz, 1H), 4.26 (d, J=2.7Hz, 1H), 4.15 (d, J=2.7Hz, 1H), 3.93 (s, 3H),
3.85 (t, J=5.7Hz, 1H), 3.70-3.66 (m, 1H), 3.28-3.19 (m, 1H), 2.60-2.55 (m, 2H), 2.18 (d, J
=8.7Hz, 3H), 1.32 (d, J=6.9Hz, 6H).
Embodiment 17:4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-
Methoxyphenyl)-5,6-dihydropyridine-1 (2H)-formic acid
By obtain in embodiment 1 the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,
2,3,6-tetrahydropyridine-4-bases) phenyl) pyrimidine-2,4-diamidogen (50mg, 0.097mmol) is dissolved in the CH of 1ml2Cl2In, stirring
Mix down and be added thereto to Et3N(0.2ml).Be added thereto to glycolic (0.01ml, 0.15mmol), EDCI (24mg,
0.15mmol) with DMAP (20mg, 0.15mmol), it is stirred at room temperature 18 hours subsequently.After completion of the reaction, and then should
Mixture MC/H2O extracts.By organic layer MgSO4It is dried, then concentrates.Carry out column chromatography, to obtain target compound
(28.4mg)。
1H-NMR (300MHz, CDC l3), δ 9.57 (s, 1H), 8.58 (d, J=8.7Hz, 1H), 8.27 (d, J=8.1Hz,
1H), 8.17 (s, 1H), 7.94 (d, J=7.2Hz, 1H), 7.68-7.60 (m, 1H), 7.31 (d, J=8.1Hz, 1H), 6.92-
6.87 (m, 2H), 4.31-4.20 (m, 3H), 3.96 (s, 2H), 3.68 (s, 1H), 3.52-3.49 (m, 1H), 3.26-3.19 (m,
1H), 2.60 (s, 2H), 1.32 (d, J=6.9Hz, 6H).
The chloro-N2-of embodiment 18:5-(4-(1-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-bases)-2-methoxyphenyl)-N4-
(2-(isopropelsulfonyl) phenyl) pyrimidine-2, the preparation of 4-diamidogen
By obtain in embodiment 1 the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,
2,3,6-tetrahydropyridine-4-bases) phenyl) pyrimidine-2,4-diamidogen (50mg, 0.097mmol) is dissolved in the EtOH of 1ml, is stirring
Mix down and be added thereto to DIPEA (0.08ml, 0.45mmol).It is added thereto to iodomethane (0.01ml, 0.15mmol), exists subsequently
Stir 18 hours under room temperature.After completion of the reaction, and then by this mixture MC/H2O extracts.By organic layer MgSO4Dry
Dry, then concentrate.Carry out column chromatography, to obtain target compound (6.1mg).
1H-NMR (300MHz, CDCl3), δ 9.56 (s, 1H), 8.55-8.53 (m, 1H), 8.29-8.26 (m, 1H), 8.17
(s, 1H), 7.94 (d, J=8.1Hz, 1H), 7.70-7.63 (m, 2H), 6.90 (s, 2H), 5.97 (s, 1H), 3.93 (s, 3H),
3.74 (s, 2H), 3.64 (s, 1H), 3.24-3.21 (m, 1H), 2.97-2.94 (m, 2H), 2.85 (s, 3H), 1.32 (d, J=
6.9Hz, 6H).
Table 1 shows the chemical formula of the compound of preparation in embodiment 1～embodiment 18.
Table 1
EXPERIMENTAL EXAMPLE 1: the suppression of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) activity
Pyrimidine-2,4-the diamine derivative represented to measure formula 1 suppresses anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase on enzyme level
(ALK) activity, carries out following experiment.
In order to measure the activity of suppression ALK, each compound (2 μ l) of preparation in embodiment 1～18 is carried in 96
In the round bottom plate of hole.Then, by each compound and ALK enzyme (1 μ l) be conjugated with the peptide substrates (2 μ l) of biotin and mix, subsequently
Cultivate 15 minutes.It is added thereto to ATP solution (5 μ l), the most at room temperature carries out kinase reaction 30 minutes.Second two will be dissolved in
The XL 665 (5 μ l) being conjugated with Streptavidin in amine tetraacethyl solution and be conjugated with europium (Eu3+) anti-phosphotyrosine
Antibody (5 μ l) adds to reaction solution, to terminate reaction.After completion of the reaction, and then carry out the cultivation of a hour, use subsequently
Homogeneous phase time discrimination fluorescence method (HTRF, Cisbio) is analyzed.OD is measured with Wallac Envision 2103615nm/665nm。
Use the prism software (version 5.01, the Graphpad) IC to each compound50It is measured.
Lower list 2 shows the IC of each compound50, its be suppression 50% ALK enzymatic activity and L1196M (containing ALK
Lines) activity concentration.
Table 2
As shown in table 2, compared to comparison 1 and the compound of comparison 2, the ALK suppression of the compound display excellence of the present invention
Activity.
Specifically, all compounds of embodiment 1～embodiment 18 demonstrate higher suppression than comparison 1 (gram azoles replaces Buddhist nun)
Activity.In addition to the compound of embodiment 7 and embodiment 9, the most of comparison of these compounds of embodiment 1～embodiment 18
Higher activity is shown according to 2 (LDK-378).
Confirm from the experimental result of the present invention: even if at low concentrations, pyrimidine-2 of the present invention, 4-diamine derivative is pressing down
In ALK activity processed effectively, especially, Buddhist nun's (positive control) phase is replaced with the conventional gram azoles being commonly used for treating nonsmall-cell lung cancer
Ratio, pyrimidine-2 of the present invention, 4-diamine derivative is more effective.
Therefore, pyrimidine-2 of the present invention, 4-diamine derivative is excellent in suppression ALK activity, therefore, not only can be by
It effectively serves as ALK inhibitor, also can be used as prevention or treat the compositions of following cancer: non-small cell lung
Cancer, neuroblastoma, inflammatory haematogonium tumor, rhabdomyosarcoma, myofibroblastoma, breast carcinoma, gastric cancer, pulmonary carcinoma and
Melanoma.EXPERIMENTAL EXAMPLE 2: the suppression of cancer cell multiplication
Carry out following experiment, to study pyrimidine-2 that formula 1 represents, 4-diamine derivative anticancer propagation
Activity.
<2-1>experiment material
Reagent
RPMI 1640, cell culture medium, FBS (hyclone) and trypsin are purchased from Gibco (Grand Island, NY), carbon
Acid hydrogen sodium, amphotericin B and gentamycin are purchased from SigmaChemical.
Reagent SRB (Sulforhodamine) B, trisma alkali, trichloroacetic acid (TCA) for cytotoxicity test are purchased from
Sigma Chemical.For MTS analyzes, CellTiter 96RAqueous non-radioactive cell proliferation assay kit
(CellTiter 96RAqueous Non-RadioactiveCell Proliferation Assay kit) it is purchased from
Promega。
For cell is cultivated, T-25 culture vessel, 96 orifice plates and other disposable glass drying oven are purchased from Falcon
(Lincoln Park, NJ).
Device
Use E-max or SpectraMax250 of Molecular Devices (Sen Niweier, CA), as cell
The ELISA reader of toxotest.
<2-2>experimental technique
1st step: cell is cultivated
Final dimethyl sulfoxide concentration is at most 0.5%.
Cancerous cell line used herein is humanized's cancerous cell line, more properly, uses non-small cell lung cancer cell
It is H2228 and Lines H3122.
For culture medium, use the RPMI 1640 being supplemented with 10%FBS (hyclone).At 37 DEG C, 5%CO2's
Incubator carries out cell cultivation, within every 3～4 days, carries out successive transfer culture.
2nd step: according to the process of compound, the evaluation to proliferation inhibition activity
By cell with every hole 1 × 104The Density Distribution of individual cell in the 96 flat microplates in hole, subsequently cultivate 24 hours until
Cell is adhered to bottom.Then, culture medium is discarded.Each of dilution embodiment 1 in the medium～embodiment 18 is changed
Compound is added thereto, and cultivates 72 hours the most further.After having cultivated with these compounds, and then use SRB, albumen
Staining reagent or use MTS analyze and measure cytotoxicity.Cultivating with the compound of embodiment 1～embodiment 18
After, culture medium is removed, and with cold TCA solution, each hole will be processed.Culture plate is placed 1 hour at 4 DEG C,
With fixing cell.TCA solution is removed, and cell is dried at room temperature for.(1% acetic acid will be dissolved in molten containing 0.4%SRB
In liquid) staining solution add to cell, ambient temperatare is put 30 minutes, with by cell dyeing.By being somebody's turn to do with 1% acetic acid solution washing
Culture plate, removes the excessive SRB puted together with cell not yet.By the tris buffer of 10mM that pH is 10.3～10.5
(Trisma alkali；Do not buffer) add to dyeing cell, eluting SRB subsequently.Use the Microplate Reader OD to each hole520nmEnter
Row is measured.
By following equation, by the OD value (C) in the untreated hole of compound, the OD value (T) and first in compound treatment hole
The cytotoxicity of each compound is calculated by the OD value (Tz) of disposal hole,
As Tz=T, [(T-Tz)/(C-Tz)] 100；Or
As Tz > T time, [(T-Tz)/(Tz)] 100.
By using following MTS to analyze, the activity of compound anticancer propagation is measured.Specifically, when
When having cultivated with the compound of embodiment 1～embodiment 18, by CellTiter96RAqueous non-radioactive cell proliferation is analyzed
The PMS solution contained in test kit (Promega) and the mixing of MTS solution, load solution described in 20 μ l in each hole.After 4 hours,
Described culture plate is at room temperature placed 10 minutes.Use SpectraMax250 (Molecular Device) to OD490nmCarry out
Measure.To GI50(growth inhibited 50%) calculates, and to evaluate proliferation inhibition activity, shows the result in lower list 3.
Table 3
As shown in table 3, the compound of the embodiment of the present invention is at Lines H2228 and nonsmall-cell lung cancer
Cell line H3122 suppresses ALK activity, causes the suppression of cell proliferation.From experiment as a result, it was confirmed that non-with having been used for treating
The control compound 1 of small cell lung cancer is compared with control compound 2, and cancerous cell is had by the most compounds of the embodiment of the present invention
There is the proliferation inhibiting effect of excellence.
Therefore, pyrimidine-2 of the present invention, 4-diamine derivative is excellent in suppression ALK activity, therefore, not only can be by
It effectively serves as ALK inhibitor, also can be used as prevention or treat the compositions of following cancer: non-small cell lung
Cancer, neuroblastoma, inflammatory haematogonium tumor, rhabdomyosarcoma, myofibroblastoma, breast carcinoma, gastric cancer, pulmonary carcinoma and
Melanoma.EXPERIMENTAL EXAMPLE 3: the Cytotoxic evaluation in the BaF3 cell of EML4-ALK transfection
Carrying out following experiment, to evaluate pyrimidine-2 that formula 1 represents, 4-diamine derivative is at BaF3EML4-ALK
Cytotoxicity in L1196M cell and BaF3EML4-ALK WT cell.
Specifically, by using slow virus, BaF3 cell is made to transfect through EML4-ALK wt (wild type), stable to build
Express the BaF3EML4-ALK wt cell line of EML4-ALK wt.Additionally, by using slow virus, make BaF3 cell through EML4-
ALK L1196M transfects, to build the BaF3EML4-ALK L1196M cell line stably expressing EML4-ALK L1196M.To upper
The cell quantity stating two cell lines counts.By cell with the Density Distribution in 4,000, every hole cell (90 μ l) in 96 holes
In plate.With 10 μMs, 2 μMs, 0.4 μM, 0.08 μM, 0.016 μM, 0.0032 μM, 0.00064 μM and the concentration of 0 μM, by embodiment
Compound add to each hole of plate.Cell is cultivated 3 days in the incubator of 37 DEG C.WST-1 solution is added to described cultivation
Each hole (10 μ l/ hole) of plate.When the color of solution changes in hole, use ELISA reader (EMax Endpoint
ELISA Microplate Reader, Molecular Devices) to OD450nmMeasure.By using the OD obtained to cyton
Amass and calculate, thus calculate IC50, to show the cytotoxicity of each compound.Show the result in table 4.
Table 4
As shown in table 4, have gram azoles for Buddhist nun's drug resistance BaF3EML4-ALK WT (wild type) cell and
In BaF3EML4-ALK L1196M cell, the most compounds of the embodiment of the present invention is than control compound 1 and control compound
2 show lower IC50.The above results shows and control compound 1 and the comparison having been used for treating nonsmall-cell lung cancer
Compound 2 is compared, and the most compounds of the embodiment of the present invention has the ALK inhibitory activity of excellence.
Therefore, pyrimidine-2 of the present invention, 4-diamine derivative is excellent in suppression ALK activity, therefore, not only can be by
It effectively serves as ALK inhibitor, also can be used as prevention or treat the compositions of following cancer: non-small cell lung
Cancer, neuroblastoma, inflammatory haematogonium tumor, rhabdomyosarcoma, myofibroblastoma, breast carcinoma, gastric cancer, pulmonary carcinoma and
Melanoma.
Table 5 shows EXPERIMENTAL EXAMPLE 1～the result of EXPERIMENTAL EXAMPLE 3 (table 2～table 4).
Table 5
Meanwhile, can be according to the purpose used, pyrimidine-2 represented by formula 1,4-diamine derivative is configured to multiple
Form.It is below pyrimidine-2 of formula 1 expression, the embodiment of the preparation of 4-diamine derivative, but described embodiment is not
Can be limited the invention to this.
Manufacture embodiment 1: the preparation of pharmaceutical preparation
The preparation of 1-1 powder
Derivant 500mg that formula 1 represents
Lactose 100mg
Talcum 10mg
According to the conventional method for preparing powder, by being mixed by all above-mentioned components, described component is filled in gas
Close packaging prepares powder.
The preparation of 1-2 tablet
By the conventional method for preparing tablet, tablet is prepared in the mixing of all above-mentioned components.The system of 1-3 capsule
Standby
According to the conventional method for preparing capsule, by all above-mentioned components are mixed, described component is filled in
Gelatine capsule is prepared capsule.
The preparation of 1-4 injectable solutions
Derivant 500mg that formula 1 represents
Sterile purified water is appropriate
PH adjusting agent is appropriate
By the conventional method for preparing injectable solutions, by all above-mentioned components are mixed, mixture is put
Enter in the ampoule of 2ml and prepare injectable solutions.
The preparation of 1-5 liquid preparation
All above-mentioned components are dissolved in purified water.After adding citrus scented agent, by adding purified water by cumulative volume
Regulate to 100ml.By the conventional method for preparing liquid preparation, mixture is put into brown bottle and be prepared by its sterilizing
Liquid preparation.
Industrial applicability
The compounds of this invention is excellent in suppression anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK), therefore the compounds of this invention energy
Enough therapeutic effect improved the cancerous cell especially containing ALK fusion protein (such as EML4-ALK and NPM-ALK), due to this
Invention compound it is contemplated that in prophylaxis of cancer recurrence effectively, can be effectively served as prevention or the drug regimen for the treatment of cancer
Thing.
It will be appreciated by those skilled in the art that concept disclosed in description above and detailed description of the invention can be easy to
With making an amendment or the basis of other embodiment of the identical purpose of the design implementation present invention.Those skilled in the art it will also be understood that
It is that the embodiment of these equivalents is without departing from the spirit and scope of the present invention illustrated in appended claims.
Claims (10)
1. pyrimidine-2,4-diamine derivative or its pharmaceutically acceptable salt, described pyrimidine-2,4-diamine derivative by under
Column 1 represents:
[formula 1]
In formula 1,
Represent singly-bound or double bond；
WhenWhen being singly-bound,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-10Straight chained alkyl；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-10Straight or branched alkyl；Or-C (=O) R5, this
Time R5It is-H ,-OH or C1-10Straight or branched alkyl；
WhenWhen being double bond,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-10Straight or branched alkane
Base；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-10Straight or branched alkyl；Or-C (=O) R5, this
Time R5It is-H ,-OH or C1-10Straight or branched alkyl.
2. pyrimidine-2 as claimed in claim 1,4-diamine derivative or its pharmaceutically acceptable salt, wherein,
WhenWhen being singly-bound,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-5Straight chained alkyl；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-5Straight or branched alkyl；Or-C (=O) R5, now
R5It is-OH or C1-5Straight or branched alkyl；
WhenWhen being double bond,
R1、R2And R3Independently be-H, halogen or the unsubstituted or substituted C having one or more halogen1-5Straight or branched alkane
Base；
R4It is-H；The unsubstituted or substituted C having one or more-OH group1-5Straight or branched alkyl；Or-C (=O) R5, now
R5It is-OH or C1-5Straight or branched alkyl.
3. pyrimidine-2 as claimed in claim 1,4-diamine derivative or its pharmaceutically acceptable salt, wherein,
WhenWhen being singly-bound,
R1It is-Cl or-CF3；
R2It is-H ,-CH3Or-F；
R3It is-CH3Or-CHF2；
R4It is-H ,-CH3、-CH2CH3、-CH2CH2OH ,-C (=O) CH3Or-C (=O) OH；
WhenWhen being double bond,
R1It is-Cl or-CF3；
R2It is-H ,-CH3Or-F；
R3It is-CH3、-CH(CH3)2Or-CHF2；
R4It is-H ,-CH3、-CH2CH3、-CH2CH2OH ,-C (=O) CH3Or-C (=O) OH.
4. pyrimidine-2 as claimed in claim 1,4-diamine derivative or its pharmaceutically acceptable salt, wherein, formula 1 represents
Described pyrimidine-2,4-diamine derivative is selected from the group being made up of following compound:
(1) the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-base)
Phenyl) pyrimidine-2,4-diamidogen；
(2) the chloro-N2-of 5-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl
Base sulfonyl) phenyl) pyrimidine-2,4-diamidogen；
(3) the chloro-N2-of 5-(2-(difluoro-methoxy)-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl sulphur
Aminosulfonylphenyl) pyrimidine-2,4-diamidogen；
(4) the chloro-N2-of 5-(2-(difluoro-methoxy)-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) is phonetic
Pyridine-2,4-diamidogen；
(5) the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(piperidin-4-yl) phenyl) pyrimidine-2,
4-diamidogen；
(6) N4-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-
5-(trifluoromethyl) pyrimidine-2,4-diamidogen；
(7) N2-(2-isopropoxy-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl sulphonyl
Base) phenyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen；
(8) N2-(2-(difluoro-methoxy)-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropelsulfonyl)
Phenyl)-5-(trifluoromethyl) pyrimidine-2,4-diamidogen；
(9) N2-(2-(difluoro-methoxy)-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl)-5-(three
Methyl fluoride) pyrimidine-2,4-diamidogen；
(10) the chloro-N2-of 5-(5-fluoro-2-methoxyl group-4-(1,2,3,6-tetrahydropyridine-4-base) phenyl)-N4-(2-(isopropyl sulphur
Acyl group) phenyl) pyrimidine-2,4-diamidogen；
(11) the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-5-methyl-4-(1,2,3,6-tetrahydrochysene pyrrole
Pyridine-4-base) phenyl) pyrimidine-2,4-diamidogen；
(12) the chloro-N2-of 5-(5-fluoro-2-methoxyl group-4-(piperidin-4-yl) phenyl)-N4-(2-(isopropelsulfonyl) phenyl) is phonetic
Pyridine-2,4-diamidogen；
(13) the chloro-N4-of 5-(2-(isopropelsulfonyl) phenyl)-N2-(2-methoxyl group-5-methyl-4-(piperidin-4-yl) phenyl)
Pyrimidine-2,4-diamidogen；
(14) the chloro-N2-of 5-(4-(1-ethyl-1,2,3,6-tetrahydropyridine-4-base)-2-methoxyphenyl)-N4-(2-(isopropyl
Sulfonyl) phenyl) pyrimidine-2,4-diamidogen；
(15) (2-is (different for-N4-for the chloro-N2-of 5-(4-(1-hydroxyethyl-1,2,3,6-tetrahydropyridine-4-base)-2-methoxyphenyl)
Sulfonyl propyl base) phenyl) pyrimidine-2,4-diamidogen；
(16) 1-(4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-methoxyl group
Phenyl)-5,6-dihydropyridine-1 (2H)-yl) ethyl ketone；
(17) 4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-methoxybenzene
Base)-5,6-dihydropyridine-1 (2H)-formic acid；And
(18) 4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) phenyl) amino) pyrimidine-2-base) amino)-3-methoxybenzene
Base)-1 (2H)-methyl-5,6-dihydropyridine.
5. one kind for preparing described pyrimidine-2 of claim 1, the method for 4-diamine derivative, described method include following instead
Answer the following steps shown in formula 1:
Step 1: reacted by the compound making compound that formula 2 represents and formula 3 represent, the compound that formula 4 represents；And
Step 2: the compound that the compound represented by the formula 4 making in step 1 preparation and formula 5 are represented reacts, and formula 1 represents
Described compound.
[reaction equation 1]
In described reaction equation 1, R1、R2、R3And R4As defined in formula 1.
6., for preventing or treat a pharmaceutical composition for cancer, the formula 1 that described pharmaceutical composition contains claim 1 represents
Described pyrimidine-2,4-diamine derivative or its pharmaceutically acceptable salt as active component.
7. the pharmaceutical composition for preventing or treat cancer as claimed in claim 6, wherein, described pharmaceutical composition passes through
Suppression anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) activity is carried out anticancer and is expressed and growth.
8. the pharmaceutical composition for preventing or treat cancer as claimed in claim 6, wherein, described cancer selected from by with
Lower formed group: nonsmall-cell lung cancer, neuroblastoma, inflammatory haematogonium tumor, rhabdomyosarcoma, muscle fiber are female thin
Born of the same parents' tumor, breast carcinoma, gastric cancer, pulmonary carcinoma, melanoma, large B cell lymphoid tumor, generalized tissue cellular proliferative disorder, inflammatory muscle fiber
Blastoma and esophageal squamous cell carcinoma.
9. a pharmaceutical composition, described pharmaceutical composition contains described pyrimidine-2 of claim 1,4-diamine derivative or its
Pharmaceutically acceptable salt is as active component, for preventing or treating by the overactivity of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK)
Caused disease.
10. anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) inhibitor, described inhibitor contains described pyrimidine-2 of claim 1,4-
Diamine derivative or its pharmaceutically acceptable salt are as active component.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2014-0023897 | 2014-02-28 | ||
| KR1020140023897A KR101656382B1 (en) | 2014-02-28 | 2014-02-28 | pyrimidine-2,4-diamine derivatives and pharmaceutical composition for anti cancer containing the same as an active ingredient |
| PCT/KR2015/000737 WO2015130014A1 (en) | 2014-02-28 | 2015-01-23 | Pyrimidine-2,4-diamine derivative and pharmaceutical anticancer composition containing same as active ingredient |
Publications (2)
| Publication Number | Publication Date |
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| CN106029646A true CN106029646A (en) | 2016-10-12 |
| CN106029646B CN106029646B (en) | 2018-04-03 |
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| CN201580010933.1A Expired - Fee Related CN106029646B (en) | 2014-02-28 | 2015-01-23 | The diamine derivative of pyrimidine 2,4 and contain anticancer pharmaceutical composition of the derivative as active component |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR101656382B1 (en) |
| CN (1) | CN106029646B (en) |
| WO (1) | WO2015130014A1 (en) |
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| CN106880629A (en) * | 2017-02-23 | 2017-06-23 | 常俊杰 | A kind of pharmaceutical composition of reducing blood lipid |
| CN108047204A (en) * | 2018-01-08 | 2018-05-18 | 沈阳药科大学 | 2,4- diarylamino pyrimidine derivatives and its preparation method and application |
| CN108689994A (en) * | 2017-07-01 | 2018-10-23 | 浙江同源康医药股份有限公司 | Compound as ALK kinase inhibitors and its application |
| CN108707120A (en) * | 2018-06-27 | 2018-10-26 | 苏州市贝克生物科技有限公司 | A kind of synthetic method of Ceritinib intermediate |
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| CN110835320A (en) * | 2018-08-15 | 2020-02-25 | 江苏奥赛康药业有限公司 | Diaminopyrimidine compound and application thereof |
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| CN108689994A (en) * | 2017-07-01 | 2018-10-23 | 浙江同源康医药股份有限公司 | Compound as ALK kinase inhibitors and its application |
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| CN110835320A (en) * | 2018-08-15 | 2020-02-25 | 江苏奥赛康药业有限公司 | Diaminopyrimidine compound and application thereof |
| CN110143947A (en) * | 2019-05-29 | 2019-08-20 | 华东师范大学 | A kind of preparation method of Ceritinib analog |
| CN110143947B (en) * | 2019-05-29 | 2021-10-15 | 华东师范大学 | Preparation method of ceritinib analogue |
| WO2020259553A1 (en) * | 2019-06-25 | 2020-12-30 | Ascentage Pharma (Suzhou) Co., Ltd. | Combination of fak inhibitor and btk inhibitor for treating a disease |
| CN111777592A (en) * | 2020-06-22 | 2020-10-16 | 温州医科大学 | N4- (2, 5-dimethoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof |
| CN111777592B (en) * | 2020-06-22 | 2021-06-18 | 温州医科大学 | N4- (2, 5-dimethoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof |
| CN112168773A (en) * | 2020-08-13 | 2021-01-05 | 重庆医药高等专科学校 | Preparation method of anticancer drug containing pyrimidine-2, 4-diamine derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20150102252A (en) | 2015-09-07 |
| WO2015130014A1 (en) | 2015-09-03 |
| KR101656382B1 (en) | 2016-09-09 |
| CN106029646B (en) | 2018-04-03 |
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