CN102838601A - Selective phosphatidylinositol-3 kinase delta inhibitor - Google Patents

Selective phosphatidylinositol-3 kinase delta inhibitor Download PDF

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CN102838601A
CN102838601A CN2012102041859A CN201210204185A CN102838601A CN 102838601 A CN102838601 A CN 102838601A CN 2012102041859 A CN2012102041859 A CN 2012102041859A CN 201210204185 A CN201210204185 A CN 201210204185A CN 102838601 A CN102838601 A CN 102838601A
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吴永谦
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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Abstract

The invention belongs to the field of medical technology, and in particular relates to a selective phosphatidylinositol-3 kinase delta inhibitor shown in the formula (I), a salt of the selective phosphatidylinositol-3 kinase delta inhibitor, accepted in pharmacy, and a stereoisomer or a deuterated material of the selective phosphatidylinositol-3 kinase delta inhibitor, wherein X1, X2, X3, X4, Y, Z, W, R1 and R2 are defined as specification. The invention also relates to a preparation method of the compounds, medicinal preparations containing the compounds and application of the compounds in preparation of drugs for treating and/or preventing inflammatory diseases or tumors.

Description

Selectivity phosphinylidyne inositol 3-kinase delta suppressor factor
Technical field
The invention belongs to medical technical field; Be specifically related to selectivity phosphinylidyne inositol 3-kinase delta suppressor factor, its pharmacy acceptable salt, its steric isomer or its deuterium for thing; The preparation method of these compounds; The pharmaceutical prepn that contains these compounds, and the purposes of these compounds in the medicine of preparation treatment inflammatory diseases or tumour.
Background technology
Tumour be body under the effect of the various tumorigenesis factor, cause the cytogenetics substance change, cause genetic expression not normal, cellular abnormality propagation and the true tumor that forms.Tumour cell loses the normal growth regulatory function, has independently or autonomous relatively energy for growth, even the tumorigenesis factor stops, tumour cell still can continued growth, the nutritive substance of mass consumption human body.If find and treat untimely, cancer cells also can be transferred to whole body growth and breeding everywhere, and discharges multiple toxin, causes that human body is become thin, anaemia, organ function be impaired to dead.
The method of oncotherapy mainly comprises three aspects: pharmacological agent, operative treatment and radiotherapy.Because operative treatment, radiotherapy are difficult to thoroughly eradicate tumour, and the effect of centering patients with advanced cancer is not obvious, so the status of pharmacological agent in oncotherapy is more and more obvious.The traditional antineoplastic thing can't be distinguished tumour cell and normal tissue cell, often causes severe side effect.The target series antineoplastic medicament with cancer cells as the specificity target spot; Can accurately act on tumour, improve treatment level greatly, and alleviate the untoward reaction rate; For example make the median survival time of advanced CRC increase by 66.7%, the efficient raising 71.3% of the treatment of advanced breast cancer.
Because it is sought-after to the antitumour drug of this classification that each drugmaker, adds market to the development acceleration of target class antitumour drug, molecular targeted agents has become fastest-rising unit in the global antitumor drug market.Phosphatidyl-inositol 3-kinase (phosphoinositide 3-kinase; PI3K) signal transduction path is one of system of topnotch sudden change in the human cancer; The conduction of PI3K signal also is the key factor in the human multiple other diseases; Various disease conditions is participated in the conduction of PI3K signal, comprises the inflammatory complication such as the acute coronary syndrome of contact dermatitis, rheumatoid arthritis, osteo-arthritis, inflammatory bowel, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, the obstacle that relates to diabetic complication and cardiovascular systems.
PI3K is member unique and the lipid within endothelial cells kinases family of guarding, 3 '-OH on its phosphorylation PI or the phosphoinositide.PI3K family comprises 15 kinds of kinases with different substrate specificities, expression pattern and regulative mode.I class PI3K (p110 α, p110 β, p110 δ, p110 γ) passes through Tyrosylprotein kinase or g protein coupled receptor activation usually with generation PIP3, and PIP3 combines those effector in downstream effect thing such as Akt/PDK1 approach, mTOR, Tec family kinase and the GTP of the Rho family enzyme.II class and III class PI3K bring into play keying action in transporting in cell through synthetic PI (3) P and PI (3,4) P2.PIKK is the protein kinase (mTORC1) of control cell growth or keeps watch on the protein kinase (ATM, ATR, DNA-PK and hSmg-1) of genomic integrity.
The δ hypotype that in multiple disease and bioprocess, relates to I class PI3K.PI3K δ mainly comprises in white corpuscle such as T cell, dendritic cell, neutrophilic granulocyte, mastocyte, B cell and the scavenger cell at hematopoietic cell and expressing.The requisite PI3K δ that relates in immune system function such as T cell function, B cell activation, mastocyte activation, dendritic cell function and neutrophilic granulocyte activity.Because PI3K δ requisite effect in function of immune system; PI3K δ also participates in multiple corresponding relevant disease with abnormal immune, for example transformation reactions, inflammatory diseases, inflammation mediated blood vessel generation, rheumatoid arthritis, autoimmunization systemic disease such as lupus, asthma, wind-puff and other respiratory tract diseases.
The downstream media of PI3K signal transduction pathway comprises the Mammals target (mTOR) of Akt and rapamycin.Akt has thrombocyte white corpuscle C kinase substrate homology (PH) structural domain that combines PIP3, wherein with PIP3 combine to cause the kinase whose activation of Akt.The multiple substrate of Akt sulfation, and be that PI3K is for the corresponding core downstream effect of various kinds of cell thing.A kind of critical function of Akt is through the activity of phosphorylation TSC2 with other mechanism enhancings mTOR.MTOR is and the relevant serine-threonine kinase of PI3K family lipid kinase.MTOR participates in a variety of bioprocesss, comprises cell growth, cell proliferation, cell mobility and survival.In polytype cancer, reported the imbalance of mTOR approach.MTOR integrates growth factor and trophic signals with adjusting protein translation, nutrition intake, have a liking for multi-functional kinases with mitochondrial function certainly.Therefore, kinases, particularly PI3K are the main targets of drug development.
Among Intellikine patent WO2009088990 and the Icos patent US6667300, all reported the validity of PI3K δ suppressor factor in tumour and inflammation treatment.At present, do not have the listing of PI3K δ suppressor factor class medicine temporarily, therefore, need the more PI3K δ inhibitor structure type of research and development, select validity and better security compound, be used for the treatment of cancer and inflammation.
Summary of the invention
Concrete technical scheme of the present invention is following:
Compound shown in the general formula (I), its deuterium are for thing, its pharmacy acceptable salt or its steric isomer:
Figure BDA00001790023900021
Wherein
X 1, X 2, X 3, X 4, Y independently is N respectively, or CR 3, R 3Be hydrogen, amino ,-N (R a) 2,-NH (R a), cyanic acid, halogen, trifluoromethyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 2-6Thiazolinyl, C 2-6Alkynyl, 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, or 7-12 unit bridged ring base;
R 1For
(1) hydrogen,
(2) C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl,
(3)-(P 1) m-L-(P 2) n-A, A represents 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, 7-12 unit bridged ring base, and A can be further by 1 ~ 3 R bReplace, L represent covalent linkage ,-O-,-N (R a)-,-C (O)-,-C (O) O-,-C (O) N (R a)-,-C (S) N (R a)-,-SO 2-,-SO 2N (R a)-,-S (O)-,-S (O) N (R a)-, P 1And P 2Independently be C respectively 1-6Alkyl, m and n independently are respectively 0 or 1;
R aRepresent hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, or 7-12 unit bridged ring base;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, C 1-6Alkyl, or 3-14 unit naphthenic base perhaps as Z are-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form the 3-8 unit saturated mono heterocyclic radical that contains a nitrogen-atoms at least together with the atom that links to each other;
R 2Be hydrogen, or be not substituted or by at least one R bSubstituted C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, 7-12 unit bridged ring base;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, formamyl C 1-6Alkyl, C 1-6Alkyl-carbonyl, C 1-6Alkyl carbonyl oxy, C 1-6Alkoxy carbonyl, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido, C 2-6Thiazolinyl, C 2-6Alkynyl, 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, or 7-12 unit bridged ring base.
Be preferably
Wherein
X 1, X 2, X 3, X 4, Y independently is N respectively, or CR 3, R 3Be hydrogen, amino ,-N (R a) 2,-NH (R a), cyanic acid, halogen, trifluoromethyl, C 1-6Alkyl, or C 1-6Alkoxyl group;
R 1For
(1)-and L-A, A represents fused heterocycle base, the 7-12 unit volution base of single heterocyclic radical, 6-14 unit's aromaticity or the fractional saturation of 6-14 unit aryl, 3-8 unit's aromaticity or fractional saturation, and A can be further by 1 ~ 3 R bReplace, L represent covalent linkage ,-O-,-N (R a)-,-C (O)-,-C (O) O-,-C (O) N (R a)-,-SO 2-,-SO 2N (R a)-;
R aRepresent hydrogen, C 1-6Alkyl, 3-8 unit monocyclic cycloalkyl, phenyl, or the single heterocyclic radical of 3-8 unit;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-6Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form the 3-6 unit saturated mono heterocyclic radical that contains a nitrogen-atoms at least together with the atom that links to each other;
R 2For not being substituted or by at least one R bThe fused heterocycle base of substituted 8-11 unit's aromaticity or fractional saturation;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, or formamyl C 1-6Alkyl.
Be preferably:
Wherein
X 1, X 2, X 3, X 4Independently be CR respectively 3, Y is N, R 3Be hydrogen, amino, halogen, trifluoromethyl, C 1-6Alkyl, or C 1-6Alkoxyl group;
R 1For
(1)-and L-A, A represents single heterocyclic radical of phenyl, naphthyl, 3-8 unit's aromaticity or fractional saturation, and A can be further by 1 ~ 3 R bReplace, L represent covalent linkage ,-O-,-N (R a)-;
R aRepresent hydrogen, or C 1-6Alkyl;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-6Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form the 3-6 unit saturated mono heterocyclic radical that contains a nitrogen-atoms at least together with the atom that links to each other;
R 2For not being substituted or by at least one R bThe fused heterocycle base of substituted 9-10 unit's aromaticity or fractional saturation, wherein the fused heterocycle base comprises at least 2 nitrogen-atoms;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, or C 1-6Alkoxyl group.
Be preferably:
Wherein
X 1, X 2, X 3, X 4Independently be CR respectively 3, Y is N, R 3Be hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, or C 1-6Alkoxyl group;
R 1For
(1)-and L-A, A represents phenyl, pyridyl, pyrimidyl, and A can be further by 1 ~ 3 R bReplace, L represents covalent linkage;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-4Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form together with the atom that links to each other
Figure BDA00001790023900051
Figure BDA00001790023900052
R 2For not being substituted or by at least one R bSubstituted
Figure BDA00001790023900053
Figure BDA00001790023900054
R bBe halogen, amino, hydroxyl, amino-sulfonyl, formamyl, C 1-6Alkyl, or C 1-6Alkoxyl group.
Be preferably
Wherein
X 1, X 2, X 3Independently be CH respectively, X 4Be CR 3, Y is N, R 3Be hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, or C 1-6Alkoxyl group;
R 1For
(1)-and L-A, A represents phenyl, and A can be further by 1 ~ 3 R bReplace, L represents covalent linkage;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-4Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form together with the atom that links to each other
Figure BDA00001790023900055
Figure BDA00001790023900056
R 2For not being substituted or by at least one R bSubstituted
Figure BDA00001790023900057
R bBe halogen, amino, hydroxyl, C 1-6Alkyl, or C 1-6Alkoxyl group.
Be preferably:
Wherein
X 1, X 2, X 3Independently be CH respectively, X 4Be CR 3, Y is N, R 3Be fluorine or chlorine;
R 1For
(1)-and L-A, A represents phenyl, and A can be further by 1 ~ 3 R bReplace, L represents covalent linkage;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-4Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form together with the atom that links to each other
Figure BDA00001790023900062
R 2For not being substituted or by 1 ~ 3 R bSubstituted
R bBe fluorine, chlorine, amino, hydroxyl, methyl, or methoxyl group.
" C of the present invention 1-6Alkyl " expression straight or branched the alkyl that contains 1-6 carbon atom; like methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methylbutyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1; 3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc." C of the present invention 1-4Alkyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned instance.
" C of the present invention 2-6Thiazolinyl " be meant that the carbonatoms that contains two keys is 2 ~ 6 straight or branched or cyclic thiazolinyl; like vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-crotonyl, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-crotonyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-crotonyl, 2-methyl-3-crotonyl, 3-methyl-3-crotonyl, 1; 1-dimethyl--2-propenyl, 1; 2-dimethyl--1-propenyl, 1; 2-dimethyl--2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl--crotyl, 1,1-dimethyl--3-crotonyl, 1; 2-dimethyl--1-butylene base, 1; 2-dimethyl--crotyl, 1,2-dimethyl--3-crotonyl, 1,3-dimethyl--1-butylene base, 1; 3-dimethyl--crotyl, 1; 3-dimethyl--crotyl, 2,2-dimethyl--3-crotonyl, 2,3-dimethyl--1-butylene base, 2; 3-dimethyl--crotyl, 2; 3-dimethyl--3-crotonyl, 3,3-dimethyl--1-butylene base, 3,3-dimethyl--crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-crotonyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-crotonyl, 1; 1; 2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl isophthalic acid-propenyl, 1-ethyl-2-methyl-2-propenyl, 1,3-butadiene, 1,3-pentadiene, 1; 4-pentadiene, 1; The 4-hexadiene, " carbonatoms that contains two keys is 2 ~ 6 cyclic thiazolinyl " is meant " C 3-6" cycloalkenyl group, the example includes but not limited to for example cyclobutene base, cyclopentenyl, 1 base, cyclohexenyl, 1 base etc.
" C of the present invention 2-6Alkynyl " be meant that the carbonatoms that contains three key is the alkynyl of the straight or branched of 2-6; like ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1; 1-dimethyl--2-propynyl, 1-ethyl-2-propynyl, 2-hexyn, 3-hexyn, 4-hexyn, 5-hexyn, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1; 1-dimethyl--2-butyne base, 1; 1-dimethyl--3-butynyl, 1; 2-dimethyl--3-butynyl, 2,2-dimethyl--3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl etc.
" C of the present invention 1-6Alkoxyl group " be meant with C 1-6The group that alkyl-the O-mode connects, C 1-6Alkyl such as preceding text definition.Like methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec.-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc." C of the present invention 1-4Alkoxyl group " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned instance.
" C of the present invention 1-6Alkyl amine group ", " two (C 1-6Alkyl) amido ", " C 1-6Alkyl carbonyl oxy ", " C 1-6Alkoxy carbonyl ", " C 1-6Alkyl-carbonyl " be meant with C 1-6Alkyl-NH-, (C 1-6Alkyl) 2N-, C 1-6Alkyl-C (O)-O-, C 1-6Alkyl-O-C (O)-, C 1-6The group that alkyl-C (O)-mode connects, wherein " C 1-6Alkyl " such as preamble definition.
" hydroxyl C of the present invention 1-6Alkyl " be meant that one or more hydroxyls replace " C 1-6Alkyl " formed group, wherein " C 1-6Alkyl " such as preamble definition.
" amino C of the present invention 1-6Alkyl " be meant that one or more amino replace " C 1-6Alkyl " formed group, wherein " C 1-6Alkyl " such as preamble definition.
" carboxyl C of the present invention 1-6Alkyl " be meant one or more carboxyl substituted " C 1-6Alkyl " formed group, wherein " C 1-6Alkyl " such as preamble definition.
" formamyl C of the present invention 1-6Alkyl " be meant that one or more formamyls replace " C 1-6Alkyl " formed group, wherein " C 1-6Alkyl " such as preamble definition.
" halogen atom " of the present invention is meant fluorine atom, chlorine atom, bromine atoms, iodine atom.
" 3-14 unit naphthenic base " of the present invention is meant that annular atoms all is a carbon atom, removes a Wasserstoffatoms deutero-cyclic alkyl group, comprises 3-8 unit's monocyclic cycloalkyl and 6-14 unit condensed ring naphthenic base.
3-8 unit monocyclic cycloalkyl, the example includes but not limited to: Trimetylene base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethyl-tetramethylene base, methylcyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyl cyclohexane base etc.
6-14 unit condensed ring naphthenic base is meant this condensed ring by shared each other two the formed cyclic groups of adjacent carbon atom of two or more ring texturees, and the example includes but not limited to: two ring [3.1.0] hexyls, two ring [4.1.0] heptane bases, two ring [2.2.0] hexyls, two ring [3.2.0] heptane bases, two ring [4.2.0] octyls, octahydro pentalene base, octahydro-1H-indenyl, naphthane base, ten tetrahydrochysene phenanthryl, dicyclo [3.1.0] oneself-2-thiazolinyl, dicyclo [4.1.0] heptan-3-thiazolinyl, dicyclo [3.2.0] heptan-3-thiazolinyl, dicyclo [4.2.0] suffering-3-thiazolinyl, 1,2,3,3a-tetrahydrochysene pentalene base, 2; 3,3a, 4,7,7a-six hydrogen-1H-indenyl, 1,2; 3,4,4a, 5,6; 8a-octalin base, 1,2,4a, 5,6; 8a-hexahydro-naphthyl, 1,2,3,4,5; 6,7,8,9,10-decahydro phenanthryl etc.
" 6-14 unit aryl " of the present invention is meant that annular atoms all is the ring-type aromatic group of carbon atom, comprises 6-8 unit's monocyclic aryl and 8-14 unit fused ring aryl.
6-8 unit monocyclic aryl is meant that annular atoms all is the monocyclic aromatic group of carbon atom, for example phenyl, cyclooctatetraene base etc.
8-14 unit fused ring aryl is meant by shared each other two the adjacent carbon atoms of two or more monocyclic aromatic group formed, for example naphthalene, phenanthrene etc.
" 7-12 unit bridged ring base " of the present invention is meant that the shared atom that neither directly links to each other of any two rings forms contains 7-12 carbon atom or/and heteroatomic structure, and described heteroatoms has nitrogen, oxygen and sulphur etc.Specific examples include, but are not limited to:
Figure BDA00001790023900081
Figure BDA00001790023900082
Figure BDA00001790023900083
and so on.
" 7-12 unit volution " of the present invention be meant one type have that two rings share that atoms form at least contain 7-12 carbon atom or/and heteroatomic structure, described heteroatoms has nitrogen, oxygen and sulphur etc.Specific examples include, but are not limited to:
Figure BDA00001790023900084
Figure BDA00001790023900085
Figure BDA00001790023900092
etc.
" 3-14 unit heterocyclic radical " of the present invention is meant and contains 3-14 the annular atoms cyclic group of (wherein containing a heteroatoms at least), comprises the single heterocyclic radical of 3-8 unit, 6-14 unit fused heterocycle base, and described heteroatoms has nitrogen, oxygen and sulphur etc.
The single heterocyclic radical of 3-8 unit is meant and contains 3-8 the annular atoms monocyclic heterocycles base of (wherein containing a heteroatoms at least), comprises the single heterocyclic radical of 3-8 unit aromaticity, the single heterocyclic radical of 3-8 unit fractional saturation, 3-8 unit saturated mono heterocyclic radical.The single heterocyclic radical of 3-8 unit aromaticity is meant heteroatomic cyclic group of containing of aromaticity, is preferably the single heterocyclic radical of 5-6 unit aromaticity.Specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl group 、 oxazolyl 、 oxadiazole base, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, 1,4-Dioxin base, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1; 2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1; 2,3-triazinyl, 1,2,4-triazinyl, 1; 3,5-triazinyl, 1,2; 4,5-tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1,3-diazacyclo heptantriene base, nitrogen heterocyclic octatetraene base etc.The single heterocyclic radical of 3-8 unit fractional saturation is meant the heteroatomic cyclic group that contains that contains two keys, and specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl etc.3-8 unit saturated mono heterocyclic radical; Be meant all be heteroatomic cyclic group of containing of saturated bond; Specific examples includes but are not limited to: ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, 1; 4-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.R of the present invention 4With R 5', or R 4With R 5Can form the 3-6 unit saturated mono heterocyclic radical that contains a nitrogen-atoms at least together with the atom that links to each other, be meant the saturated cyclic group that contains 3-6 annular atoms in the 3-8 unit saturated mono heterocyclic radical and contain a nitrogen-atoms at least.
6-14 unit fused heterocycle base; Be meant that containing 6-14 annular atoms (wherein containing a heteroatoms at least) couples together the condensed ring structure that forms by shared each other two the adjacent atoms of two or more ring texturees, comprise 6-14 unit aromaticity fused heterocycle base, 6-14 unit fractional saturation fused heterocycle base, the saturated fused heterocycle base of 6-10 unit.
6-14 unit aromaticity fused heterocycle base; Be meant heteroatomic condensed ring structure of containing of aromaticity; Structure like the single heterocyclic radical formation of benzo 3-8 unit aromaticity; The structures that single heterocyclic radical of 3-8 unit aromaticity and the 3-8 unit single heterocyclic radical of aromaticity form etc., specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl etc.
6-14 unit fractional saturation fused heterocycle base is meant the condensed ring structure that contains a fractional saturation ring at least, like the structure of the single heterocyclic radical formation of benzo 3-8 unit fractional saturation; The structure that single heterocyclic radical of 3-8 unit fractional saturation and the 3-8 unit single heterocyclic radical of fractional saturation form etc., specific examples includes but not limited to: 1,3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, chromanyl, 1; 2; 3, the 4-Pyrrolidine is [3,4-c] pyrryl etc. also.
The saturated fused heterocycle base of 6-10 unit; Be meant that whole rings is saturated condensed ring structure; Like 3-8 unit's saturated mono heterocyclic radical and the formed structure of 3-8 unit's saturated mono heterocyclic radical, specific examples includes but are not limited to: tetramethylene and Pyrrolidine base, pentamethylene and Pyrrolidine base, azetidine and imidazolidyl etc.
R of the present invention 2The 8-11 unit's aromaticity of definition or the fused heterocycle base of fractional saturation are meant in the fused heterocycle base of 6-14 unit's aromaticity or fractional saturation, contain the fused heterocycle group of 8-11 annular atoms.R of the present invention 2The 9-10 unit's aromaticity of definition or the fused heterocycle base of fractional saturation are meant in the fused heterocycle base of 6-14 unit's aromaticity or fractional saturation, contain the fused heterocycle group of 9-10 annular atoms.
Part of compounds of the present invention:
Figure BDA00001790023900101
Figure BDA00001790023900111
The present invention also provides the preparation method of above-claimed cpd:
Figure BDA00001790023900112
With raw material 1, raw material 2 and suitable reagent react, obtain formula I compound of the present invention.X in the last reaction equation 1, X 2, X 3, X 4, Y, Z, W, R 1, R 2Such as preamble definition.In case of necessity, the protective material of available routine is protected the functional group that needs protection, and after this sloughs blocking group through ordinary method.
The present invention requires to protect " pharmacy acceptable salt " of formula I compound, comprises the salt that forms with basic metal such as sodium, potassium, lithium etc.; Salt with formation such as earth alkali metal such as calcium, magnesium; The salt that forms with other metals such as aluminium, iron, zinc, copper, nickel, cobalt etc.; Salt with formation such as mineral alkali such as ammoniums; With organic bases such as uncle's octyl amine, dibenzyl amine, morpholine, glycosamine, phenylglycocoll alkyl ester, quadrol, N-NMG, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, the salt that N '-dibenzyl-ethylenediamin, chloroprocaine, PROCAINE HCL, PHARMA GRADE, diethylolamine, N-benzyl-styroyl amine, piperazine, tetramethyl-amine, three (methylol) amido methane etc. form; The salt that forms with mineral acid such as nitric acid, perchloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI etc.; The salt that forms with sulfonic acid such as methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, P-TOLUENE SULFO ACID 99 etc.; The salt that forms with organic acid such as acetic acid, oxysuccinic acid, fumaric acid, succsinic acid, Hydrocerol A, tartrate, oxalic acid, toxilic acid etc.; The salt that forms with amino acid such as glycocoll, Trimethyl glycine, l-arginine, ornithine, L-glutamic acid, aspartic acid etc.
The present invention requires to protect " steric isomer " of formula I compound, when having one or more unsymmetrical carbon in the compound structure, can produce enantiomer; When compound contains thiazolinyl or ring texture, can produce suitable/trans isomer; When compound has ketone or oxime, can produce tautomer or the like.All these isomer and mixture category all of the present invention.
The present invention requires to protect " deuterium is for the thing " of formula I compound, and when the Wasserstoffatoms in the compound during by the some or all of replacement of its isotropic substance deuterium (symbol is D), the material that is produced also belongs to category of the present invention.
Formula I compound of the present invention, its deuterium can be processed pharmaceutical prepn with one or more pharmaceutical carriers for thing, its pharmacy acceptable salt or its steric isomer.Said pharmaceutical prepn refers to the conventional formulation that uses clinically, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.Like tablet, particle, capsule, powder, injection, inhalation, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, sprays, preparation capable of permeating skin etc.These preparations can pass through ordinary method, add pharmaceutical carrier such as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc. and are prepared from.
Below further set forth the beneficial effect of The compounds of this invention through the external the enzyme activity of The compounds of this invention; Cited The compounds of this invention has identical beneficial effect in other compounds of the present invention and the test, but should this be interpreted as that The compounds of this invention only has following beneficial effect.
The external zymetology of experimental example The compounds of this invention suppresses active
Tester: The compounds of this invention, self-control, its chemical name and structural formula are seen the preparation embodiment of each compound;
Experimental technique:
1. compound is preserved with the mother liquor that DMSO is formulated as 1mM, during experiment, mother liquor is diluted 100 times to 10 μ M with 100% DMSO.10 μ M are the maximum concentration of this experiment, continuous then 4 times of dilutions, and totally 10 concentration are respectively 2.5 μ M, 0.625 μ M, 0.156 μ M, 0.039 μ M, 0.009 μ M, 0.00244 μ M, 0.61nM, 0.15nM, 0.04nM;
2. get the good compound solution of 4 μ L dilution in 96 orifice plates;
3. getting 1 μ L, 1 * kinase buffer liquid joins in 96 orifice plates.1 * kinase buffer liquid: 50mM HEPES, pH 7.5; 3mMMgCl 2, 1mM EGTA, 100mM NaCl, 0.03% CHAPS, 2mM DTT;
4. with step 2 and step 3 liang solution mixing, hatch 10min;
5. get the above-mentioned mixed solution of 2.5 μ L in 384 orifice plates, multiple hole, subsequent use;
6. get 2.5 μ L kinase solution in 384 orifice plates, concussion, the ultimate density of PI3K δ enzyme is 5.7nM;
7. get the substrate solution (PIP of 5 μ L in 384 orifice plates 2) and the ATP reaction buffer in 384 orifice plates, the concussion;
8. at room temperature hatch 2h;
9. get 10 μ L reaction solutions termination reaction in 384 orifice plates, concussion 15min, Caliper reading.
10.IC 50Calculate
Calculate inhibiting rate (%)=(maximum turnover ratio-turnover ratio)/(maximum turnover ratio-minimum transition rate) * 100, adopt XL fit software to carry out curve fitting, draw IC 50Value.
Experimental result:
The external zymetology of table 1 The compounds of this invention suppresses active
Tester PI3K δ zymetology suppresses active IC 50（nM）
Compound 4 ++
Compound 5 +++
Compound 6 ++
" +++" represent 0-500nM, represent very good to the inhibition activity of PI3K δ enzyme;
" ++ " represented 500-1000nM, and expression is active good to the inhibition of PI3K δ enzyme;
"+" represents 1000-5000nM, representes general to PI3K δ enzyme inhibition activity.
Experiment conclusion:
Can find out that by table 1 The compounds of this invention has good inhibition activity to PI3K δ enzyme.
Embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation (compound 4) of embodiment 1 2-(2-(9H-purine-6-yl) diazanyl)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone
(1) preparation of 2-fluoro-6-nitro-N-phenylbenzamaide
Figure BDA00001790023900142
(3.7g 20.0mmol) is dissolved in 40mL CH with 2-fluoro-6-nitrobenzoic acid 2Cl 2With 1.0mL DMF, to wherein slowly drip oxalyl chloride (3.81g, 30.0mmol), stirring at room is after two hours, concentrates to remove to desolvate, and is dissolved in the 4mL dioxane then, cooling down with its splash into aniline (1.86g, 20.0mmol), NaHCO 3(3.36g in dioxane 40.0mmol) (10mL) and water (10mL) solution, dropwises and is raised to stirring at room half a hour, adds 200mL water, separates out solid, and suction filtration, drying solid get product 5.13g, yield: 98.6%.
(2) preparation of 2-amino-6-fluoro-N-phenylbenzamaide
Figure BDA00001790023900143
(5.2g 20.0mmol) is dissolved in 50mL THF and 50mL methyl alcohol, to wherein adding NH with 2-fluoro-6-nitro-N-phenylbenzamaide 4Cl (10.84g, 202.6mmol), zinc powder (13.0g, 199mmol), after the stirred overnight at room temperature, solids removed by filtration, concentrated filtrate obtains the 4.45g faint yellow solid, yield 96.5%.
(3) preparation of 3-fluoro-2-(anilino carbonyl) anilino methyl-formiate
Figure BDA00001790023900144
With 2-amino-6-fluoro-N-phenylbenzamaide (20.0g, 86.9mmol) (73.56g 778mmol) mixes back 105 ° of C reaction 3 hours with methyl-chloroformate; Cooling, the ethanol of adding 80mL, mixed solution underpressure distillation; Obtain brown oil, directly be used for next step.
(4) 5-fluoro-3-phenylquinazoline-2,4 (1H, 3H)-preparation of diketone
Last 3-fluoro-2-(anilino carbonyl) the anilino methyl-formiate bullion that obtains of step is dissolved in the ethanol of 120mL, add KOH (14.6g, 260.2mmol); Reaction refluxed 3 hours, cooling, underpressure distillation; Be dissolved in then in the water of 60mL, transfer pH to 6-7, ethyl acetate extraction 3 times with glacial acetic acid; Concentrate and obtain the 17.0g brown solid, two step yields 76.4%.
(5) preparation of 2-chloro-5-fluoro-3-phenylquinazoline-4 (3H)-ketone
Figure BDA00001790023900152
With 5-fluoro-3-phenylquinazoline-2,4 (1H, 3H)-(17.0g 66.4mmol) is heated to 110 ° of C with 150mL POCl3 and 20mL xylidine to diketone; Reacted 70 hours, cooling concentrates, and is dissolved in the water; The shrend on the rocks remaining POCl3 that goes out is regulated pH to 7, uses ethyl acetate extraction, Na 2SO 4Dry organic phase concentrates, and column chromatography gets product 9.6g, yield 52.6%.
(6) preparation of 6-chloro-9H-purine
Figure BDA00001790023900153
(25.0g 183.7mmol) is dissolved in the xylidine of 15mL to xanthoglobulin under the ice bath, drips the 160mL POCl3 then; Refluxed 20 minutes after finishing, underpressure distillation, residuum is poured in the frozen water; Ethyl acetate extraction twice, water is regulated pH to 9 with ammoniacal liquor, uses twice of ethyl acetate extraction again; The water concentrating under reduced pressure, and recrystallization obtains the 26.0g faint yellow solid, yield 91.6%.
(7) preparation of 6-diazanyl-9H-purine
Figure BDA00001790023900154
(2.0g 12.9mmol) is heated to 90 ° of C with 20mL ethanol and 85% Hydrazine Hydrate 80 1.2mL, reacts 5 hours, separates out yellow solid, cools off, and suction filtration washs three times with ethanol and frozen water respectively, dry product 1.71g, the yield: 88.4% of getting with 6-chloro-9H-purine.
(8) preparation of 2-(2-(9H-purine-6-yl) diazanyl)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone
Figure BDA00001790023900161
With 6-diazanyl-9H-purine (660mg, 4.40mmol) (400mg 1.46mmol) is dissolved in and is heated to 100 ° of C among the 20mL DMA with 2-chloro-5-fluoro-3-phenylquinazoline-4 (3H)-ketone; Nitrogen protection reaction 4 hours; Cooling is poured into and is used ethyl acetate extraction, drying in the frozen water; Column chromatography gets product 85mg, yield 4.98%.
Molecular formula: C 19H 13FN 8O molecular weight: 388.12 mass spectrums (M+H): 389.1
1H-NMR(d 6-DMSO+D 2O,400MHz,60℃)：δ8.20-7.95(2H,m),7.66-7.40(6H,m),7.04(1H,s),6.86(1H,dd)。
The preparation (compound 5) of embodiment 2 2-((9H-purine-6-yl) methylamino-)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone
Figure BDA00001790023900162
(1) preparation of 2-fluoro-6-nitro-N-phenylbenzamaide
Figure BDA00001790023900163
(3.7g 20.0mmol) is dissolved in 40mL CH with 2-fluoro-6-nitrobenzoic acid 2Cl 2With 1.0mL DMF, to wherein slowly drip oxalyl chloride (3.81g, 30.0mmol), stirring at room is after two hours, concentrates to remove to desolvate, and is dissolved in the 4mL dioxane then, cooling down with its splash into aniline (1.86g, 20.0mmol), NaHCO 3(3.36g in dioxane 40.0mmol) (10mL) and water (10mL) solution, dropwises and is raised to stirring at room half a hour, adds 200mL water, separates out solid, and suction filtration, drying solid get product 5.13g, yield: 98.6%.
(2) preparation of 2-amino-6-fluoro-N-phenylbenzamaide
Figure BDA00001790023900171
(5.2g 20.0mmol) is dissolved in 50mL THF and 50mL methyl alcohol, to wherein adding NH with 2-fluoro-6-nitro-N-phenylbenzamaide 4Cl (10.84g, 202.6mmol), zinc powder (13.0g, 199mmol), after the stirred overnight at room temperature, solids removed by filtration, concentrated filtrate obtains the 4.45g faint yellow solid, yield 96.5%.
(3) preparation of 3-fluoro-2-(anilino carbonyl) anilino methyl-formiate
Figure BDA00001790023900172
With 2-amino-6-fluoro-N-phenylbenzamaide (20.0g, 86.9mmol) (73.56g 778mmol) mixes back 105 ° of C reaction 3 hours with methyl-chloroformate; Cooling, the ethanol of adding 80mL, mixed solution underpressure distillation; Obtain brown oil, directly be used for next step.
(4) 5-fluoro-3-phenylquinazoline-2,4 (1H, 3H)-preparation of diketone
Last 3-fluoro-2-(anilino carbonyl) the anilino methyl-formiate bullion that obtains of step is dissolved in the ethanol of 120mL, add KOH (14.6g, 260.2mmol); Reaction refluxed 3 hours, cooling, underpressure distillation; Be dissolved in then in the water of 60mL, transfer pH to 6-7, ethyl acetate extraction 3 times with glacial acetic acid; Concentrate and obtain the 17.0g brown solid, two step yields 76.4%.
(5) preparation of 2-chloro-5-fluoro-3-phenylquinazoline-4 (3H)-ketone
Figure BDA00001790023900174
With 5-fluoro-3-phenylquinazoline-2,4 (1H, 3H)-(17.0g 66.4mmol) is heated to 110 ° of C with 150mL POCl3 and 20mL xylidine to diketone; Reacted 70 hours, cooling concentrates, and is dissolved in the water; The shrend on the rocks remaining POCl3 that goes out is regulated pH to 7, uses ethyl acetate extraction, Na 2SO 4Dry organic phase concentrates, and column chromatography gets product 9.6g, yield 52.6%.
(6) preparation of 6-chloro-9H-purine
Figure BDA00001790023900181
(25.0g 183.7mmol) is dissolved in the xylidine of 15mL to xanthoglobulin under the ice bath, drips the 160mL POCl3 then; Refluxed 20 minutes after finishing, underpressure distillation, residuum is poured in the frozen water; Ethyl acetate extraction twice, water is regulated pH to 9 with ammoniacal liquor, uses twice of ethyl acetate extraction again; The water concentrating under reduced pressure, and recrystallization obtains the 26.0g faint yellow solid, yield 91.6%.
(7) 6-iodo-9H-purine
Figure BDA00001790023900182
(20.0g 129.4mmol) slowly joins in the 45%HI aqueous solution of 210mL in batches, and system temperature can not surpass 10 ° of C with 6-chloro-9H-purine under the ice bath; The afterreaction that finishes filtered in 2 hours; Filter cake is scattered in the 80mL frozen water and with ammoniacal liquor regulates pH to 7.5, and cooling is filtered; Frozen water washing three times, drying.Further purify for solid dispersed in the strong aqua of 150mL water and 10mL, regulate pH to 5.0 with glacial acetic acid, filtration, drying obtains the dark white solid of 14.0g, yield 44.0%.
(8) preparation of 9H-purine-6-formonitrile HCN
Figure BDA00001790023900183
With 6-iodo-9H-purine (10.0g, 40.7mmol) with 250mL pyridine and cuprous cyanide (5.5g 61.4mmol) is heated to 90 ° of C under nitrogen atmosphere, react 5 hours, revolves to steam to remove to desolvate, and adds ETHYLE ACETATE, filtration, filtrate decompression directly is used for next step after distilling.
(9) preparation of 9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-formonitrile HCN
Figure BDA00001790023900184
9H-purine-6-formonitrile HCN bullion 10.0g and DL-camphorsulfonic acid 1.0g that a last step is obtained are dissolved among the 150mL exsiccant THF, and 80 ° of C add 3 down, and 4-dihydro-2H-pyrans (8.6g, 102.3mmol), spend the night by the nitrogen protection refluxed.The column chromatography for separation product obtains the 5.6g white solid after the removal of solvent under reduced pressure, two step yields 60.0%.
(10) preparation of (9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl) methylamine
Figure BDA00001790023900185
With 9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-formonitrile HCN (3.0g; 13.1mmol) be dissolved in 20mL methyl alcohol; Add 10%Pd-C(300mg) under nitrogen atmosphere, reacted 10 hours; Filter solid, revolve and steam filtrating, the carrene dissolving; Add a small amount of washing; Dry organic facies is revolved dried product 2.4g, yield 78.6%.
(11) preparation of 5-fluoro-3-phenyl-2-((9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl) methylamino-) quinazoline-4 (3H)-ketone
Figure BDA00001790023900191
With (9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl) methylamine (520mg; 2.23mmol) and 2-chloro-5-fluoro-3-phenylquinazoline-4 (3H)-ketone (400mg; 1.46mmol) be dissolved in the 20mL trimethyl carbinol and be heated to 95 ° of C, reacted 24 hours, revolve to steam to remove and desolvate; Column chromatography gets product 520mg, yield 75.3%.
(12) preparation of 2-((9H-purine-6-yl) methylamino-)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone
(250mg 0.53mmol) is dissolved in the 60mL absolute ethyl alcohol, and ice bath adds 2N HCl solution 0.5mL, room temperature reaction 15 hours down with 5-fluoro-3-phenyl-2-((9-(tetrahydrochysene-2H-pyrans-2-yl)-9H-purine-6-yl) methylamino-) quinazoline-4 (3H)-ketone.After the removal of solvent under reduced pressure, add the 50mL absolute ethyl alcohol, ammoniacal liquor is regulated pH and is approximately 8, revolves to steam to remove to desolvate, and column chromatography gets product 75mg, yield 36.6%.
Molecular formula: C 20H 14FN 7O molecular weight: 387.12 mass spectrums (M+H): 388.1
1H-NMR(d 6-DMSO,400MHz)：δ13.50(1H,s),8.72(1H,s),8.46(1H,s),7.67-7.44(6H,m),7.00(1H,d),6.84(1H,dd),6.59(1H,s),4.97(2H,d).
The preparation (compound 6) of embodiment 3 2-((9H-purine-6-yl) methoxyl group)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone
(1) preparation of 6-chloro-9-((2-(TMS) oxyethyl group) methyl)-9H-purine
Under the nitrogen protection, and throwing 6-chloro-9H-purine in the four neck round-bottomed flasks of 250mL (20g, 129.40mmol), N, dinethylformamide (200mL) ,-10 ° of C drop into sodium hydride (5.2g, 130.00mmol, content 60%) in batches, stir 30min.-10 ° of C, in the 20min while stirring dropwise to wherein add (2-(chlorine methoxyl group) ethyl) trimethyl silane (20.1g, 120.56mmol), 25 ° of C stirred overnight of gained solution add the cancellation of 1000mL frozen water, with ethyl acetate extraction three times, 500mL at every turn.The organic layer that merges is with brine wash three times, 50mL at every turn, and anhydrous sodium sulfate drying, vacuum concentration, (ETHYLE ACETATE: sherwood oil=1:10) obtains yellow oil (22g, 60%) with silica gel column chromatography.
(2) 9-((2-(TMS) oxyethyl group) methyl)-9H-purine-6-ethyl formate
Figure BDA00001790023900203
Under the nitrogen protection, and throwing 6-chloro-9-((2-(TMS) oxyethyl group) methyl)-9H-purine in 1000mL pressure reaction still (8atm) (22g, 77.24mmol), 200mL ethanol, 200mL CH 3CN, 47.14mL N, N-diisopropylethylamine and Pd (dppf) Cl 2(2.2g 3.01mmol), charges into the CO of capacity, and 100 ° of C stir 7h, are cooled to 25 ° of C, vacuum concentration, silica gel column chromatography (ETHYLE ACETATE: sherwood oil=1:10) must yellow solid (4g, 16%).
(3) (9-((2-(TMS) oxyethyl group) methyl)-9H-purine-6-yl) methyl alcohol
Figure BDA00001790023900211
Under the nitrogen protection, (5g is 15.51mmol) with 50mL methyl alcohol in 100mL three neck round-bottomed flasks, to add 9-((2-(TMS) oxyethyl group) methyl)-9H-purine-6-ethyl formate.-10 ° of C, add in batches Peng Qinghuana (1.18g, 32.04mmol).Gained solution stirred overnight at room temperature adds the cancellation of 100mL frozen water, with ethyl acetate extraction three times, and 100mL at every turn.The organic layer that merges is with brine wash three times, each 30mL, anhydrous sodium sulfate drying, vacuum concentration, prepare liquid phase purify yellow solid (1.2g, 28%).
(4) the 5-fluoro-2,4-dihydro-1H-3,1-benzoxazine-2, the preparation of 4-diketone
Figure BDA00001790023900212
(18g 116.03mmol) and THF (200mL), dropwise adds TRIPHOSGENE 99.5 (11.5g, THF 38.75mmol) (20mL) solution while stirring in 20min in the four neck round-bottomed flasks of 500mL, to throw 2-amino-6-fluorobenzoic acid under 25 ° of C.Gained solution keeps 25 ° of C, continues to stir 4h, is cooled to-20 ° of C then, filters, and vacuum-drying obtains faint yellow solid 12.5g (59%).
(5) preparation of 2-amino-6-fluoro-N-phenylbenzamaide
In the three neck round-bottomed flasks of 250mL, throw 5-fluoro-2,4-dihydro-1H-3,1-benzoxazine-2, the 4-diketone (12g, 66.25mmol), N, dinethylformamide (120mL), aniline (18.5g, 198.65mmol).100 ° of C stirred overnight of gained solution are cooled to 25 ° of C then, and vacuum concentration, liquid concentrator be with 100mL frozen water dilution, with ethyl acetate extraction three times, and 100mL at every turn.The organic layer that merges is with brine wash three times, 30mL at every turn, and anhydrous sodium sulfate drying, vacuum concentration get yellow oil (18g, bullion).
(6) 5-fluoro-3-phenyl-1,2,3,4-tetrahydro quinazoline-2, the preparation of 4-diketone
Figure BDA00001790023900221
In the four neck round-bottomed flasks of 500mL, drop into 2-amino-6-fluoro-N-phenylbenzamaide (18g under the 0-10 ° of C; 39.09mmol; Content 50%) and THF (200mL); Dropwise add TRIPHOSGENE 99.5 (11.6g, THF 39.09mmol) (100mL) solution, gained solution stirred overnight at room temperature in the 30min while stirring.Filter, the filtrating vacuum concentration, the preparation liquid phase is purified and is obtained yellow solid (5.5g, 55%).
(7) 2-chloro-5-fluoro-3-phenyl-3, the preparation of 4-dihydroquinazoline-4-ketone
Figure BDA00001790023900222
Under the nitrogen protection, in the four neck round-bottomed flasks of 250mL, throw 5-fluoro-3-phenyl-1,2,3,4-tetrahydro quinazoline-2, the 4-diketone (5.3g, 20.68mmol), POCl3 (150mL) and phosphorus pentachloride (4.8g, 23.05mmol).100 ° of C stirred overnight of gained solution, vacuum concentration, liquid concentrator are cooled to 28 ° of C, add the cancellation of 150mL frozen water, with ethyl acetate extraction three times, 100mL at every turn.The organic layer that merges is with brine wash three times, 30mL at every turn, and anhydrous sodium sulfate drying, vacuum concentration, (ETHYLE ACETATE: sherwood oil=1:200-1:50) obtains yellow solid (3.0g, 53%) with silica gel column chromatography.
(8) 5-fluoro-3-phenyl-2-((9-((2-(TMS) oxyethyl group) methyl)-9H-purine-6-yl) methoxyl group)-3, the preparation of 4-dihydroquinazoline-4-ketone
Under the nitrogen protection; (1.7g is 6.06mmol) with the 150mL THF, under 5 ° of C in the three neck round-bottomed flasks of 250mL, to throw (9-((2-(TMS) oxyethyl group) methyl)-9H-purine-6-yl) methyl alcohol; Dropwise add in the 30min positive fourth lithium (2.5mL, 2.4M).Dropwise add 2-chloro-5-fluoro-3-phenyl-3 while stirring, and 4-dihydroquinazoline-4-ketone (1.5g, tetrahydrofuran solution 5.46mmol) (50mL), 25 ° of C stirred overnight, with the cancellation of 50mL frozen water, with ethyl acetate extraction three times, each 50mL.The organic layer that merges is with brine wash three times, and each 30mL uses anhydrous sodium sulfate drying, vacuum concentration, silica gel column chromatography (ETHYLE ACETATE: sherwood oil=1:10) must yellow solid (1.8g, 52%).
(9) 5-fluoro-3-phenyl-2-(9H-purine-6-ylmethoxy)-3, the preparation of 4-dihydroquinazoline-4-ketone
Figure BDA00001790023900231
Under the nitrogen protection; In the three neck round-bottomed flasks of 100mL, throw 5-fluoro-3-phenyl-2-((9-((2-(TMS) oxyethyl group) methyl)-9H-purine-6-yl) methoxyl group)-3; 4-dihydroquinazoline-4-ketone (600mg; 1.16mmol), 50mL THF and 1.51g tetrabutylammonium (TBAF).100 ° of C stirred overnight of gained solution, cooling, vacuum concentration, liquid concentrator dilutes with 100mL ETHYLE ACETATE; Water, brine wash are three times successively, each 30mL, anhydrous sodium sulfate drying; Vacuum concentration, the normal hexane recrystallization, the gained solid is with normal hexane washing three times; Each 30mL gets off-white color solid (210mg, 47%).
Molecular formula: C 20H 13FN 6O 2Molecular weight: 388.35
H-NMR(DMSO,300MHz)δ5.86(s,2H),7.16~7.09(m,2H),7.51~7.44(m,5H),7.72~7.65(m,1H),8.61(s,1H),8.83(s,1H),13.49(s,1H).
LC-MS:389[M+H] +
With reference to above-mentioned preparation method, can also prepare following compound:
Figure BDA00001790023900241

Claims (9)

1. compound, its pharmacy acceptable salt, its steric isomer or its deuterium shown in the logical formula I is for thing:
Figure FDA00001790023800011
Wherein
X 1, X 2, X 3, X 4, Y independently is N respectively, or CR 3, R 3Be hydrogen, amino ,-N (R a) 2,-NH (R a), cyanic acid, halogen, trifluoromethyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 2-6Thiazolinyl, C 2-6Alkynyl, 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, or 7-12 unit bridged ring base;
R 1For
(1) hydrogen,
(2) C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl,
(3)-(P 1) m-L-(P 2) n-A, A represents 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, 7-12 unit bridged ring base, and A can be further by 1 ~ 3 R bReplace, L represent covalent linkage ,-O-,-N (R a)-,-C (O)-,-C (O) O-,-C (O) N (R a)-,-C (S) N (R a)-,-SO 2-,-SO 2N (R a)-,-S (O)-,-S (O) N (R a)-, P 1And P 2Independently be C respectively 1-6Alkyl, m and n independently are respectively 0 or 1;
R aRepresent hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, or 7-12 unit bridged ring base;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, C 1-6Alkyl, or 3-14 unit naphthenic base perhaps as Z are-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form the 3-8 unit saturated mono heterocyclic radical that contains a nitrogen-atoms at least together with the atom that links to each other;
R 2Be hydrogen, or be not substituted or by at least one R bSubstituted C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, 7-12 unit bridged ring base;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, formamyl C 1-6Alkyl, C 1-6Alkyl-carbonyl, C 1-6Alkyl carbonyl oxy, C 1-6Alkoxy carbonyl, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido, C 2-6Thiazolinyl, C 2-6Alkynyl, 3-14 unit naphthenic base, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, or 7-12 unit bridged ring base.
2. compound as claimed in claim 1, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing:
Wherein
X 1, X 2, X 3, X 4, Y independently is N respectively, or CR 3, R 3Be hydrogen, amino ,-N (R a) 2,-NH (R a), cyanic acid, halogen, trifluoromethyl, C 1-6Alkyl, or C 1-6Alkoxyl group;
R 1For
(1)-L-A, A represents fused heterocycle base, the 7-12 unit volution base of single heterocyclic radical, 6-14 unit's aromaticity or the fractional saturation of 6-14 unit aryl, 3-8 unit's aromaticity or fractional saturation, and A can further replace by 1 ~ 3 Rb, L represent covalent linkage ,-O-,-N (R a)-,-C (O)-,-C (O) O-,-C (O) N (R a)-,-SO 2-,-SO 2N (R a)-;
R aRepresent hydrogen, C 1-6Alkyl, 3-8 unit monocyclic cycloalkyl, phenyl, or the single heterocyclic radical of 3-8 unit;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-6Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form the 3-6 unit saturated mono heterocyclic radical that contains a nitrogen-atoms at least together with the atom that links to each other;
R 2For not being substituted or by at least one R bThe fused heterocycle base of substituted 8-11 unit's aromaticity or fractional saturation;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, or formamyl C 1-6Alkyl.
3. compound as claimed in claim 2, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing:
Wherein
X 1, X 2, X 3, X 4Independently be CR respectively 3, Y is N, R 3Be hydrogen, amino, halogen, trifluoromethyl, C 1-6Alkyl, or C 1-6Alkoxyl group;
R 1For
(1)-and L-A, A represents single heterocyclic radical of phenyl, naphthyl, 3-8 unit's aromaticity or fractional saturation, and A can be further by 1 ~ 3 R bReplace, L represent covalent linkage ,-O-,-N (R a)-;
R aRepresent hydrogen, or C 1-6Alkyl;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-6Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form the 3-6 unit saturated mono heterocyclic radical that contains a nitrogen-atoms at least together with the atom that links to each other;
R 2For not being substituted or by at least one R bThe fused heterocycle base of substituted 9-10 unit's aromaticity or fractional saturation, wherein the fused heterocycle base comprises at least 2 nitrogen-atoms;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, or C 1-6Alkoxyl group.
4. compound as claimed in claim 3, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing:
Wherein
X 1, X 2, X 3, X 4Independently be CR respectively 3, Y is N, R 3Be hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, or C 1-6Alkoxyl group;
R 1For
(1)-and L-A, A represents phenyl, pyridyl, pyrimidyl, and A can be further by 1 ~ 3 R bReplace, L represents covalent linkage;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-4Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form together with the atom that links to each other
Figure FDA00001790023800031
Figure FDA00001790023800032
R 2For not being substituted or by at least one R bSubstituted
Figure FDA00001790023800033
Figure FDA00001790023800034
R bBe halogen, amino, hydroxyl, amino-sulfonyl, formamyl, C 1-6Alkyl, or C 1-6Alkoxyl group.
5. compound as claimed in claim 4, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing:
Wherein
X 1, X 2, X 3Independently be CH respectively, X 4Be CR 3, Y is N, R 3Be hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, or C 1-6Alkoxyl group;
R 1For
(1)-and L-A, A represents phenyl, and A can be further by 1 ~ 3 R bReplace, L represents covalent linkage;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-4Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form together with the atom that links to each other
Figure FDA00001790023800041
R 2For not being substituted or by at least one R bSubstituted
Figure FDA00001790023800043
R bBe halogen, amino, hydroxyl, C 1-6Alkyl, or C 1-6Alkoxyl group.
6. compound as claimed in claim 5, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing:
Wherein
X 1, X 2, X 3Independently be CH respectively, X 4Be CR 3, Y is N, R 3Be fluorine or chlorine;
R 1For
(1)-and L-A, A represents phenyl, and A can be further by 1 ~ 3 R bReplace, L represents covalent linkage;
Z is-O-, or-N (R 4)-;
W is-C (R 5' R 5)-, or-N (R 5)-;
R 4, R 5, R 5' independently be hydrogen respectively, or C 1-4Alkyl perhaps as Z is-N (R 4)-, W is-C (R 5' R 5)-or-N (R 5)-time, R 4With R 5', or R 4With R 5Can form together with the atom that links to each other
Figure FDA00001790023800044
Figure FDA00001790023800045
R 2For not being substituted or by 1 ~ 3 R bSubstituted
Figure FDA00001790023800046
R bBe fluorine, chlorine, amino, hydroxyl, methyl, or methoxyl group.
7. compound as claimed in claim 6, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing, and said compound is selected from:
Figure FDA00001790023800051
8. comprise each described compound of claim 1～7, its pharmacy acceptable salt, its steric isomer or its deuterium pharmaceutical composition, it is characterized in that said pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation for thing and one or more pharmaceutical carriers.
9. each described compound of claim 1～7, its pharmacy acceptable salt, its steric isomer or its deuterium treat and/or prevent the purposes in the medicine of inflammatory diseases or tumour for thing in preparation.
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CN104341437A (en) * 2013-07-30 2015-02-11 山东亨利医药科技有限责任公司 SYK inhibitor containing bicyclo-radical
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CN108285451A (en) * 2018-04-16 2018-07-17 浙江工业大学 A kind of synthetic method of 6-benzyl aminopurine
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
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WO2014023083A1 (en) * 2012-08-08 2014-02-13 山东亨利医药科技有限责任公司 PI3Kδ INHIBITOR
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CN104768952B (en) * 2012-08-08 2016-10-19 山东亨利医药科技有限责任公司 PI3K δ inhibitor
US9840498B2 (en) 2013-07-24 2017-12-12 Novartis Ag Substituted quinazolin-4-one derivatives
CN104341437A (en) * 2013-07-30 2015-02-11 山东亨利医药科技有限责任公司 SYK inhibitor containing bicyclo-radical
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CN108285451A (en) * 2018-04-16 2018-07-17 浙江工业大学 A kind of synthetic method of 6-benzyl aminopurine
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
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