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CN102838600A - Phenylquinazoline PI3Kdelta inhibitors - Google Patents

Phenylquinazoline PI3Kdelta inhibitors Download PDF

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CN102838600A
CN102838600A CN2011101721954A CN201110172195A CN102838600A CN 102838600 A CN102838600 A CN 102838600A CN 2011101721954 A CN2011101721954 A CN 2011101721954A CN 201110172195 A CN201110172195 A CN 201110172195A CN 102838600 A CN102838600 A CN 102838600A
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吴永谦
松山皓治
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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 present invention belongs to the technical field of medicine, and particularly relates to phenylquinazoline PI3Kdelta inhibitors represented by a general formula (I), pharmaceutically acceptable salts, stereoisomers or deuterated compounds thereof, wherein X1, X2, X3, X4, Y, Z, B, W, R1 and R2 are defined in an instruction. The present invention further relates to preparation methods for the compounds, pharmaceutical preparations containing the compounds, and uses of the compounds in preparations of drugs for treatments and/or preventions of inflammatory diseases or cancers.

Description

Phenylquinazoline class PI3K δ suppressor factor
1, technical field
The invention belongs to medical technical field; Be specifically related to phenylquinazoline class PI3K δ 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.
2, 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, still can continued growth after the tumorigenesis factor stops, and 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 human body sale, anaemia, organ function 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 cause severe side effect, targeted drug as the specificity target spot, can accurately act on tumour with cancer cells; Improved treatment level greatly; And alleviated 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.
3, 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:
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;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl, halo C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, formamyl C 1-6Alkyl, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido, C 1-6Alkyl carbonyl oxy, C 1-6Alkoxy carbonyl, C 1-6Alkyl-carbonyl, 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, W independently are covalent linkage respectively ,-O-,-S-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, C 1-6Alkyl, or 3-14 unit naphthenic base;
Ring B is a 3-8 unit monocyclic cycloalkyl, or the single heterocyclic radical of 3-8 unit;
R 2Be hydrogen, or be not substituted or by at least one R cSubstituted 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 cBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl, halo C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, formamyl C 1-6Alkyl, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido, C 1-6Alkyl carbonyl oxy, C 1-6Alkoxy carbonyl, C 1-6Alkyl-carbonyl, C 1-6Alkyl-carbonyl, 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 6-14 unit aryl, 3-14 unit is unsaturated or the heterocyclic radical of fractional saturation, 7-12 unit volution 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)-,-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;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, fluoro C 1-6Alkyl, fluoro C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, or formamyl C 1-6Alkyl;
Z, W independently be respectively covalent linkage ,-O-,-S-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or C 1-6Alkyl;
Ring B is the saturated monocyclic cycloalkyl of 3-8 unit, or 3-8 unit saturated mono heterocyclic radical;
R 2For not being substituted or by at least one R cThe fused heterocycle base of the unsaturated or fractional saturation of substituted 8-11 unit;
R cBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, fluoro C 1-6Alkyl, fluoro 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 1-4Alkyl, or C 1-4Alkoxyl group;
R 1For
(1)-and L-A, A represents phenyl, naphthyl, 3-8 unit is unsaturated or single heterocyclic radical of 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 1-4Alkyl;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-4Alkyl, C 1-4Alkoxyl group, or fluoro C 1-6Alkyl.
Z, W independently be respectively covalent linkage ,-O-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or C 1-4Alkyl;
Ring B is the saturated monocyclic cycloalkyl of 3-6 unit, or 3-6 unit saturated mono heterocyclic radical;
R 2For not being substituted or by at least one R cThe fused heterocycle base of the unsaturated or fractional saturation of substituted 9-10 unit, and this fused heterocycle base comprises at least 2 nitrogen-atoms;
R cBe amino, hydroxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-4Alkyl, C 1-4Alkoxyl group, or fluoro C 1-6Alkyl.
Be preferably:
Wherein
X 1, X 2, X 3, X 4Independently be CR respectively 3, Y is N, R 3Be hydrogen, halogen, trifluoromethyl, C 1-4Alkyl, or C 1-4Alkoxyl 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;
R bBe halogen, amino, hydroxyl, amino-sulfonyl, formamyl, C 1-4Alkyl, C 1-4Alkoxyl group, or trifluoromethyl.
Z, W independently be respectively covalent linkage ,-O-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, methyl or ethyl;
Ring B is the saturated monocyclic cycloalkyl of 3-6 unit, or the saturated mono heterocyclic radical of a nitrogen-atoms is contained at least in 3-6 unit;
R 2For not being substituted or by at least one R cSubstituted
Figure BSA00000524314800051
Figure BSA00000524314800052
R cBe amino, hydroxyl, amino-sulfonyl, formamyl, C 1-4Alkyl, C 1-4Alkoxyl group, or trifluoromethyl.
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 1-4Alkyl, or C 1-4Alkoxyl group;
R 1For
(1)-and L-A, A represents phenyl, and A can be further by 1～3 R bReplace, L represents covalent linkage;
R bBe halogen, amino, hydroxyl, methyl, methoxyl group, or trifluoromethyl.
Z, W independently be respectively covalent linkage ,-O-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, methyl or ethyl;
Figure BSA00000524314800053
R 2For not being substituted or by at least one R cSubstituted
Figure BSA00000524314800062
R cBe amino, hydroxyl, methyl, or trifluoromethyl.
For the compound shown in the general formula (I), a preferred version of the present invention is:
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 L represents covalent linkage;
Z, W independently be respectively covalent linkage or-O-, and when Z and W are covalent linkage simultaneously, Z and W and the link position that encircles B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or methyl;
Ring B is
Figure BSA00000524314800063
R 2For
Figure BSA00000524314800065
For the compound shown in the general formula (I), another preferred version of the present invention is:
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 L represents covalent linkage;
Z, W independently be respectively covalent linkage or-C (R 4' R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or methyl;
Ring B is
Figure BSA00000524314800071
R 2For
Figure BSA00000524314800072
For the compound shown in the general formula (I), another preferred version of the present invention is:
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 L represents covalent linkage;
Z, W independently be respectively covalent linkage or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or methyl;
Ring B is
Figure BSA00000524314800073
Figure BSA00000524314800074
R 2For
Figure BSA00000524314800075
" 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-divinyl, 1; 3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, cyclopentenyl, 1; 3-cyclopentadienyl moiety, cyclohexenyl, 1 base etc.
" C of the present invention 2-6Alkynyl " be meant and contain the alkynyl that the triple-linked carbonatoms is the straight or branched of 3-6; 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 etc.
" 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 comprises 3-8 saturated monocyclic cycloalkyl of unit and 3-8 unit fractional saturation monocyclic cycloalkyl.The saturated monocyclic cycloalkyl of 3-8 unit; Be meant that this monocycle is whole saturated carbocyclic rings, 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.3-8 unit fractional saturation monocyclic cycloalkyl; Be meant that this monocycle is the carbocyclic ring of fractional saturation; The example includes but are not limited to cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, 1; 4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadiene base, cyclooctene base, 1,5-cyclooctadiene base etc." the saturated monocyclic cycloalkyl of 3-6 unit " of the present invention is meant the cyclic group that contains 3-6 ring courtyard in the saturated monocyclic cycloalkyl of 3-8 unit.
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, comprises 6-14 saturated condensed ring naphthenic base of unit and 6-14 unit fractional saturation condensed ring naphthenic base.The saturated condensed ring naphthenic base of 6-14 unit; Be meant that this condensed ring is whole saturated carbocyclic rings, 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 encircle [4.2.0] octyls, octahydro pentalene base, octahydro-1H-indenyl, naphthane base, ten tetrahydrochysene phenanthryl etc.6-14 unit fractional saturation condensed ring naphthenic base is meant that at least one ring is the carbocyclic ring of fractional saturation in this and the ring, and the example includes but not limited to: dicyclo [3.1.0] is own-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 whole undersaturated aryl, 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 ring texturees formed, and having a ring at least is the cyclic group of whole undersaturated aromatic nucleus, comprises the whole unsaturated fused ring aryl of 8-14 unit; For example naphthalene, phenanthrene etc. also comprise 8-14 unit fractional saturation fused ring aryl, for example the saturated monocyclic cycloalkyl of benzo 3-8 unit, benzo 3-8 unit fractional saturation monocyclic cycloalkyl; Specific examples is as 2; 3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3; 4-tetralyl, 1,4-dihydro naphthyl 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 heteroatomic structure, and described heteroatoms has nitrogen, oxygen and sulphur etc." 7-12 unit bridged ring " comprises the saturated bridged ring of 7-12 unit, 7-12 unit fractional saturation bridged ring.
The saturated bridged ring of 7-12 unit; Be meant that all rings in this bridged ring are saturated cyclic group; Be preferably the saturated bridged ring of 7-8 unit, specific examples includes but not limited to:
Figure BSA00000524314800101
Figure BSA00000524314800102
7-12 unit fractional saturation bridged ring; Being meant has in this bridged ring that to have a ring at least be undersaturated cyclic group; Be preferably 7-8 unit fractional saturation bridged ring, specific examples includes but not limited to:
Figure BSA00000524314800103
Figure BSA00000524314800104
" 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 heteroatomic structure, described heteroatoms has nitrogen, oxygen and sulphur etc.7-12 unit volution comprises the saturated volution of 7-12 unit, 7-12 unit fractional saturation volution.
The saturated volution of 7-12 unit; Be meant that all rings in this volution are saturated cyclic group, specific examples includes but are not limited to:
Figure BSA00000524314800105
Figure BSA00000524314800106
7-12 unit fractional saturation volution; Be meant that having a ring in this volution at least is undersaturated cyclic group, specific examples includes but are not limited to:
Figure BSA00000524314800107
Figure BSA00000524314800111
" 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 unsaturated single heterocyclic radical of 3-8 unit, the single heterocyclic radical of 3-8 unit fractional saturation, 3-8 unit saturated mono heterocyclic radical.The unsaturated single heterocyclic radical of 3-8 unit is meant heteroatomic cyclic group of containing of aromaticity, and 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, 6 H-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.
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 the unsaturated fused heterocycle base of 6-14 unit, 6-14 unit fractional saturation fused heterocycle base, the saturated fused heterocycle base of 6-10 unit.
The unsaturated fused heterocycle base of 6-14 unit; Be meant that whole rings is undersaturated condensed ring structure; Structure like the unsaturated single heterocyclic radical formation of benzo 3-8 unit; The structures that the unsaturated single heterocyclic radical of 3-8 unsaturated single heterocyclic radical of unit and 3-8 unit forms 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] pyrroles 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." the fused heterocycle base of the unsaturated or fractional saturation of 8-11 unit " according to the invention is meant in the fused heterocycle base of the unsaturated or fractional saturation of 6-14 unit, contains 8-11 cyclic group that encircles the courtyard." the fused heterocycle base of the unsaturated or fractional saturation of 9-10 unit " of the present invention is meant in the fused heterocycle base of the unsaturated or fractional saturation of 6-14 unit, contains 9-10 cyclic group that encircles the courtyard.
Part of compounds of the present invention:
Figure BSA00000524314800121
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method:
Figure BSA00000524314800122
With formula (I '), raw material 3 and suitable reagent react, obtain formula of the present invention (I) compound.X in the last reaction equation 1, X 2, X 3, X 4, Y, Z, B, 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; In case of necessity, also can prepare, for example the preparation of formula (I ') some compound.For example when Y is nitrogen, can use following method preparation:
Figure BSA00000524314800131
When Y is CR 3The time, can or carry out suitable adjustment with reference to method for preparing.
The present invention requires " pharmacy acceptable salt " of protection (I) compound, comprises an alkali metal salt, like sodium salt, sylvite, lithium salts etc.; Alkaline earth salt is like calcium salt, magnesium salts etc.; Other metal-salts are like aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts is like ammonium salt; Organic alkali salt; Like uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-NMG salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) amido methane salt; Halogen acid salt is like hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt is like nitrate salt, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulphonate is like mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate is like benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt is like acetate, malate, fumarate, SUMATRIPTAN SUCCINATE, Citrate trianion, tartrate, oxalate, PHENRAMINE MALEATE etc.; Amino acid salts is like glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.
The present invention requires " steric isomer " of protection (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 " deuterium is for the thing " of protection (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 of the present invention (I) compound, 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.
4, embodiment
Below, foregoing of the present invention is done further to specify through the embodiment of embodiment form.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 of embodiment 1 2-(1-(9H-purine-6-yl) azelidinyl-3-base is amino)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone (compound 1)
Figure BSA00000524314800141
(1) preparation of 2-fluoro-6-nitro-N-phenylbenzamaide
With 2-fluoro-6-nitrobenzoic acid (5.5g 30mmol) joins in the 40mL methylene dichloride, drips DMF 1mL, in 30min, drip under the ice bath oxalyl chloride (6.7g, 50mmol); Stirring at room 2h, reaction solution revolves dried, adds the methylene dichloride dissolving, slowly drops to aniline (3.1g under the ice bath; 30mmol) and triethylamine (5.05g under dichloromethane solution 50mmol), 10 ℃ of controlled temperature, stirs 2h; Add entry 300mL, separate out deposition, filtration drying gets product 7.02g, yield: 90%.
(2) preparation of 2-amino-6-fluoro-N-phenylbenzamaide
Figure BSA00000524314800151
With 2-fluoro-6-nitro-N-phenylbenzamaide (26g, 1000mmol), zinc powder (195g, 300mmol), ammonium chloride (160g; 300mmol) add in 100mL THF-water (4: 1) solution, stirring at room 36h filters; Organic layer revolves dried product 18g, yield: 78.3% (thick product).
(3) 5-fluoro-3-phenylquinazoline-2,4 (1H, 3H)-preparation of diketone
With TRIPHOSGENE 99.5 (8.94g, 30mmol), add in the 100mL dichloromethane solution, ice bath adds triethylamine (10.1g down; 100mmol) (20.1g 90mmol), stirs 6h with 2-amino-6-fluoro-N-phenylbenzamaide; Reaction finishes; With saturated common salt washing, the organic layer drying is revolved and was done post and get product 11.2g, yield: 48.7%.
(4) preparation of 2-chlorine 5-fluoro-3-phenylquinazoline-4 (3H)-ketone
With 5-fluoro-3-phenylquinazoline-2,4 (1H, 3H)-diketone (11.2g, 44mmol), the 50mL POCl3 adds to 100mLN, in the accelerine, backflow 72h revolves driedly, crosses column purification, product 4.5g, yield 37.3%.
(5) preparation of 3-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazoline-2-base is amino) azetidine-1-tertiary butyl carboxylic esters
Figure BSA00000524314800154
Adding 2-chlorine 5-fluoro-3-phenylquinazoline-4 (3H)-ketone in the 50mL methylene dichloride (1.4g, 5.1mmol), the amino azetidine of 3--1-tertiary butyl carboxylic esters (0.86g; 5mmol), and triethylamine (1.01g, 10mmol); Backflow 15h; Reaction solution is washed with saturated common salt, and drying is revolved and done post and get product 1.02g, yield: 50.7%.
(6) 2-(azetidine-3-base is amino)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone preparation
Figure BSA00000524314800161
In the 50mL methylene dichloride, add 3-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazoline-2-base is amino) azetidine-1-tertiary butyl carboxylic esters (1.02g, 2.5mmol); Ice bath adds trifluoroacetic acid 3mL down; Stir 3h, reaction solution revolves dried product 1.01g, yield 97%.
(7) 2-(1-(9H-purine-6-yl) azelidinyl-3-base is amino)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone preparation
Figure BSA00000524314800162
In the 50mL trimethyl carbinol, add 2-(azetidine-3-base amino)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone (0.19g, 0.6mmol), 6-bromine purine (0.16g; 0.8mmol), triethylamine (0.1g, 1mmol); Backflow 12h, reaction finishes, evaporate to dryness; Cross column purification, get product 0.084g, yield 32.8%.
LC-MS：429.0(M+H) + 215.0(1+M/2) +
1H?NMR(400MHz，DMSO-d 6)：δ13.0(s，1H)，8.06-8.15(m，2H)，7.48-7.61(m，4H)，7.36-7.38(m，2H)，7.07-7.09(m，1H)，6.84-6.89(m，1H)，6.52-6.54(m，1H)，4.92-4.97(m，1H)，4.29-4.54(m，4H).
The preparation of embodiment 2 2-(3-(9H-purine-6-base is amino) azetidine-1-yl)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone (compound 2)
Step 1-4 is with embodiment 1.
(5) preparation of 1-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazoline-2-yl) azetidine-3-base tertiary butyl carboxylic esters
Figure BSA00000524314800163
Adding 2-chlorine 5-fluoro-3-phenylquinazoline-4 (3H)-ketone in the 50mL methylene dichloride (1.4g, 5.1mmol), the amino azetidine of 3--1-tertiary butyl carboxylic esters (0.86g; 5mmol), and triethylamine (1.0g, 10mmol); Backflow 15h; Reaction solution is washed with saturated common salt, and drying is revolved dried product 0.90g, yield: 45%.
(6) 2-(the amino azetidine of 3--1-yl)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone preparation
Figure BSA00000524314800171
In the 50mL methylene dichloride, add 1-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazoline-2-yl) azetidine-3-base tertiary butyl carboxylic esters (0.9g, 2.2mmol); Ice bath adds trifluoroacetic acid 3mL down; Stir 3h, reaction solution revolves dried product 0.85g, yield 94.4%.
(7) 2-(3-(9H-purine-6-base is amino) azetidine-1-yl)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone preparation
Figure BSA00000524314800172
In the 50mL trimethyl carbinol, add 2-(3-amino azetidine-1-yl)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone (0.40g, 1mmol), 6-bromine purine (0.4g, 2mmol); Triethylamine (1g, 10mmol), backflow 36h, reaction finishes; Evaporate to dryness is crossed column purification, gets product 0.066g, yield 30%.
LC-MS：428.9(M+H) + 215.1(1+M/2) +
1H?NMR(400MHz，DMSO-d 6)：δ13.0(s，1H)，8.09-8.11(m，3H)，7.60-7.62(m，1H)，7.51-7.55(m，3H)，7.48-7.49(m，2H)，7.40-7.42(m，1H)，7.15-7.17(m，1H)，3.70-3.79(m，4H)，3.48-3.50(m，1H).
Preparation (the compound of embodiment 3 2-(3-(9H-purine-6-base is amino) cyclobutyl)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone 3)
Step 1 is with embodiment 1 step 1.
The step 2 3-(preparation of (2-fluoro-6-oil of mirbane formyl (phenyl) formyl radical) cyclobutyl uncle's fourth oxycarboxylic acid fat
Figure BSA00000524314800182
With 2-fluoro-6-nitro-N-phenylbenzamaide (13g, 50mmol), (29.8g 250mmol) mixes, and 85 ℃ are stirred 5h for DMF (1mL) and thionyl chloride; Mixture revolves dried, with methylene dichloride 100mL dissolving, add 3-(t-butoxycarbonyl amino) cyclobutyl carboxylic acid (11.8g, 55mmol), triethylamine (7.7mL; 55mmol), controlled temperature is no more than 10 ℃, stirring at room 3h; The difference water, saturated aqueous common salt, the washing of protection sodium hydrogencarbonate; Organic layer is used anhydrous sodium sulfate drying, crosses column purification and gets product 10.5g, yield: 46%.
The preparation of step 3 3-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazoline-2-yl) cyclobutyl tertiary butyl carboxylic esters
Figure BSA00000524314800183
With 3-((2-fluoro-6-oil of mirbane formyl (phenyl) formyl radical) cyclobutyl uncle's fourth oxycarboxylic acid fat (and 4.57g 10mmol) is dissolved in during 150mL acetate is dissolved in, add zinc powder (3.9g, 60mmol); Controlled temperature is under 35 ℃, and stirring at room 2h removes by filter the zinc powder residue, and filtrating is revolved dried; Be dissolved in ETHYLE ACETATE, with washing, organic layer is dry; Cross column purification, get product 1.72g, yield 42%.
The preparation of step 4 2-(the amino cyclobutyl of 3-)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone
Figure BSA00000524314800191
In the 50mL methylene dichloride, add 3-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazoline-2-yl) cyclobutyl tertiary butyl carboxylic esters (0.409g, 1mmol), ice bath adds down trifluoroacetic acid 3mL, stirs 3h, reaction solution revolves dried product 0.0.278g, yield 90%.
Step 5 2-(3-(9H-purine-6-base is amino) cyclobutyl)-5-fluoro-3-phenylquinazoline-4 (3H)-ketone preparation
Figure BSA00000524314800192
In the 50mL trimethyl carbinol, add (0.155g, 0.5mmol), 6-bromine purine (0.119g, 0.6mmol), triethylamine (0.1g, 1mmol), backflow 36h, reaction finishes, and evaporate to dryness is crossed column purification, gets product 0.154g, yield 72%.
With reference to above-mentioned preparation method, can also prepare following compound:
Figure BSA00000524314800193
Figure BSA00000524314800201

Claims (11)

1. the compound shown in the general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterium are for thing:
Figure FSA00000524314700011
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;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl, halo C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, formamyl C 1-6Alkyl, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido, C 1-6Alkyl carbonyl oxy, C 1-6Alkoxy carbonyl, C 1-6Alkyl-carbonyl, 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, W independently are covalent linkage respectively ,-O-,-S-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, C 1-6Alkyl, or 3-14 unit naphthenic base;
Ring B is a 3-8 unit monocyclic cycloalkyl, or the single heterocyclic radical of 3-8 unit;
R 2Be hydrogen, or be not substituted or by at least one R cSubstituted 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 cBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, halo C 1-6Alkyl, halo C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, formamyl C 1-6Alkyl, C 1-6Alkyl amine group, two (C 1-6Alkyl) amido, C 1-6Alkyl carbonyl oxy, C 1-6Alkoxy carbonyl, C 1-6Alkyl-carbonyl, C 1-6Alkyl-carbonyl, 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)-and L-A, A represents 6-14 unit aryl, 3-14 unit is unsaturated or the heterocyclic radical of fractional saturation, 7-12 unit volution 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)-,-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;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, fluoro C 1-6Alkyl, fluoro C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, amino C 1-6Alkoxyl group, carboxyl C 1-6Alkyl, or formamyl C 1-6Alkyl;
Z, W independently be respectively covalent linkage ,-O-,-S-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or C 1-6Alkyl;
Ring B is the saturated monocyclic cycloalkyl of 3-8 unit, or 3-8 unit saturated mono heterocyclic radical;
R 2For not being substituted or by at least one R cThe fused heterocycle base of the unsaturated or fractional saturation of substituted 8-11 unit;
R cBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-6Alkyl, C 1-6Alkoxyl group, fluoro C 1-6Alkyl, fluoro 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 1-4Alkyl, or C 1-4Alkoxyl group;
R 1For
(1)-and L-A, A represents phenyl, naphthyl, 3-8 unit is unsaturated or single heterocyclic radical of 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 1-4Alkyl;
R bBe halogen, amino, hydroxyl, carboxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-4Alkyl, C 1-4Alkoxyl group, or fluoro C 1-6Alkyl.
Z, W independently be respectively covalent linkage ,-O-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or C 1-4Alkyl;
Ring B is the saturated monocyclic cycloalkyl of 3-6 unit, or 3-6 unit saturated mono heterocyclic radical;
R 2For not being substituted or by at least one R cThe fused heterocycle base of the unsaturated or fractional saturation of substituted 9-10 unit, and this fused heterocycle base comprises at least 2 nitrogen-atoms;
R cBe amino, hydroxyl, cyanic acid, amino-sulfonyl, formamyl, C 1-4Alkyl, C 1-4Alkoxyl group, or fluoro C 1-6Alkyl.
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 1-4Alkyl, or C 1-4Alkoxyl 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;
R bBe halogen, amino, hydroxyl, amino-sulfonyl, formamyl, C 1-4Alkyl, C 1-4Alkoxyl group, or trifluoromethyl.
Z, W independently be respectively covalent linkage ,-O-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, methyl or ethyl;
Ring B is the saturated monocyclic cycloalkyl of 3-6 unit, or the saturated mono heterocyclic radical of a nitrogen-atoms is contained at least in 3-6 unit;
R 2For not being substituted or by at least one R cSubstituted
Figure FSA00000524314700031
Figure FSA00000524314700032
R cBe amino, hydroxyl, amino-sulfonyl, formamyl, C 1-4Alkyl, C 1-4Alkoxyl group, or trifluoromethyl.
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 1-4Alkyl, or C 1-4Alkoxyl group;
R 1For
(1)-and L-A, A represents phenyl, and A can be further by 1～3 R bReplace, L represents covalent linkage;
R bBe halogen, amino, hydroxyl, methyl, methoxyl group, or trifluoromethyl.
Z, W independently be respectively covalent linkage ,-O-,-C (R 4' R 4)-or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, methyl or ethyl;
Ring B is
Figure FSA00000524314700041
Figure FSA00000524314700042
R 2For not being substituted or by at least one R cSubstituted
Figure FSA00000524314700043
R cBe amino, hydroxyl, methyl, or trifluoromethyl.
6. compound as claimed in claim 5, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing:
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 L represents covalent linkage;
Z, W independently be respectively covalent linkage or-O-, and when Z and W are covalent linkage simultaneously, Z and W and the link position that encircles B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or methyl;
Ring B is
Figure FSA00000524314700044
Figure FSA00000524314700045
R 2For
Figure FSA00000524314700046
7. compound as claimed in claim 5, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing:
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 L represents covalent linkage;
Z, W independently be respectively covalent linkage or-C (R 4' R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or methyl;
Ring B is
Figure FSA00000524314700051
Figure FSA00000524314700052
R 2For
Figure FSA00000524314700053
8. 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 L represents covalent linkage;
Z, W independently be respectively covalent linkage or-N (R 4)-, and when Z and W were covalent linkage simultaneously, the link position of Z and W and ring B can not be the ortho position;
R 4, R 4' independently be hydrogen respectively, or methyl;
Ring B is
Figure FSA00000524314700054
Figure FSA00000524314700055
R 2For
Figure FSA00000524314700056
9. compound as claimed in claim 8, its pharmacy acceptable salt, its steric isomer or its deuterium are for thing, and said compound is selected from:
Figure FSA00000524314700061
10. comprise each described compound of claim 1～9, 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.
11. each described compound of claim 1～9, its pharmacy acceptable salt, its steric isomer or its deuterium treat and/or prevent the application in inflammatory diseases or the tumour medicine for thing in preparation.
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