CN105315283A - Bruton tyrosine kinases inhibitor - Google Patents
Bruton tyrosine kinases inhibitor Download PDFInfo
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- CN105315283A CN105315283A CN201410350340.7A CN201410350340A CN105315283A CN 105315283 A CN105315283 A CN 105315283A CN 201410350340 A CN201410350340 A CN 201410350340A CN 105315283 A CN105315283 A CN 105315283A
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- alkyl
- cycloalkyl
- heterocyclylalkyl
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- compound
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- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title claims abstract description 6
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title claims abstract 4
- 239000003112 inhibitor Substances 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 96
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 50
- -1 nitro, carboxyl Chemical group 0.000 claims description 45
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 16
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000001118 alkylidene group Chemical group 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 4
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 2
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 230000009885 systemic effect Effects 0.000 claims description 2
- 125000003968 arylidene group Chemical group [H]C(c)=* 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 22
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- 238000002560 therapeutic procedure Methods 0.000 abstract 1
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- 238000010189 synthetic method Methods 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000003973 alkyl amines Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229960001507 ibrutinib Drugs 0.000 description 4
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 4
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- SNANINYFIFMJBX-UHFFFAOYSA-N 3-bromo-2,4-dimethylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(C)=C1Br SNANINYFIFMJBX-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
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- 239000003513 alkali Substances 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
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- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 3
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to pyrazolo[3,4-d]pyrimidine derivatives, and a preparation method and application thereof to medicines. Concretely, the invention relates to new pyrazolo[3,4-d]pyrimidine derivatives shown as general formulas I and IA, a preparation method of the derivatives, a pharmaceutical composition containing the derivatives, and application of the derivatives as therapy equipment especially as a Bruton tyrosine kinases inhibitor.
Description
Technical field
The present invention designs pyrazole also [3,4-d] pyrimidines or its pharmacologically acceptable salt, and its preparation method and this compounds are separately or and the application of other drug conbined usage in treatment cell proliferate diseases and autoimmune disease.
Background technology
Bruton Tyrosylprotein kinase (Btk) is a kind of plasmosin, belongs to non-receptor tyrosine Tec family, is expressed in most hematopoietic cell as B cell, mastocyte, megalokaryocyte etc.Btk comprises 5 structural domains: PH structural domain (Pleckstrinhomologydomain), TH structural domain (Techomologydomain), SH3 structural domain (Srchomology3domain), SH2 structural domain (Srchomology2domain) and catalyst structure domain (Tyrosinekinasedomain) (DinittoJP etc., BiochimBiophysActa, 2006,1761 (8): 850-867; D.Kristufek etc., MolImmunol, 2007,44 (7), 1639-1643; K.Murayama, BiochemBiophysResCommun, 2008,377 (1): 23-28; Y.Qiu, Oncogene, 2000,19 (49): 5651-5661).These structural domains can identify and in conjunction with multi-signal molecule, lay the foundation for Btk participates in many A signal pathways (comprising the many A signal pathways such as the signal path of B cell mediation, the signal path of Toll-like receptor mediation, mast cell degranulation and Fas, g protein coupled receptor, cytokine).Important regulating and controlling effect is played to the propagation of cell, differentiation and apoptosis.
Btk is great expression (M.C.Verschuren etc. in the B cell malignant tumor patients such as leukemia precursor B-cell acute lymphoblastic (ALL), chronic leukemia (CLL), non-Hodgkin′s leukemia (NHL), EurJImmunol, 1993,23:3109 – 3114; N.Mart í nez etc., ClinCancerRes, 2004,10:6796 – 6806; S.Ortolano etc., EurJImmunol, 2006,36:1285 – 1295; F.Uckun etc., Arzneimittelforschung, 2011,61:252 – 259), recent research shows that btk also has expression (C.Eifert, AnRNAiScreenTargetingtheProteinTyrosineKinasesIdentifies Bruton ' sTyrosineKinase (BTK) asaBreastCancerCellSurvivalFactor [dissertation] .Albany:StateUniversityofNewYork in solid tumor cell; 2009; D.S.Conklin etc., US20120165395; M.Lavitrano, US8232085); Btk also participates in anaphylactoid process, major function (A.M.Gilfillan etc. are exercised in the anaphylaxis of the IgE mediation of mastocyte participation, ImmunolRev, 2009,, and in inflammatory reaction, play the part of important role (M.Liljeroos etc., CellSignal 228 (1): 149-169), 2007,19 (3): 625-633).Become an important target of tumour and autoimmune disorder.
In the btk inhibitor of exploitation, ibrutinib goes on the market, is used for the treatment of lymphoma mantle cell and lymphocytic leukemia; AVL292 is in clinical I stage phase.
Summary of the invention
The invention provides a series of compound represented by general formula (I), general formula (IA) and pharmacy acceptable salt thereof, solvate, prodrug, comprise the pharmaceutical composition of these compounds, and by the method for this compounds for treating disease relevant to Btk overactivity and illness.
One aspect of the present invention provides the compound of a kind of structural formula I:
Or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein
X is for being substituted or unsubstituted-(CH
2)
m-,-O-(CH
2)
n-,-CO-,-S-(CH
2)
n-,-SO-,-SO
2-,-NH-(CH
2)
n-,-NH-CO-, wherein m is 0,1,2,3; N is 0,1,2;
R
1be selected from H, or be substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl;
R
2be selected from H, halogen, alkyl, hydroxyl, cyano group, amino, nitro, carboxyl, ester group, alkylamino, hydroxyalkyl, trifluoromethyl, alkoxyl group;
A is selected from alkylidene group, cycloalkylidene, sub-Heterocyclylalkyl, sub-assorted alkyl, arylidene, inferior heteroaryl, alkylenearylene, alkylidene group inferior heteroaryl, alkylidene group cycloalkylidene and alkyleneheterocycloalkylene;
B is selected from C (=O), S (=O), S (=O)
2, NR
6c (=O), NR
6s (=O), NR
6s (=O)
2, wherein R
6for H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl;
R
3for H, or be substituted or unsubstituted C
1-6alkyl, C
1-6assorted alkyl, C
1-6alkoxyalkyl, C
1-8alkylaminoalkyl group, C
1-8hydroxyalkylaminoalkyl, C
1-8alkoxyalkylamino alkyl, C
3-8cycloalkyl, C
1-8alkyl-C
3-8cycloalkyl, aryl, 3-8 unit Heterocyclylalkyl, heteroaryl, C
1-4alkyl-aryl-group, C
1-4alkyl-heteroaryl, C
1-8alkyl oxide, C
1-8alkylamide or C
1-6alkyl-(3-8 unit Heterocyclylalkyl);
R
4and R
5separately be selected from H, or be substituted or unsubstituted C
1-6alkyl, C
1-6assorted alkyl, C
1-6alkylaminoalkyl group, C
3-8cycloalkyl, C
1-4alkyl-C
3-6cycloalkyl, 3-8 unit Heterocyclylalkyl, C
1-4alkyl-aryl-group, C
1-4alkyl-heteroaryl, C
1-6alkyl oxide, C
1-4alkyl-(3-6 unit Heterocyclylalkyl); Or
R
4and R
5form key together;
R
7and R
8separately be selected from hydrogen, C
1-8alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and Heterocyclylalkyl can be selected from C
1-4the substituting group of alkyl, hydroxyl, halogen, oxo replaces;
R
9for hydrogen, amino, hydroxyl, C
1-6alkyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, aryl, heteroaryl, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl can be optionally substituted.
In one embodiment of the present invention, X is substituted or unsubstituted-(CH
2)
m-, wherein any methylene radical can be selected from C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, hydroxyl, amino, halogen ,-CF
3,-CN ,-O-C
1-4alkyl replaces; M is 1 or 2.
In another embodiment of the invention, R
1be selected from H, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl optionally further by one or more be selected from the substituting group of alkyl, cycloalkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, aryloxy, heteroaryloxy, halogen, hydroxyl, cyano group, amino, nitro, carboxyl, ester group, alkylsulfonyl, sulfinyl, hydroxyalkyl, Heterocyclylalkyl, heterocyclylalkoxy groups, trifluoromethyl, trifluoromethoxy, carboxyl or carboxylicesters replace.
In the third embodiment of the compounds of this invention, R
2be selected from H, halogen, hydroxyl, C
1-6alkyl, C
1-4alkoxyl group.
In the 4th kind of embodiment of the compounds of this invention,
A is selected from C
1-8alkylidene group, C
3-8cycloalkylidene, 3-8 unit sub-Heterocyclylalkyl, C
2-9sub-assorted alkyl;
B is selected from C (=O), S (=O), S (=O)
2, NR
6c (=O), NR
6s (=O), NR
6s (=O)
2, wherein R
6for H; And
R
3for H, or be substituted or unsubstituted C
1-6alkyl, C
1-6assorted alkyl, C
1-6alkoxyalkyl, C
1-8alkylaminoalkyl group, C
1-8hydroxyalkylaminoalkyl, C
3-8cycloalkyl, C
1-8alkyl-C
3-8cycloalkyl, aryl, 3-8 unit Heterocyclylalkyl, heteroaryl, C
1-4alkyl-aryl-group, C
1-4alkyl-heteroaryl, C
1-8alkyl oxide, C
1-8alkylamide or C
1-6alkyl-(3-8 unit Heterocyclylalkyl);
R
4and R
5separately be selected from H, or be substituted or unsubstituted C
1-6alkyl, C
1-6assorted alkyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl; Or
R
4and R
5form key together;
In the 5th kind of embodiment of the compounds of this invention, A is the sub-Heterocyclylalkyl of 3-8 unit.
In the 6th kind of embodiment of the compounds of this invention, R
4and R
5for H; And
R
3for H, substituted or unsubstituted C
1-6alkyl, substituted or unsubstituted C
1-6assorted alkyl, substituted or unsubstituted C
3-8cycloalkyl, substituted or unsubstituted 3-8 unit Heterocyclylalkyl.
In the 6th kind of embodiment of the compounds of this invention, described formula (IA) represents:
Or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein, X is substituted or unsubstituted-(CH
2)
m-, wherein any methylene radical can be selected from C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, hydroxyl, amino, halogen ,-CF
3,-CN ,-O-C
1-4alkyl replaces; M is 1 or 2;
R
1be selected from H, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl optionally further by one or more be selected from the substituting group of alkyl, cycloalkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, aryloxy, heteroaryloxy, halogen, hydroxyl, cyano group, amino, nitro, carboxyl, ester group, alkylsulfonyl, sulfinyl, hydroxyalkyl, Heterocyclylalkyl, heterocyclylalkoxy groups, trifluoromethyl, trifluoromethoxy, carboxyl or carboxylicesters replace.
R
7and R
8separately be selected from hydrogen, C
1-8alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and Heterocyclylalkyl can be selected from C
1-4the substituting group of alkyl, hydroxyl, halogen, oxo replaces.
In the embodiment that another kind is such, R
7and R
8be H.
A kind of compound, it is selected from:
or
The invention provides compound described herein or its pharmacy acceptable salt is preparing the purposes in medicine, described medicine is for preventing and/or treating the disease improved because Bruton tyrosine kinase activity suppresses.
The disease improved because Bruton tyrosine kinase activity suppresses of the present invention is selected from B-cell lymphoma, acute lymphoblastic leukemia, mastadenoma, rheumatoid arthritis, systemic lupus erythematous.
The present invention relates to all optical isomers of formula (I) and formula (IA) compound and all steric isomers, comprise the racemic mixture of this compounds and other enantiomorph and diastereomer, and composition thereof, and contain or adopt their composition respectively.
The present invention includes isotope-labeled compound, they be equal to described by formula (I) those, but one or more atom be different from by atomic mass or total mass number the atom of the common atomic mass of nature or total mass number replace.The isotopic example can introduced in the compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, the isotropic substance of fluorine and chlorine, respectively such as
2h,
3h,
13c,
11c,
14c,
15n,
18o,
17o,
31p,
32p,
35s,
18f and
36cl.The pharmacy acceptable salt of other the isotopic the compounds of this invention containing above-mentioned isotropic substance and/or other atom, its prodrug and described compound or described prodrug all belongs to scope of the present invention.Some isotope-labeled the compounds of this invention, such as introduce radio isotope (as
3h and
14c) those can be used for medicine and/or substrate tissue measure of spread.Tritium, namely
3h and carbon-14, namely
14c isotropic substance is particularly preferred, because their easy preparation and determination methods.And then, replaced by heavier isotropic substance, such as deuterium, namely
2h, due to the higher benefit that can provide in treatment of metabolic stability, such as extending Half-life in vivo or reduce volume requirements, may be thus preferred in some cases.Isotope-labeled formula (I) compound and prerequisite medicine thereof generally can be prepared like this, when carrying out the technique disclosed in following flow process and/or embodiment and preparation example, replace nonisotopically labelled reagent with the facile isotope-labeled reagent of appearance.
Formula (I) compound can generate pharmaceutically acceptable preparation further, and salt, the solvate of contained (I) compound, salt includes but not limited to acid salt and/or alkali salt.
The present invention also provides pharmaceutical preparation, comprises treatment formula (I) compound of significant quantity or its therapeutically acceptable salt and its pharmaceutically acceptable carrier, thinner or vehicle.All these forms all belongs to the present invention.
Definition
The diradical when suffix " Asia " being additional to group shows such group.Only for example, methylene radical is the diradical of methyl group, and namely, it is-CH
2-group; Ethylidene is the diradical of ethyl group, i.e.-CH
2-CH
2-.
C used herein
1-xcomprise C
1-C
2, C
1-C
3c
1-C
x.
Term " alkyl " refers to not containing heteroatomic alkyl.Therefore, this term comprises straight chained alkyl as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl etc.This term also comprises the branched chain isomer of branched-chain alkyl, includes but not limited to the group such as :-CH (CH
3)
2,-CH (CH
3) (CH
2cH
3) ,-CH (CH
2cH
3)
2,-C (CH
3)
3,-C (CH
2cH
3)
3,-CH
2cH (CH
3)
2,-CH
2cH (CH
3) (CH
2cH
3) ,-CH
2cH (CH
2cH
3)
2,-CH
2c (CH
3)
3,-CH
2c (CH
2cH
3)
3,-CH (CH
3)-CH (CH
3) (CH
2cH
3) ,-CH
2cH
2cH (CH
3)
2,-CH
2cH
2cH (CH
3) (CH
2cH
3) ,-CH
2cH
2cH (CH
2cH
3)
2,-CH
2cH
2c (CH
3)
3,-CH
2cH
2c (CH
2cH
3)
3,-CH (CH
3) CH
2cH (CH
3)
2,-CH (CH
3) CH (CH
3) CH (CH
3)
2,-CH (CH
2cH
3) CH (CH
3) CH (CH
3) (CH
2cH
3) etc.Therefore term alkyl comprises primary alkyl, secondary alkyl and tertiary alkyl.
Term " thiazolinyl " refers to wherein at least one unsaturated point, that is, wherein two adjacent carbonss connect alkyl as defined above by double bond.Term " alkynyl " relates to the alkyl that wherein two adjacent carbonss are connected by triple bond.
Term " alkoxyl group " refers to-OR, and wherein R is alkyl.
Term " halogen " refers to fluorine, chlorine, bromine and iodine group.
Term " hydroxyalkyl " refers to the alkyl group as herein defined replaced through at least one hydroxyl.The limiting examples of hydroxyalkyl includes but not limited to hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methyl-propyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxyl butyl, 3,4-dihydroxyl butyl and 2-(hydroxymethyl)-3-hydroxypropyl.
Term " alkoxyalkyl " refers to the alkyl group as herein defined replaced through alkoxyl group defined herein.
Term " alkylamine " refers to-N (alkyl)
xh
ygroup, wherein x and y is selected from x=1, y=1 and x=2, y=0.As x=2, alkyl optionally forms cyclic rings system together with its atom N connected.
Term " alkylaminoalkyl group " refers to the alkyl group as herein defined replaced through alkylamine as herein defined.
Term " hydroxyalkylaminoalkyl " refers to the alkyl group as herein defined replaced through alkylamine as herein defined and alkyl hydroxy.
Term " Alkoxyalkylamino alkyl " refers to the alkyl group as herein defined replacing through alkylamine as herein defined and replace through alkyl alkoxy as herein defined.
Term " ester " refers to the chemical part with formula-COOR, and wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (by ring bond with carbon) and heteroalicyclic group (by ring bond with carbon).Any hydroxyl on compound described herein or carboxylic side-chain all can esterifications.
Term " ring " refers to arbitrary covalence closed structure.Ring comprises (such as) carbocyclic ring (such as, aryl and cycloalkyl), heterocycle (such as, heteroaryl and non-aromatic heterocyclic), aromatic series (such as aryl and heteroaryl) and non-aromatic (such as, cycloalkyl and non-aromatic heterocyclic).Ring is optionally substituted.Ring can be monocycle or many rings.
Arbitrary ring texture can be contained in term " polynary ring ".Term " unit " represents the quantity of the skeletal atom of makeup ring.Therefore, such as, hexanaphthene, pyridine, pyrans are 6 rings, and pentamethylene, pyrroles, furans and thiophene are 5 rings.
Term " assorted alkyl " refers to alkyl, alkenyl or alkynyl that one or more (preferably 1,2 or 3) carbon atom is replaced by oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulphur atom (preferred oxygen, sulphur or nitrogen).
Term " cycloalkyl " refers to the carbocyclic alkyl substituent of list-or many rings.Comprise cyclic alkyl, thiazolinyl and alkynyl.Cycloalkyl can make monocycle or many rings (such as containing condensing, bridging and/or spiro system), and wherein carbon atom is positioned at inside ring system or outside.Cycloalkyl can have 3-14 annular atoms (such as have 3-8 carbon atom with regard to monocyclic cycloalkyl, have 7-14 carbon atom with regard to polycyclic naphthene base) as a whole.The ring position suitable arbitrarily of cycloalkyl can be covalently bound with defined chemical structure.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene base, norcamphyl, norpinanyl, norcarane alkyl, adamantyl and spiral shell [4.5] decyl and homologue and isomer etc.
Term " Heterocyclylalkyl " refers to have at least one be selected from the heteroatoms of O, N and S and optionally contain one or more double bond or triple bond non aromatic cycloalkyl.Heterocyclylalkyl can have 3-14 annular atoms as a whole and contain 1-5 heteroatoms (such as have 3-6 annular atoms with regard to monocyclic heterocycloalkyl, have 7-14 annular atoms with regard to many rings Heterocyclylalkyl).Heterocyclylalkyl can to produce the chemical structure with defined on any heteroatom of rock steady structure or carbon atom covalently bound.One or more N or S atoms on Heterocyclylalkyl can oxidized (such as morpholine N-Oxide, parathiazan S-oxide compound, parathiazan S, S-dioxide).Heterocyclylalkyl can also contain one or more oxo group, such as phthalimido group, piperidone base, oxazolidine ketone group, 2,4 (1H, 3H)-dioxo-pyrimidyl, pyridine-2 (1H)-one base etc.The example of Heterocyclylalkyl also comprises morpholinyl, parathiazan base, pyranyl, imidazolidyl, imidazolinyl, oxazolidinyl, pyrazolidyl, pyrazolinyl, pyrrolidyl, pyrrolinyl, tetrahydrofuran base, tetrahydro-thienyl, thiazolidine base, piperidyl, azetidine, piperazinyl etc.
Term " aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely sharing the right ring of adjacent carbons) group, has many rings (namely with the ring that adjacent carbons the is right) group of the π-electron system of conjugation.Aryl can on any carbon atom producing rock steady structure chemical structure with defined covalently bound.In some instances, aryl only can have aromatic carbocyclic, as phenyl, anthryl, phenanthryl etc.In other instances, aryl can be wherein many rings ring system of condensing of at least one aromatic carbocyclic and one or more Heterocyclylalkyl or cycloalkyl ring, and nonrestrictive example comprises indanyl (i.e. the benzo derivative of pentamethylene), tetralyl (i.e. the benzo derivative of hexanaphthene), benzimidazoline base, chromenyl (i.e. the benzo derivative of pyrans), benzdioxan base, benzodioxole base, chromanyl, different chromanyl, indolinyl etc.
Term " heteroaryl " refers to and comprises 1 to 5 heteroatoms, and the heteroaromatic system of 5 to 14 annular atomses, wherein heteroatoms comprises O, S and N.In some instances, heteroaryl can comprise the bicyclic heteroaryl condensed with one or more aromatic carbocyclic, non-aromatic carbocycle or non-aromatic heterocyclic alkyl.Heteroaryl can to produce the chemical structure with defined on any heteroatom of rock steady structure or carbon atom covalently bound.One or more N or S atoms in heteroaryl can oxidized (as pyridine N-oxides, thiophene S-oxide compound, thiophene S, S-dioxide).The example of this heteroaryl comprises furyl, pyrryl, pyridyl, thienyl, pyrimidyl, pyridazinyl, triazolyl, pyrazinyl, tetrazyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazoles base, indyl, pseudoindoyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, 2-toluquinoline base, quinazolyl, quinoxalinyl, benzotriazole base, benzothiazolyl, benzimidazolyl-, benzisothiazole base, benzisoxa oxazolyl, benzisoxa oxazolyl, benzo oxadiazoles base, cinnolines base, 1H-indyl, 2H-indyl, indolizine base, isobenzofuran-base, naphthyridinyl, phthalazinyl, pteridyl, purine radicals, oxazole pyridyl, thiazolopyridinyl, imidazopyridyl, furopyridyl, thienopyridine base, Pyridopyrimidine base, pyrido-pyrazine base, pyrido pyridazinyl, thieno-thiazolyl, thieno-oxazolyl, Thienoimidazole base, tetrahydric quinoline group, thionaphthene pyridyl, cumarone pyridyl, 4,5,6,7-tetrahydro indole base etc.
Embodiment
Explain general method of the present invention further below, compound of the present invention can be prepared by method as known in the art, is described in detail below but the preparation method of the compounds of this invention is not limited to this for the preparation method of preferred compound of the present invention.
Embodiment
The compounds of this invention can be prepared according to general flow 1.Intermediate II and intermediate III react as methylene dichloride, tetrahydrofuran (THF), ether, toluene etc. in a suitable solvent, obtain formula (I) compound.Wherein, L
1for leavings group.
Flow process 1
IIIA is the representational structure of intermediate III, can prepare according to flow process 2.First intermediate compound IV and V generation linked reaction obtain intermediate VI.This reaction generally uses palladium catalyst, as Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(PPh
3)
2, Pd
2(dba)
3deng; The alkali that this reaction is commonly used is as Na
2cO
3, CsCO
3deng; Typical solvent comprises DME/H
2o etc.; Reaction is carried out usually in a heated condition.Intermediate VI removes protecting group PG under suitable conditions
1, obtain intermediate III A.
Flow process 2
The representation compound f of intermediate compound IV can be prepared according to flow process 3.Starting raw material a directly can be bought by commercial sources, is suspended in by a in methane amide, and reaction is carried out usually in a heated condition, obtains intermediate b.The pyrazole ring of intermediate b introduces a leavings group, and if intermediate b is under N-N-iodosuccinimide exists, at suitable solvent as in DMF, THF etc., there is iodide reaction and obtain intermediate c in heating.Those skilled in the art also can introduce the leavings group such as bromine or chlorine easily according to prior art on intermediate b.Raw material d and methylsulfonyl chloride as under triethylamine, N, N-diisopropyl ethyl amine etc. exist, are obtained by reacting intermediate e with methylsulfonyl chloride at alkali.In the basic conditions, as cesium carbonate, sodium carbonate, triethylamine etc., generally reaction provides intermediate f to intermediate c and e in a heated condition.
Flow process 3
The synthesis of intermediate V can be prepared according to the scheme 1,2 or 3 of flow process 4.
Flow process 4
The reaction process of scheme 1 is: first the carboxyl ester of 2-methyl-4-bromo-benzoic acid is obtained 2-methyl-4-methyl-bromobenzoate, subsequently by the methyl-iodide generation of 2, obtains 2-brooethyl-4-methyl-bromobenzoate, and then and R
1nH
2be obtained by reacting intermediate g.There is ring closure reaction and obtain intermediate h in intermediate g, this reaction is generally carried out in suitable solvent (as methyl alcohol, tetrahydrofuran (THF) etc.), and generally use alkali, as triethylamine, DBU, pyridine etc., this reaction is carried out usually in a heated condition.
Scheme 1
The reaction process of scheme 2 is: 2-brooethyl-4-methyl-bromobenzoate (preparation method is with scheme 1) and R
1nH
2in the basic conditions, heating, prepares intermediate h.This reaction is carried out improving productive rate in tube sealing.
Scheme 2
The reaction process of scheme 3 is: intermediate i open loop obtains intermediate j, and the carboxyl generation esterification of j, obtains intermediate k subsequently.The hydroxyl oxygen of intermediate k changes into carbonyl, obtains intermediate l.L and R
1nH
2reaction generates imines m, and then m is reduced into intermediate n, Guan Huan obtains h.
Scheme 3
The following example intends to set forth specific invention embodiment, never the scope of plan restriction specification sheets or claims.Those skilled in the art are by accreditation, and raw material can be different, can adopt additional step to generate the compound contained by the present invention, prove as the following example.The following example only supplies purposes of illustration, neither intends, also should not be interpreted as restriction invention in any way.Those skilled in the art will recognize that, can carry out changing and revising, and without prejudice to the spirit or scope of the present invention.
Embodiment 1
Prepare compound 1:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-p-methoxy-phenyl) 1-isoindolinone
A: prepare intermediate
Step 1: preparation 2-methyl-4-methyl-bromobenzoate
By 2-methyl-4-bromo-benzoic acid (3g, 13.4mM, 1.0equiv) be suspended in methyl alcohol (30mL), be cooled to 0 DEG C, instillation thionyl chloride (2.4mL, 33.5mM, 2.5equiv), be transferred in oil bath pan after stirring 15min, be heated to backflow, react completely through TLC monitoring, be cooled to room temperature, concentrating under reduced pressure solvent.Column chromatography (sherwood oil: ethyl acetate=5:1) process obtains brown yellow oil liquid (2.995g, yield 94%).
Step 2: preparation 2-brooethyl-4-methyl-bromobenzoate
Toward 2-methyl-4-methyl-bromobenzoate (2.995g, 12,584mM, N-bromo-succinimide (2.338g is added in tetracol phenixin (40mL) solution 1.0equiv), 13.2mM, 1.05equiv), benzoyl peroxide (152mg, 0.629mM, 0.05equiv), and be heated in nitrogen backflow.React completely through TLC monitoring, be cooled to room temperature, filter, concentrating under reduced pressure solvent.Column chromatography (sherwood oil: ethyl acetate=10:1) process obtains yellow-brown solid (2.78g, yield 72%).
1HNMR(400MHz,CDCl
3):δ＝7.87(d,J＝8.4Hz,1H),7.65(d,J＝2.0Hz,1H),7.53(dd,J＝8.4,2.0Hz,1H),4.92(s,2H),3.96(s,3H)。
Step 3: preparation 2-(4-anisidine methyl)-4-methyl-bromobenzoate
By P-nethoxyaniline (3.844g, 31.2mM, 2.5equiv) be dissolved in acetone (40mL), add triethylamine (5.2mL, 37.5mM, 3.0equiv), in reaction solution, at room temperature slowly drip 2-brooethyl-4-methyl-bromobenzoate (3.823g, 12.5mM, 1.0equiv) acetone (20mL) solution, continue at stirring at room temperature 17h.Concentration of reaction solution, adds water and ethyl acetate, is separated organic layer, uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine respectively, anhydrous sodium sulfate drying, filter and concentrate.Column chromatography (sherwood oil: ethyl acetate=7:1) process obtains white solid (2.187g, yield 50%).
1HNMR(400MHz,CDCl
3):δ＝7.85(d,J＝8.3Hz,1H),7.743-7.739(m,1H),7.48(dd,J＝8.3,1.9Hz,1H),6.79-6.76(m,2H),6.60-6.57(m,2H),4.62(s,2H),3.92(s,3H),3.76(s,3H)。
Step 4: preparation 5-bromo-2-(4-p-methoxy-phenyl) 1-isoindolinone
2-(4-anisidine methyl)-4-methyl-bromobenzoate (2.187mg, 6.27mM, 1.0equiv) is dissolved in methyl alcohol (25mL), add triethylamine (3.5mL, 25.08mM, 4.0equiv), and in nitrogen, be heated to backflow.React completely through TLC monitoring, be cooled to room temperature, concentrated a large amount of methyl alcohol, filters, and with methanol wash column, drains through oil pump, obtain white solid (1.867g, yield 94%).
1HNMR(400MHz,CDCl
3):δ＝7.80(d,J＝8.2Hz,1H),7.75-7.71(m,2H),7.70(brs,1H),7.68-7.66(m,1H),7.01-6.97(m,2H),4.83(s,2H),3.86(s,3H)。
Step 5: preparation 5-(4,4,5,5-tetramethyl--[1,3,2] dioxaborolan-2-base)-2-(4-p-methoxy-phenyl) 1-isoindolinone
By bromo-for 5-2-(4-p-methoxy-phenyl) 1-isoindolinone (1.5g, 4.73mM, 1.0equiv), diborane pinacol ester (1.322g, 5.20mM, 1.1equiv), [1,1 '-bis-(diphenylphosphino) ferrocene] mixture (116mg of-dichloro palladium and methylene dichloride (1:1), 0.14mM, 0.03equiv) with Potassium ethanoate (1.391g, 14.20mM, 3.0equiv) mixture in dimethyl sulfoxide (DMSO) (15mL), at 80 DEG C, in nitrogen atmosphere, heat 19h.This mixture is cooled to room temperature, and adds ethyl acetate, by diatomite filtration, filtrate uses water, brine respectively, anhydrous sodium sulfate drying, filters and concentrates.Column chromatography (sherwood oil: ethyl acetate=7:1) obtains white solid (1.208g, yield 70%).
B: prepare intermediate
Step 1: preparation 1H-pyrazolo [3,4-d] pyrimidine-4-yl amine
3-amino-4-pyrazolyl first cyanogen (2g) is suspended in methane amide (10mL), and at 170 DEG C, heats 5h in nitrogen.Reaction mixture is cooled to room temperature, and adds water (15mL).Collect solid, and fully wash with water, methyl alcohol, and dry in atmosphere, obtain compound as white solid 2 (2.337g, yield 94%).
1HNMR(400MHz,DMSO-d
6):δ＝13.34(s,1H),8.14(s,1H),8.07(s,1H),7.65(brs,2H)。
Step 2: preparation 3-iodo-1H-pyrazolo [3,4-d] pyrimidine-4-yl amine
By 1H-pyrazolo [3,4-d] pyrimidine-4-yl amine (953mg, 7.055mM, 1.0equiv), N-N-iodosuccinimide (2.381g, 10.58mM, 1.5equiv) be suspended in DMF (15mL), and in nitrogen at 80 DEG C heated overnight.Reaction mixture is cooled to room temperature, and adds water (60mL).Collect solid, respectively wash 2 times with the saturated sodium sulfite aqueous solution, water respectively, and dry in atmosphere, obtain compound as white solid 2 (1.58g, yield 86%).
1HNMR(400MHz,DMSO-d
6):δ＝13.82(s,1H),8.17(s,1H),2.74(s,1H),2.57(s,1H)。
Step 3: preparation (S)-3-(mesyloxy) piperidines-1-carboxylic acid tert-butyl ester
By (S)-3-hydroxy piperidine-1-carboxylic acid tert-butyl ester (4g, 19.88mM, 1.0equiv) be dissolved in methylene dichloride (25mL), be cooled to 0 DEG C, add triethylamine (3.32mL, 23.86mM, 1.2equiv), slow dropping methylsulfonyl chloride (1.69mL, 21.86mM, 1.1equiv) methylene dichloride (5mL) solution, through TLC monitoring react completely, add water and methylene dichloride, be separated organic layer, use 1N hydrochloric acid and brine respectively, anhydrous sodium sulfate drying, filter and concentrate, being directly used in next step reaction.
Step 4: preparation (R)-3-(4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-carboxylate
By 3-iodo-1H-pyrazolo [3, 4-d] pyrimidine-4-yl amine (4.3g, 16.57mM, 1.0equiv) be dissolved in N, dinethylformamide (60mL), and add cesium carbonate (6.753g successively, 35mM, 2.1equiv), (S)-3-(mesyloxy) piperidines-1-carboxylic acid tert-butyl ester (5.549g, 19.88mM, 1.2equiv), and heat at 80 DEG C in nitrogen, after TLC detection reaction completes, concentrating under reduced pressure major part N, dinethylformamide, add water (60mL), extract by ethyl acetate (3 × 30), merge organic layer, use water respectively, normal saline flushing.Organic layer, through anhydrous sodium sulfate drying, filters and concentrates.White solid compound 4 (5.8g, 79%) is obtained after column chromatography (sherwood oil: ethyl acetate=2:1) process.
1HNMR(400MHz,CDCl
3):δ＝8.34(s,1H),6.08(bs,2H),4.80-4.73(m,1H),4.15(brs,2H),3.40(brs,1H),2.88-2.83(m,1H),2.22-2.11(m,2H),1.91-1.88(m,1H),1.70-1.66(m,1H),1.46(s,9H)。
C: prepare compound 1
Step 1: preparation (R)-3-(4-amino-3-[2-(4-p-methoxy-phenyl) 1-isoindolinone-5-base]-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-carboxylate
By (R)-3-(4-amino-3-iodo-1H-pyrazolo [3, 4-d] pyrimidine-1-base) piperidines-1-carboxylate (400mg, 0.9mM, 1.0equiv), 4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxaborolan-2-base)-2-(4-p-methoxy-phenyl) 1-isoindolinone (362mg, 0.99mM, 1.1equiv), tetrakis triphenylphosphine palladium (62mg, 0.054mM, 0.06equiv) with sodium carbonate (200mg, 1.89mM, mixture 2.1equiv) is in the mixture of dioxane (4mL) and water (1mL), 24h is heated under nitrogen atmosphere at 100 DEG C.Reaction mixture is cooled to room temperature and removal of solvent under reduced pressure, resistates is two-phase partitioning in saturated sodium bicarbonate aqueous solution and ethyl acetate, and be separated organic layer, water layer is extracted with ethyl acetate twice again, the organic extract anhydrous sodium sulfate drying merged, filters and concentrates.Column chromatography (sherwood oil: ethyl acetate=1:2) process obtains white solid (340mg, yield 68%).
Step 2: preparation (R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-p-methoxy-phenyl) 1-isoindolinone
By (R)-3-(4-amino-3-[2-(pyridine-2-base) 1-isoindolinone-5-base]-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-carboxylate (340mg, 0.61mM, 1.0equiv)) be dissolved in methylene dichloride (20mL), instillation trifluoroacetic acid (2mL), at room temperature stir 3h, concentrating under reduced pressure.In resistates, add methylene dichloride (5mL), triethylamine (171 μ L, 1.22mM, 2.0equiv), is cooled to 0 DEG C, slowly instills acrylate chloride (59 μ L, 0.64mM, 1.05equiv).Stop this reaction after 1.5h, add saturated aqueous ammonium chloride and methylene dichloride, be separated organic layer, water layer uses dichloromethane extraction twice again, and the organic extract anhydrous sodium sulfate drying of merging, filters and concentrate.Column chromatography (methylene dichloride: methyl alcohol=25:1) process obtains white solid (170mg, yield 54.5%).
1HNMR(400MHz,CDCl
3):δ＝8.41(d,J＝11.6Hz,1H),8.01(d,J＝7.8Hz,1H),7.88(s,1H),7.82(d,J＝7.8Hz,1H),7.74-7.72(m,2H),6.97-6.95(m,2H),6.68–6.55(m,1H),6.34–6.27(m,1H),5.83(brs,2H),5.75-5.66(m,1H),4.90(brs,3.5H),4.59-4.56(m,0.5H),4.24-4.21(m,0.5H),4.07-4.04(m,0.5H),3.84–3.77(m,3.5H),3.46–3.40(m,0.5H),3.27–3.21(m,0.5H),3.00–2.94(m,0.5H),2.45–2.28(m,2H),2.05–2.02(m,1H),1.81–1.75(m,1H).ESI-MSm/z:510.2(M+H)
+。
Embodiment 2
Prepare compound 2:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(pyridine-2-base) 1-isoindolinone
A: prepare intermediate
method with embodiment 1
B: prepare compound 2
Step 1: preparation (R)-3-(4-amino-3-[2-(pyridine-2-base) 1-isoindolinone-5-base]-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-carboxylate
By (R)-3-(4-amino-3-iodo-1H-pyrazolo [3, 4-d] pyrimidine-1-base) piperidines-1-carboxylate (483mg, 1.09mM, 1.0equiv), 4-(4, 4, 5, 5-tetramethyl--[1, 3, 2] dioxaborolan-2-base)-2-(pyridine-2-base) 1-isoindolinone (402mg, 1.2mM, 1.1equiv), tetrakis triphenylphosphine palladium (72mg, 0.062mM, 0.06equiv) with sodium carbonate (232mg, 2.18mM, mixture 2.1equiv) is in the mixture of glycol dimethyl ether (3mL) and water (1.5mL), 48h is heated under nitrogen atmosphere at 85 DEG C.Reaction mixture is cooled to room temperature and removal of solvent under reduced pressure, resistates is two-phase partitioning in saturated sodium bicarbonate aqueous solution and ethyl acetate, and be separated organic layer, water layer is extracted with ethyl acetate twice again, the organic extract anhydrous sodium sulfate drying merged, filters and concentrates.Column chromatography (sherwood oil: ethyl acetate=1:4) process obtains white solid (440mg, yield 77%).
Step 2: preparation (R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(pyridine-2-base) 1-isoindolinone
By (R)-3-(4-amino-3-[2-(pyridine-2-base) 1-isoindolinone-5-base]-1H-pyrazolo [3,4-d] pyrimidine-1-base) piperidines-1-carboxylate (195mg, 0.37mM, 1.0equiv)) be dissolved in methylene dichloride (22mL), instillation trifluoroacetic acid (1.5mL), at room temperature stir 3h, concentrating under reduced pressure.In resistates, add methylene dichloride (5mL), triethylamine (103 μ L, 0.74mM, 2.0equiv), is cooled to 0 DEG C, slowly instills acrylate chloride (30 μ L, 0.37mM, 1.0equiv).Stop this reaction after 4h, add saturated aqueous ammonium chloride and methylene dichloride, be separated organic layer, water layer uses dichloromethane extraction twice again, and the organic extract anhydrous sodium sulfate drying of merging, filters and concentrate.Column chromatography (methylene dichloride: methyl alcohol=25:1) process obtains white solid (60mg, yield 33.8%).
1HNMR(400MHz,CDCl
3):δ＝8.59(d,J＝8.08Hz,1H),8.40-8.32(m,2H),8.01(d,J＝5.08Hz,1H),7.9(s,1H),7.79–7.72(m,2H),7.11–7.08(m,1H),6.66-6.54(m,1H),6.33–6.27(m,1H),5.76-5.67(m,1H),5.16(brs,2H),4.92–4.84(m,1.5H),4.60-4.75(m,0.5H),4.24-4.21(m,0.5H),4.06-4.03(m,0.5H),3.81-3.76(m,0.5H),3.43-3.38(m,0.5H),3.28-3.21(m,0.5H),2.97-2.91(m,0.5H),2.44-2.26(m,2H),2.05-2.02(m,1H),1.80-1.71(m,1H)。ESI-MSm/z:481.2(M+H)
+。
Embodiment 3
Prepare compound 3:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-(trifluoromethyl) pyridine-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 2, replaces the PA in embodiment 2 with 2-amino-4-5-flumethiazine, obtains compound 3.ESI-MSm/z:549.1(M+H)
+。
Embodiment 4
Prepare compound 4:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-picoline-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with 2-AMINO-4-PICOLINE, obtains compound 4.ESI-MSm/z:495.6(M+H)
+。
Embodiment 5
Prepare compound 5:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-(pyrroles-1-base) pyridine-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with 2-amino-4-(1-pyrrolidyl) pyridine, obtains compound 5.ESI-MSm/z:550.3(M+H)
+。
Embodiment 6
Prepare compound 6:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-cyanopyridine-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 2, replaces the PA in embodiment 2 with 2-amino-4-cyanopyridine, obtains compound 6.ESI-MSm/z:528.2(M+Na)
+。
Embodiment 7
Prepare compound 7:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-fluorine pyridine-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 2, replaces the PA in embodiment 2 with 2-amino-4-fluorine pyridine, obtains compound 7.ESI-MSm/z:499.3(M+H)
+。
Embodiment 8
Prepare compound 8:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-phenyl 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with aniline, obtains compound 8.ESI-MSm/z:502.2(M+Na)
+。
Embodiment 9
Prepare compound 9:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(p-methylphenyl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with open-chain crown ether, obtains compound 9.ESI-MSm/z:494.2(M+H)
+。
Embodiment 10
Prepare compound 10:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-fluorophenyl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with para-fluoroaniline, obtains compound 10.ESI-MSm/z:498.0(M+H)
+。
Embodiment 11
Prepare compound 11:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-(trifluoromethyl) phenyl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 2, replaces the PA in embodiment 2 with p-trifluoromethylaniline, obtains compound 11.ESI-MSm/z:548.2(M+H)
+。
Embodiment 12
Prepare compound 12:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-(dimethylamino) phenyl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with p-trifluoromethylaniline, obtains compound 12.ESI-MSm/z:523.3(M+H)
+。
Embodiment 13
Prepare compound 13:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-1-isoindoline-2-base) benzonitrile
The compounds of this invention, by the synthetic method of embodiment 2, with the PA replaced cyano-aniline in embodiment 2, obtains compound 13.ESI-MSm/z:505.0(M+H)
+。
Embodiment 14
Prepare compound 14:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-1-isoindoline-2-base) phenylformic acid
The compounds of this invention, by the synthetic method of embodiment 2, with the PA replaced carboxyanilino in embodiment 2, obtains compound 14.ESI-MSm/z:524.6(M+H)
+。
Embodiment 15
Prepare compound 15:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-(pyrroles-1-base) phenyl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with 4-(1-pyrrolidyl) aniline, obtains compound 15.ESI-MSm/z:549.3(M+H)
+。
Embodiment 16
Prepare compound 16:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(3-(trifluoromethyl) phenyl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 2, replaces the PA in embodiment 2 by 3-Aminotrifluorotoluene, obtains compound 16.ESI-MSm/z:548.5(M+H)
+。
Embodiment 17
Prepare compound 17:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(2-p-methoxy-phenyl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 by ORTHO ANISIDINE, obtains compound 17.ESI-MSm/z:510.3(M+H)
+。
Embodiment 18
Prepare compound 18:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-cyclohexyl 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 by cyclo-hexylamine, obtains compound 18.ESI-MSm/z:486.1(M+H)
+。
Embodiment 19
Prepare compound 19:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(1-methyl piperidine-4-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with 4-amino-1-methyl piperidine, obtains compound 19.ESI-MSm/z:501.3(M+H)
+。
Embodiment 20
Prepare compound 20:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(tetrahydrochysene-2H-pyrans-4-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with 4-amino tetrahydro pyran, obtains compound 20.ESI-MSm/z:488.1(M+H)
+。
Embodiment 21
Prepare compound 21:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-cyclopentyl 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 by cyclopentamine, obtains compound 21.ESI-MSm/z:472.5(M+H)
+。
Embodiment 22
Prepare compound 22:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-cyclobutyl 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with cyclopropylamine, obtains compound 22.ESI-MSm/z:444.2(M+H)
+。
Embodiment 23
Prepare compound 23:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-methylisoindoline-1-ketone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with methylamine, obtains compound 23.ESI-MSm/z:418.2(M+H)
+。
Embodiment 24
Prepare compound 24:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-tetrapropylisoindoline-1-ketone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with propylamine, obtains compound 24.ESI-MSm/z:446.0(M+H)
+。
Embodiment 25
Prepare compound 25:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-sec.-propyl 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with Isopropylamine, obtains compound 25.ESI-MSm/z:446.4(M+H)
+。
Embodiment 26
Prepare compound 26:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(2-methoxy ethyl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 by 2-methoxyethyl amine, obtains compound 26.ESI-MSm/z:462.6(M+H)
+。
Embodiment 27
Prepare compound 27:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(Cvclopropvlmethvl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with cyclopropylmethylamine, obtains compound 27.ESI-MSm/z:458.3(M+H)
+。
Embodiment 28
Prepare compound 28:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-benzyl 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with benzylamine, obtains compound 28.ESI-MSm/z:494.1(M+H)
+。
Embodiment 29
Prepare compound 29:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(thiazol-2-yl) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with thiazolamine, obtains compound 29.ESI-MSm/z:487.7(M+H)
+。
Embodiment 30
Prepare compound 30:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(oxazole-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1, obtains compound 30 with the amino oxazole of 2-.ESI-MSm/z:471.5(M+H)
+。
Embodiment 31
Prepare compound 31:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(1H-pyrroles-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with 2-amino-pyrroles, obtains compound 31.ESI-MSm/z:469.1(M+H)
+。
Embodiment 32
Prepare compound 32:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(1,3,4-thiadiazoles-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with 2-amido-1,3,4-thiadiazoles, obtains compound 32.ESI-MSm/z:488.6(M+H)
+。
Embodiment 33
Prepare compound 33:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(pyrimidine-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with 2-aminopyrimidine, obtains compound 33.ESI-MSm/z:482.2(M+H)
+。
Embodiment 34
Prepare compound 34:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(pyrazine-2-base) 1-isoindolinone
The compounds of this invention, by the synthetic method of embodiment 1, replaces the P-nethoxyaniline in embodiment 1 with Aminopyrazine, obtains compound 34.ESI-MSm/z:482.4(M+H)
+。
Embodiment 35
Prepare compound 35:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-(methylamino)-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-(trifluoromethyl) pyridine-2-base) 1-isoindolinone
The compounds of this invention 35 is obtained by compound 1 and iodomethane reaction.ESI-MSm/z:563.2(M+H)
+。
Embodiment 36
Prepare compound 36:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-(ethylamino)-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-(trifluoromethyl) pyridine-2-base) 1-isoindolinone
The compounds of this invention 36 is obtained by reacting by compound 1 and monobromethane.ESI-MSm/z:577.6(M+H)
+。
Embodiment 37
Prepare compound 37:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-(cyclopropylamino)-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(4-(trifluoromethyl) pyridine-2-base) 1-isoindolinone
The compounds of this invention 37 is obtained by reacting by compound 1 and cyclopropane bromide.ESI-MSm/z:589.7(M+H)
+。
Embodiment 38
Prepare compound 38:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(5-(trifluoromethyl) pyridine-2-base) 1-isoindolinone
The compounds of this invention synthesizes by the synthetic method of embodiment 2, obtains compound 38.ESI-MSm/z:549.7(M+H)
+。
Embodiment 39
Prepare compound 39:(R)-5-(1-(1-acryloylpiperidine-3-base)-4-amino-1H-pyrazoles [3,4-d] pyrimidin-3-yl)-2-(6-(trifluoromethyl) pyridine-2-base) 1-isoindolinone
The compounds of this invention synthesizes by the synthetic method of embodiment 2, obtains compound 39.ESI-MSm/z:549.2(M+H)
+。
Biological activity test
Experimental technique
Btk, reaction buffer is contained (containing DTT, MnCl in 100 μ L reaction systems
2), ATP, kinase substrate and sample, set up blank (not containing enzyme and sample) and negative control (not containing sample) simultaneously, room temperature reaction 120min, add ADP-GloReagent, room temperature reaction 40min makes unnecessary ATP inactivation, add KinaseDetectionReagent again, room temperature reaction 30min, measure chemiluminescence intensity L.Inhibiting rate is calculated, inhibiting rate=[1-(L sample-L is blank)/(L feminine gender-L is blank)] × 100% according to chemiluminescence intensity L value.Each sample list concentration during primary dcreening operation, the sample that inhibiting rate is greater than 50% carries out IC
50pH-value determination pH, during mensuration, each sample gradient dilutes six concentration.According to inhibiting rate, the 4ParameterLogisticModel in application Xlfit software calculates IC
50.
Table 1:
Note: the Ibrutinib of a. bibliographical information is IC to the inhibit activities of BTK enzyme
50<0.5nM, the compd A of report, B, C, D are to the IC of BTK enzyme
50be respectively 5.6nM, 6.3nM, 4.16nM, 3.48nM (H.Lee etc., WO2008039218A2).
Upper table result shows that the activity of certain embodiments compound is significantly better than positive compound Ibrutinib, and the activity of Multi-instance compound is better than positive compound Ibrutinib, is significantly better than bibliographical information compd A, B, C, D.
Claims (12)
1. the compound of structural formula I:
Or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein
X is for being substituted or unsubstituted-(CH
2)
m-,-O-(CH
2)
n-,-CO-,-S-(CH
2)
n-,-SO-,-SO
2-,-NH-(CH
2)
n-,-NH-CO-, wherein m is 0,1,2,3; N is 0,1,2;
R
1be selected from H, or be substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl;
R
2be selected from H, halogen, alkyl, hydroxyl, cyano group, amino, nitro, carboxyl, ester group, alkylamino, hydroxyalkyl, trifluoromethyl, alkoxyl group;
A is selected from alkylidene group, cycloalkylidene, sub-Heterocyclylalkyl, sub-assorted alkyl, arylidene, inferior heteroaryl, alkylenearylene, alkylidene group inferior heteroaryl, alkylidene group cycloalkylidene and alkyleneheterocycloalkylene;
B is selected from C (=O), S (=O), S (=O)
2, NR
6c (=O), NR
6s (=O), NR
6s (=O)
2, wherein R
6for H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl;
R
3for H, or be substituted or unsubstituted C
1-6alkyl, C
1-6assorted alkyl, C
1-6alkoxyalkyl, C
1-8alkylaminoalkyl group, C
1-8hydroxyalkylaminoalkyl, C
1-8alkoxyalkylamino alkyl, C
3-8cycloalkyl, C
1-8alkyl-C
3-8cycloalkyl, aryl, 3-8 unit Heterocyclylalkyl, heteroaryl, C
1-4alkyl-aryl-group, C
1-4alkyl-heteroaryl, C
1-8alkyl oxide, C
1-8alkylamide or C
1-6alkyl-(3-8 unit Heterocyclylalkyl);
R
4and R
5separately be selected from H, or be substituted or unsubstituted C
1-6alkyl, C
1-6assorted alkyl, C
1-6alkylaminoalkyl group, C
3-8cycloalkyl, C
1-4alkyl-C
3-6cycloalkyl, 3-8 unit Heterocyclylalkyl, C
1-4alkyl-aryl-group, C
1-4alkyl-heteroaryl, C
1-6alkyl oxide, C
1-4alkyl-(3-6 unit Heterocyclylalkyl); Or
R
4and R
5form key together;
R
7and R
8separately be selected from hydrogen, C
1-8alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and Heterocyclylalkyl can be selected from C
1-4the substituting group of alkyl, hydroxyl, halogen, oxo replaces;
R
9for hydrogen, amino, hydroxyl, C
1-6alkyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, aryl, heteroaryl, wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl can be optionally substituted.
2. compound as claimed in claim 1, X is substituted or unsubstituted-(CH
2)
m-, wherein any methylene radical can be selected from C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, hydroxyl, amino, halogen ,-CF
3,-CN ,-O-C
1-4alkyl replaces; M is 1 or 2.
3. compound as claimed in claim 1, R
1be selected from H, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl optionally further by one or more be selected from the substituting group of alkyl, cycloalkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, aryloxy, heteroaryloxy, halogen, hydroxyl, cyano group, amino, nitro, carboxyl, ester group, alkylsulfonyl, sulfinyl, hydroxyalkyl, Heterocyclylalkyl, heterocyclylalkoxy groups, trifluoromethyl, trifluoromethoxy, carboxyl or carboxylicesters replace.
4. compound as claimed in claim 1, R
2be selected from H, halogen, hydroxyl, C
1-6alkyl, C
1-4alkoxyl group.
5. the compound as described in claim arbitrary in claim 1-4, wherein:
A is selected from C
1-8alkylidene group, C
3-8cycloalkylidene, 3-8 unit sub-Heterocyclylalkyl, C
2-9sub-assorted alkyl; B is selected from C (=O), S (=O), S (=O)
2, NR
6c (=O), NR
6s (=O), NR
6s (=O)
2, wherein R
6for H; And
R
3for H, or be substituted or unsubstituted C
1-6alkyl, C
1-6assorted alkyl, C
1-6alkoxyalkyl, C
1-8alkylaminoalkyl group, C
1-8hydroxyalkylaminoalkyl, C
3-8cycloalkyl, C
1-8alkyl-C
3-8cycloalkyl, aryl, 3-8 unit Heterocyclylalkyl, heteroaryl, C
1-4alkyl-aryl-group, C
1-4alkyl-heteroaryl, C
1-8alkyl oxide, C
1-8alkylamide or C
1-6alkyl-(3-8 unit Heterocyclylalkyl);
R
4and R
5separately be selected from H, or be substituted or unsubstituted C
1-6alkyl, C
1-6assorted alkyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl; Or
R
4and R
5form key together.
6. compound as claimed in claim 5, wherein A is the sub-Heterocyclylalkyl of 3-8 unit.
7. compound, wherein R as claimed in claim 6
4and R
5for H; And
R
3for H, substituted or unsubstituted C
1-6alkyl, substituted or unsubstituted C
1-6assorted alkyl, substituted or unsubstituted C
3-8cycloalkyl, substituted or unsubstituted 3-8 unit Heterocyclylalkyl.
8. compound as claimed in claim 1, wherein said formula (IA) represents:
Or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein, X is substituted or unsubstituted-(CH
2)
m-, wherein any methylene radical can be selected from C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, hydroxyl, amino, halogen ,-CF
3,-CN ,-O-C
1-4alkyl replaces; M is 1 or 2;
R
1be selected from H, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl optionally further by one or more be selected from the substituting group of alkyl, cycloalkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, aryloxy, heteroaryloxy, halogen, hydroxyl, cyano group, amino, nitro, carboxyl, ester group, alkylsulfonyl, sulfinyl, hydroxyalkyl, Heterocyclylalkyl, heterocyclylalkoxy groups, trifluoromethyl, trifluoromethoxy, carboxyl or carboxylicesters replace.
R
7and R
8separately be selected from hydrogen, C
1-8alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and Heterocyclylalkyl can be selected from C
1-4the substituting group of alkyl, hydroxyl, halogen, oxo replaces.
9. compound, wherein R as claimed in claim 8
7and R
8be H.
10. a compound, it is selected from:
or
11. are preparing the purposes in medicine according to the compound in claim 1-10 described in any one or its pharmacy acceptable salt, and described medicine is for preventing and/or treating the disease improved because Bruton tyrosine kinase activity suppresses.
12. according to the purposes in claim 11, and the wherein said disease improved because Bruton tyrosine kinase activity suppresses is selected from B-cell lymphoma, acute lymphoblastic leukemia, mastadenoma, rheumatoid arthritis, systemic lupus erythematous.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410350340.7A CN105315283A (en) | 2014-07-22 | 2014-07-22 | Bruton tyrosine kinases inhibitor |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410350340.7A CN105315283A (en) | 2014-07-22 | 2014-07-22 | Bruton tyrosine kinases inhibitor |
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Family
ID=55243678
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019526550A (en) * | 2016-08-15 | 2019-09-19 | ニューファーマ， インコーポレイテッド | Specific chemical entities, compositions and methods |
| CN113214265A (en) * | 2020-01-21 | 2021-08-06 | 江苏先声药业有限公司 | Pyrimido five-membered ring compounds |
| US11865120B2 (en) | 2013-08-23 | 2024-01-09 | Neupharma, Inc. | Substituted quinazolines for inhibiting kinase activity |
-
2014
- 2014-07-22 CN CN201410350340.7A patent/CN105315283A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11865120B2 (en) | 2013-08-23 | 2024-01-09 | Neupharma, Inc. | Substituted quinazolines for inhibiting kinase activity |
| US12403145B2 (en) | 2013-08-23 | 2025-09-02 | Neupharma, Inc | Substituted quinazolines for inhibiting kinase activity |
| JP2019526550A (en) * | 2016-08-15 | 2019-09-19 | ニューファーマ， インコーポレイテッド | Specific chemical entities, compositions and methods |
| JP2022058912A (en) * | 2016-08-15 | 2022-04-12 | ニューファーマ， インコーポレイテッド | Specific chemical entities, compositions, and methods |
| JP7101165B2 (en) | 2016-08-15 | 2022-07-14 | ニューファーマ， インコーポレイテッド | Specific chemical entities, compositions, and methods |
| US12018002B2 (en) | 2016-08-15 | 2024-06-25 | Neupharma, Inc | Certain chemical entities, compositions, and methods |
| CN113214265A (en) * | 2020-01-21 | 2021-08-06 | 江苏先声药业有限公司 | Pyrimido five-membered ring compounds |
| CN113214265B (en) * | 2020-01-21 | 2023-07-07 | 江苏先声药业有限公司 | Pyrimido five-membered ring compounds |
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Application publication date: 20160210 |