CN101124227A - Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity - Google Patents
Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity Download PDFInfo
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- CN101124227A CN101124227A CNA200580046345XA CN200580046345A CN101124227A CN 101124227 A CN101124227 A CN 101124227A CN A200580046345X A CNA200580046345X A CN A200580046345XA CN 200580046345 A CN200580046345 A CN 200580046345A CN 101124227 A CN101124227 A CN 101124227A
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Abstract
Chemical entities chosen from compounds of Formula (I), and pharmaceutically acceptable salts, solvates, crystal forms, chelates, non-covalent complexes, prodrugs, and mixtures thereof, are described herein. Pharmaceutical compositions comprising at least one chemical entity of Formula 1, together with at least one pharmaceutically acceptable vehicle chosen from carriers adjuvants, and excipients, are described. Methods of treating patients suffering from certain diseases responsive to inhibition of Btk activity and/ or B-cell proliferation are described. Methods for determining the presence of Btk in a sample are described.
Description
Related application
The application requires in the U. S. application No.10/985 of submission on November 10th, 2004,023, the application No.60/630 that submitted on November 24th, 2004,860, the application No.60/630 that submitted on November 24th, 2004, the application No.60/630 that on November 24th, 645 and 2004 submitted to, 861 right of priority, it is incorporated into herein as a reference separately in full.
Technical field
The invention provides some imidazos [1,2-a] pyrazinyl amine and related compound, contain this compound compositions and using method thereof.
Background technology
Human maximum class of enzymes protein kinase contains 500 multiple proteins.The Bruton Tyrosylprotein kinase (Bruton ' sTyrosine Kinase, Btk) be a member in the Tec Family Tyrosine Kinases, and be the conditioning agent of early stage B cell development and mature B cell activation, signal conduction and survival.
B cell signaling by B-cell receptor (BCR) produces a large amount of biological outputs, and this depends on the B cells whose development stage again.The quantity of BCR signal and time length be control accurately.The signal conduction of BCR mediation occurs can causing unusually that the B cell activation is out of control and/or generates pathogenic autoantibody and cause various autoimmune and/or inflammatory diseases.The sudden change of human BtK cause the chain agammaglobulinemia of X-(X-linkedagammaglobulinaemia, XLA).The generation ripe impaired, immunoglobulin (Ig) of this disease and B cell reduces, the autonomous immune response of T cell is impaired and when BCR stimulates the remarkable decay of lasting calcium signal relevant.
The effect of Btk in supersensitivity illness (allergic disorder) and/or autoimmune disorder and/or inflammatory disease confirmed in the mouse model that Btk lacks.For example, show in the Muridae preclinical models of the systemic lupus erythematous (SLE) of standard that Btk lacks and causes the course of disease significantly to be improved.And the mouse that Btk lacks is also resisted the arthritic development of collagen-induced property and reduces the arthritic susceptibility of staphylococcus inductive.
A large amount of evidences are supported B cell and the effect of immunity system in the pathogeny of autoimmunization and/or inflammatory diseases.Be developed based on proteic therapy (as Rituxan) and be used to consume the B cell, it represents a kind of important method for the treatment of many autoimmunizatioies and/or inflammatory diseases.Because the effect of Btk in the B cell activation suppresses the inhibitor that Btk can be used as the cell-mediated pathogenic activity of B (as the generation of autoantibody).
Btk mastocyte and unicellular in the importance of expressing and having demonstrated for these cell functions is also arranged.For example, mouse Btk lacks that to slacken (release of TNF-α and other inflammatory cytokine significantly reduces) relevant with the mastocyte activation of IgE-mediation, and human Btk to lack be that minimizing is relevant in a large number for the TNF-α that is generated by activated monocyte.
Therefore, suppress the Btk activity and can be used for treating supersensitivity illness and/or autoimmunization and/or inflammatory diseases, these diseases include but not limited to: SLE, rheumatoid arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type i diabetes, membranous type ephritis, inflammatory bowel, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and Febrile Agglutinins is sick, the Evan syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, the house gorlin's syndrome (Sjogren ' s syndrome), peripheral neuropathy (as Green-barre syndrome), pemphigus vulgaris and asthma.
In addition, existing report discloses the effect that Btk is survived in some B cell cancers at control B cell.For example, shown that Btk is very important for the survival of the positive B cell of BCR-Abl-acute lymphoblastic leukemia cell.Therefore, suppress the Btk activity and can be used for treating B cell lymphoma and leukemia.
Summary of the invention
The invention provides the modulators of kinase activity that is referred to as imidazo [1,2-a] pyrazinyl amine.
The invention provides at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from the compound of general formula 1:
Wherein:
R
1Be selected from randomly substituted phenylene, randomly substituted pyridylidene, optional 2-oxo-1,2-dihydropyridine base,
The tie point of * representative and-L-G group wherein, and scission of link representative and amino tie point; And X wherein
1Be selected from N and CR
7X
2Be selected from N and CR
7X
3Be selected from N and CR
7X wherein
1, X
2And X
3In no more than one be N and R
7Be selected from hydrogen, hydroxyl, cyano group, halogen, randomly substituted low alkyl group and randomly substituted lower alkoxy;
L is selected from covalent linkage, substituted C randomly
1-C
4Alkylidene group ,-O-,-O-(randomly substituted C
1-C
4Alkylidene group)-,-(C=O)-,-(randomly substituted C
1-C
4Alkylidene group) (C=O)-, (SO)-,-(randomly substituted C
1-C
4Alkylidene group) (SO)-, (SO
2)-,-(randomly substituted C
1-C
4Alkylidene group) (SO
2)-,-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9The R of)-wherein
9Be selected from hydrogen, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl;
G be selected from hydrogen, halogen, hydroxyl, alkoxyl group, nitro, randomly substituted alkyl ,-NR
16R
17, randomly substituted Heterocyclylalkyl, randomly substituted cycloalkyl, randomly substituted aryl and randomly substituted heteroaryl, wherein R
16And R
17Be independently selected from hydrogen, randomly substituted acyl group, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl; Or be selected from-(C=NR as L
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9) time ,-R
9And R
16And the nitrogen of institute's bonding forms randomly substituted 5 to 7 member heterocyclic ring containing nitrogen alkyl together, and it randomly further comprises one or two extra heteroatoms that is selected from N, O and S, and R
17Be selected from hydrogen, randomly substituted acyl group, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl;
T, V and W are selected from C and N, and U is selected from-CH and N, and condition is that T, U, V and W have one to be N at most;
R
2, R
3And R
4Be independently selected from hydrogen, randomly substituted low alkyl group, randomly substituted lower alkoxy, halogen and hydroxyl, condition be when A be covalent linkage, G is-NR
16R
17And L is not selected from-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-time, R
2, R
3And R
4Have at least one not to be hydrogen, and work as R
2, R
3Or R
4When corresponding T, the V of institute's bonding or W are N, R
2, R
3Or R
4Do not exist;
Q is selected from:
Wherein:
R
10And R
11Be independently selected from hydrogen, C
1-C
6Alkyl and C
1-C
6Haloalkyl; And
R
12, R
13, R
14And R
15Be independently selected from respectively
Hydrogen,
C
1-C
6Alkyl,
C
1-C
6Haloalkyl,
Phenyl,
Be selected from the substituted phenyl of single replacement, two replacements, trisubstd phenyl, wherein said substituting group is independently selected from hydroxyl, nitro, cyano group, amino, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, (C
1-C
6Alkyl oxy) C
1-C
6Alkoxyl group, C
1-C
6Perfluoroalkyl, C
1-C
6Perfluoro alkoxy, list (C
1-C
6Alkyl) amino, two (C
1-C
6Alkyl) amino and amino (C
1-C
6Alkyl),
Heteroaryl, and
Be selected from the substituted heteroaryl of single replacement, two replacements, trisubstituted heteroaryl, wherein said substituting group is independently selected from hydroxyl, nitro, cyano group, amino, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, (C
1-C
6Alkyl oxy) C
1-C
6Alkoxyl group, C
1-C
6Perfluoroalkyl, C
1-C
6Perfluoro alkoxy, list (C
1-C
6Alkyl) amino, two (C
1-C
6Alkyl) amino and amino (C
1-C
6Alkyl);
A be selected from covalent linkage and-(CH=CH)-;
R
5Be selected from randomly substituted cycloalkyl, randomly substituted Heterocyclylalkyl, randomly substituted aryl and randomly substituted heteroaryl; And
R
6Be selected from hydrogen, randomly substituted alkyl, cycloalkyl and Heterocyclylalkyl.
The present invention also provides a kind of pharmaceutical composition, and it comprises at least a chemical entities of the present invention and at least a acceptable media of pharmacology (vehicle) that is selected from carrier (carrier), adjuvant (adjuvant) and vehicle (excipient).
The present invention also provides a kind of pharmaceutical composition through packing, and it comprises
A kind of pharmaceutical composition, it comprises at least a chemical entities of the present invention and at least a acceptable media of pharmacology that is selected from carrier, adjuvant and vehicle; And
Use said composition to suffer from the patient's of the disease that inhibition Btk activity is responded operation instruction with treatment.
The present invention also provides a kind of treatment to suffer from the patient's of the disease that inhibition Btk activity is responded method, and it comprises the chemical entities at least a of the present invention to described patient's effective dosage.
The present invention also provides the patient's of the disease that a kind of treatment suffers from the cancer of being selected from, autoimmune disorder, inflammatory diseases, acute inflammatory reaction and supersensitivity illness method, and it comprises the chemical entities at least a of the present invention to described patient's effective dosage.
The present invention also provides a kind of method that increases cancer cells for the susceptibility of chemotherapy, and it comprises to carrying out the patient of chemotherapy to be enough to increasing cancer cells at least a chemical entities of the present invention of the amount administration of the susceptibility of described chemotherapeutics with chemotherapeutics.
The present invention also provides a kind of and reduces medication errors and increase owing to suffer from patient that the disease that suppresses the active response of Btk the is treated method to the compliance for the treatment of, this method comprises provides a kind of pharmaceutical preparation through packing of the present invention, and wherein said specification sheets further comprises contraindication relevant with this packaged pharmaceuticals composition and side reaction information.
The present invention also provides a kind of method that is used to suppress the ATP hydrolysis, and this method is included in the external cell of expressing Btk that contacts with the chemical entities at least a of the present invention that enough can reduce the amount of ATP hydrolysis level with detecting.
The present invention also provides the method that has Btk in a kind of definite sample, it is included in and allows to detect under the active condition of Btk with at least a chemical entities contact sample of the present invention, Btk activity level in the test sample, thus determine to exist or do not exist in the sample Btk.
The present invention also provides a kind of method that is used to suppress the B cytoactive, and this method is included in the external cell of expressing Btk that contacts with the chemical entities at least a of the present invention that enough can reduce the amount of B cytoactive with detecting.
The present invention also provides at least a chemical entities of the present invention to be used for the treatment of the application of suffering from the patient's of the disease that suppresses the active response of Btk the medicine in preparation.
The present invention also provides a kind of preparation to be used for the treatment of to suffer from the method to the patient's of the disease that suppresses the active response of Btk medicine, and it is included in and adds at least a chemical entities of the present invention in the described medicine.
As used in the present invention, more than aleatory variable occurred once in chemical structural formula, then each definition that occurs was independent of the definition of other appearance.As common implication, comprise one or more kinases for " a " kinases or " the " kinases according to " a " in patent, the reference and " the ".
General formula 1 comprises its all submolecule formulas.For example general formula 1 comprises the compound of general formula 1 to 4.
The dash ("-") between two letters or symbol is not used to represent substituent tie point.For example-CONH
2Be to connect by carbon atom.
" optional " or " randomly " is meant that described thereafter incident or situation can occur or not occur, and this description comprises that described incident or situation occur and absent variable situation.For example, " randomly substituted alkyl " comprises that following defined " alkyl " reaches " substituted alkyl ".For containing one or more substituent any groups, one skilled in the art should appreciate that these groups are not to be intended to introduce any spatially unrealistic, synthetic infeasible and/or unsettled substituting group of nature or replacement mode.
" alkyl " comprises the carbon atom with specified quantity, is generally 1 to 20 carbon atom, and 1 to 8 carbon atom for example is as the straight chain and the side chain of 1 to 6 carbon atom.For example, C
1-C
6Alkyl comprises the straight chain and the branched-chain alkyl of from 1 to 6 carbon atom.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl amyl etc.Alkylidene group is another subclass of alkyl, be meant identical with alkyl, but have the residue of two tie points.Alkylidene group has 2 to 20 carbon atoms usually, and 2 to 8 carbon atoms for example are as 2 to 6 carbon atoms.For example, C
0Alkylidene group is meant covalent linkage, C
1Alkylidene group is meant methylene radical.When mentioning the alkyl residue of carbon atom, be meant to comprise all geometrical isomers with this number of carbon atoms with specific quantity; Therefore, for example " butyl " is meant and comprises normal-butyl, sec-butyl, isobutyl-and the tertiary butyl; " propyl group " comprises n-propyl and sec.-propyl." low alkyl group " is meant the alkyl with 1 to 4 carbon atom.
" thiazolinyl " is meant from the single carbon atom of parent alkene and removes the undersaturated branched-chain or straight-chain alkyl with at least one carbon-to-carbon double bond that hydrogen atom obtains.Two keys of this group can be cis or transoid conformation.Typical thiazolinyl includes but not limited to vinyl; Propenyl is as third-1-alkene-1-1-base, third-1-alkene-2-1-base, third-2-alkene-1-1-base (allyl group), third-2-alkene-2-base, ring third-1-alkene-1-base, ring third-2-alkene-1-base; Butenyl such as but-1-ene-1-base, but-1-ene-2-base, 2-methyl-third-1-alkene-1-base, but-2-ene-1-base, but-2-ene-1-base, but-2-ene-2-base, fourth-1,3-diene-1-base, fourth-1,3-diene-2-base, ring but-1-ene-1-base, ring but-1-ene-3-base, ring fourth-1,3-diene-1-base etc.In some specific embodiments, thiazolinyl has 2 to 20 carbon atoms, and has 2 to 6 carbon atoms in other specific embodiments.
" alkynyl " is meant from the single carbon atom of parent alkynes and removes a unsaturated side chain with at least one carbon-to-carbon triple bond or the straight chained alkyl that hydrogen atom obtains.Typical alkynyl includes but not limited to ethynyl; Proyl is as third-1-alkynes-1-base, third-2-alkynes-1-base; Butynyl such as fourth-1-alkynes-1-base, fourth-1-alkynes-3-base, fourth-3-alkynes-1-base etc.In some specific embodiments, thiazolinyl has 2 to 20 carbon atoms and have 3 to 6 carbon atoms in other specific embodiments.
" cycloalkyl " is meant non-aromatic carbocyclic, contains 3 to 7 carbon atoms usually.This ring can be saturated or have one or more carbon-to-carbon double bonds.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, reaches cyclohexenyl and bridge type and cage shape saturated rings group such as norcamphane.
" alkoxyl group " is meant the alkyl that specifies number carbon atom that connects by oxo bridge such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, pentyloxy, 2-amyl group oxygen base, isopentyloxy, neopentyl oxygen, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methyl pentyloxy etc.Alkoxyl group has 1 to 6 carbon atom that links to each other with oxo bridge usually." lower alkoxy " is meant the alkoxyl group with 1 to 4 carbon atom.
" monoalkyl methane amide and dialkylformamide " comprises the NR of molecular formula-(C=O)
aR
bGroup, R wherein
aAnd R
bBe independently selected from hydrogen and specify carbonatoms purpose alkyl, condition is R
aAnd R
bNot all be hydrogen.
" alkylthio " is meant the appointment carbonatoms purpose alkyl that connects by sulphur bridge.
" acyl group " be meant (alkyl)-C (O)-, (cycloalkyl)-C (O)-, (aryl)-C (O)-, (heteroaryl)-C (O)-and (Heterocyclylalkyl)-C (O)-, wherein this group links to each other with precursor structure by the carbonyl functional group and wherein alkyl, cycloalkyl, aryl, heteroaryl and Heterocyclylalkyl be as described herein.Acyl group has in the carbon atom that the carbon atom that specifies number and carbonyl carbon be included in counting.C for example
2Acyl group is for having molecular formula CH
3(C=O)-ethanoyl.
" alkoxy carbonyl " be meant the molecular formula that connects by carbonyl carbon for (alkoxyl group) (C=O)-ester group, wherein alkoxyl group has the carbon atom that specifies number.Therefore, C
1-C
6Alkoxy carbonyl is meant the alkoxyl group with 1 to 6 carbon atom that is connected with carbonyl by its oxygen.
" amino " is meant group-NH
2
" alkyl monosubstituted amino and two (alkyl) amino " comprises secondary alkylamino and tertiary alkyl amino, and wherein alkyl is as above-mentioned definition and have the appointment carbon atom number.The tie point of alkylamino is on nitrogen.The amino example of alkyl monosubstituted amino and two (alkyl) comprises ethylamino, dimethylamino and methyl-propyl group-amino.
" alkyl monosubstituted amino alkyl and two (alkyl) aminoalkyl group " contains " alkyl monosubstituted amino alkyl and two (alkyl) amino " of the above-mentioned definition that is connected on the alkyl.
" amino (alkyl) " is meant and is connected to the amino that has on the alkyl of specifying carbon atom.Similarly " hydroxyalkyl " is meant the hydroxyl that is connected on the alkyl.
Term " aminocarboxyl " is meant-CONR
bR
cGroup, wherein
R
bBe selected from H, substituted C randomly
1-C
6Alkyl, randomly substituted aryl and randomly substituted heteroaryl, and
R
cBe independently selected from hydrogen and randomly substituted C
1-C
4Alkyl; Or
R
bAnd R
cNitrogen with its bonding forms randomly substituted 5 to 7 member heterocyclic ring containing nitrogen alkyl, and this Heterocyclylalkyl randomly contains 1 or 2 extra heteroatoms that is selected from O, N and S on described heterocycloalkyl ring;
Wherein each substituting group is replaced by one or more substituting groups that are independently selected from following groups independently: C
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo base (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl), and-NHSO
2(C
1-C
4Haloalkyl).
" aryl " contained:
5 and 6 yuan of aromatic carbocyclics, for example benzene;
Wherein at least one ring is the bicyclic system of aromatic carbocyclic, for example naphthalene, indane and tetraline; And
Wherein at least one ring is for the three-loop system of aromatic carbocyclic, as fluorenes.
For example, aryl comprises with 5 to 7 yuan of cycloalkyl rings or contains heteroatomic 5 to 7 yuan of heterocycloalkyl ring condensed 5 and 6 yuan of aromatic carbocyclics that one or more are selected from N, O and S.For this condensed-bicyclic system that wherein a ring only to be arranged be aromatic carbocyclic, its tie point can be positioned on aromatic carbocyclic or another ring.Form and on annular atoms, have the substituted phenylene group of divalent group called after of free chemical valence by substituted benzene derivative.The name of deutero-divalent group is to add " Ya " to the title of corresponding univalent perssad by remove a hydrogen atom from the free valency carbon atom by the monovalence multi-ring alkyl with " yl " ending, as the naphthyl with two tie points is called naphthylidene.But aryl does not comprise or is overlapping with the heteroaryl of following independent definition in any form.Therefore, if one or more aromatic carbocyclic and Heterocyclylalkyl aromatic ring condense, the ring of gained is defined heteroaryl of the present invention rather than aryl.
Term " aryloxy " is meant-the O-aryl.
Term " halo " comprises fluoro, chloro, bromo, reaches iodo, and term " halogen " comprises fluorine, chlorine, bromine and iodine.
" haloalkyl " is meant the alkyl of the aforesaid carbon atom with given number that is replaced until the halogen atom of the maximum number that is allowed at most by one or more halogen atoms.The example of haloalkyl includes but not limited to trifluoromethyl, difluoromethyl, 2-fluoro ethyl and pentafluoroethyl group.
" heteroaryl " contained:
Contain one or more as 1 to 4 or in some specific embodiments, contain 1 to 3 and be selected from N, O, and the heteroatoms of S and 5 to 7 yuan of fragrant monocycles that remaining annular atoms is carbon atom; And
Contain one or more as 1 to 4 or in some specific embodiments, contain 1 to 3 be selected from N, O, and the heteroatoms of S and remaining annular atoms be carbon atom and wherein at least one heteroatoms be present in bicyclic heterocycle alkyl ring on the aromatic ring.
For example, heteroaryl comprises 5 to 7 yuan of Heterocyclylalkyl aromatic rings that are fused on 5 to 7 yuan of cycloalkyl or the heterocycloalkyl ring.Wherein only have a ring to contain one or more heteroatomic condensed bicyclic heteroaryl ring systems for these, its tie point can be positioned at arbitrary ring.The sum of S on heteroaryl and O atom surpasses 1, these heteroatomss can not be connected with each other.In some specific embodiments, the sum of S on the heteroaryl and O atom is no more than 2.In some specific embodiments, the sum of S on the aromatic heterocycle and O atom is no more than 1.The example of heteroaryl includes but not limited to (preferentially being numbered 1 from link position) 2-pyridyl, the 3-pyridyl, the 4-pyridyl, 2, the 3-pyrazinyl, 3, the 4-pyrazinyl, 2, the 4-pyrimidyl, 3, the 5-pyrimidyl, 2, the 3-pyrazolinyl, 2,4-imidazolinyl isoxazoline-3-yl oxazolinyl, thiazolinyl, the Thiadiazoline base, tetrazolium, thienyl (thienyl), benzothienyl (benzothiophenyl), furyl, benzofuryl, the benzimidazoline base, indolinyl, pyridizinyl, triazolyl, quinolyl, pyrazolyl, and 5,6,7, the 8-tetrahydroisoquinoline.The name of deutero-divalent group is to add " Ya " corresponding univalent perssad title by remove a hydrogen atom from the free valency carbon atom by the monovalence heteroaryl with " yl " ending, as the pyridyl with two tie points is called pyridylidene.Heteroaryl does not comprise or is overlapping with the defined aryl of the present invention, cycloalkyl or Heterocyclylalkyl.
Substituted heteroaryl also comprises by one or more oxidation (O
-) ring system that substituting group replaced, as pyridyl N-oxide compound.
In the term " heteroaralkyl ", heteroaryl and alkyl such as the present invention define, and tie point is on alkyl.This term includes but not limited to pyridylmethyl, thienyl methyl (thiophenylmethyl), reaches (pyrroles) 1-ethyl.
" Heterocyclylalkyl " is meant the single non-aromatic ring that has 3 to 7 annular atomses usually, and it also contains at least 2 carbon atoms except 1-3 is independently selected from the heteroatoms of oxygen, sulphur and nitrogen and contains at least one aforementioned heteroatomic combination.This ring can be saturated or contain one or more carbon-carbon double bonds.Suitable Heterocyclylalkyl comprises, as (preferentially being numbered 1 from link position) 2-pyrrolinyl, 2,4-imidazolinyl, 2,3-pyrazolidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl and 2,5-piperazinyl (piperzinyl).Also consider morpholinyl, comprise 2-morpholinyl and morpholinyl (wherein preferably being numbered 1) with oxygen.Substituted Heterocyclylalkyl also comprise by one or more oxygen (=O) or oxidation (O
-) ring system that substituting group replaced, as piperidyl N-oxide compound, morpholinyl-N-oxide compound, 1-oxo-1-thio-morpholinyl and 1,1-dioxo-1-thio-morpholinyl.
" Heterocyclylalkyl " also comprises bicyclic ring system, one of them is for having the non-aromatic ring of 3 to 7 annular atomses usually, and it also contains at least 2 carbon atoms except 1-3 is independently selected from the heteroatoms of oxygen, sulphur and nitrogen and contains at least one aforementioned heteroatomic combination; And another ring has 3 to 7 annular atomses usually, randomly contains 1-3 and independently is selected from the heteroatoms of oxygen, sulphur and nitrogen and is non-aromaticity.
" adjusting " used in the present invention is meant the direct or indirect response as the existence of mutual-through type 1 compound, and kinase activity is with respect to the change that does not contain the kinase activity when having this compound.This change can be active increases or activity reduces, and may be because compound and kinase whose direct interaction or owing to compound and one or more other factor interactions that influence kinase activity produce.For example, the existence of compound can by directly combine with kinases, by causing (directly or indirectly) other factors increasing or to reduce kinase activity, or the kinase whose quantity that exists in cell or body by (directly or indirectly) increase or minimizing increases or reduces kinase activity.
Term " sulfane base " (sulfanyl) comprising :-S-(randomly substituted (C
1-C
6) alkyl) ,-S-(randomly substituted aryl) ,-S-(randomly substituted heteroaryl), and-S-(randomly substituted Heterocyclylalkyl).Therefore, the sulfane base comprises C
1-C
6Alkyl alkylthio base.
Term " sulfinyl " comprising :-S (O)-(randomly substituted (C
1-C
6) alkyl) ,-the substituted aryl of S (O)-randomly) ,-the substituted heteroaryl of S (O)-randomly) ,-S (O)-(randomly substituted Heterocyclylalkyl) and-S (O)-(randomly substituted amino).
Term " alkylsulfonyl " comprising :-S (O
2Randomly substituted (C of)-(
1-C
6) alkyl) ,-S (O
2)-randomly substituted aryl) ,-S (O
2)-randomly substituted heteroaryl) ,-S (O
2Randomly substituted Heterocyclylalkyl of)-() ,-S (O
2Randomly substituted alkoxyl group of)-() ,-S (O
2)-randomly substituted aryloxy) ,-S (O
2)-randomly substituted heteroaryloxy) ,-S (O
2Randomly substituted heterocyclyloxy base of)-() and-S (O
2Randomly substituted amino of)-().
Term used in the present invention " substituted " is meant that the group that any or a plurality of hydrogen on specified atom or group is selected from specifies group replaces, and condition is the normal valency that can not surpass specified atom.When substituting group is that (promptly=O) time, 2 hydrogen on the described atom are replaced oxo.The combination of substituting group and/or variable only allows when this combination results stable compound or useful synthetic intermediate.Stable compound or stable structure are meant the enough stable compound that can separate and prepare as the compound that has practicality at least then from reaction mixture.Unless stated otherwise, substituting group is named in the core texture.For example, should understand when (cycloalkyl) alkyl is classified possible substituting group as, the tie point of this substituting group and core texture is at moieties.
Unless otherwise expressly defined, term " substituted " alkyl, cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl are meant that respectively wherein one or more (as maximum 5, as maximum 3) hydrogen atoms are independently selected from the alkyl that substituting group replaced, cycloalkyl, aryl, Heterocyclylalkyl and the heteroaryl of following group:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(as, methylene-dioxy-) ,-SR
b, the guanidine that replaced by low alkyl group of guanidine, wherein one or more guanidine radicals hydrogen ,-NR
bR
c, halogen, cyano group, nitro, oxo base (as the substituting group of cycloalkyl, Heterocyclylalkyl and heteroaryl) ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
cCOR
b,-NR
cCO
2R
a,-NR
cCONR
bR
c,-CO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cAnd-NR
cSO
2R
a,
R wherein
aBe selected from randomly substituted C
1-C
6Alkyl, randomly substituted alkene, randomly substituted alkynyl, randomly substituted aryl and randomly substituted heteroaryl;
R
bBe selected from H, substituted C randomly
1-C
6Alkyl, randomly substituted aryl and randomly substituted heteroaryl; And
R
cBe independently selected from hydrogen and randomly substituted C
1-C
4Alkyl; Or
R
bAnd R
cTogether form randomly substituted Heterocyclylalkyl with its nitrogen that is connected; And
Each randomly substituted group is unsubstituted or is independently selected from the substituting group replacement of following groups: C independently by one or more (as one, two or three)
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo base (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl), and-NHSO
2(C
1-C
4Haloalkyl).
Term " substituted acyl group " be meant group (substituted alkyl)-C (O)-;-(substituted cycloalkyl)-C (O)-; (substituted aryl)-C (O)-; (substituted heteroaryl)-C (O)-; and (substituted Heterocyclylalkyl)-C (O)-; wherein this group links to each other with precursor structure by the carbonyl functional group; and wherein substituted alkyl; cycloalkyl; aryl; heteroaryl; and Heterocyclylalkyl is meant that respectively wherein one or more (as maximum 5, as maximum 3) hydrogen atoms are independently selected from the alkyl that substituting group replaced of following group; cycloalkyl; aryl; heteroaryl; and Heterocyclylalkyl:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(as methylene-dioxy-) ,-SR
b, the guanidine that replaced by low alkyl group of guanidine, wherein one or more guanidine radicals hydrogen ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
cCOR
b,-NR
cCO
2R
a,-NR
cCONR
bR
c,-CO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
c, and-NR
cSO
2R
a,
R wherein
aBe selected from randomly substituted C
1-C
6Alkyl, randomly substituted alkene, randomly substituted alkynyl, randomly substituted aryl and randomly substituted heteroaryl;
R
bBe selected from H, substituted C randomly
1-C
6Alkyl, randomly substituted aryl and randomly substituted heteroaryl; And
R
cBe independently selected from hydrogen and randomly substituted C
1-C
4Alkyl; Or
R
bAnd R
cTogether form randomly substituted Heterocyclylalkyl with its nitrogen that is connected; And
Each randomly substituted group is unsubstituted or is independently selected from the substituting group replacement of following group: C independently by one or more (as one, two or three)
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo base (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl), and-NHSO
2(C
1-C
4Haloalkyl).
Term " substituted alkoxyl group " is meant wherein the substituted alkoxyl group of alkyl composition (promptly-O-(substituted alkyl)), wherein " substituted alkyl " is meant that wherein one or more (as maximum 5, as maximum 3) hydrogen atoms are independently selected from the alkyl that substituting group replaced of following group:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(as methylene-dioxy-) ,-SR
b, the guanidine that replaced by low alkyl group of guanidine, wherein one or more guanidine radicals hydrogen ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
cCOR
b,-NR
cCO
2R
a,-NR
cCONR
bR
c,-CO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cWith-NR
cSO
2R
a,
R wherein
aBe selected from randomly substituted C
1-C
6Alkyl, randomly substituted alkene, randomly substituted alkynyl, randomly substituted aryl, and randomly substituted heteroaryl;
R
bBe selected from H, substituted C randomly
1-C
6Alkyl, randomly substituted aryl, and randomly substituted heteroaryl; And
R
cBe independently selected from hydrogen and randomly substituted C
1-C
4Alkyl; Or
R
bAnd R
cTogether form randomly substituted Heterocyclylalkyl with its nitrogen that is connected; And
Each randomly substituted group is unsubstituted or is independently selected from the substituting group replacement of following group: C independently by one or more (as one, two or three)
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo base (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl), and-NHSO
2(C
1-C
4Haloalkyl).In some specific embodiments, substituted alkoxyl group be " poly-alkoxyl group " or-O-(randomly substituted alkylidene group)-(randomly substituted alkoxyl group), and comprise that group is as-OCH
2CH
2OCH
3, the residue of glycol ethers such as polyoxyethylene glycol and-O (CH
2CH
2O)
xCH
3, wherein x is the integer of 2-20, as 2-10, and 2-5 for example.Another kind of substituted alkoxyl group be the hydroxy alkoxy base or-OCH
2(CH
2)
yOH, wherein y is the integer of 1-10, as 1-4.
Term " substituted alkoxy carbonyl " be meant group (substituted alkyl)-O-C (O)-, wherein this group is to link to each other with precursor structure by the carbonyl functional group, and wherein substituted alkyl is meant that wherein one or more (as maximum 5, as maximum 3) hydrogen atoms are independently selected from the alkyl that substituting group replaced of following group:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(as methylene-dioxy-) ,-SR
b, the guanidine that replaced by low alkyl group of guanidine, wherein one or more guanidine radicals hydrogen ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
cCOR
b,-NR
cCO
2R
a,-NR
cCONR
bR
c,-CO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cWith-NR
cSO
2R
a,
R wherein
aBe selected from randomly substituted C
1-C
6Alkyl, randomly substituted alkene, randomly substituted alkynyl, randomly substituted aryl, and randomly substituted heteroaryl;
R
bBe selected from H, substituted C randomly
1-C
6Alkyl, randomly substituted aryl, and randomly substituted heteroaryl; And
R
cBe independently selected from hydrogen and randomly substituted C
1-C
4Alkyl; Or
R
bAnd R
cTogether form randomly substituted Heterocyclylalkyl with its nitrogen that is connected; And
Each randomly substituted group is unsubstituted or is independently selected from the substituting group replacement of following group: C independently by one or more (as one, two or three)
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo base (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl), and-NHSO
2(C
1-C
4Haloalkyl).
Term " substituted amino " is meant group-NHR
dOr-NR
dR
eR wherein
dBe to be selected from: hydroxyl, randomly substituted alkoxyl group, randomly substituted alkyl, randomly substituted cycloalkyl, randomly substituted acyl group, randomly substituted aryl, randomly substituted heteroaryl, randomly substituted Heterocyclylalkyl, alkoxy carbonyl, sulfinyl and alkylsulfonyl, and R wherein
eBe selected from: randomly substituted alkyl, randomly substituted cycloalkyl, randomly substituted acyl group, randomly substituted aryl, randomly substituted heteroaryl, randomly substituted Heterocyclylalkyl, alkoxy carbonyl, sulfinyl and alkylsulfonyl; and wherein substituted alkyl, cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl are meant that respectively wherein one or more (as maximum 5, as maximum 3) hydrogen atoms are independently selected from the alkyl that substituting group replaced of following group, cycloalkyl, aryl, Heterocyclylalkyl, reach heteroaryl:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(as methylene-dioxy-) ,-SR
b, the guanidine that replaced by low alkyl group of guanidine, wherein one or more guanidine radicals hydrogen ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
cCOR
b,-NR
cCO
2R
a,-NR
cCONR
bR
c,-CO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cWith-NR
cSO
2R
a,
R wherein
aBe selected from randomly substituted C
1-C
6Alkyl, randomly substituted alkene, randomly substituted alkynyl, randomly substituted aryl, and randomly substituted heteroaryl;
R
bBe selected from H, substituted C randomly
1-C
6Alkyl, randomly substituted aryl, and randomly substituted heteroaryl; And
R
cBe independently selected from hydrogen and randomly substituted C
1-C
4Alkyl; Or
R
bAnd R
cTogether form randomly substituted Heterocyclylalkyl with its nitrogen that is connected; And
Each randomly substituted group is unsubstituted or is independently selected from the substituting group replacement of following group: C independently by one or more (as one, two or three)
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo (as the replacement of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl), and-NHSO
2(C
1-C
4Haloalkyl), and
Wherein randomly substituted acyl group, alkoxy carbonyl, sulfinyl and alkylsulfonyl such as the present invention define.
Term " substituted amino " also refers to aforesaid separately group-NHR
d, and NR
dR
dThe N-oxide compound.The N-oxide compound can be by obtaining with handling corresponding amino as hydrogen peroxide or metachloroperbenzoic acid.Those skilled in the art are afamiliar with the reaction conditions that carries out the N-oxidation.
" amidino groups " be meant-C (=NH)-NH
2
" substituted amidino groups " is meant group-C (=NR
e)-NR
fR
g, R wherein
e, R
f, and R
gBe independently selected from: hydrogen, randomly substituted alkyl, randomly substituted cycloalkyl, randomly substituted aryl, randomly substituted heteroaryl, and randomly substituted Heterocyclylalkyl, condition is R
e, R
f, and R
gAt least one for hydrogen and wherein substituted alkyl, cycloalkyl, aryl, Heterocyclylalkyl, and heteroaryl be meant that respectively wherein one or more (as maximum 5, as maximum 3) hydrogen atoms are independently selected from the alkyl that substituting group replaced of following group, cycloalkyl, aryl, Heterocyclylalkyl, and heteroaryl:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(as methylene-dioxy-) ,-SR
b, the guanidine that replaced by low alkyl group of guanidine, wherein one or more guanidine radicals hydrogen ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
cCOR
b,-NR
cCO
2R
a,-NR
cCONR
bR
c,-CO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cAnd-NR
cSO
2R
a,
R wherein
aBe selected from randomly substituted C
1-C
6Alkyl, randomly substituted alkene, randomly substituted alkynyl, randomly substituted aryl, and randomly substituted heteroaryl;
R
bBe selected from H, substituted C randomly
1-C
6Alkyl, randomly substituted aryl, and randomly substituted heteroaryl; And
R
cBe independently selected from hydrogen and randomly substituted C
1-C
4Alkyl; Or
R
bAnd R
cTogether form randomly substituted Heterocyclylalkyl with its nitrogen that is connected; And
Wherein each randomly substituted group is that substituting group unsubstituted or that be independently selected from following group by one or more (as, two or three) independently replaces: C
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo (as the replacement of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl), and-NHSO
2(C
1-C
4Haloalkyl).
The compound of general formula 1 includes but not limited to optical isomer, racemoid and other mixtures thereof of the compound of general formula 1.In these cases, can obtain single enantiomorph or diastereomer by the fractionation of asymmetric synthesis or racemic modification, promptly optically active form.The fractionation of racemic modification can by as conventional method as in the presence of resolving agent, carrying out crystallization, or use realizes as the chromatography of chirality high-pressure liquid phase (HPLC) chromatographic column.In addition, the compound of general formula 1 comprises the Z-formula of the compound with carbon-to-carbon double bond and E-formula (or suitable-Shi and anti--Shi).When the compound of general formula 1 existed with multiple tautomeric forms, chemicals entity of the present invention comprised all tautomeric forms of this compound.
Chemical entities of the present invention includes but not limited to the compound and the acceptable form of all pharmacology thereof of general formula 1.The acceptable form of the pharmacology of compound of the present invention comprises the acceptable salt of pharmacology, solvate, crystalline form (comprising polymorphic form and inclusion compound), inner complex, non-covalent complex, prodrug and their mixture.In some specific embodiments, compound of the present invention is the form that adopts the acceptable salt of pharmacology.Therefore, term " chemical entities " also comprises the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and their mixture.
" the acceptable salt of pharmacology " includes but not limited to the salt with mineral acid formation, example hydrochloric acid salt, phosphoric acid salt, diphosphate, hydrobromate, vitriol,-sulfinate, nitrate etc.; And the salt that forms with organic acid, as malate, maleate, fumarate, tartrate, succinate, Citrate trianion, acetate, lactic acid salt, mesylate, tosilate, 2-isethionate, benzoate, salicylate, stearate and alkyl salt such as acetate, HOOC-(CH
2)
n-COOH, wherein n is 0-4 etc.Equally, the acceptable positively charged ion of pharmacology includes but not limited to sodium, potassium, calcium, aluminium, lithium, reaches ammonium.
In addition, if the compound of general formula 1 then can obtain free alkali by the alkalizing of solution with this acid-salt with the form acquisition of acid salt.On the contrary, as fruit product is free alkali, then can be according to the ordinary method that is used for preparing acid salt by free alkali being dissolved in suitable organic solvent and obtaining additive salt with this solution of acid treatment by basic cpd, pharmacology acceptable addition salt especially.Person of skill in the art will appreciate that multiple synthetic method can be used for preparing nontoxic pharmacology acceptable addition salt.
As above put down in writing, prodrug also is encompassed in the scope of chemical entities, as the ester or the amide derivatives of the compound of general formula 1.When term " prodrug " comprises patient's administration as any compound of the compound that in the prodrug metabolic process, can become general formula 1.The example of prodrug includes but not limited to acetate, formic acid, and the benzoic acid derivative of the functional group's (as alcohol or amido) in the compound of general formula 1.
Term " solvate " is meant the chemical entities that solvent and compound interact and form.The The suitable solvent thing is a pharmacology acceptable solvent thing, as hydrate, comprises monohydrate and semihydrate.
Term " inner complex " is meant the chemical entities that compound and metal ion form in two point (or more) coordinations.
Term " non-covalent complex " is meant the chemical entities that forms by the interaction that can not form covalent linkage between wherein this compound of compound and another kind of molecule and the described molecule.For example can be undertaken compound by Van der Waals interaction, hydrogen bond and electrostatic interaction (also claiming ionic linkage).
Term " active substance " is used in reference to the chemical entities of biologically active.In some specific embodiments, " active substance " is the compound with pharmaceutical use.For example active substance can be the anticancer therapy medicine.
" the treatment significant quantity " of term chemical entities of the present invention be meant when to people or non-human patients administration, can effectively provide the treatment benefit as improve symptom, slow down disease progression or prophylactic amount, for example treating significant quantity and can being be enough to reduce the amount of symptom that Btk is suppressed the disease of response.In some specific embodiments, the treatment significant quantity is meant the amount that is enough to reduce cancer symptoms, supersensitivity illness symptom, autoimmunization and/or inflammatory diseases symptom or acute inflammatory reaction symptom.In some specific embodiments, the treatment significant quantity is the amount that is enough to reduce detectable cancer cells quantity in the organism, is enough to slow down with detecting or to stop tumor growth.In some specific embodiments, the treatment significant quantity is the amount that is enough to dwindle tumour.There is not illness symptom (symptoms of being affected) in the patient who suffers from cancer in some cases.In some specific embodiments, the treatment significant quantity of chemical entities be enough to prevent in blood samples of patients, serum or the tissue can detected cancer cells or the obvious increase of cancer markers level or obvious less blood samples of patients, serum or tissue in can detected cancer cells or the amount of cancer markers level.In the method that is used for the treatment of supersensitivity illness and/or autoimmunization and/or inflammatory diseases and/or acute inflammatory reaction of the present invention, the treatment significant quantity can also be to be enough to slow down disease progression when to patient's administration with detecting, or prevents the patient of this chemical entities institute administration the amount of the symptom of supersensitivity illness and/or autoimmunization and/or inflammatory diseases and/or acute inflammatory reaction to occur.In some method that is used for the treatment of supersensitivity illness and/or autoimmunization and/or inflammatory diseases and/or acute inflammatory reaction of the present invention, the treatment significant quantity can also be the amount that is enough to make the amount of labelled protein in blood samples of patients or the serum or cell type to reduce with detecting.For example, in some specific embodiments, the treatment significant quantity is the amount that is enough to significantly to reduce the chemical entities of the present invention of B cytoactive.In another example, in some specific embodiments, the treatment significant quantity is the amount that is enough to significantly to reduce the chemical entities of the present invention of B cell number.In another example, in some specific embodiments, the treatment significant quantity is the amount that is enough to reduce the chemical entities of the present invention of the level of anti-acetylcholine receptor antibodies in the blood samples of patients of suffering from disease myasthenia gravis.
The baseline of term " inhibition " expression biological activity or process is active significantly to descend." suppress Btk activity " is meant that the active speech of Btk when not having at least a chemical entities is directly or indirectly in response to the active reduction of Btk of the existence of at least a chemical entities of the present invention.This active reduction may be because the direct interaction of compound and Btk, perhaps influences active other factor interactions of Btk owing to chemical entities of the present invention and one or more.For example, the existence of this chemical entities may be by directly combining with Btk, by causing (directly or indirectly) another kind of factor to reduce the Btk activity, perhaps by (directly or indirectly) thus the Btk that exists in reduction cell or the body measures reduction Btk activity.
Suppressing the Btk activity also refers to be used for the active observable inhibition of ATP hydrolysis experiment Btk as described below of the active standard biochemical test of Btk.In some specific embodiments, the IC of chemical entities of the present invention
50Value is less than or equal to 10 micromoles.In some specific embodiments, the IC of this chemical entities
50Value is less than or equal to and is lower than 1 micromole.In some specific embodiments, the IC of this chemical entities
50Value is less than or equal to 0.1 micromole.
" suppress B cytoactive " is meant for the B cytoactive when not having at least a chemical entities directly or indirectly the reduction in response to the B cytoactive that has at least a chemical entities of the present invention.This active reduction may be because the direct interaction of compound and Btk perhaps causes with one or more other factor interactions that influence the B cytoactive.
Suppress the observable inhibition that the B cytoactive refers to that also CD86 expresses in standard test test as described below.In some specific embodiments, the IC of chemical entities of the present invention
50Value is less than or equal to 10 micromoles.In some specific embodiments, the IC50 value of this chemical entities is less than or equal to and is lower than 1 micromole.In some specific embodiments, the IC of this chemical entities
50Value is less than or equal to 500 nmoles.
" B cytoactive " also comprises activation, heavily distribution (redistribution), recombinates (reorganization) or adds one or more different B cell-membrane receptor or membrane bound immunoglobulins of cap (capping), as IgM, IgG and IgD.Most of B cells also have membrane receptor with antigen-antibody complex form or accumulative IgG form to the Fc of IgG part.The B cell also carries the activating component that is used for complement such as the membrane receptor of C3b, C3d, C4 and Clq.Thereby membrane receptor that these are different and membrane bound immunoglobulin have the film movability and can and or add cap and start signal transduction through overweight distribution.
The B cytoactive also comprises the synthetic of antibody or immunoglobulin (Ig) or generates.Immunoglobulin (Ig) is synthetic and have common constitutional features and a structural unit by B clone.Comprise that according to the textural difference of its heavy chain aminoacid sequence and polypeptide chain length determined five immunoglobulin like protein, i.e. IgG, IgA, IgM, IgD and IgE.The immunoglobulin (Ig) of single type or subclass can be found or can be defined as to given antigenic antibody in all or some kinds of immunoglobulin (Ig)s.Autoantibody or autoimmune antibody can belong to a kind of or some kinds of immunoglobulin (Ig)s equally.For example, the rheumatism factor (antibody of IgG) is often to be considered to the IgM immunoglobulin (Ig), but also can be made up of IgG or IgA.
In addition, the B cytoactive also is intended to comprise a series of B of causing cells from precursor bone-marrow-derived lymphocyte clonal expansion (propagation) and be divided into the incident of antibody dextran cell, and it takes place relevant and relevant with the cytokine signaling from other cell with the antigen combination.
" inhibition B cell proliferation " be meant suppress unusual B cell such as cancer B cell, as the propagation of lymphoma B cell and/or suppress normal non-disease B cell.Any remarkable reduction of the quantity of the external or intravital B cell of term " inhibition B cell proliferation " expression.Therefore, whether the vitro inhibition B cell proliferation can be to compare with the coupling sample that does not or not contact described chemical entities, the remarkable reduction of the B cell quantity of the vitro samples that contacts with at least a chemical entities of the present invention.
Suppressing B cell proliferation also refers in the inhibition of the standard thymus pyrimidine that is used for B cell proliferation in conjunction with the test observable B cell proliferation of test as described below.In some specific embodiments, the IC of this chemical entities
50Value is less than or equal to 10 micromoles.In some specific embodiments, the IC of this chemical entities
50Value is less than or equal to and is lower than 1 micromole.In some specific embodiments, the IC of this chemical entities
50Value is less than or equal to 500 nmoles.
" transformation reactions " or " supersensitivity illness " is meant the acquired hypersensitivity to material (anaphylactogen).The supersensitivity illness comprises eczema, allergic rhinitis or cold, ragweed fever, bronchial asthma, rubella (measles) and food anaphylaxis and other hereditary anaphylactic diseases.
" asthma " is meant the respiratory system disease that the reactivity of inhaled material is increased to feature with inflammation, tracheae contraction and tracheae.Asthma usually but not relevant with atopy or allergic symptom not exclusively.
" significantly " be meant any can detectedly variation, it has significance on the statistics in the check of canonical parameter of significance,statistical, for example Student (Student ' s T-test), wherein p＜0.05.
" to suppressing the disease of the active response of Btk " is meant that wherein suppressing the Btk kinases provides the treatment benefit as improving symptom, reduce progression of disease, prevent or delay seizure of disease or suppress the disease of the abnormal activity of some cell type (monocyte, B cell and mastocyte).
" handle or treatment " and be meant any processing, comprising patient disease:
A) preventing disease promptly causes the clinical symptom of this disease not develop;
B) suppress this disease;
C) slow down or stop the development of clinical symptom; And/or
D) palliate a disease, promptly cause clinical symptom to disappear.
The animal of the object that " patient " is meant to be become or will become treatment, observe or test is as Mammals.The inventive method can be used for the human treatment and the animal doctor uses.In some specific embodiments, this patient is a Mammals; In some specific embodiments, this patient behaves; And in some specific embodiments, this patient is selected from cat and dog.
Embodiment
In some specific embodiments, the invention provides at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from the compound of general formula I:
Wherein:
R
1Be selected from randomly substituted phenylene, randomly substituted pyridylidene, 2-oxo-1 arbitrarily, 2-dihydropyridine base,
Wherein
*The tie point of representative and-L-G group, scission of link representative and amino tie point; And X wherein
1Be selected from N and CR
7X
2Be selected from N and CR
7X
3Be selected from N and CR
7X wherein
1, X
2And X
3In no more than one be N and R
7Be selected from hydrogen, hydroxyl, cyano group, halogen, randomly substituted low alkyl group and randomly substituted lower alkoxy;
L is selected from covalent linkage, substituted C randomly
1-C
4Alkylidene group ,-O-,-O-(randomly substituted C
1-C
4Alkylidene group)-,-(C=O)-,-(randomly substituted C
1-C
4Alkylidene group) (C=O)-, (SO)-,-(randomly substituted C
1-C
4Alkylidene group) (SO)-, (SO
2)-,-(randomly substituted C
1-C
4Alkylidene group) (SO
2)-,-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-, be R wherein
9Be selected from hydrogen, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl;
G be selected from hydrogen, halogen, hydroxyl, alkoxyl group, nitro, randomly substituted alkyl ,-NR
16R
17, randomly substituted Heterocyclylalkyl, randomly substituted cycloalkyl, randomly substituted aryl and randomly substituted heteroaryl, wherein R
16And R
17Be independently selected from hydrogen, randomly substituted acyl group, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl; Or be selected from-(C=NR as L
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9) time ,-R
9And R
16Nitrogen with its bonding forms randomly substituted 5 to 7 member heterocyclic ring containing nitrogen alkyl, and this Heterocyclylalkyl randomly further comprises one or two extra heteroatoms that is selected from N, O and S and R
17Be selected from hydrogen, randomly substituted acyl group, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl;
T, V and W are selected from C and N, and U is selected from-CH and N, and condition is that T, U, V and W have one to be N at most;
R
2, R
3And R
4Be independently selected from hydrogen, randomly substituted low alkyl group, randomly substituted lower alkoxy, halogen and hydroxyl, condition be when A be covalent linkage, G is-NR
16R
17And L is not selected from-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-time, R
2, R
3And R
4In have one at least for hydrogen, work as R
2, R
3Or R
4When bonded T, V or W are N respectively, R
2, R
3Or R
4Do not exist.
Q is selected from
Wherein:
R
10And R
11Be independently selected from hydrogen, C
1-C
6Alkyl and C
1-C
6Haloalkyl; And
R
12, R
13, R
14And R
15Be independently selected from respectively
Hydrogen,
C
1-C
6Alkyl,
C
1-C
6Haloalkyl,
Phenyl,
Be selected from the substituted phenyl of single replacement, two replacements, tri-substituted phenyl, wherein said substituting group is independently selected from hydroxyl, nitro, cyano group, amino, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, (C
1-C
6Alkyl oxy) C
1-C
6Alkoxyl group, C
1-C
6Perfluoroalkyl, C
1-C
6Perfluoro alkoxy, list (C
1-C
6Alkyl) amino, two (C
1-C
6Alkyl) amino and amino (C
1-C
6Alkyl),
Heteroaryl, and
Be selected from that single replacement, two replaces and three substituted heteroaryls substituted heteroaryl, wherein said substituting group is independently selected from hydroxyl, nitro, cyano group, amino, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, (C
1-C
6Alkyl oxy) C
1-C
6Alkoxyl group, C
1-C
6Perfluoroalkyl, C
1-C
6Perfluoro alkoxy, list (C
1-C
6Alkyl) amino, two (C
1-C
6Alkyl) amino and amino (C
1-C
6Alkyl);
A be selected from covalent linkage and-(CH=CH)-;
R
5Be selected from randomly substituted cycloalkyl, randomly substituted Heterocyclylalkyl, randomly substituted aryl and randomly substituted heteroaryl; And
R
6Be selected from hydrogen, randomly substituted alkyl, cycloalkyl and Heterocyclylalkyl.
In some specific embodiments, A is a covalent linkage.In some specific embodiments, A is-(CH=CH)-.
In some specific embodiments, R
12, R
13, R
14, and R
15Be independently selected from hydrogen, C
1-C
6Alkyl, C
1-C
6Haloalkyl, and phenyl.In some specific embodiments, R
13Be selected from hydrogen and C
1-C
6Alkyl.
In some specific embodiments, Q is
R wherein
13Be selected from hydrogen and C
1-C
6Alkyl.
In some specific embodiments, R
5Be selected from
Phenyl,
Be selected from the substituted phenyl of single replacement, two replacements and tri-substituted phenyl; wherein said substituting group is independently selected from hydroxyl, low alkyl group, sulfane base, alkylsulfonyl, randomly substituted amino, lower alkoxy, the low alkyl group that is replaced by one or more halogens, the lower alkoxy that is replaced by one or more halogens, the low alkyl group that is replaced by hydroxyl, and heteroaryl
Pyridyl,
Be selected from the substituted pyridyl of single replacement, two replacements and three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Pyrimidyl,
Be selected from the substituted pyrimidyl of single replacement, two replacements and three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Pyrazinyl,
Be selected from the substituted pyrazinyl of single replacement, two replacements and three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Pyridazinyl,
Be selected from the substituted pyridazinyl of single replacement, two replacements and three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Oxazole-2-base,
The Bei that is selected from single replacement, two replacements and San substituted oxazole-2-base replaces De oxazole-2-base, and wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
The 2H-pyrazole-3-yl,
Be selected from the substituted 2H-pyrazole-3-yl of single replacement, two replacements and three replacement 2H-pyrazole-3-yls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
[1,2,3] thiadiazoles-4-base,
Be selected from substituted [1,2, the 3] thiadiazoles-4-base of single replacement, two replacements and three replacement [1,2,3] thiadiazoles-4-bases, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Isoxazole-5-base,
Be selected from the substituted isoxazole-5-base of single replacement, two replacements and three substituted isoxazoles-5-base, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
4,5,6,7-tetrahydro benzo [b] thiophene-2-base,
Be selected from single replacement, two replacements and three replacements 4,5,6; substituted 4,5,6 of 7-tetrahydro benzo [b] thiophene-2-base; 7-tetrahydro benzo [b] thiophene-2-base, wherein said substituting group are independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reach heteroaryl
4,5,6,7-tetrahydrochysene benzfuran-2-base,
Be selected from single replacement, two replacements and three replacements 4,5,6; substituted 4,5,6 of 7-tetrahydrochysene benzfuran-2-base; 7-tetrahydrochysene benzfuran-2-base, wherein said substituting group are independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reach heteroaryl
4,5,6,7-tetrahydrochysene-1H-indoles-2-base,
Be selected from single replacement, two replacements and three replacements 4; 5; 6; substituted 4,5,6 of 7-tetrahydrochysene-1H-indoles-2-base; 7-tetrahydrochysene-1H-indoles-2-base; wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl, and the low alkyl group that the amido nitrogen of wherein said indole ring randomly is optionally substituted replaces
1H-indoles-2-base,
Be selected from the substituted 1H-indoles-2-base of single replacement, two replacements and three substituted 1 H-indoles-2-base; wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl; and the low alkyl group that the amido nitrogen of wherein said indole ring randomly is optionally substituted replaces
The 1H-indol-3-yl,
Be selected from the substituted 1H-indol-3-yl of single replacement, two replacements and three substituted 1 H-indoles-3-base; wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl; and the low alkyl group that the amido nitrogen of wherein said indole ring randomly is optionally substituted replaces
Cumarone-2-base,
Be selected from the substituted cumarone-2-base of single replacement, two replacements and trisubstituted benzene and furans-2-base, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Benzo [b] thiophene-2-base,
Be selected from also substituted benzo [b] thiophene-2-base of [b] thiophene-2-base of single replacement, two replacements and trisubstituted benzene, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Quinoline-3-base, and
Be selected from the substituted quinoline-3-base of single replacement, two replacements, three substd quinolines-3-base, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
In some specific embodiments, R
5Be selected from phenyl and substituted phenyl; wherein said substituted phenyl is selected from single replacement, two and replaces and trisubstd phenyls, and wherein said substituting group is independently selected from hydroxyl, low alkyl group, sulfane base, alkylsulfonyl, randomly substituted amino, lower alkoxy, the low alkyl group that is replaced by one or more halogens, the lower alkoxy that is replaced by one or more halogens, the low alkyl group and the heteroaryl that are replaced by hydroxyl.
In some specific embodiments, R
5Single replacement, two replaces and the substituted phenyl of tri-substituted phenyl in order to be selected from, and wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy and heteroaryl.In some specific embodiments, R
5For 4-low alkyl group-phenyl-.In some specific embodiments, R
5Be the 4-tertiary butyl-phenyl.
In some specific embodiments, R
1Be selected from adjacent phenylene, metaphenylene, to phenylene, adjacent pyridylidene, a pyridylidene, to pyridylidene,
In some specific embodiments, R
1Be selected from adjacent phenylene, metaphenylene, to phenylene, adjacent pyridylidene, a pyridylidene with to pyridylidene.In some specific embodiments, R
1Be selected from phenylene and metaphenylene.In some specific embodiments, R
1For to phenylene.
In some specific embodiments, L be selected from covalent linkage ,-(C=O)-,-CH
2-,-SO
2-,-CH
2(C=O)-,-CH (CH
3) (C=O)-,-CH
2CH
2(C=O)-,-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-.In some specific embodiments, L is selected from-(C=O)-,-CH
2-,-SO
2-,-CH
2(C=O)-and-CH (CH
3) (C=O)-.In some specific embodiments, L is-(C=O)-.
In some specific embodiments, G is selected from
Hydrogen,
Hydroxyl,
-NR
16R
17、
Randomly substituted Heterocyclylalkyl,
Randomly substituted 5,6-dihydro-8H-imidazo [1,2-a] pyrazine-7-base,
Lower alkoxy and
1H-tetrazolium-5-base.
In some specific embodiments, G is selected from
Hydrogen,
Hydroxyl,
N-methyl ethanol amino,
Randomly substituted 4,5-dihydro-1H-imidazoles-2-base;
Randomly substituted morpholine-4-base,
Randomly substituted piperazine-1-base, and
Randomly substituted high piperazine (homopiperazin) 1-base.
In some specific embodiments, G is selected from
Hydrogen,
Morpholine-4-base,
4-acyl group-piperazine-1-base,
4-low alkyl group-piperazine-1-base,
3-oxo-piperazine-1-base,
High piperazine-1-base, and
4-low alkyl group-Gao piperazine-1-base.
In some specific embodiments, G is selected from-NR
16R
17, and randomly substituted Heterocyclylalkyl.In some specific embodiments, G is selected from randomly substituted morpholine-4-base and substituted piperazine-1-base randomly.In some specific embodiments, G is morpholine-4-base.
In some specific embodiments, L is selected from-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-, and G are-NR
16R
17
In some specific embodiments, R
16And R
17Be independently selected from hydrogen and randomly substituted alkyl.In some specific embodiments, when L is selected from-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9) time ,-R
9And R
16Form randomly substituted 5 to 7 member heterocyclic ring containing nitrogen alkyl with its bonded nitrogen, it randomly further comprises one or two extra heteroatoms that is selected from N, O and S and R
17Be selected from hydrogen, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl;
In some specific embodiments, R
9Be selected from hydrogen and low alkyl group.In some specific embodiments, R
9Be selected from hydrogen and methyl.
In some specific embodiments, R
6Be hydrogen.
In some specific embodiments, R
2Be selected from methyl, trifluoromethyl, difluoromethyl, methoxyl group, trifluoromethoxy, difluoro-methoxy and fluorine.In some specific embodiments, R
2Be methyl.In some specific embodiments, R
3And R
4Be hydrogen.
In some specific embodiments, R
3Be selected from methyl, trifluoromethyl, difluoromethyl, methoxyl group, trifluoromethoxy, difluoro-methoxy and fluorine.In some specific embodiments, R
3Be methyl.In some specific embodiments, R
2And R
4Be hydrogen.
In some specific embodiments, R
4Be selected from methyl, trifluoromethyl, difluoromethyl, methoxyl group, trifluoromethoxy, difluoro-methoxy and fluorine.In some specific embodiments, R
4Be methyl.In some specific embodiments, R
2And R
3Be hydrogen.
In some specific embodiments, T, V and W are that C and U are-CH.
The present invention also provides at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from general formula 2 compounds,
R wherein
5, R
2, R
3, R
4, T, U, V, W, R
6, L and G be as described in the general formula 1.
The present invention also provides at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from general formula 3 compounds:
R wherein
2, R
3, R
4, T, U, V, W, R
6, L and G be as described in the general formula 1; And wherein
X is selected from O, S, NR
18,-CH=N-and-N=CH-;
R
18Be selected from hydrogen, randomly substituted alkyl, randomly substituted aryl, and randomly substituted heteroaryl; And
R
20Represent 0 to 3 to be independently selected from hydroxyl, nitro, cyano group, amino, halogen, C
1-C
6Alkyl, C
1-C
2Haloalkyl, C
1-C
2Halogenated alkoxy, C
1-C
6Alkoxyl group, list (C
1-C
4Alkyl) amino, two-(C
1-C
4Alkyl) amino, and amino (C
1-C
4Alkyl) substituting group.
In some specific embodiments, X is selected from O, NR
18,-CH=N-and-N=CH.In some specific embodiments, X is selected from O and NR
18
In some specific embodiments, R
20Do not exist.
The present invention also provides at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from general formula 4 compounds:
R wherein
2, R
3, R
4, T, U, V, W, R
6, L and G be as described in general formula 1 compound; And wherein
Y and Z are independently selected from CH and N;
R
19Be selected from hydrogen, hydroxyl, low alkyl group, alkylsulfonyl, randomly substituted amino, lower alkoxy, the low alkyl group that is replaced by one or more halogens, the lower alkoxy that is replaced by one or more halogens, the low alkyl group that is replaced by hydroxyl, and heteroaryl; And
R
20Be selected from hydrogen, low alkyl group, halogen, lower alkoxy and hydroxyl.
In some specific embodiments, Y and Z are CH.
In some specific embodiments, R
19Be selected from hydrogen and low alkyl group.In some specific embodiments, R
19Be selected from hydrogen, sec.-propyl and the tertiary butyl.In some specific embodiments, R
19Be the tertiary butyl.
In some specific embodiments, R
20Do not exist.
In some specific embodiments, at least a chemical entities is to be selected from
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
N-(5-{8-[4-(4-ethanoyl-piperazine-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-the 4-tertiary butyl-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(N-methyl-hydroxyethyl-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(N, N-dimethyl-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(N-methyl isophthalic acid-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(acid amides)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(4-methyl-piperazine-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
N-(5-{8-[4-(4-ethanoyl-piperazine-1-yl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-the 4-tertiary butyl-benzamide;
The 4-tertiary butyl-N-(2-fluoro-5-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-{2-methyl-5-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(3-oxo-piperazine-1-ylmethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
N-(5-{8-[4-(4-ethanoyl-piperazine-1-ylmethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-the 4-tertiary butyl-benzamide;
The 4-tertiary butyl-N-(5-{8-[4-(5,6-dihydro-8H-imidazo [1,2-a] pyrazine-7-ylmethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
(4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenyl)-acetate;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(2-morpholine-4-base-2-oxo-ethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-{5-[8-(4-{[(2-hydroxyl-ethyl)-methyl-formamyl]-methyl }-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide;
The 4-tertiary butyl-N-[2-methyl-5-(8-{4-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-phenyl amino }-imidazo [1,2-a] pyrazine-6-yl)-phenyl]-benzamide;
(3-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenyl)-acetate;
The 4-tertiary butyl-N-(2-methyl-5-{8-[3-(2-morpholine-4-base-2-oxo-ethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-[2-methyl-5-(8-{3-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-phenyl amino }-imidazo [1,2-a] pyrazine-6-yl)-phenyl]-benzamide;
The 4-tertiary butyl-N-{5-[8-(3-formyl-dimethylamino methyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide;
2-(3-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenyl)-propionic acid;
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methoxyl group-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(1-methyl-2-morpholine-4-base-2-oxo-ethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-fluoro-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(4-methyl-piperazine-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl hydroxyethyl-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methylethyl-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
4-{6-[5-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
The 4-tertiary butyl-N-(4-methyl-3-{8-[4-(N-methyl hydroxyethyl-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-ethyl benzoate;
The 4-tertiary butyl-N-(2-fluoro-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 6-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
[1,2,3] thiadiazoles-4-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
Isoxazole-5-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
Pyridine-2-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
The 6-tertiary butyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-niacinamide;
The 4-tertiary butyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
4-sec.-propyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
The 6-hydroxy-n-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
The 5-tertiary butyl-oxazoles-2-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-4-methyl sulfane base-benzamide;
4-(1H-imidazoles-2-yl)-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(1H-tetrazolium-5-yl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
4-methylsulfonyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
2-hydroxyl-6-methyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(1H-tetrazolium-5-ylmethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
2,5-dimethyl-2H-pyrazoles-3-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
The 4-tertiary butyl-N-{2-methyl-5-[8-(4-sulfamyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
The 4-tertiary butyl-N-{3-[8-(4-amidino groups-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N '-dimethyl-amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(imino--morpholine-4-base-methyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N-dimethyl-amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(2-imino--2-morpholine-4-base-ethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N '-dimethyl-amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(4,5-dihydro-1H-imidazoles-2-yl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
The 4-tertiary butyl-N-{3-[8-(4-amidino groups-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide;
The 4-tertiary butyl-N-{3-[8-(4-amidino groups methyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl amidino groups methyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N '-dimethyl-amidino groups methyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N-dimethyl-amidino groups methyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
Coumarilic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-3-pyridin-3-yl-acrylamide;
Quinoline-3-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
1-Methyl-1H-indole-3-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
The 1H-indole-3-carboxylic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
The 6-tertiary butyl-N-(2-methyl-3-{8-[4-(1-oxo-114-thiomorpholine-4-yl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
N-{3-[8-(3-amino-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-the 4-tertiary butyl-benzamide; And
Tetrahydrofuran (THF)-2-formic acid (3-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenyl)-acid amides;
And the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture.
The method that obtains novel cpd of the present invention will be readily apparent to persons skilled in the art, and has for example put down in writing suitable method in the reference that following reaction scheme and embodiment and the present invention quote.Also can be referring to PCT/US04/18227 and PCT/US04/025884.
Reaction scheme 1
Step 1 referring to reaction scheme 1, mixture about 3h of reflux in inert solvent such as dioxane of 1: 1 compound of two (neopentyl glycol) two boron (bis (neopentylglycolato) diboron) of the compound of general formula 101, excessive (as about 1.2 equivalents) and about 0.3 normal and methylene dichloride [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride and alkali such as Potassium ethanoate.Separate and the compound of purified product general formula 103 randomly.
Referring to the step 2 of reaction scheme 1, under the room temperature with the mixture of palladium carbon in inert solvent such as ethyl acetate methanol of the compound of general formula 103 and 10% the about 2h of hydrogen treat with 40psi.Separate and the compound of purified product general formula 105 randomly.
Referring to the step 3 of reaction scheme 1, dropwise the general formula with equivalent is R
5The acyl chlorides of C (O) Cl is handled compound and the alkali such as the solution of triethylamine in inert solvent such as THF of general formula 105, and with mixture stir about 15min under room temperature.Separate and the compound of purified product general formula 107 randomly.
Referring to the step 4 of reaction scheme 1, the compound of the general formula 107 of the compound of general formula 108, excessive (as about 1.2 equivalents) and catalyzer are closed the mixture of palladium in alkaline aqueous solution (as the 1N aqueous sodium carbonate) and inert solvent such as DME in 95 ℃ of about 16h of heating in sealed reaction tube as four (triphenylphosphines).Separate the also compound of purified product general formula 109.
Reaction scheme 2
Referring to reaction scheme 2, add in the solution of polarity, non-protonic solvent such as methylene dichloride to the compound of general formula 105 and amine alkali such as diisopropylethylamine and to have general formula X-C (R
10) (R
11)-R
5Compound, R wherein
5As mentioned above and X be leavings group (as halogenide).With gained solution room temperature or heated and stirred a few hours under nitrogen.Separate the also compound of purified product general formula 203.
Perhaps, the general formula that adds excessive (as about 1.2 equivalents) to the compound of general formula 105 in the solution of inert solvent (as toluene) is X-C (O)-R
5Aldehyde, R wherein
5As mentioned above, and excessive reductive agent such as sodium triacetoxy borohydride.The gained mixture is heated (as in about 65 ℃) down in nitrogen stir some hrs.Separate the also compound of purified product general formula 203.
Referring to the step 2 of reaction scheme 2, with the compound of the general formula 203 of the compound of general formula 108, excessive (as about 1.2 equivalents) and catalyzer as four (triphenylphosphines) close palladium in alkaline aqueous solution (as the 1N aqueous sodium carbonate) and inert solvent mixture such as DME in 95 ℃ of about 16h of heating in sealed reaction tube.Separate the also compound of purified product general formula 205.
Reaction scheme 3
Referring to the step 1 of reaction scheme 3, with the compound of general formula 105 in the presence of alkali such as the triethylamine in nonpolar, non-protonic solvent such as methylene dichloride with excessive a little isocyanic ester R
5-N=C=O handles.Separate the also compound of purified product general formula 303.
Referring to the step 2 of reaction scheme 3, the compound of the general formula 303 of the compound of general formula 108, excessive (as about 1.2 equivalents) and catalyzer are closed the mixture of palladium in alkaline aqueous solution (as the 1N aqueous sodium carbonate) and inert solvent such as DME in 95 ℃ of about 16h of heating in sealed reaction tube as four (triphenylphosphines).Separate the also compound of purified product general formula 305.
Reaction scheme 4
Referring to the step 1 of reaction scheme 4, dropwise the acyl chlorides of the general formula 403 of usefulness equivalent is handled compound and the alkali such as the solution of triethylamine in inert solvent such as THF of general formula 105, and with mixture stir about 15min under room temperature.Separate and the compound of purified product general formula 405 randomly.
Referring to the step 2 of reaction scheme 4, the compound of the general formula 405 of the compound of general formula 108, excessive (as about 1.2 equivalents) and catalyzer are closed the mixture of palladium in alkaline aqueous solution (as the 1N aqueous sodium carbonate) and inert solvent such as DME in 95 ℃ of about 16h of heating in sealed reaction tube as four (triphenylphosphines).Separate the also compound of purified product general formula 407.
Reaction scheme 5
Referring to reaction scheme 5, in the solution of polarity, non-protonic solvent such as methylene dichloride, add the compound of general formula 503 to the compound of general formula 105 and amine alkali such as diisopropylethylamine, wherein X is leavings group (as a halogenide).With gained solution room temperature or heated and stirred a few hours under nitrogen.Separate the also compound of purified product general formula 505.
Perhaps, aforesaid general formula H-C (O)-C (H)=CH (R that in the solution of inert solvent (as toluene), adds excessive (as about 1.2 equivalents) to the compound of general formula 105
5) aldehyde, and excessive reductive agent such as sodium triacetoxy borohydride.With the gained mixture in following heating (as at the about 65 ℃) stirred for several hour of nitrogen.Separate the also compound of purified product general formula 505.
Referring to the step 2 of reaction scheme 5, the compound of the general formula 505 of the compound of general formula 108, excessive (as about 1.2 equivalents) and catalyzer are closed the mixture of palladium in alkaline aqueous solution (as the 1N aqueous sodium carbonate) and inert solvent such as DME in 95 ℃ of about 16h of heating in sealed reaction tube as four (triphenylphosphines).Separate the also compound of purified product general formula 507.
Reaction scheme 6
Referring to the step 1 of reaction scheme 6, the compound of general formula 105 is being handled with the isocyanic ester of excessive a little general formula 603 in nonpolar, non-protonic solvent such as methylene dichloride in the presence of alkali such as the triethylamine.Separate the also compound of purified product general formula 605.
Referring to the step 2 of reaction scheme 6, the compound of the general formula 605 of the compound of general formula 108, excessive (as about 1.2 equivalents) and catalyzer are closed the mixture of palladium in alkaline aqueous solution (as the 1N aqueous sodium carbonate) and inert solvent such as DME in 95 ℃ of about 16h of heating in sealed reaction tube as four (triphenylphosphines).Separate the also compound of purified product general formula 607.
In some specific embodiments, general formula 109,205,305,407,507 or 607 compound further transform other compound that generates general formula 1.For example, wherein G is that the compound of the general formula 109 of alkoxyl group is handled with the aqueous solution of alkali and can be converted into wherein that G is the compound of the general formula 1 of hydroxyl.Equally, wherein G is that the compound of general formula 109 of hydroxyl is with suitable amine and randomly can be converted into wherein G in the presence of catalyzer be the compound of the general formula 1 of substituted amino randomly.Other conversion, for example reduction, alkylation, acidylate etc. are known and within those skilled in the art's skill for those skilled in the art.
In some specific embodiments, chemical entities of the present invention can pharmaceutical composition or preparation administration.Therefore, the invention provides and contain at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture and at least a pharmaceutical preparation that is selected from the acceptable media of pharmacology of carrier, adjuvant and vehicle that is selected from the compound of general formula 1.
The acceptable media of pharmacology must have sufficiently high purity and enough low toxicity to make it to be suitable for the animals administer to being treated.This media can have the pharmacology benefit for inertia or it.The amount that combines the media of using with chemical entities should be enough to be provided for the actual amount of material of the chemical entities of administration per unit dosage.
Exemplary pharmacology acceptable carrier or its composition are sugar, as lactose, dextrose plus saccharose; Starch such as W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof are as Xylo-Mucine, ethyl cellulose and methylcellulose gum; Tragacanth gum powder; Fructus Hordei Germinatus; Gelatin; Talcum; Solid lubricant such as stearic acid and Magnesium Stearate, calcium sulfate; Synthetic oil; Vegetables oil such as peanut oil, Oleum Gossypii semen, sesame oil, sweet oil and Semen Maydis oil; Polyol such as propylene glycol, glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Alginic acid; Phosphate buffered saline buffer; Emulsifying agent such as tween; Wetting agent such as sodium lauryl sulphate; Tinting material; Seasonings; The film-making agent; Stablizer; Antioxidant; Sanitas; Former water reduces phlegm and internal heat; Isotonic saline solution and phosphate buffered saline buffer.
Optically active substance also can be included in the pharmaceutical composition, and it is the activity of substantial effect chemical entities of the present invention not.
The chemical entities of at least a compound that is selected from general formula 1 and effective enriched material of the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture thereof are mixed mutually with the acceptable media of appropriate drug.Under the insufficient situation of this chemical entities solvability, can use the method that increases the compound dissolution degree.These methods are as well known to those skilled in the art, include but not limited to use solubility promoter such as dimethyl sulfoxide (DMSO) (DMSO), use tensio-active agent such as tween or be dissolved in the sodium bicarbonate aqueous solution.
After mixing or adding chemical entities of the present invention, the gained mixture can be solution, suspension, emulsion etc.The form of gained mixture depends on many factors, comprises the administering mode and the solvability of chemical entities in selected media of expection.The effective concentration that is enough to improve the symptom of the disease of being treated can rule of thumb come to determine.
Chemical entities of the present invention can be oral, local, parenteral route, intravenously, by intramuscular injection, by suction or spraying, hypogloeeis, transdermal, by contain clothes administration, rectum, as ophthalmic solution or by the mode administration of other way Jing with dosage unit preparations.
The formulation that is suitable for orally using (dosage formulation) but comprise as tablet, lozenge, dragee, water-based or oil-based suspension dispersed powders or particle, emulsion, hard or soft capsule or syrup or elixir.The composition that is used to orally use can be prepared and said composition can contain one or more materials according to any method that is used to produce pharmaceutical composition known in the art, as sweeting agent, seasonings, tinting material and sanitas, to provide pharmacology attractive in appearance and delicious preparation.In some specific embodiments, oral preparations comprises 0.1 to 99% chemical entities at least a of the present invention.In some specific embodiments, oral preparations comprises the chemical entities at least a of the present invention of at least 5% (weight %).Some specific embodiments contain 25% to 50% or 5% to 75% chemical entities at least a of the present invention.
Liquid preparations for oral administration also comprises liquor, emulsion, suspension, powder, granule, elixir, tincture, syrup etc.The pharmacology acceptable carrier that is suitable for preparing this composition is known in the art.Oral preparations can comprise sanitas, seasonings, sweeting agent, as sucrose or asccharin, odor mask and tinting material.
The typical composition of the carrier of syrup, elixir, emulsion and suspension comprises ethanol, glycerine, propylene glycol, polyoxyethylene glycol, liquid sugar, sorb alcohol and water.Syrup and elixir can prepare with sweeting agent such as glycerine, propylene glycol, sorbyl alcohol or sucrose.These preparations can also contain negative catalyst.
Chemical entities of the present invention can be contained in oral liquid such as water-based or oil-based suspension, solution, emulsion, syrup or the elixir.And the preparation that contains these chemical entities can be formed for the drying products form that water before use or other suitable media redissolve.These liquid preparations can contain conventional additive, as suspending agent (as, sorbitol syrups, methylcellulose gum, glucose/sugar, syrup, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel, and hydrogenation edible-fat), emulsifying agent (as, lecithin, polyoxyethylene-sorbitan mono-oleate or Sudan Gum-arabic), non-hydrophily is situated between, its can comprise edible oil (as, Prunus amygdalus oil, fractionated coconut oil, silyl ester (silyl ester), propylene glycol and ethanol) and sanitas (as, methyl p-hydroxybenzoate or propylparaben and Sorbic Acid).
For suspension, typical suspending agent comprises methylcellulose gum, Xylo-Mucine, AVICEL RC-591, tragacanth gum and sodiun alginate, typical wetting agent comprises Yelkin TTS and polysorbate80, and typical preservatives comprises Tegosept M and Sodium Benzoate.
The mixture that aqueous suspension contains active substance and is suitable for the vehicle of suspension production.These vehicle are suspending agent, as Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and Sudan Gum-arabic; Dispersion agent or wetting agent; Can be naturally occurring phosphatide, condensation product as Yelkin TTS or alkylene oxide and lipid acid, condensation product as polyoxyethylene stearic acid ester or oxyethane and long chain aliphatic alcohol, as heptadecaethylene oxycetanol (heptadecaethyleneoxycetanol), or oxyethane and, or oxyethane and by the condensation product such as the polyethylene anhydro sorbitol substitute of lipid acid and hexitan deutero-partial ester by the condensation product such as the polyoxyethylene glycol sorbyl alcohol substitute of lipid acid and hexitol deutero-partial ester.Aqueous suspension also can contain one or more sanitass, as ethyl p-hydroxybenzoate or or P-hydroxybenzoic acid n-propyl.
Oil-based suspension can be prepared by activeconstituents is scattered in vegetables oil such as peanut oil, sweet oil, sesame oil or Oleum Cocois or mineral oil such as the whiteruss.Oil-based suspension can contain thickening material such as beeswax, solid paraffin or hexadecanol.Sweeting agent as mentioned above and can add seasonings so that delicious oral preparations to be provided.These compositions can be preserved by adding antioxidant such as xitix.
Pharmaceutical composition of the present invention can also be an oil-in-water emulsion.Oil phase can be a vegetables oil, as sweet oil or peanut oil or mineral oil such as whiteruss or their mixture.Examples of suitable emulsifiers can be for naturally occurring glue such as Sudan Gum-arabic or tragacanth gum, naturally occurring phosphatide such as soybean phospholipid, Yelkin TTS and by lipid acid and hexitol, acid anhydrides deutero-ester or partial ester, as polyoxyethylene-sorbitan mono-oleate, and the condensation product of described partial ester and oxyethane, as polyoxyethylene sorbitan monooleate.
But be applicable to by adding entry and prepare the dispersed powders of aqueous suspension and particle mixing of activeconstituents and dispersion agent or wetting agent, suspending agent and one or more sanitass is provided.Suitable dispersion agent or wetting agent and suspending agent are in above-illustrated.
Tablet comprises conventional acceptable adjuvant of pharmacology such as inert diluent usually, as lime carbonate, yellow soda ash, N.F,USP MANNITOL, lactose, Mierocrystalline cellulose; Tackiness agent such as starch, gelatin and sucrose; Disintegrating agent such as starch, alginic acid and cross-linked carboxymethyl cellulose (croscarmelose); Lubricant such as Magnesium Stearate, stearic acid and talcum.Glidant such as silicon-dioxide can be used to improve the flowability of powdered mixture.Can add tinting material such as FD﹠amp; The C dyestuff is used to improve outward appearance.Sweeting agent and seasonings such as aspartame, asccharin, menthol, peppermint and fruit flavor can be used as the adjuvant of chewable tablet.Capsule (comprise and regularly discharge (time release) and sustained release preparation) comprises one or more above-mentioned solid diluents usually.The selection of carrier components depends on less important Consideration such as mouthfeel, cost and package stability usually.
These compositions also can carry out dressing with pH or time-dependent manner clothing layer usually by conventional method, and near the gi tract of this chemical entities required topical application position are discharged, or discharge to prolong required effect in the different time.This formulation generally includes but is not limited to one or more cellulose acetate phthalic esters, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethyl cellulose, Eudragit dressing, wax and shellac.
Being used for the form that oral preparation also can hard gelatin capsule exists, wherein activeconstituents mixes with inert solid diluent such as lime carbonate, calcium phosphate or kaolin, perhaps as soft gelatin capsule, wherein activeconstituents and water or oil medium such as peanut oil, whiteruss or mixed with olive oil.
Pharmaceutical composition can adopt the form of aseptic parenteral solution or oil-based suspension.This suspension can use above-mentioned suitable dispersion agent or wetting agent and suspending agent preparation according to known technology.This aseptic injection preparation also can be aseptic injectable solution or the suspension in the acceptable media of nontoxic parenteral route, as the solution in 1,3 butylene glycol.Adaptable acceptable media comprises water, Ringer's solution, reaches isotonic sodium chlorrde solution.In addition, aseptic fixed oil is usually as solvent or suspension medium.The fixed oil of any gentleness all can be used for this reason, comprises synthetic monoglyceride or Diglyceride.In addition, lipid acid such as oleic acid can be used to prepare injection.
Chemical entities of the present invention can be through parenteral administration in sterile media.Parenteral administration comprises subcutaneous injection, intravenous injection, intramuscular injection, intrathecal injection or infusion techniques.According to applied media and concentration, chemical entities of the present invention can suspendible or is dissolved in the described media.Adjuvant such as local anesthetic, sanitas and buffer reagent can advantageously be dissolved in the media.At many compositions that are used for parenteral administration, carrier accounts at least 90% of total composition weight.In some specific embodiments, the carrier that is used for parenteral administration is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil.
Chemical entities of the present invention can also suppository form be used for the medicine rectal administration.Thereby these compositions can be by preparing for nonirritating mixed with excipients that liquid will melt in rectum with the release medicine under rectal temperature for solid under medicine and the suitable normal temperature.These materials comprise theobroma oil and polyoxyethylene glycol.
The form that chemical entities of the present invention can be prepared into gel, emulsion and washing lotion is used for topical application, as is locally applied to skin and as the mucous membrane of intraocular.Topical composition can be arbitrary form, comprises as solution, emulsion, ointment, gel, washing lotion, emulsion, sanitising agent, wetting Agent for Printing Inks, sprays, skin patch etc.
This solution can be mixed with the isotonic solution of the 0.01%-10% of pH 5-7 with suitable salt.Chemical entities of the present invention also can be mixed with the film patch and be used for transdermal administration.
The topical composition that contains at least a chemical entities of the present invention can mix with variety carrier material well known in the art such as water, alcohol, Aloe gel, wallantoin, glycerine, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 Tetradecyl propionate etc.
Be applicable to that the other materials in the topical carrier comprises as negative catalyst, solvent, wetting agent, thickening material and powder (powders).These class materials example separately that wherein can use separately or use as one or more mixtures of material is as follows:
Typical negative catalyst comprises Stearyl alcohol, single ricinolic acid glyceryl ester, glyceryl monostearate, propane-1, the 2-glycol, butane-1, the 3-glycol, mink oil, hexadecanol, the Unimac 5680 isopropyl esters, stearic acid, the palmitinic acid isobutyl, stearic acid isocetyl ester, oleyl alcohol, laurostearic acid sec.-propyl fat, the own ester of laurostearic acid, decyl oleate, octadecane-2-alcohol, different hexadecanol, palmitinic acid spermaceti ester, dimethyl polysiloxane, sebacic acid di-n-butyl ester, the tetradecanoic acid isopropyl esters, the palmitinic acid isopropyl esters, the stearic acid isopropyl esters, butyl stearate, polyoxyethylene glycol, triethylene glycol, lanolin, sesame oil, Oleum Cocois, peanut oil, Viscotrol C, Acetylated lanolin alcohols, oil, mineral oil, the nutmeg acid butyl ester, Unimac 5680, palmitinic acid, the linolic acid isopropyl esters, Lauryl lactate, lactic acid meat myristyl ester, decyl oleate and tetradecanoic acid Semen Myristicae alcohol ester; Propelling agent such as propane, butane, Trimethylmethane, dme, carbonic acid gas and nitrous oxide; Solvent such as ethanol, methylene dichloride, Virahol, Viscotrol C, ethylene glycol monoethyl ether, Diethylene Glycol butyl ether, diethylene glycol ether, dimethyl sulfoxide (DMSO), dimethyl formamide, tetrahydrofuran (THF); Wetting agent such as glycerine, sorbyl alcohol, 2-Pyrrolidone-5-sodium formiate, soluble collagen matter, phthalic acid dibutyl ester and gel; The neusilin of powder such as chalk, talcum, Fuller's earth, kaolin, starch, resin, silicon dioxide colloid, sodium polyacrylate, tetraalkyl montmorillonite ammonium, tetraalkyl aryl montmorillonite ammonium, chemical modification, organically-modified illiteracy unsticking soil, hydrated aluminium silicates, pyrogenic silica, carboxy vinyl polymer (carboxyvinyl), Xylo-Mucine and ethylene glycol monostearate.
The form topical of all right liposome release system of chemical entities of the present invention such as small unilamellar vesicle, large unilamellar vesicle and multilamelar liposome.Liposome can be formed by multiple phosphatide such as cholesterol, stearylamide or phosphatidylcholine.
Other compositions that are effective to make this chemical entities obtain whole body release comprise hypogloeeis, oral cavity and nasal cavity dosage form.These compositions contain one or more solubility weighting agents such as sucrose, sorbyl alcohol and N.F,USP MANNITOL usually, and wedding agent such as Sudan Gum-arabic, Microcrystalline Cellulose, carboxymethyl cellulose and Vltra tears.Also can comprise aforesaid glidant, lubricant, sweeting agent, tinting material, antioxidant and seasonings.
The composition that is used to suck can adopt the form of solution, suspension or emulsion usually, they can be used as dry powder or with use conventional thruster (as, Refrigerant 12 or trichlorofluoromethane) the form administration of aerosol.
Composition of the present invention also can randomly comprise active reinforcing agent.The molecule that this active reinforcing agent can be selected from multiple function with different aspect is with the result of treatment that strengthens chemical entities of the present invention or irrelevant with its result of treatment.The special sort of active reinforcing agent comprises enhancer of cutaneous penetration and absorption enhancer.
Pharmaceutical composition of the present invention can also comprise other active substances that are selected from multiple molecule, and these molecules have the function of different aspect to strengthen the curative effect of at least a chemical entities of the present invention.When these other optional active substances exist, its normally with the horizontal application of 0.01% to 15% scope in composition of the present invention.Some specific embodiments contain 0.1% to 10% of said composition weight.Other specific embodiments contain 0.5% to 5% of said composition weight.
The present invention includes pharmaceutical preparation through packing.These preparations through packing comprise the chemical entities that contains at least a compound that is selected from general formula 1 and the pharmaceutical composition of the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture, and the specification sheets that uses said composition treatment Mammals (being generally human patients).In some specific embodiments, this specification sheets suffers from the patient of the disease of and/or inhibition B cell proliferation response active to inhibition Btk for using this pharmaceutical composition with treatment.The present invention can comprise as to patient or health care personnel, perhaps provide prescription information as the label in the pharmaceutical preparation of packing.Prescription information can comprise for example relevant with pharmaceutical preparation effect, dosage and medication, contraindication and side effect.
Aforementioned all chemical entities can be separately, as mixture or with other active compound combined administrations.
Therefore, the present invention includes and a kind ofly treat Mammals as suffering from the method to the mankind of the disease that suppresses the active response of Btk, it comprises at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from the compound of general formula 1 to the Mammals effective dosage of suffering from this disease.
With regard to regard to Btk is relevant, any one of following scope of the present invention that all belongs to: alleviate disease, disease symptoms, prevention and prophylactic treatment.In some specific embodiments, chemical entities of the present invention can also suppress other kinases, also belongs to scope of the present invention thereby alleviate disease, disease symptoms, prevention and the prophylactic treatment symptom relevant with these kinases.
Methods of treatment also comprises by at least a chemical entities and pharmacology acceptable salt, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that are selected from the compound of general formula 1 of administration in the active effective concentration of vitro inhibition Btk, thus in suffering to patient's body of the disease that suppresses the active response of Btk by suppress ATP in conjunction with or Btk hydrolysis or to suppress Btk by some other mechanism active and/or suppress B cell proliferation.Effective concentration can be determined with experimental technique, as obtaining through theoretical method by the haemoconcentration of this chemical entities of mensuration or by calculating bioavailability.
The present invention includes by effective dosage at least a be selected from the chemical entities of compound of general formula 1 and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture treat suffer from cancer, the patient's of autoimmunization and/or inflammatory diseases or acute inflammatory reaction method.
In some specific embodiments, be cancer, autoimmunization and/or inflammatory diseases or acute inflammatory reaction to suppressing Btk the symptom active and/or response of inhibition B cell proliferation.
In some specific embodiments, can use the illness and the disease of chemical entities treatment of the present invention to include but not limited to:
Autoimmunization and/or inflammatory diseases, include but not limited to psoriatic, irritated, Crohn disease, irritable bowel syndrome, the house gorlin's syndrome, tissue transplantation repulsion and organ transplantation hyperacute rejection, asthma, systemic lupus erythematous (and relevant glomerulonephritis), dermatomyositis, the multiple sclerosis disease, scleroderma, vasculitis (ANCA relevant with other vasculitises), the less disease of autoimmune hemolytic anemia and thrombocyte, Goodpasture ' s syndrome (and relevant glomerulonephritis and pulmonary apoplexy), arteriosclerosis, rheumatoid arthritis, chronic primary thrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease, degenerative brain disorder, diabetes, septic shock, myasthenia gravis etc.
Acute inflammatory reaction, include but not limited to skin sunburn, inflammatory pelvic disease, inflammatory bowel, urethritis, uveitis, sinusitis paranasal sinusitis, pneumonia, encephalitis, meningitis, myocarditis, ephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, ecphyaditis, pancreatitis and cholecystitis, and
Cancer includes but not limited to B cell lymphoma, lymphoma (comprising Huo Qijin and non-Hodgkin lymphoma), hairy cell, multiple myeloma, chronic and acute myelogenous leukemia and chronic and acute lymphoblastic leukemia.
Btk is a kind of known lymphoma B apoptosis inhibitor.Defective apoptosis causes human leukemia and lymphadenomatous morbidity and resistance.Therefore, the present invention also provide a kind of promote or the cell of abduction delivering Btk in the apoptosis method, this method comprises with at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from the compound of general formula 1 and contacts described cell.
The invention provides wherein at least a chemical entities and the acceptable salt of pharmacology thereof that is selected from the compound of general formula 1, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture are the methods of treatment that gives unique active substance of patient, and the present invention also comprises wherein at least a chemical entities and the acceptable salt of pharmacology thereof that is selected from the compound of general formula 1, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture and one or more other active compound combined methods of treatment that gives the patient.
Therefore, in a specific embodiments, the invention provides a kind of method for the treatment of cancer, autoimmune disease and/or inflammatory diseases or acute inflammatory reaction, comprising at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture and second kind of active substance that can be used for treating cancer, autoimmune disease and/or inflammatory diseases or acute inflammatory reaction that is selected from the compound of general formula 1 to the Mammals effective dosage that these needs are arranged.For example, described second kind of active substance can be antiphlogiston.With the treatment of second kind of active substance can be before treatment with the chemical entities of at least a compound that is selected from general formula 1 and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture, while or afterwards.In some specific embodiments, at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from the compound of general formula 1 is to combine with another kind of active substance with single dose form.The antitumor therapy that is suitable for being used in combination with at least a chemical entities of the present invention includes but not limited to chemotherapeutics, as ametycin, carboplatin, safe plain (taxol), cis-platinum, taxol, Etoposide, Zorubicin or contain the combination of at least a aforementioned chemotherapeutics.Antitumor radiotherapeutic agents also can be separately or with the chemotherapeutics combined utilization.
Chemical entities of the present invention can be used as chemotherapeutic sensitizer (chemosensitizing agent), and therefore can be used for other particularly the chemotherapeutics of cell death inducing be used in combination.
The present invention also provides a kind of method that increases cancer cells to chemosensitivity, and this method comprises to the patient's administration chemotherapeutics that carries out chemotherapy and is enough to increase at least a chemical entities and pharmacology acceptable salt, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that are selected from the compound of general formula 1 of cancer cells to the amount of the susceptibility of described chemotherapeutics.
Other can comprise topoisomerase I inhibitor (camptothesin or topotecan), topoisomerase II inhibitor (as daunorubicin and Etoposide), alkylating agent (as endoxan, melphalan and BCNU), tubulin modulating agents (as safe element and vinealeucoblastine(VLB)) and biotechnological formulation (as antibody such as anti-CD20 antibodies, IDEC8, immunotoxin and cytokine) with the example of the chemotherapeutics of chemical entities combined utilization of the present invention.
The present invention includes the chemical entities of the wherein at least a compound that is selected from general formula 1 and the methods of treatment of the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture and anti-inflammatory drug Combined Preparation thereof.Anti-inflammatory drug includes but not limited to NSAID, non-specific and COX-2 specificity cyclooxygenase-2 inhibitors, gold compound, corticosteroid, methotrexate, Tumor Necrosis Factor Receptors (TNF) receptor antagonist, immunosuppressor and methotrexate.
The example of NSAID includes but not limited to combination, sulindac, Taisho), diflunisal, piroxicam, indomethacin, R-ETODOLAC, fenoprofen calcium, Ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium and the Oxychloroquine of Ibuprofen BP/EP, flurbiprofen, Naproxen Base and naproxen sodium, diclofenac, diclofenac sodium and Misoprostol.The example of NSAID also comprises the COX-2 specific inhibitor (IC that promptly suppresses COX-2
50Than the IC that suppresses COX-1
50At least hang down 50 times compound) examine former times and/or rofecoxib as celecoxib, valdecoxib, Prexige, support.
In other specific embodiments, described anti-inflammatory drug is a salicylate.Salicylate includes but not limited to acetylsalicylic acid or acetylsalicylic acid, sodium salicylate and choline salicylate and magnesium salicylate.
This anti-inflammatory drug can also be a cortin.For example, this cortin can be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone phosphate sodium and prednisone.
In other specific embodiments, described anti-inflammatory treatment medicine is a gold compound, as disodium aurothiomalate or auranofin.
The present invention comprises that also wherein anti-inflammatory drug is the specific embodiments of metabolic poison such as dihydrofolate reductase inhibitor such as methotrexate or dhodh inhibitors such as leflunomide.
Other specific embodiments of the present invention comprise wherein at least a anti-inflammatory compound for anti--C5 monoclonal antibody (as eculizumab or pexelizumab), for the TNF antagonist of anti-TNF alpha monoclonal antibody as according to that cloth or the combination of infliximab former times.
The combination that it is immunosuppressive compounds such as methotrexate, leflunomide, ciclosporin, tacrolimus, azathioprine or mycophenlate mofetil that other specific embodiments of the present invention also relate to wherein at least a active substance.
The dosage level of per kilogram of body weight 0.1mg to 140mg can be used for treating above-mentioned symptom (each patient 0.5mg to 7g every day) as about every day.The amount with the activeconstituents of preparation single dose form of can combining with media depends on the main body of being treated and specific administering mode.Dosage unit form contains 1mg to 500mg activeconstituents usually.Dose frequency also depends on employed compound and the specified disease of being treated usually.In some specific embodiments, for example, for the treatment of autoimmunization and/or inflammation, the dosage that uses as every day 4 times or still less.In some specific embodiments, the dosage that uses is every day 1 time or 2 times.Yet the concrete dosage level that should understand for any particular patient will depend on many factors, comprise activity, age, body weight, general health, sex, diet, administration time, route of administration and excretion pathway, the drug regimen of the specific compound of application and the severity of the specified disease that the patient suffered from of receiving treatment.
The form of the mark of compound of the present invention can be used to discern and/or obtain having the compound of regulating kinase activity effect of the present invention as diagnostic reagent.Compound of the present invention can be used as conclusive evidence, optimization and stdn biological test in addition.
" mark " of the present invention is meant that this compound is directly or indirectly with providing the mark of detectable signal to carry out mark, as radio isotope, fluorescent mark, enzyme, antibody, particle such as magnetic particle, chemiluminescent labeling or specific binding molecules etc.Specific binding molecules comprises paired material such as vitamin H and Streptavidin (streptavidin), digoxin and anti-digoxin etc.For specific binding members, complementary member (complementary member) is usually with providing the molecule of detection to carry out mark as mentioned above according to currently known methods.This mark can directly or indirectly provide detectable signal.
The present invention further illustrates by following non-restrictive example.
Embodiment
Embodiment 1
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide synthetic
Step 1:2-(2-methyl-3-nitro phenyl)-5,5-dimethyl [1,3,2] two oxa-boron heterocycle hexanes (dioxaborinane)
With 2-bromo-6-nitrotoluene (3.2g; 14.8mmol), two (neopentyl glycol base) two boron (4g; 17.7mmol), with methylene dichloride (362mg; 0.44mmol) 1: 1 blended [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride, Potassium ethanoate (7.3g; 73.8mmol) and the mixture heating up backflow 3h of dioxane (75mL).
Then mixture is cooled to room temperature, water (100mL) is handled, and (3 * 80mL) extract with ethyl acetate.The extraction liquid water (2 * 50mL) and salt solution (1 * 50mL) washing, through anhydrous sodium sulfate drying and vacuum concentration.Resistates obtains 2-(2-methyl-3-nitro phenyl)-5, the white solid (3.3g) of 5-dimethyl [1,3,2] two oxa-boron heterocycle hexanes through fast silica gel chromatogram (with hexane/ethyl acetate 95/5-6/1 gradient elution) purifying.
Step 2:3-(5,5-dimethyl [1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-aminotoluene
With 2-(2-methyl-3-nitro phenyl)-5,5-dimethyl [1,3,2] two oxa-boron heterocycle hexane (6.7g; 27.7mmol), the mixture of 10% palladium carbon (670mg), ethyl acetate (75mL) and methyl alcohol (75mL) under room temperature with the hydrogen treat 2h of 40psi.
By diatomite filtration, (2 * 100mL) wash and the filtrate vacuum concentration are obtained the white solid (6.0g) of 3-(5,5-dimethyl [1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-aminotoluene with DCM with this mixture.
The step 3:4-tertiary butyl-N-[3-(5,5-dimethyl [1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-aminomethyl phenyl]-benzamide
To 3-(5,5-dimethyl [1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-aminotoluene (3.1g; 14.2mmol) and triethylamine (3.0mL; 21.2mmol) solution in THF (110mL) drips 4-(tertiary butyl) Benzoyl chloride (2.6mL; 14.2mmol) handle, and mixture is stirred 15min under room temperature.
Then with this mixture by diatomite filtration, and with the ethyl acetate washing, filtrate obtains the 4-tertiary butyl-N-[3-(5,5-dimethyl [1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-aminomethyl phenyl through vacuum concentration]-white solid (4.0g) of benzamide.
Step 4:4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-aminomethyl phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-ethyl benzoate
With 4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-ethyl benzoate (687mg; 1.9mmol), the 4-tertiary butyl-N-[3-(5,5-dimethyl [1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-aminomethyl phenyl]-benzamide (866mg; 2.3mmol), four (triphenylphosphines) close palladium (220mg; 0.19mmol), the mixture of 1N aqueous sodium carbonate (3mL) and DME (13mL) in airtight reaction tubes in 95 ℃ of heating 16h.
Then this mixture is cooled to room temperature, water (30mL) is handled and (3 * 40mL) extract with ethyl acetate.(1 * 50mL) washs anhydrous sodium sulfate drying and vacuum concentration to extraction liquid with salt solution.Resistates grinds with hexane and filters and obtains 4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-aminomethyl phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-the dark yellow solid (600mg) of ethyl benzoate.
Step 5:4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-aminomethyl phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid
With 4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-aminomethyl phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-ethyl benzoate (600mg; 1.1mmol), the mixture heating up backflow 1h of ethanol (50mL) and 1N aqueous sodium hydroxide solution (50mL).
Then this mixture is cooled to room temperature, is adjusted to pH 6 and uses ethyl acetate (3 * 100ml) extractions with 1N HCl.(1 * 50mL) washing is through anhydrous sodium sulfate drying and vacuum concentration with salt solution for extraction liquid.Resistates grinds with ethyl acetate and obtains 4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-aminomethyl phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-benzoic white solid (300mg).
The step 6:4-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide
With 4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-aminomethyl phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid (52mg; 0.1mmol), benzotriazole-1-oxygen base three (dimethylamino) phosphonium hexafluorophosphate (49mg; 0.11mmol), diisopropylethylamine (0.05mL; 0.3mmol) and the mixture of DMF (1.7mL) under room temperature, stir 20min.Add morpholine (0.04mL) and mixture is stirred 2h under room temperature.
Add then entry (10mL) and with mixture filter obtain the 4-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl-phenyl)-white solid (40mg) of benzamide.
Embodiment 2
The 6-tertiary butyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-niacinamide synthetic
Step 1:4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-phenylformic acid
With 4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-ethyl benzoate (10.0g; 27.7mmol) be dissolved in 200mL ethanol (200 strength criterion) and add 100mL 1N NaOH.Reactant was refluxed 2 hours, be cooled to room temperature then.Filter and collection gained solid, sneak into 0.1N HCl (75mL) pulp then and use CH
2Cl
2(2 * 75mL) extractions.The CH that merges
2Cl
2Layer salt water washing obtains 4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-benzoic white solid (8g) through anhydrous sodium sulfate drying and vacuum concentration then.
Step 2:[4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-phenyl]-morpholine-4-base-ketone (methanone)
With 4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-phenylformic acid (4.0g; 12.0mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphonium hexafluorophosphate (6.0g; 13.6mmol) and diisopropylethylamine (6mL; 34.4mmol) mixture be dissolved in the N,N-DIMETHYLACETAMIDE (50mL) and under room temperature and stir 20min.Add morpholine (5mL; 57mmol) and with mixture under room temperature, stir 16h.
Add entry (100mL) and mixture filtered the emulsifiable paste shape solid (2.65g) obtain [4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-phenyl]-morpholine-4-base-ketone.
Step 3:{4-[6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-base is amino]-phenyl }-morpholine-4-base-ketone
With [4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-phenyl]-morpholine-4-base-ketone (500mg; 1.24mmol), 3-(5,5-dimethyl-[1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-methyl-aniline (340mg; 1.6mmol), four (triphenylphosphines) close palladium (200mg; 0.17mmol), the mixture of 1M yellow soda ash (10mL) and DME (25mL) in airtight reaction tubes in 95 ℃ of heating 16h.
Mixture is cooled to room temperature, and water (75mL) is handled and (3 * 80mL) extract with ethyl acetate.The extraction liquid water (2 * 100mL) and salt solution (1 * 100mL) washing, through anhydrous sodium sulfate drying and vacuum concentration.Resistates grinds and filters and obtain the brown solid (540mg) of { 4-[6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-base is amino]-phenyl }-morpholine-4-base-ketone with ether.
Step 4:[6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-yl]-(4-morpholine-4-ylmethyl-phenyl)-amine
Under nitrogen, room temperature, incite somebody to action 4-[6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-base is amino]-phenyl }-morpholine-4-base-ketone (350mg; 0.82mmol) be dissolved among the anhydrous THF (50mL).Join lithium aluminum hydride solid (0.5g) gradation in the reactant under stirring and with reactant in refluxed under nitrogen 2h.Reactant is cooled to 0 ℃ in ice bath also carefully dropwise adding entry (0.5mL) adds 15%NaOH then
(aq)(0.5mL), add more water (5mL) at last and come termination reaction.Reactant is stirred 15min in 0 ℃, then with soup compound by diatomite filtration to remove aluminium salt.Filtrate is distributed between water and ethyl acetate, and water (1 * 50mL) and salt solution (1 * 50mL) washing ethyl acetate layer, obtain [6-(3-amino-2-methyl-phenyl)-imidazo [1 through anhydrous sodium sulfate drying and vacuum concentration then, 2-a] pyrazine-8-yl]-the brown solid (300mg) of (4-morpholine-4-ylmethyl-phenyl)-amine, its purity is enough to be used in the next step.
The step 5:6-tertiary butyl-nicotinic acid
Stir down nicotinic acid (1.0g, 7.3mmol) water-soluble (10mL) and dense H
2SO
4In the mixture (0.5mL).Add tertiary butyl carboxylic acid, and the crystallization soup compound of gained is stirred down in nitrogen.The AgNO that adds catalytic amount then
3And ammonium persulphate (140mg; 0.61mmol), flask is heated 3hs with lucifuge and with reactant in 90 ℃ with the aluminium foil parcel.Reactant is cooled to 0 ℃, alkalizes to pH 10 and usefulness ethyl acetate extraction (4 * 50mL).The organic layer that merges with saturated sodium carbonate (2 * 50mL) and the salt water washing, through anhydrous sodium sulfate drying and vacuum concentration.Gained oily matter obtains the white solid of the 6-tertiary butyl-nicotinic acid (1.1g) through the fast silica gel chromatogram purifying.
The step 6:6-tertiary butyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-niacinamide
With [6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-yl]-(4-morpholine-4-ylmethyl-phenyl)-amine (150mg; 0.36mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphonium hexafluorophosphate (450mg; 1.0mmol) and diisopropylethylamine (0.3mL; 1.7mmol) mixture be dissolved in the N,N-DIMETHYLACETAMIDE (1mL) and under room temperature and stir 20min.(200mg 1.1mmol) and with mixture stirs 16h under room temperature to add the 6-tertiary butyl-nicotinic acid.
Add entry (100mL) and mixture filtered and obtain the 6-tertiary butyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-the rough solid of brown (120mg) of niacinamide.It is canescence emulsifiable paste shape solid (100mg) that this rough solid obtains the finished product through fast silica gel chromatogram.
Embodiment 3
Synthesizing of 3-(5,5-dimethyl-[1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-fluoro-aniline
Step 1:2-(2-fluoro-3-nitro-phenyl)-5,5-dimethyl-[1,3,2] two oxa-boron heterocycle hexanes
With 1-bromo-2-fluoro-3-oil of mirbane (800mg; 3.63mmol), two (neopentyl glycol) two boron (900mg; 3.98mmol), with methylene dichloride (100mg; 0.12mmol) 1: 1 blended [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride, Potassium ethanoate (1.0g; 10.2mmol) and the mixture heating up backflow 16h of dioxane (20mL).
Mixture is cooled to room temperature, and water (100mL) is handled, and (3 * 25mL) extract with ethyl acetate.
The extraction liquid water (2 * 25mL) and salt solution (1 * 25mL) washing, through anhydrous sodium sulfate drying and vacuum concentration.Resistates obtains 2-(2-fluoro-3-nitro-phenyl)-5, the faint yellow solid (350mg) of 5-dimethyl-[1,3,2] two oxa-boron heterocycle hexanes through fast silica gel chromatogram (with ether/hexane 1/2 wash-out) purifying.
Step 2:3-(5,5-dimethyl-[1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-fluoro-aniline
With 2-(2-fluoro-3-nitro-phenyl)-5,5-dimethyl-[1,3,2] two oxa-boron heterocycle hexane (240mg; 1.1mmol), 10% palladium carbon (100mg) and mixture hydrogenation 2h under room temperature and 40psi hydrogen of ethyl acetate (75mL).
Mixture is used CH through diatomite filtration
2Cl
2(2 * 100mL) wash and the filtrate evaporation are obtained the brown solid (200mg) of 3-(5,5-dimethyl-[1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-fluoro-aniline.
Embodiment 4
Following compounds is to use with the foregoing description 1 to 3 described similar approach and is prepared.
Embodiment 5
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide synthetic
Step 1:4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-cyanobenzene
(220mg, 1.89mmol) with 6, (500mg, mixture 1.81mmol) form soup compound and heat 20min in 140 ℃ 8-two bromo-imidazos [1,2-a] pyrazine in DMF (1mL) with the 4-anthranilo nitrile.With reactant cooling, and reach 75 ℃, add ethyl acetate (40mL), and stir soup compound and bulk solid is broken be fine powder when bathing temperature.4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-cyanobenzene of pulverizing is filtered, and (2 * 50mL) washings and vacuum-drying obtain orange/brown solid (600mg) with ether.
Step 2:4-[6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-base is amino]-cyanobenzene
With 4-(6-bromo-imidazo [1,2-a] pyrazine-8-base is amino)-cyanobenzene (1.02g; 3.27mmol) solution ethylene glycol, dme (DME, form pulpous state in 60mL) and under stirring at room to reactant drum nitrogen 15min.
Add 3-(5,5-dimethyl-[1,3,2] two oxa-boron heterocycle hexane-2-yls)-2-methyl-phenyl amine (950mg; 3.63mmol) and four (triphenylphosphines) close palladium (500mg; 0.43mmol) and under room temperature, continue pulpous state reactant drum nitrogen 10min.Add the sodium carbonate solution of 20mL 1.0N and two-phase mixture vigorous stirring under nitrogen is heated to 95 ℃ of 16h.With mixture between ethyl acetate (100mL) and water (100mL) layering and with water layer with ethyl acetate (2 * 50mL) extraction.Merge organic layer, with the salt water washing and use anhydrous sodium sulfate drying.Then filtrate is carried out vacuum concentration and thick oily matter is dissolved in the CH of minimal volumes
2Cl
2In.Add diethyl ether, with the sedimentation and filtration of gained and to obtain 4-[6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-base with the diethyl ether washing amino]-the light brown brown solid (650mg) of cyanobenzene.
The step 3:4-tertiary butyl-N-{3-[8-(4-cyano group-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide
Under nitrogen that 4-[6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-base is amino]-cyanobenzene (380mg; 1.12mmol) and diisopropylethylamine (187mg; 1.45mmol) solution in anhydrous THF (25mL) at room temperature stirs.Then with the 4-tertiary butyl-Benzoyl chloride (230mg; 1.17mmol) drips of solution in the anhydrous THF of 5mL is added in the reaction soln of stirring.Behind the 30min, with mixture between ethyl acetate (75mL) and water (75mL) layering and with water layer with ethyl acetate (2 * 50mL) extraction.Merge organic layer, with the salt water washing and use anhydrous sodium sulfate drying.Then filtrate is carried out vacuum concentration and thick oily matter is dissolved in the CH of minimal volumes
2Cl
2In.Add diethyl ether, obtain the 4-tertiary butyl-N-{3-[8-(4-cyano group-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl with the sedimentation and filtration of gained and with the diethyl ether washing]-2-methyl-phenyl }-the light orange solid (450mg) of benzamide.
Step 4:4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-the benzenecarboximidic acid carbethoxy hydrochloride
With the 4-tertiary butyl-N-{3-[8-(4-cyano group-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide forms soup compound and reactant is cooled to 0 ℃ in ice bath in 200mL ethanol (200 strength criterion).Then that reactant is saturated and under agitation rise to room temperature gradually in 16h with hydrogen chloride gas.Solvent removed in vacuo; the 4-{6-[3-of gained (the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-the directly use of benzenecarboximidic acid (benzimidic acid) carbethoxy hydrochloride (500mg) brown solid without being further purified.
The step 5:4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide
In a withstand voltage reaction flask of glass, with 4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-benzenecarboximidic acid carbethoxy hydrochloride (150mg; 0.26mmol) be dissolved in the methyl alcohol (1mL) and add methylamine at THF (2.0N; Solution 2mL).Reactant is heated 2h, vacuum concentration then in 50 ℃.Oily matter is dissolved in 2mL CH
2Cl
2In, and add diethyl ether (20mL) be settled out the 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl-phenyl)-the shallow brown solid (140mg) of benzamide.
Embodiment 6
Following compounds is to use with the foregoing description 5 described similar approach and is prepared.
Embodiment 7
N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-3-pyridin-3-yl-acrylamide synthetic
With 3-pyridin-3-yl vinylformic acid (31mg; 0.21mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphonium hexafluorophosphate (100mg; 0.23mmol), diisopropylethylamine (0.11mL; 0.63mmol) and the mixture of DMF (3mL) under room temperature, stir 30min.Add 4-[6-(3-amino-2-methyl-phenyl)-imidazo [1,2-a] pyrazine-8-base is amino]-phenyl }-morpholine-4-base-ketone (90mg; 0.21mmol) and this mixture is stirred 16h under room temperature.
Add entry (10mL) and with mixture filter obtain N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl-phenyl)-the light brown solid (50mg) of 3-pyridin-3-yl-acrylamide.
Embodiment 8
Following compounds is to use with the foregoing description 7 described similar approach and is prepared.
Embodiment 9
The Btk biochemical test
The general step that can be used for testing a kind of standard biological chemistry Btk kinase assay of disclosed compound among the application is as follows.
Preparation contains 1X cell signaling kinase buffer liquid (25mM Tris-HCl, pH 7.5,5mM β-Phosphoric acid glycerol esters, 2mM dithiothreitol (DTT), 0.1mM Na
3VO
4, 10mM MgCl
2), the premix reagent (master mix) of the no Btk enzyme of the 0.5 biotin labeled peptide substrates 2 of μ M Promega PTK and 0.01%BSA.Preparation contains the premix reagent that adds the Btk enzyme of 1X cell signaling kinase buffer liquid, the biotin labeled peptide substrates 2 of 0.5 μ M PTK, 0.01%BSA and 50ng/ hole Btk enzyme.The Btk enzyme is prepared as follows: (go into to hide registration number: NM-000061) subclone has the Btk baculovirus of this epi-position label to the pFastBac carrier with preparation will to have total length people's wild-type Btk of the terminal V5 of C-and 6 * His label.According to the specification sheets of Invitrogen company write up in open scheme " Bac-toBacBaculovirus Expression Systems " (Cat.Nos.10359-016 and 10608-016) to baculovirus go down to posterity (generation).Third generation virus is used to infect the Sf9 cell to cross the Btk albumen of express recombinant.Use afterwards the Ni-NTA post with this Btk protein purification to homogeneous.Determine that according to sensitive Sypro-Ruby staining the purity of final protein product is greater than 95%.The solution that in water, prepares 5mMATP by the 5mM stock solution that transfers to pH 7.4 with 1N NaOH.The compound in 5%DMSO of 1.25 μ L amount is transferred in (1/2area) Costar polystyrene board in 1/2 zone, 96 holes.(initial concentration is 10 μ M with 11-dose point response curve to compound separately; Dilution in 1: 2) tests.In the appropriate well with the Costar polystyrene board in the premix reagent (as negative control) of the no enzyme of 18.75 μ L amount and enzyme-added 1/2 zone, premix agent transfer to 96 hole.The 5mM ATP of 5 μ L being added to making the ATP ultimate density in the Costar polystyrene board in 1/2 zone, 96 holes is 1mM.Reactant is incubation 1 hour at room temperature.With the Perkin Elmer 1 that contains 30mM EDTA, 20nMSA-APC and 1nM PT66Ab * detection damping fluid termination reaction.The time-resolved fluorescence method that uses band PerkinElmer Envision is with exciting filter disc 330nm, emission filter disc 665nm and 2nd emission filter disc 615nm to the plate reading.Calculate IC afterwards
50Value.
Embodiment 10
Ramos cell Btk test
The general step of standard cell lines Btk kinase assay that can be used for testing disclosed compound among the application is as follows.
With the Ramos cell in 37 ℃ in the presence of test compounds with 0.5 * 10
7The density incubation of cell/ml 1 hour.Pass through then at 37 ℃ down with 10 μ g/ml anti-people IgM F (ab)
2Incubation came irritation cell in 5 minutes.Cell is agglomerating, cracking, and to the clarification (cleared) lysate carry out analysis of protein.The equal protein of each sample is carried out SDS-PAGE and Western blotting, use anti--phosphoBtk (Tyr223) antibody (Cell SignalingTechnology#3531) with estimate the Btk autophosphorylation or by anti-Btk antibody (BD Transduction Labs#611116) to control the total amount of Btk in each lysate.
Embodiment 11
The B cell proliferation test
The general step of standard cell lines B cell proliferation test that can be used for testing disclosed compound among the application is as follows.
(Miltenyi Biotech is Cat#130-090-862) from the spleen purifying B cell of the Balb/c mouse in 8-16 age in week to use B cellular segregation test kit.Test compounds being diluted in 0.25%DMSO and added the anti-mouse IgM of 10 μ g/ml antibody (SouthernBiotechnology Associates Cat#1022-01) to final volume in 30 minutes then with the mouse spleen B cell incubation of 2.5 * 105 purifying is 100 μ l.Through 24 hours incubations, add 1 μ Ci
3The H-thymidine also continued incubation 36 hours with culture plate, used SPA[then
3H] producer's scheme of thymidine picked-up analytical system (Amersham Biosciences#RPNQ 0130) measures.Carry out counting with microbeta counter (Wallace Triplex 1450, Perkin Elmer) based on the fluorescence of SPA pearl.
Embodiment 12
The T cell proliferation test
The general step of standard T cell proliferation test that can be used for testing disclosed compound among the application is as follows.
(Miltenyi Biotech is Cat#130-090-861) from the spleen purifying T cell of the Balb/c mouse in 8-16 age in week to use Pan T cellular segregation test kit.Test compounds diluted in 0.25%DMSO and with 2.5 * 10
5The mouse spleen T cell of purifying is in advance applying in 90 minute flat culture plate incubation with anti--CD3 (BD#553057) of each 10 μ g/ml and anti--CD28 (BD#553294) antibody in 37 ℃ with the final volume of 100 μ l.Through behind 24 hours incubations, add 1 μ Ci
3The H-thymidine also continued incubation 36 hours with culture plate, used SPA[then
3H] producer's scheme of thymidine picked-up analytical system (Amersham Biosciences#RPNQ 0130) measures.Carry out counting with microbeta counter (Wallace Triplex 1450, Perkin Elmer) based on the fluorescence of SPA pearl.
Embodiment 13
The CD86 inhibition test
The general step that can be used for testing the standard test that disclosed compound among the application suppresses the B cytoactive is as follows.
By the spleen purifying mouse whole splenocytes of erythrocyte cracking (BD Pharmingen#555899) by the Balb/c mouse in age in 8-16 week.Test compounds diluted in 0.5%DMSO and with 1.25 * 106 splenocytes with the final volume of 200 μ l in flat culture plate (Falcon 353072) in 37 ℃ of incubations 60 minutes.Then by adding 15 μ g/ml IgM (Jackson Immunoresearch 115-006-020) irritation cell, and in 37 ℃, 5%CO
2Following incubation 24 hours.Behind the incubation 24 hours, with cell transfer to transparent 96 orifice plates of conical bottom and by centrifugal agglomerating at 1200 * g * 5min.With cell with the pre-retardance of CD16/CD32 (BD Pharmingen#553142), then with CD 19-FITC (BD Pharmingen#553785), CD86-PE (BD Pharmingen#553692), reach 7AAD (BD Pharmingen#51-68981E) and carry out triple staining.Pair cell classification and on BD FACSCalibur to CD19
+/ 7AAD-population carries out gate.Measure CD86 surface expression level in the gate population, contrast with test compounds concentration.
Embodiment 14
The test of B-ALL cell survival
The following step that is to use the standard B-ALL cell survival research of the number that the XTT reader measures viable cell.This test can be used for testing disclosed compound among the application suppresses the B-ALL cell survival in culture ability.Applicable human B cell acute lymphoblastic leukemia cell system is the human Pre-B-cell ALL clone SUP-B15 that can obtain from ATCC.
With SUP-B15 pre-B-ALL cell with concentration 5 * 10
5Cell/ml is laid in a plurality of 96 hole microtiter plates of 100 μ l Iscove ' s substratum+20%FBS.Adding test compounds then, to make ultimate density be 0.4%DMSO.With cell in 37 ℃, 5%CO
2Maximum 3 days of incubation.After 3 days cell is separated at 1: 3 in new 96 orifice plates that contain test compounds and continued growth 3 days.Every 24 hours, in each hole of 96 orifice plates, add 50 μ l XTT solution (Roche) and read light absorption ratio according to producer's explanation at 2,4 and 20 hours.Read then the cell of only handling with DMSO that reads with OD in linearity range (0.5-1.5) reading and be determined at per-cent with survivaling cell in the hole of described compound treatment, contrast with the cell of only handling with DMSO.
Embodiment 15
In Btk biochemical test of the present invention (embodiment 9), disclosed compound among the synthetic embodiment 1 to 8 has been carried out measuring and showing its IC
50Value is less than or equal to 10 micromoles.Some shows its IC in these compounds
50Value is less than or equal to 1 micromole.Some shows its IC in these compounds
50Value is less than or equal to 0.1 micromole.
In B cell proliferation test (as described in Example 11), test among the synthetic embodiment 1 to 8 discloseder compounds and shown its IC
50Value is less than or equal to 10 micromoles.Some shows its IC in these compounds
50Value is less than or equal to 1 micromole.Some shows its IC in these compounds in this test
50Value is less than or equal to 500nM.
Show its IC
50Value is less than or equal to 10 micromolar some compound and can not suppressor T cell breeds and (as described in Example 12) its IC when testing under condition of the present invention
50Value is more than or equal to 5 micromoles.
Disclosed some compound exhibits in embodiment 1 to 8, it is to the IC of suppressor T cell propagation
50Value suppresses the IC of B cell proliferation than these compounds
50At least 3 times of value height are high in some cases 5 times or even 10 times.
In B cytoactive inhibition test (in describe condition under) as embodiment 13 to embodiment 1 to 8 in discloseder compounds test, and show its IC
50Value is less than or equal to 10 micromoles.Some shows its IC in these compounds
50Value is less than or equal to 1 micromole's value.Some shows its IC in these compounds in this test
50Value is less than or equal to 500nM.
In B cell leukemia cell survival test (under the condition of description) as embodiment 14 to embodiment 1 to 8 in discloseder compounds test, and show its IC
50Value is less than or equal to 10 micromoles.
Discloseder compounds have biochemical activity and simultaneously based on cell activity among the embodiment 1 to 8.For example, discloseder compounds show its IC among the embodiment 1 to 8 in Btk biochemical test of the present invention (embodiment 9)
50Value is less than or equal to 10 micromoles and its IC in one of the test based on cell (except the T test cell line) of (embodiment 10,11,13 or 14) of the present invention at least
50Value is less than or equal to 10 micromoles.Some compound shows its IC in Btk biochemical test of the present invention (embodiment 9)
50Value is less than or equal to 1 micromole and its IC in one of the test based on cell (except the T test cell line) of (embodiment 10,11,13 or 14) of the present invention at least
50Value is less than or equal to 10 micromoles.Its IC of some compound exhibits
50Value is less than or equal to 0.1 micromole and is its IC in one of the test based on cell (except the T test cell line) of (embodiment 10,11,13 or 14) of the present invention at least
50Value is less than or equal to 10 micromoles.
Show chemical-biological activities and can not suppressor T cell propagation simultaneously based on some compound of cell activity.For example, some compounds of describing among the embodiment 1 to 8 show its IC in Btk biochemical test of the present invention (embodiment 9)
50Value is less than or equal to 10 micromoles, at least at its IC in one of the test based on cell (except the T test cell line) of (embodiment 10,11,13 or 14) of the present invention
50Value is less than or equal to 10 micromoles and for the IC of T cell inhibitory effect
50The IC that value comparison B cell proliferation suppresses
50Be worth high at least 3 times.Some compound shows in Btk biochemical test of the present invention (embodiment 9) and is less than or equal to 1 micromolar IC
50Value, IC in one of the test based on cell (except the T test cell line) of (embodiment 10,11,13 or 14) of the present invention at least
50Value is less than or equal to 10 micromoles and for the IC of T cell inhibitory effect
50The IC that value comparison B cell proliferation suppresses
50At least 5 times of value height.Its IC of some compound exhibits
50Value is less than or equal to 0.1 micromole, at least its IC in one of the test based on cell (except the T test cell line) of (embodiment 10,11,13 or 14) of the present invention
50Value is less than or equal to 10 micromoles and for the IC of T cell inhibitory effect
50The IC that value comparison B cell proliferation suppresses
50At least 10 times of value height.
Though some specific embodiments are illustrated and put down in writing, the present invention can carry out multiple improvement and replacement and not deviate from spirit of the present invention and scope.For example, for the purpose of explaining claim, being intended to the following claim of enumerating is interpreted as narrower than its literal meaning absolutely not, therefore is not to be intended to the exemplary specific embodiments from specification sheets is added claims.Therefore, should understand the present invention and be illustrated by way of example, and be not restricted in the claim scope.
Claims (92)
1. at least a chemical entities and the acceptable salt of pharmacology, solvate, crystalline form, inner complex, non-covalent complex, prodrug and their mixture that is selected from the compound of general formula 1:
(general formula 1)
Wherein:
R
1Be selected from randomly substituted phenylene, randomly substituted pyridylidene, optional 2-oxo-1,2-dihydropyridine base,
With
The tie point of * representative and-L-G group wherein, and scission of link representative and amino tie point; And X wherein
1Be selected from N and CR
7X
2Be selected from N and CR
7X
3Be selected from N and CR
7X wherein
1, X
2And X
3In no more than one be N and R
7Be selected from hydrogen, hydroxyl, cyano group, halogen, randomly substituted low alkyl group and randomly substituted lower alkoxy;
L is selected from covalent linkage, substituted C randomly
1-C
4Alkylidene group ,-O-,-O-(randomly substituted C
1-C
4Alkylidene group)-,-(C=O)-,-(randomly substituted C
1-C
4Alkylidene group) (C=O)-, (SO)-,-(randomly substituted C
1-C
4Alkylidene group) (SO)-, (SO
2)-,-(randomly substituted C
1-C
4Alkylidene group) (SO
2)-,-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-, be R wherein
9Be selected from hydrogen, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl;
G be selected from hydrogen, halogen, hydroxyl, alkoxyl group, nitro, randomly substituted alkyl ,-NR
16R
17, randomly substituted Heterocyclylalkyl, randomly substituted cycloalkyl, randomly substituted aryl and randomly substituted heteroaryl, wherein R
16And R
17Be independently selected from hydrogen, randomly substituted acyl group, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl; Or be selected from-(C=NR as L
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9) time, then-R
9And R
16And the nitrogen of institute's bonding forms randomly substituted 5 to 7 member heterocyclic ring containing nitrogen alkyl together, and this Heterocyclylalkyl randomly further comprises one or two extra heteroatoms that is selected from N, O and S, and R
17Be selected from hydrogen, randomly substituted acyl group, randomly substituted alkyl, randomly substituted aryl and randomly substituted heteroaryl;
T, V and W are selected from C and N, and U is selected from-CH and N, and condition is to have to be a N among T, U, V and the W at most;
R
2, R
3And R
4Be independently selected from hydrogen, randomly substituted low alkyl group, randomly substituted lower alkoxy, halogen and hydroxyl, condition be when A be covalent linkage, G is-NR
16R
17And L is not selected from-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-time, R
2, R
3And R
4In have one at least for hydrogen, and work as R
2, R
3Or R
4When corresponding T, the V of institute's bonding or W are N, R
2, R
3Or R
4Do not exist;
Q is selected from:
Wherein:
R
10And R
11Be independently selected from hydrogen, C
1-C
6Alkyl and C
1-C
6Haloalkyl; And
R
12, R
13, R
14And R
15Be independently selected from respectively
Hydrogen,
C
1-C
6Alkyl,
C
1-C
6Haloalkyl,
Phenyl,
Be selected from the substituted phenyl of single replacement, two replacements, trisubstd phenyl, wherein said substituting group is independently selected from hydroxyl, nitro, cyano group, amino, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, (C
1-C
6Alkyl oxy) C
1-C
6Alkoxyl group, C
1-C
6Perfluoroalkyl, C
1-C
6Perfluoro alkoxy, list (C
1-C
6Alkyl) amino, two (C
1-C
6Alkyl) amino and amino (C
1-C
6Alkyl),
Heteroaryl, and
Be selected from the substituted heteroaryl of single replacement, two replacements, trisubstituted heteroaryl, wherein said substituting group is independently selected from hydroxyl, nitro, cyano group, amino, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, (C
1-C
6Alkyl oxy) C
1-C
6Alkoxyl group, C
1-C
6Perfluoroalkyl, C
1-C
6Perfluoro alkoxy, list (C
1-C
6Alkyl) amino, two (C
1-C
6Alkyl) amino and amino (C
1-C
6Alkyl);
A be selected from covalent linkage and-(CH=CH)-;
R
5Be selected from randomly substituted cycloalkyl, randomly substituted Heterocyclylalkyl, randomly substituted aryl and randomly substituted heteroaryl; And
R
6Be selected from hydrogen, randomly substituted alkyl, cycloalkyl and Heterocyclylalkyl.
2. at least a chemical entities as claimed in claim 1, wherein A is a covalent linkage.
3. at least a chemical entities as claimed in claim 1, wherein A be-(CH=CH)-.
4. at least a chemical entities any, wherein R as claim 1 to 3
12, R
13, R
14And R
15Be independently selected from hydrogen, C
1-C
6Alkyl, C
1-C
6Haloalkyl and phenyl.
5. at least a chemical entities as claimed in claim 4, wherein R
13Be selected from hydrogen and C
1-C
6Alkyl.
6. at least a chemical entities any as claim 1 to 3, wherein Q is
R wherein
13Be selected from hydrogen and C
1-C
6Alkyl.
7. at least a chemical entities any, wherein R as claim 1 to 6
1Be selected from adjacent phenylene, metaphenylene, to phenylene, adjacent pyridylidene, a pyridylidene, to pyridylidene,
8. at least a chemical entities as claimed in claim 7, wherein R
1Be selected from adjacent phenylene, metaphenylene, to phenylene, adjacent pyridylidene, a pyridylidene with to pyridylidene.
9. at least a chemical entities as claimed in claim 8, wherein R
1Be selected from phenylene and metaphenylene.
10. at least a chemical entities as claimed in claim 9, wherein R
1For to phenylene.
11. at least a chemical entities as claimed in claim 1, the compound of wherein said general formula 1 is selected from the compound of general formula 2:
(general formula 2)
12. at least a chemical entities any, wherein R as claim 1 to 11
5Be selected from
Phenyl,
Be selected from the substituted phenyl of single replacement, two replacements and tri-substituted phenyl; wherein said substituting group is independently selected from hydroxyl, low alkyl group, sulfane base, alkylsulfonyl, randomly substituted amino, lower alkoxy, the low alkyl group that is replaced by one or more halogens, the lower alkoxy that is replaced by one or more halogens, the low alkyl group that is replaced by hydroxyl, and heteroaryl
Pyridyl,
Be selected from the substituted pyridyl of single replacement, two replacements and three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Pyrimidyl,
Be selected from the substituted pyrimidyl of single replacement, two replacements and three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Pyrazinyl,
Be selected from the substituted pyrazinyl of single replacement, two replacements and three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Pyridazinyl,
Be selected from the substituted pyridazinyl of single replacement, two replacements and three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Oxazole-2-base,
The Bei that is selected from single replacement, two replacements and San substituted oxazole-2-base replaces De oxazole-2-base, and wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
The 2H-pyrazole-3-yl,
Be selected from the substituted 2H-pyrazole-3-yl of single replacement, two replacements and three replacement 2H-pyrazole-3-yls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
[1,2,3] thiadiazoles-4-base,
Be selected from substituted [1,2, the 3] thiadiazoles-4-base of single replacement, two replacements and three replacement [1,2,3] thiadiazoles-4-bases, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Isoxazole-5-base,
Be selected from the substituted isoxazole-5-base of single replacement, two replacements and three substituted isoxazoles-5-base, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
4,5,6,7-tetrahydro benzo [b] thiophene-2-base,
Be selected from single replacement, two replacements and three replacements 4,5,6; substituted 4,5,6 of 7-tetrahydro benzo [b] thiophene-2-base; 7-tetrahydro benzo [b] thiophene-2-base, wherein said substituting group are independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reach heteroaryl
4,5,6,7-tetrahydrochysene benzfuran-2-base,
Be selected from single replacement, two replacements and three replacements 4,5,6; substituted 4,5,6 of 7-tetrahydrochysene benzfuran-2-base; 7-tetrahydrochysene benzfuran-2-base, wherein said substituting group are independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reach heteroaryl
4,5,6,7-tetrahydrochysene-1H-indoles-2-base,
Be selected from single replacement, two replacements and three replacements 4; 5; 6; substituted 4,5,6 of 7-tetrahydrochysene-1H-indoles-2-base; 7-tetrahydrochysene-1H-indoles-2-base; wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl, and the low alkyl group that the amido nitrogen of wherein said indole ring randomly is optionally substituted replaces
1H-indoles-2-base,
Be selected from the substituted 1H-indoles-2-base of single replacement, two replacements and three substituted 1 H-indoles-2-base; wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl; and the low alkyl group that the amido nitrogen of wherein said indole ring randomly is optionally substituted replaces
The 1H-indol-3-yl,
Be selected from the substituted 1H-indol-3-yl of single replacement, two replacements and three substituted 1 H-indoles-3-base; wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl; and the low alkyl group that the amido nitrogen of wherein said indole ring randomly is optionally substituted replaces
Cumarone-2-base,
Be selected from the substituted cumarone-2-base of single replacement, two replacements and trisubstituted benzene and furans-2-base, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Benzo [b] thiophene-2-base,
Be selected from also substituted benzo [b] thiophene-2-base of [b] thiophene-2-base of single replacement, two replacements and trisubstituted benzene, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl,
Quinoline-3-base, and
Be selected from the substituted quinoline-3-base of single replacement, two replacements, three substd quinolines-3-base, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, reaches heteroaryl.
13. at least a chemical entities, wherein R as claim 12
5Be selected from phenyl and substituted phenyl; wherein said substituted phenyl is selected from single replacement, two and replaces and trisubstd phenyls, and wherein said substituting group is independently selected from hydroxyl, low alkyl group, sulfane base, alkylsulfonyl, randomly substituted amino, lower alkoxy, the low alkyl group that is replaced by one or more halogens, the lower alkoxy that is replaced by one or more halogens, the low alkyl group and the heteroaryl that are replaced by hydroxyl.
14. at least a chemical entities, wherein R as claim 13
5Single replacement, two replaces and the substituted phenyl of tri-substituted phenyl in order to be selected from, and wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy and heteroaryl.
15. at least a chemical entities, wherein R as claim 14
5For 4-low alkyl group-phenyl-.
16. at least a chemical entities, wherein R as claim 15
5Be the 4-tertiary butyl-phenyl.
17. at least a chemical entities, wherein R as claim 12
5Be selected from pyridyl and be selected from that single replacement, two replaces and the substituted pyridyl of three substituted pyridinyls, wherein said substituting group is independently selected from hydroxyl, low alkyl group, alkylsulfonyl, halogen, lower alkoxy, and heteroaryl.
18. at least a chemical entities, wherein R as claim 17
5Be pyridin-3-yl.
19. at least a chemical entities as claimed in claim 1, the compound of wherein said general formula 1 is selected from the compound of general formula 3:
(general formula 3)
Wherein
X is selected from O, S, NR
18,-CH=N-and-N=CH-;
R
18Be selected from hydrogen, randomly substituted alkyl, randomly substituted aryl, and randomly substituted heteroaryl; And
R
20Represent 0 to 3 to be independently selected from hydroxyl, nitro, cyano group, amino, halogen, C
1-C
6Alkyl, C
1-C
2Haloalkyl, C
1-C
2Halogenated alkoxy, C
1-C
6Alkoxyl group, list (C
1-C
4Alkyl) amino, two-(C
1-C
4Alkyl) amino, and amino (C
1-C
4Alkyl) substituting group.
20. at least a chemical entities as claim 19, wherein X is selected from O, NR
18,-CH=N-and-N=CH.
21. at least a chemical entities as claim 20, wherein X is selected from O and NR
18
22. at least a chemical entities as claimed in claim 1, the compound of wherein said general formula 1 is selected from the compound of general formula 4:
(general formula 4)
Wherein
Y and Z are independently selected from CH and N;
R
19Be selected from hydrogen, hydroxyl, low alkyl group, alkylsulfonyl, randomly substituted amino, lower alkoxy, the low alkyl group that is replaced by one or more halogens, the lower alkoxy that is replaced by one or more halogens, the low alkyl group that is replaced by hydroxyl, and heteroaryl; And
R
20Be selected from hydrogen, low alkyl group, halogen, lower alkoxy and hydroxyl.
23. at least a chemical entities any as claim 1 to 22, wherein L be selected from covalent linkage ,-(C=O)-,-CH
2-,-SO
2-,-CH
2(C=O)-,-CH (CH
3) (C=O)-,-CH
2CH
2(C=O)-,-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-.
24. at least a chemical entities as claim 23, wherein L be selected from-(C=O)-,-CH
2-,-SO
2-,-CH
2(C=O)-and-CH (CH
3) (C=O)-.
25. at least a chemical entities as claim 24, wherein L be-(C=O)-.
26. at least a chemical entities any as claim 1 to 25, wherein G is selected from
Hydrogen,
Hydroxyl,
-NR
16R
17、
Randomly substituted Heterocyclylalkyl,
Randomly substituted 5,6-dihydro-8H-imidazo [1,2-a] pyrazine-7-base,
Lower alkoxy and
1H-tetrazolium-5-base.
27. at least a chemical entities as claim 26, wherein G is selected from
Hydrogen,
Hydroxyl,
N-methyl ethanol amino,
Randomly substituted 4,5-dihydro-1H-imidazoles-2-base,
Randomly substituted morpholine-4-base,
Randomly substituted piperazine-1-base, and
Randomly substituted high piperazine-1-base.
28. at least a chemical entities as claim 27, wherein G is selected from
Hydrogen,
Morpholine-4-base,
4-acyl group-piperazine-1-base,
4-low alkyl group-piperazine-1-base,
3-oxo-piperazine-1-base,
High piperazine-1-base, and
4-low alkyl group-Gao piperazine-1-base.
29. at least a chemical entities any as claim 1 to 25, wherein G is selected from-NR
16R
17, and randomly substituted Heterocyclylalkyl.
30. at least a chemical entities as claim 29, wherein G is selected from randomly substituted morpholine-4-base and substituted piperazine-1-base randomly.
31. at least a chemical entities as claim 30, wherein G is morpholine-4-base.
32. at least a chemical entities any as claim 1 to 22, wherein L is selected from-(C=NR
9)-and-(randomly substituted C
1-C
4Alkylidene group) (C=NR
9)-, and G are-NR
16R
17
33. at least a chemical entities, wherein R as claim 32
9Be selected from hydrogen and low alkyl group.
34. at least a chemical entities, wherein R as claim 33
9Be selected from hydrogen and methyl.
35. at least a chemical entities any, wherein R as claim 1 to 34
6Be hydrogen.
36. at least a chemical entities any, wherein R as claim 1 to 35
2Be selected from methyl, trifluoromethyl, difluoromethyl, methoxyl group, trifluoromethoxy, difluoro-methoxy and fluorine.
37. at least a chemical entities, wherein R as claim 36
2Be methyl.
38. at least a chemical entities, wherein R as claim 36 or 37
3And R
4Be hydrogen.
39. at least a chemical entities any, wherein R as claim 1 to 35
3Be selected from methyl, trifluoromethyl, difluoromethyl, methoxyl group, trifluoromethoxy, difluoro-methoxy and fluorine.
40. at least a chemical entities, wherein R as claim 39
3Be methyl.
41. at least a chemical entities, wherein R as claim 39 or 40
2And R
4Be hydrogen.
42. at least a chemical entities any, wherein R as claim 1 to 35
4Be selected from methyl, trifluoromethyl, difluoromethyl, methoxyl group, trifluoromethoxy, difluoro-methoxy and fluorine.
43. at least a chemical entities, wherein R as claim 42
4Be methyl.
44. at least a chemical entities, wherein R as claim 42 or 43
2And R
3Be hydrogen.
45. at least a chemical entities any as claim 22 to 44, wherein Y and Z are CH.
46. at least a chemical entities any, wherein R as claim 22 to 45
19Be selected from hydrogen and low alkyl group.
47. at least a chemical entities, wherein R as claim 46
19Be selected from hydrogen, sec.-propyl and the tertiary butyl.
48. at least a chemical entities, wherein R as claim 47
19Be the tertiary butyl.
49. at least a chemical entities any, wherein R as claim 19 to 48
20Do not exist.
50. at least a chemical entities any as claim 1 to 49, wherein T, V and W are that C and U are-CH.
51. at least a chemical entities any, the wherein IC that shows at least a chemical entities described in the active external biological chemical test of Btk as claim 1 to 50
50Value is 10 micromoles or lower.
52. at least a chemical entities, the wherein IC that shows at least a chemical entities described in the active external biological chemical test of Btk as claim 51
50Value is 1 micromole or lower.
53. at least a chemical entities, the wherein IC that shows at least a chemical entities described in the active external biological chemical test of Btk as claim 52
50Value is 0.1 micromole or lower.
54. at least a chemical entities any, the wherein IC that shows at least a chemical entities described in the B cytoactive inhibition test as claim 1 to 53
50Value is 10 micromoles or lower.
55. at least a chemical entities, the wherein IC that shows at least a chemical entities described in the B cytoactive inhibition test as claim 54
50Value is 1 micromole or lower.
56. at least a chemical entities, the wherein IC that shows at least a chemical entities described in the B cytoactive inhibition test as claim 55
50Value is 500 nmoles or lower.
57. at least a chemical entities any as claim 1 to 56, the IC that wherein said at least a chemical entities shows in the suppressor T cell proliferation test
50The IC that value shows in suppressing the B cell proliferation test than described at least a chemical entities
50At least 3 times of value height.
58. at least a chemical entities as claim 57, the IC that wherein said at least a chemical entities shows in the suppressor T cell proliferation test
50The IC that value shows in suppressing the B cell proliferation test than described at least a chemical entities
50At least 5 times of value height.
59. at least a chemical entities as claim 58, the IC that wherein said at least a chemical entities shows in the suppressor T cell proliferation test
50The IC that value shows in suppressing the B cell proliferation test than described at least a chemical entities
50At least 10 times of value height.
60. at least a chemical entities any, the wherein IC that shows at least a chemical entities described in the test of B-ALL cell survival as claim 1 to 59
50Value is 10 micromoles or lower.
61. at least a chemical entities as claimed in claim 1, the compound of wherein said general formula 1 is selected from:
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
N-(5-{8-[4-(4-ethanoyl-piperazine-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-the 4-tertiary butyl-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(N-methyl-hydroxyethyl-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(N, N-dimethyl-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(N-methyl isophthalic acid-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(acid amides)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(4-methyl-piperazine-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
N-(5-{8-[4-(4-ethanoyl-piperazine-1-yl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-the 4-tertiary butyl-benzamide;
The 4-tertiary butyl-N-(2-fluoro-5-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-{2-methyl-5-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(3-oxo-piperazine-1-ylmethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
N-(5-{8-[4-(4-ethanoyl-piperazine-1-ylmethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-the 4-tertiary butyl-benzamide;
The 4-tertiary butyl-N-(5-{8-[4-(5,6-dihydro-8H-imidazo [1,2-a] pyrazine-7-ylmethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
(4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenyl)-acetate;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(2-morpholine-4-base-2-oxo-ethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-{5-[8-(4-{[(2-hydroxyl-ethyl)-methyl-formamyl]-methyl }-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide;
The 4-tertiary butyl-N-[2-methyl-5-(8-{4-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-phenyl amino }-imidazo [1,2-a] pyrazine-6-yl)-phenyl]-benzamide;
(3-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenyl)-acetate;
The 4-tertiary butyl-N-(2-methyl-5-{8-[3-(2-morpholine-4-base-2-oxo-ethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-[2-methyl-5-(8-{3-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-phenyl amino }-imidazo [1,2-a] pyrazine-6-yl)-phenyl]-benzamide;
The 4-tertiary butyl-N-{5-[8-(3-formyl-dimethylamino methyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide;
2-(3-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenyl)-propionic acid;
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-methoxyl group-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
The 4-tertiary butyl-N-(2-methyl-5-{8-[4-(1-methyl-2-morpholine-4-base-2-oxo-ethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-4-fluoro-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(4-methyl-piperazine-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl hydroxyethyl-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methylethyl-1-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
4-{6-[5-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenylformic acid;
The 4-tertiary butyl-N-(4-methyl-3-{8-[4-(N-methyl hydroxyethyl-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
4-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-ethyl benzoate;
The 4-tertiary butyl-N-(2-fluoro-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 6-tertiary butyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
[1,2,3] thiadiazoles-4-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
Isoxazole-5-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
Pyridine-2-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
The 6-tertiary butyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-niacinamide;
The 4-tertiary butyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
4-sec.-propyl-N-{2-methyl-3-[8-(4-morpholine-4-ylmethyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
The 6-hydroxy-n-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
The 5-tertiary butyl-oxazoles-2-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-4-methyl sulfane base-benzamide;
4-(1H-imidazoles-2-yl)-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(1H-tetrazolium-5-yl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
4-methylsulfonyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
2-hydroxyl-6-methyl-N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(1H-tetrazolium-5-ylmethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
2,5-dimethyl-2H-pyrazoles-3-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
The 4-tertiary butyl-N-{2-methyl-5-[8-(4-sulfamyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
The 4-tertiary butyl-N-{3-[8-(4-amidino groups-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-phenyl }-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N '-dimethyl-amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(imino--morpholine-4-base-methyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N-dimethyl-amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(2-imino--2-morpholine-4-base-ethyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N '-dimethyl-amidino groups)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(4,5-dihydro-1H-imidazoles-2-yl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
The 4-tertiary butyl-N-{3-[8-(4-amidino groups-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide;
The 4-tertiary butyl-N-{3-[8-(4-amidino groups methyl-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-benzamide;
The 4-tertiary butyl-N-(2-methyl-3-{8-[4-(N-methyl amidino groups methyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N '-dimethyl-amidino groups methyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
The 4-tertiary butyl-N-(3-{8-[4-(N, N-dimethyl-amidino groups methyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-2-methyl-phenyl)-benzamide;
Coumarilic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
N-(2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-3-pyridin-3-yl-acrylamide;
Quinoline-3-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
1-Methyl-1H-indole-3-formic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
The 1H-indole-3-carboxylic acid (2-methyl-3-{8-[4-(morpholine-4-carbonyl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-acid amides;
The 6-tertiary butyl-N-(2-methyl-3-{8-[4-(1-oxo-114-thiomorpholine-4-yl)-phenyl amino]-imidazo [1,2-a] pyrazine-6-yl }-phenyl)-niacinamide;
N-{3-[8-(3-amino-phenyl amino)-imidazo [1,2-a] pyrazine-6-yl]-2-methyl-phenyl }-the 4-tertiary butyl-benzamide; And
Tetrahydrofuran (THF)-2-formic acid (3-{6-[3-(the 4-tertiary butyl-benzoyl-amido)-2-methyl-phenyl]-imidazo [1,2-a] pyrazine-8-base is amino }-phenyl)-acid amides;
62. a pharmaceutical composition, it comprises at least a chemical entities and at least a pharmacology acceptable media that be selected from carrier, adjuvant and vehicle any one as claim 1 to 61.
63. as the pharmaceutical composition of claim 62, wherein said composition is mixed with the form that is selected from injecting fluid, aerosol, emulsifiable paste, gel, tablet, pill, capsule, syrup, ophthalmic solution and transdermal patch.
64. the pharmaceutical composition through packing, it comprises
Pharmaceutical composition as claim 62 or 63; And
Use the said composition treatment to suffer from the patient's of the disease that inhibition Btk activity is responded specification sheets.
65. as the pharmaceutical composition through packing of claim 64, wherein said is cancer to suppressing the active disease that responds of Btk.
66. as the pharmaceutical composition through packing of claim 65, wherein said disease to the active response of inhibition Btk is selected from supersensitivity illness, autoimmune disease, inflammatory diseases and acute inflammatory reaction.
67. a treatment suffers from the method to the patient of the disease that suppresses the active response of Btk, it comprises at least a as any one chemical entities of claim 1 to 61 or as the pharmaceutical composition of claim 62 or 63 to described patient's effective dosage.
68. as the method for claim 67, wherein said patient is human.
69. as the method for claim 67, wherein said patient is selected from cat and dog.
70. the method any as claim 67 to 69, wherein said is cancer to suppressing the active disease that responds of Btk.
71. as the method for claim 70, wherein said is B cell lymphoma and leukemia to suppressing the active disease that responds of Btk.
72. the method any as claim 67 to 71, wherein the described at least a chemical entities of significant quantity is by being selected from the method administration of intravenously, intramuscular and parenteral route.
73. the method any as claim 67 to 71, wherein the described at least a chemical entities of significant quantity is an oral administration.
74. a treatment suffers from patient's the method for the disease of the cancer of being selected from, autoimmune disease, inflammatory diseases, acute inflammatory reaction and supersensitivity illness, it comprises at least a as any one chemical entities of claim 1 to 61 or as the pharmaceutical composition of claim 62 or 63 to described patient's effective dosage.
75. as the method for claim 74, wherein said patient is human.
76. as the method for claim 74, wherein said patient is selected from cat and dog.
77. the method any as claim 74 to 76, wherein the described at least a chemical entities of significant quantity is by being selected from the method administration of intravenously, intramuscular and parenteral route.
78. the method any as claim 74 to 76, wherein the described at least a chemical entities of significant quantity is an oral administration.
79. a method that increases cancer cells for the susceptibility of chemotherapy, it comprises to the patient who is carrying out chemotherapy with chemotherapeutics at least a as any one chemical entities of claim 1 to 61 or as the pharmaceutical composition of claim 62 or 63 to the dosed administration of the susceptibility of chemotherapeutics to be enough to increase cancer cells.
80. one kind is reduced medication errors and increases because of suffering from the method to the treatment compliance that suppresses the patient that the active disease that responds of Btk treats, the pharmaceutical preparation through packing that provides as claim 64 is provided this method, and wherein said specification sheets further comprises and this relevant contraindication and side reaction information of pharmaceutical composition through packing.
81. a method that is used to suppress the ATP hydrolysis, this method comprise with enough at the external at least a cell of expressing Btk that contacts as any one chemical entities of claim 1 to 61 that reduces the amount of ATP hydrolysis level with detecting.
82. as the method for claim 81, wherein said cell is present in the Mammals.
83. as the method for claim 82, wherein said Mammals is human.
84. as the method for claim 82, wherein said Mammals is selected from cat and dog.
85. there is the method for Btk in the definite sample, it is included in and allows to detect under the active condition of Btk with at least a chemical entities contact sample any as claim 1 to 61, Btk activity level in the test sample, thus determine to exist or do not exist in the sample Btk.
86. a method that is used to suppress the B cytoactive, it comprises enough to contact the cell of expressing Btk external at least a of amount that reduces the B cytoactive as any one chemical entities of claim 1 to 61 with detecting.
87. at least a chemical entities any as claim 1 to 61, wherein said at least a chemical entities is with providing the mark of detectable signal directly or indirectly to carry out mark.
88. at least a chemical entities as claim 87, wherein said mark is selected from radio isotope, fluorescent mark, enzyme, antibody, particle, chemiluminescent labeling and specific binding molecules.
89. at least a chemical entities is used for the treatment of the application of suffering from the patient's of the disease that suppresses the active response of Btk the medicine in production, wherein said at least a chemical entities is the chemical entities any as claim 1 to 61.
90., wherein the disease that suppresses the active response of Btk is selected from cancer, autoimmune disease, inflammatory diseases, acute inflammatory reaction and supersensitivity illness as the application of claim 89.
91. a production is used for the treatment of the method for the patient's who suffers from the disease that inhibition Btk activity is responded medicine, it is included in and adds at least a chemical entities any as claim 1 to 61 in the described medicine.
92. as the method for claim 91, wherein said disease to the active response of inhibition Btk is selected from cancer, autoimmune disease, inflammatory diseases, acute inflammatory reaction and supersensitivity illness.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/985,023 | 2004-11-10 | ||
| US10/985,023 US20050288295A1 (en) | 2003-11-11 | 2004-11-10 | Certain imidazo[1,2-a]pyrazin-8-ylamines, method of making, and method of use thereof |
| US60/630,645 | 2004-11-24 | ||
| US60/630,861 | 2004-11-24 | ||
| US60/630,860 | 2004-11-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101124227A true CN101124227A (en) | 2008-02-13 |
Family
ID=39086026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200580046345XA Pending CN101124227A (en) | 2004-11-10 | 2005-11-10 | Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101124227A (en) |
| ZA (1) | ZA200705035B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102307474B (en) * | 2008-12-08 | 2015-04-01 | 吉利德康涅狄格股份有限公司 | Imidazopyrazine SYK inhibitors |
| CN104662018A (en) * | 2012-04-20 | 2015-05-27 | 阿迪维纳斯治疗有限公司 | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof |
| US9567348B2 (en) | 2008-12-08 | 2017-02-14 | Gilead Connecticut, Inc. | Substituted pyrazolo[1,5-a]pyrimidines as Syk inhibitors |
| US11339168B2 (en) | 2019-02-22 | 2022-05-24 | Kronos Bio, Inc. | Crystalline forms of 6-(6-aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine as Syk inhibitors |
| US11384082B2 (en) | 2017-08-25 | 2022-07-12 | Kronos Bio, Inc. | Hydrates of polymorphs of 6-(1H-indazol-6-YL)-N-(4-morpholinophenyl)-2,3-dihydroimidazo[1,2-A]pyrazin-8-amine bisemsylate as Syk inhibitors |
| US11517570B2 (en) | 2013-12-23 | 2022-12-06 | Kronos Bio, Inc. | Crystalline succinate salt of 6-(6-aminopyrazin-2-yl)-n-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine |
-
2005
- 2005-11-10 CN CNA200580046345XA patent/CN101124227A/en active Pending
-
2007
- 2007-06-06 ZA ZA200705035A patent/ZA200705035B/en unknown
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102307474B (en) * | 2008-12-08 | 2015-04-01 | 吉利德康涅狄格股份有限公司 | Imidazopyrazine SYK inhibitors |
| US9567348B2 (en) | 2008-12-08 | 2017-02-14 | Gilead Connecticut, Inc. | Substituted pyrazolo[1,5-a]pyrimidines as Syk inhibitors |
| US9796718B2 (en) | 2008-12-08 | 2017-10-24 | Gilead Connecticut, Inc. | 6-(benzo[d]thiazol-5-yl)-n-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine |
| US10093684B2 (en) | 2008-12-08 | 2018-10-09 | Gilead Connecticut, Inc. | Substituted imidazo[1,2-a]pyrazines as Syk inhibitors |
| CN104662018A (en) * | 2012-04-20 | 2015-05-27 | 阿迪维纳斯治疗有限公司 | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof |
| CN104662018B (en) * | 2012-04-20 | 2017-10-24 | 阿迪维纳斯治疗有限公司 | Substituted Heterobicyclic compounds, composition and its medical applications |
| US11517570B2 (en) | 2013-12-23 | 2022-12-06 | Kronos Bio, Inc. | Crystalline succinate salt of 6-(6-aminopyrazin-2-yl)-n-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine |
| US11384082B2 (en) | 2017-08-25 | 2022-07-12 | Kronos Bio, Inc. | Hydrates of polymorphs of 6-(1H-indazol-6-YL)-N-(4-morpholinophenyl)-2,3-dihydroimidazo[1,2-A]pyrazin-8-amine bisemsylate as Syk inhibitors |
| US11339168B2 (en) | 2019-02-22 | 2022-05-24 | Kronos Bio, Inc. | Crystalline forms of 6-(6-aminopyrazin-2-yl)-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyrazin-8-amine as Syk inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200705035B (en) | 2009-06-24 |
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