CN101228160A - Azaindoles useful as inhibitors of protein kinases - Google Patents
Azaindoles useful as inhibitors of protein kinases Download PDFInfo
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- CN101228160A CN101228160A CNA2005800259621A CN200580025962A CN101228160A CN 101228160 A CN101228160 A CN 101228160A CN A2005800259621 A CNA2005800259621 A CN A2005800259621A CN 200580025962 A CN200580025962 A CN 200580025962A CN 101228160 A CN101228160 A CN 101228160A
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Abstract
The present invention relates to pyrrolo [2, 3-b] pyridine compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing the compounds of the invention.
Description
Technical field
The present invention relates to can be used as the compound of kinases inhibitor.The present invention also provides pharmaceutically acceptable composition that comprises The compounds of this invention and the method for using the various illness of these combination treatments.The present invention also provides the method for preparing The compounds of this invention.
Background technology
In recent years, understand the enzyme relevant and the structure of other biological molecule better, go far towards to seek new therapeutical agent with disease.The important enzyme of a class that has become the theme of broad research is a protein kinase.
Protein kinase constitutes structurally involved enzyme of extended familys, they be responsible for controlling intracellular multiple signal transduction process (referring to Hardie, G.and Hanks, S.The ProteinKinase Facts Book, I and II, Academic Press, San Diego, CA:1995).Protein kinase is considered to evolve from the common gene, and this is owing to preserved their structure and catalysis.Nearly all kinases all contains similar 250-300 amino acid catalytic structure function territory.Kinases can be divided into some families (for example protein-tyrosine, protein-serine/threonine, lipid etc.) according to the substrate of their phosphorylations.Differentiated generally sequence motifs corresponding to every kind of kinases family (for example referring to Hanks, S.K.Hunter, T.FASEB J.1995,
9, 576-596; People .Science1991 such as Knighton, 253,407-414; People .Cell 1992,70 such as Hiles, 419-429; People .Cell 1993,73 such as Kunz, 585-596; People .EMBO such as Garcia-Bustos J.1994,13,2352-2361).
Generally speaking, protein kinase is transferred to the protein acceptor that participates in the signal pipeline and signal transmission in the mediated cell by influencing phosphoryl from nucleoside triphosphate.These phosphorylation events serve as molecular switch, can regulate and control or regulate the biological function of target protein.These phosphorylation events finally are in response to outside the various kinds of cell and other stimulations are excited.The example that this class stimulates comprises environment and chemical stress reaction signal (for example osmotic shock, heat shock, uv-radiation, bacterial endotoxin and H
2O
2), cytokine (for example il-1 (IL-1) and tumor necrosis factor alpha (TNF-α)) and somatomedin (for example rHuGM-CSF (GM-CSF) and fibroblast growth factor (FGF)).Extracellular stimulus can influence one or more cell responses, described reply relate to that cell is grown, divided a word with a hyphen at the end of a line, differentiation, hormone secretion, transcription factor activation, Muscle contraction, carbohydrate metabolism, protein synthesis control and Cycle Regulation.
A lot of diseases are replied relevant with the abnormal cells that is excited by above-mentioned protein kinase mediated incident.These diseases include but not limited to that autoimmune disease, inflammatory diseases, osteopathia, metabolic trouble, neurological and neurodegenerative disease, cancer, cardiovascular disorder, transformation reactions and asthma, Alzheimer and hormone are diseases related.Therefore, medical chemistry circle strives to find as therapeutical agent effective protein proteins kinase inhibitor always.
Tec family nonreceptor tyrosine kinase plays central role in antigen-receptor signal sends, for example TCR, BCR and Fc epsilon receptor (at Miller A, wait people Current Opinionin Immunology 14; 331-340 has commentary in (2002).The Tec family kinase is that the T-cell activation is necessary.Three kinds of member Itk, Rlk of Tec family and the Tec antigen receptor in the T-cell participates in incident (engagement) downstream and is activated, and sends a signal to the downstream effect device, comprises PLC-γ.In the mouse disappearance of Itk cause T-cell receptors (TCR)-inductive cytokine IL-2, IL-4, IL-5, IL-10 and IFN-γ propagation reduce with secretion (people such as Schaeffer, Science 284; 638-641 (1999), people such as Fowell, Immunity 11; 399-409 (1999), people .Nature Immunology 2,12 such as Schaeffer; 1183-1188 (2001))).The immunology symptom of atopic asthma Itk-/-weakened in the mouse.In response to the attack of allergen OVA, pneumonia, eosinocyte soak into and mucus be created in Itk-/-reduced in the mouse people such as (, Journal ofImmunology 170:5056-5063 (2003)) Mueller hurriedly.Also implication in atopic dermatitis of Itk.It is reported this gene in from the peripheral blood T-cell of medium and/or serious atopic dermatitis patients than in contrast or slight atopic dermatitis patients by the expression of height more (people such as Matsumoto, International archives of Allergy andImmunology 129; 327-340 (2002)).
Be connected in response to TCR, from Rlk-/-the secreted IL-2 of splenocyte of mouse be the IL-2 that produces by the wild-type animal half (people such as Schaeffer, Science 284; 638-641 (1999)), and the extreme that disappearance causes that the TCR-inductive is replied of uniting of Itk and Rlk suppresses in the mouse, comprises the propagation of cytokine IL-2, IL-4, IL-5 and IFN-γ and generation (people .Nature Immunology 2,12 such as Schaeffer; 1183-1188 (2001); People such as Schaeffer, Science 284; 638-641 (1999)).TCR takes place in Itk/Rlk defective T-cell participate in signal transmission in the incident cell afterwards; The activation of the generation of inositoltriphosphoric acid, the activity of calcium, map kinase and the activation of transcription factor NFAT and AP-1 all reduced (people such as Schaeffer, Science 284; 638-641 (1999), people .Nature Immunology 2,12 such as Schaeffer, 1183-1188 (2001)).
The Tec family kinase also is that B-cell development and activation are necessary.Btk sudden change patient has the cytocerastic extreme retardance of B-, causes the extreme of the humoral response of bone-marrow-derived lymphocyte and plasmacytic almost completely shortage, the serious reduction of Ig level and recall antigen to suppress (in people .Frontiers in Bioscience 5:d917-928 such as Vihinen commentary being arranged).The mouse of Btk defective also has the quantity minimizing of periphery B-cell and the reduction greatly of IgM and IgG3 level.Btk in mouse disappearance is to having deep effect by anti--IgM inductive B-cell proliferation, suppresses thymus gland-antigenic immunne response of independence II type people such as (, J Exp Med 192:1611-1623 (2000)) Ellmeier.
By high-affinity IgE acceptor (Fc ε RI), the Tec kinases also works in the mastocyte activation.Itk and Btk are expressed in mastocyte, are activated (people such as Kawakami, Journal of Immunology by Fc ε RI cross-coupling; 3556-3562 (1995)).Btk defective mouse mastocyte has reduced threshing after Fc ε RI cross-coupling, reduced the generation (people .Journal of leukocyte biology65:286-290 such as Kawakami) of pro-inflammatory cytokine.The Btk defective also causes reduction (people such as Mukhopadhyay, the Journal of Immunology of scavenger cell effector functions; 168,2914-2921 (2002)).
Janus kinases (JAK) is a family of Tyrosylprotein kinase, is made up of JAK1, JAK2, JAK3 and TYK2.JAK plays decisive role in cytokine signaling sends.The downstream substrate of JAK family kinase comprises transcribes sensing and activation (STAT) albumen.The JAK/STAT signal sends implication in the mediation that a lot of abnormal immunes are replied, for example transformation reactions, asthma, autoimmune disease, for example transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and entity and hematologic malignancies, for example leukemia and lymphoma.Existing [Frank Mol.Med.1999,5, the 432-456 of commenting of the drug intervention of JAK/STAT approach; People .Oncogene 2000,19 such as Seidel, 2645-2656].
JAK1, JAK2 and TYK2 are generally expressed, and JAK3 is mainly expressed in hematopoietic cell.JAK 3 is exclusively in conjunction with public cytokine receptor γ chain (γ
c), activated by IL-2, IL-4, IL-7, IL-9 and IL-15.In fact shown by IL-4 and IL-9 inductive mouse mastocyte propagation and survival and to have depended on JAK3-and γ
c-signal sends people such as [, Blood 2000,96,2172-2180] Suzuki.
The cross-coupling of high-affinity immunoglobulin (Ig) (Ig) the E acceptor of sensitization mastocyte causes the release of short inflammatory mediator, comprise a large amount of vasoactive cytokines, cause acute allergy or instantaneity (I type) anaphylaxis [people .Nature 1990 such as Gordon, 346,274-276 ﹠amp; Galli, N.Engl.JMed.1993,328,257-265].The decisive role of JAK3 in the mastocyte of IgE acceptor-mediation is replied determined [people .Biochem.Biophys.Res.Commun.1999 such as Malaviya, 257,807-813] in vitro and in vivo.In addition, prevent by the type i allergic reaction of mastocyte activation mediation, comprise that supersensitivity also had report people .J.Biol.Chem.1999274 such as [, 27028-27038] Malaviya by suppressing JAK3.With the threshing of the external regulation and control mastocyte of JAK3 inhibitor target mastocyte, the anaphylaxis of prevention IgE acceptor/antigen-mediation in the body.
There is research to describe successful JAK3 target recently, is used for immunosuppression and homotransplant and accepts.This studies have shown that in the dosage-dependency survival of buffalo cardiac allograft thing after the administration of JAK3 inhibitor in Wistar Furth recipient, shown the possibility [Kirken that in graft versus host disease, regulates undesirable immunne response, Transpl.Proc.2001,33,3268-3270].
The STAT-phosphorylation of IL-4-mediation has become the mechanism that participates in early stage and rheumatoid arthritis in late period (RA).The incremental adjustments of pro-inflammatory cytokine is that this disease is peculiar in RA synovial membrane and the synovia.Verified, the IL-4/STAT pathway activation of IL-4-mediation is that (JAK 1 by the Janus kinases; 3) mediation, and the jak kinase relevant with IL-4 expressed [people .J.Immunol.2000 such as Muller-Ladner, 164,3894-3901] in the RA synovial membrane.
Familial amyotrophic lateral sclerosis (FALS) is a kind of mortality neurodegenerative disease, influences about 10% ALS patient.After handling with the JAK3 specific inhibitor, the survival rate of FALS mouse increases.This has pointed out JAK3 work [people .Biochem.Biophys.Res.Commun.2000 such as Trieu, 267,22-25] in FALS.
Transcribe sensing and activation (STAT) albumen and especially be subjected to the activation of JAK family kinase.From the results suggest of nearest research send the possibility of approach by intervene the JAK/STAT signal with specific inhibitor target JAK family kinase, be used for the treatment of leukemia [people .Clin.Cancer Res.1999 such as Sudbeck, 5,1569-1582].The JAK3 specific compounds suppresses JAK3-expressivity clone DAUDI, RAMOS, LCl; 19, the clonal growth of NALM-6, MOLT-3 and HL-60.
In animal model, it is illness that the TEL/JAK2 fusion rotein is induced spinal cord propagation and hematopoietic cell, people .EMBO such as Schwaller J.1998 the introducing of TEL/JAK2 causes the activation of STATl, STAT3, STAT5 and cytokine-dependency growth [, 17,5321-5333].
Suppress the tyrosine phosphorylation that JAK3 and TYK2 have cancelled STAT3, suppressed the cell growth of mycosis fungoides, the latter is a kind of form of skin T-cell lymphoma.These results have hinted JAK family kinase implication in being present in the composing type activation JAK/STAT approach of mycosis fungoides [people .Proc.Nat.Acad.Sci.U.S.A.1997 such as Nielsen, 94,6764-6769].Similarly, STAT3, STAT5, JAK1 and JAK2 are proved to be in the mouse T-cell lymphoma that with the LCK overexpression is feature at first and are activated by composing type, thereby further hinted JAK/STAT implication in abnormal cell growth [people .J.Immunol.1997 such as Yu, 159,5206-5210].In addition, the STAT3 of IL-6-mediation activation is blocked by the JAK inhibitor, causes the dead sensitization of myeloma cell's pair cell program people .Immunity 1999,10 such as [, 105-115] Catlett-Falcone.
Therefore, there is great demand in the compound that can be used as kinases inhibitor for exploitation.Definite, need to develop the compound that can be used as Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) and JAK family protein kinase inhibitor, particularly still insufficient in view of the treatment that can be used for the great majority illness relevant at present with their activation.
Summary of the invention
Have now found that The compounds of this invention and pharmaceutically acceptable composition thereof are effective as the inhibitor of protein kinase.In some embodiments, these compounds are effective as Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) and the kinase whose inhibitor of JAK family protein.These compounds have general formula I or its pharmacy acceptable salt as herein defined.
These compounds and pharmaceutically acceptable composition thereof can be used for treatment or prevent multiple disease, illness or illness, include but not limited to the disease of autoimmunization, inflammatory, proliferative or excess proliferative disease or immunology-mediation.These compositions also are useful in the method for prevention zymoplasm-inductive platelet aggregation.Study by the kinases that compound provided by the present invention also can be used in biology and the pathology phenomenon; By the kinase mediated intracellular signal transduction approach research of this class; Comparative evaluation with new kinase inhibitor.
The invention detailed content
1, the general remark of The compounds of this invention:
The present invention relates to formula I compound:
(I)
Or its pharmacy acceptable salt, wherein:
Ring A is optional substituted five-ring, is selected from:
Or
X is 0,1 or 2;
Each R that occurs
1Be halogen, CN, NO independently
2Or U
mR;
R
2Be independently selected from T
n-R '
X
1, X
2And X
3Be CR independently of one another
1, N, S or O;
R
3, R
4And R
5Be halogen, CN, NO independently of one another
2Or V
p-R ';
Each T, U or V that occurs is optional substituted C independently
1-6Alkylidene chain, wherein two MU (methylene unit) at the most of this chain alternatively and independently by-NR-,-S-,-O-,-CS-,-CO
2-,-OCO-,-CO-,-COCO-,-CONR-,-NRCO-,-NRCO
2-,-SO
2NR-,-NRSO
2-,-CONRNR-,-NRCONR-,-OCONR-,-NRNR-,-NRSO
2NR-,-SO-,-SO
2-,-PO-,-PO
2-or-POR-replaces;
M, n and p are 0 or 1 independently of one another;
Each R that occurs is hydrogen or optional substituted C independently
1-6Aliphatic group; Each R ' that occurs is hydrogen or optional substituted C independently
1-6Aliphatic group, have 0-3 the heteroatomic 3-8 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle or have 0-5 the heteroatomic 8-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated bicyclic ring system; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance constitutes optional the substituted 0-4 of having with the atom of their institute's bondings the heteroatomic 3-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle or two rings;
Its condition is the R that at least once occurs
3, R
4, R
5Be V
p-R ', wherein R ' is not a hydrogen.
For fear of query, (R
1)
xBe bonded in the optional position of ring A if present, by R
2Except the position that occupies.
In one embodiment,
If a) n is 0, R ' is not H so;
B) if encircle A be
, R
4Be 2-Phenoxyphenyl, R so
2Not COOH or CONHR
x, R wherein
xBe n-propyl, phenyl, cyclohexyl, benzyl ,-CH
2CH
2OH ,-CH
2-cyclopropyl ,-CH
2CH
2OCH
3, 3-pyridyl, 4-hydroxyl-cyclohexyl or-CH
2-C ≡ CH.
In another embodiment, The compounds of this invention is not included on the WO 2004/078756 A2 152-166 page or leaf cited compound in the claim 9, quotes at this as a reference.
2, compound and definition:
The compounds of this invention comprises as above general those that describe, further is illustrated as big class disclosed herein, group and kind.Unless indication is arranged in addition, will be suitable for to give a definition.For purposes of the present invention, chemical element will be according to periodic table of elements CAS version Handbook ofChemistry and Physics, 75
ThEd discerns.In addition, vitochemical General Principle is described in " Organic Chemistry ", Thomas Sorrell, UniversityScience Books, Sausalito:1999 and " March ' s Advanced Or ganicChemistry ", 5
ThEd.Ed.Smith, M.B.and March, J.John Wiley﹠amp; Sons, among the New York:2001, its complete content is quoted at this as a reference.
As described herein, The compounds of this invention can be replaced by one or more substituting groups alternatively, and for example top general introduction is set forth, perhaps as specific big class of the present invention, group and kind institute illustration.Should be appreciated that wording " optional substituted " and wording " replacement or unsubstituted " are used interchangeably.Generally speaking, no matter the front has or not term " optional " to term " replacement ", represents that all rolling into a ball designated substituent atomic group to the hydrogen atom in the fixed structure replaces.Unless indication is arranged in addition, optional substituted group can have substituting group on each commutable position of this group, if substituting group that can be selected from designated groups more than one for arbitrarily in the fixed structure an above position replaces, then substituting group can be identical or different on each position.Those of the stable or chemically feasible compound of substituting group combination preferably can formation that the present invention paid close attention to.Term used herein " stable " is illustrated in and is subjected to being used for their preparations, detects, preferably reclaim, the condition of purifying and constant basically compound when being used for one or more purposes disclosed herein.In some embodiment, stable compound or chemically feasible compound be do not have moisture or other chemical reactivity conditions in the presence of, under 40 ℃ or following temperature, keep at least one week and the compound that do not change basically.
As described herein, specified atomicity comprises arbitrary integer wherein.For example, the group with 1-4 atom may have 1,2,3 or 4 atom.
The replacement or the unsubstituted hydrocarbon chain of term used herein " aliphatic series " or " aliphatic group " expression straight chain (promptly not branch) or side chain, it is saturated fully or contains one or more unsaturated units, perhaps represent monocyclic hydrocarbon or bicyclic hydrocarbon, it is saturated fully or contains one or more unsaturated units, but be (this paper also is referred to as " carbocyclic ring ", " cyclic aliphatic " or " cycloalkyl ") of aromatics, it has the single point that is connected with the molecule rest part.Except as otherwise noted, aliphatic group contains 1-20 aliphatic carbon atom.In some embodiment, aliphatic group contains 1-10 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-8 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-6 aliphatic carbon atom, and in other embodiments, aliphatic group contains 1-4 aliphatic carbon atom.In some embodiment, " cyclic aliphatic " (perhaps " carbocyclic ring " or " cycloalkyl ") expression monocycle C
3-C
8Hydrocarbon or two ring C
8-C
12Hydrocarbon, it is fully saturated or contains one or more unsaturated units, but is not aromatics, and it has the single point that is connected with the molecule rest part, and to be that 3-7 is first encircle any single ring in the wherein said bicyclic ring system.The aliphatic group that is fit to includes but not limited to replacement or unsubstituted alkyl, thiazolinyl, alkynyl and the heterocomplex thereof of straight or branched, for example (cycloalkyl) alkyl, (cycloalkenyl group) alkyl or (cycloalkyl) thiazolinyl.
Term used herein " heterolipid family " represents that one of them or two carbon atoms are independently by the displaced aliphatic group of one or more oxygen, sulphur, nitrogen, phosphorus or silicon.Heterolipid family group can be to replace or unsubstituted, straight or branched, ring-type or acyclic, comprises " heterocycle ", " heterocyclic radical ", " heterocycle aliphatic series " or " heterocyclic " group.
Term used herein " heterocycle ", " heterocyclic radical ", non-aromatics, the monocyclic, bicyclic or tricyclic ring system of " heterocycle aliphatic series " or " heterocyclic " expression, wherein one or more ring memberses are independent heteroatomss of selecting.In some embodiment, " heterocycle ", " heterocyclic radical ", " heterocycle aliphatic series " or " heterocyclic " group have three to 14 ring memberses, wherein one or more ring memberses are the heteroatomss that independently are selected from oxygen, sulphur, nitrogen or phosphorus, and each ring contains 3 to 7 ring memberses in this system.The heterocycle that is fit to includes but not limited to 3-1H-benzimidazolyl-2 radicals-ketone, 3-(1-alkyl)-benzimidazolyl-2 radicals-ketone, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-tetrahydro-thienyl, the 3-tetrahydro-thienyl, 2-morpholino base, 3-morpholino base, 4-morpholino base, the 2-parathiazan is for base, the 3-parathiazan is for base, the 4-parathiazan is for base, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, 1-tetrahydrochysene piperazinyl, 2-tetrahydrochysene piperazinyl, 3-tetrahydrochysene piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 1-pyrazolinyl, the 3-pyrazolinyl, the 4-pyrazolinyl, the 5-pyrazolinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 2-thiazolidyl, the 3-thiazolidyl, the 4-thiazolidyl, the 1-imidazolidyl, the 2-imidazolidyl, the 4-imidazolidyl, the 5-imidazolidyl, indolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, the benzo thiacyclopentane, benzo dithiane and 1,3-dihydro-imidazol--2-ketone.
One or more oxygen, sulphur, nitrogen, phosphorus or silicon (any oxidised form that comprises nitrogen, sulphur, phosphorus or silicon represented in term " heteroatoms "; Basic nitrogen or heterocycle can replace the quaternized form of nitrogen, for example N (as 3, in the 4-dihydro-2 h-pyrrole base), NH (as in pyrrolidyl) or NR arbitrarily
+(in the pyrrolidyl that replaces at N-)).
Term used herein " undersaturated " means that this part has one or more unsaturated units.
Term used herein " alkoxyl group " or " alkylthio " expression are connected with the main body carbochain by oxygen (" alkoxyl group ") or sulphur (" alkylthio ") atom as the defined alkyl of preamble.
Term " haloalkyl ", " haloalkenyl group " and " halogenated alkoxy " expression are depended on the circumstances by alkyl, thiazolinyl or alkoxyl group that one or more halogen atoms replace.Term " halogen " expression F, Cl, Br or I.
Have monocycle, two rings and the three ring ring systems that amount to five to 14 ring memberses separately or as term " aryl " expression that the part of more most of " aralkyl ", " aralkoxy " or " aryloxy alkyl " is used, wherein at least one ring is an aromatics in this system, and wherein in this system each ring contain 3 to 7 ring memberses.Term " aryl " can exchange with term " aryl rings " and use.
Have monocycle, two rings and the three ring ring systems that amount to five to 14 ring memberses separately or as term " heteroaryl " expression that the part of more most of " heteroaralkyl " or " heteroaryl alkoxyl group " is used, wherein at least one ring is an aromatics in this system, at least one ring contains one or more heteroatomss in this system, and wherein in this system each ring contain 3 to 7 ring memberses.Term " heteroaryl " can exchange with term " heteroaryl ring " or term " heteroaromatic " and use.The heteroaryl ring that is fit to includes but not limited to the 2-furyl, the 3-furyl, the TMSIM N imidazole base, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl, benzimidazolyl-, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the N-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, pyridazinyl (for example 3-pyridazinyl), the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, tetrazyl (for example 5-tetrazyl), triazolyl (for example 2-triazolyl and 5-triazolyl), the 2-thienyl, the 3-thienyl, benzofuryl, benzothienyl, indyl (for example 2-indyl), pyrazolyl (for example 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazole base, 1,2,5-oxadiazole base, 1,2,4-oxadiazole base, 1,2, the 3-triazolyl, 1,2, the 3-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, purine radicals, pyrazinyl, 1,3, the 5-triazinyl, quinolyl (2-quinolyl for example, the 3-quinolyl, the 4-quinolyl) and isoquinolyl (1-isoquinolyl for example, 3-isoquinolyl or 4-isoquinolyl).
Aryl (comprising aralkyl, aralkoxy, aryloxy alkyl etc.) or heteroaryl (comprising heteroaralkyl and assorted aralkoxy etc.) can contain one or more substituting groups.The substituting group that is fit on the unsaturated carbon atom of aryl or heteroaryl generally be selected from halogen ,-R
o,-OR
o,-SR
o, 1,2-methylene-dioxy, ethylenedioxy, optional by R
oThe phenyl (Ph) that replaces, optional by R
oReplace-O (Ph), optional by R
oReplace-(CH
2)
1-2(Ph), optional by R
oReplace-CH=CH (Ph) ,-NO
2,-CN ,-N (R
o)
2,-NR
oC (O) R
o,-NR
oC (S) R
o,-NR
oC (O) N (R
o)
2,-NR
oC (S) N (R
o)
2,-NR
oCO
2R
o,-NR
oNR
oC (O) R
o,-NR
oNR
oC (O) N (R
o)
2,-NR
oNR
oCO
2R
o,-C (O) C (O) R
o,-C (O) CH
2C (O) R
o,-CO
2R
o,-C (O) R
o,-C (S) R
o,-C (O) N (R
o)
2,-C (S) N (R
o)
2,-OC (O) N (R
o)
2,-OC (O) R
o,-C (O) N (OR
o) R
o,-C (NOR
o) R
o,-S (O)
2R
o,-S (O)
3R
o,-SO
2N (R
o)
2,-S (O) R
o,-NR
oSO
2N (R
o)
2,-NR
oSO
2R
o,-N (OR
o) R
o,-C (=NH)-N (R
o)
2Or-(CH
2)
0-2NHC (O) R
o, wherein each independent R that occurs
oBe selected from hydrogen, optional substituted C
1-C
6Aliphatic group, unsubstituted 5-6 unit's heteroaryl or heterocycle, phenyl ,-O (Ph) or-CH
2(Ph), although as above definition is perhaps arranged, twice independent R that occurs on identical substituting group or different substituents
oWith each R
oThe atom of group institute bonding constitutes 5-8 unit heterocyclic radical, aryl or heteroaryl ring together, and perhaps 3-8 unit cycloalkyl ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.R
oAliphatic group on optionally substituting group be selected from NH
2, NH (C
1-4Aliphatic group), N (C
1-4Aliphatic group)
2, halogen, C
1-4Aliphatic group, OH, O (C
1-4Aliphatic group), NO
2, CN, CO
2H, CO
2(C
1-4Aliphatic group), O (halo C
1-4Aliphatic group) or halo C
1-4Aliphatic group, wherein R
oEach above-mentioned C
1-4Aliphatic group is unsubstituted.
Aliphatic series or heterolipid family group or non-aromatic heterocyclic can contain one or more substituting groups.Above the substituting group that is fit on the saturated carbon atom of aliphatic series or heterolipid family group or non-aromatic heterocyclic is selected from about cited those of aryl or heteroaryl unsaturated carbon, and comprise in addition following groups :=O ,=S ,=NNHR
*,=NN (R
*)
2,=NNHC (O) R
*,=NNHCO
2(alkyl) ,=NNHSO
2(alkyl) or=NR
*, each R wherein
*Be independently selected from hydrogen or optional substituted C
1-C
6Aliphatic group.R
*Aliphatic group on optionally substituting group be selected from NH
2, NH (C
1-4Aliphatic group), N (C
1-4Aliphatic group)
2, halogen, C
1-4Aliphatic group, OH, O (C
1-4Aliphatic group), NO
2, CN, CO
2H, CO
2(C
1-4Aliphatic group), O (halo C
1-4Aliphatic group) or halo C
1-4Aliphatic group, wherein R
*Each above-mentioned C
1-4Aliphatic group is unsubstituted.
Optional substituting group is selected from-R on the non-aromatic heterocyclic nitrogen
+,-N (R
+)
2,-C (O) R
+,-CO
2R
+,-C (O) C (O) R
+,-C (O) CH
2C (O) R
+,-SO
2R
+,-SO
2N (R
+)
2,-C (=S) N (R
+)
2,-C (=NH)-N (R
+)
2Or-NR
+SO
2R
+R wherein
+Be hydrogen, optional substituted C
1-C
6Aliphatic group, optional substituted phenyl, optional substituted-O (Ph), optional substituted-CH
2(Ph), optional substituted-(CH
2)
1-2(Ph), optional substituted-CH=CH (Ph) or unsubstituted 5-6 unit's heteroaryl or heterocycle, have one to four heteroatoms that independently is selected from oxygen, nitrogen or sulphur, although as above definition is perhaps arranged, twice independent R that occurs on identical substituting group or different substituents
+With each R
+The atom of group institute bonding constitutes 5-8 unit heterocyclic radical, aryl or heteroaryl ring together, and perhaps 3-8 unit cycloalkyl ring has 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.R
+Aliphatic group or benzyl ring on optionally substituting group be selected from NH
2, NH (C
1-4Aliphatic group), N (C
1-4Aliphatic group)
2, halogen, C
1-4Aliphatic group, OH, O (C
1-4Aliphatic group), NO
2, CN, CO
2H, CO
2(C
1-4Aliphatic group), O (halo C
1-4Aliphatic group) or halo C
1-4Aliphatic group, wherein R
+Each above-mentioned C
1-4Aliphatic group is unsubstituted.
Term " alkylidene chain " expression straight or branched carbochain, it can be saturated fully or have one or more unsaturated units, and have two points that are connected with the molecule rest part, wherein one or more MU (methylene unit) can be alternatively and are replaced by a kind of group so independently, include but not limited to CO, CO
2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO
2, NRCONR, SO, SO
2, NRSO
2, SO
2NR, NRSO
2NR, O, S or NR.
Term used herein " blocking group " expression is used for temporarily sealing the composition of the one or more required reactive behavior of polyfunctional compound position.In some embodiments, blocking group has one or more in the following feature or all preferred: a) with good yield selective reaction, obtain protected substrate, it is stable for the reaction that occurs in one or more other reactive behavior positions; And b) reagent place's selectivity of not attacked regenerated functional group of institute with good yield is removed.Exemplary blocking group is referring to Greene, T.W.Wuts, P.Gin " Protective Groups in Organic Synthesis ", Third Edition, John Wiley ﹠amp; Sons, New York:1999, its complete content is quoted at this as a reference.Term used herein " nitrogen-protecting group group " expression is used for temporarily sealing the composition of the reactive position of the one or more required nitrogen of polyfunctional compound.Preferred nitrogen-protecting group is rolled into a ball also possesses above-mentioned feature, some exemplary nitrogen-protecting group is rolled into a ball also referring to Chapter 7 in Greene, T.W.Wuts, P.G in " Protective Groups in Organic Synthesis ", ThirdEdition, John Wiley ﹠amp; Sons, New York:1999, its complete content is quoted at this as a reference.
As mentioned above, in some embodiment, twice independent R that occurs
o(perhaps R
+Or any other has the variable of similar definition in this article) constitute 5-8-unit heterocyclic radical, aryl or heteroaryl ring or 3-8-unit cycloalkyl ring with the atom of each variable institute bonding, have 0-3 heteroatoms that independently is selected from nitrogen, oxygen or sulphur.Twice independent R that occurs
o(perhaps R
+Or any other has the variable of similar definition in this article) include but not limited to following with the exemplary ring that atom constituted of each variable institute bonding: a) twice independent R that occurs
o(perhaps R
+Or any other has the variable of similar definition in this article) be bonded to same atom, and constitute a ring, for example N (R with this atom
o)
2, two R of Chu Xianing wherein
oConstitute piperidines-1-base, piperazine-1-base or morpholine-4-base with nitrogen-atoms; And b) twice independent R that occurs
o(perhaps R
+Or any other has the variable of similar definition in this article) be bonded to not homoatomic, and constitute a ring with these atoms, for example
Wherein phenyl is by the OR of twice appearance
oReplace the R of this twice appearance
oSauerstoffatom with their institute's bondings constitutes condensed 6-unit ether ring:
That will be understanded is twice independent R that occurs
o(perhaps R
+Or any other has the variable of similar definition in this article) can constitute multiple other rings with the atom of each variable institute bonding, and above-mentioned detailed example not plan be restrictive.
Unless otherwise prescribed, the structure that this paper described also means all isomeries (for example enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism)) form that comprises this structure; The for example R of each asymmetric center and S configuration are (Z) with (E) double bond isomer and (Z) and (E) conformer.Therefore, the single three-dimensional chemical isomer of these compounds and enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism) mixture all belong to scope of the present invention.Unless otherwise prescribed, all tautomeric forms of The compounds of this invention all belong to scope of the present invention.In addition, unless otherwise prescribed, the structure that this paper described also means and only comprises compound different in the existence of one or more isotopic enrichment atoms.For example, replaced or the carbon quilt by deuterium or tritium except hydrogen
13C-or
14The compound that has structure of the present invention beyond the carbon of C-enrichment replaces all belongs to scope of the present invention.This compounds for example can be used as analysis tool or the probe in the biological assay.
3, the explanation of exemplary compound:
All explanations of this paper embodiment can be applied to formula I, II, III, IV, V and VI compound.
In some embodiments of the present invention, R
4And R
5Be V independently of one another
p-R '.
In other embodiments, R
3, R
4And R
5One of be V
p-R ', wherein R ' is a complete undersaturated bicyclic ring system of the monocycle of the optional substituted 0-3 of having heteroatomic 5-who independently is selected from nitrogen, oxygen or sulphur or 6-unit unsaturated fully (being aromatics) or the optional substituted 0-5 of having a heteroatomic 9-who independently is selected from nitrogen, oxygen or sulphur or 10-unit.
In other embodiments, R
3, R
4And R
5One of be V
p-R ', wherein R ' is optional substituted C independently
1-6Aliphatic group, the optional substituted 0-3 of having be selected from independently that the heteroatomic 3-8 unit of nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle or optional the substituted 0-5 of having the heteroatomic 8-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated bicyclic ring system.
In other embodiments, R
4Be V
p-R ', wherein R ' is optional substituted C independently
1-6Aliphatic group, the optional substituted 0-3 of having be selected from independently that the heteroatomic 3-8-unit of nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle or optional the substituted 0-5 of having the heteroatomic 8-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated bicyclic ring system.In some these embodiment, R
3And R
5Be V
p-R ', wherein p is 0, R ' is a hydrogen.
In other embodiments, R
4Be V
p-R ', wherein R ' is optional substituted C independently
1-6The heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle for aliphatic group or optional the substituted 0-3 of having.
In other embodiments, R
4Be V
p-R ', wherein R ' is optional the substituted 0-3 of having the heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle.
In other embodiments, R
4Be V
p-R ', wherein R ' is the optional substituted 0-3 of having the complete undersaturated monocycle of heteroatomic 5-6-unit that independently is selected from nitrogen, oxygen or sulphur independently.
In other embodiments, R
4Be V
p-R ', wherein R ' is the complete undersaturated monocycle of the optional substituted 0-3 of having nitrogen heteroatom or the unit of the 6-with 0-1 nitrogen heteroatom.
In other embodiments, R
4Be V
p-R ', wherein R ' is the optional substituted 0-3 of having the saturated monocycle of heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur.
In other embodiments, R
4Be V
p-R ', wherein R ' is the optional substituted 0-2 of having the saturated monocycle of heteroatomic 6-unit that independently is selected from nitrogen, oxygen or sulphur.
In other embodiments, R
4Be V
p-R ', wherein R ' is optional substituted C
1-6Aliphatic group.In some embodiments, R ' is C
1-6Alkynyl.In some embodiments, R ' is-C ≡ CH.
In other embodiments, p is 0.
In other embodiments, p is 1.
In other embodiments, V be-NR-,-S-or-O-.
In other embodiments, R
3Be V
p-R ', wherein p be 0 and R ' be hydrogen.
In other embodiments, R
5Be halogen or V
p-R ', wherein p be 0 and R ' be hydrogen or C
1-6Aliphatic group.In other embodiments, this C
1-6Aliphatic group is C
1-3Alkyl.
In other embodiments, ring A is:
In some these embodiment, X
2Be CR
1
In other embodiments, ring A is:
In other embodiments, ring A is:
In some embodiments, R
1Be U
mR.In other embodiments, R
1Be U
mR, wherein m be 0 and R be H or CH
3
In some embodiments, R
2Be T
nR ', wherein n is 1.
In other embodiments, R
2Be T
nR ', wherein n is 0.
In some embodiments, T be-NR-,-O-,-CO-,-CONR-or-NRCO-.
In some embodiments, T is-NR-.In some embodiments, T is-O-.In some these embodiment, R ' is C
1-6Aliphatic group.In other these embodiments, R and R ' are H.
In some embodiments, T is-NR-that R ' is C
1-6Aliphatic group.In some these embodiment, R is C
1-6Aliphatic group.In some embodiment, R and R ' are C
1-6Alkyl.
In some embodiments, T is C
1-6Alkylidene chain, wherein this alkylidene chain is connected with ring A by MU (methylene unit).In some these embodiment, T is-(C
1-5Alkyl) NR-.In some embodiment, T is-CH
2NR-.In some these embodiment, R ' is C
1-6Aliphatic group.
In other embodiments, T is C
1-6Alkylidene chain, wherein 0 MU (methylene unit) is replaced by group disclosed herein.
In other embodiments, R
2Be that the optional substituted 5-7 N-of unit connects heterocyclic radical.In some embodiments, described N-connection heterocyclic radical is selected from morpholinyl, piperidyl, pyrrolidyl and piperazinyl.In some embodiments, described N-connects heterocyclic radical alternatively with independently by amino, alkylamino, dialkyl amido or the C of 0-4 appearance
1-6Alkyl replaces.
As institute's general description above, another kind of The compounds of this invention has formula II:
II
Or its pharmacy acceptable salt.
In other embodiments, The compounds of this invention has formula III:
III
Or its pharmacy acceptable salt.
In other embodiments, this compound has formula IV:
IV
Or its pharmacy acceptable salt.
In other embodiments, this compound has formula V:
V
Or its pharmacy acceptable salt.
In other embodiments, this compound has formula VI:
VI
Or its pharmacy acceptable salt.
What will be understanded is that with regard to formula II-VI compound, the variable in the formula II-VI compound is defined as any embodiment of this paper.
As institute's general description above, preferred substituted and variable (for example R ' group) they are as table 1 compound institute illustration.
Therefore, the representative example of formula I compound is to describe as following table 1 and 2.
Table 1: formula I examples for compounds
Table 2: formula I examples for compounds
4, universal synthesis method:
The compounds of this invention generally can be prepared by the method that those skilled in the art become known for similar compound, as described in following generalized flowsheet and following preparation embodiment.
Use following abbreviation:
EtOH is an ethanol; RT is a room temperature; Ts is a tosyl group; Ph is a phenyl; DME is a dimethyl ether; Bu is a butyl; EDC is 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide; DMF is a dimethyl formamide; O/N spends the night; Et
2O is an ether; CDI is N, N '-carbonyl dimidazoles; LCMS is a liquid chromatography-mass spectrography; P-is the blocking group that is fit to.
Flow process I
Reagent and condition: (a) AlCl
3, CH
2Cl
2, RT, 16 hours; (b) EtOH, microwave irradiation, 120 ℃, 10mins.
Above-mentioned flow process I shows the general route of synthesis that is used to prepare The compounds of this invention 5, at this moment R
1To R
5Be as described herein.Utilize Friedel-Craft process for acylating well known in the art to prepare intermediate 3.This reaction is applicable to the chloroacetyl chloride of multiple replacement, production 3 compounds.At last, according to step (b) cyclisation intermediate 3, obtain formula 5 compounds.This reaction is applicable to the thioamides that multiple formula 4 replaces.
Flow process II
Reagent and condition: (a) Br
2, CHCl
3, 0 ℃ to RT; (b) n-BuLi, THF, TsCl; (c) PdCl
2(dppf)
2The ， diox, KOAc, two (tetramethyl ethylene ketone generation, pinacolato) two boron, 18 hours; (d) Pd (PPh
3)
4, Na
2CO
3, DME, EtOH/H
2O, microwave irradiation, 120 ℃, 2 hours; (e) 3N NaOH, MeOH.
Above-mentioned flow process II shows the general route of synthesis that is used to prepare The compounds of this invention 11, at this moment A, R
1To R
5With x be as described herein.Brominated structures formula 1 compound succeeded by with tosyl group protection intermediate 6, prepares intermediate 7.Generate for boric acid ester 8 according to flow process II step (c).Utilize Suzuki coupling method well known in the art, in the presence of palladium catalyst, bromide 9 usefulness are handled for boric ester derivative 8, realize that dibenzyl connects the generation of derivative 10.This reaction is applicable to the aryl or the heteroaryl bromide 9 of multiple replacement.At last,, in alkaline condition, remove the tosyl group blocking group, obtain structural formula 11 compounds according to flow process II step (e).
Flow process III
Reagent and condition: (a) Br
2, CHCl
3, 0 ℃ to RT; (b) n-BuLi, THF, TsCl; (c) Pd (PPh
3)
4, Na
2CO
3, DME, EtOH/H
2O, microwave irradiation, 120 ℃, 2 hours; (d) 3N NaOH, MeOH.
Above-mentioned flow process III shows the another kind of general route of synthesis that is used to prepare The compounds of this invention 11, A, R at this moment
1To R
5With x be as described herein.As above prepare intermediate 7 according to flow process II.In this case, utilize Suzuki coupling method well known in the art, in the presence of palladium catalyst, bromide 7 usefulness are handled for boric acid derivatives 12, realize that biaryl connects the generation of derivative 10.This reaction is applicable to that the aryl of multiple replacement or heteroaryl are for boric acid 12.According to flow process III step (d), still in alkaline condition, remove the tosyl group blocking group, obtain structure 11 compounds.
Flow process IV
Reagent and condition: (a) LawessonShi reagent, toluene, 110 ℃, O/N; (b) EtOH refluxes O/N; (c) EtOH, 1N NaOH, 12 hours; (d) EDC, HOBt, DMF, NHR ' R, RT, O/N.
Above-mentioned flow process IV shows the general route of synthesis that is used to prepare The compounds of this invention 18, at this moment R, R ' and R
1To R
5Be as described herein.By preparing raw material 13:Schneller and LuoJ.Org.Chem.1980,45,4045 with the described similar methods of document basically.Compound 13 and LawessonShi reagent react generate derivative 14.In the presence of beta-keto esters 15, the cyclic action of compound 14 obtains intermediate 16.This reaction is applicable to multiple beta-keto esters 15.Under alkaline condition, after the deprotection of ester 16, generate derivative 18 by coupling step well known to those skilled in the art.
Flow process V
Reagent and condition: (a) n-BuLi, THF, PCl; (b) t-BuLi i), Et
2O ,-78 ℃, 1h, ii) R ' SSR '; (c) deprotection condition.
Above-mentioned flow process V shows the general route of synthesis that is used to prepare The compounds of this invention 18, and this moment, R ' was as described herein.By Mazeas, wait the people, Heterocycles 1999,50, and 1065 described methods can prepare raw material 19.According to flow process V step (b), will handle with the suitable disulphide R ' SSR ' of blocking group (P) protection 19 gained intermediates 20 usefulness that are fit to.After the deprotection of indazole 21, production 22 compounds.
Flow process VI
Reagent and condition: (a) R
1OH, NaOMe, CuBr, DMF, heating, 2.5 hours.
Above-mentioned flow process VI shows the general route of synthesis that is used to prepare The compounds of this invention 23, and this moment, R ' was as described herein.According to flow process VI step (a), the pure R ' OH that raw material 19 usefulness are suitable handles.
Flow process VII
Reagent and condition: (a) n-BuLi, THF, PCl; (b) NHR ' R, PdCl
2(dppf), NaO
tBu, THF, heating; Perhaps HNR ' R, Cu, K
2CO
3, oil of mirbane, heating; (c) deprotection condition.
Above-mentioned flow process VII shows the general route of synthesis that is used to prepare The compounds of this invention 25, and this moment, R and R ' were as described herein.Utilize Buchwald-Hartwig cross-coupling reaction well known in the art, in the presence of palladium catalyst, will use amine RR ' NH to handle with blocking group (P) the protection 19 gained intermediates 20 that are fit to.This cross-coupling reaction also can be realized like this, utilizes Ullmann reaction well known in the art, in the presence of copper catalyst, uses amine RR ' NH to handle in intermediate 20.These reactions all are applicable to the amine of multiple replacement.After the deprotection of indazole 24, production 25 compounds.
Flow process VIII
Reagent and condition: (a) R
4B (OH)
2, Pd (PPh
3)
4, EtOH, H
2O, DME, 100 ℃, O/N; (b) Br
2, CHCl
3, 0 ℃ to RT; (c) n-BuLi, THF, TsCl; (d) Pd (PPh
3)
4, Na
2CO
3, DME, EtOH/H
2O, microwave irradiation, 120 ℃, 2 hours; (e) 3N NaOH, MeOH.
Above-mentioned flow process VIII shows the general route of synthesis that is used to prepare The compounds of this invention 30, at this moment A, R
1To R
4With x be as described herein.Utilize Suzuki coupling method well known in the art, in the presence of palladium catalyst, structural formula 19 compounds are used for boric acid derivatives R
4B (OH)
2Handle.This reaction is applicable to that the aryl of multiple replacement or heteroaryl are for boric acid.Brominated structures formula 26 compound intermediates 27 are succeeded by protecting intermediate 27 with tosyl group.Realize another kind of Suzuki cross-coupling reaction according to flow process VIII step (d).According to flow process VIII step (e), in alkaline condition, remove the tosyl group blocking group at last, obtain structural formula 30 compounds.
Flow process IX
Reagent and condition: (a) n-BuLi, THF, PCl; (b) t-BuLi i), Et
2O ,-78 ℃, 1h, ii) R ' CHO; (c) deprotection condition.
Above-mentioned flow process IX shows the general route of synthesis that is used to prepare The compounds of this invention 32, and this moment, R ' was as described herein.According to flow process IX step (b), will handle with the suitable aldehyde R ' CHO of blocking group (P) protection 19 gained intermediates 20 usefulness that are fit to.After the deprotection of indazole 31, production 32 compounds.
Flow process X
Reagent and condition: (a) n-BuLi, THF, PCl; (b) t-BuLi i), Et
2O ,-78 ℃, 1h, ii) R ' CH
2Br; (c) deprotection condition.
Above-mentioned flow process X shows the general route of synthesis that is used to prepare The compounds of this invention 32, and this moment, R ' was as described herein.According to flow process X step (b), will be with the suitable R ' CH of blocking group (P) protection 19 gained intermediates, 20 usefulness that is fit to
2Br handles.After the deprotection of indazole 33, production 34 compounds.
Flow process XI
Reagent and condition: (a) CDI, DMF; (b) P
2S
5, pyridine.
Above-mentioned flow process XI shows the general route of synthesis that is used to prepare The compounds of this invention 38, at this moment R
2To R
5Be as described herein.By preparing people such as raw material 35:Allegreti, Org.Proc.Res.Dev.2003,7,209 with the described method of document basically.According to flow process XI step (a), intermediate 35 and amine 36 reactions.This reaction is applicable to various kinds of amine 36.At P
2S
5Existence under, the cyclic action of compound 37 obtains derivative 38.
Flow process XII
Reagent and condition: (a) AlCl
3, CH
2Cl
2, RT, 16 hours; (b) NH
2OHHCl, EtOH, heating, 1 hour.
Above-mentioned flow process XII shows the general route of synthesis that is used to prepare The compounds of this invention 41, at this moment R
2To R
5Be as described herein.Utilize Friedel-Craft process for acylating well known in the art to prepare intermediate 40.This reaction is applicable to the derivative 39 of multiple replacement, production 40 compounds.According to step (b), the cyclic action of intermediate 40 obtains formula 41 compounds.
Although above describe and described some exemplary embodiment with this paper, what but will be understanded is, by the general available method of those of ordinary skills, The compounds of this invention can be according to above method, the suitable raw material of use of general description are prepared.
Therefore, in another embodiment, the invention provides the method for preparing The compounds of this invention, as described herein basically, definitely as described in flow process and the embodiment.
5, purposes, preparation and administration:
Pharmaceutically acceptable composition
Just as discussed above, the invention provides such compound, they are inhibitor of protein kinase, thereby these compounds can be used for treating disease, illness and illness, include but not limited to the disease of autoimmunization, inflammatory, propagation or hyperproliferation disease or immunology-mediation.Therefore, in another aspect of this invention, provide pharmaceutically acceptable composition, wherein these compositions comprise compound as described herein arbitrarily, and comprise pharmaceutically acceptable carrier, auxiliary agent or vehicle alternatively.In some embodiments, these compositions further comprise one or more other treatment agent alternatively.
What also will be understanded is that some The compounds of this invention can exist for treatment with free form, perhaps is its pharmaceutically acceptable derivates in appropriate circumstances.According to the present invention, pharmaceutically acceptable derivates includes but not limited to the salt of pharmacy acceptable salt, ester, this class ester or other adductss or derivative arbitrarily, in case promptly can directly or indirectly provide compound or its meta-bolites or resistates as described herein to patient's administration of needs.
The salt that term used herein " pharmacy acceptable salt " expression is such, in rational medical judgment scope, they are suitable for contacting with the lower animal tissue with human body, do not have unsuitable toxicity, pungency, transformation reactions etc., match with rational interests/risk ratio.Any non-toxic salts or the ester salt of " pharmacy acceptable salt " expression The compounds of this invention are in case to recipient's administration, promptly can directly or indirectly provide The compounds of this invention or its to suppress active metabolite or resistates.Term used herein " it suppresses active metabolite or resistates " means that its meta-bolites or resistates also are the inhibitor of Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase.
Pharmacy acceptable salt is well known in the art.For example, S.M.Berge etc. are at J.Pharmaceutical Sciences, and 1977,66, describe pharmacy acceptable salt among the 1-19 in detail, quote as a reference at this.The pharmacy acceptable salt of The compounds of this invention comprise from the inorganic and organic acid that is fit to and alkali deutero-those.The example of pharmaceutically acceptable non-toxic acid addition salt is the amide that generates with mineral acid or organic acid, mineral acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid for example, organic acid is acetate, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid for example, perhaps utilize the used additive method in this area, for example the salt of ion-exchange formation.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, glucoheptose salt, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, the 2-isethionate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, right-tosylate, the undecane hydrochlorate, valerate etc.Comprise basic metal, alkaline-earth metal, ammonium and N from suitable alkali deutero-salt
+(C
1-4Alkyl)
4Salt.The quaternization of any alkaline nitrogen-containing group of compound is as disclosed herein also contained in the present invention.Can obtain water soluble or the oily product that maybe can be dispersed in water or the oil by this class quaternization.Representative basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.When suitable the time, other pharmacy acceptable salts comprise nontoxic ammonium salt, quaternary ammonium salt and amine cationic salts, utilize counter ion to generate, for example halogenide, oxyhydroxide, carboxylate salt, vitriol, phosphoric acid salt, nitrate, low-grade alkane sulfonate and arylsulphonate.
As mentioned above, pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, auxiliary agent or vehicle in addition, described in the present invention, they comprise be suitable for required particular dosage form arbitrarily and all solvents, thinner or other liquid excipients, dispersion or suspension aids, tensio-active agent, isotonic agent, thickening or emulsifying agent, sanitas, solid binder, lubricant etc.Remington ' s Pharmaceutical Sciences, SixteenthEdition, (Mack Publishing Co.Easton Pa.1980) discloses the known technology that is used to prepare the various carriers of pharmaceutically acceptable composition and is used for its preparation to E.W.Martin.Except any conventional mounting medium is incompatible with The compounds of this invention, for example produce any worthless biological effect or interact in any other component of pharmaceutically acceptable composition in harmful mode, its use is contained within the scope of the invention.Some examples that can serve as the material of pharmaceutically acceptable carrier include but not limited to ion-exchanger; Aluminum oxide; Aluminum stearate; Yelkin TTS; Serum protein, for example serum albumin; Buffer substance, for example phosphoric acid salt; Glycine; Sorbic Acid or potassium sorbate; The partial glyceride mixture of saturated vegetable fatty acid; Water; Salt or ionogen, for example protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt; Colloid silica; Magnesium Trisilicate; Polyvinylpyrrolidone; Polyacrylic ester; The wax class; Polyethylene-polyoxytrimethylene-block polymer; Lanolin; Carbohydrate, for example lactose, dextrose plus saccharose; Starch, for example W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and rhodia; The tragacanth gum of pulverizing; Fructus Hordei Germinatus; Gelatin; Talcum; Vehicle, for example theobroma oil and suppository wax; Oils, for example peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycol, for example propylene glycol or polyoxyethylene glycol; Ester class, for example ethyl oleate and Laurate ethyl; Agar; Buffer reagent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol; Phosphate buffer soln; And other nontoxic compatible lubricant, for example Sodium Lauryl Sulphate BP/USP and Magnesium Stearates; According to preparation personnel's judgement, in composition, also can exist toner, releasing agent, Drug coating, sweeting agent, seasonings and spices, sanitas and antioxidant.
The purposes of compound and pharmaceutically acceptable composition
On the other hand, disease for the treatment of Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediation or the method that alleviates its seriousness are provided, comprise that the curee to needs gives the compound of significant quantity or the pharmaceutically acceptable composition of inclusion compound.In some embodiments of the present invention, " significant quantity " of compound or pharmaceutically acceptable composition is with regard to the disease for the treatment of Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediation or alleviates effective amount with regard to its seriousness.Can utilize with regard to the disease for the treatment of Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediation or alleviate with regard to its seriousness effective any amount and in addition administration of route of administration arbitrarily according to the compound of the inventive method and composition.Required definite amount will be different because of the curee, depend on seriousness, the certain drug of curee's kind, age and general state, infection, mode of its administration etc.The compounds of this invention preferably is formulated into dosage unit form, and the consistence of administration of being easy to and dosage is arranged.The drug unit that phraseology used herein " dosage unit form " expression is physically discrete is suitable for the patient who is treated.But will be understood that total every day of the consumption of The compounds of this invention and composition will reasonably determined in the medical judgment scope by the attending doctor.The concrete effective dose level of any specific patient or organism will depend on multiple factor, comprise the illness of being treated and the seriousness of illness; The activity of the particular compound that is adopted; The concrete composition that is adopted; Patient's age, body weight, general health situation, sex and diet; The discharge rate of the approach of time of administration, administration and the particular compound that is adopted; The time length of treatment; With particular compound associating of being adopted or the medicine that uses simultaneously; Other factors of knowing with field of medicaments.Term used herein " patient " expression animal, preferred mammal, optimum is chosen.
Pharmaceutically acceptable composition of the present invention can be oral to people and other animals, in the rectum, parenteral, brain pond, intravaginal, intraperitoneal, part (with pulvis, ointment or drops), cheek, with mouth with or mode administration such as nasal spray, this depends on the seriousness that infection is treated by institute.In some embodiments, The compounds of this invention can be by oral or administered parenterally, dosage level be every day about 0.01mg/kg to about 50mg/kg, preferred about 1mg/kg about 25mg/kg curee's body weight extremely, once a day or repeatedly, to obtain required result of treatment.
The liquid dosage form of oral administration includes but not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active compound, liquid dosage form can contain this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, phenylformic acid benzyl ester, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oil (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, wheat germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and the fatty acid ester of anhydro sorbitol and their mixture.Except inert diluent, oral compositions can also comprise auxiliary agent, for example wetting agent, emulsification and suspension agent, sweeting agent, correctives and spices.
Use the dispersion or wetting agent and the suspension agent that are fit to, can prepare injectable formulation according to known technique, for example the water-based of sterile injectable or oiliness suspension.Sterile injectable preparation also can be at nontoxic parenteral acceptable diluent or sterile injectable solution, suspension or the emulsion in the solvent, for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution.In addition, conventionally adopt aseptic expressed oil as solvent or suspension medium.For this reason, can adopt the fixed oil of any gentleness, comprise synthetic list-or two-glyceryl ester.In addition, in the preparation of injection, also can use lipid acid, for example oleic acid.
Injectable formulation can be sterilized like this, for example filters by the bacterium property held back filter, perhaps mixes the disinfectant of aseptic solid composite form, can be before use with its dissolving be dispersed in aseptic water or other sterile injectable medium in.
In order to prolong the effect of The compounds of this invention, often need delay the absorption of compound after subcutaneous or intramuscularly.This can utilize the crystallinity of poorly water-soluble or the liquid suspension of amorphous substance to realize.The uptake rate of compound depends on its dissolution rate, and the latter may be depended on crystallographic dimension and crystal formation again conversely.Select as an alternative, with compound dissolution or be suspended in the oils carrier, realize that the delay of administered parenterally compound form absorbs.Injectable depot forms is like this preparation, and in Biodegradable polymeric, polylactide-poly-glycollide for example generates the microencapsulation matrix of compound.According to the ratio of compound and polymkeric substance and the attribute of the particular polymers that adopts, can control the rate of release of compound.The example of other biological degradable polymer comprises poly-(ortho ester) and poly-(acid anhydrides).The depot injectable formulation also can prepare the compound inclusion in liposome compatible with body tissue or micro emulsion.
Rectum or vagina administration composition be suppository preferably, they can prepare like this, The compounds of this invention is mixed with the nonirritant excipient or the carrier that are fit to, for example theobroma oil, polyoxyethylene glycol or suppository wax, they are solid at ambient temperature, but under body temperature, be liquid, therefore in rectum or vaginal canal, melt, discharge active compound.
The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granule.In this class solid dosage, active compound is mixed with pharmaceutically acceptable vehicle of at least a inert or carrier, for example Trisodium Citrate or Lin Suanergai, and/or a) weighting agent or expanding material, starch for example, lactose, sucrose, glucose, mannitol and silicic acid, b) tackiness agent, carboxymethyl cellulose for example, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) wetting agent, glycerine for example, d) disintegrating agent, for example agar, lime carbonate, potato or tapioca (flour), alginic acid, some silicate and yellow soda ash, e) dissolving retarding agent, paraffin for example, f) absorption enhancer, for example quaternary ammonium compound, g) wetting agent, for example hexadecanol and Zerol, h) absorption agent, for example kaolin and wilkinite, and i) lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and composition thereof.Under the situation of capsule, tablet and pill, this formulation can also comprise buffer reagent.
The solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft or hard filling, and the capsule used excipient is lactose or toffee and macromolecule polyethylene glycol etc. for example.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example other dressings of knowing of enteric coating and medicine formulation art.They can contain opalizer alternatively, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, alternatively the mode for postponing.The example of operable embedding composition comprises polymeric material and wax class.The solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft and hard filling, and the capsule used excipient is lactose or toffee and macromolecule polyethylene glycol etc. for example.
Active compound also can be the form of microencapsulation, wherein contains one or more above-mentioned vehicle.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example enteric coating, discharge other dressings that controlled dressing and medicine formulation art are known.In this class solid dosage, active compound can be mixed with at least a inert diluent, for example sucrose, lactose or starch.Under normal circumstances, this class formulation can also comprise other materials except that inert diluent, for example compressing tablet lubricant and other compression aids, for example Magnesium Stearate and Microcrystalline Cellulose.Under the situation of capsule, tablet and pill, formulation can also comprise buffer reagent.They can contain opalizer alternatively, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, alternatively the mode for postponing.The example of operable embedding composition comprises polymeric material and wax class.
The part of The compounds of this invention or transdermal administration formulation comprise ointment, paste, creme, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch.Active ingredient is mixed with pharmaceutically acceptable carrier and any essential sanitas or buffer reagent under aseptic condition, decide as required.Ophthalmic preparation, ear drop and eye drops also covered in the scope of the present invention.In addition, the use of transdermal patch is contained in the present invention, and they have the attendant advantages that the control compound is sent to body.This class formulation can be by with compound dissolution or be dispersed in the appropriate medium and prepare.Can also use absorption enhancer to increase the flux that compound passes skin.Can control speed by rate controlling membranes being provided or compound being dispersed in polymeric matrix or the gel.
As general describe above, The compounds of this invention can be used as the inhibitor of protein kinase.In one embodiment, The compounds of this invention and composition are the kinase whose inhibitor of one or more Tec families (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk), thereby do not wish to be subjected to any specific theory to limit, compound and composition are particularly useful for treatment a kind of like this disease, illness or illness or alleviate its seriousness, wherein one or more Tec families (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase whose activation implication in this disease, illness or illness.When the kinase whose activation of Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) in specified disease, illness or illness during implication, this disease, illness or illness also can be called as " disease of Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)-mediation " or disease symptoms.Therefore, on the other hand, the invention provides a kind of like this disease of treatment, illness or illness or alleviate the method for its seriousness, wherein activation implication in this morbid state of one or more Tec families (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk).
Can or be measured in the clone in external, body as the activity of the compound of Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase inhibitor in the present invention.The external test method comprises the restraining effect of mensuration to activation Tec family's (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase whose phosphorylation activity or atpase activity.But external test method quantitative assay inhibitor and Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinases bonded ability optionally.The combination of inhibitor can be measured like this, and radio-labeling inhibitor before combination separates inhibitor/Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) mixture, measures the radiolabeled amount of institute's bonded again.Perhaps, the combination of inhibitor can be measured like this, in competitive assay, with novel inhibitors with known radioligand bonded Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinases incubation.
Term used herein " can suppress " to be illustrated in with measuring and comprise described composition and Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase whose sample and comprise Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinases and Tec family between the sample (for example Tec, Btk, Itk/Emt/Tsk, Bmx, the Txk/Rlk) kinase activity that is equal to that do not have described composition to exist has measurable change.
Any disease or other harmful illnesss that the known Tec family kinase of term used herein " illness of Tec family Tyrosylprotein kinase-mediation " expression works therein.This class illness comprises the disease of autoimmunity, inflammatory, proliferative and excess proliferative disease and immunology-mediation without limitation, comprises the repulsion and the acquired immune deficiency syndrome (AIDS) (AIDS) of transplant organ or tissue.
For example, the illness of Tec family Tyrosylprotein kinase-mediation comprises respiratory tract disease, comprise the reversibility obstructive airway diseases without limitation, comprise asthma, for example segmental bronchus, allergy, endogenous, exogen and dust asthma, particularly chronic or obstinate asthma (for example late period, the asthma airway reactivity was too high) and bronchitis.In addition, Tec family Tyrosylprotein kinase disease comprises without limitation with the nasal mucosa inflammation being those illnesss of feature, comprise acute rhinitis, allergy and atopic rhinitis and chronic rhinitis, comprise caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, rhinitis sicca and medicamentous rhinitis; Membranous rhinitis comprises croup, fibrin and pseudomembranous rhinitis and scrofula rhinitis; The seasonal rhinitis comprises nervous rhinitis's (spring fever) and vasomotor rhinitis; Sarcoidosis; Farmer lung and relative disease; The fiber-like lung; With spontaneous interstitial pneumonia.
The Tec family Tyrosylprotein kinase-illness of mediation also comprises the disease in bone and joint, comprises rheumatoid arthritis (in pannus form), seronegativity spondyloarthropathy (comprising ankylosing spondylitis, arthritic psoriasis and Reiter's disease), Behcet, siogren's syndrome and systemic sclerosis without limitation.
The illness of Tec family kinase-mediation also comprises the disease and the illness of skin, comprises psoriasis, systemic sclerosis, atopic dermatitis, contact dermatitis and other eczematoid dermatitiss, seborrheic dermatitis, lichen planus, pemphigus, BP, epidermolysis bullosa, urticaria, xeroderma, nodular vasculitis, erythroderma, skin eosinophilia, uveitis, alopecia, bunch property and vernal conjunctivitis without limitation.
The illness of Tec family Tyrosylprotein kinase-mediation also comprises GI disease and illness, comprise celiaca, rectitis, eosinocyte gastro-enteritis, mast cell disease, pancreatitis, Crohn disease, ulcerative colitis without limitation, away from the food dependency transformation reactions of stomach, for example migraine, rhinitis and eczema.
The illness of Tec family Tyrosylprotein kinase-mediation also comprises disease and the illness and the general disease of its hetero-organization, comprises multiple sclerosis without limitation, atherosclerosis, acquired immune deficiency syndrome (AIDS) (AIDS), lupus erythematosus, systemic lupus, erythema, struma lymphomatosa, myasthenia gravis, type i diabetes, nephrotic syndrome, the eosinophilia fascitis, the too high syndrome of IgE, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenic purpure, postangioplasty restenosis, tumour (leukemia for example, lymphoma), atherosclerosis and systemic lupus erythematous.
The illness of Tec family Tyrosylprotein kinase-mediation also comprises homograft rejection, comprises acute and chronic homograft rejection without limitation, for example is secondary to after the transplantation of kidney, the heart, liver, lung, marrow, skin and cornea; With the chronic graft versus host disease.
What also will be understanded is, compound of the present invention and pharmaceutically acceptable composition can be used in the conjoint therapy, that is to say, compound and pharmaceutically acceptable composition can one or more other required therapeutical agent or medical program simultaneously, before or administration subsequently.Be used in that specific therapy combination (therapeutical agent or program) in the scheme for combining will be considered required therapeutical agent and/or program and the tolerability of the required result of treatment that will reach.What also will be understanded is, used therapy can (for example reach required effect to same illness, The compounds of this invention can be used for the treatment of the medicine administration simultaneously of same illness with another kind), perhaps they can reach different effects (for example controlling any side effect).As used herein, administration under normal circumstances is called as " is suitable " with the other therapeutical agent of treatment or prevention specified disease or illness with regard to the disease of being treated or illness.
For example, chemotherapeutics or other antiproliferatives can with The compounds of this invention treatment proliferative disease linked together and cancer.Other can be used for comprising operation with the therapy or the carcinostatic agent of carcinostatic agent combination of the present invention, (some examples have gamma-irradiation to radiotherapy, the neutron beam radiotherapy, the electron beam radiotherapy, proton therapy, short range therapy and systemic radio isotope, only lift numerical example), endocrinotherapy, biological response properties-correcting agent (Interferon, rabbit, interleukin and tumour necrosis factor (TNF), only lift numerical example), high temperature and psychrotherapy, weaken medicine (for example antiemetic) and other chemotherapeutic of any side effect, include but not limited to alkyl chemical drug (mustargen through ratifying, Chlorambucil, endoxan, melphalan, ifosfamide), antimetabolic product (methotrexate), purine antagonist and pyrimidine antagonist (Ismipur, 5 FU 5 fluorouracil, cytosine arabinoside, gemcitabine), spindle poison (vincaleucoblastine, vincristine(VCR), vinorelbine, taxol), podophyllotoxin (Etoposide, irinotecan, Hycamtin), microbiotic (Zorubicin, bleomycin, mitomycin), nitrosourea (carmustine, lomustine), mineral ion (cis-platinum, carboplatin), enzyme (asparaginase), hormone (tamoxifen, leuprorelin acetate, flutamide and megestrol), Gleevec
TM, Zorubicin, dexamethasone and endoxan.Discussion more comprehensively about up-to-date cancer therapy, tumour medicine tabulation http://www.fda.gov/cder/cancer/druglistframe.htm and The Merck Manual referring to http://www.nci.nih.gov/, FDA approval, Seventeenth Ed.1999, its complete content is quoted at this as a reference.
Other also can comprise without limitation with the exemplary drugs of inhibitor associating of the present invention: the therapeutical agent of Alzheimer formula disease, for example
With
Parkinsonian therapeutical agent, for example levodopa/carbidopa, Entacapone, Ropinirole, pramipexole, bromocriptine, pergolide, Trihexyphenidyl and amantadine; The medicine of treatment multiple sclerosis (MS), for example beta-interferon (for example
With
),
And mitoxantrone; The treatment of asthma agent, for example salbutamol and
Treat schizoid medicine, for example Zyprexa, Wei Sitong, Seroquel and haloperidol; Anti-inflammatory agent, for example corticosteroid, tnf blockers, IL-1RA, azathioprine, endoxan and sulfasalazine; Immunoregulation and immunosuppressor, for example S-Neoral, tacrolimus, rapamycin, mycophenolic acid mofetil mycophenolate, Interferon, rabbit, corticosteroid, endoxan, azathioprine and sulfasalazine; Neurotrophic factor, for example acetylcholinesterase depressant, MAO inhibitor, Interferon, rabbit, anticonvulsive agent, ionic channel retarding agent, Riluzole and anti-Parkinson agent; The medicine of treatment cardiovascular disorder, for example beta-Blocking agent, ACE inhibitor, diuretic(s), nitric ether, calcium channel blocker and Statins; The medicine of treatment hepatopathy, for example reflunomide, Colestyramine, Interferon, rabbit and antiviral agent; Treat hemopathic medicine, for example reflunomide, leukemia agent and somatomedin; With the medicine of treatment immunodeficiency diseases, for example gamma globulin.
The content of other therapeutical agent in the present composition will be no more than comprise this therapeutical agent as unique composition of active components in common dosage.Preferably, the other amount of therapeutical agent in present disclosed composition will be common to comprise this medicine as about 50% to 100% of the content in the composition of unique therapeutic activity composition.
The compounds of this invention or its pharmaceutically acceptable composition also can be incorporated in the composition that applies implantable medical devices, for example artificial limb, artificial valve, vascular graft, support and conduit.Therefore, the present invention comprises the composition that applies implantable device on the other hand, and it comprises as above general describe and at big class and the The compounds of this invention described in the group of this paper be suitable for applying the carrier of described implantable device.On the other hand, the present invention includes the implantable device that scribbles composition, described composition comprises as above general describe and at the The compounds of this invention described in big class of this paper and the group be suitable for applying the carrier of described implantable device.
Vascular stent for example has been used to overcome restenosis (restenosis of damage back vessel wall).But, the patient of use Si Tanteshi die or other implantable devices faces the danger of grumeleuse generation or platelet activation.By this device being applied in advance the pharmaceutically acceptable composition that comprises kinase inhibitor, can prevent or alleviate these undesirable effects.The general method of the implantable device that coating that is fit to and preparation apply is described in United States Patent (USP) 6,099, in 562,5,886,026 and 5,304,121.Coating is the polymeric material of bio-compatible normally, for example aquogel polymer, poly-methyl sily oxide, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), vinyl-vinyl acetate copolymer and their mixture.Coating can further be covered by the top layer of the fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its combination that are fit to alternatively, to give the release characteristics of composition.
Another aspect of the present invention relates in biological sample or patient and to suppress Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) activity, and this method comprises the patient is given or makes described biological sample contact I compound or comprise described compound compositions.Term used herein " biological sample " comprises cell culture and extract thereof without limitation; Biopsy material from Mammals or the acquisition of its extract; With blood, saliva, urine, ight soil, seminal fluid, tear or other body fluid or its extract.
In biological sample, suppress Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity and can be used for multiple purpose well known by persons skilled in the art.This classification example include but not limited to that blood transfusion, organ transplantation, biological specimen are stored and biology is measured.
Embodiment
Synthetic embodiment
Used herein
1H NMR is a nucleus magnetic resonance.HPLC is a high performance liquid chromatography.The HPLC retention time that term " Rt (min) " expression is relevant with compound, in minute.Unless indication is arranged in addition, the HPLC method that is used to obtain the retention time reported is as follows:
Pillar: Ace 5C8,15cm * 4.6mm id
Gradient: 0-100% acetonitrile+methyl alcohol (50: 50) (20mM Tris phosphoric acid salt, pH 7.0)
Flow velocity: 1.5ml/min
Detect: 225nm
Embodiment 1
5-phenyl-1H-pyrrolo-[2,3-b] pyridine
With 5-bromo-1H-pyrrolo-[2,3-b] pyridine (2g, 10.15mmol), phenyl for boric acid (1.24g, 10.15mmol) and four (triphenyl phosphine) palladium (117mg, 0.10mmol) be suspended among ethanol (5ml), water (6ml) and the DME (22ml), be heated to 100 ℃ and spend the night.Remove in a vacuum and desolvate, reaction is through the column chromatography purifying, and the petroleum ether solution wash-out with 30% ethyl acetate obtains title compound, is pale solid (1.51g, 77%).
MS(ES
+)195，(ES-)193.δH(CDCl
3)6.60(1H，s)，7.36-7.43(2H，m)，7.68(2H，d)，8.18(1H，s)，8.62(1H，s)，10.39(1H，br s).
Embodiment 2
2-chloro-1-(5-phenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl)-ethyl ketone
With 5-phenyl-1H-pyrrolo-[2,3-b] pyridine (200mg, 1.03mmol) and aluminum chloride (412mg, 3.09mmol) be suspended among the anhydrous DCM, at room temperature stirred 1 hour, drip chloroacetyl chloride (98 μ l, 1.24mmol), the gained amber solution at room temperature stirred spend the night.To react with methyl alcohol (5ml) cancellation, at room temperature stir 2 hours.Evaporating solvent obtains orange oil then.It is distributed between DCM and water.Concentrate organic phase in a vacuum, product is developed with diethyl ether, obtains title compound, is beige solid (188mg, 67%).
MS(ES
+)271，(ES-)269.δH(CDCl
3)4.57(2H，s)，7.44(1H，t)，7.50(2H，t)，7.70(2H，d)，8.23(1H，s)，8.70(1H，s)，8.91(1H，s)，11.59(1H，br s).
Embodiment 3
Diethyl-[4-(5-phenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl)-thiazol-2-yl]-amine
(50mg, 0.18mmol) with 1, (24mg, in the ethanol (2ml) that 0.18mmol) suspends/be dissolved in, heating is 10 minutes in 120 ℃ of microwaves for the 1-diethyl thiourea with 2-chloro-1-(5-phenyl-1H-pyrrolo-[2,3-b] pyridin-3-yl)-ethyl ketone.Crude product mixture is used the acetonitrile/water wash-out through the HPLC purifying, obtains title compound, is cream-colored solid (9.5mg, 15%).
MS(ES+)349，(ES-)347.δH(CDCl3)1.31(6H，t)，3.59(4H，q)，6.61(1H，s)，7.38(1H，t)，7.50(2H，t)，7.69(2H，d)，7.78(1H，s)，8.56-8.62(2H，m)，8.94(1H，br s)，
Prepare multiple other formulas I compound by being substantially similar to this paper embodiment 3 described methods.The authentication data of these compounds is summarised in the following table 3, comprise HPLC, LC/MS (observation) and
1H NMR data.
Table 3: the authentication data of selected formula I compound
| Compound number I- | M+1(obs) | Rt(min) | 1H-NMR |
| 1 | 292 | 9.60 | (CDCl 3)2.82(3H，s)，7.26(1H，s)，7.40(1H，t)， 7.52(2H，t)，7.70(2H，d)，7.89(1H，s)，8.53(1H， s)，8.62(1H，s)，9.07(1H，br s) |
| 2 | 349 | 10.72 | (CDCl3)1.31(6H，t)，3.59(4H，q)，6.61(1H，s)， 7.38(1H，t)，7.50(2H，t)，7.69(2H，t)，7.78(1H， s)，8.56-8.62(2H，m)，8.94(1H，br s) |
| 3 | 306 | 9.96 | (CDCl 3)2.56(3H，s)，2.75(3H，s)，7.39(1H，t)， 7.46-7.53(3H，m)，7.68(2H，d)，8.58(1H，s)， 8.61(1H，s)，9.44(1H，br s) |
| 4 | 363 | 10.98 | (CDCl 3)1.33(6H，t)，2.47(3H，s)，3.54(4H，q)， 7.36(1H，t)，7.45-7.51(3H，m)，7.69(2H，d)， 8.60(1H，s)，8.76(1H，s)，9.14(1H，br s) |
| 5 | 307 | 8.74 | (CDCl 3)2.40(3H，s)，5.02(2H，s)，7.34-7.39(2H， m)，7.46(2H，t)，7.65(2H，d)，8.51(1H，s)，8.59 (1H，s)，9.96(1H，br s) |
| 6 | 364 | 10.17 | (CDCl 3)1.48(3H，t)，2.70(3H，s)，4.50(2H，q)， 7.39(1H，t)，7.48(2H，t)，7.61(1H，s)，7.70(2H， d)，8.65(2H，s)，9.07(1H，br s) |
| 7 | 350 | 9.89 | (CDCl 3)1.50(3H，t)，4.54(2H，q)，7.41(1H，t)， 7.52(2H，t)，7.66-7.72(3H，m)，8.03(1H，s)，8.55 (1H，s)，8.65(1H，s)，9.26(1H，br s) |
| 9 | 363 | 9.78 | (CDCl 3)3.55-3.63(4H，m)，3.86-3.92(4H，m)， 6.76(1H，s)，7.36-7.44(1H，m)，7.46-7.54(1H， m)，7.83(1H，s)，8.53(1H，s)，8.59(1H，s)，9.64 (1H，s) |
| 12 | 390 | 8.63 | (DMSO)3.25-3.45(4H，m)，3.90(2H，br s)，4.76 (2H，br s)，7.42(1H，t)，7.54(2H，t)，7.79(2H，d)， 8.20(1H，s)，8.36(1H，s)，8.63(2H，d)，8.82(1H， br s)，12.20(1H，s). |
| 14 | 391 | 9.20 | (CDCl 3)3.81-3.90(4H，m)，4.66(2H，br s)，7.41 (1H，t)，7.54(2H，t)，7.62-7.69(3H，m)，7.84(1H， s)，8.55(1H，s)，8.65(1H，s)，9.11(1H，br s). |
| 16 | 404 | 8.89 | (CDCl 3)1.18-1.34(2H，m)，1.73-1.82(2H，m)， 1.98-2.37(3H，m)，2.58-2.70(2H，m)，3.20(3H， s)，3.42-3.53(2H，m)，6.62(1H，s)，7.33-7.42 (1H，m)，7.45-7.54(2H，m)，7.65-7.71(2H，m)， 7.80(1H，s)，8.54-8.59(2H，m)，9.42(1H，br s) |
| 18 | 362 | (DMSO)2.81-2.87(4H，m)，3.35-3.44(4H，m)， 7.27(1H，s)，7.37(1H，t)，7.45-7.52(2H，m)， 7.73-7.77(2H，m)，7.84(1H，s)，8.54(1H，s)， 8.59(1H，s)，11.88(1H，s) | |
| 46 | 335 | 8.92 | (DMSO)2.18(3H，s)，7.43(1H，t)，7.49-7.56 (3H，m)，4.79-4.82(2H，m)，7.94(1H，s)，8.58 (1H，s)，8.71(1H，s)，12.00(1H，s)，12.19(1H，s) |
| 48 | 418 | 8.48 | (DMSO)：1.40(2H，t)，1.80-1.95(3H，m)，2.88 (2H，t)，3.22-3.31(4H，m)，7.39(1H，t)，7.51(2H， t)，7.85(2H，d)，8.15(1H，s)，8.29(2H，br s)，8.60 (1H，s)，8.78(1H，s)，8.99(1H，t)，12.17(1H，s). |
| 49 | 293 | (DMSO)6.95(1H，s)，7.00(1H，s)，7.37(1H，t)， 7.46-7.51(2H，m)，7.75-7.79(3H，m)，8.54(1H， s)，8.59(1H，s)，11.84(1H，s) | |
| 50 | 321 | 10.00 | (DMSO)3.13(6H，s)，7.10(1H，s)，7.39(1H，t)， 7.46-7.54(2H，m)，7.75-7.78(2H，m)，7.85(1H， s)，8.54(1H，s)，8.62(1H，s)，11.88(1H，s) |
| 50 | 538 | 10.9 | (CDCl 3)1.60-1.80(4H，m)，2.03-2.16(1H，m)， 2.73-2.83(2H，m)，3.21(3H，s)，3.2-3.50(2H，m)， 4.10-4，32(2H，m)，5.15(2H，s)，6.65(1H，s)， 7.26-7.40(6H，m)，7.44-7.55(2H，m)，7.65-7.70 (2H，m)，7.80(1H，s)，8.59(2H，s)，9.20(1H，s) |
| 52 | 365 | 10.0 | (CDCl 3)3.25(3H，s)，3.44(3H，s)，3.68-3.74(2H， m)，3.75-3.80(2H，m)，6.65(1H，s)，7.36-7.44 (1H，m)，7.46-7.54(2H，m)，7.65-7.72(2H，m)， 7.84(1H，s)，8.58(1H，s)，8.61(1H，s)，9.51(1H， br s) |
| 53 | 389 | 11.22 | (CDCl 3)0.28-0.40(2H，m)，0.53-0.63(2H，m)， 0.93-1.02(3H，m)，1.15-1.26(1H，m)，1.72-1.85 (2H，m)，3.38-3.45(2H，m)，3.45-3.55(2H，m)， 6.61(1H，s)，7.32-7.42(1H，m)，7.42-7.53(2H， m)，7.62-7.72(2H，m)，7.78(1H，s)，8.60(1H，s)， 8.66(1H，s)，9.21(1H，br s) |
| 54 | 379 | 10.6 | (DMSO)1.2-1.3(6H，m)，3.4-3.6(4H，m)，3.8- 3.9(3H，s)，6.9(1H，m)，7.0(1H，s)，7.3(2H，m)， 7.4(1H，m)，7.8-7.9(1H，s)，8.5-8.6(1H，s)， 8.7(1H，s)，11.8-11.9(0.7H，s) |
| 55 | 323 | 8.5 | (DMSO)3.7-3.8(3H，s)，6.8-7.0(3H，m)，7.2- 7.3(2H，m)，7.3-7.4(1H，m)，7.7-7.8(1H，s)，8.5- 8.6(2H，m)，11.8(0.6H，s) |
| 56 | 347 | 10.38 | (CDCl 3)2.05-2.14(4H，m)，3.54-3.61(4H，m)， 6.65(1H，s)，7.36-7.43(1H，m)，7.46-7.54(2H， m)，7.76-7.83(2H，m)，7.86(1H，s)，8.54-8.59 (2H，m)，9.56(1H，br s) |
| 57 | 379 | 10.39 | (CDCl 3)1.27-1.33(3H，m)，3.43(3H，s)，3.55- 3.62(2H，m)，3.67-3.77(4H，m)，6.64(1H，s)， 7.35-7.42(1H，m)，7.46-7.54(2H，m)，7.66-7.71 (2H，m)，7.80(1H，s)，8.60(2H，s)，9.42(1H，br s) |
| 58 | 335 | 10.35 | (CDCl 3)1.24-1.34(3H，m)，3.27(3H，s)，3.55- 3.64(2H，m)，6.64(1H，s)，7.35-7.41(1H，m)， 7.45-7.53(2H，m)，7.65-7.72(2H，m)，7.85(1H， s)，8.58-8.63(2H，m)，9.57(1H，br s) |
| 59 | 376 | 9.82 | (CDCl 3)2.41(3H，s)，2.53-2.63(4H，m)，3.58- 3.66(4H，m)，6.72(1H，s)，7.37-7.43(1H，m)， 7.46-7.53(2H，m)，7.65-7.71(2H，m)，8.52(1H， s)，8.60(1H，s)，9.39(1H，br s) |
| 60 | 365 | 9.61 | (CDCl 3)1.29-1.35(3H，m)，3.46-3.53(2H，m)， 3.74-3.81(2H，m)，3.95-4.02(2H，m)，6.66(1H， s)，7.34-7.40(1H，m)，7.47-7.54(2H，m)，7.65- 7.70(2H，m)，7.78(1H，s)，8.44(1H，s)，8.61(1H， s)，9.80(1H，br s) |
| 61 | 363 | 9.61 | (DMSO)1.14(6H，d，J＝6.8Hz)，2.72-2.8491H， m)，7.35-7.56(4H，m)，7.75-7.82(2H，m)，7.90 (1H，brs)，8.58(1H，brs)，8.70(1H，brs)，11.98 (1H，brs)，12.13(1H，brs). |
| 62 | 363 | 10.97 | (CDCl 3)0.80-0.92(6H，m)，1.25-1.35(3H，m)， 3.41-3.52(2H，m)，4.25-4.35(1H.m)，6.60(1H， s)，7.33-7.40(1H，m)，7.45-7.52(2H，m)，7.64- 7.71(2H，m)，7.81(1H，s)，7.56(1H，s)，7.60(1H， s)，9.90(1H，br s) |
| 63 | 392 | 10.27 | (CDCl 3)1.34(3H，t)，2.46(6H，s)，2.82-2.99 (2H，m)，3.52-3.59(2H，q)，3.65-3.80(2H，m)， 6.66(1H，s)，7.35-7.41(1H，m)，7.43-7.52(2H， m)，7.63-7.70(2H，m)，7.80(1H，s)，8.56(1H，s)， 8.60(1H，s)，9.29(1H，br s) |
| 64 | 381 | 9.64 | (DMSO)1.14(6H，d，J＝6.9Hz)，2.72-2.86(1H， m)，7.30-7.40(2H，m)，7.52(1H，s)，7.79-7.91 (3H，m)，8.56(1H，brs)，8.66(1H，brs)，11.99 (1H，brs)，12.12(1H，brs). |
| 65 | 353 | 8.98 | (DMSO)1.15(6H，d，J＝6.8Hz)，2.72-2.86(1H， m)，7.18(1H，s)，7.53(1H，s)，7.78-7.89(2H，m)， 8.30(1H，s)，8.56-8.62(1H，m)，11.90(1H，brs)， 12.14(1H，brs). |
| 66 | 298 | 9.58 | (DMSO)1.21(6H，t，J＝7.0Hz)，3.51(4H，q，J＝ 7.0Hz)，7.08(1H，s)，8.04(1H，brs)，8.65(1H， brs)，8.91(1H，brs)，12.48(1H，brs). |
| 67 | 405 | 10.68 | (DMSO)1.00(6H，d)，1.40(3H，t)，2.11-2.23 (1H，m)，2.63(2H，d)，4.34(2H，q)，7.34-7.41 (1H，m)，7.46-7.54(3H，m)，7.73-7.75(2H，m)， 7.99(1H，s)，8.56(1H，s)，8.76(1H，s)，11.95 (1H，s) |
| 68 | 363 | 9.80 | (DMSO)1.42(3H，t)，2.46(3H，s)，4.35(2H，q)， 7.34-7.40(1H，m)，7.51-7.56(3H，m)，7.76-7.71 (2H，m)，8.01(1H，s)，8.60(1H，s)，8.74(1H，s)， 12.00(1H，s) |
| 69 | 349 | 10.59 | (DMSO)1.2(6H，q)，3.5(4H，t)，6.9(1H，s)，7.4 (1H，m)，7.5(2H，m)，7.7(1H，m)，7.9(1H，s)，8.1 (2H，m)，8.5(1H，d)，11.8(NH，s) |
| 70 | 392 | 9.9 | (DMSO)1.2-1.3(6H，m)，3.5-3.6(4H，m)，6.9(1H， s)，7.5-7.6(3H，m)，7.7(1H，s)，7.9-8.1(3H，m)， 8.4-8.5(1H，d)，10.6(1H，s)，11.5-11.6(1H，s) |
| 71 | 364 | 10.1 | (DMSO)1.2-1.3(6H，m)，3.5(4H，m)，6.6-6.7(1H， d)，6.8(1H，s)，6.8-6.9(1H，m)，7.2-7.3(2H，m)， 7.4(1H，s)，7.8(2H，m)，8.2(1H，d)，9.0(1H，s)， 11.3-11.4(1H，s) |
| 72 | 311 | 8.82 | (CDCl3)1.51(3H，t)，2.48(3H，s)，3.18(1H，s)， 4.42(2H，q)，7.10(1H，s)，7.84(1H，s)，8.51(1H， s)，8.66(1H，s)，9.91(1H，br s) |
| 73 | 406 | 7.73 | (DMSO)1.14(6H，d，J＝6.8HZ)，2.74-2.86(1H， m)，7.42(1H，brs)，7.58(1H，s)，7.84-7.94(3H， m)，7.98-8.12(3H，m)，8.65(1H，brs)，8.75(1H， brs)，12.01(1H，brs)，12.15(1H，brs). |
| 74 | 330 | 8.32 | (DMSO)1.23(6H，t，J＝7.0Hz)，2.85(3H，d，J＝ 4.4Hz)，3.52(4H，q，J＝7.0Hz)，6.98(1H，s)，7.90 (1H，brs)，8.50-8.60(1H，m)，8.74(1H，brs)，8.86 (1H，brs)，12.01(1H，brs). |
| 75 | 297 | 9.86 | (DMSO)1.31(6H，t，J＝7.0Hz)，3.16(1H，s)， 3.59(4H，q，J＝7.0Hz)，6.60(1H，s)，7.80(1H， brs)，8.49(1H，brs)，8.55(1H，brs)，9.75(1H， brs). |
Embodiment 4
3-iodo-5-phenyl-1H-pyrrolo-[2,3-b] pyridine
With 5-phenyl-1H-pyrrolo-[2,3-b] pyridine (2.96g, the 15.24mmol that is stirring at ambient temperature, (7.74g, 30.50mmol 2eq) handle dry DMF 1eq) (60ml) solution with iodine, add then potassium hydroxide (3.20g, 57.14mmol, 3.75eq).Reaction mixture is at room temperature stirred 15h, use the mixture diluted of sodium thiosulfate solution and ethyl acetate then.Separate organic layer,, use dried over sodium sulfate, filter, concentrate in a vacuum then with the saturated sodium-chloride water solution washing.Then gained oil is dissolved in the DCM/MeOH mixture, is adsorbed onto on the silica gel.With the dry upper prop that loads of product, carry out silica gel chromatography and handle then, use ethyl acetate (1): the mixture of 40-60 sherwood oil (2) obtains 3-iodo-5-phenyl-1H-pyrrolo-[2,3-b] pyridines (1) (3.16g, 65%) as eluent, is white solid.
1H NMR，(400Mhz，DMSO)7.34-7.41(1H，m)，7.46-7.56(2H，m)，7.70-7.80(3H，m)，7.81-7.89(1H，m)，8.53-8.60(1H，m)，12.21(1H，brs).
Embodiment 5
3-iodo-5-phenyl-1-tosyl group-1H-pyrrolo-[2; 3-b] the mineral oil suspension (79mg of pyridine 60% sodium hydride that will stir at ambient temperature; 1.98mmol; 1.2eq) dry DMF (30ml) suspension with 3-iodo-5-phenyl-1H-pyrrolo-[2; 3-b] pyridine (1) (530mg; 1.66mmo l, DMF 1.0eq) (5m l) solution-treated.Then reaction mixture is at room temperature stirred 1h, be cooled to 0 ℃ then.(dry DMF 1.0eq) (5ml) solution is gone through 15h and is made reaction mixture be warming up to room temperature for 316mg, 1.66mmol to add p-toluenesulfonyl chloride then.With the mixture diluted of reaction mixture water and ethyl acetate,, use dried over sodium sulfate then, filter, concentrate in a vacuum then with the saturated sodium-chloride water solution washing.Gained is handled through silica gel chromatography after spontaneously, and use ethyl acetate (1): the mixture of 40-60 sherwood oil (2) obtains 3-iodo-5-phenyl-1-tosyl group-1H-pyrrolo-[2,3-b] pyridines (2) (743mg, 95%) as eluent, is white solid.1H NMR，(400Mhz，DMSO)2.37(3H，s)，7.39-7.56(5H，m)，7.75(2H，d)，7.91(1H，s)，8.05(2H，d)，8.20(1H，s)，8.71(1H，s).
Embodiment 6
5-phenyl-3-(1H-pyrroles-2-yl)-1-H-pyrrolo-[2,3-b] pyridine
With 3-iodo-5-phenyl-1-tosyl group-1H-pyrrolo-[2; 3-b] pyridine (2) (150mg; 0.32mmol; 1eq), four (triphenyl phosphine) palladium (0) (4mg; 0.0035mmol; 0.01eq) (mixture 1eq) places the microwave test tube for 67mg, 0.32mmol for boric acid with 1-(tertbutyloxycarbonyl)-1H-pyrroles-2-base-2-.Then mixture is handled with DME (4ml), EtOH (0.86ml), water (1.14ml) and 2N aqueous sodium carbonate (0.63ml).Test tube is placed in the microwave, heat 40min down at 160 ℃.Make test tube be cooled to room temperature, water/ethyl acetate dilution.Separate organic layer,, concentrate in a vacuum, obtain jelly through dried over sodium sulfate.This peptization in DMSO, is carried out reverse-phase chromatography and handles, use ACN/ water, obtain 5-phenyl-3-(1H-pyrroles-2-yl)-1-H-pyrrolo-[2,3-b] pyridines (3), be solid as the gradient elution agent.
1H NMR，(400Mhz，DMSO)6.10-6.16(1H，m)，6.45-6.50(1H，m)，6.78-6.84(1H，m)，7.32-7.54(3H，m)，8.37-8.42(1H，m)，8.52-8，58(1H，m)，11.05(1H，brs)，11.75(1H，brs).
By preparing multiple other formulas I compound with this paper embodiment 6 described similar methods basically.The authentication data of these compounds is summarised in the following table 4, comprise HPLC, LC/MS (observation) and
1H NMR data.
Table 4: the authentication data of selected formula I compound
| Compound number II- | M+1(obs) | Rt(min) | 1H-NMR |
| 2 | 319 | 9.70 | (DMSO)2.55(3H，s)，7.36-7.45(1H，m)， 7.47-7.59(2H，m)，7.61-7.69(1H，m)， 7.75-7.85(2H，m)，7.92-7.99(1H，m)， 8.19-8.25(1H，m)，8.41-8.4891H，m)， 8.59-8.6691H，m)，12.34(1H，brs). |
Embodiment 7:ITK restraining effect assay method
Utilize radiophosphorus hydrochlorate binding assay SCREENED COMPOUND to suppress the ability of Itk.Mensuration is under 25 ℃, in the presence of 30nM Itk, is comprising 100mM HEPES (pH 7.4), 10mM MgCl
2, 25mM NaCl, 0.01%BSA and 1mM DTT damping fluid in carry out.Final concentration of substrate be 15 μ M[γ-
33P] ATP (400 μ Ci
33P ATP/ μ mol ATP, AmershamPharmacia Biotech/Sigma Chemicals) and 2 μ M peptides (SAM68 albumen Δ 332-443).Formation determination deposit buffered soln wherein contains whole above-listed reagent, except ATP and the relevant test compound.50 μ l stock solutions are placed 96 hole flat boards, contain the 1.5 μ l DMSO stock solutions (starting from the ultimate density of 15 μ M usually, 2 times of serial dilutions) of test compound serial dilutions, duplicate (final DMSO concentration 1.5%) succeeded by adding.With flat board 25 ℃ of following preincubation 10 minutes, add 50 μ l[γ-
33P] ATP initiation reaction (ultimate density 15 μ M).
Add 50 μ l TCA/ATP mixture (20%TCA, 0.4mM ATP) termination reactions after 10 minutes.Unifilter GF/C 96 hole flat boards (Perkin Elmer Life Sciences, Cat no.6005174) with 50 μ l Milli Q water pretreatments, are added complete reaction mixture (150 μ l) then.With flat board with 200 μ l Milli Q water washings, succeeded by 200 μ l TCA/ATP mixtures (5%TCA, 1mM ATP).This cycles of washing repeats other 2 times.After the drying, add 30 μ l Optiphase ' SuperMix ' liquid scintillation cocktail reagents (PerkinElmer) to aperture, carry out then scintillation counting (1450 Microbeta Liquid ScintillationCounter, Wallac).
(San Diego California USA), calculates IC from the nonlinear regression analysis of initial rate data for GraphPad Prism version 3.0a for Macintosh, GraphPad Software to utilize the Prism software package
50Data.
Mensuration is at 20mM MOPS (pH 7.0), 10mM MgCl
2, 0.1%BSA and 1mM DTT mixture in carry out.Final concentration of substrate be 7.5 μ M[γ-
33P] ATP (400mCi
33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 3 μ M peptides (SAM68 protein D 332-443).Mensuration is under 25 ℃, carry out in the presence of 50nM Itk.Formation determination deposit buffered soln wherein contains whole above-listed reagent, except ATP and the relevant test compound.50 μ l stock solutions are placed 96 hole flat boards, contain the 2 μ l DMSO stock solutions (starting from the ultimate density of 50 μ M usually, 2 times of serial dilutions) of test compound serial dilutions, duplicate (final DMSO concentration 2%) succeeded by adding.With flat board 25 ℃ of following preincubation 10 minutes, add 50 μ l[γ-
33P] ATP initiation reaction (ultimate density 7.5 μ M).
Add 100mL 0.2M phosphoric acid+0.01% polysorbas20 termination reaction after 10 minutes.Dull and stereotyped (Millipore, Cat no.MAPHN0B50) filtered with 100 μ L 0.2M phosphoric acid+0.01% polysorbas20 pre-treatment in multiscreen phosphorylated cotton 96 holes, add 170mL then and stop measuring mixture.Flat board is washed with 4 * 200 μ L 0.2M phosphoric acid+0.01% polysorbas20.After the drying, add 30 μ L Optiphase ' SuperMix ' liquid scintillation cocktail reagents (Perkin Elmer) to aperture, carry out then scintillation counting (1450 MicrobetaLiquid Scintillation Counter, Wallac).
Utilize the Prism software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA), from nonlinear regression analysis calculating K i (app) data of initial rate data.
Embodiment 8:ITK restraining effect assay method (AlphaScreen
TM)
Utilize AlphaScreen at Vertex Pharmaceuticals
TMTyrosine O-phosphate assay method SCREENED COMPOUND suppresses the ability of Itk.Mensuration is at 20mM MOPS (pH 7.0), 10mMMgCl
2, 0.1%BSA and 1mM DTT mixture in carry out.Final concentration of substrate in the mensuration is 100 μ M ATP (Sigma Chemicals) and 2 μ M peptides (biotinyl SAM68 Δ 332-443).Mensuration is under 25 ℃, carry out in the presence of Itk (30nM).Formation determination deposit buffered soln wherein contains whole above-listed reagent, except ATP and the relevant test compound.25 μ l stock solutions are placed every hole of 96 hole flat boards, contain 1 μ l DMSO (starting from the ultimate density of 15 μ M usually) of test compound serial dilutions, duplicate (final DMSO concentration 2%) succeeded by adding.Flat board 25 ℃ of following preincubation 10 minutes, is added 25 μ l ATP initiation reactions (ultimate density 100 μ M).Before causing with ATP, add 5 μ l 500mM EDTA to containing the contrast aperture of measuring deposit damping fluid and DMSO, measure background count.
225 times of reaction mixtures of dilution are to the MOPS damping fluid that contains 50mM EDTA (20mM MOPS (pH 7.0), 1mM DTT, 10mM MgCl after 30 minutes
2, 0.1%BSA), the ultimate density that makes vitamin H-SAM68 is 9nM.
Instruct preparation AlphaScreen according to manufacturer
TMReagent (AlphaScreen
TMTyrosine O-phosphate (P-Tyr-100) is measured test kit, PerkinElmer catalogue number6760620C).Under fill light shines, with 20 μ l AlphaScreen
TMReagent places white partly to distinguish the every hole of 96 hole flat boards (Corning Inc.-COSTAR 3693), contains the kinase reaction thing of 30 μ l terminated dilution.With flat board incubation 60 minutes in the dark, on Fusion Alpha plate reader (Perkin Elmer), read then.
After removing the average background value of all data point, utilize Prism software package (GraphPadPrism version 3.0cx for Macintosh, GraphPad Software, San DiegoCalifornia is USA) from nonlinear regression analysis calculating K i (app) data.
Generally speaking, The compounds of this invention, comprise that table 1 and table 2 compound are effective with regard to the inhibition of ITK.
Embodiment 9:ITK restraining effect assay method (UV)
Utilize standard conjugate enzyme assay method SCREENED COMPOUND to suppress ability people .Protein Sci. (1998) 7,2249 such as () Fox of Itk.Mensuration is at 20mM MOPS (pH 7.0), 10mM MgCl
2, 0.1%BSA, 1mM DTT, 2.5mM phosphoenolpyruvic acid, 300 μ M NADH, 30 μ g/m l pyruvate kinases and 10 μ g/ml serum lactic dehydrogenases mixture in carry out.Final concentration of substrate in the mensuration is 100 μ M ATP (Sigma Chemicals) and 3 μ M peptides (biotinyl SAM68 Δ 332-443).Mensuration is under 25 ℃, carry out in the presence of 100nM Itk.
Formation determination deposit buffered soln wherein contains whole above-listed reagent, except ATP and the relevant test compound.60 μ l stock solutions are placed every hole of 96 hole flat boards, contain 2 μ l DMSO (starting from the ultimate density of 15 μ M usually) of test compound serial dilutions succeeded by adding.Flat board 25 ℃ of following preincubation 10 minutes, is added 5 μ l ATP initiation reactions.Utilize Molecular Devices SpectraMax Plus plate reader to measure 10 minutes initial reaction rate.(San Diego California USA), calculates IC from nonlinear regression analysis for GraphPad Prismversion 3.0cxfor Macintosh, GraphPad Software to utilize the Prism software package
50With the Ki data.
Generally speaking, The compounds of this invention, comprise that table 1 and table 2 compound are effective with regard to the inhibition of ITK.
Embodiment 10:BTK restraining effect assay method
Utilize radiophosphorus hydrochlorate binding assay SCREENED COMPOUND to suppress the ability of Btk at Vertex Pharmaceuticals.Mensuration is at 100mM HEPES (pH 7.5), 10mM MgCl
2, 25mM NaCl, 0.01%BSA and 1mM DTT mixture in carry out.Final concentration of substrate in the mensuration is 100 μ M ATP (Sigma Chemicals) and 5 μ M peptides (SAM68 Δ 332-443).Mensuration is under 25 ℃, at Btk (25nM) and [γ
33P] ATP (100 μ Ci
33P ATP/ μ mol ATP, Amersham Pharmacia Biotech, Amersham carries out under existence UK).Formation determination deposit buffered soln wherein contains whole above-listed reagent, except SAM68 and the relevant test compound.75 μ l stock solutions are placed 96 hole flat boards, contain 1.5 μ l DMSO stock solutions (starting from the ultimate density of 15 μ M usually) of test compound serial dilutions, duplicate (final DMSO concentration 1.5%) succeeded by adding.Flat board 25 ℃ of following preincubation 15 minutes, is added 25 μ l SAM68 initiation reactions (ultimate density 5 μ M).Before causing with SAM68, add 50 μ L 20%TCA+0.4mM ATP to containing the contrast aperture of measuring deposit damping fluid and DMSO, measure background count.
Add 50 μ l 20%TCA+0.4mM ATP, termination reaction after 60 minutes.Adding complete reaction mixture (150 μ L) before, with Unifilter GF/C 96 hole flat boards (PerkinElmer Life Sciences, Cat no.6005174) with 50 μ L Milli Q water pretreatments.With flat board with 200 μ L Milli Q water, wash succeeded by 200 μ L 5%TCA+1mM ATP.Water/TCA cycles of washing repeats other 2 times.After the drying, add 30 μ L Optiphase ' SuperMix ' liquid scintillation cocktail reagents (Perkin Elmer) to aperture, then scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wakllac).
After removing the average background value of all data point, utilize Prism software package (GraphPadPrism version 3.0a for Macintosh, GraphPad Software, San DiegoCalifornia is USA) from nonlinear regression analysis calculating K i (app) data.
Utilize AlphaScreen at Vertex Pharmaceuticals
TMSCREENED COMPOUND suppresses the ability of Btk.Mensuration is at 20mM MOPS (pH 7.0), 10mM MgCl
2, 0.1%BSA and 1mM DTT mixture in carry out.Final concentration of substrate in the mensuration is 50 μ M ATP (Sigma Chemicals) and 2 μ M peptides (biotinyl SAM68 Δ 332-443).Mensuration is under 25 ℃, carry out in the presence of BtK (25nM).Formation determination deposit buffered soln wherein contains whole above-listed reagent, except vitamin H-SAM68 and the relevant test compound.37.5 μ l stock solutions are placed every hole of 96 hole flat boards, contain 1 μ l DMSO (starting from the ultimate density of 15 μ M usually) of test compound serial dilutions, duplicate (final DMSO concentration 2%) succeeded by adding.Flat board 25 ℃ of following preincubation 15 minutes, is added 12.5 μ l vitamin H-SAM68 initiation reactions (ultimate density 2 μ M).Before causing with vitamin H-SAM68, add 5 μ l 500mM EDTA to containing the contrast aperture of measuring deposit damping fluid and DMSO, measure background count.
225 times of reaction mixtures of dilution are to the MOPS damping fluid that contains 50mM EDTA (20mM MOPS (pH 7.0), 1mM DTT, 10mM MgCl after 30 minutes
2, 0.1%BSA), the ultimate density that makes vitamin H-SAM68 is 9nM.
Instruct preparation AlphaScreen according to manufacturer
TMReagent (AlphaScreen
TMTyrosine O-phosphate (P-Tyr-100) is measured test kit, PerkinElmer catalogue number6760620C).Under fill light shines, with 20 μ l AlphaScreen
TMReagent places white partly to distinguish the every hole of 96 hole flat boards (Corning Inc.-COSTAR 3693), contains the kinase reaction thing of 30 μ l terminated dilution.With flat board incubation 60 minutes in the dark, on Fusion Alpha plate reader (PerkinElmer), read then.
After removing the average background value of all data point, utilize Prism software package (GraphPadPrism version 3.0cx for Macintosh, GraphPad Software, San DiegoCalifornia is USA) from nonlinear regression analysis calculating K i (app) data.
Generally speaking, The compounds of this invention, comprise that table 1 and table 2 compound are effective with regard to the inhibition of Btk.
Embodiment 11:RLK restraining effect assay method
Utilize standard conjugate enzyme assay method SCREENED COMPOUND to suppress ability people .Protein Sci. (1998) 7,2249 such as () Fox of Rlk.Mensuration is at 20mM MOPS (pH 7.0), 10mM MgCl
2, 0.1%BSA and 1mM DTT mixture in carry out.Final concentration of substrate in the mensuration is 100 μ M ATP (Sigma Chemicals) and 10 μ M peptide (Poly Glu: Tyr4: 1).Mensuration is under 30 ℃, carry out in the presence of 40nM Rlk.The ultimate density of conjugate enzyme system components is 2.5mM phosphoenolpyruvic acid, 300 μ M NADH, 30 μ g/ml pyruvate kinases and 10 μ g/ml serum lactic dehydrogenases.
Formation determination deposit buffered soln wherein contains whole above-listed reagent, except ATP and the relevant test compound.60 μ l stock solutions are placed every hole of 96 hole flat boards, contain 2 μ l DMSO (starting from the ultimate density of 7.5 μ M usually) of test compound serial dilutions succeeded by adding.Flat board 30 ℃ of following preincubation 10 minutes, is added 5 μ l ATP initiation reactions.Utilize Molecular Devices SpectraMax Plus plate reader to measure 10 minutes initial reaction rate.(San Diego California USA), calculates IC from nonlinear regression analysis for GraphPad Prism version 3.0cxfor Macintosh, GraphPad Software to utilize the Prism software package
50With the Ki data.
Generally speaking, The compounds of this invention, comprise that table 1 and table 2 compound are effective with regard to the inhibition of RLK.
Embodiment 12:JAK3 restraining effect assay method
Utilize and show that down assay method suppresses the ability SCREENED COMPOUND of JAK at it.Reaction is carried out in kinase buffer liquid, wherein contains 100mM HEPES (pH 7.4), 1mM DTT, 10mMMgCl
2, 25mM NaCl and 0.01%BSA.
Concentration of substrate in the mensuration is 5 μ M ATP (200 μ Ci/ μ mol ATP) and 1 μ Mpoly (Glu)
4Tyr.Reaction is carried out under 25 ℃ and 1nM JAK3.
Add 1.5 μ l candidate JAK3 inhibitor and 50 μ l kinase buffer liquid to every hole of 96 hole polycarbonate flat boards, wherein contain 2 μ M poly (Glu)
4Tyr and 10 μ M ATP.Mix it then, add the 50 μ l kinase buffer liquid that contain 2nM JAK3 enzyme and begin reaction.After following 20 minutes, use 50 μ l, 20% trichoroacetic acid(TCA)s (TCA) termination reaction that also contains 0.4mM ATP in room temperature (25 ℃).Utilizing the TomTek cell harvester that every hole entire contents is transferred to 96 hole glass fibre then filters dull and stereotyped.After the washing, add 60 μ l flicker fluid, on Perkin Elmer TopCount, detect
33The combination of P.
Generally speaking, The compounds of this invention, comprise that table 1 and table 2 compound are effective with regard to the inhibition of JAK (for example JAK-3).
Claims (60)
1. formula I compound:
Or its pharmacy acceptable salt, wherein:
Ring A is optional substituted five-ring, is selected from:
X is 0,1 or 2;
Each R that occurs
1Be halogen, CN, NO independently
2Or U
mR;
R
2Be independently selected from T
n-R ';
X
1, X
2And X
3Be CR independently of one another
1, N, S or O;
R
3, R
4And R
5Be halogen, CN, NO independently of one another
2Or V
p-R ';
Each T, U or V that occurs is optional substituted C independently
1-6Alkylidene chain, wherein two MU (methylene unit) at the most of this chain alternatively and independently by-NR-,-S-,-O-,-CS-,-CO
2-,-OCO-,-CO-,-COCO-,-CONR-,-NRCO-,-NRCO
2-,-SO
2NR-,-NRSO
2-,-CONRNR-,-NRCONR-,-OCONR-,-NRNR-,-NRSO
2NR-,-SO-,-SO
2-,-PO-,-PO
2-or-POR-replaces;
M, n and p are 0 or 1 independently of one another;
Each R that occurs is hydrogen or optional substituted C independently
1-6Aliphatic group; Each R ' that occurs is hydrogen or optional substituted C independently
1-6Aliphatic group, the heteroatomic 3-8 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle to have 0-3, perhaps has 0-5 the heteroatomic 8-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated bicyclic ring system; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance constitutes optional the substituted 0-4 of having with the atom of their institute's bondings the heteroatomic 3-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle or two rings;
Its condition is the R that at least once occurs
3, R
4, R
5Be V
p-R ', wherein R ' is not a hydrogen;
If n is 0, R ' is not H so;
If ring A is
R
4Be 2-Phenoxyphenyl, R so
2Not COOH or CONHR
x, R wherein
xBe n-propyl, phenyl, cyclohexyl, benzyl ,-CH
2CH
2OH ,-CH
2-cyclopropyl ,-CH
2CH
2OCH
3, 3-pyridyl, 4-hydroxyl-cyclohexyl or-CH
2-C ≡ CH.
2. the compound of claim 1, wherein R
3, R
4And R
5One of be V
p-R ', wherein R ' is the optional substituted 0-3 of having the complete undersaturated monocycle of heteroatomic 5-or 6-unit that independently is selected from nitrogen, oxygen or sulphur, and the perhaps optional substituted 0-5 of having the complete undersaturated bicyclic ring of heteroatomic 9-or 10-unit that independently is selected from nitrogen, oxygen or sulphur is.
3. the compound of claim 1, wherein R
3, R
4And R
5One of be V
p-R ', wherein R ' is optional substituted C
1-6Aliphatic group, the optional substituted 0-3 of having are selected from independently that the heteroatomic 3-8 unit of nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle, and the perhaps optional substituted 0-5 of having the heteroatomic 8-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated bicyclic ring system.
4. any one compound of claim 1-3, wherein R
4Be V
p-R ', wherein R ' is optional substituted C
1-6Aliphatic group, the optional substituted 0-3 of having are selected from independently that the heteroatomic 3-8 unit of nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle, and the perhaps optional substituted 0-5 of having the heteroatomic 8-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated bicyclic ring system.
5. the compound of claim 4, wherein R
4Be V
p-R ', wherein R ' is optional substituted C
1-6The heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle for aliphatic group or optional the substituted 0-3 of having.
6. the compound of claim 5, wherein R
4Be V
p-R ', and R ' is C ≡ CH.
7. the compound of claim 5, wherein R
4Be V
p-R ', and R ' is optional the substituted 0-3 of having the heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle.
8. the compound of claim 7, wherein R
4Be V
p-R ', wherein R ' is the optional substituted 0-3 of having the complete undersaturated monocycle of heteroatomic 5-6-unit that independently is selected from nitrogen, oxygen or sulphur.
9. the compound of claim 8, wherein R
4Be V
p-R ', and R ' is the complete undersaturated monocycle of 6-unit of the optional substituted 0-3 of having nitrogen heteroatom.
10. the compound of claim 9, wherein this complete undersaturated monocycle of 6-unit has 0-1 nitrogen heteroatom.
11. the compound of claim 7, wherein R
4Be V
p-R ', and R ' is the optional substituted 0-3 of having the saturated monocycle of heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur.
12. the compound of claim 11, wherein R
4Be V
p-R ', and R ' is the optional substituted 0-2 of having the saturated monocycle of heteroatomic 6-unit that independently is selected from nitrogen, oxygen or sulphur.
13. the compound that claim 1-12 is any, wherein p is 0.
14. the compound that claim 1-12 is any, wherein p is 1.
15. the compound of claim 14, wherein V be-NR-,-S-or-O-.
16. the compound that claim 1-15 is any, wherein R
3Be V
p-R ', wherein p be 0 and R ' be hydrogen.
17. the compound that claim 1-16 is any, wherein R
5Be halogen or V
p-R ', wherein p be 0 and R ' be hydrogen or C
1-6Aliphatic group.
18. the compound of claim 17, wherein R
5Be halogen or V
p-R ', wherein p be 0 and R ' be hydrogen or C
1-3Alkyl.
19. the compound that claim 1-18 is any wherein encircles A and is:
20. the compound of claim 19, wherein X
2Be CR
1
21. the compound of claim 19 wherein encircles A and is:
22. the compound of claim 21 wherein encircles A and is:
23. the compound that claim 1-22 is any, wherein R
1Be U
mR.
24. the compound that claim 1-23 is any, wherein R
2Be T
nR ', wherein n is 1.
25. the compound of claim 24, wherein T be-NR-,-O-,-CO-,-CONR-or-NRCO-.
26. the compound that claim 1-23 is any, wherein R
2Be T
nR ', wherein n is 0.
27. the compound of claim 1 is selected from following formula
Or its pharmacy acceptable salt.
28. the compound of claim 27 is selected from following formula
Or its pharmacy acceptable salt.
29. the compound that claim 27-28 is any, wherein R
1Be U
mR, wherein m be 0 and R be H or CH
3
30. the compound that claim 27-29 is any, wherein R
2Be T
nR ', wherein n is 1.
31. the compound of claim 30, wherein T be-NR-,-O-,-CO-,-CONR-or-NRCO-.
32. the compound of claim 31, wherein T is-NR-.
33. the compound of claim 32, wherein R and R ' are C
1-6Aliphatic group.
34. the compound that claim 27-29 is any, wherein R
2Be T
nR ', wherein n is 0.
35. the compound of claim 34, wherein R ' is that optional substituted N-connects heterocyclic radical, is selected from morpholinyl, piperidyl, pyrrolidyl and piperazinyl.
36. the compound that claim 27-35 is any, wherein R
4And R
5Be V independently of one another
p-R '.
37. the compound of claim 36, wherein R
4Be V
p-R ' and R ' are C ≡ CH.
38. the compound that claim 27-35 is any, wherein R
3, R
4And R
5One of be V
p-R ', wherein R ' is optional the substituted 0-3 of having and independently is selected from the heteroatomic 5-of nitrogen, oxygen or sulphur or the monocycle of 6-unit unsaturated fully (being aromatics), complete undersaturated bicyclic ring system of the perhaps optional substituted 0-5 of having heteroatomic 9-who independently is selected from nitrogen, oxygen or sulphur or 10-unit.
39. the compound that claim 27-35 is any, wherein R
3, R
4And R
5One of be V
p-R ', wherein R ' is optional substituted C independently
1-6Aliphatic group, the optional substituted 0-3 of having are selected from independently that the heteroatomic 3-8-unit of nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle, and the perhaps optional substituted 0-5 of having the heteroatomic 8-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated bicyclic ring system.
40. the compound of claim 39, wherein R
4Be V
p-R ', wherein R ' is optional substituted C independently
1-6Aliphatic group, the optional substituted 0-3 of having are selected from independently that the heteroatomic 3-8-unit of nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle, and the perhaps optional substituted 0-5 of having the heteroatomic 8-12 unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated bicyclic ring system; R
3And R
5Be V
p-R ', wherein p be 0 and R ' be hydrogen.
41. the compound of claim 40, wherein R
4Be V
p-R ', wherein R ' is optional substituted C independently
1-6The heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle for aliphatic group or optional the substituted 0-3 of having.
42. the compound of claim 41, wherein R
4Be V
p-R ', wherein R ' is optional the substituted 0-3 of having the heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur is saturated, part is unsaturated or complete undersaturated monocycle.
43. the compound of claim 42, wherein R
4Be V
p-R ', wherein R ' is the optional substituted 0-3 of having the complete undersaturated monocycle of heteroatomic 5-6-unit that independently is selected from nitrogen, oxygen or sulphur independently.
44. the compound of claim 43, wherein R
4Be V
p-R ', wherein R ' is the complete undersaturated monocycle of 6-unit of the optional substituted 0-3 of having nitrogen heteroatom.
45. the compound of claim 44, wherein this complete undersaturated monocycle of 6-unit has 0-1 nitrogen heteroatom.
46. the compound of claim 42, wherein R
4Be V
p-R ', wherein R ' is the optional substituted 0-3 of having the saturated monocycle of heteroatomic 3-8-unit that independently is selected from nitrogen, oxygen or sulphur.
47. the compound of claim 46, wherein R
4Be V
p-R ', wherein R ' is the optional substituted 0-2 of having the saturated monocycle of heteroatomic 6-unit that independently is selected from nitrogen, oxygen or sulphur.
48. the compound that claim 27-47 is any, wherein p is 1.
49. the compound of claim 48, wherein V be-NR-,-S-or-O-.
50. the compound that claim 27-47 is any, wherein p is 0.
51. claim 27, any one compound of 29-50, wherein R
3Be V
p-R ', wherein p is 0, R ' is a hydrogen.
52. the compound that claim 27-51 is any, wherein R
5Be halogen or V
p-R ', wherein p is 0, R ' is hydrogen or C
1-6Aliphatic group.
53. the compound of claim 52, wherein R
5Be halogen or V
p-R ', wherein p be 0 and R ' be hydrogen or C
1-3Alkyl.
54. the compound of claim 1 is selected from:
55. composition comprises any one compound of claim 1-54 or its pharmacy acceptable salt and pharmaceutically acceptable carrier or thinner.
56. the composition of claim 55, further comprise other therapeutical agent, be selected from the disease for the treatment of autoimmunization, inflammatory, propagation or hyperproliferation disease or immunology-mediation, the medicine that comprises transplant organ or tissue rejection and acquired immune deficiency syndrome (AIDS) (AIDS).
57. (a) patient or (b) suppress the method for Tec family (for example Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity in the biological sample, this method comprises described patient is given or make the described biological sample contact compound any according to claim 1-54.
58. treatment disease or illness or alleviate the method for its seriousness, described disease or illness are selected from the disease of autoimmunization, inflammatory, propagation or hyperproliferation disease or immunology-mediation, and this method comprises that the patient to needs comprises the compound compositions any according to claim 1-54.
59. the method for claim 58, comprise the additional step that described patient is given other therapeutical agent, described other therapeutical agent is selected from the disease for the treatment of autoimmunization, inflammatory, propagation or hyperproliferation disease or immunology-mediation, the medicine that comprises transplant organ or tissue rejection and acquired immune deficiency syndrome (AIDS) (AIDS), wherein:
Described other therapeutical agent is suitable with regard to the disease of being treated;
Described other therapeutical agent with described composition with single formulation administration or as a part and the described composition separate administration of multi-form.
60. the method for claim 58 or claim 59, wherein this disease or illness are asthma, acute rhinitis, allergy, atrophic rhinitis, chronic rhinitis, membranous rhinitis, the seasonal rhinitis, sarcoidosis, farmer lung, the fiber-like lung, spontaneous interstitial pneumonia, rheumatoid arthritis, the seronegativity spondyloarthropathy (comprises ankylosing spondylitis, arthritic psoriasis and Reiter's disease), Behcet, siogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopic dermatitis, contact dermatitis and other eczematoid dermatitiss, seborrheic dermatitis, lichen planus, pemphigus, BP, epidermolysis bullosa, urticaria, angiodermatitis, nodular vasculitis, erythroderma, the skin eosinophilia, uveitis, alopecia, bunch property vernal conjunctivitis, celiaca, rectitis, eosinocyte gastro-enteritis, mast cell disease, pancreatitis, Crohn disease, ulcerative colitis, food dependency transformation reactions, multiple sclerosis, atherosclerosis, acquired immune deficiency syndrome (AIDS) (AIDS), lupus erythematosus, systemic lupus, erythema, struma lymphomatosa, myasthenia gravis, type i diabetes, nephrotic syndrome, the eosinophilia fascitis, the too high syndrome of IgE, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenic purpure, postangioplasty restenosis, tumour, atherosclerosis, systemic lupus erythematous, homograft rejection, comprise acute and chronic homograft rejection without limitation, for example at kidney, the heart, liver, lung, marrow, after the transplantation of skin and cornea; With the chronic graft versus host disease.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US58438304P | 2004-06-30 | 2004-06-30 | |
| US60/584,383 | 2004-06-30 | ||
| US60/584,721 | 2004-07-01 | ||
| US11/098,751 | 2005-04-04 | ||
| USPCT/US2005/11358 | 2005-04-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101228160A true CN101228160A (en) | 2008-07-23 |
Family
ID=39859564
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800259621A Pending CN101228160A (en) | 2004-06-30 | 2005-06-29 | Azaindoles useful as inhibitors of protein kinases |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101228160A (en) |
| ZA (1) | ZA200700751B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104603105A (en) * | 2012-08-09 | 2015-05-06 | 菲尼克斯药品股份公司 | Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ROR Gamma |
| CN104603118A (en) * | 2012-05-31 | 2015-05-06 | 菲尼克斯药品股份公司 | Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma] |
| WO2016026078A1 (en) * | 2014-08-19 | 2016-02-25 | Changzhou Jiekai Pharmatech Co., Ltd. | Heterocyclic compounds as erk inhibitors |
| CN112313232A (en) * | 2018-05-02 | 2021-02-02 | Jw中外制药公司 | Novel heterocyclic derivatives |
| CN113423707A (en) * | 2018-11-16 | 2021-09-21 | 加利福尼亚技术学院 | ERK inhibitors and uses thereof |
| CN113735859A (en) * | 2021-08-12 | 2021-12-03 | 安徽医科大学 | Kinase inhibitor |
-
2005
- 2005-06-29 ZA ZA200700751A patent/ZA200700751B/en unknown
- 2005-06-29 CN CNA2005800259621A patent/CN101228160A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104603118A (en) * | 2012-05-31 | 2015-05-06 | 菲尼克斯药品股份公司 | Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma] |
| CN107007597A (en) * | 2012-05-31 | 2017-08-04 | 菲尼克斯药品股份公司 | It is used as the thiazole of orphan nuclear receptor ROR γ instrumentalities through formamide or sulfonamide substitutions and the pharmaceutical applications of related derivatives |
| CN104603118B (en) * | 2012-05-31 | 2017-10-03 | 菲尼克斯药品股份公司 | It is used as the thiazole and related derivatives through formamide or sulfonamide substitutions of orphan nuclear receptor ROR γ instrumentalities |
| CN104603105A (en) * | 2012-08-09 | 2015-05-06 | 菲尼克斯药品股份公司 | Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ROR Gamma |
| CN104603105B (en) * | 2012-08-09 | 2017-09-08 | 菲尼克斯药品股份公司 | It is used as the formamide or nitrogenous 5 circle heterocycles of sulfonamide substitutions of orphan nuclear receptor ROR gamma modulators |
| WO2016026078A1 (en) * | 2014-08-19 | 2016-02-25 | Changzhou Jiekai Pharmatech Co., Ltd. | Heterocyclic compounds as erk inhibitors |
| CN112313232A (en) * | 2018-05-02 | 2021-02-02 | Jw中外制药公司 | Novel heterocyclic derivatives |
| CN112313232B (en) * | 2018-05-02 | 2024-03-08 | Jw中外制药公司 | Novel heterocyclic derivatives |
| CN113423707A (en) * | 2018-11-16 | 2021-09-21 | 加利福尼亚技术学院 | ERK inhibitors and uses thereof |
| CN113735859A (en) * | 2021-08-12 | 2021-12-03 | 安徽医科大学 | Kinase inhibitor |
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|---|---|
| ZA200700751B (en) | 2008-08-27 |
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