CN103304552B - Substituted pyridine compounds and using method thereof and purposes - Google Patents
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- 0 CCC(CC)CC(CC1CC(CC)*=CCC)CC1C=C Chemical compound CCC(CC)CC(CC1CC(CC)*=CCC)CC1C=C 0.000 description 12
- YTGOUBMLMMAZBE-UHFFFAOYSA-O CC(C=C(C([NH3+])=NC)OC(C)c(c(Cl)c(cc1)F)c1Cl)c1c[n](C2CC(CC(C3)NC)C3C2)nc1 Chemical compound CC(C=C(C([NH3+])=NC)OC(C)c(c(Cl)c(cc1)F)c1Cl)c1c[n](C2CC(CC(C3)NC)C3C2)nc1 YTGOUBMLMMAZBE-UHFFFAOYSA-O 0.000 description 1
- XDEYUPVOZHXNNZ-UWTIGNOOSA-N CCC(CC(CN)F)[n]1ncc(-c2cc(O[C@H](C)c(c(Cl)ccc3F)c3Cl)c(N)nc2)c1 Chemical compound CCC(CC(CN)F)[n]1ncc(-c2cc(O[C@H](C)c(c(Cl)ccc3F)c3Cl)c(N)nc2)c1 XDEYUPVOZHXNNZ-UWTIGNOOSA-N 0.000 description 1
- OLNNYFLGFISZTP-NNSTWZCHSA-N C[C@H](C/C(/Cl)=C(\C=C/C)/F)Oc1c(N)ncc(-c2c[n]([C@H]3C[C@@H](C[N](C)(C)C4)C4CC3)nc2)c1 Chemical compound C[C@H](C/C(/Cl)=C(\C=C/C)/F)Oc1c(N)ncc(-c2c[n]([C@H]3C[C@@H](C[N](C)(C)C4)C4CC3)nc2)c1 OLNNYFLGFISZTP-NNSTWZCHSA-N 0.000 description 1
- JZKLBPYPTANCQR-VVAGSORKSA-N C[C@H](c(c(Cl)c(cc1)F)c1Cl)Oc1c(N)ncc(-c2c[n](C(CCNC3)[C@H]3O)nc2)c1 Chemical compound C[C@H](c(c(Cl)c(cc1)F)c1Cl)Oc1c(N)ncc(-c2c[n](C(CCNC3)[C@H]3O)nc2)c1 JZKLBPYPTANCQR-VVAGSORKSA-N 0.000 description 1
- XHVAHLFVLRFLQL-CPONVNJPSA-N C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1cc(-c2c[n](C(CNC3)C3O)nc2)cnc1N Chemical compound C[C@H](c(c(Cl)ccc1F)c1Cl)Oc1cc(-c2c[n](C(CNC3)C3O)nc2)cnc1N XHVAHLFVLRFLQL-CPONVNJPSA-N 0.000 description 1
Abstract
The invention provides the substituted pyridine compounds with formula (I) structure, its pharmaceutically acceptable salt, and pharmaceutical preparation, for regulating the activity of protein kinase, and regulate iuntercellular or the response of intracellular signal.The present invention also relates to comprise the pharmaceutical composition of the compounds of this invention, and uses this medicine composite for curing mammal, the particularly method of mankind's hyperproliferative disease.
Description
This application claims and submitted Patent Office of the People's Republic of China, Application No. 201210061335.5, invention on 03 09th, 2012 to
The Chinese patent application of entitled " substituted pyridine compounds and using method thereof and purposes " and carrying on 03 21st, 2012
Hand over Patent Office of the People's Republic of China, Application No. 201210076143.1, invention entitled " substituted spiral shell dicyclo and fused bicyclic compound and
Its using method and purposes " the priority of Chinese patent application, entire contents is hereby incorporated by the application.
Technical field
The invention belongs to technical field of pharmaceuticals, particularly relate to a kind of substituted pyridine compounds and using method thereof and use
On the way.
Background technology
Protein kinase, as the important regulator of cell function, is the member that in gene family, quantity is maximum, function is the widest
One of.They by increasing phosphate group, the regulation activity of multiple protein, position and allomeric function to substrate protein, and participates in
Layout many cellular processes.Kinases is in the cooperation of signal conduction and sophisticated functions, such as: cell cycle, occupies very prominent
Position.In 518 kinds of human kinase proteins, have 478 kinds due to catalytic domain Sequences similar, be included into a superfamily, according to growth
The similarity of sequence and biochemical activity, they are segmented into again different group, family or subfamilies.
Wherein said kinases partial list include abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk,
csk、c-kit、c-Met、c-src、c-fins、CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8、CDK9、
CDK10、cRaf1、CSF1R、CSK、DDR1、DDR2、EPHA、EPHB、EGFR、ErbB2、ErbB3、ErbB4、Erk、Fak、fes、
FER、FGFR1、FGFR2、FGFR3、FGFR4、FGFR5、Fgr、flt-1、Fps、Frk、Fyn、GSG2、GSK、Hck、ILK、
INSRR、IRAK4、ITK、IGF-1R、INS-R、Jak、KSR1、KDR、LMTK2、LMTK3、LTK、Lck、Lyn、MATK、MERTK、
MLTK、MST1R、MUSK、NPR1、NTRK、MEK、PLK4、PTK、p38、PDGFR、PIK、PKC、PYK2、RET、ROR1、ROR2、
RYK、ros、Ron、SGK493、SRC、SRMS、STYK1、SYK、TEC、TEK、TEX14、TNK1、TNK2、TNNI3K、TXK、
TYK2, TYRO3, tie, tie2, TRK, Yes and Zap70.
Receptor tyrosine kinase (PTKs) is the transmembrane protein that a type is abundant, can as cytokine, growth because of
Son, hormone and the receptor of other signaling molecules.Receptor tyrosine kinase is expressed in polytype cell, enters at various cells
Journey is played an important role, including cell growth, differentiation and angiogenesis.Kinase whose activation starts from extracellular regions and ties with part
Close, then cause conformation change, cause Receptor dimerization, mutual phosphorylation between the receptor of dimerization, subsequently autophosphorylation catalysis
Tyrosine residue outside region.This autophosphorylation can the conformation of stable activation receptor, again can be at Cellular Signaling Transduction Mediated
Albumen is set up phosphorylation heap plot point.
Being suddenlyd change by receptor activation, the approach such as gene amplifies, growth factor activation, receptor tyrosine kinase is many mankind
Solid tumor and malignant hematologic disease show as high activity.The acceleration of PTKs activates has facilitation to various tumorigenesis factors, as
Hypertrophy, surviving, invade, shift and angiogenesis, therefore, the activity of suppression receptor tyrosine kinase is considered as treatment of cancer
Effective scheme (Sharma PS, et al. (2009) " Receptor tyrosine kinase inhibitors as potent
weapons in war against cancers.”Curr Pharm Des.15(7):758-76.)。
Receptor tyrosine kinase anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK), belongs to Insulin receptor INSR superfamily, swells with multiple human body
The generation of tumor is relevant.It is true that the most tentatively confirmation ALK is presented in constitutively activate and oncogene merge, to exist
(NPM)-ALK-in primary cutaneous type (the lymphadenomatous a kind of separate type of Fei Huojinsen) is most commonly seen
(Morris,S.W.;et al“Fusion of a kinase gene,ALK,to a nucleolar protein gene,
NPM,in non-Hodgkin's lymphoma.”Science1994,263:1281–4.)。
Additionally, people are also found that ALK fusion gene in Inflammatory myofibroblastic tumor (IMTs), and at esophageal squamous cell
In the subspecies of shape cell carcinoma, it has been found that ALK fusion gene TPM4-ALK.Research display, familial form and diversity are neural
In blastoma, all there is the sudden change of multiple ALK gene.This sudden change being present in neuroblastoma cell can cause group
Molding ALK phosphorylation and hypofunction.Contrary, use sRNA and little molecule ALK inhibitor can suppress the quick of cell strain
Increase (Palmer, R.H.;et al“Anaplastic lymphoma kinase:signalling in development
and disease.”Biochem J.2009,420:345–61.)。
Recent years, people confirm in nonsmall-cell lung cancer (NSCLC) cell, exist by the micro-pipe of part echinoderm
Associated protein sample 4(EML4) gene and the multiple hypotype of fusion gene of ALK gene composition.The NSCLC patient of about 3-7%
It is detected EML4-ALK fusion gene transcript.Internal and external test confirms, EML4-ALK fusion gene albumen has cause
The mankind are suffered from NSCLC and have a major impact (Soda, M by cancer activity of conversion;et al“Identification of the
transforming EML4-ALK fusion gene in non-small-cell lung cancer.”Nature.2007,
448:561–6.)。
The fusion gene of ALK demonstrates obvious carcinogenecity, and the tyrosine kinase activity of its exception can strengthen cell proliferation
And survival, cause cytoskeleton rearrangement, make cell shape change.During carcinogenic ALK signal transduction, ALK and downstream
Interaction of molecules, then signal path in active cell, as most of normal and carcinogenic tyrosine kinase, ALK melts
Closing gene and can activate multiple different path, these paths are closely coupled, overlap, and eventually form a complicated signal
Transduction network.According to the literature, the most relevant, and research the most clearly path have three: Ras-ERK(extracellular signal regulation
Kinases) path, JAK3(Janus kinases 3)-STAT3 path and PI3K(phosphatidyl-inositol 3-kinase)-Akt path.These three lead to
Many sites in road can mediate the activation of ALK.In a word, cell is deposited by JAK3-STAT3 path and PI3K-Akt path
Live and phenotypic alternation plays vital effect (Nat Rev Cancer.2008,8:11 23;Barreca,A.;et al
“Anaplastic lymphoma kinase(ALK)in human cancer.”JMolEndocrinol.2011,47:R11–
23.).
Completely, normal ALK receptor there is also with the generation of other malignancy diseases and associate, such as, glioblast
Tumor, neuroblastoma, breast carcinoma, etc..In the collection of human cancer cell's strain is investigated, Dirks et al. confirms, god
There is the expression of ALK transcript in system cells strain and major part ectoderm solid cancer cell strain, these cell strains include
Retinoblastoma, melanoma and breast carcinoma (Dirks, P.B., Nature Medicine2008,14,373 375.).
C-Met, i.e. C-MET HGFr (HGFR), its main application point is at endotheliocyte, and has proven to
It all has expression in endotheliocyte, myogenous cell, hematopoietic cell and motor neuron.Part natural for c-Met is hepatocyte
Somatomedin (HGF), it is a multi-functional somatomedin, i.e. dispersion factor (SF).In fetus and adult, activate c-Met
Can promote the formation of some form, such as, invasive growth will cause the fast-growth of cell, intercellular division, and carefully
Born of the same parents to about migrate (" From Tpr-Met to Met, tumorigenesis and tubes. " Oncogene2007,26,
1276;“Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target.”Cancer
Letter,2009,280,1-14)。
There is lasting c-Met stimulation, process LAN or variation in the human malignancies being widely present, including breast carcinoma, liver
Cancer, pulmonary carcinoma, ovarian cancer, renal carcinoma, thyroid carcinoma, colon cancer, glioblastoma, carcinoma of prostate etc..C-Met involves tremulous pulse medicated porridge equally
Sample hardening and pulmonary fibrosis.By the interaction of mesenchyma stroma of tumors, including HGF/c-Met approach, make the invasion and attack of these cancerous cell
The property speed of growth thoroughly improves.Therefore, the response of a large amount of evidences display c-Me signal has with certain cancers advancing of disease speed
Close, and improve its role status (" Molecular in developing with the cancer drug with c-Met as major target class
cancer therapy:can our expectation be MET.”Euro.J.Cancer,2008,44,641-651;
“Targeting the c-Met Signaling Pathway in Cancer.”Clin.Cancer Res.2006,12,
3657).Agents targeting c-Met signaling pathway are now under clinical
investigation.(“Novel Therapeutic Inhibitors of the c-Met Signaling Pathway
in Cancer.”Clinical Cancer Research,2009,15,2207).“Drug development of MET
inhibitors:targeting oncogene addiction and expedience.”Nature Review Drug
Discovery,2008,7,504)。
Clinically, there have been many ALK and/or c-Met inhibitor for treating cancer.Ke Zhuo replaces Buddhist nun (Crizotinib)
It is a kind of little molecule ATP competitiveness ALK inhibitor, simultaneously, it is possible to act on c-Met receptor tyrosine kinase.August 26 in 2008
Day, U.S. FDA approval gram Zhuo is used for for Buddhist nun (Pfizer ' s Xalkori, originally known as PF-02341066)
, there is the nonsmall-cell lung cancer of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (ALK) gene rearrangement in treatment Locally Advanced or metastatic.ALK
(EML4-ALK) rearrangement of gene causes cell mutation, promotes the malignant phenotype of lung carcinoma cell.Therefore, the kinases of mutation inhibiting
ALK is effective for treatment cancer.
Summary of the invention
In view of this, the invention provides a kind of new substituted pyridine compounds, this compound for protein tyrosine-kinase
Enzyme is inhibited, may be used for the medicine of preparation treatment cell proliferation disorders.
The compound for protein tyrosine kinase activity of the present invention has inhibitory action, more satisfactory, the present invention's
Compound can suppress as ALK(includes ALK fusion gene, such as: EML4-ALK, NPM-ALK etc.), or c-Met receptor (hepatocyte
Growth factor receptors) signal response.Correspondingly, present invention also offers some new protein tyrosine kinase receptor signal responses
Inhibitor, as ALK receptor signal respond, or c-Met receptor signal response.
Especially, compound involved in the present invention, and pharmaceutically acceptable compositions, can be effective as
Tyrosine kinase receptor, such as the inhibitor of ALK or c-Met.
On the one hand, the present invention relates to a kind of compound as shown in formula (I):
Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmacy
Upper acceptable salt or its prodrug, wherein, R1, R2, R3, R4, R5, R6With Z, there is implication as described in the present invention.
At some embodiments, each R1, R2, R3, R4, R5And R6Independently be H, D or F；
Z is
(1) (C3-C7) heterocyclic radical, and it is independently selected from D, F, Cl, Br, I, N by 1,2,3,4 or 53, (C1-C6) alkyl,
(C1-C6) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C4) alkylidene-CN ,-(C1-C4) alkylidene-OH ,-(C1-C4)
Alkylidene-ORaOr-(C1-C4) alkylidene-NRbRcSubstituent group replaced；
When the ring members of heterocyclic radical comprise-N (H)-time ,-N (H)-in hydrogen atom can not be replaced；
Work as R1、R2、R3、R4、R5And R6When being mono-substituted piperidyl for H, Z, the 4-position on piperidine ring can not be replaced by D；
(2)-(C1-C4) alkylidene-(C3-C7) heterocyclic radical, and it is independently selected from D, F, Cl, Br, I, N by 1,2,3,4 or 53,
(C1-C6) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C4) alkylidene-OH ,-(C1-C4) alkylidene-ORaOr-(C1-
C4) alkylidene-NRbRcSubstituent group replaced；
-(C1-C4) alkylidene-(C3-C7) heterocyclic radical in heterocyclic radical can not be monosubstituted by-OH；
(3) (C5-C12) condensed-bicyclic base, and optionally it is independently selected from D, F, Cl, Br, I, N by 1,2,3,4 or 53, (C1-
C6) alkyl, (C1-C6) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C4) alkylidene-CN ,-(C1-C4) alkylidene-
OH ,-(C1-C4) alkylidene-ORaOr-(C1-C4) alkylidene-NRbRcSubstituent group replaced, and the ring in bicyclic system is permissible
It is carbocyclic ring or heterocycle；Or
(4)-(C1-C4) alkylidene-(C5-C12) condensed-bicyclic base, and optionally it is independently selected from D, F by 1,2,3,4 or 5,
Cl, Br, I, N3, (C1-C6) alkyl, (C1-C6) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C4) alkylidene-CN ,-
(C1-C4) alkylidene-OH ,-(C1-C4) alkylidene-ORaOr-(C1-C4) alkylidene-NRbRcSubstituent group replaced, and dicyclo body
Ring in system can be carbocyclic ring or heterocycle；
Wherein, RaFor (C1-C6) alkyl, (C1-C6) thiazolinyl, (C1-C6) alkynyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclic radical,
(C6-C10) aryl, (C1-C9) heteroaryl ,-(C1-C4) alkylidene-(C3-C6) cycloalkyl ,-(C1-C4) alkylidene-(C3-C6) miscellaneous
Ring group ,-(C1-C4) alkylidene-(C6-C10) aryl or-(C1-C4) alkylidene-(C1-C9) heteroaryl, described each (C1-C6) alkyl,
(C1-C6) thiazolinyl, (C1-C6) alkynyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclic radical, (C6-C10) aryl, (C1-C9) heteroaryl ,-
(C1-C4) alkylidene-(C3-C6) cycloalkyl ,-(C1-C4) alkylidene-(C3-C6) heterocyclic radical ,-(C1-C4) alkylidene-(C6-C10)
Aryl and-(C1-C4) alkylidene-(C1-C9) heteroaryl is optionally independently selected from D, F, Cl, N by 1,2,3 or 43,-CN ,-OH ,-
NH2, the substituent group of alkoxyl or alkyl amino is replaced；
RbAnd RcIndependently be H, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclic radical, (C6-C10) aryl, (C1-
C9) heteroaryl ,-(C1-C4) alkylidene-(C3-C6) cycloalkyl ,-(C1-C4) alkylidene-(C3-C6) heterocyclic radical ,-(C1-C4) alkylene
Base-(C6-C10) aryl or-(C1-C4) alkylidene-(C1-C9) heteroaryl；Described each (C1-C6) alkyl, (C3-C6) cycloalkyl,
(C3-C6) heterocyclic radical, (C6-C10) aryl, (C1-C9) heteroaryl ,-(C1-C4) alkylidene-(C3-C6) cycloalkyl ,-(C1-C4) sub-
Alkyl-(C3-C6) heterocyclic radical ,-(C1-C4) alkylidene-(C6-C10) aryl and-(C1-C4) alkylidene-(C1-C9) heteroaryl is optional
Ground by 1,2,3, or 4 be independently selected from D, F, Cl, N3,-CN ,-OH ,-NH2, the substituent group of alkoxyl or alkyl amino is replaced；
Work as RbAnd RcWhen being connected with same nitrogen-atoms, Rb, RcAnd together with the nitrogen-atoms being connected with them, it is also possible to it is optionally formed (C3-
C6) heterocyclic radical.
In other embodiments, R1, R2, R3, R4, R5And R6Independently be H or D.
In other embodiments, Z is:
(1) (C3-C7) heterocyclic radical, and it is independently selected from D, F, N by 1,2,3,4 or 53, (C1-C3) alkyl, (C1-C3) halo
Alkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-CN ,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORa
Or-(C1-C3) alkylidene-NRbRcSubstituent group replaced；
(2)-(C1-C4) alkylidene-(C3-C7) heterocyclic radical, and it is independently selected from D, F, N by 1,2,3,4 or 53, (C1-C3)
Haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-C3) alkylene
Base-NRbRcSubstituent group replaced；
(3) (C5-C12) condensed-bicyclic base, and optionally it is independently selected from D, F, Cl, Br, I, N by 1,2,3,4 or 53, (C1-
C3) alkyl, (C1-C3) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-CN ,-(C1-C3) alkylidene-OH ,-
(C1-C3) alkylidene-ORaOr-(C1-C3) alkylidene-NRbRcSubstituent group replaced, and the ring in bicyclic system can be carbon
Ring or heterocycle；Or
(4)-(C1-C4) alkylidene-(C5-C12) condensed-bicyclic base, and optionally it is independently selected from D, F by 1,2,3,4 or 5,
Cl, Br, I, N3, (C1-C3) alkyl, (C1-C3) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-CN ,-
(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-C3) alkylidene-NRbRcSubstituent group replaced, and dicyclo body
Ring in system can be carbocyclic ring or heterocycle.
In other embodiments, RaFor (C1-C3) alkyl, (C1-C3) thiazolinyl, (C1-C6) alkynyl, (C3-C6) cycloalkanes
Base or-(C1-C3) alkylidene-(C3-C6) cycloalkyl, described each (C1-C3) alkyl, (C1-C3) thiazolinyl, (C1-C6) alkynyl, (C3-
C6) cycloalkyl and-(C1-C3) alkylidene-(C3-C6) the cycloalkyl substituent group that is optionally independently selected from D or F by 1,2,3 or 4
Replaced.
In other embodiments, RbAnd RcIndependently be H, (C1-C3) alkyl, (C3-C6) cycloalkyl or-(C1-C4)
Alkylidene-(C3-C6) alkyl；Described each (C1-C3) alkyl, (C3-C6) cycloalkyl and-(C1-C4) alkylidene-(C3-C6) alkyl appoints
The substituent group that selection of land is independently selected from D or F by 1,2,3 or 4 is replaced；Work as RbAnd RcWhen being connected with same nitrogen-atoms, Rb, Rc
And together with the nitrogen-atoms being connected with them, it is also possible to it is optionally formed (C3-C6) heterocyclic radical.
In other embodiments, any one in formula (a)～the minor structure shown in (k) of Z:
Or its stereoisomer, wherein:
N is 0,1,2 or 3；
Each X and X' be-O-or-N (H)-；
Minor structure shown in formula (a)～(k) or its stereoisomer are independently selected from D, F by 1,2,3,4 or 5 independently,
(C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-C3) sub-
Alkyl-NRbRcSubstituent group replaced；
When n is 1,2 or 3, above-mentioned each minor structure or its stereoisomer can not be monosubstituted by-OH；
When each X and X' independently be-N (H)-time ,-N (H)-in hydrogen atom can not be replaced；
Work as R1,R2,R3,R4,R5And R6When being mono-substituted piperidyl for H, Z, the 4-position of piperidine ring can not be replaced by D.
In other embodiments, Z selected from formula (l)～(x) shown in minor structure in any one:
Or its stereoisomer, wherein:
N is 0,1,2 or 3；
Each W and W' is-O-,-N (H)-or-N (C1-C3) alkyl-；
Formula (l)～(x) shown minor structure or its stereoisomer are optionally independently selected from D, F by 1,2,3,4 or 5,
(C1-C3) alkyl, (C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORa
Or-(C1-C3) alkylidene-NRbRcSubstituent group replaced.
In other embodiments, any one in formula (101)～the minor structure shown in (111) of Z:
Or its stereoisomer, wherein:
Minor structure shown in formula (101)～(111) or its stereoisomer are independently selected from by 1,2,3,4 or 5 independently
D, F, (C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-
C3) alkylidene-NRbRcSubstituent group replaced.
In other embodiments, any one in formula (201)～the minor structure shown in (214) of Z:
Or its stereoisomer, wherein:
Minor structure shown in formula (201)～(214) or its stereoisomer are independently selected from by 1,2,3,4 or 5 independently
D, F, (C1-C3) haloalkyl ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-C3) sub-
Alkyl-NRbRcSubstituent group replaced.
In other embodiments, any one in formula (301)～the minor structure shown in (323) of Z:
Or its stereoisomer, wherein:
Minor structure shown in formula (301)～(323) or its stereoisomer are optionally independently selected from by 1,2,3,4 or 5
D, F, (C1-C3) alkyl, (C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-
ORaOr-(C1-C3) alkylidene-NRbRcSubstituent group replaced.
In other embodiments, RaFor (C1-C2) alkyl, and optionally it is independently selected from D or F by 1,2,3 or 4
Substituent group replaced.
In other embodiments, RbAnd RcIndependently be H or (C1-C2) alkyl；Described (C1-C2) alkyl and (C3-
C6) the heterocyclic radical substituent group that is optionally independently selected from D or F by 1,2,3 or 4 replaced；Work as RbAnd RcWith same nitrogen-atoms phase
Lian Shi, Rb, RcAnd together with the nitrogen-atoms being connected with them, it is also possible to it is optionally formed (C3-C6) heterocyclic radical.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises the compounds of this invention, and pharmaceutically acceptable
Carrier, excipient, diluent, adjuvant, vehicle or combinations thereof.
At some embodiments, pharmaceutical composition of the present invention, further comprising additional treatment agent, these are attached
With therapeutic agent selected from chemotherapeutic agent, antiproliferative, it is used for treating atherosclerotic medicine, is used for treating pulmonary fibrosis
Medicine, or combinations thereof.
At other embodiment, pharmaceutical composition of the present invention, wherein involved additional treatment agent is benzene
Butanoic acid chlormethine (chlorambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), different ring phosphinylidyne
Amine (ifosfamide), busulfan (busulfan), carmustine (carmustine), lomustine (lomustine), chain urea
Assistant rhzomorph (streptozocin), cisplatin (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin),
Dacarbazine (dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate
(methotrexate), fluorouracil (fluorouracil), cytosine arabinoside (cytarabine), gemcitabine
(gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vinblastine
(vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), paclitaxel (paclitaxel),
Docetaxel (docetaxel), topotecan (topotecan), irinotecan (irinotecan), etoposide
(etoposide), ET-743 (trabectedin), dactinomycin (dactinomycin), doxorubicin
(doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone
(mitoxantrone), bleomycin (bleomycin), ametycin (mitomycin), ipsapirone
(ixabepilone), tamoxifen (tamoxifen), flutamide (flutamide), gonadorelin analog
(gonadorelinanalogues), megestrol (megestrol), prednisone (prednidone), dexamethasone
(dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-ALPHA
(interferon alfa), calcium folinate (leucovorin), sirolimus (sirolimus), temsirolimus
(temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib,
A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), SKI-606
(bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replaces Buddhist nun
(crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib,
Erlotinib (erlotinib), foretinib, ganetespib, gefitinib (gefitinib), ibrutinib, Ai Ke
For Buddhist nun (icotinib), imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib,
Linifanib, linsitinib, Masitinib (masitinib), momelotinib, not for husky Buddhist nun (motesanib), comes that
For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib
(pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib,
Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), relaxes
Buddhist nun replace Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib,
Trametinib, ZD6474 (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib,
Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card
Appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab
(gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), method wood monoclonal antibody difficult to understand
(ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab
(tositumomab), Herceptin (trastuzumab) or combinations thereof.
On the other hand, it is possible to use the compounds of this invention or pharmaceutical composition are prepared for protecting, process, treat or subtracting
The purposes of the medicine of light patient's proliferative disease.
In some embodiments, proliferative disease of the present invention is metastatic carcinoma, colon cancer, adenocarcinoma of stomach, bladder cancer, breast
Adenocarcinoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, thyroid carcinoma, head and neck cancer, carcinoma of prostate, cancer of pancreas, CNS(central nervous system) cancer,
Glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
On the other hand, the present invention relates to use the compounds of this invention or pharmaceutical composition to prepare in biological sample
The purposes of the medicine of suppression or regulation protein kinase activity, described purposes comprises use the compounds of this invention and described biological mark
This contact.
Some embodiments wherein, kinases of the present invention is receptor tyrosine kinase.
In other embodiment, receptor tyrosine kinase of the present invention is ALK, c-Met, or combinations thereof.
On the other hand, the present invention provides some pharmaceutical compositions, and it comprises the present invention and suppresses as tyrosine kinase receptor
The compound of agent, or its stereoisomer, geometric isomer, tautomer, solvate, metabolite, or it is pharmaceutically
Acceptable salt, pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or combinations thereof.In some embodiments
In, pharmaceutical composition provided by the present invention comprises can be as suppression ALK receptor signal response or the change of c-Met receptor signal response
Compound, or its stereoisomer, geometric isomer, tautomer, solvate, metabolite, or it is pharmaceutically acceptable
Salt, or pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or combinations thereof.In other embodiment
In, pharmaceutical composition of the present invention further comprises additional treatment agent.
On the other hand, the method that the present invention relates to suppress protein tyrosine kinase activity, the method comprises chemical combination of the present invention
Thing or its pharmaceutical composition contact with described kinases.In some embodiments, the present invention relates to suppress ALK receptor signal to ring
Should, the method for c-Met receptor signal response, the method comprises the compounds of this invention or its pharmaceutical composition connects with described receptor
Touch.Other embodiment is, suppresses protein kinase receptor activity, particularly suppress in cell or multicellular organisms
The activity of ALK or c-Met receptor signal response.According to method of the present invention, the method comprises use the compounds of this invention
Or described multicellular organisms is administered by its pharmaceutical composition.In some embodiments, described multicellular organisms refers to
Mammal.In other embodiment, described multicellular organisms refers to the mankind.In some embodiments, institute of the present invention
Method of stating further comprises additional treatment agent and contacts with described kinases.
On the other hand, the present invention relates to a kind of method suppressing cell-proliferation activity, described method comprises the use present invention
Compound or effective therapeutic dose of its pharmaceutical composition energy Inhibit proliferaton and cells contacting.In some embodiments, institute of the present invention
Method of stating further comprises additional treatment agent and cells contacting.
On the other hand, the present invention relates to a kind of method treating Patient cells's proliferative disease, described method comprises use
Patient is administered by effective therapeutic dose of the compounds of this invention or its pharmaceutical composition.In some embodiments, institute of the present invention
Method of stating further comprises the administration of additional treatment agent.
On the other hand, the present invention relates to a kind of method suppressing patient tumors to grow, described method comprises the use present invention
Patient is administered by effective therapeutic dose of compound or its pharmaceutical composition.In some embodiments, the method for the invention
Further comprise the administration of additional treatment agent.
On the other hand, the method that the present invention relates to the preparation of compound, separation and purification that formula (I) is comprised.
Test result indicate that, the compound that the present invention provides shows good half-life and good pharmacokinetics
Matter, has good inhibitory action to ALK and c-Met, and the growth to tumor also has good inhibitory action.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and
The content of his aspect will make more specific complete description below.
Detailed description of the invention
Definition and general terms
The present invention will list the document corresponding to the content of the materialization determined in detail, and embodiment is all attended by structure
Formula and the diagram of chemical formula.The present invention has and expectedly contains all of choice, variant and coordinate, and these may be as right
Existing invention field it is included in like that defined in requirement.Those skilled in the art will identify many similar or equivalent to
This described method and material, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material
Description.Have a lot of document and similar material distinguish with the present patent application or conflict, including but be not limited to term
Definition, the usage of term, the technology of description, or the scope controlled as the present patent application.
Unless other aspects show, the present invention will apply defined below:
According to the purpose of the present invention, chemical element according to the periodic table of elements, CAS version and chemical drugs handbook, 75,thEd,
1994 define." Organic Chemistry, " the Thomas Sorrell it addition, organic chemistry General Principle is shown in,
University Science Books,Sausalito:1999,and"March's Advanced Organic
Chemistry, " by Michael B.Smith and Jerry March, John Wiley&Sons, New York:2007,
The most all of content has all merged list of references.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as
General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised.
Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use." optionally " or
" optionally " be meant that subsequently described event or situation can but may not occur, and this description includes wherein this event
Or the situation of situation, and wherein there is not the situation of this event or situation.Such as: " heterocyclic radical is optionally by 1 or 2 independence
Group selected from D, F is replaced " be meant that this D, F can but may not exist, and this description includes that wherein heterocyclic radical is by 1
Or 2 substituted situations of group being independently selected from D, F, and the unsubstituted situation of heterocyclic radical.
It is said that in general, term " substituted ", represent that the one or more hydrogen atoms in given structure can specifically be replaced
Base is replaced.Unless other aspects show, an optional substituted radical can have a substituent group, and at group, each may replace
Position replace.When in given structural formula, more than one position can be selected from one or more replacements of concrete group
Base is replaced, then substituent group can replace in each position identical or differently.Wherein said substituent group is it may be that but also
It is not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano group, nitro, azido, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy alkyl, alkane
Epoxide alkyl, aminoalkyl, alkyl amino alkyl, cyanoalkyl, hydroxyl, alkoxyl, sulfydryl, alkylthio group, amino, alkylamino, ammonia
Base acyl group, alkylamino acyl group, aminoacyl epoxide, alkylamino acyloxy, aryl, heteroaryl etc..
The term " undersaturated " used in the present invention represents that part is containing one or more degrees of unsaturation.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise
Content.
Term " H " represents single hydrogen atom.Such atomic group can be connected with other groups, such as with oxygen atom phase
Even, oh group is formed.
Term " D " or "2H " represent single D-atom.One such atomic group and a methyl are connected, and form list-deuterium
Acute pyogenic infection of nails base (-CDH2), two D-atoms and a methyl are connected, and form double-deuterated methyl (-CD2H), and three D-atoms with
One methyl is connected, and forms three-deuterated methyl (-CD3).
Term " N3" represent a nitrine structure.This group can be connected with other groups, such as, with methyl group
It is connected, triazonmethane (methyl azide, MeN can be formed3)；And be connected with phenyl group, then form aziminobenzene
(PhN3)。
Term " halogen " refers to F, Cl, Br or I.
Terminology used in the present invention " alkyl " or " alkyl group ", represent the saturated straight chain containing 1-20 carbon atom or side chain
Monovalent hydrocarbon.Unless otherwise indicated, alkyl group contains 1-20 carbon atom；Some of them embodiment is that alkyl group contains
1-10 carbon atom, in other embodiment, alkyl group contains 1-6 carbon atom, in other embodiment, alkyl base
Group is containing 1-3 carbon atom, and in further embodiments, alkyl group contains 1-2 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-
Pr ,-CH2CH2CH3), isopropyl (i-Pr, i-propyl ,-CH (CH3)2), normal-butyl (n-Bu, n-butyl ,-
CH2CH2CH2CH3), isobutyl group (i-Bu, i-butyl ,-CH2CH(CH3)2), sec-butyl (s-Bu, s-butyl ,-CH (CH3)
CH2CH3), the tert-butyl group (t-Bu, t-butyl ,-C (CH3)3), n-pentyl (n-pentyl ,-CH2CH2CH2CH2CH3), 2-amyl group (-
CH(CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-fourth
Base (-CH (CH3)CH(CH3)2), 3-methyl isophthalic acid-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butene base (-CH2CH(CH3)
CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3)CH2CH2CH2CH3), 3-hexyl (-CH
(CH2CH3)(CH2CH2CH3)), 2-methyl-2-amyl group (-C (CH3)2CH2CH2CH3), 3-methyl-2-amyl group (-CH (CH3)CH
(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-amyl group (-C (CH3)(CH2CH3)2),
2-methyl-3-amyl group (-CH (CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C (CH3)2CH(CH3)2), 3,3-diformazans
Base-2-butyl (-CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..And alkyl can be substituted or non-substituted, its
Middle substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano group, hydroxyl, alcoxyl
Base, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl amino alkyl, etc..
Term used in the present invention " alkyl " and its prefix " alkane ", all comprise the saturated carbon chains of straight chain and side chain.
Terminology used in the present invention " alkylidene ", represents that two hydrogen of cancellation are former from straight or branched saturated hydrocarbon
The saturated bivalent hydrocarbon radical that son obtains.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and some of them are implemented
Example is, alkylidene group contains 1-6 carbon atom, and other embodiment is, alkylidene group contains 1-4 carbon atom, also
Having some embodiments is that alkylidene group contains 1-3 carbon atom.The example of alkylidene group includes, but is not limited to, methylene
Base (-CH2-), ethylidene (-CH2CH2-), isopropylidene (-CH (CH3)CH2-) etc..Alkylidene can be further substituted, and replaces
Base is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl, ammonia
Base, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl amino alkyl, etc..
Term " thiazolinyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon atom
The monovalent hydrocarbon of straight or branched, at least one of which position is undersaturated condition, and i.e. one C-C is sp2Double bond, thiazolinyl base
Can there be " suitable ", negation or " E ", the location of " Z " in group, and concrete example includes, but is not limited to, vinyl (-CH=CH2), alkene
Propyl group (-CH2CH=CH2), etc..Thiazolinyl of the present invention can be further substituted individually optionally, substituent group it may be that but
It is not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanogen
Base alkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl amino alkyl, etc..
Term " alkynyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon atom
The monovalent hydrocarbon of straight or branched, at least one of which position is undersaturated condition, and i.e. one C-C is sp tri-key, concrete reality
Example includes, but is not limited to, acetenyl (-C ≡ CH), propargyl (-CH2C ≡ CH) etc..Wherein hydrocarbyl group can independently be appointed
Selection of land is further substituted, substituent group it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl,
Cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkylamino alkane
Base, etc..
Term " alkoxyl " used in the present invention or " alkoxy base ", refer to that alkyl is connected to by oxygen atom main
In the carbochain wanted, wherein, alkyl has definition as described in the present invention.Unless otherwise indicated, alkoxy base contains 1-20
Carbon atom；Some of them embodiment is, alkoxy base contains 1-10 carbon atom；In other embodiment, alkoxyl base
Group is containing 1-8 carbon atom；In other embodiment, alkoxy base contains 1-6 carbon atom；In further embodiments,
Alkoxy base contains 1-4 carbon atom.
The instantiation of alkoxy base includes, but are not limited to: methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-
OCH2CH3), 1-propoxyl group (n-PrO, n-propoxy ,-OCH2CH2CH3), 2-propoxyl group (i-PrO, i-propoxy ,-OCH
(CH3)2), 1-butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2-methyl-l-propoxyl group (i-BuO, i-
butoxy,-OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH3)CH2CH3), 2-methyl-2-propoxyl group
(t-BuO,t-butoxy,-OC(CH3)3), 1-amoxy (n-pentoxy ,-OCH2CH2CH2CH2CH3), 2-amoxy (-OCH
(CH3)CH2CH2CH3), 3-amoxy (-OCH (CH2CH3)2), 2-methyl-2-butoxy (-OC (CH3)2CH2CH3), 3-methyl-
2-butoxy (-OCH (CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-
OCH2CH(CH3)CH2CH3), etc..
" alkoxyalkyl " represents that alkyl group is replaced by one or more alkoxy bases, wherein alkyl group to term
Having implication as described in the present invention with alkoxy base, such example includes, but is not limited to methoxy, ethyoxyl
Methyl, ethoxyethyl group etc..
" hydroxy alkyl " includes the C replaced by one or more hydroxyls to term1-10Straight or branched alkyl group.Wherein
Some embodiments are, the C that hydroxy alkyl is replaced by one or more oh groups1-6" hydroxy alkyl of lower level ", so
Example include, but is not limited to, methylol, ethoxy, hydroxypropyl, hydroxyl butyl and hydroxyl hexyl.
Term " haloalkyl " and " halogenated alkoxy " represent that alkyl or alkoxy base are by one or more identical or not
Same halogen atom is replaced, and wherein alkyl and alkoxyl have implication as described in the present invention, and such example includes, but also
It is not limited to, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, etc..
Term " alkylamino " or " alkyl amino " include " N-alkyl amino " and " N, N-dialkyl amido ", wherein amino base
Group is separately replaced by one or two alkyl group.Some of them embodiment is, alkyl amino is one or two
C1-6The alkylamino group of the lower level that alkyl is connected on nitrogen-atoms.Other embodiment is, alkyl amino is C1-3's
The alkylamino group of lower level.Suitably alkylamino group can be alkyl monosubstituted amino or dialkyl amido, such reality
Example includes, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc..
Term " aminoalkyl " includes the C replaced by one or more amino1-10Straight or branched alkyl group.Wherein
Some embodiments are, the C that aminoalkyl is replaced by one or more amino groups1-6" aminoalkyl of lower level ", so
Example include, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
Term " cyanoalkyl " includes the C replaced by one or more cyano group1-10Straight or branched alkyl group.Wherein
Some embodiments are, the C that cyanoalkyl is replaced by one or more cyano groups1-6" cyanoalkyl of lower level ", so
Example include, but is not limited to, cyano methyl, cyano ethyl, cyanopropyl, cyanobutyl and cyano group hexyl.
Term " alkyl amino alkyl " includes the alkyl group replaced by alkylamino.Some of them embodiment is, alkylamino alkane
Base is C1-6The alkyl amino alkyl of lower level.Other embodiment is, alkyl amino alkyl is C1-3The alkyl amino alkyl of lower level.
Suitably alkyl amino alkyl group can be monoalkyl or dialkyl group substituted, such embodiment includes, but is not limited to, N-
Methylaminomethyl, N, N-dimethyl aminoethyl, N, N-diethylamino methyl etc..
Term " cycloalkyl " refers to the alkyl of monovalence or multivalence, is the single ring systems containing 3-12 carbon atom.Some of them are real
Executing example is, cycloalkyl comprises 3-8 carbon atom, and other embodiment is, cycloalkyl comprises 3-6 carbon atom.And cycloalkyl
Can be further substituted, substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyanogen
Base, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl amino alkyl,
Etc..
Term " cycloalkyl alkylidene " represents that alkyl group can be replaced by one or more groups of naphthene base, wherein alkane
Base and group of naphthene base have implication as described in the present invention.Some of them embodiment is, cycloalkyl alkylidene group refers to " relatively
Rudimentary cycloalkyl alkylidene " group, i.e. group of naphthene base be connected to C1-6Alkyl group on.Other embodiment is, ring
Alkyl group is connected to C1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to C1-3Alkyl group
On.Such example includes, but is not limited to, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..Cycloalkyl alkylene
Base can be further substituted, and this substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, alkyl halide
Base, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkylamino
Alkyl, etc..
Term " hetero atom " represents one or more O, S, N, P and Si, including the form of any oxidation state of N, S and P；The primary,
Secondary, tertiary amine and the form of quaternary ammonium salt；Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N(as 3,4-dihydro-
N in 2H-pyrrole radicals), NH(is as the NH in pyrrolidinyl) or NR(as the NR in the substituted pyrrolidinyl of N-).
Term " heterocycle ", " heterocyclic radical " or " heterocycle " is used interchangeably herein, all referring to single ring systems, on its medium ring
One or more atoms are replaced by hetero atom individually optionally, and ring can be fully saturated or comprise one or more insatiable hunger
And degree, but it being definitely not the fragrance same clan, only one of which junction point is connected to other molecules up.One or more ring hydrogens are former
Son is replaced by one or more substituent groups described in the invention individually optionally.Some of them embodiment is, " heterocycle ",
" heterocyclic radical " or " heterocycle " group be 3-7 ring monocycle (2-6 carbon atom and selected from N, 1-3 the hetero atom of O, P, S,
Optionally replaced by one or more oxygen atoms at this S or P and obtain as SO, SO2, PO, PO2Group, when described ring is three
During ring, only one of which hetero atom).
Heterocyclic radical can be carbon back or hetero atom base.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrochysene furan
Mutter base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, sulfur
For morpholinyl, thiophene alkyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl,
Glycidyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulfur azatropylidene base, 2-
Pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranose, 4H-pyranose, dioxacyclohexyl, 1,3-dioxy amyl group,
Pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl, imidazolinyl, imidazolidinyl, heterocyclic group
Example also includes, on ring, two carbon atoms are by oxygen (=O) substituted hybar X base and 1,1-dioxidothiomorpholinyl.And institute
Stating heterocyclic radical to be replaced by the one or more substituent groups in the present invention, wherein substituent group is not it may be that but limit individually optionally
In, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl,
Hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkyl amino alkyl, etc..
Term " heterocycloalkylene " represents that alkyl group can be replaced by one or more heterocyclyl groups, wherein alkane
Base and heterocyclyl groups have implication as described in the present invention.Some of them embodiment is, heterocycloalkylene group refers to " relatively
Rudimentary heterocycloalkylene " group, i.e. heterocyclyl groups be connected to C1-6Alkyl group on.Other embodiment is, miscellaneous
Cyclic groups is connected to C1-4Alkyl group on.Such example includes, but is not limited to, 2-pyrrolidine ethyl etc..Heterocycle
Base alkylidene can be further substituted, this substituent group it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl,
Haloalkyl, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl,
Alkyl amino alkyl, etc..
Term " aryl " and " aromatic ring ", be used interchangeably herein, represents and contains the monocycle of 6-14 ring altogether, dicyclo, and
The carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and each of which member ring systems comprises 3-7 ring, and only
An attachment point is had to be connected with the remainder of molecule.Aromatic rings can include phenyl, naphthyl and anthracene.And described aryl is permissible
Being substituted or non-substituted, wherein substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, halo
Alkyl, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkane ammonia
Base alkyl, etc..
Term " aryl alkylene " represent alkyl group can be replaced by one or more aromatic yl groups, wherein alkyl and
Aromatic yl group has implication as described in the present invention, and some of them embodiment is, arylalkylene groups refers to the " virtue of lower level
Base alkylidene " group, i.e. aromatic yl group be connected to C1-6Alkyl group on.Other embodiment is, arylalkylene groups
Refer to containing C1-4" the benzene alkylene " of alkyl.Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..Aryl alkene
Base can be further substituted, and this substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, alkyl halide
Base, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, aminoalkyl, alkylamino
Alkyl, etc..
Term " heteroaryl ", " heteroaromatic " and " heteroaromatics ", is used interchangeably in this article, represents containing 5-14
The monocycle of annular atoms, dicyclo, and three-ring system, at least one of which member ring systems is aromatic, and an at least member ring systems
Comprising one or more hetero atom, each of which member ring systems comprises 5-7 ring, and only one of which attachment point and its remaining part of molecule
Split-phase is even.And described heteroaryl can be substituted or non-substituted, wherein substituent group it may be that but be not limited to, deuterium, fluorine,
Chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl,
Alkoxyalkyl, aminoalkyl, alkyl amino alkyl, etc..
Other embodiment is, heteroaryl includes following monocycle, but is not limited to these monocycles: 2-furyl, 3-
Furyl, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,
2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4-pyrrole
Piperidinyl, 2-pyrimidine radicals, 4-pyrimidine radicals, 5-pyrimidine radicals, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazole
Base, tetrazole radical (such as 5-tetrazole radical), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl
(such as 2-pyrazolyl), isothiazolyl, 1,2,3-di azoly, 1,2,5-di azoly, 1,2,4-di azoly, 1,2,3-triazoles
Base, 1,2,3-thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole base, pyrazinyl, 1,3,5-triazines base；Also
Including following dicyclo, but it is not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indyl (as
2-indyl), purine radicals, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl,
3-isoquinolyl or 4-isoquinolyl).
Term " heteroarylalkylenyl " represents that alkyl group can be replaced by one or more heteroaryl groups, wherein alkane
Base and heteroaryl groups have implication as described in the present invention, and some of them embodiment is, heteroarylalkylenyl group refers to " relatively
Rudimentary heteroarylalkylenyl " group, i.e. heteroaryl groups be connected to C1-6Alkyl group on.Other embodiment is, miscellaneous
Aromatic yl group is connected to C1-4Alkyl group on.Wherein instantiation includes 2-picolyl, 3-furylethyl etc..Heteroaryl
Can be replaced further on base alkylidene, this substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkane
Base, haloalkyl, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, amino alkane
Base, alkyl amino alkyl, etc..
Term " virtue amino " represents that amine groups is replaced by one or two aromatic yl group, and such example includes, but also
It is not limited to N-phenylamino.Some of them embodiment is, the aromatic ring on virtue amino can be replaced further.
Term " carboxyl ", is either used alone and is still used in conjunction, such as " carboxyalkyl ", expression-CO with other terms2H；Term
" carbonyl ", is either used alone and is still used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represent-(C=O)-.
Term " condensed-bicyclic ", " fused rings ", " condensed-bicyclic base " or " condensing ring group ", as shown in formula a-c, represent two
Between five-membered ring, (formula a), between two hexatomic rings, (between formula b), and a five-membered ring and a hexatomic ring, (formula c) shares one
The bridged-ring system of individual C-C key.System can comprise unsaturated bond that is isolated or that be conjugated, but core ring structure does not include virtue
Fragrant ring or hetero-aromatic ring (substituent group can be armaticity).Each ring in condensed-bicyclic can be carbocyclic ring or heterocycle.
The example of condensed-bicyclic includes, but not limited to hexahydro furyl also [2,3-b] furan-3-base, hexahydro furyl also [3,
2-b] furan-3-base, octahydro Pentamethylene. also [c] pyrroles-5-base, octahydro pentalene-2-base, octahydro-1H-iso-indoles-5-
Base, etc..Condensed-bicyclic base can be substituted or non-substituted, wherein substituent group it may be that but be not limited to, deuterium, fluorine, chlorine,
Bromine, iodine, azido, alkyl, haloalkyl, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkane
Epoxide alkyl, aminoalkyl, alkyl amino alkyl, etc..
Term " condensed-bicyclic base alkylidene " represents that alkyl is replaced by one or more condensed-bicyclic base groups, wherein alkane
Base group and condensed-bicyclic base group have implication as described in the present invention, and such example includes, but are not limited to hexahydro furyl
And [2,3-b] furan-3-ylmethyl, the hexahydro furyl also deuterated methyl of [2,3-b] furan-3-base two, etc..Condensed-bicyclic base is sub-
Alkyl can be substituted or non-substituted, and wherein substituent group is it may be that but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkane
Base, haloalkyl, cyano group, hydroxyl, alkoxyl, amino, alkylamino, cyanoalkyl, hydroxy alkyl, alkoxyalkyl, amino alkane
Base, alkyl amino alkyl, etc..
As described in the invention, substituent group draws the member ring systems formed on a ring being bonded the center of receiving (such as following formula institute
Show) represent substituent group any commutable position on ring and can replace.Such as, formula d represents and any on B ring may be replaced
Position, as shown in formula e.
Unless other aspects show, structural formula described in the invention includes that all of isomeric forms is (as mapping is different
Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism)): such as contain R, S configuration of asymmetric center, (Z) of double bond,
(E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or it is right
Reflect isomer, diastereomer, or the mixture of geometric isomer (or conformer) and broadly fall into the scope of the present invention.
Term used in the present invention " tautomer " or " tautomeric form " represent the structure with different-energy
Isomers can cross low energy barrier, thus inversion of phases mutually.Such as, proton tautomer (i.e. prototropic change) includes passing through
Proton migrates and carries out change, such as keto-enol formula change and imine-enamine isomerization.Valence tautomers bag
Include and recombinated by some bonding electronss and carry out change.
Unless other aspects show, all tautomeric forms of the compound of the present invention are included in the scope of the present invention
Within.It addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different former
The enriched isotope of son.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.
Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This
Bright prodrug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as prodrug
(C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one
Compound comprises OH group, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form bag
Include phosphate ester, if these phosphate compounds are that the di on parent obtains.Complete about prodrug
Discussion is referred to documents below: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery
Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible
Carriers in Drug Design,American Pharmaceutical Association and Pergamon
Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature
Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of
Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345,
Every document is incorporated herein by this.
" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change
The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention
Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound
Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes chemical combination
The metabolite of thing, is fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
The definition of neutral body of the present invention chemistry and the use of convention are typically referenced to documents below: S.P.Parker, Ed.,
McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New
York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John
Wiley&Sons, Inc., New York, the compound of 1994. present invention can comprise asymmetric center or chiral centre, therefore
There is different stereoisomers.The all of stereoisomeric forms in any ratio of compound of the present invention, include, but not limited to, diastereomeric
Body, enantiomer, atropisomer, and their mixture, such as racemic mixture, constitute the part of the present invention.
A lot of organic compound all exist with optical active forms, and i.e. they are had the ability the plane of Plane of rotation polarized light.Light is being described
When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use
Compound is left-handed to name the symbol that compound linearly polarized light rotates, (-) or l to refer to, prefix (+) or d refer to chemical combination
Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.Specific vertical
Body isomer can be enantiomer, and the mixture of isomer is commonly referred to enantiomeric mixture.The enantiomer mixing of 50:50
Thing is referred to as racemic mixture or racemic modification, and this may cause not having stereo selectivity or three-dimensional fixed in chemical reaction process
Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack light
Learn activity.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine
On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe
pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:
1-19,1977. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group
The inorganic acid salt that should be formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate,
Oxalates, maleate, tartrate, citrate, succinate, malonate, or pass through described on books document
Additive method such as ion exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, and alginate are anti-bad
Hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, camphorsulfonic acid
Salt, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal
Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid
Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulphur
Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, bitterness
Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through
The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any
The quaternary ammonium salt that the compound of the group of comprised N is formed.Water solublity or oil-soluble or dispersion product can be turned into by quaternary ammonium
With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes to fit
When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphuric acid
Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed
Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance
Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks
Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl
(BOC), benzyloxycarbonyl group (CBZ) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to the replacement of hydroxyl
Base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl-protecting group
Group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes-
CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-is (to toluene
Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection
The description that group is general refers to document: T W.Greene, Protective Groups in Organic Synthesis,
John Wiley&Sons,New York,1991;and P.J.Kocienski, Protecting Groups,Thieme,
Stuttgart,2005。
Compound
The heterocyclic compound that the present invention relates to, its pharmaceutically acceptable salt, and pharmaceutical preparation, tyrosine kinase is subject to
Body, the disease of especially ALK and c-Met regulation or the treatment of disease have potential purposes.Particularly, the present invention relates to one
Kind compound as shown in formula (I):
Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmacy
Upper acceptable salt or its prodrug.
Wherein, R1, R2, R3, R4, R5, R6With Z there is implication as described below:
R1, R2, R3, R4, R5And R6Independently be H, D or F, in other embodiments, H or D can be independently be.
Z can be:
(1) (C3-C7) heterocyclic radical, and it is independently selected from D, F, Cl, Br, I, N by 1,2,3,4 or 53, (C1-C6) alkyl,
(C1-C6) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C4) alkylidene-CN ,-(C1-C4) alkylidene-OH ,-(C1-C4)
Alkylidene-ORaOr-(C1-C4) alkylidene-NRbRcSubstituent group replaced；Described (C3-C7) heterocyclic radical other implement
In scheme, D, F, N can be independently selected from by 1,2,3,4 or 53, (C1-C3) alkyl, (C1-C3) haloalkyl ,-CN ,-OH ,-
ORa,-NRbRc,-(C1-C3) alkylidene-CN ,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-C3) alkylene
Base-NRbRcSubstituent group replaced；
Z is (C3-C7) heterocyclic radical time, meet following condition simultaneously:
When the ring members of heterocyclic radical comprise-N (H)-time ,-N (H)-in hydrogen atom can not be replaced；
Work as R1、R2、R3、R4、R5And R6When being mono-substituted piperidyl for H, Z, the 4-position on piperidine ring can not be replaced by D,
It is i.e. (R)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(piperidin-4-yl)-1H-pyrrole when formula (I) compound
Azoles-4-base) pyridine-2-aminated compounds time, the 4-position on piperidine ring can not be replaced by D.
Z can also be:
(2)-(C1-C4) alkylidene-(C3-C7) heterocyclic radical, and it is independently selected from D, F, Cl, Br, I, N by 1,2,3,4 or 53,
(C1-C6) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C4) alkylidene-OH ,-(C1-C4) alkylidene-ORaOr-(C1-
C4) alkylidene-NRbRcSubstituent group replaced；Described-(C1-C4) alkylidene-(C3-C7) heterocyclic radical is other embodiment party
In case, D, F, N can be independently selected from by 1,2,3,4 or 53, (C1-C3) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-
C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-C3) alkylidene-NRbRcSubstituent group replaced；
-(C1-C4) alkylidene-(C3-C7) heterocyclic radical in heterocyclic radical can not be monosubstituted by-OH.
Z can also be:
(3) (C5-C12) condensed-bicyclic base, and optionally it is independently selected from D, F, Cl, Br, I, N by 1,2,3,4 or 53, (C1-
C6) alkyl, (C1-C6) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C4) alkylidene-CN ,-(C1-C4) alkylidene-
OH ,-(C1-C4) alkylidene-ORaOr-(C1-C4) alkylidene-NRbRcSubstituent group replaced, and the ring in bicyclic system is permissible
It is carbocyclic ring or heterocycle；Described (C5-C12) condensed-bicyclic base in other embodiments, can be optionally by 1,2,3,4 or 5
The individual D that is independently selected from, F, Cl, Br, I, N3, (C1-C3) alkyl, (C1-C3) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-
C3) alkylidene-CN ,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-C3) alkylidene-NRbRcSubstituent group institute
Replace, and the ring in bicyclic system can be carbocyclic ring or heterocycle.
Z can also be:
(4)-(C1-C4) alkylidene-(C5-C12) condensed-bicyclic base, and optionally it is independently selected from D, F by 1,2,3,4 or 5,
Cl, Br, I, N3, (C1-C6) alkyl, (C1-C6) haloalkyl ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C4) alkylidene-CN ,-
(C1-C4) alkylidene-OH ,-(C1-C4) alkylidene-ORaOr-(C1-C4) alkylidene-NRbRcSubstituent group replaced, and dicyclo
Ring in system can be carbocyclic ring or heterocycle；Described-(C1-C4) alkylidene-(C5-C12) condensed-bicyclic base other implement
In scheme, optionally can be independently selected from D, F, Cl, Br, I, N by 1,2,3,4 or 53, (C1-C3) alkyl, (C1-C3) alkyl halide
Base ,-CN ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-CN ,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-
(C1-C3) alkylidene-NRbRcSubstituent group replaced, and the ring in bicyclic system can be carbocyclic ring or heterocycle.
Specifically, Z can be selected from the minor structure shown in following (a)～(k) or any one in its stereoisomer:
In the minor structure shown in described (a)～(k):
N is 0,1,2 or 3；
X and X' be-O-or-N (H)-；
Minor structure shown in described (a)～(k) or its stereoisomer are independently selected from D by 1,2,3,4 or 5 independently,
F, (C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-C3)
Alkylidene-NRbRcSubstituent group replaced；
When n is 1,2 or 3, the minor structure shown in described (a)～(k) or its stereoisomer can not be monosubstituted by-OH；
When each X and X' independently be-N (H)-time ,-N (H)-in hydrogen atom can not be replaced；
Work as R1,R2,R3,R4,R5And R6When being mono-substituted piperidyl for H, Z, the 4-position of piperidine ring can not be replaced by D.
Z can also be selected from any one in (l)～(x) shown minor structure or its stereoisomer:
In described (l)～(x) shown minor structure:
N is 0,1,2 or 3；
W and W' is-O-,-N (H)-or-N (C1-C3) alkyl-；
Described (l)～(x) shown minor structure or its stereoisomer are optionally independently selected from D by 1,2,3,4 or 5,
F, (C1-C3) alkyl, (C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-
ORa or-(C1-C3) alkylidene-NRbRcSubstituent group replaced.
Z is also selected from the minor structure shown in (101)～(111) or any one in its stereoisomer:
Minor structure shown in described (101)～(111) or its stereoisomer are independently by 1,2,3,4 or 5 independent choosing
From D, F, (C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-
C3) alkylidene-NRbRcSubstituent group replaced.
Z is also selected from the minor structure shown in (201)～(214) or any one in its stereoisomer:
Minor structure shown in described (201)～(214) or its stereoisomer are independently by 1,2,3,4 or 5 independent choosing
From D, F, (C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylidene-ORaOr-(C1-
C3) alkylidene-NRbRcSubstituent group replaced.
Z is also selected from the minor structure shown in (301)～(323) or any one in its stereoisomer:
Minor structure shown in described (301)～(323) or its stereoisomer are optionally by 1,2,3,4 or 5 independent choosing
From D, F, (C1-C3) alkyl, (C1-C3) haloalkyl ,-OH ,-ORa,-NRbRc,-(C1-C3) alkylidene-OH ,-(C1-C3) alkylene
Base-ORaOr-(C1-C3) alkylidene-NRbRcSubstituent group replaced.
In above-mentioned each structure of Z, RaFor (C1-C6) alkyl, (C1-C6) thiazolinyl, (C1-C6) alkynyl, (C3-C6) cycloalkyl,
(C3-C6) heterocyclic radical, (C6-C10) aryl, (C1-C9) heteroaryl ,-(C1-C4) alkylidene-(C3-C6) cycloalkyl ,-(C1-C4) sub-
Alkyl-(C3-C6) heterocyclic radical ,-(C1-C4) alkylidene-(C6-C10) aryl or-(C1-C4) alkylidene-(C1-C9) heteroaryl, described
Respectively (C1-C6) alkyl, (C1-C6) thiazolinyl, (C1-C6) alkynyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclic radical, (C6-C10) aryl,
(C1-C9) heteroaryl ,-(C1-C4) alkylidene-(C3-C6) cycloalkyl ,-(C1-C4) alkylidene-(C3-C6) heterocyclic radical ,-(C1-C4)
Alkylidene-(C6-C10) aryl and-(C1-C4) alkylidene-(C1-C9) heteroaryl is optionally independently selected from-D by 1,2,3 or 4 ,-
F ,-Cl, N3,-CN ,-OH ,-NH2, the substituent group of alkoxyl or alkyl amino is replaced；In other embodiments, RaCan
Think (C1-C3) alkyl, (C1-C3) thiazolinyl, (C1-C6) alkynyl, (C3-C6) cycloalkyl or-(C1-C3) alkylidene-(C3-C6) ring
Alkyl, described each (C1-C3) alkyl, (C1-C3) thiazolinyl, (C1-C6) alkynyl, (C3-C6) cycloalkyl and-(C1-C3) alkylidene-(C3-
C6) the cycloalkyl substituent group that is optionally independently selected from D or F by 1,2,3 or 4 replaced；, in other embodiments, Ra
Can also be (C1-C2) alkyl, and the substituent group being optionally independently selected from D or F by 1,2,3 or 4 replaced；
RbAnd RcIndependently be H, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclic radical, (C6-C10) aryl, (C1-
C9) heteroaryl ,-(C1-C4) alkylidene-(C3-C6) cycloalkyl ,-(C1-C4) alkylidene-(C3-C6) heterocyclic radical ,-(C1-C4) alkylene
Base-(C6-C10) aryl or-(C1-C4) alkylidene-(C1-C9) heteroaryl；Described each (C1-C6) alkyl, (C3-C6) cycloalkyl,
(C3-C6) heterocyclic radical, (C6-C10) aryl, (C1-C9) heteroaryl ,-(C1-C4) alkylidene-(C3-C6) cycloalkyl ,-(C1-C4) alkylene
Base-(C3-C6) heterocyclic radical ,-(C1-C4) alkylidene-(C6-C10) aryl and-(C1-C4) alkylidene-(C1-C9) heteroaryl optionally by
1,2,3, or 4 be independently selected from D, F, Cl, N3,-CN ,-OH ,-NH2, the substituent group of alkoxyl or alkyl amino is replaced；At other
In some embodiments, Rb、RcH, (C can also be independently be1-C3) alkyl, (C3-C6) cycloalkyl or-(C1-C4) alkylidene-(C3-
C6) alkyl；Described each (C1-C3) alkyl, (C3-C6) cycloalkyl and-(C1-C4) alkylidene-(C3-C6) alkyl optionally by 1,2,3 or
4 substituent groups being independently selected from D or F are replaced；In other embodiments, Rb、RcH or (C can also be independently be1-C2)
Alkyl；Described (C1-C2) alkyl and (C3-C6) the heterocyclic radical substituent group that is optionally independently selected from D or F by 1,2,3 or 4 replaced；
In the present invention, R is worked asbAnd RcWhen being connected with same nitrogen-atoms, Rb, RcAnd together with the nitrogen-atoms being connected with them,
(C can also be optionally formed3-C6) heterocyclic radical, i.e. Rb, RcAnd together with the nitrogen-atoms being connected with them, (C can be formed3-C6) miscellaneous
Ring group, it is also possible to be formed without heterocyclic radical, other structures being well known to those skilled in the art, such as N-Ra-RbOr Ra-N-RbDeng.
The compound of formula (I) structure of the present invention includes but not limited to compound or its nitrogen oxides in detail below,
Hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug:
Unless other aspects show, all of stereoisomer of compound of the present invention, geometric isomer, tautomerism
Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug broadly fall into the model of the present invention
Enclose.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes that material or compositions must
Must be suitable for chemistry or toxicologically, with composition preparation other components and for treatment mammal relevant.
The salt of the compound of the present invention also includes the intermediate for compound shown in preparation or purification formula (I) or formula (I)
The salt of the enantiomer that shown compound separates, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, the most conceivable salt can by provide on document any suitably
Method prepares, and such as, uses mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid etc..Or use organic
Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, acetone acid, oxalic acid, glycolic and salicylic acid；Pyrans
Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Aminoacid, such as aspartic acid and paddy
Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethyl sulfonic acid, etc..
If the compound of the present invention is acid, the most conceivable salt can be prepared by suitable method, e.g.,
Use inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc.
Deng.Suitably salt includes, but is not limited to, the organic salt obtained from aminoacid, and such as glycine and arginine, ammonia, such as primaquine, secondary
Ammonia and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium
Inorganic salt.
The present invention also comprises the compound of the present invention and the application of pharmaceutically acceptable salt thereof, is i.e. used for producing medicine product
There is the disease of mediation in product treatment acute and chronic blood vessel, including the application in producing cancer therapy drug that those are described in the invention.
The compound of the present invention is equally used for producing a kind of medical supplies and alleviates, and stops, controls or treat to be situated between by ALK or c-Met
The disease led.The present invention comprises pharmaceutical composition, and this pharmaceutical composition includes the compound representated by formula (I) and at least one medicine
Consumption is effectively treated needed for the combination of acceptable carrier on, adjuvant or diluent.
The present invention comprises treatment patient vessel equally and the disease of mediation, or the method sensitive to this disease, the method occurs
Comprise the therapeutically effective amount of compound representated by use formula (I) patient is treated.
Compositions
According on the other hand, present invention also offers a kind of pharmaceutical composition, including the compound of formula (I), institute of the present invention
The compound listed, or the compound of embodiment 1-24, and pharmaceutically acceptable carrier, adjuvant, or excipient.The present invention's
In compositions, the amount of compound can effectively, detectably suppress biological sample or protein kinase in the patient.
There is free form in the compound of the present invention, or suitably, as pharmaceutically acceptable derivates.According to this
Bright, pharmaceutically acceptable derivates includes, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of esters, or energy
Directly or indirectly according to other any adduct or derivants of needing to be administered of patient, described by other aspects of the present invention
Compound, its metabolite or his residue.
As described in the invention, the pharmaceutically acceptable compositions of the present invention comprises pharmaceutically acceptable load further
Body, adjuvant, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, point
Powder or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, etc.,
It is suitable for distinctive target formulation.As described by documents below: In Remington:The Science and Practice
of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,
Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick
And J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of document, shows difference the most herein
Carrier can be applicable to the preparation of pharmaceutically acceptable compositions and preparation method known to them.Load except any routine
The scope that the compound of body medium and the present invention is incompatible, such as produced any bad biological effect or with pharmaceutically may be used
The interaction that any other component of the compositions accepted produces in harmful manner, their purposes is also that the present invention is examined
The scope considered.
Can include, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminum, aluminium stearate, ovum
Phospholipid, serum albumin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable butter
The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination
Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymerization
Body, lanoline, sugar, such as lactose, dextrose plus saccharose；Starch such as corn starch and potato starch；Cellulose and its derivant
Such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate；Natural gum powder；Fructus Hordei Germinatus；Gelatin；Pulvis Talci；Adjuvant such as cacao bean
Fat and suppository wax；Oil is such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines；Glycols chemical combination
Thing, such as propylene glycol and Polyethylene Glycol；Esters such as ethyl oleate and Ethyl Lauroyl acid esters；Agar；Buffer agent such as magnesium hydroxide and
Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol, phosphate buffer solution, and other are nontoxic
Proper lubrication agent such as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating agents, sweeting agent, flavoring agent and perfume (or spice)
Material, preservative and antioxidant.
The compositions of the present invention can be oral administration, drug administration by injection, Aerosol inhalation, topical, and per rectum is administered,
Nose administration, buccal administration, vagina administration or be administered by implantable medicine box.Term used herein " through injection " includes
Subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, ophthalmic, in liver, focus
In, and the injection of intracranial or infusion techniques.Preferably compositions is oral administration, to Intraperitoneal medication or intravenous injection.This
The injection system of the composition sterile of invention can be water or oleaginous suspension.These suspensions can be according to known skill
Art uses suitable dispersant, wetting agent and suspending agent to press formula manufacture.Aseptic injection can be aseptic parenteral solution or suspension
Liquid, is to inject nontoxic acceptable diluent or solvent, such as 1,3 butylene glycol solution.These acceptable excipient and solvents
Can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil is the most permissible
As solvent or suspension media.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG of synthesis.Fat
Acid, as oleic acid and its glyceride ester derivatives can be used for the preparation of injectable, as natural pharmaceutically acceptable oil
Fat, such as olive oil or Oleum Ricini, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain
Alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, be generally used for the medicine system of pharmaceutically acceptable dosage form
Agent includes emulsion and suspension.Other conventional surfactants, such as Tweens, spans and other emulsifying agents or biological medicament
The hardening agent of efficiency, is generally used for pharmaceutically acceptable solid, liquid, or other dosage forms, it is possible to be applied to drug target
The preparation of preparation.
The pharmaceutically acceptable compositions of the present invention can be to carry out oral administration with any acceptable peroral dosage form, its
In include, but is not limited to, capsule, tablet, water suspension or solution.Orally using about tablet, carrier generally comprises breast
Sugar and corn starch.Lubricant, such as magnesium stearate, is the most typically added.Capsule oral is administered, suitable diluent bag
Include lactose and dry corn starch.When oral administration is water suspension, its effective ingredient is made up of emulsifying agent and suspending agent.
If it is desired to obtain these dosage forms, some sweeting agent, flavoring agent or coloring agent can also be added.
It addition, the pharmaceutically acceptable compositions of the present invention can be with the form rectally of suppository.These can pass through
Reagent is mixed with suitable non-perfusing accessory drugs and forms, this accessory drugs be at room temperature solid but at a temperature of rectum then
For liquid, thus melt in the rectum and discharge medicine.Such material includes cocoa butter, Cera Flava, and polyethylene glycols.This
Inventing pharmaceutically acceptable compositions can be topical, particularly during local application, relates to controlling of region or organ
Treat target easily to reach, such as the disease of eye, skin or lower intestinal tract.Suitably topical preparations can prepare and be applied to
These fields or organ.
Above-mentioned rectal suppository or suitably enema can apply to the local application of lower intestine.Local skin speckle also may be used
With such medication.For local application, pharmaceutically acceptable compositions can be prepared as suitable ointment by formulation method, should
Ointment packets is suspended or dissolved in one or more carrier containing active component.The carrier compound of topical of the present invention includes,
But it is not limited to mineral oil, liquid paraffin, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifing wax and water.
It addition, pharmaceutically acceptable compositions can be prepared as suitable lotion or Emulsion, this lotion or Emulsion comprise active component
It is suspended in or is dissolved in one or more pharmaceutically acceptable carrier.Suitably carrier includes, but is not limited to, mineral oil, department
Dish-60(Arlacel-60), polysorbate60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2-octyl group 12
Alkanol, benzyl alcohol and water.
Preparation be can be prepared as, such as isotonic micronized suspension, pH for ophthalmically acceptable, pharmaceutically acceptable compositions
The Sterile Saline of regulation or other aqueous solutions, it is preferable that isosmotic solution and the Sterile Saline of pH regulator or other aqueous solutions, permissible
Add disinfection preservative such as benzalkonium chloride.It addition, for ophthalmically acceptable, pharmaceutically acceptable compositions can be by pharmaceutical formulation system
Standby one-tenth ointment such as vaseline oil.The pharmaceutically acceptable compositions of the present invention can by the gaseous solvents of nose or inhalant carry out to
Medicine.Such compositions can prepare according to the known technology of pharmaceutical formulation, or can be prepared as saline solution, uses benzene first
Alcohol or other suitable preservative, absorption enhancer, fluorocarbon or other conventional solubilizing agents or dispersant improve biology
Availability.
The liquid dosage form of oral administration includes, but is not limited to, pharmaceutically acceptable Emulsion, microemulsion, solution, suspends
Liquid, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, such as, water
Or other solvents, solubilizing agent and emulsifying agent, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
Propylene glycol, 1,3 butylene glycol, dimethylformamide, oils and fats (particularly Semen Gossypii, Semen arachidis hypogaeae, Semen Maydis, microorganism, Fructus Canarii albi, Semen Ricini and
Oleum Sesami), glycerol, Tetrahydrofurfuryl Alcohol, Polyethylene Glycol, sorbitan alcohol fatty acid ester, and their mixture.Except lazy
Outside the diluent of property, Orally administered composition can also comprise adjuvant such as wetting agent, emulsifying agent or suspending agent, sweeting agent, flavoring agent
And aromatic.
Injection, as aseptic parenteral solution or oleaginous suspension can according to known technology use suitable dispersant,
Wetting agent and suspending agent are prepared by pharmaceutical formulation.Aseptic injection can be nontoxic through the most acceptable diluent
Or aseptic parenteral solution, suspension or the emulsion that solvent is made, such as, 1,3 butylene glycol solution.Acceptable excipient and solvent
Can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.It addition, aseptic nonvolatile oil is by convention
As solvent or suspension media.The nonvolatile oil of the most any gentleness can include that the list of synthesis or two glycosyl are sweet
Oil diester.It addition, fatty acid such as oleic acid can apply to injection.
Injection can be aseptic, as filtered by antibacterial defence filter, or the form with aseptic solid composite
Mix biocide, during biocide can be dissolved in or be scattered in disinfectant or other sterile injectable medium before use.In order to prolong
The effect of the compound of the long present invention, it usually needs slowed down the absorption of compound by subcutaneous injection or intramuscular injection.So
Can realize utilizing liquid suspension to solve crystal or the problem of amorphous material poorly water-soluble.The absorbance of compound depends on
Its dissolution, depends on grain size and crystal shape successively.Furthermore it is possible to dissolved in oil vehicles by compound
Or the delay having disperseed compound injection to be administered absorbs.
Injection storage form is to form chemical combination by biodegradable polymer, such as many lactic acid-polyglycolide
The microcapsule matrix of thing completes.The controlled release ratio of compound depends on that compound forms ratio and the particular polymer of polymer
Character.Other biodegradable polymers include poly-(positive esters) and poly-(anhydride).Injection storage form can also be passed through
Compound embeds the liposome compatible with bodily tissue or microemulsion prepares.
Some of them embodiment is, the compositions of rectum or vagina administration is suppository, and suppository can be by by the present invention's
The adjuvant of compound and suitable non-perfusing or carrier mix and prepare, as wax-like in cocoa butter, Polyethylene Glycol, or suppository
Thing, they are solid in room temperature but are the most then liquid, therefore just melt release of active in vagina or cavity of tunica vaginalis and close
Thing.
The solid dosage forms of oral administration includes capsule, tablet, pill, powder and granule.In these dosage forms, active ingredient
Thing mixes with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or filler or a)
Filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binding agent such as carboxymethyl cellulose, alginate, bright
Glue, polyvidon, sucrose and arabic gum, c) wetting agent such as glycerol, d) disintegrating agent such as agar, calcium carbonate, potato starch
Or tapioca, alginic acid, some silicate and sodium carbonate, e) blocker solution such as paraffin, f) absorption enhancer such as quaternary ammonium
Compound, g) wetting agent such as hexadecanol and glyceryl monostearate, h) absorbent such as kaolin and Bentonite, i) lubricant such as Talcum
Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium laurylsulfate, and their mixture.As for capsule, tablet and ball
Agent, these dosage forms can comprise buffer agent.
The solid composite of similar type can be that filler riddles soft or hard capsule, and the adjuvant used has breast
Sugared and high molecular Polyethylene Glycol etc..Solid dosage forms photo agent, lozenge, capsule, pill and granule can pass through coating, shell adding
Coating method as known on enteric coating and other drug preparation prepares.They can optionally comprise opacifier, or
Preferably, in certain part of intestinal, at random, with the sole active agent in the method release composition of delay.As implanted
Compositions can comprise multimeric species and wax.
Reactive compound can form microcapsule formulations together with one or more excipient described in the invention.Solid
Dosage form photo agent, lozenge, capsule, pill and granule can pass through coating or shell adding, such as enteric coating, controlled release coat and other public affairs
The drug formulation process known.In these solid dosage formss, reactive compound can mix with at least one inert diluent, such as sugarcane
Sugar, lactose or starch.Such dosage form can also comprise substance besides inert diluents as general application, as
Tableting lubricant and other compression aids such as magnesium stearate and microcrystalline Cellulose.As for capsule, tablet and pill, these dosage forms can
To comprise buffer agent.They can optionally comprise tranquilizer, or preferably, in certain part of intestinal, with arbitrarily postpone
Sole active agent in method release composition.Applicable implant compositions can include, but is not limited to, polymer and
Wax.
The compound of the present invention by local or include ointment through the dosage form of percutaneous drug delivery, paste, Emulsion, lotion, solidifying
Colloid, powder, solution, spray, inhalant, paster.Active component under sterile conditions with pharmaceutically acceptable carrier
Mix mutually with any required preservative or required buffer agent.The pharmaceutical preparation of ophthalmology, ear drop and eye drop are all these
The scope of bright consideration.It addition, present invention further contemplates that the application of transdermal patch, it is delivered to internal aspect at control compound has
More advantage, such dosage form can be prepared in suitable medium by dissolving or decentralized compound.Absorb and promote
Enter agent and can increase compound through the flow of skin, through-rate control thin film or compound is scattered in polymer matrix or
Gelatin controls its speed.
The compound of the present invention is preferably prepared as dosage unit form to alleviate the equal of dosage and dosage by pharmaceutical formulation
Even property.Term " dosage " unit type " the physical dispersion unit of required medicine is suitably treated referred to herein as patient.But, should
Understand the compound of the present invention or total usage compositions every day will judge to come according to reliable medical science scope by the doctor in charge
Determine.For any one special patient or organism, concrete effective dose level will depend upon which that many factors include being controlled
The disease treated and the seriousness of disease, the activity of particular compound, concrete compositions used, the age of patient, body weight, health
Situation, sex and dietary habit, administration time, route of administration and the discharge rate of particular compound used, during treatment lasting
Between, medicinal application is combined in drug combination or with specific compound, and factor known to some other pharmaceutical field.
The change of the consumption that can produce the compound of the present invention of single dosage form composition in conjunction with carrier mass is depended on
Cure mainly and special mode of administration.Some of them embodiment is, compositions can be prepared as dosage at 0.01-by formulation method
The inhibitor of 200mg/kg body weight/day, the amount being accepted compositions by patient is administered.
The compound of the present invention can be with only pharmaceutical agents or combine other additional treatment (pharmacy one or more
) agent is administered, wherein drug combination causes acceptable untoward reaction, and this has for the treatment of high proliferative disease such as cancer
There is special meaning.In this case, the compound of the present invention can be in conjunction with known cytotoxic agent, and single transduction suppresses
Agent or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, additional treatment agent is normally administered and controls
Treat special disease, it is simply that known " treating disease suitably "." additional treatment agent " used in the present invention includes Chemo-Therapy
Treat medicine or other antiproliferative medicines can be in conjunction with the compounds for treating proliferative disease of the present invention or cancer.
Chemotherapeutic agent or other anti-proliferative drugs include histon deacetylase (HDAC) (HDAC) inhibitor, including but also
It is not limited to, SAHA, MS-275, MGO103, and those compounds described by following patent: WO2006/010264, WO03/
024448,WO2004/069823,US2006/0058298,US2005/0288282,WO00/71703,WO01/38322,
WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/092899, and demethylation examination
Agent includes, but is not limited to, the miscellaneous nitrogen of 5--2 '-deoxycytidine (5-aza-dC), azacitidine (Vidaza), decitabine
(Decitabine) compound and described by documents below: US6,268137, US5,578,716, US5,919,772, US6,
054,439, US6,184,211, US6,020,318, US6,066,625, US6,506,735, US6,221,849, US6,953,
783,US11/393,380。
Other embodiment is, chemotherapy agents or other anti-proliferative drugs can increase in conjunction with the compounds for treating of the present invention
Growing property disease and cancer.Known chemotherapy agents includes, but is not limited to, can use with anti-cancer agent in combination of the present invention other
Therapy or cancer therapy drug, operation, X-ray therapy (a little example such as gamma-radiation, neutron beam X-ray therapy, electron beam evaporation therapy,
Proton therapy, brachytherapy and system isotope therapy), incretotherapy, taxanes (paclitaxel
(Taxol), Docetaxel (Taxotere) etc.), platinum derivatives (cisplatin (Cisplatin), carboplatin (Carboplatin), difficult to understand
Husky profit platinum (oxaliplatin), Satraplatin (satraplatin)), biological response modifier (interferon, interleukin), tumor
Necrosin (TNF, TRAIL receptor target thing), overheated and cryotherapy, alleviate the reagent of any untoward reaction (such as emesis
Medicine), and other approved chemotherapeutics, include, but are not limited to, alkylating drug (chlormethine (mechlorethamine), benzene fourth
Acid chlormethine (chlorambucil), cyclophosphamide (cyclophosphamide), melphalan (melphalan), ifosfamide
(Ifosfamide)), antimetabolite (methotrexate (Methotrexate), pemetrexed (Pemetrexed) etc.), purine
Antagonist and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5-fluorouracil (5-Fluorouracil), arabinose
Cytidine (Cytarabile), gemcitabine (Gemcitabine)), spindle poison (vinblastine (Vinblastine), Changchun
New alkali (Vincristine), vinorelbine (Vinorelbine)), (etoposide (Etoposide), Yi Li replaces podophyllotoxin
Health (Irinotecan), hycamtin (Topotecan)), antibiotic (amycin (Doxorubicin), bleomycin
(Bleomycin), mitomycin (Mitomycin)), nitroso ureas (carmustine (Carmustine), lomustine
(Lomustine)), (KSP passes through mitotic kinesin inhibitors to cell division cycle inhibitor, CENP-E and CDK suppresses
Agent), enzyme (asparaginase (Asparaginase)), hormone (tamoxifen (Tamoxifen), leuprorelin
(Leuprolide), flutamide (Flutamide), megestrol (Megestrol), dexamethasone (Dexamethasone) etc.
Deng).Angiogenesis inhibitor reagent (Avastin (Avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (Belimumab), Brentuximab,
Cetuximab (Cetuximab), gemtuzumab Ozogamicin Mylotarg CDP 771 (Gemtuzumab), her monoclonal antibody (Ipilimumab), Ofatumumab, handkerchief
Buddhist nun's monoclonal antibody (Panitumumab), Lucentis (Ranibizumab), Rituximab (Rituximab), tositumomab
(Tositumomab), Herceptin (Trastuzumab)).Inhibitors of kinases (imatinib (Imatinib), Sutent
(Sunitinib), Sorafenib (Sorafenib), Erlotinib (Erlotinib), gefitinib (Gefitinib), reach sand
For Buddhist nun (Dasatinib), AMN107 (Nilotinib), Lapatinib (Lapatinib), gram Zhuo replaces Buddhist nun (Crizotinib),
Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, etc.).The approach of Drug inhibition or activation cancer is such as
MTOR, HIF (hypoxia inducible factor) approach and other.Http sees in the wide forum for the treatment of of cancer: //
Http:// www.fda.gov/cder/cancer/ is shown in by the oncologic inventory of www.nci.nih.gov/, FAD accreditation
Druglist-rame.htm, and Merck Manual, the 18th edition .2006, all of content is all combined with list of references.
Other embodiment is, the compound of the present invention can be in conjunction with cytotoxic anticancer agent.Such anticarcinogen can
To find the 13rd edition Merck index (2001) is inner.These anticarcinogen include, but are not limited to, asparaginase, rich next
Mycin, carboplatin, carmustine, chlorambucil, cisplatin, L-ASP, cyclophosphamide, cytosine arabinoside, dacarbazine, put
Line rhzomorph D, daunorubicin, amycin (doxorubicin), epirubicin, etoposide, 5-fluorouracil, hexamethyl melamine
Amine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, chlormethine, Ismipur, mesna, first ammonia butterfly
Purine, ametycin, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, sulfur
Guanine, hycamtin, vinblastine, vincristine, and vindesine.
Include, but is not limited to other suitable cytotoxic drugs of the compound drug combination of the present invention, these
It is applied to the compound of neoplastic disease treatment admittedly, as described in documents below: Goodman and Gilman's
The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；This
A little anticarcinogen include, but are not limited to, aminoglutethimide (Aminoglutethimide), ASP, azathioprine, 5-
Azacytidine, cladribine (Cladribine), busulfan (Busulfan), diethylstilbestrol, 2,2'-difluoro dCDP gallbladders
Alkali, Docetaxel, red hydroxyl nonyl adenine (Erythrohydroxynonyladenine), ethinylestradiol, 5-fluorine
Uracil deoxynucleoside, floxuridine monophosphate, fludarabine phosphate (Fludarabine phosphate), Fluoxymesterone
Ketone (Fluoxymesterone), flutamide (Flutamide), hydroxyprogesterone caproate, idarubicin (Idarubicin), interferon,
Medroxyprogesterone acetate, megestrol acetate, melphalan (Melphalan), mitotane (Mitotane), paclitaxel, pentostatin
(Pentostatin), N-phosphate base-L-Aspartic acid (PALA), plicamycin (Plicamycin), methyl cyclohexane nitrous
Urea (Semustine), teniposide (Teniposide), testosterone propionate, phosphinothioylidynetrisaziridine (Thiotepa), trimethyl melamine
Amine, urine nucleoside and vinorelbine.
Other are suitably and the cytotoxin class anticarcinogen of compound use in conjunction of the present invention includes newfound cell
Toxic substance, including, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), card training
His shore (Capecitabine), Macrolide antineoplastic agent and naturally occurring or synthetic derivant, temozolomide
(Temozolomide) (Quinn et al., J.Clin.Oncology, 2003,21 (4), 646-651), tositumomab
(Bexxar), Trabedectin (Vidal et al., Proceedings of the American Society for
Clinical Oncology, 2004,23, abstract3181), and kinesin spindle protein inhibitor Eg5 (Wood
et al.,Curr.Opin.Pharmacol.2001,1,370-377)。
Other embodiment is, the compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is letter
Number transduction inhibitor using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000,
60(Suppl.l),15-23;Harari et al., Oncogene, 2000,19 (53), 6102-6114) and the joining of each of which
Body.Such reagent includes, but is not limited to, antibody therapy such as Herceptin (Trastuzumab), Cetuximab
(Cetuximab), her monoclonal antibody (Ipilimumab) and handkerchief trastuzumab (Pertuzumab).Such therapy also includes, but
It is not limited to, small molecule kinase inhibitors such as imatinib (Imatinib), Sutent (Sunitinib), Sorafenib
(Sorafenib), Erlotinib (Erlotinib), gefitinib (Gefitinib), Dasatinib (Dasatinib), Ni Luo
For Buddhist nun (Nilotinib), Lapatinib (Lapatinib), gram Zhuo replaces Buddhist nun (Crizotinib), Ruxolitinib,
Vemurafenib, Vandetanib, Pazopanib, Afatinib (Afatinib), amuvatinib, Axitinib
(axitinib), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171
(cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib,
Ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib
(masitinib), momelotinib, not for husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib,
Oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib,
Rucaparib, saracatinib (saracatinib), saridegib, tandutinib, tasocitinib, telatinib,
Tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib,
Volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941(Folkes, et al.,
J.Med.Chem.2008,51,5522), BZE235, etc..
Other embodiment is, the compound of the present invention can be with bonding histone deacetylase inhibitors.Such
Reagent includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings
of the American Society for Clinical Oncology,2004,23,abstract3024),LBH-589
(Beck et al.,Proceedings of the American Society for Clinical Oncology,2004,
23,abstract3025),MS-275(Ryan et al.,Proceedings of the American Association
of Cancer Research,2004,45,abstract2452),FR-901228(Piekarz et al.,Proceedings
Of the American Society for Clinical Oncology, 2004,23, abstract3028) and MGCDOI03
(US6,897,220)。
Other embodiment is, the compound of the present invention can be in conjunction with other anticarcinogen such as proteasome inhibitor and m-
TOR inhibitor.These include, but are not limited to, bortezomib (Bortezomib) (Mackay et al., Proceedings
Of the American Society for Clinical Oncology, 2004,23, Abstract3109), and CCI-779
(Wu et al.,Proceedings of the American Association of Cancer Research,2004,
45,abstract3849).The compound of the present invention can be combined with other anticarcinogen such as topoisomerase enzyme inhibitor, including but
It is not limited to camptothecine.
Those additional treatment agent can separate administration with the compositions of the compound comprising the present invention, as many dosage regimens
A part.Or, those therapeutic agents can be a part for one-pack type, mixes formation list with the compound of the present invention
Individual compositions.If being administered as the parts of many dosage regimens, two activating agents can be simultaneously continuously or in a period of time
Interior transmission mutually, thus obtain destination agent activity.
The compound of one-pack type and additional treatment agent can be produced in conjunction with carrier mass, its consumption (those comprise one attached
With the compositions of therapeutic agent as described in the invention) change depend on curing mainly and special mode of administration.Normally, the present invention
The amount of compositions additional treatment agent will comprise the therapeutic agent normal amount being administered as unique activating agent less than compositions.
On the other hand, the scope of the amount of existing disclosed compositions additional treatment agent is about the 50%-100% of existing compositions normal amount,
The reagent comprised is as sole active therapeutic agent.In those comprise the compositions of additional treatment agent, additional treatment agent will be with this
The compound of invention plays synergism.
Compound and the application of compositions
Above-claimed cpd and pharmaceutical composition that the present invention provides can be used for preparation for protecting, process, treat or alleviating
The medicine of proliferative disease, it is also possible to for preparation for suppressing or regulate the medicine of protein kinase activity.
Specifically, in the compositions of the present invention compound can the most detectably suppress protein kinase such as ALK or
The activity of c-Met.Patient can be treated as antitumor drug or reduce ALK and c-Met signal by the compounds of this invention
The illeffects of response.
The compound of the present invention can apply to, but is not limited to, and uses the compound of the present invention or the effective of compositions
Patient is administered by amount prevents or treats patient's proliferative disease.Such disease includes cancer, especially metastatic carcinoma, tremulous pulse medicated porridge
Sample hardening and pulmonary fibrosis etc..
The compound of the present invention and pharmaceutical composition can apply to the treatment of tumor, including cancer and metastatic carcinoma, further
Including, but are not limited to, cancer such as bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma (includes small cell lung cancer), esophagus
Cancer, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, gastric cancer, cervical cancer, thyroid carcinoma, carcinoma of prostate, and skin carcinoma (include squamous cell
Cancer)；Lymphsystem hematopoetic tumor (include leukemia, the Cystic leukemia of acute lymphoblastic, acute lymphoblastic leukemia, B
Cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and primary
Base spy's lymphoma)；(including acute and chronic myelocytic leukemia, myeloproliferative disorder is comprehensive for bone marrow system hematopoetic tumor
Disease, and promyelocitic leukemia)；The tumor of mesenchymal cell origin (includes fibrosarcoma and rhabdomyosarcoma, and Other Meat
Tumor, such as soft tissue and cartilage)；Maincenter peripheral nervous system tumor (include astrocytoma, neuroblastoma, glioma,
And schwannoma)；(melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma is included with other tumors
Pigmentosum, keratoctanthoma, thyroid follicle tumor and Ka Bo Ji (family name) sarcoma).
The compound of the present invention and pharmaceutical composition can be additionally used in treatment eye disease such as corneal graft rejection, eye new
Angiogenic is formed, and retinal neovascularazation includes that damage or metainfective new vessels are formed；Diabetic retinopathy；
Retrolental fibroplasia, and neovascular glaucoma；Retinal ischemia；Vitreous hemorrhage；Ulcer disease is such as
Gastric ulcer；Pathological but non-malignant situation such as hemangioma is bad including baby's hemangioendothelioma, nasopharynx and avascular bone
Dead fibrohemangioma；Female repro ductive system is disorderly such as endometriosis.These compounds equally be also used for treat edema and
The situation that vascular permeability is too high.
The compound of the present invention and pharmaceutical composition can be also used for processing the situation such as diabetic relevant to diabetes
Retinopathy and microangiopathy.The compound of the present invention and pharmaceutical composition are equally used for the feelings that cancer patient's blood flow reduces
Condition.Patient tumors transfer is reduced by the compound of the present invention and pharmaceutical composition also beneficial effect.
The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on
Thing, the animal of introduced variety and the animal on farm, including mammal, rodent etc..The example of other animal
Including horse, Canis familiaris L. and cat.Here, the compound of the present invention includes its pharmaceutically acceptable derivates.
Plural form is being applied to compound, and in the case of salt etc., it also means single compound, salt etc..
Present invention also offers the compound comprising the present invention or the Therapeutic Method of compositions administration, farther include trouble
The administration of person's additional treatment agent (therapeutic alliance), wherein additional treatment agent is selected from: chemotherapy, antiproliferative or antiinflammatory, its
Middle additional treatment agent is applicable to treated disease, and additional treatment agent can with the compound of the present invention or compositions combine to
Medicine, the compound of the present invention or compositions are as single dosage form, or separate compound or compositions are as one of multi-pharmaceutics
Point.Additional treatment agent can be administered simultaneously with the compound of the present invention or not be administered simultaneously.The situation of the latter, administration can be staggered
Carry out such as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, within 1 month or 2 months, carry out.
The present invention comprises equally to the cytostatic method expressing ALK or c-Met, and the method includes the present invention's
Compound or compositions and cells contacting, thus cell growth inhibiting.The cell that can be suppressed growth includes: breast cancer cell,
Colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate gland cancer cell, lymphoma cell, colon cancer cell, pancreas
Cancerous cell, ovarian cancer cell, cervical cancer cell, central nervous system's cancerous cell, human osteosarcoma cell, kidney cancer cell, liver is thin
Born of the same parents' cancerous cell, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukaemia.
The invention provides the method suppressing ALK or c-Met kinase activity in biological sample, the method includes this
Bright compound or compositions contact with biological sample.Term used in the present invention " biological sample " refers to the mark of vitro
This, include, but not limited to, and cell is cultivated or cell extraction；The biopsy thing obtained from mammal or its extract
Matter；Blood, saliva, urine, feces, seminal fluid, tear, or other living tissue liquid substance and extracts thereof.Suppression biological sample
Middle kinase activity, particularly ALK or c-Met kinase activity, can be used for multiple use known to one of ordinary skill in the art.So
Purposes include, but be not limited to, hematometachysis, organ transplantation, biological sample storage and bioassay.
The compound of the present invention or " effective dose " of pharmaceutically acceptable compositions or " effective dose " refer to process or
Alleviate the effective dose that one or more present invention is previously mentioned the severity of disease.The method according to the invention, compound and combination
Thing can be any dosage and any route of administration is efficiently used for the order of severity that processes or palliate a disease.Required standard
Situation according to patient is changed by true amount, and this depends on race, the age, the generic condition of patient, the order of severity of infection,
Special factor, administering mode, etc..Compound or compositions can with one or more other therapeutic agents administering drug combinations, as
The present invention is discussed.
The compound of the present invention or its pharmaceutical composition can apply to the coating of implantable medical device, such as prosthese,
Artificial valve, artificial blood vessel, stem and catheter.Such as, vascular stem, have been used for overcoming restenosis (vessel wall after injury
Shrink again).But, patient uses stem or other implantable devices to be formed having clot or the risk of platelet activation.These
Disadvantageous effect can be hindered by the pharmaceutically acceptable compositions precoating device of the compound that use comprises the present invention
Stop or alleviate.
Suitably the method that is typically prepared of the coating of coating and implantable device is at document US6,099,562;US5,886,
026;And US5, it being described in 304,121, coating is the most biocompatible polymeric material such as hydrogel polymeric
Body, poly-methyl two silicon ether, polycaprolactone, Polyethylene Glycol, polylactic acid, ethane-acetic acid ethyenyl ester, and mixture.Coating can
Optionally further to be covered by suitable coating, such as fluoro simethicone, polyase, Polyethylene Glycol, phospholipid, or
Combinations thereof, carrys out performing combination thing and controls the feature of release.Another aspect of the present invention includes the compound using the present invention
The implantable device of coating.The compound of the present invention can also be coated on the medical instruments in implantable, such as pearl, or
There is provided " medicine storage institute " with polymer or other molecular mixing, therefore compare with pharmaceutical aqueous solution administering mode, it is allowed to medicine
Thing release has longer time limit.
The synthetic method of compound
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further
Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this
The content of invention.
The professional of art is it will be appreciated that chemical reaction described in the invention can be used to prepare perhaps suitably
Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention
Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art
Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention
, or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business
Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical
Company, unless other aspects show, the most not through being further purified during use.General reagent is western Gansu Province chemical industry from Shantou
Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemistry in morning
Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited and Haiyang Chemical Plant, Qingdao purchase
Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride
It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N-
Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects
Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with
CDC13、d6-DMSO、CD3OD or d6-acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform (7.25ppm)
As reference standard.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, double
Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of
Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
The condition of Algorithm (MS) data is: Agilent1200 or Agilent6120Series LCMS (pillar
Model: Zorbax SB-C18,2.1 × 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Flowing phase: 5-95%(is containing 0.1%
The CH of formic acid3CN) at (H containing 0.1% formic acid2O) ratio in, detects at 210/254nm UV, by low-response EFI pattern
(ESI)。
The characteristic manner of pure compound is: Agilent1100Series high speed liquid chromatography (HPLC), at 210nm
Detect with 254nm UV.Pillar generally operates under 40 ° of C.
BBr3Boron tribromide
Double diphenyl phosphine-1,1'-the dinaphthalene of BINAP 2,2'-
BOC, Boc tert-butoxycarbonyl
BSA bovine serum albumin
CDC13Deuterochloroform
CHCl3Chloroform
CH2Cl2, DCM dichloromethane
CH3SO2Cl, MsCl paratoluensulfonyl chloride
Cs2CO3Cesium carbonate
Cu copper
CuI Hydro-Giene (Water Science).
DAST diethylaminosulfur trifluoride
DBU 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene
DEAD diethyl azodiformate
DIAD diisopropyl azodiformate
DIBAL diisobutyl aluminium hydride
DIEA, DIPEA diisopropyl ethyl amine
DMAP DMAP
DMF DMF
DMSO dimethyl sulfoxide
DPPA diphenyl phosphate azide
EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc, EA ethyl acetate
Et2O ether
Et3N, TEA triethylamine
FBS hyclone
Fe ferrum
G gram
H hour
HATU O-(7-nitrogen BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester
HBr hydrobromic acid
HBTU O-BTA-N, N, N', N'-tetramethylurea hexafluorophosphate
HCl hydrochloric acid
H2Hydrogen
H2O water
H2O2Hydrogen peroxide
HOAc, AcOH acetic acid
HOBt I-hydroxybenzotriazole
K2CO3Potassium carbonate
KOH potassium hydroxide
LiHMDS LHMDS
LDA lithium diisopropyl amido
MCPBA metachloroperbenzoic acid
MeCN, CH3CN acetonitrile
MeI iodomethane
MeOH, CH3OH methanol
2-MeTHF 2-methyltetrahydrofuran
MgSO4Magnesium sulfate
ML, ml milliliter
N2Nitrogen
NaBH4Sodium borohydride
NaBH3CN sodium cyanoborohydride
NaCl sodium chloride
NaClO2Sodium chlorite
NaH sodium hydride
NaHCO3Sodium bicarbonate
NaH2PO4Sodium dihydrogen phosphate
NaI sodium iodide
NaO (t-Bu) sodium tert-butoxide
NaOH sodium hydroxide
Na2SO4Sodium sulfate
NBS N-bromo-succinimide
NH3Ammonia
NH4C1 ammonia chloride
NIS N-N-iodosuccinimide
NMP N-Methyl pyrrolidone
PBS phosphate buffered saline (PBS)
P(t-Bu)3Three (tert-butyl group) phosphine
Pd/C palladium/carbon
Pd2(dba)3Double (dibenzyl subunit acetone) palladium
Pd(dppf)Cl2Double (diphenylphosphino) the ferrocene palladium chloride of 1,1-
Pd(OAc)2Palladium
Pd(OH)2Palladium dydroxide
Pd(PPh3)4Tetrakis triphenylphosphine palladium
Pd(PPh3)2Cl2Double (triphenylphosphine) palladium chloride
PE petroleum ether (60-90 ° of C)
POC13Phosphorus oxychloride
PyBop 1H-benzotriazole-1-base oxygen tripyrrole alkyl hexafluorophosphate
RT, rt, r.t. room temperature
Rt retention time
TBAB tetrabutyl ammonium bromide
TBAHSO44-butyl ammonium hydrogen sulfate
TBTU O-(1H-benzotriazole-1-base)-N, N, N', N'-tetramethylurea Tetrafluoroboric acid ester
TFA trifluoroacetic acid
TEAC bis-(tetraethyl ammonium) carbonate
THF oxolane
μ L microlitre
Following synthetic schemes describes the preparation present invention and comes into the open the step of compound.Unless otherwise indicated, R1, R2, R3, R4,
R5, R6With Z, there is definition as described in the present invention.
Synthetic method 1
Compound shown in formula (I) can be prepared by following process:
Formula (1(R)-aryl alcohol shown in) and formula (2Substituted fluorinated pyridine shown in) is under the effect of sodium hydride, non-
In proton solvent such as oxolane react, obtain formula (3Coupled product shown in).Formula (3Pyridine ring in coupled product shown in)
On nitro under the conditions of acidic reduction, use reducing agent such as iron powder change an accepted way of doing sth (4Amino-compound shown in).Then exist
Under NBS effect, by the regioselectivity bromination on pyridine ring, obtain formula (5Compound shown in).Finally, formula (5Shown in)
Compound and formula (6Alkynes shown in), such as 2-methyl butyl-3-alkynes-2 alcohol, under suitable Pd catalyst action, coupling production
(I) compound shown in, course of reaction is as follows:
Synthetic method 2
Compound shown in formula (I) can be prepared by following process:
According to the method in synthetic method 1 or additive method prepare formula (5Compound shown in), formula (5Shown in)
Compound and Boc anhydride in the presence of alkali such as sodium carbonate, sodium bicarbonate or triethylamine, production (8Amino shown in) is protected
Protect compound.Formula (8Amino protecting compound shown in) and connection boric acid pinacol ester are at applicable Pd catalyst, such as Pd (dppf)
Cl2·CH2Cl2With Pd (PPh3)2Cl2The lower coupling of effect, obtain formula (9Boronic acid compounds shown in), this reaction is at aprotic
Solvent (e.g., dimethyl sulfoxide, DMF or dioxane) is carried out.Afterwards, at alkali and catalyst such as Pd (dppf)
Cl2·CH2Cl2In the presence of, formula (9Boronic acid compounds shown in) and formula (10Nitrogen-containing heterocycle compound shown in) occurs
Suzuki reacts, production (11Compound shown in).The alkali being suitable in Suzuki reaction includes sodium bicarbonate, potassium bicarbonate,
Sodium carbonate, potassium carbonate, cesium carbonate, and other.This reaction is preferably at mixed solvent, such as glycol dimethyl ether/water, dioxane/water
In carry out, temperature controls between 70～100 ° of C.Finally, in acid condition, such as the dichloromethane solution of trifluoroacetic acid, chlorine
Change the ethyl acetate solution of hydrogen, slough Boc and other protection groups, obtain the compound shown in formula (I), the following institute of course of reaction
Show:
The present invention uses following methods that the compound shown in formula (I) carries out biologic test:
1, bioanalytical method
LC/MS/MS system is used to be analyzed, including Agilent1200 series vacuum degassing furnace, binary syringe pump, hole
Plate automatic sampler, post calorstat, tri-grades of level Four bar mass spectrographs of Agilent G6430 in charged spray ionization (ESI) source.Quantitatively
Analyze carry out under MRM pattern, MRM conversion parameter as in Table A:
The parameter of Table A MRM conversion
| Many reaction detection scan | 490.2→383.1 |
| Fragmentation voltage | 230V |
| Capillary voltage | 55V |
| Dryer temperature | 350°C |
| Nebulizer | 40psi |
| Exsiccator flow velocity | 10L/min |
Analyze and use Agilent XDB-C18,2.1x30mm, 3.5 μM post, inject 5 μ L sample.Analysis condition: flowing phase
It is aqueous formic acid (A) and the formic acid methanol solution (B) of 0.1% of 0.1%.Flow velocity is 0.4mL/min.Eluent gradient such as table B
Shown in:
Table B eluent gradient
| Time | The gradient of Mobile phase B |
| 0.5min | 5% |
| 1.0min | 95% |
| 2.2min | 95% |
| 2.3min | 5% |
| 5.0min | Stop |
Additionally, also have Agilent6330 series LC/MS/MS spectrogrph for analyze, inject equipped with G1312A binary
Pump, G1367A automatic sampler and G1314C UV detector；LC/MS/MS spectrogrph uses ESI radioactive source.Use titer
Each analyte is carried out suitable cation models treated and MRM conversion carries out optimal analysis.Use during analyzing
Capcell MP-C18 post, specification is: 100x4.6mm I.D., 5 μMs (Phenomenex, Torrance, California,
USA).Flowing is 5mM ammonium acetate mutually, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30,
v/v)；Flow velocity is 0.6mL/min；Column temperature is maintained at room temperature；Inject 20 μ L sample.
2, compound stability analysis in people and rat liver microsomes
(1) people or rat liver microsomes are placed in polypropylen tubes hatch, and guide it to replicate.Typically hatch mixing
Liquid includes people or rat liver microsomes (0.5mg protein/mL), and compound to be analyzed (5 μMs) and cumulative volume are 200 μ L
NADPH (1.0mM) kaliumphosphate buffer (PBS, 100mM, pH value is 7.4), is analysed to compound dissolution in DMSO, and makes
Diluted with PBS so that it is the concentration of final DMSO solution is 0.05%.And the water-bath communicated with air under 37 ° of C is entered
Row is hatched, and adds albumen and start reaction in 3 minutes backward mixed liquors of preincubate.At different time points (0,5,10,15,30
And 60min), add same volume ice-cold acetonitrile and terminate reaction.Sample preserves until carrying out LC/MS/MS analysis under-80 ° of C.
Compound concentration in people or rat liver microsomes mixtures incubated is that the method by LC/MS/MS measures
's.The range of linearity of concentration range is determined by each test-compound.
Parallel hatch test and use the microsome of degeneration as negative control, hatch under 37 ° of C, react when different
Between point (0,15 and 60 minute) terminate.
Dextromethorphan (70 μ Μ), as positive control, is hatched under 37 ° of C, react different time point (0,5,10,
15,30 and 60 minutes) terminate.Each assay method all includes the positive and negative control sample, to ensure that microsome is hatched
The integrity of system.
(2) compound of the present invention stability data in people or rat liver microsomes also can be obtained by tests below
To: people or rat liver microsomes are placed in polypropylen tubes and hatch, and guide it to replicate.Typical mixtures incubated includes people
Or rat liver microsomes (ultimate density: 0.5mg albumen/mL), compound to be analyzed (ultimate density: 1.5 μMs) and cumulative volume are
The K-buffer solution (containing 1.0mM EDTA, 100mM, pH7.4) of 30 μ L.It is analysed to compound dissolution in DMSO, and uses K-
Buffer solution dilutes, and the ultimate density making DMSO is 0.2%.After preincubate 10 minutes, add 15 μ L NADPH (ultimate density:
2mM) carrying out enzymatic reaction, whole test is carried out in the incubation tube of 37 ° of C.At different time points (0,15,30 and 60 point
Clock), add 135 μ L acetonitrile (containing IS) and terminate reaction.It is centrifuged 10 minutes with 4000rpm, removes albumen, collect the supernatant, use
LC-MS/MS analyzes.
In above-mentioned test, ketanserin (1 μM) is selected as positive control, hatches under 37 ° of C, and reaction is in the different time
Point (0,15,30 and 60 minute) terminates.Each assay method all includes positive control sample, to ensure that microsome hatches body
The integrity of system.
The present invention uses following methods to carry out data analysis, to obtain stability analysis result:
Each is reacted, compound concentration (as a percentage) in people or rat liver microsomes are hatched is pressed
The plotted as percentage of Relative Zero time point, infers internal CLint CL with thisint(ref.:Naritomi Y,
Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human
hepatic clearance from in vivo animal experiments and in vitro metabolic
studies with liver microsomes from animals and humans.Drug Metabolism and
Disposition2001,29:1316-1324.)
3, the compounds of this invention Pharmacokinetic Evaluation in animal body
The present invention uses following methods to the compounds of this invention pharmacokinetics in mice, rat, dog or monkey body
Research is estimated:
The compounds of this invention with aqueous solution or the aqueous solution of 2%HPMC+1% twen-80, the saline solution of 5%DMSO+5%, 4%
MC or capsule form are administered.For intravenous administration, animal gives the dosage of 1 or 2mg/kg.For oral dose
(p.o.), rat and mice are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25 at time point, 0.5,1.0,2.0,
Within 3.0,4.0,6.0,8.0,12 and 24 hours, take blood (0.3mL), and 3,000 or 4, be centrifuged 10 minutes under 000rpm.Collect blood
Slurry solution, and preserve under-20 ° of C or-70 ° of C until carrying out above-mentioned LC/MS/MS and analyzing.
4, kinase assay
Kinase assay by detection mix γ-33The myelin basic protein (MBP) of P-ATP completes.Prepare 20 μ g/
MBP (Sigma#M-1891) trishydroxymethylaminomethane buffer salt solution (TBS of ml;50mM Tris pH8.0,138mM
NaCl, 2.7mM KCl), it is coated white 384 orifice plates (Greiner) of high associativity, every hole 60 μ L.4 ° of C, hatch 24h.Use afterwards
100 μ L TBS wash plate 3 times.Kinase reaction is at kinase buffer liquid (the 5mM Hepes pH7.6,15mM that cumulative volume is 34 μ L
NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl2, 1mM DTT, 0.02%TritonX-100) in enter
OK.By compound dissolution in DMSO, adding in each hole, the ultimate density of DMSO is 1%.Each data determination twice, Mei Gehua
The mensuration of compound at least carries out twice test.Such as, the ultimate density of enzyme is 10nM or 20nM.Add and do not have markd ATP (10
μM) and γ-33ATP (every hole 2x10 of P labelling6Cpm, 3000Ci/mmol) start reaction.Reflection at room temperature concussion carries out 1
Hour.The PBS of 384 orifice plate 7x, is subsequently adding the scintillation solution of every hole 50 μ L.Detect with Wallac Trilux enumerator
Result.To those of ordinary skill in the art, this is only the one in numerous detection method, and other method also may be used.
The IC that above-mentioned test method can be inhibited50And/or inhibition constant Ki。IC50It is defined as under test conditions, pressing down
Make compound concentration during 50% enzymatic activity.The extension rate utilizing 1/2log makes the curve comprising 10 concentration point, estimation
IC50Value (such as, make a typical curve by following compound concentration: 10 μMs, 3 μMs, 1 μM, 0.3 μM, 0.1 μM, 0.03
μM, 0.01 μM, 0.003 μM, 0.001 μM, 0 μM).
Kinase assay in the present invention by Millipore company of Britain complete (Millipore UK Ltd,
Dundee Technology Park,Dundee DD21SW,UK)。
4.1ALK (h) kinase assays
People ALK is the MOPS of 7.0,0.2mM EDTA at 8mM pH value, 250 μMs of KKKSPGEYVNIEFG, 10mM magnesium acetates
[γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determines according to demand) hatches under conditions of existing.Add
Reaction is started after MgATP mixture.After incubated at room temperature 40 minutes, it is added thereto to 3% phosphoric acid solution and terminates reaction.Will
The reactant liquor of 10 μ L is mottled being distributed on P30 filter, and cleans 3 times in 5 minutes with 75mM phosphoric acid, and be dried and
Put at once before scinticounting in methanol solution and preserve.
4.2c-Met (h) kinase assays
People c-Met is the MOPS of 7.0,0.2mM EDTA at 8mM pH value, 250 μMs of KKKSPGEYVNIEFG, 10mM acetic acid
Magnesium and [γ-33P-ATP] (specific activity about 500cpm/ pmol, concentration determines according to demand) hatch under conditions of existing.Add
Reaction is started after entering MgATP mixture.After incubated at room temperature 40 minutes, it is added thereto to 3% phosphoric acid solution and terminates reaction.
It is mottled being distributed on P30 filter by the reactant liquor of 10 μ L, and cleaned 3 times in 5 minutes with 75mM phosphoric acid, and be dried
Preserve with putting at once before scinticounting in methanol solution.
5, Xenograft Tumor Models
The drug effect of the compounds of this invention is that the standard Murine models by transplantation tumor is evaluated, and method is as follows:
Human tumor cells (such as, U87MG neuroblastoma cell) cultivates, collect after, in rear veutro subcutaneous vaccination in
(BALB/cA nu/nu, Shanghai SLAC Animal Lab.) in the female nude mice body of 6-7 week old (for group of solvents n=10, for
Each dosage group n=8).When gross tumor volume reaches 100-250mm3Time, animal is divided into solvent control group (2%HPMC+ randomly
The aqueous solution of 1% twen-80) and compound group.Follow-up employing compound on animals carry out gastric infusion (3-50mpk/dose, molten
Solution is in the aqueous solution of 2%HPMC+1% twen-80), from 0 to 15 days after tumor cell inoculation Anywhere from the beginning of, and
And generally carry out once every day in test.
5.1 Tumor growth inhibition (TGI) are analyzed
The crystallization growth of tumor is to be evaluated by the relation of gross tumor volume Yu time.The major axis of Subcutaneous tumor
(L) being measured weekly twice by caliper with short axle (W), the volume (TV) of tumor passes through formula (L × W2)/2) calculate.
TGI is calculated by the intermediate value of group of solvents mouse tumor volume and the difference of medicine group mouse tumor volume-median, with solvent
The percentage ratio of matched group gross tumor volume intermediate value represents, is calculated by following formula:
Primary statistics analysis completes by repeating variance mensuration analysis (RMANOVA).Followed by Scheffe
Psot hoc test method carries out multiple comparisons.Separate solvent (2%HPMC+1% twen-80, etc.) it is negative control.
Result shows, the compound that the present invention provides shows good half-life and good pharmacokinetic property,
Have good inhibitory action to ALK and c-Met, the growth to tumor also has good inhibitory action.
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
Embodiment 13-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(4-fluorine oxolane-3-base)-
1H-pyrazoles-4-base) pyridine-2-amine
Step 1) (R)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-2-nitropyridine
(R)-1-(2,6-bis-chloro-3-fluorophenyl) ethanol (10g, 47.84mmol) is dissolved in oxolane (150mL)
In, it is cooled to 0 DEG C, in 30 minutes, (2.3g, 57.41mmol, 60% are suspended in mineral oil to be dividedly in some parts sodium hydride wherein
In).After mixture is stirred at room temperature 2 hours, again it is cooled to 0 DEG C, in 20 minutes, in system, drips 3-fluoro-2-nitro pyrrole
Oxolane (80mL) solution of pyridine (8.2g, 57.41mmol).Reactant liquor is stirred at room temperature 3 hours.Reaction is finished, with frozen water
(10mL) cancellation, and concentrating under reduced pressure.Being dispersed in by residue in ethyl acetate (150mL) and water (150mL), the aqueous phase of separation is used
Ethyl acetate (150mL × 2) extracts.The organic facies merged is successively with saturated sodium bicarbonate solution (400mL), saline (400mL)
Washing, anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1)
Purification, obtaining title compound is white solid (13.4g, 84.6%).
LC-MS(ESI,pos.ion)m/z:331[M+H]+。
Step 2) (R)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
(R)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-2-nitropyridine (13.4g, 40.47mmol) is dissolved
In ethanol (250mL), and it is added thereto to iron powder (11g, 197mmol).Mixture is after 90 DEG C of stirrings 20 minutes, at 15 points
In clock, in system, add hydrochloric acid (1M, 8mL) in two batches.Reactant liquor continues to stir 2 hours at 90 DEG C.Reaction is finished, and is cooled to room
Temperature, filters with kieselguhr, and filter cake ethanol (80mL × 3) washs.The filtrate reduced in volume that will merge, obtains title compound
For light tan solid (12g, 98.5%).
LC-MS(ESI,pos.ion)m/z:301[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):1.75(d,J=6.6Hz,3H),5.67(brs,2H),5.97-5.92
(q,J=6.6Hz,1H),6.38-6.35(dd,J=5.0Hz,7.7Hz,1H),6.61(d,J=7.1Hz,1H),7.47-7.42(m,
2H),7.56-7.52(dd,J=5.0Hz,7.7Hz,1H)。
Step 3) the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
(R)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (12g, 39.8mmol) is dissolved in second
In nitrile (250mL), it is cooled to 0 DEG C, in 20 minutes, is dividedly in some parts NBS (9.2g, 51.7mmol) wherein.Reactant liquor is at 0 DEG C
Stir 1 hour.Reaction is finished, and concentrating under reduced pressure, gained residue is pure through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1)
Changing, obtaining title compound is light tan solid (10g, 66%).
LC-MS(ESI,pos.ion)m/z:379[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):1.82(d,J=6.6Hz,3H),4.82(brs,2H),6.01-5.96
(q,J=6.6Hz,1H),6.83(d,J=1.8Hz,1H),7.10-7.06(t,J=8.0Hz,1H),7.33-7.30(dd,J=
4.8Hz,8.9Hz,2H),7.66(d,J=5.0Hz,1.8Hz,1H)。
Step 4) double (tertbutyloxycarbonyl)-3-(1-(the 2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyrrole of (R)-5-bromo-N, N-
Pyridine-2-amine
By the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (4.5g, 11.8mmol),
DMAP (1.46g, 11.8mmol) and Boc anhydride (7.33g, 35.4mmol) are dissolved in oxolane (100mL), and wherein
Add triethylamine (3.65g, 36mmol).Reactant liquor is stirred overnight at 70 DEG C.Reaction is finished, concentrating under reduced pressure.Gained residue is through silicon
Plastic column chromatography (PE/EtOAc (v/v)=10/1) purification, obtaining title compound is viscous liquid (6g, 87.28%).
Step 5) double (tertbutyloxycarbonyl)-3-(1-(2,6-bis-chloro-3-fluorophenyl) the ethyoxyl)-5-of (R)-N, N-(4,4,
5,5-tetramethyl-1,3,2-dioxaborolanes-2-base) pyridine-2-amine
By double to the bromo-N of (R)-5-, N-(tertbutyloxycarbonyl)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-
Amine (6g, 11.8mmol), connection boric acid frequency sodium alcohol ester (3.6g, 14.6mmol) and potassium acetate (3.54g, 35.4mmol) are suspended in two
In first sulfoxide (150mL), after being placed in blanket of nitrogen, in system, add Pd (dppf) Cl2·CH2Cl2(0.48g,0.59mmol)。
Reactant liquor, after 80 ° of C heat 5 hours, is cooled to room temperature, and add water (300mL) dilution, and extracts by ethyl acetate (300mL × 3)
Take.Being washed by the organic facies saline (200mL) merged, anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained residue is through silicagel column
Chromatography (petrol ether/ethyl acetate (v/v)=6/1) purification, obtaining title compound is colorless oil (5.8g, 89.25%).
LC-MS(ESI,pos.ion)m/z:627[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):8.37(s,1H),7.52(s,1H),7.06-7.02(m,1H),6.13-
6.08(q,1H,J=6.64Hz),1.80-1.78(q,3H,J=6.68Hz),1.34-1.32(m,18H),1.26(s,12H)。
Step 6) 3,6-dioxa bicyclo-[3.1.0] hexane
DHF (5.3mL, 71.3mmol) is dissolved in dichloromethane (250mL), is added thereto to m-
CPBA(24.6g,142.6mmol).Reactant liquor is stirred at room temperature 48 hours.Reaction is finished, and filters with kieselguhr, filter cake dichloromethane
(50mL) wash.Filtrate being washed with saline (200mL), anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and obtaining thick product is colorless oil
Thing (4.12g, 67%).
GC-MS m/z:86(M)；
1H NMR(400MHz,CDCl3)δ(ppm):3.65-3.65(d,J=10.5Hz,2H),3.80(s,2H),4.02-
4.04(d,J=10.5Hz,2H)。
Step 7) 4-(4-iodo-1H-pyrazol-1-yl) oxolane-3-alcohol
Iodo-for 4-1H-pyrazoles (10.8g, 57.6mmol) is dissolved in dry oxolane (60mL), is cooled to-78
DEG C, it is added thereto to LDA (31.2mL, 62.4mmol).Solution, after-40 DEG C of stirrings 1 hour, adds 3,6-dioxy in system
Oxolane (50mL) solution of miscellaneous bicyclo-[3.1.0] hexane (4.12g, 48mmol).Reactant liquor is stirred at room temperature 1 hour, then
It is warming up to 80 DEG C, continues stirring 36 hours.Reaction is finished, and solution is cooled to room temperature, and add water (50mL) dilution, and uses ethyl acetate
(100mL × 3) extract.The organic facies saline (100mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained remains
Thing through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, obtain title compound be white solid (5g,
37%)。
LC-MS(ESI,pos.ion)m/z:281(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):3.44(s,1H),3.79-3.82(dd,J=2.8,10.0Hz,1H),
4.15-4.22(m,2H),4.29-4.33(m,1H),4.55(s,1H),4.75-4.78(m,1H),7.53(s,1H),7.55(s,
1H)。
Step 8) 1-(4-fluoro oxolane-3-base)-4-iodo-1H-pyrazoles
4-(4-iodo-1H-pyrazol-1-yl) oxolane-3-alcohol (1.5g, 5.4mmol) is dissolved in dichloromethane
(15mL), in, after being cooled to-78 DEG C, DAST (1.53mL, 10.8mmol, 95%) it is slowly added to wherein.Reactant liquor is at-78 DEG C
After stirring 2 hours, recover to room temperature, continue stirring 40 hours.Reaction is finished, and mixed liquor adds water (30mL) cancellation, and uses dichloromethane
Alkane (80mL × 3) extracts.Being washed by the organic facies saline (100mL) merged, anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained
Residue through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1), obtain title compound be yellow oil (1.1g,
72%)。
LC-MS(ESI,pos.ion)m/z:283(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):4.07-4.25(m,3H),4.33-4.37(m,1H),4.95-5.02
(m,1H),5.26-5.27(d,J=3.6Hz,0.5H),5.39-5.40(d,J=3.8Hz,0.5H),7.52(s,1H),7.58(s,
1H)。
Step 9) double (tertbutyloxycarbonyl)-3-((R)-1-(the 2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(4-of N, N-
Fluorine oxolane-3-base)-1H-pyrazoles-4-base) pyridine-2-amine
By double to (R)-N, N-(tertbutyloxycarbonyl)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(4,4,5,5-
Tetramethyl-1,3,2-dioxaborolanes-2-bases) pyridine-2-amine (266mg, 0.43mmol), 1-(4-fluorine oxolane-3-
Base)-4-iodo-1H-pyrazoles (0.1g, 0.35mmol) and sodium carbonate (150mg, 1.42mmol) be dissolved in glycol dimethyl ether/water
(3mL/0.7mL), in mixed liquor, after being placed in blanket of nitrogen, in system, Pd (PPh is added3)2Cl2(25mg,0.035mmol).Reaction
Liquid stirs 16 hours at 90 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate (60mL) dilution, and filters with kieselguhr.Filtrate
Wash through saline (20mL × 2), after vacuum drying, with purifying (petrol ether/ethyl acetate (v/v)=2/1) through silica gel column chromatography,
It is yellow solid (136mg, 59%) to title compound.
LC-MS(ESI,pos.ion)m/z:655(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):1.30-1.53(m,18H),1.82-1.84(d, J=6.7Hz,3H),
4.11-4.29(m,3H),4.78-4.42(m,1H),4.98-5.05(m,1H),5.30-5.46(m,1H),6.02-6.07(q,J
=6.6Hz,1H),7.05-7.09(t,J=8.6Hz,1H),7.15-7.16(t,J=1.8Hz,1H),7.70-7.73(m,3H),
8.17(d,J=1.8Hz,1H)。
Step 10) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(4-fluorine oxolane-3-base)-
1H-pyrazoles-4-base) pyridine-2-amine
By double to N, N-(tertbutyloxycarbonyl)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(4-fluorine four
Hydrogen furan-3-base)-1H-pyrazoles-4-base) pyridine-2-amine (136mg, 0.2mmol) is dissolved in dichloromethane (5mL), cooling
To 0 ° of C, it is slowly added to the ethyl acetate solution (3M, 1.5mL) of hydrogen chloride wherein.Reactant liquor stirred overnight at room temperature.Reaction is finished,
Concentrating under reduced pressure.Residue is dissolved in water (10mL), is 10 with saturated sodium carbonate solution regulation pH value, and uses dichloromethane
(50mL × 3) extract.The organic facies merged is dried through anhydrous sodium sulfate, after concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc
(v/v)=1/1) purification, obtaining title compound is white solid (90mg, 95%).
LC-MS(ESI,pos.ion)m/z:455(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):1.85-1.87(d,J=6.6Hz,3H),4.09-4.27(m,3H),
4.36-4.40(m,1H),4.83(s,2H),4.95-5.00(m,1H),5.30-5.43(m,1H),6.04-6.09(q,J=
6.4Hz,1H),6.84(s,1H),7.03-7.07(m,1H),7.29-7.32(m,1H),7.54(s,1H),7.60(s,1H),
7.75(s,1H)。
Embodiment 24-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-
Pyrazol-1-yl) oxolane-3-alcohol
Step 1) the iodo-1-of 4-(4-(tetrahydrochysene-2H-pyrans-2-base epoxide) oxolane-3-base)-1H-pyrazoles
By 4-(4-iodo-1H-pyrazol-1-yl) oxolane-3-alcohol (1g, 3.57mmol), PPTS (113mg,
0.43mmol) it is suspended in dichloromethane (46mL), is added thereto to DHP (788mg, 9.4mmol).Reactant liquor is stirred at room temperature 48
Hour.Reaction is finished, concentrating under reduced pressure.Gained residue, through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, obtains titled
Compound is colorless oil (1.3g, 100%).
LC-MS(ESI,pos.ion)m/z:365(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):1.50-1.65(m,4H),1.71-1.80(m,2H),1.80-1.84
(m,2H),3.47-3.51(m,1H),3.77-3.89(m,2H),4.11-4.27(m,3H),4.47-4.58(m,1H),4.59-
4.75(m,1H),4.79-5.04(m,1H),7.53(s,1H),7.54(s,1H)。
Step 2) double (tertbutyloxycarbonyl)-3-((R)-1-(the 2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(4-of N, N-
((tetrahydrochysene-2H-pyrans-2-base) epoxide) oxolane-3-base)-1H-pyrazoles-4-base) pyridine-2-amine
Title compound is prepared by the method described by embodiment 1 step 9, will double (the tertiary fourth oxygen of (R)-N, N-
Carbonyl)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-
2-yl) pyridine-2-amine (224mg, 0.357mmol), the iodo-1-of 4-(4-(tetrahydrochysene-2H-pyrans-2-base epoxide) oxolane-3-
Base)-1H-pyrazoles (100mg, 0.275mmol), sodium carbonate (117mg, 1.1mmol) and Pd (PPh3)2Cl2(21.6mg,
0.031mmol) being suspended in the mixed liquor of glycol dimethyl ether/water (2.5mL/0.6mL) preparation, thick product is through silica gel column chromatography
(PE/EtOAc (v/v)=2/1) purification, obtaining title compound is white solid (87mg, 44%).
LC-MS(ESI,pos.ion)m/z:737(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):1.35-1.50(m,18H),1.50-1.60(m,4H),1.71-1.85
(m,5H),3.45-3.54(m,1H),3.77-3.93(m,2H),4.17-4.33(m,3H),4.52-4.79(m,2H),4.82-
5.06(m,1H),6.02-6.07(q,J=6.6Hz,1H),7.04-7.08(t,J=8.2Hz,1H),7.15(s,1H),7.29-
7.33(m,1H),7.69-7.73(m,2H),8.17(d,J=1.5Hz,1H)。
Step 3) 4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-
Pyrazol-1-yl) oxolane-3-alcohol
Title compound is prepared by the method described by embodiment 1 step 10, i.e. uses the double (tertiary butyloxycarbonyl of N, N-
Base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) tetrahydrochysene
Furan-3-base)-1H-pyrazoles-4-base) dichloromethane (12mL) solution of pyridine-2-amine (264mg, 0.36mmol) and hydrogen chloride
Prepared by ethyl acetate solution (3.5mL, 3M), thick product, through silica gel column chromatography (100% ethyl acetate) purification, obtains title compound
Thing is yellow solid (131mg, 80%).
LC-MS(ESI,pos.ion)m/z:453(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):1.85-1.86(d,J=6.6Hz,3H),3.83-3.86(m,1H),
4.18-4.26(m,2H),4.32-4.38(m,1H),4.58-4.61(m,1H),4.71-4.79(m,1H),4.85(s,2H),
6.01-6.09(m,1H),6.83(s,1H),6.98-7.07(m,1H),7.29-7.33(m,1H),7.49-7.51(d,J=
8.6Hz,1H),7.57(s,1H),7.67(s,1H)。
Embodiment 33-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(4-fluoropyrrolidine-3-base)-1H-
Pyrazoles-4-base) pyridine-2-amine
Step 1) t-butyl carbamate
Bis(tert-butoxycarbonyl)oxide (10g, 45.8mmol) is dissolved in methanol (200mL), is cooled to 0 ° of C, is passed through NH3。
Reactant liquor, after 0 ° of C stirs 2 hours, is warmed to room temperature, and continues stirring 5 hours.Reaction is finished, by mixture concentrating under reduced pressure, residue
Dilute with normal hexane, and be heated to 65 ° of C, be incubated 30 minutes.It is cooled to room temperature, filters, filter cake normal hexane drip washing, marked
Topic compound is white solid (5g, 94%).
1H NMR(400MHz,CDCl3)δ(ppm):4.48(brs,2H,),1.46(s,9H)。
Step 2) 1-(tertbutyloxycarbonyl)-2,5-dihydro-1H-pyrroles
T-butyl carbamate (5g, 42.5mmol) is dissolved in DMF (50 mL), is cooled to 0 °
C, in 15 minutes, is dividedly in some parts sodium hydride (3.1g, 106mmol) wherein.Mixture after 0 ° of C stirs 1 hour, continue to
Cis-1,4-dichloro-2-butene (8mL) is dripped in system.Reactant liquor stirs 5 hours at 80 ° of C, is cooled to room temperature, adds water
(150mL) cancellation, and extract by ethyl acetate (150mL × 3).The organic facies saline (400mL) merged is washed, anhydrous sodium sulfate
It is dried, and concentrating under reduced pressure, obtaining thick product is yellow oil (6.5g), and this product is the most purified, is directly used in next step anti-
Should.
Step 3) 4-bromo-1-(tertbutyloxycarbonyl) pyrrolidine-3-alcohol
1-(tertbutyloxycarbonyl)-2,5-dihydro-1H-pyrroles (6.4g, 37.8mmol) is dissolved in dimethyl sulfoxide/water
(30mL/3mL) in mixed liquor, it is cooled to 0 ° of C, is dividedly in some parts NBS (8g, 45.4mmol) wherein.Reactant liquor is stirred at room temperature 2
Hour.Reaction is finished, and add water (100mL) cancellation, and extracts by ethyl acetate (100mL × 3).The organic facies saline merged
(300mL) washing, anhydrous sodium sulfate is dried, and concentrating under reduced pressure, residue through silica gel column chromatography (petrol ether/ethyl acetate (v/
V)=3/1) purification, obtaining title compound is white solid (5g, 60%).
1H NMR(400MHz,CDCl3)δ(ppm):4.47-4.46(t,J=1.94Hz,1H),4.18-4.16(t,J=
2.36Hz,1H),4.05-4.01(dd,J=4.86Hz,1H),3.88-3.70(m,2H),3.40(t,J=13.2Hz,1H),3.03
(brs,1H),1.47(s,9H)。
Step 4) 3-(tertbutyloxycarbonyl)-6-oxa--3-azabicyclo [3.1.0] hexane
Bromo-for 4-1-(tertbutyloxycarbonyl) pyrrolidine-3-alcohol (2.5g, 9.4mmol) is dissolved in 2M sodium hydroxide/tetrahydrochysene furan
Mutter in the mixed liquor of (20mL/10mL).Reactant liquor is stirred at room temperature 2 hours.Reaction is finished, and add water (40mL) dilution, and uses dichloromethane
Alkane (50mL × 3) extracts.The organic facies saline (50mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure, obtains title
Compound is yellow oil (1.6g, 98%).
1H NMR(400MHz,CDCl3)δ(ppm):3.83-3.72(dd,J=12.8Hz,2H),3.67-3.66(m,2H),
3.34-3.30(dd,J=5.1Hz,12.8Hz,2H),1.45(s,9H)。
Step 5) 1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) pyrrolidine-3-alcohol
Title compound is prepared by the method described by embodiment 1 step 7, will 4-iodo-1H-pyrazoles (1.8g,
9.7mmol), 3-(tertbutyloxycarbonyl)-6-oxa--3-azabicyclo [3.1.0] hexane (1.5g, 8mmol), LDA (5.2mL, 1M
In THF) it is dissolved in preparation in oxolane (20mL), thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/
1) purification, obtaining target product is white solid (2g, 67%).
1H NMR(400MHz,CDCl3)δ(ppm):7.54(s,1H),7.48(s,1H),4.64-4.60(m,2H),3.99-
3.97(m,1H),3.80-3.72(m,2H),3.40-3.35(m,2H),1.47(s,9H)。
Step 6) 1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-base)-4-iodo-1H-pyrazoles
1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) pyrrolidine-3-alcohol (1g, 2.5mmol) is dissolved in two
In chloromethanes (20mL), it is cooled to-78 ° of C, drips dichloromethane (2mL) solution of DAST (1.5mL) wherein.Mixed liquor-
After 78 ° of C stir 1 hour, recover to room temperature, be stirred overnight.Reaction is finished, by mixed liquor concentrating under reduced pressure, and residue 1M bicarbonate
Sodium (30mL) dilutes, and extracts by ethyl acetate (30mL × 3), and the organic facies saline (70mL) of merging is washed, anhydrous sodium sulfate
It is dried, and concentrating under reduced pressure, gained residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purification, obtains title
Compound is yellow oil (0.5g, 50%).
1H NMR(400MHz,CDCl3)δ(ppm):7.54(s,1H),7.48(s,1H),5.34-5.21(m,1H),4.93-
4.91(m,1H),3.96-3.68(m,4H),1.47(s,9H).
Step 7) 1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-base)-4-(4,4,5,5-tetramethyl-1,3,2-dioxy
Polymorphs borine-2-base)-1H-pyrazoles
Nitrogen protection under, by 1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-base)-4-iodo-1H-pyrazoles (0.5g,
1.3mmol), connection boric acid pinacol ester (0.4g, 1.5mmol), Pd (dppf) Cl2(60mg, 0.13mmol) and potassium acetate
Dimethyl sulfoxide (10mL) suspension of (0.38g, 3.9mmol) stirs 2 hours at 75 ° of C.Reaction is finished, and is cooled to room temperature, adds water
(30mL) cancellation, and extract by ethyl acetate (30mL × 3).The organic facies saline (70mL) merged is washed, and anhydrous sodium sulfate is done
Dry, and concentrating under reduced pressure, gained residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, obtains titled
Compound is yellow oil (0.4g, 80%).
LC-MS(ESI,pos.ion)m/z:382[M+1]。
Step 8) 5-(1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-base)-1H-pyrazoles-4-base)-3-((R)-1-
(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
Nitrogen protection under, by the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (0.48g,
1.26mmol), 1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-base)-4-(4,4,5,5-tetramethyl-1,3,2-dioxas
Ring pentaborane-2-base)-1H-pyrazoles (0.4g, 1.05mmol), Pd (OAc)2(84mg, 0.37mmol), Cs2CO3(0.86g,
2.63mmol) with (t-Bu)3Glycol dimethyl ether (20mL) suspension of P (toluene solution of 0.925mmol, 1M) stirs at 87 ° of C
Mix 36 hours.Reaction is finished, and add water (50mL) cancellation, and extracts by ethyl acetate (50mL × 3), the organic facies saline of merging
(100mL) washing, anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/
V)=1/1) purification, obtaining title compound is yellow solid (0.16g, 32%).
1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H),7.59(s,1H),7.48(s,1H),7.33-7.30
(m,1H),7.07-7.04(m,1H),6.84(s,1H),6.09-6.04(t,J=6.64Hz,1H),5.37-5.24(m,1H),
4.94-4.85(m,3H),3.92-3.72(m,4H),2.18-2.15(d,J=6.64Hz,3H),1.49(s,9H)。
Step 9) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(4-fluoropyrrolidine-3-base)-1H-
Pyrazoles-4-base) pyridine-2-amine
By 5-(1-(1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-3-base)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-
Two chloro-3-fluorophenyls) ethyoxyl) pyridine-2-amine (0.16g, 0.29mmol) is dissolved in ethyl acetate (5mL), and wherein
Add HCl (ethyl acetate solution of 5mL, 1M).Reactant liquor stirs 1 hour at 40 ° of C.Reaction is finished, and uses 2M sodium carbonate liquor successively
(5mL), water (20mL) processes, and is extracted with ethyl acetate (20mL × 3).The organic facies merged is with saturated aqueous common salt (60mL)
Washing, anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and gained residue is through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1)
Purification, obtaining title compound is yellow solid (0.1g, 78%).
LC-MS(ESI,pos.ion)m/z:227.6[M+2]/2；
1H NMR(400MHz,CDCl3)δ(ppm):7.56(s,1H),7.53-7.31(m,2H),7.30-7.26(s,1H),
7.08-7.04(m,1H),6.85(s,1H),6.09-6.04(t,J=6.64Hz,1H),5.38-5.22(m,1H),4.85-4.74
(m,3H),3.58-3.21(m,4H),1.87-1.85(d,J=6.64Hz,3H)。
Embodiment 44-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-
Pyrazol-1-yl) pyrrolidine-3-alcohol
Step 1) 1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-3-yl)-4-is iodo-
1H-pyrazoles
1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) pyrrolidine-3-alcohol (1g, 2.6mmol) is dissolved in two
In chloromethanes (20mL), it is added thereto to DHP (1mL) and PPTS (0.065g, 0.26mmol).It is little that reactant liquor is stirred at room temperature 12
Time.Reaction is finished, concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, and obtaining title compound is
White solid (1.1g, 92%).
LC-MS(ESI,pos.ion)m/z:464(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):7.54(s,1H),7.48(s,1H),4.70-4.50(m,3H),3.94-
3.73(m,3H),3.66-3.40(m,3H),1.77-1.60(m,3H),1.62-1.51(m,3H),1.47(s,9H)。
Step 2) double (tertbutyloxycarbonyl)-5-(1-(1-(the tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) of N, N-
Epoxide) pyrrolidin-3-yl)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
By double to (R)-N, N-(tertbutyloxycarbonyl)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(4,4,5,5-
Tetramethyl-1,3,2-dioxaborolanes-2-bases) pyridine-2-amine (0.6g, 1.1mmol), 1-(1-(tertbutyloxycarbonyl)-4-
((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-3-yl)-4-iodo-1H-pyrazoles (0.5g, 1.05mmol) and sodium carbonate
(0.22g, 2.1mmol) is dissolved in the mixed liquor of glycol dimethyl ether/water (30mL/2mL), and solution is placed in blanket of nitrogen, to
Pd (dppf) Cl is added in system2·CH2Cl2(0.075g,0.01mmol).Reactant liquor stirs 12 hours at 87 ° of C, and reaction is finished,
Concentrating under reduced pressure.Residue is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purification, and obtaining title compound is light yellow solid
(250mg,92%)。
LC-MS(ESI,pos.ion)m/z:836(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm):8.16(s,1H),7.32-7.12(m,1H),7.65(s,1H),7.33-
7.30(m,1H),7.16(m,1H),7.09-7.04(m,1H),6.07-6.02(t,J=6.64Hz,1H),3.99-3.61(m,
3H),3.58-3.41(m,3H),1.83-1.81(d,J=6.64Hz,1H),1.52-1.48(2H,m),1.48-1.44(m,
13H)。
Step 3) 4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-
Pyrazol-1-yl) pyrrolidine-3-alcohol
By double to N, N-(tertbutyloxycarbonyl)-5-(1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide)
Pyrrolidin-3-yl)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
(0.23g, 0.275mmol) is dissolved in ethyl acetate (10mL), is added thereto to HCl (ethyl acetate solution of 10mL, 1M).
Reactant liquor stirs 3 hours at 40 ° of C, and reaction is finished, and is cooled to room temperature, and (20mL) dilution that adds water.The aqueous phase ethyl acetate separated
After (20mL × 2) are washed, adding 2M sodium carbonate liquor (10mL) and process, gained mixture ethyl acetate (20mL × 3) extracts.To close
And organic facies saline (60mL) wash, anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and obtaining title compound is white solid
(70mg,62%)。
LC-MS(ESI,pos.ion)m/z:452(M+1);
1H NMR(400MHz,CDCl3)δ(ppm):7.50(s,1H),7.47(s,1H),7.30-7.29(m,1H),7.29-
7.28(m,1H),7.03-6.99(m,1H),6.85-6.84(m,1H),6.09-6.04(t,J=6.64Hz,1H),4.87(s,
2H),4.56-4.54(m,2H),3.56-3.52(m,1H),3.46-3.41(dd,J=5.5Hz,1H),3.34-3.31(dd,J=
4.2Hz,1H),3.01-2.97(m,1H),1.87-1.86(d,J=6.64Hz,1H).
Embodiment 5 ((2S)-4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-3-
Base)-1H-pyrazol-1-yl) pyrrolidin-2-yl) methanol
Step 1) (3R, 5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl group) pyrrolidin-3-yl methanesulfonates
(3R, 5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl group) pyrrolidine-3-alcohol (0.50g, 2.04mmol) is dissolved
In dichloromethane (20mL), it is added thereto to DMAP (3mg, 0.02mmol) and triethylamine (0.28mL, 2.04mmol), mixing
After liquid is cooled to 0 ° of C, continue to drip mesyl chloride (0.16mL, 2.04mmol) in system.Reactant liquor stirs 1 hour at 0 ° of C,
Recover to room temperature, continue stirring 24 hours.Reaction is finished, and by mixture concentrating under reduced pressure, obtaining thick product is yellow, viscous liquid
(0.64g, 100%), this product is the most purified, is directly used in next step reaction.
LC-MS(ESI,pos.ion)m/z:224.0[M-Boc+H].
Step 2) 1-((5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl group) pyrrolidin-3-yl)-4-iodo-1H-pyrazoles
Iodo-for 4-1H-pyrazoles (0.35g, 1.80mmol) is dissolved in dry DMF (6mL), cold
But to 0 ° of C, it is added thereto to sodium hydride (0.15g, 3.75mmol, 60% are dispersed in mineral oil).It is little that mixture stirs 1 at 0 ° of C
Shi Hou, adds (3R, 5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl group) pyrrolidin-3-yl methanesulfonates in system
Dry N,N-dimethylformamide (4mL) solution of (0.64g, 1.98mmol).Reactant liquor stirs 12 hours at 100 ° of C, reaction
Finishing, be cooled to room temperature, add water (40mL) cancellation, and extracts with dichloromethane (30mL × 4).By the organic facies of merging successively with 5%
Lithium chloride solution (100mL × 2), saline (100mL) are washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained residue is through silica gel
Column chromatography (PE/EtOAc (v/v)=4/1) purification, obtaining title compound is yellow solid (0.58g, 76%).
LC-MS(ESI,pos.ion)m/z:365.9[M-56+H]。
Step 3) ((2S)-1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) pyrrolidin-2-yl) methanol
By 1-((5S)-1-(tertbutyloxycarbonyl)-5-(methoxycarbonyl group) pyrrolidin-3-yl)-4-iodo-1H-pyrazoles (0.46g,
1.09mol) be dissolved in oxolane (10mL), be cooled to 0 ° of C, be dividedly in some parts wherein lithium borohydride (0.12g,
5.46mmol).Mixture, after 0 ° of C stirs 30 minutes, recovers to room temperature, is stirred overnight.Reaction is finished, and add water (10mL) cancellation,
And extract by ethyl acetate (30mL × 4).Being washed by the organic facies saline (30mL) merged, anhydrous sodium sulfate is dried, and reduces pressure
Concentrate.Gained residue is by silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and it is viscous for obtaining title compound
Thick liquid (0.21g, 28%).
LC-MS(ESI,pos.ion)m/z:338.0[M-56+H]；
1H NMR(400MHz,CDCl3)δ(ppm):7.53(s,1H),7.49(s,1H),4.68-4.82(m,1H),4.00-
4.18(m,2H),3.52-3.82(m,3H),2.50-2.68(m,1H),2.11-2.38(m,1H),1.47(s,9H)。
Step 4) ((2S)-1-(tertbutyloxycarbonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-
2-yl)-1H-pyrazol-1-yl) pyrrolidin-2-yl) methanol
By ((2S)-1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) pyrrolidin-2-yl) methanol (0.50g,
1.27mmol) it is dissolved in dimethyl sulfoxide (12mL), after being added thereto to join boric acid frequency sodium alcohol ester (0.48g, 1.91mmol), puts
In blanket of nitrogen, continue to be added thereto to Pd (dppf)2Cl2·CH2Cl2(0.10g, 0.13mmol) and potassium acetate (0.50g,
5.09mmol).Reactant liquor is stirred overnight at 90 ° of C, and reaction is finished, and is cooled to room temperature, and add water (40mL) dilution, and uses ethyl acetate
(50mL × 3) extract.Being washed by the organic facies saline (50mL) merged, anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained remains
Thing is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and obtaining title compound is thick yellow liquid
(0.38g,76%)。
LC-MS(ESI,pos.ion)m/z:394.2[M+H]；
1H NMR(400MHz,CDCl3)δ(ppm):7.79(s,1H),7.74(s,1H),4.70-4.82(m,1H),4.04-
4.18(m,2H),3.55-3.85(m,3H),2.52-2.66(m,1H),2.12-2.30(m,1H),1.46(s,9H),1.30(s,
12H)。
Step 5) ((2S)-4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-3-
Base)-1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) pyrrolidin-2-yl) methanol
By the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (0.30g, 0.79mmol) and
((2S)-1-(tertbutyloxycarbonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-pyrazoles-
1-yl) pyrrolidin-2-yl) methanol (0.46g, 1.18mmol) is dissolved in glycol dimethyl ether (10mL), after being placed in blanket of nitrogen,
It is added thereto to cesium carbonate (0.77g, 2.37mmol), Pd (dppf) Cl2·CH2Cl2(64mg, 0.08mmol) and water (2mL).
Reactant liquor refluxes overnight.Reaction is finished, and is cooled to room temperature, and add water (30mL) dilution, and extracts with dichloromethane (40mL × 3).Will
The organic facies saline (50mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained residue is through silica gel column chromatography
(PE/EtOAc (v/v)=2/1) purification, obtaining title compound is yellow solid (0.26g, 58%).
LC-MS(ESI,pos.ion)m/z:566.2[M+H]；
1H NMR(400MHz,CDCl3)δ(ppm):7.71(d,J=1.7Hz,1H),7.56(s,1H),7.49(s,1H),
7.28-7.34(dd,J=8.8Hz,4.8Hz,1H),7.01-7.08(t,J=8.0Hz,1H),6.84(d,J=1.6Hz,1H),
6.02-6.10(q,J=6.7Hz,1H),4.91(s,2H),4.69-4.82(m,1H),4.04-4.18(m,2H),3.60-3.80
(m,2H),2.52-2.79(m,2H),2.12-2.30(m,1H),1.84(d,J=6.7Hz,3H),1.47(s,9H)。
Step 6) ((2S)-4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-3-
Base)-1H-pyrazol-1-yl) pyrrolidin-2-yl) methanol
Will ((2S)-4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) pyrrolidin-2-yl) methanol (0.26g, 0.46mmol) is dissolved in dichloromethane
(10mL), in, it is added thereto to HCl (ethyl acetate solution of 3mL, 3M).Reactant liquor stirred overnight at room temperature.Reaction is finished, and reduces pressure dense
Contracting.Residue saturated sodium carbonate solution (10mL) and ethyl acetate (10mL) are diluted, after stirring 10 minutes, the aqueous phase of separation
Extract with the mixed liquor (30mL × 3) of ethyl acetate/methanol (v/v, 10/1).Merge organic facies, wash with saline (40mL), anhydrous
Sodium sulfate is dried, and concentrating under reduced pressure.Gained residue, through silica gel column chromatography (DCM/MeOH (v/v)=8/1) purification, obtains title
Compound is yellow solid (84mg, 39%).
LC-MS(ESI,pos.ion)m/z:466.2[M+H]；
1H NMR(400MHz,CDCl3)δ(ppm):7.71(d,J=1.4Hz,1H),7.56(s,1H),7.51(s,1H),
7.27-7.32(dd,J=8.8Hz,4.8Hz,1H),6.99-7.07(t,J=8.5Hz,1H),6.83(d,J=1.4Hz,1H),
6.01-6.09(q,J=6.7Hz,1H),4.90(br,2H),4.77-4.85(m,1H),3.81-3.87(m,1H),3.74(m,
1H),3.64(m,1H),3.44-3.53(m,1H),3.27(m,2H),2.42-2.53(m,1H),2.08-2.19(m,1H),
1.82(d,J=6.7Hz,3H)。
Embodiment 63-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((S)-pyrrolidin-3-yl)-1H-
Pyrazoles-4-base) pyridine-2-amine
Step 1) (R)-1-(tertbutyloxycarbonyl) pyrrolidin-3-yl methanesulfonates
By (R)-1-(tertbutyloxycarbonyl) pyrrolidine-3-alcohol (1g, 5.3mmol), triethylamine (1.2mL) is dissolved in dichloromethane
In alkane (15mL), it is cooled to 0 ° of C, drips mesyl chloride (0.62mL) wherein.Reactant liquor is stirred at room temperature 2 hours, and reaction is finished, and subtracts
Pressure concentrates.Residue use water (35mL) dilutes, and extracts by ethyl acetate (25mL × 3).Merge organic facies, use 1M sulphuric acid successively
Hydrogen potassium solution (20mL), water (20mL) are washed, and are dried through anhydrous sodium sulfate, and after concentrating under reduced pressure, obtaining thick product is yellow oily
Thing (1.4g), this compound is the most purified, is directly used in next step.
Step 2) (S)-1-(1-(tertbutyloxycarbonyl) pyrrolidin-3-yl)-4-iodo-1H-pyrazoles
Iodo-for 4-1H-pyrazoles (840mg, 7.4mmol) is dissolved in DMF (15mL), is cooled to
0 ° of C, is added thereto to sodium hydride (320mg, 12mmol, 90% are dispersed in mineral oil).Mixture after 0 ° of C stirs 1 hour,
The N,N-dimethylformamide of (R)-1-(tertbutyloxycarbonyl) pyrrolidin-3-yl methanesulfonates (1.4g) is added in system
(5mL) solution.Reactant liquor stirs 6 hours at 70 ° of C, is cooled to room temperature, and add water (50mL) cancellation, and with ethyl acetate (30mL ×
3) extraction.The organic facies saline (20mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and gained residue is through silica gel
Column chromatography (PE/EtOAc (v/v)=5/1) purification, obtaining title compound is colorless oil (1.6g, 80%).
LC-MS(ESI,pos.ion)m/z:308[M+H-56]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.52(s,1H),7.47(s,1H),4.89-4.85(m,1H),3.84-
3.51(m,4H),2.36-2.32(m,2H).
Step 3) (S)-1-(1-(tertbutyloxycarbonyl) pyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxy
Polymorphs borine-2-base)-1H-pyrazoles
Nitrogen protection under, by (S)-1-(1-(tertbutyloxycarbonyl) pyrrolidin-3-yl)-4-iodo-1H-pyrazoles (1g,
2.75mmol), connection boric acid frequency sodium alcohol ester (0.8g, 3.32mmol), Pd (dppf) Cl2·CH2Cl2(0.22g, 0.275mmol) and
Dimethyl sulfoxide (15mL) suspension of potassium acetate (0.53g, 5.3mmol) stirs 2 hours at 80 ° of C.Reaction is finished, and is cooled to room temperature,
Add water (30mL) dilution, and extracts by ethyl acetate (25mL × 3).The organic facies saline (75mL) merged is washed, anhydrous slufuric acid
Sodium is dried, and concentrating under reduced pressure.Gained residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, obtains mesh
Mark compound is white solid (800mg, 80%).
LC-MS(ESI,pos.ion)m/z:364[M+H]+。
Step 4) 5-(1-((S)-1-(tertbutyloxycarbonyl) pyrrolidin-3-yl)-1H-pyrazoles-4-base)-3-((R)-1-(2,
6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
Nitrogen protection under, by the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (500mg,
1.32mmol), (S)-1-(1-(tertbutyloxycarbonyl) pyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxanes
Pentaborane-2-base)-1H-pyrazoles (500mg, 1.32mmol), Pd (PPh3)2Cl2(108mg, 0.15mmol) and sodium carbonate
Glycol dimethyl ether/water (15mL/1.5mL) suspension of (2.64mmol, 280mg) stirs 16 hours at 87 ° of C.Reaction is finished, and subtracts
Pressure concentrates, and gained residue is through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purification, and obtaining target compound is brown solid
(300mg,42.4%)。
LC-MS(ESI,pos.ion)m/z:536[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H,),7.59-7.57(m,1H),7.52-7.48(m,
1H),7.47-7.29(m,2H),7.07-7.03(t,J=8.4Hz,1H),6.85(s,1H),6.09-6.04(q,J=6.64Hz,
1H),4.88-4.83(m,3H),3.85-3.54(m,3H),2.39-2.37(m,2H),1.86(d,J=6.64Hz,3H),1.66
(s,9H)。
Step 5) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((S)-pyrrolidin-3-yl)-1H-
Pyrazoles-4-base) pyridine-2-amine
By 5-(1-((S)-1-(tertbutyloxycarbonyl) pyrrolidin-3-yl)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-
Chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (280mg, 0.523mmol) is dissolved in ethyl acetate (5mL), is added thereto to
HCl (ethyl acetate solution of 5mL, 1M).Reactant liquor stirs 1 hour at 40 ° of C.Reaction is finished, and is cooled to room temperature, and add water (35mL)
Dilution, and wash by ethyl acetate (20mL).After mixed liquor is processed with 2M sodium carbonate liquor (3mL), by ethyl acetate (containing 1% first
Alcohol, 15mL × 3) extraction.The organic facies merged is washed through saline (40mL), and anhydrous sodium sulfate is dried, and concentrating under reduced pressure, obtains title
Compound is yellow solid (180mg, 80%).
LC-MS(ESI,pos.ion)m/z:436[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.75(s,1H),7.54-7.51(m,2H),7.31-7.28(m,1H),
7.07-7.03(t,J=8.4Hz,1H),6.09-6.04(q,J=6.64Hz,1H),4.80-4.73(m,3H),3.33-3.24(m,
3H),3.19-3.15(m,1H),2.33-2.09(m,2H),1.87(d,J=6.64Hz,3H).
Embodiment 73-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((4,4-dimethyl oxygen heterocycle butyl-
2-yl) methyl)-1H-pyrazoles-4-base) pyridine-2-amine
Step 1) 2-methylpent-4-alkene-2-alcohol
Under argon shield, allylic bromination magnesium (diethyl ether solution of 20mL, 0.02mol, 2M) is placed in two-neck bottle, and uses
Ice bath is cooled to 0 DEG C, drips acetone (1.7mL, 0.02mol) in 10 minutes wherein.After reactant liquor return stirring 2 hours,
Use water (10mL) cancellation of cooling limit, limit.Being cooled to 0 DEG C, dripping hydrochloric acid (3mL, 6M) regulation pH value in mixture is 2, separates
Aqueous phase with ether (50mL × 2) extract.. merging organic facies, wash with saline (50mL), anhydrous magnesium sulfate is dried, and it is dense to reduce pressure
Contracting, obtaining thick product is colorless oil (1g, 50%).
LC-MS(ESI,pos.ion)m/z:101[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.20(s,6H),2.21-2.23(d,J=7.5Hz,2H),5.07-
5.04(m,2H),5.81-5.93(m,1H).
Step 2) 4-(iodomethyl)-2,2-dimethyl oxygen azetidine
By 2-methylpent-4-alkene-2-alcohol (510mg, 5.1mmol), iodine (1.81g, 7.14mmol) is suspended in dichloromethane
(43mL), in, after being placed in blanket of nitrogen, it is added thereto to double (2，4，6-trimethylpyridine) silver perchlorate (3.5g, 7.14mmol).
Reactant liquor is stirred at room temperature 24 hours.Reaction is finished, and filters with kieselguhr, and filter cake ethyl acetate (50mL) is washed.Filtrate is successively through 10%
After sodium thiosulfate (10mL × 2), 10% hydrochloric acid (50mL × 2) are washed, concentrating under reduced pressure.Gained residue silica gel column chromatography (oil
Ether/dichloromethane (v/v)=1/2) purification, obtaining title compound is colorless oil (629mg, 55%).
LC-MS(ESI,pos.ion)m/z:226[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.41(s,3H),1.45(s,3H),2.05-2.09(m,1H),2.44-
2.49(m,1H),3.22-3.27(m,1H),3.34-3.38(m,1H),4.57-4.64(m,1H).
Step 3) 1-((4,4-dimethyl oxygen heterocycle butyl-2-yl) methyl)-4-iodo-1H-pyrazoles
Iodo-for 4-1H-pyrazoles (1.13g, 5.85mmol) is dissolved in dry DMF (32mL), fall
Temperature, to 0 ° of C, is dividedly in some parts sodium hydride (296mg, 11.7mmol, 95%) wherein.After mixture is stirred at room temperature 1.5 hours, Xiang Ti
4-(iodomethyl)-2,2-dimethyl oxygen azetidine (1.32g, 5.85mmol) is added in system.It is little that reactant liquor stirs 19 at 90 ° of C
Time.Reaction is finished, and is cooled to room temperature, adds saturated ammonium chloride solution (20mL) cancellation, and extracts by ethyl acetate (80mL × 2).Close
And organic facies be dried through anhydrous sodium sulfate, after concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1)
Purification, obtaining title compound is colorless oil (890mg, 53%).
1H NMR(400MHz,CDCl3)δ(ppm):1.19(s,3H),1.45(s,3H),2.17-2.22(m,1H),2.36-
2.41(m,1H),4.30(d,J=4.5Hz,2H),4.84-4.90(m,1H),7.52(s,1H),7.58(s,1H)。
Step 4) 1-((4,4-dimethyl oxygen heterocycle butyl-2-yl) methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxy
Polymorphs borine-2-base)-1H-pyrazoles
Connection boric acid frequency sodium alcohol ester (995mg, 3.9mmol) is dissolved in dimethyl sulfoxide (22mL), is added thereto to 1-
((4,4-dimethyl oxygen heterocycle butyl-2-yl) methyl)-4-iodo-1H-pyrazoles (880mg, 3.0mmol) and potassium acetate (1.22g,
12mmol), after nitrogen protection, continue to add Pd (PPh in system3)2Cl2(218mg,0.3mmol).Reactant liquor stirs at 80 ° of C
Mix 3 hours.Reaction is finished, and is cooled to room temperature, and filters with kieselguhr, and filtering residue ethyl acetate (100mL) is washed.By filtrate saline
(50mL × 2) are washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)
=4/1) purification, obtaining title compound is colorless oil (650mg, 74%).
LC-MS(ESI,pos.ion)m/z:293[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.21(s,3H),1.31(s,12H),1.45(s,3H),2.21-2.26
(m,1H),2.37-2.42(m,1H),4.32(d,J=4.9Hz,2H),4.87-4.92(m,1H),7.79(s,1H),7.81(s,
1H)。
Step 5) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((4,4-dimethyl oxygen heterocycle butyl-
2-yl) methyl)-1H-pyrazoles-4-base) pyridine-2-amine
By the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (1.27g, 3.3mmol), 1-
((4,4-dimethyl oxygen heterocycle butyl-2-yl) methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-
1H-pyrazoles (650mg, 2.2mmol), Pd (OAc)2(50mg, 0.22mmol) is suspended in glycol dimethyl ether (20mL), Xiang Qi
Water (3.25mL) solution of middle addition sodium carbonate (707mg, 6.7mmol), after nitrogen protection, continues to add (t-in system
Bu)3P (toluene solution of 0.7mL, 1M).Reactant liquor stirs 16 hours at 90 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate
(30mL) dilution, and filter with kieselguhr, filtering residue ethyl acetate (50mL) is washed.Filtrate is washed with saline (20mL × 2), anhydrous
Sodium sulfate is dried, and concentrating under reduced pressure.Gained residue through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purification,
Obtaining title compound is yellow solid (370mg, 36%).
LC-MS(ESI,pos.ion)m/z:465[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.37(s,3H),1.40(s,3H),1.84-1.86(d,J=6.7Hz,
3H),2.18-2.29(m,2H),2.17(d,J=4.5Hz,2H),4.80(s,2H),4.87-4.93(m,1H),6.05-6.10
(q,J=6.5Hz,1H),6.88(d,J=1.3Hz,2H),7.02-7.07(m,1H),7.29-7.32(m,1H),7.57-7.60
(m,2H),7.77(s,1H)。
Embodiment 83-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3-fluoropyrrolidine-3-base) first
Base)-1H-pyrazoles-4-base) pyridine-2-amine
Step 1) 5-(tertbutyloxycarbonyl)-1-oxa--5-azaspiro [2.4] heptane
Trimethylsulfoxonium Iodide (2.57g, 11.7mmol) is dissolved in dimethyl sulfoxide (8.8mL), is cooled to 10 DEG C, to
Wherein add sodium hydride (351mg, 80% is dispersed in mineral oil).After mixture is stirred at room temperature 2 hours, in system, add 1-
Dimethyl sulfoxide (3.0mL) solution of (tertbutyloxycarbonyl) pyrrolidine-3-ketone (2.00g, 10.8mmol).Reactant liquor continues stirring 3
Hour.Reaction is finished, and successively with frozen water (50mL), saline (50mL) cancellation, and extracts with dichloromethane (100mL × 3).To merge
Organic facies saline (50mL) wash, anhydrous sodium sulfate is dried, and concentrating under reduced pressure, obtains viscous liquid, and this liquid is without pure
Change, be directly used in next step reaction.
Step 2) 1-(tertbutyloxycarbonyl)-3-((4-iodo-1H-pyrazol-1-yl) methyl) pyrrolidine-3-alcohol
Iodo-for 4-1H-pyrazoles (2.1g, 10.8mmol) is dissolved in DMF (20mL), is cooled to 0 °
C, is added thereto to sodium hydride (390mg, 80% is dispersed in mineral oil), and mixture, after 0 ° of C stirs 1 hour, adds in system
Enter the N,N-dimethylformamide of 5-(tertbutyloxycarbonyl)-1-oxa--5-azaspiro [2.4] heptane (2.1g, 10.8mmol)
(10ml) solution.Reactant liquor was 70 ° of C heated and stirred 36 hours.Reaction is finished, and is cooled to room temperature, and add water (10mL) cancellation, and reduces pressure
Concentrate.Being dispersed in by residue in dichloromethane (100mL) and water (100mL), the organic facies saline (50mL) of separation is washed, nothing
Aqueous sodium persulfate is dried, and concentrating under reduced pressure.Residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purification, obtains
Title compound is colorless oil (1.15g, 27%, two step yield).
LC-MS(ESI,pos.ion)m/z:338[M+H-56]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):1.38(s,9H),1.57-1.73(m,1H),1.74-1.90(m,
1H),3.05-3.13(m,1H),3.21-3.32(m,3H),4.23(d,J=3.6Hz,2H),5.16(d,J=1.6Hz,2H),
7.54(s,1H),7.82(d,J=2.9Hz,2H)。
Step 3) 1-((1-(tertbutyloxycarbonyl)-3-fluoropyrrolidine-3-base) methyl)-4-iodo-1H-pyrazoles
DAST (0.5mL, 4mmol) is dissolved in dichloromethane (30mL), is cooled to-78 ° of C, drips 1-(uncle wherein
Butoxy carbonyl) dichloromethane of-3-((4-iodo-1H-pyrazol-1-yl) methyl) pyrrolidine-3-alcohol (786mg, 2.0mmol)
(10mL) solution.Reactant liquor is stirred at room temperature 6 hours.Reaction finish, add methylene chloride dilution (50mL), and successively use water (20mL) and
Saline (20mL) is washed.Solution anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained residue through silica gel column chromatography (petroleum ether/
Ethyl acetate (v/v)=4/1) purification, obtaining title compound is colorless oil (600mg, 76%).
LC-MS(ESI,pos.ion)m/z:340[M+H-56]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.45(s,9H),1.96-2.03(m,2H),3.40-3.70(m,4H),
3.97-4.20(m,1H),4.38-4.55(m,2H),7.45-7.60(m,2H).
Step 4) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3-fluoropyrrolidine-3-base) first
Base)-1H-pyrazoles-4-base) pyridine-2-amine
By 1-((1-(tertbutyloxycarbonyl)-3-fluoropyrrolidine-3-base) methyl)-4-iodo-1H-pyrazoles (215mg,
0.54mmol) (tertbutyloxycarbonyl)-3-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(4,4,5,5-s double with (R)-N, N-
Tetramethyl-1,3,2-dioxaborolanes-2-base) pyridine-2-amine (284mg, 0.45mmol) is dissolved in glycol dimethyl ether
(40mL), in, be sequentially added into water (10mL) solution of sodium carbonate (148mg, 1.4mmol) wherein, after nitrogen protection, continue to
Pd (dppf) Cl is added in system2·CH2Cl2(35mg,0.05mmol).Reactant liquor was 88 ° of C heated and stirred 16 hours.Reaction
Finishing, concentrating under reduced pressure, be dispersed in by residue in dichloromethane (60mL) and water (60mL), the organic facies of separation is with saline (30mL)
Washing, anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained residue, through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purification, obtains
To thick product.This product is dissolved in dichloromethane (40mL), after being cooled to 0 ° of C, is added thereto to the HCl (second of 8mL, 1M
Acetate solution).Reactant liquor stirs 12 hours.Reaction is finished, concentrating under reduced pressure.Residue water (100mL) is dissolved again, adds full
It is 10 with sodium carbonate liquor regulation pH value, and extracts with methylene chloride/methanol mixed liquor (8/1,50mL × 3).Merge is organic
It is dried through anhydrous sodium sulfate, and after concentrating under reduced pressure, with residue through silica gel column chromatography (DCM/MeOH (v/v)=7/1) purification,
Obtaining title compound is yellow solid (75mg, 31%).
LC-MS(ESI,pos.ion)m/z:234.5(M+2)/2；
1H NMR(400MHz,DMSO-d6)δ(ppm):1.79(d,J=6.6Hz,3H),1.80-2.05(m,3H),2.82-
3.13(m,4H),4.47(s,1H),4.52(s,1H),5.67(s,2H),6.09(q,J=6.6Hz,1H),6.88(d,J=
1.5Hz,1H),7.40-7.47(m,1H),7.52-7.58(m,1H),7.59(s,1H),7.75(d,J=1.7Hz,1H),7.84
(s,1H)。
Embodiment 93-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((S)-pyrrolidin-2-yl first
Base)-1H-pyrazoles-4-base) pyridine-2-amine
Step 1) (S)-(1-(tertbutyloxycarbonyl) pyrrolidin-2-yl) methylmethanesulfonate ester
Title compound is prepared by the method described by embodiment 6 step 1, will (S)-(1-(tertiary butyloxycarbonyl
Base) pyrrolidin-2-yl) methanol (1g, 4.9mmol), mesyl chloride (0.6mL) and triethylamine (1.1mL) are dissolved in dichloromethane
(15mL) preparation in, obtaining thick product is yellow oil (1.4g), and this product is the most purified, is directly used in next step.
Step 2) (S)-1-((1-(tertbutyloxycarbonyl) pyrrolidin-2-yl) methyl)-4-iodo-1H-pyrazoles
Title compound is prepared by the method described by embodiment 6 step 2, will 4-iodo-1H-pyrazoles
(840mg, 7.4mmol), (S)-(1-(tertbutyloxycarbonyl) pyrrolidin-2-yl) methylmethanesulfonate ester (1.4g) and sodium hydride
(320mg, 12mmol, 90% are dispersed in mineral oil) is dissolved in preparation in DMF (20mL), and thick product is through silicon
Plastic column chromatography (PE/EtOAc (v/v)=5/1) purification, obtaining target product is colorless oil (1.6g, 89%).
LC-MS(ESI,pos.ion)m/z:378.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.40(1H,s),7.31(1H,s),4.26-3.96(3H,m),3.30-
3.06(2H,m),2.80-1.64(4H,m),1.42(9H,s)。
Step 3) (S)-1-((1-(tertbutyloxycarbonyl) pyrrolidin-2-yl) methyl)-4-(4,4,5,5-tetramethyl-1,3,
2-dioxaborolanes-2-base)-1H-pyrazoles
Title compound is prepared by the method described by embodiment 6 step 3, will (S)-1-((1-(tertiary fourth oxygen
Carbonyl) pyrrolidin-2-yl) methyl)-4-iodo-1H-pyrazoles (1g, 2.65mmol), connection boric acid frequency sodium alcohol ester (3.9mmol, 1g),
Pd(dppf)Cl2·CH2Cl2(0.2g, 0.265mmol) and potassium acetate (0.53g, 5.3mmol) are suspended in dimethyl sulfoxide (15mL)
Middle preparation, thick product is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, and obtaining target product is white solid
(800mg,80%)。
LC-MS(ESI,pos.ion)m/z:378.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.69(1H,s),7.58(1H,s),4.29-4.07(3H,m),3.31-
3.07(2H,m),2.00-1.66(4H,m),1.43(9H,s),1.18(12H,s).
Step 4) 5-(1-(((S)-1-(tertbutyloxycarbonyl) pyrrolidin-2-yl) methyl)-1H-pyrazoles-4-base)-3-
((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
Title compound is prepared by the method described by embodiment 6 step 4, will the bromo-3-of (R)-5-(1-(2,
6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (500mg, 1.32mmol), (S)-1-((1-(tertbutyloxycarbonyl) pyrroles
Alkane-2-base) methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-pyrazoles (500mg,
1.32mmol), Pd (PPh3)2Cl2(108mg, 15.3mmol) and sodium carbonate (2.64mmol, 280mg) are suspended in glycol dinitrate
Preparation in ether/water (15mL/1.5mL), thick product, through silica gel column chromatography (PE/EtOAc (v/v)=1/1) purification, obtains targeted
Compound is brown solid (200mg, 27%).
LC-MS(ESI,pos.ion)m/z:550[M+H]+。
Step 5) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((S)-pyrrolidin-2-yl methyl)-
1H-pyrazoles-4-base) pyridine-2-amine
Title compound is prepared by the method described by embodiment 6 step 5, will 5-(1-(((S)-1-(tertiary fourth
Oxygen carbonyl) pyrrolidin-2-yl) methyl)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyrrole
Pyridine-2-amine (160mg, 0.29mmol) and HCl (ethyl acetate solution of 5mL, 1M) are dissolved in preparation in ethyl acetate (5mL),
Obtaining title compound is yellow solid (60mg, 46%).
LC-MS(ESI,pos.ion)m/z:225.7(M+2)/2；
1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H),7.55-7.52(m,2H),7.32-7.30(m,2H),
7.07-6.86(m,1H),6.07(q,J=6.64Hz,1H),4.85(s,2H),4.28-4.23(dd,J=4.4Hz,1H),4.13-
4.08(dd,J=7.4Hz,1H),3.73-3.68(m,1H),3.04-3.02(m,2H),1.86-1.84(m,2H),1.81(d,J=
6.64Hz,3H),1.49-1.47(m,2H)。
Embodiment 103-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(((2S)-4-fluoropyrrolidine-2-
Base) methyl)-1H-pyrazoles-4-base) pyridine-2-amine
Step 1) (2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-methyl formate
Title compound is prepared by the method described by embodiment 1 step 8, will (2S)-1-(tertiary butyloxycarbonyl
Base)-4-hydroxyl pyrrolidine-2-methyl formate (1g, 4.1mmol) and DAST (1.1mL, 8.2mmol) is dissolved in dichloromethane
(5mL) preparation in, thick product, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purification, obtains target product for Huang
Color grease (0.93g, 93%).
LC-MS(ESI,pos.ion)m/z:248[M+H]+。
Step 2) ((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-base) methanol
(2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-methyl formate (0.95g, 3.85mmol) is dissolved tetrahydrochysene furan
Mutter in (18mL), be cooled to 0 ° of C, be slowly added to lithium borohydride (0.13g, 5.78mmol) wherein.Reactant liquor is warmed to room temperature,
It is stirred overnight.Reaction is finished, and adds acetic acid,diluted (0.5mL is dissolved in 60mL water) cancellation, and extracts by ethyl acetate (20mL × 3).Close
And organic facies wash with 1M sodium bicarbonate solution (50mL), saline (50mL) successively, anhydrous sodium sulfate is dried, and concentrating under reduced pressure,
Gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, and obtaining title compound is yellow oily
Thing (0.82g, 97%).
LC-MS(ESI,pos.ion)m/z:242[M+Na]+。
Step 3) ((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-base) methylmethanesulfonate ester
By ((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-base) methanol (0.41g, 1.87mmol) and DMAP
(22.8mg, 0.1mmol) is dissolved in dichloromethane (6mL), is cooled to 0 ° of C, be added thereto to successively triethylamine (0.52mL,
3.74mmol) with mesyl chloride (0.23mL, 2.81mmol).Reactant liquor is stirred at room temperature 2.5 hours.Reaction is finished, and adds 1M bicarbonate
Sodium solution (25mL) cancellation, and extract with dichloromethane (30mL × 3), the organic facies saline (25mL) of merging is washed, anhydrous sulfur
Acid sodium is dried, and concentrating under reduced pressure, and gained residue is the most purified, is directly used in next step reaction.
Step 4) 1-(((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-base) methyl)-4-iodo-1H-pyrazoles
Iodo-for 4-1H-pyrazoles (0.51g, 2.64mmol) is dissolved in dry DMF (45mL), cold
But to 0 ° of C, being dividedly in some parts sodium hydride (0.17g, 7.0mmol) wherein, mixture, after 0 ° of C stirs 8 hours, is warmed to room temperature,
And it is added thereto to ((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-base) methylmethanesulfonate ester.Reactant liquor is heated to
100 ° of C, stirring reaction 8 hours.Reaction is finished, and adds NH4Cl aqueous solution (50mL), and extract by ethyl acetate (50mL × 3).Close
And organic facies saturated aqueous common salt (25mL) wash, anhydrous Na2SO4It is dried, and concentrating under reduced pressure, gained residue is through silica gel column layer
Analysis (petrol ether/ethyl acetate (v/v)=6/1) purification, obtaining title compound is colorless oil (700mg, 95%).
LC-MS(ESI,pos.ion)m/z:396[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),1.56-2.39(m,2H),3.49-3.75(m,2H),
4.14-4.58(m,3H),5.18-5.32(m,1H),7.42(s,1H),7.53(s,1H)。
Step 5) 1-(((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-base) methyl)-4-(4,4,5,5-tetramethyl
Base-1,3-dioxaborolanes-2-base)-1H-pyrazoles
Title compound is prepared by the method described by embodiment 7 step 4, will 1-(((2S)-1-(tertiary fourth oxygen
Carbonyl)-4-fluoropyrrolidine-2-base) methyl)-4-iodo-1H-pyrazoles (0.7g, 1.77mmol), connection boric acid pinacol ester (0.68g,
2.66mmol), KOAc (0.38g, 3.9mmol) and Pd (PPh3)2Cl2(62mg, 0.09mmol) is suspended in dimethyl sulfoxide (10mL)
Middle preparation, thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and obtaining target product is yellow oil
Shape thing (0.66g, 94%).
LC-MS(ESI,pos.ion)m/z:398[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.30(s,12H),1.46(s,9H),2.01-2.31(m,2H),
3.52-3.79(m,2H),4.09-4.15(m,1H),4.32-4.37(m,1H),4.45-4.60(m,1H),5.16-5.29(m,
1H),7.67(s,1H),7.79(s,1H)。
Step 6) 5-(1-(((2S)-1-(tertbutyloxycarbonyl)-4-fluoropyrrolidine-2-base) methyl)-1H-pyrazoles-4-base)-
3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
Title compound is prepared by the method described by embodiment 7 step 5, will the bromo-3-of (R)-5-(1-(2,
6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (0.54g, 1.44mmol), 1-(((2S)-1-(tertbutyloxycarbonyl)-4-fluorine
Pyrrolidin-2-yl) methyl)-4-(4,4,5,5-tetramethyl-1,3-dioxaborolanes-2-base)-1H-pyrazoles (0.38g,
0.96mmol), Pd (OAc)2(22mg, 0.096mmol), Na2CO3(0.3g, 2.87mmol) and (t-Bu)3P(49mg,
0.24mmol) being suspended in preparation in glycol dimethyl ether/water (6mL/1.5mL), thick product is through silica gel column chromatography (petroleum ether/second
Acetoacetic ester (v/v)=1/2) purification, obtaining target product is yellow solid (0.5g, 55%).
LC-MS(ESI,pos.ion)m/z:569[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),1.84-1.86(d,J=6.6Hz,3H),2.04-
2.45(m,2H),3.49-3.76(m,2H),4.09-4.14(m,1H),4.30-4.36 (m,1H),4.43-4.59(m,1H),
4.77(s,2H),5.16-5.32(m,1H),6.04-6.09(q,J=6.6Hz,1H),6.85(s,1H),7.03-7.07(m,
1H),7.28-7.32(m,1H),7.41(s,1H),7.54-7.58(m,1H),7.75-7.76(d,J=1.6Hz,1H)。
Step 7) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(((2S)-4-fluoropyrrolidine-2-
Base-) methyl)-1H-pyrazoles-4-base) pyridine-2-amine
The method that title compound is described by embodiment 1 step 10 prepares, will 5-(1-(((2S)-1-(tertiary fourth
Oxygen carbonyl)-4-fluoropyrrolidine-2-base) methyl)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethoxy
Base) pyridine-2-amine (0.4g, 0.52mmol) and HCl (ethyl acetate solution of 5mL, 3M) be dissolved in dichloromethane (15mL)
Preparation, thick product, through silica gel column chromatography (methylene chloride/methanol/triethylamine (v/v/v)=200/20/1) purification, obtains titled
Compound is yellow solid (0.29g, 90%).
LC-MS(ESI,pos.ion)m/z:468[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.80-2.05(m,1H),1.84(d,J=6.0Hz,3H),2.05-
2.24(m,1H),2.95-3.08(m,1H),3.30-3.39(m,1H),3.64-3.68(m,1H),4.12-4.18(m,1H),
4.21-4.26(m,1H),4.78(s,2H),5.14-5.30(m,1H),6.05-6.10(q,J=6.7Hz,1H),6.86-6.87
(d,J=1.5Hz,1H),7.03-7.07(t,J=1.7Hz,1H),7.29-7.32(m,1H),7.54(s,1H),7.58(s,1H),
7.76-7.77(d,J=1.7Hz,1H)。
Embodiment 113-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(((S)-4,4-difluoro pyrroles
Alkane-2-base) methyl)-1H-pyrazoles-4-base) pyridine-2-amine
Step 1) (2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidine-2-formic acid first
Ester
(2S)-1-(tertbutyloxycarbonyl)-4-hydroxyl pyrrolidine-2-methyl formate (2.0g, 8.15mmol) is suspended in two
Chloromethanes (100mL), and it is added thereto to DHP (1.71g, 20.4mmol) and PPTS (246mg, 0.978mmol).Reactant liquor exists
35 ° of C heated and stirred 36 hours.Reaction is finished, concentrating under reduced pressure, and with silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, obtains
Title compound is colorless oil (2.65g, 99%).
1H NMR(400MHz,CDCl3)δ(ppm):1.41-1.46(d,9H),1.50-1.63(m,5H),1.64-1.75
(m,1H),1.75-1.86(m,1H),2.01-2.18(m,2H),2.23-2.51(m,1H),3.39-3.72(m,3H),3.73
(s,3H),3.78-3.90(m,1H),4.28-4.46(m,2H),4.61-4.69(m,1H).
Step 2) ((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl) first
Alcohol
By (2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidine-2-methyl formate
(1.0g, 3.0mmol) is dissolved in oxolane (15mL), after being cooled with an ice bath, be added thereto to lithium borohydride (94.5mg,
4.5mmol).Reactant liquor is stirred overnight at 35 ° of C.Reaction is finished, and is cooled with an ice bath, is slowly added to saturated ammonium chloride solution (20mL)
Cancellation, and extract by ethyl acetate (60mL × 3).The organic facies merged, is dried with anhydrous sodium sulfate, and concentrating under reduced pressure.Gained
Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, and obtaining title compound is colorless oil
(850mg,94%)。
LC-MS(ESI,pos.ion)m/z:324[M+Na]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.47(s,9H),1.49-1.75(m,6H),1.75-1.87(m,1H),
1.87-2.02(m,1H),2.05-2.24(m,1H),3.25-3.79(m,5H),3.79-3.86(m,1H),3.78-3.90(m,
1H),4.22-4.39(m,1H),4.61-4.69(m,1H),4.82-5.02(m,1H)。
Step 3) ((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl) first
Base methanesulfonates
The method that title compound is described by embodiment 10 step 3 prepares, will ((2S)-1-(tertiary butyloxycarbonyl
Base)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl) methanol (1.0g, 3.3mmol), mesyl chloride
(0.38mL, 4.95mmol), DMAP (40mg, 0.33mmol) and triethylamine (0.92mL, 6.6mmol) are dissolved in dichloromethane
(10mL) preparing thick product (1.25g, 100%) in, this product is the most purified, is directly used in next step reaction.
Step 4) 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl)
Methyl)-4-iodo-1H-pyrazoles
Iodo-for 4-1H-pyrazoles (704.2mg, 3.63mmol) is dissolved in dry DMF (15mL),
After being cooled to 0 DEG C, it is dividedly in some parts sodium hydride (7.6mmol, 192mg, 95%) wherein.Suspension is after 0 DEG C of stirring 8 hours, extensive
Multiple to being stirred at room temperature 1.5 hours, and continue to add in system ((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-
2-yl) epoxide) pyrrolidin-2-yl) N,N-dimethylformamide (3mL) solution of methylmethanesulfonate ester (1.25g, 3.3mmol).
Reactant liquor stirs 13 hours at 100 DEG C.Reaction is finished, and is cooled to room temperature, adds saturated ammonium chloride solution (30mL) cancellation, and use acetic acid
Ethyl ester (50mL × 2) extracts.The organic facies saline (25mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained is residual
Stay thing through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, obtain title compound be white solid (1.3g,
83%)。
LC-MS(ESI,pos.ion)m/z:478[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.40-1.59(m,13H),1.60-1.70(m,1H),1.70-1.95
(m,2H),1.95-2.05(m,1H),2.05-2.20(m,1H),3.02-3.72(m,3H),3.73-3.86(m,1H),3.80-
4.02(m,1H),4.05-4.39(m,3H),4.45-4.69(m,2H),7.35-7.40(m,1H),7.48(s,1H)。
Step 5) (5S)-1-(tertbutyloxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl) methyl) pyrrolidine-3-alcohol
By 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl) first
Base)-4-iodo-1H-pyrazoles (200mg, 0.42mmol) is suspended in the mixed liquor of oxolane/water (5mL/5mL), adds wherein
Enter acetic acid (1mL, 16.8mmol).Reactant liquor stirs 16 hours at 70 DEG C.Reaction is finished, and is cooled to room temperature.Mixture saturated carbon
Acid sodium solution regulation pH value is 10, and extracts by ethyl acetate (50mL × 3).The organic facies anhydrous sodium sulfate of merging is done
Dry, after concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purification, it is colourless for obtaining title compound
Grease (157mg, 95%).
LC-MS(ESI,pos.ion)m/z:394[M+H]+。
Step 6) (S)-1-(tertbutyloxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl) methyl) pyrrolidine-3-ketone
By (5S)-1-(tertbutyloxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl) methyl) pyrrolidine-3-alcohol (1.39g,
3.54mmol) it is suspended in dichloromethane (44mL), is added thereto to Dess-Martin oxidant (3g, 7.07mmol).Reaction
Liquid is stirred at room temperature 16 hours, filters.After filtrate reduced in volume, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1)
Purification, obtaining title compound is white solid (1.2g, 87%).
1H NMR(400MHz,CDCl3)δ(ppm):1.49(s,9H),2.60-2.90(m,2H),2.90-3.29(m,1H),
3.50-3.98(m,1H),4.20-4.27(m,1H),4.61(s,2H),7.34(s,1H),7.49(s,1H)。
Step 7) (S)-1-((1-(tertbutyloxycarbonyl)-4,4-difluoropyrrolidin-2-base) methyl)-4-iodo-1H-pyrazoles
By (S)-1-(tertbutyloxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl) methyl) pyrrolidine-3-ketone (100mg,
0.26mmol) be dissolved in dichloromethane (3mL), be cooled to-78 DEG C, be added thereto to DAST (95%, 0.15mL,
1.04mmol).Reactant liquor, after-40 ° of C stir 2 hours, recovers to room temperature, continues stirring 21 hours.Reaction is finished, concentrating under reduced pressure,
Residue use water (30mL) is diluted, and extracts with dichloromethane (30mL × 3).The organic facies saline (30mL) merged is washed,
Anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained residue, through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, obtains
Target product is yellow oil (100mg, 93%).
LC-MS(ESI,pos.ion)m/z:414[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.49(s,9H),2.29-2.70(m,2H),3.25-3.60(m,1H),
3.60-3.98(m,1H),4.12-4.55(m,3H),7.44(s,1H),7.51(s,1H)。
Step 8) (S)-1-((1-(tertbutyloxycarbonyl)-4,4-difluoropyrrolidin-2-base) methyl)-4-(4,4,5,5-tetra-
Methyl-1,3-dioxy Pentamethylene .-2-base)-1H-pyrazoles
Will connection boric acid frequency sodium alcohol ester (128mg, 0.504mmol) be dissolved in dimethyl sulfoxide (3mL), be added thereto to (S)-
1-((1-(tertbutyloxycarbonyl)-4,4-difluoropyrrolidin-2-base) methyl)-4-iodo-1H-pyrazoles (80mg, 0.194mmol) and second
Acid potassium (76mg, 0.776mol), is placed in system in blanket of nitrogen, continues to be added thereto to Pd (PPh3)2Cl2(16.3mg,
0.023mmol).Reactant liquor, after 80 ° of C stir 3 hours, is cooled to room temperature, and add water (30mL) dilution, and uses ethyl acetate
(30mL × 3) extract.The organic facies merged is dried through anhydrous sodium sulfate, and after concentrating under reduced pressure, with silica gel column chromatography (petroleum ether/
Ethyl acetate (v/v)=5/1) purification, obtaining title compound is yellow oil (30mg, 37.5%).
LC-MS(ESI,pos.ion)m/z:414[M+H]+。
Step 9) 5-(1-(((S)-1-(tertbutyloxycarbonyl)-4,4-difluoropyrrolidin-2-base) methyl)-1H-pyrazoles-4-
Base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
By the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (195mg, 0.51mmol),
(S)-1-((1-(tertbutyloxycarbonyl)-4,4-difluoropyrrolidin-2-base) methyl)-4-(4,4,5,5-tetramethyl-1,3-dioxy ring
Pentane-2-base)-1H-pyrazoles (141mg, 0.34mmol) and Pd (OAc)2(7.7mg, 0.034mmol) is suspended in glycol dinitrate
In ether/water (3mL/0.5mL), being added thereto to water (0.5mL) solution of sodium carbonate (145mg, 1.37mmol), nitrogen is protected
After, continue to add (t-Bu) in system3P (toluene solution of 0.15mL, 1M).Reactant liquor, after 90 ° of C stir 13 hours, drops
To room temperature, adding ethyl acetate (40mL) dilution, and filter with kieselguhr, filtering residue ethyl acetate (40mL) is washed.Collect filtrate, warp
Saline (30mL × 2) is washed, and after concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/2) purification, obtains mesh
Mark product is yellow solid (80mg, 44%).
LC-MS(ESI,pos.ion)m/z:586[M+H]+。
Step 10) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(((S)-4,4-difluoropyrrolidin-
2-yl) methyl)-1H-pyrazoles-4-base) pyridine-2-amine
Target compound is prepared by the method described by embodiment 1 step 10, will 5-(1-(((S)-1-(uncle
Butoxy carbonyl)-4,4-difluoropyrrolidin-2-base) methyl)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorobenzene
Base) ethyoxyl) pyridine-2-amine (140mg, 0.24mmol) and HCl (ethyl acetate solution of 2mL, 3M) be dissolved in dichloromethane
(6mL) preparation in, thick product is through silica gel column chromatography (ethyl acetate/methanol (v/v)=20/1) purification, and obtaining title compound is
Yellow solid (80mg, 69%).
LC-MS(ESI,pos.ion)m/z:243(M+1/2)；
1H NMR(400MHz,CDCl3)δ(ppm):1.85-1.87(d,J=6.5Hz,3H),1.95-2.10(m,1H),
2.32-2.45(m,1H),3.12-3.35(m,2H),3.75-3.86(m,1H),4.06-4.18(m,1H),4.19-4.29(m,
1H),4.84(s,2H),6.05-6.10(q,J=6.3Hz, 1H),6.86(s,1H),7.03-7.08(t,J=8.4Hz,1H),
7.28-7.33(m,1H),7.51(s,1H),7.57(s,1H),7.75(s,1H)。
Embodiment 12 (5S)-5-((4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-3-
Base)-1H-pyrazol-1-yl) methyl) pyrrolidine-3-alcohol
Step 1) 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl)
Methyl)-4-(4,4,5,5-tetramethyl-1,3-dioxaborolanes-2-base)-1H-pyrazoles
Title compound is prepared by the scheme described by embodiment 11 step 8, will 1-(((2S)-1-(tertiary fourth
Oxygen carbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl) methyl)-4-iodo-1H-pyrazoles (100mg,
0.21mmol), connection boric acid frequency sodium alcohol ester (140mg, 0.54mmol), Pd (PPh3)2Cl2(16mg, 0.23mmol) and potassium acetate
(82mg, 0.84mol) is suspended in preparation in dimethyl sulfoxide (3mL), and thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/
V)=1/4) purification, obtaining target compound is white solid (80mg, 80%).
LC-MS(ESI,pos.ion)m/z:477[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.25-1.27(m,12H),1.40-1.59(m,13H),1.60-1.85
(m,3H),1.95-2.05(m,1H),2.05-2.22(m,1H),2.98-3.72(m,3H),3.73-3.86(m,1H),3.80-
4.02(m,1H),4.05-4.30(m,2H),4.31-4.42(m,1H),4.43-4.62(m,2H),7.62-7.70(s,1H),
7.75-7.76(m,1H)。
Step 2) 5-(1-(((2S)-1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidine-2-
Base) methyl)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
The scheme that title compound is described by embodiment 11 step 9 prepares, will (R)-5-bromo-3-(1-(2,6-
Two chloro-3-fluorophenyls) ethyoxyl) pyridine-2-amine (96mg, 0.25mmol), 1-(((2S)-1-(tertbutyloxycarbonyl)-4-((four
Hydrogen-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl) methyl)-4-(4,4,5,5-tetramethyl-1,3-dioxaborolanes-
2-yl)-1H-pyrazoles (100mg, 0.21mmol), Pd (OAc)2(4.7mg, 0.021mmol), sodium carbonate (89mg, 0.84mmol)
(t-Bu)3P (toluene solution of 0.06mL, 1M) is suspended in the mixed liquor of glycol dimethyl ether/water (3mL/0.5mL) system
Standby, thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purification, and obtaining title compound is yellow solid
(60mg,44%)。
LC-MS(ESI,pos.ion)m/z:650[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.45-1.59(m,13H),1.60-1.70(m,2H),1.70-1.95
(m,1H),1.95-2.20(m,2H),3.02-3.25(m,1H),3.25-3.52(m,2H),3.52-4.02(m,2H),4.15-
4.39(m,3H),4.45-4.69(m,2H),4.79(s,2H),6.05-6.10(q,J=6.6Hz,1H),6.84-6.87(m,
1H),7.03-7.07(t,J=8.7Hz,1H),7.29-7.33(m,1H),7.35-7.45(m,1H),7.52-7.60(m,1H),
7.74(d,J=1.5Hz,1H).
Step 3) (5S)-5-((4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-3-
Base)-1H-pyrazol-1-yl) methyl) pyrrolidine-3-alcohol
Target compound is prepared by the method described by embodiment 1 step 10, will 5-(1-(((2S)-1-(uncle
Butoxy carbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pyrrolidin-2-yl) methyl)-1H-pyrazoles-4-base)-3-((R)-
1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (250mg, 0.385mmol) and HCl (the acetic acid second of 3.5mL, 3M
Ester solution) it is dissolved in preparation in dichloromethane (12mL), thick product is through silica gel column chromatography (ethyl acetate/methanol (v/v)=5/1)
Purification, obtaining title compound is yellow solid (120mg, 67%).
LC-MS(ESI,pos.ion)m/z:233(M+1/2)；
1H NMR(400MHz,CDCl3)δ(ppm):1.41-1.50(m,1H),1.59-1.65(m,1H),1.80(d,J=
6.6Hz,3H),1.89(s,1H),2.62-2.65(m,1H),2.84-2.89(m,1H),3.55-3.62(m,1H),3.96-
3.96(d,J=6.2Hz,2H),4.11-4.18(m,1H),4.57(s,1H),5.65(s,2H),6.06-6.11(q,J=6.6Hz,
1H),6.87-6.88(d,J=1.6Hz,1H),7.42-7.47(t,J=8.8Hz,1H),7.51(s,1H),7.55-7.59(m,
1H),7.73-7.74(d,J=1.7Hz,1H),7.87(s,1H)。
Embodiment 13
4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-pyrazoles-1-
Base) tetrahydrochysene-2H-pyrans-3-alcohol (13a)
3-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-pyrazoles-1-
Base) tetrahydrochysene-2H-pyrans-4-alcohol (13b)
Step 1) 3,6-dihydro-2H-pyrans
Tetrahydrochysene-2H-pyrans-4-alcohol (20.4g, 0.2mol) and triethylamine (36.2mL, 0.26mol) are dissolved in dichloromethane
In alkane (200mL), it is cooled to 0 ° of C, is added thereto to mesyl chloride (17mL, 0.22mol).After reactant liquor is stirred at room temperature 3 hours,
Pour in water (100mL).The organic facies separated is washed through saline (100mL × 2), and anhydrous sodium sulfate is dried, and is concentrated under reduced pressure to give
Orange.This grease is heated to 50 ° of C, drips DBU (40mL) the most wherein.It is little that mixture stirs 2 at 100 ° of C
Time.Residue is through decompression distillation (92-93 ° of C) purification, and obtaining title compound is colourless liquid (10.0g, 60%).
GC-MS m/z:84(M)。
Step 2) 3,7-dioxa dicyclo [4.1.0] heptane
M-CPBA (25.6g, 296mmol) is suspended in dichloromethane (200mL), is cooled to 0 ° of C, drips 3 wherein,
6-dihydro-2H-pyrans (8.3g, 98.7mmol).Reactant liquor stirred overnight at room temperature.Reaction is finished, concentrating under reduced pressure, residue dichloro
Methane (30mL) dilutes.Mixture being cooled to 0 ° of C, filters, filtrate is colorless oil through being concentrated under reduced pressure to give title compound
Thing (7.5g, 76%).
GC-MS m/z:100(M)。
Step 3)
3-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-pyran-4-ol(13.3a)
4-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-pyran-3-ol(13.3b)
Sodium hydride (1.6g, 40.0mmol, 60% are dispersed in mineral oil) is suspended in N,N-dimethylformamide (30mL)
In, it is cooled to 0 ° of C, is added thereto to 4-iodo-1H-pyrazoles (5.8g, 30.0mmol).Mixture after 0 ° of C stirs 2.5 hours,
Continue to be added thereto to the N,N-dimethylformamide (5mL) of 3,7-dioxa dicyclo [4.1.0] heptane (2.0g, 20.0mmol)
Solution.Reactant liquor after 100 ° of C stir 18 hours, concentrating under reduced pressure.Residue is dispersed in ethyl acetate (300mL) and water
(150mL), in, separate aqueous phase, and extract by ethyl acetate (300mL).The organic facies merged is dried through anhydrous sodium sulfate, decompression
After concentration, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purification, obtain (13.3a) and the mixing of (13.3b)
Thing is yellow oil (4.2g, 36%).
LC-MS(ESI,pos.ion)m/z:295[M+H]+。
Step 4
4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-pyrazoles-1-
Base) tetrahydrochysene-2H-pyrans-3-alcohol (13a)
3-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-pyrazoles-1-
Base) tetrahydrochysene-2H-pyrans-4-alcohol (13b)
The mixture (530mg, 1.8mmol) of (13.3a) and (13.3b) is dissolved in glycol dimethyl ether (25mL),
It is added thereto to double (tertbutyloxycarbonyl)-3-(1-(the 2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(4,4,5,5-of (R)-N, N-
Tetramethyl-1,3,2-dioxaborolanes-2-base) pyridine-2-amine (941mg, 1.5mmol) and cesium carbonate (1467mg,
Water (5mL) solution 4.5mmol), after nitrogen protection, continues to add Pd (dppf) Cl in system2·CH2Cl2(122mg,
0.15mmol).Reactant liquor stirs 18 hours at 90 ° of C.Reaction finish, pour in saline (50mL), and with ethyl acetate (100mL ×
3) extraction.The organic facies merged is dried through anhydrous sodium sulfate, after concentrating under reduced pressure, by silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=2/1) purification, obtaining title compound is off-white color solid.This solid is dissolved in dichloromethane (20mL), cooling
To 0 ° of C, it is added thereto to HCl (ethyl acetate solution of 3mL, 3M).Reactant liquor stirred overnight at room temperature, concentrating under reduced pressure.Residue
Dilute with water (15mL), add saturated sodium carbonate solution regulation pH10, and extract mixed liquor by ethyl acetate (100mL × 3).Merge
Organic facies be dried through anhydrous sodium sulfate, after concentrating under reduced pressure, wash with ether (5mL), the mixture obtaining (13a) and (13b) is
Brown solid (55mg, 7%).
LC-MS(ESI,pos.ion)m/z:467[M+H]+。
Embodiment 143-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(5-fluorine resources-3-base)-1H-
Pyrazoles-4-base) pyridine-2-amine
Step 1) 1-(tertbutyloxycarbonyl) piperidin-4-yl methanesulfonates
1-(tertbutyloxycarbonyl) piperidines-4-alcohol (10g, 49.3mmol) and triethylamine (10g, 74mmol) are dissolved in dichloro
In methane (150mL), after being cooled to 0 DEG C, drip mesyl chloride (8.6g, 59mmol) wherein.It is little that reactant liquor is stirred at room temperature 2
Time.Reaction is finished, and is diluted by mixed liquor dichloromethane (100mL), successively with saturated sodium carbonate solution (250mL), saline (250
ML) wash.Organic facies is dried through anhydrous sodium sulfate, and concentrating under reduced pressure, and obtaining thick product is yellow oil (14g, 97%), this change
Compound is the most purified, is directly used in next step reaction.
Step 2) 1-(tertbutyloxycarbonyl)-1,2,3,6-tetrahydropyridine
DBU (80mL) solution of 1-(tertbutyloxycarbonyl) piperidin-4-yl methanesulfonates (14g, 48mmol) is heated to 80
DEG C, stir 16 hours.Reaction is finished, and is cooled to room temperature, and add water (200mL) dilution, and extracts by ethyl acetate (150mL x3), closes
And organic facies wash with 1M hydrochloric acid (450mL × 3), saturated sodium carbonate solution (450mL × 2) successively.Gained solution is through anhydrous sulfur
Acid sodium is dried, and to be concentrated under reduced pressure to give title compound be brown oil (8g, 100%), and this compound is the most purified, directly
For next step.
LC-MS(ESI,pos.ion)m/z:128[M+H-56]+；
1H NMR(400MHz,CDCl3)δ(ppm):5.83-5.80(m,1H),5.66(m,1H),3.87(m,2H),3.49-
3.47(t,J=5.2Hz,2H),2.13(m,2H),1.47(s,9H)。
Step 3) 3-(tertbutyloxycarbonyl)-7-oxa--3-azabicyclo [4.1.0] heptane
M-CPBA (20g, 87.4mmol) is dissolved in dichloromethane (150mL), is cooled to 0 DEG C, drips 1-wherein
(tertbutyloxycarbonyl)-1,2,3,6-tetrahydropyridine (8g, 43.7mmol).Reactant liquor is stirred at room temperature 14 hours.Reaction is finished, and filters.
Filter cake dichloromethane (50mL × 2) is washed, and the filtrate of merging is washed with saturated sodium carbonate solution (300mL × 2).Gained solution is through nothing
Aqueous sodium persulfate is dried, and after concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, obtains title
Compound is colorless oil (8g, 93%).
1H NMR(400MHz,CDCl3)δ(ppm):3.92-3.82(m,1H),3.71(m,1H),3.44(m,1H),3.29-
3.28(m,1H),3.21-3.10(m,2H),2.04(m,1H),1.95-1.88(m,1H),1.45(s,9H)。
Step 4) 1-(tertbutyloxycarbonyl)-4-iodine piperidin-3-ol
3-(tertbutyloxycarbonyl)-7-oxa--3-azabicyclo [4.1.0] heptane (100mg, 0.5mmol) is dissolved in N,
Dinethylformamide (5mL), after ice bath cooling, ISiMe wherein3(0.078mL,0.55mmol).Reactant liquor is stirred at room temperature
Overnight.Reaction finish, add ethyl acetate (50mL) dilution, successively with 1M hydrochloric acid (25mL × 2), saturated sodium carbonate solution (20mL ×
2) wash.Mixed liquor is dried through anhydrous sodium sulfate, after concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, obtains
It is yellow oil (60mg, 37%) to title compound.
LC-MS(ESI,pos.ion)m/z:350[M+Na]+,254[M+H-56-18]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),2.05-2.16(m,1H),2.33-2.39(m,1H),
2.59-3.00(m,3H),3.65-3.87(m,2H),4.05-4.11(m,1H),4.17-4.21(m,1H)。
Step 5) the iodo-3-of 1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidines
1-(tertbutyloxycarbonyl)-4-iodine piperidin-3-ol (1g, 3.1mmol), PPTS (77mg, 0.31mmol) are suspended in
In dichloromethane (20mL), it is added thereto to DHP (0.56mL, 9.4mmol).Reactant liquor stirred overnight at room temperature.Reaction is finished, decompression
Concentrating, gained residue silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, obtaining title compound is nothing
Color grease (1.0g, 80%).
LC-MS(ESI,pos.ion)m/z:434[M+Na]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.45(s,9H),1.54-1.82(m,4H),1.82-2.14(m,2H),
2.27-2.41(m,1H),2.80-3.05(m,1H),3.30-3.59(m,3H),3.59-3.78(m,1H),3.79-3.95(m,
2H),3.98-4.15(m,1H),4.15-4.39(m,1H),4.81-4.96(m,1H)。
Step 6) 1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-base) epoxide)-1,2,3,6-tetrahydropyridine
To the iodo-3-of 1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidines (7.7g, 18.7mmol)
Middle addition DBU (50mL).Reactant liquor stirs 27 hours at 80 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate (50mL) dilute
Release.Mixed liquor is washed with 1M hydrochloric acid (50mL × 3), saturated sodium carbonate solution (50mL × 2) successively, and anhydrous sodium sulfate is dried, and subtracts
Pressure concentrates.Gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=15/1) purification, and obtaining title compound is
Colorless oil (4.2g, 72%).
LC-MS(ESI,pos.ion)m/z:306[M+Na]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.47(s,9H),1.50-1.68(m,4H),1.69-1.79(m,1H),
1.79-1.90(m,1H),3.30-4.15(m,6H),4.15-4.32(m,1H),4.70-4.85(m,1H),5.82-5.93(m,
2H)。
Step 7) 1-(tertbutyloxycarbonyl)-1,2,3,6-tetrahydropyridine-3-alcohol
By 1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-base) epoxide)-1,2,3,6-tetrahydropyridine (500mg,
1.64mmol) it is dissolved in methylene chloride/methanol (25mL/5mL) mixed liquor, is cooled to 0 ° of C, is slowly added to HCl wherein
(ethyl acetate solution of 11mL, 3M).After reactant liquor stirred overnight at room temperature, it is concentrated under reduced pressure to give thick product, and by straight for this product
Connect in the mixed liquor being dissolved in oxolane/water (76mL/60mL).Solution saturated sodium carbonate solution is regulated pH10, Xiang Qi
Middle addition Boc anhydride (1.5mL).Reactant liquor stirred overnight at room temperature.Reaction is finished, and adds ethyl acetate/water (30mL/30mL) dilution,
The aqueous phase separated ethyl acetate (80mL × 2) extracts.The organic facies merged is dried through anhydrous sodium sulfate, and after concentrating under reduced pressure,
With silica gel column chromatography (PE/EtOAc (v/v)=2/1) purification, obtaining title compound is colorless oil (0.30g, 92%).
MS(ESI,pos.ion)m/z:126[M+H-56-18]+。
Step 8) 1-(tertbutyloxycarbonyl)-1,6-dihydropyridine-3 (2H)-one
1-(tertbutyloxycarbonyl)-1,2,3,6-tetrahydropyridine-3-alcohol (350mg, 1.76mmol) is dissolved in dichloromethane
(12mL), in, it is added thereto to Dess-Martin oxidant (1.5g, 3.52mmol).After reactant liquor is stirred at room temperature 2 hours, mistake
Filter.Filtrate is washed with saturated sodium carbonate solution (50mL), and concentrating under reduced pressure, gained residue by silica gel chromatography (PE/EtOAc (v/v)
=2/1) purification, obtaining title compound is colorless oil (340mg, 98%).
LC-MS(ESI,pos.ion)m/z:142[M+H-56]+,220[M+Na]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.48(s,9H),4.11(s,2H),4.24(s,2H),6.16-6.20
(m,1H),7.04(s,1H)。
Step 9) 1-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) piperidines-3-ketone
Iodo-for 4-1H-pyrazoles (389.9mg, 2.01mmol) is dissolved in acetonitrile (6mL), is added thereto to 1-(tertiary fourth oxygen
Carbonyl)-1,6-dihydropyridine-3 (2H)-one (260mg, 1.34mmol).Reactant liquor is stirred overnight at 80 ° of C.Reaction is finished, cooling
To room temperature, add water (20mL) dilution, and extracts by ethyl acetate (30mL × 2).The organic facies merged is dried through anhydrous sodium sulfate,
After concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=2/1) purification, obtaining title compound is white solid
(110mg,21%)。
LC-MS(ESI,pos.ion)m/z:336[M+H-56]+,414[M+Na]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.39(s,9H),2.86-2.92(m,1H),2.80-3.05(m,1H),
3.09-3.15(m,1H),3.50-4.42(m,4H),4.78-4.82(m,1H), 7.49(s,1H),7.51(s,1H).
Step 10) 1-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) piperidin-3-ol
1-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) piperidines-3-ketone (3.45g, 8.82mmol) is dissolved in
In methanol (50mL), it is cooled to 0 DEG C, is added thereto to sodium borohydride (670mg, 17.64mmol).It is little that reactant liquor is stirred at room temperature 1
Time.Reaction is finished, and adds saturated ammonium chloride solution (50mL) cancellation, and extracts by ethyl acetate (100mL × 2).The organic facies merged
It is dried through anhydrous sodium sulfate, and after concentrating under reduced pressure, with silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, obtains titled
Compound is white solid (2.1g, 60.7%).
LC-MS(ESI,pos.ion)m/z:394[M+H]+。
Step 11) the fluoro-5-of 1-(tertbutyloxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl) piperidines
Title compound can be prepared by the method described by embodiment 11 step 7, will 1-(tertiary butyloxycarbonyl
Base)-5-(4-iodo-1H-pyrazol-1-yl) piperidin-3-ol (240mg, 0.61mmol), DAST (95%, 0.15mL, 1.04mmol)
Being dissolved in preparation in dichloromethane (5mL), thick product, through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purification, obtains target
Product is yellow solid (900mg, 45%).
MS(ESI,pos.ion)m/z:340[M+H-56]+。
Step 12) the fluoro-5-of 1-(tertbutyloxycarbonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-
2-yl)-1H-pyrazol-1-yl) piperidines
Target compound is prepared by the step described by embodiment 11 step 8, will 1-(tertbutyloxycarbonyl)-3-
Fluoro-5-(4-iodo-1H-pyrazol-1-yl) piperidines (900mg, 2.07mmol), connection boric acid frequency sodium alcohol ester (1.04g, 4.14mmol),
Pd(PPh3)2Cl2(174.6mg, 0.12mmol) and potassium acetate (608mg, 6.21mol) are suspended in system in dimethyl sulfoxide (50mL)
Standby, thick product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purification, and obtaining target product is yellow oil
(650mg,72%)。
LC-MS(ESI,pos.ion)m/z:396[M+H]+。
Step 13) 5-(1-(1-(tertbutyloxycarbonyl)-5-fluorine resources-3-base)-1H-pyrazoles-4-base)-3-((R)-1-(2,
6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
Target compound is prepared by the step described by embodiment 11 step 9, will the bromo-3-of (R)-5-(1-(2,
6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (195mg, 0.5139mmol), 1-(tertbutyloxycarbonyl)-3-fluoro-5-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-pyrazol-1-yl) piperidines (521.5mg,
1.32mmol), Pd (OAc)2(35.5mg, mmol), sodium carbonate (560mg, 5.28mmol) and (t-Bu)3P (the first of 0.15mL, 1M
Benzole soln) it is suspended in preparation in glycol dimethyl ether/water (15mL/4mL), thick product is through silica gel column chromatography (petroleum ether/acetic acid second
Ester (v/v)=1/1) purification, obtaining title compound is yellow solid (350mg, 47%).
MS(ESI,pos.ion)m/z:568[M+H]+。
Step 14) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(5-fluorine resources-3-base)-1H-pyrrole
Azoles-4-base) pyridine-2-amine
Target compound is prepared by the method described by embodiment 1 step 10, will 5-(1-(1-(tertiary butyloxycarbonyl
Base)-5-fluorine resources-3-base)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
(350mg, 0.62mmol) and HCl (ethyl acetate solution of 4mL, 3M) are dissolved in preparation, thick product warp in dichloromethane (6mL)
Silica gel column chromatography (ethyl acetate/methanol (v/v)=6/1) purification, obtaining title compound is yellow solid (235mg, 81%).
LC-MS(ESI,pos.ion)m/z:234.5(M+1/2)；
1H NMR(400MHz,CDCl3)δ(ppm):1.86-1.88(d,J=6.6Hz,3H),2.16-2.24(m,1H),
2.59-2.75(m,1H),2.90-3.00(m,1H),3.25-339(m,2H),4.20-4.32(m,1H),4.53-4.75(m,
1H),4.83(s,2H),6.06-6.11(q,J=6.5Hz,1H),6.88(s,1H),7.04-7.08(t,J=8.4Hz,1H),
7.28-7.33(m,1H),7.54(s,1H),7.58(s,1H),7.77(s,1H)。
Embodiment 155-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl) piperidin-3-ol
Step 1) 1-(tertbutyloxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-
1H-pyrazol-1-yl) piperidin-3-ol
By 1-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) piperidin-3-ol (1.5g, 3.81mmol) and connection boron
Acid frequency sodium alcohol ester (1.94g, 7.62mmol) be dissolved in dimethyl sulfoxide (20mL), be added thereto to potassium acetate (1.5g,
15.24mmol), under nitrogen protection, continue to add Pd (dppf) Cl in system2·CH2Cl2(310mg,0.38mmol).Reaction
Liquid, after 90 ° of C stir 12 hours, is cooled to room temperature, and pours in water/ethyl acetate (100mL/300mL) mixed liquor.To separate
Organic facies saline (100mL) wash, anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (PE/
EtOAc (v/v)=2/1) purification, obtaining title compound is brown solid (720mg, 48%).
LC-MS(ESI,pos.ion)m/z:394.20[M+H]+。
Step 2) 5-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-
Pyrazol-1-yl)-1-(tertbutyloxycarbonyl) piperidin-3-ol
By the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (515mg, 1.36mmol) and
1-(tertbutyloxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-pyrazol-1-yl)
Piperidin-3-ol (800mg, 2.03mmol) is dissolved in glycol dimethyl ether (25mL), be added thereto to cesium carbonate (1.33g,
After water (5mL) solution 4.08mmol), under nitrogen protection, continue to add Pd (dppf) Cl in system2·CH2Cl2
(114mg,0.14mmol).Reactant liquor stirs 12 hours at 90 ° of C, is cooled to room temperature, and add water (20mL) dilution, and uses dichloromethane
Alkane (3 × 50mL) extracts.Being washed by the organic facies saline (100mL) merged, anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained
Residue is through silica gel column chromatography (methylene chloride/methanol (v/v)=60/1) purification, and obtaining title compound is yellow oil
(400mg,52%)。
LC-MS(ESI,pos.ion)m/z:566.20[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.72(s,1H),7.50-7.54(m,2H),7.28-7.32(m,1H),
7.02-7.07(m,1H),6.85(s,1H),6.02-6.10(m,1H),4.96(s,2H),4.31-4.34(m,1H),3.86(s,
1H),3.76-3.80(m,1H),3.64-3.67(m,1H),3.52-3.60(m,1H),3.42-3.47(m,1H),2.38-2.41
(m,1H),2.15-2.21(m,1H),1.84-1.86(d,J=6.6Hz,3H),1.36(s,9H)。
Step 3) 5-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-
Pyrazol-1-yl) piperidin-3-ol
Target compound is prepared by the method described by embodiment 1 step 10, will 5-(4-(6-amino-5-
((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) piperidines-
3-alcohol (350mg, 0.62mmol) and HCl (ethyl acetate solution of 4mL, 3M) are dissolved in preparation in dichloromethane (5mL), slightly produce
Product through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1) purification, obtain title compound be yellow-brown solid (60mg,
21%)。
LC-MS(ESI,pos.ion)m/z:466.20[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):7.92(s,1H),7.75(s,1H),7.54-7.58(m,1H),
7.52(s,1H),7.41-7.45(m,1H),6.89(s,1H),6.04-6.10(m,1H),5.63(s,2H),4.87(s,1H),
4.07-4.16(m,1H),3.46-3.58(m,4H),3.05-3.10(m,1H),2.96-3.01(m,1H),2.26-2.31(m,
1H),2.13-2.19(m,1H),1.78-1.81(d,J=6.6Hz,3H)。
Embodiment 165-(1-(2,2-bis-deuterated-4-base)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorine
Phenyl) ethyoxyl) pyridine-2-amine
Step 1) 4-hydroxy piperidine-2-ketone
By piperidines-2,4-diketone (1g, 8.8mmol) is dissolved in methanol (25mL), is cooled to 0 DEG C, is added thereto to boron
Sodium hydride (1g, 26.55mmol).Reactant liquor stirred overnight at room temperature.Reaction is finished, concentrating under reduced pressure.Gained residue is through silica gel column layer
Analysis (methylene chloride/methanol (v/v)=5/1) purification, obtaining title compound is yellow solid (960mg, 87%).
LC-MS(ESI,pos.ion)m/z:138[M+Na]+。
Step 2) 4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidines-2-ketone
4-hydroxy piperidine-2-ketone (1.4g, 12.18mmol), PPTS (367mg, 1.462mmol) are suspended in dichloromethane
(200mL), in, it is added thereto to DHP (4.1g, 48.72mmol).Reactant liquor after 35 ° of C stir 48 hours, concentrating under reduced pressure.Institute
Residue through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1) purification, obtaining title compound is white solid
(2.16g,89%)。
LC-MS(ESI,pos.ion)m/z:200[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm):1.50-1.70(m,4H),1.71-1.80(m,1H),1.80-2.10
(m,4H),2.40-2.71(m,3H),3.21-3.35(m,1H),3.36-3.62(m,2H),3.80-3.95(m,1H),4.11-
4.20(m,1H),4.65-4.79(m,1H),6.50(s,1H)。
Step 3) 1-(tertbutyloxycarbonyl)-2,2-two deuterated piperidines-4-alcohol
4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidines-2-ketone (1.17g, 5.88mmol) is dissolved in oxolane
(33.3mL) in, it is cooled with an ice bath, and is added thereto to LiAlD4(272mg,6.47mmol).Reactant liquor is stirred at 70 ° of C
Night.Reaction is finished, and is again cooled with an ice bath, is slowly added to saturated ammonium chloride solution (50mL) cancellation.By mixture ethyl acetate
(50mL × 2) extract, the organic facies of merging is dried through anhydrous sodium sulfate, and concentrating under reduced pressure, obtains thick product, this product immediately by
Use.
MS(ESI,pos.ion)m/z:188[M+H]+。
Deuterated for 2,2-bis--4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidines is dissolved in methylene chloride/methanol (45mL/
In 9mL), it is cooled to 0 ° of C, is added thereto to HCl (ethyl acetate solution of 26mL, 3M).After reactant liquor stirred overnight at room temperature, subtract
Pressure concentrates.
Gained residue and sodium carbonate (16.80g, 158.5mmol) are dissolved in oxolane/water (76mL/60mL)
In mixed liquor, it is added thereto to Boc anhydride (5mL).Reactant liquor stirred overnight at room temperature.Reaction is finished, and is dispersed in ethyl acetate
(50mL) with in water (50mL), the aqueous phase of separation ethyl acetate (50mL × 2) extracts.The organic facies merged is through anhydrous sodium sulfate
Being dried, after concentrating under reduced pressure, with silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, it is white for obtaining title compound
Color solid (0.52g, 17%).
LC-MS(ESI,pos.ion)m/z:149[M+H-56]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),1.73(s,2H),1.82-1.86(m,2H),2.99-
3.06(m,1H),3.81-3.87(m,2H)。
Step 4) deuterated-4-of 1-(tertbutyloxycarbonyl)-2,2-two (4-iodo-1H-pyrazol-1-yl) piperidines
By deuterated for 1-(tertbutyloxycarbonyl)-2,2-two piperidines-4-alcohol (490mg, 2.41mmol) and DMAP (29.4mg,
0.241mmol) it is dissolved in dichloromethane (15mL), is cooled to 0 DEG C, be added thereto to triethylamine (0.67mL, 4.82mmol)
After, continue dropping mesyl chloride (0.223mL, 2.897mmol).Reactant liquor is stirred at room temperature 5 hours.Reaction is finished, and adds 1M bicarbonate
Sodium solution (25mL) cancellation, and extract with dichloromethane (50mL × 2).The organic facies merged is washed through saline (25mL), anhydrous sulfur
Acid sodium is dried, and concentrating under reduced pressure, obtains residue, and this residue is used immediately.
Iodo-for 4-1H-pyrazoles (467.5mg, 2.41mmol) is dissolved in dry DMF (8mL),
It is cooled to 0 DEG C, is dividedly in some parts sodium hydride (193mg, 4.82mmol, 60% are dispersed in mineral oil) wherein.Mixture room temperature is stirred
After mixing 2 hours, continue to add DMF (4mL) solution of above-mentioned residue in system.Reactant liquor is at 100 DEG C
Stir 12 hours.Reaction is finished, and is cooled to room temperature, adds saturated ammonium chloride solution (50mL) cancellation, and with ethyl acetate (50mL × 2)
Extraction.The organic facies saline (25mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Residue is through silica gel column chromatography
(PE/EtOAc (v/v)=4/1) purification, obtaining title compound is yellow solid (620mg, 68%).
LC-MS(ESI,pos.ion)m/z:324[M+H-56]+；
1H NMR(400MHz,CDCl3)δ(ppm):1.47(s,9H),1.83-1.89(m,2H),2.07-2.11(m,2H),
2.85-2.90(m,1H),4.23-4.30(m,2H),7.46(s,1H),7.51(s,1H)。
Step 5) deuterated-4-of 1-(tertbutyloxycarbonyl)-2,2-two (4-(4,4,5,5-tetramethyl-1,3,2-dioxane penta
Borine-2-base)-1H-pyrazol-1-yl) piperidines
Title compound is prepared by the method described by embodiment 11 step 8, will 1-(tertbutyloxycarbonyl)-2,
Deuterated-the 4-of 2-bis-(4-iodo-1H-pyrazol-1-yl) piperidines (300mg, 0.792mmol), connection boric acid frequency sodium alcohol ester (281.6mg,
1.11mmol), potassium acetate (310.5mg, 3.17mol) and Pd (PPh3)2Cl2(33.36mg, 0.0475mmol) is suspended in diformazan
Preparation in sulfoxide (6mL), thick product is through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purification, and it is white for obtaining title compound
Color solid (250mg, 83%).
LC-MS(ESI,pos.ion)m/z:380[M+H]+。
Step 6) 5-(1-(the deuterated piperidin-4-yl of 1-(tertbutyloxycarbonyl)-2,2-two)-1H-pyrazoles-4-base)-3-((R)-
1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
By the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (300.8mg,
0.792mmol), the deuterated-4-of 1-(tertbutyloxycarbonyl)-2,2-bis-(4-(4,4,5,5-tetramethyl-1,3,2-dioxane penta boron
Alkane-2-base)-1H-pyrazol-1-yl) piperidines (250mg, 0.66mmol) and sodium carbonate (245mg, 2.31mmol) be suspended in second two
In the mixed liquor of diethylene glycol dimethyl ether/water (6mL/1mL), under nitrogen protection, it is added thereto to Pd (PPh3)2Cl2(37mg,
0.053mmol).Reactant liquor stirs 14 hours at 90 ° of C.Reaction is finished, and is cooled to room temperature, adds ethyl acetate (150mL) dilution, and
Filtering with kieselguhr, filter cake ethyl acetate (50mL) is washed.The filtrate merged is washed through saline (50mL × 2), and after concentrating under reduced pressure,
With silica gel column chromatography (PE/EtOAc (v/v)=1/1) purification, obtaining title compound is yellow solid (180mg, 50%).
LC-MS(ESI,pos.ion)m/z:552[M+H]+。
Step 7) 5-(1-(2,2-bis-deuterated-4-base)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorobenzene
Base) ethyoxyl) pyridine-2-amine
Target compound is prepared by the method described by embodiment 1 step 10, will 5-(1-(1-(tertiary butyloxycarbonyl
Base) the deuterated piperidin-4-yl of-2,2-two)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyrrole
Pyridine-2-amine (440mg, 0.80mmol) and HCl (ethyl acetate solution of 5mL, 3M) are dissolved in preparation in dichloromethane (20mL),
Thick product is through silica gel column chromatography (DCM/MeOH/Et3N (v/v/v)=100/20/1) purification, obtain title compound solid for white
Body (180mg, 50%).
LC-MS(ESI)m/z:226.6(M+2/2)；
1H NMR(400MHz,CDCl3)δ(ppm):1.85-1.86(d,J=6.7Hz,3H),1.86-1.95(m,2H),
2.13-2.18(m,2H),2.76-2.81(t,J=10.6Hz,1H),3.24-3.28(m,1H),4.18-4.24(m,1H),4.78
(s,2H),6.05-6.10(q,J=6.6Hz,1H),6.87(s,1H),7.03-7.07(t,J=8.5Hz,1H),7.27-7.32
(m,1H),7.50(s,1H),7.56(s,1H),7.76(s,1H)。
Embodiment 17
3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3S, 4R)-3-fluorine resources-4-base)-1H-
Pyrazoles-4-base) pyridine-2-amine (17a)
3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3R, 4S)-3-fluorine resources-4-base)-1H-
Pyrazoles-4-base) pyridine-2-amine (17b)
Step 1)
1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) piperidin-3-ol (17.1a)
1-(tertbutyloxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl) piperidines-4-alcohol (17.1b)
Iodo-for 4-1H-pyrazoles (3g, 16mmol) is dissolved in oxolane (20mL), is cooled to-78 ° of C, at 30 minutes
Drip LDA (10mL, 2M in THF) the most wherein.After mixture stirs 3 hours, in 20 minutes, drip 3-(tertiary fourth wherein
Oxygen carbonyl) oxolane (20mL) solution of-7-oxa--3-azabicyclo [4.1.0] heptane (3g, 14mmol).Reaction liquid chamber
Temperature stirring 1 hour, is then heated to 70 ° of C, continues stirring 12 hours.Reaction is finished, and is cooled to room temperature, and add water (4mL) cancellation, subtracts
After pressure concentrates, through silica gel column chromatography (PE/EtOAc (v/v)=4:1) purification, obtain (17.1a) (2.5g, 41%) and 1-(tertiary fourth oxygen
Carbonyl)-3-(4-iodo-1H-pyrazol-1-yl) piperidines-4-alcohol (17.1b) is white solid.
(17.1a):
LC-MS(ESI,pos.ion)m/z:394[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.56(s,1H),7.24(s,1H),4.39-4.04(m,2H),4.02-
3.99(m,1H),3.87(m,1H),2.82-2.70(m,2H),2.12-2.04(m,1H),2.00-1.95(m,1H),1.46(s,
9H)。
(17.1b):
LC-MS(ESI,pos.ion)m/z:394[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.55(s,2H),4.34-4.16(m,3H),3.95-3.89(m,1H),
3.08(m,2H),2.88-2.82(t,J=12Hz,1H),2.07-2.03(m,1H),1.65-1.56(m,1H),1.47(s,9H)。
Step 2) 1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)-3-((tetrahydrochysene-2H-pyrans-2-base) oxygen
Base) piperidines
By 1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl) piperidin-3-ol (0.5g, 1.27mmol) and PPTS
(0.032g, 0.127mmol) is dissolved in dichloromethane (20mL), is added thereto to DHP (0.5mL).Reactant liquor is stirred at room temperature 3
After hour, concentrating under reduced pressure.Gained residue silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, obtains title compound
For light yellow oil (0.5g, 84%).
LC-MS(ESI,pos.ion)m/z:478[M+H]+。
Step 3) 1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-base) epoxide)-4-(4-(4,4,5,5-tetramethyl
Base-1,3,2-dioxaborolanes-2-base)-1H-pyrazol-1-yl) piperidines
Under nitrogen protection, by 1-(tertbutyloxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)-3-((tetrahydrochysene-2H-pyrans-2-
Base) epoxide) piperidines (0.5g, 1mmol), connection boric acid frequency sodium alcohol ester (0.8g, 3mmol), potassium acetate (0.2g, 2mmol) and Pd
(dppf)Cl2·CH2Cl2Dimethyl sulfoxide (15mL) suspension of (0.08g, 0.1mmol) stirs 4 hours at 50 ° of C.Reaction is finished,
Being cooled to room temperature, add water (40mL) dilution, and extracts by ethyl acetate (30mL × 3).Organic facies saline (the 80mL merged
X2) washing, anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1)
Purification, obtaining title compound is white solid (0.45g, 90%).
LC-MS(ESI,pos.ion)m/z:478[M+H]+。
Step 4) 5-(1-(1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidin-4-yl)-1H-
Pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
By 1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-base) epoxide)-4-(4-(4,4,5,5-tetramethyl-1,
3,2-dioxaborolanes-2-bases)-1H-pyrazol-1-yl) piperidines (0.45g, 0.94mmol), the bromo-3-of (R)-5-(1-(2,
6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (0.4g, 1mmol), Pd (OAc)2(22mg, 0.1mmol) and sodium carbonate
(0.22g, 2mmol) is suspended in the mixed liquor of glycol dimethyl ether/water (20mL/1mL), under nitrogen protection, is added thereto to
(t-Bu)3P (toluene solution of 0.25mL, 1M).Reactant liquor after 100 ° of C stir 36 hours, concentrating under reduced pressure.Gained residue warp
Silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/2) purification, obtain title compound be light tan solid (0.38g,
61%)。
LC-MS(ESI,pos.ion)m/z:650[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.75-7.73(m,1H),7.67(s,1H),7.61-7.50(m,1H),
7.31-7.29(m,1H),7.07-7.02(m,1H),6.88-6.86(m,1H),6.10-6.05(t,J=6.64Hz,1H),4.80
(s,2H),4.70-4.18(m,2H),4.12-3.65(m,4H),3.57-2.98(m,1H),2.91-2.45(m,2H),2.40-
1.92(4H,m),1.86-1.84(d,J=6.64Hz,3H),1.78-1.45(m,13H)。
Step 5)
(3R, 4R)-4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) piperidin-3-ol (17.5a)
(3S, 4S)-4-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl)-1-(tertbutyloxycarbonyl) piperidin-3-ol (17.5b)
By 5-(1-(1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidin-4-yl)-1H-pyrazoles-
4-yl)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (1g, 1.54mmol) and PPTS (0.12g,
Methanol (30mL) solution 0.46mmol) stirs 30 hours at 75 ° of C.Reaction is finished, concentrating under reduced pressure, and add water (40mL) dilution, and uses
Dichloromethane (30mL × 3) extracts.The organic phase washed with water (90mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained
Residue is through silica gel column chromatography (DCM/MeOH (v/v)=40/1) purification, and the mixture obtaining (17.5a) and (17.5b) is brown
Solid (0.6g, 71%).
LC-MS(ESI,pos.ion)m/z:565[M+H]+。
Step 6)
5-(1-((3S, 4R)-1-(tertbutyloxycarbonyl)-3-fluorine resources-4-base)-1H-pyrazoles-4-base)-3-((R)-1-
(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (17.6a)
5-(1-((3R, 4S)-1-(tertbutyloxycarbonyl)-3-fluorine resources-4-base)-1H-pyrazoles-4-base)-3-((R)-1-
(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (17.6b)
The mixture (0.6g, 1mmol) of (17.5a) and (17.5b) is dissolved in dichloromethane (15mL), be cooled to-
78 ° of C, drip dichloromethane (5mL) solution of DAST (0.34g, 2mmol) wherein.Reactant liquor stirring stirs 30 points at-78 ° of C
Zhong Hou, is warming up to-40 ° of C, continues stirring 4 hours.Reaction is finished, and adds 1M sodium bicarbonate solution (30mL) cancellation, and uses dichloromethane
(30mL × 3) extract.The organic phase washed with water (90mL), the saline (90mL) that merge are washed, and anhydrous sodium sulfate is dried, and it is dense to reduce pressure
Contracting.Gained residue, through silica gel column chromatography (methylene chloride/methanol (v/v)=40/1) purification, obtains (17.6a) and (17.6b)
Mixture is brown solid (0.28g, 47%).
LC-MS(ESI,pos.ion)m/z:568[M+H]+。
Step 7)
3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3S, 4R)-3-fluorine resources-4-base)-1H-
Pyrazoles-4-base) pyridine-2-amine (17a)
3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3R, 4S)-3-fluorine resources-4-base)-1H-
Pyrazoles-4-base) pyridine-2-amine (17b)
HCl (ethyl acetate solution of 10mL, 1M) is added drop-wise to (17.6a) and (17.6b) mixture (0.28g,
In 0.49mmol).Reactant liquor is stirred at room temperature 2 hours.Reaction is finished, concentrating under reduced pressure.Residue 2M sodium carbonate liquor (20mL) place
After reason, extract with dichloromethane (20mL x3).The organic facies saline (60mL) merged is washed, and anhydrous sodium sulfate is dried, and reduces pressure
Concentrate.Residue is through silica gel column chromatography (DCM/MeOH/NH4OH (v/v/v)=50/1/1) purification, obtain (17a) and (17b)
Mixture is light yellow solid (0.15g, 75%).
LC-MS(ESI,pos.ion)m/z:234.7(M+2)/2；
1H NMR(400MHz,CDCl3)δ(ppm):7.77(s,1H),7.62(s,1H),7.58-7.52(m,1H),7.32-
7.29(dd,J=4.80Hz,1H),7.07-7.03(t,J=8.60Hz,1H),6.88(s,1H),6.10-6.05(t,J=
6.68Hz,1H),4.80(s,2H),4.69-4.60(m,1H),4.23-4.13(m,1H),3.52-3.47(m,1H),3.19-
3.15(m,1H),2.74-2.70(m,2H),2.20-2.16(m,2H),1.86-1.84(d,J=6.68Hz,3H)。
Embodiment 18
(3R, 4R)-4-(4-(6-amido-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl) piperidin-3-ol (18a)
(3S, 4S)-4-(4-(6-amido-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl) piperidin-3-ol (18b)
HCl (ethyl acetate solution of 5mL, 1M) is added drop-wise to 5-(1-(1-(tertbutyloxycarbonyl)-3-((tetrahydrochysene-2H-pyrrole
Mutter-2-base) epoxide) piperidin-4-yl)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyrrole
In pyridine-2-amine (0.25g, 0.38mmol).Reactant liquor is stirred at room temperature 2 hours.Reaction is finished, and add water (20mL) dilution, and uses acetic acid
Ethyl ester (20mL × 2) is washed.After being processed with 2M sodium carbonate liquor (10mL) by mixed liquor, add ethyl acetate (20mL × 3) extraction.Close
And organic facies wash through saline (60mL), anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and obtaining title compound is white solid
(0.12g,70%)。
LC-MS(ESI,pos.ion)m/z:233.7(M+2)/2；
1H NMR(400MHz,CDCl3)δ(ppm):7.75(d,J=1.68Hz,1H),7.60(s,1H),7.54(s,1H),
7.33-7.29(m,1H),7.07-7.04(t,J=7.92Hz,1H),6.86(s,1H),6.10-6.05(t,J=6.64Hz,1H),
4.78(s,2H),3.99-3.95(m,2H),3.41-3.19(m,2H),2.78-2.59(m,2H),2.19-1.97(m,2H),
1.86-1.84(d,J=6.64Hz,3H).
Embodiment 19
(3R, 4R)-3-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl) piperidines-4-alcohol (19a)
(3S, 4S)-3-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl) piperidines-4-alcohol (19b)
Step 1) 1-(tertbutyloxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl)-4-((tetrahydrochysene-2H-pyrans-2-base) oxygen
Base) piperidines
The method that title compound is described by embodiment 17 step 2 prepares, will 1-(tertbutyloxycarbonyl)-3-
(4-iodo-1H-pyrazol-1-yl) piperidines-4-alcohol (1g, 2.6mmol), PPTS (0.064g, 0.26mmol) and DHP (1mL) suspend
Preparation in dichloromethane (30mL), thick product, through silica gel column chromatography (PE/EtOAc (v/v)=6/1) purification, obtains title compound
Thing is light yellow oil (0.5g, 84%).
LC-MS(ESI,pos.ion)m/z:478[M+H]+。
Step 2) 1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide)-3-(4-(4,4,5,5-tetramethyl
Base-1,3,2-dioxaborolanes-2-base)-1H-pyrazol-1-yl) piperidines
Title compound is prepared by the method described by embodiment 17 step 3, will 1-(tertbutyloxycarbonyl)-3-
(4-iodo-1H-pyrazol-1-yl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidines (0.6g, 1.25mmol), connection boric acid frequency sodium
Alcohol ester (0.9g, 3.8mmol), potassium acetate (0.25g, 2.5mmol) and Pd (dppf) Cl2·CH2Cl2(0.1g,0.125mmol)
It is suspended in preparation in dimethyl sulfoxide (20mL).Thick product, through silica gel column chromatography (PE/EtOAc (v/v)=2/1) purification, obtains title
Compound is yellow solid (0.58g, 94%).
LC-MS(ESI,pos.ion)m/z:478[M+H]+。
Step 3) 5-(1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidines-3-base)-1H-
Pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
Title compound is prepared by the method described by embodiment 17 step 4, will the bromo-3-of (R)-5-(1-(2,
6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (0.6g, 1.58mmol), 1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrrole
Mutter-2-base) epoxide)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-pyrazol-1-yl)
Piperidines (0.58g, 1.2mmol), Pd (OAc)2(34mg, 0.15mmol), sodium carbonate (0.26g, 2.5mmol) and (t-Bu)3P
(toluene solution of 0.38mL, 1M) is suspended in the suspension of glycol dimethyl ether/water (30mL/1mL) preparation.Thick product is through silicon
Plastic column chromatography (PE/EtOAc (v/v)=1/1) purification, obtaining title compound is light tan solid (0.5g, 60%).
LC-MS(ESI,pos.ion)m/z:650[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.75-7.40(m,1H),7.62-7.60(m,1H),7.53-7.51
(m,1H),7.34-7.28(m,1H),7.08-7.02(dd,J=8.02Hz,1H),6.87-6.86(m,1H),6.10-6.05(t,
J=6.64Hz,1H),4.48-4.01(m,3H),3.95-3.80(m,3H),3.41-3.37(m,1H),3.01-2.78(m,1H),
2.15-2.12(m,1H),1.86-1.84(d,J=6.64Hz,3H),1.66-1.62(m,3H),1.58-1.36(m,13H).
Step 4)
(3R, 4R)-3-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl) piperidines-4-alcohol (19a)
(3S, 4S)-3-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridin-3-yl)-
1H-pyrazol-1-yl) piperidines-4-alcohol (19b)
Title compound is prepared by the method described by embodiment 18, i.e. uses the HCl (ethyl acetate of 5mL, 1M
Solution) and 5-(1-(1-(tertbutyloxycarbonyl)-4-((tetrahydrochysene-2H-pyrans-2-base) epoxide) piperidines-3-base)-1H-pyrazoles-4-
Base) prepared by-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (0.25g, 0.38mmol), gained mesh
Mark product is white solid (0.09g, 50%).
LC-MS(ESI,pos.ion)m/z:233.7(M+2)/2；
1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H),7.60(s,1H),7.50-7.49(d,J=3.2Hz,
1H),7.32-7.28(m,1H),7.07-7.03(m,1H),6.85(s,1H),6.09-6.04(t,J=6.64Hz,1H),4.78
(s,2H),4.15-4.08(m,1H),3.96-3.90(m,1H),3.42-3.38(m,1H),3.18-3.15(m,1H),3.00-
2.93(m,1H),2.77-2.70(m,1H),2.17-2.13(m,1H),1.86-1.84(d,J=6.64Hz,3H)。
Embodiment 203-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((hexahydro furyl also [2,3-b]
Furan-3-base) methyl)-1H-pyrazoles-4-base) pyridine-2-amine
Step 1) (2R, 3S)-2-(allyloxy)-3-iodine oxolane
NIS (15.1g, 66.6mmol) is suspended in dichloromethane (150mL), is cooled to 0 ° of C, in 30 minutes, Xiang Qi
Middle addition dihydrofuran (5.1mL, 66.6mmol) and dichloromethane (50mL) solution of 1-propenol-3 (6.8mL, 100mmol).Instead
Liquid is answered to stir 3 hours under 0 ° of C.Reaction is finished, and recovers to room temperature, and (200mL) dilution that adds water.Gained mixture continues in room temperature
After stirring 1 hour, extract with dichloromethane (200mL).Organic facies saline solution (400mL) is washed, and anhydrous sodium sulfate is dried, and subtracts
Pressure concentrates, and gained residue is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=9/1) purification, and obtaining title compound is
Yellow oil (15.53g, 91.8%).
1H NMR(400MHz,CDCl3)δ(ppm):5.88(m,1H),5.39(s,1H),5.29(m,1H),5.23(m,
1H),4.20-3.95(m,5H),2.63(m,1H),2.21(m,1H)。
Step 2) 3-(iodomethyl) hexahydro furyl also [2,3-b] furan
(2R, 3S)-2-(allyloxy)-3-iodine oxolane (2g, 7.87mmol) is suspended in water (100mL), nitrogen
Under gas shielded, it is added thereto to boron triethyl (tetrahydrofuran solution of 0.7mL, 1M).Reactant liquor is stirred at room temperature 3 hours.Reaction
Finish, extract by ethyl acetate (100mL × 3).The organic facies saline (300mL) merged is washed, and anhydrous sodium sulfate is dried, and subtracts
Pressure concentrates, and obtaining title compound is yellow oil (1.6g, 80%), and this product is the most purified, is directly used in next step anti-
Should.
MS(ESI,pos.ion)m/z254[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):5.78(d,J=4.92Hz,1H),4.05-4.02(m,1H),3.92-
3.88(m,2H),3.48-3.43(dd,J=8.6Hz,1H),3.19-3.15(dd,J=7.68Hz,1H),3.10-3.05(dd,J=
8.46Hz,1H),2.93-2.76(m,2H),1.94-1.80(m,2H)。
Step 3) 1-((hexahydro furyl also [2,3-b] furan-3-base) methyl)-4-iodo-1H-pyrazoles
Iodo-for 4-1H-pyrazoles (2g, 9.48mmol) is dissolved in anhydrous DMF (30mL), is cooled to
0 ° of C, after being dividedly in some parts sodium hydride (0.7g, 23.7mmol, 80% are dispersed in mineral oil) wherein, continuously adds 3-(iodine first
Base) N,N-dimethylformamide (10mL) solution of hexahydro furyl also [2,3-b] furan (1.6g, 7.9mmol).Reactant liquor exists
80 ° of C stir 10 hours, and reaction is finished, and is cooled to room temperature, and add water (80mL) cancellation, and extract by ethyl acetate (100mL × 3).Close
And organic facies saline (300mL) wash, anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and gained residue is through silica gel column chromatography (stone
Oil ether/ethyl acetate (v/v)=3/1) purification, obtaining title compound is yellow oil (1.5g, 60%).
LC-MS(ESI,pos.ion)m/z:321[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.47(s,1H),7.40(s,1H),5.70(d,J=4.8Hz,1H),
4.28-4.23(dd,J=7.32Hz,1H),4.16-4.11(dd,J=7.7Hz,1H),3.95-3.85(m,3H),3.63-3.58
(dd,J=8.64Hz,1H),2.91-2.79(m,2H),1.93-1.88(m,2H)。
Step 4) 1-((hexahydro furyl also [2,3-b] furan-3-base) methyl)-4-(4,4,5,5-tetramethyl-1,3,2-two
Oxa-ring pentaborane-2-base)-1H-pyrazoles
By 1-((hexahydro furyl also [2,3-b] furan-3-base) methyl)-4-iodo-1H-pyrazoles (1.2g, 3.75mmol), connection
Boric acid pinacol ester (1.14g, 4.5mmol) and potassium acetate (1.1g, 11.25mmol) are dissolved in dimethyl sulfoxide (25mL), nitrogen
Under gas shielded, it is added thereto to Pd (dppf) Cl2·CH2Cl2(153mg,0.19mmol).Reactant liquor stirs 3 hours at 80 ° of C,
Reaction is finished, and is cooled to room temperature, and add water (60mL) dilution, and extracts by ethyl acetate (50mL × 3).The organic facies salt merged
Water (120mL) is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and gained residue is through silica gel column chromatography (petrol ether/ethyl acetate
(v/v)=2/1) purification, obtaining title compound is yellow oil (0.6g, 50%).
1H NMR(400MHz,CDCl3)δ(ppm):7.78(s,1H),7.67(s,1H),5.73(d,J=4.3Hz,2H),
4.29-4.26(m,1H),4.20-4.14(m,1H),3.98-3.88(m,3H),3.67-3.65(m,1H),1.97-1.93(m,
2H),1.32(s,6H),1.25(m,6H)。
Step 5) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((hexahydro furyl also [2,3-b] furan
Mutter-3-base) methyl)-1H-pyrazoles-4-base) pyridine-2-amine
By the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (0.8g, 1.8mmol), 1-
((hexahydro furyl also [2,3-b] furan-3-base) methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-
Base)-1H-pyrazoles (0.8g, 2mmol) and sodium carbonate (0.4g, 3.6mmol) be dissolved in glycol dimethyl ether/water (20mL/
In mixed liquor 0.2mL), under nitrogen protection, it is sequentially added into Pd (OAc) wherein2(40mg, 0.18mmol) and (t-Bu)3P
(toluene solution of 0.6mL, 1M).Reactant liquor stirs 16 hours at 100 ° of C.Reaction is finished, and is cooled to room temperature, and concentrating under reduced pressure.Institute
Residue through silica gel column chromatography (petrol ether/ethyl acetate/methanol (v/v/v)=10/10/1) purification, obtain title compound
For white solid (0.3g, 25%).
LC-MS(ESI,pos.ion)m/z:493[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.74(d,J=1.76Hz,1H),7.56(s,1H),7.42(s,1H),
7.30-7.28(m,1H),7.08-7.05(m,1H),6.85(dd,J=1.52Hz,1H),6.10-6.05(q,J=2.66Hz,
1H),5.76(d,J=4.84Hz,1H),4.85(s,2H),4.13-4.11(m,1H),4.01-3.88(m,3H),3.70-3.65
(m,1H),2.96-2.84(m,2H),1.99-1.95(m,2H),1.86(d,J=2.66Hz,3H)。
Embodiment 21 (3S, 3aS, 6aS)-6-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)
Pyridin-3-yl) methyl)-1H-pyrazol-1-yl) hexahydro furyl also [3,2-b] furan-3-ol
Step 1)
(3R, 3aR, 6S, 6aS)-6-hydroxyl hexahydro furyl also [3,2-b] furan-3-p-toluenesulfonic esters (21.1a)
(3S, 3aR, 6R, 6aS)-6-hydroxyl hexahydro furyl also [3,2-b] furan-3-p-toluenesulfonic esters (21.1b)
(3R, 3aR, 6S, 6aR)-hexahydro furyl also [3,2-b] furan-3,6-is double (p-toluenesulfonic esters) (21.1c)
Isosorbide (5g, 34.2mmol) is dissolved in water (20mL), is cooled to 0 ° of C, is sequentially added into wherein first
Toluene (25mL) solution of benzene sulfonyl chloride (7.34g, 38.5mmol) and the water (9mL) of potassium hydroxide (2.5g, 44.6mmol) are molten
Liquid.Reactant liquor, after 5 ° of C stir 4 hours, recovers to room temperature, continues to be stirred overnight.Reaction finish, mixture add water (100mL) quench
Go out, and extract by ethyl acetate (100mL × 3).The organic facies saline (120mL) merged is washed, and anhydrous sodium sulfate is dried, and subtracts
Pressure concentrate, gained residue through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=2/1) purification, obtain (21.1a) and
(21.1b) (2.8g, 28%), and (21.1c) (0.6g, 5%) is white solid.
LC-MS(ESI,pos.ion)m/z:301[M+H]+。
Step 2) (3R, 3aR, 6S, 6aS)-6-((tetrahydrochysene-2H-pyrans-2-base) epoxide) hexahydro furyl also [3,2-b] furan
Mutter-3-p-toluenesulfonic esters
DHP is dissolved in dichloromethane (20mL), cryosel bath cooling, is added thereto to PPTS (0.2g, 0.9mmol),
Under nitrogen protection, continue to add dichloromethane (20mL) solution of (21.1a) and (21.1b) (2.7g, 9mmol) in system.
Reactant liquor, after 0 ° of C stirs 30 minutes, recovers to room temperature, continues to be stirred overnight.Reaction is finished, by mixture concentrating under reduced pressure, residual
Thing add water (50mL) dilution, and with ethyl acetate (50mL × 3) extraction.The organic facies saline (150mL) merged is washed, anhydrous sulfur
Acid sodium is dried, and concentrating under reduced pressure, and gained residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=3/1) purification, obtains
Title compound is colorless oil (3.1g, 88.5%).
LC-MS(ESI,pos.ion)m/z:407[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.84(d,J=1.36Hz,2H),7.82(d,J=1.44Hz,2H),
4.67-4.64(m,1H),4.53-4.51(m,2H),4.44-4.39(dd,J=4.28Hz,2H),4.22-4.2(m,1H),
3.88-3.73(m,4H),3.52-3.33(m,2H),2.43(s,3H),1.72-1.43(m,6H)。
Step 3) the iodo-1-of 4-((3aS, 6S, 6aR)-6-((tetrahydrochysene-2H-pyrans-2-base) epoxide) hexahydro furyl also [3,2-
B] furan-3-base)-1H-pyrazoles
Iodo-for 4-1H-pyrazoles (0.89g, 4.5mmol) is dissolved in anhydrous DMF (15mL), cooling
To 0 ° of C, it is dividedly in some parts sodium hydride (0.3g, 9mmol, 80% are dispersed in mineral oil) wherein.Mixture stirs 1 hour at 0 ° of C
After, in system, add (3R, 3aR, 6S, 6aS)-6-((tetrahydrochysene-2H-pyrans-2-base) epoxide) hexahydro furyl also [3,2-b] furan
Mutter N,N-dimethylformamide (10mL) solution of-3-p-toluenesulfonic esters (1.6g, 5.2mmol).Reactant liquor stirs 30 at 0 ° of C
Minute, it is then heated to 80 ° of C, continues stirring 10 hours.Reaction finish, add water (70mL) cancellation, and with ethyl acetate (70mL ×
3) extraction.The organic facies saline (180mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and gained residue is through silica gel
Column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purification, obtaining title compound is yellow solid (0.9g, 50%).
LC-MS(ESI,pos.ion)m/z:429[M+Na]+。
Step 4) 1-((3aS, 6S, 6aR)-6-((tetrahydrochysene-2H-pyrans-2-base) epoxide) hexahydro furyl also [3,2-b] furan
Mutter-3-base)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-pyrazoles
By iodo-for 4-1-((3aS, 6S, 6aR)-6-((tetrahydrochysene-2H-pyrans-2-base) epoxide) hexahydro furyl also [3,2-b] furan
Mutter-3-base)-1H-pyrazoles (0.9g, 2.2mmol), connection boric acid pinacol ester (1.5g, 6.6mmol) and potassium acetate (646mg,
6.6mmol) it is dissolved in dimethyl sulfoxide (20mL), under nitrogen protection, is added thereto to Pd (dppf) Cl2(179mg,
0.22mmol).Reactant liquor stirs 2 hours at 60 ° of C.Reaction is finished, and is cooled to room temperature, and add water (50mL) dilution, and uses ethyl acetate
(40mL × 3) extract.The organic facies saline (100mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and gained remains
Thing through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/1) purification, obtain title compound be yellow solid (0.6g,
67%)。
LC-MS(ESI,pos.ion)m/z:407[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.93(s,1H),7.80(s,1H),5.12-4.92(m,1H),4.81-
4.68(m,3H),4.44-4.41(m,2H),4.36-3.73(m,4H),3.54-3.53(m,1H),2.05-1.50(m,6H),
1.25(s,12H)。
Step 5) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3aS, 6S, 6aR)-6-((four
Hydrogen-2H-pyrans-2-base) epoxide) hexahydro furyl also [3,2-b] furan-3-base)-1H-pyrazoles-4-base) pyridine-2-amine
By 1-((3aS, 6S, 6aR)-6-((tetrahydrochysene-2H-pyrans-2-base) epoxide) hexahydro furyl also [3,2-b] furan-3-
Base)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-pyrazoles (857mg, 2.3mmol), (R)-
The bromo-3-of 5-(1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (0.77g, 1.89mmol) and sodium carbonate (0.4g,
3.78mmol) it is dissolved in the mixed liquor of glycol dimethyl ether/water (25mL/2mL), under nitrogen protection, is sequentially added into Pd
(OAc)2(43mg, 0.19mmol) and (t-Bu)3P (toluene solution of 0.57mL, 2N).Mixture stirs 18 hours at 87 ° of C.Instead
Should finish, be cooled to room temperature, and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (petrol ether/ethyl acetate/methanol (v/v/v)
=10/10/1) purification, obtaining title compound is yellow solid (0.7g, 54%).
LC-MS(ESI,pos.ion)m/z:579[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.75(s,1H),7.69(d,J=6.04Hz,1H),7.58(s,1H),
7.29-7.27(m,1H),7.05-7.01(m,1H),6.08-6.03(q,J=6.64Hz,1H),4.97-4.91(m,1H),4.85
(m,2H),4.82-4.69(m,3H),4.46-4.33(m,2H),4.18-3.98(m,3H),3.86-3.78(m,1H),3.56-
3.52(m,1H),1.84(d,J=6.64 Hz,3H),1.58-1.23(m,6H)。
Step 6) (3S, 3aS, 6aS)-6-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyrrole
Pyridine-3-base)-1H-pyrazol-1-yl) hexahydro furyl also [3,2-b] furan-3-ol
By 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3aS, 6S, 6aR)-6-((tetrahydrochysene-2H-
Pyrans-2-base) epoxide) hexahydro furyl also [3,2-b] furan-3-base)-1H-pyrazoles-4-base) pyridine-2-amine (0.5g,
0.86mmol) it is dissolved in methanol (25mL), is added thereto to 2M hydrochloric acid (2mL).Reactant liquor stirs 1 hour at 45 ° of C, reaction
Finish, concentrating under reduced pressure.By residue dichloromethane (30mL), water (30mL) and 2M sodium carbonate liquor (5mL) dilution, gained mixes
Thing dichloromethane (30mL × 2) extracts.The organic facies saline (100mL) merged is washed, and anhydrous sodium sulfate is dried, and it is dense to reduce pressure
Contracting, residue, through silica gel column chromatography (petrol ether/ethyl acetate/methanol (v/v/v)=10/10/1) purification, obtains title compound
For yellow solid (0.3g, 70%).
LC-MS(ESI,pos.ion)m/z:495[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.77(d,J=1.4Hz,1H),7.69(d,J=6.04Hz,1H),7.59
(s,1H),7.31(s,1H),7.07-7.03(m,1H),6.86(d,J=1.4Hz,1H),6.08-6.03(q,J=6.68Hz,
1H),4.99-4.95(m,1H),4.81(s,2H),4.73-4.71(m,2H),4.44-4.40(m,2H),4.19-4.14(t,J=
8.84Hz,2H),3.98-3.95(dd,J=5.76Hz,1H),3.80-3.77(dd,J=5.76Hz,1H),1.85(d,J=
6.68Hz,3H)。
Embodiment 22 ((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-((3aS, 6R, 6aR)-6-fluorine hexahydro
Furo [3,2-b] furan-3-base)-1H-pyrazoles-4-base) pyridine-2-amine
By (3S, 3aS, 6aS)-6-(4-(6-amino-5-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-
3-yl)-1H-pyrazol-1-yl) hexahydro furyl also [3,2-b] furan-3-ol (0.14g, 0.28mmol) is dissolved in dichloromethane
(4mL) in, it is cooled to-78 ° of C, in system, drips dichloromethane (1mL) solution of DAST (70mg, 0.43mmol).Reactant liquor
After-78 ° of C stir 1 hour, recover to room temperature, and be stirred overnight.Reaction is finished, and concentrating under reduced pressure, gained residue is through silica gel column layer
Analysis (petrol ether/ethyl acetate/methanol (v/v/v)=20/20/1) purification, obtaining title compound is yellow solid (40mg,
28.5%)。
LC-MS(ESI,pos.ion)m/z:497[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.75(d,J=1.68Hz,1H),7.69(s,1H),7.59(s,1H),
7.33-7.28(s,1H),7.08-7.03(m,1H),6.86(d,J=1.48Hz,1H),6.09-6.04(q,J=6.68Hz,1H),
5.24-5.10(dd,J=2.8Hz,1H),4.98-4.93(m,4H),4.84-4.82(m,1H),4.34-4.32(m,1H),
4.26-3.97(m,3H),1.87-1.85(d,J=6.68Hz,3H)。
Embodiment 234-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(octahydro Pentamethylene. also [c] pyrroles
5-yl)-1H-pyrazoles-4-base) pyridine-2-amine
Step 1) 2-(tertbutyloxycarbonyl)-2,3,3a, 4,7,7a-hexahydro-1H-iso-indoles
Lithium aluminium hydride (3.04g, 80mmol) is dissolved in oxolane (80mL), is dividedly in some parts 3a wherein, 4,7,
7a-tetrahydrochysene-1H-iso-indoles-1,3 (2H)-diketone (5.26g, 34.8mmol).Reactant liquor stirs 21 hours at 60 ° of C.Reaction is finished,
It is cooled to room temperature, after adding ethyl acetate (25mL) dilution, successively with water (3mL) and 15% potassium hydroxide solution (3mL) cancellation.
Gained mixture continues to be stirred at room temperature 1 hour, then filters with kieselguhr, and filter cake dichloromethane (40mL) is washed.Will filter
Liquid concentrating under reduced pressure, obtains 2,3,3a, and 4,7,7a-hexahydro-1H-iso-indoles are yellow oil.
By 2,3,3a, 4,7,7a-hexahydros-1H-iso-indoles (3.89g, 31.3mmol) are dissolved in dichloromethane (40mL),
It is cooled to 0 ° of C, is added thereto to Boc anhydride (10.3g, 47mmol).Reactant liquor, after 0 ° of C stirs 0.5 hour, recovers to room
Temperature, continues stirring 21 hours.Reaction is finished, and by mixture concentrating under reduced pressure, residue with Ethyl acetate (80mL) dilutes.Gained solution
Wash with 1M citric acid (17mL × 2), water (17mL × 2), saturated sodium bicarbonate solution (17mL × 2) and saline (17mL) successively.
Organic solution is dried through anhydrous sodium sulfate, and after concentrating under reduced pressure, by silica gel column chromatography (n-hexane/ethyl acetate (v/v)=85/
15) purification, obtaining title compound is orange red grease (4.7g, 54.5%).
MS(ESI,pos.ion)m/z168.2[(M+H)+-C4H8]；
1H NMR(400MHz,CDCl3)δ(ppm):5.64(s,2H),3.40(m,2H),3.16(m,1H),3.07(m,
1H),2.25(m,4H),1.90(m,2H),1.46(s,9H)。
Step 2) 2,2'-(1-(tertbutyloxycarbonyl) pyrrolidine-3,4-diyl) oxalic acid
2-(tertbutyloxycarbonyl)-2,3,3a, 4,7,7a-hexahydro-1H-iso-indoles (4.7g, 21mmol) are dissolved in CCl4
(50mL), in the mixed liquor of MeCN (50mL) and water (75mL), and NaIO it is sequentially added into wherein4(18g, 84.2mmol) and
RuO2(0.16g,1.2mmol).After reactant liquor is stirred at room temperature 24 hours, dilute with DCM (60mL), and filter with kieselguhr,
Aqueous phase DCM (50mL) extracts.The organic facies saline (60mL) merged is washed, Na2SO4It is dried, and concentrating under reduced pressure, residue
Through silica gel column chromatography (100%DCM) purification, obtaining title compound is yellow oil (3g, 49.6%).
MS(ESI,pos.ion)m/z232.2[(M+H)+-C4H8]；
1H NMR(400MHz,CDCl3)δ(ppm):3.53(m,2H),3.04(m,2H),2.80(m,2H),2.44(m,
4H),1.43(s,9H)。
Step 3) 2-(tertbutyloxycarbonyl) hexahydro Pentamethylene. also [c] pyrroles-5 (1H)-one
2,2'-(1-(tertbutyloxycarbonyl) pyrrolidine-3,4-diyl) oxalic acid (3g, 10.4mmol) is dissolved in acetic anhydride
(30mL), in, it is added thereto to sodium acetate (0.79g, 9.6mmol).Reactant liquor, after 120 ° of C stir 3 hours, is cooled to room temperature,
And filter.Filter cake ethyl acetate (20mLx2) is washed, filtrate reduced in volume.Gained residue is through silica gel column chromatography (normal hexane/second
Acetoacetic ester (v/v)=1/1) purification, obtaining title compound is orange-yellow grease (0.55g, 23.4%).
1H NMR(400MHz,CDCl3)δ(ppm):3.69(m,2H),3.00(m,4H),2.61(dd,J =8.2,
18.4Hz,2H),2.29(dd,J=5.8,18.4Hz,2H),1.43(s,9H)。
Step 4) 2-(tertbutyloxycarbonyl) octahydro Pentamethylene. also [c] pyrroles-5-alcohol
2-(tertbutyloxycarbonyl) octahydro Pentamethylene. also [c] pyrroles-5-alcohol (0.9g, 4mmol) is dissolved in ethanol (20mL)
In, it is dividedly in some parts sodium borohydride (0.82g, 21.7mmol) wherein.Reactant liquor is stirred at room temperature 4.5 hours.Reaction is finished, and reduces pressure dense
Contracting.Residue with Ethyl acetate (50mL) is diluted, and washes with water (50mL), saline (50mL) successively.Gained solution is through anhydrous
Sodium sulfate is dried, concentrating under reduced pressure, and obtaining title compound is yellow oil (0.99g, 100%).This compound is not required to purification,
It is directly used in next step.
Step 5) 2-(tertbutyloxycarbonyl) octahydro Pentamethylene. also [c] pyrroles-5-base methanesulfonates
2-(tertbutyloxycarbonyl) octahydro Pentamethylene. also [c] pyrroles-5-alcohol (0.91g, 3.56mmol) is dissolved in dichloromethane
In alkane (8mL), it is cooled to 0 ° of C, is sequentially added into triethylamine (0.8mL, 5.74mmol) wherein, mesyl chloride (0.35mL,
4.52mmol) and dichloromethane (2mL) suspension of DMAP (5mg, 0.04mmol).Reactant liquor is stirred at room temperature 16 hours, reaction
Finish, wash with water (15mL), saline solution (15mL) successively.Gained solution is dried through anhydrous sodium sulfate, and concentrating under reduced pressure, obtains title
Compound is yellow oil (1.3g, 100%).This product is the most purified, is directly used in next step.
Step 6) 2-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) octahydro Pentamethylene. also [c] pyrroles
Iodo-for 4-1H-pyrazoles (1.16g, 6mmol) is dissolved in anhydrous DMF (10mL), is cooled to
0 ° of C, is dividedly in some parts sodium hydride (538mg, 17.9mmol, 80% are dispersed in mineral oil) wherein.It is little that mixture stirs 1 at 0 ° of C
Shi Hou, adds 2-(tertbutyloxycarbonyl) octahydro Pentamethylene. also [c] pyrroles-5-base methanesulfonates (1.22g, 4mmol) in system
N,N-dimethylformamide (5mL) solution.Reactant liquor stirs 21 hours at 100 ° of C.Reaction is finished, and is cooled to room temperature, adds acetic acid
Ethyl ester (30mL) dilutes.Mixture is washed with water (20mL × 3), saline (20mL) successively, and anhydrous sodium sulfate is dried, and it is dense to reduce pressure
Contracting, gained residue, through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1) purification, obtains title compound light yellow
Solid (1.37g, 85.1%).
MS(ESI,pos.ion)m/z348.0[(M+H)+-C4H8]；
1H NMR(400MHz,CDCl3)δ(ppm):7.50(s,1H),7.45(s,1H),4.82(m,1H),3.55(brs,
2H),3.23(brs,2H),2.92(m,2H),2.33(m,2H),2.05(brs,2H), 1.47(s,9H)。
Step 7) 2-(tertbutyloxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-
1H-pyrazol-1-yl) octahydro Pentamethylene. also [c] pyrroles
By 2-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) octahydro Pentamethylene. also [c] pyrroles (0.48g,
1.2mmol) it is dissolved in dimethyl sulfoxide (8mL) with connection boric acid pinacol ester (0.36g, 1.44mmol), is added thereto to acetic acid
Potassium (0.35g, 3.6mmol), after nitrogen protection, continues to add Pd (dppf) Cl in system2(98mg,0.12mmol).Reaction
Liquid stirs 1 hour at 80 ° of C.Reaction is finished, and add water (10mL) cancellation, and extracts by ethyl acetate (20mL × 3).Merge is organic
Washing with saline (30mL) mutually, anhydrous sodium sulfate is dried, and concentrating under reduced pressure.Gained residue is through silica gel column chromatography (petroleum ether/acetic acid
Ethyl ester (v/v)=2/1) purification, obtaining title compound is yellow oil (256mg, 53.3%).
MS(ESI,pos.ion)m/z404.3[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.79(s,1H),7.71(s,1H),4.84(m,1H),3.56(brs,
2H),3.23(brs,2H),2.93(brs,2H),2.34(m,2H),2.08(brs,2H),1.47(s,9H),1.27(s,12H)。
Step 8) 5-(1-(2-(tertbutyloxycarbonyl) octahydro Pentamethylene. also [c] pyrroles-5-base)-1H-pyrazoles-4-base)-4-
((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
By 2-(tertbutyloxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-
Pyrazol-1-yl) octahydro Pentamethylene. also [c] pyrroles (256mg, 0.64mmol) and the bromo-3-of (R)-5-(1-(2,6-bis-chloro-3-fluorobenzene
Base) ethyoxyl) pyridine-2-amine (326mg, 0.95mmol) is dissolved in glycol dimethyl ether (8mL), is added thereto to 1.2M carbon
Acid sodium solution (2mL, 1.91mmol), after nitrogen protection, continues to add Pd (dppf) Cl in system2(104mg,
0.13mmol).Reactant liquor stirs 8 hours at 100 ° of C, and reaction is finished, and is cooled to room temperature, and add water (20mL) dilution, and uses acetic acid second
Ester (20mL × 3) extracts.The organic facies saline (30mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure, residue warp
Silica gel column chromatography (petrol ether/ethyl acetate (v/v)=1/2) purification, obtain title compound be yellow solid (157mg,
42.9%)。
LC-MS(ESI,pos.ion)m/z:576.2[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.74(d,J=1.6Hz,1H),7.56(s,1H),7.46(s,1H),
7.30(m,1H),7.05(t,J=8.0Hz,1H),6.85(d,J=1.4Hz,1H), 6.07(m,1H),4.82(m,3H),3.57
(brs,2H),3.25(brs,2H),2.95(brs,2H),2.35(m,2H),2.05(brs,2H),1.85(d,J=6.7Hz,
1H),1.47(s,9H)。
Step 9) 4-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(octahydro Pentamethylene. also [c] pyrroles 5-
Base)-1H-pyrazoles-4-base) pyridine-2-amine
By 5-(1-(2-(tertbutyloxycarbonyl) octahydro Pentamethylene. also [c] pyrroles-5-base)-1H-pyrazoles-4-base)-4-((R)-
1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (157mg, 0.27mmol) is dissolved in dichloromethane (10mL),
It is slowly added to HCl (ethyl acetate solution of 4mL, 3M) wherein.After reactant liquor is stirred at room temperature 2 hours, concentrating under reduced pressure.Will residual
Thing use water (30mL) and dichloromethane (50mL) dilution, then regulate pH10 with saturated sodium carbonate solution, and use dichloromethane
(50mL × 3) extract.The organic facies saline (80mL) merged is washed, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure, and residue is through silicon
Plastic column chromatography (methylene chloride/methanol/triethylamine (v/v/v)=500/50/1) purification, obtaining title compound is yellow solid
(0.1g,76.9%)。
LC-MS(ESI,pos.ion)m/z:476.1[M+H]；
1H NMR(400MHz,CDCl3)δ(ppm):7.72(d,J=1.6Hz,1H),7.54(s,1H),7.48(s,1H),
7.30(m,1H),7.05(t,J=8.2Hz,1H),6.85(d,J=1.4Hz,1H),6.07(m,1H),4.91(s,2H),4.88
(m,1H),3.66(s,1H),3.29(m,2H),3.03(m,2H),2.43(m,2H),2.11(m,2H),2.07(d,J=
17.2Hz,2H),1.85(d,J=6.7Hz,1H)。
Embodiment 243-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(octahydro-1H-iso-indoles-5-
Base)-1H-pyrazoles-4-base) pyridine-2-amine
Step 1) 2-(tertbutyloxycarbonyl) octahydro-1H-iso-indoles-5-alcohol
2-(tertbutyloxycarbonyl)-2,3,3a, 4,7,7a-hexahydro-1H-iso-indoles (3.16g, 14.2mmol) are dissolved in nothing
In water oxolane (35mL), after nitrogen protection, it is cooled to 0 DEG C, drips BH wherein3-DMS(1.5mL,15.0mmol,10M
Tetrahydrofuran solution).Reactant liquor stirred overnight at room temperature, reaction is finished, is cooled to 0 DEG C.Reactant liquor is successively with methanol (8mL), 3M
Sodium hydroxide (5mL) and 30% hydrogen peroxide (5mL) mixed liquor cancellation.Gained suspension, after 60 DEG C of stirrings 1.5 hours, is down to room
Temperature, add diethyl ether/water (30mL/30mL) dilution, and extracts by ethyl acetate (30mL × 3).Organic facies saline (the 30mL merged
× 3) washing, anhydrous sodium sulfate is dried, and concentrating under reduced pressure, obtains orange (2.46g, 71.7%), and this product is the most purified,
It is directly used in next step.
LC-MS(ESI,pos.ion)m/z:186.2[M+H-56]+；
1H NMR(400MHz,CDCl3)δ(ppm):3.89(m,1H),3.35(m,2H),3.22(m,2H),2.47(m,
1H),2.10(m,1H),1.82(m,4H),1.62(m,1H),1.54(m2H),1.46(s,9H)。
Step 2) 2-(tertbutyloxycarbonyl) octahydro-1H-iso-indoles-5-base methanesulfonates
Title compound is prepared by the method described by embodiment 23 step 5, will 2-(tertbutyloxycarbonyl) eight
Hydrogen-1H-iso-indoles-5-alcohol (4.51g, 18.69mmol), triethylamine (4mL, 28.70mmol), mesyl chloride (2.2mL,
28.41mmol) being suspended in dichloromethane (50mL) prepare with DMAP (34.3mg, 0.28mmol), obtaining thick product is brown
Grease (5.30g, 88.8%), this product is the most purified, is directly used in next step.
LC-MS(ESI,pos.ion)m/z:264.0[M+H-56]+。
Step 3) 2-(tertbutyloxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl) octahydro-1H-iso-indoles
Title compound is prepared by the method described by embodiment 23 step 6, will 2-(tertbutyloxycarbonyl) eight
Hydrogen-1H-iso-indoles-5-base methanesulfonates (5.30g, 16.6mmol), 4-iodo-1H-pyrazoles (4.83g, 24.9mmol) and hydrogenation
Sodium (2.26g, 56.4mmol, 60% are dispersed in mineral oil) is suspended in preparation in anhydrous DMF (60mL), slightly
Product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=6/1) purification, and obtaining title compound is white solid
(2.67g,38.6%)。
LC-MS(ESI,pos.ion)m/z:362.2[M+H-56]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.50(d,J=4.1Hz,1H),7.46(s,1H),3.32(m,4H),
2.30(brs,1H),2.28(m,1H),2.02(m,2H),1.73(m,5H),1.46(d,J=6.8Hz,9H)。
Step 4) 2-(tertbutyloxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanes-2-base)-
1H-pyrazol-1-yl) octahydro-1H-iso-indoles
Title compound is prepared by the method described by embodiment 23 step 7, will 2-(tertbutyloxycarbonyl)-5-
(4-iodo-1H-pyrazol-1-yl) octahydro-1H-iso-indoles (2.67g, 6.40mmol), connection boric acid pinacol ester (1.95g,
7.68mmol), potassium acetate (1.88g, 19.20mmol) and Pd (dppf) Cl2(523mg, 0.64mmol) is suspended in dimethyl sulfoxide
(50mL) preparation in, thick product is through silica gel column chromatography (PE/EtOAc (v/v)=4/1) purification, and obtaining title compound is orange oil
Shape thing (1.34g, 50.2%).
LC-MS(ESI,pos.ion)m/z:418.1[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.78(d,J=2.3Hz,1H),7.74(s,1H),3.36(m,4H),
2.42(br.s,1H),2.28(m,1H),2.05(m,2H),1.84(m,5H),1.46(d,J=8.0Hz,9H),1.32(d,J=
5.4Hz,12H)。
Step 5) 5-(1-(2-(tertbutyloxycarbonyl) octahydro-1H-iso-indoles-5-base)-1H-pyrazoles-4-base)-3-((R)-
1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine
Title compound is prepared by the method described by embodiment 23 step 8, will the bromo-3-of (R)-5-(1-(2,
6-bis-chloro-3-fluorophenyl) ethyoxyl) pyridine-2-amine (1.83g, 4.82mmol), 2-(tertbutyloxycarbonyl)-5-(4-(4,4,5,
5-tetramethyl-1,3,2-dioxaborolanes-2-base)-1H-pyrazol-1-yl) octahydro-1H-iso-indoles (1.34g,
3.21mmol), Pd (dppf) Cl2(524mg, 0.642mmol) and 1.2M sodium carbonate liquor (8mL, 9.63mmol) are suspended in second
Preparation in glycol dimethyl ether (40mL), thick product, through silica gel column chromatography (PE/EtOAc (v/v)=1/2) purification, obtains title compound
Thing is orange solids (230mg, 12.1%).
LC-MS(ESI,pos.ion)m/z:590.0[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H),7.55(d,J=4.2Hz,1H),7.48(s,1H),
7.30(m,1H),7.05(t,J=8.1Hz,1H),6.88(s,1H),6.07(m,1H),4.90(s,2H),3.41(m,2H),
3.33(m,2H),2.44(br.s,1H),2.31(m,1H),2.04(m,2H),1.86(d,J=6.7Hz,3H),1.71(br.s,
5H),1.46(d,J=7.6 Hz,9H).
Step 6) 3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl)-5-(1-(octahydro-1H-iso-indoles-5-base)-
1H-pyrazoles-4-base) pyridine-2-amine
Title compound is prepared by the method described by embodiment 23 step 9, will 5-(1-(2-(tertiary butyloxycarbonyl
Base) octahydro-1H-iso-indoles-5-base)-1H-pyrazoles-4-base)-3-((R)-1-(2,6-bis-chloro-3-fluorophenyl) ethyoxyl) pyrrole
Pyridine-2-amine (0.23g, 0.39mmol) and HCl (ethyl acetate solution of 4mL, 3M) are dissolved in preparation in dichloromethane (10mL).
Thick product is through silica gel column chromatography (methylene chloride/methanol/triethylamine (v/v/v)=250/50/1) purification, and obtaining title compound is
Yellow solid (100mg, 52.4%).
LC-MS(ESI,pos.ion)m/z:489.9[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.75(d,J=1.7Hz,1H),7.53(d,J=8.4Hz,2H),7.30
(m,1H),7.05(t,J=8.4Hz,1H),6.87(d,J=1.6Hz,1H),6.07(m,1H),4.78(s,2H),4.10(m,
1H),3.66(m,2H),3.18(m,1H),3.07(m,2H),2.88(d,J=11.0Hz,1H),2.37(br.s,1H),2.30
(m,1H),2.04(m,2H),1.95(br.s,5H),1.85(d,J=6.7Hz,3H)。
Biologic test
The compound using method as discussed above and equipment to prepare the embodiment of the present invention carries out bioanalysis.
Embodiment A stability in people and rat liver microsomes
People or rat liver microsomes are placed in polypropylen tubes and hatch, and guide it to replicate.Typically hatch mixed liquor
Including people or rat liver microsomes (0.5mg protein/mL), target compound (5 μMs) and the NADPH that cumulative volume is 200 μ L
(1.0mM) kaliumphosphate buffer (PBS, 100mM, pH value is 7.4), by compound dissolution in DMSO, and uses PBS that it is dilute
Release so that it is the concentration of final DMSO solution is 0.05%.And the water-bath communicated with air under 37 ° of C is hatched, incubate in advance
Educate and 3 minutes backward mixed liquors add albumen and starts reaction.At different time points (0,5,10,15,30 and 60min), add
Enter same volume ice-cold acetonitrile and terminate reaction.Sample preserves until carrying out LC/MS/MS analysis under-80 ° of C.
Compound concentration in people or rat liver microsomes mixtures incubated is that the method by LC/MS/MS measures
's.The range of linearity of concentration range is determined by each test-compound.
Parallel hatch test and use the microsome of degeneration as negative control, hatch under 37 ° of C, react when different
Between point (0,15 and 60 minute) terminate.
Dextromethorphan (70 μ Μ), as positive control, is hatched under 37 ° of C, react different time point (0,5,10,
15,30 and 60 minutes) terminate.Each assay method all includes the positive and negative control sample, to ensure that microsome is hatched
The integrity of system.
Each is reacted, compound concentration (as a percentage) in people or rat liver microsomes are hatched is pressed
The plotted as percentage of Relative Zero time point, infers internal CLint CL with thisint(ref.:Naritomi Y,
Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human
hepatic clearance from in vivo animal experiments and in vitro metabolic
studies with liver microsomes from animals and humans.Drug Metabolism and
Disposition2001,29:1316-1324.), result sees table 1, and the compound that table 1 provides for the embodiment of the present invention is people
With the experimental result of stability in rat liver microsomes.
Compound experimental result of stability in people and rat liver microsomes that table 1 embodiment of the present invention provides
As shown in Table 1, when the compound incubation present invention provided is in people and rat liver microsomes, of the present inventionization
Compound shows good half-life (T1/2)。
Embodiment B the compounds of this invention Pharmacokinetic Evaluation in animal body
The compounds of this invention pharmacokinetic in mice, rat, dog or monkey body is commented by the present invention
Estimate.
The compounds of this invention is administered as an aqueous solution.For oral dose (p.o.), rat and mice be 5 or
10mg/kg, dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0,12 and 24 little at time point
Time take blood (0.3mL), and 3,000 or 4, under 000rpm centrifugal 10 minutes.Collect plasma solutions, and under-20 ° of C or-70 ° of C
Preserve until carrying out above-mentioned LC/MS/MS and analyzing.Result shows, during the compound oral administration that the present invention is provided, and its performance
Go out good pharmacokinetic property, including preferable clearance rate (Cl), half-life (T1/2) oral administration biaavailability become reconciled.
The compounds of this invention is administered as an aqueous solution.For intravenous administration, animal gives 1 or 2mg/kg
Dosage.It is within 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0,12 and 24 hour, to take blood (0.3mL) at time point, and 3,
It is centrifuged 10 minutes under 000 or 4,000rpm.Collect plasma solutions, and preserve under-20 ° of C or-70 ° of C until carrying out above-mentioned
LC/MS/MS analyzes.Result shows, during the compound Bolos intravenous administration present invention provided, it shows good pharmacokinetics
Character, including preferable clearance rate (Cl), half-life (T1/2) oral administration biaavailability become reconciled.
Embodiment C kinase assay
The compound that the embodiment of the present invention is provided by method as described above carries out ALK (h) kinase assays and c-Met
H () kinase assays, result sees table 2, the kinase assay result that table 2 provides for the embodiment of the present invention.
The kinase assay result that table 2 embodiment of the present invention provides
As shown in Table 2, compound of the present invention generally demonstrates the highest work in the test of ALK and c-Met (h)
Property.
Embodiment D Xenograft Tumor Models
Use method as discussed above to set up U87MG Transplanted tumor model, and use method as discussed above to be analyzed.?
In U87MG Transplanted tumor model, by embodiment compound every day (QD) oral administration (p.o.), and continuing 13-21 days, result sees
Table 3, the transplanted tumor result of study that table 3 provides for the embodiment of the present invention.
The transplanted tumor result of study that table 3 embodiment of the present invention provides
As shown in Table 3, under 60mg/kg dosage, embodiment compound all has meaning statistically, can suppress nude mice
The growth of Subcutaneous tumor.
Finally it should be noted that also have other modes to be used for implementing the present invention.Correspondingly, embodiments of the invention are
To illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made within the scope of the present invention
Amendment or the equivalents added in the claims.All publications or patent cited in the present invention all will be as these
Bright list of references.
Claims (8)
1. a compound, has a structure of one of:
2. a pharmaceutical composition, comprises the compound described in claim 1 or pharmaceutically acceptable carrier.
Pharmaceutical composition the most according to claim 2, described carrier is excipient and/or diluent.
Pharmaceutical composition the most according to claim 2, it is characterised in that also comprise additional treatment agent, these additional treatment
Agent is selected from chemotherapeutic agent, antiproliferative, is used for treating atherosclerotic medicine, for treating the medicine of pulmonary fibrosis
Or combinations thereof.
Pharmaceutical composition the most according to claim 4, it is characterised in that wherein said additional treatment agent is benzenebutanoic acid nitrogen
Mustard, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin,
Oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytosine arabinoside, gemcitabine, sulfydryl
Purine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, Docetaxel, topotecan, irinotecan, depend on
Torr pool glycosides, ET-743, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitogen is mould
Element C, ipsapirone, tamoxifen, flutamide, gonadorelin analog, megestrol, prednisone, dexamethasone, first sprinkles Buddhist nun
Dragon, Thalidomide, interferon-ALPHA, calcium folinate, sirolimus, temsirolimus, everolimus, Afatinib,
Alisertib, amuvatinib, Ah handkerchief replaces Buddhist nun, Axitinib, bortezomib, SKI-606, Bu Linibu, and card is rich for Buddhist nun, west
Ground Buddhist nun's cloth, crenolanib, gram Zhuo replaces Buddhist nun, dabrafenib, and dacomitinib, Da Lushe replace, Dasatinib, and many Weis replace Buddhist nun, strategic point
Buddhist nun, foretinib, ganetespib are replaced in Lip river, and gefitinib, according to Shandong for Buddhist nun, Conmana, imatinib, iniparib, La Pa
For Buddhist nun, lenvatinib, linifanib, linsitinib, Masitinib, momelotinib, for husky Buddhist nun, HKI-272,
Nilotinib, niraparib, oprozomib, Aura handkerchief Buddhist nun, pazopanib, pictilisib, handkerchief is received for Buddhist nun,
Quizartinib, Rui Gefeini, rigosertib, rucaparib, Luso profit replaces Buddhist nun, saracatinib, saridegib, Suo La
Non-Buddhist nun, Sutent, tasocitinib, Telatinib, tivantinib, tivozanib, expelling pathogens by strengthening vital QI replaces Buddhist nun, and Sibutramine Hydrochloride replaces Buddhist nun, all
De Tani, veliparib, Wei Luofeini, Wei Modeji, volasertib, alemtuzumab, bevacizumab,
Brentuximabvedotin, blocks appropriate rope monoclonal antibody, Cetuximab, ground promise monoclonal antibody, lucky trastuzumab, her monoclonal antibody, the appropriate pearl of Buddhist nun
Monoclonal antibody, method wood monoclonal antibody difficult to understand, Victibix, Rituximab, tositumomab, Herceptin or combinations thereof.
6. one kind uses compound described in claim 1 or the pharmaceutical composition described in claim 2～5 any one to prepare
For protecting, process, treat or alleviate the purposes of the medicine of the proliferative disease of patient ALK and/or c-Met mediation.
Compound or the purposes of pharmaceutical composition the most according to claim 6, it is characterised in that wherein said ALK and/or
The proliferative disease of c-Met mediation is metastatic carcinoma, colon cancer, adenocarcinoma of stomach, bladder cancer, breast carcinoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, first shape
Adenocarcinoma, head and neck cancer, carcinoma of prostate, cancer of pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, tremulous pulse medicated porridge sample
Hardening or pulmonary fibrosis.
8. the compound used described in claim 1 or the pharmaceutical composition system described in claim 2～5 any one
It is ready for use on the purposes of the medicine suppressing or regulating ALK, c-Met or combinations thereof activity in biological sample, described purposes bag
Containing using compound described in claim 1 or using the pharmaceutical composition described in claim 2～5 any one and described life
Thing specimen contacts.
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| CN106573042A (en) * | 2014-08-05 | 2017-04-19 | 埃克塞里艾克西斯公司 | Drug combinations to treat multiple myeloma |
| CN105061410B (en) * | 2015-08-03 | 2018-04-20 | 江苏红豆杉药业有限公司 | A kind of Afatinib and its preparation method and application |
| CN105424842A (en) * | 2015-12-29 | 2016-03-23 | 河北神威药业有限公司 | Method for detecting Afatinib and relevant substances thereof |
| US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
| CN110016013B (en) * | 2019-05-22 | 2020-08-11 | 北京凯恩梅格医药科技有限公司 | Novel c-Met/HDAC double-target inhibitor and synthetic method and application thereof |
| CN110615753A (en) * | 2019-09-02 | 2019-12-27 | 南京新酶合医药科技有限公司 | Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid |
| CN110577974B (en) * | 2019-09-10 | 2021-07-20 | 杭州澳赛诺生物科技有限公司 | Synthesis method of chiral 3-hydroxy-1, 2,3, 6-tetrahydropyridine |
| CN113624665A (en) * | 2021-07-30 | 2021-11-09 | 中国药科大学 | Application of anti-tumor candidate compound in medicine for treating colorectal cancer and determination method |
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| CN101018780A (en) * | 2004-08-26 | 2007-08-15 | 辉瑞大药厂 | Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors |
| CN103509008A (en) * | 2012-06-22 | 2014-01-15 | 康瑟特制药公司 | Derivatives of pyrazole-substituted amino-heteroaryl compounds |
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| CN103509008A (en) * | 2012-06-22 | 2014-01-15 | 康瑟特制药公司 | Derivatives of pyrazole-substituted amino-heteroaryl compounds |
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